The hydrometallation, carbometallation, and metallometallation of heteroalkynes SHARON CASSON" and PHILIP KOCIENSKI Department of Chemistry, The University, Southampton, SO1 7 1 BJ, U. K . Reviewing the literature published up to the end of July 1994 1 2 2.1 2.2 3 3.1 3.2 3.3 3.4 3.4.1 3.4.2 3.4.3 4 4.1 4.2 4.3 4.4 5 6 Introduction Hydrometallation 1-Alkoxy- 1 -alkynes 1 -Phenylthio- 1-alkynes Carbometallation Organolithium reagents Organoborane reagents Organocopper reagents Metallacycles Zirconium-alkyne complexes Tantalum-alkyne complexes Titanium-alkyne complexes Metallometallation 1 -Trimethylsilyl- 1 -alkynes 1 -Alkoxy- 1 -alkynes 1-( Pheny1thio)- 1-alkynes 1 -Amino- 1-alkynes ( ynamines) Conclusion References 1 Introduction The hydrometallation and carbometallation of terminal and internal alkynes (Scheme 1 ) is a powerful method for generating alkenylmetals.The former proceeds well for Al, Zr, B, Sn, and Ge, while Cu and A1 have proved useful for the 1atter.l More recently, metallometallation has emerged as a means of simultaneously generating two adjacent regio- and stereo-defined alkenylmetal bonds of differential reactivity. To date metallometallation has been used mainly to introduce Si or Sn in conjunction with Li, Mg, Al, Cu, B, or Zn. Unfortunately, poor regiocontrol detracts from many hydrometallations and M'-M2 Metalkmetallation H-M 3; * Hydrometallatbn Carbometallatbn r: Scheme 1 metallometallations and in some cases stereocontrol is a problem too. Regio- and stereo-control in carbometallations exhibit a marked sensitivity to proximal heterofunctionalities.In this review we survey the valuable influence of heteroatoms (0, S, N) on the crucial issue of regio- and stereo-control in hydrometallations, carbometallations, and metallometallations of alkynes. 2 Hydrometallation The hydrometallation of alkynes offers the simplest and most direct route to alkenylmetals. There are over 50 potentially useful metals (including the lanthanides and actinides) which participate in the reaction, though in practice only a handful of metal hydrides have found general favour and these include B,2-10 Al,11-14 Zr,15-23 and Sn.24-30 In the case of Sn, Si,31-3x Ge,32,34330 and Mg,4Q-42 the reaction is best achieved under transition metal catalysis. The hydrometallation of unactivated terminal or internal alkynes generally proceeds with clean cis-stereoselectivity initially although isomerization can subsequently take place.On a simplistic level, the uncatalysed hydrometallation of an alkyne involves two principal steps (Scheme 2 ): (i) reversible coordination of the alkyne to a vacant orbital on the metal atom and (ii) insertion of the coordinated metal-hydride bond into the alkyne n-bond. The overall rate of formation of 2 will be related to the product of the equilibrium and rate constants K and k. The concentration of intermediate 1 should decrease as the size of substituents attached to the unsaturated bond increase but the effect can be comparatively small since coordination takes place at the centre of the alkyne bond where steric effects are minimized.On the other hand, the concentration of 1 should increase as the electron density in the n-system increases; hence the 1 2 3 4 X=O,N 5 X=S,P Scheme 2 Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 19presence of electron-donating substituents should favour formation of the intermediate 1 and promote reaction. However, if intermediate 1 is too stable, the In keeping with the vast store of precedent, hydrometallations of 1 -alkoxy- 1 -alkynes adhere to the preference for syn-addition. An apparent exception is second step (insertion) may be slow or precluded alt~gether.,~ regiochemistry of the hydrometallation by polarizing the alkyne bond. In the case of trialkylsilyl and other electron-releasing metal groups, polarization is governed by a-bond hyperc~njugation~~ resulting in stabilization of electron deficiency p to the M-C bond as in 3; hence the metal is attracted to the carbon bearing the silyl group.In the case of mesomeric donors such as N or 0, the metal is attracted to the electron-rich /3-carbon as in 4. Mesomeric donors with non-bonded electrons in the third shell show inverted regiochemistry relative to their second shell siblings. Thus, thio- and phospha-alkynes react as if they were polarized in the sense depicted in 5 . In the following sections we will consider in more detail the hydrometallation of 1 -heteroalkynes R'-C = C-X-R2 where X = 0 and S. The heteroatoms under consideration determine the 2.1 1-Alkoxy-1-alkynes The benefits of increased functional diversity and improved rate and regiocontrol offered by dialkylamino and alkoxy substituents has hardly impinged on hydrometallation chemistry.No doubt one reason for the paucity of data is the comparative instability of 1 -( dialky1amino)- 1 -alkynes and 1 -alkoxy- 1 -alkynes, making them awkward compounds to handle and prepare. Information has mostly been gleaned from reactions with the only alkoxyalkyne which is commercially available: ethoxyethyne. Hydroboration,2.3 hydrozirconation, ' 5.' 