4 Reaction Mechanisms Part (iii)Free-radical Reactions By D. CRlCH Department of Chemistry University CollegeLondon 20 Gordon Street London WC1H OAJ 1 Synthesis Cyc1izations.-1987 saw the publication of numerous examples of the now classical 5-hexenyl-cyclopentylmethyltype rearrangement in the synthesis of natural and other products only a limited number of examples of radical cyclizations of a more unusual nature are presented here. Treatment of bromide (1) with tri-n-butylstannane and azoisobutyronitrile (AIBN) in benzene at reflux allowed Wehle and Fitjer to prepare' (3) the first example of a new class of polycyclic hydrocarbons-the coronanes albeit in low yield (7% ). Side products included the reduction product (2) (8%) and the regioisomer (4) (32%).(1) X = Br (3) (4) (2) X = H Bachi demonstrated* that provided the double bond is activated carbapenams can be formed by treatment of an appropriate halide with tri-n-butylstannane (Scheme 1). Similar results were obtained for cyclization onto alkynes. H Scheme 1 ' D. Wehle and L. Fitjer Angew. Chem. Int. Ed. Engl. 1987 26 130. ' M. D. Bachi A. De-Mesmaeker and N. Stevenart-De-Mesmaeker Tetrahedron Lett. 1987 28 2637 2887; also see G. Just and G. Sacripante Can. J. Chem. 1987 65 104. 81 82 D. Crich Walton observed3 that treatment of cyclohept-4-enylmethyl bromide with tri-n- butylstannane gives mixtures of 5-methylcycloheptene and bicycle[3,2,l]octane and that the yield of the latter increases with temperature. On the other hand Bloodworth took advantage4 of the relatively slow transannular cyclization of the cyclo-oct-4-enyl radical to prepare cyclo-oct-4-enyl hydroperoxide by working in the presence of oxygen and a thiol.The key step in a synthesis of the avermectin southern part accomplished5 by the Julia group was one of several 1987 examples of vinyl radical cyclizations initiated by stannyl radical addition to an alkyne (Scheme 2). X C0,Me I,Yl Bu,SnH AIBN ll0"C X I C02MeBu3snwX = H 30% X = SiMe 50-60°!0 Scheme 2 Bu,SnH AIBN. ll0"C OAc Scheme 3 Danishefsky and Panek generated6 a regiospecific enol ether by the radical cyclization with elimination (S,2') procedure outlined in Scheme 3. Subsequent to their 1986 rediscovery (Annu. Rep. Progr. Chem.Sect. B 1986,83 67) of the efficient cyclization of hexan-6-alyl radicals to cyclohexyloxyl radicals Fraser-Reid and co-workers have shown' that this cyclization is more rapid than the more usual 5-hexenyl-cyclopentylmethyl type (Scheme 4). OH Scheme 4 F. MacCorquodale and J. C. Walton J. Chem. SOC.,Chem. Commun. 1987 1456. A. J. Bloodworth D. Crich and T. Melvin J. Chem. Soc. Chem. Commun. 1987 786. J. Ardisson J. P. Fkrtzou M. Julia and A. Pancrazi Tefrahedron Lett. 1987 28 2001. S. J. Danishefsky and J. Panek J. Am. Chern. Soc. 1987 109 917. 'R. Tsang J. K. Dickson H. Pak R. Walton and B. Fraser-Reid J. Am. Chem. SOC.,1987 109 3484; this particular radical cyclization was first demonstrated in 1976 F. Flies R. Lalande and B. Maillard Tetrahedron Lett.1976 439. Reaction Mechanisms -Part (iii) Free-radical Reactions Curran has expanded the range of his atom-transfer cyclizations to include esters of 2-iodohept-6-enoic acid' and even a tandem radical addition-cyclization process.' Fragmentations and Rearrangements.-Crimmins and Mascarella treated" the iodide (5) with tri-n-butylstannane and AIBN in benzene at reflux and obtained the angular triquinane (7) together with the alkane (6). The ratio of (6) to (7) was found to with reaction conditions and a more expeditious process involved the Curran atom-transfer method. Thus photolysis of (5) and 10 mole YO hexabutyldistannane in benzene at reflux gave the iodide (8) in 85% yield so providing a rare example of the efficient ring-opening of a cyclobutylmethyl radical.