Unexpected new examples of the Thyagarajan-Majumdar tandem cyclization of aryl propargyl sulfoxides

We observed an unexpected cyclization of aryl propargyl sulfoxides to 1-benzothiophenes while attempting the in situ preparation of a particular class of allenyl sulfoxides as substrates for intramolecular hydride-shift experiments. A mechanistic rationale for explaining this result, involving a sequence of [2,3] and [3,3] sigmatropic rearrangements and a final conjugate addition, is provided by the previous work of Thyagarajan and Majumdar.


Introduction
During the last few years our research group has become involved in the investigation of the hydride donor ability of acetalic functions in a series of intramolecular processes.In these reactions the released hydride is transferred to the electrophilic central carbon atom of certain heterocumulene fragments (ketenimines, carbodiimides) and other electrophilic functions.2][3][4][5] Thus, for example, the [1,5]-H shift step in acetal-ketenimines (X = CR2) and acetal-carbodiimides (X = NAr) 1 leads to the o-azaxylylene intermediates 2, which quickly undergo a 6π-electrocyclization to give quinolines and quinazolines 3 respectively (Scheme 1).
Following our efforts in this area, we reasoned that related tandem processes are conceivable by replacing the heterocumulenic hydride-acceptor unit by other electrophilic functional groups, while keeping the acetal function as the hydride-releasing fragment.In this line, we assumed that the sp-hybridized central carbon atom of an allene moiety might also act as the terminus of a similar 1,5-hydride shift from an acetal function, thus promoting sequential transformation from acetal-allenes 4 to spirodioxolanes 5 (Scheme 2), closely related with those shown in Scheme 1.

Scheme 2. Proposed [1,5]-H/ 6π-ERC tandem sequence in acetal-allenes
In order to secure the electrophilic character of the central carbon atom of the cumulenic function in 4 we decided to synthesize acetal-allenes bearing electron-withdrawing functions, such as the sulfoxide group, at the terminal carbon atom of the allene fragment.
Surprisingly, when we attempted the in situ preparation of a particular class of sulfoxidesubstituted acetal-allenes from the respective propargylic sulfoxides, built on an ortho-phenylene scaffold bearing an hydride-releasing acetal function, an unexpected cyclization of the aryl propargyl sulfoxide moiety took place instead of the presumed [1,5]-H/6π-ERC tandem process.
With the aim of promoting the designed hydride shift in a putative equilibrium fraction of acetalallenes 8 we heated toluene solutions of the propargylic sulfoxides 9 in the presence of a catalytic amount of Et3N (10 %) for 5 h.To our surprise, the reaction products were mixtures of the 3-aroyl-2,3-dihydro-1-benzothiophenes 10 and 3-aroyl-1-benzothiophenes 11, which differ only in the degree of hydrogenation at the five-membered ring.In these mixtures the dihydro derivatives 10 were always the major components, obtained in 41-43 % yield (Scheme 4).Scheme 3. Reagents and conditions: i) HC≡CMgBr, THF, 0 ºC, 40 min; ii) 4-NO2-C6H4-SCl, Et3N, THF, -78 ºC → rt, 3 h Scheme 4. Synthesis of 2,3-dihydro-1-benzothiophenes 10 and 1-benzothiophenes 11 The formation of the 3-acyl-1-benzothiophene unit present in 10 and 11 only involves the aryl propargyl sulfoxide moiety, and may be rationalized by a mechanism involving as a first step a [2,3]-sigmatropic rearrangement of the propargyl sulfoxide function to give the allenylsulfenate 12 followed by a [3,3]-sigmatropic rearrangement and further tautomerization of the initially formed thione 13 leading to the thiol-enone intermediate 14.Finally, an internal conjugate nucleophilic addition of the thiol group to the C =C bond of the enone fragment in 14 would account for the formation of the 3-aroyl-2,3-dihydro-1-benzothiophenes 10.Clearly, a proportion of 10 seems to become air-oxidized to the fully aromatic 1-benzothiophenes 11 (Scheme 5).
From the results of these experiments, it seems that this type of tandem cyclization in 9 is globally faster than the desired hydride migration in acetal-allene 8, thus precluding the occurrence of this latter transformation, as far as an equilibrium fraction of 8 is present in the toluene solution of 9.
Following the experimental study showing the conversion of sulfoxides 9 into benzothiophenes 10 and 11 we carried out an extensive bibliographic search, finding out a similar transformation previously reported by Thyagarajan and Majumdar, who explained this type of tandem cyclization by the mechanism represented in Scheme 5. A recent review on this transformation is available, 8 disclosing that it was first reported in 1972 as result of the PhD work of K. C. Majumdar under the supervision of Professor B. S. Thyagarajan. 9,10As summarized in that review, this synthetic strategy has been scarcely utilized, almost exclusively by the research groups of its two discoverers.This is why, as indicated in the title of this article, we propose this type of one-pot conversion of aryl propargyl sulfoxides into benzo[b]thien-3-yl ketones to be named as the Thyagarajan-Majumdar tandem cyclization.Scheme 5. Mechanism of the conversion 9 → 10.

