Generation of ortho-quinone methides upon thermal extrusionof sulfur dioxide from benzosultones

Krzysztof Wojciechowskia,* and Karolina Dolatowskab

aInstitute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, PO Box 58, 01-224 Warszawa 42, PolandbDepartment of Chemistry, Technical University, ul. Koszykowa 75, 00-664 Warszawa, Poland

Received 21 April 2005; revised 2 June 2005; accepted 23 June 2005

Available online 18 July 2005

Abstract—3H-1,2-Benzoxathiole 2,2-dioxides (benzosultones) undergo thermal extrusion of sulfur dioxide to form ortho-quinone methidesthat enter Diels–Alder reaction with maleimides to form chroman 2,3-dicarboxylic acid derivatives.q 2005 Elsevier Ltd. All rights reserved.

1. Introduction

Thermal extrusion of sulfur dioxide from 1,3-dihydro-benzo[c]thiophene 2,2-dioxides (1a) and 1,3-dihydro-2,1-benzisothiazole 2,2-dioxides (benzosultams, 1b) is a wellestablished method for the generation of the correspondingquinodimethanes (ortho-xylylenes, 2a)1 and quinonemethyl-eneimines (aza-ortho-xylylenes, 2b).2 These reactive inter-mediates enter Diels–Alder reactions leading to tetrahydro-naphthalenes (3a) and 1,2,3,4-tetrahydroquinolines (3b),respectively (Scheme 1). There is also one reportconcerning the synthesis of thiochromans (3c) via additionof thioquinone methide (2c) generated via thermal extrusionof SO2 from 1,2-benzodithiole 2,2-dioxide (1c).3

Scheme 1.

Scheme 2.

In the only report dealing with an application of theanalogous oxygen derivative 4a, namely the sultone of2-hydroxytoluene-a-sulfonic acid, as a precursor ofo-quinone methide 5a, extrusion of SO2 upon photo-chemical irradiation has been described.4 The intermediate5a was trapped in a [4C2] cycloaddition with 1,1-dimeth-

0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2005.06.087

Keywords: o-Quinone methide; Diels–Alder; Cycloaddition; Cheletropicextrusion; Chroman.* Corresponding author. Tel.: C48 22 343 2101; fax. C48 22 632 6681;

e-mail: kris@icho.edu.pl

oxyethene leading to 2,2-dimethoxychroman (6) (Scheme2). Such decomposition in methanol led to o-hydroxybenzylmethyl ether (7) formed via addition of a nucleophile tointermediate 5a. However, no experimental details of thesereactions were given.

The chemistry of ortho-quinone methides has been recentlyreviewed by Van De Water and Pettus.5 These reactiveintermediates play an important role in numerous biologicalprocesses.6 Thermal reactions were used for the generationof o-quinone methides from such heterocycles as chro-mans,7,8 4H-1,3-benzodioxins,9 1,2-benzoxazines.10 Ther-mal extrusion of SO2 from 4,4-bis(trifluoromethyl)-4H-benzo-1,3,2-dioxathiin 2-oxide leading to the correspondingquinone methide has also been described.11

2. Results and discussion

In the present study we report our results on the thermalextrusion of sulfur dioxide from 3H-1,2-benzoxathiole2,2-dioxides (benzosultones, 4). Benzosultones can beeasily obtained from 2-hydroxytoluene-a-sulfonic acidupon treatment with phosphorus oxychloride.12

Tetrahedron 61 (2005) 8419–8422

Scheme 3.

Table 1

Product X Y R R1 Yield (%)

9 H H Ph H 3710 H H Ph Me 3211 H H Me H 6412 Cl Cl Ph H 5813 Cl Cl Ph Me 3214 H NO2 Ph H 4115 H NO2 Ph Me 40

K. Wojciechowski, K. Dolatowska / Tetrahedron 61 (2005) 8419–84228420

Heating of benzosultone 4a with N-phenylmaleimide(NPMI, 8a) (1:1 mixture) in boiling 1,2-dichlorobenzene(180 8C) led to the formation of a mixture of products. MSanalysis of the crude reaction mixture revealed the presenceof products with molecular mass corresponding to dimersand trimers of methylene quinone, as well as the expected[4C2] cycloadduct 9. Using a two- or three-fold excess ofthe NPMI, the amount of these by-products was diminishedand the cycloadduct 9 was formed in 37% yield. Thereactions of benzosultones 4b and 4c proceeded in a similarway (Scheme 3, Table 1).

