Lactones, Part 28: [1] A New Approach for the Synthesis of α-Methylene Lactones from Alkenes

Abstract

A facile two-step procedure for synthesis of α-methylene lactones from alkenes and cycloalkenes is presented. Reactions ­carried out on some monoterpene alkenes afforded corresponding lactones in enantiomerically pure forms.

α-methylene lactone - CAN - Meldrum’s acid

References and Notes

1 Gadkowski W. Grabarczyk M. Wińska K. Biaońska A. Ciunik Z. Wawrzeńczyk C. J. Mol. Catal. B: Enzym.  2006,  39:  31 

2 Lee KH. Huang BR. Eur. J. Med. Chem.  2002,  37:  333 

3 Kupchan SM. Fessler DC. Eakin MA. Giacobbe TJ. Science  1970,  168:  376 

4 Neerman MF. Int. J. Aromather.  2003,  13:  114 

5 Ohno S. Tomita-Yokotani K. Kosemura S. Node M. Suzuki T. Amano M. Yasui K. Goto T. Yamamura S. Hasegawa K. Phytochemistry  2001,  56:  577 

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7 Zhang S. Won YK. Ong CN. Shen HM. Curr. Med. Chem.: Anti-Cancer Agents  2005,  5:  239 

8 Grieco A. Synthesis  1975,  67 

9 Hoffmann HMR. Rabe J. Angew. Chem., Int. Ed. Engl.  1985,  24:  94 

10 Petragnani N. Ferraz HMC. Silva GVJ. Synthesis  1986,  157 

11 Datta S. Saxena D. Pest. Manag. Sci.  2001,  57:  95 

12a Paruch E. Ciunik Z. Wawrzeńczyk C. Eur. J. Org. Chem.  1998,  2677 

12b Dams I. Biaońska A. Ciunik Z. Wawrzeńczyk C. J. Agric. Food Chem.  2004,  54:  1630 

12c Dams I. Biaońska A. Ciunik Z. Wawrzeńczyk C. Eur. J. Org. Chem.  2004,  12:  2662 

12d Paruch E. Ciunik Z. Wawrzeńczyk C. Liebigs Ann./Recl.  1997,  2341 

13 Szumny A. Olejniczak T. Gabryś T. Halarewicz-Pacan A. Dancewicz K. Krystkowiak K. Wawrzeńczyk C. Arthropods. Chemical, Physiological and Environmental Aspects   Konopińska D. University of Wrocaw; Poland: 2001.  p.234 

14 Murta MM. de Azevedo MBM. Greene AE. J. Org. Chem.  1993,  58:  7537 

15 Solabannavar SB. Helavi VB. Desai UV. Mane RB. Tetrahedron Lett.  2002,  43:  4535 

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General Procedure.
CAN (20 mmol) was slowly added to a cooled (ice bath) and vigorously stirred solution of alkene (10 mmol) and Meldrum’s acid (or ethyl acetoacetate for compound 10) (10 mmol) in 50 mL MeCN. The reaction was complete when the orange color of the mixture turned to pale-yellow (usually after 1 h). Then the solvent was evaporated (below 50 °C, because of possible decarboxylation reaction). Then, H₂O (100 mL) was added to the residue and the product was extracted with EtOAc (3 × 40 mL). Combined ethereal solutions were washed with brine. The purification of crude product via NaHCO₃-HCl procedure significantly decreased the yield of this reaction. So in the next step crude α-car-boxylactone was stirred overnight with 3 mL of stock solution containing Et₂NH (3 mL), 30% formaldehyde (6 mL), NaOAc (0.2 g) and AcOH (8 mL). The reaction mixture was acidified with 10% HCl (50 mL) and extracted with Et₂O. Crude product was purified by column chromatography (eluent hexane-Et₂O, starting from 20:1 and next 2:1).The physical and spectral data of compounds obtained are presented below.

