摘要:

Transition metal complexes in organic synthesis. Part 47.1 Organic synthesis via tricarbonyl(h4-diene)iron complexes Hans-Joachim Kn�olker Institut f�ur Organische Chemie Universit�at Karlsruhe Richard-Willst�atter-Allee 76131 Karlsruhe Germany Received 25th July 1998 The protection of conjugated dienes by coordination to the tricarbonyliron fragment offers many potential applications of the resulting complexes to organic synthesis. The preparation of tricarbonyl(h4-1,3-diene)iron complexes is readily achieved by a 1-azabutadiene-catalyzed complexation of the free ligands. An asymmetric catalytic complexation of prochiral cyclohexa-1,3-dienes with pentacarbonyliron using chiral 1-azabutadienes affords chiral nonracemic complexes. The chiral tricarbonyliron complexes of acyclic butadienes represent versatile starting materials for the synthesis of a broad range of polyunsaturated natural products.Consecutive carbon–carbon and carbon–nitrogen bond formations of the tricarbonyliron–cyclohexa-1,3-diene complexes and arylamines provide many biologically active carbazole alkaloids and a tetracyclic subunit of the discorhabdin alkaloids. The iron-mediated [2+2+1] cycloaddition of trimethylsilylacetylenes and carbon monoxide affords stable 2,5-bis(trimethylsilyl)-substituted cyclopentadienones which are useful substrates for further cycloadditions. 1 Introduction Tricarbonyl(h4-1,3-diene)iron complexes represent important intermediates and offer versatile applications for organic Hans-Joachim Kn�olker was born in 1958 and studied chemistry at the universities of G�ottingen and Hannover where he obtained his diploma degree in 1983 and his PhD in 1985 with Professor E.Winterfeldt. He undertook post-doctoral research studies in 1986 with Professor K. P. C. Vollhardt at the University of California in Berkeley and became interested in organometallic chemistry. In 1987 he returned to the University of Hannover and finished his habilitation in 1990. Since 1991 he is a full Professor of Organic Chemistry at the University of Karlsruhe. He is the recipient of a fellowship of the Japan Society for the Promotion of Science in 1998. His current research interests include organotransition metal chemistry organosilicon chemistry isocyanate chemistry and the synthesis of fluorescent imidazole derivatives.synthesis.2 The tricarbonyliron fragment may be used as a protecting group since coordination of a conjugated diene leads to a decreased reactivity of the resulting transition metal complex in which the diene does not undergo hydrogenation or Diels–Alder cycloaddition. Moreover highly reactive molecules containing labile diene systems can be stabilized. The coordination to the tricarbonyliron fragment prevents the Diels– Alder dimerization of cyclobutadiene and cyclopentadienone as well as the aromatization of cyclohexa-2,4-dien-1-one and 4b,8a-dihydrocarbazol-3-one. Because of its steric demand the tricarbonyliron fragment is often utilized as a stereodirecting group.Over recent years the reactivity of tricarbonyliron complexes of acyclic butadienes3 and cyclohexadienes2,4 has been extensively investigated resulting in a broad range of synthetic applications. This review describes some of the recent advances directed towards the application of tricarbonyl(h4-diene)iron complexes to organic synthesis. Scheme 1 2 Selective complexation of dienes by the tricarbonyliron fragment The standard protocol for the synthesis of tricarbonyl(h4- diene)iron complexes involves either thermal or photochemical reaction of the diene with pentacarbonyliron nonacarbonyldiiron or dodecacarbonyltriiron. However complexations are achieved under much milder reaction conditions by using tricarbonyliron transfer reagents.5 The (h4-1-azabuta-1,3- diene)tricarbonyliron complexes 2 represent useful tricarbonyliron transfer reagents.They are easily prepared in high yields from the corresponding 1-azabuta-1,3-dienes 1 on sonication with nonacarbonyldiiron. On reaction of complex 2 with cyclohexa-1,3-diene 3 at elevated temperatures the metal fragment is transferred and provides the tricarbonyliron– cyclohexadiene complex 4 in excellent yield (Scheme 1).6 A highly efficient catalytic complexation of conjugated dienes was developed by reaction with either pentacarbonyliron Chem. Soc. Rev. 1999 28 151–157 151 or nonacarbonyldiiron in the presence of the 1-azabuta- 1,3-diene 1. Thus the 1-azabuta-1,3-diene-catalyzed complexation of cyclohexa-1,3-diene 3 with pentacarbonyliron affords complex 4 quantitatively (Scheme 2).7 Scheme 2 The catalytic complexation of cyclohexadiene 3 is proposed to be initiated by a nucleophilic attack of the imine nitrogen of the 1-azabutadiene 1 at one of the carbonyl ligands of pentacarbonyliron (Scheme 3).7 Loss of carbon monoxide by internal ligand displacement transforms the resulting (carbamoyl) tetracarbonyliron complex 5 into the (h3-allyl) (carbamoyl) tricarbonyliron complex 6.Complex 6 isomerizes by haptotropic migration of the tetracarbonyliron fragment first to the (h2-olefin)tetracarbonyliron complex 7 and then to the (h1- imine)tetracarbonyliron complex 8. Further loss of a carbonyl ligand from 8 generates the (h1-imine)tricarbonyliron complex 9 which is in equilibrium with the stable (h4-1-azabutadiene)- tricarbonyliron complex 2 (cf.Scheme 1) by haptotropic migration of the tricarbonyliron fragment. Reaction of the tricarbonyliron complex 2 with excess pentacarbonyliron leads to the hexacarbonyldiiron complex 11 which was structurally confirmed by X-ray analysis.7 The vacant coordination site of the crucial 16-electron intermediate 9 may be filled by h2- coordination of cyclohexadiene 3 to provide complex 10. Loss of the 1-azabutadiene regenerates the catalyst 1 and haptotropic (h2 ? h4) migration of the tricarbonyliron fragment affords complex 4. Optically active planar chiral tricarbonyliron–diene complexes can be obtained directly by catalytic asymmetric complexation of the corresponding prochiral ligands with the transition metal fragment.Using chiral 1-azabuta-1,3-dienes in the catalytic complexation described above an enantioselective coordination of prochiral 1,3-dienes to the tricarbonyliron fragment with useful asymmetric inductions was achieved.8 Catalytic complexation of 1-methoxycyclohexa-1,3-diene (12) with pentacarbonyliron using the (R)-camphor-derived 1-azadiene (R)-13 afforded the tricarbonyliron complex (S)-14 while catalyst (S)-13 led to complex (R)-14 (Scheme 4). Current research in this area focusses on the development of more efficient chiral catalysts useful for the asymmetric Scheme 3 Chem. Soc. Rev. 1999 28 151–157 152 Scheme 4 catalytic complexation of a broad range of prochiral buta- 1,3-diene and cycloalka-1,3-diene ligands.Thus this method should facilitate the access to chiral nonracemic tricarbonyliron –diene complexes as starting materials for enantioselective organic synthesis. 3 Applications of tricarbonyliron–butadiene complexes 4 methyl ester 18. Acyclic tricarbonyliron–butadiene complexes represent useful starting materials for the synthesis of acyclic polyunsaturated natural products e.g. the metabolites resulting from the 5-lipoxygenase pathway of the arachidonic acid cascade.3 The stereoselective Friedel–Crafts acylation of tricarbonyliron –butadiene complexes initially affords the Z-dienones which on acid-catalyzed isomerization provide the thermodynamically more stable E-dienones.9 This method was applied to an enantioselective total synthesis of the natural leukotriene (2)-5(S),6(S)-LTA4 methyl ester (18) (Scheme 5).10 Friedel– Crafts acylation of the enantiopure iron complex of trans-penta- 2,4-dienoic 2,2,2-trichloroethyl ester 15 using the acid chloride of adipic acid monomethyl ester afforded complex 17 which was subsequently converted to the LTA The planar chiral complex tricarbonyl[h4-methyl (2E,4E)- 6-oxohexa-2,4-dienoate]iron (19) is easily separated into ters by resolution with ephedrine.11,12 Starting from this chiral building block an eight-step enantioselective total Scheme 5 synthesis of 5(R)-hydroxyeicosatetraenoic acid (HETE) methyl ester (23) was recently accomplished (Scheme 6).12 Borohydride reduction of the (2)-complex 19 followed by treatment of the intermediate alcohol 20 with hexafluorophosphoric acid Scheme 6 afforded the enantiopure 1(R)-tricarbonyl[1-(methoxycarbonyl) pentadienylium]iron hexafluorophosphate 21.Addition of the organocuprate prepared from deca-1,4-diyne occurred with complete regioselectivity and provided the 2(R)-methyl (2E,4Z)-hexadeca-2,4-diene-7,10-diynoate complex 22. The next steps involve conversion to the (7Z,10Z)-diene system by stereoselective hydrogenation using Lindlar catalyst transformation of the ester function into the aldehyde by DIBAL reduction followed by oxidation with manganese dioxide and nucleophilic addition of a C4-building block containing a protected ester function (2 1 stereoselectivity). The synthesis of 5(R)-HETE methyl ester 23 was completed by demetallation of the complex using ceric ammonium nitrate.Current applications of the iron-complexed methyl (2E,4E)-6-oxo-hexa- 2,4-dienoate 19 focus on the enantioselective total synthesis of macrolactin A.13,14 Scheme 7 The first asymmetric synthesis of the piperidine alkaloid SS20846A (27) was achieved by a diastereoselective lithium perchlorate-promoted cycloaddition of the enantiopure tricarbonyliron-complexed 1-azatriene 24 with Danishefsky’s diene 25 (Scheme 7).15 The resulting enone 26 was reduced to the saturated alcohol. The final oxidation using ceric ammonium nitrate resulted in simultaneous demetallation of the butadiene moiety and deprotection of the nitrogen atom. Scheme 8 4 Applications of tricarbonyliron–cyclohexadiene complexes The most characteristic feature of tricarbonyl(h4-1,3-diene)iron complexes is the activation of the allylic C–H bonds which enables hydride abstraction by triphenylmethyl tetrafluoroborate.Thus cyclohexa-1,3-diene (3) is transformed via the tricarbonyliron complex 4 to the tricarbonyl(h5-cyclohexadienylium) iron tetrafluoroborate (28). For steric reasons the bulky tricarbonyliron fragment of the metal-coordinated cation exhibits a strong stereodirecting effect which on reaction with nucleophiles results in an approach of the reagent from the face opposite to the iron (anti selectivity). Therefore reaction of the complex salt 28 with appropriate nucleophiles provides the 5-anti-substituted tricarbonyl(h4-cyclohexa-1,3-diene)iron complexes 29 by regio- and stereoselective formation of carbon–carbon or carbon–heteroatom bonds.Demetallation of the complexes 29 using trimethylamine N-oxide affords the free dienes 30 which are substituted in the allylic position (Scheme 8). Because of the high degree of regio- and stereoselectivity in bond forming reactions at the coordinated ligand this chemistry has found diverse applications in synthetic organic chemistry including natural product synthesis.2,4 4.1 Total synthesis of carbazole alkaloids Over the past two decades a broad range of carbazole alkaloids with useful biological activities were isolated from diverse natural sources.16 A highly convergent access to these natural products was developed based on consecutive iron-mediated C– C and C–N bond formation.17 The tricarbonyliron-complexed cyclohexadienyl cations represent very efficient reagents for the electrophilic aromatic substitution of arylamines.18 Oxidative cyclization of the resulting arylamine-substituted tricarbonyl( h4-cyclohexa-1,3-diene)iron complexes provides carbazoles.Different techniques for the oxidative cyclization to carbazole derivatives were elaborated depending on the substitution pattern of the arylamine. The oxidative cyclization of arylamine-substituted tricarbonyl( h4-cyclohexa-1,3-diene)iron complexes to the 9H-carbazoles can be performed as a one-pot transformation with concomitant aromatization and demetallation by using very active manganese dioxide (iron-mediated arylamine cyclization).An application of this method was shown by the five-step synthesis of the antibiotic carbazomycins G and H.19 These 153 Chem. Soc. Rev. 1999 28 151–157 novel carbazole alkaloids isolated from Streptoverticillium ehimense are structurally unique because of the quinol moiety. The electrophilic substitution of the arylamine 31 with the complex salt 28 to the iron complex 32 demonstrates that even hexasubstituted arylamines can be generated in this transformation (Scheme 9). After protection by chemoselective OScheme 9 acetylation an iron-mediated arylamine cyclization to the carbazole 33 was achieved by treatment with very active manganese dioxide. Oxidation of 33 with ceric ammonium nitrate (CAN) to the quinone and subsequent addition of methyllithium afforded carbazomycin G (34).Starting from the 3-methoxy-substituted complex salt carbazomycin H became available following the same reaction sequence. The iron-mediated arylamine cyclization with concomitant aromatization was recently also applied to the total synthesis of the marine natural product hyellazole,20 the furo[3,2-a]carbazole alkaloid furostifoline,21 and the 5-lipoxygenase inhibitor carbazomycin C.22 An extension of this methodology using a two-directional synthesis by simultaneous annulation of two indole units at a central phenylenediamine opens up a simple two-step route to indolocarbazoles (Scheme 10).23 Two-fold electrophilic substitution of commercial m-phenylenediamine (35) by reaction with 2.2 equivalents of the complex salt 28 afforded the dinuclear iron complex 36.Double iron-mediated arylamine cyclization of 36 by oxidation with an excess of iodine in pyridine provided indolo[2,3-b]carbazole (37). Scheme 10 An alternative procedure for oxidative cyclization of the arylamine-substituted tricarbonyl(h4-cyclohexa-1,3-diene)iron complexes is the iron-mediated quinone–imine cyclization.24 Application of this procedure to the total synthesis of the antibiotic carbazomycin D required a regioselective cyclization at an unsymmetrically substituted cyclohexadiene ligand (Scheme 11).22 Reaction of the 3-methoxy-substituted complex salt 38 with the arylamine 39 provided the iron complex 40. Chemoselective oxidation of the aromatic nucleus to the quinone imine followed by oxidative cyclization gave the tricarbonyliron-complexed 6-methoxy-substituted 4b,8a-dihy- Chem.Soc. Rev. 1999 28 151–157 154 Scheme 11 drocarbazol-3-one 41. The regioselectivity of this oxidative cyclization could be rationalized by previous studies using deuterium-labelled cyclohexadiene ligands.25 Treatment with manganese dioxide as a two-electron oxidant initially leads to cyclization by exclusive attack of the amino group at C-4 of the cyclohexadiene ligand. The proton-catalyzed rearrangement of this kinetic product the 8-methoxy isomer leads to the 6-methoxy isomer 41 and is controlled by the regio-directing effect of the 2-methoxy substituent of the intermediate ironcomplexed cyclohexadienyl cation.Demetallation of complex 41 and subsequent O-methylation of the intermediate 3- hydroxycarbazole provided carbazomycin D (42).22 The iron-mediated quinone–imine cyclization is of broad scope and currently provides the best route to 3-hydroxycarbazole alkaloids.24 Further recent applications of this method in the total synthesis of biologically active carbazole alkaloids include the marine alkaloid hyellazole20 and the free radical scavenger carazostatin.26 Scheme 12 More recently a third method for oxidative cyclization of the arylamine-substituted tricarbonyliron–cyclohexadiene complexes to the carbazole framework was developed. Oxidation of the iron complexes in acidic medium by molecular oxygen provides selectively the tricarbonyliron-complexed 4a,9a-dihydro-9H-carbazole derivatives.The first synthesis of mukonidine was accomplished by this method.27 The electrophilic substitution of the arylamine by the iron-complexed cyclohexadienyl cation can be combined with the oxidative cyclization in the air thus providing access to the carbazole skeleton in a one-pot process. This novel construction of the carbazole framework was applied to the total syntheses of the potent neuronal cell protecting substances (±)-carquinostatin A (46)28 and (±)-lavanduquinocin (47)29 isolated by Seto et al. from Streptomyces (Scheme 12). The reaction of the arylamine 43 with the complex salt 28 in the air for 7 days at room temperature provided with concomitant oxidative cyclization the tricarbonyliron-complexed 4a,9a-dihydro-9H-carbazole 44.Demetallation of complex 44 followed by dehydrogenation and electrophilic bromination afforded the bromocarbazole 45 which represents a crucial precursor for the total synthesis of 6-allyl-substituted carbazole-3,4-quinone alkaloids. A nickel-mediated coupling with prenyl bromide (for 46)28 or with b-cyclolavandulyl bromide (for 47)29 respectively followed by cleavage of the acetate and oxidation with CAN afforded the natural products. The one-pot construction of the carbazole framework was also used for the first total syntheses of the potent lipid peroxidation inhibitor carbazoquinocin C30 and the free radical scavenger (±)-neocarazostatin B.31 4.2 Diastereoselective spiroannulations The addition of nucleophiles to tricarbonyl(h5-1-alkyl- 4-methoxycyclohexadienyl)iron cations offers a simple method for the stereoselective generation of quaternary carbon centers.The observed selectivity is a consequence of the regiodirecting effect of the methoxy-substituent which directs the incoming nucleophile to the 1-position (para selectivity) and the stereodirecting effect of the tricarbonyliron moiety which enforces an attack of the nucleophile from the face opposite to the transition metal (anti selectivity).2,4 Based on this chemistry a diastereoselective one-pot annulation of different spiroquinoline ring systems was developed by reaction of the iron complex salt 48 with arylamines.4 The complex salt 48 is readily prepared in 50–60% overall yield starting from p-methoxyphenylacetic acid by the following simple six-step sequence 1.Birch reduction 2. esterification 3. complexation with pentacarbonyliron 4. DIBAL reduction 5. acylation with pnitrobenzoylchloride and 6. hydride abstraction using triphenylmethyl tetrafluoroborate. The cyclohexadienyl cation of 48 represents a 1,3-double acceptor since it has a leaving group at a C2-side chain in the 1-position. Therefore stereoselective construction of a quarternary carbon by regioselective electrophilic aromatic substitution at the o-amino position of the arylamine and subsequent cyclization via nucleophilic displacement of the p-nitrobenzoate by the amino group provide directly benzo-annulated 3-azaspiro[5.5]undecanes.4 The iron-mediated spiroannulation was used for a synthetic approach to the discorhabdin alkaloids.32 The discorhabdins are the major cytotoxic pigments isolated from marine sponges of the genus Latrunculia.They contain an unprecedented pyrrolo- [1,7]phenanthroline framework with a spiroannulated cyclohexenone ring and exhibit strong cytotoxic and antimicrobial activities. Reaction of the iron complex salt 48 with 1-acetyl- 6-amino-4,7-dimethoxyindoline (49) at 230 °C afforded diastereoselectively the spirocyclic iron complex 50 in 72% yield (Scheme 13). N-Acylation of complex 50 followed by demetallation with trimethylamine N-oxide and hydrolysis of the enol ether provided the spirocyclohexenone 51. This product represents a functionalized tetracyclic substructure of the discorhabdins and appears to be a promising precursor for a projected total synthesis of discorhabdin C (52).The stereodirecting effect of the tricarbonyliron fragment leading to an attack of the nucleophile at the cyclohexadienyl Scheme 13 cation exclusively from the face anti to the metal (anti selectivity) strongly applies only under kinetic reaction conditions. Using thermodynamic reaction conditions for the spirocyclization step the attack of the nucleophile syn to the tricarbonyliron fragment becomes feasible. This reversal of stereoselectivity was demonstrated for the spirolactonization of the complex salt 53 resulting in 3 steps from p-methoxycinnamic acid. Cleavage of the ester under acidic conditions and subsequent base-induced cyclization at room temperature stereospecifically provided the spirolactone anti-54 resulting from approach of the carboxylate ion anti relative to the tricarbonyliron fragment (Scheme 14).However application of thermodynamic reaction conditions by refluxing complex anti- 54 with triethylammonium hexafluorophosphate in acetonitrile afforded the diastereoisomeric spirolactone complexes anti-54 and syn-54 in a ratio of 1.8 1 as the thermodynamic mixture.33 Scheme 14 5 Synthesis of cyclopentadienones The thermal reaction of pentacarbonyliron with alkynes provides tricarbonyl(h4-cyclopentadienone)iron complexes.34 This iron-mediated formal [2+2+1] cycloaddition of two alkynes and carbon monoxide was recently reinvestigated.35239 Cycloaddition of pentacarbonyliron and two equivalents of trimethylsilylacetylene (55) at 140 °C in a sealed tube provided the tricarbonyliron complex of 2,5-bis(trimethylsilyl)cyclopentadienone (56) as a single regioisomer (Scheme 15).35 Chem.Soc. Rev. 1999 28 151–157 155 Scheme 15 The bicyclization of the diynes 57 and carbon monoxide by iron-mediated [2+2+1] cycloaddition afforded the tricarbonyliron-complexed bicyclo[n.3.0]alkanones 58 (Scheme 16). Vari- Scheme 16 ation of the diyne precursor provided a broad range of carboand heterobicyclic ring systems.37 The demetallation of the bicyclic tricarbonyliron(h4-cyclopentadienone)iron complexes at low temperature afforded the corresponding cyclopentadienones 59. At higher temperatures a subsequent double bond isomerization with concomitant monoprotodesilylation provided the dienones 60.37 These compounds are potential double Michael acceptors and promise useful applications to the synthesis of cyclopentanoid natural products.Scheme 17 Although protected against Diels–Alder dimerization for steric reasons by the two bulky trimethylsilyl substitutents the bicyclic cyclopentadienones 59 represent highly reactive dienes for Diels–Alder cycloadditions with appropriate dienophiles. The Diels–Alder reaction of the bicyclic cyclopentadienone 59b with p-benzoquinone 61 afforded stereoselectively the endocycloadduct 62 (Scheme 17). A subsequent photochemically initiated intramolecular [2+2] cycloaddition provided quantitatively the hexacyclic cage compound 63.40 Chem.Soc. Rev. 1999 28 151–157 156 6 Conclusion The 1-azabutadiene catalyzed complexation of dienes with pentacarbonyliron represents a very efficient procedure for the synthesis of tricarbonyliron–diene complexes. Chiral 1-azabutadienes were used for the asymmetric catalytic complexation of prochiral diene ligands providing optically active planar chiral tricarbonyliron complexes. Many enantioselective syntheses of polyunsaturated natural products were elaborated starting from chiral acyclic tricarbonyliron–butadiene complexes. Convergent routes to different natural product frameworks are provided by the tricarbonyliron-mediated annulation of cyclohexadienes and arylamines. The iron-mediated synthesis of carbazoles currently represents the best access to biologically active highly substituted carbazole alkaloids isolated from different Streptomyces species over the past years.A one-pot construction of the carbazole framework was achieved by oxidative cyclization in the air and applied to a short and simple route to carbazole- 3,4-quinone alkaloids. The diastereoselective iron-mediated spiroannulation of arylamines provided a one-pot access to spiroquinoline derivatives related to the cytotoxic discorhabdin alkaloids. The iron-mediated [2+2+1] cycloaddition of terminally silylated alkynes and carbon monoxide afforded the tricarbonyliron complexes of 2,5-disilylcyclopentadienones. Their free ligands are useful dienes for subsequent cycloadditions to highly substituted cage compounds.7 Acknowledgements I wish to thank my coworkers who contributed to this project and whose names are given in the corresponding references. We are grateful to the Deutsche Forschungsgemeinschaft the Volkswagen Foundation the Fonds der Chemischen Industrie and the Alexander von Humboldt Foundation for their financial support of our work. 8 References 1 Part 46 H.-J. Kn�olker M. Graf and U. Mangei J. Prakt. Chem. 1998 340 530. 2 A. J. Pearson Iron Compounds in Organic Synthesis Academic Press London 1994 chap. 4 and 5; and references cited therein. 3 R. Gr�ee and J. P. Lellouche in Advances in Metal-Organic Chemistry ed. L. S. Liebeskind JAI Press Greenwich (CT) 1995 vol. 4 p. 129; and references cited therein. 4 H.-J.Kn�olker Synlett 1992 371; and references cited therein. 5 H.-J. Kn�olker in Encyclopedia of Reagents for Organic Synthesis ed. L. A. Paquette Wiley Chichester 1995 vol. 1 p. 333; and references 6 H.-J. Kn�olker G. Baum N. Foitzik H. Goesmann P. Gonser P. G. 7 H.-J. Kn�olker E. Baum P. Gonser G. Rohde and H. R�ottele 8 H.-J. Kn�olker and H. Hermann Angew. Chem. 1996 108 363; Angew. 9 M. Franck-Neumann M. Sedrati and M. Mokhi Angew. Chem. 1986 cited therein. Jones and H. R�ottele Eur. J. Inorg. Chem. 1998 993. Organometallics 1998 17 3916. Chem. Int. Ed. Engl. 1996 35 341. 98 1138; Angew. Chem. Int. Ed. Engl. 1986 25 1131. 10 M. Franck-Neumann and P.-J. Colson Synlett 1991 891. 11 A. Monpert J. Martelli R. Gr�ee and R. Carri�e Tetrahedron Lett.1981 22 1961. 12 C. Tao and W. A. Donaldson J. Org. Chem. 1993 58 2134. 13 W. A. Donaldson P. T. Bell Z. Wang and D. W. Bennett Tetrahedron Lett. 1994 32 5892; V. Prahlad and W. A. Donaldson Tetrahedron 14 T. J. Benvegnu L. J. Toupet and R. Gr�ee Tetrahedron 1996 52 11811; 15 C. Iwata and Y. Takemoto Chem. Commun. 1996 2497; and references 16 D. P. Chakraborty in The Alkaloids ed. A. Brossi Academic Press Lett. 1996 37 9169. T. J. Benvegnu and R. Gr�ee Tetrahedron 1996 52 11821. cited therein. New York 1993 vol. 44 p. 257; and references cited therein. 17 H.-J. Kn�olker in Advances in Nitrogen Heterocycles ed. C. J. Moody JAI Press Greenwich (CT) 1995 vol. 1 p. 173; and references cited therein. 18 H.-J. Kn�olker M. Bauermeister and J.-B.Pannek Chem. Ber. 1992 125 2783. 19 H.-J. Kn�olker and W. Fr�ohner Tetrahedron Lett. 1997 38 4051. 20 H.-J. Kn�olker E. Baum and T. Hopfmann Tetrahedron Lett. 1995 36 5339. 21 H.-J. Kn�olker and W. Fr�ohner Tetrahedron Lett. 1996 37 9183. 22 H.-J. Kn�olker and G. Schlechtingen J. Chem. Soc. Perkin Trans. 1 1997 349. 23 H.-J. Kn�olker and K. R. Reddy Tetrahedron Lett. 1998 39 4007. 24 H.-J. Kn�olker M. Bauermeister J.-B. Pannek and M. Wolpert Synthesis 1995 397. 25 H.-J. Kn�olker F. Budei J.-B. Pannek and G. Schlechtingen Synlett 1996 587. 26 H.-J. Kn�olker and T. Hopfmann Synlett 1995 981. 27 H.-J. Kn�olker and M. Wolpert Tetrahedron Lett. 1997 38 533. 28 H.-J. Kn�olker and W. Fr�ohner Synlett 1997 1108. 29 H.-J. Kn�olker and W. Fr�ohner Tetrahedron Lett. 1998 39 2537. 30 H.-J. Kn�olker and W. Fr�ohner Tetrahedron Lett. 1997 38 1535. 31 H.-J. Kn�olker W. Fr�ohner and A. Wagner Tetrahedron Lett. 1998 39 2947. 32 H.-J. Kn�olker and K. Hartmann Synlett 1991 428. 33 H.-J. Kn�olker G. Baum and M. Kosub Synlett 1994 1012. 34 E. Weiss R. Mer�enyi and W. H�ubel Chem. Ber. 1962 95 1170. 35 H.-J. Kn�olker J. Heber and C. H. Mahler Synlett 1992 1002. 36 A. J. Pearson R. J. Shively and R. A. Dubbert Organometallics 1992 11 4096. 37 H.-J. Kn�olker and J. Heber Synlett 1993 924. 38 H.-J. Kn�olker J. Prakt. Chem. 1994 336 277. 39 A. J. Pearson and R. J. Shively Organometallics 1994 13 578. 40 H.-J. Kn�olker E. Baum and J. Heber Tetrahed