In reactions of quinonemethides 5 with 2-methyl-N-phenylmaleimide (8b) two regioisomeric products can beformed (Fig. 1). GC–MS analysis of the crude reactionmixture revealed the formation of only one product with amolecular mass corresponding to the expected cyclo-addition product. The structure of these adducts wasdeduced from the 1H NMR spectra. The spectra ofcompounds 10, 13, and 15 revealed the presence of anABX system corresponding to 3a-methyl substitutedderivatives. The alternative structures 16 would show anAB system of protons at C-9 and a singlet of hydrogen atC-3a position.

Figure 1.

Attempts to trap the generated quinone methides 5a–c withother dienophiles were unsuccessful. When the sultones 4were thermolysed in the presence of dimethyl maleate andfumarate, and 2,3-dimethyl-N-phenylmaleimide, GC–MSanalysis showed only trace amounts of chromane-2,3-dicarboxylates or the corresponding imide, but their

isolation proved impossible. Similarly, in the reaction with2-phenoxyethyl vinyl ether, an electron rich alkene, nocycloaddition product was formed. In all of these instanceslarge amounts of dimers and trimers of o-quinone methidewere formed.

In summary, we describe a novel method for the synthesisof practically unknown chroman-2,3-dicarboxylic acidderivatives. The synthesis was performed under neutralconditions. In the only known report13 chroman-2,3-dicarboxylates were obtained via addition of dimethylfumarate to ortho-quinone methides generated by a thermalelimination of water from 2-hydroxybenzyl alcohols.

3. Experimental

3.1. General remarks

Melting points are uncorrected. 1H and 13C NMR andspectra were obtained with Varian Mercury 400 BBinstrument with TMS as internal standard. Couplingconstants J are given in Hz. IR were obtained using aPerkin–Elmer 2000 FTIR instrument. Mass spectra (elec-tron impact, 70 eV) were obtained on AMD 604 (AMDIntectra GmbH, Germany) instrument. HRMS weremeasured in the presence of perfluorokerosene as thereference compound. Column chromatography was per-formed using silica gel 240–400 mesh (Merck).

3.2. Starting materials

Starting benzosultones 4a and 4b were obtained fromthe corresponding 2-hydroxybenzyl alcohols following theknown procedure.12

3.2.1. 3H-1,2-Benzoxathiole 2,2-dioxide (4a). Colorlesscrystals. Mp 86–88 8C (lit.,14 mp 86–87 8C). 1H NMR(400 MHz, CDCl3): d 4.50 (s, 2H), 7.10 (d, JZ8.2 Hz, 1H),

K. Wojciechowski, K. Dolatowska / Tetrahedron 61 (2005) 8419–8422 8421

7.20 (dd, JZ8.2, 7.6 Hz, 1H), 7.33 (d, JZ7.4 Hz, 1H), 7.40(dd, JZ7.6, 7.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): d50.2, 112.5, 119.3, 124.7, 125.8, 130.4, 151.0. IR (KBr,cmK1) n: 2999, 2945, 1477, 1463, 1364, 1213. MS (m/z, %):170 (MC, 88), 106 (69), 78 (100).

3.2.2. 5,7-Dichloro-3H-1,2-benzoxathiole 2,2-dioxide(4b). Colorless crystals. Mp 139–141 8C. 1H NMR(400 MHz, CDCl3): d 4.56 (s, 2H), 7.24 (d, JZ1.4 Hz,1H), 7.43 (d, JZ1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):d 51.0, 119.3, 120.2, 121.5, 124.1, 130.8, 146.2. IR (KBr,cmK1) n: 3091, 2995, 2943, 1585, 1459, 1400, 1368, 1209,1163. MS (m/z, %): 238 (MC, 46), 174 (100), 146 (38), 111(38), 75 (24). HRMS calcd for C7H4O3S35Cl2: 237.9258.Found 237.9262. Elemental analysis calcd for C7H4SO3Cl2(239.07): C, 35.17; H, 1.69. Found: C, 35.18; H, 1.93.

