CA1116616A - 2-cyano-3-azobicyclo(3.1.0)hexane derivatives and their preparation - Google Patents
2-cyano-3-azobicyclo(3.1.0)hexane derivatives and their preparationInfo
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- CA1116616A CA1116616A CA000335720A CA335720A CA1116616A CA 1116616 A CA1116616 A CA 1116616A CA 000335720 A CA000335720 A CA 000335720A CA 335720 A CA335720 A CA 335720A CA 1116616 A CA1116616 A CA 1116616A
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel compounds of the general formula I, useful as intermediates in the preparation of biologically active molecules:
(I) in which R1, R2, R3, R4, R5, R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms, may be prepared by addition of a cyanide of formula XCN
to the corresponding imine.
Novel compounds of the general formula I, useful as intermediates in the preparation of biologically active molecules:
(I) in which R1, R2, R3, R4, R5, R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms, may be prepared by addition of a cyanide of formula XCN
to the corresponding imine.
Description
This invention relates to a process for the preparation of certain derivatives of 2-cyano-3-azabicyclo[3.1.0]hexane.
2-Carboxy-3-azabicyclo[3.1 0]hexane and certain salts and esters thereof have useful biological properties, being capable of sterilising the male anthers in plants. Therefore there is considerable interest in methods for the preparation of these compounds. The available preparation methods, however, have proved to be relatively complex. One possible synthetic route involves the hydrolysis of the corresponding 2-cyano compound, but so far this cyano compound could not be easily synthesised.
Canadian Patent Application No. 321,300 discloses that 2-cyano-3-azabicyclo[3.1.0]hexane and certain substituted derivatives thereof can be prepared by reaction of the corresponding 2-cyano-4-oxo compound with a trialkyl oxoniumfluoroborate and subsequently with a reducing agent. This reaction however is a two-step process which may require the use of expensive reagents.
Canadian Patent Application No. 329,752 discloses that 2-cyano-3-azabicyclo[3.1.0]hexane can be prepared by reacting 3-azabicyclo[3.1.0]hex-2-ene with an alkali metal bisulphite, and subsequently with an alkali metal cyanide.
This process too is a two-stage process.
A process has now been found by which a cyano group can be introduced into the bicyclohexane ring system in a single step, producing novel compounds useful for the preparation of 2-carboxy-3-azabicyclo[3.1.0]hexane and derivatives thereof.
The invention provides a compound of the general formula: -R3 ~ R2 R6 ~ Rl (I~
R7 ~ N '''''-`~CN
`~' .
h i h f Rl R2 R3 R4 R5 R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms. The invention also provides a process for the preparation of such a compound, which is characterised in that a compound of the general formula Il and/or the trimer thereof:
R3 ~ R2 R6 ~ N ~ Rl (II) wherein Rl, R2, R3, R4, R5, R6 and R7 have the meanings given for the general formula I, is reacted with a cyanide of the general formula XCN in which X
has the meaning given above.
Preferably, Rl represents a hydrogen atom or a methyl group; and R2, R3, R4, R5, R6 and R7 each independently represents a hydrogen atom or a methyl group.
Most preferably, each of Rl, R2 R3 R4 R5 R6 d R7 a hydrogen atom.
X may for example be an alkanoyl group, for example an acetyl group, or an aroyl group, for example a benzoyl group. In a trialkylsilyl group X, two or three of the alkyl groups may be the same or different, and each alkyl group preferably has up to 4, especially 1 or 2, carbon atoms. An especially preferred trialkylsilyl group is the trimethylsilyl group.
61~
The process according to the invention is suitably carried out in the presence of an inert solvent, for example an alcohol, an ether such as diethyl ether or a hydrocarbon or chlorinated hydrocarbon such as dichloro-methane. A mixture of solvents may be used. The reaction temperature may, for example, be in the range of from 0 to 60C, preferably 10 to 30C. For example, the reaction may be conducted at the reflux temperature of the solvent used.
It is however most conveniently conducted at room temperature.
In some cases, it is preferable, and may indeed be essential, to conduct the reaciion un~er moisture-free conditions. This is especially ~he case when using a trialkylsilyl cyanide as reagent.
