Methods of making 2-halonicotinonitriles

Patent metadata

Field	Value
Publication number	US-9951020-B2
Application number	US-201615048319-A
Country	US
Kind code	B2
Filing date	Feb 19, 2016
Priority date	Aug 29, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

A method of making a 2-halonicotinonitrile comprises reacting an alkylidene nitrile with a C1-compound in an organic solvent and a dehydrating agent. The dehydrating agent substantially retards dimerization of the alkylidene nitrile during the reaction. The enamine intermediate that forms from the reaction is cyclized using a halide donor to make the 2-halonicotinonitrile.

First claim

That which is claimed is:

1. A method of making a 2-halonicotinonitrile, the method comprising:
(a) reacting an alkylidene nitrile having the formula

with a C1-compound in an organic solvent and sufficient dehydrating agent to substantially retard dimerization of the alkylidene nitrile during the reaction, thereby forming an enamine intermediate; and
(b) cyclizing the enamine intermediate with a gaseous halide (X) donor, thereby forming a 2-halonicotinonitrile having the formula

wherein
i) R1 is methyl, ethyl, phenyl, methoxyphenyl, halogen substituted phenyl or thiophene and R2 is absent or is methyl or phenyl, or
ii) R1 and R2 are atoms in a 5- or 6-membered aliphatic ring or a tetralin bicyclic ring system,
iii) R3 is CN,
iv) the dehydrating agent is an anhydride, and
vi) the C1-compound is dimethylformamide dimethyl acetal.

2. The method of claim 1 , wherein the dehydrating agent is acetic anhydride.

3. The method of claim 1 , wherein the organic solvent is selected from dichloromethane, toluene, tetrahydrofuran, an ether, ethyl acetate, and chloroform.

4. The method of claim 1 , wherein the gaseous halide donor is selected from a hydrogen halide, an alkyl halide, and a silyl halide.

5. The method of claim 1 , wherein X is Br, Cl, or I.

6. The method of claim 1 , wherein sufficient dehydrating agent to substantially retard dimerization of the alkylidene nitrile during the reaction is 10 mol % to 200 mol % of dehydrating agent.

7. The method of claim 1 , wherein the C1-compound is present in stoichiometric excess relative to the alkylidene nitrile.

8. The method of claim 1 , wherein sufficient dehydrating agent to substantially retard dimerization of the alkylidene nitrile during the reaction is 10 mol % to 50 mol % of dehydrating agent; and the C1-compound is present in stoichiometric excess relative to the alkylidene nitrile.

9. A method of making a 2-halonicotinonitrile, the method comprising:
(a) reacting an alkylidene malononitrile having the formula

with N,N-dimethylformamide dimethylacetal in a solution containing an organic solvent and sufficient dehydrating agent to substantially retard dimerization of the alkylidene malononitrile during the reaction, thereby forming an enamine intermediate; and
(b) cyclizing the enamine intermediate with a gaseous halide (X) donor, thereby forming a 2-halonicotinonitrile having the formula

wherein
i) R1 is methyl, ethyl, phenyl, methoxyphenyl, halogen substituted phenyl or thiophene and R2 is absent or is methyl or phenyl, or
ii) R1 and R2 are atoms in a 5- or 6-membered aliphatic ring or a tetralin bicyclic ring system, and
ii) the dehydrating agent is an anhydride.

10. The method of claim 9 , wherein the dehydrating agent is acetic anhydride.

11. The method of claim 9 , wherein the organic solvent is selected from dichloromethane, toluene, tetrahydrofuran, an ether, ethyl acetate, and chloroform.

12. The method of claim 9 , wherein the gaseous halide donor selected from a hydrogen halide, an alkyl halide, and a silyl halide.

13. The method of claim 9 , wherein X is Br, Cl, or I.

14. The method of claim 9 , wherein sufficient dehydrating agent to substantially retard dimerization of the alkylidene malononitrile during the reaction is 10 mol % to 200 mol % of dehydrating agent.

15. The method of claim 9 , wherein the N,N-dimethylformamide dimethylacetal is present in stoichiometric excess relative to the alkylidene malononitrile.

16. The method of claim 9 , wherein sufficient dehydrating agent to substantially retard dimerization of the alkylidene malononitrile during the reaction is 10 mol % to 50 mol % of dehydrating agent; and the N,N-dimethylformamide dimethylacetal is present in stoichiometric excess relative to the alkylidene nitrile.

17. A method of making a 2-bromo-4-methylnicotinonitrile, the method comprising:
(a) reacting an alkylidene malononitrile having the formula

with N,N-dimethylformamide dimethylacetal in a solution containing an organic solvent and sufficient acetic anhydride to substantially retard dimerization of the alkylidene malononitrile during the reaction, thereby forming an enamine intermediate; and
(b) cyclizing the enamine intermediate with a gaseous bromide donor, thereby forming a 2-bromo-4-methylnicotinonitrile having the formula

18. The method of claim 17 , wherein the organic solvent is at least one organic solvent selected from dichloromethane, toluene, tetrahydrofuran, an ether, ethyl acetate, and chloroform.

19. The method of claim 17 , wherein the gaseous bromide donor is at least one gaseous bromide donor selected from a hydrogen bromide and an alkyl bromide.

20. The method of claim 17 , wherein sufficient acetic anhydride to substantially retard dimerization of the alkylidene malononitrile during the reaction is 10 mol % to 200 mol % of acetic anhydride.

21. The method of claim 17 , wherein the N,N-dimethylformamide dimethylacetal is present in stoichiometric excess relative to the alkylidene malononitrile.

22. The method of claim 17 , wherein: sufficient acetic anhydride to substantially retard dimerization of the alkylidene malononitrile during the reaction is 10 mol % to 50 mol % of dehydrating agent; and the N,N-dimethylformamide dimethylacetal is present in stoichiometric excess relative to the alkylidene nitrite.

Assignees

• Mcquade D Tyler
• Gupton Frank B
• Longstreet Ashley R
• Opalka Suzanne M
• Univ Virginia Commonwealth
• The Florida State Univ Research Foundation Incorporated

Inventors

• Mcquade D Tyler
• Gupton Frank B
• Longstreet Ashley R
• Opalka Suzanne M

Classifications

• C07D221/16

  containing carbocyclic rings other than six-membered · CPC title

• C07D217/26

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D221/10

  Aza-phenanthrenes · CPC title

• C07D213/85 Primary

  in position 3 · CPC title