Hetero-Diels-Alder reactions of new sulfonylsulfines generated from α-substituted methylsulfones

Hetero-Diels-Alder reaction with sulfines generated in situ from methylsulfones 5a-e substituted in α-position with a phosphonyl, carboxyl, carboxyoxazolidinyl, pyridyl, or a quinolyl substituent, respectively, led to new highly functionalized thiopyrans cycloadducts. When in the substrates (i.e. 5a-c ) the sulfonyl group and the second substituent on the methylene carbon have comparable electronwithdrawing effect, a mixture of cis and trans isomers of the corresponding cycloadducts is obtained with low to moderate selectivities. In the case of substrates 5d and 5e , due to the strong electronwithdrawing effect of the sulfonyl compared to the pyridyl or quinolyl groups, a single isomer is obtained for cycloadducts 7d and 7e . The stereochemical arrangements in the two cycloadducts resulting from 5b and 5d (carboxylate and pyridine derivatives) have been determined by single-crystal X-ray analysis and showed that the trans isomer was favored in both cases.


Introduction
Although less explored than the oxa and aza hetero-Diels-Alder (HDA) reactions, the thia-Diels−Alder version represents an efficient and atom-economical synthetic method to obtain dihydrothiopyrans, which were then used as precursors for the synthesis of some bioactive molecules, 1 in particular thiosugars. 2 In the main reported cases, the functionalities required in the target molecule (obtained via a thia-HDA step) were introduced directly in the cycloaddition step, as they belong to the thiocarbonyl heterodienophile or to the diene, or they were introduced by subsequent reactions in particular on the cycloadduct double bond.
In some recent publications, in order to introduce new functionalities in the thiopyran structure, the cycloadduct was oxidized into the corresponding sulfoxide and a nucleophile was introduced via a Pummerer reaction.1k, 3 For this purpose, in our laboratory, three substrates have been selected, namely sulfoxides 3a-c, which can be obtained by HDA reaction between dithioesters 1a-c and 1,3-butadiene, and subsequent S-oxidation of the resulting cycloadducts 2ac (Scheme 1).This required a selective oxidation of the endocyclic sulfur atom of 2 versus the exocyclic one.The oxidation of 2a and 2b by m-CPBA at -78 °C afforded sulfoxides 3a 3a and 3b, 4 respectively, as the major products (> 80% in the crude reaction mixture), however together with a little amount of the isomer 3'.In the case of the pyridine derivative 2c, the oxidation by m-CPBA led to a complexe mixture. 4To avoid these problems, a solution is to access directly compound 3 by using as heterodienophile the sulfine 4, which could be obtained by S-oxidation of dithioester 1 (Scheme 1). 5 However, it was described that oxidation by m-CPBA of dithioester 1c led to the corresponding sulfine, which was unstable and easily rearranged and decomposed into S-methyl 2-pyridylthiocarboxylate [2-PyC(O)SMe]. 6Indeed, similar results were obtained also with the phosphonate and carboxylate derivatives, and the corresponding thiocarboxylates ZC(O)SMe have been detected in the mixture of the reaction products.Therefore, the use as heterodienophiles of sulfonylsulfines 6 was envisaged (Scheme 2).This type of sulfines bearing two electronwithdrawing groups cannot be isolated because of their high reactivity, but they can be generated as already described in the literature, from the corresponding α-substituted methylsulfones 5 (as doubly activated methylene compounds) and thionyl chloride (SOCl2), in the presence of a base, 5,7

Scheme 2
This paper describes our results obtained in the thia-Diels-Alder reaction of sulfonylsulfines generated from α-substituted methylsulfones.The newly obtained cycloadducts represent highly functionalized thiopyrans and interesting substrates for Pummerer reactions.

Figure 1
It is known that when the substituents at the sulfine carbon are different, the sulfine exists as two geometrical isomers and the Diels-Alder reaction is stereospecific, as the geometry of the sulfine (Z/E) is retained in the cycloadduct (cis/trans).In our cases, Z/E (for the sulfine) and cis/trans (for the cycloadduct 7) indicate the relative position between the sulfonyl group and the oxygen of the thiocarbonyl S-oxide function (Scheme 3).Sulfones 5 reacted with thionyl chloride in the presence of a base (triethylamine or 2,6-lutidine) to generate the corresponding non-isolable sulfines, which reacted in situ with 2,3-dimethyl-1,3-butadiene or 1,3-butadiene to afford the expected cycloadducts 7.
The reaction between the sulfine prepared from phenylsulfonyl methylphosphonate 5a, SOCl2 and triethylamine, and 2,3-dimethyl-1,3-butadiene was complete, leading to product 7a as a mixture of trans and cis isomers, in 75% yield (Table 1, entry 1).The ratio of the two isomers (major/minor) was 67/33, but the corresponding relative configuration was not assigned.
Similarly, the reaction with 1,3-butadiene afforded cycloadduct 7a' with a ratio of isomers of 53/47 (Table 1, entry 2).In the case of phenylsulfonyl ethyl acetate 5b the base of choice was the 2,6-lutidine.Cycloaddition of sulfine 6b with 2,3-dimethyl-1,3-butadiene led to 7b as a mixture of two isomers in a 81/19 ratio and with 1,3-butadiene to cycloadduct 7b' in a 57/43 ratio (Table 1, entries 3 and 4).Crystallization of 7b' afforded a sample of pure minor isomer, from which a single crystal was isolated.The X-ray analysis showed a relative configuration in which the phenylsulfonyl group is located cis to the sulfinyl oxygen atom (Figure 2).The results obtained with phenylsulfonylacetyl oxazolidinone 5c were similar to those obtained with 5a and 5b.Cycloadduct 7c resulting from 2,3-dimethyl-1,3-butadiene was obtained with a diastereomeric ratio of 87/13 and cycloadduct 7c' resulting from 1,3-butadiene with 67/33 dr (Table 1, entries 5 and 6).The assignment of the trans relative configuration for the major isomer of 7b' let suppose that the major isomer obtained in the other similar cases (7a,a', 7b, and 7c,c') also possesses the trans configuration.The differences observed in the cis/trans ratios of the cycloadducts resulting from the same sulfine (but different dienes) suggest sulfine isomerization, which could maybe occur under the reaction conditions via addition/elimination of a nucleophile (the tertiary amine used as the base or the Cl -ion).Then, we performed the reaction between the sulfine generated from methyl-2-pyridyl phenylsulfone 5d with the 2,3-dimethyl-1,3-butadiene.The expected cycloadduct 7d was obtained with a good isolated yield of 88% and as a single isomer (Table 1, entry 7).It was possible again to obtain a single crystal of this product and its analysis by X-ray diffraction showed a relative trans stereochemical arrangement between the phenylsulfonyl group and the sulfinyl oxygen atom (Figure 3).This supposes that the E sulfine 11 was selectively formed in situ.A similar result was obtained starting from the quinoline sulfone derivative 5e, which led to cycloadduct 7e in 74% yield and as a single isomer, having very probably also trans configuration (Table 1, entry 8).

