Phenylthio, radical cyclization

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

Annelation.1 This reagent is used for conversion of 3-substituted aldehydes (or acetals) into methylenecyclohexanes. The conversion involves addition of the allylsilane group to the aldehyde or acetal to provide an adduct that undergoes radical cyclization via the allylic sulfide group. The phenylthio group is used to enhance 6-endo cyclization over the usual 5-exo cyclization. In addition it allows use of bis(tributyltin) as the initiator (14,173-174). Unfortunately the radical cyclization shows only slight stereoselectivity. 

Irradiation of a benzene solution of 5-phenyl Af-benzoylformyl-A-p-tolylthiocar-bamate 48a (Scheme 23) gave 5-phenyl-5-phenylthio-3-p-tolyloxazolidine-2,4-dione 49a in 61% yield accompanied by oxazolidine-2,4-dione dimer (15%), p-tolyl isocyanate (22%), and diphenyl disulfide [29]. Photolysis of 48a in the solid state gave oxazolidine-2,4-dione 49a in 96% yield. For the N-methyl derivative, 48b, compared to the solution photochemistry in which only 8% of oxazolidinedi-one 49b was obtained with a complex mixture, radical cyclization proceeds selectively to give oxazolidinedione in 75% yield in the solid state. Whereas N-p-tolyl and A-methyl derivatives, 48a and 48b, formed achiral crystals, the N-benzyl derivative 48c crystallized in chiral space group P2. Photolysis of the chiral... 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

The cyclization of cyclohexenylethanamines 15 mediated by electrophiles gave the hexahy-droindolines 16 and 17 stcrcoselectively while the radical cyclization of the corresponding A -phenylthio amines proved unsuccessful253. 

A mixture of a Grignard reagent and C0CI2 has also been used to initiate aryl radical cyclizations. Titanium(III)-mediated radical cyclizations are known, and Sml2-mediate reactions are possible in the presence of a nickel catalyst. Organoborane-mediated radical cyclizations are known.Electrochemically generated radicals also cyclize. The influence of the halogen atom on radical cyclization has been studied.Both phenylthio and phenylseleno... 

Radical cyclization is not limited to reaction with a C=C unit (see 15-29 and 15-30), and reactions with both C=N and C=0 moieties are known. Reaction of MeON=CH(CH2)3CHO with Bu3SnH and AIBN, for example, led to trans-2-(methoxyamino)cyclopentanol in good yield.Conjugated ketones add to aldehyde via the p-carbon under radical conditions (2 equivalents of Bu3SnH and 0.1 equivalent of CuCl) to give a p-hydroxy ketone.Addition of radical to the C=N unit of R C=N SPh ° or R—C=N—led to cyclic imines. Radical addition to simple imines leads to aminocycloalkenes. Radical also add to the carbonyl unit of phenylthio esters to give cyclic ketones. 

Eliminations. Specially designed sulfones undergo elimination which is initiated by a remote radical. The alkyl moiety is converted to an alkene. The core of the squalene synthase inhibitor CP-225917 has been synthesized via a radical cyclization with ejection of an allylic phenylthio group. The radical precursor is an a-bromoacetic ester. 

Chiral auxiliaries are capable of controlling the absolute steric course of radical reactions. 8-Phenylmenthyl ester or an amide derived from Oppolzer s camphor sultam can be utilized for enantioselective ring closure to cyclopentane, the chiral auxiliary directing the addition to the alkene. The reductive radical cyclization of 8-phenylmenthyl 2-phenylthio-6-heplenoale at 80 °C gives four isomeric cyclopentane derivatives in an overall yield of 90 % 3. The reaction proceeds with modest cis irons ratio, but a considerably higher RiS selectivity of 80 20. 

Phenylthio radicals add to the alkyne 40 to yield, after 1,5 intramolecular hydrogen transfer, the captodative a-alkoxyester 41, which cyclizes in good yield to the 2,3-disubstituted tetrahydrofurans 42 and 43 [31]. 

Beckwith pioneered the use of a Thiol-Oxygen-Co-Oxidation (TOCO) process for the transformation of 1,4-dienes and 1,3,6-trienes to 1,2-dioxolanes [90], As illustrated by the example in Scheme 51 [90a], this process involves phenylthio radical addition to the least substituted double bond, oxygen entrapment, peroxyl radical cyclization, oxygen entrapment and hydrogen atom transfer from the thiol. In accord with the Beckwith-Houk transition state model [91, 92], cyclization provides preferentially the c/s-3,5-disubstituted 1,2-dioxolanes. 

Addition of the phenylthio radical to the alkenyl cyclopropane generates an a-alkoxy radical that can fragment to release benzophenone and an a-keto radical. This radical then adds to the a,p-unsaturated ester to give a new radical that can cyclize onto the allylic sulfide to give the mixture of diastereomeric cyclohexanones 10 (and releasing the phenylthio radical). See K. S. Feldman and A. K. K. Vong, Tetrahedron Lett., 31 (1990), 823. 

Another route to (+)-lentiginosine (127) employing radical-mediated cyclization was developed by Chen and Tsai, who began by Mitsunobu coupling between the dithioacetal 338 and the 1-tartarimide 339 (Scheme 47) Chemoselective reduction of the product 340 with sodium borohy-dride was followed by conversion of the 5-hydroxypyrrohdin-2-one 341 via the acetate 342 into the 5-phenylthio derivative 343. Hydrolysis of the dithioacetal with iodobenzene bis(trifluoroacetate) then produced the acyl-silane 344. The key radical cyclization was performed with tributyltin hydride and AIBN as initiator to give the indolizidin-3-one 345 as a 4 1... 

Sulfide groups can also be introduced by this methodology (entry 24) [405]. Simpkins and coworkers found that the reaction of acceptor-substituted alkenes 363 with diphenyl disulfide in the presence of 10 mol% of Co(eobe)2 344 and PhSiH3 as the stoichiometric hydrogen source furnished 31-71% of a-(phenylthio) carbonyl compounds 364. The intermediacy of radicals was proven by a 5-exo cyclization occurring in competition to the SH2 reaction at sulfur. 

An attempted enantioselective synthesis of ipalbidine from the protected (S)-prolinol 860 was based on the regioselective 6-exo-trig cyclization of the radical intermediate derived from the reaction of the phenylthio compound 861 with tributyltin hydride (Scheme 111) (577). The reaction gave a 1 1 mixture of two indolizidin-5-one diastereomers 862 in 65% yield. At the end of the synthesis, the target 842 was found to possess virtually no optical activity. The most likely candidate for racemization is the aldehyde 863, which might scramble under the basic conditions required for the subsequent Wittig reaction. 

Furthermore, this methodology was developed to afford the synthesis of e t-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (160). Photolysis of 4-(4/ )-hydroxy-6-[(2-methoxycar-bonyl-4,5-methylenedioxy)phenyl]-25,35-0-isopropylidenehex-5-ynal O-benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce l-(A-benzyloxy-amino)-5-phenylthiocyclohex-5-ene 246. Cleavage of the N-O bond and reductive elimination of the phenylthio group in 246 with Sml2 in THF... 

The reaction of diphenyl disulfide with a variety of substituted acetylenes, promoted by thermal decomposition of di-rert-butyl peroxide, provides l,2-bis(phenylthio)ethylene adducts together with the corresponding benzothiophenes in reasonable yield ". The mechanism conceived for these transformations is depicted in Scheme 3, where the key step is the intramolecular cyclization of vinyl radicals. 

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