7.18 and uncatalysed hydr~stannylation~~ of ethoxyethyne have all been accomplished and in every case the metal became attached to the distal carbon in accord with the electronic effects discussed above. Hydroalumination of somewhat more interesting alkoxyalkynes was investigated by Eisch and co-workers with the same regiochemical consequence.13 An example which illustrates the improved opportunities for exploiting the heteroatom is shown in Scheme 3.Hydroboration of ethoxyethyne3 with diborane gave trialkenylborane 8 which underwent Pdo-catalysed coupling under basic conditions with iodobenzene. The significance of this transformation lies in the effective appendage of acetaldehyde to an sp2 centre-a reaction normally beyond the pale of traditional enolate chemistry. A similar transformation was accomplished using hydrozirconation followed by Nio-catalysed coupling. A synthesis of the aurantioclavine precursor 11 attests to the synthetic utility of the sequence.' The p-alkoxy-alkenylzirconium derivative 10 of ethoxyethyne has also been employed in the two and four carbon homologation of aldehydes;22 thus alkenylmetal 10 adds cleanly to an aldehyde in the presence of silver perchlorate and subsequent hydrolysis provides end 12 in high yield and excellent ( E)-selectivity.the uncatalysed hydrostannylation of ethoxyethyne (Scheme 3 )24 which gives the anti-adduct 9 in excellent yield contaminated with minor amounts of the syn-adduct 7. However, once again this was no exception: the syn-adduct forms as the kinetic product which then easily isomerizes by addition-elimination of stannane. In the case of transition metal catalysed hydrostannylation, only syn-adducts are observed though with diminished regioselectivity. For example, Guibe and co-workers found that the Pdo-catalysed hydrostannylation of ethoxyethyne produced regioisomers 6 and 7 in a 58:42 ratio.25 HIH + EtO SnBuB 6 5 8 : 42 7 Pd', M F Bu3SnH.r.t. I 10 min. PhL P d I 3fr!Y.!E' h I +s 11 Scheme 3 The electronic bias in favour of p-metallation in the hydrometallation of ethoxyethyne amply demonstrated in Scheme 3 is subverted in higher alkoxyalkynes: hydrostannylation of 1 -( benzy1oxymethoxy)- 1 -hexyne 13 (Scheme 4 ) occurs rapidly and efficiently on reaction with 1.1 eq. of Bu,SnH in benzene at ambient temperature in the presence of 1 mol% of Pd( PPh,), to give an inseparable mixture of the a-regioisomer 14 and /?-regioisomer 1 5 ( 14: 15 = 2 : 1 ). However, selective destruction of the p-regioisomer to the (Z)-enol ether 16 occurs on rapid passage of the mixture through a column of basic alumina allowing 20 Contemporary Organic Synthesisisolation of pure 14.Hydrostannylation of a further nine alkoxyalkynes revealed that the preference for the a-regioisomer is general but the regioselectivity is strongly dependent on the size of the alkyl substituents. Bu ‘OBn ca. 100% ‘OBn 13 ‘OBn 14 15 16 Scheme 4 2.2 1-Phenylthio- 1-alkynes Thioalkynes are more stable than their oxygen counterparts in accord with diminished communication between the non-bonded 3 p electron pairs on the sulfur atom and the n-system of the alkyne at level 2. Their improved stability and ease of preparation makes thioalkynes more practical substrates for hydrometallation studies. The phenylthio group is an electron sink and polarizes the alkyne in a sense opposite to that observed with alkoxyalkynes (see Scheme 2 ).The net reversal of polarization determines the regiochemistry of hydrometallation as shown in Scheme 5: there is a strong preference for attachment of the metal to the a-position. With a putative CuH reagent prepared by reaction of stiochiometric amounts of CuBr with LiAlH( OMe),, thioalkyne 19 undergoes syn-hydrocupration (path a) affording the diene 1 8.45946 Furthermore, the same combination of reagents-but with CuBr present in catalytic amounts-accomplished the hydroalumination of alkyne 19 (path b), giving the diene product 17. The regiochemistry of both reactions was determined by deuterolysis experiments. Complementary anti-stereochemistry can be obtained by hydroalumination of 19 with LAH (path c).Kim and Magriotis4’ have prepared the (2)-iodoalkene 2 1 in excellent yield by the hydroalumination of 1-phenylthio-1-propyn-3-0120. In the example shown in Scheme 6, anti-hydroalumination was predominant ( 10 : 1 ). The (Z)-iodoalkene 2 1 served as a precursor to a-phenylthioalkenyl silane 22 via 1,4 0 -+ C silyl migration of an alkenyl-lithium intermediate. 1 -phenylthio- 1 -alkynes undergo easy and efficient Pdo-catalysed hydro~tannylation.~~~~~ Scheme 7 illustrates the procedure and shows that the reaction is both regioselective and stereoselective. Stannane 23 Two groups have recently shown that I AH CUH.L~BPAI(OM~), MF-HMPA 18 Scheme 5 - I1 I (ii) 12, -78 -c I SPh 20 path c LiAIH, (1 eq.) M F , 50-60 OC 1 H r O H 21 (11 TBSCI. DMAP (ii) Bu’Li (2 eq.) Et3N / CH&l2 THF, -78 “c + r.t.I HroH PhS SiMe2But 22 Scheme 6 does not participate readily in Pdo-catalysed cross-coupling reactions but the corresponding a-( pheny1thio)alkenyl zinc reagent 24 reacts with a wide variety of substrates under mild conditions, thus providing a significant enhancement to the cross-coupling chemistry of a-heteroalkenyl metals. Since a-( pheny1thio)alkenes can be hydrolysed to ketones or cross-coupled with Grignard reagents in the presence of Ni’ catalysts, reagent 24 serves as an exceptionally mild substrate for the nucleophilic acylation and alkylation of arenes and hetarenes. The catalytic hydroboration of 24 with catecholborane provides the corresponding (E)-isomer with high regio- and stereo-selectivity Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 21Bu&H TBso PhH, r.t.95% 23 I -78-+0%, 1 h (I) Bu"Li I THF, (io ihBrz/THF. -78 "c. 15 min. SPh Pdo I M F 76% from 23 24 Scheme 7 (Scheme 8). The usual syn addition of the metal hydride occurs with the boron atom sited at the carbon /3 to the sulfur atom.x Cross-coupling reactions with aryl, alkynyl, and vinylic halides occurs with retention of configuration, thus providing a new method for the synthesis of stereodefined vinylic sulfides. 