Preparation of homoallylic compounds by reaction of cyclopropylvinyl precursors with bronstedt acids

Abstract

A method of forming homoallylic compounds 2 from cyclopropylvinyl precursors 1 in the presence of a Bronsted acid HQ ##STR00001##

Claims

1. A method of forming homoallylic compounds 2 from cyclopropylvinyl precursors 1 in the presence of a Bronsted acid HQ ##STR00033## wherein, the Bronsted acid HQ is selected from RCO.sub.2H and/or a hydrogen halide selected from HCl, HBr or HI, wherein R is a C.sub.1-30 cyclic, polycyclic or acyclic alkyl residue, or an aryl or polyaryl residue, each of which may be saturated or unsaturated, branched or linear, and substituted or unsubstituted; R is a C.sub.1-30 alkyl or aryl residue, which may be linear or branched and may be substituted or unsubstituted, and wherein Q is RCO.sub.2 and/or a halide atom.

2. The method of forming a homoallylic alcohol according to claim 1 ##STR00034## by hydrolysis of rearrangement product 2.

3. The method of forming a homoallylic alcohol according to claim 2, wherein the E/Z ratio is greater than 70:30.

4. The method according to claim 1, wherein the residue R contains carbon-carbon unsaturation.

5. The method according to claim 1, wherein the precursor 1 is a polyprenoid ##STR00035## wherein n is 1, 2 or 3.

6. The method according to claim 5 wherein the precursor 1 is a cyclopropanated farnesene.

7. A method of forming the compound: ##STR00036## comprising the step of forming E,E-homofarnesol in accordance with the method defined in claim 1, and cyclizing the E,E-homofarnesol so formed using the bacterial enzyme squalene hopene cyclase.

8. The method of forming a homoallylic alcohol according to claim 3, wherein the E/Z ratio is greater than 75:25.

9. The method of forming a homoallylic alcohol according to claim 3, wherein the E/Z ratio is greater than 80:20.

10. The method of forming a homoallylic alcohol according to claim 1 ##STR00037## by transesterification and/or nucleophilic substitution of rearrangement product 2 to esters of the general structure 2, said esters being hydrolyzed with aqueous base to homoallylic alcohols of the general structure 3.

Description

EXAMPLE 1

Preparation of ((5E)-6,10-dimethylundeca-2,5,9-trien-2-yl)cyclopropane ?-1a

(1) ##STR00013##

(2) For the synthesis of substrate ?-1a see Y. Peng, J.-H. Yang, W.-D. Z. Li, Tetrahedron 62, 1209 (2006) and references therein.

(3) A homogeneous mixture of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (0.5 g, 2.1 mmol), acetic acid (1 g, 17.5 mmol), tetrahydrofurane (2 ml) and water (25 mg) is heated under stirring at 65? C. After 5 days at this temperature GC reveals 11% ?-isomer (t.sub.R 8.0 min), 69% ?-isomer (t.sub.R 8.2 min) and 13% of acetate 2a (t.sub.R 9.75 (Z) and 9.9 (E) min, E/Z 79:21). The homogeneous mixture is cooled to 25? C. and poured upon water (20 ml) and tert-butyl methyl ether (20 ml). After phase separation the organic phase is washed with conc. aqueous Na.sub.2CO.sub.3 (20 ml) and water (20 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography over silicagel with eluent hexane to give pure ?-1a as colorless liquid with an ?,?-ratio of 92:8 according to GC and an E/Z-ratio of 3:2 according to NMR.

(4) Analytical data of ?-1a: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1-5.2 (s?3H), 2.85 (dd, 1H, 3,4-Z), 2.7 (dd, 1H, 3,4-E), 1.95-2.1 (2?4 H), 1.7 (s, 2?3 H), 1.6 (2 s, 2?6 H), 1.5 (3H, 3,4-E), 1.4 (3H, 3,4-Z), 0.4-0.6 (5H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) of the E/Z-mixture: 135.4 (s), 134.94 (s), 134.89 (s), 134.5 (s), 131.3 (2 s), 124.6 (d), 124.4 (d), 124.3 (d), 123.3 (d), 123.1 (d), 122.0 (d), 39.69 (t), 39.67 (t), 26.9 (t), 26.72 (t), 26.69 (t), 26.5 (t), 25.6 (2 q), 18.9 (d), 18.7 (q), 17.6 (2 q), 16.03 and 16.01 (2 q), 13.8 (q), 12.3 (d), 4.1 and 3.9 (2 t). ppm. GC/MS (E/Z overlap): 203 (3%, [M-15].sup.+), 175 (8%), 147 (24%), 134 (12%), 133 (14%), 121 (10%), 107 (45%), 105 (11%), 95 (14%), 93 (25%), 91 (20%), 81 (34%), 79 (40%), 69 (100%), 67 (25%), 55 (18%), 53 (24%), 41 (86%), 39 (20%). IR (film): 2967 (s), 2916 (s), 2855 (s), 1443 (s), 1377 (s), 1170 (w), 1105 (m), 1044 (m), 1017 (m), 972 (m), 883 (m), 815 (s), 734 (w).

