Organic compounds

Abstract

A process of converting a carbon-carbon multiple bond to a cyclopropane ring, comprising the addition of a N-alkyl-N-nitroso compound to a mixture of alkene precursor, aqueous base and Pd(II)-catalyst, with the N-alkyl-N-nitroso compound obtained directly from an alkyl amine derivative, NaNO.sub.2 and an acid via phase separation of the N-alkyl-N-nitroso compound from the aqueous phase.

Claims

1. A process of ring formation across a carbon-carbon multiple bond, the process comprising the steps of reacting a N-alkyl-N-nitroso compound with a substrate bearing a carbon-carbon multiple bond, wherein the N-alkyl-N-nitroso compound has been generated in-situ, and the generated N-alkyl-N-nitroso compound is reacted with the substrate without being first isolated.

2. The process according to claim 1, wherein the N-alkyl-N-nitroso compound is an organic solution of N-alkyl-N-nitroso urea, and wherein the N-alkyl-N-nitroso urea is reacted with the substrate without being first isolated in solid form.

3. The process according to claim 1, wherein the N-alkyl-N-nitroso compound is a N-methyl-N-nitroso compound (MNC).

4. The process according to claim 1, wherein the N-alkyl-N-nitroso compound is selected from the group consisting of N-methyl-N-nitroso-urea (MNU), N-methyl-N-nitroso-p-toluenesulfonamide, N-nitroso-dimethylurethane, nitroso-EMU and N-nitroso-β-methylaminoisobutyl methyl ketone (NMK).

5. The process according to claim 1, wherein the N-alkyl-N-nitroso compound is generated in-situ from a mixture of a HNRR′ compound, water, NaNO.sub.2 and an acid, before partitioning into an organic solvent to form an organic solution of N-alkyl-N-nitroso compound.

6. The process according to claim 5 wherein the N-alkyl-N-nitro compound is formed in-situ from a N-alkylamine.

7. The process according to claim 1, wherein a biphasic mixture is formed with the N-alkylN-nitroso compound in an organic layer.

8. The process according to claim 1, wherein the N-alkyl-N-nitroso compound in liquid phase is separated from an aqueous phase in a phase separation step, before being reacted with the substrate bearing a carbon-carbon multiple bond.

9. The process according to claim 1, wherein the N-alkyl-N-nitroso compound is reacted with the substrate bearing a carbon-carbon multiple bond in the presence of an aqueous base and a catalyst.

10. The process of converting a carbon-carbon double bond to a cyclopropane ring according to claim 1.

11. A process of converting a carbon-carbon double bond to a cyclopropane ring comprising the steps of: I) synthesis of a N-alkyl-N-nitroso compound in liquid phase, II) separation of an organic N-alkyl-N-nitroso compound-containing liquid phase from an aqueous phase, and III) transferring the N-alkyl-N-nitroso compound in the organic liquid phase into a mixture comprising an alkene substrate, thereby to cyclopropanate the alkene substrate, wherein the alkene substrate is a terminal (monosubstituted) isoprenoid alkene.

12. The process according to claim 6, wherein the N-alkylamine is methyl, ethyl, propyl or higher alkyl amine, which may be substituted or unsubstituted and linear or branched.

13. The process according to claim 3, wherein a liquid phase comprises an organic solvent for the MNC that is selected from the group consisting of ethers and toluene.

14. The process according to claim 13 wherein the ether is selected from the group consisting of tetrahydrofurane, dimethoxyethane, dioxane and dimethylisosorbide.

15. The process according to claim 9, wherein the aqueous base is selected from the group consisting of alkali hydroxides.

16. The process according to claim 9, wherein the catalyst is a transition metal catalyst, optionally a palladium catalyst, further optionally Pd(acac).sub.2, Pd(OAc).sub.2 or PdCl.sub.2 catalysts.

17. The process according to claim 1, which is conducted in flow mode.

18. The process according to claim 1, wherein the substrate bearing a carbon-carbon multiple bond is a terminal (monosubstituted) alkene.

19. The process according to claim 1, wherein the substrate bearing a carbon-carbon multiple bond is a compound of the formulae ##STR00027## wherein R.sup.1 and R.sup.2 may, independently of each other, be hydrogen, alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted; and R.sup.3 may be an alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted.

20. The process according to claim 18, wherein the substrates are isoprenoids.

21. A compound according to the formula ##STR00028## in which n=1 or 3.

22. A compound according to claim 21 comprising ##STR00029##

Description

(1) FIG. 1 is a schematic representation of a specific embodiment that illustrates the process according to the invention. In a first reaction vessel MNU-precursor I is formed from a mixture of NaNO.sub.2, methyl amine and urea in an aqueous medium. An organic solvent is added to this aqueous phase and the whole is pumped onto concentrated acid in a second vessel where after elimination of water, MNU is formed. Alternatively the organic solvent can be added at this stage. Phase separation is carried out in the same vessel (2). The lower aqueous salt solution phase is drained off to waste, whereas the upper organic layer containing the generated MNU is pumped into a third vessel containing the alkene substrate, aqueous basic phase and catalyst. The cyclopropanation reaction proceeds as the two phases are mixed with vigorous stirring, and after the reaction is complete the organic phase containing the cyclopropanated alkene is recovered.

(2) ##STR00003##

(3) As the acid quench of MNU precursor I in vessel 2 is highly exothermic and the cyclopropanation in vessel 3 is also temperature sensitive, cooling is preferably used for these two steps. In a first aspect, uncontrolled decomposition of MNU needs to be avoided, which might occur above 20° C. and produces methyl isocyanate (MIC). Furthermore, the cyclopropanation is preferably carried out at lower temperature, to avoid release of the low-boiling diazomethane (bp=−23° C.) into the atmosphere and/or dimerization of this reagent to ethylene and nitrogen, which decreases the efficiency of the cyclopropanation step. Both steps are therefore preferably carried out under cooling, e.g. at −20 to +10° C., more preferably around 0° C. These temperatures are nevertheless easily maintained and controlled by the addition rate of MNU precursor I to the acid (step 1) or the addition rate of MNU to the alkene substrate. In flow reactors it should be possible to use higher reaction temperatures.

