A New Asymmetric Photoisomerization of 2,3-Dihydropyrrolo[1,2-b]benzisothiazole 5,5-Dioxides

2,3-Dihydropyrrolo[1,2-b]benzisothiazole 5,5-Dioxide들의 비대칭성 광이성질화 반응

Abstract

A tricyclic ring system bearing new stereogenic center namely 2,3-dihydro[1]benzothieno[3,2-b]pyrrole 4,4-dioxide was synthesized by asymmetric photoisomerization of 2,3-dihydropyrrolo[1,2-b]benzisothiazole 5,5-dioxide by irradiation with 245 nm emission of the low-pressure mercury lamp. The chemical structure and the purity of the photoproduct were delineated preliminarily by IR, NMR, and MS and finally confirmed by single crystal X-ray crystallography.

245 nm mercury lamp를 사용하여 2,3-dihydropyrrolo[1,2-b]benzisothiazole 5,5-dioxide를 광이성질화 반응시켜서 2,3-dihydro[1]benzothieno[3,2-b]pyrrole 4,4-dioxide를 가지고 있는 tricyclic ring system 화합물을 합성하는 방법을 개발하였다. 합성한 화합물들에 대한 구조는 IR, NMR, MS 및 single crystal X-ray crystallography를 이용하여 결정하였다.

INTRODUCTION

Asymmetric photochemistry1,2 has attracted enormous interest in recent years as an appealing alternative or substitute for their thermal and enzymatic counterparts in the asymmetric syntheses.3-6 Chirality control in the electronically excited state is central to photochirogensis but in general is still a difficult task to achieve. This is mainly due to the lack of a well established methodology and in-depth knowledge of the mechanism and factors that govern the chirality transfer process in the excited state.1

 

RESULTS AND DISCUSSION

In a recent work we reported a new interamolecular photoisomerization of 2,3-dihydropyrrolo[1,2-b]benzisothiazole 5,5-dioxide (1) (R = CN, CO2Et, CO2Me) into 2,3-dihydro [1]benzothieno[3,2-b]pyrrole 4,4-dioxide (2) (Scheme 1).7 This transformation provides a new and efficient access to a tricyclic ring-system bearing a new stereogenic center. Here we report another application of this photoisomerization by introducing a chiral auxiliary at the ester group in substrate 1, which is proposed to influence the stereoselectivity and the formation of the photoproduct 2.

Thus, esters 1a-c with chiral auxiliaries were synthesized from acid chloride which in turn refluxed in the presence of chiral alcohols [(-)-menthol, (-)-borneol and (-)-2-methyl-1-butanol] in dry benzene to afford the substrate esters 1a-c respectively, in almost quantitative yield. Ester groups were used because they allow the easy removal of the chiral auxiliary. Now, when compounds 1a-c were irradiated with 254 nm emission of the low-pressure mercury lamp in Argonpurged acetonitrile through a quartz jacket retaining the 185 nm emission, the photoproducts 2a-c were obtained in excellent yield.

The transformation proceeds via homolytic cleavage at S-N bond to produce relatively stable biradical 3 which in turn recylcizes to the final product 2 (Scheme 1).

The spectroscopic data of the photoproducts 2a-c revealed two main events namely photodecojugation of α,β-unsaturated ester and the stereoselectivity in the photoisomerization process. Firstly, in the ultra violet spectra the values of the longest wave length of 1a-c (being α,β-unsaturated esters and the carbonyl group extends the pi-electron system) is υmax = 325 nm (log ε = 4.10, 3.24, and 4.10 respectively), this value is dramatically shifted to 245 (4.01), 275 (3.26) and 275 (3.30) in photoproducts 2a-c respectively. Also, in the infrared spectra, the carbonyl absorption bands in 1a-c appeared at 1689, 1696 and 1688 cm-1 are shifted towards higher wavenumber and appeared at 1733, 1721, and 1734 cm-1 in 2a-c respectively.

Scheme 1

Table 1.Specific rotation and Uv for 1a-c and 2a-c

Fig. 1.ORTEP-plot of molecular structure 2a in the crystal. The crystallographic numbering does not reflect the systematic number.

Secondly, The photoisomerization of 1a,b to 2a,b proceed with the retention of the stereoselectivity however in the case of 1c to 2c the diastereomeric purity is lost: By 1H NMR of the photoproducts 2a,b revealed only one set of signals even when a chiral shift agent8 was used with different concentration and the absolute configuration of the photoproduct 2a at the new stereogenic center at Carbon-3a is assigned by the single crystal X-ray structure analysis as R configuration (Figure 1).