ISSN:0306-0012    

DOI:10.1039/a705401g

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Metallobiosites and their synthetic analogues—a belief in synergism 1997–1998 Tilden Lecture David E. Fenton Department of Chemistry Dainton Building The University of Sheffield Sheffield UK S3 7HF Received 20th July 1998 Just as it is possible to use coordination compounds to try and gain insight into the nature of metallobiosites so it is also possible to use the knowledge acquired through crystallography concerning the structure of a metallobiosite to try to develop new chemistry. The aim of this lecture was to illustrate this philosophy by referring to the interplay that led to the confirmation of the dicopper site in haemocyanin and by speculating on the use of knowledge acquired concerning the dinuclear site in urease to facilitate simulation of the functioning of the site.If one regards a metalloprotein or a metalloenzyme as a highly elaborated coordination complex the metal-containing site (metallobiosite) of which comprises one or more metal atoms and their ligands then it is possible to contemplate simulating the immediate coordination environment of the metallobiosite by use of synthetic analogues derived from small molecule compounds. The purpose of this lecture is to promote the philosophy that there is a synergism between the knowledge acquired from model studies and that acquired from direct studies on metallobiosites which enables both a fuller understanding of the metallobiosite and the generation of new coordination chemistry. The first part will concern the application of models to understanding metallobiosites and the second the generation of new chemistry inspired by biology.David Fenton is Professor of Inorganic Chemistry at the University of Sheffield. He obtained a BSc in 1963 and a PhD in 1966 both at Queen Mary College London before moving to Cornell University as a postdoctoral fellow. He was a member of the Agricultural Research Council’s Unit of Structural Chemistry in London (1969–1972) and was appointed Lecturer at the University of Sheffield in 1973. His research interests lie in the general areas of macrocyclic coordination chemistry and the use of coordination compounds in metallobiosite mimicry. He has been a Kelvin Lecturer of The British Association for the Advancement of Science and a recipient of a Daiwa Anglo- Japanese Foundation Daiwa Award.Br R¢ O– N N NR2 ‘Life has evolved from inorganic materials . . . and in that evolution has incorporated every facet of inorganic chemistry that was profitable to it’ R. J. P. Williams The discovery in 1926 that enzymes could be crystallised led to James B. Sumner being awarded a share in the 1946 Nobel Prize for Chemistry.1 He also proposed that ‘enzymes could be proteins devoid of organic coenzymes and metal ions’. It has also been remarked that ‘life has evolved from inorganic materials (generating organic chemistry as it went) and in that evolution has incorporated every facet of inorganic chemistry that was profitable to it’.2 In the case of the enzyme that Sumner had crystallised jack bean urease this turned out to be true as in 1975 it was shown that the enzyme contained nickel.The discovery by Blakely and his research group of the presence of nickel came from a critical analysis of the uv-visible spectrum that showed a distinct long wavelength absorption characteristic of octahedral nickel(ii) in an oxygen- and nitrogen-donor environment.3 Further studies by the same group using site inhibitors indicated that there were two nickel ions per active site and this led to the postulation that the two nickel ions acted cooperatively in catalysing the hydrolysis of urea to ammonia and carbonic acid [reaction (1)].3 Each nickel(ii) was proposed (1) (NH2)2CNO + 2H2O ? 2NH3 + H2CO3 to undertake a different role in the mechanism of the reaction with one serving to polarise the urea and the second enhancing the nucleophilicity of water so that the hydroxide formed can attack the polarised carbonyl of the urea.In 1995 Jabri and co-workers reported the crystal structure of microbial urease from Klebsiella aerogenes and this revealed that the active site did indeed consist of two nickel atoms.4 These are sited 3.5 Å apart and were bridged by a carbamate group that had been formed by reaction of carbon dioxide with the e-amino acid of a lysine residue. One of the nickel atoms is three coordinate and therefore coordinatively unsaturated thus presenting a likely site for the binding of urea. The second nickel is pentacoordinated and the water molecule attached to the metal may be activated towards nucleophilic attack at the urea either by utilising the Lewis acidity of the metal or by basecatalysis promoted by a basic side chain proximal to the site (Fig.1). It is quite evident that a close inspection of urease and its activity demonstrates the vitality of inorganic chemistry an area which through time has been didactically linked to the inanimate. From the above it is evident that the crystal structure of a metalloenzyme serves to act as a guide to the associated mechanistic pathway. In order to elucidate mechanisms further studies would require specific chemical modifications or site directed mutagenesis. The coordination chemist can provide the 159 Chem. Soc. Rev. 1999 28 159–168 Fig.1 A proposal for the mechanism of urease (based on S. J. Lippard Science 1995 268 996). opportunity to work with small molecule model compounds or synthetic analogues. These can be designed to approach or duplicate the biological unit in terms of ligand and donor atom type and assembly metal atom oxidation level and coordination geometry. They have been classified as speculative or corroborative. 5 A speculative model occurs when the structure of the microenvironment of the metal ion is unknown and the object is to reproduce some spectroscopic property of the metallobiomolecule using a simple complex. A corroborative model is used to try and directly imitate the coordination features of a structurally established site; the information recovered here can then be used to ascertain whether the properties of the site are dominated by interactions within the first coordination sphere of the metal.It is useful to recall that ‘the extent to which a model resembles what it represents depends on its purpose’ and so the Holy Grail for the bioinorganic modeller would be the acquisition of a functional model that simulated the natural site in terms of both structure and function. It is crucial to remember that the models may not be able to simulate the environmental effects of and whatever structural constraints are imposed by the natural environment—interactions beyond the first coordination sphere. Focused modelling therefore has a useful role to play in helping elucidate fundamental aspects of the structure spectroscopic magnetic and electronic properties reactivity and mechanism pertaining at metallobiosites.The relationship Fig. 2 The synergism between coordination chemistry and the chemistry of metallobiosites. What is a macrocycle? A macrocycle has been defined as a cyclic molecule with three or more potential donor atoms in a heteroatom ring of at least Chem. Soc. Rev. 1999 28 159–168 160 between coordination chemistry and bioinorganic chemistry may be regarded as synergistic (Fig. 2). There is a learning process from Nature and an opportunity to adopt the knowledge retrieved to the generation of new chemistry and potential catalysts based on metalloenzymic processes; it is this aspect on which this lecture is focused. The philosophy is not new having first been expounded by Ken Karlin,6 hence my creed is sequential.My interest in the modelling of metallobiosites stems from a period of involvement with the Agricultural Research Council and the chemistry of macrocyclic polyethers and their selective coordination of alkali metal cations. Two structural motifs (Fig. 3)—the entrapment of two cations within the cavity of a single macrocycle7 and the total encapsulation of a cation by a single macrocycle8—held my attention and stimulated interest in whether such motifs could be obtained for transition metals. The prospect of dinuclear encapsulation was further stimulated by the growing literature on the occurrence of dinuclear metallobiosites. 9 Fig. 3 Structural motifs from two crown ether complexes.Dibenzo- 24-crown-8·2KNCS7 (upper) and dibenzo-30-crown-10·KNCS8 (lower). nine atoms. Nature has exploited macrocycles—porphyrins and related systems—for an aeon but man has only used them in this century. Until the 1960’s only the phthalocyanines and various isolated compounds such as van Alphen’s cyclam (1,4,8,11-tetraazatetracyclodecane) and the polyethers of Luttringhaus were available. The early 1960’s saw the advent of a range of polyazamacrocyclic ligands formed by metal-template procedures and of Pedersen’s crown polyethers. These discoveries led to more systematic studies of macrocycles and their metal complexes and as such provided the corner stones upon which supramolecular chemistry has been built (Fig.4). Fig. 4 The growth of supramolecular chemistry. The synthesis of Schiff base macrocycles Macrocycles containing Schiff base linkages have provided three of the corner stones mentioned above (Fig. 5a–c). The earliest example of a synthetic macrocyclic ligand containing an imine linkage stems from the work of Curtis and was derived from the mixed-aldol condensation of acetone with nickel(ii) ethylenediamine complexes.10 In 1964 Curry and Busch reported the iron(ii)-templated condensation of 2,6-diacetylpyridine with triethylenetetramine to give iron(iii) complexes of a pentaazadiimino macrocycle,11 and J�ager showed that the reaction of b-ketoiminato complexes with 1,2-diaminoethane gave metal complexes of a tetraazadiimino macrocycle.12 In all of these examples the product was recovered as a metal complex and no macrocycle was obtained in the absence of a metal ion.The requirement for a metal to be present in the reaction forming the macrocycle became known as the template effect. The fourth cornerstone (Fig. 5d) was added by Pedersen with his discovery of the cyclic or ‘crown’ polyethers first synthesised from the reaction of catechol with a,w-chloroethers in the presence of alkali metal cations.13 In this case the metal Fig. 5 The cornerstone macrocycles. cation was not retained by the product and so it was proposed that the role of the metal was to organize the transition state which preceded formation of the macrocycle. ‘I don’t believe that any scientist should be deprived of the joy of getting a research idea from the chance juxtaposition of two titles in a journal’ Ephraim Banks A wide range of Schiff base macrocycles has now evolved from the early studies.Many involve the use of 2,6-diacetylpyridine (PDA) or 2,6-diformylpyridine (PDF) as building blocks and it is possible to find an oligomeric series of macrocycles based on the condensation of these pyridine dicarbonyls with 1,ndiaminoalkanes. 14 Routes to the formation of [1 + 1] and [2 + 2] Schiff base macrocycles that is macrocycles based on the condensation of one dicarbonyl with one diamine and two dicarbonyls with two diamines respectively are shown in Fig. 6. The reaction of PDA with a,w-diaminoethers is used as an example as these were the first that we attempted.The principle of using units from both the transition metal orientated template procedures of Busch and the ether donors exploited by Pedersen was based on the Banksian philosophy shown in the above heading. The role of the metal ion in these metal-ion templated cyclisations is to control the supramolecular assembly of precyclisation fragments most likely through metal complexes derived from the precursors. The desired cyclisation product then results from an intramolecular interaction in the transition state. In the syntheses using a,w-diaminoethers alkali metal cations and transition metal ions are ineffective as templates but alkaline earth cations and lead(ii) promote cyclisation. The size and ionic potential of the template were shown to be important factors in these reactions.In the formation of [1 + 1] macrocycles the larger cations Ca2+ Sr2+ and Ba2+ give metal complexes of the hexadentate 18-membered macrocycle derived from 1,11-diamino-3,6,9-trioxaundecane whereas the smaller Mg2+ cation gives only a complex of the pentadentate 15-membered macrocycle derived from 1,8-diamino-3,6-dioxaoctane. The reaction of Ba2+ under conditions which could have given the [1 + 1] product derived from 1,8-diamino- 3,6-dioxaoctane promotes formation of a mononuclear complex of a 30-membered [2 + 2] macrocycle and interestingly when Pb2+ is used as the template a homodinuclear complex of the [2 + 2] macrocycle is found. The influence of the donor atoms is noted here as in the former the Ba2+ is located centrally within 161 Chem.Soc. Rev. 1999 28 159–168 Fig. 6 Routes to macrocyclic Schiff bases. the macrocycle cavity and interacts with all of the ligand donors whereas in the Pb2+ complex the metal is coordinated by the softer donors from the head units. By varying the nature of the heterocyclic dicarbonyl (‘head unit’) and the 1,n-diamine (‘lateral unit’) a wide range of dinucleating tetraimine Schiff base macrocycles can be synthesised (Fig. 7). Fig. 7 The range of Schiff base macrocycles. That cation size is not the ultimate factor involved in delineating the success of a templated cyclocondensation has recently been demonstrated by Busch and his co-workers.15 If in the above synthesis a 20-membered [1 + 1] macrocycle is synthesised rather than the 18-membered [1 + 1] macrocycle by using a linker modified by addition of two methylene units— NH2(CH2)3O(CH2)2O(CH2)3NH2—to increase the flexibility of the ligand then Cu2+ may be used as a template.The copper is coordinated by the head unit and a chloride ion the ether oxygens are not involved and this shows that as long as the resultant macrocycle can accommodate the preferred coordination geometry of the metal it is likely that cyclocondensation will occur. Chem. Soc. Rev. 1999 28 159–168 162 ‘The extent to which a model resembles what it represents depends on its purpose’ Jonathan Miller Haemocyanin is the dioxygen-carrying metalloprotein in arthropods and molluscs. Cumulative spectroscopic studies on oxyhaemocyanin led to the presentation of a proposal that the active site was a dinuclear copper centre in which the two copper atoms were each coordinated by three histidine units together with an endogenously bridging donor atom proposed as an oxygen from a tyrosine residue and an exogenously bridging cis-1,2-peroxide.16 This speculation led to the derivation of many modelling studies the thrust of which were to produce an endogenous bridge capable of holding the copper atoms ca.3.6 Å apart and mediating strong antiferromagnetic coupling. Our system was derived from the barium-templated cyclocondensation of 2,6-diacetylpyridine and 1,3-diaminopropan- 2-ol followed by transmetallation with copper to give the dinuclear complex 1 shown in Fig.8 the crystal structure of which was obtained.17 This revealed a CuÉCu separation of 3.64 Å and provided the first example of a structurallycharacterised copper dimer with a single alkoxo-bridge. The complex showed a charge-transfer band at 330 nm and a small antiferromagnetic coupling (2J = 284 cm21) and so complex 1 was viewed as a speculative model for the spectroscopicallyderived haemocyanin site. This however was a false dawn and indeed part of a cautionary tale as when the structure of colourless deoxy-haemocyanin from Panulirus interruptus (spiny lobster) was solved it showed no endogenous or exogenous bridging group to be present at the active site. Each CuI ion was co-ordinated by three histidine residues with an inter-copper distance of ca.3.7 Å.18 The natu of the spectroscopically-derived site was questioned and it fell to the coordination chemist to present a route forward with the publication of ‘an accurate synthetic model of oxyhaemocyanin’ by Kitajima and his co-workers.19 Fig. 8 Proposed replication of features of the spectroscopically-derived dinuclear site in oxyhaemocyanin [tetragonal Cu lmax 345 nm (e 20 000) (spectroscopy); CuÉCu 3.64 Å (EXAFS); n(O–O) 750 cm21 (resonance Raman); diamagnetic]. Using sterically hindered tripodal ligands Kitajima showed that it was possible to prepare dinuclear complexes bearing the ‘CuO2Cu’ group in the absence of an endogenous ligand bridge and that these complexes closely replicated the spectroscopic properties of the natural site.19 The crystal structure of the complex derived from hydrotris(3,5-diisopropylpyrazolyl)borate revealed the presence of an unexpected and unusual m- h2 h2-peroxide bridge and when the X-ray crystal structure of oxyhaemocyanin from limulus polyphemus was solved by Magnus et al.,20 it confirmed that there is no endogenous bridge present at the dinuclear site in oxyhaemocyanin and that the structure contains a m-h2 h2-peroxide bridge as shown schematically in Fig.9. In this instance the validity of using small molecule models to help in the understanding of the coordination environment of a metallobiosite is clear.19 Fig. 9 Schematic representation of the dinuclear site in oxyhaemocyanin. A change in direction—the post-endogenous bridge era During the course of studies on ligands capable of providing endogenous bridges it became apparent from the structures of several mononuclear barium complexes of functionalised tetraimine Schiff base macrocycles that the macrocyclic ligands had folded to present molecular clefts into which the metal ions coordinated—particularly if the ‘lateral unit’ of the macrocycle contained an odd number of carbon atoms the central one of which was functionalised.21 This mode of metal incorporation is not dissimilar to that of metalloproteins in which the requisite metal is bound in a pocket or cleft produced by the conformational arrangement of the protein.The objective then became the synthesis of flexible macrocycles capable of generating clefts for metal coordination without the presence of a ligandbased endogenous bridge.In order to do this a series of bibracchial macrocycles containing two pendant arms strategically attached to the heteroatom ring were synthesised from 2,6-diacetylpyridine and a range of N,N-bis(3-aminopropyl)- and N,N-bis(2-aminoethyl)-alkylamines using barium or silver( i) templates (Fig. 10).22 The resulting mononuclear barium Fig. 10 Bibracchial tetraimine Schiff base macrocycles. complexes and dinuclear silver(i) complexes were found to have the required conformation and in the latter cases the metals were separated by distances ranging from 2.9–6.0 Å depending on the nature of the donor groups in the pendant arms and on the length of the carbon atom chains present in the lateral diamine derived spacers.The transmetallation of the barium complex of the corresponding macrocycle derived from N,N-bis(2-aminoethyl)-2-methoxyethylamine readily gave a dinuclear copper(ii) complex. However the X-ray crystal structure of this copper complex showed that the cleft conformation had been destroyed to give a much more planar macrocyclic conformation.23 Back to the drawing board All was not entirely lost as it was possible to use the bibracchial macrocycle derived from tris(2-aminoethyl)amine and 2,6-diacetylpyridine as a precursor for the derivation of a trinuclear copper complex which served as a first generation model for the trinuclear site in ascorbate oxidase—this has been recounted Chem. Soc. Rev. 1999 28 159–168 163 elsewhere.21 A fresh route was required to try to place the dinuclear copper fragment in a molecular cleft and here serendipity played its hand.The reaction of a diprotonated hexaiminocryptand (2) prepared by [2 + 3] cyclocondensation of 2,6-diacetylpyridine and tris(2-aminoethyl)amine in the presence of hydrochloric acid with Cu(BF4)2·nH2O in methanol (Fig. 11) gave the Fig. 11 Synthesis of the dicopper(ii) complex. dinuclear complex [LCu2](BF4)4·H2O 3.21 The crystal structure confirms that a single ring-opening of the Schiff base cryptand caused by scission of one pyridinyl-diimine unit has occurred such that the dicopper(ii) moiety is held inside a cleft with a Cu(ii)ÉCu(ii) separation of 4.53 Å. Although this separation is comparable with the dicopper(i) separation of 4.6 Å found in deoxygenated haemocyanin from Limulus polyphemus, 20 we have not yet been able to prepare a dicopper(i) complex of L.The N-donor atoms of the pendant arms in this complex approach the metal atoms from the same side of the macrocyclic ring (‘cis’) consistent with the clipping out of one Fig. 12 Models and the synergism between coordination chemistry and the chemistry of metallobiosites. Site asymmetry at metallobiosites Homodinuclear metallobiosites may be exemplified by those structurally characterised in non-haeme manganese catalase [Mn,Mn],24 urease [Ni,Ni],4 alkaline phosphatase25 and phospholipase C [Zn,Zn],26 the last two sites are actually trinuclear constellations [Zn2Mg] and [Zn3] respectively and it is the homodinuclear fragment that has relevance here.Representative heterodinuclear metallobiosites are those structurally characterised in purple acid phosphatase [Fe,Zn]27 and human protein phosphatase 1 [Mn,Fe].28 Chem. Soc. Rev. 1999 28 159–168 164 bridge from the cryptate precursor. This may be contrasted with the approach of the pendant arms from opposing sides (‘trans’) found when the dicopper(ii) complex of the directly related tetraimine macrocycle bearing methoxyethyl pendant arms is prepared by transmetallation of the mononuclear barium precursor complex.23 Although we have not yet been able to prepare a dicopper(i) complex of L it has been possible to prepare related complexes of bibracchial tetraimine Schiff base macrocycles in which the head units are derived from furan-2,5-dicarbaldehyde or thiophene-2,5-dicarbaldehyde and the arms are simply aliphatic chains.In these complexes the heterocyclic head group serves as an inert spacer unit and the copper(i) atoms are four coordinate with ligation from three donors from the lateral units and a tightly bound acetonitrile of solvation. The inter copper separations are ca. 5.2 Å and the molecules are quite air-stable presumably due to the coordinative saturation at each copper(i). This area of our work has recently been reviewed.21 Learning from biology—a new chemistry At this point in time there is no precise model for the reversible uptake and release of dioxygen by haemocyanin. However it is clear that the use of small molecule models has provided useful information relating to the mode of binding of dioxygen to the dinuclear copper centre therein.At the same time it is apparent that the biological problem stimulated the interest of coordination chemists and that this in turn has provided seminal studies on the nature of interaction of dioxygen with copper particularly by the groups of Karlin Kitajima Martell Sorrell and Tollman. This area therefore serves as an excellent example of the interplay alluded to in the title with biologists learning from chemistry and chemists applying knowledge from biology to generate new chemistry (Fig. 12). To further illustrate this latter approach the development of unsymmetric dinucleating ligands will be discussed.The roles of the individual metal ions present at a biosite may be quite distinct in character. For example one metal may play a structural role by helping to maintain the structural integrity of the protein whilst the second metal has a functional role through binding to a substrate.5 The role of the metals may also be defined as co-catalytic whereby the two metal atoms in close proximity operate together as a catalytic site.29 In order to facilitate these modes of behaviour the metal ions can be found in chemically distinct environments. These have been classified in four distinct groupings (Fig. 13). (a) Symmetric—in which an Fig. 13 A classification of metal coordination environments found at transition metal-derived dinuclear centres present in metallobiosites (M is a transition metal and W X Y and Z are ligand donor atoms such as N O S etc.).identical number of donor atoms of the same type are bound to each metal atom in similar geometries. (b) Donor asymmetry— different types of donor atom coordinate to each metal atom. (c) Geometric asymmetry—there are inequivalent geometric arrangements of the donor atoms about each metal atom. (d) Coordination number asymmetry—an unequal number of donor atoms are coordinated to each metal atom.30 To a first approximation the nature of the donor atom may be restricted to simply O N S etc. but a more accurate definition would specify the functional grouping associated with the donor atom and so differentiate between O in water and carboxylate or S in a thiolate or a thioether.The combination of different types of asymmetry may also occur at a dinuclear centre. ‘For modellingÉunsymmetrical binuclear complexes are desirable synthetic targets’ T. N. Sorrell Although many examples of coordination complexes derived from symmetric acyclic dinucleating ligands have been prepared and investigated as potential model complexes for metallobiosites polydentate ligand systems that would give necessarily asymmetric dinuclear complexes remain rare; site asymmetry was often only accessed through good fortune. This and the awareness of the asymmetric nature of many metallobiosites led to the suggestion that for modelling studies unsymmetrical dinucleating ligands should be viewed as desirable targets.31 Complexes of dinucleating ligands have been divided into two general classes (Fig.14).32 The first group consists of those complexes in which the metals share at least one donor atom in species containing adjacent sites in which the central donor atom(s) provide a bridge; the ligands giving these ‘bridging donor sets’ have been collectively termed compartmental ligands. The second group consists of those complexes in which donor atoms are not shared and so isolated donor sets exist. If the arms are constituted of different donor atoms then an unsymmetric ligand results. Fig. 14 Schematic representations of dinucleating ligands. Mono- or bibracchial pendant arms may be attached to the N atoms in the ‘end-off’ compartmental ligands and to the X atoms in the isolated donor sets.The spacers in the isolated donor sets do not provide bridging atoms. 3. Dinuclear access through use of unsymmetric endogenous phenoxo-bridge ligands Our inaugural work on this topic utilised ‘end-off’ compartmental ligands and involved the introduction of a single pendant arm into 5-bromosalicylaldehyde by using the Mannich reaction followed by condensation of the resulting aminomethylsalicylaldehyde with a primary amine (Scheme 1) to give Scheme 1 Reagents and conditions (i) R2NCH2CH2NHRA CH2Oaq; (ii) 2-aminomethylpyridine HC(OEt) a range of unsymmetric dinucleating Schiff base proligands exemplified by HL1 HL2 HL5 HL6 H2L7 and H2L8.33 The first four of these proligands have N5O donor sets and are donor atom unsymmetric as one donor set incorporates two sp3 N atoms and the second set has present two sp2 N atoms the last two proligands are built up to adjacent N2O and NO2 donor sets.The reaction of the asymmetric proligands with copper(ii) salts gave homodinuclear copper(ii) complexes. The crystal structures of [Cu2Br(HCO2)L1]ClO4·H2O (4)33 showed that both copper atoms present in 4 are five-coordinate and in distorted square pyramidal environments with one copper atom (Cu1) more distorted towards a trigonal bipyramid than the second copper atom (Cu2). The indices of trigonality (t) are 0.4 and 0.29 respectively where t is the index of the degree of trigonality within the structural continuum between square pyramidal and trigonal bipyramidal geometries and has values of 0 for a square pyramid and 1 for a trigonal bipyramid.34 Each copper is coordinated by the oxygen atom of the nonsymmetrically bridging phenoxide and by atoms from two exogenous bridging groups—a bromide and a formate anion.Coordination at each metal is completed by interaction with two nitrogen atoms from the appropriate pendant arm.There is also a spatial asymmetry present in that the square pyramidal environment at Cu1 has a formate oxygen atom at its apex whilst that at Cu2 has the bromide anion at its apex; the CuÉCu separation is 3.24 Å. In order to introduce a wider range of O and N donor atoms into the proligands and so extend the range of this type of ‘endoff’ ligand the necessary Mannich bases have been prepared under non-aqueous aprotic conditions prior to Schiff base condensation.33 Here it was found that the preponderance of O donors led mainly to the synthesis of mononuclear complexes.33 Chem. Soc. Rev. 1999 28 159–168 165 Feringa35 later applied the Mannich-derived synthetic procedure to the generation of unsymmetric proligands such as HL3 and HL4 and showed that reduction of the Schiff base ligand gave the corresponding diamino compound e.g. HL9. Such compounds were also prepared by reductive amination of the monoaminomethylated salicylaldehyde with a secondary amine (HL10) or by starting from p-cresol and employing sequential Mannich reactions using two different amines (HL11). 2(CH3CO2)L4]ClO4] The dinuclear copper(ii) complex [Cu (5)35 was studied and the structure revealed that each copper is five coordinate.One copper (Cu1) is less distorted towards a trigonal bipyramid than is the second copper atom (Cu2) with Chem. Soc. Rev. 1999 28 159–168 166 indices of trigonality of 0.07 and 0.25 respectively and a CuÉCu separation of 3.029 Å. In addition to the geometric asymmetry spatial asymmetry is again noted; copper(1) has an oxygen atom from a bidentate acetate at an apex whilst copper(2) has the oxygen atom of a monodentate acetate at its apex. Both of the copper(ii) complexes referred to here exhibit small antiferromagnetic couplings [J = 242 cm21 (4) and 215 cm21 (5)]. Although these values do not model accurately the strongly antiferromagnetically coupled Type 3 copper centres found in haemocyanin and tyrosinase it has been remarked that the presence of different environments for the two copper atoms may be related to the different modes of bonding proposed for the two copper atoms in tyrosinase.35 A recent study by Reim and Krebs on the catecholase activity of dinuclear copper(ii) complexes has included complexes derived from unsymmetric dinucleating Schiff base proligands.In this study it was shown that the unsymmetric complexes did show high catecholase activity compared with that of related symmetric complexes. 36 Unsymmetric ligands have also been used to prepare manganese(ii) complexes which have been exploited in the functional modelling of manganese catalase a dimetalloenzyme which catalyses the disproportionation of hydrogen peroxide into dioxygen and water.37 The proligands HL12 and HL13 were synthesised by the Mannich route and provide donor asymmetric ligands in which one compartment includes one sp2 and one sp3 nitrogen and the second compartment includes two sp3 nitrogen atoms.The structure of the dimanganese(ii) complex [Mn2L13(MeCOO)2NCS] (9) shows that three types of asymmetry are involved—donor atom coordination number and geometrical. One manganese atom Mn1 is in a distorted square pyramidal geometry (t = 0.34) provided by the imino-N two acetato-O the phenoxo-O and an amino-N atom whereas the second manganese atom Mn2 is in a distorted octahedral environment provided by the thiocyanate anion two acetato-O the phenoxo-O and two amino-N atoms; the manganese atoms are separated by 3.376 Å.There is a significant difference between the behaviour of the unsymmetric complexes and the corresponding symmetric complexes with respect to their disproportionation. For the symmetric complexes the theoret-ical yield of dioxygen is evolved whereas for the unsymmetric complexes only 60–70% of the expected dioxygen is evolved and a side reaction is found to occur to consume H2O2 when the manganese atoms are not in electronically equivalent environments. These results support the view that a symmetric environment is required for the active dimetallobiosite in the metalloenzyme to operate efficiently. Scheme 2 X = range of functionalites. The ongoing problem In our present work we have adopted a synthetic procedure based on that reported by Latour and co-workers.38 This derives from 2-(chloromethyl)-6-formyl-4-methylphenol (7) which is available in 2 steps from commercial 2,6-bishydroxymethyl- 4-methylphenol.Reaction of 7 with functionalised secondary amines followed by Schiff base condensation with functionalised primary amines provides a further range of unsymmetric ligands (Scheme 2).39 The reaction of HL14 with copper(ii) and nickel(ii) salts is given in Scheme 3 and serves as a representative example.39 The crystal structure of the dicopper(ii) complex 8 showed that whilst the two copper(ii) atoms were both square pyramidal the two environments were spatially asymmetric. CuA has the bridging bromide in an axial position and the non-bridging bromide in an equatorial position whereas CuB has the bridging Scheme 3 bromide equatorial and the non-bridging bromide axial.This results in the square planes being tilted at 180° to each other. As a consequence of this and despite the copper–copper separation of 3.23 Å the magnetic properties of the complex show no coupling between the two copper atoms.39 This is presumably the result of an orbital mismatch and corresponding loss of exchange pathway. Changing the anion to perchlorate gives a different result and a hydroxo-bridged dicopper(ii) complex [Cu2L14](ClO4)2 (9) is obtained. Good crystals of this compound proved elusive but the crystal structure of the directly related complex [Cu2L15]- (ClO4)2 prepared from proligand HL15 in which the positions of the N-alkyl groups on the saturated arm have been reversed was solved and showed that each copper(ii) was in a square coplanar environment composed of the articular nitrogen donors the bridging phenolate oxygen atom and the bridging hydroxide oxygen atom.The copper(ii)–copper(ii) separation was 2.97 Å and there was antiferromagnetic coupling with J = 2215 cm21.39 The nickel(ii) complex [Ni2(L)2](ClO4)2·2H2O (10) resulted from slow evaporation of a methanolic solution and is the consequence of hydrolysis of the Schiff base arm. The crystal structure showed that each nickel(ii) atom is in an octahedral environment with the planar environment at each nickel(ii) 167 Chem. Soc. Rev. 1999 28 159–168 being provided by a NEt atom an aldehydic O atom and two bridging phenolato-O atoms.The apical sites are occupied by the terminal NMe2 atom and a water molecule; the two water molecules are trans to each other. It is possible to speculate that the initial product in this reaction might be a m-hydroxo bridged species as in the copper complexes above. The hydroxide would then be available to initiate hydrolytic cleavage of the side-arm. In effect we have almost come through a circle starting with urease and in reaching dinickel(ii) complexes that circle is beginning to close. Recently it has been shown that urea will bind to a nickel(ii) atom in dinuclear complexes of phenolbased ‘end-off’ compartmental ligand.40 One proligand used was HL12 and from this the complex [Ni2(L12)(NCS)3(urea)] (11) was obtained.The crystal structure showed that the nickel– nickel separation was 3.16 Å and that the nickel atoms were coordination number asymmetric. The nickel held by the iminic arm was 5-coordinated and that held by the aminic arm was 6-coordinated. The urea was bound through its oxygen atom to the nickel in the aminic compartment (Ni–O 2.13 Å). If the proligand is changed to HL16 then the dinickel(ii) complex [Ni2(L16)(OAc)(NCS)2] can be prepared. The structure of this complex reveals that there is an asymmetric dinuclear core with a mixed 5/6 coordination number set—the pair of nickel atoms are bridged by a phenolate and acetate group and an isothiocyanate group coordinates to each nickel atom together with the nitrogen atoms of the appropriate arm.Reaction with urea then generates [Ni2(L16)(OAc)(NCO)(NCS)].41 As a very slow dissociation of urea into ammonium and isocyanate ions is known under acidic conditions it is of interest to note that the dinickel core appears to assist in the conversion of urea to isocyanate at moderate pH with absolute alcohol or acetonitrile as the solvent. To close the circle completely it is necessary to demonstrate that a synthetic dinuclear core can hydrolyse urea. This serves as a goal and may be possible perhaps not with the efficiency of nature but even a fraction of that efficiency would constitute a significant advance. Acknowledgements I am indebted to my co-workers and collaborators whose names appear on the original publications for their inspired contributions to this work.I thank the EPSRC the British Council and the Daiwa Anglo–Japanese Foundation for their support. References 1 J. B. Sumner J. Biol. Chem. 1926 69 435; J. Biol. Chem. 1926 70 97. 2 R. J. P. Williams Nature 1974 248 302. Chem. Soc. Rev. 1999 28 159–168 168 3 N. E. Dixon C. Gazzola R. L. Blakeley and B. Zerner J. Am. Chem. Soc. 1975 97 4130; N. E. Dixon P. W. Riddles C. Gazola R. L. Blakeley and B. Zerner Can. J. Biochem. 1980 58 1335. 4 E. Jabri M. B. Carr R. P. Hausinger and P. A. Karplus Science 1995 268 998. 5 H. A. O. Hill Chem. Br. 1976 12 119. 6 K. D. Karlin Science 1993 262 1499. 7 D. E. Fenton M. Mercer N. S. Poonia and M. R. Truter J.Chem. Soc. 8 M. A. Bush and M. R. Truter J. Chem. Soc. Perkin Trans. 2 1972 9 D. E. Fenton Adv. Inorg. Bioinorg. Mech. 1983 2 187 and references Chem. Commun. 1972 66. 345. therein. 10 N. F. Curtis and D. A. House Chem. Ind. 1961 42 1708. 11 J. D. Curry and D. H. Busch J. Am. Chem. Soc. 1964 86 592. 12 E.-G. J�ager Z. Chem. 1964 4 437. 13 C. J. Pedersen J. Am. Chem. Soc. 1967 89 7017. 14 D. E. Fenton in Transition Metals in Supramolecular Chemistry L. Fabbrizzi and A. Poggi (eds.) NATO ASI Series Kluwer Academic Publishers Dordrecht 1994 C448 153 and references therein. 15 A. L. Vance N. W. Alcock D. H. Busch and J. A. Heppert Inorg. Chem. 1997 36 5132. 16 E. I. Solomon in Copper Coordination Chemistry Biochemical and Inorganic Perspectives K.D. Karlin and J. A. Zubieta (eds.) Academic Press New York 1983 p. 1. 17 N. A. Bailey D. E. Fenton R. Moody C. O. Rodriguez de Barbarin I. N. Sciambarella J. M. Latour D. Limosin and V. McKee J. Chem. Soc. Dalton Trans. 1987 2519. 18 W. J. P. Gaykema A. Volbeda and W. G. J. Hol J. Mol. Biol. 1985 187 255; A. Volbeda and W. G. J. Hol J. Mol. Biol. 1989 209 249. 19 N. Kitajima Adv. Inorg. Chem. 1992 39 1; N. Kitajima and W. B. Tolman Progr. Inorg. Chem. 1995 43 533 and references therein. 20 K. A. Magnus H. Tonthat and J. E. Carpenter Chem. Rev. 1994 94 727 and references therein. 21 S. R. Collinson and D. E. Fenton Coord. Chem. Rev. 1996 48 19 and references therein. 22 D. E. Fenton and G. Rossi Inorg. Chim. Acta 1985 98 L29; H.Adams N. A. Bailey W. D. Carlisle D. E. Fenton and G. Rossi J. Chem. Soc. Dalton Trans. 1990 1271. 23 N. A. Bailey D. E. Fenton P. C. Hellier P. D. Hempstead U. Casellato and P. A. Vigato J. Chem. Soc. Dalton Trans.,1992 2809. 24 V. V. Barynin A. A. Vagin V. R. Melik-Adamyan A. I. Grebenko S. V. Khangulov A. N. Popov M. E. Andrionova and B. K. Vainshtein Dokl. Akad. Nauk. SSSR 1986 288 877. 25 E. E. Kim and H. W. Wyckoff J.Mol. Biol. 1991 218 449. 26. Hough L. K. Hansen R. Birknes K. Jynge S. Hansen A. Hordvik C. Little E. J. Dodson and Z. Derewanda Nature (London) 1989 338 357. 27 N. Str�ater T. Klabunde P. Tucker H. Witzel and B. Krebs Science 268 1995 1489. 28 M.-P. Egloff P. T. W. Cohen P. Reinemer and D. Barford J. Mol. Biol. 254 1995 942. 29 B. L. Vallee and D. S. Auld Biochemistry 1993 32 6493. 30 J. H. Satcher Jr. M. W. Droege T. J. R. Weakley and R. T. Taylor Inorg. Chem. 1995 34 3317. 31 T. N. Sorrell Tetrahedron 1989 45 3. 32 D. E. Fenton Adv. Inorg. Bioinorg. Mech. 1983 2 187 and references therein. 33 D. E. Fenton and H. Okawa Chem. Ber/Recl. 1997 130 433 and references therein. 34 A. W. Addison T. N. Rao J. Reedijk J. van Rijn and G. C. Verschoor J. Chem. Soc. Dalton Trans. 1984 1349. 35 M. Lubben and B. L. Feringa J. Org. Chem. 1994 59 2227; M. Lubben R. Hage A. Meetsma K. Byma and B. L. Feringa Inorg. Chem. 1995 34 2217. 36 J. Reim and B. Krebs J. Chem. Soc. Dalton Trans. 1997 3793. 37 H. Wada K. Motoda M. Ohba H. Sakiyama N. Matsumoto and H. Okawa Bull. Chem. Soc. Jpn. 1995 68 1105 and references therein. 38 E. Lambert B. Chabut S. Chardon-Noblat A. Deronzier G. Chottard A. Bousseksou J.-P. Tuchagues J. Laugier M. Dardet and J.-M. 39 D. E. Fenton S. R. Haque D. Dye H. Adams S. L. Heath N. Fukita 40 T. Koga H. Furutachi T. Nakamura N. Fukita M. Ohba K. Takahashi 41 S. Uozumi H. Furutachi M. Ohba H. Okawa D. E. Fenton K. Shindo Latour J. Am. Chem. Soc. 1997 119 9424. M. Ohba and H. Okawa unpublished results. and H. Okawa Inorg. Chem. 1998 37 989. M. Murata and D. J. Kitko Inorg. Chem. 1998 37 6281. Review 8/0564

