GB2191774A - Preparation of cyclopropane derivatives - Google Patents

Abstract

Process for preparing trans isomers of formula: <IMAGE> wherein R<1> to R<6> are H, alkyl or halogen; and X and Y are H, alkyl, trimethylsilyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy or aryloxy the process comprising reacting the trans isomer of a cinnamyl alcohol having the formula (IV): <IMAGE> wherein R<3>, R<4>, R<5>, R<6>, X and Y have their previous meanings, under the conditions of the Simmons-Smith reaction with a compound CR<1>R<2>Z<1>Z<2>,where Z<1> and Z<2> have their previous significance and Z<1> and Z<2> are halogen atoms which may be the same or different. The compounds are useful as intermediates in the production of certain fungicidal tertiary amine compounds.

Description

SPECIFICATION Chemical process This invention relates two a processforthe preparation of certain cyclopropane derivatives which arevaluable as intermediates in the manufacture of cyclopropane ring-containing tertiary amines having fungicidal activity.

In our British Specification No.8501169 we have described compounds of the general formula (I):

wherein R1, R2, R3, R4, R5 and R6each represent a hydrogen atom, an alkyl group containing 1 to4carbon atoms or a halogen atom, R7 and R8 each represent an alkyl group containing 1 to 4 carbon atoms ortogether with the adjacent nitrogen atom form a heterocyclic ring which may contain an additional hetero atom, X and Yeach represent a hydrogen ora halogen atom, or an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxyor aryloxy group, or a

groupwherein R9, R10 and R" can be alkyl, alkenyl, alkynyl, cycloalkyl, oraryl.These compounds, including the stereoisomersthereof, and their acid addition salts, arevaluable asfungicides. In particular, a high de gree offungicidal activity is observed in these compounds in which the two molecuiar residues

and

are attached to the cyclopropane ring in the trans position relative to one another.

In the above-mentioned specification, we also describe processes for producing the compounds ofthe general formula (I). These processes involve a number of successive reaction steps, including the preparation as an intermediate a carboxylic acid having the general formula (it) :

wherein R1, R2, R5 and R6 have their previous meanings, or of a reactive derivative of this acid, such as the acid chloride, or an ester. In the processes in question, however, we have not up to the present time succeeded in carrying out any ofthe reaction steps with a marked degree of stereospecificity, so that the final product (I) is normally obtained as a mixture of stereoisomers from which the particularly desired trans isomer has to be separated in a further operation.

We have now devised a process, which is highly stereospecific, for the preparation of hydroxymethyl cyclopropane derivatives corresponding to the carboxylic acids (II), from which the compounds (I) can readily be obtained. The process yields substantially exclusively the trans isomer of the hydroxymethyl compound and this stereospecificity is retained during the conversion to the tertiary amine (I), thus avoiding the needfora separation step.

Thus according to the present invention there is provided a process for the preparation of the trans isomer of a compound of the general formula (III):

wherein R1, R2, R3, P4 P5 and Reach represent a hydrogen atom or an alkyl group containing from 1 to4 carbon atoms, and X and Y each represent a hydrogen atom or an alkyl, trimethylsilyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy or aryloxy group, the process comprising reacting the trans isomer of a cinnamyl alcohol having the formula (IV)::

wherein R3, R4, R5, R6, X and have their previous meanings, underthe conditions of the Simmons-Smith reaction with a compound CRaR2Z1Z2,where R1 and R2 have their previous significance and Za and Z2 are halogen atoms which may be the same or different. Z1 and Z2 are preferably chlorine or bromine.

The Simmons-Smith reaction was originally described in J.Amer.Chem. Soc., 1958,80,5323, and is well known to consist essentially in the addition to a

double bond of a carbenoid

with the resulting formation of a cyclopropane ring. The conditions underwhich the reaction is carried out depend two some extent own the particular reactants involved; for example the reaction may be facilitated by the use of ultrasound and/or an iodine catalyst, if necessary with the addition of a copperco-catalyst.

