A Convergent Construction of Quaternary Centres and Polycyclic Structures

Abstract

Various xanthates, made by conjugate addition of xanthic acid to electrophilic olefins, add in a inter- or intra-molecular fashion to olefins allowing a direct introduction of a quaternary centres and the construction of polycyclic structures.

radical additions - xanthates - quaternary centres - polycycles - cycloalkenones

References

1 Giese B. Kopping B. Göbel T. Dickhaut J. Thoma G. Kulicke KJ. Trach F. Org. React.  1996,  48:  301 ; and references there cited

2a Curran DP. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  p.715-831  

2b Curran DP. Synthesis  1988,  417 

2c Curran DP. Synthesis  1988,  489 

2d Radicals in Organic Synthesis   Renaud P. Sibi M. Wiley VCH; Weinheim: 2001. 

3 See for example: Curran DP. Xu J. Lazzarini E. J. Am. Chem. Soc.  1995,  117:  6603 

4a Zard SZ. Angew. Chem., Int. Ed. Engl.  1997,  36:  672 

4b Quiclet-Sire B. Zard SZ. Phosphorus, Sulfur Silicon Relat. Elem.  1999,  153 

4c Quiclet-Sire B. Zard SZ. Phosphorus, Sulfur Silicon Relat. Elem.  1999,  137 

5a Matsui S. Bull Chem. Soc. Jpn  1987,  60:  1853 

5b Maslak V. Cekovic Z. Saicic R. Synlett  1998,  1435 

5c Gagosz F. Moutrille C. Zard SZ. Org. Lett.  2002,  4:  2707 

6a Bouhadir G. Legrand N. Quiclet-Sire B. Zard SZ. Tetrahedron Lett.  1999,  40:  277 

6b Thang SH. Chong YK. Mayadunne RTA. Moad G. Rizzardo E. Tetrahedron Lett.  1999,  40:  2435 