ISSN:0306-0012    

DOI:10.1039/a805645e

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Synthetic variations based on low-valent chromium new developments Martín Avalos Reyes Babiano Pedro Cintas José L. Jiménez and Juan C. Palacios Departamento de Química Orgánica Facultad de Ciencias Universidad de Extremadura E-06071 Badajoz Spain. Fax (+34-924)-271304; E-mail pecintas@unex.es Received 4th August 1998 This article presents an overview of the synthetic chemistry of low-valent chromium presumably Cr(ii) species and highlights most of the recent developments. These organometallic reactions represent a convenient strategy for the construction of carbon–carbon bonds displaying unique elements of stereocontrol chemoselectivity and functionalgroup compatibility. The introduction of milder protocols catalytic versions and the discovery of ligand tuning effects as a means of controlling carbanion selectivity are the most salient improvements in this expansive field.1 Introduction and background The interest in organochromium species as reagents only arose in the late 1970s when Nozaki and Hiyama et al.1 as well as Heathcock and Buse2 recognized that these species could mediate Barbier–Grignard carbonyl additions thereby taking part in carbon–carbon bond-forming reactions in organic solvents. Shortly afterwards other research groups independently described this coupling with a variety of halides and tosylates unveiling a series of important and unique features:3,4 (a) an exquisite chemoselectivity revealed by the ability of these reagents to add selectively to aldehydes in the presence of Martín Avalos Juan C.Palacios Reyes Babiano José L. Jiménez and Pedro Cintas received their graduate degrees in chemistry and their PhD degrees from the University of Extremadura (UEX) where they are Professors of Organic Chemistry. Together with a group of talented and enthusiastic collaborators they are investigating diverse areas of organic chemistry with a focus on the wide domain of asymmetric Juan C. Palacios Martín Avalos Reyes Babiano RCHO R CrIIIX2 OH ketones; (b) an unprecedented compatibility with numerous functional groups such as esters or nitriles which would otherwise be affected by other organometallics; (c) allylchromium reagents react with excellent 1,2-stereochemical control to afford in general anti adducts regardless of halide geometry either (E)- or (Z)-configured; (d) such a preference may be reversed for very bulky aldehydes and notably it depends on the solvent system; (e) disubstituted alkenyl derivatives react with complete retention of their double bond configuration.An illustrative example is provided by the separate addition of (E)- bromostyrene and (Z)-bromostyrene to benzaldehyde yielding stereospecifically (E)- and (Z)-configurated products respectively. However trisubstituted (E)- and (Z)-alkenyl halides react with aldehydes in a stereoconvergent manner to produce the (E)-isomers in both cases; (f) alkyl and alkenyl halides remain unaffected under the conditions utilized in the preparation of allylchromium reagents. There are however a series of practical limitations Cr(ii) is a good one-electron transfer donor and at least two moles of this reagent per mole of halide or donor are required although in practice a large excess is usually employed.Water should be avoided because the formation of aquaorganochromium(iii) species leads to reduction of organic halides. The mechanism proceeds by single-electron reduction of the C–X bond followed by reduction of the resulting radical by a second equivalent of Cr(ii) and finally protonolysis of the organochromium(iii) reactions. Their current research interests include the use of chiral ligands derived from carbohydrates conformational analysis solvent-free reactions and the use of nonconventional techniques to accomplish organic transformations under milder conditions and the use and development of metal reagents in synthesis.José L. Jiménez Pedro Cintas 169 Chem. Soc. Rev. 1999 28 169–177 intermediate.3 Moreover both Cr(ii) and Cr(iii) species are strongly oxophilic and oxygen-free solvents are recommended. Generally referred to as Nozaki–Hiyama reactions4 after two of the discoverers these carbon–carbon couplings have acquired great importance in preparative organic chemistry. Other authors have also significantly contributed to the development and further understanding of this methodology and their names are often associated with those of Nozaki and Hiyama. In particular Kishi5 and Nozaki6 made the independent and almost simultaneous discovery that Ni(ii) employed as a catalyst has a pronounced effect on the formation of the C–Cr bond.Furthermore Kishi studied the scope and stereochemistry with chiral derivatives en route to the synthesis of palytoxin.4,5 Important advances have also been reported by Takai and his group who have extended the process to organochromium reagents other than allyl derivatives; they have found a useful protocol for the olefination of aldehydes and have rationalized the use of other catalysts as well.3,4,7 Low-valent chromium reagents although utilized for various unrelated types of couplings tend to react under very mild conditions affording synthetically useful yields. The reagents themselves formally at least are hard nucleophiles. Although Cr(ii) species represent a borderline case between hard and soft acids (while Cr(iii) is in fact a hard acid) the carbon of a carbonyl is a hard acceptor and the oxygen is a hard donor.Since organochromium species undergo 1,2-additions exclusively they are prototype examples of hard nucleophiles. Nevertheless in many cases without the presence of counterions capable of enhancing Lewis acid character most couplings do not occur. Such properties impart high chemoselectivity patterns not witnessed with other reactive organometallic species (organoalkali Grignard or organozinc reagents). The remarkable tendency for organochromium reagents to add to carbonyl groups in a 1,2-fashion together with their relative inertness towards conjugate additions in the case of a,b- unsaturated carbonyl systems combine to enhance their worth as selective agents.Morever their low basicity encourages displacement over competing elimination pathways. An important feature of low-valent chromium which has not yet been sufficiently appreciated is its ability to effect macrocyclization reactions and intramolecular couplings are largely independent of the size of the ring formed. It is well established that additions of organochromium reagents to chiral aldehydes are not chelation controlled so that an explanation based on a strong template effect as invoked in the case of other transition metals should be questioned. Presumably the cyclization is driven by the gain in enthalpy owing to the formation of the very stable Cr(iii)–O bond. A further and unanswered complex physical question involves the exact nature of chromium salts in solution.Whereas Cr(ii) chloride can be successfully utilized to form in situ the putative organochromium(iii) reagents the action of several reducing agents on Cr(ii) depending on the method of preparation may lead to the formation of low-valent chromium species a common aspect of other transition metals having different structures and modes of action. Comprehensive reviews dealing with the preparation and applications of low-valent chromium species were reported by Saccomano3 and one of us4 covering the literature up to 1991. Since then numerous articles and specific revisions notably the applications of these protocols as key steps in some syntheses of natural products have also been published.The purpose of this article is to provide the reader with a concise description and critical analysis of the more recent developments in this fascinating chemistry such as the application to processes other than Barbier-type reactions newer radical reactions the introduction of a catalytic method or an electrochemicallydriven coupling. It is not within the scope of Chem. Soc. Rev. to provide a full rather comprehensive account of a particular Chem. Soc. Rev. 1999 28 169–177 170 area but it is hoped that the present article will be a springboard for further reading. 2 OH Ph Pr Bu 75% (>99:1) 2 Stoichiometric reactions As previously mentioned allyl halides are favorite substrates of the chromium-mediated addition reactions.g-Monosubstituted organochromium reagents will usually react through the (E)- allyl organometallic species and it is therefore irrelevant which allyl halide is used because both isomers converge to the same product. The loss of stereochemical integrity could occur during the formation of the allyl radical intermediate or perhaps by the h1–h3 haptotropic rearrangement of the allyl metal species.8 Such a rearrangement can be faster or slower than their addition to aldehydes and this fact critically affects syn/anti selectivity. In contrast with these stereoconvergent processes g-disubstituted allyl derivatives react with aldehydes and CrCl2 in a stereodivergent manner to afford homoallylic alcohols with high stereoselectivity (Scheme 1).9 The use of LiI is essential OP(O)(OEt) Bu Pr PhCHO CrCl2 LiI DMPU 25 °C Pr L OEt O Bu P Cr OEt Ph O O L H Scheme 1 because without this additive low yields were obtained.The presence of the two substituents at the g-position slows down the equilibration between the (E)- and (Z)-organochromium(iii) intermediates which results in retention of the geometrical integrity in the coupling step. The stereochemical outcome can be rationalized assuming a chair transition state. It should be noted that allylic phosphates and not halides were used as electrophiles but this leaving group is not responsible for the high stereoselection. In fact (E)- and (Z)-monosubstituted allylic phosphates both stereoconverge to the anti alcohol as major diastereoisomer.Stereoconvergence has been observed in the reactions of silyl-substituted allylchromium reagents and the coupling occurs through the most substituted end of the organometallic species (Scheme 2 eqn. (1)).10 However the trimethylsilyl group imparts high levels of regio- and stereoselectivity. Importantly reversal of the anti diastereoselectivity occurs in the reactions of silyl-substituted crotyl halides at the 2-position which clearly contrasts with simple crotylchromium reagents (Scheme 2 eqn. (2)). The coupling of aldehydes with (Me3Si)2CBr2 in the presence of CrCl2 in DMF at room temperature gives rise to 1,1-bis(trimethylsilyl) alkenes.11 Likewise the synthetically useful vinylstannanes can be readily prepared by a direct synthesis involving the coupling of aldehydes with the alkylchromium reagent derived from Me3SnCHBr2.Again it is necessary to use LiI as an additive.12 An important improvement of the Nozaki–Hiyama reaction of allyl and propynyl halides has been the development of a lowtemperature version.13 The protocol is based on the fact that the redox potential of Cr(ii) can be altered by the presence of electron-rich ligands. Consequently a Ph2Cr–tetramethylethylenediamine complex mediates addition reactions of either allyl iodides or bromides to aldehydes ketones and enones at a Br Me3Si OH CrCl2 PhCHO + (1) Ph Me3Si THF 25 °C 2 h SiMe3 Br (2:1 mixture) 69% (100% anti) OH SiMe3 SiMe3 Ph Br CrCl2 PhCHO (2) + + THF 25 °C 2 h SiMe3 OH SiMe3 Ph Br 91% ( syn:anti = 67:33) ( E/Z = 2:1) Scheme 2 temperature as low as 260 °C.The reagent is readily prepared by addition of PhMgBr to CrCl2 in THF in the presence of TMEDA. The use of such a complex leads to a considerable rate enhancement (reactions are usually complete within 30 min versus several hours following the standard protocol) and a wide tolerance of sensitive substrates. Scheme 3 illustrates the selective 1,2-addition to a spirodienone which would otherwise be cleaved under regular Nozaki–Hiyama reaction conditions. O OH HO Ph2Cr (TMEDA) + + Br THF –60 °C O O O O O O 57% (1.5:1) Scheme 3 In previous studies it has been demonstrated that free radicals generated from organic halides and (ethylenediamine)- chromium(ii) complexes can be trapped by electron-withdrawing alkenes to afford the corresponding coupling products in moderate to good yields.14,15 The coupling reactions work well in DMF a solvent in which Cr(ii) is a stronger reducing agent either with alkyl or aryl halides although the trapping of benzyl radicals by alkyl-substituted alkenes (e.g.cyclohexene) was unsuccessful leading almost exclusively to bibenzyl formation. Likewise 1-iodo-4-nitrobenzene failed to react with methyl methacrylate and neither coupling nor reduction products were obtained. Alkyl halides react faster than aryl derivatives and sometimes the reactions proceed slowly at room temperature especially with bromides but can be accelerated by heating the reaction mixture.Acrylates as well as vinyl sulfones and phosphonates can be equally utilized as deficient alkenes (Scheme 4). CN Cr(en)2 2+ DMF + I CN 6 h 25 °C 68% I Cl Cr(en) PO(OEt)2 2 2+ DMF + Cl 16 h 80 °C PO(OEt)2 60% Scheme 4 The positive effects of complexation with nitrogenated ligands were also investigated by Kishi and his associates during their synthetic studies in which the key bond-forming step involves an intermolecular Cr(ii)–Ni(ii)-mediated coupling and only a catalytic amount of Ni(ii) is needed. The most plausible mechanism accounting for the catalytic role of nickel(ii) is shown in Scheme 5. The process may be initiated by CrIII CrII X NiX Ni0 NiII CrIII NiII RCHO R CrIIIX2 OH Scheme 5 reduction of NiCl2 to nickel(0) by two equivalents of CrCl2 followed by oxidative addition of the unsaturated halide (or a related substrate) to afford an organonickel(ii) reagent.This species may then undergo transmetallation with Cr(iii) to give the corresponding organochromium(iii) reagent which then reacts with the carbonyl compound. The nickel(ii) generated in the oxidative addition step reenters the catalytic cycle.3,4,6 In view of the intermediacy of coordinating transition metal species Kishi et al. suggested that a chiral ligand could enhance the rate of coupling and induce a higher level of stereoselection. 16 However a suitable ligand for this purpose must form labile complexes with Ni(ii) but sufficiently strong with Cr(ii).After a preliminary screening dipyridyls with a substituent at the 6-position were found to be the ligands of choice. In the presence of NiCl2 as catalyst the coupling proceeded rapidly even at 220 °C and the unwanted homocoupling reaction was completely suppressed (Scheme 6). Even ketones react with Me O TBSO CHO O Me OSBT TBSO O TBSO CrCl2–NiCl2 (1:2) OMe + THF L* –20 °C I TBSO OH OSBT ( dr = 4.2 1) Me Me O OMe Pr N L* N Scheme 6 iodoolefins at an appreciable rate. It should be noted that the coupling took place in the presence of pyridine but not with 2,2’-dipyridyl 1,10-phenanthroline or CHIRAPHOS (bis(diphenylphospino) butane). Chiral pyridines were also tested but these ligands gave poor diastereomeric ratios.Furthermore the authors anticipate that the results may suggest that the stability and/or reactivity of the Cr- versus Ni-complexes correlates to the ability of the ligands to adopt a nonplanar conformation. This surmise was reinforced by the observation that coupling was effective in the presence of (S)-BINAPH but did not progress with CHIRAPHOS. It is also evident that Scheme 6 shows an example of double stereodifferentiation the starting aldehyde itself is chiral. The 171 Chem. Soc. Rev. 1999 28 169–177 coupling in the presence of the enantiomeric ligand gave an approximate diastereomeric ratio of 1 1.9 at room temperature so that the chiral centre(s) present in the sugar has an effect on the stereoselection.In a further study it has been shown that 4-tert-butylpyridine is a beneficial additive in the Nozaki–Hiyama–Kishi coupling reaction.17 The use of this substance allows for homogeneous reactions improves reproducibility and avoids homocoupling side reactions. Thus solutions of CrCl2(98–67%)–NiCl2(2– 33%) in THF–4-tert-butylpyridine (4 1) or in DMF–4-tertbutylpyridine (3 1) can be prepared by stirring the mixture at room temperature for 5–15 min though in both solvent systems a suspension of NiCl2 is observed. It is unclear what is the role of this additive but the authors suggest that it facilitates the selective solubilization of Cr(ii) over Ni(ii) because 4-tertbutylpyridine alone does not provide a homogeneous solution of CrCl2.Likewise an improved workup using chromium ion chelators such as ethylenediamine or sodium or potassium serinate produces a better yield. Italian authors have reported the coupling of allylchromium reagents with alkyl and aryl imines in the presence of a Lewis acid catalyst. The diastereoselectivity is in general poor but better results were obtained in the reaction of allylchromium and the imine derived from benzaldehyde and (S)-valine (Scheme 7 eqn. 1).18 In a related work the Cr(ii)-mediated allylation of N-protected a-amino aldehydes led to a versatile synthon which could further be converted into a polypeptide containing a hydroxyethylene isostere which allows a variation of the amino acid sequence found in naturally-occurring peptides (Scheme 7 eqn.2).19 Although this Cr(ii)-promoted Br CrCl2 BF3–OEt2 (cat) + (1) COOMe HN THF 4Å molecular sieves Ph COOMe N 75% (86% de) Ph CH2Ph O BocValHN CH2Ph H several steps CrCl2 + BocValHN THF COOEt COOEt OH Br (2) BocVal–PheY[CH(OH)CH2]Ala–Ile–ProOMe Scheme 7 allylation of oligopeptide aldehydes proceeds with moderate stereoselectivity the use of other allylating reagents such as allylsilanes allylstannanes or allylcuprates gave poor yields along with a complex reaction mixture. In contrast allylzincs gave comparable yields and also a comparable stereoselectivity to that of chromium reagents. In an interesting work Chinese researchers have reported the chromium-mediated activation of polyfluorohaloethanes which add to electron-deficient alkenes to give the corresponding coupling products in good yields.20 It should be pointed out that reactions can be conducted in hot ethanol and low-valent chromium was generated from anhydrous CrCl3 and the inexpensive iron (Scheme 8 eqn.(1)). The latter metal has found so far limited applications in organic synthesis since activated iron should be an acid-washed finely divided material that oxidizes rapidly in air.21 This methodology has also been applied to the preparation of polyhaloalkylmethyl-substituted electrophilic cyclopropanes (Scheme 8 eqn. (2)).22 The reaction with this Cr–Fe redox system proceeds apparently by two steps combining radical addition and cyclopropanation. Chem. Soc.Rev. 1999 28 169–177 172 CF3CCl3 COOEt F3C CrCl3 Fe + (1) EtOH 65 °C 10 h Cl Cl COOEt 78% CF3CF2CH2 COOEt CF3CF2I CrCl3 Fe (2) + COOEt EtOH 65 °C 15 h COOEt 89% COOEt Scheme 8 A recent contribution highlights the use of CrCl2 in Reformatsky reactions,23 old processes that enjoy a new renaissance in synthetic organic chemistry. Reactions are run in THF at room temperature in the presence of LiI and can be applied to aldehydes and ketones. Aldehydes exhibit excellent selectivities ( � 50 1) versus methyl ketones and larger ketones ( � 200 1). Methyl ketones also react preferentially in the presence of higher ketones (Scheme 9). Ph COOMe PhCHO + PhCOMe CrCl OH 2 LiI (cat) + THF rt Ph COOMe COOMe Br Me OH 46% (50:1) Scheme 9 The reactivity of alkylchromium reagents generated from halides and tosylates towards aldehydes has been largely studied by Takai and coworkers.3,4,7 Reactions can be conducted in DMF under mild conditions in the presence of cobalt catalysts such as vitamin B12 or cobalt phthalocyanine.These species are thought to form an organocobalt intermediate which cleaves to an alkyl radical that further adds to Cr(ii) to give the alkylchromium reagent. Curran and his associates utilized this hypothesis to develop a tandem carbon–carbon bond-forming reaction involving a sequence of 5-exo-trigonal cyclization transmetallation to organochromium species and coupling to an aldehyde (Scheme 10).24 I CrCl2 DMF cobalt phthalocyanine PhCHO Ph OH 71% Scheme 10 The sequential generation of radical and anionic species can be harnessed to devise a three-component coupling of alkyl iodides 1,3-dienes and carbonyl compounds.25 The use of CrCl2 as a mild reductant constitutes the driving force and controls the selectivity as illustrated in Scheme 11.Reactions are performed in an aprotic solvent such as DMF in which the reduction of alkyl halides by CrCl2 proceeds more easily. Even under such conditions however primary alkyl iodides are converted preferentially into alkyl chlorides because the rate of substitution by the chloride ion is faster than that of CrII • R R• polymerization R I CrII CrII R R1CHO R R1 R– CrIII OH Scheme 11 one-electron reduction with Cr(ii).Only secondary and tertiary alkyl radicals will survive for a sufficient lifetime to undergo intermolecular addition to a 1,3-diene to form radical or anionic species. The competitive radical polymerization does not occur because the one-electron reduction of the allyl radicals is fast affording the reactive allylchromium reagents. The overall process is highly selective two regioisomeric homoallylic alcohols are obtained both of them as a mixture of two stereoisomers. The major regioisomer contains essentially one stereoisomer which displays an anti geometry. Nevertheless coupling with cyclic systems having a fixed double bond proceeds stereospecifically affording only one stereoisomer (Scheme 12). CrCl2 DMF tBu + tBu–I + PhCHO 25 °C 1 h Ph OH 72% Scheme 12 Another interesting result from Takai and his group describes for the first time the umpolung reactivity of diaryliodonium salts.26 These substances are precursors of aryl cation equivalents and because of their electron-deficient character they undergo arylation with numerous nucleophiles.However in the presence of CrCl2 plus a catalytic amount of NiCl2 the iodonium reagents are converted into arylchromium(iii) species thereby behaving as aryl anion equivalents that can react with aldehydes. Benzyl alcohols are obtained in good yields in DMF solution and the reaction works well either with aromatic or aliphatic aldehydes (Scheme 13). In some cases by-products Ph2I+ BF4 – OH CrCl2 NiCl2 (cat) + Cl DMF rt 5 h Ph CHO Cl 82% Scheme 13 such as iodoarenes and arenes resulting from reductive dehalogenation are also obtained.Steric effects are quite important and pivalaldehyde does not react under these conditions. 3 Catalytic reactions It is fair to say that the most important goal in modern organometallic chemistry is the introduction of multicomponent catalysis for reductive bond formations,27 since this strategy enables the assembly of various structural frameworks avoiding the use of an excess of toxic and expensive reagents. Although chromium is an essential element in trace amounts chromium anions are described as toxic and from a physiological viewpoint this is probably due to generating Cr(iii) bound in a special site from which it will not exchange.In fact the effects of chromium and other transition metals on the immune system have been reported.28 Consequently the development of equally efficient alternate methods that diminish the need for stoichiometric chromium halides has obvious significance. Recently Fürstner and Shi have been able to accomplish this objective with the use of the triplet CrCl3– trimethylchlorosilane–Mn which renders Nozaki–Hiyama-type reactions catalytic in chromium.29 The nucleophilic addition of an aldehyde to the intermediate organochromium reagent forms the corresponding chromium alkoxide. The latter impedes a catalytic cycecause of the inherent oxophilicity of Cr(iii). However these authors reasoned that s-bond metathesis with a more oxophilic element such as silicon would permit ligand exchange thereby liberating Cr(iii).Finally Cr(iii) could be reduced by a massive metal having the appropriate redox potential. In principle Zn an inexpensive and rather nontoxic element could satisfy this requirement; however this metal may also insert into reactive halides and more importantly zinc halides generated during the course of the reaction have a sufficient Lewis acidity to react with enolizable aldehydes. Manganese was chosen as the best substitute for zinc in view of the low acidity of manganese salts and the fact that insertion reactions will only occur with highly activated manganese (Scheme 14).21 RCHO X CrX2 OCrX2 R 2 CrX2 CrX3 Mn Me3SiX3 MnX2 OSiMe3 R Scheme 14 It should also be noted that the catalytic cycle depicted in Scheme 14 will proceed regardless of whether it starts with Cr(ii) or Cr(iii).Accordingly catalytic reactions were also highly effective using chromium metallocenes such as Cp2Cr or CpCrCl2 and with the latter reagents carbon–carbon bond formation took place with less than 1 mol% of chromium.29 A highly stereoselective synthesis of anti diols involves the chromium(ii)-catalyzed reaction of acrolein acetals with aldehydes. 30 Anew the catalytic system consists of a mixture of CrCl2 Mn powder and TMSI which is generated by use of TMSCl and NaI. Diols were obtained in good yields with excellent diastereomeric ratios (anti syn > 10 1). However diminished yields and diastereoselectivities were observed for a,b-unsaturated aldehydes mainly due to pinacol coupling.Likewise modest facial selectivity was obtained in the case of chiral aldehydes bearing an a heteroatom a fact attributable to the absence of coordination with the chromium reagent. An electrochemically-driven catalytic coupling has also been devised by Grigg and his associates.31 Reactions of both aryl and vinyl halides with aromatic aldehydes were conducted in a thermostatted electrochemical cell in DMF and in the presence of a catalytic combination of Cr(ii) and Pd(0). The supporting electrolyte LiClO4 also serves as the oxophilic mediator capable of cleaving the O–Cr(iii) bond thereby liberating Cr(iii) that is further reduced to Cr(ii) on the electrode surface (Scheme 15).As in the case of other cocatalysts the Pd(0) first undergoes oxidative addition to the substrate and the resulting organopalladium(ii) species likely undergoes a subsequent transmetallation with Cr(ii). The current density is a critical 173 Chem. Soc. Rev. 1999 28 169–177 OH CrCl2 (cat) Pd(OAc)2 (cat) + PhCHO Ph PPh3 LiClO4 DMF Br + n e– (40 mA cm-2) 69% Scheme 15 parameter that must be carefully controlled to avoid side reactions such as biaryl formation. Anyway the importance of this contribution lies in the fact that electrons (or electrochemically-generated solvated electrons) might be utilized as the ultimate reducing agents. (1) (2) O 25% 4 Cyclizations and construction of natural fragments Employing Kishi’s conditions namely the Cr(ii)-mediated– Ni(ii)-catalytic coupling Hodgson and Wells described an interesting cyclization of both iodoaryl-substituted alkynes and alkynals to afford five- and six-membered rings under mild conditions (Scheme 16).32 It is interesting to note that only the I CrCl2 NiCl2 (cat) DMF 25 °C 18 h O O 57% HO I O CrCl2 NiCl2 (cat) DMF 25 °C 15 h O Scheme 16 products resulting from syn-vicinal difunctionalization of the triple bond were detected as evidenced by NOE studies.The mechanism of this carbometallation involving an alkyne rather than aldehyde addition occurs anew by oxidative addition of low-valent nickel followed by intramolecular syn-arylnickelation of the triple bond prior to transmetallation to Cr(iii) with retention of geometry and further nucleophilic attack on the aldehyde moiety if present.As mentioned above the intramolecular coupling of carbonyls with organic halides represents a convenient methodology for the stereocontrolled preparation of cyclic fragments present in numerous natural products and their analogs.3–5,33 Perhaps one of the most striking applications of this methodology and the paradigm of Cr(ii)–Ni(ii)-mediated reactions was the total synthesis of palytoxin33 involving several chromium-induced steps. The recent literature is full of elegant examples including synthetic approaches to enediyne antibiotics,33 taxane and taxamycin precursors,17,33 a total synthesis of brevetoxin B,33 or a one-pot access to two different aldol fragments of the cytotoxic epothilones,34 a remarkable new class of antitumor agents.Scheme 17 shows an unprecedented SN2A intramolecular coupling leading to a C9–C12 eight-membered ring closure of a seco-taxoid precursor.35 It is noteworthy that the stereochemistry of the starting material is a crucial factor and determines the steric course. When the precursor having cis stereochemistry (referred to the protected 1,2-diol function) was subjected to the Cr(ii)–Ni(ii)-mediated coupling in DMSO at 20 °C for 4 days no cyclization product was observed but a diene resulting from iodine–hydrogen exchange could be isolated in 65% yield. This result means that iodine–metal exchange took place Chem.Soc. Rev. 1999 28 169–177 174 I O O O O but the subsequent attack on the aldehyde group did not occur. However the above-mentioned conditions applied to the trans iodovinyl aldehyde gave after further acylation the allenic derivative depicted in Scheme 17 whose structure was unequivocally established by X-ray crystallography. The authors reasoned that an oxygen–metal complexation should favor a chair-like six-membered transition state proposed for the sterochemical outcome of Nozaki–Hiyama reactions,3,4 a condition that can be reached in the trans isomer but not in the case of its cis counterpart owing to angular distortions and nonbonding repulsive interactions between the gem-dimethyl group and the eclipsed aromatic moiety.The preparation of taxamycins an enediyne family of anticancer antibiotics entails an intramolecular Nozaki–Kishi ring closure of iodoaldehydes.36 Scheme 18 shows the synthesis a) I CHO H MOMO b) R CHO H MeO c) OAc H MOMO of (a) taxamycin-12 and (b) taxamycin-11. Reactions were run in THF using the CrCl2(THF) complex which gave the best results. Attempts to generate Cr(ii) species in situ by reduction of CrCl3 with LiAlH4 plus a catalytic amount of NiCl2 afforded low yields of taxamycins. The coupling in the presence of SmI2 an excellent one-electron transfer donor was unsuccessful. It is worthy of mention that taxamycin-11 could also be obtained by base-induced cyclization of the acetylene precursor with 2 equiv.of potassium hexamethyldisilazide at 278 °C. The latter protocol however gave lower yields of cyclized material. Finally allylic oxidation with SeO2 in dioxane gave the desired ketone characteristic of taxoid systems (Scheme 18c). 1) CrCl2 NiCl2 (cat) 2) Ac2O py Scheme 17 CrCl2(THF) (6 equiv.) NiCl2 (1.6 equiv.) THF 30 min 40% CrCl2(THF) (8 equiv.) NiCl2 (1.6 equiv.) THF 45 min 37% (R = I) KN[SiMe3]2 –78 °C 15-25% (R = H) SeO2 dioxane 60-70°C 3 h 89% Scheme 18 OAc . O O O 52% overall OH H MOMO HO H MOMO OAc H O Macrocyclization induced by a Cr(ii)–Ni(ii) system has been utilized in an enantioselective total synthesis of an eunicellin diterpene a family of marine metabolites.37 The construction of the oxonane ring was accomplished by treating the iodoaldehyde precursor with CrCl2–NiCl2 in DMSO (Scheme 19).The resulting tricyclic ether was obtained in 65% yield with an excellent stereoselectivity ( > 20 1). Further acetylation followed by cleavage of the silyl ether gave the desired diterpene in 88% yield. CrCl2–NiCl2 H H H H H H H H DMSO 65% O O TBDMSO TBDMSO HO I O 1) Ac2O py 2) Bu4NF 88% H H H H HO O AcO Scheme 19 In a total synthesis of pinnatoxin A,38 a toxic substance with a pronounced biological activity as a Ca2+-channel activator the key step was a Cr(ii)–Ni(ii)-mediated coupling again. The synthetic strategy depicted in Scheme 20 involves the intermolecular reaction of an aldehyde with a vinyl iodide which afforded a mixture of diastereomeric allylic alcohols.Removal of the primary TBS group and further oxidation furnished a single diketo-aldehyde. A second Cr(ii)–Ni(ii)- mediated coupling was also conducted in the presence of a bispyridinyl ligand. It should be pointed out that the vinylchromium species adds selectively to the aldehyde moiety even in the presence of sensitive groups such as a carbamate carbonyl and enone and a ketone. A previous paper by Kishi and his associates described the total syntheses of halichondrin B and norhalichondrin B,39 a CHO O HO O + I O O O O TBSO CH2OTBS NHAlloc O O HO COOtBu I O CrCl2 NiCl2 THF O O O O TBSO CHO Scheme 20 5 Conclusions The selected examples described through this article illustrate the continuing interest and potential of Cr(ii)-based couplings often in the presence of other metal catalysts.It is noteworthy the recent introduction of elegant and versatile catalytic methods that require a few mol% of chromium and have therefore an important environmental significance. Complexa- NHAlloc O HO O O 1) CrCl2 NiCl2 DMSO 2) HF•py py–THF 3) Dess-Martin oxidation Chem. Soc. Rev. 1999 28 169–177 family of complex polyether macrolides with pronounced in vitro and in vivo antitumor activity. Remarkably the synthetic strategy contains more than one Cr(ii)-mediated coupling. During the synthesis of the right half of the halichondrin B the coupling of two segments was accomplished by an intermolecular Nozaki–Kishi reaction to yield a ~ 6 1 mixture of the two possible allylic alcohols which were then subjected to base-induced cyclization to produce the tetrahydropyran system in 50–60% overall yield.It should be pointed out that the starting mesylate was found to be quite labile but survived under the mild conditions of the Cr(ii)–Ni(ii) coupling. The tetrahydropyran was deprotected the alcohol functionality was oxidized (Dess–Martin) and the resulting aldehyde was subjected to a further Cr(ii)–Ni(ii)-mediated coupling with a vinyl iodide followed by Dess–Martin oxidation removal of the MPM group and lactonization (Scheme 21). Remarkably coupling of the right half moiety of halichondrin B with the left half (in the form of an iodo derivative) was also successfully effected by a Cr(ii)–Ni(ii) reagent.The synthesis of norhalichondrin B was performed in the same way and gave a yield comparable with that of halichondrin B. An additional example from carbohydrate chemistry also illustrates the enormous versatility of this low-valent chromium-based methodology for the construction of carbon– carbon bonds. Unsaturated keto carbocycles (pseudosugars) can be obtained by means of an intramolecular Nozaki–Kishi reaction of w-haloaldehydes (Scheme 22).40 Preliminary attempts to cyclize the unsaturated aldehyde under Barbier-type conditions either with magnesium or lithium were unsuccessful and no reaction was detected at room temperature while at 40 °C b-elimination took place.However the Cr(ii)– Ni(ii) system promoted the cyclization and gave a mixture of anomeric alcohols in 61% yield. Further oxidation of these allylic alcohols furnished the desired enone which was also debenzylated to give gabosine I in 74% yield. NHAlloc O O O O OH TBSO COOtBu 175 TBSO OBn Br OBn O BnO OBn tion with nitrogen ligands does enhance the redox potential of Cr(ii) a fact that can be harnessed to evaluate the effect of a chiral ligand in asymmetric versions. The wide functional group compatibility and mildness of this methodology make it an ideal process to be utilized for the construction and carbon homologation of complex skeleta through inter- and intramolecular pathways.6 Acknowledgements We thank the Spanish Ministry of Education and Culture (DGICYT PB95-0259-CO2-01) and the Junta de Extremadura –Fondo Social Europeo (PRI97-C175) for financial support. We also thank a series of leading experts especially Professors A. Fürstner and D. Hodgson who kindly provided us copies of their intellectual contributions and Professors T. Chem. Soc. Rev. 1999 28 169–177 176 Me H TBSO OMPM O O TBSO H CHO Me H OMPM O O TBSO H O Me O + MeO H O O O H OTBS TBSO TBSO I OBn CrCl2 NiCl2 (cat) OBn DMF BnO 61% OH OH HO 74% Scheme 22 I MsO + O OPiv 3) CrCl2–NiCl2 DMF (4 additional steps) 1) LAH Et2O 0 °C 2) Dess-Martin oxidation Scheme 21 TBSO OH OBn 1) PCC AcONa 2) BCl3 CH2Cl2 O OH 1) CrCl2–NiCl2 (0.5%) DMF–THF rt Me 2) KH DME 80 °C OPiv Me H O O H O O O O TBSO H OTBS H TBSO TBSO O Me O O Hiyama and H.Nozaki for their encouragement when our interest in this area began. 7 References 1 Y. Okude S. Hirano T. Hiyama and H. Nozaki J. Am. Chem. Soc. 1977 99 3179. 2 C. T. Buse and C. H. Heathcock Tetrahedron Lett. 1978 1685. 3 N. A. Saccomano in Comprehensive Organic Synthesis eds. B. M. Trost I. Fleming and S. L. Schreiber Pergamon Press Oxford 1991 vol. 1 p. 173 and references therein. 4 P. Cintas Synthesis 1992 248 and references therein. 5 Y. Kishi Pure Appl. Chem. 1992 64 343.6 K.Takai M. Tagashira T. Kuroda K. Oshima K. Utimoto and H. Nozaki J. Am. Chem. Soc. 1986 108 6048. 7 K. Takai in Encyclopedia of Reagents for Organic Synthesis ed. L. A. Paquette Wiley New York 1995 p. 1266. 8 R. W. Hoffmann and A. Polachowski Chem. Eur. J. 1998 4 1724. 9 C. Jubert S. Nowotny D. Kornemann I. Antes C. E. Tucker and P. Knochel J. Org. Chem. 1992 57 6384. 10 D. M. Hodgson and C. Wells Tetrahedron Lett. 1992 33 4761. 11 D. M. Hodgson and P. J. Comina Tetrahedron Lett. 1994 35 9469. 12 M. D. Cliff and S. G. Pyne Tetrahedron Lett. 1995 36 763. 13 P. Wipf and S. Lim J. Chem. Soc. Chem. Commun. 1993 1654. 14 H. I. Tashtoush and R. Sustmann Chem. Ber. 1992 125 287. 15 H. I. Tashtoush and R. Sustmann Chem. Ber. 1993 126 1759. 16 C.Chen K. Tagami and Y. Kishi J. Org. Chem. 1995 60 5386. 17 D. P. Stamos X. C. Sheng S. S. Chen and Y. Kishi Tetrahedron Lett. 18 M. Giammaruco M. Taddei and P. Ulivi Tetrahedron Lett. 1993 34 1997 38 6355. 3635. 19 P. Ciapetti M. Taddei and P. Ulivi Tetrahedron Lett. 1994 35 3183. 20 J. Chen and C.-M. Hu Chin. J. Chem. 1995 13 274. 21 P. Cintas Activated Metals in Organic Synthesis CRC Press Inc. Boca Raton 1993. 22 J. Chen and C.-M. Hu Chin. J. Chem. 1995 13 368. 23 L. Wessjohann and H. Wild Synlett 1997 731. 24 D. P. Curran T. L. Fevig C. P. Jasperse and M. J. Totleben Synlett 1992 943. 25 K. Takai N. Matsukawa A. Takahashi and T. Fujii Angew. Chem. Int. Ed. Engl. 1998 37 152. 26 D.-W. Chen K. Takai and M. Ochiai Tetrahedron Lett. 1997 38 8211. 27 A. Fürstner Chem. Eur. J. 1998 4 567. 28 J. J. R. Fraústo da Silva and R. J. P. Williams The Biological Chemistry of the Elements Clarendon Press Oxford 1993 p. 540. 29 A. Fürstner and N. Shi J. Am. Chem. Soc. 1996 118 12349. 30 R. K. Boeckman Jr. and R. A. Hudack Jr. J. Org. Chem. 1998 63 3524. 31 R. Grigg B. Putnikovic and C. J. Urch Tetrahedron Lett. 1997 38 6307. 32 D. M. Hodgson and C. Wells Tetrahedron Lett. 1994 35 1601. 33 K. C. Nicolaou and E. J. Sorensen Classics in Total Synthesis VCH Weinheim 1996 p. 712 and references therein. 34 T. Gabriel and L. Wessjohann Tetrahedron Lett. 1997 38 1363. 35 B. Muller J.-P. Férézou J.-Y. Lallemand A. Pancrazi J. Prunet and T. Prangé Tetrahedron Lett. 1998 39 279. 36 C. W. Harwig S. Py and A. G. Fallis J. Org. Chem. 1997 62 7902. 37 D. W. C. MacMillan and L. Overman J. Am. Chem. Soc. 1995 117 10391. 38 J. A. McCauley K. Nagasawa P. A. Lander S. G. Mischke M. A. Semones and Y. Kishi J. Am. Chem. Soc. 1998 120 7647. 39 T. D. Aicher K. R. Buszek F. G. Fang C. J. Forsyth S. H. Jung Y. Kishi M. C. Matelich P. M. Scola D. M. Spero and S. K. Yoon J. Am. Chem. Soc. 1992 114 3162. 40 A. Lubineau and I. Billault J. Org. Chem. 1998 63 5668. Review 8/06117C 177 Chem. Soc. Rev. 1999 28 169–177

