4 Reaction Mechanisms Part (iii) Free-radical Reactions By S. CADDICK" and K. ABOUTAYAB School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton BNl 9QJ UK 1 Introduction Free-radical intermediates continue to attract a good deal of interest from both synthetic and mechanistic standpoints. A lively debate regarding the intermediacy of radical intermediates in certain Gif systems continues;' evidence to suggest a non-dissociative mechanism for the synthetically useful b-(acy1oxy)alkyl radical rearrangement has also recently been disclosed;2 Newcomb and Chestney have developed a mechanistic probe for distinguishing between carbocation and radical intermediates3 and Jenkins has discussed the 'b-oxygen effect' in radical reactions which can be both activating and deactivating and can be attributed to polar effect^.^ 2 Initiators Promoters and Mediators Developments in experimental procedures utilizing the ubiquitous tin-based radical reducing agents have featured extensively.Nakamura and coworkers for e~arnple,~ have described sonochemical (as opposed to AIBN) initiated hydro and hydroxystan- nylation of C-C multiple bonds with triphenyltin hydride. These tin-based reagents whilst widespread in their synthetic use are far from ideal for preparative purposes. One of the disadvantages of utilizing tributyltinhydride (TBTH) in radical-based transformations is the decomposition of the reagent unless carefully stored and used. Podesta Mascaretti and coworkers have recently utilized trineophyltin hydride as an alternative to TBTH and further recent disclosures from their laboratories detail the preparation of trineophyltin deuteride as a useful reagent for the deuteriation of sensitive organic molecules.6 The reagent is soluble in a range of organic solvents is apparently stable to air and undergoes no noticeable decomposition when kept at room temperature for months.In order to avoid contamination of products with ' F. Minisci and F. Fontana Tetrahedron Lett. 1994 35 1427; F. Minisci F. Fontana S. Araneo and F. Recupero Tetrahedron Lert. 1994 35 3759; D. H. R.Barton and D. R. Hill Tetrahedron Lert. 1994 35 1431. D. Crich and Q. Yao J. Am. Chem. SOC. 1994 116 2631. M. Newcomb and D. L. Chestney J. Am. Chem. Soc. 1994 116 9753. I.D. Jenkins J. Chem. Soc. Chem. Commun. 1994 1227. E. Nakamura Y. Imanishi and D. Machii J. Org. Chem. 1994 59 8178. J. C. Podesta N. Giagante A. E. Zuniga G. 0.Danelon and 0.A. Mascaretti J. Org. Chem. 1994,59,3747. 103 S. Caddick and K. Aboutayab organotin residues from reactions using TBTH a number of polymer-bound tin reagents have been described. However such appealing reagents have yet to gain widespread recognition and utility in synthesis. Dumartin and coworkers have recently reported an alternative preparation to their own polymer-bound reagent; the ease of preparation may encourage synthetic chemists to utilize this in preference to TBTH.7 Maitra and coworkers have reported the use of water as a solvent for tin-mediated halide reduction.* The experimental procedure involves heating (90"C) a suspension of the halide TBTH AIBN and NaHCO for 24 hours; and a phase-transfer catalyst can aid the reduction of water-insoluble substrates.Collum and coworkers have also reported developments in this area using (1) in conjunction with sodium borohydride and 4,4'-azobis(4-cyanovaleric acid) (ACVA). A range of halide reduction and reductive cyclizations are reported to proceed in good yields.' The development of silicon-based radical chain promoters has in recent years also been the subject of interest although the strength of the Si-H bond is crucially important for the successful application of these reagents to radical reactions. Oba and Nishiyama have reported the use of silanes (2) to promote reduction of organic halides and thioxocarbamates.The reagents appear to be simple to prepare and may provide a useful alternative to TBTH." Moving away from Group 14 hydrides Jones and coworkers have reported an interesting approach to aryl radicals as illustrated in Scheme 1. Thus treatment of iodide (3) with CoCl and methylmagnesium bromide led to the isolation of cyclization product (4) in 71YOyield.' Murphy and coworkers have continued exploring the synthetic application of radical cyclizations mediated by tetrathiofulvalene (TTF). This method appears very promising as illustrated in the formation of (6) from substrate (5) uia tandem cyclization (Scheme 2).12 Following early investigations Schwartz and Liu have examined reduction of aryl G.Dumartin G. Ruel J. Kharboutli B. Delmond M.