8 Synthetic methods By N. J. LAWRENCE Department of Chemistry UMIST PO Box 88 Manchester UK M60 1QD 1 Introduction The predominant theme of new synthetic methods this year has been the development of cleaner reactions and transformations. Methods that detail asymmetric catalysis and selective processes have as in recent years been prominent in 1996. The importance of such methods is highlighted in two reviews covering the industrial manufacture of enantiomerically pure pharmaceuticals and agrochemicals.1,2 The number of reports describing combinatorial chemistry and organic chemistry on solid supports3 has increased this year and has included some very useful reviews.4,5 An excellent collection of reviews provides an interesting overview of many frontiers in organic synthesis.6 Specialist reference works published in 1996 include volume 487 of Organic Reactions which reviews asymmetric epoxidation of allylic alcohols the Katsuki–Sharpless epoxidation reaction,7a and radical cyclisation reactions.7b Books covering synthetic methods published this year include those on asymmetric synthesis;8,9 organic synthesis; 10 organosulfur reagents;11 total synthesis;12 b-amino acid synthesis;13 palladium reagents;14 organozinc reagents.15 2 Carbon–carbon bond formation The nucleophilic allylation of aldehydes and ketones is a reaction that has seen great attention over the period covered by this review.Many of these methods involve asymmetric allylation,16 a topic that has been reviewed this year. For example Kobayashi and co-workers have developed a very e¶cient protocol for the asymmetric allylation of aldehydes using phosphoramides as substoichiometric catalysts.17 The best results were obtained for the reaction of benzaldehyde and allyltrichlorosilane with the catalyst 1 derived from (S)-proline (Scheme 1a).Kobayashi et al. have also found that the trichloroallylsilane 3 is a useful precursor in the synthesis of a- methylene-c-lactones 5 (Scheme 1b).18 The allylsilane 3 was prepared from methyl a-(bromomethyl)acrylate 2 in the presence of copper(I) chloride and diisopropylamine. The intermediate 3 reacts with aldehydes to give the corresponding a-methylene-c- hydroxy esters 4 which readily cyclise to the lactones 5 upon treatment with acid. It is not often that reports appear describing asymmetric catalysis using a silver Royal Society of Chemistry–Annual Reports–Book B 249 Cl3Si Ph OH N P N Pri 2N O CO2Me Br CO2Me SiCl3 R OH CO2Me O O R PhCHO (10 mol%) –78 °C 168 h 83% 88% ee HSiCl3 cat.CuCl 2 3 RCHO DMF–CH3CN 0 °C 5 71% for R = Ph H+ 4 Pri 2NEt Et2O (a) (b) 1 Scheme 1 SnBu3 Ph OH PhCHO ( R)-BINAP•AgOTf (5 mol%) –20 °C THF 75% 92% ee Scheme 2 catalyst. However a particularly e¶cient process for the catalytic asymmetric allylation of aldehydes using a chiral silver(I) complex has been described by Yamamoto and co-workers.19 Having screened a range of metal catalysts and found that the e¶ciency of the silver trifluoromethanesulfonate (triflate)-catalysed allylation of benzaldehyde is greatly improved by the presence of triphenylphosphine the group developed an asymmetric process. The catalyst BINAP·AgOTf prepared from 2,2@-bis(diphenylphosphino)- 1,1@-binaphthyl (BINAP) and silver(I) triflate gives the highest enantioselectivity in the reaction of methallyltributyltin (Scheme 2).Although the catalytic mechanism has not yet been fully elucidated the BINAP·AgOTf complex is thought to act as a chiral Lewis acid rather than as a precursor to an allylsilver reagent. The enantioselective addition of tributylallylstannane to aldehydes is known to proceed particularly e¶ciently with the (R)- or (S)-BINOL (binaphthalene-2,2@-diol) and Ti(OPr*) 4 . Faller et al. have developed a cheaper alternative process that avoids 250 N. J. Lawrence Bu3Sn Ph OH Ti(OPri)4 (0.3 equiv.) PhCHO –23 °C 70 h 6 (1.1 equiv.) 7 63% 91% ee (±)-BINOL (0.2 equiv.) D-DIPT (0.3 equiv.) Scheme 3 O SiMe3 O NH Ph Ph COCF3 Me3SiO NH Ph Ph COCF3 O Sn O O Sn O O O CO2But CO2But Br HO HO CO2But CO2But 10 (1 equiv.) (2 equiv.) (2 equiv.) 11 95% de 89% TMSOTf (0.1 equiv.) TfOH (0.1 equiv.) 10 (b) DBUH+ DBU 8 9 (a) Scheme 4 the use of very expensive resolved BINOL.20 They showed that there is a non-linear relationship between the enantiomeric excess of the product and the BINOL catalyst.Exploiting this finding they showed that a catalyst prepared from racemic BINOL–Ti(OPr*) 4 and D-diisopropyl tartrate [(DIPT)–Ti(OPr*) 4 ] (both of which are poor catalysts on their own) was e§ective for the process (6]7) (Scheme 3). The addition of the (DIPT)–Ti(OPR*) 4 poison appears to deactivate the (R)-BINOLderived catalyst far more e§ectively than the (S)-BINOL-derived catalyst. Mazaleyrat and Wakselman have developed a new procedure for the resolution of BINOL and 2,2@-bis(bromomethyl)-1,1@-binaphthalene.The diastereoisomeric ethers from the Williamson reaction of these compounds can easily be separated by crystallisation or chromatography; the parent compounds can be regenerated by treatment with boron tribromide.21 The chiral allylating reagent 9 readily generated in situ from the benzodioxastannole 8 allyl bromide (])-di-tert-butyl tartrate and 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU) smoothly reacts stoichiometrically with aromatic aldehydes at [78 °C in the presence of a catalytic amount of a copper salt to a§ord the corresponding homoallylic alcohols in high yields with high enantioselectivities (Scheme 4a).22 The 251 Synthetic methods BaCl Ph H NBn NHBn Ph NHBn Ph a at 0 °C 74% a:g >99:1 at –78 °C 94% a:g <1:99 g Scheme 5 new 2-amino alcohol derivative 10 and its application in the stereoselective allylation of ethyl methyl ketone has been described by Tietze et al.23 The allylation of ethyl methyl ketone with allyltrimethylsilane is catalysed by 10 allowing the synthesis of tert-homoallylic ether 11 with high enantio- and diastereo-selectivity (de 89%) (Scheme 4b).Many non-asymmetric allylation procedures have been developed in the past year. For example Aggarwal and Vennall24 have found that scandium triflate (2–10 mol%) is a highly e¶cient catalyst for the addition of allyltrimethylsilane to both aromatic and aliphatic aldehydes. Kobayashi and Nagayama have shown that scandium(III) chloride supported on Nafion (NR-50) catalyses the allylation of aldehydes with tetrallylstannane in a continuous flow system.25 Young and co-workers also describe a convenient allylation procedure.26 They have found that tetrallyltin adds to aldehydes in methanol at 30 °C with no additional catalysts.Tin-mediated addition of allylic bromides to aldehydes leads to adducts with high diastereo- and diastereo-facial selectivity in the presence of indium trichloride in water.27 Trehan and co-workers demonstrate that the Brønsted acid bis(fluorosulfuryl)imide catalyses the addition of allyltrimethylsilane to carbonyl compounds.28 The e§ective allylation of aldehydes ketones and imines is accomplished by allylic tributyltin species in the presence of SnCl 2 in acetonitrile solution.29 Aldimines are transformed into homoallylic amines by treatment with allylbarium reagents.30 The a- and c-adducts are selectively obtained by simply changing the reaction temperature; the a-adduct is favoured at 0 °C while the c-adduct is favoured at[78 °C (Scheme 5).A mild and simple zinc-promoted Barbier-type allylation of aromatic aldehydes in liquid ammonia has been published by Makosza and Grela.31 The authors comment that procedures involving liquid ammonia are often considered inconvenient; however they argue that their procedure is simple and convenient. The ammonia is introduced into a cold reaction flask (dry ice–acetone) and the reaction temperature is kept constant at [33 °C by allowing the ammonia to evaporate slowly. The use of ammonia on a large scale is also convenient since it is cheap readily available and easily recycled. Whitesell and Apodaca detail a procedure for the allylation of aldehydes with allyltributyltin in the presence of 10mol% dibutyltin dichloride and either an acid chloride or trimethylsilyl chloride.Homoallylic esters carbonates trimethylsilyl ethers and alcohols were obtained in up to 99% yield.32 The use of bis(penta- fluorophenyl)tin dibromide as a catalyst for the same reactions has been described by Otera and co-workers.33 252 N. J. Lawrence Ph H O HO Ph ButOK (10 mol%) DMSO 70% Scheme 6 The Lewis acid-mediated reaction of an aldehyde with allylstannanes and allylsilanes is usually faster than the reaction of the corresponding imine. Yamamoto and co-workers outline a reaction with the entirely opposite chemoselectivity.34 They found that imines are allylated chemoselectively in the presence of aldehydes using allylstannanes with a p-allylpalladium chloride dimer catalyst.Kang and co-workers report the palladium-catalysed carbonyl allylation of aldehydes with allylic phosphates35 and diethylzinc in the presence of catalytic Pd(PPh 3 ) 4 probably via addition of a nucleophilic allylzinc species to the aldehyde. Several new methods involving the nucleophilic addition of alkynes to carbonyl compounds have appeared this year. A useful procedure for the addition of terminal alkynes to ketones has been devised by Babler et al.36 Examination of the equilibrium acidities in DMSO of phenylacetylene (pKa \28.7) and tert-butyl alcohol (pKa \32.2) indicated that potassium tert-butoxide would be a good choice in the alkynylation reaction. This turned out to be true (Scheme 6).Indeed since the product of the addition to the ketone is initially a tertiary alkoxide the base can be used catalytically. The procedure clearly has advantages over the strong bases used traditionally to facilitate this transformation. Yoon and co-workers have found that sodium trimethyl(ethynyl)aluminate (STEA) prepared from sodium acetylide and trimethylaluminium is an excellent chemoselective reagent for the addition of acetylide anion to ketones and aldehydes.37 The reagent did not react with representative alkyl or benzyl halides epoxides amides or nitriles at room temperature or esters at 0 °C. Zwierzak and Tomassy report a procedure for the reaction of alkynylmagnesium bromides with paraformaldehyde thereby avoiding the use of gaseous formaldehyde. 