WO2022130403A1 - New quaternary ammonium salts for trifluoromethylation and process for the preparation thereof - Google Patents
New quaternary ammonium salts for trifluoromethylation and process for the preparation thereof Download PDFInfo
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- WO2022130403A1 WO2022130403A1 PCT/IN2021/051167 IN2021051167W WO2022130403A1 WO 2022130403 A1 WO2022130403 A1 WO 2022130403A1 IN 2021051167 W IN2021051167 W IN 2021051167W WO 2022130403 A1 WO2022130403 A1 WO 2022130403A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C19/00—Acyclic saturated compounds containing halogen atoms
- C07C19/08—Acyclic saturated compounds containing halogen atoms containing fluorine
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- the present invention relates to a new quaternary ammonium salt for trifluoromethylation and process for the preparation thereof. More particularly, the present invention relates to a new quaternary ammonium trifluoromethyl salts of formula (I), process for the preparation thereof and its application in trifluoromethylation.
- Trifluoromethylation (CF 3 ) containing scaffolds are found in various agrochemicals and pharmaceuticals and material industries. Incorporation of trifluoromethylation (CF 3 ) group in the drug molecule enhances the lipophilicity, biological activity, metabolic stability of the molecules. Whereas electrophilic or radical trifluoromethylation reagents have been employed with success in many applications, nucleophilic trifluoromethylation appeared poised to provide progress towards facile, catalytic arene trifluoromethylation analogous to well-established, metal-catalyzed cross-coupling reactions Unfortunately, the use of nucleophilic “CF 3 ” sources present difficulties, which has limited their use in metal- catalyzed reactions.
- Triethyl(trifluoromethyl) silane Trimethyl(trifluoromethyl)silane are the two agents known for conducting fluorinating gents, but suffer from sever drawbacks.
- the principal objective of the present invention is to provide a stable, non- hygroscopic quaternary ammonium salt of formula (I) as a trifluoro methylating agent for trifluoromethylation .
- One more objective of the present invention is to provide a process for the preparation of quaternary ammonium salts of formula (I), wherein said quaternary ammonium salts of formula (I) are for trifluoromethylation.
- Yet another objective of the present invention is to provide a process for the trifluoromethylation by using above said quaternary ammonium trifluoromethyl salts of formula (I).
- the present invention provides a stable, non-hygroscopic quaternary ammonium salts of formula (I) as a trifluoro methylating agent for trifluoromethylation.
- the present invention provides quaternary ammonium trifluoromethyl salt of formula (I), wherein the salt acts as a trifluoro methylating agents and remains stable up to 20 minutes at a temperature in the range of 25-30°C.
- R 1 , R 2 , R 3 and R 4 are branched or linear C 1 -C 4 alkyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is -OH substituted C 1 -C 4 alkyl; preferably, R 1 , R 2 , R 3 and R 4 are independently selected from -CH 3 , -CH 2 -C(OH)-(CH 3 ) 2 ; provided R 1 , R 2 , R 3 and R 4 are all not -CH 3 at the same time.
- the quaternary ammonium salt of formula (I) is selected from below quaternary ammonium trifluoride salt of formula (3), and formula (5).
- Another embodiment of the present invention provides a process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the general process comprises the steps of: a) reacting Isobutylene oxide of formula (1) with alkyl amine at a temperature in the range of 25-30 °C for 12 hours and then at 60 °C for 3 days to afford viscous liquid; b) dissolving the viscous liquid obtained at step a) in THF and reacting with alkyl halides e at a temperature of 60 °C for 2 hours to get quaternary ammonium iodide salts; c) passing the obtained quaternary ammonium iodide salts through the Amberlite® IRA400 in cl form ion exchange resin in HF from H 2 O as a solvent and then removing the water at 40 °C to get quaternary ammonium trifluoromethyl salt.
- Another aspect of an embodiment provides an alternative process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the process comprises the steps of: i. adding alkyl halide into the reaction mixture containing compound of formula (6) and maintaining the reaction mixture at a temperature in the range of 55 °C- 60°C for a period in the range of 1-2 hours; ii. concentrating the reaction mixture obtained at step i) at reduced pressure to give yellow solid; iii. passing the yellow solid obtained at step ii) through Amberlite® IRA400 in chloroform ion exchange resin in HF from H 2 O as a solvent; iv.
- Yet another embodiment of the present invention provides a process for the trifluoromethylation by using quaternary ammonium trifluoromethyl salts of formula (I), wherein said process comprises of reacting a compound of formula (A) with quaternary ammonium trifluoromethyl salt of formula (I) in the presence of metal catalyst/Lewis acid/Bronsted acid in a suitable solvent at a temperature in the range of 30-105 °C for 10-24 hours to get fluorinated products of formula (II) in 55% to 90% yield.
- Figure 1 illustrates hygroscopicity of fluoride salt
- the present invention provides a stable, non-hygroscopic quaternary ammonium salts of formula (I) as a trifluoro methylating agent for trifluoromethylation.
- the present invention provides quaternary ammonium trifluoromethyl salt of formula (I), wherein the salt acts as a trifluoro methylating agents and remains stable up to 20 minutes at a temperature in the range of 25-30°C.
- R 1 , R 2 , R 3 and R 4 are branched or linear C 1 -C 4 alkyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is -OH substituted C 1 -C 4 alkyl; preferably, R 1 , R 2 , R 3 and R 4 are independently selected from -CH 3 , -CH 2 -C(OH)-(CH 3 ) 2 ; provided R 1 , R 2 , R 3 and R 4 are all not -CH 3 at the same time.
- the quaternary ammonium salt of formula (I) is selected from below quaternary ammonium trifluoride salt of formula (3), and formula (5).