In the casewhere R3 and R4are both hydrogen,the cinnamyl alcohol (IV) may be obtained, for example, from a corresponding trans- cinnamic acid ester by the action of di-isobutylaluminium hydride. More generally, the compound (IV) may be obtained by treating an alpha, beta-unsaturated ketone offormula (V) with a Grignard reagentP4MgHal:

The process of the present invention is of especial interest for the preparation ofthetrans isomers of the alcohols falling within the general formula (III) but having the particularformula (VI):

whereX is an alkyl group containing 3,4or5carbon atoms; ora cycloalkyl group; oratrimethylsilyl group; In the case where Xis a tert-butyl group, for example, the starting material is frans-4-tert-butylcinnamyl alcohol, and by reacting this with dibromomethane in the presence of a zinc-copper couple under the influence of ultrasonic radiation, a high yield may be obtained of a product which consists exclusively ofthe desired trans 1-(4-tert-butylphenyl)-2-hydroxymethylcyclopropane; none ofthe corresponding cis isomer has been detected in this product.

The hydroxymethyl cyclopropanes (VI) resulting from the process of the invention may be converted into the fungicidally active tertiary amines (I) by various routes. The following reaction sequence, for example, passes through the carboxylic acid (II) as an intermediate and thereafter follows the steps outlined in Specif ication No. 85011 The alcohol (VI) is first oxidised to the cyclopropane carboxylic acid (ll),the latter is then converted to the acid chloride and this in turn is reacted with a primary or secondary amine NHR7R3 (see formula (I)). Finally, the carbonyl group in the resulting amide is reduced to a methylene group. All ofthese reaction steps may be carried out by known standard methods.Thus, for example, the oxidation ofthe trans isomer of the alcohol (VI) may be carried out in two stages: firstly to the aldehyde by the Swern method (oxalyl chloride in dimethylsulphoxidefoIlowed bytreatmentwith triethylamine) and subsequently to the acid by means of silver oxide, or in a single stage by means of potassium permanganate. After isolation ofthe acid, this is converted to the acid chloride by means of oxalyl chloride, and the acid chloride reacted with 2,6-dimethylmorpholine. The resulting 4-[trans-2-(p-tert-butylphenyl)cyclopropanecarbonyl]-2,6- dimethylmorpholine is finally reduced with lithium aluminium hydride in ether to yield the tertiary amine 4-[trans-2-(p-tert-butyl-phenyl)cyclopropylmethyl]-2,6-dimethylmorpholine.

Anotherway in which the hydroxymethyl compound (VI) may be converted to the tertiary amine (I), without passing through the carboxylic acid (II) as an intermediate, involves first of all oxidation of (VI) to the corresponding aldehyde by the Swern method referred to above, followed by reductive amination ofthe aldehyde with the amine NHR7R3 in the presence of formic acid.

The stereospecificity of the process of the invention, resulting in the production of substantially exclusively of substantially exclusively the transform of the alcohol (III), is preserved during the subsequent conversion of the alcohol to the tertiary amine (I ), so that the latter also is obtained wholly as the highlyfungicidally active trans isomer. There is thus no need, in contrast to the processes described in our Specification No.8501169, for any final step ofseparat- ing the stereoisomers of the tertiary amine.

The invention is illustrated bythefollowing Examples in which temperatures are expressed in degrees Centigrade.

Example 1 Preparation oftrans 1-(4-t-butylphenyl)-2-hydroxymethyl cyclopropane Zinodust(13.0g, 200mmol), copper (I) chloride (2.0g, 20mmol) and dibromomethane (7.1 ml, 100mmol) were added to anhydrous ether (20ml) and the mixture placed in a sonic bath at approximately 45 C. trans-4t Butyl-cinnamyl alcohol (8.74g, 46mmol) in an hydros ether (15ml) was added. After approximately 20 minutes reaction could be seen to initiate. After refluxing in the sonic bath for a total of 3.5 hours hexane (some) was added and the mixture cooled to 0 C. Saturated aqueous ammonium chloride (1 50ml) was slowly added.