24 SMe Scheme 8 OTBS OTBS I BySnH, Pdo CH c SnBua CH20TBS ___) '11 PhH. r.t. p h - s ~ s n B u ~ Ph,SAH II 0 II 80% PhO'*O 0 2 : l Scheme 9 methodology. Such carbometallations are usually highly stereoselective and they are sufficiently mild in many cases to tolerate the presence of some functional groups.The resultant alkenylmetal can be further transformed in such a way that the overall result is the introduction of two new substituents in a cis manner. The kinetic and thermodynamic effects of proximate heteroatoms in directing carbometallation across C-C multiple bonds have been exploited in organic s y n t h e s i ~ ~ ~ , ~ ~ and their virtues extolled in some of the extensive reviews on carbometallation reactions which are e ~ t a n t . ~ ~ . ~ ~ - ~ ' However, in this review we restrict attention to the activation and regiochemical advantages of heteroalkynes as substrates in carbometallation reactions. 3.1. Organolithium reagents Organolithium compounds are generally too strongly basic to be of appreciable synthetic utility in addition reactions to terminal and unactivated internal alkynes.There are some exceptions however. Kooyman and co-workerss3 showed that prolonged heating of a solution of ethoxyhexyne and hexynyllithium in dioxane at 100°C followed by hydrolysis of the adduct 25 afforded diyne 27 in addition to a small amount of the ether 26 (Scheme 10). The latter compound became the main product when the reaction time was shortened to 12 hours. Rapid trans-elimination of LiOC,H, from the intermediates precluded the isolation of addition products of other alkynylation reactions. Bu dioxane- id Bu-OEt + 100 "C, 12 h - Bu-Li Bu OEt (1 -0 eq.) 25 11""" Alkynes with sulfur substituents in higher oxidation states are also known to undergo hydrometallation.12 h, HZO 70 % -LiiEt The enhanced polarization of the n-system should, if anything, reinforce the regiochemical preference for a-attachment of the metal. Hydroalumination of alkynyl sulfones behave as expected in a regiochemical sense but they give anti-add~cts.'~ However, Pdo-catalysed hydrostannylation of alkynyl sulfoxides Bu OEt exemplified in Scheme 9. - - - H JBU Bu 27:26=4: -:- 26 1 Bu has been reported28 to give mixtures of regioisomers as 26 Scheme 10 3 Carbometallation Perhaps the most cogent illustration of the powerful activating effect of heteroatoms on alkyne The addition of a C-M bond to an unactivated alkyne represents a significant advance in synthetic carbometallation was recently provided by Funk and c o - ~ o r k e r s ~ ~ who discovered that alkylthio- and 22 Contemporary Organic Synthesisalkoxy-alkynes participate in cyclization reactions with a variety of stabilized lithio-carbanions to provide functionalized exocyclic and endocyclic enol and thioenol ethers.Thus, treatment of sulfone 28 with BuLi at 0"C, followed by a methyl iodide quench provided cyclopentene 32 in 96% yield (Scheme 11). The proposed mechanism for the transformation involves trans-carbometallation of alkoxyalkyne 29 by the a-phenylsulfonyl anion to afford the alkenyl anion 30 whose equilibration to 3 1 and regiospecific methylation with methyl iodide furnished 32. The a-methylated sulfone 33 also cyclized smoothly to 32 suggesting that the cyclization reaction was not driven by the formation of stable anion 3 1.However, attempts to trap the vinyl anion intermediates were unsuccessful owing to deprotonation of the solvent (THF ) and ortho-metallation of the phenylsulfonyl moiety. OEt 'k (i) Bu"Li THF,O"C* (1 eq.) yL (ii) Me1 S02Ph 96% S02Ph 28 OEt 29 1 OEt 31 30 ?Et S02Ph (i) Bu"Li (1 .O eq.) THF,-78 -0 "c 88 % 32 33 Scheme 11 High (2)-stereoselectivity was observed in the formation of the exo-adducts, possibly due to an atypical trans-carbometallation reaction or, alternatively, to cis-carbometallation followed by equilibration of the intermediate allyl/a-phenylsulfonyl anion to the (Z)-stereoisomer as a result of stabilization by coordination of the lithium atom with the enol ether heteroatom. Preference for nucleophilic addition at the a-carbon of the alkoxyalkyne moiety was not sufficient to overcome a kinetically favoured attack at the P-carbon leading to a smaller ring system.However, the preferred site of intermolecular attack by nucleophiles on thioalkynes is at the @-carbon; consequently these cyclizations were completely regioselective (Scheme 12). Other carbanion stabilizing groups such as phosphorus ylides, ester and ketone enolates, and cyano-derivatives could be employed in the c yclization. Scheme 13 provides a typical example of carbocyclic annulations highlighting the potential of the carbolithiation reaction in natural product synthesis. YEt , XEt V x=o, 66 : 34 (54%) x=s, loo : 0 (57%) Scheme 12 LDA (2.1 eq.) OH HMPA(5q.) THF b EtO 0 Hp OEt 0 0 P H Scheme 13 3.2 Organoborane reagents In contrast to boron hydrides, triorganoboron compounds do not readily add to alkynes unless exceptionally reactive substrates are employed.For example, 1,2-bis( trimethylstanny1)ethyne reacts quantitatively with triorganoboranes (Scheme 14). Allylboranes, like other allylmetal reagents derived from zinc, boron, magnesium, and aluminium can add to alkynes via a six-centred transition state (metallo-ene reaction) leading to alkenylmetal adducts. However, with simple terminal alkynes allylmetallation is complicated by side-reactions such as hydrogen abstraction