(4) This set up is relatively non-complex and has the considerable advantage that it avoids separation and handling of solid MNU and reduces human exposure to MNU and diazomethane to a minimum as MNU is generated only in vessel 2 and destroyed (by cyclopropanation) in vessel 3. Furthermore some steps of the reaction sequence can be run in flow reactors, e.g. the MNU generation step (vessel 2), and the phase separation step can be automatized.

(5) As in case of the cyclopropanation reaction with MNU any unreacted diazomethane (DAM) can be quenched after the reaction is complete, by the addition of a sacrificial alkene with high reactivity (such as ethylene, styrene, limonene, myrcene or farnesene) or alternatively or additionally, acetic acid or other carboxylic acids, which in the presence of a strong base will decompose any diazomethane by methylation of the acid.

(6) It is preferred that the MNC immediately and completely reacts to DAM, and that DAM immediately and completely reacts with the unsaturated substrate in the reaction mixture, and that these compounds (MNC and/or DAM) are not detectable during and after complete addition of the MNC (in vessel 3). It is therefore preferred that the stationary concentration of both compounds (MNC and/or DAM) is kept at <10%, <5%, <1%, <0.1% and ideally at 0% versus alkene substrate and cyclopropanated product in the reaction mixture. Such a low or close to zero concentration of MNC or DAM (in vessel 3) prevents release of MNC into the environment in case of a reactor damage and thus prevents a spill of a toxic reaction mass. It also prevents release of DAM from the reaction mixture into the headspace of vessel 3 and beyond the confinements of the reactor. In particular, in case of MNU, a low or close to zero concentration of DAM also prevents the formation of other hazardous products, e.g. methylation of the waste product potassium isocyanate to give the highly toxic methyl isocyanate (MIC).

(7) To avoid a stationary concentration of MNC and/or DAM the skilled chemist will adjust the reaction parameters as described above, namely catalyst concentration, temperature and MNC/alkene substrate/cyclopropanated product ratios. It may be of advantage to add a sacrificial alkene with slightly lower reactivity than the target alkene. This sacrificial alkene can be covalently attached to the target alkene (as in any polyene). Alternatively, substoichiometric amounts of MNC versus the alkene substrate may be used. Thus, MNC would be completely consumed and DAM formation would be stopped before the target alkene is completely cyclopropanated. The skillful combination of reaction parameters and ratios of catalysts and reactants guarantee a close to zero stationary concentration of MNC and/or DAM during and after complete MNC addition.

(8) The process according to the present invention can be used to cyclopropanate all mono- and disubstituted alkene substrates as well as ethylene. Preferred, however, are terminal (monosubstituted) alkenes, i.e. those alkenes wherein R.sup.2 is H. R.sup.1 may be an alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted. Other preferred alkenes are exo-methylene compounds (i.e. those in which R.sup.1 and R.sup.2=alkyl, alkylidene or aryl, which may be branched or unbranched and substituted or unsubstituted).

(9) In terminal non-activated isoprenes, wherein R.sup.3 is alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted, first the terminal and then the exo-methylene double bond will react.

(10) ##STR00004##

(11) Terminal isoprenoid compounds, with one or more trisubstituted double bonds in the substituent R.sup.3, are cyclopropanated with high selectivity at the monosubstituted double bond or are double-cyclopropanated at the terminal isoprene unit depending on the reaction conditions. This provides a selective access to mono- or bis-cyclopropanated Myrcene, Farnesene or higher polyprenoid derivatives. Especially the vinylcyclopropanes (monocyclopropanated) are valuable intermediates for further transformations e.g. to flavor & fragrance compounds or their precursors, e.g. pseudo-Georgywood.

(12) In another aspect of the present invention there are provided cyclopropanated isoprenes according to the formula IIIa

(13) ##STR00005##
in which n=0, 1, 2 or 3.

(14) In a particular embodiment of the present invention there is provided a cyclopropanated isoprene, myrcene, or farnesene. Depending on the E/Z- and α,β-purity of the polyprene, different double bond isomers or isomer mixtures II can be used as starting material giving after cyclopropanation III.

(15) ##STR00006##

(16) In a particular embodiment of the present invention there are provided mono- or bis-cyclopropanated myrcenes of the formulae 1 or 2, or a mono-cyclopropanated ocimene of the formula 3.

(17) ##STR00007##

(18) In another particular embodiment of the present invention there are provided mono- or bis-cyclopropanated β-farnesenes of the formulae 4 or 5, or a mono-cyclopropanated α-farnesene of the formula 6.

(19) ##STR00008##

(20) It is known from the literature that cyclopropanation of monosubstituted alkenes is commonly performed with the aid of diazo compounds, such as diazomethane (DAM) for methylenation, and transition metal catalysts, typically comprising palladium complexes. Useful information regarding the transition-metal catalyzed selective methylenation of the monosubstituted double bond in polyenes such as II to monocyclopropanated polyenes such as III, however, is scarce and limited only to precursor isoprene (n=0 in II and III). Although the selectivities towards III (n=0) are relatively good, no hint was given how to improve selectivities and reaction conditions further, e.g. using less catalyst and/or DAM generated in situ in the reaction vessel. The reaction was also not tested on higher polyenes II (with n≧1), probably because more complex mixtures were expected in case of a higher degree of unsaturation. The selective methylenation of polyenes II (with n≧1) has not been reported so far. Compounds III with n≧1 are therefore either unknown, or have been synthesized by more complex routes. A simple access to such compounds (III, n≧1) is nevertheless strongly desired, due to the value of these products in further reactions to useful fragrance compounds.