Scheme 2

While 2c revealed a broad set of signals but after adding the chiral shift agent, the 1H NMR signals split into two sets with integration ratio of the two stereoisomers formed upon photolysis of 1c is 3:1 (no further attempts were made to separate use any other techniques). It was reported that, the bulk of the substituents at the chiral center improves the stereoselectivity of the photoisomerization therefore, difference in the stereoselectivity in the photoconversion 1a,b to 2a,b and 1c to 2c can be attributed to the size of the introduced chiral auxiliaries.1,2 Furthermore, the specific rotations of the photoproducts 2a-c were measured and compared with those of the starting materials (Table 1). Therefore, the value of the specific rotation [α]20 shifted from -57.0 to -36.0 for 1a and 2a respectively. Furthermore, the basic hydrolysis of 2a afforded the enantiomeric pure free acid 3 with specific rotation [α]20 + 14.0 (C = 1 ethanol) (Scheme 2). Also, the 1H NMR of the free acid 3 revealed one set of signals even after adding the chiral shift agent.8

 

CONCLUSION

In conclusion, the influence of introducing chiral auxiliaries in substrate 1 on the stereoselectivity and the formation of the photoproduct 2 was studied. It was noticed that, the photoisomerization of 1a,b with bulk chiral auxiliaries to 2a,b proceeds with the retention of the stereoselectivity however in the case of 1c to 2c the diastereomeric purity is lost.

 

EXPERIMENTAL

General

All commercially available solvents and reagents were purchased from commercial sources and used without further purification unless otherwise noted. NMR spectra were recorded on Bruker WM 300 and DRX 500 spectrometers (300 MHz and 500 MHz, respectively for 1H-NMR, 75 and 125 MHz, respectively, for 13C-NMR) using TMS as internal standard and the deuterated solvent as lock. IR spectra were obtained by using a Perkin-Elmer 983 spectrophotometer. Electron impact ionisation mass spectrometry (EIMS) was performed on a Varian AMD 604 instrument using 70 eV ionization energy. The specific rotation was measured on a Polarimater. Melting points are uncorrected. All the chromatographic separations were performed on 48 × 20 cm glass plates covered with an air-dry layer (1 cm thick) of silica gel (Merck Kiesegel PF254).

General Procedure for Synthesis of Esters with Chiral Auxiliaries 1a-c

A mixture of 2,3-Dihydropyrrolo[1,2-b][1,2]benzisothiazole-5,5-dioxo-1-carboxylic acid [7] (1.10 g, 4.4 mmol) and excess thionyl chloride (5 mL) was refluxed for 4 h at 85 - 90 ℃. Then the unreacted thionyl chloride was evaporated in vacuo to give the crude acid chloride as a pale yellow solid which was used directly in the next step.

A mixture of the acid chloride (0.86 g, 3.2 mmol) and the chiral alcohol (3.2 mmol) was refluxed overnight in dry benzene (50 mL). The solvent was evaporated completely in vacuo and the residue was washed several times with 10% NaHCO3 solution and then with water, and air dried.

(-)-Menthyl 2,3-Dihydropyrrolo[1,2-b][1,2]benzisothiazole-1-carboxylate 5,5-dioxide (1a): Colourless crystals (from acetone, 98%), mp: 160 - 161 ℃, Uv (acetonitrile): υmax (log ε) = 325 (4.10), 242 (3.97), 208 (4.54). IR (KBr): ν = 1689s (CO), 1634s (C=C), 1367s ,1168s (SO2) cm-1. 1H NMR (CDCl3): δ = 0.79 (m, 3H), 0.98 (m, 7H), 1.21 (m, 2H), 1.51 (m, 2H), 1.82 (m, 2H ), 1.89 (m, 1H), 2.15 (m, 1H), 3.35 (m, 2H), 3.84 (m, 2H), 4.85 (m, 1H), 7.83 (m, 3H, Ar- H), 8.91 (m, 1H, Ar-H), 13C NMR (CDCl3): δ = 16.5, 20.8, 22.1, 23.8, 27.5, 31.3, 33.8, 34.1, 41.2, 41.8, 46.5, 74.5, 108.3, 121.4, 125.1, 129.1, 132.3, 133.2, 139.5, 157.4, 164.3.

MS: m/z (%) = 390 (M+ +1, 0.4), 389 (M+, 0.5), 252 (32.6), 234 (100), 187 (83.3), 138 (82.8); Anal.Calcd. for C21H27N O4S (389.27): C, 64.79; H, 6.99; N, 3.59; S, 8.24. Found: C, 64.81; H, 7.01; N, 3.61; S, 8.11.