-F. Connil B. Jousseaume and M. Pereyre SYNLETT 1994 952. U. Maitra and K. Das Sarma Tetrahedron Lett. 1994 35 7861. R. Rai and D. B. Collum Tetrahedron Lett. 1994 35 6221. M. Oba and K. Nishiyama J. Chem. Soc. Chem. Commun. 1994 1703. A. D. Clark D.I. Davies K. Jones and C. Millbanks J. Chem. Soc. Chem. Commun. 1994,41. C. Lampard J. A. Murphy F. Rasheed N. Lewis M. B. Hursthouse and D. E. Hibbs Tetrahedron Lett. 1994 35 8675. Reaction Mechanisms -Part (iii) Free-radical Reactions (3) (4) 71% Reagents i CoCl, MeMgI Scheme 1 halides using the [TiCl,Cp,]/NaBH system. They find that by changing the solvent from DMF to DMA they are able to promote radical cyclizations as illustrated in the transformation of (7) into (8) (Scheme 3).13 (7) (8) Reagents i Cp,TiCl (0.5eq) NaBH, DMA 75 "C Scheme 3 Zard and coworkers have examined the utility of nickel-mediated radical formation and detail a number of synthetically useful transformations as exemplified in the isolation of (10) from (9) in Scheme 4.14 Photolytic methods remain particularly appealing for the generation of alkyl radicals.Cossy and coworkers have recently detailed a useful cyclization method in which irradiation of alkyl halides in the presence of triethylamine leads to alkyl radicals which undergo cyclization in good yield as shown in Scheme 5." Mattay and Kirschberg have also described a similar cyclization strategy. Thus a range of cyclopropyl ketones undergo photoinduced cleavage with subsequent cyclization as shown in the transformation of (13) into (14) (Scheme 6).16 Enones have also been shown to serve as useful precursors to alkyl radicals.Pandey l3 Y. Liu and J. Schwartz J. Org. Chem. 1994 59 940. J. Boivin M. Yousfi and S.Z. Zard Tetrahedron Lett. 1994 35 5629. J. Cossy J.-L. Ranaivosata and V. Bellosta Tetrahedron Lett. 1994 35 8161. l6 T. Kirschberg and J. Mattay Tetrahedron Lett. 1994 35 7217. S. Caddick and K. Aboutayab (9) (10) 76% Reagents i Ni powder AcOH Pr'OH t-dodecanethiol Scheme 4 Reagents i NEt, hv (254nm) MeCN Scheme 5 Reagents i NEt, hv (300nm) MeCN Scheme 6 aCO2Et La.-CO2Et (15) (16)98% Reagents i hv (405 nm) DCA Ph,P DMF/Pr'OH H,O Scheme 7 and coworkers have found that photolysis of enones such as (15) with Ph,P and dicyanoanthracene (DCA) leads to (16) in excellent overall yields (Scheme 7).17 The addition of triphenylsilanethiol to alkenes has been illustrated.This useful reagent has been used as an H,S equivalent and as a mediator of cyclization as highlighted in Scheme 8.'* Burton and coworkers have reported a novel radical addition process which has been used in the preparation of fluorinated phosphonates as shown in Scheme 9. Thus l7 G. Pandey S. Hajra and M. K. Ghorai Tetrahedron Lett. 1994 35 7837. '* B. Hache and Y. Gareau Tetrahedron Lett. 1994,35 1837. Reaction Mechanisms -Part (iii) Free-radical Reactions (17) (18) 80% cis:tmns 4:l Reagents i Ph,SiSH AIBN hv; ii TFA Scheme 8 (ROkP + F$-(F (RO)~P(0)CF2CF21 Br Scheme 9 irradiation of trialkyl phosphite (19) with halide (20) leads to phosphonate (2l).I9 Samarium-promoted transformations continue to find use in a range of synthetic applications such as Julia alkenylation,20 deoxygenation of aldonolactones2 and ulosonic acids,22 and Reformatsky reactions.23 3 Intramolecular Reactions General.-With a potentially useful 6-endo-dig cyclization reaction Marco-Contelles and coworkers have prepared cyclitols.They explain that the strained nature of the transition state required for the 5-exo-dig mode governs the regiochemical outcome of the cyclization as illustrated in the isolation of (23) from (22) (Scheme (22) (23)66% Reagents i TBTH AIBN toluene Scheme 10 The formation of larger rings has been cleverly exploited as part of a tandem cyclization strategy by Pattenden and coworkers.Scheme 11 shows one example of the l9 H.K. Nair and D. J. Burton J. Am. Chem. SOC. 1994 116,6041. 