3.2.3. 5-Nitro-3H-1,2-benzoxathiole 2,2-dioxide (4c).To the solution of benzosultone (4a, 0.85 g, 5 mmol) inconcentrated sulfuric acid (10 mL) sodium nitrate (0.43 g,5 mmol) was added in one portion at 5–10 8C. The reactionmixture was stirred for 15 min at room temperature and thenpoured into ice. The solid was separated, washed with water,dissolved in dichloromethane and dried with MgSO4. Afterevaporation of the solvent product was recrystallized fromhexane–ethyl acetate (2:1).

Yield 0.86 g (80%). Colorless crystals. Mp 144–146 8C.(Lit.,14 mp 148–150 8C). 1H NMR (400 MHz, CDCl3): d4.64 (s, 2H), 7.26–7.30 (m, 1H); 8.31–8.37 (m, 2H). 13CNMR (100 MHz): d 50.0, 113.2, 120.4, 122.0, 126.7, 144.3,154.8. IR (KBr, cmK1): n 3114, 2947, 1593, 1531, 1475,1380, 1342, 1210. MS (m/z, %): 215 (MC, 44), 151 (100),135 (4), 121 (2), 93 (7), 79 (10), 74 (2), 65 (7).

3.3. Cycloaddition of ortho-quinonemethides (generalprocedure)

Benzosultone 4a–c (1 mmol) and maleimide 8a–c (3 mmol)were refluxed in 1,2-dichlorobenzene (5 mL) for 2 h. Aftercooling, the reaction mixture was subjected to columnchromatography. The solvent was eluted with hexane–ethylacetate (50:1) and then the product was eluted with hexane–ethyl acetate (5:1). The following compounds were obtained.

3.3.1. 2-Phenyl-9,9a-dihydro-3aH-chromeno[2,3-c]pyr-role-1,3-dione (9). Colorless crystals. Mp 147–149 8C. 1HNMR [400 MHz, (CD3)2SO]: d 3.04 (dd, JZ15.1, 4.8 Hz,1H), 3.07 (dd, JZ15.1, 7.0 Hz, 1H), 3.77 (ddd, JZ8.7, 7.0,4.8 Hz, 1H), 5.29 (d, JZ8.7 Hz, 1H), 6.95–7.05 (m, 4H),7.20–7.24 (m, 2H), 7.31–7.50 (m, 3H). 13C NMR[100 MHz, (CD3)2SO]: d 24.3, 41.3, 73.9, 117.6, 123.1,125.4, 126.6, 128.2, 128.5, 128.6, 129.0, 131.6, 153.4,173.2, 176.5. IR (KBr, cmK1): n 3042, 1721, 1708, 1585,1486, 1405, 1228, 1201. MS (m/z, %): 279 (MC, 100), 251(5), 186 (14), 160 (26), 159 (12), 132 (35), 131 (83), 103 (6),93 (41), 77 (11). HRMS calcd for C17H13NO3: 279.0895.Found: 279.0896. Elemental analysis calcd for C17H13NO3

(279.30): C, 73.11; H, 4.69; N, 5.02. Found: C, 72.99; H,4.90; N, 4.97.

3.3.2. 3a-Methyl-2-phenyl-9,9a-dihydro-3aH-chromeno-[2,3-c]pyrrole-1,3-dione (10). Colorless crystals. Mp 137–