38 An excellent method for the enantioselective synthesis of alcohols involves the asymmetric catalytic addition of an organometallic reagent usually organozinc to an aldehyde.This area of research is proving as popular as ever (Fig. 1). Some of the new catalysts used to promote the addition of diethylzinc to aldehydes include the diselenide 11 the proline-derived b-amino disulfide 12,39 the oxazolidine derivative 13,40 the oxazolidine 14 derived from the natural product abrine41 and the zinc alkoxide 15.42 While much research has focused on the catalytic asymmetric addition of dialkylzinc species to aldehydes much less attention has been paid to the corresponding addition to imines. This is somewhat surprising in view of the synthetic importance of enantio pure amines. This year Andersson et al. have investigated the addition of diethylzinc to the diphenylphosphinoylimine 16.43 The aziridino alcohol 18 was the ligand that gave the best enantioselectivity in the synthesis of the phosphinoylamine 17 (Scheme 7).The use of alkylzinc chemistry for the highly e¶cient enantioselective catalytic asymmetric automultiplication of chiral pyrimidine alcohol 20 has been impressively described by Soai and co-workers.44 This is a rare case of a catalytic reaction that uses 253 Synthetic methods Se)2 N S S N Me N Me NH O Ph Ph HO NH MeN O nPr Ar Ar O O Ph Ph Zn 11 ( S) 1 mol% 91% 98% ee 12 ( R) 2.5 mol% 76% 86.6% ee 13 ( S) 6 mol% 95% 100% ee 14 ( S) 10 mol% 58% 60% ee 15 ( R) 10 mol% 89% 98% ee Fig. 1 Selectivity in the addition of ZnEt 2 to PhCHO [configuration of PhCH(OH)Et catalyst mol% yield ee] Ph O P N Ph Ph Ph O P HN Ph Ph N OH CH2Ph 16 17 63% 94% ee Et2Zn 18 (1 equiv.) 18 Scheme 7 the product as catalyst.In such reactions separation of the product and catalyst is clearly not an issue. In addition once the first reaction has been performed the catalyst will be readily available. Soai and his group found that the addition of diisopropylzinc to pyrimidine-5-carbaldehyde is catalysed by the product of the reaction the alcohol 20. When the reaction is performed with enantio-enriched 20 (93.4% ee) the stereoreplication is highly e¶cient giving the product 20 with the similar enantio purity (90.8% ee) (Scheme 8a). The process recently highlighted,45 has been described as a paradigm for the origin of the homochirality of natural biomolecules since it was found that when 20 (5% ee) is used as the catalyst the product alkanol has an enantiomeric excess of 39%.46 The process therefore provides a mechanism by which a small initial imbalance in chirality can become overwhelming.The same principle of asymmetric autocatalysis has been demonstrated in the reaction of diisopropylzinc with quinoline- 3-carbaldehyde.47,48 Another organozinc reagent the carbenoid species XZnCFBr 2 prepared by treatment of tribromofluoromethane with diethylzinc reacts smoothly and chemoselectively with aldehydes (Scheme 8b).49 The method described by Shimizu and co-workers is a good one for the synthesis of a a-dibromofluoromethyl alcohols. Secondary and 254 N. J. Lawrence N N H O N N N N OH Bun H O O Bun CFBr2 O OH 20 (93.4% ee) (20 mol%) Pri 2Zn 0 °C 19 20 79% (90.8% ee) CFBr3 Et2Zn (a) 69% (b) OH DMF –60 °C 14 h Scheme 8 Scheme 9 tertiary alkylzinc bromides have been found to add conjugatively to a,b-unsaturated ketones in the presence of trimethylsilyl chloride and BF 3 ·OEt 2 without a copper catalyst.50 Greeves and Pearce have illustrated in two reports that novel organocerium reagents incorporating TADDOL (a,a,a@,a@-tetraaryl-1,3-dioxolane 4,5-dimethanol) can be used to generate enantiomerically enriched alcohols from aldehydes.It was found that the tris(TADDOL) derivative 21 can be used to add a butyl group to aldehydes with enantioselectivity (Scheme 9)51 much higher than when the complex 22 with only one TADDOL ligand is used.52 Procedures that involve organocerium reagents are somewhat capricious. This behaviour is associated with the activity of anhydrous CeCl 3 which depends strongly on the drying procedure.Two reports illustrate this particularly well. Dimitrov et al. have shown that deactivation of CeCl 3 occurs during the drying process as a result of hydrolysis by the hydrate water when heating above 90 °C. The highly active CeCl 3 prepared by an improved drying procedure (sequential heating at 50 °C 4 h; 60 °C 4 h; 70 °C 5 h; 80 °C 7 h; and 140 °C for 20 h at 0.05–0.01 Torr) is demonstrated to activate rapidly (in catalytic and stoichiometric amounts) ketones at room temperature providing excellent addition of 255 Synthetic methods R OSO2CF3 O O O H O O R OH i. CrCl2 (15 mol%) ii. TBAF 80% Mn TMSCl Scheme 10 Scheme 11 organometallic reagents.53 Dehydration of CeCl 3 (H 2 O) 7 by the usual procedures (150 °C at 0.03 Torr for 12 h) has been shown by X-ray di§raction studies to produce [CeCl 3 (H 2 O)]n.54 The evident di¶culties in obtaining anhydrous CeCl 3 may explain the unpredictable reactivity sometimes encountered in its use.The Nozaki–Hiyama–Kishi coupling of organochromium compounds to aldehydes provides a powerful method for the synthesis of alcohols. However the toxicity of chromium salts greatly reduces the attractiveness of this reaction for large-scale applications. Fu� rstner and Shi have devised a modified process that involves a catalytic amount of chromium chloride [doped with nickel(II) chloride] and stoichiometric manganese (Scheme 10).55 Many important procedures concerning the aldol reaction have been published in the past year. Denmark et al.report a new system for e§ecting catalytic asymmetric aldol reactions. They have found that trichlorosilyl enolates (derived from tributylstannyl enolates and silicon tetrachloride) are highly reactive in the chiral phosphoramide- catalysed asymmetric aldol reactionScheme 11).56 For example the trichlorosilyl enolate 23 derived from cyclohexanone reacts in the presence of the phosphoramide 25 with (E)-cinnamaldehyde to give the anti-aldol product 24 with excellent diastereoselectivity and high enantioselectivity. Evans et al. have developed an excellent asymmetric variant of the Mukaiyama aldol reaction of a-benzyloxy aldehydes 26 (Scheme 12).57 This type of aldehyde reacts with trimethylsilylketene acetals in the presence of the C 2 -symmetric copper(II) complex 27 with exceptionally high enantioselectivity.The success of the reaction is due in part to coordination of the copper atom in a bidentate fashion by the aldehyde. The 256 N. J. Lawrence BnO H O OEt OTMS BnO OH O OEt N N Cu N O O Ph Ph 99% 98% ee 27 (0.5 mol%) –78 °C 26 2+ (SbF5)2 27 Scheme 12 O HN R1 O O HN R1 O R OH N N O Ph O N N O Ph O Ph OH i ii 28 29 74% anti:syn 95:5 30 31 de 84% iii iv (b) (a) R1 = p-MeC6H4SO2 R = Ph Scheme 13 Reagents i TiCl 4 Pr* 2 NEt 23°C; ii RCHO TiCl 4 CH 2 Cl 2 [78°C; iii TiCl 4 Pr* 2 NEt 0°C; iv PhCHO,[78°C. indium trichloride-catalysed Mukaiyama aldol reaction has been reported by Loh et al.58 They found that ketone trimethylsilyl enol ethers react in water with aldehydes in the presence of indium(III) chloride (20 mol%) to a§ord the corresponding aldol products in good yields.The ever e§ective Lewis acid scandium triflate catalyses the aldol reaction of polymer-supported silyl enol ethers with aldehydes providing a convenient method for the preparation of b-hydroxy ester libraries.59 The use of the cis-1-aminoindan-2-ol as an auxiliary for the synthesis of enantiomerically pure anti-aldol products (Scheme 13a) has been described by Ghosh and Onishi.60 The reaction of the (Z)-titanium enolate of 28 with aldehydes is both highly diastereo- and enantio-selective. The methodology provides convenient access to either anti-aldol enantiomer 29 since both enantiomers of cis-1-aminoindan-2-ol from which 28 is derived are commercially available. Palomo et al. have shown that the chiral imide acetamide 30 reacts on lithium and titanium enolate formation with 257 Synthetic methods OMe OMe O SMe MgBr N MeO O Cl Me MeS O Cl Br Ph O (a) (PriO)2Ti(NTf2)2 (5 mol%) (b) 34 90% i.ii. 2 M HCl 33 32 i. Zn Et2O ii. PhCH2COCl (c) 92% Ac2O MeNO2 room temp 10 min Scheme 14 aldehydes in a stereoselective manner (Scheme 13b).61 For example the reaction of the lithium enolate with benzaldehyde (30]31) provides a rare example of a stereoselective reaction of a chiral enolate that bears no a-substituents other than hydrogen. An important carbon–carbon bond forming reaction involves the acylation of carbon nucleophiles. Tillyer