Title of Invention

CYCLOPROPANATION PROCESS

Abstract

A process for the cyclopropanation of a substituted alkene. comprising the reaction of the alkene with a carbenoide, generated from dibromomethane and a tri-(C2 - Cgj-alkyl aluminium compound, in the presence of a catalytic amount of a metal compound selected from the group consisting of Lewis acids, metallocenes and metal carbonyl complexes. The process advantageously uses transition metal compounds as catalysts and the dibromomethane can be recovered. The process is especially useful for the preparation of ingredients for the flavour and fragrance industry.

Full Text

CYCLOPROPANATION PROCESS This invention relates to a process of preparing cyclopropanated compounds. A common cyclopropanation reaction is the Simmons-Smith reaction (see Simmons. H. E; Cairns, T. L.; Vladuchick, S. A.: Hoiness. C. M Org. React. (N. Y.) 1973. 20. 1 - 131). which utilises diiodomethane and Zn(Cu). The reaction takes place via the formation of a carbenoide, that is an intermediate of the type M~CH2-X (M = metal, X = halide), which is generated and consumed during a cyclopropanation reaction. Modifications of this reaction have been introduced by Furukawa (Furukawa. J.: Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53 - 58) and later on by Friedrich et ah. who replaced diiodomethane by dibromomethane. The latter carbenoide precursor is not only less expensive, but it also avoids undesirable iodine and iodide wastes. The use of dibromomethane, however, has the disadvantage that it is less reactive than diiodomethane in this reaction. In order to activate the zinc-copper couple for carbenoide formation, it is necessary to use ultrasound (Friedrich, E. C; Domek, J. M.; Pong, R. Y. J. Org. Chem. 1985, 50, 4640 - 4642) or additives such as copper halides and acetyl halides (Friedrich, E. C; Niyati-Shirkhodaee, F. J. Org. Chem. 1991, 56, 2202 - 2205). An example of a compound whose preparation utilizes the latter method is a molecule that has been commercialized successfully as a fragrance component (see EP 0 801 049). A remaining disadvantage of this method, however, is the generation of environmentally-unfriendly zinc- and copper-based wastes. One theoretical possibility of circumventing these disadvantages is the combination of dibromomethane and a trialkyl aluminum compound. However, this was hitherto not regarded as a viable option. For example, in his paper in 7. Org. Chem. 1991, 56, 2202 - 2205, Friedrich states that ".. .the use of CH2Br2 was examined only (for cyclopropanation) when the Zn/Cu procedure was employed because, with ZnEt2 or AlEt3, dibromomethane has not been reported to react." The theoretical possibility was mentioned in EP 0 801 049, but no teaching on how to achieve it was supplied. it has now been found that it is possible to utilise dibromomethane and a trialkyl aluminum compound efficiently in a cyclopropanation reaction, if certain metal compounds are added in catalytic amounts. The invention therefore provides a process for the cyclopropanation of a substituted alkene. comprising the reaction of the alkene with a carbenoide. generated from dibromomethane and a tri-(C2 - Cg)-alkyl aluminium compound in the presence of a catalytic amount of a metal compound selected from the group consisting of Lewis acids other than tri-(C2 - C8)-alkyl aluminium compounds, metallocenes and metal carbonyl complexes. By "catalytic amount" is meant an amount of less than one molar equivalent of metal compound with more than one molar equivalent of reactant with the result that more than one molar equivalent of product is obtained. This method not only gives good yields of the product but is also free from the generation of zinc- and