The molar ratio of the reactants may vary over a wide range. An excess of the cyanide reactant, for example up to a 5-fold, preferably up to a
Canadian Patent Application No. 321,300 discloses that 2-cyano-3-azabicyclo[3.1.0]hexane and certain substituted derivatives thereof can be prepared by reaction of the corresponding 2-cyano-4-oxo compound with a trialkyl oxoniumfluoroborate and subsequently with a reducing agent. This reaction however is a two-step process which may require the use of expensive reagents.
Canadian Patent Application No. 329,752 discloses that 2-cyano-3-azabicyclo[3.1.0]hexane can be prepared by reacting 3-azabicyclo[3.1.0]hex-2-ene with an alkali metal bisulphite, and subsequently with an alkali metal cyanide.
This process too is a two-stage process.
A process has now been found by which a cyano group can be introduced into the bicyclohexane ring system in a single step, producing novel compounds useful for the preparation of 2-carboxy-3-azabicyclo[3.1.0]hexane and derivatives thereof.
The invention provides a compound of the general formula: -R3 ~ R2 R6 ~ Rl (I~
R7 ~ N '''''-`~CN
`~' .
h i h f Rl R2 R3 R4 R5 R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms. The invention also provides a process for the preparation of such a compound, which is characterised in that a compound of the general formula Il and/or the trimer thereof:
R3 ~ R2 R6 ~ N ~ Rl (II) wherein Rl, R2, R3, R4, R5, R6 and R7 have the meanings given for the general formula I, is reacted with a cyanide of the general formula XCN in which X
has the meaning given above.
Preferably, Rl represents a hydrogen atom or a methyl group; and R2, R3, R4, R5, R6 and R7 each independently represents a hydrogen atom or a methyl group.
Most preferably, each of Rl, R2 R3 R4 R5 R6 d R7 a hydrogen atom.
X may for example be an alkanoyl group, for example an acetyl group, or an aroyl group, for example a benzoyl group. In a trialkylsilyl group X, two or three of the alkyl groups may be the same or different, and each alkyl group preferably has up to 4, especially 1 or 2, carbon atoms. An especially preferred trialkylsilyl group is the trimethylsilyl group.
61~
The process according to the invention is suitably carried out in the presence of an inert solvent, for example an alcohol, an ether such as diethyl ether or a hydrocarbon or chlorinated hydrocarbon such as dichloro-methane. A mixture of solvents may be used. The reaction temperature may, for example, be in the range of from 0 to 60C, preferably 10 to 30C. For example, the reaction may be conducted at the reflux temperature of the solvent used.
It is however most conveniently conducted at room temperature.
In some cases, it is preferable, and may indeed be essential, to conduct the reaciion un~er moisture-free conditions. This is especially ~he case when using a trialkylsilyl cyanide as reagent.
The molar ratio of the reactants may vary over a wide range. An excess of the cyanide reactant, for example up to a 5-fold, preferably up to a
3-fold, especially up to a 1.5-fold, excess, may be used. However, it may be desirable to use approximately stoichiometric quantities, especially when the cyanide reactant is ben70yl cyanide, since this may avoid separation problems during work-up.
The cyanide reagent may if desired be prepared and used in situ.
Trialkylsilyl cyanides may be prepared by the reaction of a trialkylsilyl chloride with potassium cyanide, optionally in ~ -3-~ .
6i~
the presence of zinc iodide, by the method described in J. Org.
Chem. 39 No. 7 (1974) p.916. Whether the resulting trialkylsilyl cyanide is isolated or used in situ, it is suitably kept moisture-free.
The compound of the general formula II and/or its trimer may for example be produced by direct oxidation of a compound of the general formula R6 ~ Rl (III) H
in which Rl-R7 have the meanings given for the general formula I.
Manganese dioxide is a suitable reagent, and the oxidation can 10 be performed simply by stirring the compound of the general formula III with manganese dioxide in the presence of a suitable solvent, for example a hydrocarbon such as benzene or light petroleum conveniently at room temperature.
Alternatively, the compound of the general formula II and/or its trimer may be produced by dehydrohalogenation of a compound of the general formula ~ (IV) R ~ / ~ Rl /\ /
R7 Nl H
Hal i61~
i h f Rl R2 R3 R4 R5, R6 and R7 has the meaning given for the general forrnula I, and Hal represents a chlorine or bromine atorsl.