et al. report62 a simple high yielding synthesis of a-chloro ketones 34 by the reaction of organometallic reagents with N-methoxy-N-methylchloroacetamide a process pioneered by Wienreb. Addition of Grignard and organolithium reagents to N-methoxy-N-methylchloroacetamide 32 prepared by the Schotten–Baumann reaction of N,O-dimethylhydroxylamine and chloroacetyl chloride gives after acidic work-up the corresponding chloro ketone (e.g.33]34) (Scheme 14a). The e¶ciency of the procedure was greatly increased by the regeneration of the chloroacetamide directly by chloroacetylation of the aqueous phase using chloroacetyl chloride–K 2 CO 3 . The procedure is also e§ective for the synthesis of a-fluoro ketones from N-methoxy-N-methylfluoroacetamide. Metal bis(trifluoromethylsulfonyl)amides have been used by Mikami et al. as highly e¶cient Lewis acid catalysts for the Friedel–Crafts acylation of arenes (Scheme 14b).63 Unlike most of the existing catalysts used to accomplish this type of reaction the bistriflylamides of aluminium titanium and ytterbium can be used in substoichiometric quantities.The same research group have also found that lithium perchlorate greatly accelerates the scandium or ytterbium triflate-catalysed Friedel–Crafts reactions. The mixture of rare-earth triflate and lithium perchlorate is easily recovered from the reaction mixture by simple extraction and can be reused without a decrease in its catalytic activity.64 The combined catalyst system TiCl(OTf) 3 and TfOH developed by Izumi and Mukaiyama also e§ects e¶cient Friedel–Crafts acylation of aromatic compounds.65 The reaction of an acid chloride allyl bromide and commercial zinc dust in diethyl ether conveniently generates b,c-unsaturated ketones (Scheme 14c).66 A facile synthesis of conjugated acetylenic ketones involving copper(I)-catalysed acyla- 258 N.J. Lawrence Ph OH O Ph O O O O Ph O Et Ph Li (5.6 equiv.) naphthalene (10 mol%) BusCl (1.2 equiv.) 75% (a) EtMgBr CH2Cl2 (b) 88% Scheme 15 O O CHO N N OMe i. TDSOTf THF –78 °C 35 ii. TBAF iii. HCl 78% >98% ee Scheme 16 tion of terminal alkynes with acyl halides is reported by Chowdhury and Kundu.67 The synthesis of a variety of ketones in moderate yield by the lithium-mediated coupling of carboxylic acids and alkyl or aromatic chlorides has been detailed by Yus and co-workers (Scheme 15a).68 Rapoport and Mattson have also devised a method for the conversion of carboxylic acids to ketones.69 They found that the addition of a Grignard reagent (100 mol%) to an acyl hemiacetal in dichloromethane generates the corresponding ketone with little tertiary alcohol formation (Scheme 15b).If desired the formation of the acyl hemiacetal and Grignard addition can be carried out in the same pot. An interesting synthesis of enantio-enriched b-formyl ketones from a,b-unsaturated ketones (Scheme 16) has been reported by Lassaetta et al.70 This is achieved by an enantioselective Michael addition of the neutral formyl anion equivalent 35. The addition of the formaldehyde (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone 35 is promoted by dimethylthexylsilyl (TDS) triflate. Trehan and co-workers have found thatN-trimethylsilyl bis(fluorosulfonyl)imide 36 is an e¶cient catalyst for the addition of trimethylsilyl cyanide to ketones and aldehydes to give cyanohydrins (Scheme 17).71 In the presence of 36 (1 mol%) trimethylsilyl cyanide adds e¶ciently to carbonyl compounds to give the corresponding O-trimethylsilyl cyanohydrin.The imide 36 is a more e§ective catalyst for the reaction than trimethylsilyl triflate. A combination of dibutyltin dichloride and diphenyltin dichloride also functions as an e§ective catalyst for the trimethylsilylcyanation of aldehydes and ketones.72 Numbered among the various catalysts that have been used for the asymmetric trimethylsilylcyanation of aldehydes are the (salen) complexes 3773 and 38;74 (Fig. 2) both of which are used in combination with Ti(OPr*) 4 . 259 Synthetic methods O 36 (1 mol%) TMSCN (1.1 equiv.) –78°C TMSO CN FSO2 SO2F N TMS 36 98% Scheme 17 OH N N HO Ph Ph N N HO OH 38 ( R) 84% ee 37 ( S) 68% ee Fig. 2 Enantioselectivities in the addition of TMSCN to PhCHO with Ti(OPr*) 4 (configuration of the product TMS cyanohydrin ee) A convenient method for the synthesis of enantiomerically enriched bicyclic alcohols has been described by Hodgson and Lee.75 They found that the enantioselective a-deprotonation–rearrangement of medium-sized cycloalkene oxides can be achieved using organolithium reagents in the presence of stoichiometric amounts of ([)-sparteine (e.g 39]40) (Scheme 18a).The methylaluminoimidazoline 43 has been used by Kocienski and co-workers to catalyse the enantioselective [2]2] cycloaddition of (trimethylsilyl)ketene to aldehydes (Scheme 18b).76 The process (41]42) is a useful asymmetric route to b-lactones. Alkene and alkyne synthesis Several reports have appeared this year detailing new ways to make alkenes via Wittig methods.An interesting review of asymmetric Wittig-type reactions has also appeared. 77 Patil and Ma� vers found that the Wittig reaction between aldehydes and ethoxycarbonylmethylene(triphenyl)phosphorane can be carried out in hexane in the presence of silica gel.78 This protocol is a convenient method for the synthesis of (E)-a,b-unsaturated esters. The silica gel both accelerates the reaction a absorbs the triphenylphosphine oxide by-product. The product ester can be obtained pure by simply filtering the reaction mixture. The use of ethylmagnesium bromide as the base in the Wittig reaction has been investigated by Shen and Yao.79 The reaction of benzylidene(triphenyl)phosphorane derived in this manner with the a variety of aldehydes has been shown to be highly stereoselective in the synthesis of (E)-alkenes.Two complementary methods for the conversion of an aldehyde to its corresponding N-alkenyl-N-methylformamide derivative 44 (Scheme 19) have been disclosed by Paterson et al.80 The first method involves a Wittig reaction of the phosphonium salt 45 to produce the (Z)-formamide 44 as the major product (E:Z 1.4 to 1 10). Isomerisa- 260 N. J. Lawrence (a) (b) O H H OH R H O O O SiMe3 R Ph Ph N Al N X X Me Me3Si C O 39 PriLi (2.4 equiv.) 40 97% 77% ee (0.3 equiv.) 43 41 R = p-MeOC6H4CH2 42 X = 2,6-(CH3)2-4-Bu tC6H2SO2 77% 83% ee (–)-sparteine (2.5 equiv.) Scheme 18 Scheme 19 tion to the (E)-alkene is achieved by treating the alkene with molecular iodine (5 mol% CH 2 Cl 2 20 °C) in the absence of light. The second method involves the acid-catalysed condensation of the aldehyde with the N-methylformamide.Phosphorus pentoxide is the best catalyst serving both as acid and dehydrating agent. An excellent review of the stereocontrol imparted by the diphenylphosphoryl group in the Horner–Wittig olefination was published this year.81 The Horner–Wittig reaction has been used by Liu and Schlosser in the synthesis of trans alkenes. They found that the reaction of the anions derived from alk-2-enyldiphenylphospine oxides react with aldehydes with excellent trans selectivity (e.g. 46]47) (Scheme 20).82 The same excellent trans selectivity was also observed in the Horner–Wittig reaction of alk-2- enylphosphonates.83 An Organic Syntheses article describing the synthesis of bis(trifluoroethyl)phosphonate a Horner–Wadsworth–Emmons reagent particularly useful for the synthesis of (Z)-alkenes appeared this year.84 Miyaura and co-workers85 have used the boron–Wittig reaction to prepare alkenes from aldehydes and Knochel-like (dialkoxyboryl)methylcopper reagents (Scheme 21).The in situ preparation of 49 from Knochel’s (dialkoxyboryl)methylzinc reagent 48 and 261 Synthetic methods Ph2P O CHO i. Bu nLi ii. 46 47 71% E:Z 96:4 Scheme 20 B O O IZn(CN)Cu CHO B O O F2BO HO OH 48 BF3•OEt2 heat H2O2 NaOH 50 84% 51 90% 49 Scheme 21 CuCN·2LiCl in THF followed by its addition to aldehydes in the presence of boron trifluoride–diethyl ether yielded the rather stable b-hydroxyalkylboronate derivative 49. The thermally promoted boron–Wittig reaction or the alkaline hydrogen peroxide oxidation of 49 gave the corresponding alkenes 50 or alkane-1,2-diol 51 in high yields.The reaction provides a very simple procedure for the olefination or the hydroxymethylation of aldehydes. A general and convenient synthetic method to produce geometrically pure (Z)-1- bromoalk-1-enes 53 has been developed by Uenishi et al. (Scheme 22).86 Palladiumcatalysed hydrogenolysis of 1,1-dibromoalk-1-enes 52 by tributyltin hydride proceeds smoothly to give (Z)-1-bromoalk-1-enes 53 with excellent stereoselectivity in good yields. Dibromomethylenation of aldehydes by a combination of CBr 4 and PPh 3 in methylene chloride and the successive hydrogenolysis a§ords the (Z)-1-bromoalk-1- enes 53 in a one-pot procedure. The protocol has been applied to the stepwise and one-pot synthesis of enediynes and dienynes.87 262 N. J.Lawrence R Br Br R Br cat. Pd(Ph3)4 52 53 Z E >98 2 Bu3SnH Scheme 22 R1 R2 N N Ph R1 R2 R1 R2 N N Ph Li R1 R2 Li LDA (0.3 equiv.) –20 °C 1 h; 0 °C 3 h 54 84% cis:trans 99.4:0.6 55 R1 = n-CH3(CH2)4 R2 = n-CH3(CH2)3 56 Scheme 23 An intriguing synthesis of alkenes from the N-(2-phenylaziridin-1-yl)imine derivative of ketones is illustrated in Scheme 23.88 This catalytic Shapiro reaction devised by Yamamoto and co-workers is e§ected by a substoichiometric quantity of LDA. The high