EXAMPLE 2

Preparation of E,E-Homofarnesylacetate 2a from ?-Farnesene ?-1a

(5) ##STR00014##

(6) A homogeneous mixture of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and acetic acid (1.4 g, 23 mmol) in a pressure tube is heated under stirring at 125? C. After 5 h GC reveals 5% substrate ?-1a, 41% ?-isomer and 54% acetate 2a (E/Z 74:26). After 42 h at 125? C., GC reveals complete conversion to 3% ?-isomer and 97% of acetate 2a (E/Z 74:26). After cooling to 25? C. the pressure tube is opened and the homogeneous mixture poured upon water (50 ml) and tert-butyl methyl ether (50 ml). The phases are separated and the aqueous phase extracted with tert-butyl methyl ether (25 ml). The combined organic layers are washed with conc. aqueous Na.sub.2CO.sub.3 (30 ml) and water (2?50 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give an orange-yellow clear liquid (1 g). Bulb-to-bulb distillation at 130? C./0.1 mbar gives 0.95 g (75%) of homoallyl acetate 2a.

(7) Analytical data of homofarnesol acetate 2a: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H), 4.03 (2H), 2.35 (2H), 2.05 (s, 3H), 1.95-2.1 (8H), 1.72, 1.68, 1.63, 1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 171.1 (2 s, C?O), 138.3 and 138.2 (2 s), 135.4 (Z, s) and 135.1 (E, s), 131.2 (2 s), 124.32, 124.3, 123.9 and 123.8 (2?2 d), 119.8 (Z, d), 119.0 (E, d), 64.3 (Z, t), 64.1 (E, t), 39.7 and 39.6 (2 t), 39.1 (Z, t), 27.5, 27.4, 26.72, 26.66, 26.5, 26.4 (2?3 t), 25.6, 23.4, 21.0, 17.6, 16.1, 16.0, 15.9 (4?2 q) ppm. GC/MS: r.sub.T 9.77 (2,3-Z-isomer), 9.91 (3,4-E-Isomer) min. E/Z=74:26. MS (E-isomer): 278 (1%, M.sup.+), 175 (3%), 149 (6%), 136 (28%), 123 (9%), 121 (13%), 107 (16%), 95 (10%), 94 (10%), 93 (20%), 82 (10%), 81 (67%), 79 (13%), 69 (100%), 68 (13%), 67 (20%), 43 (42%), 41 (36%). The MS-data of the Z-isomer are nearly identical. IR (film): 2966 (w), 2915 (w), 2855 (w), 1740 (s), 1442 (w), 1382 (w), 1363 (w), 1230 (s), 1032 (m), 975 (w), 891 (w), 836 (w), 636 (w).

EXAMPLE 3

Preparation of E,E-homofarnesyl acetate 2a from ?-famesene ?,?-1a

(8) ##STR00015##

(9) For the preparation of substrate ?,?-1a see the patent literature (priority to Givaudan, 2013). Purity: 39% ?-isomer, 46% ?-isomer, 10% Farnesene.

(10) Acetate 2a was prepared described in example 4 (table 1, run 4) from A-farnesene ?,?-1a (0.65 g, 3 mmol) in acetic acid (0.9 g, 15 mmol). After 11 h at 150? C., work-up and bulb-to-bulb distillation 0.64 g (89%) of acetate 2a was obtained as clear colorless oil. E/Z-ratio 73:27.