(21) In another particular embodiment of the present invention there are provided substituted meta- or para-substituted cyclopropylbenzenes of the general formula IV in which R′ is a branched or unbranched C.sub.1-C.sub.5 alkyl radical with n=0, 1 or 2 located in the 1- and/or 2-position of the cyclopropane, and R″ is a C.sub.3-C.sub.10 radical, optionally substituted, unsaturated, which contains optionally one or more heteroatoms, carbonyl groups, imines, alcohols, acetals.

(22) ##STR00009##

(23) The substituted cyclopropylbenzenes IV can give, after appropriate chemical transformation and purification, as known to the skilled chemist, fragrance compounds of the floral and preferably of the Lilly of the Valley family.

(24) The vinylcyclopropanes of the general formula V can be transformed by vinylcyclopropane rearrangement, known to the chemist skilled in the art, to useful precursors of known fragrance compounds, e.g. using the Rh(I)-catalyzed cycloaddition of vinylcyclopropanes as described by P. Kraft in Synthesis, 695, 1999 and references therein. The cycloaddition products VI give after further transformation valuable fragrance products of the woody-amber family.

(25) ##STR00010##

(26) Application of this method to monocyclopropanated myrcene 1 for example gives homomyrcene 10 and pseudo-Georgywood 12 which are both valuable precursors of Georgywood™ depending on the exact reaction conditions.

(27) ##STR00011##

(28) Cyclopropanes generated by the method of the present invention can be also used directly as fragrance compounds, e.g. without further derivatization, such as Δ-Myrcenol 13 and Δ.sub.2-Myrcenol 14:

(29) ##STR00012##

(30) There now follows a series of examples that further act to illustrate the invention.

(31) General Analytical Conditions:

(32) Non-polar GC/MS: 50° C./2 min, 20° C./min 200° C., 35° C./min 270° C. GC/MS Agilent 5975C MSD with HP 7890A Series GC system. Non-polar column: BPX5 from SGE, 5% phenyl 95% dimethylpolysiloxane 0.22 mm×0.25 mm×12 m. Carrier Gas: Helium. Injector temperature: 230° C. Split 1:50. Flow: 1.0 ml/min. Transfer line: 250° C. MS-quadrupol: 106° C. MS-source: 230° C.

Example 1. Preparation of MNU in THF

(33) ##STR00013##

(34) A solution of urea (175 g, 2.9 mol) and methylamine hydrochloride (198 g, 2.9 mol) in water (400 ml) is heated at reflux (105° C.) for 3.5 h under stirring. At 40° C. NaNO.sub.2 (101 g, 1.45 mol) dissolved in water (200 ml) is added. After 15 min THF (1000 ml) is added which results in a transparent 2-phase mixture. Conc. H.sub.2SO.sub.4 (110 g, 1.1 mol) is added at 0-5° C. and stirring within 1.5 h. After another 0.5 h at 0-5° C. the two transparent phases are separated at 25° C. The organic phase (A, 1065 ml, theoretically 1.35 M) is stored for a few days at 0-5° C. or forwarded immediately to the cyclopropanation reactor.

(35) The water phase is extracted twice with THF (2×1 l). This gives 1100 ml of phase B and 1075 of phase C. Whereas phase A gives a 51% conversion of a terminal alkene to a cyclopropane in a subsequent cyclopropanation reaction, phase B gives <0.5% cyclopropane and phase C gives no detectable conversion. We conclude that >99% MNU are extracted after the first phase separation. Usually the water phase is therefore discarded after the first phase separation (from organic phase A) after treatment with conc. aqueous KOH and acetic acid.

Example 2. Preparation of N-Nitroso-Dimethylurethane in Toluene

(36) ##STR00014##

(37) H.sub.3PO.sub.4 50% in water (9.2 g, 48 mmol) is added to dimethylcarbamate (4.9 g, 55 mmol) at 10-20° C. under stirring. To the colorless 2-phase mixture is added NaNO.sub.2 30% in water (20.1 g, 67 mmol) at 10-15° C. over 1-1.5 h. Nitrous gases are formed at the end of the addition and the orange solution is stirred for 17 h at 25° C. Nitrogen is bubbled through the reaction mixture to expel remaining nitrous gases. Stirring is stopped and a sample is taken from the orange organic layer for analytical analysis which shows a conversion of 88-92% according to GCMS and NMR. The reaction mixture is extracted twice with toluene (15 ml, 10 ml) to give 30 ml of a clear light orange solution which is used as such in the cyclopropanation step.

(38) Analytical data of the organic layer before toluene addition: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.1 (s, 3H), 3.2 (s, 3H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 154.2 (s), 54.9 (q), 28.0 (q) ppm. GC/MS: 118 (20%, M.sup.+), 87 (10%), 59 (100%), 56 (20%), 43 (77%), 42 (26%), 30 (74%), 28 (21%).

Example 3. Preparation of Nitroso-Emu

(39) ##STR00015##

(40) H.sub.3PO.sub.4 50% in water (683 g, 3.44 mol) is added to ethyl methylcarbamate (412 g, 4 mol) at 10-20° C. under stirring (300 rpm). To the colorless 2-phase mixture is added NaNO.sub.2 30% in water (1123 g, 4.9 mol) at 10-15° C. over 6 h. Nitrous gases are formed after 50% addition which are absorbed in two washing bottles containing 10% (NH.sub.4).sub.2SO.sub.4 in water. The orange solution is stirred for 17 h at 25° C. and is purged with nitrogen until the remaining nitrous gases are removed. Stirring is stopped and a sample is taken from the orange organic layer for analytical analysis which shows a 76-82% conversion according to GCMS and NMR. The reaction mixture is extracted twice with toluene (2×1 l) to give 2.5 l of a clear light orange solution which is used as such in the cyclopropanation step. Analytical data of the organic layer before toluene addition: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.55 (q, 2H), 3.2 (s, 3H), 1.5 (t, 3H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 153.8 (s), 64.5 (t), 28.0 (q), 14.25 (q) ppm. GC/MS: 132 (6%, M.sup.+), 87 (10%), 60 (48%), 58 (20%), 56 (14%), 43 (83%), 30 (56%), 29 (100%).