levels of cis stereoselectivity and regioselectivity are explained by a-deprotonation of the hydrazone 54 to give the organolithium derivative 55 which decomposes to the vinyllithium species 56 with the extrusion of styrene and nitrogen. The LDA is regenerated from the diisopropylamine formed in the first step and the vinyllithium 56.Taber et al. have shown that a-diazo ketones undergo b-hydride elimination with rhodium(II) trifluoroacetate to produce (Z)-a,b-unsaturated ketones in high yield (57]58) (Scheme 24a).89 This constrasts with the rhodium(II) acetate-catalysed reaction which also produces carbocycles from a competing 1,5-insertion process. Terminal alkenes can be prepared in useful yields via a [2,3]-Wittig type fragmentation by the treatment of benzyl ethers with n-butyllithium (e.g. 59]60) (Scheme 24b).90 Bandgar and co-workers have found that the Envirocat EPZG' is also an e¶cient and environmentally benign catalyst for the synthesis of conjugated nitroolefins via the Henry reaction of aldehydes and nitroalkanes (Scheme 24c).91 Alkenes are obtained via b-elimination of water when tertiary alcohols are treated with oxalyl chloride triethylamine and dimethyl sulfoxide.92 Unfortunately the process shows little regioselectivity.It has long been known that the addition of the anion of dimethyl diazomethylphosphonate 61 (which has seen an improved synthesis this year93) to aldehydes generates alkynes. Bestmann and co-workers94 have developed an improved one-pot procedure for the synthesis of terminal alkynes (62]63) from aldehydes using the phosphonate 64 (Scheme 25). The one-pot procedure is high yielding under very mild conditions without requiring low temperatures or inert gas techniques and avoids the use of strong bases. The anion of 61 is generated in situ by mild base-promoted acyl cleavage 263 Synthetic methods Envirocat EPZG® 90% O O H O NO2 (c) n-C7H15 O N2 n-C7H15 O Rh2(O2CCF3)4 58 92% Z:E >95:5 57 (a) Bn O (CH2)8OTBS 90% (CH2)8OTBS BunLi 59 60 (b) CH2Cl2 –78 °C MeNO2 100 °C Scheme 24 Scheme 25 of 64.The procedure is likely to be a valuable alternative to the commonly used Corey–Fuchs dibromomethylenation–elimination protocol. 3 Reduction The development of new reagents for the e¶cient reduction of aldehydes and ketones has featured widely this year. For example Kobayashi et al. report that a combination of trichlorosilane and dimethylformamide e¶ciently reduces aldehydes and imines.95 The reagent system also e§ects reductive amination of aldehydes under mild conditions. Hypervalent hydridosilicates generated by the coordination ofDMFto Cl 3 SiH are the active reducing species and enable e¶cient and selective reduction under mild conditions.An aryl chloride and nitro groups and carbon–carbon double and triple bonds are tolerated by the system. Uemura and co-workers also describe the reduction 264 N. J. Lawrence Ph O Ph OH Ph OH PPh2 N O Ph Ph ( R) 100% 91% ee ( S) 100% 96% ee Ph2SiH2 [Rh(COD)Cl]2 ( S)-DIPOF 65 Et2O 25 °C Ph2SiH2 [Ir(COD)Cl]2 ( S)-DIPOF 65 Et2O 25 °C Fe ( S)-DIPOF 65 Scheme 26 of ketones using a silane but in this case the reaction is asymmetric. They found that the chiral oxazolylferrocenylphosphine hybrid ligand (DIPOF) 65 is a very e¶cient ligand for the iridium(I)-catalysed asymmetric hydrosilylation of simple ketones (Scheme 26).96 Iodotrichlorosilane prepared in situ from SiCl 4 –NaI e§ects the chemoselective reduction of a,b-unsaturated ketones to their saturated counterparts.97 Similarly Cu–SiO 2 can be conveniently used for the hydrogenation of conjugated enones to saturated ketones in the presence of isolated alkene functionality present within the same molecule.98 Molecular hydrogen or propan-2-ol can also be used as the hydrogen source. The H 2 –Lindlar catalyst system has been found to be highly e§ective for the reduction of carbon–carbon double bonds of a,b-unsaturated carbonyl compounds.99 Both Williams100 and Helmchen101 and their co-workers have described the rhodium- catalysed asymmetric reduction of ketones using phosphorus-containing oxazoline ligands. The rhodium-catalysed hydrosilylation of acetophenone in the presence of the oxazolinyl phosphine ligand 66 proceeds with good enantioselectivity (Scheme 27).Asymmetric protocols using oxazaborolidine catalysts have seen widespread use for the borane reduction of ketones. Among many new catalysts introduced over the past year are the pinene-derived oxazaborolidine 67,102 the oxazaphospholidine oxide 68103 and the thiol 69 (Fig. 3).104 The use of diphenyloxazaborolidine for enantioselective reduction of ketones has been reviewed.105,106 The same monograph contains a comparative review of the use of tartrate TADDOL and binaphtholate-derived ligands for the enantioselective LiAlH 4 reduction of ketones.107 The asymmetric hydrosilylation of ketones using triethoxysilane and (R)-BINOL–Ti(OPr*) 2 as a catalyst occurs in excellent yield and moderate enantioselectivity (70]71) (Scheme 28a).108 The combination of BINOL–Ti(OPr*) 4 provides an excellent catalyst for the reduction of aldehydes with Bu 3 SnD (Scheme 28b).109 The method provides an excellent way for the synthesis of chiral primary alcohols.265 Synthetic methods 66 Ph O Ph OH i. [Rh(COD)Cl]2 (1 mol%) 66 (10 mol%) Ph2SiH2 (4 equiv.) THF –78 °C 86% 82% ee PPh2 O N ii. HCl MeOH Scheme 27 i. 10 mol% [( S)-BINOL–Ti(OPri)4] HSi(OEt)3 70 71 (a) Ph O Ph OSi(OEt)3 ii. 92% 94% ee Ph H O DSnBu3 HO D Ph (b) ( R)-BINOL–Ti(OPri)2 Et2O Scheme 28 Fig. 3 Selectivity in the borane reduction of PhCOMea or PhCOEtb (configuration of product catalyst mol% yield ee) Prasad and Joshi have shown that the oxazaborolidinone-catalysed borane reduction of diaryl-1,2-diones leads to the corresponding enantiomerically pure 1,2-diol.110 For example benzil 72 gives (1S,2S)-dihydrobenzoin 73 (ee[99%) when treated with borane–dimethyl sulfide and the oxazaborolidine catalyst 74 (Scheme 29a).In this case the ratio of threo to erythro diastereoisomers is 88 12. The asymmetric reduction of diacylaromatic compounds has also been achieved with the B-chlorodiisopinocampheylborane provides the product diols in excellent diastereoisomeric and enantiomeric purity.111 These procedures provide useful alternatives to the Sharpless asymmetric dihydroxylation protocol. Parker and Ledeboer have revealed that the related oxazaborolidine 75 is an excellent catalyst for the borane reduction of alkynyl ketones (Scheme 29b).112 The ketones are reduced rapidly with high enantioselectivities. The process was particularly e§ective where other procedures (BINAL-H and Alpine-borane') were ine§ective due to the associated long reaction times.266 N. J. Lawrence Ph Ph O O Ph Ph HO OH N B O Ph Ph R O HO Me2S•BH3 74 (10 mol%) 72 73 85% (ee >99%) 74 R = H 75 R = Me Me2S•BH3 75 (2 equiv.) –30 °C (a) 81% (ee 98%) (b) Scheme 29 79 O N N O O O O Co O OH MeO MeO O OH 78 78 (2.5 mol%) NaBH4 EtOH 79 CHCl3 77 98% 93% ee 76 Scheme 30 The enantioselective borohydride reduction of ketones catalysed by the optically active (b-oxoaldiminato) cobalt(II) complex 78 has been remarkably improved by using a borohydride species modified with the tetrahydrofurfuryl alcohol 79 and ethanol (Scheme 30). In the presence of the complex catalyst 78 the asymmetric reduction of aromatic ketones proceeds smoothly to give the corresponding optically active alcohols in quantitative yields within 6–12 h with high enantiomeric excesses (e.g.76]77).113,114 Diisopropoxytitanium(III) tetrahydroborate is an excellent reducing agent for the chemoselective reduction of ketones.115 With this reagent cyclic ketones are reduced with excellent axial hydride delivery. a,b-Unsaturated aldehydes are reduced e¶ciently to give allylic alcohols. The reagent is prepared in situ by the reaction of diisopropoxytitanium dichloride with benzyltriethylammonium borohydride (2 equiv.). An- 267 Synthetic methods O OH N Me Me N O O NHPh PhNH Ph Ph O Ph Ph OH 80 (b) 87% 80% ee [Rh(COD)Cl]2 (5 mol%) 80 (50 mol%) PriOH ButOK 60 °C (a) syn:anti 96:4 H2 RuCl2[( p-MeOC6H4)3P]3 (0.2 mol%) H2N(CH2)2NH2 KOH Scheme 31 other borohydride reagent methyltriphenylphosphonium borohydride reduces aldehydes and ketones in dichloromethane to their corresponding alcohols in high yield; a,b-unsaturated carbonyl compounds undergo 1,2-reduction.116 A ruthenium(II) catalyst formed in situ from RuCl 2 (PPh 3 ) 3 a 1,2-diamine and potassium hydroxide in 1 1 2 molar ratio e§ects easy reduction of various ketones in propan-2-ol in 1–8 atm of hydrogen.117 The process developed by Noyori and coworkers represents a good method for the diastereoselective synthesis of alcohols.For example the reduction of 4-tert-butylcyclohexanone occurs with excellent cis selectivity (cis trans 4-tert-butylcyclohexanol 98.4 1.6). The reducing system shows excellent Cram selectivity when tris(p-methoxyphenyl)phosphine is part of the catalyst (Scheme 31a). Lemaire and co-workers found that the ligand 80 containing two urethane groups gave the best enantioselectivity in the rhodium-catalysed reduction of propiophenone using propan-2-ol as the hydrogen source (Scheme 31b).118 Rubidium- and strontium-modified L-zeolite-supported platinum catalysts are highly selective for the chemoselective hydrogenation of cinnamaldehyde to cinnamyl alcohol.119 A convenient asymmetric synthesis of a-1-arylalkylamines has been described by Burk et al.For example hydrogenation of the enamide 81 in the presence of a rhodium catalyst and the DuPHOS ligand 83 gave the amide 82 quantitatively and with excellent enantioselectivity (Scheme 32).120 Several reductive methods involving substituted tin hydrides as the active reducing species have appeared in the past year. A useful method for the conjugate reduction of a,b-unsaturated ketones using catalytic tributyltin hydride (Scheme 33a) has been disclosed by Fu and co-workers.121 A combination of phenylsilane and tributyltin hydride (cat.) in the presence of a radical initiator reduced the enone 84 to the silyl enol ether 85 from which the corresponding ketone could be generated by alkaline hydrolysis.The process has the obvious advantage of involving substoichiometric quan- 268 N. J. Lawrence NHAc NHAc P P Me Me Me Me (Me-DuPHOS)-Rh+OTf– ( S,S)-Me-DuPHOS 83 H2 (60 psi) 81 82 95.4% ee Scheme 32 O OSiPhH2 O Ph OH Ph Ph Ph O Ph Ph O Ph OH 84 85 80% i. Bu3SnH (cat.) PhSiH3 (1.2 equiv.) AIBN PhH heat Bu3SnH (10 mol%) 88 (a) 86 87 trans:cis 1.2:1 Bu2SnIH 89 47% syn:anti 4:1 (b) (c) PhCHO ii. TBAF PhSiH3 (1.2 equiv.) ButOOBut PhMe heat Scheme 33 tities of the toxic tin hydride.The same workers have also shown that the Bu 3 SnH(cat.)