Process for the cyclopropanation of olefins using N-methyl-N-nitroso compounds

Abstract

A process of converting a carbon-carbon double bond on a substrate into a cyclopropane ring, which method comprises the step of treating the substrate with a N-alkyl-N-nitroso compound, a transition metal catalyst and an aqueous base, wherein the N-alkyl-N-nitroso compound is formed by reacting an alkyl amine with an alkali metal nitrite in the presence of a mono-basic or di-basic acid, or a mixture thereof, and wherein the N-alkyl-N-nitroso compound is not distilled before it is mixed with the substrate, catalyst and base.

Claims

1. A process of converting a carbon-carbon double bond on a substrate into a cyclopropane ring, the process comprising treating the substrate with (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone, a transition metal catalyst and an aqueous base, and thereby forming the cyclopropane ring, wherein the (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone is formed by reacting (N-methyl)-4-amino-4-methyl-2-pentanone with an alkali metal nitrite in the presence of formic acid and wherein the (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone N is not distilled before it is mixed with the substrate, catalyst and base.

2. The process according to claim 1, wherein the substrate is a compound according to the general formulae ##STR00010## wherein R.sup.1 and R.sup.2, independently, represent H, alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted; and R.sup.3 represents an alkyl, alkylidene, or aryl, which may be branched or unbranched and substituted or unsubstituted.

3. The process according to claim 2, wherein the substrate is an isoprenoid.

4. The process according to claim 1, wherein a compound of the formula ##STR00011## in which n=0, 1, 2 or 3 is formed.

5. The process according to claim 1, wherein a compound of the formula, ##STR00012## is formed.

6. The process according to claim 3, wherein the isoprenoid is alpha farnesene or beta farnesene.

7. The method according to claim 1, wherein the catalyst is a palladium catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Although the preparation of a N-alkyl-N-nitroso compound, and its subsequent use, without purification or isolation, in the conversion of a carbon-carbon double bond to a cyclopropane ring is known in the art, there is a clear prejudice in the art to do this if the acid employed in the preparation of the N-alkyl-N-nitroso compound is an acid which can be methylated, such as a mono basic carboxylic acid and more particularly acetic acid.

(2) The applicant was surprised to find, therefore, that the cyclopropanation reaction proceeded to produce reliably high yields of cyclopropanated product on an industrial scale. Furthermore, the use of these acids is relatively inexpensive compared with the use of tribasic acids such as H.sub.3PO.sub.4. Further still, the reaction is advantageous from a sustainability point of view due to the generation and degradation of carboxylic acids in the biosphere.

(3) In exercising the present invention the preferred mono- or di-basic acids are sulphuric acid, or mono- or di-basic carboxylic acids, such as C.sub.1-C.sub.20 carboxylic acids, which may be linear, branched or cyclic, and which may be saturated, or contain saturation, and may or may not be substituted with functional groups. Of course, for reasons related to economy, it is preferred to use low-cost carboxylic acids with low molecular weight such as formic acid, acetic acid or propionic acid, most preferably acetic acid. C.sub.1-C.sub.20 mono-, bis, tri and polyacids are also an option as well as mixtures of carboxylic acids or mixtures of carboxylic acids and inorganic acids such as dibasic sulfuric acid or mixtures of mono-and dibasic inorganic acids.

(4) In a particular embodiment of the invention mixtures of a carboxylic acid, e.g. acetic acid, with stronger (i.e. lower pKa) organic and inorganic acids can be employed in the formation of N-alkyl-N-nitroso compounds. Typical solutions might include 5 to 50% solutions of said stronger acid in said carboxylic acid, and more particularly 5 to 20% is preferred, as higher levels of the stronger acid in the carboxylic acid can be detrimental to phase separation, yield and purity of N-alkyl-N-nitroso compounds, as well as produce high levels of nitrous gases, which as stated above, can poison the catalyst in the subsequent cyclopropanation step. An exception to this appears to be use of H.sub.2SO.sub.4 as the acidification reagent in the nitrosation reaction. In contrast to other strong acids, such as HCl, HNO.sub.3 and methyl sulphonic acid for example, H.sub.2SO.sub.4 can be used without a carboxylic acid, although it can also be employed 0.1-1.5 eq, more preferably with 0.5-1 eq., in combination with acetic acid.