Example 4. Preparation of Δ-Myrcene 1 and Δ2-Myrcene 2

(41) ##STR00016##

(42) N-Methyl-N-nitroso urea 1.35 M in THF (810 ml, 1.1 mol, from example 1) is added at 0° C. to myrcene 94% tech. (100 g, 0.69 mol) and 40% aqueous KOH (300 ml) under strong stirring. After the addition of 20 ml MNU in THF, palladium acetylacetonate (0.45 g, 0.2%) pre-dissolved in dichloromethane (20 ml) is added. The remaining 790 ml MNU in THF are added within 5.5 h at 0° C. After another 1.5 h at 0° C. complete conversion is detected by GC which shows 85% Δ-Myrcene and 11% Δ.sub.2-Myrcene (rpa).

(43) Acetic acid (300 ml) is added within 3 h at 0-5° C., then 2M HCl (500 ml) at 25° C. After phase separation the water phase is extracted with 2×400 ml tert-butyl methyl ether. The combined organic phases are washed with 2×500 ml water, 500 ml 10% NaOH and 500 ml NaCl, are dried over MgSO.sub.4, filtered and concentrated under reduced pressure. To the remaining yellow liquid (109 g) paraffin oil (20 g) and K.sub.2CO.sub.3 (0.5 g) are added. Distillation over a 30 cm steel coil column at 40-50 mbar gives 1 g Myrcene (1% corr) at 75° C., 81.2 g Δ-Myrcene 1 (78% corr) at 93-98° C. and 9.3 g Δ.sub.2-Myrcene 2 (8% corr) at 95-105° C. The fractions are pooled to give 70.5 g Δ-Myrcene of 100% purity and 5.3 g Δ.sub.2-Myrcene of 87% purity.

(44) Analytical data of Δ-Myrcene 1: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (m, 1H), 4.6 (2H), 2.15 (2H), 2.0 (1H), 1.7 (s, 3H), 1.6 (s, 3H), 1.3 (1H), 0.6 (2H), 0.4 (2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 150.9 (s), 135.5 (s), 124.2 (d), 106.0 (t), 35.9 (t), 26.8 (t), 25.6 (q), 17.7 (q), 16.1 (d), 6.95 (t) ppm. GC/MS: 150 (1%, M.sup.+), 135 (6%, [M−15].sup.+), 121 (3%), 107 (88%), 93 (11%), 91 (18%), 79 (62%), 77 (11%), 69 (82%), 67 (26%), 53 (18%), 41 (100%). IR (film): 3081 (m), 3003 (w), 2968 (m), 2915 (m), 2856 (m), 1642 (m), 1440 (m), 1376 (m), 1239 (w), 1211 (w), 1172 (w), 1102 (m), 1047 (m), 1018 (m), 984 (w), 958 (w), 937 (w), 875 (s), 820 (m), 627 (m). Anal. calcd. for C.sub.11H.sub.18: C, 87.93; H, 12.07. Found: C, 87.22; H, 12.00.

(45) Analytical data of Δ.sub.2-Myrcene 2: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (m, 1H), 2.15 (m, 2H), 1.7 (s, 3H), 1.6 (s, 3H), 1.35 (m, 2H), 1.15 (m, 1H), 0.3 (2H), 0.1 (4H), −0.1 (m, 2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 130.9 (s), 125.1 (d), 40.0 (t), 25.7 (q), 25.6 (t), 20.3 (s), 17.5 (q), 14.3 (d), 9.2 (2C, t), 1.9 (2C, t) ppm. GC/MS: 149 (12%, [M−15].sup.+), 136 (11%), 121 (38%), 107 (17%), 95 (13%), 93 (46%), 91 (15%), 81 (17%), 79 (47%), 77 (15%), 69 (100%), 67 (47%), 65 (10%), 55 (30%), 53 (23%), 41 (100%), 39 (26%). IR (film): 3075 (m), 3002 (m), 2968 (m), 2914 (m), 2854 (m), 2730 (w), 2053 (w), 1642 (w), 1450 (m), 1376 (m), 1244 (w), 1107 (m), 1097 (m), 1045 (m), 1011 (s), 984 (w), 952 (m), 884 (m), 858 (w), 819 (m), 742 (w), 665 (w), 631 (w).

Example 5. Cyclopropanation of Myrcene with Mnu in Various Solvents

(46) TABLE-US-00001 equiv % β-E- % monocyclo- % biscyclo- run scale MNU solvent catalyst time Farnesene propane 1 propane 2  .sup. .sup. 1 .sup.a 20 g  1.7 NMP .sup.b Pd(OAc).sub.2 1 h 4% 82% 10%  3 5 g 1.3 DME Pd(acac).sub.2 2 h 7% 85% 7% 4 2 g 1.5 DMIS Pd(acac).sub.2 2 h 7% 80% 6% 5 5 g 1.5 THF Pd(acac).sub.2 2 h 8% 84% 7% Conditions: Addition of MNU in different solvents to Myrcene, 0.2% Pd(II)-catalyst and 40% aqueous KOH at 0-5° C. under stirring until maximum conversion of Myrcene to monocyclopropane 1 is reached. .sup.a 0.5 equiv of internal standard tetradecane. .sup.b gas bubbles in MNU/NMP dropping funnel.