–PhSiH 3 system can be used to e§ect the reductive cyclisation of enals and enones (e.g. 86]87) (Scheme 33b).122 Baba and co-workers describe the use of dibutyliodotin hydride for the reduction of a,b-unsaturated ketones.123 The reagent reduces aldehydes in poor yield. This chemoselectivity can be exploited to enable aldol reactions to be carried out between a,b-unsaturated ketones and aldehydes (e.g. 88]89) (Scheme 33c). The conjugate reduction of a,b-unsaturated ketones and 269 Synthetic methods Ar H O Ar Ar HO OH Ti Cl THF Ph Et O Ph Ph Et Me Me Et (a) 88% ( dl:meso 94:6) when Ar = p-OMe 90 i. MeMgBr VCl2(TMEDA)2 91 89% meso:dl 1:1 THF:H2O (4:1) 0 °C (b) ii. O2 (0.2 equiv.) THF reflux 15 h iii.H2O Scheme 34 aldehydes is also e§ected by the combined action of the Lewis acid aluminium tris(2,6- diphenylphenoxide) and the complex DIBAlH–n-BuLi.124 The pinacol coupling of aldehydes and ketones is a particularly useful route to glycols. However most methods require rigorously dry reaction conditions and are incompatible with the protic functionality. A procedure that avoids these restrictions has been developed by Barden and Schwartz.125 They have found that reaction of titanocene chloride with the aromatic aldehydes in a mixture of THF and brine yields the corresponding 1,2-diol with very high stereoselectivity (Scheme 34a). A simple and rapid procedure for e§ecting the pinacol reaction of aromatic aldehydes has been devised by Khurana et al. The pinacol reaction is e§ected by the inexpensive combination of aluminium powder and potassium hydroxide in methanol at room temperature.126 Hindered ketones are reduced to the corresponding alcohols by the same reagent.A reaction related to the pinacol coupling reported by Kataoka and Tani and co-workers involves a new C–C single bond-forming reaction by reductive coupling mediated by a system consisting of a Grignard reagent low-valent vanadium and a catalytic amount of oxygen (Scheme 34b).127 For example the coupled product 91 is formed by reaction of the ketone 90 with methylmagnesium bromide in the presence of vanadium(II) dichloride (TMEDA) 2 . The intermediate alkoxyvanadium species undergoes reductive coupling by the action of oxygen to give 91. Examples of the synthesis of aldehydes and ketones via reductive methods are rarer than those involving the oxidation of alcohols.One example involves the use of catecholalane 92 prepared by the reaction between catechol and aluminium hydride in THF at 0 °C. It is an excellent reagent for the partial reduction of nitriles to aldehydes (Scheme 35).128 The reagent reduces aldehydes ketones esters and acid chlorides to the corresponding alcohols and primary amides to the corresponding amines.129 Several new methods for the reductive amination of aldehydes and ketones have been reported in the past year. A very useful full paper130 and review131 describing various methods for the reductive amination of aldehydes and ketones with sodium triacetoxyborohydride have been published by Abdel-Magid and co-workers. An 270 N. J. Lawrence O Al O H CN CHO 92 ii.H3O+ THF 25 °C 72 h 95% i. Scheme 35 (b) (c) R H N Ph Ph R N Ph Ph Ph H N Ph Ph Ph N Ph Ph Ph ButOK (1.2 equiv.) 97 92% ButOK (0.1 equiv.) 95 96 O OMe OMe MeO MeO OMe OMe MeO MeO NH O H HCONH2 HCO2H microwave irradiation 94 75% 93 (a) THF room temp. PhCH2Br (1.2 equiv.) THF room temp. Scheme 36 intriguing example of reductive amination has been described by Turnbull and coworkers. Treatment of 4-substituted aroyl azides with NaBH 4 –TFA leads to the corresponding novel 4-substituted N,N-bis(2,2,2-trifluoroethyl)aniline derivatives in excellent yield except where electron-withdrawing groups are present.132 The classical transformation of ketone 93 to its corresponding formamide derivative 94 the Leuckart reaction has been significantly improved by Loupy et al.133 They found that the formamides were obtained rapidly and in excellent yield when the ketone is heated with a mixture of formamide and formic acid in a microwave reactor (Scheme 36a).An e¶cient transamination protocol under mild conditions has been revealed by Cainelli Giacomini and co-workers.134 This is not really a reduction but is included here since it represents a reaction equivalent to the reductive amination of an aldehyde. The method is ideal for the transformation of aldehydes to amines via their imines 95 derived from aminodiphenylmethane (Scheme 36b). Treatment of the imine 95 with a catalytic amount of potassium tert-butoxide generates the isomerised product 96 in excellent yield. Subsequent hydrolysis with hydrochloric acid generated the amine. When the aldehyde is benzaldehyde or 2-furaldehyde the intermediate 2-azaallyl anion can be trapped with a variety of electrophiles to generate a secondary 271 Synthetic methods N H O N O Et Et MeO OMe N H N F3C OH OH F3C O O Ph OMe O 98 (DHQD)2AQN Ph OMe O (DHQD)2AQN OsO4 [O] 99 TsNH OH 100 81% ee with 98 64% ee with (DHQD)2PHAL (DHD)2PHAL K2OsO2(OH)2 102 66% 81% ee 101 (a) (b) TsNClNa•3H2O Scheme 37 amine derivative 97 (Scheme 36c).The corresponding reaction of ketones has only been reported for 1,2-diones. A review of the selective catalytic reduction of aromatic nitro compounds has been published this year.135 A new method for the chemoselective reduction of azides with iron powder and nickel(II) chloride hexahydrate has been disclosed by Sandhu and co-workers.136 Azides can also be reduced to amines in good yields and under mild conditions with SmI 2 or Cp 2 TiCl 2 –Sm systems.137 4 Oxidation One of the most successful oxidative synthetic methods of recent years the Sharpless asymmetric dihydroxylation (AD) reaction has been refined and exploited extensively this year.Whilst much attention has focused on the mechanism of the reaction138–142 the process has inter alia been applied to the synthesis of tetraols,143 dendrimers144 and pyrrolizidine natural products.145 Several examples of the reaction using polymer- supported ligands have been reported this year.146–148 A new class of anthraquinone- based ligands [e.g. (DHQD) 2 AQN 98] has been found to give superior enantioselectivities in the Sharpless asymmetric dihydroxylation of olefins that bear only alkyl substituents (99]100) (Scheme 37a).149 Chang and Sharpless have syn- 272 N.J. Lawrence thesised enantiopure 2-amino alcohols from the corresponding diols by activation of the diols as cyclic carbonates azide ring-opening of the carbonates and hydrogenation of the resulting azido alcohols.150 Sharpless and co-workers have also developed a more direct route to derivatives of 2-amino alcohols–the catalytic asymmetric aminohydroxylation of alkenes a close relative of the asymmetric dihydroxylation reaction.151 For example ethyl cinnamate 101 when treated with chloramine-T a cinchona alkaloid ligand and a source of osmium tetroxide gives the hydroxy sulfonamide 102 (Scheme 37b). The ligand a§ects not only the enantioselectivity of the process but also the regioselectivity.The procedure has been used to prepare the side-chain of taxol.152 By far the most commonly used method for the synthesis of aldehydes and ketones is the oxidation of alcohols. Many new oxidative methods have been described over the period covered in this review. Several are variants of well studied oxidising agents. For example Khadilkar and co-workers153 report the preparation of silica gel-supported chromium trioxide and describe its use in the selective oxidation of alcohols. The reagent oxidises alcohols to their corresponding carbonyl compound; primary alcohols are not over-oxidised to the carboxylic acid. The oxidation is carried out in 1,2-dichloroethane and is complete after 15 min at room temperature. The product of the reaction is obtained simply by filtration of the reaction mixture.Another chromium- based reagent quinolinium chlorochromate (ACC) has been shown to be an e¶cient reagent for the selective oxidation of primary and secondary alcohols.154 The related quinolinium bromochromate reported by OÆ zgu� n and Degirmenbasi and co-workers,155 is also a new reagent for the