Download PDF
Synlett 2008(3): 329-332  
DOI: 10.1055/s-2008-1032049
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Approach to Cannabinoids by Radical Cyclisation of 1,7-Dienes Using Diethyl Thiophosphite

Mark P. Healya, Andrew F. Parsons*b, James G. T. Rawlinsonb
a GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax: +44(1904)432516; e-Mail: afp2@york.ac.uk;
Further Information

Publication History

Received 24 September 2007
Publication Date:
16 January 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Various 1,7-dienes, prepared efficiently in five steps from salicylaldehyde, react with diethyl thiophosphite (in the presence of AIBN) to form substituted chromans, which are potential precursors to cannabinoids. The influence of the substitution of the 1,7-diene on the efficiency of the radical cyclisation is discussed.

Key words

addition reactions - cyclisations - ethers - radical reactions - substituent effects

7

All new compounds gave consistent spectral and high resolution mass spectroscopic data.

9

( Z )-1-(2-Methylpent-3-en-2-yloxy)-2-vinylbenzene (13a): yellow oil. IR (CDCl3): 3085, 3065, 2958, 2927, 1603, 1487, 1456, 1439, 1377, 1174, 1120 cm-1. 1H NMR (400 MHz, CDCl3): δ = 6.80-7.70 (m, 4 H, 4 × ArCH), 7.10 (dd, J = 17.5, 11.0 Hz, 1 H, CH=CHAHB), 5.72 (dd, J = 17.5 1.5 Hz, 1 H, CH=CH AHB), 5.64 (dq, J = 12.0, 1.5 Hz, 1 H, CH=CHMe), 5.54 (dq, J = 12.0, 7.0 Hz, 1 H, CH=CHMe), 5.22 (dd, J = 11.0, 1.5 Hz, 1 H, CH=CHA H B), 1.70 (d, J = 7.0 Hz, 3 H, Me), 1.53 (s, 6 H, MeCMe). 13C NMR (100 MHz, CDCl3): δ = 153.5 (ArCO), 135.1, 132.0, 128.4, 127.4, 126.1, 120.7, 118.1 (4 × ArCH, CH=CHAHB, CH=CHMe), 128.6 (ArCCH=C), 113.7 (CH=CHAHB), 79.4 (MeCMe), 28.8 (MeCMe), 13.7 (CH=CHMe). MS (CI, NH3): m/z (%) = 203 (8) [MH+], 83 (100). HRMS (CI): m/z calcd for C14H19O [M + H+]: 203.1436; found: 203.1436.

10

Synthesis of O , O -Diethyl (3-Ethyl-2,2-dimethyl-3,4-dihydro-2 H -chromen-4-yl)methylphosphonothioate (14a): 1,7-Diene 13a (0.150 g, 0.74 mmol, 1 equiv), diethyl thiophosphite (0.114 g, 0.74 mmol, 1 equiv) and AIBN (0.097 g, 0.59 mmol, 0.8 equiv, 1 portion) were heated to reflux in degassed cyclohexane (20 mL) overnight. After cooling to r.t., the solvent was evaporated and purification of the crude product by column chromatography (silica, petrol) afforded 14a (0.073 g, 28%) as a colourless oil, as an inseparable 1:1 mixture of cis- and trans-diastereoisomers as indicated by the 1H NMR spectrum. IR (CH2Cl2): 3055, 2983, 2937, 2904, 2879, 1606, 1581, 1487, 1452, 1387, 1371, 1302, 1261, 1225, 1159, 1026 cm-1. 1H NMR (400 MHz, CDCl3; both diastereoisomers): δ = 7.40, 7.29 (2 × d, 2 × J = 8.0 Hz, 1 H, ArCH), 7.11, 7.09 (2 × t, 2 × J = 8.0 Hz, 1 H, ArCH), 6.98, 6.86 (2 × t, 2 × J = 8.0 Hz, 1 H, ArCH), 6.78, 6.74 (2 × d, 2 × J = 8.0 Hz, 1 H, ArCH), 3.96-4.28 (m, 4 H, 2 × OCH 2Me), 3.58, 3.32 (2 × app. ddt, J = 19.0, 6.0, 5.0 Hz and J = 24.0, 5.5, 5.0 Hz, 1 H, PCHAHBCH), 2.40-2.62, 2.27 (m and app. td, J = 16.0, 5.0 Hz, 2 H, PCH A H B), 1.19-1.83 (m, 15 H, MeCMe, CHCH 2Me, 2 × OCH2 Me), 1.04, 1.02 (2 × t, 2 × J = 7.5 Hz, 3 H, CHCH2 Me). 13C NMR (100 MHz, CDCl3; both diastereoisomers): δ = 153.6, 152.9 (ArCO), 127.8, 127.7, 127.5, 2 × 125.7 (2 × d, 3 J CP = 10.5, 7.0 Hz, PCHAHBCHArC), 120.5, 120.0, 2 × 117.3 (4 × ArCH), 78.7 (MeCMe), 62.7, 62.6, 62.3, 62.2 (4 × d, 2 J CP = 4 × 7.0 Hz, 2 × OCH2Me), 48.1 (d, 3 J CP = 5.5 Hz, PCHAHBCHCH), 42.3, 34.6 (2 × d, 1 J CP = 109.0, 110.5 Hz, PCHAHB), 33.1, 32.0 (2 × d, 2 J CP = 2.5, 1.5 Hz, PCHAHB CH), 28.7, 27.8, 26.3, 24.3 (MeCMe), 23.2, 19.5 (CHCH2Me), 3 × 16.2, 16.1 (4 × d, 3 J CP = 4 × 7.0 Hz, 2 × OCH2 Me), 14.2, 13.7 (CHCH2 Me). MS (CI, NH3): m/z (%) = 357 (100) [MH+]. HRMS (CI): m/z calcd for C18H30O3PS [M + H+]: 357.1653; found: 357.1652.