(-)-Bornyl 2,3-Dihydropyrrolo[1,2-b][1,2]benzisothiazole-1-carboxylate 5,5-dioxide (1b): Colourless crystals (from ethanol, 95%), mp: 175 - 176 ℃. Uv (acetonitrile): υmax (log ε) = 325 (3.24), 274 (3.06). IR (KBr): ν = 1696s (CO), 1636s (C=C), 1374s ,1137s (SO2) cm-1. 1H NMR (CDCl3): δ = 0.81 (m, 6H), 0.95 (s, 3H), 1.21 (m,1H), 1.35 (m, 2H), 1.84 (m, 3H), 1.45 (m, 1H), 3.39 (m, 2H), 3.75 (m, 2H), 5.11 (m, 1H), 7.85 (m, 3H, Ar-H), m, 1H, Ar-H).13C NMR (CDCl3): δ = 13.6, 19.1, 20.1, 26.9, 27.3, 33.5, 37.3, 42.5, 45.1, 48.2, 49.3, 80.9, 107.8, 121.5, 124.9, 128.3, 132.1, 133.5, 139.5, 147.3, 164.1. MS: m/z (%) = 388 (M+ +1, 0.3), 387 (M+, 12.6), 251 (40.5), 234 (100), 207 (30.5), 186 (9.3), 164 (5.1). Anal.Calcd. for C21H25N O4S (387.49): C, 65.09; H, 6.50; N, 3.61; S, 8.27. Found: C, 64.91; H, 6.31; N, 3.52; S, 8.21.

S (-)-2-(methyl)butyl2,3-Dihydropyrrolo[1,2-b][1,2]benzisothiazole-1-carboxylate 5,5-dioxide (1c): Colourless crystals (from aqueous ethanol, quantitative), mp: 75 - 76 ℃. Uv (acetonitrile): υmax (log ε) = 325 (4.10), 252 (3.95), 208 (4.54). IR (KBr): ν = 1688s (CO), 1640s (C=C), 1322s, 1179s (SO2) cm-1. 1H NMR (CDCl3): δ = 0.95 (m, 6H), 1.25 (m,1H), 1.49 (m, 1H), 1.85 (m, 1H), 3.36 (t, 2H, J = 9), 3.85 (t, 2H, J = 9), 4.13 (m, 1H), 4.24 (m, 1H), 7.75 (m, 3H, Ar-H), 8.94 (m, 1H, Ar-H). 13C NMR (CDCl3): δ = 11.2, 16.5, 26.1, 33.8, 34.3, 41.9, 69.4, 107.5, 121.8, 125.2, 128.7, 132.1, 133.4, 139.8, 147.3, 164.4. MS: m/z (%) = 322 (M+ +1, 8.0), 321 (M+, 41.1), 251 (70.0), 234 (48.3), 207 (100), 186 (30.9), 143 (30.0). Anal.Calcd. for C16H19N O4S (321.39): C, 59.79; H, 5.96; N, 4.36; S, 9.98. Found: C, 59.64; H, 6.01; N, 4.25; S, 10.01.

General Photolysis Procedure

Samples of 1a-c (0.5 mmol) in acetonitrile (100 mL) were irradiated for the period given below using a quartz immersion well in connection with a Hanau TNN 15 low-pressure mercury lamp (15 W input) with continuous argon purging. After concentration the residue was subjected to chromatography on two silica gel plates each with EtOAc/n-hexane (1:1). The Rf values of the appropriate zones are given below.

R-(-)-Menthyl-2,3-dihydro-[1]benzothieno[3,2-b]pyrrole-3a-carboxylate 4,4-dioxide (2a): It was obtained in 91% conversion after 5 h of irradiation, as colourless crystals (from acetone), Rf = 0.63, mp: 202 ℃. Uv (acetonitrile): λmax (log ε) = 245 (4.01), 209 (4.42). IR (KBr): ν = 1733s (CO), 1647s (C=N), 1321s, 1152s (SO2) cm-1.1H NMR (CDCl3): δ = 0.67 (m, 6H), 0.77 (m, 5H), 0.98 (m, 1H), 1.08 (m, 1H), 1.35 (m, 2H ), 1.55 (m, 2H), 2.02 (m, 1H), 2.78 (m, 1H), 2.92 (m, 1H), 4.22 (m, 1H), 4.62 (m, 2H), 7.82 (m, 4H, Ar- H). 13C NMR (CDCl3): δ = 15.5, 20.8, 21.9, 22.7, 25.4, 30.1, 31.4, 33.9, 40.1, 46.8, 66.5, 77.0, 82.2, 122.4, 123.9, 131.9, 132.7, 133.9, 147.9, 163.2, 168.0. MS: m/z (%) = 390 (M+ +1, 3.2), 389 (M+, 12.0), 252 (18.4), 251 (100), 206 (21.0), 186 (25.0). Anal.Calcd. for C21H27N O4S (389.27): C, 64.79; H, 6.99; N, 3.59; S, 8.24. Found: C, 64.71; H, 6.91; N, 3.60; S, 8.30.