(5) These findings were all the more surprising given that from the literature, one would predict, substantially reduced yields both of N-alkyl-N-nitroso compound and the final cyclopropanated substrate if mono- or di-basic acids, and in particular acetic acid is employed instead of the favoured tribasic acids, and in particular H.sub.3PO.sub.4. In fact, applicant found that the yields of cyclopropanated product were comparable irrespective of whether one employs acetic acid or other mono- and dibasic acids in the acidification step or H.sub.3PO.sub.4. As stated above, although the use of H.sub.3PO.sub.4 may carry with it certain advantages, the applicant believes that the generation of nitrous gases may play a negative role, and it was observed that lower levels of nitrous gases were formed when using acetic acid compared with the use of H.sub.3PO.sub.4. In the case of the acidification with acetic acid less nitrous gases were generated, based on the observation that the less brownish coloration of the N-alkyl-N-nitroso compound layer and less brown vapors in the nitrogen waste stream, compared with a process wherein acidification was carried out using H.sub.3PO.sub.4.

(6) Any of the N-alkyl-N-nitroso compounds disclosed in WO 2015059290 may be employed in the present invention. The N-alkyl-N-nitroso compounds may be made in accordance with prior art methods, in which an alkyl amine, alkyl amide, alkyl urethane or alkyl urea HNRR′ is reacted with an acid and an alkali metal nitrite, such as NaNO.sub.2. The alkyl amine may be commercially available material, or it may be formed by reacting an aliphatic amine H.sub.2NR with a suitable starting material reactive with the aliphatic amine, such as an α,β-unsaturated ketone. Preparative methods are set out in WO 2015059290. A particularly preferred N-alkyl-N-nitroso compound is N-nitroso-β-methylaminoisobutyl methyl ketone (NMK). This particular material may be prepared when methylamine is reacted with the α,β-unsaturated ketone—mesityl oxide—to form a methylamine mesityl oxide adduct (corresponding to HNRR′, above). The adduct can then be further reacted with NaNO.sub.2 and an acid to provide NMK. Methods of forming NMK are described in WO2013110932, which is hereby incorporated by reference.

(7) The reaction to produce the N-alkyl-N-nitroso compounds may be carried out in a biphasic mixture. Before, during, or after the reaction is completed, one can add an organic solvent, which is a solvent for the alkyl-N-nitroso compound, and the organic layer, containing the crude N-alkyl-N-nitroso compound can be separated and used in the subsequent cyclopropanation reaction without further purification, for example by distillation. Optionally, however, the organic layer containing the N-alkyl-N-nitroso compound may be washed with an aqueous washing procedure known in the art, for example washing with a salt solution, provided no further acidification takes place or any basification does not increase the pH above a level of moderate basicity, e.g. 7 to 8.5, to prevent liberation of diazomethane. Such a washing procedure ideally removes nitrous gases, traces of acid, e.g. acetic acid, and other impurities. In a further optional procedure, one may subject the organic layer to a degassing procedure using inert gas (e.g. nitrogen) to remove any traces of nitrous gases.

(8) The cyclopropanation reaction is carried out in a biphasic mixture, in which the organic phase is a solvent for the N-alkyl-N-nitroso compound. Suitable solvents include ethers and toluene, and more particularly tetrahydrofuran, dimethoxyethane, dioxane and dimethylisosorbide. In a first step, the organic phase containing the N-alkyl-N-nitroso compound is added to a mixture containing the substrate to be converted, aqueous base and catalyst. The aqueous base decomposes the N-alkyl-N-nitroso compound to form the diazoalkane, which in the presence of the catalyst converts the carbon-carbon double bond into a cyclopropyl group. Upon completion of the cyclopropanation reaction, the mixture is phase separated and the organic phase, containing the target cyclopropanated compound is obtained.

(9) The methods herein described may be carried out under flow conditions in a flow reactor. Methods and apparatus for carrying out flow chemistry are well known in the art and do not require further elaboration here.

(10) Details of the cyclopropanation process, as well as the reagents, solvents and reaction conditions and work-up conditions employed are set forth in WO 2015059290, which is hereby incorporated by reference for this purpose.

(11) Catalysts useful in the present invention are transition metal catalysts, more particularly palladium catalysts, still more particularly the palladium catalysts, Pd(acac).sub.2, Pd(OAc).sub.2 or PdCl.sub.2.

(12) Any double bond-containing substrate may be converted in accordance with the method of the present invention, to form all manner of useful and desirable cyclopropanated target compounds. Suitable double bond-containing substrates and the target cyclopropanated compounds, especially useful in fragrance, cosmetic and flavour applications are set forth and described in WO 2015059290, which is hereby incorporated by reference for this purpose.

(13) Particular substrates include terminal (i.e. mono-substituted) alkenes. More particularly, compounds according to the general formulae

(14) ##STR00002##

(15) wherein R.sup.1 and R.sup.2 may, independently, represent H, alkyl, alkylidene, or aryl, which 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.

(16) Still more particularly, the substrate may be an isoprenoid, such as alpha or beta farnesene.

(17) Target compounds that may be formed by a method according to the present invention include compounds of the formula

(18) ##STR00003##

(19) in which n=0, 1, 2 or 3.