copper-containing residues. The advantage gained by the metal compounds is that the reaction rate of the cyclopropanation reaction is enhanced, thus allowing the use of less dibromomethane and trialkyl aluminum as well as a significantly decreased reaction temperatures. The C2 - Cg alkyl moieties may include alkanes, substituted alkanes, cycloalkanes and substituted cycloalkanes. The (C2 - Cs) alkyl aluminium compound is preferably triisobutyl aluminium (TIBA). The method is applicable to electron-rich alkenes. Examples of such alkenes include mono-, di-. tri- or tetra-substituted alkenes. The substituents may be selected from saturated and unsaturated alkyl and aryl groups, which themselves may be substituted with functional groups, such as (but not limited to) acids, esters, alcohols, ethers, allyl alcohols, allyl ethers, amines, allyl amines, imines, alkenes, aldehydes, cyclopropanes and ketones. Alkenes with which the invention works especially well are alkenes bearing at least three substituents including alkenes embedded in ring structures with ring sizes of 3 to 20 carbon- or hetero-atoms, which rings themselves can be substituted, for example, with the same substituents as hereinabove described. Examples of alkenes that undergo the cyclopropanation reaction of this invention, including combinations of reactive alkenes and unreactive alkenes in the same molecule, include those with the following structures: The alkenes may also include in the same molecule alkene moieties that are not electron-rich or alkenes that contain functional groups in their allylic position, which undergo complex formation with the alkyl aluminium compound, e.g. thus shielding these alkenes sterically against cyclopropanation. Examples of these unreactive alkenes are allylic alcohols, allylic amines, as well as electron-deficient alkenes such as conjugated carbonyl compounds, conjugated nitriles, conjugated imines and conjugated oximes. If these unreactive alkenes are combined in the same molecule with electron-rich reactive ones, only the latter will undergo cyclopropanation, with high chemoselectivity. The metal compounds whose presence is essential to the working of the invention are selected from the group consisting of metallocenes, metal carbonyl complexes and Lewis acids other than tri-(C2 - Cg)-alkyl aluminium compounds. One or more of these metal compounds can be used. Although tri-(C2 - Cg)-alkyl aluminium compounds are themselves weak Lewis acids, it 'has been found that they alone do not give the benefits of the invention, and when Lewis acids are desired as the metal compounds. Lewis acids other than these tri-(C2 - C8)-alkyl aluminium compounds must be added. ! The rate enhancement brought about by the use of these metal compounds ranges from slight to very significant. Examples of efficient Lewis acids include FeCfe and FeCl3. which are preferably used at a concentration of 0.01 - 30%, preferably 1 - 10%, with respect to the alkene to be cyclopropanated (the starting material). Examples of efficient metallocenes are those with at least one cyclopentadienyl-ligand e.g. cyclopentadienyltitanium trichloride CpTiCl3 or cyclopentadienyliron dicarbonyl dimer [CpFe(CO)2]2? which are used at the concentrations hereinabove described. An example of a metal carbonyl complex is iron pentacarbonyl Fe(CO)5. The addition has the advantage of allowing the reaction to be carried out in less dibromomethane, typically 20 molar equivalents instead of 30 eq, and at lower temperatures, thus increasing the margin of safety, because above 85°C an exothermic decomposition of the reaction mass is possible. For example, with FeCh, this reaction proceeds as follows: In a preferred embodiment, the excess