- Another embodiment of the present invention provides a process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the general process comprises the steps of: a) reacting Isobutylene oxide of formula (1) with alkyl amine at a temperature in the range of 25-30 °C for 12 hours and then at 60 °C for 3 days to afford viscous liquid; b) dissolving the viscous liquid obtained at step a) in THF and reacting with alkyl iodide at a temperature of 60 °C for 2 hours to get quaternary ammonium iodide salts; c) passing the obtained quaternary ammonium iodide salts at step c) through the Amberlite® IRA400 in cl form ion exchange resin in HF (excess) from H 2 O as a solvent and then removing the water at 40°C to get quaternary ammonium trifluoromethyl salt (I).
- Alkyl amine at step a) is selected from Ci-Cio alkyl amine or Ci-Cio dialkyl amine.
- methyl amine is used to prepare salt of formula (3) and dimethyl amine is used to prepare salt of formula (5).
- Alkyl halide at step b) is methyl iodide, methyl bromide.
- Another aspect of an embodiment provides an alternative process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the process comprises the steps of: i. adding alkyl iodide into the reaction mixture containing compound of formula (6) and maintaining the reaction mixture at a temperature in the range of 55 °C- 60°C for a period in the range of 1-2 hours; ii. concentrating the reaction mixture obtained at step i) at reduced pressure to give yellow solid; iii. passing the yellow solid obtained at step ii) through Amberlite® IRA400 in chloroform ion exchange resin in HF from H 2 O as a solvent; iv.
- R 1 , R 2 , R 3 and R 4 are branched or linear C 1 -C 4 alkyl, wherein at least one of R 1 , R 2 , R 3 and R 4 is -OH substituted C 1 -C 4 alkyl; preferably, R 1 , R 2 , R 3 and R 4 are independently selected from -CH 3 , -CH 2 -C(OH)-(CH 3 ) 2 ; provided R 1 , R 2 , R 3 and R 4 are all not -CH 3 at the same time;
- Yet another embodiment of the present invention provides a process for the trifluoromethylation by using quaternary ammonium trifluoromethyl salts of formula (I), wherein said process comprises of reacting compound of formula (A) with quaternary ammonium trifluoromethyl salt of formula (I) in the presence of metal catalyst /Lewis acid/ Bronsted acid in a suitable solvent at a temperature in the range of 30-105 °C for 10-24 h to get fluorinated products of formula (II) in 55% to 90% yield.
- Suitable solvent is selected from toluene, xylene, hexane, heptane, octane, methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide, dichloroethane, fluorobenzene, dioxane.
- toluene or THF is used as a solvent.
- X C, N, O or S
- R same or different and selected form the group comprising of C 1 -C 10 alkyl, C 1 -C 10 cycloalkyl, aryl, alkoxy, cyano, -COOR b , ketone, aldehyde, NO 2 ; wherein, R b is C 1 -C 10 alkyl or aryl;
- P CF 3 or -R a -C(OH)-CF 3 -; or any two or more adjacent carbon atoms of ring ‘Y’ may form 5-6 membered aromatic ring.
- Compound of formula (A) is selected from ethyl 4-iodobenzoate, l-chloro-4- iodobenzene, l-(tert-butyl)-4-iodobenzene, 2-chloro-5-iodopyridine, 2bromoquinolin, 5- Methyl-2-trifluoromethylthiophene, 3bromopyridine, 4-iodopyridine, 2-Chloro-6- bromopyridine, 2-Bromo-6-iodopyridin, 5-Bromo-2-iodopyridine, 2-Bromo-
- Compounds of formula (II) is selected from 4-Trifluoromethylbenzonitrile, Ethyl 4-
- Trifluoromethylbenzoate 4 Chloro(trifluoromethyl)benzene, 4- Butyl(trifluoromethyl)benzene, 2-Chloro-5-(trifluoromethyl)pyridine, 2- Trifluoromethylquinoline 5-Methyl-2-trifluoromethylthiophene, 3- (Trifluoromethyl)pyridine, 4-(Trifluoromethyl)pyridine: 2-Chloro-6- (trifluoromethyl)pyridine, 2-Bromo-6-(trifluoromethyl)pyridine 5-Bromo-2- (trifluoromethyl)pyridine, 2-Bromo-5-(trifluoromethyl)pyridine, 3-Bromo-5- (trifluoromethyl)pyridine, 2 -Chloro- 3 -(trifluoromethy Ijpyridine , 2-Chloro-4-
- Figure 1 depicts the hygroscopicity of the quaternary ammonium tifluoromethyl salts of formula (3) and formula (5).
- the trifluoro methylating agents of this invention remain non-hygroscopic for 15-20 minutes at 25-30 °C and it takes around 30 minutes for the salt to turn into a liquid.
- the salts have a charge on CF 3 , so there is no need to generate anion.
- the -OH group in the compound is necessary for their stability and so also at least one butyl group.
- step b) For fluorination, if equivalents of epoxide are increased, the step b) does not proceed. Other amberlites are also being tried and more molecules are being attempted for synthesis. The present process provides 82-93% yield, comparable to existing processes, but with a more stable and non-hygroscopic and economically more favourable agent. Thermal stability of the trifluoro methylating agents is also good.
- Step-1 Isobutylene oxide and respective amine were added into a sealed tube. The mixture was stirred at 25 °C for 12 hours and then heated at 60 °C for 3 days. The compounds were concentrated at reduced pressure to give viscous liquid.
- Step-2 In the sealed tube viscous liquid was dissolved in THF then methyl iodide (3mmol) was added and heated at 60 °C for 2 hours. The compounds were concentrated at reduced pressure to give yellow solid.
- Step-3 The yellow solid then pass through Amberlite® IRA400 in cl form ion exchange resin in HF from H 2 O as a solvent. Water was removed at 40 °C to get quaternary ammonium trifluoro methyl salt.
- Example-2 Alternative general process for the synthesis of quaternary ammonium trifluoromethyl salt (I)
- Step-1 In the sealed tube viscous liquid 6 and alkyl iodide (3mmol) was added and heated at 60 °C for 2 hours. The compounds were concentrated at reduced pressure to give yellow solid.