7a Barton DHR. George MV. Tomoeda M. J. Chem. Soc.  1962,  1967 

7b Delduc P. Tailhan C. Zard SZ. J. Chem. Soc., Chem. Commun.  1988,  308 

7c Forbes JE. Saicic RN. Zard SZ. Tetrahedron  1999,  55:  3791 

7d Quiclet-Sire B. Zard SZ. Tetrahedron Lett.  1998,  39:  1073 

8 Kreutzkamp N. Peschel H. Pharmazie  1970,  25:  322 

9

Typical Experimental Procedures: 5,5-Dimethyl-2-cyclohexenone 9a. A degassed solution of 6a [8] (186 mg; 0.84 mmol) and vinyl acetate (0.35 mL; 3.87 mmol) in ClCH₂CH₂Cl (1.2 mL), was heated to reflux under an inert atmosphere. After a few minutes of refluxing, solid lauroyl peroxide (5 mol%) was added and heating was continued for 1.5 h. Another small amount of lauroyl peroxide (2 mol%) was added followed by further similar lots every hour until TLC indicated completion of the reaction (13 mol% in total). After cooling to r.t., the solvent was removed under reduced pressure and the residue purified by silica gel chromato-graphy (EtOAc-petroleum ether, 5:95) to afford 7a as a yellowish oil (180 mg; 70%). IR (film): 2957, 1751, 1715, 1367, 1218, 1051, 488 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 6.68 (dd, J ₁ = 5.1, J ₂ = 7.6 Hz, 1 H), 4.65 (q, J = 7.1 Hz, 2 H), 2.46 (s, 2 H), 2.20-2.04 (m, 8 H), 1.42 (t, J = 6.1 Hz, 3 H), 1.08 (s, 3 H), 1.07 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 212.7, 207.5, 170.3, 78.3, 70.4, 53.0, 44.9, 32.8, 31.7, 27.5, 27.4, 28.0, 13.3. MS (IC, NH₃): m/z = 324 [M + NH₃]. Anal. Calcd for C₁₃H₂₂O₄S₂: C, 50.95; H, 7.24. Found: C, 50.92; H, 7.31. A solution of ketone 7a (100 mg; 0.4 mmol), p-TsOH (30 mg) and H₂O (0.1 mL) in THF (4 mL) was refluxed for 48 h. The reaction mixture was cooled to r.t. and neutralised with a sat. solution of NaHCO₃. The organic layer was extracted with Et₂O, washed with brine, dried over Na₂SO₄, filtered, and the solvent removed in vacuo. The residue was purified by silica gel chromatography (elution by diethyl ether-pentane, 0.5:9.5) to afford the known enone [12] 9a (39 mg, 82%). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 6.86 (dt, J ₁ = 4.1, J ₂ = 10.1 Hz, 1 H), 6.02 (dt, J ₁ = 2.0, J ₂ = 10.1 Hz, 1 H), 2.27 (s, 2 H), 2.24 (dd, J ₁ = 2.0, J ₂ = 4.1 Hz, 2 H), 1.04 (s, 6 H): ¹³C NMR (100 MHz; CDCl₃): δ (ppm) = 199.7 (C=O), 148.1 (CH), 128.6 (CH), 51.4 (CH₂), 39.5 (C_quat.), 29.3 (CH₂), 28.9 (2 CH₃). MS (IC, NH₃) m/z = 125 [M + H], 142 [M + NH₄].
Methyl 1-Methyl-2-cyclohexenecarboxylate 16. To a stirred solution of freshly distilled diisopropylamine (1.31 mL, 9.3 mmol, 1.4 equiv) in of THF (8 mL) maintained at 0 °C under argon were added dropwise n-BuLi (5.53 mL, 1.56 M in hexanes, 8.6 mmol, 1.3 equiv). After 15 min the solution was cooled down to -78 °C and dry HMPA (1.50 mL, 8.6 mmol, 1.3 equiv) was added. The mixture was stirred for 30 min at the same temperature and commercial 1-cyclohexenylmethyl-carboxylate (0.93 g, 6.6 mmol, 1.0 equiv) was then added followed after 10 min by (0.62 mL, 10.0 mmol, 1.5 equiv) of methyl iodide. The solution was then allowed to warm to -5 °C over 2 h when a sat. aq solution of NH₄Cl was poured into the orange mixture. After dilution with petroleum ether and washing with brine, the organic layer was dried over NaSO₄ and carefully concentrated in vacuo to give ester 16 as a yellow liquid, which was used as such in the next step (0.98 g, crude yield: 96%). ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.27 (s, 3 H, CH ₃ C), 1.45 (ddd, ² J _HH = 13.1 Hz, ³ J _HH = 9.7 Hz and ³ J _HH = 3.4 Hz1 H), 1.56-1.71 (m, 2 H), 1.96-2.02 (m, 2 H), 2.13-2.19 (m, 1 H), 3.69 (s, 3 H, CH ₃ O), 5.68 (dm, ³ J _HH = 10.1 Hz, 1 H), 5.78 (dt, ³ J _HH = 10.1 Hz and ³ J _HH = 3.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 19.3 (CH₃), 24.4 (CH₂), 26.1 (CH₂), 32.7 (CH₂), 42.8 (C_quat.), 51.6 (CH₃O), 127.6 (CH), 130.3 (CH), 177.2 (C=O).