(5) x = I (7) X = H (6) X = H (8) X = I Rearrangements involving alkyl or aryl radical addition to ketones or nitriles followed by fragmentation of the adduct radical have been p~blished'~"*'~ by three groups. Examples of intermediate 3- 5- and 6-membered rings were given (Schemes 5 and 6). C0,Me Scheme 5 Scheme 6 Maillard and co-workers ob~erved'~ an interesting radical rearrangement when upon photolysis of the iodide (9) with chlorotributylstannane/sodium borohydride in the presence of acrylonitrile they obtained the ring-expanded products (10) and (11) together with the expected product (12) in 24 35 and 28% yields respectively. D. P. Curran and C.-T. Chang Tetrahedron Lett. 1987 28 2477. D. P.Curran and M.-H. Chen 1. Am. Chem. Soc. 1987 109 6558. lo M. T. Crimmins and S. W. Mascarella Tetrahedron Lett. 1987 28 5063. " A. L. J. Beckwith D. M. O'Shea S. Gerba and S. W. Westwood J. Chem. SOC.,Chem. Commun. 1987 666. 12 P. Dowd and S.-C. Choi 1.Am. Chem. Soc. 1987 109 3493 6548. 13 B. Arregey San Miguel B. Maillard and B. Delmond Tetrahedron 1987 28 2127. rn 8D. Crich COzMe COzMe (9) CN ;J-i" COzMe Et (11) Radical-induced fragmentations of fused bicyclic tertiary alcohols and lactols as a route to medium and macrocyclic ketones and lactones figured largely in 1987. Thus Suginome and Yamada ~ynthesized'~ exaltone from cyclododecanone; the key step was the fragmentation outlined in Scheme 7. Muscone was prepared in an analogous manner from methylcyclododecanone.The relationship between this reasonably well established methodology and that developed by Beckwith and Dowd (Schemes 5 and 6) is evident. 1. HgO I - 96% 2. hu :-ji Scheme 7 Spanish workers generally the combination iodoxybenzene diacetate- iodine to mercuric oxide-iodine for the generation of alkoxyl radicals in their fragmentation studies. Under oxygen at 10 atmospheres pressure the alkoxyl radical derived from (13) ~nderwent'~ a series of fragmentations additions of oxygen and hydrogen abstractions to give the A,A' ring system model (17) for limonin. In an approach to the A ring of the a-methylene-8-lactone vernolepin these workers also noted16 that the steroidal lactol (14) suffered indiscriminate cleavage of the 2,3 and 3,4 bonds to give the lactones (18) and (19) in 35 and 27% yields respectively.However inclusion of a radical leaving-group at the la position of the substrate I4 H. Suginome and S. Yarnada. Tetrahedron Lett. 1987 28. 3963; Tetrahedron 1987 43 3371. I5 R. Freire R. Hernandez M. S. Rodriguez and E. Suarez Tetrahedron Left. 1987 28 981. C. G. Francisco R. Freire M. S. Rodriguez and E. Suarez Tetrahedron Lett. 1987 28 3397. Reaction Mechanisms -Part (iii) Free-radical Reactions as in (15) and (16) channelled all the reaction into 2,3 bond cleavage giving (20) in 60 and 65% yields respectively. This observation is probably a reflection of the reversibility of the key fragmentation step rather than of a concerted fragmentation- elimination.Japanese workers also used17 lactol cleavage with subsequent stannyl radical elimination to generate unsaturated medium-ring lactones. AH17 (13) X = H,Y= Me (14) X = H,Y = H (15) X = SnBu,,Y = H (16) X = ySPh Y p= H H17 sH17 I I I I 0 H H I (19) (20) Giese has published’* further examples of his 2-deoxyglycoside preparation involving acyl migration from the 2-position to a glycosyl radical. Furthermore chemical evidence has now been provided” to support the claim that the stereoselec- tivity experienced in glucosyl radical reactions and in the above 2-deoxy sugar method is a result of the boat conformation adopted by glucosyl radicals. Thus tributylstannane treatment of (21) gave 53% of the cyclized products (22) indicating a boat or inverted chair conformation for the first-formed glucosyl radical; the latter of the two possibilities was eliminated when stannane treatment of (23) did not OAc c Aco&--j AcO-AcO-@-I OAc OAc OAc AcO OAc hl.Ochiai S. Iwaki T. Ukita and Y. Nagao Chem. Lett. 1987 133. B. Giese K. S. GrSninger T. Witzel H.