2o M. Ihara S. Suzuki T. Taniguchi Y. Tokunaga and K. Fukumoto SYNLETT 1994 859. 21 S. Hannesian and C. Girard SYNLETT 1994 861. 22 S. Hannesian and C. Girard SYNLETT 1994 863. 23 S. Hannesian and C. Girard SYNLETT 1994 865. 24 J. Marco-Contelles M. Bernabe D. Ayala and B. Sanchez J. Org. Chem. 1994 59 1234. S. Caddick and K. Aboutayab H (24) (25) 55% Reagents i TBTH AIBN benzene Scheme 11 (26) (27)56% Reagents i TBTH AIBN Scheme 12 type of impressive transformation which can be achieved by such a method.2s Kim and coworkers have detailed an interesting new approach to N-heterocycles by addition of a carbon-centred radical to an azide as shown in Scheme 12.26 The formation of cyclopropanes by radical cyclization has been reported by several groups in the past year.Gravel and Denis have utilized an addition-elimination terminated cyclopropanation reaction as illustrated in Scheme 13. It is interesting to note that under the reaction conditions no products resulting from addition of phenylthio or tri-n-butylstannyl radical to the vinyl cyclopropane are ob~erved.~’ PhS Reagents i (Bu,Sn), hv AIBN Scheme 13 An alternative method is described by Malacria and coworkers. In this work the addition of a vinyl radical to an alkyne initiates a tandem cyclization reaction; a 3-em-trig cyclization gives the cyclopropane-containing product (3 1) (Scheme 14).28 25 G.Pattenden A.J. Smithies and D.S. Walter Tetrahedron Lett. 1994 35 2413; M.J. Begley G. Pattenden A. J. Smithies and D. S. Walter Tetrahedron Lett. 1994 35,2417. S. Kim G.H. Joe and J. Y. Do J. Am. Chem. Soc. 1994 116 5521. ” R.C. Denis and D. Gravel Tetrahedron Lett. 1994 35,4531. M.Journet and M. Malacria J. Org. Chem. 1994 59 718. Reaction Mechanisms -Part (iii) Free-radical Reactions 'I' f9J (31) 48% Reagents i TBTH AIBN benzene Scheme 14 q~i * O P E I (32) (33)46% Reagents i TBTH AIBN benzene Scheme 15 The intermediacy of a diene in the aforementioned example has been recognized and utilized in an intramolecular Diels-Alder reaction.This powerful new synthetic methodology has excellent potential for use in target synthesis (Scheme 15).29 Indoles have been prepared by radical cyclizations which illustrate the versatility of organostannane chemistry. Fukuyama and coworkers3' use TBTH to initiate cyclization of an isonitrile (Scheme 16).The resulting tin-substituted indole is then used most economically in palladium(0)-induced cross couplings to yield a range of substituted indoles. rR NC i'ii -H (34) (35) Reagents i TBTH AIBN; ii Pd(o) R'X NEt Scheme 16 Acyl radicals are readily generated from a number of precursor^^^ and have been used recently to good effect in a novel macrocyclization methodology described by 29 M. Journet and M.Malacria J. Org. Chem. 1994 59 6885. 30 T. Fukuyama X. Chen and G. Peng J. Am. Chem. SOC. 1994 116 3127. 31 J.H. Penn and F. Liu J. Org. Chem. 1994 59 2608. S. Caddick and K. Aboutayab 0 (37)78% Reagents i (TMS),SiH AIBN CO (10 atm) Scheme 17 (38) Reagents i TBTH AIBN Scheme 18 Ryu Sonoda and coworkers. In this interesting tandem process intermolecular carbonylation is used to generate an intermediate acyl radical which then undergoes macrocyclization as shown in Scheme 17.32 Acyl radicals also feature in a novel tandem-cyclization approach to steroid skeleta. Thus treatment of acyl selenide (38) with TBTH under standard conditions led to the isolation of tetracycle (39) in 53% yield as a single isomer (Scheme 18).33 A number of interesting reports highlight the synthetic utility of intramolecular addition of radicals to aromatic systems.Zard and coworkers have described a useful application to the synthesis of indoles as shown in the transformation of halides or xanthates into indolones using di-t-butyl peroxide or nickel powder (Scheme 19).34 Addition of vinyl radicals to furans has also been shown to be effective in an elegant approach to cyclopentenes as shown in the transformation of vinyl iodide (42)into (43) (Scheme 20).35 Two interesting reports have also described approaches to fused heterocyclic aromatic systems involving radical addition to pyrroles and in dole^.