2 Synthetic methods Part (i) Free-radical reactions By S. CADDICK N. J. PARR and S. SHANMUGATHASAN The Chemistry Laboratory School of Chemistry Physics and Environmental Science University of Sussex Falmer Brighton UK BN1 9QJ 1 Introduction It is with great regret that at the time of writing this report we note the recent death of Professor Sir Derek H. R. Barton. Professor Barton’s numerous pioneering contributions to the area of free-radical research are well-known and his contributions to chemistry will be sorely missed. Most notably in recent times his desire to clarify and develop the mechanistically complex and synthetically valuable GIF chemistry has been impressive and once again over the last year he sought to add to1 and clarify the state-of-play2 with regard to the involvement of free-radicals in these systems.The e§ect of radicals in biology is of fundamental importance and chemists continue to provide important mechanistic detail on which new developments can be based. Recent model studies on 4@-DNA radicals have shown a radical cation as an intermediate in strand cleavage.3 Moreover double-stranded 4@-DNA radicals are pyramidalised have half-lives of milliseconds and undergo highly stereoselective H-abstraction with suitable donors to give natural DNA double strands.4 2 Initiators promoters and reagents One of the di¶culties with using tin-based systems to initiate free-radical reactions is the isolation of products with high purity. In the last year there have been a number of reports on the use of fluorous tin reagents.5 The main benefit of these procedures is in their simplified purification achieved by partitioning into a triphasic mixture of organic aqueous and perfluoroalkane allowing the tin species and the product to be separated and isolated.6 The ability to conduct these reactions in fluorinated or supercritical fluids7 is also significant and it is likely that these protocols will gain widespread application in synthesis.The understanding of relative rates of radical reactions is critical for the development of synthetic procedures and in particular the strategic introduction of additional propagation steps can improve levels of synthetic e¶ciency. Recent reports have detailed the use of (PhSe) 2 to improve the rate of H-donation in the fragmentation of b-lactones as highlighted in the transformation of 1 to 2 and 3 which is poor in the absence of (PhSe) 2 (Scheme 1).8 3 O Ph Ph Ph Br (PhSe)2 AlBN TBTH 1 2 3 Yield 84% (2:3 � 95:5) O Scheme 1 Br O S OEt CN S Br O CN Dilauroyl peroxide (1 equiv.) DCE 4 5 Yield 56% Scheme 2 It is now accepted that methods for initiation need to be carefully considered when carrying out radical reactions.A nice example of the use of a stoichiometric quantity of a conventional initiator has been recently reported in the synthesis of a-tetralones.9 Thus treatment of a substrate such as 4 (itself synthesised via an intermolecular radical addition process) with stoichiometric dilauroyl peroxide generates the product 5 (Scheme 2).It is assumed that the presumed intermediate cyclohexadienyl radical cannot propagate the chain and eventually undergoes aromatisation hence the requirement for stoichiometric peroxide.This protocol is particularly noteworthy because it avoids the use of an organotin reagent. The employment of the more conventional initiator AIBN in conjunction with TBTH needs to be carefully studied in order to avoid the generation of undesirable products. In a recent report it has been shown that the cyanoisopropyl radical undergoes addition reactions with certain substituted alkynes (TMS Ph CO 2 R) but not with others (alkyl) and that unusual cyclisations onto the cyano triple bond can take place.10 Deoxygenation has long been recognised as important in organic synthesis. In an exciting piece of synthetic method development a new deoxygenation protocol for primary and secondary alcohols has been described.11 A single-step Mitsunobu procedure is employed to prepare a monoalkyl diazene which has been detected spectroscopically.This then undergoes a concerted sigmatropic elimination of dinitrogen generating an alkyl radical. The involvement of a free-radical is likely in view of the transformations of 6 and 8 to 7 and 9 respectively and the isolation of hex-1-ene from cyclisation of 8 when the reaction was carried out at room temperature. The procedure has been found to be sensitive to steric hindrance as is evident by the selective deoxygenation of 10 to give 11. Elimination can in some cases intervene as is illustrated in the preparation of interesting polyene systems e.g. 13 from 12 (Scheme 3). 