Dimethyl [2-(1-Methyl-cyclohex-2-enyl)-2-oxo-ethyl]-phosphonate 17. n-BuLi (1.56 M in hexanes, 7.8 mL, 12.2 mmol, 2.1 equiv) was added at -78 °C under argon to a stirred solution of commercial dimethyl methylphosphonate (1.55 mL,14.3 mmol, 2.5 equiv) in THF (20 mL). After 30 min at -78 °C, ester 16 was added with a syringe over 10 min and the mixture was stirred for 6 h at the same temperature. At this point a sat. aq solution of NH₄Cl was poured into the flask and the mixture was diluted with EtOAc. The organic layer was washed successively with sat. aq solutions of NH₄Cl and NaCl then dried over NaSO₄. Concentration under reduced pressure afforded a yellowish oil which was purified by flash column chromatography in petroleum ether-EtOAc (40% to 100%) to yield 17 as a colourless oil (0.99 g, 70%). IR (film): 2937, 1707, 1458, 1257, 1036
cm^-1. MS (IC, NH₃) m/z = 264 [M + NH₄]⁺, 247 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.21 (s, 3 H, CH ₃ C), 1.41 (ddd, ² J _HH = 12.5 Hz, ³ J _HH = 8.6 Hz and ³ J _HH = 3.5 Hz, 1 H), 1.52-1.66 (m, 2 H), 2.00-2.08 (m, 3 H), 3.18 (dd, ² J _HP = 21.6 Hz and ² J _HH = 15.4 Hz, 1 H), 3.24 (dd, ² J _HP = 21.1 Hz and ² J _HH = 15.4 Hz, 1 H), 3.78 (d, ³ J _HP = 2.1 Hz, 3 H), 3.81 (d, ³ J _HP = 2.1 Hz, 3 H), 5.66 (dt, ³ J _HH = 10.1 Hz and ⁴ J _HH = 2.1 Hz, 1 H), 5.90 (dt, ³ J _HH = 10.1 Hz and ³ J _HH = 3.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 18.8 (CH₃), 23.9 (CH₂), 24.5 (CH₂), 31.4 (CH₂), 35.9 (d, ¹ J _CP = 136 Hz, 1 C, CH₂P), 49.9 (C_quat.), 52.6 (CH₃O), 129.2 (CH), 129.8 (CH), 205.3 (d, ¹ J _CP = 7 Hz, 1 C, C=O).
O -Ethyl- S -[3-(1-methyl-cyclohex-2-enyl)-3-oxo-1-phenyl-propyl] Dithiocarbonate 18a. To a suspension of NaH (60% in mineral oil; 16 mg, 0.40 mmol) in THF (1 mL) maintained at 0 °C under argon was added drop wise a solution of 17 (82 mg, 0.33 mmol) in THF (0.5 mL). The resulting mixture was stirred for 30 min before adding benzaldehyde (41 µL, 0.40 mmol) slowly, leading rapidly to a yellow solution. After 2 h at 0 °C, a TLC analysis showed no more starting material. A sat. aq solution of NH₄Cl was poured into the flask and the mixture diluted with Et₂O. The organic layer was washed successively with sat.aq solutions of NH₄Cl and NaCl then dried over Na₂SO₄. Removal of solvent under reduced pressure afforded crude 1-(1-methyl-cyclohex-2-enyl)-1-oxo-3-phenyl-prop-2-ene as a yellow oil. This compound was dissolved in a (3:2) mixture of CH₂Cl₂ and HOAc (2.5 mL) and the solution was cooled down to 0 °C. Commercial potassium O-ethyl xanthate (0.26 g, 1.64 mmol) was added portion-wise over 2 h, followed by one more hour of stirring. After addition of water and dilution with Et₂O, the organic layer was washed successively with H₂O and brine and dried over Na₂SO₄. After concentration in vacuo the resulting yellow oil was submitted to flash column chromatography using petroleum ether-EtOAc (5%) as eluent to give 18a as a viscous pale yellow oil (81 mg, 71%) and as a (2:1) mixture of diastereoisomers. IR (film): 3062, 3025, 2935, 2868, 1707, 1602, 1453, 1221, 1111, 1048 cm^-1. MS (IC, NH₃) m/z = 349 [M + H]⁺, 229 {M - [(SC(S)OEt] + H}⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 0.98 (s, 2 H, CH ₃ C), 1.10 (s, 1 H, CH ₃ C), 1.18-1.32 (m, 2 H), 1.35 (t, ³ J _HH = 7.1 Hz, 1.5 H, CH ₃ CH₂O), 1.37 (t, ³ J _HH = 7.1 Hz, 1.5 H, CH ₃ CH₂O), 1.38-1.43 (m, 1 H), 1.49-1.58 (m, 1 H,), 1.92-1.99 (m 4 H), 3.22 (d, ³ J _HH = 7.2 Hz, 2 H), 4.59 (q, ³ J _HH = 7.1 Hz, 2 H, CH ₂ O), 5.28 (t, ³ J _HH = 7.2 Hz, 1 H, CH-Ph), 5.51 (dt, ³ J _HH = 10.1 Hz and ⁴ J _HH = 1.9 Hz, 2/3 H), 5.60 (dt, ³ J _HH = 10.1 Hz and ⁴ J _HH = 1.9 Hz, 1/3 H), 5.78-5.84 (m, 1 H), 7.11 (d, ³ J _HH = 15.7 Hz, 1 H), 7.18-7.31 (m, 3 H, H_arom.), 7.34-7.36 (m, 2 H, H_arom.). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 13.3 (CH₃), 18.9 and 19.0 (CH₂), 24.2 (CH₃), 24.5 (CH₂), 31.4 and 31.6 (CH₂), 43.8 (C_quat.), 47.0 (CH₂), 48.7 (CH), 69.6 (CH₂), 127.3 (CH), 127.7 and 127.8 (CH), 128.2 (CH), 129.2 (CH), 129.5 (CH), 139.6 and 139.7 (C_{quat. arom.}), 209.8 and 209.9 (C=O), 212.0 (C=S).