oxidation of alcohols to carbonyl compounds. The reagent also functions as a brominating agent for aromatic compounds. An improved protocol for the oxidation of secondary alcohols by copper permanganate is described by Craig and Ansari. The reaction is carried out in a homogeneous medium (acetic acid) a§ording rapid and complete conversion of the alcohols to ketones.156 Chromium trioxide and tricapryl(methyl)ammonium chloride (Aliquot 336) also serves as an e¶cient system for the oxidation of alcohols.157 Hexadecyl silica-supported cupric nitrate in carbon tetrachloride oxidises alcohols to their corresponding carbonyl compounds.It oxidises primary alcohols in the presence of secondary alcohols with absolute chemoselectivity in high yields.158 The catalytic activity of cerium(IV) doped Weakley-type heteropolyoxometalates for the H 2 O 2 oxidation of primary and secondary alcohols has been evaluated for the first time. It was found that this catalyst exhibits mild and selective activity especially for benzyl alcohols.159 Delaude and Laszlo160 describe full details of the use of another oxidising reagent potassium ferrate(VI) and K10 Montmorillonite clay. The reagent is a strong and environmentally benign oxidant for the oxidation of benzyl alcohols. Bis(trimethylsilyl) chromate generated from chromic anhydride and hexamethyldisiloxane in chloromethane has been supported on silica gel and was excellent for oxidising alcohols of various types to the corresponding carbonyl compounds.161 The development of other clean oxidising systems has seen much activity this year.Systems that use only a catalytic quantity of a metal complex are particularly attractive. A practical procedure for the molybdenum-catalysed oxidation of alcohols by sodium percarbonate is detailed by Muzart and co-workers.162 The oxidation is carried out at reflux in acetonitrile or 1,2-dichloroethane in the presence of catalytic molybdenyl acetylacetonate and Adogen 464. The process is generally applicable for the synthesis 273 Synthetic methods 103 laccase–ABTS(NH4)2 103 O2 87–100% R R OH N S NH4O3S Et N N S N Et SO3NH4 Scheme 38 of a wide range of carbonyl compounds.Catalytic amounts of cis-dioxomolybdenum( VI) complexes in association with sulfoxides can be used to oxidise alcohols to carbonyl compounds.163 For primary alcohols the oxidation to aldehydes is selective no further oxidation to carboxylic acid being observed. The oxidation is most e§ective for benzylic and allylic alcohols. Processes that have no metal catalyst and use oxygen or air as the terminal oxidant have even greater potential as clean synthetic methods. One such process a simple and convenient method for the oxidation of secondary alcohols using molecular oxygen and benzaldehyde in 1,2-dichloroethane in the absence of metal catalysis is described by Choudary and Sudha for the first time.164 Rodrigues and co-workers have found that acyl nitrates can be used to oxidise primary and secondary alcohols to aldehydes and ketones.165 Acetyl nitrate supported on Montmorillonite clay gives the best results.The reaction is explained by a mechanism involving the formation of an intermediate alkyl nitrate which decomposes to give the carbonyl compound. Although the authors do not report any problems with this procedure they do not present any safety analysis which would have been welcome considering the known hazards associated with the use of acetyl nitrate. Chen and co-workers also describe an environmentally benign and potentially useful enzymemediated molecular oxygen oxidation of substituted benzyl alcohols to the corresponding aldehydes (Scheme 38).166 The enzyme used laccase requires an artificial co-factor diammonium 2,2@-azinobis(3-ethylbenzothiazoline-6-sulfonate) [ABTS(NH 4 ) 2 ] 103.The reaction proceeds under physiological conditions to yield the product aldehydes quantitatively. A new procedure for the oxidation of primary and secondary alcohols with tertbutyl hydroperoxide employing catalytic Zr(OBu5) 4 or Zr(OPrn) 4 –3Å molecular sieves has been reported by Krohn et al.167 Secondary alcohols–if not severely sterically hindered–are usually converted quantitatively to the corresponding ketones. Aldehydes are obtained from primary alcohols in good yield by lowering the reaction temperature decreasing the amount of ButOOH or replacing ButOOH by cumene hydroperoxide (CHP) and/or exchanging the catalyst Zr(OBut) 4 by Zr(OPrn) 4 or silica gel-supported zirconium(IV).In certain cases a remarkable selectivity for equatorial alcohol groups is observed in contrast to chromium(VI)-based oxidations. tert-Butyl hydroperoxide has also been used as the oxidant for converting benzylic alcohols into the corresponding carbonyl compounds; the process requires the use of chromium(VI)-incorporated zeolite CRS-2 as a catalyst.168 274 N. J. Lawrence N O Cl OH Cl OH NaOCl (0.6–0.7 equiv.) 104 (1 mol%) 104 70% conversion 89% ee Scheme 39 RO O PdCl2(CH3CN)2 (5 mol%) DMF–acetone–water 110 °C R = Me2(Bu t )Si PPh3 (22 mol%) 2-bromomesitylene (1.1 equiv.) 110 °C 76% i. ii. Scheme 40 An intriguing and e¶cient enantioselective protocol for the oxidation of secondary alcohols is reported by Rychnovsky et al. (Scheme 39).169 They used the optically pure nitroxide catalyst 104 which is essentially a ‘chiral version’ of 2,2,6,6-tetramethylpiperidine- N-oxyl (TEMPO) a well studied oxidation catalyst.The azepine 104 oxidises activated secondary alcohols in the presence of the terminal oxidant sodiumhypochlorite (0.6–0.7 equiv.). The resolution of the benzylic alcohol is e¶cient; the (S) isomer is oxidised six times faster than the (R) enantiomer. A procedure for the one-pot desilylation–oxidation of aliphatic tert-butyldimethylsilyl ethers using a palladium(II) catalyst is reported by Wilson and Keay.170 The desilylation involves heating the silyl ether in acetone–DMF containing water (5 equiv.) in the presence of PdCl 2 (CH 3 CN) 2 (5 mol%). Once the desilylation is complete triphenylphosphine (22 mol%) and 2-bromomesitylene (1.08 equiv.) are added and the mixture heated at 110 °C (Scheme 40) to e§ect the oxidation of the alcohol.A review of the use of stable organic nitroxyl radicals for the oxidation of primary and secondary alcohols has appeared this year.171 The e¶cient and highly selective oxidation of primary alcohols to aldehydes using one such nitroxyl radical is described by Einhorn et al.172 They found that TEMPO catalyses the e¶cient oxidation of primary alcohols to aldehydes by N-chlorosuccinimide in a biphasic dichloromethane –aqueous pH8.6 bu§er system in the presence of tetrabutylammonium chloride. Aliphatic benzylic and allylic alcohols are readily oxidised with no over-oxidation to carboxylic acids. Secondary alcohols are oxidised to ketones with much lower e¶ciency.(Arene)tricarbonylchromium alcohols are oxidised to aldehydes or ketones by either DMSO–TFAA (trifluoroacetic anhydride) or DMSO–SO 3 -pyridine reagents with minimal complications from decomplexation.173 275 Synthetic methods Ph Ph O Ph Ph O O Et2N NEt2 NEt2 Ph Ph O Ph Ph O O O (a) 105 106 99% NaOCl aq. CH2Cl2 107 Cl– 107 poly-L-leucine H2O2–NaOH– CH2Cl2 (b) ee > 98% Scheme 41 Several methods for the epoxidation of alkenes have appeared over the past year. For example Mioskowski and co-workers have found that sodium hypochlorite is a convenient oxidant for the epoxidation of a,b-unsaturated ketones (105]106) (Scheme 41a).174 This is made possible by employing a two-phase system and hexaethylguanidinium chloride 107 as a phase-transfer agent. An intriguing asymmetric process for the epoxidation of a,b-unsaturated ketones and dienones has been disclosed by Roberts and co-workers (Scheme 41b).175 In these reactions poly-L-leucine and poly-D-leucine are used as asymmetric catalysts.Noyori and co-workers describe a particularly e¶cient method for the epoxidation of terminal olefins with the 30% hydrogen peroxide using conditions that are both organic and inorganic halide-free. The catalytic system consists of Na 2 WO 4 (aminomethyl)phosphonic acid and methyl(tri-n-octyl)ammonium hydrogensulfate under halide-free conditions.176 A non-transition metal-catalysed process for the catalytic asymmetric oxidation of unfunctionalised alkenes has been disclosed by Aggarwal and Wang.177 They found that just 5mol% of the binaphthyl-based iminium salt 108 is su¶cient to catalyse the oxidation of alkenes to epoxides with moderate to good enantioselectivity (Scheme 42a).The active epoxidising agent in this process is an oxaziridinium salt derived from the iminium salt 108 via oxidation by Oxone. An optimised process for the direct asymmetric epoxidation of aldehydes using an ingenious reagent system with a catalytic sulfide is also described by Aggarwal et al.178 A mixture of aldehyde diazo compound catalytic enantiopure sulfide 111 and copper(II) acetylacetonate provides an e¶cient route to epoxides (109]110) with trans selectivity. The sulfur ylide is generated from the copper-catalysed reaction of the sulfide and diazo compound. The ylide reacts with the aldehyde to provide the epoxide of exceptionally high enantiopurity and returns the sulfide to the catalytic cycle (Scheme 42b).The use of the C 2 -symmetric chiral ketone 112 for the asymmetric epoxidation of unfunctionalised olefins (Scheme 37) has been described by Yang et