ISSN:0306-0012    

DOI:10.1039/a806117c

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Current and future applications of nanoclusters Günter Schmid,* Monika Bäumle Marcus Geerkens Ingo Heim Christoph Osemann and Thomas Sawitowski Institut für Anorganische Chemie der Universität Essen Universitätsstrasse 5-7 D-45117 Essen Germany Received 9th November 1998 This article deals with some recent developments in metal and in semiconducting nanocluster science. Our studies on the properties mainly of metal nanoclusters with respect to G�unter Schmid was born in Villingen Germany in 1937 and studied chemistry at the University of Munich. He received his Diploma in 1962 and his Doctor’s Degree in Inorganic Chemistry in 1965 both at the University of Munich. In 1966 he moved to the University of Marburg Germany and finished his Habilitation in 1969.In 1971 he received a professorship at the University of Marburg and then he moved to the University of Essen Germany where he became the director of the Institute for Inorganic Chemistry (1977). His main research interests include the synthesis and investigation of large transition metal clusters and colloids the generation of three- two- and onedimensional arrangements of quantum dots and heterogeneous catalysis. Thomas Sawitowski was born in Essen Germany in 1965. He worked for 12 years as an industrial chemist in the department for research and development of Th. Goldschmidt AG Essen. After studying chemistry at the University of Essen he left G�unter Schmid Thomas Sawitowski Ingo Heim Christoph Osemann future and also to current applications are reviewed including a series of unpublished results.The general properties of metal clusters of one up to a few nanometers industry and obtained his diploma in 1996. Currently he is finishing his doctoral thesis under the supervision of Professor G�unter Schmid dealing with the preparation and properties of alumina nanocomposites. Christoph Osemann was born in Haltern Germany in 1967. After an apprenticeship and working for three years as a laboratory assistant he left the catalytic research group of H�uls AG Marl Germany and studied chemistry at the University of Essen. He obtained his diploma in 1997 and is currently preparing a doctoral thesis in the field of bimetallic clusters under the supervision of Professor G�unter Schmid.Ingo Heim was born in K�oln Germany in 1968. He studied chemistry at the University of K�oln and received his diploma in 1997. At present he is preparing a doctoral thesis in the field of semiconductor nanoparticles under the supervision of Professor G�unter Schmid. Marcus Geerkens was born in Wuppertal Germany in 1970. He studied chemistry at the University of Essen and received his Diploma in 1998. At present he is preparing a doctoral thesis in the field of semiconductor nanoparticles under the supervision of Professor G�unter Schmid. Monika B�aumle was born in Bad S�ackingen Germany in 1968. After an apprenticeship as Diet-assistant in Bad Hersfeld Germany she studied chemistry at the University of Essen and received her diploma in 1996.At present she is preparing a doctoral thesis in the field of metal cluster synthesis and application under the supervision of Professor G�unter Schmid. Monika B�aumle Marcus Geerkens 179 Chem. Soc. Rev. 1999 28 179–185 are discussed on the basis of numerous physical investigations in the course of the last few years. Quantum size effects open the door to novel future technologies. The success of future applications of nanoclusters will strongly depend on the availability of three- two- or one-dimensionally organized materials. Our own very recent results are promising but also indicate that much more work will be necessary. Much more realistic is the use of metal nanoclusters in heterogeneous catalysis. Finally novel developments in generating semiconducting nanomaterials in transparent nanoporous alumina membranes are discussed.CdS and GaN can easily be prepared inside the pores to give photoluminescent foils of unlimited size. 1 Introduction The term ‘nanocluster’ is used to name particles of any kind of matter the size of which is greater than that of typical molecules but which is too small to exhibit characteristic bulk properties. The special nature of such nanoclusters whether consisting of atoms or composed of building blocks is to be traced back to a quantum confinement of electrons leading to a change of the relevant properties compared to the bulk. Even common materials such as water or carbon change their behaviour if they become small enough the stability of buildings at temperatures below 0 °C is guaranteed by a decisive decrease of the freezing point of water in the nanopores of cement and the extraordinary behaviour of slices of graphite too small to exist as a usual elementary modification is ending up in fullerenes and nanotubes having initiated a completely novel branch in chemistry and in material science.Particles of metals and semiconductors in a size-regime where the wavelength of the electrons is of the same order as the particle size itself are of extraordinary interest because they behave electronically as zero-dimensional quantum dots. That means that the laws of classical physics valuable for bulk materials have to be substituted by quantum mechanical rules. The transition from a bulk to a nanosized material is best explained by the sketch in Fig.1 where the electronic situation Fig. 1 Illustration of the transition of a bulk metal via a nanocluster to a molecule. The metallic band structure in (a) turns to a discrete electronic energy level in (b) where the particle diameter corresponds with the de Broglie wavelength. In (c) are shown bonding and antibonding molecular orbitals occupied by electrons localized in bonds. in three different particles of metal atoms is illustrated. The situation in (a) is that of a quasi-delocalized electronic state of overlapping valence (VB) and conductivity bands (CB) as is the case in a metallic bulk situation. In a semiconductor there exists a gap between both bands the size of which determines the energy of electron transitions to achieve conductivity.On the way from (a) to (b) in the case of a metal the overlap of VB and CB becomes continuously smaller finally ending up as a band gap too. Fig. 1(b) illustrates the extreme situation where the particle diameter d corresponds with l/2 (l = de Broglie Chem. Soc. Rev. 1999 28 179–185 180 wavelength) in the ground state. This energy state can be compared with the s orbital of a giant metal atom (n = 0) which can be occupied by two electrons. The first excited state (n = 1) then corresponds to an atomic p orbital etc. In (c) bonding (MOb) and antibonding (MOab) molecular orbitals characterize the localized bonds between a few atoms in a molecular cluster. This article will deal exclusively with particles of type (b) either consisting of metal atoms or semiconducting materials.The difference between both is only of quantitative and not of principal nature. In practice quantum size effects are to be expected even if the ultimate situation (b) is not reached but already in larger particles where d corresponds with some multiples of the electronic wavelength. The investigations of a series of nanoclusters in the last decade showed that it is reasonable to expect quantum confinement in metal particles between 1 and 10 nm whereas nanoclusters of semiconductors show quantum size behavior at larger sizes due to the different conditions in the bulk. It can be predicted that the very special situation in (b) or in particles of similar size if ‘metallic’ or ‘semiconducting’ should enable manifold applications on very different fields of science and technology.Some of them which have been the object of our own interest will be described in the following. Many others of course are under investigation by other groups. Before discussing possible practical aspects of nanoclusters a first chapter will deal with the detection of quantum size effectclusters are exclusively considered in connection with this because semiconductor nanoclusters have not been so intensively studied by ourselves on the one hand and on the other hand because very good reviews have been published.1 2 Quantum size effects in metal nanoclusters To study quantum size behaviour of nanoclusters there is one condition to be fulfilled the particles must be separated from each other to avoid coalescence and to keep the individual nature of the particles.The availability of numerous ligand protected metal clusters indeed enabled the systematic investigation of the properties of nanoclusters. Synthetic aspects however will not be considered in this article. They are described in detail in previous papers.2–6 The most frequently investigated cluster type is Au55(PPh3)12Cl6 and some of its derivatives. This so-called two-shell cluster (a central atom is embedded by two closely packed shells consisting of 12 and 42 atoms respectively) is of special interest as its size of 1.4 nm (without ligands) seems to represent the borderline between the situations (a) and (c) in Fig.1. The generation of hot electrons in gold clusters of different size by femtosecond laser pulses allowed the observation of their relaxation behavior.7 The relaxation behaviour of excited electrons is determined by two opposite effects the electron– phonon coupling on the one hand decreasing with decreasing cluster size and on the other hand the collision rate on the cluster surface increasing with decreasing cluster size. For small particles the latter process is dominating. So on changing from ca. 15 nm gold particles to the 1.4 nm Au55 cluster the electronic relaxation increases characteristically whereas a Au13 ( ~ 0.7 nm) cluster shows a considerable decrease of the relaxation compared with the 1.4 nm cluster.This can only mean than on changing from Au55 to Au13 there is an expressed transition from a nanosized metal to a molecule. Impedance measurements on Au55(PPh3)12Cl6 clusters in a densely pressed pelleted form gave valuable information on the intrinsic conduction behaviour of single clusters and also on that between the perfectly packed grains.8–10 Following these results the individual cluster behavior can be understood as being caused by a doubly occupied electronic ground state corresponding with the situation shown in Fig. 1(b). Using the formula for a three-dimensional electron gas d = Hp (2mEF)21/2 (d = lateral dimension of the quantum box m = mass of the electron EF = Fermi energy) d ( = l/2) can be determined as 1.4 nm in perfect agreement with the calculated data for a 55 atom cluster.Conductivity in the pellet is reached by exciting the electrons to the first excited state and so halving l. In Au55(PPh3)12Cl6 there is a special geometric situation insofar as the thickness of the ligand shell is about 0.7 nm i.e. half of the diameter of the cluster core itself. Two ligand shells of 1.4 nm in total separating two Au55 clusters from each other are of the appropriate dimensions to enable perfect tunneling of electrons through densely packed clusters. Indeed the experiments allow us to ‘metallize’ the cluster material or to reduce conductivity to a minimum. Fig. 2 elucidates these processes in a simplified manner. As will be shown thicker ligand shells or spacer molecules enable tunneling processes too but under different energetic conditions.Fig. 2 Illustration of the electronic situation in a row of nanoclusters separated by barriers (ligand shells). In the ground state electronic tunneling between the clusters is in principle not possible. In the excited state tunneling is enabled by halving the electronic wavelength. Quantum size effects in nanoclusters have also been shown by studying the susceptibility of variously sized Pd particles at low temperatures.11 Odd and even numbers of electrons in Pd clusters of identical size are expected to be present in a 50 50 ratio depending on marginal deviations in geometry. Clusters with a single electron couple more intensively the smaller they are. Indeed 2.2 nm Pd clusters show the most intensive maximum of susceptibility compared with those of 3.0 3.6 and 15 nm.Using the same clusters thermodynamic properties have been shown to follow quantum size behaviour with respect to the electronic specific heat for the first time. Again 2.2 nm Pd clusters show the most significant deviations from bulk behaviour at very low temperatures.11 These and several other experiments clearly indicate that quantum behaviour of metal nanoclusters is observable and is most strongly expressed between 1 and 2 nanometers. Referring to possible applications based on the quantum confinement of electrons particles in that size region should be of most interest. There are also several important results concerning the electronic situation in single clusters all indicating that they follow quantum size behaviour when the current–voltage characteristics are studied.Instead of a linear relationship typical for the Ohm behaviour of bulk metals so-called Coulomb blockades are observed indicating single electron transitions (SETs) between a tip and the cluster.12–14 The temperature dependence of quantum size effects based on the relation Eel = e2/2C >> ET = kT has also been demonstrated. 12,13 This relation means that for initiating SET processes the electrostatic energy Eel must be large compared with the thermal energy ET. As the capacity C is smaller the smaller the particle is it becomes clear that SETs can only be observed at relevant working temperatures if C is very small.From various experiments we know C to be of the magnitude of 10219 Farad for Au55 clusters. In other words the use of ca. 1.5 nm metal clusters in principle enables switching with single electrons around room temperature. This would not be possible with semiconducting materials which lose their semiconducting properties long before being miniaturized to 1.5 nm. This knowledge prompted us and numerous other groups to look for appropriate techniques to organize clusters in a three- (3D) two- (2D) or one- (1D) dimensional manner. The use of nanoclusters in future nanoelectronics is unambiguously linked to the availability of well-ordered cluster arrangements. Indeed some considerable progress has been made during the last five years.However it is still difficult to make 3D 2D or even 1D arrangements routinely and in larger amounts. Therefore the following chapter deals with some very recent results in this field as a contribution to the development of suitable conditions for the realization of future nanoelectronic devices. 3 On the way to organized clusters Metal and semiconductor clusters promise to substitute traditional materials in the micrometer size regime in the future. This substitution would not only be linked with the miniaturization of devices but would especially be a big jump into a world of novel technologies. First of all there is the above mentioned chance to work with single electrons at room temperature a condition for the development of new computer and laser generations.Data storage capacities of orders of magnitude better than at present are to be expected and even threedimensional neuronal networks impossible to realize with traditional materials become possible. However there are numerous possible applications to be realized in shorter periods of time e.g. in the field of electroluminescence non-linear optics surface-enhanced Raman spectroscopy sensors or catalysis. For some of these applications organized clusters are not necessary e.g. in catalysis or in sensoric. However just for the most attractive fields of nanoelectronics ordering is an unambiguous condition. As spheric particles in the size range of 1–10 nm do not tend to form larger crystals this usual route to optimized 3D arrangements is in principle not possible although some crystalline particles on the micrometer scale have been found even consisting of relatively large nanoparticles of gold.15 Selfassembled multilayers of nanosized particles have also been observed however only with submicron dimensions.16–18 Our own activities in this field are based on the use of bifunctional spacer molecules linking clusters three-dimensionally.The use of simple linear molecules such as H2N– C6H4–(CH2)2–C6H4–NH2 and similar compounds indeed gave three-dimensional cluster arrangements but not with ordered structures. We were not yet able to see larger cluster arrangements by high resolution tunneling electron microscopy (HRTEM).19 However these 3D cluster materials gave another important result namely a direct relation between cluster spacing and the activation energy needed to start electronic tunneling via the spacers from one cluster to the next.14,20 Well-ordered cluster assemblies can be seen in Fig.3 where multiple layers of ca. 17 nm bimetallic particles can be seen consisting of a gold core covered by a 3–4 atom layer thick palladium shell. The very uniformly sized nanoclusters are stabilized by a ligand shell of disodium 4,7-diphenyl-1,10-phenanthrolinedisulfonate. This sulfonated phenanthroline derivative obviously favours ordered particle arrangements owing to strong ionic interactions between the clusters. This example demonstrates that appropriate interactions between nanoclusters Chem. Soc. Rev. 1999 28 179–185 181 Fig.3 A transmission electron microscopic (TEM) image of some ordered layers of shell-structured gold–palladium particles. may lead to 3D arrangements which could be used for a regulated communication between quantum dots. However it is to be stated that we are still at the beginning of a development which will need much more effort to get routinely 3D assemblies of nanoclusters of acceptable size. Considering 2D nanocluster arrangements there is some progress to be registered during the last few years. Important contributions by Shiffrin,16 Whetten,15 Andres,18 Möller,21,22 and others show that two-dimensionally organized nanoclusters on suitable supports are possible. But as already mentioned for 3D assemblies routine work is still not possible.It may be that the use of micelles in block copolymers as used by Möller et al. is one of the most promising future techniques as the dimensions of the 2D array can be varied over a wide range and the ordering of the particles is almost perfect. Our own efforts in this field were focused on self-assembly processes between functionalized clusters and modified surfaces.14,19,23 However as it turned out strong chemical bondings between clusters and surfaces do not usually give ordered 2D layers but instead give randomly oriented densely packed particles. It seems that good ordering is only obtained if there is no or only weak cluster– surface interactions including the disadvantage that the structure can easily be destroyed by touching it e.g.with the tip of an AFM or STM. One-dimensional cluster arrangements (cluster wires) are of remarkable interest for several reasons they can be used for the study of electron transitions in one direction probably much easier to understand than those in 3D probes and as semiconducting nanopaths for several technical applications. 1D cluster arrangements need a template to be formed. We chose nanoporous alumina which has numerous advantages compared to other porous materials it is easy to prepare the pores in the transparent oxide sheets are all running parallel through the membrane perpendicular to the surface and most importantly there is a broad variability of the pore width between ca. 5 and 200 nm.24–26 If special conditions during the preparation are considered even hexagonally perfectly ordered pores can be reached.Fig. 4 shows an atomic force microscopic (AFM) image of a surface of such an ordered pore system. Filling the pores with clusters of an appropriate size leads to assemblies of cluster wires isolated from each other by the alumina material but open for being contacted from one or from both sides to study electronic behavior. Such measurements have not yet Chem. Soc. Rev. 1999 28 179–185 182 Fig. 4 Atomic force microscopic (AFM) image of the surface of a nanoporous alumina membrane. The pore diameter is ~ 40 nm. The sample has been ion-beam milled previously. been performed but promising success has been achieved in making cluster wires.27 Fig. 5 shows a TEM image of a cluster wire containing membrane sectioned along the pores.The clusters consist of 1.4 nm Au55 cores enlarged to 4.2 nm by a ligand shell of thiolfunctionalized silsequioxanes.28 The difficulty is to fill the pores without interruptions. This is obviously not possible if the pores are longer than ten nanometers. Such thin alumina films Fig. 5 TEM image of a single 1.4 nm Au cluster wire in a nanoporous alumina membrane (a) (b) is a schematic representation of the helical situation in the 7 nm pore. Reproduced with permission from Chem. Eur. J. 1997 3 1951. Copyright 1997 Wiley-VCH. are obtained by ion beam milling processes. Electronic measurements are just at the beginning. 4 Catalysis The use of ligand stabilized transition metal clusters on the one hand and of unprotected bare nanoparticles on the other hand as homogenous and heterogeneous catalysts respectively is extensively described in the literature.29 In particular supported metal particles are traditionally applied in industrial catalysis for many purposes.The catalytic behavior of bare particles on supports has been studied as a function of size and shape in a huge number of papers in the course of the last decades whereas ligand protected clusters are much less investigated as immobilized catalysts. The main interest was focused on the function of the ligands. Indeed they can increase or reduce activity however it has also been shown that the influence of ligands with respect to selectivity may also be of some interest.We have been able to show that ligand stabilized Pd clusters in the size range of 3–4 nm show very good activities and selectivities on various supports when they are used for the semihydrogenation of hex-2-yne to cis-hex-2-ene.30,31 The ligands consisted of variously substituted phenanthrolines. It could be observed that depending on the kind of substituent e.g. alkyl groups of various lengths the activities changed considerably whereas the selectivity was in any case close to 100%. Here we report for the first time on the use of very small Pd nanoparticles (1.5 nm) in a supported form with and without ligands to semihydrogenate hex-2-yne. This comparison of protected and bare clusters for the same catalytic reaction is important since there is to our knowledge no information on comparable reactions.This type of cluster is formed when palladium acetate and 1,10-phenanthroline in a 1.3 10 molar ratio are dissolved in 3-methylbutanol and heated to 60 °C for 7 days. The clusters which can be isolated from solution by centrifugation as a black powder can be redissolved in a 1 1 water–pyridine mixture. Immobilization occurs from solution by the addition of supports such as active carbon TiO2 Al2O3 or various zeolites. Catalysis was performed with 1 wt.% Pd on support. The ligands were removed by heating the immobilized clusters to 100–130 °C for 4–5 hours in high vacuum. Transmission electron microscopy was used to prove that the particle size was the same before and after heating.The hydrogenation reactions were carried out in ethanol at room temperature and with hydrogen gas at 1 atm. Figs. 6(a) and 6(b) show the results. It is clearly to be seen that the selectivity in the case of phenanthroline protected clusters (a) is only ca. 80–90% whereas in the case of the bare clusters (b) it is 100%. From our experience this result could not be expected. Whatever the reason for that behavior may be it becomes clear that catalytic studies with clusters of definite size and environment are valuable materials to work out principles. 5 Luminescence of semiconducting nanoclusters The well-defined nanoporous alumina membranes briefly described in Chapter 3 can not only be used to fill in clusters which have been prepared before but they offer the unique chance to synthesize nanoparticles inside tubes of defined length and width.The advantage of that system is the absolute transparency in the visible range so that the generation of optically interesting materials in the membrane can directly lead to useful materials. Fig. 6 Semihydrogenation of hex-2-yne to cis-hex-2-ene by ligand protected (a) and bare (b) 1.5 nm Pd clusters on active carbon in ethanol at room temperature and 1 atm of hydrogen pressure. Among the possible candidates to form photoluminescent nanoclusters inside the pores the compounds CdS and GaN have been selected owing to their large band gaps of 2.3832 and 3.4033 eV respectively. To generate crystalline CdS nanoclusters in the pores membranes which are open on both sides have been used and aqueous solutions of CdCl2 beginning with 5 wt.% up to saturated ones have been filled in by vacuum induction followed by the reaction with gaseous H2S which diffuses rapidly into the pores to precipitate CdS.GaN was produced by the ligand precursor compound (C2H5)2GaNH2 34 which after its transfer into the pores was decomposed at 350–550 °C in an atmosphere of nitrogen corresponding to eqn. (1). The gaseous DT (1) (C2H5)2GaNH2 —? GaN + 2C2H4 + H2 products ethene and hydrogen leave the pores and GaN is deposited. In contrast to the CdS nanoclusters the size and structure of the GaN particles has not yet been determined. The luminescence of CdS monocrystals was observed between 2.08 eV (595 nm) and 2.05 eV (605 nm).35 The luminescence of the CdS in the pores was found between 1.94 eV (640 nm) and 1.70 eV (730 nm) depending on the conditions to be discussed in the following.Fig. 7 shows the photoluminescence spectrum of a 25 nm pore-containing membrane filled and dried at room temperature. Besides the broad peak at ca. 650 nm there is a high-energetic excitonic fluorescence at 2.84 eV (437 nm). Excitonic fluorescence of CdS nanoclusters is normally only observed after modification of the particle surface.1,36 The modification consists of a substitution of free valences on the surface by Cd ions blocking the S and SH radicals. These are responsible for the non-radiative recombination by trapping holes and preventing activation of fluorescence.Excess Cd ions on the surface allow radiative deactivation of electrons from the conductivity band and holes from the valence band to give the high-energetic emission. The excitonic emission of CdS nanoclusters in the alumina pores is obviously caused by the 183 Chem. Soc. Rev. 1999 28 179–185 Fig. 7 Photoluminescence spectrum at 300 K of a CdS filled nanoporous alumina membrane with 25 nm pores. interaction of the particle surface with the pore walls consisting of reactive Al–OH functional groups and by excess Cd ions blocking the hole-trapping by free reactive valences of the clusters. We also studied the effect of repeated CdS precipitation in the pores and observed that the luminescence intensity increased considerably by a second CdS formation in 20 nm pores but decreased with further CdS depositions.Fig. 8 shows this behavior. As can also be seen there is no significant effect on the wavenumbers. We interpret the intensity maximum after the Fig. 8 Dependence of the photoluminescence intensity of CdS containing alumina membranes on the number of CdS precipitations. second filling by the formation of additional active particles the decrease of intensity after three- or four-fold precipitations is to be traced back to the progressive formation of bulk-like larger and inactive particles. This agrees with the fact that membranes Chem. Soc. Rev. 1999 28 179–185 184 with larger pores e.g. 30 nm show the maximum of luminescence only after the fourth filling followed by an intensity decrease with further CdS formations.The situation in the CdS-containing pores is best seen from TEM images of ion-beam milled very thin membranes. In Fig. 9(a) a larger cutout of an ion-beam milled membrane is shown. The pores have been filled by CdS precipitated from a concentrated CdCl2 solution leading to a relatively high particle loading. Most of the pores at the distinct positions accidentically reached by the milling process are completely or partially filled depending on the local situation. In Fig. 9(b) a single pore is shown filled with polycrystalline CdS matter. Fig. 9 Transmission electron microscopic images of CdS filled alumina membranes. (a) shows the surface of an ion-beam milled very thin membrane. Most of the pores show the presence of CdS; (b) shows a magnified pore filled with crystalline CdS.Finally we studied the temperature dependence of the luminescence. It was found that tempering of the filled membranes leads to a continuous decrease of luminescence completely ending at ca. 350 °C. The disappearance of the orange luminescence by thermal treatment is known from literature and is caused by the phase transition from the cubic to the hexagonal modification.37 The GaN loaded membranes showed a luminescence signal at 3.62 eV (341 nm). Compared with literature data of cubic or hexagonal GaN this is a short-wave shift of 41 and 21 nm respectively.38 A relationship between the photoluminescence intensity the time of tempering and the number of GaN depositions can not yet be confirmed.However as mentioned above these results are still preliminary and should just show that photoluminescent foils of unlimited size can be produced in a very simple way if appropriate reactions can be performed in the pores or if suitable precursors are available. In this connection it should be mentioned that luminescent silicon probably in the form of a siloxene has also been generated in the pores by us recently.39 6 Outlook Nanoclusters of metals or semiconductors can more and more be considered as the building blocks of future modern technologies. This is due to the size dependant electronic properties of these particles. Nanoclusters of transition metals become semiconductors if small enough. If the more technological problems such as organization and addressing of these quantum dots can be solved there is an almost unlimited field of applications to be foreseen.The properties of nanosized semiconductors have long been known to depend very sensitively on the particle size. There are numerous and important applications which become possible considering these facts. The use of transparent alumina membranes (and of course other comparable materials) gives an additional chance to prepare and to apply semiconducting nanoclusters in new fields in the near future. 7 Acknowledgements We gratefully acknowledge financial support by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. We also wish to thank the BASF AG Ludwigshafen for their support of the catalytic work.8 References 1 H. Weller Angew. Chem. Int. Ed. Engl. 1993 32 41. 2 G. Schmid Inorg. Synth. 1990 7 214. 3 G. Schmid B. Morun and J.-O. Malm Angew. Chem. Int. Ed. Engl. 1989 28 778. 4 G. Schmid M. Harms J.-O. Malm J.-O. Bovin J. v. Ruitenbeck H. W. Zandbergen and Wen T. Fu J. Am. Chem. Soc. 1993 115 2046. 5 G. Schmid S. Emde V. Maihack W. Meyer-Zaika and St. Peschel J. Mol. Catal. A 1996 107 95. 7 B. A. Smith J. Z. Zhang U. Giebel and G. Schmid Chem. Phys. Lett. 6 G. Schmid R. Pugin J.-O. Malm and J.-O. Bovin Eur. J. Inorg. Chem. 1998 6 813. 1997 270 139. 8 U. Simon G. Schmid and G. Schön Angew. Chem. Int. Ed. Engl. 1993 32 250. 9 G. Schön and U. Simon Colloid Polym. Sci. 1995 273 101.10 G. Schön and U. Simon Colloid Polym. Sci. 1995 273 202. 15 R. L. Whetten J. T Khoury M. M. Alvarez S. Murthy I. Vezmar Z. 11 Y. Volokitin J. Sinzig L. J. de Jongh G. Schmid and I. I. Moiseev Nature 1996 384 621. 12 A. Bezryadin C. Dekker and G. Schmid Appl. Phys. Lett. 1997 71 1273. 13 L. F. Chi M. Hartig T. Drechsler Th. Schwaack C. Seidel H. Fuchs and G. Schmid Appl. Phys. A 1998 A66 187. 14 G. Schmid and L. F. Chi Adv. Mater. 1998 10 515. Wang P. W. Stephens C. L. Cleveland W. D. Luedtke and U. Landmann Adv. Mater. 1996 8 428. 16 M. Brust M. Walker D. Bethell D. J. Shiffrin and R. Whyman J. Chem. Soc. Chem. Commun. 1994 801. 17 M. Brust D. Bethell D. J. Shiffrin and C. J. Kiely Adv. Mater. 1995 7 795. 18 R P. Andres J. D. Bielefeld J.I. Henderson D. B. Janes V. R. Kolagunta C. P. Kubiak W. J. Mahoney and R. G. Osifchin Science 1996 273 1690. 19 G. Schmid and St. Peschel New J. Chem. 1998 7 669. 20 U. Simon R. Flesch H. Wiggers G. Schön and G. Schmid J. Mater. Chem. 1998 8 517. 21 J. P. Spatz A. Roescher and M. Möller Adv. Mater. 1996 8 337. 22 J. P. Spatz S. Mößner and M. Möller Chem. Eur. J. 1997 3 1552. 23 St. Peschel and G. Schmid Angew. Chem. Int. Ed. Engl. 1995 34 1442. 24 J. P. O’Sullivan and G. C. Wood Proc. R. Soc. London Ser. A 1970 317 511. 25 H. Masuda and F. Fukada Science 1995 248 1466. 26 C. Martin Science 1994 266 1961. 27 G. L. Hornyak M. Kröll R. Pugin Th. Sawitowski G. Schmid J.- O. Bovin G. Karsson H. Hofmeister and S. Hopfe Chem. Eur. J.1997 3 1951. 28 G. Schmid R. Pugin J.-O. Malm and J.-O. Bovin Eur. J. Inorg. Chem. 1998 6 813. 29 For a summarizing review containing ca. 400 references see L. N. Lewis Chem. Rev. 1993 93 2693 30 G. Schmid S. Emde V. Maihack W. Meyer-Zaika and St. Peschel J. Mol. Catal. A 1996 107 95. 31 G. Schmid V. Maihack F. Lantermann and St. Peschel J. Chem. Soc. Dalton Trans. 1996 589. 32 I. Broser R. Broser and M. Rosenzweig Landolt-Börnstein Vol. III p. 166 Springer Berlin 1982. 33 R. D. Dupris J. A. Edmond S. Nakamura and F. A. Ponce Gallium Nitride and Related Materials Vol. 395 p. 551 Mater. Res. Soc. Symp. Proc. 1997. 34 J. Andrews and M. Littlejohn J. Electrochem. Soc. 1975 122 1273. 35 N. Susa H. Watanabe and M. Wada Jpn. J. Appl. Phys. 1976 15 36 L. Spanhel M. Haase H. Weller and A. Henglein J. Am. Chem. Soc. 37 H. Ariza-Caderon R. Lozada-Morales O. Zelaya-Angel G. Mendoza- 38 R. P. Dubois J. A. Edmond S. Nakamura and F. A. Ponce Gallium 2365. 1987 109 5649. Alvares and L. Banos J. Vac. Sci. Technol. A 1990 14 2480. Nitride and Related Materials Vol. 395 p. 551 Mater. Res. Soc. Symp. Proc. 1997. 39 A. Heilmann P. Jutzi A. Klipp U. Kreibig R. Neuendorf Th. Sawitowski and G. Schmid Adv. Mater. 1998 10 398. Review 8/01153B 185 Chem. Soc. Rev. 1999 28 179–185