Conclusions
In this communication we have summarized our results on what we interpret as an unexpected cyclization involving an aryl propargyl sulfoxide fragment, which was in fact a reaction already in the literature, although not widely known.We have proposed this reaction to be named after its discoverers.

Experimental Section
General Methods.All melting points are uncorrected.Infrared (IR) spectra were recorded as Nujol emulsions or neats. 1 H NMR spectra were recorded in CDCl3 or CD2Cl2 at 300 or 400 MHz. 13 C NMR spectra were recorded in CDCl3 or CD2Cl2 at 75 or 100 MHz.The chemical shifts are expressed in ppm, relative to Me4Si at δ = 0.00 ppm for 1 H, while the chemical shifts for 13 C are reported relative to the resonance of CDCl3 δ = 77.1 ppm or CD2Cl2 δ = 54.0 ppm.Mass spectra were recorded on a HPLC/MS TOF 6220 Agilent Technologies apparatus.Materials: 2-(1,3-Dioxolan-2-yl)benzaldehyde (6a) 11 and 2-(dimethoxymethyl)benzaldehyde (6b) 12 were prepared according to previously reported procedures.

Preparation of propargylic alcohols 7
To a solution of the 2-(1,3-dioxolan-2-yl)benzaldehyde 6a (0.53 g, 3 mmol) or 2-(dimethoxy methyl)benzaldehyde 6b (0.54 g, 3 mmol) in anhydrous tetrahydrofuran (30 mL), under nitrogen and at 0 ºC, 0.5 M solution of ethynylmagnesium bromide in THF (6 mL, 3 mmol) was added.The reaction mixture was stirred at 0 °C for 40 min.Then a saturated aqueous solution of NH4Cl (10 mL) was added and the resulting mixture was extracted with dichloromethane (2 × 30 mL).The combined organic layers were washed with water (2 × 100 mL) and dried over anhydrous MgSO4.The solvent was removed under reduced pressure and the resulting oil was purified by silica gel column chromatography.

Synthesis of propargylic sulphoxides 9
To a solution of the appropriate propargylic alcohol 7 (3.5 mmol) and triethylamine (1 mL, 7 mmol) in anhydrous THF (10 mL) cooled at -78 °C 4-nitrobenzenesulfenyl chloride (0.55 g, 3.8 mmol) was added.The reaction mixture was stirred at -78 °C for 1 h.Then, the reaction was quenched by addition of a saturated aqueous solution of NH4Cl (20 mL), and extracted with dichloromethane (2 × 30 mL).The organic layers were combined, washed with water (50 mL), and dried over anhydrous MgSO4.The solvent was evaporated under reduced pressure and the residue was purified by column chromatography.© ARKAT-USA, Inc.