The dehydrohalogenation may be carried out using any suitable 5 dehydrohalogenating agent, for example a strong organic base such as triethylamine or pyridine in non-aqueous solution, or a strong inorganic base, for example sodiurn hydroxide, in aqueous or non-aqueous solution. Suitable polar solvents are for example ethers, alcohols, or water. The reaction is preferably carried out at 10 a temperature of up to 150 C, preferably at a temperature in the range 20 to 80 C. The process can conveniently be carried out at the reflux temperature of the solvent used.
An advantage of carrying out the dehydrohalogenation in a non-aqueous reaction medium is that the resulting solution may 15 if desired by used directly 1n situ in the cyanide addition process according to the invention even if a moisture-sensitive cyanide reagent is used. On the other hand, generally shorter reaction times are required when an aqueous reaction medium is used: in this case however the desired compound may have to be isolated, 20 so that the subsequent cyanide addition can proceed in the absence of moisture.
It is believed that the dehydrohalogenation process leads to a solution consisting largely of the monomer of the general formula II. On removal of the solvent, a solid is produced which 25 has a complex NMR spectrum and is believed to be the trimer:
~1 Rl \l N ~ (IIa) N
R ~ ~
illustrated here with subst1tuents R to R not shown. When the solid trimer is re-dissolved, a solution is formed in which the trimer is in equilibrium with the monomer, the concentration of each species being dependent on the dilution of the solution.
.
The process according to the invention may be carried out irrespective of the relative proportions of monomer and trimer in the reaction solution.
The compound of the general for-..ul~ IV may for example be 5 prepared by the N-chlorination or N-bromination of a compound of the general formula III given above. Any suitable chlorinating or brominating agent may be used, for example an N-halo compound, for example N-bromo- or, especially, N-chlorosuccinimide, or an inorganic hypohalite, for example sodium hypochlorite. Sodium 10 hypochlorite may conveniently be used in the form of sodium hydroxide plus chlorine. This process is suitably carried out by admixing a slight excess of the halogenating agent with the compound of the general formula IV. Any suitable solvent, for example an ether, may be used. The reaction may for example be 15 carried out at room temperature.
Thus the invention also provides a process for the preparation of a compound of the general formula I, which comprises converting a compound of the general forml~a III into a compound of the general formula II and/or the trimer thereof, and reacting at 20 least part of said compound with a compound of the formula XCN.
The compounds of the general formula III wherein each Or R , R and R7 represents a hydrogen atom may be prepared by reacting a compound of the general formula R3 ~ R2 ~ (V) wherein each of R , R3, R and R5 have meanings given above, or 25 a mono- or di-acyl halide or a mono- or di-ester or the anhydride thereof, with ammonia and optionally water; effecting cyclisation by subjecting the resultant product to elevated temperature to produce a compound of the general formula 61~
R X R
_L~
(VI) ~ N ~ ~
O l O
H
wherein each of R , R3 and R have the meanings given above; and reducing the carbonyl groups in the 2 and 4 positions of the compound of the general formula VI, for example using lithium aluminium hydride. Compounds of the general formula IV wherein Rl, R6 and/or R7 represent moieties other than hydrogen atoms, may be prepared by introducing these moieties by methods analogous to those known in the art.
A compound of the general formula I may be hydrolysed to form a compound of the general formula R3 ~ Rl (VII) H
10 in which R - R7 have the meanings given above. Such compounds have interesting pollen-suppressing and plant growth regulating properties. The hydrolysis may for example be carried out by refluxing the compound of the general formula I in the presence of an aqueous acid. This hydrolysis may lead to an acid addition salt of the compound of the general formula VII. Refluxing of a compound of the general formula I in the presence of an alcohol and dry hydrogen chloride produces an ester of the compound of the general formula VII or the HCl salt thereof.
Thus, the invention also provides a process for the preparation 20 of a compound of the general formula VIII, or a salt and/or ester thereof, which comprises hydrolysing or alcoholising a compound ', '' , : , .
, 6~
of the general formula I which has been prepared by the process according to the invention.