which accompanies the allylzincation of terminal alkynes;' 7 s and allylmetallation of internal alkynes fails altogether in the absence of electron-donating groups such as alkoxy substitutents. A case in point is the cis-addition of triallylborane 34 to 1-ethoxyethyne (Scheme 15)58 which proceeds at - 50 --+ 20°C to provide adducts 35,36, and 37 in 85, 80, and 65% yield respectively depending on the ratio of reagents.Cleavage of the B-C bond of compounds 35-37 with alcohols, water, and bases at 20-100°C gave 2-ethoxy- 1,4-pentadiene and thermally-induced cyclization of adduct 35 occurred at 120°C to provide the boracycle 38. Crotylboration of ethoxyethyne also occurs at room temperature to form stable a d d ~ c t s . ~ ~ A rnetallo-ene reaction of tribenzylborane 39 with ethoxyethyne occurs in ether, THF, isopentane, or neat to provide intermediate 40 which ethanolyses to 1-ethoxy-1-o-tolylethylene 4 1 in 79% yield (Scheme 16). Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 23Scheme 14 E'op d 38 l , , t E t O w 0 ri 34 f EtO 47 37 nonanol, r.t.87% 1 Eton Scheme 15 85% EtOCSH 65 % - r;' 35 I / EtO L -9 OEt 39 -p OEt 41 Scheme 16 24 Contemporary Organic Synthesis Wrackmeyer and co-workers60 observed easy cis-addition of triethylborane to alkynylstannane 42 to give adduct 44 via rearrangement of alkynyl borate intermediate 43 (Scheme 17). r 1 BEb hexane -78 "c-+ r.t. SnMe3 65% 42 44 43 Scheme 17 3.3 Organocopper reagents Carbocupration of alkynes by lithium-and magnesium-derived copper reagents can be an efficient means of preparing stereoisomerically pure di- and tri- or tetra-substituted double bonds but the method has some synthetic limitations: (i) internal alkynes are usually inert towards carbocupration; (ii) aryl-, alkenyl-, and alkynyl-copper derivatives do not add to alkynes; (iii) methylcupration of alkynes is sluggish; and (iv) carbocupration of alkynes with secondary alkylcopper compounds has, in some cases, been found to be less regio- and stereo-selective!1*62 Pioneering experiments on the carbocupration of various heteroalkynes carried out by the groups of Vermee~-~~ and N ~ r m a n t ~ ~ more than 20 years ago established that carbocupration of 1 -heteroalkynes is much easier than simple terminal alkynes and that regioselectivity depends on the nature of the heteroatom and its influence on the polarity of the n-system.For example, in 1 -alkylthioalkynes the complementary inductive effect of the P-alkyl substituent and electron-withdrawing effect of the S heteroatom causes location of the copper on the carbon atom adjacent to sulfur in adduct 45 (Scheme 1 8)!3 Improved yields and regioselectivity were achieved when THF was used instead of ether.In the absence of Cu' salts, reaction of Grignard reagents with 1-thioalkynes can lead either to substitution at the sulfur group with the formation of alkynylmagnesium derivatives or proton removal to form allenic sulfides. SMe I (i) PhMgBr (1.1 eq.) CuBr (55 d%) THF H+Me c 20 + 30 OC, 10 min. Ph '1' (b) NH&VNaCN 89% Et L. 45 Scheme 18 A major limitation to the traditional methods for accomplishing carbocupration has been the incompatibility of most functional groups with the highly nucleophilic and basic organomagnesium and lithium reagents used to prepare the requisite cuprates.A significant extension of the synthetic utility of carbocupration with the stereoselective construction of tri- and tetra-substituted alkenes was recentlyachieved by the use of mixed clusters of copper, zinc, and lithium which are gentle enough to tolerate the presence of esters, nitriles, and chlorideP2 The method is illustrated (Scheme 19) by the regio- and stereo-selective addition of the cuprate 46 to 1 -( methylthio )- 1 -hexyne leading to alkenylcopper derivative 47 which reacted with electrophiles such as water, iodine, allylic halides, and trimethyltin chloride to provide stereochemically pure tri- and tetra-substituted olefins in good yields (67-92%). Copper-zinc reagents such as 48 harbouring simple alkyl ligands are more reactive than their functionalized counterparts and add at lower temperature. I n Et02C CU (CN ) Li.ZnM+*Li I allyl bromide (3 eq.) -60 + 0 "C, 1 h (7996) I C I Scheme 19 Addition of the Gilman reagent EtCu to 1 -ethoxy- 1 -hexyne and 1 -diphenylamino- 1 -propyne, catalysed by magnesium bromide, illustrates the influence of mesomeric electron-donation on the regioselectivity of carbocupration. In the case of 1-ethoxy- 1 -hexyne, the reaction is not regioselective due to the conflicting inductive effect of the P-alkyl substituent and the mesomeric effect of the 0 atom (Scheme 20) whereas the analogous reaction with 1 -diphenylamino- 1 -propyne is dominated by the donor properties of the amine substituent, giving rise to exclusive p-metallation (Scheme 2 1).Configurational stability at reflux in THF was observed for alkenylcuprates possessing a S heteroatom and at 20°C for the corresponding N intermediates. Alkoxyalkenyl cuprates, however, undergo facile trans elimination above - 20°C (Scheme 2 1 ). Notwithstanding the less favourable regiocontrol and configurational stability exhibited by alkoxyalkynes compared to the sulfur and nitrogen analogues, Normant and co-workers6s were able to utilize vinylcuprates, prepared via the syn-addition of ' H + Scheme 20 (I) EtCu, MgBr2 (1 eq.) THFEt20, 4 + O ° C , 1 h HO,C (ii) HMPT, P(OEt)3 c r2 -40+20°C,4h Me (72% overall) (Iii) IN HCI, 10 min. Scheme 21 lithium derived dialkylcuprates to ethoxyethyne, in the synthesis of stereochemically pure