Example 6. Cyclopropanation of Myrcene 1 with of N-Nitroso-Dimethylurethane

(47) Pd(acac).sub.2 (5.6 mg, 0.05%) in toluene (1 ml) is added at 0-5° C. to a stirred mixture of myrcene 85% tech. (5 g, 31 mmol) in toluene (25 ml) and 40% aqueous KOH (15 ml). N-Nitroso-dimethylurethane 1.8 M in toluene (30 ml, 55 mmol, from example 2) is added at 0-5° C. over 1 h. The strong yellow reaction mixture shows after 1 h at 0-5° C. a 87% conversion and after 18 h at room temperature a 96% conversion to Δ-Myrcene (77%) and Δ.sub.2-Myrcene (7%) according to GC. The organic phase is separated and the aqueous phase extracted with toluene (50 ml). Both organic phases are washed with acetic acid (25 ml), water (25 ml), 10% NaOH (25 ml) and water (3×25 ml). The organic phases are combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The remaining yellow oil (4.2 g) is bulb-to-bulb distilled at 100-120° C./20 mbar giving 2.9 g (61%) of a product mixture containing 2% Myrcene, 84% Δ-Myrcene 1 and 8% Δ.sub.2-Myrcene 2. The analytical data of these components are identical with the ones obtained in example 4.

Example 7. Cyclopropanation of myrcene 1 with n-nitroso-3-methylaminoisobutyl methyl Ketone (nmk)

(48) Pd(acac).sub.2 (21 mg, 0.5%) is added at 0-5° C. to a stirred mixture of freshly distilled myrcene (2 g, 15 mmol) and 40% aqueous KOH (5 ml). NMK (4.6 g, 29 mmol), prepared as described in WO 2013110932, is added dropwise at 0-5° C. within 0.5 h. After another hour at 0-5° C. the brown suspension is stirred for another 2 h at 25° C. (87% conversion according to GC). After 21 h the mixture is quenched with acetic acid (10 ml) and the biphasic mixture is extracted with tert-butyl methyl ether (2×50 ml). The organic layers are washed with water (25 ml), 10% NaOH (25 ml) and water (25 ml). Both organic phases are combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The remaining yellow oil (4.1 g) is bulb-to-bulb distilled at 50-150° C./10 mbar giving 1 g mesityl oxide (35%), 0.26 g myrcene (14%), 1.4 g Δ-Myrcene 1 (69%) and 0.07 g Δ.sub.2-Myrcene 2 (3%). The analytical data of the main components are identical with the ones obtained in example 4.

Example 8. Preparation of Δ-Ocimene 3 from Ocimene

(49) ##STR00017##

(50) Prepared as described in example 5 from MNU 1.35 M in THF (38 ml, 51 mmol), E/Z-Ocimene (3 g, 22 mmol), 40% aqueous KOH (10 ml) and palladium acetate (15 mg, 0.3%) pre-dissolved in THF (1.5 ml). After 1 h at 0° C. and 4 h at 25° C. GC shows 94% Δ-Ocimene and 6% Ocimene (rpa). Work-up gives 3.1 g of crude Δ-Ocimene 3 (E/Z 3:1) as crude yellowish oil.

(51) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.2 and 5.1 (2H), 2.85 and 2.7 (1H, CH.sub.2), 1.7 (1H), 1.7 (s, 3H), 1.65 (s, 3H), 1.55 and 1.4 (2 s, E/Z, 3H), 0.45 (2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz, E-isomer and selected signals of the Z-isomer): 135.4 (s), 131.3 (s), 123.3 (d), 121.9 (d), 27.0 (t), 25.7 (q), 25.675 (q), 18.7 (d), 17.7 (q), 13.8 (q), 4.2 (t) ppm. 26.6 (t, Z), 18.9 (q, Z), 4.0 (t, Z). GC/MS (E/Z overlap): 150 (14%, M.sup.+), 135 (43%, [M-15].sup.+), 121 (17%), 109 (16%), 107 (100%), 105 (39%), 94 (17%), 93 (57%), 91 (67%), 82 (36%), 81 (40%), 79 (75%), 77 (39%), 69 (22%), 67 (56%), 65 (15%), 55 (24%), 53 (27%), 41 (65%), 39 (43%).

Example 9. Preparation of e-ΔFamesene 4 and e-Δ2-Famesene 5 using MNU in THF

(52) ##STR00018##

(53) N-Methyl-N-nitroso urea 1.35 M in THF (136 ml, 184 mmol) is added dropwise at 0° C. to a rapidly stirred mixture of β-E-Famesene (CAS 18794-84-8) (25 g, 122 mmol) and aqueous KOH (50 ml, 40%) at 0-5° C. After the addition of 4 ml of the MNU solution, Pd(acac).sub.2 (7.4 mg, 0.024 mmol, 0.02%) pre-dissolved in 0.5 ml dichloromethane is added. The remaining MNU solution is added over 4 h at 0-5° C. A GC at this stage showed 28% unconverted E-β-Famesene, 65% monocyclopropane 4 and 3% biscyclopropane 5. After 16 h at 25° C. acetic acid (100 ml) is added at 0-5° C., then tert-butyl methyl ether (250 ml). After phase separation the organic phase is washed with 2M HCl (250 ml) and the aqueous phase extracted with tert-butyl methyl ether (250 ml). The combined organic layers are washed with water (2×100 ml), aqueous 10% NaOH (2×100 ml) and water (2×100 ml), dried over MgSO4, filtered and concentrated to give 26.9 g of a slightly yellow liquid which contains 9% E-β-Famesene, 82% monocyclopropane 4 and 6% biscyclopropane 5.

Example 10. Distillative Purification of E-Δ-Famesene 4 and E-Δ2-Famesene 5 Prepared from MNU in NMP

(54) Under similar conditions as described in example 9, E-β-Famesene (193.4 g, 0.945 mol) is cyclopropanated in the presence of Pd(acac).sub.2 (0.58 g, 1.9 mmol, 0.2%) pre-dissolved in dichloromethane (40 ml) and 40% KOH (400 ml) with MNU (1.3 mol) in 800 ml NMP (under slight but constant gas evolution in the MNU/NMP dropping funnel). Work-up gives a slightly yellow liquid (202 g) which contains 3% E-β-Famesene, 75% monocyclopropane 4 and 12% biscyclopropane 5. Addition of 1 g K.sub.2CO.sub.3 (1 g) and distillation over a 30 cm steel coil column at 40-60 mbar gives 6.3 g E-β-Farnesene (3% corr) at 125-135° C., 147 g monocyclopropane 4 (68% corr) at 135-145° C., 20.3 g biscyclopropane 5 (10% corr) at 145-155° C. and 18 g of residue. The fractions are pooled to give 92 g monocyclopropane 4 of 100% purity and 10 g biscyclopropane 5 of 93% purity as colorless liquids.