(20) In a particular embodiment the target compound is

(21) ##STR00004##

(22) In another particular embodiment the target compound is

(23) ##STR00005##

(24) Target compounds according to the present invention are useful precursors to compounds that are useful ingredients in perfumery.

(25) There now follows a series of examples serving to further illustrate the invention.

EXAMPLES

(26) .sup.1H-NMR: The reported NMR spectra were measured in CDCl.sub.3 at 400 MHz if not stated otherwise. The chemical shifts are reported in ppm downfield from TMS. The quantification of Liquizald was performed using an internal standard (anisaldehyde) with known purity in d.sub.6-DMSO. Additionally, to guarantee full relaxation of the signals, the relaxation time d1 was set to 56 s.

Example 1

Preparation of (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) by Nitrosation in the Presence of Carboxylic Acids

(27) ##STR00006##

(28) Mesityl oxide (10 g, 0.1 mol) is added dropwise over 15 min to methylamine (40% in water, 8.3 g, 0.11 mol) at 5-15° C. under external cooling and stirring. The resulting orange solution is stirred for one hour at room temperature and cooled to 10° C. where formic acid (98%, 8.4 g, 0.18 mol) is added dropwise over 15 min at 10-20° C. Then a 30% solution of sodium nitrite (8.85 g, 0.125 mol) in water (21 g) is added dropwise over 10 min at 10-15° C. The biphasic mixture is left under stirring and at room temperature overnight (16 h). After phase separation (1 h) 15.25 g (68% based on mesityl oxide) of an organic layer is obtained consisting mainly of (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) with a purity of 72% according to .sup.1H-NMR with internal standard.

(29) The following table shows results from the variation of this procedure using different carboxylic acids:

(30) TABLE-US-00001 mol-eq acid/ formation of run acid acid conc mesityl oxide NOx gases.sup.b purity.sup.a yield.sup.c comparison phosphoric 75% in H.sub.2O 0.9 insignificant 77% 73% 1 formic pure 1.75 weak 72% 68% 2 acetic pure 1.75 insignificant 69% 66% 3 acetic pure 1.6 insignificant 70% 62% 4 α-hydroxy- 75% in H.sub.2O 1.75 middle 59% 38% isobutyric 5 lactic pure 1.75 insignificant 71% 62% 6 glyolic pure 1.75 insignificant 74% 61% Conditions: Addition of carboxylic acids to the methyl amine/mesityl adduct followed by NaNO.sub.2 addition and phase separation as described above. .sup.adetermination of the purity by .sup.1H-NMR with internal standard anisaldehyde. .sup.bbrown coloration of reaction mixture, brown vapors over reaction surface and in the exhaust tube. .sup.cbased on quantity of organic phase and purity.

Example 2

Preparation of (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) by Nitrosation in the Presence of Acetic Acid and Stronger Acids

(31) ##STR00007##

(32) Mesityl oxide (10 g, 0.1 mol) is added dropwise over 15 min to methylamine (40% in water, 8.5 g, 0.11 mol) at 5-15° C. under external cooling and stirring. The resulting orange solution is stirred for one hour at room temperature and cooled to 10° C. where acetic acid (100%, 10 g, 0.1 mol) is added dropwise over 15 min at 10-20° C. Then a 30% solution of sodium nitrite (8.85 g, 0.125 mol) in water (21 g) is added dropwise over 10 min at 10-15° C. The biphasic mixture is left under stirring and at room temperature overnight (16 h). After phase separation (1 h) 14.25 g (62% based on mesityl oxide) of an organic layer is obtained consisting mainly of (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) with a purity of 70% according to .sup.1H-NMR with internal standard.

(33) The following table shows results from the variation of this procedure using acetic acid in combination with different stronger acids