allylic sulfides as shown in Scheme 22.hCuLi c EtCuLi (0.5 eq.) E t P EtO -50-+-25"C H (I) CICHZSCH, (1.Oeq.) Et2O/THF. -30 "c r.t., 4 h (ii) 5N HCI, -10 OC 76 96 Scheme 22 L Nakamura and co-workers studied the addition of MeLi, MeCu, and Me,CuLi to heteroalkynes using ab initio molecular orbital calculations and found an excellent correlation between experimental regioselectivity and the calculated energies of the regioisomeric transition structures, indicating that the activation enthalpy is an important determinant of regioselecti~ityP~(~) They concluded that a heteroatom substituent controls the regiochemistry of carbometallation mainly by affecting the electron population of the alkyne fragment in the transition state. The addition of MeLi and MeCu to the alkyne were found to proceed through two stages involving the x-complex 49 and the transition structure 50 to the product 5 1 (Scheme 23).No indication of coordination between the heteroatom and the metal was found in any of the transition states, whereas some coordination was found in the products. In addition to their regiochemical influence, heteroatoms increased the rate of carbometallation while alkyl groups retarded the reaction. Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 251- 1 2- RMn WCuBr 1 .o 10.1 1.010.5 1.013.0 Scheme 23 ( E ) (2) 75 25 88 12 99 1 The enhanced reactivity of 1-heteroalkynes allows addition of alkenyl cuprates which are generally less reactive than alkyl cuprates (Schemes 24 and 25).65 Protonolysis of adduct 52 was accompanied by hydrolysis of the enol ether and isomerization of the double bond gave ketone 53 in 75% overall yield whereas protonolysis of adduct 54 gave the acid-stable 1-alkylthio- 1,3-butadiene 55.+ $Lcuu hle (0.5 eq.) Scheme 24 A (0.5 eq.) EtO \ hCuLi THF, 0 "c, 1 h 40+-5"C THF -5 "C, 30 mln. US E> EtS 55 Scheme 25 Carbocupration of 1 -( pheny1thio)ethyne is the first step in a new stereoselective synthesis of trisubstituted alkenes (Scheme 26)."6 Addition of BuLi (2 eq.) to a-( pheny1thio)alkenyl cuprate 56 generated a putative higher order cuprate 57 whose 172-metallate rearrangement occurred with inversion of configuration, leading to the alkenylcuprate 58 and thence to a variety of trisubstituted alkenes via reaction with electrophiles such as iodine, methyl propiolate, and ally1 bromide.Vermeer6' and Truce68 described the easy reaction of 1-alkynyl sulfoxides with organocopper( I) reagents. Reaction of Pr'Cu-prepared from the corresponding 56 57 1- Iu+ 58 Scheme 26 Grignard reagent and 1 eq. of copper( I ) bromide-with 1 -propynylsulfoxide 59 provided syn-adduct 60 in almost quantitative yield (Scheme 27). Attack at sulfur rather than the triple bond occurs with some lithium dialkylcuprates. For example, lithium dimethylcuprate adds normally but the more reactive lithium di-n-butylcuprate gives appreciable quantities of n-butyl ethyl sulfoxide. Similarly, treatment of 1-alkynyl sulfoxides with Grignard reagents in THF at - 70°C results in attack on the sulfur at0rn.6~ S(O)Ph I! (ii) NH,CVNaCN (i) (i 4&H7)Cu (2 eq.YMgBr THF.-70% 15 min. + X3H7 H 95 % Me 59 60 Scheme 27 Mainly polymeric products are formed by the slow reaction of 1-alkynyl sulfones with Grignard reagents in THF at O°C;69 however, Vermeer and co-w~rkers~~ found that Cur-catalyses addition to Grignard reagents to 1-alkynyl sulfones. The stereochemistry depends on the ratio of Grignard reagent to Cu' with high concentrations of Cu' forming the (E)-isomer-Le., syn-addition (Scheme 28). Similar results were observed for methylthioethyne. Discrepancies were also reported in the stereocontrol exhibited in the addition of monoalkylcopper( I ) reagents and lithium dialkylcuprates to 1 -alkynyl sulfones. Lithium di-n-butylcuprate provided an 8 1 O/O yield of the trans-adduct when reacted with ethyl 1-propynyl sulfone whereas n-butylcopper gave a 90% yield of the cis-adduct.6x Scheme 28 26 Contemporary Organic SynthesisNaso and co-workers7' observed that the stereochemistry of the addition of dialkyl- and diphenyl-cuprates to benzenesulfonylethyne depended on temperature, time allowed for equilibration, and the size of the ligands on the cuprates (Scheme 29).Up to 30% of the (2)-isomer was isolated from the reaction of dimethyl- and diphenyl-cuprates at 0°C when the reaction was quenched immediately after mixing of the reagents (entry 2). Equilibration for 30 minutes provided the (E)-isomer exclusively (entry 1). With di-n-butyl and di-sec-butylcuprates 5-20% of the (Z)-isomer was isolated even after equilibration at 0°C. At - 78°C almost no stereoselectivity was observed (entry 4).Absolute stereocontrol was achieved with di-t-butylcuprate to form the (2)-isomer even at lower temperatures (entries 5,6). Two possible explanations were cited for the inconsistent stereochemistry: the presence of two different reaction pathways with two different activation energies and/or isomerization of the two intermediates. 1 2 3 4 5 6 c R-CU - Me 0 30 100 Me 0 a 20-30 80-70 Blf 0 0.5 5 95 Blf -78 0.5 42 58 100 But -30 10 But -78 0.5 100 - - PhSOp HH H R R-CU ] i4 PhSOp HR H H Entry I R T "C Time(min.) (Z) (0 Scheme 29 Eisch and co-workers14 were able to effect the syn-carbocupration of phenyl trimethylsilylethyl sulfone in high yield using lithium dialkylcuprates (LiCuR,, R = Me, Ph, allyl) as illustrated in Scheme 30.(i) Me&uLi (1.25 eq.) THF. -78 "c, 1.5 h Me3si)fPh Me (ii) MeOH. -78 "c. NH4CI SiMes 95% Scheme 30 Treatment of phospha- and thiophospha-alkynes with an excess of alkyl Grignard reagent in the presence of an equimolar amount of copper( I ) chloride provides alkenylphosphine sulfides with excellent regio- and stereo-~ontrol.