Cyclopropanation of substituted alkenes

Abstract

Disclosed is a cyclopropanation process comprising the step of reacting an alkene compound having at least one carbon-carbon double bond with at least one dihaloalkane. The reaction is carried out in the presence of (i) particulate metal Zn, (ii) catalytically effective amount of particulate metal Cu or a salt thereof, (iii) at least one haloalkylsilane, and (iv) at least one solvent.

Claims

1. A cyclopropanation process comprising the step of reacting an alkene compound having at least one carbon-carbon double bond with at least one dihaloalkane in the presence of (i) particulate metal Zn, (ii) catalytically effective amount of particulate metal Cu, (iii) at least one haloalkylsilane, and (iv) at least one solvent; thereby producing a cyclopropane derivative of said compound, wherein said at least one dihaloalkane is chlorobromomethane.

2. The cyclopropanation process according to claim 1, wherein said alkene compound has at least two carbon-carbon double bonds.

3. The cyclopropanation process according to claim 1, wherein said particulate metal Zn has particle size of less than 10 m.

4. The cyclopropanation process according to claim 1, wherein said particulate metal Cu has particle size of less than 50 m.

5. The cyclopropanation process according to claim 1, wherein said haloalkylsilane is chlorotrialkyl silane.

6. The cyclopropanation process according to claim 5, wherein said chlorotrialkyl silane is selected from the group consisting of chlorotrimethylsilane, chlorotriethylsilane, chlorotributylsilane, chlorotriisobutylsilane, chlorotrihexylsilane, and any combinations thereof.

7. The cyclopropanation process according to claim 1, wherein said at least one solvent is an ether solvent.

8. The cyclopropanation process according to claim 7, wherein said at least one ether solvent is selected from diethyl ether, 1,2-dimethoxyethane (DME), methyl tert-butyl ether, (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME) and any combinations thereof.

9. The cyclopropanation process according to claim 7, wherein said at least one solvent further comprises dichloromethane.

10. The cyclopropanation process according to claim 9, wherein said solvent is a mixture of cyclopentyl methyl ether and dichloromethane having a ratio of between 1:5 to 10:1.

11. The cyclopropanation process according to claim 1, wherein when said alkene compound comprises one double bond, said particulate metal Zn is added in an amount of 1-10 molar equivalents relative to said alkene compound.

12. The cyclopropanation process according to claim 1, wherein said particulate metal Cu is presented in an amount of 0.1 to 1 wt % of said particulate metal Zn.

13. The cyclopropanation process according to claim 1, having a yield of between about 50% to about 95%.

14. A method of manufacturing a flavor or fragrance ingredient, comprising the cyclopropanation process according to claim 1.

Description

DETAILED DESCRIPTION

Example 1. [1-methyl-2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)cyclopropyl]methanol (VI)

(1) ##STR00008##

(2) To a reactor equipped with a reflux condenser was charged under nitrogen zinc dust (100 g, 1.48 mol), copper dust (0.5 g, 7.86 mmol), chlorotrimethylsilane (1.5 g, 0.0136 mol), CPME (100 g), and DCM (100 g). The mixture was stirred at 53-55 C. for 0.5 hours (hrs) followed by the addition of a mixture of (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-en-1-ol (V, 53 g, purity 92.5%, 0.25 mol) and CBM (165 g, purity 99%, 1.27 mol) during 2 hrs under gentle reflux. Ethylene is continuously evolved. After the addition was complete, the resultant reaction mixture was stirred at 58 C. for additional 1-1.5 hrs.

(3) A solution of 50 wt % ammonium chloride in water (500 g) was cooled to 5 C. under stirring. After diluted with CPME (100 g), the reaction mixture was slowly added to the stirred aqueous ammonium chloride solution at 5 C. (exothermic). The temperature was allowed to rise during the addition up to 25 C. The organic phase was separated and washed with 10% aqueous sodium bicarbonate.

(4) To the aqueous phase was added CPME (150 g) and stirred at room temperature for 15 minutes (min). The organic phase was collected and combined with the first organic phase obtained above. After distillation of solvent and the crude product at 190-220 C. and 0.1 mmHg in presence of 1 wt % sodium carbonate and 10% thermal oil, 43.6 g of VI was obtained, which had a purity of 82.5% (isomer 1-37.73%; isomer 2-44.73%). The weight yield is 89% (78% molar yield).