ISSN:0306-0012    

DOI:10.1039/a801153b

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Annulation reactions of chromium carbene complexes scope selectivity and recent developments K. H. Dötz* and P. Tomuschat Kekulé-Institut für Organischen Chemie und Biochemie der Universität Bonn Gerhardt-Domagk-Straße 1 D-53121 Bonn Germany Received 19th February 1998 Over the past three decades Fischer-type carbene complexes have received increasing interest as selective reagents in organic synthesis. Apart from its electron-acceptor properties exploited in carbene ligand centered reactions the metal carbonyl fragment provides a template for non-classical cycloaddition reactions. The most useful among them is the chromium-mediated benzannulation which allows a one-pot access to densely functionalized oxygenated arenes coordinated to a Cr(CO)3 fragment.It is compatible with a variety of functional groups occurs under mild conditions with remarkable chemo- regio- and diastereoselectivity and thus has considerable potential in the synthesis of complex targets and natural products. 1 Introduction Metal carbenes (CO)nMNC(ORA)R introduced by E. O. Fischer in 1964 as a novel class of compounds bearing a carbene stabilized by coordination to a metal carbonyl fragment have been developed to provide valuable reagents in selective carbon–carbon bond formation over the last 2 decades.1 They have been applied to either ligand-centered or metal-centered processes.2 Representative examples of Fischer carbene complexes are shown in Scheme 1. The central carbene carbon is connected via a formal metal–carbon double bond to a lowvalent Group VI to VIII transition metal.Typically one carbene Karl Heinz D�otz was born in 1943 and received his PhD from the Technical University of Munich with Professor E. O. Fischer. He then moved towards the borderline between Inorganic and Organic Chemistry focusing during his habilitation on the organic chemistry of metal carbenes which he applied to novel metal-assisted cycloaddition patterns. In 1986 he became Professor of Organometallic Chemistry at the University of Marburg. In 1992 he joined the University of Bonn where he was appointed Professor of Organic Chemistry and Co-Director of the Kekul�e Institute. He held visiting appointments in Princeton and Paris and is a recipient of the Victor Grignard–Georg Wittig Lectureship.His research interests concentrate K. H. D�otz OC OC M M –CO OR OR OC A B OH O Ox. M OR O D C M = Cr(CO)3 W(CO)3 Mo(CO)3 Mn(h5-C5H4Me) W(CO)5 Fe(CO)4 Cr(CO)5 OEt Ph OMe Me Ph Ph Cr(CO)5 Mn(CO)2(h5-C5H4Me) p-tolyl OSiMe3 NMe2 Ph Scheme 1 Representative Fischer-type metal carbenes. substituent acts as a p-donor which allows for an electronic stabilization of the electron-deficient carbene carbon atom whereas the other carbene substituent may be either a saturated or an unsaturated group. The low-valent metal center is stabilized by p-acceptors such as carbon monoxide phosphine or cyclopentadienyl ligands. The electrophilic nature of the metal coordinated carbene carbon illustrated by remarkable downfield shifts of 250–400 ppm in the 13C NMR spectra reflects the isolobal nature of Fischer type metal carbenes and carboxylic acid derivatives and is exploited in both nucleophilic addition reactions and a-C–H acidity of alkyl side chains.2 Synthesis of carbene complexes The most general synthetic route to Fischer-type metal carbenes is based on the addition of an organolithium nucleophile to a on organometallic template reactions stereoselective synthesis asymmetric catalysis and on carbohydrate chemistry. Philipp Tomuschat born in 1968 studied chemistry at the University of Bonn. He joined Professor D�otz’s group and completed his Diploma Degree in 1995 with a research project on axial-chiral chromium biscarbenes.Currently he is finishing his PhD Thesis. His research interests focus on synthetic challenges of chiral organometallic and organic compounds as well as their application in chiroptics electrochemistry and asymmetric catalysis. P. Tomuschat Chem. Soc. Rev. 1999 28 187–198 187 metal carbonyl to give an acyl metalate 1 which undergoes subsequent O-alkylation by strong alkylating reagents such as trialkyloxonium salts alkyl fluorosulfonates or alkyl trifluoromethanesulfonates to form alkoxycarbene complexes 2. This strategy provides direct access to a great variety of carbene complexes and is only limited by the availibility of the organolithium compound. Treatment of alkoxycarbene complexes 2 with amine or thiol nucleophiles affords amino and thiol complexes 3 or 4 (Scheme 2).O–Li+ R2 O RX R1Li M(CO)6 (CO)5M (CO)5M R1 R1 2 1 M = Cr Mo W R1 = alkyl aryl vinyl R3 HS R3 HN RX = R2 3O+BF4 – R2OSO3F R4 R3 R4 = H alkyl R3 R4 R3 N S (CO)5M (CO)5M R1 R1 4 3 Scheme 2 Standard Fischer route to metal carbenes. The addition of alcohols requires even more electrophilic acyloxycarbene complexes 6 accessible via acylation of ionseparated tetraalkylammonium acyl metalates 5. This strategy allows the synthesis of more complex chiral metal carbenes 7 bearing terpene and sugar auxiliaries (Scheme 3). O O O–NMe4 + R2 X Me4N+Br– 1 (CO)5M –LiBr R1 (CO)5M R2 O R1 6 HO R3 R3 O M = Cr W 5 R1 = alkyl aryl vinyl R2 = Me tBu X = Br Cl R3 = terpene sugar skeletons (CO)5M R1 7 Scheme 3 Alcoholysis of acyloxy metal carbenes.An alternative approach combining an organoelectrophile and a metal nucleophile has been developed by Hegedus and Semmelhack.2 Reduction of the hexacarbonyl metal by the intercalation compound C8K affords the pentacarbonyl dianion 8 which undergoes low-temperature addition to acid chlorides or carboxylic amides. Alkylation of acyl metalate 9 as described above generates alkoxycarbene complex 10 whereas TMSClassisted deoxygenation of the tetrahedral intermediate 11 affords aminocarbene complex 12 (Scheme 4). 3 Annulation reactions 3.1 Metal-centered annulation reactions—scope and limitations The most unique type of metal carbene reactions is the benzannulation of complexes A bearing unsaturated (aryl or vinyl) alkoxycarbene ligands by an alkyne and a carbon monoxide.3 This process is most efficiently mediated by a Cr(CO)3 template (B) and provides a one-pot access to densely substituted oxygenated arenes C which remain coordinated to the metal fragment (Scheme 5).Subsequent oxidative demetalation may be applied to generate the corresponding quinones D. Chem. Soc. Rev. 1999 28 187–198 188 C8K K2[M(CO)5] M(CO)6 8 M = Cr W O NR R 2 O– (CO)5M R NR2 11 Me3SiCl –KCl –Me3SiO–K+ NR2 (CO)5M R 12 Scheme 4 Hegedus–Semmelhack approach to alkoxy- and aminocarbene complexes. OC M –CO OR OC A O Ox. O D M = Cr(CO)3 W(CO)3 Mo(CO)3 Mn(h5-C5H4Me) Scheme 5 Benzannulation of carbene complexes.Chromium is the metal template of choice for the benzannulation; it allows excellent chemo- and regioselectivity under mild conditions (tert-butyl methyl ether 50 °C). Other transition metal templates (Mo W Mn) have been used in isolated cases but generally suffer from modest chemoselectivity and harsher reaction conditions. For instance molybdenum carbenes favour the cocyclization of carbene carbonyl and alkyne ligands to give furans in moderate yields;4 the increased thermostability of the tungsten homologues results in the formation of relevant amounts of formal [3+2]cycloaddition products without incorporation of the carbonyl ligand. Application of a h5- cyclopentadienylmanganese template requires additional electrophilic activation in terms of a titaniumoxycarbene ligand under more drastic thermal (or photochemical) conditions to give only poor annulation yields.5 The chromium-mediated benzannulation is compatible with a broad substitution pattern both in the alkyne and in the unsaturated carbene side chain.6 Aryl carbene complexes with methoxy methyl or trifluoromethyl substituents in the ortho- para- or meta-position work as well as naphthyl and heteroaryl carplexes derived from furans thiophenes pyrroles pyrazoles and indoles.Vinyl carbene complexes have been studied extensively bearing alkyl substituents (and in a few cases oxygen and silicon substituents) in a variety of cyclic and acyclic systems.The benzannulation has been reported to give moderate to excellent yields with alkynes bearing aryls esters lactones O Cl R O–K+ (CO)5M R 9 alkylation OR (CO)5M R 10 OC M OR B OH M OR C ketones amides acetals a-ethers enol ethers sulfides tosylates and nitrile groups. However only moderate yields are observed with alkynes bearing electron withdrawing groups such as conjugated carbonyl groups as pointed out in the reaction of carbene complex 13 with the alkynyl ketone to give 14 in 42% or with the alkynyl ether to give 15 in 54% (Scheme 6).7 The even more electron-deficient hexafluorobutyne is inert towards chromium carbene 13. The bifunctionality of alkynols results in a competition of benzannulation and lactonization.For instance the reaction of 16 with but-3-yn-1-ol affords the ketene intermediate 17 which either may undergo 6p electrocyclization to the benzannulation product 18 or addition of the alcohol nucleophile to the ketene to give lactone 19.8 Direct substitution of the alkyne with oxygen increases the nucleophilicity of the CáC bond and reduces the yield of the annulation product; the more nucleophilic enamines undergo insertion into the metal–carbon bond to give C2-homologous aminocarbene complexes.9 Sterically overcrowded alkynes such as bis- (trimethylsilyl)acetylene prevent the final electrocyclization step and stable vinyl ketenes e.g. 20 and 21 result from the benzannulation attempt10 (Scheme 6).The extension from alkynes to “heteroalkynes” is limited; as a rare example the kinetically stabilized tert-butylphosphaethyne which exhibits an alkyne-like coordination chemistry has been incorporated into furanophosphahydroquinone 24 along the reaction with 2-furylcarbene complex 22; a sidereaction based on a competing ligand coupling process results in the formation of the 1,3-oxaphosphole 23 as the minor product11 (Scheme 7). 3.2 Mechanism of the benzannulation The benzannulation is supposed to involve a stepwise alkyne– carbene–carbon monoxide coupling sequence occurring at the Cr(CO)3 template (Scheme 8). The mechanism has been supported both by kinetic studies and the isolation of presumed model intermediates.12 An early kinetic investigation13 and the observation that the reaction of the metal carbene with the alkyne is suppressed in the presence of external carbon monoxide demonstrated that the rate-determining step is a OH O i Me 42 % OMe 14 COMe i H OTBDMS H ii Ac2O NEt3 EtO Me HO Cr(CO)5 OMe Me 16 Cr(CO)5 SiMe3 Me3Si OMe 72 % 13 Cr(CO)5 ii OMe 54 % 13 OMe H Me O HO 17 OMe (CO)3Cr Me Si 3 20 Scheme 6 Limitations of the benzannulation reaction.Cr(CO)5 P C tBu P O O OMe 66 % O 22 23 Scheme 7 Hetero-benzannulation with phosphaalkynes. reversible decarbonylation of carbene complex A followed by coordination of the alkyne to form the h2-alkyne–carbene complex intermediate B.Extended Hückel calculations14 together with structural studies on h2-alkyne carbene complex analogues15 indicate only a weak metal–alkyne interaction. Subsequent insertion of the alkyne into the metal–carbene bond generates h3-allylidene complex C. A stable analogue of this type of complex has been isolated as the decarbonylation product of a chromium pentacarbonyl aminovinylcarbene complex precursor and characterized by NMR and X-ray analysis. Depending on the electron-donation ability of the a- heteroatom the reaction may follow two different pathways. In the alkoxycarbene series the subsequent insertion of carbon monoxide results in the formation of the h4-vinyl ketene complex intermediate D a stable analogue of which has been characterized in the case of enaminoketene complexes.Electrocyclic ring closure affords the cyclohexadienone complex E which tautomerizes to give the Cr(CO)3-coordinated hydroquinone F. An arrested cyclohexadienone complex has been isolated in the molybdenum series. In accordance with the experimental results the mechanism has been supported by DFT calculations.16 Due to the superior donor properties of amino groups over alkoxy substituents aminocarbene complexes require harsher conditions for the primary decarbonylation step. Similarly the CO insertion to give the vinyl ketene intermediate D is hampered and cannot compete successfully with an electrocyclization of amino-substituted h3-allylidene complex intermediate C which results in the formation of chromacyclohexadiene intermediate G.Reductive elimination and metal migration afford aminoindene complex H which may be hydrolized upon chromatographic workup to give indanone complex I as the final cyclopentannulation product. OAc OTBDMS OEt OMe 15 OMe Cr(CO)3 + OH Me OH 18 17 % OMe SiMe3 SiMe3 + O O Me Si 3 21 2.6 1 Chem. Soc. Rev. 1999 28 187–198 OMe tBu O P Cr(CO)3 + OMe tBu 1 2 OH 24 OMe Me O O 19 33 % 189 XR –CO (CO)5Cr (CO)4Cr + CO A OR (CO)3Cr O D OR (CO)3Cr H O E OR (CO)3Cr OH F Scheme 8 Suggested mechanism for the chromium-mediated benzannulation and cyclopentannulation. 3.3 Experimental methodology The standard protocol for the benzannulation involves a thermal decarbonylation carried out in an ethereal solvent e.g.tert-butyl methyl ether or tetrahydrofuran at 45–65 °C. Reflux conditions favour the removal of evolved carbon monoxide and speed up the reaction. An alternative photodecarbonylation allows lowtemperature conditions; however as a consequence of the photosensitive intermediates photoinduced benzannulations generally proceed less cleanly and selectively17 and thus have gained synthetic importance only in cases where the thermal protocol fails.18 A few examples have been reported in which the benzannulation has been promoted by high intensity ultrasound or carried out by dry state adsorption conditions.19 These techniques may allow comparable yields within shorter reaction times as observed with the thermal protocol; however they did not allow the isolation of Cr(CO)3-coordinated hydroquinone annulation products (which—due to their inherent plane of chirality—are promising reagents for stereoselective synthesis vide infra) and instead led to quinones after oxidative workup as shown for the benzannulation of complex 13 to give 25 and 26 (Scheme 9).4 Selectivity 4.1 Regiochemistry When the benzannulation is carried out with unsymmetrical alkynes the major regioisomer generally bears the larger alkyne substituent next to the phenolic group suggesting that the Chem. Soc. Rev. 1999 28 187–198 190 XR XR Cr (CO)4 C B X = O X = NR2 NR2 Cr (CO)4 G –CO H Cr(CO)3 NR2 H H3O+ Cr(CO)3 O I Cr(CO)5 + Et OMe 13 Conditions Photochemical 1) –78 °C 13.5 h UV irradiation; 2) (NH4)2[Ce(NO3)6] 44 % Thermal 1) 45 °C 24 h; 2) (NH4)2[Ce(NO3)6] 88 % Cr(CO)5 + Ph OMe 13 Conditions Ultrasound 1) RT 10 min; 2) (NH4)2[Ce(NO3)6] 66 % Dry state adsorption 1) SiO2 60-65 °C 90 min; 2) (NH4)2[Ce(NO3)6] 81 % Thermal 1) 45 °C 23 h; 2) (NH4)2[Ce(NO3)6] 67 % Scheme 9 Comparison of benzannulation protocols.regioselectivity is mainly governed by the different steric demands of both alkyne substituents (Scheme 10).3 This result Cr(CO)5 OMe 13 RL OMe RS RL OC Cr CO OC CO 28 OMe RS Cr(CO)3 RL OH 29 major Scheme 10 Regioselective alkyne incorporation.can be rationalized in terms of the minimization of the repulsive steric interaction between the alkyne substituents and the carbonyl ligands of the metal fragment in the insertion product 28 compared with its regioisomer 30. This argument takes into account the fact that the smaller alkyne substituent RS is closer to the apical CO ligand than the larger RL is to the equatorial CO ligand.14 Subsequent CO insertion of the h3-allylidene complexes electrocyclization and tautomerization afford naphthol 29 as the major and naphthol 31 as the minor annulation product. Synthetically useful regioselectivities are encountered with terminal alkynes which give a single regioisomer whereas unsymmetrical internal alkynes generally afford regioisomeric mixtures.The regioselectivity is lost with diarylalkynes bearing two differerent para-substituents.20 Scheme 11 demonstrates the distribution of both regioisomers 32 and 33 resulting from the benzannulation of 13 with some unsymmetrical alkynes. O Et Et Et O 25 O Ph H H O 26 Cr(CO)4 –CO OMe 27 RS RS RL OMe RL RS OC Cr CO OC CO 30 OMe RL Cr(CO)3 RS OH 31 minor Cr(CO)5 OMe 13 RL RS OMe OMe RS + Cr(CO)3 RL OH OH 33 a–d 32 a–d Ratio 32 33 Entry RS RL 100 0 90 10 70 30 54 46 H C3H7 CH3 tBu CH3 C2H5 C6H5 p-CH3C6H4 a b c d Scheme 11 Alkyne-dependent regioselectivity. A complementary regiochemistry can be achieved exploiting a stannyl acetylene incorporation–deprotection strategy.21 4.2 Chemoselectivity The h3-allylidene intermediate (Z)-A formed upon alkyne insertion may give rise to the formation of various types of cyclization products.The benzannulation affords the most valuable product but has to compete with the formation of indenes and cyclobutenones. The competing pathways are outlined in Scheme 12. Insertion of CO generates the vinyl ketene complex B which—instead of 6p-benzannulation to C— may undergo a 4p-electrocyclization to give cyclobutenone D. Direct electrocyclic ring closure of A generates chromacyclohexadiene E which is regarded to afford the indene F after reductive elimination and tautomerization. A less obvious OMe RS RL Cr (CO)4 (Z)-A MeO Cr(CO)4 RL RS (E)-A Scheme 12 Competitive benzannulation cyclopentannulation cyclobutenone and furan formation.cyclization/alkyl migration sequence starting from the (E)- isomer of A is believed to be responsible for the formation of the furan skeleton H.22 The chemoselectivity depends on the nature of the metal template the carbene substitution pattern and the reaction conditions. The role of the solvent and the alkyne concentration has been addressed17 but no consistent results are available so far. The trends outlined in Scheme 13 indicate that donor solvents like ethers favour selective benzannulation whereas a RS Cr(CO)3 RL H OMe RS Cr(CO)3 RL O B OMe RS Cr(CO)3 RL O B OMe RS RL Cr H (CO)4 E O MeO RL RS Cr(CO)3 G Cr(CO)5 OMe 13 1) Ph Ph solvent 45 °C 2 d 2) oxidation O Ph Ph O 34 Ph Ph + Ph Ph OMe O 37 36 35 + 36 + 37 34 Solvent THF Hexane CH3CN DMF — 38 19 83 59 41 — — Scheme 13 Solvent-dependent chemoselectivity.OMe RS Cr(CO) RL OH C RS OMe RL –Cr(CO)3 O D OMe RS RL (CO)3Cr H F OMe O RL –Cr(CO)3 RS H Chem. Soc. Rev. 1999 28 187–198 H Ph Ph + OMe 35 O + Ph MeO Ph 38 38 — — 51 — 3 191 H H13C6 (CO) Cr (CO) Cr 4 5 ii i H N H N H N OMe OMe OMe (CO)3Cr non-cordinating solvent (hexane) increases the amount of cyclopentannulation products for which a more polar solvent such as DMF is the medium of choice.Cyclobutenone 38 is the major product when the reaction of alkoxycarbene complex 13 with diphenylacetylene is carried out in strongly coordinating acetonitrile. 41 39 40 iii H H13C6 i toluene reflux ii oct-1-yne 90 °C iii SiO2 O The competition of benzannulation and cyclopentannulation depends further on the concentration of metal carbene and alkyne as well as on the temperature.17 An increase of the concentration and a decrease of the temperature favour benzannulation (which is best carried out at 45–65 °C) over cyclopentannulation. OMe (CO)3Cr 42 Scheme 15 Cyclopentannulation via allylaminocarbene chelate 40. O Cr Cr (CO)5 (CO)5 The most striking influence on the competition between benzannulation and cyclopentannulation results from the donor ability of the heteroatom carbene side chain.The substitution of the alkoxy group for a better electron donor such as a dialkylamino group results in exclusive cyclopentannulation. Amino(aryl)carbene complexes of chromium react with alkynes at 125 °C to give indene derivatives E as formal [3+2] cycloaddition products without incorporation of CO (Scheme 14).23 The increased temperatures required for the primary Boc2O DMAP H N N OtBu R2 R2 R1 R1 RS RL + 44 43 R1 = NR1R2 Cr(CO)5 RT –CO RS O (CO) Cr 4 NR1R2 Me R2 = OtBu N R2 RL R1 NR1R2 A Cr (CO)4 C 45 60 % from 43 –CO RS Scheme 16 Boc-activation of aminocarbene complexes.(CO)3Cr RL NR1R2 Cr(CO)5 E RS tion of six-membered rings prevails (46a/47a = 1:5) or is observed exclusively (47b) (Scheme 17).24 NR1R2 RL Cr (CO)4 O (CO) Cr 4 D B 1) hex-3-yne 60 °C 2) Ac2O–NEt3–DMAP 3) Fe(III) OtBu N R2 67 % Scheme 14 Cyclopentannulation of aminocarbene complexes. R1 N Boc R1 45 a,b R1 = 46a 46b Me 45a R2 = + OAc decarbonylation as well as the absence of CO incorporation reflect the increased back-donation from the metal to the carbonyl ligands as indicated by the resonance forms A–D describing the aminocarbene starting materials and the alkyne insertion intermediates. 