Conclusions
These results show that in the 5a-c sulfones series, when the sulfonyl group and the second substituent on the sulfine carbon have comparable electronwithdrawing effect, the sulfine is formed as a mixture of Z and E isomers, leading respectively to the corresponding cis and trans isomers of the cycloadduct, with low to moderate selectivities (53/47 to 87/13 ratio).For sulfones 5d and 5e, due to the much stronger electronwithdrawing effect of the sulfonyl group compared to pyridyl or quinolyl substituent, only one isomer of the cycloadduct was obtained.Crystals of cycloadducts 7b' (carboxylsulfonylsulfine with butadiene) and 7d (2-pyridyl sulfonylsulfine with 2,3-dimethylbutadiene) were isolated and analyzed by X-ray diffraction; the stereochemical arrangement was cis for the minor isomer of 7b' and trans for the single isomer of 7d.Synthetic applications of the obtained cycloadducts are currently under examination in our laboratory.

Experimental Section
General.The solvents used in the reactions were purified using a PURESOLV™ apparatus developed by Innovative Technology Inc. Reactions were monitored by TLC using 0.25 mm thick Merck plates, silica gel 60 F254.Products were purified by flash column chromatography on silica gel Merck (40-63 m, 60.08 g/mol).NMR spectra were recorded with a Bruker DRX 400 MHz or a Bruker DRX 500 MHz spectrometer in CDCl3. 13C and 31 P NMR spectra were obtained with complete proton decoupling.The chemical shifts () are given in parts per millions (ppm) relative to tetramethylsilane (TMS) for 1 H and 13 C nuclei, and to H3PO4 for 31 P nucleus.Conventional abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, br = broad.Coupling constants (J) are given in Hertz (Hz).Mass spectra were obtained on a GC/MS Saturn 2000 spectrometer.High-resolution mass spectra (HRMS) were performed on Q-TOF Micro WATERS by electrospray ionisation (ESI).Infrared (IR) spectra were recorded with a Perkin Elmer 16 PC FT-IR spectrometer.Sulfones 5a (RN: 206256-73-7), 12 5b (RN: 7605-30-3), 5 5d, 10 and 5e (RN: 65492-27-5) 10 have been prepared as previously described in the literature.

Synthesis of 3-(2-phenylsulfonylacetyl)oxazolidin-2-one (5c).
A mixture of 3-(2chloroacetyl)oxazolidin-2-one (RN: 460313-68-2; 10 mmol), sodium benzenesulfinate (15 mmol), and catalytic amount of tetrapropylammonium bromide (2 mmol), in acetonitrile (20 mL), was refluxed for 12h.Then the solvent was removed under vacuum and the residue was dissolved in dichloromethane (20 mL), washed with brine (20 mL), dried (MgSO4) and the solvent removed.The crude product was obtained in 56% as a white solid and was used without purification in the next step. 1 General procedure for the thia-Diels-Alder reaction Under a nitrogen atmosphere a solution of sulfone 5 (1 mmol) and, as a base, 2,6-lutidine or triethylamine (2.1 mmol) in THF (5 mL), was added dropwise to a cooled (-78 °C) solution of thionyl chloride (88 L, 1.2 mmol) and diene (2,3-dimethyl-1,3-butadiene or 1,3-butadiene, 5 to 10 mmol) in THF (10 mL).Once addition was complete, the temperature was allowed to rise slowly to room temperature and stirring was continued overnight.In the cases of substrates 5a-c, the crude reaction mixture was filtered, then the filtrate directly purified by chromatography on a silica gel column.In the cases of substrates 5d and 5e, the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (10 mL), the organic layer separated, the aqueous layer extracted again with CH2Cl2 (20 mL), and the combined organic layers were dried (MgSO4) and filtered.Removal of the solvents in vacuum gave the cycloadduct 7, which was purified by column chromatography (silica gel, ethyl acetate/pentane).

Figure 3 .
Figure 3. X-ray structure of the single trans isomer of cycloadduct 7d.

Table 1
a Diastereomeric ratio determinated by 1 H NMR; trans and cis isomers were not assigned.b Trans relative configuration was assigned to the major isomer.