Phenacyl sulfide

A variety of 2-substituted indoles can be prepared by the Gassman process. For example, when methyl phenacyl sulfide 22 was employed with aniline, the 2-phenyl indole was obtained in 81% yield as shown here. 

The cyclization of aryl phenacyl sulfides invariably leads to a mixture of the 2- and 3-phenylbenzo[6]thiophene derivatives, in ratios which depend to some extent on the nature of the acid catalyst. Formation of the 3-phenyl isomer is favored in PPA, but hydrofluoric acid favors formation of the 2-isomer (58CB172). 3-Phenylbenzo[6]thiophene is converted into 2-phenylbenzo[6]thiophene by hydrofluoric acid, but only isomerizes to a small extent in PPA. The suggested mechanism for these rearrangements, shown in Scheme 14, involves... 

Under these strong acid conditions, products from other rearrangements and acid cleavage reactions are sometimes found. For example, a mixture of 5-r-butyl-3-methyl-benzo[6]thiophene (the expected product), 6-f-butyl-3-methyIbenzo[6]thiophene and 3-methy benzo[6]thiophene was obtained on cyclization of p-t- butylphenylthioacetone with phosphorus pentoxide. During the cyclization of phenyl phenacyl sulfide to give a mixture of 2- and/or 3-phenylbenzo[Z ]thiophenes, small amounts of diphenyl disulfide and 5-pheny thio-3-phenylbenzo[6]thiophene were also formed (70AHC(11)177). 

Methyl- or 2-ethyl-benzo[Z> ]thiophenes are conveniently prepared by treatment of 2-benzo[6]thienyllithium with the appropriate alkyl sulfate <70AHC(11)177). Clemmensen or Wolff-Kishner reductions of the 2-acylbenzo[Z>]thiophenes are useful, but since acylation produces a mixture of the 2- and 3-acyl isomers (Section 3.14.2.4), these must be separated. Cyclization of phenyl phenacyl sulfide with hydrofluoric acid leads exclusively to 2-phenyl-benzo[6]thiophene, and 3-phenylbenzo[6]thiophene can be rearranged to the 2-isomer in hydrofluoric acid (Section 3.15.2.3.2). Aromatization of 2-cycIohexenylbenzo[6]thiophene, obtained by condensation of the 2-lithio reagent with cyclohexanone, gives 2-phenyl-benzo[6]thiophene, and the reaction is adaptable to the 2-(l-naphthyl) derivative also. 

Photolysis of phenacyl sulfides [125] and the base-mediated 1,2 elimination reaction of sulfenyl derivatives [126] are other general methods of preparation of these reactive species. 

In the following sections we have attempted to classify the methods available for the synthesis of benzo[6]thiophenes. (Arylthio)acetalde-hyde dialky] acetals, (arylthio)acetones, aryl phenacyl sulfides, and S-arylthioglycolic acids are the most common starting materials. A number of the syntheses, which we have included in Section IV, A, may become general methods in the future, e.g., cyclohexanone and a number of substituted cyclohexanones have been used recently as starting materials. 

C. Cyclization op (Arylthio)acetones and Aryl Phenacyl Sulfides... 

TABLE IV. BBsrzo[6]THioPHEisrEs by Ringi-Closube of (Abylthio)acetostes oe Abyl Phenacyl Sulfides [Eq. (5)]... 

Attempted preparation of 3-phenylbenzo[6]thiophenes by an extension of the above method invariably proceeds with rearrangement to give the 2-phenyl isomer186,299,303,304,307 308 or a mixture of the 2- and 3-phenyl isomers.186,308 In this case, use of PPA appears to favor formation of the 3-isomer,186,299, 309 whereas use of hydrofluoric acid usually affords the 2-isomer.299 It is interesting to note that 3-phenylbenzo[6]thiophene is converted into its 2-isomer by hydrofluoric acid,290 but is only isomerized to a small extent by hot PPA.186,308 During the cyclization of phenyl phenacyl sulfide to give 2- and/or 3-phenylbenzo[6]thiophene, small amounts of diphenyl disulfide and 5-phenylmercapto-3-phenylbenzo[6]thiophene are also formed.186,209 3,3 -Dibenzo[6]thienyl,305 2,3 -dibenzo[6]thienyl,305 and mixtures of 2- and 3-(2-thienyl)benzo[6]thiophene, 2- and 3-(2-naphthyl)benzo[6]thiophene, and 3-(1-naphthyl)- and 2-(2-naph-thyl)benzo[6]thiophene309 have been prepared by the appropriate modification of the Werner procedure. 

