Experimental1.1. GeneralAnalyses by HPLC were carried out with a Waters 600 HPLC equipped with a UV Gilson 116 detector and a Spherisorb NH2 (in the case of aldehydes a Spherisorb silica) 5m column (25 cm x 4.6 mm) using 98:2 hexane/2-propanol as eluent. IR spectra were recorded on a Perkin–Elmer 1310 grating spectrophotometer.
1H and
13C NMR spectra were recorded on a Varian VXR-300 spectrometer. Mass spectra were obtained at 70 eV with a Hewlett–Packard 5989A mass spectrometer, using the direct inlet system. Microanalyses were carried out on a Carlo Erba 1106 element analyser.
1.2. MaterialsReagent-grade commercially available reagents and solvents were used. 2-Hydroxybenzenethiol (1a), 1,2-benzodiol derivatives (1b–f) and 1,2-dimercaptobenzene (1g) were purchased (Aldrich).
1.3. General method of methylenation of compounds 1a–hTo a suspension of the starting compound 1a–h (50 mmol), cesium carbonate (24.4 g, 75 mmol) and anhydrous N,N-dimethylformamide (120 mL), was added dropwise bromochloromethane (9.6 g, 75 mmol) and the resulting mixture was vigorously stirred under a nitrogen atmosphere and then heated at 107–110°C for 2 h. The mixture was poured into water, the organic layer separated and the aqueous layer extracted with ether and then with dichloromethane, because ether is able to extract only the monomeric product while the dimeric ones are extracted by dichloromethane. The organic phases were dried (Na
2SO
4). The solvent was evaporated in vacuo and the residue was analysed by HPLC.
1.3.1. Methylenation of 1a. The HPLC analysis showed the presence of two products. The extract was flash-chromatographed using light petroleum as eluent. The first fraction was identified as 2a by comparison of its NMR and mass spectra with those of an authentic sample; yield 32%; pale yellow oil, bp 101–102°C/10 mm Hg (lit.17 bp 93–95°C/5 mm Hg). pale yellow oil, bp 65–66°C/10 mm Hg (lit.21 bp 60°C/9 mm Hg).
The second fraction was identified as 3b by comparison with an authentic sample; yield 11%; crystallised from acetic acid as white crystals, mp 262°C (lit.21 mp 261–262°C). [Found: C, 66.78; H, 4.91. C14H12O4 requires C, 66.85; H, 4.95%]; n
max (Nujol) 1590, 1500, 1250, 1195, 1105 cm
-1; dH (300 MHz, CDCl
3) 5.61 (4H, s, OCH2O), 7.11 (8H, s, ArH); dc (75.4 MHz, CDCl
3) 98.5, 121.4, 125.7, 150.0. m/z (EI) 244 (6, M
+), 135 (3), 122 (100), 121 (68), 80 (11), 77 (6).
1.3.3. Methylenation of 1c. The HPLC analysis showed three peaks: two peaks had very close retention times (4.38 and 4.59 min, respectively) so that their separation appeared to be very difficult.
The extract was flash-chromatographed using light petroleum as eluent. The first fraction was identified as 2c by comparison of its NMR and mass spectra with those of an authentic sample; yield 70%; pale yellow oil, bp 60°C/3 mm Hg (lit.22 bp 45°C/1.2 mm Hg). The
1H NMR analysis of the second fraction showed the presence of two isomers 3c and 3’c in a 1.1:1 ratio; total yield 26%; crystallised from acetic acid as white crystals, mp 190–192°C. [Found C, 70.48; H, 5.87. C
16H
16O
4 requires C, 70.57; H, 5.92%]; n
max of the mixture (Nujol) 1570, 1515, 1250, 1200, 1115 cm
-1.
Compound 3c. dH (300 MHz, CDCl
3) 2.28 (6H, s, CH3), 5.57 (2H, s, OCH2O), 5.62 (2H, s, OCH2O), 7.08 (6H, m, ArH); dc (75.4 MHz, CDCl
3) 20.5, 98.1, 98.3, 120.2, 122.4, 126.0, 135.2, 147.0, 150.3.
Compound 3’c. dH (300 MHz, CDCl
3) 2.26 (6H, s, CH3), 5.56 (4H, s, OCH2O), 7.08 (6H, m, ArH); dc (75.4 MHz, CDCl
3) 20.5, 98.2, 121.5, 122.6, 125.3, 136.4, 146.6, 150.7; m/z (EI) of the mixture: 272 (7, M
+), 149 (4), 137 (9.5), 136 (100), 135 (53), 105 (3), 91 (6), 79 (5), 78 (
![Cool 8)](https://thevespiary.org/talk/Smileys/default/cool.gif)
, 77 (10).