EXAMPLE 4

Rearrangement of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a in different alkanoic acids

(11) ##STR00016##

(12) TABLE-US-00001 TABLE 1 Rearrangement of ?-Farnesene ?-1a with alkanoic acids. acid temp time % ?-1a %2 run RCO.sub.2H equiv acid [? C.] [h] product R = (GC).sup.b (GC) E/Z 1 HCO.sub.2H 12 10? C. 12 h H / 67% 72:28 2 HCO.sub.2H/HOAc 4/6 25? C. 22 h H/Me.sup.a / 86% 77:23 3 AcOH 24 110? C. 44 h Me 3% 91% 74:26 4 AcOH 5 150? C. 11 h Me 3% 93% 73:27 5 EtCO.sub.2H 5 150? C. 20 h Et 5% 91% 73:27 6 tBuCO.sub.2H 8 180? C. 43 h tBu 9% 85% 74:26 7 ClCH.sub.2CO.sub.2H 5 80? C. 1 h ClCH.sub.2 / 95% 73:27 8 ClCH.sub.2CO.sub.2H 1 40? C. 90 h ClCH.sub.2 / 100% 75:25 9 Cl.sub.2CHCO.sub.2H 1.2 25? C. 73 h Cl.sub.2CH ./. 96% 75:25 10 Cl.sub.3CO.sub.2H 1.2 25? C. 3 h CCl.sub.3 ./. 100% 75:25 11 NCCH.sub.2CO.sub.2H 2 65? C. 5 h NCCH.sub.2 100% 73:27 Conditions: ?-Farnesene ?-1a mixed with acid RCO.sub.2H and heated under stirring in a pressure tube at indicated temperature. Work-up: mixture poured upon water and tert-butyl methyl ether, phases separated, aqueous phase extracted with tert-butyl methyl ether, combined organic layers are washed with conc. aqueous Na.sub.2CO.sub.3 and water, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. .sup.aratio R = H/Me 56:30 .sup.bisolated, crude.

EXAMPLE 5

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl formate

(13) ##STR00017##

(14) Prepared as described in example 4 table 1, run 1 from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (0.5 g, 2.1 mmol) and formic acid (1.2 g, 13 mmol). Work-up after 12 h at 10? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl formate (0.32 g, 57%) as crude oil.

(15) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 8.05 (1H, HC?O), 5.1 (3H, HC?), 4.15 (2H, CH.sub.2O), 2.4 (2H), 1.95-2.15 (8H), 1.72, 1.68, 1.63, 1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 9.41 (2,3-Z-isomer), 9.53 (3,4-E-Isomer) min. E/Z=72:28. MS (E-isomer): 264 (1%, M.sup.+), 175 (2%), 149 (4%), 137 (8%), 136 (24%), 123 (10%), 121 (11%), 107 (13%), 95 (10%), 94 (10%), 93 (13%), 81 (56%), 79 (11%), 69 (100%), 68 (10%), 67 (16%), 55 (9%), 53 (11%), 41 (43%). The MS-data of the Z-isomer are nearly identical.

EXAMPLE 6

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl propionate

(16) ##STR00018##

(17) Prepared as described in example 4 (table 1, run 5) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and propionic acid (1.7 g, 23 mmol). Work-up after 20 h at 150? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl propionate (1.2 g, 88%) as crude yellow oil.

(18) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 4.05 (2H, CH.sub.2O), 2.3 (4H), 1.9-2.1 (8H), 1.72, 1.68, 1.65, 1.6 (4 s, 12H), 1.15 (3H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 10.2 (2,3-Z-isomer), 10.3 (3,4-E-Isomer) min. E/Z=73:27. MS (E-isomer): 292 (1%, M.sup.+), 203 (1%), 175 (3%), 149 (6%), 137 (8%), 136 (28%), 123 (7%), 121 (13%), 107 (19%), 95 (12%), 94 (12%), 93 (21%), 82 (15%), 81 (74%), 79 (13%), 69 (100%), 68 (12%), 67 (21%), 57 (33%), 41 (33%). The MS-data of the Z-isomer are nearly identical. IR (film): 2967 (m), 2919 (m), 1737 (s), 1450 (m), 1380 (m), 1348 (m), 1273 (w), 1179 (s), 1082 (m), 1015 (m), 836 (w), 807 (w).

EXAMPLE 7

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl pivalate

(19) ##STR00019##

(20) Prepared as described in example 4 (table 1, run 6) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.8 mmol) and pivalic acid (2.3 g, 23 mmol). Work-up after 43 h at 180? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl pivalate (1.46 g, 96%) as a yellowish oil.