139 8C. 1H NMR (400 MHz, CDCl3): d 1.85 (s, 3H), 3.09(dd, JZ14.8, 6,7 Hz, 1H), 3.22 (dd, JZ14.8, 2.8 Hz, 1H),3.32 (dd, JZ6.7, 2.8 Hz, 1H); 6.95–7.42 (m, 9H). 13C NMR(100 MHz, CDCl3): d 22.7, 25.3, 48.1, 79.3, 118.3, 123.6,124.4, 126.2, 128.4, 128.7, 128.8, 129.1, 131.2, 153.61,175.2, 175.4. IR (KBr, cmK1): n 2965, 1717, 1595, 1494,1485, 1396, 1234. MS (m/z, %): 293 (MC, 66), 265 (4), 201(11), 200 (28), 187 (18), 174 (50), 173 (14), 172 (13), 146(24), 144 (11), 107 (15), 93 (8), 91 (26), 77 (27), 63 (13).HRMS calcd for C18H15NO3: 293.1052. Found: 293.1052.Elemental analysis calcd for C18H15NO3 (293.32): C, 73.71;H, 5.15; N, 4.78. Found: C, 72.92; H, 5.55; N, 4.77.

3.3.3. 2-Methyl-9,9a-dihydro-3aH-chromeno[2,3-c]pyr-role-1,3-dione (11). Colorless crystals. Mp 97–98 8C. 1HNMR (400 MHz, CDCl3): d 2.93 (s, 3H); 3.02 (dd; JZ15.0,4.7 Hz, 1H), 3.09 (dd, JZ15.0, 4.9 Hz, 1H), 3.47 (ddd; JZ8.7, 4.7, 4.9 Hz, 1H), 5.05 (d, JZ8.7 Hz, 1H), 6.99 (dd, JZ8.4, 7.3 Hz, 1H), 7.03 (d, JZ8.4 Hz, 1H), 7.12 (d, JZ7.2 Hz, 1H), 7.20 (dd, JZ7.3, 7.2 Hz, 1H). 13C NMR(100 MHz, CDCl3): d 24.7, 25.0, 41.7, 73.5, 118.2, 123.6,124.5, 128.5, 128.7, 153.5, 173.9, 176.8. IR (KBr, cmK1) n:2959, 1702, 1484, 1435, 1384, 1343, 1322, 1284, 1225. MS(m/z, %): 217 (MC, 56), 200 (5), 199 (2), 189 (2), 186 (23),160 (32), 132 (30), 131 (100), 111 (6), 91 (2), 77 (24).HRMS calcd for C12H11NO3: 217.0739. Found 217.0761.Elemental analysis calcd for C12H11NO3 (217.22): C, 66.34;H, 5.11; N, 6.45. Found: C, 66.40; H, 5.24; N 6.24.

3.3.4. 5,7-Dichloro-2-phenyl-9,9a-dihydro-3aH-chro-meno[2,3-c]pyrrole-1,3-dione (12). Colorless crystals.Mp 212–214 8C. 1H NMR [400 MHz, (CD3)2CO]: d 3.19–3.24 (m, 2H), 3.91 (ddd, JZ8.7, 6.3, 5.6 Hz, 1H), 5.48 (d,JZ8.7 Hz, 1H), 7.14–7.17 (m, 2H), 7.29–7.33 (m, 1H),7.39–7.48 (m, 4H). 13C NMR [100 MHz, (CD3)2CO]: d25.3, 41.9, 75.7, 124.4, 127.4, 128.0, 128.2, 129.0, 129.4,129.7, 129.9, 132.9, 149.5, 172.8, 176.3. IR (KBr, cmK1) n:3062, 1718, 1598, 1462, 1401, 1185. MS (m/z, %): 351 (11,MCC4), 349 (64, MCC2), (100, MC), 329 (3), 319 (3),257 (5), 255 (7), 230 (17), 228 (26), 202 (30), 201 (49),200 (49), 199 (68), 173 (14), 165 (18), 136 (7), 93 (86).HRMS calcd for C17H11NO3

35Cl2: 347.0116. Found:347.0118. Elemental analysis calcd for C17H11NO3Cl2(348.19): C, 58.64; H, 3.19; N, 4.02. Found: C, 58.82; H,3.42; N, 4.04.