Example 2. [1-methyl-2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)cyclopropyl]methanol (VI)

(5) To a reactor equipped with a reflux condenser was charged under nitrogen zinc dust (90 g), copper dust (1 g), chlorotrimethylsilane (1.5 g) and diethyl ether (200 g). The mixture was stirred at 45 C. for 0.5 hrs followed by the addition of a mixture of (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-en-1-ol (53 g, 92.5%, 0.25 mol) and CBM (206 g, 99%, 1.57 mol) during 2 hr under gentle reflux. After the addition is complete, the resultant mixture was stirred at 45 C. for additional 2 hr.

(6) A solution of 50 wt % ammonium chloride in water (500 g) was prepared, cooled to 5 C. and kept under stirring. After diluted with diethyl ether (200 g), the reaction mixture was slowly added to the aqueous ammonium chloride solution at 5 C. (exothermic). The organic phase was separated and washed with an aqueous sodium bicarbonate solution containing sodium chloride. The organic phase was filtered. Diethyl ether was evaporated to obtain a crude product.

(7) Subsequently, the crude product was distilled at 190-220 C. under 0.1 mmHg in the presence of 1 wt % sodium carbonate and 10% thermal oil to obtain 40 g of the product. The purity was 82.5% (isomer 1-37.73%; isomer 2-44.73%). The weight yield was 80% (70% molar yield).

Example 3. [1-methyl-2-(1,2,2-trimethylbicyclo[3.1.0]hex-3-ylmethyl)cyclopropyl]methanol (VI)

(8) The procedure described in Example 1 was followed except that CBM was replaced by DBM (275 g, 99%, 1.58 mol). The weight yield was 82% (71.8% molar yield).

Example 4. (1-methyl-2-(((R)-2,2,3-trimethylcyclopent-3-en-1yl)methyl)cyclopropyl)methanol (VII)

(9) ##STR00009##

(10) The procedure described in Example 1 was followed using the same amount of (E)-2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-en-1-ol (V) except that 85 g of CBM, 35 g of zinc dust, 0.25 g copper powder and 0.2 g of trimethylchlorosilane were used. The mixture of CBM and V was added during 1.5 hr at 60 C. Upon reaction completion, the reaction mixture was added slowly to a solution of ammonium chloride (75 g) dissolved in water (200 g). Flash distillation gave 45.5 g of a colorless viscous oil consisted of 74.8% of the monocyclopropanated product VII and 11.6% of VI. The weight yield of VII is 67.4% and that of VI is 10.45%.

(11) (1-methyl-2-(((R)-2,2,3-trimethylcyclopent-3-en-1yl)methyl)cyclopropyl)-methanol (VII): 1H NR (500 MHz, CHLOROFORM-d): 5.17-5.30 (m, 1H), 3.24-3.40 (m, 2H), 2.27-2.44 (m, 1H), 1.62-1.95 (m, 3H), 1.53-1.62 (m, 3H), 1.20-1.52 (m, 2H), 1.14 (s, 50% of 3H), 1.13 (s, 50% of 3H), 0.98 (s, 50% of 3H), 0.97 (s, 50% of 3H), 0.74 (s, 50% of 3H), 0.73 (s, 50% of 3H), 0.38-0.68 (m, 2H), 0.18-0.11 (m, 1H). MS (DIP, EI): m/z 208 (Mt).

Example 5. (4S,4aR)-4,4a-dimethyl-6-(1-methylcyclopropyl)decahydrocyclopropa[d]naphthalene

(12) ##STR00010##

(13) Valencene (15 g, 80%) was cyclopropanated according to the procedure described in Example 1 except using a different starting material (i.e., (3R,4aR,5S)-4a,5-dimethyl-3-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene) to give a mixture (15 g) of two isomers of 4,4a-dimethyl-6-(1-methylcyclopropyl)decahydrocyclopropa[d]naphthalene isomers in purity of 56%.

(14) (4S,4aR)-4,4a-dimethyl-6-(1-methylcyclopropyl)decahydrocyclopropa[d]naphthalene: 1H NMR (400 MHz, CHLOROFORM-d): 0.94 (s, 3H), 0.90 (s, 3H), 0.85 (d, J=7.3 Hz, 3H), 0.10-2.43 (m, 19H). MS (DIP, EI): m/z 232 (M.sup.+).