dibromomethane is recovered. Although not essential to the working of the invention, such a recovery reduces costs and makes the process more industrially viable. The recovery is carried out by the steps of: (i) adding the reaction mixture to aqueous base at a temperature from -10° - 0°C; (ii) warming slowly the resulting twx)-phase mixture to room temperature; (iii) separating the phases; (iv) adding isopropanol to the organic phase; and (v) drying azeotropically and evaporating the dibromomethane under reduced pressure. In a typical example, using the preferred TIBA, recovery may be achieved by the following steps: (i) The reaction mixture is added to aqueous base (preferably 25% NaOH) at a temperature of from -10° - 0°C. Isobutane is cleaved from the isobutyl aluminium reagent and remains liquefied in the target vessel. '(ii) The resulting two-phase mixture is slowly and under stirring warmed to room temperature. This causes the release of gaseous isobutane. which is collected in a cooling device: fiii) after phase separation and addition of isopropanol to the organic phase, the organic phase is dried azeotropically and the excess dibromomethane is evaporated under reduced pressure and finally purified by distillation. The process described in this invention permits the cyclopropanation of electron-rich olefins in a cheap and efficient manner. The aluminium- and iron-containing wastes are environmentally of relatively low concern, the solvent dibromomethane can be recycled, and the collected isobutane can be used for other purposes or can be burned. The process has many uses, including the relatively easy and inexpensive manufacture of flavour and fragrance ingredients. The invention is now further described with reference to the following non-limiting examples. Example 1: Cyclopropanation of Campholene alcohol: rra/zs,-2-(l,2,2-trimethyl-bicyclo[3.1.0]hex-3-yl)- ethanol Campholene alcohol (EP 0 116 903) (8 g, 50 mmol) in dibromomethane (72 ml) is treated under cooling (10° - 20°C) with neat TTBA (6.5 ml, 25 mmol) via syringe. After 15 min stirring anhydrous FeCl3 (0.5 g, 3 mmol) is added followed by neat TEBA (39 ml, 0.15 mol). The mixture is stirred for 3 h at 25°C, then cooled to -10° - 0°C and pumped via double-needle on to 25% NaOH at -10° - 0°C. Under stirring the biphasic mixture is slowly warmed to room temperature. The phases are separated. The organic phase is washed with 4% oxalic acid, then with cone. NaHC03 until pH ~ 8, dried over MgS04 and filtered. After evaporation of the solvents under reduced pressure, the oily residue is purified by bulb-to-bulb-distillation (bp 108°C / 0.1 Torr), giving 7.3 g (85%) of a colorless oil. Odour: Camphoraceous, oily. 'H-NMR TCDCh, 400 MHz): 3.65 (ddd. 1 H). 3.5 (ddd. 1 H), 1.7 (dd, 1 H). 1.6 (m. 1 H). 1.4 Example 2: rram,-[l-Methyl-2-(l,2,2,5-tetramethyl-bicyclo[3.1.0]hex-3-ylmethyl)-cyclopropyl]methanol. I (i) Preparation of the precursor: rrara-[l-Methyl-2-(2,2,3,4-tetramethyl-cyclopent-3-enylmethyl)-cyclopropyl]methanol: />-arts-[l-Methyl-2-(252,3-txm (dr = 1:1) (Bajgrowicz, J. A.; Frank, L; Frater, G.; Hennig. M., Helv. Chim. Acta 1998, 81, 1349 -1358) (10 g, 48 mmol), dihydropyrane (4.3 g. 51 mmol) and a few drops of cone. HC1 (50 mg) are stirred for 4 h at 25°C. After addition of methyl ter/-butyl ether the organic phase is washed with cone. NaHC03 and cone. NaCl until pH = 7. Drying over MgSC>4, filtration and evaporation gives 14 g (93%) of the crude THP-ether as an oil (4 isomers, 93% purity and M = 292 according to GC/MS), which is subjected to the next epoxidation step without further purification. The thus-obtained crude THP-ether (11.7 g, 40 mmol) is dissolved in dichloromethane (20 ml). After addition of water-free Na2CC>3 (5.9 g, 56 mmol) the mixture is heated to 42°C, where '40% peracetic acid (10 ml. 56 mmol) are added over 2 h. The reaction is stirred for another ] h at this temperature. Water (50 ml) is carefully added and the phases are separated. The water phase is extracted with dichloromethane. The organic phase is washed with 10% NaOH and water until pH = 7. Drying over MgS04. filtration and evaporation gives 12.3 g (87%) of the crude THP-protected epoxide as an oil (4 isomers. 