- Step-2 The yellow solid then pass through Amberlite® IRA400 in cl form ion exchange resin in HF from H 2 O as a solvent. Water was removed at 40 °C to gave quaternary ammonium trifluoride salt.
- Step-3 In dry round bottom flask stirred solution of TMSCF3 was dissolved in acetonitrile under argon then compound 3 was dissolved in acetonitrile add to the RB stirred for 3 hours. Concentrate under reduced pressure.
- Example-2 General process for the trifluoromethylation aryl halides and triflates
- Example-3 General process for the trifluoromethylation of aldehydes or ketones:
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Abstract
The present invention relates to a new quaternary ammonium trifluoromethyl salts of formula (I), a process for the preparation thereof and its application in trifluoromethylation: (I) wherein, R1, R2, R3 and R4 are branched or linear C1-C4 alkyl, wherein at least one of R1, R2, R3 and R4 is -OH substituted C1-C4 alkyl; preferably, R1, R2, R3 and R4 are independently selected from -CH3, -CH2-C(OH)-(CH3)2; provided R1, R2, R3 and R4 are all not -CH3 at the same time.
Description
NEW QUATERNARY AMMONIUM SALTS FOR TRIFLUOROMETHYLATION AND PROCESS FOR THE PREPARATION THEREOF
FIELD OF THE INVENTION
The present invention relates to a new quaternary ammonium salt for trifluoromethylation and process for the preparation thereof. More particularly, the present invention relates to a new quaternary ammonium trifluoromethyl salts of formula (I), process for the preparation thereof and its application in trifluoromethylation.
BACKGROUND AND PRIOR ART OF THE INVENTION
Trifluoromethylation (CF3) containing scaffolds are found in various agrochemicals and pharmaceuticals and material industries. Incorporation of trifluoromethylation (CF3) group in the drug molecule enhances the lipophilicity, biological activity, metabolic stability of the molecules. Whereas electrophilic or radical trifluoromethylation reagents have been employed with success in many applications, nucleophilic trifluoromethylation appeared poised to provide progress towards facile, catalytic arene trifluoromethylation analogous to well-established, metal-catalyzed cross-coupling reactions Unfortunately, the use of nucleophilic “CF3” sources present difficulties, which has limited their use in metal- catalyzed reactions. The commonly employed Ruppert’s reagent (Me3SiCF3), which upon exposure to fluoride sources generates trifluoromethyl anion, is prone to decomposition leading to the formation of more stable difluorocarbene and fluorosilicon compounds.
So, there is a need for stable fluorinating agent, having observed that the reported CF3 agents reported are unstable, costly, hygroscopic and volatile.
Triethyl(trifluoromethyl)silane Trimethyl(trifluoromethyl)silane
Triethyl(trifluoromethyl) silane, Trimethyl(trifluoromethyl)silane are the two agents known for conducting fluorinating gents, but suffer from sever drawbacks.
Thus, the long felt need for a stable and non-hygroscopic trifluoro methylating agent is fulfilled by the present invention.
OBJECTS OF THE INVENTION
The principal objective of the present invention is to provide a stable, non- hygroscopic quaternary ammonium salt of formula (I) as a trifluoro methylating agent for trifluoromethylation .
One more objective of the present invention is to provide a process for the preparation of quaternary ammonium salts of formula (I), wherein said quaternary ammonium salts of formula (I) are for trifluoromethylation.
Yet another objective of the present invention is to provide a process for the trifluoromethylation by using above said quaternary ammonium trifluoromethyl salts of formula (I).
SUMMARY OF THE INVENTION
Accordingly, to accomplish the objectives, the present invention provides a stable, non-hygroscopic quaternary ammonium salts of formula (I) as a trifluoro methylating agent for trifluoromethylation.
In an embodiment, the present invention provides quaternary ammonium trifluoromethyl salt of formula (I), wherein the salt acts as a trifluoro methylating agents and remains stable up to 20 minutes at a temperature in the range of 25-30°C.
wherein, R1, R2, R3 and R4 are branched or linear C1-C4 alkyl, wherein at least one of R1, R2, R3 and R4 is -OH substituted C1-C4 alkyl; preferably, R1, R2, R3 and R4 are independently selected from -CH3, -CH2-C(OH)-(CH3)2; provided R1, R2, R3 and R4 are all not -CH3 at the same time.
In particularly useful embodiment, the quaternary ammonium salt of formula (I) is selected from below quaternary ammonium trifluoride salt of formula (3), and formula (5).
Another embodiment of the present invention provides a process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the general process comprises the steps of: a) reacting Isobutylene oxide of formula (1) with alkyl amine at a temperature in the range of 25-30 °C for 12 hours and then at 60 °C for 3 days to afford viscous liquid; b) dissolving the viscous liquid obtained at step a) in THF and reacting with alkyl halides e at a temperature of 60 °C for 2 hours to get quaternary ammonium iodide salts; c) passing the obtained quaternary ammonium iodide salts through the Amberlite® IRA400 in cl form ion exchange resin in HF from H2O as a solvent and then removing the water at 40 °C to get quaternary ammonium trifluoromethyl salt.
Another aspect of an embodiment, provides an alternative process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the process comprises the steps of: i. adding alkyl halide into the reaction mixture containing compound of formula (6) and maintaining the reaction mixture at a temperature in the range of 55 °C- 60°C for a period in the range of 1-2 hours; ii. concentrating the reaction mixture obtained at step i) at reduced pressure to give yellow solid; iii. passing the yellow solid obtained at step ii) through Amberlite® IRA400 in chloroform ion exchange resin in HF from H2O as a solvent; iv. removing the water from the reaction mixture obtained at step iii) at a temperature in the range of 40°C-45°C to give quaternary ammonium trifluoride salt (7); v. stirring the solution of TMSCF3 in acetonitrile with quaternary ammonium trifluoride salt (7) obtained at step iv) in acetonitrile at a temperature in the range of -10 to 30 °C for a period in the range of 2-3 hours;
vi. concentrating the reaction mass obtained at step v) under reduced pressure to obtain quaternary ammonium trifluoromethyl salt of formula (I).