If X in a compound of the general formula I represents a trialkyl-silyl group, it is possible with careful control of the reaction conditions to hydrolyse partially the compound to a compound of the general formula I
in which X represents a hydrogen atom. This is generally not possible with a compound of the general formula I in which X represents an acyl group. Mild reaction conditions may be used for the partial hydrolysis, for example the silyl compound may be stirred with water at room temperature.
In the compounds of the general formula I, the 2-cyano group may be cis- or trans- to the ~ CR4R5 group, and in addition, for each of these geometric isomers, a pair of optical isomers exists due the asymmetry of the 2-carbon atom. In addition, other geometric and/or optical isomers may exist depending on the meanings of R4, R5, R6 and R . In some applications of the process according to the invention, certain isomers may be formed predominantly or exclusively.
The following Examples illustrate the invention.
Example 1 Preparation of 2-cyano-3-trimethylsilyl-3-azabicyclo~3.1.0]hexane, and its partial hydrolysis (a) 3-azabicyclo[3.1.0]hex-2-ene and its trimer A solution of 3-azabicyclo[3.1.0]hexane (8.3 g; 0.1 m) in 50 ml diethyl ether was added to a suspension of N-chloro-succinimide (23.6 g) in 150 ml diethyl ether at room temperature. The suspension was stirred at room temperature for 2-l/4 hours then filtered and washed with water. The ethereal solution was dried over Na2S04, filtered, and concentrated at 70C
under a vigreaux column to about 25 ml. The resi~ue was added dropwise at 5-10C to a stirred solution of KOH (6.6 g 85%) in 50 ml methanol.
The suspension was stirred at 0-5C for 2 hours then left overnight at room temperature. The mixture was concentrated at 35C and a pressure of 18 cm Hg for 6 hours then water (50 ml) was .~ -8a-61~
g added. The mixture was continuously extracted with diethyl ether.
The diethyl ether was distilled off at atmospheric pressure then the residue was distilled at atmospheric pressure. The first fraction obtained, boiling point 77-96C, was 3 g of a colourless liquid shown by infra-red and NMR spectra to be an aqueous solution of the monomer 3-azabicycloC3.1. b]
hex-2-ene.
The second fraction boiling at 96-110 C, condensed to give 3.8 g of an off-white solid, melting point 60-63 C which was shown by infra-red and NMR spectroscopy to be the trimer of this imine. Analysis of white solid:
C H
Calculated for C15N3H21 73.2 9.1 17.2 Found 74 8.7 17.3 (b) 2-cyano-3-trimethylsilyl-3-azabicyclo L3.1.0~ hexane and its partial hydrolysis Trimethylsilyl cyanide (16 ml; 0.128 m) was added to a stirred solution of the imine trimer prepared in (a) above (7 g; 28.8 mm) in 700 ml dry CH2C12 at room temperature under nitrogen with exclusion of moisture. The solution was stirred at room temperature for 24 hours, to give a solution of 2-cyano-3-t~imethylsilyl-3-azabicyclo 3.1.0 hexane.
The solution was poured onto 1 litre of water, stirred at room temperature for 30 minutes, and extracted with CH2C12.
The extract was dried over Na2S04 and evaporated down to give 9.4 g of a yellow liquid.
I'his liquid was purified by distillation and the fraction boiling at 72-74 C under a pressure of 0.7 mm Hg (5.45 g) was identified by NMR as 2-cyano-3-azabicyclo L3.1.01hexane.
Example 2 Preparation of 2-cyano-3-benzoyl-3-azabicyclo r3.1.0¦hexane, and (a) Addition of benzoyl cyanide to an imine trimer Benzoyl cyanide (11.3 g; 86.4 mMol) was added to a solution of the imine trimer prepared as in Example 1 (a) above (7 g;
28.8 rnm) in 700 ml dry CH2C12. I'he solution was stirred at `~ .
-` ~1166~
room temperature overnight and then evaporated down. The resulting oil was distilled at a temperature of 160C and a pressure of 0.1 mm Hg, and the distillate was treated with petrol/ether and filtered.