al.179 The axially chiral ketone 112 is particularly e§ective for the asymmetric epoxidation of stilbene derivatives 113. The reaction is carried out using Oxone in an homogeneous acetonitrile –water solvent system. This was until recently the highest enantioselectivity reported for the epoxidation of an alkene via a chiral dioxirane. However Shi and co-workers have found that the fructose-derived ketone 114 surpasses the ketone 112 as an e§ective asymmetric epoxidation catalyst for a variety of trans-alkenes (Scheme 43).180 276 N. J. Lawrence N Me Ph Ph O O H O Ph Ph O S Me 108 108 (5 mol%) Oxone (1 equiv.) NaHCO3 (4 equiv.) MeCN–H2O 80% 71%ee (a) 111 (0.2 equiv.) Cu(acac)2 (5 mol%) PhCHN2 73% trans:cis >98:2 110 109 111 Scheme 42 Hiegel et al.report the potentially useful direct oxidative conversion of an aldehyde to its corresponding methyl ester in the absence of metals (Scheme 44).181 Treatment of the aldehyde with a solution of methanol pyridine and trichloroisocyanuric acid in acetone acetonitrile or dichlormethane e¶ciently gives the methyl ester. The complex HOF·MeCN has also been used to e§ect non-metal-mediated oxidations. The complex made directly by bubbling fluorine through aqueous acetonitrile reacts quickly and e¶ciently with the enolic forms of ketones to produce a-hydroxy ketones.182 5 Protection and functional group interconversion Several excellent reviews describing protecting group strategies in organic-synthesis have appeared this year.183,184 Alcohols and thiols An excellent review focuses on the selective deprotection of silyl ethers in the presence of other like and unlike silyl ethers.185 Deprotection of structurally di§erent trimethylsilyl ethers to their corresponding alcohols can be achieved rapidly in refluxing benzene in the presence of tris[trinitratocerium(IV)] paraperiodate M[(NO 3 ) 3 Ce] ·3H 2 IO 6N.The reagent has also been used successfully for the direct oxidation of trimethylsilyl ethers to their corresponding carbonyl compounds. Benzylic double 277 Synthetic methods Scheme 43 Ph O H N N N O Cl Cl Cl O O Ph O OMe MeOH pyridine 67% Scheme 44 bonds are prone to cleavage reactions with this method.186 tert-Butyldimethylsilyl and tetrahydropyranyl (THP) ethers are also cleaved oxidatively by catalytic ceric ammonium nitrate in methanol.187 TBDMS ethers of primary alcohols are deprotected more rapidly than THPethers and ketals.The deprotection of trimethylsilyl ethers can also be e§ected by the action of the modified borohydride agents BAAOTB (1-benzyl- 4-aza-1-azoniabicyclo[2.2.2]octane tetrahydroborate) and TBATB (tetrabutylammonium tetrahydroborate) in refluxing ButOH.188 An e§ective method for the cleavage of tert-butyldimethylsilyl ethers using a 1% solution of iodine in methanol is described.189 E¶cient tert-butyldimethylsilylation of alcohols including tertiary and sterically hindered secondary alcohols using N,O-bis(tert-butyldimethylsilyl)acetamide in the presence of catalytic amounts (1 mol%) of TBAF has been disclosed by Johnson and Taubner.190 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is commonly used to deprotect various methoxy substituted benzyl ethers.One drawback with this method is the need for a stoichiometric amount of DDQ. A solution to this problem has been disclosed by Yadav and co-workers who found that 4-methoxy- and 3,4-dimethoxy-benzyl ethers can be deprotected with the catalytic amounts of DDQ by oxidative recycling of the by-product DDHQ by iron(III) chloride.191 The same research group have found that the cleavage of O-allyl ethers of primary alcohols can also be e§ected with DDQ.192 Several new methods for the manipulation of acetal-based alcohol protecting groups have been described. THP ethers can be prepared from an alcohol and tetrahydropyran using heteropoly acids [e.g.H 3 [PMo 12 O 40 )] as catalysts.193 A mild and e¶cient method for selective deprotection of THP ethers has been reported by Maiti and Roy194 and simply involves heating in water and dimethyl sulfoxide at 90 °C in the presence of excess lithium chloride. Oriyama et al. have developed a variety of methods for the manipulation of THP ethers.195 For example THP ethers are 278 N. J. Lawrence N Ph OH Bn N Ph HN Bn CHO 115 116 70% Me3SiCN H2SO4 Scheme 45 transformed into trialkylsilyl ethers by the action of trialkylsilyl trifluoromethanesulfonate. When the triflate is trimethylsilyl trifluoromethanesulfonate the THP ether is cleaved to the corresponding alcohol. Silyl ethers are also produced by the reaction of THP ethers with a trialkylsilane and catalytic tin(II) triflate.A new procedure for cleavage of benzylidene acetals from glycopyranosides using tin(II) chloride is described which does not a§ect other protecting groups such as benzoyl acetyl benzyl or acetonide.196 The highly versatile 1-[(2-trimethylsilyl)ethoxy]ethyl (SEE) group readily obtainable from an alcohol and 2-(trimethylsilyl)ethyl vinyl ether in the presence of a catalytic amount of PPTS has been developed for the protection of hydroxy groups. Deprotection can be achieved under virtually neutral conditions with the use of a fluoride ion source thus allowing for e§ective protection of hydroxy groups of compounds that contain acid- and/or base-sensitive functional groups.197 Alcohols protected as their methoxyacetates can easily be regenerated by the action of ytterbium(III) triflate in methanol.198 Several useful functional group interconversions of alcohols have been disclosed this year.For example a convenient synthesis of aromatic thiols from phenols has been described by Arnould et al.199 Aromatic thiols were synthesised from phenols in good yield and under mild conditions by reaction of the corresponding triflates with sodium triisopropylsilanethiolate (NaSTIPS) and subsequent deprotection. The e¶cient inversion of a variety of secondary alcohols can be achieved by the reaction of their chloromethanesulfonates with caesium acetate in the presence of 18-crown-6. Basecatalysed or reductive hydrolysis of the product acetate gives the alcohol with the opposite stereochemical configuration.200 A novel modification of the Ritter reaction described by Goel and co-workers uses trimethylsilyl cyanide and sulfuric acid to convert alcohols to their corresponding formamides in high yields (e.g.115]116) (Scheme 45).201 Ketones and aldehydes By far the most common method for the protection of aldehydes and ketones involves the synthesis of acetals and thioacetals. Much research has focused on milder methods for their synthesis and removal. For example Bandgar and co-workers202 have found that the Envirocat EPZG' is an excellent heterogeneous catalyst for the thioacetalisation of ketones and aldehydes with the ethane-1,2-dithiol. The process o§ers high yields and easy separation of products and catalyst by filtration. The same transformation is catalysed by Fe3`-exchanged Montmorillonite,203 and kaolinitic clay.204 Schmittel and Levis205 describe the use of the one-electron oxidant iron(III) tris(phenanthrolinehexafluorophosphate) in the deprotection of benzyl-substituted 1,3-dithianes.Scandium bis(trifluoromethanesulfonamide) has been shown to be a highly e¶cient Lewis acid catalyst for the synthesis of ketals from ketones and 1,2- or 279 Synthetic methods Ph O H O O O Ph OH HO O Sc(NTf2)3 MgSO4 CH2Cl2 23 °C 20 h 83% cis:trans 93:7 Scheme 46 1,3-diols.206 The catalyst can also be used for the diastereoselective preparation of 1,3-dioxolanes from aldehydes (Scheme 46). A novel method for the deprotection of S,S-acetals using air and catalytic bismuth( III) nitrate has been reported by Komatsu et al.207 Both cyclic and acyclic S,S-acetals of ketones and aldehydes are smoothly deprotected to regenerate the parent carbonyl compound and diphenyldisulfide.Curini and co-workers have found that layered zirconium sulfophenyl phosphonate [e.g. Zr(O 3 PCH 3 ) 1.2 (O 3 PC 6 H 4 SO 3 H) 0.8 ] is an e¶cient heterogeneous catalyst for mild hydrolysis of oximes semicarbazones and tosylhydrazones.208 The same research group have also found that ketones and aldehydes can be regenerated from their corresponding 1,3-dithiolanes and 1,3-dithianes using Oxone' and wet alumina.209 Triphenylphosphine and carbon tetrabromide have been used to promote the selective deprotection of ketals and acetals under mild neutral anhydrous reaction conditions.210 An exceptionally simple and convenient method for dethioacetalization has been described by Mehta and Uma.211 Thioacetals of aldehydes and ketones give the parent carbonyl compound upon treatment with a solution of ‘oxides of nitrogen’ in dichloromethane.The ‘oxides of nitrogen’ are prepared by treating arsenious oxide with conc. HNO 3 . A number of 1,3-dithianes have been e¶ciently converted to the parent carbonyl compounds in good yields by treatment with 1.5 equiv. of DDQ in MeCN–H 2 O (9 1).212 A variety of derivatives of ketones and aldehydes are converted to the parent carbonyl compound by new protocols. For example ketone dimethylhydrazones undergo easy cleavage to the corresponding ketones using a catalytic amount of Pd(OAc) 2 –SnCl 2 .213 Sankararaman and co-workers have shown that 5M lithium perchlorate in diethyl ether is an excellent Lewis acid medium for the conversion of epoxides to carbonyl compounds (e.g.117]118) (Scheme 47). The reagent appears to be