^^ 32 1. Ryu K. Nagahara H. Yarnazaki S. Tsunoi and N. Sonoda SYNLETT 1994 643. 33 L.Chen G. B. Gill and G. Pattenden Tetrahedron Lett. 1994 35 2593. 34 J. Axon L. Boiteau J. Boivin J. E. Forbes and S. Z. Zard Tetrahedron Lett. 1994,35 1719; J. Boivin M. Yousfi and S. Z. Zard Tetrahedron Lett. 1994 35 9553. 35 P. J. Parsons M. Penverne and I. L. Pinto SYNLETT 1994 721. 36 Y. Antonio M. E. De La Cruz E. Galeazzi A. Guzrnan B. L. Bray R. Greenhouse L. J. Kurz D. A. Lustig M. L. Maddox and J. M. Muchowski Can.J. Chem.,1994,72,15; D. R. Artis I.-S. Cho S. Jaime-Figueroa and J. M. Muchoski J. Org. Chem. 1994,59 2456. Reaction Mechanisms -Part (iii) Free-radical Reactions 0 (40a) X = SCSOMe (41a) X = SCSOMe 57% (40b)X = CI (41b) X = CI 78% Reagents i (X = SCSOMe) di-t-butyl peroxide; ii (X = Cl) Ni AcOH Scheme 19 OTHP lBS0 OTBS (42) Reagents i TBTH AIBN Scheme 20 ”* XH XH Ro&H X’ 0’ “ W 0’ R RoRO OR -RoRO OR H.Ro RO - H Scheme 21 Trans1ocations.-New radical translocations continue to be developed.37 Two of the most important synthetic contributions have been reported simultaneously by Crich3* and by C~rran.~~ These groups have established independently the viability of a radical-mediated approach to inversion of p-mannose linkages. The general concept shown in Scheme 21 relies on the propensity of radicals at C-1 of the mannose to abstract a hydrogen-atom from TBTH using their least hindered a-face. The two groups have successfully illustrated this elegant concept using different 37 D.P. Curran and H. Liu J. Chem. Soc. Perkin Trans 1 1994 1377; P.J.Parsons and S. Caddick Tetrahedron 1994 47 13523; S. Bogen M. Journet and M. Malacria SYNLETT 1994 959; A. De Smaeker A. Waldner P. Hoffman and T. Winkler SYNLETT 1994 330. 38 J. Brunckova D. Crich and Q. Yao Tetrahedron Lett. 1994 35 6619. 39 N. Yamazaki E. Eichenberger and D. P. Curran Tetrahedron Lett. 1994 35 6623. 112 S. Caddick and K. Aboutayab Me. ON OMe " 0-..-I Reagents i TBTH AIBN Scheme 22 (48) (49) Reagents i TBTH AIBN Scheme 23 tactics. The Crich group utilize bromo-acetal precursors in a 1,5 hydrogen-atom translocation approach (Scheme 22).38 The Curran group exploit a 1,6 hydrogen-atom abstraction using their recently developed PRT approach (Protection and Radical Translocation) as shown in the isolation of (49) from reduction of (48) (Scheme 23).39 At present both approaches suffer from a competing reduction which quenches the radical prior to translocation.It should be possible to optimize the approach using a less-efficient hydrogen atom donor. Until recently most of the reported translocation work had been initiated by halide reduction. However Burke and coworkers have highlighted a useful alternative based on thiol addition to an alkyne as shown in Scheme 24. Thus addition of thiophenol radical to (50)leads to cyclization product (51) (69%) presumably via an intermediate vinyl radical which undergoes translocation and concomitant cyclization .40 Diazonium salts can also serve as radical precursors in translocation processes. Weinreb and coworkers4' have exploited this reactivity in their a-methoxylation of substituted pyrrolidines uia o-aminobenzamides as shown in Scheme 25.Murphy and coworkers extend the synthetic utility of their recently described TTF methodology in a translocation/cyclization sequence as illustrated in the formation of (55) from (54) in 45% yield (Scheme 26).42 40 S.D. Burke and K. W. Jung Tetrahedron Lett. 1994 35 5837. 41 G. Han M.C. McIntosh and S. M. Weinreb Tetrahedron Lett. 1994 35 5813. 42 M. J. Begley J.A. Murphy and S. J. Roome Tetrahedron Lett. 1994 35 8679. Reaction Mechanisms -Part (iii) Free-radical Reactions i i’i -(51) 69% Reagents i PhSH AIBN benzene Scheme 24 Reagents i NaNO, HCl CuCl MeOH rt Scheme 25 (54) Reagents i TTf; ii base Scheme 26 Of course heteroatom-centred radicals have long been known to undergo syntheti- cally useful atom-abstraction reactions.Recently Ryu Sonoda and Tsunoi have described an interesting sequence based on a hydrogen atom translocation/carbonyla-tion sequence,43 (56) to (57) and Kim and coworkers have described an interesting 1,5-silicon translocation process (58) to (59) (Scheme 27).44 Stereoselectivity.