87% purity and M = 308 according to GC/MS), which is subjected without further purification to the next Grignard addition elimination step. The thus-obtained THP-protected epoxide (8.6 g_ 28 mmol) is treated with 3M methyl magnesiumchloride in tetrahydrofurane (94 ml. 0.28 mol). After 3 days at 70°C the solution is poured upon NH4CI at 0°C. Methyl /erf-butyl ether extraction and washing of the organic phase with water until pH = 7, MgS04-drying, filtration and evaporation gives 10 g of an orange oil, which is treated with methanol (10 g) and/?ara-toluenesulfonic acid (0.1 g). After 16 h at 25°C the methanol is evaporated, cone. NaHC03 and methyl tert-butyl ether are added and the phases are separated. MgSCVdrying, filtration and evaporation of the organic phase gives 7 g of an orange oil, which is purified by flash chromatography (hexane / methyl /erf-butyl ether) over silicagel giving after evaporation of the solvents and Kugelrohr distillation 1.9 g (31%o) of rra^-[l-Methyl-2-(2,2r3,4-tetramethyl-cyclopent-3-enylmethyl)-cyclopropyl]-methanol as a colorless oil (dr = 1:1, 84% GC-purity). Odour: Sandalwood, substantive. IH-NMR (CDCI3, 400 MHz): 3.35 (2 H)5 2.3 (m. 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.6 (s, 3 H), 1.5 (s, 3 H), 1.5 - 1.2 (5 H), 1.15 (s, 3 H), 0.95 (s, 3 H), 0.7 (d, 3 H), 0.65 (m, 1 H), 0.5 (m. 1 H), 0 (2 m, 1 H) ppm. 13C-NMR (CDC13, 400 MHz): 139.04 and 139.03 (2 s), 128.6 and 128.5 (2 s), 72.7 and 72.6 (21), 49.7 and 49.3 (2 d), 48.0 and 47.8 (2 s), 41.62 and 41.59 (2 t), 29.1 and 28.6 (2 t), 26.2 and 26.1 (2 q), 22.7 and 21.8 (2 s), 21.3 and 21.0 (2 d), 19.7 and 19.6 (2 q), 17.0 and 16.5 (2 t), 15.7 (q), 15.1 (q), 14.2 (q), 9.45 and 9.43 (2 q). GC/MS: 222 (3%, [M]*), 150 (22), 135 (35%), 121 (55%), 107 (100%). IR (film): 3327 (m), 2951 (s), 2851 (s), 2915 (m), 2861 (m), 1445 (m), 1382 (m), 1359 (m), 1027 (s), 881 (w). '(ii) Cyclopropanation reaction: Preparation otVram'-[l-Methyl-2-( 1.2,2,5-tetramethvl-bicyclo[3.1.0]hex-3-ylmethyi)cyc]opropyl]methanol: Prepared as described in example 1 from /ram-[l-Memyl-2-(2.2,3,4-tetramethyl-cyclopent-3-enylmethyl)-cyclopropyl]-methanol (0.5 g, 2.2 mmol), dibromomethane (3 mi, 45 mmol). TIBA (2 ml 8 mmol) and FeCl3 (22 mg, 0.13 mmol) giving after bulb to bulb-distillation (bp 128°C / 0.2 Torr) 0.46 g (85%) of a colorless oil (dr = 1:1, 91% GC-purity). Odour: Sandalwood, substantive. 'H-NMR (CDC13. 400 MHz): 3.3 (m, 2 H), 1.9 (m, 1 H), 1.5 (s, 1 H, OH), 1.3 - 1.1 (3 H), 1.1 (2 s, 3 H), 1.0 (s, 1H). 0.95 (s, 1 H), 0.89 (s, 1 H), 1.0 - 0.8 (2 H), 0.75 (d, 3 H), 0.6 - 0.4 (3 H), 0.0 and -0.1 (2 t 1 H), -0.3 (d, 1 H) ppm. 13C-NMR (CDC13, 400 MHz): 72.7 and 72.6 (2 t), 44.8 and 44.4 (2 d), 42.6 and 42.5 (2 s), 39.94 and 39.89 (2 t), 34.9 and 34.8 (2 s), 29.4 and 28.8 (2 t), 26.2 and 26.1 (2 s), 23.1 and 23.0 (2 q), 22.8 and 21.9 (2 s), 21.6 and 21.2 (2d), 19.8 and 19.7 (2 t), 19.6 and 19.5 (2 q), 18.4 (2 q), 17.1 and 16.5 (2 t), 15.7 and 15.1 (2 q), 14.02 and 14.01 (2 q) ppm. GC/MS: 236 (0.2%, [M]+), 218 (1%), 203 (5%), 175 (5%), 164 (15%), 149 (30%), 135 (85%), 121 (80%), 107 (60%), 95 (80%), 82 (80%), 55 (85%), 41 (100%). IR (film): 3323 (m), 3064 (w), 2866 (s), 1452 (s), 1381 (m), 1362 (m), 1028 (s), 1012 (s), 880 (w). Example 3: Distal-selective cyclopropanation of Nor-Radjanol: fra/ty-2-Methyl-4-(l ,2,2-trimethyl-bicyclo- [3.1.0]hex-3-yl)but-2-en-1 -ol. To Nor-Radjanol (Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M., Helv. Chim. Acta 1998, 81, 1349 - 1358) (194 g, 1 mol) in dibromomethane (1.4 1, 20 mol) neat TIBA (100 g, 0.5 'mol) is added under cooling (10° - 20CC) via double-needle. After 15 min anhydrous FeCh (22 mg, 0.13 mmol) is added in one portion followed by TIB A (620 g, 3.1 mol) via double needle. The mixture is stirred for 4.5 h at 25°C then cooled to -10° - 0°C and pumped via double needle on to cooled (-10° - 0°C) 25% NaOH. Under stirring (Caution !) the biphasic mixture is slowly warmed to room temperature. The evolving isobutane is collected in a cooling trap at -78°C. The phases are separated. The organic phase is washed with 4% oxalic acid, then with cone. NaHCC>3 until pH ~ 8. Isopropanol (110 g. 1.8 mol) is added to the organic phase and the water is removed azeotropically under reduced pressure. Then, the remaining water-free dibromomethane is removed under reduced pressure, followed by distillation of the residue (bp 160°C / 0.1 Torr) giving 190 g (93%) of a colorless oil (86% GC-purity, 2% Nor-Radjanol 7% bis-cyclopropanated byproduct), whose analytical data (NMR, MS, IR, odour) are consistent with the ones described in the literature (Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M., Helv. Chim. Acta 1998, 81, 1349-1358). Example 4: This is a comparative example that uses no metal compound. /ra>w-2-Methyl-4-( 1,2,2-trimethyl-bicyclo-[3.1.0]hex-3-yl)but-2-en-1 -ol from Nor-Radj aldehyde via solvent-free DIB AH reduction, To Nor-Radjaldehyde (US 4,052,341) (192 g, 1 mol) is added at 0°C and stirring neat DIBAH (179 ml, 1 mol) via double needle. The solution is stirred for 30 min at 25°C. Dibromomethane (2.1 1, 30 mol) is added and the solution heated to 60°C, where neat TIBA (595 g, 3 mol) is added over 2 h via double-needle. The reaction temperature is maintained by slight external cooling at 65 - 75°C for another 2 - 4 h, until complete conversion is detected by GC. Work- 'up. as described in example 3. gives 227 g (>91%) of crude product as a slighth \ello\v oil. whose analytical data (NMR. IR. MS. odour) are consistent with the ones described tor this compound in the literature (Bajgrowicz. J. A.: Frank. I.; Frater. G.; Hennig, M. Helv. Chim Acta 1998. 81. 1349- 1358). In comparison with Example 1, it can be seen that.without FeCl3. more TIBA and dibromomethane are required and that a higher reaction temperature is necessary. The use of FeCU allows a better, more economic process. Example 5: Distal-selective cyclopropanation of Linalool: 5-(2,2-Dimethyl-cyclopropyl)-3-methyl-pent-l- en-3-ol Prepared as described in example 1 from Linalool (31 g, 0.2 mol), dibromomethane (280 ml), neat TIBA (140 g, 0.7 mol) and anhydrous FeCl3 (2 g, 60 mmol). Work-up after 6 h at 25°C and distillation (bp 55°C / 0.05 Torr) gives 22.5 g (67%) of the cyclopropanation product as colorless oil, whose analytical data are consistent with the ones described in WO 01/006853. Odour: citrus, green, cool, metal. Example 6: Distal-selective cyclopropanation of Geraniol: £-5-(2,2-Dimethyl-cyclopropyl)-3 -methyl -pent-2-en-1 -ol V ' Prepared as described in example 3 from £-Geraniol (154 g. ] mol), dibromomethane (1.4 1. 20 mob. neat TIBA (700 g. 3.5 mol) and anhydrous FeCh (10 g, 60 mmol). Work-up after 7 h at 25°C gives 175 g of the crude cyclopropanaiion product (81% GC-purity) as yellowish oil. which is instable to distillation (H2O elimination) and on prolonged standing. Odour: weak Geraniol. *H-NMR (CDCI3, 400 MHz): 5.4 (L 1 H). 4.15 (d. 2 H), 2.1 (dd, 2 H). 1.7 (s. 1 H). 1.6 (s. 3 H). 