4 S. Caddick N. J. Parr and S. Shanmugathasan OH N O N O OH PPh3 DEAD NBSH O2 THF 6 7 Yield 84% OH PPh3 DEAD NBSH NMM 8 9 Yield 66% H H OH H HO H H H HO H PPh3 DEAD NBSH THF 10 11 Yield 84% CH2OH CH2 PPh3 DEAD NBSH NMM 12 13 Yield 65% Scheme 3 3 Intramolecular reactions Cyclisation reactions continue to dominate the field of radical chemistry and in a very elegant atom-transfer process Nicholas and co-workers have devised highly regio- and stereo-selective annulation processes;12 irradiation of bromides 14 15 and 16 leads to products 17–20 (Scheme 4).The regio- and stereo-selectivity of the transformations are rationalised by a late product-like transition state. In the formation of bromosulfonyl dienes 24–26 by radical cyclisation of their precursor diynes 21–23 the authors rely on the use of electrophilic tosyl radicals to promote these cyclisations successfully (Scheme 5).13 Isolation of good yields of cyclic bis-sulfonyl dienes such as 28 from 27 was achieved when an excess of p-toluenesulfonyl bromide was used (Scheme 6).The formation of medium and larger rings continues to attract considerable atten- 5 Synthetic methods Part (i) Free-radical reactions Br Ph Co2(CO)6 R Ph Co2(CO)6 Ph Co2(CO)6 Ph Co2(CO)6 Ph R Br Br Br Br 14–16 18 19 17 20 Yield 73% Yield 60% (18:19 1:1) Yield 56% hn hn hn (R = Me) (R = CO2Me) (R = H) Scheme 4 X R X R Br Ts TsBr AIBN C6H6 21–23 R = H X = N 24 R = H X = O 25 R = Me X = C(CO2Me)2 26 Yields 40–91% Scheme 5 EtO2CCO2Et Ts Ts EtO2CCO2Et TsBr AIBN C6H6 27 28 Yield 91% Scheme 6 tion from synthetic chemists. A recent study demonstrates that six to nine membered cyclic amino acid derivatives can be prepared by a tin mediated radical cyclisation as illustrated in the transformation of 29 to 30 (Scheme 7).14 In a similar fashion Beckwith and co-workers have shown that macrocyclic polyethers can be synthesised 6 S.Caddick N. J. Parr and S. Shanmugathasan Boc N CO2 Me I ( ) n NBoc ( ) n CO2Me AIBN TBTH DBU 29 30 n = 0–3 Yields 52–73% Scheme 7 R O O O I O O O O R O n TBTH AIBN C6H6 31 n = 1–4 R = H CO2Et CO2But 32 Yields 29–78% n Scheme 8 I O O H O O H TBTH AIBN 33 34 Yields 45–60% Scheme 9 O I O O O TBTH AIBN 35 36 Yield 40% Scheme 10 e¶ciently by radical cyclisation (e.g. 31 to 32 Scheme 8).15 The presence of oxygen is known to accelerate the rate of small ring radical cyclisation and extensions to macrocycle formation are preparatively useful and mechanistically interesting. In studies toward the taxane skeleton Pattenden and co-workers have exploited a radical cascade of compound 33 which involves a 12-endo-dig macrocyclisation followed by a 6-exo-8-endo cyclisation a§ording 34 in good yield (45–60%) (Scheme 9).16 Success with these demanding types of cyclisation are dependent upon a number of features perhaps the most obvious appears to be related to the presence of the alkyne and indeed in related work the same group have exploited ynones in cascade processes exemplified in the transformation of 35 to 36 (Scheme 10).17 Vinyl cyclopropanes have 7 Synthetic methods Part (i) Free-radical reactions I O H H H H H H O O H H TTMSS AIBN C6H6 37 38 39 Yield 65% (38:39 2:1) R1 R2 R3 O SePh O R1 R2 R3 TBTH AIBN 40 41 Yields 40–66% R1 = H alkyl Ph R2 = H alkyl Scheme 11 O I Ph O Ph O Ph BEt3 TBTH PhCH3 O Pr I O Pr 42 43 53% ATPH 44 16% ( E/ Z = 54:46) 99% ( E/ Z = 19:81) Et3B TBTH PhCH3 45 46 95% ( cis/ trans = 3:97) ATPH 99% ( cis/ trans = 92:8) Sche 12 also been utilised as electrophores in macrocyclisation processes (37 to 38 39)18 and in a novel