Further examples of the photolytic generation of thioaldehydes from phenacyl sulfides include the synthesis of 3,6-dihydro-27/-thiopyrans bearing a variety of functions at C-2 of which some are potent acyl-CoA-cholesterol acyl-transferase inhibitors (Equation 135) <1996BMC1493>. 

Irradiation of a mixture of the ketene acetal 537 and methyl phenacyl sulfide initiates a Diels-Alder cycloaddition via generation of thioformaldehyde which produces a 5,6-dihydrocyclohexa[c]thiopyran-2-one (Equation 193) <1997CJC681>. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

Reaction with thiocarbonyl compounds. The thiocarbonyl compounds obtained by photochemical oxidation of phenacyl sulfides can be trapped efficiently by a 1,3-dipolar cycloaddition with 1 to give 2. This heterocycle can be cleaved to carbonyl compounds by Bu4N F or (CjH5)3N HF. This process is more efficient and more general than photolysis of phenacyl sulfides in the presence of oxygen. 

Thioaldehydes with almost any substituents in the a-position can be generated according to Vedejs by photofragmentation of phenacyl sulfides (86JOC1556). This is a simple, effective, and mild reaction which can be performed in neutral media. Phenacyl sulfides are known to be unstable to visible and UV light (68CC700). Hogeveen and Smit had previously... 

Indok synthesis. Gassman and van Bergen have used a modification of the above-mentioned procedure for synthesis of 2-substituted indoles from anilines. The aniline IS treated as above with a chlorinating reagent at — 65° and then an equivalent of methyl-thio-2-propanone at the same temperature. An equivalent of a base (usually triethyl-amine) is added. Workup affords the indole derivative (2) in 60-70% yield. The thio-methyl group is removed with Raney nickel (>70% yield). The keto sulfide can be varied thus nse of methyl phenacyl sulfide [CH3SCH2C(=0)C5H5]4 in the synthesis leads to 2-phenylindoles. 

Mitchell has reported that benzyl a-chlorobenzyl sulfides are cleanly converted into stilbenes on successive treatment with PPhs and Bu OK (Scheme 13). Desulfurization of an intermediate thiirane by PPh3 is a likely pathway for this reaction. Benzyl a,a-dichlorobenzyl sulfides are converted into diphe-nylacetylenes under the same conditions." Viehe has reported that pyrolysis of ot-halo-a-alkylthio esters, ketones and nitriles under reduced pressure furnishes a,p-unsaturated esters, ketones and nitriles respectively it is probable that these reactions also take place via intermediate thiiranes. a-Chlorophenacyl phenacyl sulfide is converted into ( )-dibenzoylethylene on treatment with EtsN. ... 

Sulfide alcohols from alkyl phenacyl sulfides... 

Phenacyl sulfides are known to undergo three main processes from their triplet state 1.) charge transfer from the heteroatom to the carbonyl group [27-29], 2.) cleavage of the bond between the C-atom next to the carbonyl C-atom and the S-atom (so-called P-cleavage) [28,29], and 3.) y-hydrogen abstraction by the carbonyl 0-atom with subsequent cleavage of the same C-S bond as above in the 1,4-biradical [30,31]. This last sequence is used to obtain thio-aldehydes which can be trapped by enes or dienes (Scheme 5). 

Subsequently, a silanized variant of the phenacyl sulfide was generated and employed to cover an activated silicon wafer for the subsequent irradiation in the presence of a shadow mask with a Cp-capped PEG for 60 min in differently unchanged conditions from the corresponding solution experiments. The surface attachment of the initial phenacyl sulfide silane onto the surface and the subsequent patterning of PEG-Cp was evidenced via XPS for fully irradiated samples and ToF-SIMS for spatially resolved attachment (see Figure 9.4). 

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