~~ (Scheme 3 1). E Me2P+s (i) EtMgBr (%7 eq.) - Me2pHEt CU2cI2 (1 eq.) EtzO. d U X . 4 4 h '1' (ii) NH4CW0 H Ph Ph 95 % Scheme 31 Recently, a similar protocol was applied to a,b-alkynylphosphonates to form the corresponding disubstituted vinyl phosphonates in accordance with the well established syn-selectivity of addition and p-placement of the alkyl s~bstituent~~ (Scheme 32). ( EtO)2P50 111 C3H7 Scheme 32 (i) PhMgBr (5 eq.) cu2c12 (1 ea.1 88% 8 (Et0)2pHc3H7 H Ph Vermeer and co-workers investigated the behaviour of 1 -alkynyldiphenylphosphines towards organocopper( I ) compounds in THF and found that addition of 6 1 occurred in the presence of R,Cu.MgBr or RCwMgBr, (Scheme 33):' Exclusive syn addition and high regiocontrol (exclusive attack of the R group at the p-C) was obtained.The transfer of only one of the two R groups from the homocuprate R,Cu.MgBr to the alkynylphosphine is notable because, in similar additions to l-alkynyl sulfides, both R groups are transferrable. PPh2 I 'I' the 61 EtCuMgBr2 (1.25 eq.) THF, 20-25 "C, 60 dn. 100% EtfiuMgBr (I .1 eq.) MF,-60+20"c 30 min. 100% t + Ph2 Et CuMgBr2 MeB: Et Scheme 33 The vicinal difunctionalization of acetylenes bearing an organoseleno group has recently been reported by Braga and co-worker~.~~ Reaction of lithium Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 27butylcyanocuprate with 62 (Scheme 34), followed by capture of the intermediate alkenyl cuprate with several electrophiles led to di- and tri-substituted vinylic selenides in acceptable yields.In all the cases studied, only one regioisomer was obtained-a consequence of carbanion stabilization by the selenium atom. The major stereoisomer corresponded to syn addition of the organocuprate, although in some cases, an example of which is shown in Scheme 34, the product 63 derived from the anti-adduct could be detected. B",N/\- 1 - 62 63 Scheme 34 BuLi (4.2 rnml) THF,-78%,1 h 3.4 Metallacycles The formation of metallabicycles via intramolecular reductive coupling of enynes has received much attention in recent years.7s Low-valent metallocenes (MPc,, where M = Ti, Zr, Hf) form titana-, zircona- and hafna-cycles respectively. These metallabicycles are versatile intermediates which can be elaborated into a wide range of mono-and bi-cyclic organic compounds via protonolysis, iodinolysis, and carbonylation.Efficient cyclization is enhanced by the presence of a substituent boosting the alkene nucleophilicity, the most common being the silyl group, although tin, germanium, carbon, and hydrogen have been employed. Both electronic and steric effects control the regiochemistry of the reaction but insertion often occurs at the more sterically-hindered position, which highlights electronic control as being the dominant factor.76 3.4.1 Zirconium-alkyne complexes Alkyne autodimerization, a significant side-reaction in metallocylizations, is limited by the use of 1 -trimethylsilylacetylenes, but additional difficulties arise from competitive displacement of the bulky silyl ligand prior to coupling.77 Van Wagenen and Livingh~use~~ found that the complexation of strongly ligating 1-methylthioalkynes, e.g. 64 (Scheme 35), led SMe MeS / C6H13 65 I (L=THFO~ -1 PhNCO, THF -20+25"C.l2h 51 % I 66 Scheme 35 to the generation of zirconacyclopropene 65 with a minimum ( < 3%) of dimer formation. Insertion of electrophiles, an example of which is shown in Scheme 36, followed by protonation provided the adduct 66 in good yield.The regiochemistry of the insertion is consistent with a transition state involving internal MeS -+ Zr complexation. Whitby and co-workers recently reported a zirconocene-mediated synthesis of 3,4-disubstituted piperidines and reduced isoquinolines using a methylthio activated alkyne (Scheme 36).78 Reductive coupling of the diyne 67 and protolytic workup formed the piperidine 68 containing an (E,E)-exocyclic diene moiety which was further elaborated via cycloaddition chemistry to form 69. Cp&Clp (2.1 mmol) Bn b- ' -78 %+r.t., 3 h -BuH, -- 67 69 SMe -Me Scheme 36 3.4.2 Tantalum-alkyne complexes Unsymmetrical tantalum-alkyne complexes react with carbonyl compounds to produce two regioisomeric allylic alcohols in varying ratio depending on which tantalum-carbon bond of the tantalacyclopropene inserts the carbonyl compound (Scheme 37).75-76 The enhanced electron density imparted by the methylthio moiety gave exclusive reaction at the P-position of the methylthio substituent (entry a).In contrast, the reaction between the zirconocene- 1 -( methy1thio)- 1 -alkyne complex and carbonyl compounds produced a 1 : 1 regioisomeric mixture.77 The resonance effect of the phenyl group in phenylthioalkynes weakens the influence of the sulfur on regioselectivity (entry b). The proportion of a-adducts also increased when sulfonyl-substituted acetylenes were employed (entry c). Reactivity of alkynes toward the low-valent tantalum in the formation of tantalum-alkyne complexes was directly proportional to the electron density of the triple bond and decreased in the order: R'C = CSR2 > R'C = CR2 > R'C = CS0,R2 - R'C = CC0,R2.3.4.3 Titanium-alkyne complexes The cyclization of several heteroatom-containing diynes was investigated by Nugent and co-workers using both titanium and zirconium based reagents.'' 28 Contemporary Organic SynthesisC10H21-R (9 Tact5 Zn, DME PhH. 25 %, t (h) (ii) THF.pyr. (a9 Ph(CH2)&HO I 25 %, 30 min. Ph x A NaOH. H@ 25%. 