45b R2 = N Boc R1 47a 47b (46a 47a = 16 84) (46b 47b = 0 :100) Scheme 17 Control over competition between benzannulation and cyclopentannulation.The cyclopentannulation reaction of aminocarbene complexes proceeds with similar high regioselectivity as observed for the benzannulation of chromium alkoxycarbenes. The aminocarbene chelate 40 accessible by decarbonylation from 39 in refluxing toluene reacts with oct-1-yne at 90 °C to give indene complex 41 as a single regioisomer; hydrolysis of the enamine upon chromatography on silica gel affords the indanone complex 42 as a single diastereomer bearing the alkyl substituent and the chromium fragment on the same face of the bicyclic skeleton. Obviously ring-opening of the chelate 40 occurs under milder conditions than the decarbonylation of its pentacarbonyl precursor 39 (Scheme 15).24 4.3 Intramolecular benzannulation The electron donating capability of the amino substituent can be reduced by N-acylation.Introduction of the Boc-group into carbene complex 43 generates the ‘activated’ aminocarbene 44 the reactivity of which rather ressembles that of alkoxycarbene complexes. Decarbonylation occurs at room temperature to form the tetracarbonyl chelate complex 45 (Scheme 16).24 Carbene complexes bearing an alkyne side chain may undergo intramolecular benzannulation. This strategy may be exploited in a reversal of regioselectivity as demonstrated for unsymmetric dialkylalkynes (Scheme 18). Whereas upon reaction with 5-methoxypent-2-yne and oxidative workup benzannulation of The annulation of tetracarbonyl acylaminocarbene complexes 45a,b as demonstrated for hex-3-yne requires only moderate warming (60 °C) and reveals a competition between benzannulation and cyclopentannulation.Generally the forma- Chem. Soc. Rev. 1999 28 187–198 192 i MeOCH2CH2C CMe then (NH4)2[Ce(NO3)6] ii PhC CPh (10 equiv.) then (NH4)2[Ce(NO3)6] Me i 79 % O O OMe Me Me Me 2.5 1 O O 49 48 Me O (CO) Cr 5 Me ii O 65 % Me2Si O Me 50 O 51 Scheme 18 Reversal of regiochemistry via intramolecular benzannulation. methoxycarbene complex 18 gives a 2.5:1 mixture of regioisomers in favour of the 2,6-dimethylnaphthoquinone 48 the intramolecular variant based on a pent-2-ynyloxysilyloxycarbene complex bearing a silyl linker affords after methylation the 3,6-dimethylnaphthoquinone 49 as a single isomer.25 A similar linker-assisted intramolecular benzannulation has been applied to the synthesis of the naphthoquinone antibiotic deoxyfrenolicin 54.The quinone ring is formed from the enyne carbene complex precursor 52 in perfect regiochemistry under mild conditions in refluxing ether. The final pyranoannulation was achieved by a palladium-promoted cyclization–carbonylation sequence (Scheme 19).26 HO OMe O O OMe O i Cr(CO)5 51 % O 53 52 O OH O deoxyfrenolicin 54 Scheme 19 Synthesis of deoxyfrenolicin via intramolecular benzannulation and palladium-assisted cyclization–carbonylation. The intramolecular benzannulation may be also applied to the synthesis of strained aromatic systems such as [2.2]metacyclophanes.Cyclization of the alkyne–vinylcarbene complex 3-coordinated [2.2]metacyclophane hy- 55 affords the Cr(CO) droquinone 56 (in which the chromium fragment is bound to the hydroquinone from the face opposite to the other benzene deck) Cr(CO)5 OMe 18 Me OMe Me3O+BF4 – 2,6-DTBP Me OH O nPr nPr O CO2Me which undergoes in situ or stepwise oxidation to give the planarchiral cyclophane quinone 57 (Scheme 20).27 HO 65 °C 3 h 38 % Me OMe (CO)3Cr 56 Me (CO)5Cr O 90 °C 2 h 40 % OMe 55 Me O 57 Scheme 20 Synthesis of planar-chiral [2.2]metacyclophane quinones via intramolecular benzannulation. The (alkynylanilino)carbene chromium complex 58 bearing a rigid three atom spacer between the alkyne and the carbene moiety can react in an insertion–cyclization sequence to give a mixture of the benzo[a]carbazole 59 and the indeno[1,2-b]- indole 6028 (Scheme 21).Cr(CO)5 H N 58 105 °C 1 h 48 % OH H + H N H N 59 60 71 29 Scheme 21 Competitive formation of benzo[a]carbazole 59 and indeno- [1,2-b]indole 60. The two different reaction products are caused by two different reaction pathways as outlined in Scheme 22. Decarbonylation of the (alkynylanilino)carbene complex A affords the h2-alkyne carbene complex intermediate B which undergoes subsequent alkyne insertion generating the pyrrole ring in carbene complex C intermediate; insertion of carbon monoxide results in the formation of the vinyl ketene intermediate D which cyclizes to the benzannulation product E.In contrast direct ring closure of C affords the cyclopentannulation product F which finally gives G after tautomerization and loss of the metal fragment. The product distribution is governed by the steric demand of the alkyne substituent R. In the presence of the bulky mesitylene group as alkyne substituent exclusive benzannulation is observed.29 If however the linker between the alkyne and carbene functionalities is reduced to a rigid C2-arene fragment the intramolecular insertion of the alkyne into the chromium carbene bond is kinetically blocked. Instead an intermolecular reaction may occur resulting in a formal alkyne carbene dimerization to give densely oxygenated chrysene derivatives (Scheme 23).15 The tetracarbonyl alkyne carbene chelates 62 accessible by low-temperature photodecarbonylation from their 193 Chem.Soc. Rev. 1999 28 187–198 R Cr(CO)5 H N A –CO R Cr(CO)4 H N B CO insertion R (CO)3Cr O NH D –"Cr(CO)3" R OH H N E Scheme 22 Suggested mechanism for the formation of benzo[a]carbazoles and indeno[1,2-b]indoles. pentacarbonyl precursors 61 contain a weak metal–alkyne bond as suggested by their X-ray and 13C NMR data. They are supposed to form metal-bridged dimers 63 which may undergo a double alkyne insertion to generate central ten-membered ring intermediates 64 bearing two opposite metal carbene fragments.The formation of chrysene derivatives 65 and 66 may be rationalized in terms of a final carbene dimerization and subsequent partial or complete demetalation. The peri-interaction between the substituents in positions 4,5 and 10,11 results in a steric repulsion which forces the aromatic skeleton to adopt a conformation twisted across the central arene C4b–C10b bond. As indicated by a comparative X-ray study the dihedral angle q (C5–C4b–C10b–C11) gradually increases with a decrease of the aromatic character of the two central rings; the twisting increases in the order of 66a (R = Ph q = 15°) 66b (R = nPr q = 22°) 65b (R = nPr q = 24°) and culminates for the chrysene-6,12-dione 67a (R = Ph q = 33°) obtained from 66a after cleavage of the aryl methyl ether with (CH3)3SiI followed by oxidation on air (Scheme 24).4.4 Diastereoselectivity The benzannulation affords racemic mixtures of arene Cr(CO)3 complexes (A/AA) which—due to the unsymmetric arene substitution pattern of monoprotected hydroquinones—possess a plane of chirality. The chiral plane is maintained after silylation of the remaining phenol functionality (B/B�) (in order to increase the stability of the annulation products towards oxidation) and is also compatible with the use of symmetric alkynes (Scheme 25). Enantiopure arene Cr(CO)3 complexes30 are powerful reagents in asymmetric synthesis; however their Chem. Soc. Rev. 1999 28 187–198 194 R Cr(CO)4 N H C direct ring closure R H H N Cr(CO)4 F –"Cr(CO)4" H R H N G OCH3 (CO)5Cr 2 R 61a–c OCH3 R Cr Cr R OCH3 64a–c 61–66a R = Ph 61–66b R = nPr 61–66c R = SiMe3 OCH3 R Cr(CO)3 + R OCH3 65a–c Cr = Cr(CO)4 Scheme 23 Alkynylcarbene dimerization to chrysene derivatives.OMe Ph (CH3)3SiI air Ph OMe 66a Scheme 24 Synthesis of phenanthrenedione 67a. availability is widely hampered by tedious protocols for the separation of the racemates. Three different strategies have been envisaged for the benzannulation to lure the Cr(CO)3 fragment selectively to one or the other face of the arene skeleton formed. The chiral information can be incorporated into a-alkoxyalkynes which allow good to excellent diastereoselectivities increasing markedly with the steric bulk of the alkynol protective group and depending on the type of the carbene ligand used.A very successful example is outlined in Scheme 26 combining a tritylprotected chiral alkynol with a propenylcarbene complex.31 Alternatively a chiral C-carbene side chain has been exploited in diastereoselective benzannulation. The methoxycyclohexenylcarbene complex 73 gave an 88% de in favour of the anti annulation product 74 upon reaction with pent-1-yne (Scheme 27).32 An anti annulation product was isolated as a single diastereomer from the reaction of carbene complex 75 obtained from optically pure 8a-methyl decalone with hex-5-yn-1-ol upon a tandem benzannulation–Mitsunobu reaction to give the benzoxepine complex 76 (Scheme 28).33 The most general approach to diastereoselective benzannulation aims at the incorporation of the chiral information into the OCH3 (CO)4Cr 2 R 62a–c R OCH3 Cr O H3C Cr R 63 a–c OCH3 R R OCH3 66a–c O Ph 50 % Ph O 67a Cr(CO)5 R OMe OTBDMS R MeO R Cr(CO)3 B' Scheme 25 Benzannulation approach to planar chiral arene complexes.Cr(CO)5 OMe Me 68 OR 69 R = CPh3 70 R = Me Me TBDMSO OR Me Me (OC)3Cr OMe 71a 71b Scheme 26 Diastereoselective benzannulation with a-chiral alkynes. Cr(CO)5 OMe OMe (rac)-73 nPr H EtN(iPr)2 TBDMSCl 48 % OMe OTBDMS nPr Cr(CO)3 OMe (rac)-74-anti Scheme 27 Diastereoselective benzannulation of (rac)-73.H H Cr(CO)3 1) hex-5-yn-1-ol 2) PPh3 DEAD OH O R 50 % R EtO EtO Cr(CO)5 MeO R Cr(CO)3 A 75 76 + OH Scheme 28 Stereoselective synthesis of metal modified benzoxepine derivative 76. R R MeO Cr(CO)3 A' TBDMSCl–NEt3 Cr(CO)3 OTBDMS heteroatom carbene side chain which avoids any limitation in the substitution pattern of either the alkyne or the carbon skeleton of the carbene synthon. Chiral alcohol auxiliaries are readily available from the terpene or carbohydrate pool and can be attached to the carbene carbon atom via alcoholysis of acyloxycarbene complex precursors. Diastereoselectivities up to 82% de have been achieved in the annulation of menthyloxy carbene complex 77 with tert-butylacetylene to result in a 10:1 preference of diastereoisomer 78a over 78b (Scheme 29).34 R + Cr(CO)5 R MeO O(–)-menthyl B 77 1) tBuC CH 3 2) TBDMSCl NEt 55 % OTBDMS OTBDMS t t Bu Bu + Cr(CO)3 Cr(CO)3 10 1 O(–)-menthyl O(–)-menthyl 78b 78a Scheme 29 Diastereoselective benzannulation of (2)-menthylocarbene complex 77.OR TBDMSO Me Me (OC)3Cr Benzannulation of phenylcarbene complexes carried out below 55 °C generally provides the kinetic product bearing the metal fragment on the oxygenated ring; under more drastic conditions a haptotropic metal migration occurs to give the thermodynamic 5-10-h6 isomer (Scheme 30). As demonstrated OMe OTBDMS OTBDMS 96 4 85 15 71b R = CPh3 72b R = Me t t Bu Bu 90 °C R*O R*O R* = (–)-menthyl Cr Cr CO OC CO OC CO CO 79a 78a 3 Scheme 30 Stereoselective haptotropic migration of the Cr(CO) fragment.for the pure diastereomer 78a upon warming in di-n-butyl ether to 90 °C the metal migrates intramolecularly along the same face of the naphthalene system to give pure diastereomer 79a which is in accordance with earlier Extended H�uckel-MO calculations. OMe OTBDMS nPr + Cr(CO)3 OMe 94 6 (rac)-74-syn The arene deck of [2.2]metacyclophanes can be extended via the benzannulation reaction to give densely functionalized naphthalenophane Cr(CO)3 complexes (Scheme 31).35 Annulation of the racemic [2.2]metacyclophane carbene complex 80 results in the formation of diasteroisomeric hydroquinoid naphthalenophanes anti-81a and syn-81b; the diastereoselection arising from the chiral plane in the cyclophane is only moderate (2:1).In the major diastereomer anti-81a the Cr(CO)3 fragment coordinates from the less hindered face of the arene; 195 Chem. Soc. Rev. 1999 28 187–198 OMe 80 Cr(CO)5 52 % 1) EtC CEt 2) TBDMSCl NEt3 Cr(CO)3 Et Et MeO MeO Et Et + OTBDMS OTBDMS 2 1 Cr(CO)3 81b 81a 80 °C 80 °C Et Et MeO MeO Et Et OTBDMS OTBDMS Cr(CO)3 83 82 Scheme 31 Benzannulation of [2.2]metacyclophane complex 80. warming to 80 °C induces a haptotropic metal migration to the less substituted naphthalene ring to give anti-82. In the more congested minor benzannulation diastereomer syn-81b however the steric bulk of the uncoordinated cyclophane deck prevents a similar haptotropic migration and demetalation to 83 occurs under the same conditions.Double benzannulation of the axial chiral enantiopure (R)- biscarbene complex 84 accessible in a two-step sequence from commercially available binaphthol affords biphenanthrene bischromium derivative 85 combining elements of axial and planar chirality (Scheme 32).36 Four diastereomers are formed in moderate diastereoselectivity two of which have been isolated as the major isomers. Oxidative workup of the annulation reaction affords C2-symmetric bi(phenanthrenequinones) 86 and 87; their quinone units represent independent reversible redox systems which offer new perspectives as ligands in enantioselective metal-catalyzed oxidation reactions.Another approach to C2-symmetric biaryls involves the annulation of carbene complex 88 with the diaryl alkyne 89; oxidative workup afforded the C2-symmetric bisquinone 90. The C2-symmetry of biscarbene complex 91 has been exploited in a double benzannulation with diphenylbuta-1,3-diyne to give a moderate yield of the bridged biaryl 92 as a single diastereoisomer (Scheme 33).37 5 Synthesis of natural products The compatibility with functional groups the regio- and stereoselectivity have made the benzannulation an attractive methodology for the synthesis of natural products bearing hydroquinoid quinoid or fused phenolic substructures. An early formal total synthesis of the antitumor antibiotic aglycon 11-deoxydaunomycinone started from the orthomethoxyphenylcarbene chelate complex 93 which underwent benzannulation with alkyne 94 to form regioselectively the ring C of naphthohydroquinone intermediate 95.C1-homologation of the ketone to give the carboxylic acid and subsequent acid- Chem. Soc. Rev. 1999 28 187–198 196 TBDMSO Cr(CO)5 OMe 1) hex-3-yne 2) TBDMSCl NEt3 OMe OMe 52 % OMe Cr(CO)5 TBDMSO 84 R2 R1 1) 2) (NH4)2[Ce(NO3)6] O R2 R1 56 % Et 86 Et n-Bu 36 % 87 H O Scheme 32 Double benzannulation of axial chiral biscarbene complex 84. Cr(CO)5 OMe 88 + OH Ph 1) 70 °C 2) (NH4)2[Ce(NO3)6] 60 % OMe Ph 89 Me Me Cr(CO)5 (CO)5Cr O O 91 Ph Ph 23 % OH Ph Ph HO O O H Me H Me 92 Scheme 33 Benzannulation approach to bridged and non-bridged C symmetric quinones and hydroquinones.mediated cyclization afforded in 45% overall yield the tetracyclic 6,9-diketone 96 which has been previously modified into the anthracycline aglycon (Scheme 34).38 A recent benzannulation approach to fredericamycin A 100 another potent antitumor antibiotic has been based on the assembly of an oxygenated arylcarbene ligand in 97 and a Cr(CO)3 OMe OMe OMe OMe Cr(CO)3 85 R1 R2 O OMe OMe O R2 R1 O Ph Ph O O O 90 2-O OMe OMe Me O Cr(CO)4 O OMe + O O O O OH 95 76 % 94 93 OMe OMe O O OH 96 45 % Scheme 34 Synthesis of 11-deoxydaunomycinone precursor 96.highly functionalized internal alkyne 98 (Scheme 35).39 The hydroquinone ring B has been formed as the late key step affording a 35% yield of a single regioisomer 99 which has been subsequently converted to the target spirocycle 100. The steroid skeleton has been formed via a tandem Diels– Alder reaction–two alkyne annulation starting from the triple alkyne carbene chromium complex 101. The Diels–Alder adduct 102 generated from the carbon–carbon triple bond activated by the adjacent metal carbene functionality and Danishefsky’s diene undergoes a thermal intramolecular two alkyne annulation to give a 30% yield of the fused tetracyclic skeleton 103 along with the lactone 104 as a minor product (Scheme 36).40 The yield of 103 could be improved to 63% when the chromium starting material 101 was replaced by its tungsten analogue.O O OMe MeO Cr(CO)5 + O O 97 O D C E O HO F O H N 6 Conclusion and outlook During three decades metal carbenes have evolved from organometallic curiosities to valuable tools in stereoselective organic synthesis and catalysis. The metal carbonyl fragment in Fischer-type complexes provides a template for non-classic carbene cycloaddition reactions which can be tuned by the metal and the substitution pattern of the carbene ligand. The chromium-mediated benzannulation with alkynes allows for a O OH MeO B A O OH 100 Scheme 35 Benzannulation approach to fredericamycin A 100. 7 Acknowledgements It is a pleasure to thank the group of students mentioned in the references for their enthousiastic work.We gratefully acknowledge the continuous financial support by the Deutsche For- OR OR BnO EtO N 98 O O OMe OR MeO A B O O OH OR BnO EtO 99 Chem. Soc. Rev. 1999 28 187–198 D O O TBDMSO 104 23 % Scheme 36 Formation of the steroid skeleton 103 via a tandem Diels–Alder reaction–two alkyne annulation. regio- and stereoselective one-step formation of Cr(CO)3- coordinated densely functionalized hydroquinones which may be used as building blocks in the synthesis of natural and bioactive compounds or modified into chiral quinone ligands for catalysts in oxidation reactions. Finally haptotropic metal migration to adjacent arene rings activates them for the addition of nucleophiles which occurs under the stereocontrol by the Cr(CO)3 fragment.Me OMe (CO)5Cr 101 TBDMSO OMe 12 h 87 % Cr(CO)5 Me OMe TBDMSO 102 75 °C 19 h Me Me HO + TBDMSO 103 30 % R = TBDMS 35 % E F N 197 schungsgemeinschaft and the Fonds der Chemischen Industrie. 8 References 1 K. H. Dötz H. Fischer P. Hofmann F. R. Kreissl U. Schubert and K. Weiss Transition Metal Carbene Complexes Verlag Chemie Weinheim 1983. 2 Recent reviews W. D. Wulff in Comprehensive Organometallic Chemistry II ed. A. W. Abel F. G. A. Stone and G. Wilkinson Pergamon Press Oxford 1995 vol. 12 p. 469; L. S. Hegedus ibid. vol. 12 p. 549. 3 Review K.H. Dötz Angew. Chem. Int. Ed. Engl. 1984 23 587. 4 K. H. Dötz and H. Larbig Bull. Soc. Chim. Fr. 1992 129 579. 5 B. L. Balzer M. Cazanoue M. Sabat and M. G. Finn Organometallics 1992 11 1759. 6 W. D. Wulff in Comprehensive Organic Synthesis eds. B. M. Trost I. Fleming and L. A. Paquette Pergamon Press Oxford 91 vol. 5 p. 1065. 7 A. Yamashita and A. Toy Tetrahedron Lett. 1986 27 3471. 8 K. H. Dötz and W. Sturm J. Organomet. Chem. 1985 285 205. 9 K. H. Dötz and H. Fischer Chem. Ber. 1980 113 193. 10 K. H. Dötz and B. Fügen-Köster Chem. Ber. 1980 113 1449. 11 K. H. Dötz A. Tiriliomis and K. Harms Tetrahedron 1993 49 5577. 12 The isolated and structurally characterized model intermediates are referred to in ref. 15. 13 H. Fischer J.Mühlemeier R. Märkl and K. H. Dötz Chem. Ber. 1982 115 1355. 14 P. Hofmann M. Hämmerle and G. Unfried New J. Chem. 1991 15 769. 15 F. Hohmann S. Siemoneit M. Nieger S. Kotila and K.H. Dötz Chem. Eur. J. 1997 3 853. 16 M. M. Gleichmann K. H. Dötz and B. A. Hess J. Am. Chem. Soc. 1996 118 10551. 17 K. S. Chan G. A. Peterson T. A. Brandvold K. L. Faron C. A. Challener C. Hyldahl and W. D. Wulff J. Organomet. Chem. 1987 334 9. Chem. Soc. Rev. 1999 28 187–198 198 18 B. Weyershausen and K. H. Dötz Eur. J. Org. Chem. 1998 1739. 19 J. P. A. Harrity W. D. Kerr and D. Middlemiss Tetrahedron 1993 49 5565. 20 K. H. Dötz J. Mühlemeier U. Schubert and O. Orama J. Organomet. Chem. 1983 247 187. 21 S. Chamberlin M. L. Waters and W. D. Wulff J. Am. Chem. Soc. 1994 116 3113. 22 J. S. McCallum F.-A. Kunng S. R. Gilbertson and W. D. Wulff Organometallics 1988 7 2346. 23 A. Yamashita Tetrahedron Lett. 1986 27 5915. 24 D. B. Grotjahn and K. H. Dötz Synlett 1991 381. 25 M. F. Gross and M. G. Finn J. Am. Chem. Soc. 1994 116 10921. 26 M. F. Semmelhack J. J. Bozell L. Keller T. Sato E.J. Spiess W. Wulff and A. Zask Tetrahedron 1985 41 5803. 27 K. H. Dötz and A. Gerhardt J. Organomet. Chem. 1999 in press. 28 T. Leese and K. H. Dötz Chem. Ber. 1996 129 623. 29 K. H. Dötz and T. Leese Bull. Soc. Chim. Fr. 1997 134 503. 30 G. Schmalz and S. Siegel in Transition Metals for Organic Synthesis eds. M. Beller C. Bolm Wiley-VCH Weinheim 1998 vol. 1 p. 550. 31 R. P. Hsung W. D. Wulff and A. L. Rheingold J. Am. Chem. Soc. 1994 116 6449. 32 R. P. Hsung W. D. Wulff and C. A. Challener Synthesis 1996 773. 33 R. L. Beddoes J. D. King and P. Quayle Tetrahedron Lett. 1995 36 3027. 34 C. Stinner and K. H. Dötz Tetrahedron Asymmetry 1997 8 1751. 35 A. Longen M. Nieger K. Airola and K. H. Dötz Organometallics 1998 17 1538. 36 P. Tomuschat L. Kröner E. Steckhan M. Nieger and K. H. Dötz Chem. Eur. J. 1999 5 700. 37 J. Bao W. D. Wulff M. J. Fumo E. B. Grant D. P. Heller M. C. Whitcomb and S.-M. Yeung J. Am. Chem. Soc. 1996 118 2166. 38 K. H. Dötz and M. Popall Angew. Chem. Int. Ed. Engl. 1987 26 1158. 39 D. L. Boger O. Hüter K. Mbiya and M. Zhang J. Am. Chem. Soc. 1995 117 11839. 40 J. Bao W. D. Wulff V. Dragisich S. Wenglowsky and R. G. Ball J. Am. Chem. Soc. 1994 116 7616. Review 8/01442F