(21) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 4.03 (2H, CH.sub.2O), 2.3 (2H), 1.9-2.1 (8H), 1.72, 1.68, 1.65, 1.6 (4 s, 12H), 1.24 and 1.2 (s, 9H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 10.45 (2,3-Z-isomer), 10.63 (3,4-E-Isomer) min. E/Z=74:26. MS (E-isomer): 320 (0.5%, M.sup.+), 218 (0.5%), 203 (1%), 175 (3%), 149 (8%), 137 (11%), 136 (27%), 123 (8%), 121 (13%), 107 (17%), 95 (12%), 94 (13%), 93 (21%), 82 (15%), 81 (76%), 69 (100%), 68 (12%), 67 (20%), 57 (40%), 41 (38%). The MS-data of the Z-isomer are nearly identical. IR (film): 2967 (m), 2928 (m), 1729 (s), 1480 (m), 1451 m), 1380 (m), 1397 (m), 1377 (m), 1284 (m), 1150 (s), 1036 (w), 975 (w), 939 (w), 838 (w), 770 (w).

EXAMPLE 8

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2-chloroacetate

(22) ##STR00020##

(23) Prepared as described in example 4 (table 1, run 7) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and 2-chloroacetic acid (2.2 g, 23 mmol). Work-up after 1.5 h at 80? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2-chloroacetate (1.4 g, 97%) as a yellowish oil.

(24) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 4.15 (2H, CH.sub.2O), 4.1 (2H, CH.sub.2Cl), 2.4 (2H), 1.9-2.1 (8H), 1.72, 1.68, 1.63, 1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 10.85 (2,3-Z-isomer), 10.99 (3,4-E-Isomer) min. E/Z=73:27. MS (E-isomer): 312 (0.2%, M.sup.+), 175 (1%), 149 (4%), 137 (7%), 136 (19%), 123 (10%), 121 (11%), 107 (12%), 95 (10%), 93 (13%), 82 (10%), 81 (60%), 79 (19%), 77 (15%), 69 (100%), 68 (10%), 67 (16%), 53 (10%), 41 (34%). The MS-data of the Z-isomer are nearly identical. IR (film): 2963 (m), 2916 (m), 1737 (s), 1448 (m), 1414 m), 1379 (m), 1308 (m), 1289 (m), 1257 (m), 1167 (s), 989 (m), 929 (w), 836 (w), 788 (w), 697 (w).

EXAMPLE 9

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2,2-dichloroacetate

(25) ##STR00021##

(26) Prepared as described in example 4 (table 1, run 9) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and 2,2-dichloroacetic acid (0.71 g, 5.5 mmol). Work-up after 6 h at 25? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2,2-dichloroacetate (1.6 g, quant) as a yellowish oil.

(27) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.9 (1H, CHCl.sub.2), 5.1 (3H, HC?), 4.2 (2H, CH.sub.2O), 2.4 (2H), 1.9-2.1 (8H), 1.7-1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 11.18 (2,3-Z-isomer), 11.33 (3,4-E-Isomer) min. E/Z=75:25. MS (E-isomer): 346 (0.5%, M.sup.+), 303 (0.5%), 175 (1%), 149 (4%), 137 (14%), 136 (32%), 123 (17%), 121 (18%), 107 (18%), 95 (15%), 93 (19%), 82 (12%), 81 (80%), 79 (15%), 77 (15%), 69 (100%), 68 (13%), 67 (24%), 53 (12%), 41 (42%). The MS-data of the Z-isomer are nearly identical.

EXAMPLE 10

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2,2,2-trichloroacetate

(28) ##STR00022##

(29) Prepared as described in example 4 (table 1, run 10) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and 2,2,2-trichloroacetic acid (0.9 g, 5.5 mmol). Work-up after 4 h at 25? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2,2,2-trichloroacetate (1.6 g, quant) as a yellowish oil.

(30) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 4.3 (2H, CH.sub.2O), 2.45 (2H), 1.9-2.1 (8H), 1.85-1.55 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 11.49 (2,3-Z-isomer), 11.66 (3,4-E-Isomer) min. E/Z=75:25. MS (E-isomer): 380 (0.3%, M.sup.+), 337 (0.2%), 149 (4%), 137 (10%), 136 (20%), 123 (10%), 121 (11%), 107 (10%), 95 (10%), 93 (10%), 82 (9%), 81 (59%), 69 (100%), 68 (13%), 67 (17%), 41 (31%). The MS-data of the Z-isomer are nearly identical.