The resulting compound, 4.8 g of a solid having a melting point of 74-77C, was identified by infra-red and NMR spectra as 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane. The spectral data are as follows:
IR: 1650 cm 1 : C = O Stretch 2240 cm : C = N Stretch NMR: 0.2 ppm lH (multiplet) 0.7 ppm lH (multiplet) 1.7 ppm 2H (multiplet) 3.6 ppm 2H (multiplet) 5.1 ppm lH (multiplet) 7.3 ppm 5H (singlet) (b) Preparation of 2-carboxy-3-azabicyclo[3.1.0]hexane A solution of the compound prepared in (a) above (1 g) in 50 ml CH2C12 was stirred and heated under reflux overnight. The suspension was cooled, washed with diethyl ether, and the aqueous layer evaporated to dryness.
The residue was dissolved in water and percolated through an acidic ion-exchange column "DOWEX 50" (Trade Mark). The ion-exchange bed was washed with water and the product was eluted with 2NNH40H.
0.4 g of a product was obtained. NMR showed that this product was 2-carboxy-3-azabicyclo[3.1.0]hexane, containing cis and trans isomers in 1:1 ratio.
Example 3 Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane via oxidation of 3-azabicyclo[3.1.0]hexane A mixture of 3-azabicyclo[3.1.0]hexane (1 g, 0.012 mol), manganese . .~
6~
dioxide (5 g, 0.057 mol) and petrol having a boiling point range of 40-60C~
was stirred at room temperature for 4 hours. Sodium sulphate was added and the mixture was allowed to stand for a further 4 hours, and then filtered.
Thin layer . -lOa-6~
chromatography showed the presence of the trimer of 3-azabicyclo ~3.1.0~hex-2-ene.
Trimethysilyl cyanide (3 ml, 0.024 mol) was then added, and the mixture was stirred under nitrogen at room temperature for 20 hours. The solution became cloudy, and some solid precipitated.
10 ml water were added and the mixture was stirred for 1 hour.
The aqueous layer was separated and washed with diethyl ether, and the combined organic phases were dried over sodium sulphate, filtered and evaporated down. 1.05 g of a straw coloured oil were obtained. 80% of this product was 2-cyano-3-azabicyclo ~3.1.0jhexane, and 20% was unreacted 3-azabicyclo C3.1.0~ hexane.
The cyanide reagent may if desired be prepared and used in situ.
Trialkylsilyl cyanides may be prepared by the reaction of a trialkylsilyl chloride with potassium cyanide, optionally in ~ -3-~ .
6i~
the presence of zinc iodide, by the method described in J. Org.
Chem. 39 No. 7 (1974) p.916. Whether the resulting trialkylsilyl cyanide is isolated or used in situ, it is suitably kept moisture-free.
The compound of the general formula II and/or its trimer may for example be produced by direct oxidation of a compound of the general formula R6 ~ Rl (III) H
in which Rl-R7 have the meanings given for the general formula I.
Manganese dioxide is a suitable reagent, and the oxidation can 10 be performed simply by stirring the compound of the general formula III with manganese dioxide in the presence of a suitable solvent, for example a hydrocarbon such as benzene or light petroleum conveniently at room temperature.
Alternatively, the compound of the general formula II and/or its trimer may be produced by dehydrohalogenation of a compound of the general formula ~ (IV) R ~ / ~ Rl /\ /
R7 Nl H
Hal i61~
i h f Rl R2 R3 R4 R5, R6 and R7 has the meaning given for the general forrnula I, and Hal represents a chlorine or bromine atorsl.
The dehydrohalogenation may be carried out using any suitable 5 dehydrohalogenating agent, for example a strong organic base such as triethylamine or pyridine in non-aqueous solution, or a strong inorganic base, for example sodiurn hydroxide, in aqueous or non-aqueous solution. Suitable polar solvents are for example ethers, alcohols, or water. The reaction is preferably carried out at 10 a temperature of up to 150 C, preferably at a temperature in the range 20 to 80 C. The process can conveniently be carried out at the reflux temperature of the solvent used.
An advantage of carrying out the dehydrohalogenation in a non-aqueous reaction medium is that the resulting solution may 15 if desired by used directly 1n situ in the cyanide addition process according to the invention even if a moisture-sensitive cyanide reagent is used. On the other hand, generally shorter reaction times are required when an aqueous reaction medium is used: in this case however the desired compound may have to be isolated, 20 so that the subsequent cyanide addition can proceed in the absence of moisture.