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Analytical Data for Compounds Obtained.
Compound 1a: n _D ²⁰ 1.4605. ¹H NMR (300 MHz, CDCl₃): δ = 6.19 (1 H, t, J = 2.8 Hz, =CH₂), 5.57 (1 H, t, J = 2.4 Hz, =CH₂), 2.72 (1 H, dt, J = 16.8, 2.8 Hz, CH₂ in lactone), 2.68 (1 H, dt, J = 16.8, 2.4 Hz, CH₂ in lactone), 1.71 and 1.65 [2 H, 2 d, J = 14.8 Hz ,(CH₃)₃CCH ₂, AB system], 1.44 [3 H, s, (CH₃)CO], 1.00 [9 H, s, (CH ₃)₃CCH₂]. IR (film): 1778 (s), 1675 (m), 1290 (m), 1108 (m) cm^-1. MS (EI): m/z (%) = 183 [M + H](7), 167 (1), 126 (4), 111 (100), 83 (18), 68 (5).
Compound 2a: mp 86 °C. ¹H NMR (300 MHz, CDCl₃): δ = 6.21 (1 H, t, J = 2.9 Hz, =CH₂), 5.61 (1 H, t, J = 2.4 Hz, =CH₂), 4.50 [1 H, tt, J = 7.6, 5.6 Hz, >CH(O)], 3.01 (1 H, ddt, J = 17.0, 7.6, 2.5 Hz, CH₂ in lactone), 2.56 (1 H, ddt, J = 17.0, 5.9, 2.9 Hz, CH₂ in lactone), 1.52-1.76 [2 H, m, CH₃(CH₂)₁₀CH ₂], 1.16-1.44 [20 H, m, CH₃(CH ₂)₁₀CH₂], 0.86 [3 H, t, J = 6.9 Hz, CH ₃(CH₂)₁₀CH₂]. IR (KBr): 1776 (s), 1676 (w), 1284 (m), 1124 (m), 944 (m) cm^-1. MS (EI): m/z (%) = 267 (72) [M + H], 249 (13), 227 (13), 221 (25), 171 (23), 123 (34), 109 (52), 97 (100), 83 (31), 69 (69).
Compound 3a: n _D ²⁰ 1.4885. ¹H NMR (300 MHz, CDCl₃): δ = 6.22 (1 H, m, >C=CH₂), 5.85 (1 H, dd, J = 17.2, 11.0 Hz, CH₂=CH), 5.60 (1 H, m, =CH₂), 5.22 (1 H, d, J = 17.2 Hz, CH ₂=CH), 5.17 (1 H, d, J = 11.0 Hz, CH ₂=CH), 5.06 [1 H, t, J = 5.6 Hz, (CH₃)₂C=CH], 2.82 (2 H, s, CH₂ in lactone), 2.06 (2 H, m, =CHCH ₂CH₂), 1.76 (2 H, t, J = 8.2 Hz, =CHCH₂CH ₂), 1.67 [3 H, s, =C(CH₃)₂], 1.59 [3 H, s, =C(CH₃)₂]. IR (film,): 1766 (s), 1665 (w), 1276 (m), 1072 (w), 934 (w) cm^-1. MS (EI): m/z (%) = 207 [M + H] (59), 189 (54), 173 (8), 161 (100), 145 (35), 133 (18), 121 (80), 105 (29), 93 (48), 67 (4).
Compound 4a: n _D ²⁰ 1.4962. ¹H NMR (300 MHz, CDCl₃): δ = 6.20 (1 H, d, J = 3.0 Hz, =CH₂), 5.44 (1 H, d, J = 2.7 Hz, =CH₂), 2.73 (1 H, m, >CHCH₂), 1.71-1.25 [m, 8 H, (CH₂)₄ in cyclohexyl], 1.46 (3 H, s, CH₃). IR (film): 1776 (s), 1676 (m), 1168 (m), 936 (m) cm^-1. MS (EI): m/z = 167 (100) [M + H], 151 (14), 138 (10), 123 (61), 108 (9), 95 (18), 79 (8), 67 (10).
Compound 5a: n _D ²⁰ 1.5085. ¹H NMR (600 MHz, CDCl₃): δ = 6.20 (1 H, t, J = 2.8 Hz, =CH₂), 5.58 (1 H, m, =CH₂), 5.35 (1 H, m, >C=CH), 2.87 (dt, J = 17.1, 2.8 Hz, CH₂ in lactone, diastereomer A), 2.86 (dt, J = 17.0, 3.1 Hz, CH₂ in lactone, diastereomer B), 2.57 (1 H, dt, J = 17.0, 2.8 Hz, CH₂ in lactone, diastereomer B), 2.56 (1 H, dt, J = 17.1, 2.4 Hz, CH₂ in lactone, diastereomer A), 1.70-2.12 (7 H, m, CH₂ and >CH in cyclohexyl), 1.61 [3 H, s, =C(CH₃)], 1.35 and 1.34 [3 H, 2 s, >C(O)CH₃ for both diastereomers]. IR (film): 1768 (s), 1668 (w), 1296 (s), 1060 (m) cm^-1. MS (EI): m/z (%) = 207 (40) [M + H], 189 (9), 161 (15), 121 (100), 111 (37), 93 (27), 93 (27), 83 (19).