(34) TABLE-US-00002 HOAc and mol-eq mol-eq formation of run stronger acid HOAc .sup.c stronger acid .sup.c NOx gases.sup.b purity.sup.a yield .sup.e comparison ./. 1.6 ./. insignificant 70% 62% 1 65% HNO.sub.3 1.8 0.1 insignificant 69% 64% 2 65% HNO.sub.3 1.3 0.3 insignificant 76% 66% 3 65% HNO.sub.3 0.5 0.8 intermediate much less organic phase 4 65% HNO.sub.3 ./. 1.75 significant much less organic phase 5 32% HCl 1.6 0.1 insignificant 72% 68% 6 32% HCl 1.3 0.3 insignificant 74% 68% 7 32% HCl 0.5 0.8 intermediate much less organic phase 8 32% HCl ./. 1 significant 63% 32% 32% HCl ./. 1 + 1 .sup.d intermediate 61% 39% 9 98% H.sub.2SO.sub.4 1.6 0.1 insignificant 69% 64% 10  98% H.sub.2SO.sub.4 1.3 0.3 intermediate 65% 71% 11 .sup.c 80% H.sub.2SO.sub.4 ./. 0.65 insignificant 63% 58% 12 .sup.d 80% H.sub.2SO.sub.4 ./. 1 intermediate 69% 50% 13  80% H.sub.2SO.sub.4 ./. 2 significant no phase separation 14  CF.sub.3SO.sub.3H 1   0.1 insignificant 66% 65% 15  75% MeSO.sub.3H 1   0.1 insignificant 71% 68% 16  75% MeSO.sub.3H ./. 1.75 significant much less organic phase Conditions: Addition of pure acetic acid (and stronger acid) to the methyl amine/mesityl adduct followed by NaNO.sub.2 addition and phase separation as described above. .sup.aDetermination of the purity by .sup.1H-NMR with internal standard anisaldehyde. .sup.bbrown coloration of reaction mixture, brown vapors over reaction surface and in the exhaust tube. .sup.c stronger acid dissolved in acetic acid. .sup.d method described in JCS 363, 1933. .sup.e based on quantity of organic phase and purity.

Example 3

(35) Diazomethane cyclopropanation with (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) made through nitrosation in the presence of HOAc

(36) ##STR00008##

(37) Mesityl oxide (68.8 g, 0.7 mol) is added dropwise over 1 h to methylamine (40% in water, 58.1 g, 0.75 mol) at 5-15° C. under external cooling and stirring. The resulting orange solution is stirred for one hour at room temperature. Water (140 ml) and toluene (70 ml) are added, followed by dropwise addition of acetic acid (100%, 115 g, 1.9 mol) over 1 h at 10-20° C. Then a 30% solution of sodium nitrite (49.8 g, 0.7 mol) in water (116 g) is added dropwise over 60 min at 20-25° C. The biphasic mixture is left under stirring and at room temperature overnight (16 h). After phase separation (1 h) 155.23 g of an organic layer is obtained consisting mainly of (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone (NMK) which is flushed with nitrogen through a sintered tube for 1 h which turns the opaque organic phase into a clear solution.

(38) Pd(acac).sub.2 (0.1 g, 0.33 mmol) are added to a solution of E-β-Farnesene 98% (51.5 g, 0.25 mol) in toluene (150 ml), followed by KOH (49.9 g, 0.76 mol) in water (208.5 g) under strong stirring. The (N-methyl-N-nitroso)-4-amino-4-methyl-2-pentanone layer (155.2 g) is added over 2 h at 25° C. GC after 0.5 h shows E-β-Farnesene (4%), Δ-E-β-Farnesene (88%), and Δ.sub.2-E-β-Farnesene (8%). After 17 h (same GC profile) the phases are separated. The water phase is washed with toluene (100 ml), the organic phase is washed with water (250 ml), acetic acid (250 g), water (250 ml), 10% NaOH (250 ml) and water (2×250 ml). The combined organic layers are dried over MgSO4, filtered and the solvent is removed under reduced pressure giving 63.6 g of crude Δ-E-β-Farnesene which is purified by flash distillation giving 0.73 g of E-β-Farnesene (0.5%), 48.12 g of Δ-E-β-Farnesene (89%) and 3.1 g Δ.sub.2-E-β-Farnesene (5%) whose analytical data are identical to the ones described in WO 2015059290.

(39) ##STR00009##

(40) The following table shows results from the variation of this procedure using different amounts of catalyst and/or dibasic acid H.sub.2SO.sub.4.

(41) TABLE-US-00003 mol-eq .sup.a mol % .sup.a isolated run mol-eq .sup.a acid NaNO.sub.2 Pd(acac).sub.2 conversion Δ.sub.1 Δ.sub.2 yield.sup.b comparison 2.8 H.sub.3PO.sub.4 2 0.13% 100%  91% 8% 86% 1 7.6 HOAc 2.8 0.13% 96% 88% 8% 87% 2 7.6 HOAc 2.8 0.05% 81% 76% 3% n.d. 3 7.6 HOAc 2.8 0.02% 67% 57% 1% n.d. 4 1.5 H.sub.3PO.sub.4 2.1 0.02% 68% 53% 2% n.d. 5 1.75 H.sub.2SO.sub.4 2.8 0.02% 52% 40% ./. n.d. 6 1.75 H.sub.2SO.sub.4 3 0.13% 100%  90% 10%  87% Conditions: Cyclopropanation at 25° C. .sup.a mol-eq or mol % based on farnesene. .sup.bAfter short-path distillation and corrected by purity of E-Δ.sub.1-Farnesene. n.d. = not determined.