It is believed that the dehydrohalogenation process leads to a solution consisting largely of the monomer of the general formula II. On removal of the solvent, a solid is produced which 25 has a complex NMR spectrum and is believed to be the trimer:
~1 Rl \l N ~ (IIa) N
R ~ ~
illustrated here with subst1tuents R to R not shown. When the solid trimer is re-dissolved, a solution is formed in which the trimer is in equilibrium with the monomer, the concentration of each species being dependent on the dilution of the solution.
.
The process according to the invention may be carried out irrespective of the relative proportions of monomer and trimer in the reaction solution.
The compound of the general for-..ul~ IV may for example be 5 prepared by the N-chlorination or N-bromination of a compound of the general formula III given above. Any suitable chlorinating or brominating agent may be used, for example an N-halo compound, for example N-bromo- or, especially, N-chlorosuccinimide, or an inorganic hypohalite, for example sodium hypochlorite. Sodium 10 hypochlorite may conveniently be used in the form of sodium hydroxide plus chlorine. This process is suitably carried out by admixing a slight excess of the halogenating agent with the compound of the general formula IV. Any suitable solvent, for example an ether, may be used. The reaction may for example be 15 carried out at room temperature.
Thus the invention also provides a process for the preparation of a compound of the general formula I, which comprises converting a compound of the general forml~a III into a compound of the general formula II and/or the trimer thereof, and reacting at 20 least part of said compound with a compound of the formula XCN.
The compounds of the general formula III wherein each Or R , R and R7 represents a hydrogen atom may be prepared by reacting a compound of the general formula R3 ~ R2 ~ (V) wherein each of R , R3, R and R5 have meanings given above, or 25 a mono- or di-acyl halide or a mono- or di-ester or the anhydride thereof, with ammonia and optionally water; effecting cyclisation by subjecting the resultant product to elevated temperature to produce a compound of the general formula 61~
R X R
_L~
(VI) ~ N ~ ~
O l O
H
wherein each of R , R3 and R have the meanings given above; and reducing the carbonyl groups in the 2 and 4 positions of the compound of the general formula VI, for example using lithium aluminium hydride. Compounds of the general formula IV wherein Rl, R6 and/or R7 represent moieties other than hydrogen atoms, may be prepared by introducing these moieties by methods analogous to those known in the art.
A compound of the general formula I may be hydrolysed to form a compound of the general formula R3 ~ Rl (VII) H
10 in which R - R7 have the meanings given above. Such compounds have interesting pollen-suppressing and plant growth regulating properties. The hydrolysis may for example be carried out by refluxing the compound of the general formula I in the presence of an aqueous acid. This hydrolysis may lead to an acid addition salt of the compound of the general formula VII. Refluxing of a compound of the general formula I in the presence of an alcohol and dry hydrogen chloride produces an ester of the compound of the general formula VII or the HCl salt thereof.
Thus, the invention also provides a process for the preparation 20 of a compound of the general formula VIII, or a salt and/or ester thereof, which comprises hydrolysing or alcoholising a compound ', '' , : , .
, 6~
of the general formula I which has been prepared by the process according to the invention.
If X in a compound of the general formula I represents a trialkyl-silyl group, it is possible with careful control of the reaction conditions to hydrolyse partially the compound to a compound of the general formula I
in which X represents a hydrogen atom. This is generally not possible with a compound of the general formula I in which X represents an acyl group. Mild reaction conditions may be used for the partial hydrolysis, for example the silyl compound may be stirred with water at room temperature.
In the compounds of the general formula I, the 2-cyano group may be cis- or trans- to the ~ CR4R5 group, and in addition, for each of these geometric isomers, a pair of optical isomers exists due the asymmetry of the 2-carbon atom. In addition, other geometric and/or optical isomers may exist depending on the meanings of R4, R5, R6 and R . In some applications of the process according to the invention, certain isomers may be formed predominantly or exclusively.
The following Examples illustrate the invention.