1.3.4. Methylenation of 1d. The HPLC analysis showed two peaks. The extract was flash-chromatographed using light petroleum as eluent. The first fraction was identified as 2d by comparison of its NMR and mass spectra with those of an authentic sample; yield 68%; pale yellow oil, bp 115–117°C/3 mm Hg (lit.21 bp 196–197°C/753.5 mm Hg).
The
1H NMR analysis of the second fraction (corresponding to the second HPLC peak) showed the presence of two isomers 3d and 3’d in a 1.1:1 ratio; total yield 29%; crystallised from acetic acid as white crystals, mp 219–220°C. [Found C, 70.50; H, 5.98 C
16H
16O
4 requires C, 70.57; H, 5.92%]; n
max of the mixture (Nujol) 1580, 1505, 1255, 1205, 1120 cm
-1.
Compound 3d. dH (300 MHz, CDCl
3) 2.33 (6H, s, CH3), 5.61 (2H, s, OCH2O), 5.65 (2H, s, OCH2O), 6.97 (2H, d, J=8.1 Hz, ArH), 6.99 (2H, s, ArH), 7.06 (2H, d, J=8.1 Hz, ArH); dc (75.4 MHz, CDCl
3) 20.9, 98.4, 98.6, 120.9, 121.8, 126.2, 135.6, 147.6, 149.5.
Compound 3’d. dH (300 MHz, CDCl
3) 2.33 (6H, s, CH3), 5.63 (4H, s, OCH2O), 6.97 (2H, d, J=8.1 Hz, ArH), 6.99 (2H, s, ArH), 7.06 (2H, d, J=8.1 Hz, ArH); dc (75.4 MHz, CDCl
3) 20.9, 98.5, 121.1, 121.6, 126.1, 135.5, 147.4, 149.6; m/z (EI) of the mixture 272 (8, M
+), 149 (2), 137 (9), 136 (100), 135 (25), 106 (3), 91 (2), 78 (5), 77 (3).
1.3.5. Methylenation of 1e. The HPLC analysis showed the presence of two products. The extract was flash-chromatographed using 10:1 hexane/ethyl acetate as eluent. The first fraction was identified as 2e by comparison of its NMR and mass spectra with those of an authentic sample; yield 88%; crystallised from ethanol as white crystals, mp 32–34°C (lit.23 mp 33°C).
The second fraction was identified as 3e. Yield 10%, crystallised from acetic acid as a white solid, mp 200–202°C. [Found C, 63.91; H, 3.97. C
16H
12O
6 requires C, 63.99; H, 4.03%]; n
max (Nujol) 2710, 1695, 1600, 1255, 1105 cm
-1; dH (300 MHz, CDCl
3) 5.69 (2H, s, OCH2O), 5.79 (2H, s, OCH2O), 7.31 (2H, t, J=7.5 Hz, ArH), 7.42 (2H, d, J=7.5 Hz, ArH), 7.65 (2H, d, J=7.5 Hz, ArH), 10.18 (2H, s, CHO); dc (75.4 MHz, CDCl
3) 98.4, 99.1, 121.2, 122.7, 124.2, 132.4, 136.8, 148.9, 151.2, 190.1; m/z (EI) 300 (14, M
+), 270 (5.5), 164 (15), 163 (15), 151 (17), 150 (91), 149 (100), 134 (23), 122 (14), 121 (24), 107 (15), 105 (13), 92 (21), 91 (10), 77 (18).
1.3.6. Methylenation of 1f. The HPLC analysis showed the presence of two products. The extract was flash-chromatographed using 10:1 hexane/ethyl acetate as eluent. The first fraction was identified as 2f by comparison of its NMR and mass spectra with those of an authentic sample; yield 88%; crystallised from ethanol as white crystals, mp 36–37°C (lit.24 mp 37°C).