Example 6. 5-isopropylspiro[bicyclo[3.1.0]hexane-2,1-cyclopropane

(15) ##STR00011##

(16) Sabinene (25 g, two isomers at 74/26 ratio, minor isomer -thujone) was cyclopropanated according to the procedure described in Example 1. There was complete conversion to give 29 g of product containing two isomers at 60/20 ratio.

(17) The major isomer was identified as 5-isopropylspiro[bicyclo[3.1.0]hexane-2,1-cyclopropane. 1H NMR (400 MHz, CHLOROFORM-d): 1.78-1.93 (m, 1H), 1.35-1.70 (m, 4H), 1.03-1.14 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.22-0.63 (m, 6H). MS (DIP, EI): m/z 150 (M.sup.+).

(18) Sabinene was reported to undergo cyclopropanation by dihalocarbene followed by dehalogenation with Na/liquid ammonia. See Graefe, Lam and Muehlstaedt, Zeitschrift fuer Chemie 11(8), 304, 1971).

Example 7. 4-(1-methylcyclopropyl)-1-methylbicyclo[4.1.0]heptane (X)

(19) ##STR00012##

(20) D-Limonene (38 g, 98% purity) was cyclopropanated following the procedure of Example 1. The starting material was completely converted to give 44 g of X of 65% purity. According to prior art (Friedrich and Niyati-Shirkhodaee, J. Org. Chem., 56(6), 2202, 1991) the yield of the dicyclopropanated product was reported as 29%.

(21) 4-(1-methylcyclopropyl)-1-methylbicyclo[4.1.0]heptane (X): 1H NMR (400 MHz, CHLOROFORM-d): 0.63-2.06 (m, 8H), 1.05 (s, 50% of 3H), 1.04 (s, 50% of 3H), 0.90 (s, 50% of 3H), 0.85 (s, 50% of 3H), 0.04-0.55 (m, 6H). MS (DIP, EI): m/z 164 (M.sup.+).

Example 8. 3-methyl-Bicyclo[13.1.0]hexadecan-(4/5)-one

(22) 3-Methylcyclopentadec-(4/5)-ene-1-one (25 g, purity 95%), a mixture of 4 isomers with the major isomer as Z-3-methylcyclopentadec-5-ene-1-one, was cyclopropanated according to the procedure described in Example 1. The starting material was completely converted to 25 g of cyclopropanated isomers having a purity of 60%.

(23) ##STR00013##

(24) The major isomer is 3-methyl-Bicyclo[13.1.0]hexadecan-5-one: 1H NMR (500 MHz, CHLOROFORM-d): 0.49-2.61 (m, 26H), 1.04 (d, J=6.6 Hz, 3H), 0.29-0.16 (m, 1H). MS (DIP, EI): m/z 250 (M.sup.+).

(25) As disclosed in U.S. Pat. No. 7,943,559 (2011), 3-methyl-Bicyclo[13.1.0]hexadecan-5-one was prepared by cyclopropanation of 3-Methylcyclopentadec-(5)-ene-1-one by CH.sub.2I.sub.2/Et.sub.2Zn.

Example 9. (1R,2R)-2-ethyl-Cyclopropaneethanol (XII)

(26) ##STR00014##

(27) To a reactor equipped with a reflux condenser was charged under nitrogen zinc dust (35 g, 0.535 mol), copper dust (0.1 g, 1.57 mmol), chlorotrimethylsilane (0.2 g, 1.85 mmol), CPME (60 g), and DCM (60 g). The mixture was stirred at 50 C. for 0.5 hr followed by the addition of a mixture of (Z)-3-hexen-1-ol (XI, 25 g, 0.245 mole, 98% purity) and CBM (50 g, 99% purity) during 1.5 hr at 50 C. The resultant reaction mixture was stirred for additional 2 hr and then worked up following the procedure described in Example 1. Flash distillation gave 25 g of colorless oil containing 80% of (1R,2R)-2-ethyl-cyclopropaneethanol (yield 70%).

(28) 1H NMR (500 MHz, CHLOROFORM-d) Shift: 3.73 (t, J=6.7 Hz, 2H), 1.67-1.81 (m, 1H), 1.31-1.48 (m, 3H), 1.23 (m, 1H), 0.99 (t, J=7.3 Hz, 3H), 0.56-0.83 (m, 3H), 0.29-0.18 (m, 1H). m/z 114 (M.sup.+).