Compound 6a: [α]_D ²⁰ -46 (c 1.85 CHCl₃); n _D ²⁰ 1.5321. ¹H NMR (300 MHz, CDCl₃): δ = 6.25 (1 H, d, J = 2.7 Hz, =CH₂), 5.54 (1 H, d, J = 2.3 Hz, =CH₂), 2.69 (1 H, m, CH< in lactone), 2.07 (1 H, dd, J = 14.6, 6.8 Hz, >CHCH ₂), 1.88 (1 H, dd, J = 14.6, 5.1 Hz, >CHCH ₂), 1.30 [3 H, s, (CH₃)CO<], 1.10 (1 H, m, >CHCH ₂CH<), 0.93 and 0.94 [6 H, two s, (CH₃)₂C<], 0.81 (1 H, m, >CHCH ₂CH<), 0.44-0.56 (2 H, m, cyclopropyl). IR (film): 1768 (s), 1668 (w), 1296 (s), 1060 (m) cm^-1. MS (EI): m/z (%) = 206 (53) [M⁺], 191 (23), 177 (13), 163 (53), 145 (25), 121 (22), 110 (98), 96 (73), 82 (100), 67 (30).
Compound 7a: mp 73-74 °C; ¹H NMR (600 MHz, CDCl₃): δ = 6.13 (1 H, t, J = 2.8 Hz, =CH₂), 5.57 (1 H, t, J = 2.7 Hz, =CH₂), 2.91 (1 H, dt, J = 17.0, 2.7 Hz, CH₂ in lactone), 2.80 (1 H, dt, J = 17.0, 2.8 Hz, CH₂ in lactone), 2.15 (1 H, dd, J = 6.4, 1.1 Hz, H-1), 2.10 (1 H, dd, J = 10.4, 1.8 Hz, CH₂-7), 1.85 (1 H, d, J = 1.8 Hz, H-4), 1.58 (1 H, ddd, J = 12.4, 10.1, 3.2 Hz, CH₂-6), 1.52 (1 H, ddd J = 13.2, 6.5, 3.2 Hz, CH₂-5), 1.33 (1 H, ddd, J = 12.4, 6.5, 1.3 Hz, CH₂-6), 1.25 (1 H, ddd, J = 13.2, 10.1, 1.3 Hz CH₂-5), 1.21 (1 H, d, J = 10.4 Hz, CH₂-7), 0.99 [3 H, s, C(CH₃)₂], 0.95 [3 H, s, C(CH₃)₂]. ¹³C NMR (CDCl₃): 169.9, 136.5, 120.5, 93.7, 49.2, 49.1, 44.0, 34.8, 32.1, 25.7, 24.4, 24.1, 22.2. The NMR assignments were aided by ¹³C DEPT, ¹H-¹H and ¹³C-¹H COSY spectroscopy. IR (KBr): 1759 (s), 1667 (w), 1120 (w), 975 (w) cm^-1. MS (EI): m/z (%): 207 (40) [M + H], 191 (13), 133 (24), 138 (72), 123 (100), 121 (67), 108 (56), 95 (64), 79 (45), 67 (94).
Compound 8a: [α]_D ²⁰ +35 (c 2.01 CHCl₃); mp 73-75 °C. ¹H NMR (300 MHz, CDCl₃): δ = 6.25 (1 H, d, J = 2.9 Hz, =CH₂), 5.61 (1 H, d, J = 2.5 Hz, =CH₂), 2.95 (1 H, dq, J = 10.8, 2.8 Hz, H-6), 2.54 (1 H, ddt, J = 13.5, 10.8, 2.2 Hz, CH₂-7), 2.22 (1 H, ddd, J = 12.0, 6.0, 2.2 Hz H-8), 2.21 (1 H, d, J = 5.4 Hz, H-1), 1.93 (1 H, dddd, J = 11.0, 6.0, 5.4, 2.2 Hz, CH₂-10), 1.76 (1 H, dt, J = 13.5, 3.3 Hz, CH₂-7), 1.47 (3 H, s, CH₃, C-2), 1.28 [3 H, s, (CH₃)₂C<], 1.02 (1 H, dd, J = 12.0, 11.0 Hz, CH₂-10), 0.90 [3 H, s, (CH₃)₂C<]. IR (KBr): 1758 (s), 1655 (m), 1288 (m), 1066 (m), 1016 (m) cm^-1. MS (EI): m/z (%) = 207 (100) [M + H], 191 (16), 136 (41), 151 (21), 135 (22), 121 (26), 107 (25), 91 (34), 79 (44).
Compound 9a: [α]_D ²⁰ -30 (c 1.29 CHCl₃).
Compound 10: yield 70%; n _D ²⁰ 1.4673. ¹H NMR (300 MHz, CDCl₃): δ = 4.14 (2 H, q, J = 7.1 Hz, CH₃CH₂O-), 2.80 (1 H, dq, J = 11.3 Hz, J ⁵ = 1.5 Hz, CH₂), 2.57 (1 H, dq, J = 11.3, 1.5 Hz, CH₂), 2.14 [3 H, t, J ⁵ = 1.5 Hz, C(O)CH₃], 1.70 and 1.63 [2 H, two d, J = 14.6 Hz (CH₃)₃CCH₂, AB system], 1,37 [3 H, s, (CH₃)CO], 1.26 (3 H, t, J = 7.1 Hz, CH₃CH₂O), 0.99 [9 H, s, (CH₃)₃CCH₂]. ¹³C NMR (CDCl₃): 166.7, 166.6, 101.0, 89.2, 59.3, 53.2, 43.5, 31.2, 28.2, 14.5. IR (film): 2960 (s), 1708 (s), 1660 (s), 1268 (m), 1224 (m), 1096 (m) cm^-1. MS (EI): m/z (%) = 241 (11) [M + H], 222 (21), 207 (20), 198 (42), 166 (43), 141 (100), 111 (56), 95 (70), 67 (43).