13

Synthesis of Methyl 2-{4-[(Diethoxyphosphoro­-thioyl)methyl]-2,2-dimethyl-3,4-dihydro-2 H -chromen-3-yl}acetate (14c): 1,7-Diene 13c (0.250 g, 1.02 mmol, 1 equiv), diethyl thiophosphite (0.782 g, 5.08 mmol, 5 equiv) and AIBN (0.042 g, 0.25 mmol, 0.25 equiv, 5 portions, 1 h between additions) were heated to reflux in anhyd degassed THF (20 mL) overnight. After cooling to r.t., the solvent was evaporated and excess diethyl thiophosphite was removed by distillation (75 °C/3 mmHg). Purification of the residue by column chromatography (silica; PE-Et2O, 9:1) afforded 14c (0.221 g, 54%) as a yellow oil. IR (CH2Cl2): 2982, 2953, 2853, 1735, 1608, 1582, 1488, 1453, 1437, 1388, 1372, 1302, 1249, 1228, 1170, 1138, 1116, 1098, 1026 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 7.5 Hz, 1 H, ArCH), 7.11 (t, J = 7.5 Hz, 1 H, ArCH), 6.90 (t, J = 7.5 Hz, 1 H, ArCH), 6.76 (d, J = 7.5 Hz, 1 H, ArCH), 4.06-4.28 (m, 4 H, 2 × OCH 2Me), 3.70 (s, 3 H, CO2Me), 3.05-3.18 (m, 1 H, PCH2CH), 2.69 (dd, J = 16.0, 3.5 Hz, 1 H, CH AHB), 2.32-2.55 (m, 4 H, PCH 2CHCHCHA H B), 1.35 (s, 3 H, MeCMe), 1.34 (t, J = 7.0 Hz, 6 H, 2 × OCH2 Me), 1.21 (s, 3 H, MeCMe). 13C NMR (100 MHz, CDCl3): δ = 173.6 (CO2Me), 152.6 (ArCO), 129.3, 127.7, 120.7, 117.3 (4 × ArCH), 125.5 (d, 3 J CP = 7.5 Hz, PCH2CHArC), 76.8 (MeCMe), 62.8, 62.6 (2 × d, 2 J CP = 2 × 7.0 Hz, 2 × OCH2Me), 51.9 (CO2 Me), 44.1 (d, 3 J CP = 7.0 Hz, PCH2CHCH), 41.3 (d, 1 J CP = 111.0 Hz, PCH2), 35.6 (CH2CO2), 33.6 (d, 2 J CP = 1.5 Hz, PCH2 CH), 27.3, 21.7 (MeCMe), 16.2, 16.1 (2 × d, 3 J CP = 2 × 7.0 Hz, 2 × OCH2 Me). MS (CI, NH3): m/z (%) = 401 (100) [MH+]. HRMS (CI): m/z calcd for C19H29O5PS [M + H+]: 401.1552; found: 401.1551.

14

4-(2,2-Diphenylvinyl)-3-ethyl-2,2-dimethylchromane (15): colourless oil (6.5:1 mixture of diastereoisomers). IR (CH2Cl2): 3019, 2958, 2931, 1598, 1581, 1484, 1451, 1386, 1302, 1148, 1030 cm-1. 1H NMR (400 MHz, CDCl3; both diastereoisomers): δ = 7.20-7.42 (m, 11 H, 11 × ArCH), 7.11 (t, J = 7.0 Hz, 1 H, ArCH), 6.85 (t, J = 7.0 Hz, 1 H, ArCH), 6.77 (d, J = 7.0 Hz, 1 H, ArCH), 6.29, 5.95 (2 × d, J = 2 × 10.5 Hz, 1 H, cis-C=CH and trans-C=CH), 3.42 (app. t, J = 10.5 Hz, 1 H, CHCH=C), 1.54 (dt, J = 10.5, 4.5 Hz, 1 H, CHCH2Me), 0.98, 1.42 (2 × s, 2 × 3 H, MeCMe), 1.20-1.40 (m, 2 H, CH 2Me), 0.80-0.92 (m, 3 H, CH2 Me). 13C NMR (100 MHz, CDCl3; both diastereoisomers): δ = 153.1 (ArCO), 143.2, 142.3, 139.8 (3 × ArC), 131.1, 2 × 129.6, 2 × 128.4, 2 × 128.2, 127.8, 2 × 127.3, 2 × 127.2, 124.1, 119.7, 117.0 (14 × ArCH, C=CH), 78.0 (MeCMe), 48.9 (CHCH2Me), 40.1 (CHCH=C), 28.3 (MeCMe), 23.6 (CH2Me), 20.3 (MeCMe), 15.2 (CH2 Me). MS (CI, NH3): m/z (%) = 369 (45) [MH+], 357 (100). HRMS (CI): m/z calcd for C27H28O [M + H+]: 369.2218; found: 369.2217.