(55) Analytical Data of E-Δ-Farnesene 4:

(56) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.1 (2 m, 2H), 4.6 (2H), 2.2 (2H), 2.1 (4H), 2.0 (2H), 1.7 (s, 3H), 1.6 (2 s, 6H), 1.3 (1H), 0.6 (2H), 0.45 (2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 150.9 (s), 135.1 (s), 131.2 (s), 124.4 (d), 124.1 (d), 106.0 (t), 39.7 (t), 35.9 (t), 26.7 (t), 25.7 (q), 17.7 (q), 16.0 (d), 6.0 (t) ppm. GC/MS: 218 (2%, M.sup.+), 203 (5%, [M−15].sup.+), 175 (11%), 147 (31%), 134 (15%), 133 (20%), 121 (12%), 107 (55%), 95 (16%), 93 (30%), 91 (20%), 82 (11%), 81 (33%), 79 (42%), 69 (100%), 67 (22%), 55 (20%), 53 (21%), 41 (75%). IR (film): 3081 (w), 2967 (m), 2915 (m), 2854 (m), 1642 (m), 1439 (m), 1377 (m), 1107 (w), 1047 (w), 1018 (m), 875 (s), 819 (m), 629 (w). Anal. calcd. for C.sub.16H.sub.26: C, 88.00; H, 12.00. Found: C, 87.80; H, 12.01.

(57) Analytical Data of E-Δ.sub.2-Famesene 5:

(58) .sup.1H-NMR (CDCl.sub.3, 400 MHz): 5.15 (2 m, 2H), 2.25 (m, 2H), 2.05 (m, 2H), 2.0 (m, 2H), 1.7 (s, 3H), 1.65 (2 s, 6H), 1.4 (m, 2H), 1.05 (m, 1H), 0.3 (m, 2H), 0.15 (4H), −0.05 (m, 2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 134.5 (s), 131.2 (s), 124.9 (d), 124.4 (d), 40.0 (t), 39.7 (t), 26.7 (t), 25.7 (q), 25.5 (t), 20.3 (s), 17.6 (q), 15.9 (q), 14.3 (d), 9.2 (2C, t), 1.9 (2C, t) ppm. GC/MS: 232 (0.2%, M.sup.+), 217 (3%, [M−15].sup.+), 204 (4%), 189 (10%), 161 (8%), 147 (12%), 121 (22%), 107 (20%), 95 (27%), 93 (31%), 91 (13%), 81 (42%), 79 (30%), 69 (100%), 67 (33%), 55 (24%), 53 (16%), 41 (67%). IR (film): 3075 (w), 3001 (w), 2967 (m), 2913 (m), 2849 (m), 1669 (w), 1448 (m), 1377 (m), 1107 (m), 1045 (m), 1011 (s), 984 (w), 952 (w), 884 (w), 819 (m), 740 (w), 664 (w). Anal. calcd. for C.sub.17H.sub.28: C, 87.86; H, 12.14. Found: C, 87.59; H, 12.09.

Example 11. Preparation of a E-α-Δ-Famesene 6 mixture from E-α,β-Famesene

(59) ##STR00019##

(60) Prepared as described in example 9 from N-methyl-N-nitroso urea 1.35 M in THF (10 ml, 13.5 mmol), E-α,β-Famesene (1 g, 5 mmol, purity Zα/β/Eα 17:50:26, GC, rpa), aqueous KOH (2.5 ml, 40%) and Pd(OAc).sub.2 (3.3 mg, 0.015 mmol, 0.3%) pre-dissolved in 0.75 ml THF. Work-up and bulb-to-bulb distillation gives 0.76 g of a colorless liquid which contains E-β-Famesene 4 (46%), E-α-Δ-Famesene 6 (39%) and 10% unconverted famesenes. GC/MS: 218 (0.2%, M.sup.+), 203 (3%, [M−15].sup.+), 175 (4%), 149 (8%), 147 (9%), 133 (13%), 123 (50%), 121 (22%), 119 (15%), 107 (70%), 105 (30%), 95 (35%), 93 (90%), 91 (57%), 81 (80%), 79 (55%), 77 (33%), 69 (95%), 67 (27%), 55 (36%), 53 (21%), 41 (75%).

Example 12. Ethyl 8-Cyclopropyloctanoate 7

(61) ##STR00020##

(62) Prepared as described in example 4 from N-methyl-N-nitroso urea 1.35 M in THF (31 ml, 42 mmol), ethyl decenoate (5 g, 25 mmol), 40% aqueous KOH (10 ml) and palladium acetylacetonate (15 mg, 0.2%) pre-dissolved in dichloromethane (1 ml). Work-up gives 4.5 g (88%) of crude ethyl 8-cyclopropyloctanoate 7 as slightly yellow liquid.

(63) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.15 (q, 2H), 2.3 (t, 2H), 1.6 (m, 2H), 1.3-1.5 (8H), 1.3 (t, 3H), 1.2 (dt, 2H), 0.65 (m, 1H), 0.4 (m, 2H), 0.0 (m, 2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 134.5 (s), 131.2 (s), 124.9 (d), 124.4 (d), 40.0 (t), 39.7 (t), 26.7 (t), 25.7 (q), 25.5 (t), 20.3 (s), 17.6 (q), 15.9 (q), 14.3 (d), 9.2 (2C, t), 1.9 (2C, t) ppm. GC/MS: 212 (0.2%, M.sup.+), 197 (0.2%, [M−15].sup.+), 169 (1%), 167 (2%), 166 (3%), 149 (3%), 138 (8%), 124 (15%), 123 (8%), 110 (7%), 101 (37%), 96 (30%), 73 (20%), 69 (30%), 67 (20%), 61 (15%), 60 (17%), 55 (100%), 41 (50%). IR (film): 3076 (w), 2997 (w), 2923 (m), 2857 (m), 1735 (s), 1463 (m), 1427 (w), 1372 (m), 1348 (w), 1301 (w), 1247 (w), 1175 (m) 1115 (m), 1097 (m), 1035 (m), 1014 (m), 946 (w), 856 (w), 820 (w), 723 (w), 629 (w).