-G. Korth and R. Sustmann Angew. Chem. Inr. Ed. Engl. 1987 26 233. K. S. Groninger K. F. Jager and B. Giese Liebigs Ann. Chem. 1987 731. D. Crich yield any cyclized product. Giese also reported2' on a novel benzoyl migration observed during the addition of alkyl radicals to a carbohydrate-based 2-benzoyl- oxyenone (Scheme 8). OCOPh OCOPh Bu,SnH -OCOPh 83% -OCoPh Bu'1,AlBN * PhCOO 0 b 0 OCOPh Scheme 8 Stereochemical Aspects.-Watanabe demonstrated2' that significantly improved stereoselectivities can be obtained in hetero-5-hexenyl type cyclizations by introduc- ing further halogen substituents at the radical centre and removing them after cyclization (Scheme 9).single diastereoisomer Scheme 9 RajanBabu reported22 a highly stereoselective 1-substituted 5-hexenyl cyclization in which the stereochemistry about the newly formed 1,5-bond was exclusively trans (Scheme 10) in contrast to the more usual preference for 1,2-cis-disubstituted cyclopentane formation in similar systems. It was readily demonstrated that the observed stereoselectivity was a result of the presence of the 1,3-dioxane ring and the suggestion was made that in the transition state for cyclization the dioxane ring takes up a boat conformation stabilized by a favourable SOMO-p C-0 u*orbital interaction.H. 07" f I Scheme 10 20 B. Giese and T. Witzel Tetrahedron Lett. 1987 28 2571. 21 Y. Watanabe Y. Ueno C. Tanaka M. Okawara and T. Endo Tetrahedron Lett. 1987 28 3953. 22 T. V. RajanBabu J. Am. Chem. SOC.,1987 109 609. Reaction Mechanisms -Part (iii) Free-radical Reactions Hanessian and Kametani have both looked23 at the formation of six-membered rings by radical addition onto ap-unsaturated esters and report good yields. In the case of substituted substrates cis/ trans mixtures of disubstituted cyclohexanes were usually obtained with some slight preference for the product resulting from cycliza- tion via a chair-like transition state with a maximum of equatorial substituents (Scheme 11).;,:;?H ov Br 3. Jones EtO2C CO2Et 96O/o trans :cis 4 1 Scheme 11 Ono made24 the observation that the elimination from P-phenylsulphonylnitroalk-ones on treatment with tri-n-butylstannane is stereospecific anti. It was concluded that the elimination proceeds uia an initial addition of the stannyl radical to the nitro group followed by fragmentation of the adduct radical and synchronous elimination of the phenylsulphonyl radical so eliminating the need for discrete carbon-centred radicals. This observation was used to refute claims that the reduction of nitroalkanes with stannanes involves an electron-transfer component.In the intermolecular radical addition field Barton noted2’ that complete diastereofacial selectivity was obtained on irradiation of the 0-acyl thiohydroxamate (24) derived from RR-tartaric acid with methyl acrylate giving the hexandioic acid esters (25). (24) (25) French workers demonstrated26 that the dibenzoyl peroxide initiated addition of bromotrichloromethane to diethyl malonate or fumarate leads to the same 3 :1 ratio of erythro threo adducts. The threo adduct is obtained exclusively when malonic anhydride is the radical trap. Japanese workers have studied2’ the radical addition 23 S. Hanessian D. S. Dhanoa and P. L. Beaulieu Can. J. Chem. 1987 65 1859; M. Ihara N. Taniguchi K. Fukurnoto and T. Karnetani J.Chem. Soc. Chem. Cornrnun. 1987 1438; also see G. Stork M. E. Krafft and S. A. Biller Tetrahedron Lett. 1987 28 1035. 24 N. Ono A. Karnimura and A. Kaji J. Org. Chem. 1987 52 5111. 25 D. H. R.Barton A. Gateau-Olesker S. D. Gero B. Lacher C. Tachdjian and S. Z. Zard J. Chem. Soc. Chem. Cornrnun. 1987 1790. 26 J.-Y. Nedelec D. Blanchet D. Lefort and J. Guilhem J. Chem. Res. (S) 1987 315. 27 M. Kaneyama N. Kamigata and M. Kobayashi J. Org. Chem. 1987 52 3312; M. Kaneyama and N. Karnigata Bull. Chem. Soc. Jpn. 1987 60,3687. 