cyclisation approach to cyclohexenones (40 to 41 Scheme 11).19 Stereocontrol This is an attractive aspect of many synthetically important cyclisation reactions and understanding of the features associated with stereoselectivity has been enhanced again this year.The use of Lewis acids is well documented and in some impressive examples aluminium tris(2,6-diphenyl)phenoxide (ATPH) has been shown to improve the stereochemical outcome (e.g. 42–44 and 45–46 Scheme 12).20 The experimental procedures involve pre-coordination of reagent and substrate followed by a Et 3 B–TBTH mediated cyclisation.The use of covalently bound stereoinducing elements is also an attractive strategy and Curran and collaborators have extended the principles of Unimolecular Chain Transfer (UMCT) to control the stereochemical outcome of cyclisation reactions. Although the governing factors have yet to be fully 8 S. Caddick N. J. Parr and S. Shanmugathasan I OSi H Ph Ph H O Si H I (Bu3Sn)2 hn C6H6 47 48 Yield 53% I OSi Ph Ph H O Si TBTH AIBN C6H6 49 50 Z/ E 95:5 Scheme 13 I OH BnO BnO BnO BnO BnO BnO OH NaOEt NaBH4 Co(Salen) air 51 52 53 Yield 57% (52:53 4:1) Scheme 14 delineated some highly stereoselective procedures have been developed as illustrated in the isolation of 48 and 50 from 47 and 49 using TBTH (Scheme 13).21,22 The control of stereochemistry by employing radical-based transformations in carbohydrate chemistry has been the subject of intensive investigations and the synthesis of carbocycles from carbohydrates has been an important part of this area.23 A cobalt-mediated oxidative cyclisation protocol is illustrated in the transformation of 51 to 52; in order to be successful the cyclisation rate must be faster than oxidation of the initially formed radical as highlighted by the formation of 53 (Scheme 14).24 The synthesis and utility of a-amin‘o acids in radical-based synthesis has also seen considerable activity.Bowman and co-workers have attempted to use the chirality of amino acids to induce stereocontrol in cyclisations for the preparation of unusual cyclic amino acids.The reactions proceed as expected but with moderate selectivities and yields exemplified in the synthesis of the proline derivative 55 from 54 (Scheme 15).25 Aryl radicals The generation of highly reactive aryl radicals from arenediazonium salts has been cleverly exploited in a novel indole synthesis involving ipso substitution of vinyl bromides (56 to 57) (Scheme 16).26 In many cases tetrathiafulvalene (TTF) is used to promote the decomposition of diazonium salts and recent studies have discounted a purely ionic mechanism for a range of established synthetic reactions.27 This ability to generate aryl radicals from arenediazonium salts has also been used to form acyl radicals by intramolecular acyl substitution. The involvement of acyl rad- 9 Synthetic methods Part (i) Free-radical reactions N N SPh H CO2 R2 R1 H CO2 R2 R1 TBTH AMBN PhMe 54 55 R1 R2 = alkyl Yields 20–48% de 20–48 Scheme 15 N NR2 R1 R2 R1 N2 Br SO2Me SO2Me BF4 – NaI Acetone 56 57 R1 = H Me Ph; R2 = H Me Yields 44–83% Scheme 16 S N2 + O S O O O NaI Acetone 58 59 60 Yields 81% 90% BF4 – Scheme 17 icals is suggested as they can be trapped in conventional addition processes e.g.58 to 59 and 60 (Scheme 7).28 Aryl radical cyclisations have provided a useful vehicle for demonstrating the feasibility of intramolecular solid-phase radical reactions. In addition to the obvious applications of such approaches in the combinatorial chemistry area a particularly attractive benefit is their ease of purification. Appropriate resin choice has been shown to be important for example the use of TentaGel resin enables the transformation of 61 to 62 using 5–6mol% AIBN and a large excess of TBTH,29 and a related samarium mediated cyclisation of 63 to 64 used Rink resins (Scheme 18).30 It is clear that radical cyclisations can be carried out on solid support and it is likely that a wide range of related reports will be forthcoming in the near future.The intramolecular addition of aryl radicals to aromatic rings to generate