3.3.5. 5,7-Dichloro-3a-methyl-2-phenyl-9,9a-dihydro-3aH-chromeno[2,3-c]pyrrole-1,3-dione (13). Colorlesscrystals. Mp 144–146 8C. 1H NMR (400 MHz, CDCl3):d 1.90 (s, 3H), 3.05 (dd, JZ15.0, 6.7 Hz, 1H), 3.25 (dd, JZ15.0, 3.1 Hz, 1H), 3.34 (dd, JZ6.7, 3,1 Hz, 1H), 7.04–7.09(m, 3H), 7.29 (d, JZ2.2 Hz, 1H), 7.34–7.45 (m, 3H). 13CNMR (100 MHz, CDCl3): d 22.5, 25.2, 47.3, 80.2, 124.4,126.0, 126.2, 127.3, 128.4, 128.9, 129.0, 129.2, 130.9,148.1, 174.0, 174.4. IR (KBr, cmK1): n 3063, 2963, 1716,1575, 1501, 1461, 1390, 1225. MS (m/z, %): 361 (MC, 100),344 (4), 269 (6), 268 (13), 242 (23), 241 (6), 240 (4), 214(13), 212 (2), 187 (61), 174 (2), 159 (3), 149 (2), 143 (7),119 (4), 115 (6), 93 (37), 77 (5). HRMS calcd forC18H13NO3

35Cl2: 361.0272. Found: 361.0270. Elementalanalysis calcd for C18H13NO3Cl2 (362.21): C, 59.69; H,3.62; N, 3.87. Found: C, 59.80; H, 3.77; N, 3.88.

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3.3.6. 7-Nitro-2-phenyl-9,9a-dihydro-3aH-chromeno[2,3-c]pyrrole-1,3-dione (14). Colorless crystals. Mp 139–141 8C. 1H NMR [400 MHz, (CD3)2SO]: d 3.20 (dd, JZ15.5, 5.8 Hz, 1H), 3.24 (dd, JZ15.5, 7.3 Hz, 1H), 3.80 (ddd,JZ8.5, 7.3, 5.8 Hz, 1H), 5.43 (d, JZ8.5 Hz, 1H), 7.16–7.23(m, 2H); 7.29–7.35 (m, 1H); 7.34–7.51 (m, 5H). 13C NMR[400 MHz, (CD3)2SO]: d 23.4, 42.7, 74.2, 124.3, 128.7,125.5, 126.8, 127.8, 128.9, 129.0, 131.5, 142.3, 170.0,172.3, 175.7. IR (KBr, cmK1): n 3077, 1722, 1709, 1594,1514, 1401, 1343, 1242, 1182. MS (m/z, %): 324 (MC, 100),306 (5), 294 (6), 279 (5), 232 (4), 205 (15), 177 (43), 176(68), 160 (9), 130 (20), 119 (16), 77 (14). HRMS calcd forC17H12N2O5: 324.0746. Found: 324.0757.

3.3.7. 3a-Methyl-7-nitro-2-phenyl-9,9a-dihydro-3aH-chromeno[2,3-c]pyrrole-1,3-dione (15). Colorless crys-tals. Yield 40%. Mp 155–156 8C. 1H NMR (400 MHz,CDCl3): d 1.88 (s, 3H), 3.14 (dd, JZ7.3, 15.9 Hz, 1H), 3.40(dd, JZ3.0, 15.9 Hz, 1H), 3.45 (dd, JZ3.0, 7.3 Hz, 1H),7.04–7.13 (m, 3H), 7.32–7.45 (m, 3H), 8.09–8.15 (m, 2H).13C NMR (100 MHz, CDCl3): d 22.7, 23.9, 46.4, 79.7,118.7, 123.8, 124.6, 124.7, 126.0, 129.0, 129.2, 130.8,143.2, 158.4, 173.7, 174.1. IR (KBr, cmK1): n 1704, 1485,1436, 1284, 1225. MS (m/z, %): 338 (91, MC), 321 (11),308 (8), 293 (7), 245 (7), 219 (33), 191 (21), 190 (36), 176(100), 144 (24), 130 (16), 121 (14), 93 (52). HRMS calcd forC18H14N2O5: 338.0903. Found: 338.0931. Elemental analy-sis calcd for C18H14N2O5 (338.32): C, 63.90; H, 4.17; N,8.28. Found: C, 63.82; H, 4.14; N, 7.93.

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