Example 13. 3-cyclopropyl-1-(spiro[4.5]Dec-7-en-7-yl)propan-1-one and 3-cyclopropyl-1-(spiro[4.5]Dec-6-en-7-yl)propan-1-one 8

(64) ##STR00021##

(65) Prepared as described in example 4 from N-methyl-N-nitroso urea 1.35 M in THF (18 ml, 24 mmol), Spirogalbanone (3 g, 25 mmol, EP 913383, priority to Givaudan 29.10.1997), 40% aqueous KOH (10 ml) and palladium acetylacetonate (8.4 mg, 0.2%) pre-dissolved in dichloromethane (0.5 ml). Work-up gives 3.2 g (quant) of crude cyclopropane 8 as a slightly yellow liquid. Purity: 98%, α/β-isomer ratio 58:42 (GC).

(66) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 6.9 and 6.6 (1H, α- and β-isomer), 2.75 (t, 2H), 2.25, 2.15 2.1 and 1.7 (4H), 1.3-1.7 (12H), 0.65 (1H), 0.35 (m, 2H), 0.0 (2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 201.9 and 201.7 (2 s, CO), 148.3 and 139.2 (2 d), 138.8 and 136.8 (2 s), 44.2 and 40.6 (2 s), 40.1, 38.13, 37.2, 37.1, 35.4, 34.4, 32.85, 30.2, 30.1, 24.8, 24.65, 24.4, 23.5, 20.1 (7×2 t), 10.7 (2 d), 4.55 and 4.5 (2 t) ppm. GC/MS (f-isomer, t.sub.R=9.84 min): 232 (24%, M.sup.+), 217 (2%, [M−15].sup.+), 204 (10%), 203 (13%), 189 (11%), 177 (15%), 176 (54%), 175 (28%), 149 (13%), 148 (21%), 147 (27%), 136 (10%), 135 (56%), 134 (24%), 133 (34%), 131 (12%), 121 (27%), 120 (15%), 119 (21%), 117 (14%), 107 (43%), 105 (39%), 93 (100%), 91 (98%), 81 (38%), 79 (78%), 77 (63%), 69 (18%), 67 (63%), 65 (24%), 55 (71%), 53 (30%), 43 (18%), 41 (77%), 39 (29%). GC/MS (α-isomer, t.sub.R=9.96 min): 232 (38%, M.sup.+), 217 (3%, [M−15].sup.+), 204 (16%), 203 (25%), 178 (8%), 175 (6%), 164 (12%), 163 (100%), 161 (9%), 147 (10%), 135 (27%), 133 (19%), 121 (22%), 119 (14%), 117 (13%), 109 (18%), 107 (58%), 105 (26%), 95 (37%), 93 (88%), 91 (73%), 81 (57%), 79 (79%), 77 (47%), 69 (27%), 67 (80%), 65 (21%), 57 (10%), 55 (78%), 53 (62%), 43 (17%), 41 (80%), 39 (30%), 29 (16%). IR (film): 3075 (w), 2998 (w), 2929 (m), 1664 (s), 1636 (w), 1446 (w), 1379 (w), 1340 (w), 1271 (w), 1212 (w), 1189 (m), 1103 (w), 1043 (w), 1013 (m), 942 (w), 819 (w), 753 (w), 697 (w).

Example 14. 1-cyclopropyl-3-methylbenzene 9

(67) ##STR00022##

(68) Prepared as described in example 4 from N-methyl-N-nitroso urea 1.35 M in THF (19 ml, 25.6 mmol), 1-methyl-3-vinylbenzene (2 g, 17 mmol), 40% aqueous KOH (10 ml) and palladium acetylacetonate (10.3 mg, 0.2%) pre-dissolved in dichloromethane (0.5 ml). Work-up gives 2.2 g (quant) of crude 1-cyclopropyl-3-methylbenzene 9 as a slightly yellow liquid.

(69) Analytical data: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 7.15 (dd, 1H), 6.95 (d, 1H), 6.85 (2H), 2.3 (s, 3H), 1.85 (m, 1H), 0.9 (m, 2H), 0.65 (m, 2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 143.9 (s), 137.8 (s), 128.2 (d), 126.5 (d), 126.2 (d), 122.7 (d), 21.4 (q), 15.3 (d), 9.1 (2C, t) ppm. GC/MS: 132 (40%, M.sup.+), 131 (17%), 118 (10%), 117 (100%), 116 (15%), 115 (44%), 105 (8%), 103 (6%), 91 (28%), 77 (12%), 65 (12%), 63 (10%), 51 (11%), 39 (16%). IR (film): 3081 (w), 3008 (m), 2919 (w), 1607 (m), 1589 (w), 1491 (m), 1462 (m), 1430 (w), 1378 (w), 1242 (w), 1170 (w), 1090 (w), 1044 (m), 1018 (m), 924 (m), 865 (w), 812 (m), 774 (s), 696 (s).