Yet another embodiment of the present invention provides a process for the trifluoromethylation by using quaternary ammonium trifluoromethyl salts of formula (I), wherein said process comprises of reacting a compound of formula (A) with quaternary ammonium trifluoromethyl salt of formula (I) in the presence of metal catalyst/Lewis acid/Bronsted acid in a suitable solvent at a temperature in the range of 30-105 °C for 10-24 hours to get fluorinated products of formula (II) in 55% to 90% yield.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates hygroscopicity of fluoride salt
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention. The detailed description will be provided herein below with reference to the attached drawing.
The present invention provides a stable, non-hygroscopic quaternary ammonium salts of formula (I) as a trifluoro methylating agent for trifluoromethylation.
In an embodiment, the present invention provides quaternary ammonium trifluoromethyl salt of formula (I), wherein the salt acts as a trifluoro methylating agents and remains stable up to 20 minutes at a temperature in the range of 25-30°C.
wherein, R1, R2, R3 and R4 are branched or linear C1-C4 alkyl, wherein at least one of R1, R2, R3 and R4 is -OH substituted C1-C4 alkyl; preferably, R1, R2, R3 and R4 are independently selected from -CH3, -CH2-C(OH)-(CH3)2; provided R1, R2, R3 and R4 are all not -CH3 at the same time.
In particularly useful embodiment, the quaternary ammonium salt of formula (I) is selected from below quaternary ammonium trifluoride salt of formula (3), and formula (5).
Another embodiment of the present invention provides a process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the general process comprises the steps of: a) reacting Isobutylene oxide of formula (1) with alkyl amine at a temperature in the range of 25-30 °C for 12 hours and then at 60 °C for 3 days to afford viscous liquid; b) dissolving the viscous liquid obtained at step a) in THF and reacting with alkyl iodide at a temperature of 60 °C for 2 hours to get quaternary ammonium iodide salts; c) passing the obtained quaternary ammonium iodide salts at step c) through the Amberlite® IRA400 in cl form ion exchange resin in HF (excess) from H2O as a solvent and then removing the water at 40°C to get quaternary ammonium trifluoromethyl salt (I).
The process for the synthesis of quaternary ammonium salt of formula (3) and formula (5) is depicted below in Scheme- la and Scheme- lb, respectively.
Alkyl amine at step a) is selected from Ci-Cio alkyl amine or Ci-Cio dialkyl amine. In a particularly useful embodiment, methyl amine is used to prepare salt of formula (3) and dimethyl amine is used to prepare salt of formula (5).
Alkyl halide at step b) is methyl iodide, methyl bromide.
Another aspect of an embodiment, provides an alternative process for the preparation of quaternary ammonium trifluoromethyl salt of formula (I), wherein the process comprises the steps of: i. adding alkyl iodide into the reaction mixture containing compound of formula (6) and maintaining the reaction mixture at a temperature in the range of 55 °C- 60°C for a period in the range of 1-2 hours; ii. concentrating the reaction mixture obtained at step i) at reduced pressure to give yellow solid; iii. passing the yellow solid obtained at step ii) through Amberlite® IRA400 in chloroform ion exchange resin in HF from H2O as a solvent; iv. removing the water from the reaction mixture obtained at step iii) at a temperature in the range of 40°C-45°C to give quaternary ammonium fluoride salt (7); v. stirring the solution of TMSCF3 in acetonitrile with quaternary ammonium fluoride salt (7) obtained at step iv) in acetonitrile at a temperature in the range of -10 to 30 °C for a period in the range of 2-3 hours; vi. concentrating the reaction mass obtained at step v) under reduced pressure to obtain quaternary ammonium trifluoromethyl salt of formula (I).
Alkyl iodide at step i) is methyl iodide.
The process is depicted below in scheme-2 generically:
wherein, R1, R2, R3 and R4 are branched or linear C1-C4 alkyl, wherein at least one of R1, R2, R3 and R4 is -OH substituted C1-C4 alkyl; preferably, R1, R2, R3 and R4 are independently selected from -CH3, -CH2-C(OH)-(CH3)2; provided R1, R2, R3 and R4 are all not -CH3 at the same time;
X= I, Br, Cl
Yet another embodiment of the present invention provides a process for the trifluoromethylation by using quaternary ammonium trifluoromethyl salts of formula (I), wherein said process comprises of reacting compound of formula (A) with quaternary ammonium trifluoromethyl salt of formula (I) in the presence of metal catalyst /Lewis acid/ Bronsted acid in a suitable solvent at a temperature in the range of 30-105 °C for 10-24 h to get fluorinated products of formula (II) in 55% to 90% yield.
Lewis acid/ Bronsted acid is selected from (M(OTf)2/ M(OTf)3 (wherein, M= Any metal selected from Ag, Bi, Cu, Fe, Ni, In, Sc), BF3-OEt2, Tf2NH, PTSA, carboxylic acids.
Suitable solvent is selected from toluene, xylene, hexane, heptane, octane, methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide, dichloroethane, fluorobenzene, dioxane. In particularly useful embodiment, toluene or THF is used as a solvent.
The process for trifluoromethylation is depicted below in Scheme-3:
wherein, ring ‘ Y’ is aromatic, 5-membered or 6-membered;
X= C, N, O or S;
Q= F, Cl, Br, I, OTf or -Ra-C(O)-;
wherein, Ra= H or C1-C10 (un)substituted alkyl, C1-C6 cycloalkyl, aryl;
R= same or different and selected form the group comprising of C1-C10 alkyl, C1-C10 cycloalkyl, aryl, alkoxy, cyano, -COORb, ketone, aldehyde, NO2; wherein, Rb is C1-C10 alkyl or aryl;
P= CF3 or -Ra-C(OH)-CF3-; or any two or more adjacent carbon atoms of ring ‘Y’ may form 5-6 membered aromatic ring.