88 D. Crich of alkyl and arylsulphonyl chlorides as well as tetrachloromethane to styrene promoted by a ruthenium(r1) catalyst in the presence of the chiral ligand DIOP" and obtained enantiomeric excesses of up to 40% although the majority were significantly below 20%.This author has obtained28 diastereoselectivities of up to 66% by photoinitiated addition of 0-acyl thiohydroxamate esters to chiral esters of acrylic acid (Scheme 12). Et 75%; d.e. = 66% Scheme 12 However the most spectacular diastereoselective radical reaction reported29 in 1987 was that of Lomolder and Schafer in which photolysis of an asymmetric diacyl peroxide as a solid at -60°C gave almost complete retention of configuration at the radical centre involved (Scheme 13). The corresponding derivative of (*)-tartaric acid gave a d.e. of 89% in a similar reaction. 0 0 II II C-O-O-CCI1H23 CIIH23 H~+:; -60"C(solid)'H+::: H hw H COzMe COzMe Scheme 13 d.e. = 92% New Radical Sources.-It has been demonstrated3' that simple photolysis of alkyl-mercury bromides in the presence of diphenyl diselenide leads to alkyl radicals which are eventually trapped by a phenylselenide moiety (Scheme 14).4+ eeph C02Me C02Me C02Me 81 Yo SePh 13% Scheme 14 Pattenden has continued to expand the use of organocobalt(n1) complexes as radical sources in describing31 the use of acylcobaloximes as precursors for acyl radicals which were then added to Michael acceptors as outlined in Scheme 15. 28 D. Crich and J. W. Davies Tetrahedron Lett. 1987,28 4205. 29 R. Lomolder and H. J. Schafer Angew. Chem. Int. Ed. EngL 1987,26 1253. 30 T. Tom Y. Yamada E. Maekawa and Y. Ueno Chem. Lett. 1987 1827. 31 D.J. Coveney V. F. Patel and G. Pattenden Tetrahedron Lett.1987,28 5949. * 2,3-(isopropylidenedioxy)-2,3-dihydroxy-l,4-bis( dipheny1phosphino)butane 89 Reaction Mechanisms -Part (iii) Free-radical Reactions 40 Yo Minisci has presented3* several elegant methods for the preparation of alkyl radicals from alkyl iodides by a process closely related to Curran's atom transfer idea. Thus methyl radicals generated by a variety of means including (i) the action of hydrogen peroxide and iron(r1) salts on dimethyl sulphoxide (ii) action of iron(n) salts on tertiary butyl hydroperoxide and (iii) action of hydrogen peroxide on acetone abstract iodine from higher alkyl iodides giving higher alkyl radicals. These higher alkyl radicals then undergo efficient addition to protonated heteroaromatic bases aryl diazonium cations and a variety of other radical traps.2 Mechanism and Physical Addition to A1kynes.-In a series of elegant experiments Stork has demon~trated~~ that the regioselectivity observed in the addition of stannyl radicals to alkynes with subsequent cyclization of the so-formed vinyl radical (Scheme 16) is a consequence of the ease of reversibility of the addition of stannyl radicals to alkynes as well as to alkenes. OH 70% Scheme 16 Japanese workers have e~tablished~~ that triethylborane catalyses the addition of stannyl germyl and thiyl radicals to alkynes enabling such reactions to be carried out at ambient temperature without having recourse to photoinitiation. Radical Clocks and Probes.-The dangers inherent in the use of 1-halogenohex-5-enes as probes for radical intermediates and hence for electron-transfer processes in the formation of organometallic species has been well demonstrated by the atom-transfer cyclization reactions developed by Curran:8 the work of Ne~cornb~~ in which it is established that the rate of iodine abstraction from ethyl iodide by the octyl radical is between 1.7 and 3.4 x lo5 M-'s-l at 50 "C puts these dangers on a very real quantitative footing.32 F. Fontana F. Minisci and E. Visrnara Tetrahedron Lett. 1987 28 6373. 33 G. Stork and R. Mook J. Am. Chem. Soc. 1987 109 2829. 34 K. Nozaki K. Oshima and K. Utirnoto J. Am. Chem. Soc. 1987 109 2547; Bull. Chem. SOC.Jpn. 1987 60,3465; Y. Ichinose K. Wakarnatsu K. Nozaki and J.L. Birbaurn Chem. Lett. 1987 1647; Y. Ichinose K. Nozaki K. Wakarnatsu K. Oshirna and K. Utirnoto Tetrahedron Lett. 1987 28 3709. 