ISSN:0306-0012    

DOI:10.1039/a801442f

出版商:RSC    

年代:1999

数据来源: RSC

摘要:

Palladium catalysed pronucleophile addition to unactivated carbon–carbon multiple bonds Yoshinori Yamamoto* and Ukkiramapandian Radhakrishnan Department of Chemistry Graduate School of Science Tohoku University Sendai 980-8578 Japan Received 21st August 1998 The addition of nucleophiles to carbon–carbon multiple bonds coordinated by Pd(ii) is one of the most popular processes for palladium promoted organic transformations. However the palladium catalysed addition of pronucleophiles to carbon–carbon multiple bonds has not been investigated widely. The compounds (H–Nu) which are prone to form nucleophilic species (Nu2) on treatment with either base or transition metals are called pronucleophiles. The additions of carbon pronucleophiles (H–CR3 hydrocarbonation) nitrogen pronucleophiles (H–NR2 hydroamination) carboxyl pronucleophiles (H–OCOR hydrocarboxylation) and sulfur pronucleophiles (H–S– hydrosulfination) to C–C multiple bonds are catalysed by palladium complexes.The hydrocarbonation of allenes enynes alkynes and methylenecyclopropanes proceeds very smoothly in the presence of palladium catalysts to give the corresponding olefinic derivatives in good to high yields. The hydroamination of allenes enynes and methylenecyclopropanes affords the corresponding allylic amines. The hydrocarboxylation of allenes gives the corresponding allylic carboxylates in high yields and the hydrosulfination of allenes with tosylhydrazine produces the corresponding allylic tosylates. Yoshinori Yamamoto was born in Kobe Japan in 1942.He received his MSc (1967) and PhD (1970) degrees from Osaka University Japan. He was appointed as an Instructor at Osaka University in 1970. While he was working as an Instructor at Osaka University he went to Professor H. C. Brown’s research group at Purdue University as a Postdoctoral Associate (1970–1972). In 1977 he was appointed as an Associate Professor at Kyoto University Japan where he remained until 1985. In 1986 he moved to Tohoku University to take up his present position Professor of Chemistry. He is also holding a Professorship at ICRS Tohoku University and a visiting Professorship at Kyushu University. He is a recipient of the Chemical Society of Japan award for Young chemists in 1976.More recently he was awarded the Chemical Society Yoshinori Yamamoto Ukkiramapandian Radhakrishnan H-Pd-O2CR H H H-Pd-CR3 Hydrocarbonation Hydrocarboxylation H-Pd-NHNHSO2R H H H-Pd-NR2 Hydroamination Hydrosulfination Ukkiramapandian Radhakrishnan was born and brought up in Tamilnadu India. He obtained his PhD (1996) at the University of Hyderabad India under the guidance of Professor M. Periasamy. He is currently working as JSPS Research Associate in Professor Yoshinori Yamamoto’s research group. 1 Introduction The construction of the carbon–carbon bond is a fundamentally important process in organic chemistry. Recent years witnessed tremendous growth in a number of reactions and reagents applicable to carbon–carbon bond formation.Among them the carbanionic additions to activated and unactivated carbon– carbon multiple bonds are regarded as one of the most important reactions for carbon–carbon bond formation. In traditional organic chemistry addition of carbon nucleophiles to activated alkenes and alkynes has been extensively used in the C–C bond forming reactions; the classical example is the Michael reaction. The later reaction involves the addition of the C–H bond of activated methylenes and methynes to activated alkenes in the presence of base (Type A).1 In modern organic syntheses the use of transition metal catalysts enables the addition of activated methylenes and methynes to activated alkenes (Type B).2 The nonfunctionalized carbon–carbon multiple bond systems are recognised as latent functional groups however they are generally unreactive towards carbon nucleophiles due to their electron rich p-orbitals.Organic chemists have developed an alternative methodology for the additions of carbon nucleophiles towards such unactivated multiple bonds which involves either transition metal mediated activation of these unsaturated of Japan Award (1995). He is the regional Editor of Tetrahedron Letters and he is the President (elect) of International Society of Heterocyclic Chemistry. He has a wide range of research interests in synthetic organic and organometallic chemistry. His recent work focussed on the use of transition metal complexes as catalytic reagents in organic synthesis and synthesis of complex natural products.Chem. Soc. Rev. 1999 28 199–207 199 systems (Type C) or carbometallation reactions (Type D). The activation of unsaturated systems can be achieved by the complexation of electrophilic transition metals to the alkenes or alkynes which makes the C–C multiple bonds susceptible towards the addition of carbon-nucleophiles (Type C).3 The reactions of the Type C category are mostly carried out with stoichiometric amounts of the reagents due to various reasons. The addition of a carbon–metal bond of an organometallic species across the carbon–carbon multiple bonds is called a carbometallation reaction (Type D).4 Most of the organometallics involved in this reaction are polar reagents such as organomagnesium and organoaluminium species and several functional groups are not compatible under the reaction conditions.All the C–C bond forming reactions (Types A–D) are shown in Fig. 1. Base (Type A) C C C EWG C C C H [M] (Type B) EWG Type C C C C + C C C M Type D C C C + C M + C C H-Pd-O2CR H M = Alkali or Transition metals Fig. 1 Carbon–carbon bond forming reactions. Despite the fact that all the above mentioned reactions (Types A to D) occupy unique positions in the carbon–carbon bond formation reactions various problems associated with the utilisation of these methods limit their applications. Consequently there has been a considerable amount of interest in developing newer reagents and methods for carbon–carbon bond formation.The pioneering efforts by various research groups resulted in the development of catalytic C–C bond forming reactions the transition metal mediated addition of the C–H bond of active methylene to unactivated carbon–carbon multiple bonds is catalytic and shows functional group compatibility (Fig 2).5 This reaction consists of the formal addition of a C–H bond across the carbon–carbon multiple bonds and is called a hydrocarbonation reaction. The synthetic applications and mechanistic implications of palladium catalysed hydrocarbonation reactions are described in this review. Also the discussion is extended to include other reactions which fall into such categories as hydroamination hydrocarboxylation and hydrosulfination of various unsaturated systems (Fig.2). The scope of this review does not allow us to present many elegant pieces of work which involve nucleophilic addition to alkenes and alkynes activated by electrophilic metal complexation. RCO2 Hydrocarboxylation H-Pd-NHNHSO2R H RO2S + N2 + H2 Hydrosulfination Fig. 2 Carbon–carbon and carbon–heteroatom bond forming reactions. Chem. Soc. Rev. 1999 28 199–207 200 C X X= CN COOEt Y= CH3 Ph Pd2(dba)3•CHCl3 H R2 CH2CXY(CN) 3 activated pronucleophiles 1 to alkyl- and arylallenes 2 was catalysed by Pd2(dba)3·CHCl3 and gave internal alkenes (3 and/ or 4) in a regio- and stereoselective fashion. In most of the cases especially with monosubstituted allenes selective formation of the E-isomer was observed and with disubstituted allenes a mixture of E- and Z-isomers was obtained.However only g- adducts were obtained in all cases. The addition reaction became sluggish with allenes containing bulkier substituents. A tentative mechanism along the following lines may be suggested for the hydrocarbonation of allenes (Scheme 1). The oxidative insertion of Pd(0) into the C–H bond of the activated H-Pd-CR3 2 Hydrocarbonation of carbon–carbon multiple bond systems The activation of the C–H bonds of alkanes and their addition to carbon–carbon multiple bonds have been sought by organic chemists for a long time. There are very few synthetic methods available for converting a C–H bond into a C–C bond. Recently Murai et. al. found that ruthenium complexes catalyse the addition of ortho C–H bonds of aromatic ketones to olefins.6 Trost et.al. reported the palladium catalysed activation of the C–H bonds of terminal alkynes and their addition to allenes and alkynes.7 Another report which is an important contribution to this hydrocarbonation area is the palladium catalysed addition of the C–H bond of pronucleophiles to 1,3-dienes.8 2.1 Hydrocarbonation of mono- and disubstituted allenes Allenes constitute an important class of organic compounds with unusual chemical properties due to the cumulated double bonds. An interesting example which attracted our attention is the palladium catalysed reaction of activated methylenes with unsubstituted allenes.9 The synthetic applications of this reaction are very limited and until recently there were no reports of similar kinds of reactions with substituted allenes.An unprecedented and mechanistically fascinating reaction was encountered between activated methylene (or methynes) and substituted allenes (eqn. (1)).10 The addition of certain cyano- CN + Y H 1 R1 (1) g CR R1 a b R2 2 R1= Ph PhCH2 R2= H Me Et CH2CXY(CN) H 4 THF (10 - 75%) R1 + R2 H 3 Hydrocarbonation H-Pd-NR2 NR H 2 Hydroamination Ph H Me Me C CN CN Ph Pd Ph Pd-H 6 Me Me H a 11 Me H Me Z Z Z C CN CN Scheme 1 Hydrocarbonation of allenes hydropalladation or carbopalladation mechanism. pronucleophiles would produce the Pd(ii) species 5 (or alternatively a tautomeric structure H3C(CN)CNCNNPdHLn may be more suitable).Carbopalladation of the allene would afford the alkenylpalladium complex 6 (carbopalladation mechanism) which would undergo reductive coupling to give the addition product and a Pd(0) species. As an alternative mechanism it may be considered that the hydropalladation of allenes with the Pd(ii) intermediate 6 gives the p-allylpalladium complex 7 which undergoes reductive coupling to afford the adduct and a Pd(0) species (hydropalladation mechanism). When we found the hydrocarbonation reaction of allenes (eqn. (1)) it was not clear whether the reaction proceeded through either the hydropalladation or carbopalladation mechanism. However as mentioned below most pronucleophile additions are well understood by the hydropalladation mechanism except for the intramolecular addition to alkynes (vide infra).It has been clearly shown that the regioselectivity of the hydrocarbonation of allenes is controlled by the steric effect of pronucleophiles and by the electronic effect of the substituents on the aromatic ring of phenylallenes (eqn. (2)).11 The H 8 + H 12 g H CH2CXY(CN) b Z= H F Cl Br CF3 OCF3 CH3 OCH3 CXY(CN) (6 – 20%) (10 – 85%) phenylallene substituted at the para-position with electron withdrawing groups makes the b-carbon of the allene electrophilic and led to predominantly or exclusively formation of internal b-adducts (10 and 11) whereas electron donating substituents such as methyl and methoxy groups at the paraposition directed the hydrocarbonation reactions in such a way as to give terminal g-adducts 12.On the other hand sterically CN H C Me CN C bulky pronucleophiles such as ethyl cyanophenylacetate led to the formation of terminal g-adducts 12 regardless of the electronic effect of the substituents at the para-position of arylallenes. Furthermore the hydrocarbonation of alkoxy- or phenoxyallenes 13 with methylmalononitrile and ethyl cyanomethylacetate gave a-adducts 15 either exclusively or predominantly in good to high yields (Scheme 2).12 An alkoxy group stabilises CN 5 RO CN H Ph R= Ph(CH2) n n= 0,1,2,3 the positive charge formed at the a-position and a nucleophilic attack at the a-position becomes more favorable.Accordingly it seems that an alkoxy group of the p-allylpalladium directed the nucleophile to the a-carbon of the p-allyl moiety. In contrast the sterically more bulky pronucleophile ethyl cyanophenylacetate gave g-adducts 16 regioselectively regardless of the electronic nature of the substituents on the allenes. The g-selectivity in the reaction of sterically bulky pronucleophiles may be due to the steric crowding around the electrophilic carbon center of the p-allylpalladium intermediate. In marked contrast to the oxygen substituted allenes the pronucleophile addition to allenyl sulfides 17 gave the g- adducts 19 in good to high yields (Scheme 3).13 It is well (19 – 84%) Scheme 2 Hydrocarbonation of alkoxyallenes.X= CN COOEt Y= CH3 Ph RS H H R= Ph PhCH2 a b 17 X= CN COOEt Y= CH3 Ph Pd(0) Z CN (2) 7 Pd2(dba)3•CHCl3 H-Pd CN Y C X 10 Me 3 CN + + H Me 9 X= CN COOEt Y= CH3 Ph dppb THF CH CXY(CN) (19 – 68%) R3Sn R= Ph Bu accepted in heteroatom substituted allyl anion and allyl cation chemistry that (1) an oxygen substituent stabilises a neighbouring carbocation and destabilises a neighbouring carbanion due to the electron donating effect of the oxygen atom and (2) a sulfur substituent destabilises a neighbouring carbocation and stabilises a neighbouring carbanion due to the electron withdrawing effect of the sulfur atom. This may be the reason for the differences in the regioselectivity of pronucleophile addition to oxygen substituted allenes and allenyl sulfides.Interestingly the addition of pronucleophiles 21 to allenyl stannanes 20 in the presence of a catalytic amount of Pd2(dba)3·CHCl3 afforded the addition–substitution products 22 in moderate to high yields (eqn. (3)).14 The prop- PdL2 Scheme 3 Hydrocarbonation of allenyl sulfides. Chem. Soc. Rev. 1999 28 199–207 CN RO g CH2 Pd2(dba)3•CHCl3 a b + Y H C dppb THF H (NC)YXC X 13 15 14 CXYZ (49 – 99%) + RO a RO H b PdL g 2 H CH2CXY(CN) 16 CN H RS g Pd2(dba)3•CHCl3 . Y C + H dppb THF H X 19 18 (59 – 99%) CXYZ b RS a g (NC)YXC Pd2(dba)3.CHCl3 Y + H H dppb THF H (NC)YXC CN C X 21 20 (3) 22 X= CN COOEt (35 - 90%) Y= CH3 Ph CH2CXY(CN) 201 2-ynylstannane derivatives also show a similar kind of reactivity with pronucleophiles and gave addition–substitution products (eqn.(4)). It is worth mentioning that an internal H (NC)YXC Bu3Sn Pd2(dba)3•CHCl3 (4) Ph + 21 dppb THF (NC)YXC Ph (50 - 55%) allene such as 3-phenyl(tributylstannyl)allene also underwent hydrocarbonation in a facile manner under these reaction conditions. In the above mentioned hydrocarbonation reactions mostly cyano activated pronucleophiles were added to simple allenes. Another independent investigation by Trost et. al. using a different palladium catalyst system [(h3-C3H5)PdCl]2–dmppp under basic conditions (t-BuOK) resulted in the addition of Meldrum’s acids and sulfonyl activated pronucleophiles to allenes (eqn (5)).15 This reaction showed excellent chemo- OR OC2H5 SO2Ph + OC2H5 SO2Ph 24 23 (5) dmppp t-BuOK [(h3-C3H5)PdCl]2 OR OC2H5 PhO2S OC2H5 SO2Ph 25 (64 – 71%) selectivity.The synthetic application of this reaction is shown by preparing a carbocycle via intramolecular hydrocarbonation. These authors clearly indicate that the addition of pronucleophiles proceeds through the hydropalladation mechanism.15 Gore Besson and Cazes reported the hydrocarbonation of allenic hydrocarbons 26 under an alternative Pd(0)–base catalytic system (eqn. (6)).16 This reaction allows the addition C7H15 C7H15 C7H15 26 + Pd(dba)2 (6) CH(CO2Me)2 CH(CO2Me)2 + 28 29 dppe RONa (30%) (12%) CH2(CO2Me)2 27 of malonate type methylenes or methines to allenes giving products in moderate yields.The product formation seems to favor a hydropalladation process to form a p-allylpalladium intermediate which on reductive elimination gives a mixture of products 28 and 29. The intramolecular pronucleophile addition to allenes will be synthetically useful for the synthesis of carbocycles. Interestingly an intramolecular cyclisation of pronucleophile tethered allenes 30 is shown to proceed very well in the presence of palladium catalyst [(h3-C3H5)PdCl]2–dppf under neutral as well as basic conditions (Scheme 4).17 The use of palladium catalyst under neutral condition gave better yields of carbocycles 31 than the use of of Pd(0) catalyst under basic conditions; [(h3- C3H5)PdCl]2–dppf–t-BuOK.Compared to six membered ring Chem. Soc. Rev. 1999 28 199–207 202 H [(h3-C3H5)PdCl]2 X X dppf THF Y Y n n 30 (10 – 88%) 31 Pd(0) H -Pd(0) PdH H X Pd Pd II X or X Y n 32 33 Y n Y n X Y= CN CO2Me SO2Ph Meldrum's acid X R Pd2(dba)3•CHCl3 X Y H dppf THF Y CN (28 – 100%) CN 36 -Pd0 R R X 34 37 Y HPd or CN 39 n = 1 or 2 Scheme 4 Intramolecular hydrocarbonation of allenes. formation the five membered ring formation proceeds smoothly. The formation of the five membered ring proceeds in a 5-exo-trig manner and no endo product formation was observed. The intramolecular cyclisation can be explained as follows; the oxidative addition of the C–H bond of the pronucleophiles would give the hydridopalladium species 32 followed by intramolecular hydropalladation 33 or carbopalladation 34 and subsequent reductive elimination would give the cyclised product.2.2 Hydrocarbonation of enynes It was envisioned that pronucleophile addition to conjugated enynes would lead to the formation of allenes and hence the reaction would serve as an alternative method for the synthesis of allenes. Indeed it was observed. After brief optimisation the Pd2(dba)3·CHCl3–dppf combination appeared to be an effective catalyst for the addition of pronucleophiles 36 to enynes 35 (Scheme 5).18 The palladium catalysed addition of certain R + 35 Pd X Y 38 CN R= Me C6H13 CH2Ph SiMe3 X= Me Ph and Y= CO2Et CN Scheme 5 Hydrocarbonation of enynes.carbon pronucleophiles 36 to conjugated enynes 35 afforded the corresponding allenes 37 in excellent yields. When an excess of reactive pronucleophiles was added to enynes further addition to the allenyl double bond took place and the 1,3-bisadducts were isolated. Similarly the active methylenes in the presence of two equivalents of enynes underwent double addition and gave 1,3-diallenylalkanes. It should be pointed out that in the pronucleophile addition to conjugated enynes the pronucleophiles were selectively added to the double bond rather than the triple bond. Probably this reaction proceeds through either the intermediate species 38 which is formed by hydropalladation to the triple bond or the intermediate 39 which is produced by the carbopalladation to the double bond.2.3 Hydrocarbonation of alkynes The palladium catalysed allylation of carbon nucleophiles using allylic substrates in basic conditions is a well recognised reaction in modern organic chemistry (Tsuji–Trost reaction).19 This procedure suffers from one serious drawback i.e. it requires a stoichiometric amount of base. An interesting allylation of pronucleophiles 41 with simple alkynes 40 in the presence of Pd(PPh3)4–AcOH was developed (Scheme 6).20 Y Z X Z Pd(PPh3)4 R + Y H AcOH dioxane R' R' R 40 X (64 – 99%) 42 HPdOAc 41 HPdOAc Z R' R HPdOAc Y H HPdOAc X R R' Pd 44 43 OAc Pd(OAc)2 R NC oct-1-ene or COD (39 – 84%) H NC 46 CN 45 Pd(0) CN Pd(0) + HPd HPd R R= Ph Et X= Me Ph MOMO; Y= CN SO2Ph; Z= CN CO2Et SO2Ph R'= H Me Et -CH2OMe -CH2NHCbz cyclopropyl Scheme 6 Hydrocarbonation of alkynes plausible mechanism.This reaction is complementary to the Tsuji–Trost reaction but with significant advantages. The present reaction does not require a stoichiometric amount of base; it works in the presence of catalytic amounts of acetic acid. The reaction carried out in the absence of acetic acid gave only a trace amount of the product. In most of the cases the products 42 were formed with perfect regioselectivity. A plausible reaction pathway for this allylation may involve the addition–elimination of HPdOAc to internal alkynes which would produce allenes 43 and the active catalyst (HPdOAc).Hydropalladation of allenes with HPdOAc would give the p-allylpalladium complexes 44 which on reaction with pronucleophiles would give the products. Also the intramolecular hydrocarbonation of alkynes with an active methine 45 proceeded very well under neutral conditions using Pd(OAc)2–cycloocta-1,5-diene (or oct-1-ene) catalyst and ethanol as a solvent (Scheme 7).21 The e-alkynylmalononi- R CN R NC CN NC 48 47 R= H Me HO(CH2)3 TBDMS-O(CH2) n Ph TMS Scheme 7 Intramolecular hydrocarbonation of alkynes. triles 45 indeed underwent cyclisation to give the Z-isomers of the corresponding carbocycles 46 in all cases (except when R = trimethylsilyl). It should be pointed out that substrates containing a hydroxy group gave carbocycles in good yields without producing furan or pyran derivatives.The cyclisation reaction for a substrate which bears a terminal alkyne unit (R = H) was sluggish; this may be due to the oxidative addition of Pd(0) into the C–H bond of the terminal alkyne. The formation of the Zisomer suggests that the reaction does not proceed through a p- allylpalladium intermediate; the E-isomer must be produced predominantly if it is involved as a reaction intermediate. Probably the reaction pathway involves the coordination of HPd+ to the triple bond and subsequent trans-carbopalladation of 47. The reductive elimination of Pd(0) from the resulting vinylpalladium species 48 would lead to the cyclisation product 46.2.4 Hydrocarbonation of methylenecyclopropanes It can be decided from the foregoing discussion that Pd(0) catalysts are of great value in the hydrocarbonation of allenes and alkynes. Also the palladium is a useful catalyst for the hydrocarbonation of nonconjugated alkenes such as methylenecyclopropanes (eqn. (7)).22 The reaction of certain pronucleo- Me Y H X 49 X Me X R X= CN CO2Et; Y= CO2Et CN Y Y Pd(PPh3)4 + (7) + Me R THF 52 51 R (55 – 95%) (10 – 88%) 50 R= Ph Ph(CH2) n n= 1 2 3 philes 49 with methylenecyclopropanes 50 was catalysed by Pd(PPh3)4 and afforded the hydrocarbonation products terminal 51 and internal alkenes 52 either exclusively or as a mixture of both. The selectivity of the product formation depends upon the mode of hydropalladation of alkenes and ring opening of cyclopropane which in turn depends upon the substituent at the exo-methylene carbon and the substituents on the pronucleophiles.In the case of cyanoactivated pronucleophiles the selectivity of the product formation depends upon the chain length of the aliphatic substituents [Ph(CH2)n] the addition of methylmalononitrile to (4-phenylbut-1-ylidene)cyclopropane (n = 3) gave 51 as the sole product whereas the ring opening of (3-phenylprop-1-ylidene)cyclopropane (n = 2) and (2-phenylethylidene) cyclopropane (n = 1) with methylmalononitrile gave a mixture of 51 and 52. The ester activated pronucleophile diethyl malonate led to the formation of product 51 exclusively regardless of the chain length of substituents.The mechanistic rationale in Scheme 8 may account for the present palladium catalysed ring opening of methylenecyclopropanes with pronucleophiles. Oxidative addition of Pd(0) into the C–H bond of pronucleophiles 49 would generate a hydridopalladium complex which on hydropalladation of methylenecyclopropanes would give either 53 or 55. The complex 53 would undergo rearrangement to the p-allylpalladium complex 54 (route A). The reductive elimination of Pd(0) from 54 would produce 51. The palladium complex 55 would isomerise to the p-allylpalladium complex 57 via 56 (route B) and the reductive elimination of Pd(0) would give 52. The reaction with deuterated pronucleophiles substantiated the hydropalladation mechanism.203 Chem. Soc. Rev. 1999 28 199–207 H-Pd-Nu R Nu Nu Pd H Pd H or R 55 R 53 R A Nu B Pd 54 Nu Nu 57 H-Nu 58 + Pd(0) 4- n Nu dppb THF R Y Pd X Y Pd Pd2(dba)3•CHCl3 R (8) 56 CN R X NC 60 Nu (43 – 89%) 51 X CN 59 R Y SnBu n 52 Scheme 8 Mechanistic pathway hydrocarbonation of methylenecyclopropane. 