more regio- and chemo-selective than the commonly used boron trifluoride.214 Carboxylic acids and derivatives Several new methods for the manipulation of esters have been described. For example trimethylsilyl trifluoromethanesulfonate has been used as a catalyst to e§ect the fast clean and e¶cient esterification of alcohols with carboxylic acid anhydrides.215 Treatment of a variety of aromatic carboxylic acids with alcohols in the presence of thionyl chloride results in excellent yields of corresponding esters.216 The transesterification of a,x-dicarboxylic acids gives the corresponding monoesters in high yields when the reaction is catalysed by strongly acidic ion exchange resins in an ester–octane biphasic mixture.217 It has been shown that prop-2-ynyl esters are useful protecting groups for carboxylic acids and that they are selectively deprotected in the presence of other esters on treatment with tetrathiomolybdate under mild conditions.218 280 N.J. Lawrence Ph O Ph O 117 75% 118 LiClO4 Et2O Scheme 47 The easy deprotection of allyl esters is achieved by allyl group transfer to anisole using the catalytic action of the superacid sulfated SnO 2 .219 The use of magnesium methoxide for the deprotection of alkyl esters has been described. This mild reagent provides a good method to cleave esters e¶ciently and more importantly allows for e§ective di§erentiation between two di§erent esters. The order of the reactivity of this reagent towards acyl cleavages was found to be p-nitrobenzoate[acetate[benzoate [pivaloate?acetamide.220 Amines and phosphines The tert-butoxycarbonyl protecting group for amines alcohols and thiols is removed e¶ciently (90–99% yields) by use of catalytic of ceric ammonium nitrate (0.20 equiv.) in refluxing acetonitrile.221 The cleavage of N-Boc groups in the presence of either TBDMS or TBDPS ethers is successfully achieved by use of a saturated solution of HCl in ethyl acetate.222 An e¶cient and high-yield method for the N-tert-butoxycarbonyl protection of sterically hindered a-amino-acids has been developed by Johnson and co-workers.223 The amino acid is treated with tetramethylammonium hydroxide and (Boc) 2 Oin acetonitrile.TheN-2,4-dimethylpent-3-yloxycarbonyl (Doc) group has been used as a new protecting group for tryptophan that is stable to nucleophiles and trifluoroacetic acid suppresses alkylation side reactions and is cleaved by strong acid along with other protecting groups used in Boc solid-phase peptide synthesis.224 The tetrachlorophthaloyl group has been used as a versatile amine protecting group.225 It can be removed to reveal the parent amine by treatment with the ethylenediamine in ethanol at 60 °C.The conditions required to remove a phthaloyl group in a similar way are much harsher. Zmijewski and co-workers have developed an enzymatic method for the selective deprotection of phthalyl protected amines.226,227 Phthalyl amidase selectively deprotects phthalimido groups under very mild aqueous conditions in a one-pot reaction to produce phthalic acid and the free amine. The enzyme has been shown to deprotect several primary amines of distinctly di§erent structure and exhibits chiral selectivity when the substrate contains extensive beta-branching.6 Organo halides Fluoro compounds Many new methods for the selective fluorination of organic compounds have appeared this year. Auseful review summarises the use of cobalt trifluoride for the fluorination of organic compounds.228 Katzenellenbogen and co-workers have developed an e¶cient route to trifluoromethyl ketones 122 via trifluoromethyl-substituted imidazolines (Scheme 48).229 The imidazolines 121 were prepared by the reaction of the silyl-N- 281 Synthetic methods Ph N Ph Ph N Ph N N CF3 R O Ph Ph Ph CF3 HN O R O SiMe3 i. LDA ii. TMSCl RCOCl CF3CN THF MeOH–H2O HCl 119 120 74% Scheme 48 benzylidenebenzylamine 120 (made from 119) with acid chlorides and trifluoroacetonitrile.The reaction proceeds via a 1,3-dipolar cycloaddition between the N-acylazomethine ylide generated from the acid chloride and the silylimine. Mild acid hydrolysis of the imidazoline generates the trifluoromethyl ketone 122. The process can also be used to generate trifluoromethyl ketones that are incorporated in bioactive peptides. A description of the synthesis of aryl trifluoromethyl ketones by a Friedel–Crafts acylation reaction has appeared from Simchen and Schmidt.230 They used 4-dimethylamino-1-trifluoroacetylpyridinium trifluoroacetate as an e§ective easy to handle and stable trifluoroacetylation agent. Arenes are converted to their corresponding trifluoromethyl ketones by its action in the presence of aluminium chloride.The use of several highly selective electrophilic fluorinating agents has been reviewed this year.231,232 a,a-Difluoro ketones are prepared from hydroxy-substituted aromatic derivatives by reaction with the 1-fluoro-4-hydroxy-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [AccufluorTM NFTh] 123 in methanol or acetonitrile (Scheme 49a).233 The same reagent has also been used for the high-yield direct a-fluorination of ketones234 and polycyclic aromatic hydrocarbons. 235 Iodotoluene difluoride can also be used to selectively fluorinate b-keto esters in the a-position.236 Similarly dialkyl fluoromalonates have been prepared by treating the sodium derivatives of the parent dialkyl malonates with elemental fluorine.237 Yokoyama and Mochida have developed a useful procedure for the formation of the trifluoromethyl anion from phenyl trifluoromethyl sulfide by the use of Et 3 GeNa.Various aldehydes were transformed into the corresponding a-trifluoromethylated alcohols in good to excellent yields (e.g. RCHO]124) (Scheme 49b).238 Acyl fluorides are prepared e¶ciently by the oxidation of aliphatic and alicyclic alcohols with the commercial reagent BrF 3 .239 Bromo compounds A useful method for the transformation of ketones and aldehydes to gem-dibromides has been developed by Takeda et al.240 The ketone or aldehyde is first converted to its corresponding hydrazone 125 which is then treated with copper(II) bromide–lithium tert-butoxide to give the gem-dibromide in good yield (Scheme 50). The bromination of 282 N. J. Lawrence OH O F F N+ N+ OH F Et3GeNa CF3Na RCHO 124 86–96% (b) (a) (BF4 –)2 123 123 MeCN room temp.0.5 h SCF3 R CF3 OH Scheme 49 Scheme 50 1,3-diketones can be achieved using a mixture of potassium bromate and potassium bromide in the presence of Dowex' 50X2-200 ion-exchange resin.241 The regiospecific bromination of benzene derivatives can be achieved by using Me 2 SO–HBr.242 Reactions of mono-substituted aromatic substrates of moderate activity with bromine in the presence of stoichiometric amounts of zeolite NaY proceed in high yield and with high selectivity to the corresponding p-bromo products; the zeolite is easily regenerated by heating.243 7 Miscellaneous preparations Mioskowski and co-workers report an interesting procedure for the conversion of primary amides to nitriles (126]127) (Scheme 51)244 involving aldehyde- and acidcatalysed water transfer from the amide to acetonitrile.Whilst various aldehydes are e§ective as catalysts only formic acid serves as a successful acid catalyst. The proposed catalytic cycle involves the formation of the nitrilium salt 128 from the aldehyde formic acid and acetonitrile. Reaction of this salt with the primary amide is thought to give the intermediate 129 which collapses with the release of the nitrile 127 to the b-hydroxy amide 130. The aldehyde is regenerated from the b-hydroxy amide 130 and at the same time produces acetamide. The mild reaction conditions should render the process useful. A potentially useful method for the synthesis of phthalimidine derivatives from o-phthalaldehyde and an amine has been revealed by Takahashi and co-workers (Scheme 52).245 They found that the reaction is e¶cient when 1,2,3-1H-benzotriazole and 2-mercaptoethanol are present in the reaction mixture.Pinacolborane (PBH) is an excellent stoichiometric hydroboration reagent for alkenes and alkynes in the presence of catalytic amounts of transition metal complexes 283 Synthetic methods R1 NH2 O R1 C N R N HO R1 NH2 O R N HO O N H R1 R N H HO O 126 RCHO HCO2H CH3CN heat 126 127 RCHO HCO2H CH3CN 128 HCO2 – 129 – R1CN 130 – MeCONH2 Scheme 51 H H O O NH N N HO SH N O R 80% R = p-CO2Me-C6H4 RNH2 Scheme 52 (Zr and Rh).246,247 While Wilkinson’s catalyst causes isomerisation of internal alkenes Rh(CO)(PPh 3 ) 2 Cl gives the internal alkyl pinacolboronates with excellent regioselectivity. Rhodium and also nickel are extremely e§ective catalysts for the hydroboration of alkynes with PBH.Dicarbonyltitanocene is also an e¶cient and highly selective catalyst for alkyne hydroborations by catecholborane and dimethyltitanocene is an e¶cient and highly selective catalyst for alkene hydroborations.248 These results contrast hydroboration chemistry with other early transition metal complexes that simply lead to decomposition of catecholborane to form diborane. The simple hydroboration of olefins with catecholborane in the absence of metal catalysts at room temperature is greatly accelerated by the presence of N,N-dimethylacetamide. 249 The removal of organotin residues from reaction mixtures particularly those from radical reactions is often problematic. 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