The second fraction was identified as 3’f. Yield 10%; crystallised from acetic acid as white crystals, mp 260–262°C. [Found C, 63.88; H, 3.98. C
126H
12O
6 (sic) requires C, 63.99; H, 4.03%]; n
max (Nujol) 2715, 1695, 1600, 1260, 1100 cm
-1; dH (300 MHz, CDCl
3) 5.70 (4H, s, OCH2O), 7.37 (2H, d, J=6.9 Hz, ArH), 7.65 (4H, m, ArH), 9.90 (2H, s, CHO); dc (75.4 MHz, CDCl
3) 98.6, 122.0, 128.8, 130.9, 134.4, 154.7, 167.7, 190.2; m/z (EI) 300 (3, M
+), 151 (10), 150 (100), 149 (79), 135 (2), 121 (14), 103 (3), 91 (5), 79 (10), 77 (6).
1.3.7. Methylenation of 1g. The HPLC analysis showed four peaks. The mixture was flash-chromatographed using 9:1 ether/light petroleum as eluent. The first fraction was identified as 2g by comparison of its NMR and mass spectra with those of an authentic sample; yield 68%; crystallised from ethanol as white crystals, mp 41–42°C (lit.15 mp 39–41°C).
The
1H NMR analysis of the second fraction (corresponding to the second HPLC peak) shows the presence of two isomers 3g and 3’g in a 1.1:1 ratio; yield 17%; crystallised from methanol as white crystals, mp 205–206°C. [Found C, 63.07; H, 5.35. C
16H
16O
6 requires C, 63.15; H, 5.30%]; n
max of the mixture (Nujol) 1600, 1500, 1250, 1150 cm
-1.
Compound 3g. dH (300 MHz, CDCl
3) 3.77 (6H, s, OCH3), 5.57 (2H, s, OCH2O), 5.73 (2H, s, OCH2O), 6.79 (4H, m, ArH), 7.11 (2H, m, ArH); dc (75.4 MHz, CDCl
3) 55.8, 94.5, 98.2, 108.4, 113.3, 124.8, 128.3, 151.1, 152.8.
Compound 3’g. dH (300 MHz, CDCl
3) 3.80 (6H, s, OCH3), 5.85 (4H, s, OCH2O), 6.42 (4H, d, J=8.0 Hz, ArH), 6.68 (2H, t, J=7.8 Hz, ArH); dc (75.4 MHz, CDCl
3) 56.4, 101.0, 102.3, 107.4, 121.9, 135.1, 143.9, 148.6; m/z (EI) of the mixture 304 (18, M
+), 165 (6), 153 (10), 152 (100), 151 (34), 137 (
![Cool 8)](https://thevespiary.org/talk/Smileys/default/cool.gif)
, 107 (13), 95 (10), 79 (6).
The third fraction was identified as a 1:1 mixture of two products 4 (or 4’) and 5 (or 5’). Yield 10%. This mixture was isolated by chromatography as a white solid with mp 219–220°C. [Found C, 62.41; H, 4.25. C
15H
12O
6 requires: C, 62.50; H, 4.20%]; m/z (EI) 288 (100,M
+), 273 (9), 245 (12), 243 (9), 230 (
![Cool 8)](https://thevespiary.org/talk/Smileys/default/cool.gif)
, 217 (17), 215 (10), 187 (5), 165 (6), 144 (
![Cool 8)](https://thevespiary.org/talk/Smileys/default/cool.gif)
, 116 (5), 77 (12).
After repeated column chromatographies on silica using light petroleum as eluent the mixture was enriched in one of the two components reaching a ratio of 5:1. The mp of this mixture was 232–234°C. The elemental analysis and mass spectrum of the 5:1 mixture were identical to those of the 1:1 mixture. One product: dH (300 MHz, CDCl
3) 3.86 (3H, s, OCH3), 4.08 (3H, s, OCH3), 5.85 (2H, s, CH2), 6.15 (1H, s, ArH), 6.43 (1H, dd, J=8.0, 1.8 Hz, ArH), 6.54 (1H, dd, J=8.0, 1.8 Hz, ArH), 6.82 (1H, t, J=8.0 Hz, ArH); dc (75.4 MHz, CDCl
3) 56.11, 60.50, 91.82, 101.04, 107.22, 109.87, 122.82, 128.99, 131.47, 132.78, 133.12, 137.08, 142.47, 143.41, 148.23. Other product: dH (300 MHz, CDCl
3) 3.87 (3H, s, OCH3), 4.05 (3H, s, OCH3), 5.86 (2H, s, CH2), 6.31 (1H, s, ArH), 6.44 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.54 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.83 (1H, t, J=8.2 Hz, ArH); dc (75.4 MHz, CDCl
3) 56.12, 60.51, 92.45, 101.06, 107.22, 109.25, 122.82, 128.98, 131.45, 132.79, 133.11, 137.08, 142.45, 143.41, 147.87.