EXAMPLE 11

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2-cyanoacetate

(31) ##STR00023##

(32) Prepared as described in example 4 (table 1, run 11) from (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol) and 2-cyanoacetic acid (0.8 g, 9.2 mmol). Work-up after 5 h at 65? C. gave (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl 2-cyanoacetate (1.37 g, 98%) as a brownish resin.

(33) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 4.15 (2H, CH.sub.2O), 3.45 (2H), 2.4 (2H), 1.9-2.1 (8H), 1.75-1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz) data are consistent. GC/MS: r.sub.T 11.3 (2,3-Z-isomer), 11.43 (3,4-E-Isomer) min. E/Z=73:27. MS (E-isomer): 303 (0.5%, M.sup.+), 260 (1%), 149 (4%), 137 (8%), 136 (17%), 123 (14%), 121 (10%), 107 (12%), 95 (10%), 93 (13%), 81 (59%), 79 (10%), 69 (100%), 68 (21%), 67 (18%), 53 (10%), 41 (26%). The MS-data of the Z-isomer are nearly identical.

EXAMPLE 12

(7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-ol

(34) ##STR00024##

(35) A mixture of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (1 g, 4.6 mmol), dodecane (0.2 g, 1.15 mmol, internal standard) and L-(+)-tartaric acid (1 g, 6.9 mmol) in a pressure tube is heated under stirring at 150? C. After 18 h and complete conversion (according to GC) the mixture is poured on water (50 ml) and toluene (50 ml). The phases are separated and the aqueous phase extracted with toluene (50 ml). The combined organic layers are washed with conc. aqueous Na.sub.2CO.sub.3 (50 ml) and conc. NaCl (2?50 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give a brownish resin (1.35 g) which is mixed with 30% aqueous KOH (4.3 ml) and stirred at 25? C. for 2 h. GC analysis reveals formation of 96% (7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-ol according to the internal standard. E/Z ratio 68:22. The analytical data of the E-isomer are consistent with the ones from the literature, see for example P. Kocienski, S. Wadman J. Org. Chem. 54, 1215 (1989).

EXAMPLE 13

Rearrangement of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a with hydrogen halides

(36) ##STR00025##

(37) TABLE-US-00002 TABLE 2 Rearrangement of ?-Farnesene ?-1a with hydrogen halides. Quantitative conversion. hydrogen equiv temp time ?-1a %2 run halide acid additive, solvent [? C.] [h] product X = (GC).sup.a (GC).sup.a E/Z 1 HCl 32% 1 MeCN 25? C. 3 h Cl / 100% 79:21 2 HCl 32% 1.2 HOAc 25? C. 3 h Cl 100% 77:23 3 HCl 32% 2 NMP 100? C. 2 h Cl 97% 78:22 4 HCl 32% 1 10% SDS.sup.b 25? C. 24 h Cl 5% 89% 82:18 5 HBr 48% 1 MeCN 0? C. 2 h Br 2% 97% 78:22 6 HBr 48% 1 HOAc 25? C. 1 h Br 100% 77:23 7 HBr 48% 1 10% SDS.sup.b 25? C. 2 h Br 100% 81:19 8 HI 67% 1.1 MeCN 0? C. 2 h I 100% 77:23 .sup.apurities fine according to NMR of the crude product. .sup.bsodium dodecyl sulfate (SDS).

EXAMPLE 14

(10E)-13-chloro-2,6,10-trimethyltrideca-2,6,10-triene

(38) ##STR00026##

(39) 32% aqueous HCl (2.6 g, 23 mmol) is added dropwise to (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (5 g, 23 mmol) in acetonitrile (75 ml) at 0? C. After 1 h at this temperature the homogeneous mixture is stirred for 3 h at 25? C., then poured upon conc. Na.sub.2SO.sub.3 (50 ml). After the addition of ethyl acetate (100 ml) and phase separation the aqueous phase is extracted with ethyl acetate (50 ml). The combined organic phases are washed with conc. aqueous NaCl, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 5.75 g (98%) of a crude yellowish oil.