1.4 (m, 2 H), 1.03 (s, 3 H), 1.02 (s. 3 H). 0.4 (1 H), 0.35 (dd. 1 H). -0.15 (dd. 1 H) ppm. 13C-NMR (CDCI3, 400 MHz): 140.0 (s). 123.2 (d). 59.3 (t), 40.0 (t), 28.2 (t). 27.6 (q). 24.3 (d), 19.9 (q)9 19.6 (t), 16.3 (q), 15.4 (s) ppm. GOMS: 153 (2%, [M - 15f). 150 (2% [M -H20]+), 137 (18%), 107 (25%), 82 (45%), 67 (55%). 55 (100%). Example 7: Reduction / Cyclopropanation of 6-Methyl-hept-5-en-2-one: 4-(252-Dimethyl-cyclopropyl)- butan-2-ol. FeCl3 (0.5 g, 3 mmol) is added under stirring to 6-Methyl-hept-5-en-2-one (6.3 g, 50 mmol) in dibromomethane (70 ml, 1 mol) at 10° - 20°C, followed by slow addition of neat TIBA (38 ml. 0.15 mol) at this temperature. The mixture is stirred for 7 h at 25°C, then poured carefully on to 25% NaOH at -10° - 0°C. Work-up as described in example 1 and distillation (bp 50°C / 0.07 Torr) gives 4.8 g (67%) of a colorless oil (80% GC-purity, dr ~ 1:1). The analytical data (NMR, MS, IR) are consistent with the ones described in the literature (Perraud, R; Arnaud, P. Bull. Chem. Soc. Chim. Fr. 1968, 1540-1542). Example 8: Cyclopropanation of Isoeugenol: /raw-2-Methoxy-4-(2-methyl-cyclopropyl)phenol 'Prepared as described in example 3 from Isoeugenol (100 g. 0.61 mol). dibromomethane (850 ml. 12.2 mol), neat TIBA (422 g. 2.15 mol) and anhydrous FeCl3 (6 g. 37 mmol). After 7 h at 25 :C (conversion 44 : 56) the mixture is cooled to -10° - 0=C and pumped via double needle on to 2 M HC1 cooled to -10° - 0°C. Under stirring (Caution !) the biphasic mixture is si owl} warmed to room temperature. The organic phase is separated and washed with 5% citric acid and water until pH = 7. Drying with MgS047 filtration and evaporation of the solvent, followed by distillation (bp 65°C / 0.03 Torr) gives 50.1 g (46%) of the cyclopropanation product as colorless oil (93% GC-purity). The analytical data (NMR, MS, IR, odour) are consistent with the ones described for this compound in EP 1 269 982. Example 9: Cyclopropanation of Eugenol: 4~Cyclopropylmethyl-2-methoxy-phenol Prepared as described in example 8 from Eugenol (50 g, 0.3 mol), dibromomethane (425 ml, 6.1 mol), neat TIBA (212 g, 1.06 mol) and anhydrous FeCl3 (3 g, 18 mmol). The mixture is worked-up after 20 h at 25°C (57:43 conversion) as described in example 8. Distillation at 75°C / 0.03 Torr separates the substrate (bp 50°C. 0.03 Torr) from the cyclopropanation product (bp 75°C, 0.03 Torr) giving 21 g (41%) of the latter compound as colorless oil whose analytical data (NMR, MS, IR, odour) are consistent with the ones described in EP 1 269 982 . Example 10: Distal-selective cyclopropanation of Geranic acid ethyl ester: £-5-(2,2-Dimethyl-cyclopropyl)- 3-methyl-pent-2-enoic acid ethyl ester 'Prepared as described in example 7 from anhydrous FeCl;, (0.1 g. 0.7 mmol). Geranic acid ethyl ester (2.2 g. 11 mmol). dibromomethane (31 ml. 0.44 mol) and neat TIBA (17 ml. 66 mmol). Work-up after 6 h at 25CC, as described in example 1, and Kugelrohr distillation (bp 92=C / 0.2 Ton) gives 1.2 g (52%) of a colorless oil. Odour: fruity, pear. 'H-NMR (CDCh. 400 MHz): 5.7 (s, 1 H), 4.15 (q, 2 H), 2.2 (t. 1 H). 2.18 (s. 3 H), 1.5(1 H). 1.3 (t. 3 H). 1.1 (s. 3 Hi. 1.0 (s. 3 H). 0.9 (2 H), 0.45 (1 H), 0.4 (1 H). -0.1 (1 H) ppm. 13C-NMR (CDC13. 400 MHz): 166.7 (s), 160.1 (s), 115.4 (d), 59.2 (t). 41.4 (t), 28.0 (t). 27.4 (q), 24.1 (d), 19.8 (q), 19.6 (t). 18.7 (q), 15.4 (s), 14.2 (q) ppm. GC/MS: 210 (0.1%. M~). 195 (4%, [M - 15]"). 153 (10%), 136 (35%), 82 (45%), 55 (100%). IR (film): 2925 (m). 2869 (m). 1719 (s), 1648 (m). 1453 (m). 1366 (m), 1219 (m), 1147 (s), 1042 (m). 