Compound of formula (A) is selected from ethyl 4-iodobenzoate, l-chloro-4- iodobenzene, l-(tert-butyl)-4-iodobenzene, 2-chloro-5-iodopyridine, 2bromoquinolin, 5- Methyl-2-trifluoromethylthiophene, 3bromopyridine, 4-iodopyridine, 2-Chloro-6- bromopyridine, 2-Bromo-6-iodopyridin, 5-Bromo-2-iodopyridine, 2-Bromo-
5bromopyridine, 2-Chloro-3bromopyridine l-(naphthalen-2-yl)ethan-l-one, l-(4- bro mopheny I )et han- 1 -one, 1 -(4-methoxyphenyl)ethan- 1 -one, 1 -(4-chlorophenyl)ethan- 1 - one, 1 -(4-fluorophenyl)ethan- 1 -one.
Compounds of formula (II) is selected from 4-Trifluoromethylbenzonitrile, Ethyl 4-
Trifluoromethylbenzoate: 4 Chloro(trifluoromethyl)benzene, 4- Butyl(trifluoromethyl)benzene, 2-Chloro-5-(trifluoromethyl)pyridine, 2- Trifluoromethylquinoline 5-Methyl-2-trifluoromethylthiophene, 3- (Trifluoromethyl)pyridine, 4-(Trifluoromethyl)pyridine: 2-Chloro-6- (trifluoromethyl)pyridine, 2-Bromo-6-(trifluoromethyl)pyridine 5-Bromo-2- (trifluoromethyl)pyridine, 2-Bromo-5-(trifluoromethyl)pyridine, 3-Bromo-5- (trifluoromethyl)pyridine, 2 -Chloro- 3 -(trifluoromethy Ijpyridine , 2-Chloro-4-
(trifluoromethy l)pyridine , 3,5-Dibromo-2-(trifluoromethyl)pyridine 1.1. l-trifluoro-2-
(naphthalen-2yl)propan-2-ol, 2-(4-bromophenyl)- 1,1,1 -trifluoropropan-2-ol, 1,1,1 -trifluoro- 2-(4-methoxyphenyl)propan-2-ol, 2-(4-chlorophenyl)- 1 , 1 , l-trifluoropropan-2-ol: 1,1,1- trifluoro-2-(4-fluorophenyl)propan-2-ol.
Figure 1 depicts the hygroscopicity of the quaternary ammonium tifluoromethyl salts of formula (3) and formula (5). The trifluoro methylating agents of this invention remain non-hygroscopic for 15-20 minutes at 25-30 °C and it takes around 30 minutes for the salt to turn into a liquid. The salts have a charge on CF3, so there is no need to generate anion. The -OH group in the compound is necessary for their stability and so also at least one butyl group.
For fluorination, if equivalents of epoxide are increased, the step b) does not proceed. Other amberlites are also being tried and more molecules are being attempted for
synthesis. The present process provides 82-93% yield, comparable to existing processes, but with a more stable and non-hygroscopic and economically more favourable agent. Thermal stability of the trifluoro methylating agents is also good.
EXAMPLES
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Example 1: General process for the synthesis of quaternary ammonium trifluoromethyl salt (I)
Step-1: Isobutylene oxide and respective amine were added into a sealed tube. The mixture was stirred at 25 °C for 12 hours and then heated at 60 °C for 3 days. The compounds were concentrated at reduced pressure to give viscous liquid.
Step-2: In the sealed tube viscous liquid was dissolved in THF then methyl iodide (3mmol) was added and heated at 60 °C for 2 hours. The compounds were concentrated at reduced pressure to give yellow solid.
Characterization :
2-hydroxy-N, N, N,2-tetramethylpropan-l- ammonium iodide (2): ' l I NMR (400MHz, MeOD-d4) δ4.75 (br s, 11 H), 2.82 (s, 6 H) 13C NMR (101MHz, MeOD-d4) 74.9, 71.0, 56.4, 31.0
2-hydroxy-N-(2-hydroxy-2-methylpropyl)-N,N,2-trimethylpropan-l- ammonium iodide (4): JH NMR (400MHz, MeOD-d4) 5.20 (s, 4 H), 4.99 (s, 6 H), 3.00 (s,
9 H) 13C NMR (101MHz, MeOD-d4) 75.0, 71.2, 55.5, 5, 31.3
Step-3: The yellow solid then pass through Amberlite® IRA400 in cl form ion exchange resin in HF from H2O as a solvent. Water was removed at 40 °C to get quaternary ammonium trifluoro methyl salt.
Characterization :
2-hydroxy-N, N, N,2-tetramethylpropan-l- ammonium Trifluomethy (3): ’l l NMR (400MHz, CH3CN-d3) 63.62 (br. s., 4 H), 3.29 (s, 6 H), 1.33 (s, 9 H) 13C NMR (101MHz, CH3CN-d3) 6, 73.3, 70.2, 55.7, 31.2, 2.0, 19F NMR (376 MHz, CDCh) 6 127;
2-hydroxy-N-(2-hydroxy-2-methylpropyl)-N,N,2-trimethylpropan-l- ammonium Trifhiomethyl (5): JH NMR (400MHz , CH3CN-d3) 63.62 (br. s., 4 H), 3.29 (s, 6 H), 1.33 (s, 9 H) 13C NMR (100|MHz ,CH3CN-d3) 6 73.3, 70.2, 55.7, 31.2, 2.0, 19F NMR (376 MHz, CDCh) 6 129;
Example-2: Alternative general process for the synthesis of quaternary ammonium trifluoromethyl salt (I)
Step-1: In the sealed tube viscous liquid 6 and alkyl iodide (3mmol) was added and heated at 60 °C for 2 hours. The compounds were concentrated at reduced pressure to give yellow solid.
Step-2: The yellow solid then pass through Amberlite® IRA400 in cl form ion exchange resin in HF from H2O as a solvent. Water was removed at 40 °C to gave quaternary ammonium trifluoride salt.
