The hydrogen halide preferably is hydrogen bromide which may be provided in the form of an aqueous solution containing 30 to 48 weight percent HBr.
The amount of hydrogen halide used relative to the alcohol determines to a large degree the yield of the reaction. The crude product thus can be recovered by decantation. Patent 5,, While a very efficient distillation will separate cyclopropylacetonitrile from 1-cyanobutene, the separation is much easier if elemental halogen is added to the crude product of the cyanide displacement reaction to selectively transform 1-cyanobutene into 1-cyano-3,4-dibromobutane.
Therefore, step 3 of the process of the present invention involves contacting the organic phase of step 1 comprising a mixture of cyclopropylacetonitrile, cyclobutyl halide, and 1-cyanobutene with sufficient elemental chlorine or, preferably, bromine, to convert 1-cyanobutene to 1-cyano-3,4-dibromobutane.
The amount of halogen added to the organic phase of step 1 normally is at least 1 mole, preferably 1 to 1. The preferred acid scavengers are the trialkylamines, including trialkanolamines, having boiling points greater than the boiling point of any of the components of the crude product being distilled, e.
The amount of acid scavenger typically required gives an acid scavenger:crude product weight ratio in the range of 0. However, the use of the less reactive chlorides necessitates a higher temperature in the phase-transfer cyanide displacement reaction and results in the formation of dark and tarry by-products which leads to difficult isolation and lowered yield of products.
Therefore the use of bromides is preferred to that of chlorides. The identities of the products obtained were confirmed by nuclear magnetic spectrometry and gas chromatography-mass spectrometry by comparison to authentic samples.
The percentages specified in the examples are by weight unless otherwise specified. Stirring was commenced and there was added 8. After 7 hours, gas chromatographic analysis of the organic phase indicated that cyclopropylmethyl bromide and 4-bromobutene i. The initially clear mixture began to phase separate by the end of the addition.
The resulting lower product phase was drawn off, washed with water twice, and analysed by gas chromatography and NMR spectroscopy. These analyses agreed that the composition of the product was 7. This product was used in Step 1 without further treatment.
Bromine, 8. The bromocyclobutane and cyclopropylacetonitrile were unchanged. Distillation of the product at The process is especially useful for preparing cyclopropylmethyl chloride and bromide using a complex comprising N-chloro- or N-bromo-succinimide and a dialkyl sulfide as the halogenation agent.
Cyclopropylmethyl halides are useful intermediates for the production of pharmaceuticals. Dialkyl sulfide and an N-halosuccinimide are reacted to produce the halogenation complex using a dialkyl sulfide:N-halosuccinimide more ratio of about to 0.
Although it is believed that dialkyl sulfides, e. Suitable process solvents include hydrocarbons such as pentane, hexane, heptane, benzene and toluene; chlorinated hydrocarbons such as dichloromethane, 1,2-dichloroethane, methyl chloroform, carbon tetrachloride, chlorobenzene, o-, m- and p-dichlorobenzene; dialkyl ethers such as t-butyl methyl ether, tetrahydrofuran; alkyl carboxylate esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; dialkylsulfoxides such as dimethylsulfoxide; dialkylformamides such as dimethylformamide; dialkylacetamides such as dimethylacetamide; and the like.
The preferred solvents are inert organic solvents such as dimethylformamide and, especially, dichloromethane which both have boilings points markedly different from the boiling point of the CPMX product and exhibit the highest selectivity for the product. Dichloromethane may be recovered by distillation and reused. The amount of solvent used can be varied substantially but normally will be in the range of about 5 to 30 volumes, preferably 10 to 20 volumes, solvent per volume of CPMO reactant.
The complex may be wholly or partially soluble in the process solvent. Alternatively, the process may be carried out by adding the dialkyl sulfide to a mixture of CPMO and the N-halosuccinimide in an organic solvent. This alternative mode of operation is not preferred due to the non-selective reaction of the N-halosuccinimde alone with CPMO.
After addition of the CPMO is complete, the reaction temperature may be increased up to the boiling point of the solvent. However, when addition of the CPMO has been completed, it is preferred to heat the reaction mixture moderately, e.
Pressure is not an important consideration and the process only is operated at ambient temperature although pressures moderately above or below ambient pressure may be used. The organic reaction solution thus obtained is washed with an aqueous base solution such as sodium bicarbonate prior to distillation. Chang, Atom transfer cyclization reactions of.
Nishiyama, Y. Ono, S. Kurokawa, S. King, G. Ostrum, Selective Bromination with copper II bromide1. Stefan, A. Weatherwax, T. Takahashi, M. Daitoh, M. Suzuki, T. Abe, M. Masuda, Halogenated metabolites from the new Okinawan red alga Laurencia yonaguniensis. Brito, M. Cueto, A. Darias, A. Stadler, Synthesis of novel, chiral bicyclo [3. Acta 98, — CrossRef Google Scholar Faust, Fascinating natural and artificial cyclopropane architectures.Claims 4 Translated from Chinese 1. Distillation step 3 is carried out by feeding the crude CPMX, i. The amount of solvent used can be varied substantially but normally will be in the range of about 5 to 30 volumes, preferably 10 to 20 volumes, solvent per volume of CPMO reactant. Kimia, M.
The amount of acid scavenger typically required gives an add scavenger:crude product weight ratio in the range of 0. The crude product obtained from the process comprises mainly CPMX along with cycilbutyl halide CBX and trace amounts of 4-halobutene. Nikishin, One-pot cascade assembling of 3-substituted tetracyanocyclopropanes from alkylidenemalononitriles and malononitrile by the only bromine direct action.
CPMO 10 g, 0. Claims 1.
The hydrohalide HX preferably is hydrogen bromide or, especially, hydrogen chloride. The use of lower amounts of cyanide requires very long reaction times whereas reactions are quicker at the upper end of the cyanide range, but the excess cyanide is wasted and is a disposal problem. The amount of acid scavenger typically required gives an add scavenger:crude product weight ratio in the range of 0. Tetrahedron Lett. Claims 5 We claim: 1. Hartman, E.
Other workers have avoided the contamination and separation problems by using more selective reagents for converting cyclopropane methanol to cyclopropylmethyl halide. Process for the preparation of a cyclopropylmethyl halide CPMX which comprises contacting cyclopropanemethanol CPMO with a complex comprising an N-halosuccinimide and a dialkyl sulfide in the presence of an organic solvent.
Pressure is not an important consideration and the process only is operated at ambient temperature although pressures moderately above or below ambient pressure may be used. The preferred acid scavengers are the trialkylamines having boiling points greater than the boiling point of any of the components of the crude product being distilled, e. This may be accomplished by the concurrent addition of an acid scavenger to the column during the distillation. The aqueous solution of alkali metal cyanide may contain from 5 up to 50 weight percent, preferably 27 to 37 weight percent, alkali metal hydroxide. The mesylates are decomposed thermally in the presence of the amine hydrohalide salts to generate the CPMX along with large amounts of amine-sulfonic acid salts.
Chang, Efficient alpha-halogenation of carbonyl compounds by N-bromosuccinimide and N-chlorosuccinimde. Das, K. Curran, C. The processes provided by the present invention are further illustrated by the following examples.
Alternatively, the process may be carried out by adding the dialkyl sulfide to a mixture of CPMO and the N-halosuccinimide in an organic solvent. King, G.