-Stereocontrol in radical cyclizations is an important issue and a number of reports have illustrated the very high levels of diastereoselectivity which can be obtained from cycli~ations.~~ Nishida and coworkers have used a chiral auxiliary approach. Cyclization of (60) under TBTH/BEt conditions led to the products (61a) 43 S.Tsunoi I. Ryu and N. Sonoda J. Am. Chem. SOC.,1994 116 5437. 44 S. Kim J. Y. Do and K. M. Lim J. Chem. SOC. Perkin Trans 1 1994 2517. 45 M. Zahouily M. Journet and M. Malacria SYNLETT 1994 366. S. Caddick and K. Aboutayab 0 (57)50% OTMS (9) (59)92% Reagents i Pb(OAc), CO; ii TBTH AIBN Scheme 27 0 (60)R* = (-)-8-phenylmenthyl Additive Yield A:B None 88% 58:42 MAD 79% 96:4 Reagents i TBTH BEt Scheme 28 and (61b) in good yield but with no diastereoselectivity; with Lewis acids such as methylaluminium bis(2,6-di-t-4-methylphenoxide)(MAD) significant enhancements in rate and moderate to excellent levels of diastereocontrol were achieved (Scheme 28).46 Curran and coworkers47 have highlighted the potential of substrate-controlled group-selective radical cyclizations.Treatment of the iodide (62) with TBTH induces a stereoselective cyclization with isolation of (63a) (82%; exolendo ratio 94 :6) (Scheme 29). Group selectivity here is rationalized in terms of preferential reaction of the radical with one of the diastereotopic alkenes via a chair transition state having the methyl group equatorial (62a). Reactions in which diastereotopic radicals compete for a single 46 M. Nishida E. Ueyama H. Hayashi Y. Ohtake Y. Yamaura E. Yanaginuma 0.Yonemitsu A. Nishida and N. Kawahara J. Am. Chem. SOC. 1994 116 6455. 47 D.P. Curran H. Qi N.C. DeMello and C.-H. Lin J. Am. Chem. SOC. 1994 116 8430. React ion Mechanisms Part (iii) Free-radical Reactions Me02C.. LP -i Me H endo Reagents i TBTH AIBN Scheme 29 Pr Pr Pr\ N r (65) Scheme 30 alkene were also described but this approach has as yet yielded only modest diastereoselectivities.The general approach is very appealing and is applicable to asymmetric synthesis either using an enantiomerically enriched substrate or by using a similar auxiliary controlled process.48 Heteroatom-centred Radicals.-Cyclization of heteroatom-centred radicals has also been an area of considerable recent activity with a great deal of emphasis on nitrogewcentred radical^.^' Tsakaniktsidis and Maxwell have found that cyclization of aminyl radical (64) is enhanced by the addition of (Bu,Sn),O although the reasons for this observation are presently unclear (Scheme 30).’O Zard and coworkers have reported tandem cyclization of amidyl radicals thus treatment of 0-benzoyl hydroxamic acid (67) with TBTH/AIBN leads to tricyclic adduct (68) in good yield (Scheme 31).’l 48 D.P. Curran S.J. Geib and C.-H. Lin Tetrahedron Asymmetry 1994 5 199. 49 W. R.Bowman D. N. Clark and R. J.Marmon Tetrahedron 1994,50 1275; W. R. Bowman D. N. Clark and R. J. Marmon Tetrahedron 1994,50,1295; J. Boivin E. Fouquet and S. Z. Zard Tetrahedron 1994,50 1745; J. Boivin E. Fouquet and S.Z. Zard Tetrahedron 1994 50 1757; J. Boivin E. Fouquet A.-M. Schiano and S. Z. Zard Tetrahedron 1994 50 1769. 50 B. J. Maxwell and J. Tsakaniktsidis J. Chem. SOC. Chem. Commun. 1994 533. 5’ A.-C. Callier B. Quiclet-Sire and S.Z. Zard Tetrahedron Lett.1994 35 6109. S. Caddick and K. Aboutayab 0 - i H (68)73% Reagents i TBTH AIBN Scheme 31 (69) (71)74% Reagents i Bu,SnCl NaBH, AIBN Scheme 32 A similar strategy has been used for the generation of iminyl radical^.'^ Oxygen-centred radicals also undergo cycli~ation~~ and recently Newcomb and coworkers have developed a convenient precursor for the generation of allylic and homoallylic alkoxycarbonyloxy radicals.54 4 Intermolecular Reactions General.-Yus and coworkers have illustrated the viability of a novel process which they suggest proceeds by intermolecular addition of a vinyl radical to an alkene as illustrated in Scheme 32.’’ With a very similar transformation Hosomi and coworkers have reported addition of iodide (72) to acrylonitrile which proceeds in good yield when carried out with intermittent addition of TBTH without an initiator at room temperature! (Scheme 33)? Narasaka and coworkers have explored the synthetic utility of electrophilic arenesulfonyl radicals.They find that treatment of sodium(toly1)sulfinate with an oxidant in the presence of an electron-rich alkene leads to addition products as exemplified in Scheme 34.57 Acyl radicals readily undergo intramolecular cyclization reactions however analog- 52 J. Boivin A.-M. Schiano and S.Z. Zard Tetrahedron Lett. 1994 35 249. 53 D.J. Pasto and F. Cottard Tetrahedron Lett. 1994 35 4303. 54 M. Newcomb and B. Dhanabalasingam Tetrahedron Lett. 1994 35 5193. 55 F. Foubelo F. Iloret and M.Yus Tetrahedron 1994 6715. 56 K. Miura D. Itoh T. Hondo and A. Hosomi Tetrahedron Lett. 1994 35 9605. ” K. Narasaka T. Mochizuki and S. Hayakawa Chern. Lett. 1994 1705. Reaction Mechanisms -Part (iii) Free-radical Reactions (72) (73) (74) 60% Reagents i TBTH benzene rt Scheme 33 SEt ArS0,Na + -SEt (75) (76) (77)87% Reagents i Mn(nI) MeOH 0 “C Scheme 34 ous intermolecular processes are far less common and in a recent report Narasaka and Sakurai show that intermolecular addition of acyl radicals to electron-deficient alkenes can be promoted by oxidation of chromium complexes (78) as shown in Scheme 35. The use of acetonitrile as a solvent is essential for high yields.’* (78) (79)68% Reagents i Cu(acac), methyl acrylate rt Scheme 35 Following an earlier report on the preparation of phosphonic acids by addition of carbon-centred radicals to white phosphorous Castagnino Barton and Jaszberenyi have shown that a similar approach can be used for the preparation of thiols by addition to elemental sulf~r.’~ Robertson and Burrows have utilized a radical rearrangement to prepare or-trimethylsilyl aldehydes as shown in the transformation of (80) into (81) (Scheme 36).60 Stereoselectivity in Intermolecular Reactions.-Stereoselective intermolecular radical reactions continue to be an area of activity,61 and Belekon and coworkers have H.Sakurai and K. Narasaka Chem. Lett. 1994 2017. 59 D. H. R. Barton E. Castagnino and J. C. Jaszberenyi Tetrahedron Lett. 1994 33,6057. 6o J.Robertson and J.N. Burrows Tetrahedron Lett. 1994 35,3777. D. P. Curran E. Eichenberger M. Collis M.G. Roepel and G. Thoma J. Am. Chem. Soc. 1994,11,4279; Y. Guindon C. Yoakim V. Gorys W. W. Ogilvie D. Delorme J. Renaud G. Robinson J.-F. Lavallee A. Slassi G. Jung J. Rancourt K. Durkin and D. Liotta J. Org. Chem. 1994 59 1166; W. Smadja SYNLETT. 1994 1; K. Paulini and H.-U. Reibig Chem. Ber. 1994 127 685; J.O. Metzger K. Schwarzkopf W. Saak and S. Pohl Chem. Ber. 1994 127 1069. S. Caddick and K. Aboutayab Reagents i PhSH AIBN Scheme 36 I. I Reagents i TBTH AIBN RX; ii HCl Scheme 37 Reagents i FeSO, H,O, DMSO Scheme 38 described a potentially useful approach to a-amino acids.62 Addition of thermally generated carbon-centred radicals to the dehydroalanine residue of enantiomerically enriched nickel(I1) Schiff base complex (82) affords amino acid (83) after hydrolysis (Scheme 37).Baciocchi and coworkers continue their excellent investigations on homolytic aromatic substitution reactions. In some of their most recent work they have demonstrated that enantiomerically enriched a-haloesters undergo diastereoselective addition to heteroaromatic systems as highlighted in Scheme 38.63 Curran and coworkers have described some asymmetric group transfer addition reactions. Addition of selenomalonitrile (87) to enol ether (88) leads to product (89) in 62 R.G. Gasanov L. V. Il'inska M. A. Misharin V. I. Maleev N. I. Raevski N. S. Ikonnikov S. A. Orlova N. A. Kuzmina and Y.N. Belokon J.Chem. SOC.,Perkin Trans. 1 1994 3343. 