970 (w), 859 (w). Example 11: Cyclopropanation of £/Z-Geranitrile: £/Z-5-(2,2-dimethyl-cyclopropyl)-3-methyl-pent-2- enenitrile. Prepared as described in example 7 but in 2 cycles from .E/Z-Geranitrile (dr = 1:1) (77 g, 0.52 mol). dibromomethane (2 x 720 ml, 10.3 mol). neat TIBA (2 x 358 g, 1.8 mol) and anhydrous FeCh (2 x 5 g, 30 mmol). Work-up after 17 h at 25°C (per cycle), as described in example 1, and distillation (bp 95°C / 0.06 Torr) (after the 2nd cycle) gives 50 g (59%) of the cyclopropanation product (71% GC-purity, 8% aldehyde, 11% alcohol, dr = 1:1) as colorless oil. 'H-NMR (CDCI3, 400 MHz): 5.1 (1 H), 2.5 (m, 1 H), 2.25 (m, 1 H), 2.05 (s, 1.5 H), 1.9 (s, 1.5 H), 1.6 - 1.3 (2 H), 1.05 (6 H), 0.45 (2 H), -0.1 (1 H) ppm. 13C-NMR (CDC13, 400 MHz): 165.43 and 165.4 (2 s), 117.2 and 117.0 (2 s), 95.6 and 95.0 (2 d), 39.1 and 36.7 (2 t), 27.6 and 27.5 (2 t), 27.39 and 27.37 (2 q), 28.9 and 23.8 (2 d), 22.9 and 21.0 (2 q), 19.9 and 19.8 (2 q), 15.6 and 15.5 (2 s) ppm. GC/MS: 162 (20%), 148 (1%, [M - 15]+), 94 (20%), 81 (55%), 55 (100%). IR (film): 2952 (s). 2867 (m). 2218 (w). 1676 (w), 1632 (w), 1454 (m). 1 3" im». 1365 (m), 1120 (w). 1020 (m). 866 (w). 801 (w). Odour: Hesperidic. powerful, fresh, geranirrile. Example 12: Cyclopropanation of E-Ambrettolide: fr Prepared as described in example 7 but in 2 cycles from £-Ambrettolide (20 g, 80 mmol). dibromomethane (2 x 110 ml, 1.6 mol), neat TTBA (2 x 47 g, 0.24 mol) and anhydrous FeCl3 (2 x 0.8 g, 5 mmol). Work-up after 6 h at 25°C (per cycle), as described in example 1, and distillation (bp 130°C / 0.04 Torr) (after the 2nd cycle) gives 6.6 g (30%) of the cyclopropanation product (97% GC-purity) as colorless oil. 'H-NMR (CDC13, 400 MHz): 4.2 (m. 1 H), 2.35 (m, 2 H), 1.85 (1 H), 1.7 -1.6 (5 H). 1.5 - 1.2 (14 H), 0.8 (m, 1 H), 0.55 (m. 1 H). 0.45 (m, 1 H), 0.35 (1 H), 0.2 (2 H) ppm. I3C-NMR (CDC13, 400 MHz): 173.9 (s), 63.9 (t). 34.8 (t), 33.9 (t), 33.5 (t), 29.8 (t), 29.5 (t), 29.5 (t). 29.1 (t), 28.6 (t), 28.31 (t), 28.29 (t), 26.4 (t), 25.6 (t), 18.63 (d), 18.56 (d), 11.9 (t) ppm. GC/MS: 266 (1%, M+), 248 (1%, [M - 18]+), 123 (10%), 109 (22%), 96 (50%), 82 (63%), 67 (75%), 55 (100%). IR (film): 2921 (s), 2851 (m), 1733 (s), 1460 (m), 1347 (w), 1237 (m), 1161 (m), 1113 (w), 1057 (w), 1022 (w), 720 (w). Example 13: Cyclopropanation of Nirvanolide ; : c/>3-Methyl-6-oxa-bicyclo[13.1.0]hexadecan-7-one. Prepared as described in example 7 from Nirvanolide (Frater, G.; Helmlinger, D.; Mueller, U. Givaudan-Roure (International) S.A.. 1999, EP 908455) (20 g, 84 mmol), dibromomethane (235 ml, 3.35 mol), neat TIBA (100 g, 0.5 mol) and anhydrous FeCl3 (0.8 g, 5 mmol). Work-up after 5 h at 25°C, as described in example 1, and distillation (bp 100°C / 0.03 Ton) gives 8 g (38%) of the cyclopropanation product as colorless oil. Odour: musky, metal, powdery. 'H-NMR (CDC13, 400 MHz): 4.2 (m, 2 H), 2.3 (m, 2 H), 1.7 (1 H), 1.7 - 1.2 (16 H), 1.0 (3 H), 0.8 (m, 1 H), 0.6 (m, 1 H), -0.3 (m, 1 H) ppm. ,3C-NMR (CDCI3, 400 MHz): 174.0 (s), 62.1 (t), 37.4 (t), 36.3 (t), 34.6 (t), 30.2 (d), 28.6 (t), 27.6 (t), 27.5 (t), 27.1 (t), 26.8 (t), 24.8 (t), 18.4 (q), 16.1 (d), 13.8 (d), 10.9 (t) ppm. GC/MS: 252 (1%, M*), 237 (1%, [M - 15]+), 223 (1%), 210 (1%), 195 (1%), 182 (1%), 109 (20%), 95 (35%), 81 (100%). IR (film): 2924 (m), 2855 (m). 1731 (s), 1458 (m), 1378 (w), 1337 (w), 1248 (m), 1151 (m), 1120 (w), 1091 (w), 1060 (m), 1021 (w), 965 (w), 848 (w). Example 14: fraws-3-(2-Ethoxymeftyl-2-m (i) Preparation of the precursor: £-4-(4-Etboxy-3-methyl-but-2-enyl)-1,5,5-trimethyl-cyclopentene: A solution of Nor-Radjanol (Bajgrowicz, J. A.; Frank, L; Frater, G.; Hennig, M. Helv. Chim. Acta 1998, 8L 1349 - 1358) (60 g, 0.3 mol) and ethyl iodide (73 ml, 0.47 mol) in non- Example 15: Cyclopropanation of Z-Cyclododecene: m-Bicyclo[10.1.0]tridecane Prepared as described in example 7 from Z-Cyclododecene (E/Z = 3:1) (1.66 g, 10 mmolj. dibromomethane (14 ml, 0.2 mol), neat TIBA (7.5 ml, 30 mmol) and anhydrous FeCl3 (O.lg. 0.6 mmol). Work-up after 2 h at 25°C as described in example 1, and Kugelrohr distillation (bp. 60°C / 0.07 Torr) gives 1.5 g (83%) of the cyclopropanation product as colorless oil (cis/trans = 3:1), whose analytical data (NMR, MS) are consistent with the ones described in the literature (O'Connor, E. J.; Brandt S.; Helquist P.; J. Am. Chem. Soc. 1987. 