1 h I + c'oH=e, H B Ph Entrv R t fhl A:B Yiild f%\ a SMe 0.2 99: 1 73 b SPh 0.5 77 : 23 85 c SO#e 2.5 54 : 46 54 Scheme 37 Noteworthy, differences in selectivity were observed in the nominally isoelectronic reagents. In the case of the bis-alkoxyalkyne 70 (Scheme 38), the titanium reagent was found to be superior to the zirconium reagent with the desired cyclized product 7 1 produced in 63% yield.(i) cp2Tci (1.3 q.1 PP hpMe (1.6 eq.) Na(0.596 Hg) (3.4 eq.) ?Et ( Y o E t [THF,457-25%. 15min.! (ii) -25 "c, 3 h - OEt (iii) 10% H,SO, 63% 70 OEt 71 Scheme 38 4 Metallometallation Metallometallation of alkynes introduces two carbon-metal bonds in a single step thereby creating the opportunity for selective chain extension on adjacent carbons. Metallometallations usually involve bimetallic reagents of the type R3Si-MR,7 or R,Sn-MR, in which M = B, Al, Mg, Mn, Cu, Zn, Si, or Sn. A noteworthy feature of these reagents is their low basicity. In many cases metallometallations can be performed on substrates which contain functional groups such as hydroxyl, ester, amine, and halide. Metallometallation reactions can be divided into four categories depending on the nature of the bimetallic reagent: (i) stoichiometric metallo-cuprations: Ge-Cu26 Sn-Cu80-97 si_cu;84,~2,~4,~6.~8- 102 (ii) metallometallations with Cur catalysis: sn-zn103- 10s Sn-A182, 103,104,106- 108 Sn-Mg82,103,104,108 Sn-B 108- I 10 Si-BI 10 Si-Al4 1,106 Si-Zn41.106 Si-Mg;4 1,1 I I (iii) metallometallations with other transition metal catalysts: Si-B/Co"' Sn-B/Co1I0 Si-Si/Mnl SnSn/MnIo3 Sn-Mg/Pd123 Sn-A1/PdIo3 Sn-Zn/Pd lo3 Sn-Sn/Pd82,106,1 13-117 Si-Mg/PdlOh,l I1,117 Si-Al/Pd106,1 I ] , I 17 Sn-Si/pd82,1 15.1 18.1 19 Si-Si/Pd31,36,120- I26 Ge-Ge/Pd36 B-B/Pt; I 27 (iv) uncatalysed metallometallations: Te-Te 1 2 8- 1 3 1 Si-Ti.132 Although terminal alkynes metallometallate with a high degree of regio- and stereo-control,' 33 internal alkynes usually require the presence of some activating group such as C02R, to achieve useful control.87J 16~134 In addition to the inherent bias in the bimetallic reagent, the regio- and stereo-chemical outcome of the reaction may be influenced by the catalyst employed, reaction conditions, solvents, Lewis acids, and the presence of suitable functional groups on the substrate.I,l l6 Unsymmetrical alkynes in which one of the substituents is a heteroatom (Si, 0, S, N) present a potentially valuable method for controlling the regioselectivity of metallometallations through mesomeric, inductive, or coordination effects.A particularly attractive feature of the metallometallation of heteroalkynes is the opportunity for further elaboration to synthetically valuable heteroalkenes provided (a) the addition is regioselectivs and (b) the two C-metal bonds can be selectively and sequentially replaced by electrophiles as depicted in Scheme 39.In the following sections the relatively small amount of data which describes the influence of Si, 0, S, and N substituents on the regiochemistry of various metallometallation reactions are examined. Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 29R2 a H 1w:O 78% b n-C6HI3 1w:o 58% c CH2OH 0:lOo 75% d CH2CH20H 0:loo 44% o CH2CH20THP 1w:O 72% 1 f CH2CH2CH20H 1w:o 74% R ' i m8H17 Hwm8H'7+ 4 + Bu3Sn-SnBu3 H SnBu3 80 Scheme 39 f 4.1 1-Trimethylsilyl-1-alkynes Oshima et al. investigated the Cut-catalysed reaction of 1 -trimethylsilyl- 1 -alkynes with the silylzinc reagent (PhMe,Si),Zn (Scheme 4O).lo6 The reaction was highly regioselective and invariably gave 1,2-disilyl- 1-alkenes regardless of the alkyne substituent.However, the stereochemistry depended on the presence of proximate hydroxyl groups. 1-(Trimethylsily1)-1 -octyne 72b and 4-( 2-tetrahydropyrany1oxy)- 1-( trimethylsily1)- 1 - butyne 72e gave syn-adducts which afforded the ( E ) - 1,2-disilyl- 1-alkenes 73b,e on workup. However, 3-( trimethylsilyl)-2-propyn- 1-01 72c and 4-( trimethylsilyl)-3-butyn- 1-01 72d provided the anti-adducts which protonated to give the (2)-isomers 74c,d. The authors postulated that the initial addition proceeds with syn-stereochemistry but that isomerization later occurs driven by intramolecular coordination of the hydroxyl group to the zinc atom.The chelation effect disappeared when the hydroxy group was separated from the alkyne by three carbons, 72f leading to the expected syn-adduct exclusively. 72 t+f ( E ) : ( Z ) Yield I I R Scheme 40 4.2 1-Alkoxy- 1-alkynes Scheme 4 1 outlines the stannylcupration of 1 -alkoxy- 1-alkynes which draws attention to one of its major limitations: reversibility. In principle the adducts 79 and 77 could be trapped in situ by a suitable electrophile, giving trisubstituted alkenyl stannanes as products. However, in practice, most electrophiles react preferentially with the bimetallic reagent rather than the adduct. Extensive chemical and NMR studies by Cabezas and Oehlschlagerx5 on the stannylcupration of terminal alkoxyalkynes has finally H -0C8H 17 75 ( BU~S~)~CU(CN) U2 + 30 Contemporary Organic Synthesisprovided conclusive evidence for the mechanism of the reaction, as well as an explanation for the presence of a number of by-products in the reaction.Reaction of 75 with 76 in THF at - 40°C followed by warming to 0°C and methanolysis gave a mixture of regioisomers 78 and 80 in a 4:6 ratio in 42% yield. The kinetic product of addition at - 78°C corresponds to intermediate 79 which rapidly equilibrates with 77. Addition of the alkoxyalkyne 75 in the presence of a protic source such as MeOH, to