R-(-)-Bornyl-2,3-dihydro-[1]benzothieno[3,2-b]pyrrole-3a-carboxylate 4,4-dioxide (2b): It was obtained in 90% conversion after 6 h of irradiation, as colourless crystals (from n-hexane), Rf = 0.41, mp: 117 - 118 ℃. Uv (acetonitrile): υmax (log ε) = 275 (3.26), 244 (3.92), 208 (4.36). IR (KBr): ν = 721s (CO), 1652s (C=N), 1321s ,1152s (SO2) cm-1. 1H NMR (CDCl3): δ = 0.75 (m, 12H), 1.61 (m, 3H), 2.31 (m,1H), 2.74 (m, 1H), 3.10 (m, 1H), 4.32 (m, 1H), 4.65 (m, 1H), 4.82 (m, 1H), 7.65 (m, 2H, Ar-H), 7.91 (m, 2H, Ar-H). MS: m/z (%) = 388 (M+ +1, 1.2), 387 (M+, 8.3), 278 (18.6), 252 (8.1), 234 (8.5), 208 (14), 136 (100). Anal.Calcd. for C21H25N O4S (387.49): C, 65.09; H, 6.50; N, 3.61; S, 8.27. Found: C, 64.96; H, 6.45; N, 3.59; S, 8.30.

S (-)-2-(methyl)butyl -2,3-dihydro-[1]benzothieno[3,2-b] pyrrole-3a-carboxylate 4,4-dioxide (2c): It was obtained as colourless crystals (from n-hexane/benzene, 1:1), Rf = 0.45, mp: 188 - 189 ℃. Uv (acetonitrile): υmax (log ε) = 273 (3.30), 209 (4.10). IR (KBr): ν = 1734s (CO), 1664s (C=N), 1331s, 1152s (SO2) cm-1. 1H NMR (CDCl3): δ = 0.85 (m, 6H), 1.25 (m,1H), 1.51 (m, 1H), 1.61 (m, 1H), 2.25 (m, 1H), 2.75 (m,1H), 3.45 (m, 1H),3.61 (m, 1H), 3.85 (m, 1H), 4.15 (m, 1H), 7.75 (m, 2H, Ar-H), 8.12 (m, 2H, Ar-H). 13C NMR (CDCl3): δ = 11.2, 16.3, 25.8, 30.2, 36.9, 39.7, 66.3, 70.4, 71.5, 130.1, 135.0, 135.9, 138.3, 164.8, 166.3, 170.5. MS: m/z (%) = 322 (M+ +1, 0.8), 321 (M+, 0.9), 252 (19.5), 209 (32.0), 183 (44.0), 133 (100). Anal. Calcd. for C16H19N O4S (321.39): C, 59.79; H, 5.96; N, 4.36; S, 9.98. Found: C, 59.72; H, 5.89; N, 4.41; S, 9.88.

2,3-Dihydro-[1]benzothieno[3,2-b]pyrrole- 4,4-dioxide R-3a-carboxylic acid (3): 10% aqueous NaOH solution (0.5 mL) was added to a solution of 1.00 g (2.57 mmol) of the ester 2a in acetone (5 mL) at 0 ℃. Then the mixture was stirred at room temperature for 4 h (TLC-monitoring) then 50 mL water was added. The resulting clear solution was neutralized with dil. HCl and the precipitate was collected by filtration and washed with water. It was obtained as colourless crystals (from acetone, 0.85 g, 87%), mp > 320 ℃. IR (KBr): ν = 3150-2800 (br, OH), 1676S (CO), 1620 (C=N), 1318, 1180 (SO2) cm-1. 1H NMR (DMSO-d6): δ = 2.80 (m, 1H), 2.97 (m, 1H), 4.28 (m, 1H), 4.68 (m, 1H), 7.92 (m, 2H, Ar-H), 8.21 (m, 1H, Ar-H), 8.82 (m, 1H, Ar-H), 12.99 (s, 1H, COOH). MS: m/z (%) = 251 (M+, 100), 234 (40.5), 208 (20.0), 136 (80.5). Anal. Calcd. for C11H9O4NS (251.12): C, 52.59; H, 3.59; N, 5.58; S, 12.75. Found: C, 52.56; H, 3.63; N, 5.64; S, 12.65.