Example 15. (E)-2-methyl-6-methylenenona-2,7-diene 10 (e-homomyrcene)

(70) ##STR00023##

(71) Methacrylonitrile (1.3 g, 19 mmol) and Wilkinson's catalyst RhCl(PPh.sub.3).sub.3 (0.3 g, 0.3 mmol) are added to Δ-myrcene 1 (1 g, 6.7 mmol) in toluene (15 ml) under nitrogen and stirring. The mixture is heated 22 h at reflux, cooled to 25° C. and filtered over silica gel. After addition of water (50 ml) and phase separation the aqueous phase is extracted with toluene. The combined organic layers are dried over NaSO.sub.4, filtered and concentrated under reduced pressure to give 1.25 g of a clear liquid. GCMS reveals 63% E-Homomyrcene 10, 26% isomers (M 150) and 11% Diels-Alder adducts 11. Bulb-to-bulb distillation at 40° C./0.1 mbar gives 0.22 g (22%) of E-homomyrcene 10 and 0.55 g of a residue. The analytical data of E-Homomyrcene 10 and of the Diels-Alder adducts 11 were identical with the ones described in the literature (Tetrahedron 65, 10495, 2009 and references therein).

Example 15. 1-((1SR,2RS)-1,2-dimethyl-4-(4-methylpent-3-EN-1-yl)cyclohex-3-en-1-yl)ethanone 12 (pseudo-georgywood)

(72) ##STR00024##

(73) 3-Methylbutan-2-one (3.7 g, 13 mmol) and Wilkinson's catalyst RhCl(PPh.sub.3).sub.3 (0.6 g, 0.7 mmol) are added to Δ-myrcene 1 (2 g, 13.3 mmol) in toluene (30 ml) under nitrogen and stirring. The mixture is heated 41 h at reflux, cooled to 25° C. and filtered over silica gel. After addition of water (50 ml) and phase separation the aqueous phase is extracted with toluene. The combined organic layers are dried over NaSO.sub.4, filtered and concentrated under reduced pressure to give 2.7 g of a clear liquid. Bulb-to-bulb distillation at 100-160° C./0.05 mbar gives 1.31 g (42%) of a 3:1 isomer mixture containing Georgywood 12 as main product, whose analytical data were identical with the ones described in the literature, see for example Tetrahedron: Asymmetry 15, 3967 (2004).

Example 16. Preparation of Δ-Myrcenol 13

(74) ##STR00025##

(75) Prepared as described in example 4 from N-methyl-N-nitroso urea 1.35 M in THF (72 ml, 97 mmol), myrcenol (10 g, 65 mmol, Chemistry Letters 15, 157-160, 1986 and references therein), aqueous KOH (32 ml, 40%) and Pd(acac).sub.2 (20 mg, 0.065 mmol, 0.2%) pre-dissolved in 2.6 ml THF. After 1 h at 0° C. quantitative conversion is detected by GC. Work-up gives 10.7 g of crude 13 as a yellowish oil which is purified by flash chromatography over silica gel with eluent hexane/tert-butyl methyl ether 1:1. Evaporation of the solvents gives 9.45 g (87%) of 13 as a colorless oil. 4.2 g of this material were further purified by bulb-to-bulb distillation at 60° C./0.03 mbar and gave 4 g of olfactorily pure Δ-Myrcenol 13. Olfactory profile: floral, rosy, slightly aldehydic. Purity: 96%. According to NMR and GC this material contains 4% of Δ.sub.2-Myrcenol 14.

(76) Analytical Data of 13: .sup.1H-NMR (CDCl.sub.3, 400 MHz): 4.6 (m, 2H), 2.05 (m, 2H), 1.6 (m, 2H), 1.5 (m, 2H), 1.3 (m, 2H), 1.2 (6H, s), 0.65 (m, 2H), 0.43 (m, 2H) ppm. .sup.13C-NMR (CDCl.sub.3, 400 MHz): 150.9 (s), 106.05 (t), 71.0 (s), 43.6 (t), 36.5 (t), 29.25 (q), 22.85 (t), 15.93 (d), 6.1 (t). GC/MS: 150 (8%, [M−18].sup.+), 135 (15%, [M−18-15].sup.+), 122 (2%), 121 (4%), 109 (11%), 107 (24%), 95 (25%), 94 (41%), 93 (19%), 91 (8%), 82 (18%), 79 (100%), 77 (10%), 69 (14%), 67 (41%), 59 (60%), 43 (28%), 41 (27%).

(77) GCMS of Δ.sub.2-Myrcenol 14: 149 (16%, [M−18-15].sup.+), 135 (10%), 121 (31%), 109 (22%), 108 (30%), 107 (24%), 95 (20%), 94 (15%), 93 (88%), 91 (18%), 81 (42%), 80 (58%), 79 (100%), 77 (10%), 69 (24%), 67 (44%), 59 (67%), 43 (34%), 41 (49%).

Example 17. Preparation of Toscanol 16

(78) ##STR00026##

(79) Pd(acac).sub.2 (0.15 g, 0.5 mmol, 0.05 mol %) is added at 0-5° C. to a stirred (300 rpm) mixture of estragol (148 g, 1 mol) in toluene (1 l) and 40% aqueous KOH (0.5 l). Nitroso-EMU 1.63 M in toluene (1.25 l, 2 mol, prepared as described in example 3) is added at 0-5° C. over 6 h. The bright yellow reaction mixture is stirred for another hour at 0-5° C., then 17 h at room temperature. GC-analysis shows a quantitative conversion to Toscanol. The organic phase is separated and the aqueous phase extracted with toluene (1 l). The organic phases are washed with water (1 l), 10% acetic acid (1 l), water (1 l), 10% NaOH (1 l) and water (2×1 l). Both organic phases are combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The remaining yellow oil (173.7 g) is short-path-distilled at 70-150° C./0.07 mbar giving 159 g (98% corr) of Toscanol 16 with a purity of 84-100% (over all fractions). The NMR data are identical with the ones reported in the literature for this compound, e.g. in S.-K. Tiana et al., Adv. Synth. & Cat. 353, 1980-1984 (2011).

(80) GCMS of Toscanol 16: 162 (22%, M.sup.+), 147 (8%), 134 (23%), 121 (100%), 119 (11%), 91 (18%), 78 (8%), 77 (10%), 65 (7%).