Example 1 Preparation of 2-cyano-3-trimethylsilyl-3-azabicyclo~3.1.0]hexane, and its partial hydrolysis (a) 3-azabicyclo[3.1.0]hex-2-ene and its trimer A solution of 3-azabicyclo[3.1.0]hexane (8.3 g; 0.1 m) in 50 ml diethyl ether was added to a suspension of N-chloro-succinimide (23.6 g) in 150 ml diethyl ether at room temperature. The suspension was stirred at room temperature for 2-l/4 hours then filtered and washed with water. The ethereal solution was dried over Na2S04, filtered, and concentrated at 70C
under a vigreaux column to about 25 ml. The resi~ue was added dropwise at 5-10C to a stirred solution of KOH (6.6 g 85%) in 50 ml methanol.
The suspension was stirred at 0-5C for 2 hours then left overnight at room temperature. The mixture was concentrated at 35C and a pressure of 18 cm Hg for 6 hours then water (50 ml) was .~ -8a-61~
g added. The mixture was continuously extracted with diethyl ether.
The diethyl ether was distilled off at atmospheric pressure then the residue was distilled at atmospheric pressure. The first fraction obtained, boiling point 77-96C, was 3 g of a colourless liquid shown by infra-red and NMR spectra to be an aqueous solution of the monomer 3-azabicycloC3.1. b]
hex-2-ene.
The second fraction boiling at 96-110 C, condensed to give 3.8 g of an off-white solid, melting point 60-63 C which was shown by infra-red and NMR spectroscopy to be the trimer of this imine. Analysis of white solid:
C H
Calculated for C15N3H21 73.2 9.1 17.2 Found 74 8.7 17.3 (b) 2-cyano-3-trimethylsilyl-3-azabicyclo L3.1.0~ hexane and its partial hydrolysis Trimethylsilyl cyanide (16 ml; 0.128 m) was added to a stirred solution of the imine trimer prepared in (a) above (7 g; 28.8 mm) in 700 ml dry CH2C12 at room temperature under nitrogen with exclusion of moisture. The solution was stirred at room temperature for 24 hours, to give a solution of 2-cyano-3-t~imethylsilyl-3-azabicyclo 3.1.0 hexane.
The solution was poured onto 1 litre of water, stirred at room temperature for 30 minutes, and extracted with CH2C12.
The extract was dried over Na2S04 and evaporated down to give 9.4 g of a yellow liquid.
I'his liquid was purified by distillation and the fraction boiling at 72-74 C under a pressure of 0.7 mm Hg (5.45 g) was identified by NMR as 2-cyano-3-azabicyclo L3.1.01hexane.
Example 2 Preparation of 2-cyano-3-benzoyl-3-azabicyclo r3.1.0¦hexane, and (a) Addition of benzoyl cyanide to an imine trimer Benzoyl cyanide (11.3 g; 86.4 mMol) was added to a solution of the imine trimer prepared as in Example 1 (a) above (7 g;
28.8 rnm) in 700 ml dry CH2C12. I'he solution was stirred at `~ .
-` ~1166~
room temperature overnight and then evaporated down. The resulting oil was distilled at a temperature of 160C and a pressure of 0.1 mm Hg, and the distillate was treated with petrol/ether and filtered.
The resulting compound, 4.8 g of a solid having a melting point of 74-77C, was identified by infra-red and NMR spectra as 2-cyano-3-benzoyl-3-azabicyclo[3.1.0]hexane. The spectral data are as follows:
IR: 1650 cm 1 : C = O Stretch 2240 cm : C = N Stretch NMR: 0.2 ppm lH (multiplet) 0.7 ppm lH (multiplet) 1.7 ppm 2H (multiplet) 3.6 ppm 2H (multiplet) 5.1 ppm lH (multiplet) 7.3 ppm 5H (singlet) (b) Preparation of 2-carboxy-3-azabicyclo[3.1.0]hexane A solution of the compound prepared in (a) above (1 g) in 50 ml CH2C12 was stirred and heated under reflux overnight. The suspension was cooled, washed with diethyl ether, and the aqueous layer evaporated to dryness.
The residue was dissolved in water and percolated through an acidic ion-exchange column "DOWEX 50" (Trade Mark). The ion-exchange bed was washed with water and the product was eluted with 2NNH40H.
0.4 g of a product was obtained. NMR showed that this product was 2-carboxy-3-azabicyclo[3.1.0]hexane, containing cis and trans isomers in 1:1 ratio.