(40) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 3.45 (2H, CH.sub.2Cl), 2.45 (2H), 1.95-2.15 (8H), 1.75-1.6 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 138.3 and 138.2 (2 s), 135.5 and 135.3 (2 s), 131.3 and 131.2 (2 s), 124.35 and 124.3 (2 d), 123.9 and 123.7 (2 d) 120.6 and 119.8 (2 d), 44.5 and 44.3 (2 t), 39.7 (2 t), 39.6 (2 t), 32.0, 31.5 and 31.4 (4 t), 26.7 and 26.4 (2 t), 25.6 (2 q), 23.4 (q), 17.6 and 16.2 (2 q), 16.0 and 15.95 (3 q) ppm. GC/MS: r.sub.T 9.17 (2,3-Z-isomer), 9.29 (3,4-E-Isomer) min. E/Z=79:21. MS (E-isomer): 254 (0.5%, M.sup.+), 211 (1%), 185 (1%), 136 (14%), 123 (11%), 95 (13%), 81 (51%), 69 (100%), 68 (10%), 67 (17%), 55 (19%), 53 (12%), 41 (41%). The MS-data of the Z-isomer are nearly identical. IR (film): 2964 (m), 2916 (s), 2854 (m), 1719 (w), 1667 (w), 1443 (s), 1377 (m), 1315 (w), 1293 (w), 1239 (w), 1151 (w), 1107 (m), 1047 (w), 983 (w), 888 (w), 832 (m), 718 (m), 657 (m).

EXAMPLE 15

(10E)-13-bromo-2,6,10-trimethyltrideca-2,6,10-triene

(41) ##STR00027##

(42) 48% aqueous HBr (3.9 g, 28 mmol) is added dropwise to a mixture of (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (5 g, 23 mmol) and sodium dodecyl sulfate (0.25 g, 0.9 mmol) at 0? C. After 30 min at this temperature the homogeneous mixture is stirred for 3 h at 25? C., then poured upon water (50 ml) and tert-butyl methyl ether (100 ml). After phase separation the aqueous phase is extracted with tert-butyl methyl ether (100 ml). The combined organic phases are washed with 10% aqueous Na.sub.2CO.sub.3 (2?50 ml) and water (2?50 ml) dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 5.89 g (86%) of a crude yellowish oil which is further purified by bulb-to-bulb distillation at 140? C./0.07 mbar to give 4.9 g (72%) of (10E)-13-bromo-2,6,10-trimethyltrideca-2,6,10-triene as yellowish oil. Purity of the main fraction: 89.1% (NMR with standard anisaldehyde).

(43) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 3.35 (2H, CH.sub.2Br), 2.55 (2H), 1.95-2.15 (8H), 1.55-1.7 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 138.7 and 138.6 (2 s), 135.5 and 135.2 (2 s), 131.3 (2 s), 124.4 and 124.3 (2 d), 123.9 and 123.7 (2 d), 121.6 and 120.9 (2 d), 39.7 and 39.6 (2 t), 32.9 and 32.8 (2 t), 32.0, 31.7 and 31.6 (4 t), 26.8 and 26.7 (2 t), 26.4 (2 t), 25.7 (2 q), 23.4 (q), 17.7 (q), 16.3 and 16.0 (4 q) ppm. GC/MS: r.sub.T 9.62 (2,3-Z-isomer), 9.75 (3,4-E-Isomer) min. E/Z=81:19. MS (E-isomer): 298 and 300 (0.1%, M.sup.+), 255 and 257 (0.2%), 229 and 231 (0.5%), 187 and 188 (2%), 137 (10%), 136 (32%), 123 (15%), 121 (10%), 95 (14%), 93 (10%), 81 (53%), 69 (100%), 68 (10%), 67 (20%), 55 (11%), 53 (10%), 41 (39%). The MS-data of the Z-isomer are nearly identical. IR (film): 2965 (m), 2915 (s), 2854 (m), 1666 (w), 1439 (s), 1377 (s), 1302 (m), 1267 (m), 1204 (m), 1151 (w), 1107 (w), 983 (w), 926 (w), 885 (w), 833 (m), 745 (w), 643 (m).