109. 3739 -3747). Example 16: [CpFe(CO)2]2-catalyzed cyclopropanation of Nor-Radjanol: /ra/w-2-methyl-4-(l,2,2-trirnethyl-bicyclo-[3.1.0]hex-3-yl)but-2-en-l-ol. Prepared, as described in example 3, from Nor-Radjanol (1.94 g, 10 mmol), dibromomethane (14 ml, 0.2 mol), neat TIBA (8.8 ml, 35 mmol), and with cyclopentadienyliron dicarbonyl dimer [CpFe(CO)2J2 (100 mg, 0.3 mmol) in place of the FeCh of that example. Work-up after 3 h at 25°C, Silicagel filtration and bulb-to-bulb distillation gives 1.9 g (91%) of a colorless oil (85% GC-purity), whose analytical data are consistent with the ones described for the same product obtained from example 3. Example 17: CpTiC^-catalyzed cyclopropanation of Nor-Radjanol: /ron5-2-methyl-4-(l,2,2-trimethyl-bicyclo-[3.1.0]hex-3-yl)but-2-en-1 -ol. Prepared, as described in example 3, from Nor-Radjanol (1.94 g, 10 mmol), dibromomethane (14 ml, 0.2 mol), neat TIBA (8.8 ml, 35 mmol), and with cyclopentadienyltitanium trichloride CpTiCl3 (100 mg, 0.3 mmol) in place of the FeCl3 of that example. Work-up after 3 h at 25°C and bulb-to-bulb distillation gives 1.8 g (85%) of a colorless oil (77% GC-purity), whose analytical data are consistent with the ones described for the same product obtained from example 3. Claims: A process for the cyclopropanation of a substituted alkene. comprising the reaction of the alkene with a carbenoide. generated from dibromomethane and a tri-(C2 - CV-alkyl aluminium compound in the presence of a catalytic amount of a metal compound selected from the group consisting of Lewis acids other than tri-(C2 - Cg)-alky] aluminium compounds, metallocenes and metal carbonyl complexes. A process according to claim 1, in which the tri-(C2 - Cg)-alkyl aluminium is triisobutyl aluminium. A process according to claim 1, in which there is used from 1 - 5 molar equivalents, preferably 2.5 - 3.5 equivalents, of tri-(C2 - C8)-alkyl aluminium reagent. A process according to claim 1, in which there is used from 5-100 molar equivalents, more preferably 25 - 35 equivalents, of dibromomethane. A process according to claim 1, in which the metal compound is a Lewis acid selected from the group consisting of copper and iron halides, preferably FeCb and FeC^. A process according to claim 1, in which the metal compound is a metallocene containing at least one cyclopentadienyl-ligand. A process according to claim 1 in which the metal compound is used at a concentration of 0.01 - 30%, preferably 1 - 10%, with respect to the alkene to be cyclopropanated. A process according to claim 5, in which 10-20 molar equivalents of dibromomethane is used. A process according to claim 1 in which excess dibromomethane is recovered for further use. A process according to claim 9, in which the recovery is carried out by the steps of: (i) adding the reaction mixture to aqueous base at a temperature from -10° - 0CC; (ii) warming slowly the resulting two-phase mixture to room temperature; (iii) separating the phases; (iv) adding isopropanol to the organic phase; and (v) drying azeotropically and evaporating the dibromomethane under reduced pressure-Manufacture of a flavour or fragrance ingredient comprising the cyclopropanation of an alkene by a process according to claim 1.

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