2.5 Hydrocarbonation of vinyltin derivatives In one of the previous sections it has been mentioned that the allenylstannanes underwent substitution–addition reactions with pronucleophiles. Encouraged by this result we subjected vinyltin derivatives to the palladium catalysed pronucleophile addition reactions. In the presence of a catalytic amount of Pd2(dba)3·CHCl3–dppb the reaction of pronucleophiles 58 with vinyltins 59 proceeded through alkylative dimerisation and gave the corresponding 1,4-disubstituted butenes 60 in good yields (eqn.(8)).23 The reaction proceeded in a stereoselective H n= 1 2 4 X= Ph MeOC6H4 ClC6H4 CF3C6H4 Y= CN CO2Et fashion to give trans isomers selectively and no cis isomers were detected in any reactions. The pronucleophiles such as malononitrile diethyl malonate and diethyl phenylmalonate did not react with vinyltins under the reaction conditions. 3 Hydroamination reactions The hydroamination reaction of an unactivated unsaturated system consists of the formal addition of an N–H bond across carbon–carbon multiple bonds. It is one of the most useful methods for synthesizing nitrogen containing compounds from unsaturated organic molecules.24 Therefore we intended to develop a catalytic process for the hydroamination of unactivated systems based upon the knowledge and mechanisms obtained from the studies on the hydrocarbonation reactions.Similar to the hydrocarbonation reactions the hydroamination of unactivated carbon–carbon multiple bonds requires the activation of either unsaturated systems or amines. The activation of carbon–carbon multiple bonds can be effected by the coordination of various electrophilic metals. Most of the Chem. Soc. Rev. 1999 28 199–207 204 amination reactions which are based on nucleophilic addition to the metal activated unsaturated systems are carried out using stoichiometric amounts of the transition metal reagents.On the other hand the N–H bond can be activated either by deprotonation using electropositive metals or by the oxidative addition of the N–H bond to a transition metal. So far reports on the oxidative additions of an N–H bond to coordinatively unsaturated metal centers are rare.24 Remarkably we could achieve the hydroamination of allenes enynes and methylenecyclopropanes which proceed most probably through the oxidative addition of N–H bond to palladium(0) under neutral or acidic conditions and the results are described here. 3.1 Hydroamination of mono- and disubstituted allenes Allylamines are important organic compounds on account of their use as synthetic intermediates and their occurrence as natural substances.The catalytic hydroamination of allenes would be a straightforward method for the synthesis of this useful product. Unsubstituted allenes are known to undergo hydroamination reactions in the presence of a palladium catalyst.9 The main products of this reaction are alkadienylamines. Cazes et. al. reported the palladium catalysed intermolecular hydroamination of substituted allenes 61 using aliphatic amines 62 (eqn. (9)).25 They utilised the beneficial NXY R 63 (16 – 89%) R Pd(OAc)2 PPh3 + (9) + HNXY H Et3NHI 62 R 61 R= C7H15 Ph X=Y= Et -(CH2)4- -(CH2)5- NXY R 64 (8 – 55%) effect of adding triethylammonium iodide salt which resulted in the hydroamination of allenes. Under these reaction conditions in addition to the normal hydroamination product 63 the allene underwent telomerisation with the amine and gave dienic amine 64 also.By employing a different palladium catalyst system under acidic conditions the hydroamination reaction with wider synthetic scope was observed. In the presence of Pd2(dba)3.CHCl3–dppf with acetic acid in THF allylamines 67 were obtained as the only product in good to excellent yields (eqn. (10)).26 This catalytic system was very effective for the R Pd2(dba)3•CHCl3 NXY R + H-NXY H dppf AcOH THF (10) 65 67 66 (32 – 100%) R= Ph Me-C6H4 F3C-C6H4 PhCH2CH2 X=Y= CH2CO2Et CH2Ph Ph intermolecular hydroamination of various monosubstituted allenes 65 with protected amines 66 to afford the E-isomer of the corresponding allylamines 67.In contrast to the hydrocarbonation reactions here the regioselectivity was not affected by either the bulkiness of the nucleophile or the electronic properties of para-substituents of arylallenes. In all cases g- adducts were obtained as the only product. In fact the aliphatic allenes gave lower yields of products than the corresponding aromatic allenes. A possible reaction pathway for this palladium(0) catalysed hydroamination is shown in Scheme 9. The oxidative addition NXY R Pd(0) R X + _ N Pd Y X R Pd N Y NH N Bn 71 70 + PhI + PhI NH O O H Pd(PPh Pd(PPh (85%) H-Pd-O2CCH3 (13) 69 3)4 K2CO3 DMF (71%) 3)4 K2CO3 DMF [(h3-C3H5)PdCl]2 dppf AcOH THF 72 N n N R CH3CO2H Ph Ph PdLn 76 -Pd(0) H Scheme 9 Hydroamination of allenes plausible mechanism.of acetic acid to Pd(0) would produce hydridopalladium species 68 which on reaction with amine would give intermediate 69 and acetic acid. The species 69 would form the p-allylpalladium intermediate 70 with allenes which after reductive elimination would give the hydroamination product with g-selectivity. An efficient intramolecular cyclisation of tethered aminoallenes is a potentially useful method for constructing nitrogen heterocycles bearing the key substituents present in naturally occurring compounds. Gallagher et al.27 and Hiemstra et al.28 reported palladium catalysed intermolecular coupling/ intramolecular cyclisation sequences based on allenes as the p- component for the synthesis of nitrogen heterocycles (eqns.(11) and (12)). In these reactions the organopalladium(ii) iodide 75 73 formed in situ activates the allenic double bond to undergo intramolecular cyclisation to give five membered ring heterocycles 72 and 74. An entirely new type of hydroamination which proceeds through the insertion of an M–H bond (M = Pd) into an allenic double bond has been developed in this laboratory.29 Amines or sulfonylamides bearing an allene 75 at the terminus of the carbon chain underwent a facile intramolecular reaction in the presence of a catalytic amount of [(h3-C3H5)PdCl]2–dppf and acetic acid (eqn. (13)). In the absence of acetic acid the reaction n NH R R = Ts Tf Bn n = 1 2 74 n N R (41 – 90%) 68 H N (11) CH3CO2H X Y (12) 77 was very sluggish.The tethered aminoallenes cyclised smoothly in 5-exo-trig or 6-exo-trig modes to afford the corresponding vinylpyrrolidines and vinylpiperidines respectively. The protecting group at the amine moiety of allenylamines plays an important role. The tethered allenylamines protected with triflate toluene-p-sulfonate and benzyl groups gave the corresponding products 77 in good yields but other protecting groups did not give the desired products. 3.2 Hydroamination of enynes The hydoamination of conjugated enynes 78 in the presence of a palladium catalyst was reasonably facile and gave the Eisomer of alkenic 1,4-diamine 80 (Scheme 10).30 Unlike the R X R X X N X H N N + dppf AcOH X X 80 78 79 (30 – 70%) X HPd-N R X X N X 81 [(h3-C3H5)PdCl]2 3 R= Me Hexyl SiMe X= PhCH2 -CH2CH=CH2 Scheme 10 Hydroamination of enynes.hydrocarbonation of enynes aminoallenes 81 (through monohydroamination) were not obtained as the products. Probably the aminoallenes 81 are very reactive and underwent further addition of the amine to give the dihydroamination products alkenic 1,4-diamines 80. It should be pointed out that the unsymmetrically substituted 1,4-diaminobut-2-enes could also be obtained using two different amines. Unfortunately the reaction did not give fruitful results with aliphatic amines and sulfonamides. These types of alkenic 1,4-diamines 80 are important organic compounds on account of their use as synthetic intermediates and as inhibitors.3.3 Hydroamination of methylenecyclopropanes Analogously to the hydrocarbonation of methylenecyclopropanes the hydroamination also proceeded smoothly in the presence of [(h3-C3H5)PdCl]2–dppp and gave either 84 or 85 (Scheme 11).31 The regioselectivity clearly depends upon the substituent on the double bond of methylenecyclopropanes 82. The palladium catalysed hydroamination of alkyl substituted methylenecyclopropanes mainly proceeds through the Markovnikov type addition to give 86 followed by distal bond cleavage to give the product 84 whereas in the case of benzylidenecyclopropanes the reaction goes through anti-Markovnikov addition followed by proximal bond cleavage and gives the product 85 exclusively.This regiochemical difference may be due to the following reason; the alkyl substituent decreases the electron density at the a-carbon of the alkene and the phenyl group increases the electron density at the a-carbon.31 Hence the hydropalladation and ring opening mode changes accordingly. The Markovnikov and anti-Markovnikov hydropalladation mechanisms were confirmed by carrying out the reactions of deuterated amines with alkyl and phenyl substituted methylenecyclopropanes. 4 Hydrocarboxylation of allenes Hydrocarboxylation of carbon–carbon multiple bonds is one of the most important processes for the synthesis of unsaturated and saturated carboxylic esters.In a classical organic reaction carboxylic esters are produced by the addition of carboxylic Chem. Soc. Rev. 1999 28 199–207 205 R + H-NX2 b a 83 82 R= Ph(CH2) n cyclohexyl Ph X= Et Benzyl [(h3-C3H5)PdCl]2 R= Ph R R Pd H Pd H NX2 X2N 87 86 R R NX dppp DME 2 84 85 R1 NX R2 R2 88 R= CH R= aliphatic 2 Pd OCOR 90 (31 – 91%) R1 Pd2(dba)3•CHCl3 dppf THF R1 R2 91 (70 – 96%) (19 – 84%) Scheme 11 Hydroamination of methylenecyclopropanes. acids to olefins mediated by protonic acids.1 In modern organic synthesis transition metal catalysts have replaced protonic acid catalysts. A number of other workers have contributed to this area which involves the nucleophilic addition of carboxylic groups to the metal coordinated carbon–carbon multiple bonds.32 We were interested in the reactions which involve the activation of carboxylic acids to form H–M–OOCR and proceed through insertion of the double bond into the H–M bond.An interesting example which demonstrates the synthetic potential of this methodology has been observed in our laboratory.33 The Pd2(dba)3·CHCl3–dppf complex catalysed the hydrocarboxylation of aromatic allenes 88 to give allyl esters 91 in excellent yields with perfect regio- and stereoselectivities (eqn. (14)).33 Regardless of the electronic nature of substituents at the + H-O2CR 89 3 -CH2CH3 Ph R1= Ph MeOC6H4 F3CC6H4 BrC6H4 ClC6H4 R2= H t-Bu FC6H4 para-position of aromatic allenes the g-adducts were obtained as the only product.In contrast to the classical electrophilic addition reaction the new version of the hydrocarboxylation Chem. Soc. Rev. 1999 28 199–207 206 -Pd(0) (14) O O R reaction of allenes most probably proceeds through the p- allylpalladium species 90. It is worth mentioning that various types of carboxylic acids 89 and an amino acid smoothly reacted with allenes affording the corresponding allyl esters in excellent yields. In general the monosubstituted allenes gave E-isomers exclusively and the disubstituted allenes provided E/Z mixtures. Unfortunately in the case of aliphatic allenes no hydrocarboxylated products were obtained instead buta-1,3-diene derivatives were formed. Propargylic (propargyl = prop-2-ynyl) derivatives are known to undergo isomerisation to give allenes.Trost et al. reported a palladium catalysed hydrocarboxylation of in situ generated allenes from propargyl derivatives (eqn. (15)).34 The R1O OAc HOAc + R 92 R= t-Bu tolyl -(CH2)9-CH2=CH2 R1= CH3 t-BuPh2Si Pd2(dba)3•CHCl3 (15) PPh3 Toluene R1O OAc R OAc 93 (54 – 79%) propargyl acetates 92 on treatment with acetic acid in the presence of a Pd(0) catalyst resulted in the formation of geminal diacetates 93. Remarkably the intramolecular version of this reaction proceeded efficiently to give macrocycles in moderate yields. nBuSO2 96 + (16) nBuSO2 97 5 Hydrosulfination of allenes Some organosulfur compounds are considered to be an important class of pharmacological agents.Until recently the transition metal mediated synthesis of organic sulfur compounds attracted much less attention. It was reasoned that organic sulfur compounds were considered to be catalytic poisons. However several transition metal mediated syntheses of organic sulfur compounds have been reported in recent years. Among various transition metals palladium complex catalysts have been found to be useful in the direct addition of organosulfur compounds to unactivated carbon–carbon multiple bonds.35 A good amount of information has been accumulated on the use of palladium catalysts for the syntheses of allyl sulfones from 1,3-dienes and sulfinic acids. Furthermore it was reported that the unsubstituted allenes 94 reacted with n-butanesulfinic acid 95 to give high yields of vinyl 96 and butadienyl sulfones 97 (eqn.(16)).35 Pd(acac)2 • + nBuSO2H PPh3 AlEt3 94 95 (82%) In our continued interest in the direct addition reaction of carbon-pronucleophiles and heteroatom-nucleophiles we be-came interested in the syntheses of organosulfur compounds using a palladium catalyst. It was envisioned that in the presence of palladium catalysts tosylhydrazine would act as a sulfinic acid equivalent by losing one equivalent of N2 and H2. As we expected a new type of hydrosulfination reaction of substituted allenes 98 with tosylhydrazine 99 in the presence of palladium catalyst was observed (Scheme 12).36 Unlike the hydro- R R Pd(OAc)2 dppf Ts TsNHNH + 2 AcOH THF 100 99 98 (44 – 84%) Hydroamination -Pd0 Pd0 N2 + H2 R R NHNHTs Pd-Ts 101 102 R= Ph MeC6H4 Heptyl t-Bu Ts= Toluene sulfonyl Scheme 12 Hydrosulfination of allenes.carbonation of allenes the regioselectivity of the product formation was not influenced by the electronic effect of the para-substituent on arylallenes. Generally the tosyl group added regioselectively to the g-position of allenes and transallyl sulfones were obtained without the formation of cis-allyl sulfones. The reaction pathway may involve the formation of intermediate 101 via the hydroamination of allenes with tosylhydrazine. Subsequently the intermediate 101 would be converted to allyl sulfones 100 via the p-allylpalladium complex 102 with releasing N2 and H2.6 Conclusions Until recently there has been dearth of catalytic methods for C– C bond formation involving pronucleophiles and unactivated unsaturated systems. We were surprised by this fact and entered this field several years ago with the aim of developing suitable catalytic systems for pronucleophile based carbon–carbon bond forming reactions. We have discovered many synthetically useful reactions and they are reported in this short review. The palladium catalysed hydrocarbonation of allenes and allylation of pronucleophiles using alkynes constitutes on important breakthrough. This methodology has also been successfully applied to the hydrocarbonation of non-conjugated alkenes such as methylenecyclopropanes.In addition to the hydrocarbonation reactions considerable progress has also been made in hydroamination hydrocarboxylation and hydrosulfination reactions also. The hydroamination reactions were utilised efficiently to obtain biologically important allylic amines and important classes of nitrogen containing heterocycles. It can be discerned from the foregoing discussion that palladium has proved to be a useful catalyst for carbon–carbon and carbon–heteroatom bond formation involving unactivated unsaturated systems and pronucleophiles. Many additional applications of the reactions and procedures discussed in this review will be forthcoming. For the future investigations aimed at promoting additional methodologies mechanistic investigations and further efforts to increase the turnover number of catalyst will be of useful to both academic and industrial synthetic chemists.7 References 1 J. March Advanced Organic Chemistry Wiley Interscience New York 4th Edition 1992 pp. 795–797. 2 T. Naota H. Taki M. Mizuno and S.-I. Murahashi J. Am. Chem. Soc. 1989 111 5954. 3 L. S. Hegedus Comprehensive Organic Synthesis B. M. Trost and I. Fleming Eds. Pergamon Press Oxford 1990 vol. 4 pp. 571–583. 4 P. Knochel Comprehensive Organic Synthesis B. M. Trost and I. Fleming Eds. Pergamon Press Oxford 1990 vol. 4 pp. 865–911. 5 Y. Yamamoto Pure Appl. Chem. 1996 68 9 and references cited therein. 6 S. Murai F. Kakiuchi S. Sekine Y. Tanaka A. Kamatani M. Sonada and N. Chatani Nature (London) 1993 366 529.7 B. M. Trost M. T. Sorum C. Chan A. E. Harms and G. Ruhter J. Am. Chem. Soc. 1997 119 698. 8 K. Takahashi A. Miyake and G. Hata Bull. Chem. Soc. Jpn. 1972 45 1183. 9 D. R. Coulson J. Org. Chem. 1973 38 1483. 10 Y. Yamamoto M. Al-Masum and N. Asao J. Am. Chem. Soc. 1994 116 6019. 11 Y. Yamamoto M. Al-Masum N. Fujiwara and N. Asao Tetrahedron Lett. 1995 36 2811. 12 Y. Yamamoto and M. Al-Masum Synlett 1995 969. 13 Y. Yamamoto M. Al-Masum and A. Takeda Chem. Commun. 1996 831. 14 Y. Yamamoto M. Al-Masum and N. Fujiwara Chem. Commun. 1996 381. 15 B. M. Trost and V. J. Gerusz J. Am. Chem. Soc. 1995 117 5156. 16 L. Besson J. Gore and B. Cazes Tetrahedron Lett. 1995 36 3853. 17 M. Meguro S. Kamijo and Y. Yamamoto Tetrahedron Lett. 1996 37 7453. 18 V. Gevorgyan C. Kadowaki M. M. Salter I. Kadota S. Saito and Y. Yamamoto Tetrahedron 1997 53 9097. 19 J. Tsuji Palladium Reagents and Catalysts; Innovations in Organic Synthesis John Wiley Chichester 1995 p. 297. 20 I. Kadota A. Shibuya Y. S. Gyoung and Y. Yamamoto J. Am. Chem. Soc. 1998 120 10262. 21 N. Tsukada and Y. Yamamoto Angew. Chem. Int. Ed. Engl. 1997 36 2477. 22 N. Tsukada A. Shibuya I. Nakamura and Y. Yamamoto J. Am. Chem. Soc. 1997 119 8123. 23 I. Nakamura N. Tsukada M. Al-Masum and Y. Yamamoto Chem. Commun. 1997 1583. 24 T. E. Muller and M. Beller Chem. Rev. 1998 98 675. 25 L. Besson J. Gore and B. Cazes Tetrahedron Lett. 1995 36 3857. 26 M. Al-Masum M. Meguro and Y. Yamamoto Tetrahedron Lett. 1997 38 6071. 27 I.W. Davies D. I. C. Scopes and T. Gallagher Synlett 1993 85. 28 W. F. J. Karstens F. P. J. T. Rutjes and H. Hiemstra Tetrahedron Lett. 1997 38 6275. 29 M. Meguro and Y. Yamamoto Tetrahedron Lett. 1998 39 5421. 30 U. Radhakrishnan M. Al-Masum and Y. Yamamoto Tetrahedron Lett. 31 I. Nakamura H. Itagaki and Y. Yamamoto J. Org. Chem. 1998 63 32 C. Bruneau and P. H. Dixneuf Chem. Commun 1997 507 and 33 M. Al-Masum and Y. Yamamoto J. Am. Chem. Soc. 1998 120 34 B. M. Trost and W. Brieden Angew. Chem. Int. Ed. Engl. 1992 31 35 U. M. Dzhemilev and R. V. Kunakova J. Organomet. Chem. 1993 36 S. Kamijo M. Al-Masum and Y. Yamamoto Tetrahedron Lett. 1998 1998 39 1037. 6458. references cited therein. 3809. 1335. 455 1. 39 691. Review 8/06581K 207 Chem. Soc. Rev. 1999 28 199–207

ISSN:0306-0012    

DOI:10.1039/a806581k

出版商:RSC    

年代:1999

数据来源: RSC