63 E. Baciocchi E. Muraglia and C. Villani SYNLETT 1994 821. Reaction Mechanisms -Part (iii) Free-radical Reactions CN (89)91% Reagents i hv AIBN Scheme 39 $p Bu' (90) Reagents i Bu'HgC1 NaBH, 25 "C Scheme 40 good yield with a high degree of stereocontrol (Scheme 39).64 The highly asymmetric selenium-transfer step is attributed to the considerable pyramidalization i.e. a product-like transition state (88a). In further studies Curran and his collaborators have examined the addition of carbon-centred radicals to axially chiral racemic imides (90). They note that addition of t-butyl radical to (90) leads to the product (91) with high levels of stereoselectivity (Scheme 40). Equilibration studies show that the reactions are kinetically controlled and enantiopure auxiliaries of this type will undoubtedly prove useful in asymmetric synthesis.Careful choice of promoter can have an important influence on the stereochemical outcome of radical reactions. Apeloig and Nakash demonstrate that simple reduction of gem-dichlorocyclopropanes can lead to different or even the reversal of product ratios as shown in Scheme 41 .66 It is suggested that the observed stereoselectivity is due to the interaction of the reagent and the y-substituent. 64 D. P. Curran S. J. Geib and L. H. Kuo,Tetrahedron Lett. 1994 35 6235. 65 D. P. Curran H. Qi S. J. Geib and N.C. DeMello J. Am. Chem. SOC. 1994 116 3131. 66 Y. Apeloig and M. Nakash J. Am. Chem. SOC.,1994 116 10781.S. Caddick and K. Aboutayab (-) (93b) i (93a)/(93b) 1.3 :1 ii (93a)/(93b) 1 4.6 Reagents i TBTB AlBN; ii (TMS),SiH AlBN Scheme 41 TMST Br (94) (954 (95b) % Lewis acid Ratio Yiild 0 1.3~1 63% 0.1 3:l 45% 1.1 8.6:l 62% Reagents i allyl(tributyl)tin AIBN Lewis acid CH,Cl, hv Scheme 42 Highly stereoselective intermolecular radical addition reactions can be promoted using a chelation-control strategy with Lewis acids and this approach is becoming increasingly popular. Europium-derived Lewis Acids appear promising in this regard as demonstrated by Nagano and K~no.~~ They report that allylation of substrate (94) proceeds in reasonable yield but with enhanced stereoselectivity when either catalytic or stoichiometric quantities of [Eu(fod),] are used (Scheme 42).A range of investigations have been carried out on stereoselective radical addition reactions of cyclic a-sulfinyl radicals by the groups of Renaud and Curran.68 In allylation studies certain Lewis acids were found to enhance stereoselectivity. The use of stoichiometric methylaluminium diphenoxides was found to provide products (97a) and (97b) with the highest levels of stereocontrol; however efficient catalysis is possible as shown in Scheme 43. It is interesting to note that the stereocontrolled transformation of (96) into (97) can also be enhanced (cisltrans 1:7) using diarylurea (98) presumably by hydrogen bonding of the intermediate radical species.69 67 H. Nagano and Y. Kuno J. Chem.SOC. Chem. Commun. 1994,987. 6a P. Renaud N. Moufid L.H. Kuo and D.P. Curran J. Org. Chem. 1994 59 3547; P. Renaud P.-A. Carrupt M. Gerster and K. Schenk Tetrahedron Lett. 1994 35 1703; P. Renaud and T. Bourquard Tetrahedron Lett. 1994 35 1707. 69 D. P. Curran and L. H. Kuo J. Org. Chem. 1994 59 3259. Reaction Mechanisms -Part (iii) Free-radical Reactions 0-0- I &ePh i + o.-v (96) (974 (97U % Lewis acid Ratio Yield 0.1 %:15 63% 1 .1 90:2 72% Reagents i ally1 (tributyl)tin MAD Scheme 43 H1&8°2C H H C02CBH17 (98) (99) X = O,CH Reagents i RCH=X AIBN THF Scheme 44 Polymers.-Porter and coworkers have examined the stereochemistry and control of dispersity in free-radical telomerizati~ns;~~ they propose a model for the low selectivity associated with telomerization of poly(ally1 acetate) from poly (camphor sultam a~rylamide).~ Waymouth and Hsiao have reported free-radical hydrosilylation of poly(phenylsi1ane) as shown in Scheme 44.72The mild and general nature of the procedure should lend itself to the preparation of a range of polymers with a view to optimizing their physicochemical properties.The synthesis of poly(sily1 enol ethers) is the subject of a recent disclosure by Endo and coworkers. The wide range of transformations which silyl enol ethers undergo obviously makes them useful intermediates for the preparation of a wide range of polymer congeners. However these useful species are not generally stable under polar 70 N. A. Porter G. S. Miracle S.M. Canniuaro R. L. Carter A.T. McPhail and L. Liu J. Am. Chem. SOC. 1994 116 10255. 7L W.-X. Wu A.T. McPhail and N.A. Porter J. Org. Chem. 1994 59 1302. 