the higher order cuprate 76 at - 78°C results in protonolysis of intermediate 79 before equilibration with 77 is possible, thus providing regioisomer 80 in 95% yield.Selective protonation of the alkenylcopper intermediates 79 and 77 occurs because they are more basic than Me,Sn(L)CuLi thereby forcing the equilibrium to the right. Cox and WudP' estimate the CuH conjugate acid of a stannylcuprate has a pK, of about 5. When the reaction is performed at 0°C in the presence of HMPA and the absence of a proton source, a mixture of 78 and 80 were isolated in 94% yield with a regioselectivity of 95:5 in favour of 78. Similar results were obtained in the reaction of (Bu,Sn)Cu( CN)Li with alkoxyalkynes, although the presence of HMPA was necessary to prevent decomposition of the copper reagent at 0°C. The regioselective formation of 7 7 under these conditions is presumed to be favoured by intramolecular interaction between the oxygen and the copper. In contrast, the reaction of the dithiane derivative 8 1 (Scheme 42) under kinetic conditions, provided 82 and 83 in a ratio of (41 :59) in favour of 83. The anomalous regioselectivity was attributed to coordination between Cu and S leading to preferential formation of regioisomer 83.81 \ (Bu$n)&u(CN)LI2 -78 "c, THF 89 % I 82 41 :59 83 Scheme 42 Despite the complexity of the stannylcupration reaction, the regiochemistry of the reaction can be tuned by deft manipulation of reaction conditions as illustrated in Scheme 43. In order to avoid the problem of regioisomeric mixtures in reversible metallocupration reaction^,^^ Casson' 3s investigated the irreversible Pdo-catalysed stannylstannylation of 1 -alkoxy- 1 -alkynes under conditions which had already been established for H-O--(CH~)SOTBS condition5 + (4 or @I ( BU~S~)~CU(CN)L~ HHO-(CH2J50TBS H SnBu3 A + Bu3Sn Hw:-(cHd50m B ..=ondltlons I Batia I Ymld(%) I T("C.1 solvent A:B (a) 0 THFRiMPA 10 : 90 91 (b) -78 TH F Scheme 43 simple terminal alkynes.82,' l4 Stannylstannylation of 1-alkoxy- 1-alkynes 84 (Scheme 44), for example, readily occurred on reaction with Me,Sn-SnMe, in benzene in the presence of 2 mol% Pd(PPh,), and galvinoxyl (added to retard radical-induced isomerization) at ambient temperature to give syn-adduct 85 in good yield. Me PdlPPhh ( 2 d %) ~ Y" galvinoxyl (cat.) 12 (1.1 e9.1 * I .SnMe3 PhH. 3 h. r.t. Y '0' 'SnMe, n I fie& I 84 A 85 Scheme 44 The regioselectivity of silylstannylation was then examined in the hope that any regiochemical differentials could be amplified with more dissimilar metals.Surprisingly, alkoxyalkyne 86 (Scheme 45) reacts very easily with Me,%-SnMe, in benzene using Pd( PPh,), as the catalyst to give syn-adduct 87 as a single regioisomer in 90% yield in which the tin atom is located on the a-carbon adjacent to the oxygen substituent. * c6H13KsiMe3 PdPPh,], Me&i-SnM& galvinoxyl (cat.) PhH. 3 h, r.t. EtO SnMe3 OEt 9 w o 86 87 Scheme 45 The results of Casson described above contrast sharply with those of Ito and co-workers136 who showed that 1-ethoxy- 1-propyne undergoes silylstannylation using Pd( OAc), and 1 , 1,3,3-tetrarnethylbuty1 isocyanide (Scheme 46) to give syn-adduct 88, in which the tin atom is located on Casson and Kocienski: The hydrometallation, carbometallation, and metallometallation of heteroalkynes 31the B-carbon remote from the oxygen substituent, as the major product.Regioselectivity in excess of 95:5 is typical of reactions involving the bulky reagent t-BuMe,Si-SnMe, whereas Me,%-SnMe, added with poor regiocontrol. The a-silylated enol ethers are amenable to further chemical manipulation as illustrated in Scheme 46. The complementary results observed by Ito and Casson suggests that the regioselectivity of other metallometallations might be tuned by simply varying the catalyst. I ~R Yield 90 H-OEt Pd(0AC)Z (0.04 q.) Bu'Me$ISnM* (1.3 eq.) Bu'CH&(M~)~NC (0.3 eq.) toluene. 24 h. r.t. 99% w Me3SnYH ' + eutMeaiYH Suh2Si AOEt Me3SnAOEt 88 95:5 PhCOCl 1 eq.) PdCI&H&N)2 (5 m ~ l % ) UCI*H20 (5 eq.) MeCN.70 "c, 30 rnln. 89% - 0 0 H,O Ph uSiMe2But 74 % Ph Scheme 46 4.3 1 -(Phenylthio)- 1 -alkynes Silylstannylation of 1 -phenylthio- 1-alkynes 89a-f with Me&-SnMe, in the presence of Pd(PPh,), occurs with the same regioselectivity as the alkoxy series described above but the reaction is more sluggish (Scheme 47).135 Up to 30 h at reflux is required to produce the R L S i M e 3 89 90 Scheme 47 OTHP 80% OH 77% OMe 78% P f 62% pPhCGH4C02 76% (CH212OH say0 silylstannanes in yields of 1 1-58%. A substantial improvement can be obtained without sacrifice of regioselectivity by using Pd,(dba), (2 mol%) in the presence of tri-2-furylphosphine (4 mol%) in Now the reactions only require 2 h at r.t. and give the silylstannane adducts in 56430% yield.4.4 1-Amino- 1-alkynes (ynamines) Ricci and co-workerslo2 recently described a highly regioselective silylcupration of N,N-diphenylaminoethyne 9 1 (Scheme 48) in which the copper atom is placed at the a-position next to the heteroatom-a result which appears to be opposite to the trend set by alkoxyalkynes. However, in this case it is likely that the regiochemistry is governed by internal coordination of the copper by the amino group in adduct 92. Ph2N -H ... 91 Scheme 48 92 (0 Me1 (1 eq.) -23OC.3h (ii) NH&I I NH3 Ph2NYe H ~ H 5 Conclusion In this review we have shown that heteroatoms both activate and control the regiochemistry of a wide variety of additions to alkynes leading to synthetically valuable heteroalkenylmetal derivatives. 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