35 M. Newcornb R. M. Sanchez and J. Kaplan J. Am. Chem. SOC.,1987 109 1195. 90 D. Crich The rates of cyclization of the radicals (26)36 and (27)” have been measured and found to be 1.0 x lo5s-’ and 2.9 x lo4s-’ for the cyclization of (26) to the cis and trans isomers respectively of the 2-methylcyclopentylmethyl radical at 298 K and 1.2 x lo6s-’ for (27) going to its ring-closed form at 230 K. Murphy has introduced38 the rapid C-C bond cleavage of 3-phenyl-2,3-epoxypropylradicals as a new radical probe. Although no quantitative data are available at present it was demonstrated by the exclusive formation of (29) on treatment of (28) with tri-n-butylstannane that this cleavage is significantly more rapid than the 5-hexenyl-cyclopentylmethyl rearrangement.Polar Effects.-The electrophilic t-butoxyl radical abstracts hydrogen regioselec- tively from the methylene group of ethyl acetate to give the 1-acetoxyethyl radical; in the presence of a catalytic amount of the trimethylamine-thexylborane complex this selectivity is completely reversed with hydrogen abstraction taking place from the acetate methyl group to give the ethoxycarbonylmethyl radical (Scheme 17). This elegant experiment was presented by Robert~’~ as an example of his concept of polarity-reversal catalysis and is explained in terms of preferential abstraction by the t-butoxyl radical from the amine-borane to give a nucleophilic amineboryl radical which itself abstracts the more electropositive hydrogen from the substrate.MeC02CH2Me * CH2C02CH2Me Me,N -,BH,+ hv Scheme 17 Minisci has investigated the effects of solvent polarity on the regiochemistry of radical addition to the pyridinium cation using radicals generated from a variety of sources. The general trend observed4’ was that the greater the nucleophilicity of the radical (and hence also the greater the stability) the greater the susceptibility to 36 J. Lusztyk B. Maillard S. Deycard D. A. Lindsay and K. U. Ingold J. Org. Chem. 1987 52 3509. 31 A. L. J. Beckwith and S. A. Glover Aust. J. Chem. 1987 40 157. 38 A. Johns J. A. Murphy C. W. Paterson and N. F. Wooster J. Chem.SOC.,Chem. Commun. 1987 1238. 39 V. Paul and B. P. Roberts J. Chem. SOC.,Chem. Commun. 1987 1322. F. Minisci F. Vismara F. Fontana G. Morini M. Serravalle and C. Giordano J. Org. Chem. 1987 52 730. Reaction Mechanisms -Part (iii) Free-radical Reactions solvent polarity. Thus whilst the n-butyl radical gave an a/yratio of 56.3:43.7 in water and 74.4:25.4 in benzene the t-butyl radical had a/?23.0:77.0 in water and 71.4:28.6 in benzene. It was suggested that the reversibility of radical addition to the cation was a factor although the solvation of polar transition states could not be ruled out. Capto-dative Effects.-Ruchardt has pointed that spin delocalization in capto- dative radicals as measured by the aHcoupling constant is not necessarily a good measure of radical stabilization and does not necessarily correlate with the enthalpy of activation for C-C bond cleavage of the dimer.Thus whilst the extent of delocalization in (31) decreased in the order X = OMe Y = CN > X = CN Y = Me > X = Y = CN > X = Y = OMe > X = OMe Y = Et the AH* for cleavage of (30) decreased in the order X = Y = OMe > X = Me Y = Et > X = OMe Y = Et > X = OMe Y = CN > X = CN Y = Me > X = Y = CN. It was suggested4' that aHpossibly only reflects the SOMO energy and not the total radical stability. xx X I 1 Ph -C -C -Ph I I YY /-Ph-C. 'Y Ruchardt went on to dispute42 the 1986 proposal of Katritzky that capto-dative stabilization is enhanced in polar solvents. The position of equilibrium (30) 2(31) (for X = OMe and Y = CN) was measured in mesitylene diphenyl ether ethylene glycol N-methylacetamide and succinic anhydride with only minor differences being found.41 H. Birkhofer J. Hadrich H.-D. Beckhaus and C. Ruchardt Angew. Chem. Int. Ed. EngL 1987,26 573. 42 H.-D. Beckhaus and C. Ruchardt Angew. Chem. Int. Ed. Engl. 1987 26 770.