Step-3. In dry round bottom flask stirred solution of TMSCF3 was dissolved in acetonitrile under argon then compound 3 was dissolved in acetonitrile add to the RB stirred for 3 hours. Concentrate under reduced pressure.
Example-2: General process for the trifluoromethylation aryl halides and triflates
In a flame dried reaction vials or round bottom flask halide precursor (A) (Immol), (di-tBuOH)2Me2NCF3 or tBuOH) Me3NCF3 (3mmol) and Pd(OAc)2 or Ni(COD), (10% mmol) was added in a toluene and stirred at 100°C forl2h. After completion of reaction mixture was concentrated under reduced pressure. The crude product was purified by flash
column chromatography using EtOAc/hexane to give fluorinated products in 55% to 90% yield.
Characterization of synthesized compound:
4-Trifluoromethylbenzonitrile :
1H NMR (400 MHz, CDC13) d 7.75 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H); 19F NMR (376 MHz, CDC13) d 98.2 (s, 3F); EI-MS m/z (%) 171 (M+, 100), 152 (33), 121 (41).
Ethyl 4- Trifluoromethylbenzoate:
1H NMR (400 MHz, CDC13) d 1.42 (t, J = 7.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H); 19F NMR (376 MHz, CDC13) d 98.8 4-Chloro(trifluoromethyl)benzene:
1H NMR (400 MHz, CDC13) d 7.46 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H); 19F NMR (376 MHz, CDC13) d 99.3.
4-Butyl(trifluoromethyl) benzene :
1H NMR (400 MHz, CDC13) d 0.52 (t, J = 8.0 Hz, 3H), 1.31-1.36 (m, 2H), 1.54- 1.61 (m, 2H), 2.67 (t, J = 7.8 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H); 19F NMR (376 MHz, CDC13) d 99.4
2-Chloro-5-(trifhioromethyl)pyridine:
1H NMR (400 MHz, CDC13) d 7.48 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8,5 Hz, 1H), 8.67 (s, 1H); 19F NMR (376 MHz, CDC13) d 99.5
2-Trifluoromethylquinoline :
1H NMR (400 MHz, CDC13) d 7.68 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), d 8.37 (d, J = 8.8 Hz, 1H); 19F NMR (376 MHz, CDC13) d 94.3
5-Methyl-2-trifluoromethylthiophene:
1H NMR (400 MHz, CDC13) d 2.41 (s, 3H), 6.63-6.67 (m, 1H), 7.15 (d, J = 4.0 Hz, 1H); 19FNMR (376 MHz, CDC13) d 107
3-(Trifluoromethyl)pyridine:
1H NMR: a 5 8.92 (s, 1 H), 8.81 (d, J 5 4.8 Hz), 7.94 (d, J 5 8.0 Hz), 7.87 (dd, J 5 7.9, 4.9 Hz). 13C NMR: a 5 153.4, 146.9 (q, J 5 4.0 Hz), 133.1 (q, J 5 3.0 Hz), 127.8 (q, J 5 33.0 Hz), 123.5 (q, J 5 273 Hz), 123.6.
4-(Trifluoromethyl)pyridine:
1H NMR: a 5 8.81 (d, J 5 5.1 Hz, 1 H), 7.54 (d, J 5 5.2 Hz, 1 H). 13C NMR: a 5 150.4, 138.3 (q, J 534.0 Hz), 122.4 (q, J 5273 Hz), 119.1.
2-Chloro-6-(trifluoromethyl)pyridine:
1H NMR: a 5 7.9 (m, 1 H), 7.65 (d, J 5 7.5 Hz, 1 H), 7.54 (d, J 5 8.1 Hz, 1 H). 13C NMR: a 5 152.0, 148.3 (q, J 5 36.0 Hz), 141.0, 127.6, 120.6 (q, J 5 274 Hz), 119.0. 19F NMR: 5268.7.
2-Bromo-6-(trifluoromethyl)pyridine:
1H NMR: a 5 7.77 (t J 5 7.9 Hz, 1 H), 7.70 (d, J 5 7.7 Hz, 1 H), 7.67 (dd, J 5 7.7, 1.0 Hz, 1 H). 13C NMR: a 5 148.8 (q, J 5 36.0 Hz), 142.4, 139.6, 131.4, 120.4 (q, J 5 274 Hz), 119.4. 19F NMR: 5 268.7
5-Bromo-2-(trifluoromethyl)pyridine:
1H NMR: a 5 8.79 (d, J 5 1.9 Hz, 1 H), 8.02 (dd, J 5 8.3, 1.9 Hz, 1 H), 7.59 (d, J 5 8.3 Hz, 1 H). 13C NMR: a 5 151.3, 146.6 (q, J 5 35.0 Hz), 140.0, 124.0, 121.7, 121.3 (q, J 5 274 Hz). 19F NMR: 5 268.4 (s).
