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

Mark P. Healy; Andrew F. Parsons; James G. T. Rawlinson

doi:10.1055/s-2008-1032049

LETTER

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

Mark P. Healy^a, Andrew F. Parsons*^b, James G. T. Rawlinson^b
^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;

Abstract

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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

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References

References and Notes

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( 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=CH_AH_B), 5.72 (dd, J = 17.5 1.5 Hz, 1 H, CH=CH _AH_B), 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=CH_A 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=CH_AH_B, CH=CHMe), 128.6 (ArCCH=C), 113.7 (CH=CH_AH_B), 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.

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, PCH_AH_BCH), 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, PCH_AH_BCHArC), 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, PCH_AH_BCHCH), 42.3, 34.6 (2 × d, ¹ J _CP = 109.0, 110.5 Hz, PCH_AH_B), 33.1, 32.0 (2 × d, ² J _CP = 2.5, 1.5 Hz, PCH_AH_B 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.

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<A NAME="RD30307ST-11A">11a</A> Studer A. Angew Chem. Int. Ed. 2000, 1108

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<A NAME="RD30307ST-12A">12a</A> Walling C. Cioffari A. J. Am. Chem. Soc. 1972, 94: 6064

<A NAME="RD30307ST-12B">12b</A> Julia M. Acc. Chem. Res. 1971, 4: 386

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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 _AH_B), 2.32-2.55 (m, 4 H, PCH ₂CHCHCH_A 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.

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.

<A NAME="RD30307ST-15">15</A> For a related cyclisation, see: Samarat A. Landais Y. Amri H. Tetrahedron Lett. 2004, 45: 2049