biaryl systems can be e§ected via ipso substitution of sulfonamides. This method compares favourably with the majority of ionic methodologies which are commonly employed particularly as the conditions would be expected to tolerate a wide range of functional groups including electron-withdrawing or -donating substituents on the aromatic ring as illustrated in the formation of 66 from 65 (Scheme 19).31 However as the authors note the scope of the procedure is not easily predicted due to the many subtle features which have a profound e§ect on the feasibility of a particular variant.32 10 S.Caddick N. J. Parr and S. Shanmugathasan O Br O O O O O H2N H2N O I NH Ph O NH Ph OMe O O OMe TBTH AlBN PhCH3 THF SmI2 HMPH 61 62 63 64 Yield >90% Yield 63% Scheme 18 I X O2 S XH S S TBTH AlBN 65 66 X = O NMe Yields 50–69% Scheme 19 N N N N Ts Ts Ts Ts ( ) n ( ) n ( ) n 67 68 69 70 n = 0,1 Yields 84–89% n = 0,1 Yields 64–73% TsSePh AlBN C6H6 TsSePh AlBN C6H6 Scheme 20 Ipso substitution of aromatic sulfones has also been used in the preparation of fused indoles as depicted in the formation of 68 and 70 from 67 and 69 respectively (Scheme 20).33 The main feature of this approach which is related to previous work from the same authors is that the reactions employ sub-stoichiometric amounts of the sulfonyl radical precursor as an alternative to stoichiometric tin reagents.Similar ipso substitu- 11 Synthetic methods Part (i) Free-radical reactions N N N N SePh Ts ( ) n ( ) n TBTH AlBN PhMe 71 72 n = 1–3 Yields 48–63% N N N N SPh SePh TBTH AlBN PhMe ( ) n ( ) n 73 74 n = 1–3 Yields 17–59% N N N N OHC OHC PhSe ( ) n ( ) n TBTH AlBN MeCN 75 76 n = 1,2 Yields 14–49% N N Br ( ) n ( ) n TBTH AlBN PhMe 77 78 n = 1–3 Yields 45–54% COMe COMe N N R1 R1 R2 SO2 R2 BsNa Cu(OAc)2 H+ 79 80 Yields 45–94% R1 = COMe CN CO2Me R2 = CO2Et SO2Ph H Scheme 21 tion of phenylsulfonyl- and phenylsulfanyl-substituted imidazoles 71 to 72 and benzimidazoles 73 to 74 have also been described as have related oxidative cyclisations of 75 77 and 79 to 76 78 and 80 respectively (Scheme 21).34–36 The majority of these reactions involve ipso substitution followed by re-aromatisation but a recent report shows that aromatisation does not have to be implicit.12 S. Caddick N. J. Parr and S. Shanmugathasan N R O CCl3 N R O Cl Cl Cl Ni CH3CO2H 81 82 R = alkyl Bn Yields 30–65% Scheme 22 O R1 O Br R2 O R1 O R2 AlBN AllylSnBu3 C6H6 83 84 R1 = H Me; R2 = Alkyl Ph Yields 58–76% Scheme 23 Reactions which involve addition of a radical to an aromatic ring can also lead to the formation of spirocyclic products e.g. 82 from 81 (Scheme 22).37 4 Intermolecular reactions As previously noted the application of solid-phase conditions to radical reactions was inevitable and in an important development Sibi and co-workers describe preliminary work for intermolecular radical reactions using a-halo esters 83.38 The precursors were supported on Wang resin and were found to undergo high yielding substitution with allylstannanes to give products 84 (Scheme 23).Unlike previously described intramolecular examples these reactions rely on the use of a large excess (3 equiv.) of initiator. Carbohydrates The preparation of stable C-glycosides is an important goal given their numerous potential applications in biological chemistry. Motherwell and coworkers have developed a procedure for the synthesis of carbohydrate-bound difluoromethylene- phosphates and -phosphonothionates 87 via addition of phosphonyl or thiophosphonyl radicals generated from 85 to carbohydrate gem-difluoroenol ether precursors 86.39 The same group have developed two useful protocols for the preparation of novel glycopeptides one involves the addition of either the iodoalanine reagent 89 to 88 or bromo-oxazolidinone 92 to 91 to give 90 and 93 respectively (Scheme 24).The second approach which appears to be of greater synthetic potential provides 96 in good yield from the addition of 94 to 95 (Scheme 25).40 The control of glycoside stereochemistry at the C1 position has been the subject of a recent investigation by Kita and