O -Ethyl- S -(7a-methyl-1-oxo-3-phenyl-octahydro-inden-4-yl) Dithiocarbonate 19a. A solution of 18a (81 mg, 0.23 mmol) in ClCH₂CH₂Cl (2.3 mL) was heated to reflux under argon for 15 min then solid lauroyl peroxide (7 mg, 0.02 mmol) was added from the top of the condenser. The reflux was continued for 7 h during which time a further four smaller portions of peroxide were added every 90 min (total: 12 mg). Cooling and removal of the solvent in vacuo gave a pale yellow solid which was purified by flash column chromatography in petroleum ether-EtOAc (5%) to yield 19a as colourless needles (57 mg, 70%) and as a (9:1) mixture of diastereoisomers. IR (film): 2935, 1742, 1452, 1216, 1112, 1050 cm^-1; MS (IC, NH₃) m/z = 366 [M + NH₄]⁺, 349 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm, major isomer): 1.37 (t, ³ J _HH = 7.2 Hz, 3 H, CH ₃ CH₂O), 1.30 (s, 3 H), 1.31-1.38 (m, 1 H), 1.51 (dt, ² J _HH = 12.4 Hz and ³ J _HH = 4.8 Hz, 1 H), 1.61-1.72 (m, 2 H), 1.58-1.77 (m, 2 H), 1.94 (dm, ² J _HH = 14.5 Hz, 1 H, CH-CH-S), 2.04 (ddt, ² J _HH = 14.5 Hz, ³ J _HH = 11.8 Hz and ³ J _HH = 4.4 Hz, 1 H, CH-CH-S), 2.33 (dm, ³ J _HH = 11.4 Hz, 1 H, CH-CHPh), 2.51 (dd, ² J _HH = 19.2 Hz and ³ J _HH = 11.2 Hz, 1 H), 2.92 (dd, ² J _HH = 19.2 Hz and ³ J _HH = 8.2 Hz, 1 H), 3.40 (ddd, ³ J _HH = 11.4 Hz, ³ J _HH = 11.2 Hz and ³ J _HH = 8.2 Hz, 1 H, CHPh), 3.97-4.01 (m, 1 H, CH-S), 4.45-4.57 (m, 2 H, CH ₂ O), 7.24-7.33 (m, 3 H, H_arom.), 7.36-7.40 (m, 2 H, H_arom.). ¹³C NMR (100 MHz, CDCl₃): δ (ppm, for major isomer) = 13.4 (CH₃), 17.3 (CH₂), 20.8 (CH₃), 26.0 (CH₂), 28.4 (CH₂), 42.0 (CH), 44.2 (CH₂), 44.3 (CH), 47.9 (C_quat.), 54.6 (CH-S), 69.3 (CH₂O), 127.0 (CH), 127.3 (CH), 128.5 (CH), 140.7 (C_{quat. arom.}), 212.8 (C=O), 218.7 (C=S). Anal. Calcd for C₁₉H₂₄O₂S₂ (%): C, 65.48; H, 6.94. Found (%): C, 65.77; H, 7.13.
7a-Methyl-3-phenyl-octahydro-inden-1-one 19c. To a refluxing solution of 19a (23 mg, 0.066 mmol) in benzene (0.7 mL) were added Bu₃SnH (20 µL, 0.073 mmol), followed by AIBN (1 mg, 6.6 µmol). After 30 min the mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by flash column chromatography in petroleum ether-EtOAc (0% to 5%) to give 19c as a white solid (9 mg, 60%) and as a single diastereoisomer (spatial structure assigned by NOE experiment). IR (CCl₄): 2933, 2860, 1739, 1455 cm^-1. MS (IC, NH₃) m/z = 246 [M + NH₄]⁺, 229 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ (ppm) = 1.21 (s, 3 H, CH ₃-), 1.26-1.33 (m, 2 H), 1.40-1.59 (m, 4 H), 1.64-1.73 (m, 2 H), 2.00 (m, 1 H, -CH-CHPh), 2.42 (dd, ² J _HH = 19.2 Hz and ³ J _HH = 11.2 Hz, 1 H), 2.88 (dd, ² J _HH = 19.2 Hz and ³ J _HH = 8.1 Hz, 1 H), 3.43 (ddd, ³ J _HH = 11.6 Hz, ³ J _HH = 11.2 Hz and ³ J _HH = 8.1 Hz, 1 H, -CH-Ph), 7.23-7.27 (m, 3 H, H_arom.) 7.32-7.36 (m, 2 H, H_arom.). ¹³C NMR (100 MHz, CDCl₃): δ (ppm) = 18.9 (CH₃), 20.1, 20.6, 20.8 (CH₂), 28.2 (CH₂), 40.4 (CH), 44.7 (CH₂), 48.0 (C_quat.), 49.8 (CH), 126.4, 127.2, 128.3 (CH_arom.), 142.2 (C_{quat. arom.}), 220.7 (C=O). Anal. Calcd for C₁₉H₂₄O₂S₂ (%): C, 84.16; H, 8.83. Found (%):C, 83.95; H, 8.97.

10 Fraga BM. Nat. Prod. Rep.  2002,  19:  650 ; and earlier papers in the series

11 Jones GB. Huber RS. Chan S. Tetrahedron  1993,  43:  369 

12 Wang X. Pan X. Cui Y. Chen Y.-Z. Tetrahedron  1996,  52:  10659