72 Y. L. Hsiao and R. M. Waymouth J. Am. Chem. SOC.,1994 116 9779. S. Caddick and K. Aboutayab Scheme 45 polymerization conditions and the use of a radical approach has allowed their preparati~n.~~ The process is outlined in Scheme 45and involves the ring opening of an appropriate cyclopropane to produce the polymers which are very soluble in organic solvents. Successful ‘living’ free-radical polymerizations depend on promoters which revers- ibly terminate a growing polymer chain; the search for such compounds continues. Following early work by Georges et describing the use of TEMPO Ha~kes~~ has identified (103) as a useful alternative giving low dispersity polymers and block copolymers with defined block lengths and end groups.Alternative promoters of such living radical polymerizations are clearly desirable and Wayland Fryd and coworkers have developed an alternative to the TEMPO based systems using (tetramesity1porphyrinato)cobalt neopentyl which promotes the formation of acrylate block copolymer^.^^ 5 Applications of Radical Processes to Synthetic and Biological Chemistry Synthetic Chemistry.-Radical reactions are often utilized as key steps in natural product synthesis77 but more routine transformations can be incorporated into elegant synthetic plans. In a beautiful example Roy and coworkers have developed a simple two-step synthesis of racemic dihydrosesamin (106) from the readily available 3,4-methylenedioxycinnamylalcohol (104) as shown in Scheme 46.78 Radical rearrangements also find use in target syntheses.Roberts and coworkers 73 S. Mizukami N. Kihara and T. Endo J. Am. Chem. Soc. 1994 116 6453. 74 M. K. Georges R. P. N. Veregin P. M. Kazmaier and G. K. Hamer Macromolecules 1993 26 2987. 7s C.J. Hawkes J. Am. Chem. Soc. 1994 116 11 185. 76 B.B. Wayland G. Poszmik S.L. Mukurjee and M. Fryd J. Am. Chem. SOC. 1994 116 7943. 77 K. A. Parker and D. Fokas J. Org. Chem. 1994,59,3927;A. M. Gomez J. C. Lopez and B. Fraser-Reid J. Org. Chem. 1994 59 4048. 78 G. Maiti S. Adhikari and S. C. Roy Tetrahedron Lett. 1994 35 3985. Reaction Mechanisms -Part (iii) Free-radical Reactions Ar -OH __ci f;fAr ii * yJAr Ar Ar” (104) Ar =3,4-Methylenedioxyphenyl (105) (106) 80% cis :frans7:1 Reagents i NBS CH,CI,; ii TBTH AIBN Scheme 46 (107a) Scheme 47 i -0@ 0e (110) (111) 78% Reagents i LiDBB THF -78 “C Scheme 48 utilize the rearrangement of (107a) to (109) in their synthesis of tribactams (Scheme 47).79 Rawal and Dufour” have developed a fragmentation-cyclization route to di- and triquinanes exemplified in Scheme 48.The sequence is initiated by reductive cleavage of the C-C bond B to the carbonyl of the strained tricyclic ketone (110)with lithium di-t-butylbiphenylide (LDBB). This yields the radical-enolate (1 10a) and the radical centre then adds to the pendant alkene to form a new ring in (111).Biological Chemistry.-Radicals are ubiquitous in biological systems and recently Falvey and Fenick have described their investigations using uracil derivatives. They find that radicals such as (1 12) and (1 13) experience more resonance stabilization than would normally have been expected.” 79 A. Padova S. M. Roberts D. Donati A. Perboni and T. Rossi J. Chem. SOC.,Chem. Commun. 1994,441. V.H. Rawal and C. Dufour J. Am. Chem. SOC. 1994 116 2613. D. J. Fenick and D. E. Falvey J. Org. Chem. 1994 59 4791. S. Caddick and K. Aboutayab [ 'y] vc L OpCGG OpCGG OpCGG Sugiyama Ohmori and Saito have described a novel oligodeoxynucleotide (114) which they have used to trap the proposed C-4' radical in bleomycin-mediated DNA damage.The isolation of exo-methylene (116) after treatment with a bleomycin derivative (Scheme 49) provides good evidence for the intermediacy of radical (115p2 Silverman and coworkers have used the ring opening of cinnamylamine oxide as a probe for the mechanism of monoamine oxidase-catalysed oxidation reactions. The authors conclude that there is no evidence to suggest a nucleophilic mechanism and an electron-transfer mechanism appears more likely.83 82 H. Suiyama K. Ohmori and I. Saito J. Am. Chem. SOC. 1994 116 10326. 83 R. B. Silverman X. Lu J. J. P. Zhou and A. Swihart J. Am. Chem. SOC. 1994 116 11 590.