co-workers. They have found that 2,2@-azobis(2,4- dimethyl-4-methoxyvaleronitrile) (V70) can act as a radical generator at room temperature. Application of this initiator to TBTH mediated C-glycoside formation (101 to 102) has led to much improved levels of stereoselectivity as is demonstrated in the comparison with the AIBN mediated procedure (97 gives 98–100) (Scheme 26).41 13 Synthetic methods Part (i) Free-radical reactions O O O O O F F O O O O O P OEt F F X OEt X (RO)2P H + AlBN TBTH C6H6 or (Bu tO)2 86 87 85 X = O S; R = Et Bn Yields 14–73% O O O O O O O O O O AlBN TBTH C6H6 88 90 Yield 14% BocN H CO2Me I F F 89 CO2Me F F NHBoc O O O 91 F F O O O AlBN TBTH C6H6 93 F F HN O O R2 R1 F3C CF3 R2 R1 O HN Br O F3C F3C 92 O O R1 = H CH2OMe; R2 = H Yields 20–41% Scheme 24 O O O 94 O O O AlBN TBTH 96 N O O R2 R1 R2 R1 O O R1 = H CH2OTBS; R2 = H Yields 71–91% SePh F F H N O O Bz 95 C6H6 Bz H Scheme 25 14 S.Caddick N. J. Parr and S. Shanmugathasan O AcO AcO OAc OAc Br O AcO AcO OAc OAc CN O AcO AcO OAc OAc CN O AcO AcO OAc OAc 97 98 99 2% 100 18% Yields 32% TBTH AlBN C6H6 Æ O AcO AcO OAc OAc Br O AcO AcO OAc OAc CN 101 102 Yield 68% TBTH V-70 Et2O RT Scheme 26 O N OH O• O N OH O NHNH2 PbO2 PhMe 103 104 Yield 80% (92:8 ds) Scheme 27 Stereocontrol The control of stereoselectivity in acyclic systems is still one of the compelling problems to be addressed in free-radical chemistry.An interesting recent development has been reported in which chiral aminoxyls have been used to e§ect diastereoselective radical reactions. Treatment of the steroidal aminoxyl 103 with a prochiral radical derived unusually from an oxidative method using lead dioxide and alkyl hydrazines led to the isolation of product 104 with a high level of diastereoselectivity (Scheme 27).42 Another stoichiometric approach utilises a covalently bound chiral auxiliary and recent developments in this area have been promising.Addition of isopropyl radicals to electron-deficient alkenes (e.g. 105 to 106) in the presence of lanthanide-based Lewis acids is found to be highly regio- and stereo-selective and a similar process involving haloalkyl radical addition has been exploited in the synthesis of nephrosteranic and rocellaric acids 109 (from 107 via 108) (Scheme 28).43 Although stoichiometric auxiliaries o§er a practical procedure for asymmetric synthesis via radical-based technology extending the principles to an achiral auxiliary with a chiral Lewis acid catalyst is another potential benefit of pursuing such 15 Synthetic methods Part (i) Free-radical reactions N O CO2 Et O O Ph Ph N O CO2 Et O O Ph Ph Er(OTf)3 Pri-I TBTH Et3B O2 105 106 Yield 91% (ds 71:1) N O CO2 Et O O N O CO2 Et O O Ph Ph Cl Sm(OTf)3 TBTH AlBN ClCH2I Et3B O2 107 108 Yield 91% (ds > 100:1) Ph Ph steps HO O 109 R = C11H23 C13H27 O O R Scheme 28 N O Ph O O N O Ph O O TBTH Et3B O2 Ligand 110 111 88% [93% ee ( R)] MgI2 PriI N O N O Ligand = 112 (4 S 5 R) Scheme 29 16 S.Caddick N. J. Parr and S. Shanmugathasan approaches. Sibi and co-workers have been actively involved in developing catalytic asymmetric conjugate radical addition reactions. They have discovered that addition of isopropyl radicals to oxazolidinone derivatives 110 e.g. to give 111 gives very high levels of enantioselectivity in the presence of sub-stoichiometric quantities of bisoxazoline ligands such as 112 (Scheme 29).44 Further work on pyrazole derivatives demonstrates that these can also serve as templates for similar reactions albeit with modest levels of selectivity.45 References 1 D.H.R.Barton F. Launay V. N. Le Gloahec L. Tingsheng and F. Smith Tetrahedron Lett. 1997 38 8491. 2 D.H.R. Barton Synlett 1997 229. 3 A. Gugger R. Batra P. Rzadek G. Rist and B. Giese J. Am. Chem. Soc. 1997 119 8740. 4 B. Giese A. Dussy E. Meggers M. Petretta U. Schesitter J. Am. Chem. Soc. 1997 119 11 130. 5 H. J. Horner N. F. Martinez M. Newcomb S. Hadida and D. P. Curran Tetrahedron Lett. 1997 38 2783. 6 I. 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Ji Tetrahedron Lett. 1997 38 5955. 17 Synthetic methods Part (i) Free-radical reactions mmmm