The aqueous layerwas separated and extracted with ether and the combined organic extracts washed suc cessivelywith water, saturated aqueous sodium hydrogen carbonate and water, dried (MgSO4) and evaporated in vacuo. Chromatography [SiO2, t-BuOMe-hexane (40:60)1 gave the title compound (7.60g, 81%) as a yellow liquid. IR (film); 3340cm-1 (br) (OH). 1H NMR (CDCl3, MHz); 7.29 (2H, d,J=8.5 Hz, Ar), 7.01 (2H,d, J=8.5Hz,Ar),3.68-3.52 (2H, m, CH2OH), 1.79 H, dt, J=8.8 and 4.7Hz, ArCH), 1.55-1.40 (2H, m, CHCH2 OH), 1.10 (9H, s, t-Bu), 1.00-0.85 (2H, m,cyclopropyl CH2).mls 204.13 (6%), 189.10(13), 145.00(11), 129.05(27), 128.05(14), 117.00(21), 115.05(14), 90.95(14), and 56.90(100).

Example 2 Preparation oftrans- 1-(4-t-butylphenyl-2-hydroxymethyl-2-methylcyclopropane Zinc dust (13.0g,200mmol),copper (I) chloride (2.0g,20mmol) and dibromomethane 7.1ml,100mmol) were added to anhydrous ether (20ml) and the mixture placed in a sonic bath at approximately 45 C. trans-3 (4-(Butyl-phenyl)-2-methylprop-2-en-l -ol (10.2g, 50mmol) in anhydrous ether(l5ml)was added. After app- roximately 20 minutes reaction could be seen to initiate. After refluxing in the sonic bath for a total of 3 hours hexane (50ml) was added and the mixture cooled to 0 C. Saturated aqueous ammonium chloride (150ml) was slowly added. The aqueous layer was separated and extracted with ether and the combined organic extracts washed successively with water, saturated aqueous sodium hydrogen carbonate and water, dried (MgSO4) and evaporated in vacuo.

Chromatography [SiO2, t-BuOMe-hexane (20:80) (60:40)] gave the title compound (6.53g,60%) as white crystals (m.p. 45-460Cfrom ethanol-water).

IR (film); 3340 cm- (br) OH 'H NMP (CDCI3, MHz); 7.29 (2H, d, J=8 Hz, Ar), 7.09 (2H, d, J=8 Hz, Ar), 3.54 (2H, br, s, CH2OH),2.00(1H, dd, J=8 and 6 Hz, ArCH), 1.43(1 H,br, s, OH), 1.30 (9H, s, t-Bu), 0.90 (3H, s, Me), 0.94-0.80 (2H, m,cyclopropyi CH2).

m/s218 (25%),203 (15), 187(22), 163(18), 145(49), 143(36), (38), and 57 (100).

Claims (5)

1. A processforthe preparation ofthe trans isomer of a compound of the general formula:

(formula III) wherein P1, P2, R3, R4, P5 and R6 each represent a hydrogen atom or an alkyl group containing from 1 to4 carbon atoms, and X and Y each represent a hydrogen atom or an alkyl, trimethylsilyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy or aryloxy group,the process comprising reacting the trans isomer of a cinnamyl alcohol havingtheformula::

wherein R3, R4, R5 and R6 have their previous meanings, underthe conditions of the Simmons-Smith reaction with a compound CR1R2Z1Z2, where R1 and R2 have their previous significance and Z1 and Z2 are halogen atoms which may be the same or different.

2. A process as claimed in claim 1 for the preparation of the trans isomers ofthe alcohols falling within the general formula (III) but having the formula (VI):

where Xis an alkyl group containing 3,4 or 5 carbon atoms; or a cycloalkyl group; or a trimethylsilyl group.

3. A process as claimed in claim 1 or claim 2 and including the further step(s) wherein the trans isomers of formula (III) or (VI) are converted to fungicidally active tertiary amines of formula (I) by either: (a) oxidation to a cyclopropanecarboxylic acid offormula (II) and thereafter converting the latter into an acid chloride and reacting this with a primary or secondary amine, reducing the carbonyl group in there- sultantamideto a methylenegroup; or (b) oxidation to the corresponding aldehyde followed by reductive amination thereof with an amine NHR7R8 in the presence of formic acid.

4. The processes of Examples 1 and 2 substantially as described herein.

5. A process as claimed in any ofthe preceding claims wherein the trans isomer ofthe compound:

is produced.