Example 3 Preparation of 2-cyano-3-azabicyclo[3.1.0]hexane via oxidation of 3-azabicyclo[3.1.0]hexane A mixture of 3-azabicyclo[3.1.0]hexane (1 g, 0.012 mol), manganese . .~
6~
dioxide (5 g, 0.057 mol) and petrol having a boiling point range of 40-60C~
was stirred at room temperature for 4 hours. Sodium sulphate was added and the mixture was allowed to stand for a further 4 hours, and then filtered.
Thin layer . -lOa-6~
chromatography showed the presence of the trimer of 3-azabicyclo ~3.1.0~hex-2-ene.
Trimethysilyl cyanide (3 ml, 0.024 mol) was then added, and the mixture was stirred under nitrogen at room temperature for 20 hours. The solution became cloudy, and some solid precipitated.
10 ml water were added and the mixture was stirred for 1 hour.
The aqueous layer was separated and washed with diethyl ether, and the combined organic phases were dried over sodium sulphate, filtered and evaporated down. 1.05 g of a straw coloured oil were obtained. 80% of this product was 2-cyano-3-azabicyclo ~3.1.0jhexane, and 20% was unreacted 3-azabicyclo C3.1.0~ hexane.
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the general formula:
(I) wherein each of R1, R2, R3, R4, R5, R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms.
(I) wherein each of R1, R2, R3, R4, R5, R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms and X represents an alkanoyl group, an aroyl group or a trialkylsilyl group in which each of the alkyl groups has up to 4 carbon atoms.
2. A compound as claimed in claim 1, in which each of R1 to R7 represents a hydrogen atom.
3. A compound as claimed in either of claim 1 or 2, in which, X represents a benzoyl or a trimethylsilyl group.
4. A process for the preparation of a compound as claimed in claim 1, characterised in that a compound of the general formula II and/or the trimer thereof:
(II) in which each of R1 to R7 have the meanings given in claim 1, is reacted with a cyanide of the general formula XCN in which X has the meaning given in claim 1.
(II) in which each of R1 to R7 have the meanings given in claim 1, is reacted with a cyanide of the general formula XCN in which X has the meaning given in claim 1.
5. A process as claimed in claim 4, characterised in that a starting material is used in which each of R1 to R7 represents a hydrogen atom.
6. A process as claimed in claim 4, characterised in that a cyanide reactant is used in which X represents a benzoyl group or a trimethylsilyl group.
7. A process as claimed in claim 5, characterised in that a cyanide reactant is used in which X represents a benzoyl group or a trimethylsilyl group.
8. A process as claimed in any one of claims 4, 6 and 7, characterised in that the reaction temperature is in the range of from 0 to 60°C.
9. A process as claimed in any one of claims 4, 6 and 7, characterised in that the reaction temperature is in the range of 10 to 30°C.
10. A process as claimed in any one of claims 4, 6 and 7, characterised in that an excess of the cyanide reactant of up to 5-fold is used.
11. A process as claimed in claim 4, characterised in that there is used as starting material a compound of the general formula II and/or the trimer thereof which has been prepared by oxidation of a compound of the general formula (III) in which R1 - R7 have the meanings given for the general formula I.
12. A process as claimed in claim 11, characterised in that the compound of the general formula III has been directly oxidised to the compound of the general formula II and/or the trimer thereof, or has been indirectly oxidised by N-chlorination or N-bromination and subsequent dehydrohalogenation to give the compound of the general formula II and/or the trimer thereof.
13. A process as claimed in any one of claims 4, 7 and 11, characterised in that it also comprises a further step in which the compound of the general formula I is hydrolysed and/or alcoholised to produce a compound of the general formula VII or a salt and/or an ester thereof:
(VI) in which R1 to R7 have the meanings given for the general formula I.
(VI) in which R1 to R7 have the meanings given for the general formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7916689 | 1979-05-14 | ||
| GB7916689 | 1979-05-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116616A true CA1116616A (en) | 1982-01-19 |
Family
ID=10505142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000335720A Expired CA1116616A (en) | 1979-05-14 | 1979-09-17 | 2-cyano-3-azobicyclo(3.1.0)hexane derivatives and their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1116616A (en) |
-
1979
- 1979-09-17 CA CA000335720A patent/CA1116616A/en not_active Expired
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