EXAMPLE 16

Homofarnesol from (10E)-13-bromo-2,6,10-trimethyltrideca-2,6,10-triene

(44) ##STR00028##

(45) Under conditions described by Moiseenkov et al. (The New Journal for Organic Synthesis 22, 225-226, 1990) a mixture of (10E)-13-bromo-2,6,10-trimethyltrideca-2,6,10-triene (1.28 g, 4.3 mmol), KOAc (2.4 g, 24.4 mmol) and 16-crown-6 (80 mg, 0.3 mmol, 7%) is refluxed in acetonitrile (15 ml) is refluxed under stirring and nitrogen for 3 h. At 25? C. water (50 ml) and tert-butyl methyl ether (50 ml) are added, the phases are separated and the water phase extracted with tert-butyl methyl (50 ml). The combined organic phases are washed with conc. aqueous NaCl (50 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 1.12 g (85%) of the homofarnesyl acetate as crude oil. The analytical data of this intermediate are identical to the ones of the same compound prepared in example 2.

(46) The thus obtained homofarnesyl acetate is added to KOH (0.5 g, 8.5 mmol) in MeOH (4 ml). The red solution is stirred 2 h at 25? C. Work-up as described for the first step (HOAc addition) gives 0.85 g Homofarnesol (84% based on the bromide) as clear yellowish liquid and E/Z 82:18. The analytical data are identical to the ones of the same compound prepared in example 12.

EXAMPLE 17

(10E)-13-iodo-2,6,10-trimethyltrideca-2,6,10-triene

(47) ##STR00029##

(48) 67% aqueous HI (0.53 g, 2.75 mmol) is added dropwise to (E)-(6,10-dimethylundeca-1,5,9-trien-2-yl)cyclopropane ?-1a (0.5 g, 2.3 mmol) in acetonitrile (10 ml) at 0? C. under stirring. After 2 h at this temperature complete conversion was checked by GC and the orange mixture is poured upon conc. aqueous Na.sub.2SO.sub.3 (20 ml). After the addition of ethyl acetate (50 ml) and phase separation the aqueous phase is extracted with ethyl acetate (25 ml). The combined organic phases are washed with conc. aqueous NaCl (25 ml), dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 0.72 g (91%) of a crude yellowish oil.

(49) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (3H, HC?), 3.1 (2H, CH.sub.2I), 2.55 (2H), 1.95-2.15 (8H), 1.6-1.7 (4 s, 12H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 138.2 and 138.1 (2 s), 135.5 and 135.2 (2 s), 131.3 and 131.2 (2 s), 124.4, 124.3, 123.9, 123.72, 121.7 and 123.0 (6 d), 39.7 and 39.6 (2 t), 32.4, 32.3 and 32.1 (4 t), 26.75 and 26.7 (2 t), 26.4 (2 t), 25.7 (2 q), 17.7 (q), 16.3 and 16.0 (3 q), 6.0 and 5.9 (2 t) ppm. GC/MS: r.sub.T 10.14 (2,3-Z-isomer), 10.28 (3,4-E-Isomer) min. E/Z=77:23. MS (E-isomer): 346 (0.2%, M.sup.+), 303 (0.4%), 149 (2%), 137 (8%), 136 (28%), 123 (12%), 121 (8%), 95 (18%), 81 (55%), 69 (100%), 67 (30%), 55 (16%), 53 (12%), 41 (43%). The MS-data of the Z-isomer are nearly identical. IR (film): 2964 (m), 2914 (s), 2853 (m), 1741 (w), 1664 (w), 1441 (s), 1376 (m), 1245 (m), 1210 (w), 1164 (s), 1108 (w), 983 (w), 833 (m), 741 (w).

EXAMPLE 18

Preparation of E-Homogeraniol Acetate from ?-Myrcene

(50) ##STR00030##

(51) For the preparation of substrate ?-Myrcene see the patent literature (priority to Givaudan, 2013).

(52) ?-Myrcene (1 g, 6.7 mmol) and acetic acid (2 g, 33.3 mmol) are heated in a pressure tube 12 h at 150? C. After complete conversion (GC) the homogeneous mixture is poured upon water (100 ml) and tert-butyl methyl ether (50 ml). After phase separation the aqueous phase is extracted with tert-butyl methyl ether (50 ml). The combined organic phases are washed with 10% aqueous Na.sub.2CO.sub.3 (50 ml) and water (2?50 ml), dried over MgSO.sub.4 and evaporated under reduced pressure. The crude product (1.4 g) contains 68% E-homogeraniol acetate, 25% Z-homogeraniol acetate and 4% ?-Ocimene.