1.3.8. Methylenation of 1h. The HPLC analysis showed the presence of 2h. The residue was flash-chromatographed using light petroleum as eluent. The first fraction was identified as 2h by comparison of its NMR and mass spectra with those of an authentic sample; yield 98%; pale yellow oil, bp 104–106°C/2 mm Hg (lit.25 bp 95–96°C/1 mm Hg).
We were not able to identify the trace amount products.
Financial support from the Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica, Rome, (National Project ‘Stereoselezione in Sintesi Organica, Metodologie ad Applicazioni’), C.N.R. (Italy), University of Cagliari and Regione Autonoma della Sardegna, is gratefully acknowledged.
References1. Cabiddu, S.; Cadoni, E.; Melis, S.; Gelli, G.; Cabiddu, M. G.; Fattuoni, C.; De Montis, S.; Ianelli, S. Tetrahedron 2001, 57, 10365–10375.
2. Cabiddu, S.; Cadoni, E.; Ianni, A.; Gelli, G.; Melis, S.; Bernard, A. M.; Cabiddu, M. G.; De Montis, S.; Fattuoni, C. Eur. J. Org. Chem. 2002, 3393–3401.
3. Snieckus, V. Chem. Rev. 1990, 90, 879–933, and references cited therein.
4. Lajide, L.; Escoubas, P.; Mizutani, J. J. Agric. Food Chem. 1993, 41, 2426–2430.
5. Friedrich, M.; Meichle, W.; Bernhard, H.; Rihs, G.; Otto, H. H. Arch. Pharm. Pharm. Med. Chem. 1996, 329, 361–370.
6. Venkata Rao, D.; Omprakash, G.; Subrahmanyam, C. Indian J. Chem. 1996, 35B, 1349–1351.
7. Majerus, S. L.; Alibhai, N.; Tripathy, S.; Durst, T. Can. J. Chem. 2000, 78, 1345–1355.
8. D’Arcangelis, S. T.; Cowan, D. O. Tetrahedron Lett. 1996, 37, 2931–2934.
9. Campbell, K. N.; Hopper, P. F.; Campbell, B. K. J. Org. Chem. 1951, 16, 1736–1740.
11. Cabiddu, S.; Maccioni, A.; Secci, M. Gazz. Chim. Ital. 1969, 99, 397–410.
12. Cabiddu, S.; Maccioni, A.; Secci, M. Gazz. Chim. Ital. 1969, 99, 1095–1106.
13. Clark, J. H.; Holland, H. L.; Miller, J. M. Tetrahedron Lett. 1976, 3361–3364.
14. Dallacker, F.; Morcinek, R.; Rabie, A. Z. Naturforsch. Sect. B 1979, 34, 1434–1436.
15. Castillo, P.; Rodriguez-Ubis, J. C. Synthesis 1986, 839–840.
16. Bashall, A. P.; Collins, J. F. Tetrahedron Lett. 1975, 3489–3490.
17. Cabiddu, S.; Maccioni, A.; Secci, M. Synthesis 1976, 797–798.
18. Zelle, R. E.; McClellan, W. J. Tetrahedron Lett. 1991, 32, 2461–2464.
19. Lee, H. H.; Denny, W. A. J. Chem. Soc., Perkin Trans. 1 1990, 1071–1074.
20. Cambie, R. C.; Janssen, S. J.; Rutledge, P. S.; Woodgate, P. D. J. Organomet. Chem. 1991, 420, 387–418.
21. Bonthrone, W.; Cornforth, J. W. J. Chem. Soc. (C) 1969, 1202–1204.
22. Archer, A. W.; Claret, P. A.; Hayman, D. F. J. Chem. Soc. (B) 1971, 1231–1240.
23. Loriot, M.; Robin, J. P.; Brown, E. Tetrahedron 1984, 40, 2529–2535.
24. Sarma, J. A. R. P.; Nagaraju, A.; Majumdar, K. K.; Sammel, P. M.; Das, I.; Roy, S.; Mcghie, A. J. J. Chem. Soc., Perkin Trans. 2 2000, 6, 1119–1124.
25. Cabiddu, S.; Fattuoni, C.; Floris, C.; Gelli, G. Heterocycles 1988, 27, 1679–1684.
Source: Tetrahedron 59 (2003) 4383-4387
DOI:
10.1016/S0040-4020(03)00619-7