2-Bromo-5-(trifluoromethyl)pyridine:
1H NMR: a 5 8.66 (s, 1 H), 7.80 (dd, J 5 8.5, 2.5 Hz, 1 H), 7.66 (d, J 5 8.4 Hz, 1 H). 13C NMR: a 5 147.1 (q, J 5 4.0 Hz), 145.9, 135.3 (q, J 5 3.0 Hz), 128.3, 126.0 (q, J 5 33.0 Hz), 123.1 (q, J 5273 Hz). 19F NMR: 5263.0
3-Bromo-5-(trifluoromethyl)pyridine:
1H NMR: a 5 8.88 (s, 1 H), 8.82 (s, 1 H), 8.08 (s, 1 H). 13C NMR: a 5 154.4, 144.9 (q, J 5 4.0 Hz), 135.8 (q, J 5 3.0 Hz), 128.0 (q, J 5 34.0 Hz), 122.6 (q, J 5 273 Hz), 120.7. 19F NMR: 5262.0
2-Chloro-3-(trifluoromethyl)pyridine:
1H NMR: a 5 8.58 (dd, J 5 4.8, 1.3 Hz, 1 H), 8.04 (dd, J 5 7.8, 1.9 Hz, 1 H), 7.40 (dd, J 5 7.4, 4.8 Hz, 1 H). 13C NMR: a 5 152.4, 149.1, 136.8 (q, J 5 5.0 Hz), 125.5 (q, J 5 33.0 Hz), 122.3 (q, J 5273 Hz), 122.1. 19F NMR: 5 264.4 2-Chloro-4-(trifluoromethyl)pyridine:
1H NMR: a 5 8.60 (d, J 55.1 Hz, 1 H), 7.58 (dq, J 51.5, 0.8 Hz, 1 H), 7.48 (dm, J 5 5.1 Hz, 1 H). 13C NMR: a 5 152.7, 151.0, 141.1 (q, 7 5 35.0 Hz), 122.2 (q, 7 5 273 Hz),
120.7 (q, J 54.0 Hz), 118.3 (q, J 53.0 Hz). 19F NMR: 5265.4
3,5-Dibromo-2-(trifluoromethyl)pyridine:
1H NMR: a 5 8.68 (d, 7 5 1.8 Hz, 1 H), 8.2 (m, 1 H). 13C NMR: a 5 148.3, 144.8,
144.7 (q, J 535.0 Hz), 123.7, 120.9 (q, J 5275 Hz), 118.4. 19F NMR: 5 266.4
Example-3: General process for the trifluoromethylation of aldehydes or ketones:
In a flame dried reaction vials or round bottom flask Aldehyde and ketones (A) (Immol), (di-tBuOH)R2NCF3 and Lewis acid/ Bronsted acid (10% mmol) was added dry
THF and stirred at for 12h. After completion of reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography using EtOAc/hexane to give fluorinated products in 55% to 91% yield.
Characterization of synthesized compound:
1.1.1-trifhioro-2-(naphthalen-2yl)propan-2-ol: 1H NMR (CDC13) 6 1.88 (s, 3H), 2.50 (s, 1H), 7.46.7.54 (m, 2H), 7.66 (d, J = 8.4Hz, 1H), 7.78.7.92 (m, 3H), 8.05 (s, 1H); 13C NMR (CDC13) δ 24.2, 75.0 (q, J = 29.1 Hz), 123.3 (d, J = 1.6 Hz), 125.4 (d, J = 1.2Hz), 125.46 (q, J = 284.5Hz), 126.2, 126.8, 127.3, 127.9, 128.2, 132.6, 132.8, 135.5; 19F NMR (CDC13) 6 .80.7
2-(4-bromophenyl)-l,l,l-trifhioropropan-2-ol: 1H NMR (CDC13) 6 1.75 (s, 3H), 2.64 (br s, 1H), 7.38.7.55 (m, 4H); 13C NMR (CDC13) δ 24.0, 74.6 (q, J = 29.1 Hz), 122.8, 125.1 (q, 7 = 284.1 Hz), 127.7, 131.2, 137.1; 19F NMR (CDC13) δ 81.1
1.1.1-trifhioro-2-(4-methoxyphenyl)propan-2-ol: 1H NMR (CDC13) δ 1.75 (s,
3H), 2.42 (br s, 1H), 3.81 (s, 3H), 6.90 (dt, J = 1.6, 8.8 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H); 13C NMR (CDC13) δ 24.0, 55.3, 74.6 (q, J = 29.1 Hz), 113.5, 125.4 (q, 7 = 284.1 Hz),
127.2, 130.3, 19F NMR (CDC13) δ .81.3
2-(4-chlorophenyl)-l,l,l-trifhioropropan-2-ol: 1H NMR (CDC13) δ 1.77 (s, 3H), 2.45 (s, 1H), 7.35 (dt, 7 = 1.8, 8.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H); 13C NMR (CDC13) δ 24.1, 74.5 (q, 7 = 29.1 Hz), 125.1 (q, J = 284.1 Hz), 127.4, 128.3, 134.5, 136.6; 19F NMR (CDC13) δ .81.2
1.1.1-trifluoro-2-(4-fluorophenyl)propan-2-ol: 1H NMR (CDC13) δ 1.78 (s, 3H), 2.43 (br s, 1H), 7.02.7.12 (m, 2H), 7.52.7.59 (m, 2H); 113.1.113.2 (m, IF); 13C NMR (CDC13) δ 24.1, 74.5 (q, 7 = 29.1 Hz), 115.0(q, 7 = 21.5 Hz), 125.3 (q, 7 = 284.9 Hz), 127.89 (d, 7 = 8.4 Hz), 127.92 (d, 7 = 8.0 Hz), 134.0 (d, 7 = 3.2 Hz), 162.5 (d, 7 = 246.6); 19F NMR (CDC13) δ .81.1
ADVANTAGES OF THE INVENTION
• stable, non-hygroscopic and cheap trifluoro methylating agents are provided.
• simple and easy method to prepare these trifluoro methylating agents is provided.
• simple and easy method of trifluoromethylation of the compounds.
Claims
Claims:
A quaternary ammonium trifluoromethyl salt of formula (I);
wherein, R1, R2, R3 and R4 are C1-C4 alkyl, wherein at least one of R1, R2, R3 and R4 is -OH substituted C1-C4 alkyl; preferably, R1, R2, R3 and R4 are independently selected from -CH3, -CH2-C(OH)- (CH3)2; provided R1, R2, R3 and R4 are all not -CH3 at the same time; wherein, said quaternary ammonium salt of formula (I) remains stable up to 20 minutes at a temperature in the range of 25-30°C.