(53) Analytical data of homogeraniol acetate: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (2H), 4.0 (2H), 2.3 (2H), 2.05 (s, 3H), 1.95-2.1 (2H), 1.72, 1.7, 1.61, 1.605, 1.6 (5 s, 9H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 171.1 (2 s, C?O), 138.3 and 138.2 (2 s), 131.7 and 131.5 (2 s), 124.1 and 124.0 (2 d), 119.9 (Z, d), 119.0 (E, d), 64.3 (Z, t), 64.1 (E, t), 39.6 (t), 32.0 (t), 27.5 and 27.4 (2 t), 27.0 (q), 25.6 and 25.5 (2 t), 25.7, 23.4, 21.0, 17.7, 17.6 and 17.1 (6 q) ppm. GC/MS: r.sub.T 7.2 (2,3-Z-isomer), 7.34 (3,4-E-Isomer) min. E/Z=74:26. MS (E-isomer): 210 (0.1%, M.sup.+), 150 (20%), 135 (12%), 121 (8%), 107 (19%), 82 (18%), 81 (48%), 69 (100%), 67 (21%), 43 (48%), 41 (37%). The MS-data of the Z-isomer are nearly identical. IR (film): 2966 (w), 2916 (w), 1739 (s), 1446 (w), 1364 (m), 1230 (s), 1108 (w), 1032 (m), 975 (w), 894 (w), 836 (w), 635 (w).

EXAMPLE 19

Preparation of E-Homogeraniol Acetate from ?-Ocimene

(54) ##STR00031##

(55) For the preparation of substrate ?-Ocimene see the patent literature (priority to Givaudan, 2013).

(56) ?-Ocimene (3 g, 20.2 mmol) and acetic acid (5 g, 0.1 mol) are heated in a pressure tube 3 h at 150? C. Work-up as described in example 17 gives 3.5 g of a dark red liquid which contains 73% E-homogeraniol acetate and 27% Z-homogeraniol acetate according to GCMS. Bulb-to-bulb distillation at 100? C./0.05 mbar gives 2.2 g (52%) homogeraniol acetate as colorless liquid whose analytical data are identical with the ones obtained from homogeraniol acetate as prepared in example 18.

EXAMPLE 20

Preparation of (E)-4,8-dimethylnon-3-ene-1,8-diol from ?-Myrcenol

(57) ##STR00032##

(58) For the preparation of substrate ?-Hydroxymyrcenol see the patent literature (priority to Givaudan, 2013).

(59) ?-Hydroxymyrcenol (0.5 g, 3 mmol) and acetic acid (0.9 g, 15 mmol) are heated 10 h at 150? C. Work-up as described in example 17 gives 0.6 g of the crude acetate (E/Z 72:28) with a purity of 75% according to GC. Methanol (6 ml) and 30% aqueous KOH (1.7 ml) are added to the residue. After 1 h stirring at 25? C. conc. aqueous NaCl (50 ml) and tert-butyl methyl ether (50 ml) are added. The phases are separated and the aqueous phase is extracted with tert-butyl methyl ether (50 ml). The organic phases are combined, washed with water (50 ml), dried over MgSO4, filtered and evaporated under reduced pressure to give 0.44 g of the crude diol (E/Z 72:28), which is purified by flash chromatography over silicagel with eluent hexane/tert-butyl methyl ether 1:1 to give (E)-4,8-dimethylnon-3-ene-1,8-diol (0.28 g, 50%) as a colorless oil.

(60) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (1H), 3.65 (2H), 2.3 (2H), 2.1 (2H), 1.45 (4H), 1.23 (s, 6H), 1.21 (s, 1H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 138.3 (s), 120.05 (d), 71.0 (s, tBuOH), 62.5 (t), 43.4 (t), 40.1 (t), 31.5 (t), 29.3 (q), 22.6 (2 t), 16.1 (q) ppm. GC/MS: r.sub.T 7.29 (2,3-Z-isomer), 7.38 (3,4-E-Isomer) min. E/Z=94:6. MS (E-isomer): 168 (3%, M.sup.+), 153 (4%), 135 (10%), 124 (15%), 112 (37%), 110 (13%), 97 (21%), 82 (18%), 81 (100%), 79 (33%), 69 (38%), 66 (25%), 67 (39%), 59 (53%), 55 (19%), 43 (38%), 41 (29%), 30 (24%). The MS-data of the Z-isomer are nearly identical.