2. The quaternary ammonium salt of formula (I) as claimed in claim 1, is selected from quaternary ammonium salts of formula (3) and formula (5);
3. A process for the preparation of quaternary ammonium salt of formula (I) as claimed in claim 1, wherein the process comprising the steps of: a) reacting Isobutylene oxide of formula (1) with alkyl amine at a temperature in the range of 25-30 °C for 12 hours and then at 60 °C for 3 days to afford viscous liquid;
b) dissolving the viscous liquid obtained at step a) in THF and reacting with alkyl iodide at a temperature of 60 °C for 2 hours to get quaternary ammonium iodide salts; c) passing the obtained quaternary ammonium iodide salts at step c) through the Amberlite® IRA400 in cl form ion exchange resin in HF from H2O as a solvent and then removing the water at 40 °C to get quaternary ammonium trifluoromethyl salt (I). The process as claimed in claim 3, wherein said alkyl amine at step a) is selected from methyl amine and dimethyl amine, and wherein said alkyl iodide at step b) is methyl iodide. A process for the preparation of quaternary ammonium salt of formula (I) as claimed in claim 1, wherein the process comprising the steps of: i. adding alkyl iodide into the reaction mixture containing compound of formula (6) and maintaining the reaction mixture at a temperature in the range of 55 °C- 60°C for a period in the range of 1-2 hours; ii. concentrating the reaction mixture obtained at step i) at reduced pressure to give yellow solid; iii. passing the yellow solid obtained at step ii) through Amberlite® IRA400 in chloroform ion exchange resin in HF from H2O as a solvent; iv. removing the water from the reaction mixture obtained at step iii) at a temperature in the range of 40°C-45°C to give quaternary ammonium trifluoride salt (7); v. stirring the solution of TMSCF3 in acetonitrile with quaternary ammonium trifluoride salt (7) obtained at step iv) in acetonitrile at a temperature in the range of -10 °C to 30 °C for a period in the range of 2-3 hours; vi. concentrating the reaction mass obtained at step v) under reduced pressure to obtain quaternary ammonium trifluoromethyl salt of formula (I). A process for the trifluoromethylation by using quaternary ammonium salts of formula (I) as claimed in claim 1, wherein said process comprises of reacting compound of formula (A) with quaternary ammonium trifluoromethyl salt of formula (I) in the presence of metal catalyst /Lewis acid/ Bronsted acid in a suitable solvent at a temperature in the range of 30-105 °C for 10-12 hours to get fluorinated products of formula (II).
The process for the trifluoromethylation as claimed in claim 6, wherein said compound of formula (A) is selected from ethyl 4-iodobenzoate, l-chloro-4- iodobenzene, l-(tert-butyl)-4-iodobenzene, 2-chloro-5-iodopyridine,
2bromoquinolin, 5-Methyl-2-trifluoromethylthiophene, 3bromopyridine, 4- iodopyridine, 2-Chloro-6-bromopyridine, 2-Bromo-6-iodopyridin, 5-Bromo-2- iodopyridine, 2-Bromo-5bromopyridine, l-(naphthalen-2-yl)ethan-l-one, l-(4- bromophenyl)ethan-l-one, l-(4-methoxyphenyl)ethan-l-one, l-(4- chlorophenyl)ethan- 1-one, l-(4-fluorophenyl)ethan- 1-one. The process for the trifluoromethylation as claimed in claim 6, wherein said compound of formula (II) is selected from 4-Trifluoromethylbenzonitrile, Ethyl 4-
T rifluoromethy Ibenzoate : 4 Chloro(trifluoromethyl)benzene, 4-
B utyl(trifluoromethyl)benzene, 2-Chloro-5-(trifluoromethyl)pyridine, 2- T rifluoromethy Iquinoline 5-Methyl-2-trifluoromethylthiophene, 3- (Trifluoromethyl)pyridine, 4-(Trifluoromethyl)pyridine: 2-Chloro-6- (trifluoromethyl)pyridine, 2-Bromo-6-(trifluoromethyl)pyridine 5-Bromo-2- (trifluoromethyl)pyridine, 2-Bromo-5-(trifluoromethyl)pyridine, 3-Bromo-5-
(trifluoromethyl)pyridine, 2-Chloro-3-(trifluoromethyl)pyridine:
2-Chloro-4-(trifluoromethyl)pyridine, 3 ,5 -Dibromo-2-(trifluoromethyl)pyridine 1.1.1 -trifluoro-2-(naphthalen-2yl)propan-2-ol 2-(4-bromophenyl)- 1,1,1- trifluoropropan-2-ol: 1,1,1 -trifluoro-2-(4-methoxyphenyl)propan-2-ol: 2-(4- chlorophenyl)- 1,1,1 -trifluoropropan-2-ol: 1,1,1 -trifluoro-2-(4-fluorophenyl)propan- 2-ol. The process for the trifluoromethylation as claimed in claim 6, wherein said metal catalyst or Lewis acid or Bronsted acid is selected from M(OTf)2/ M(OTf)3; wherein
M (metals) is selected from Ag, Bi, Cu, Fe, Ni, In, Sc, BF3*OEt2, Tf2NH, PTSA, carboxylic acids; and wherein said suitable solvent is selected from toluene and
THF. The process for the trifluoromethylation as claimed in claim 6, wherein said fluorinated product is obtained in 55% to 90% yield.
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| US3954873A (en) * | 1972-06-16 | 1976-05-04 | Robert M. Gipson | Amino alcohols |
| WO2020214692A1 (en) * | 2019-04-16 | 2020-10-22 | Angus Chemical Company | Low toxicity organic tertiary and quaternary amines and uses thereof |
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| US3954873A (en) * | 1972-06-16 | 1976-05-04 | Robert M. Gipson | Amino alcohols |
| WO2020214692A1 (en) * | 2019-04-16 | 2020-10-22 | Angus Chemical Company | Low toxicity organic tertiary and quaternary amines and uses thereof |
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| HE YU-TAO, LI LIAN-HUA, YANG YAN-FANG, WANG YU-QI, LUO JIAN-YI, LIU XUE-YUAN, LIANG YONG-MIN: "Copper-catalyzed synthesis of trifluoromethyl-substituted isoxazolines", CHEMICAL COMMUNICATIONS, vol. 49, no. 50, 1 January 2013 (2013-01-01), UK , pages 5687 - 5689, XP055951223, ISSN: 1359-7345, DOI: 10.1039/c3cc42588f * |
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