Certain n-trifluoromethyl compounds and methods of synthesizing n- trifluoromethyl compounds

Abstract

A process for synthesizing N-CF3 compounds, including N-CF3 sulfonamides and analogues thereof is disclosed. Starting materials for these syntheses include compounds with acidic N-H groups which are converted into dithiocarbamates, and then these dithiocarbamates are fluorinated to obtain N-CF3 compounds using a combination of oxidants and fluorination reagents. The reagents used in these steps are readily available and have relatively low hazard levels. The reactions can be carried out under mild conditions, for example, at or below room temperature, and can be scaled-up since the reagents can be readily obtained in large quantities. High-purity yields can be obtained. In addition, the compounds N-methyl-N-(trifluoromethyl)methanesulfonamide, having the formula H3CSO2N(CF3)(CH3), and 2-(trifluoromethyl)isothiazolidine 1,1 -dioxide, having the formula H6CSO2N(CF3), are disclosed.

Description

CERTAIN N-TRIFLUOROMETHYL COMPOUNDS AND METHODS OF SYNTHESIZING N- TRIFLUOROMETHYL COMPOUNDSRELATED APPLICATION DATA

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 63 / 623,534, filed lanuary 22, 2024, and titled “Certain N-Trifluoromethyl Compounds and Methods of Synthesizing N-Trifluoromethyl Compounds”, which is incorporated by reference herein in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure generally relates to the field of N-trifluoromethyl compounds. In particular, the present disclosure is directed to certain N-trifluoromethyl compounds and methods of synthesizing N-trifluoromethyl compounds.BACKGROUND

[0003] Compounds with N-trifluoromethyl (N-CF3) functional groups can be challenging to synthesize. Existing methods for synthesizing these compounds generally require harsh reaction conditions, unstable intermediates and expensive and / or toxic reagents, and allow for the inclusion of only limited functional groups. These existing methods therefore cannot be scaled up easily and limit the particular compounds that can be generated. Due to their potential applications in the chemical, materials, and pharmaceutical industries, there is a need for a relatively safe, economical, and high-yield method for producing N-CF3 compounds.SUMMARY OF THE DISCLOSURE

[0004] A compound having the formula:

[0005] A method of producing an N-trifluoromethyl product having a formula ofis disclosed in which Ri is selected from the group of C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, and a heteroaryl group, and R2 is selected from the group of C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, and a heteroaryl group. The method includes deprotonating a reactant having an acidic N-H group with a base, reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate compound, and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

[0006] Additionally or alternatively, the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

[0007] Additionally or alternatively, the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed in a temperature range of about 0°C to about 25°C.

[0008] Additionally or alternatively, the N-trifluoromethyl product is an N-trifluoromethyl sulfonamide product.

[0009] Additionally or alternatively, the N-trifluoromethyl product is N-methyl-N- (trifluoromethyl)methanesulfonamide.

[0010] Additionally or alternatively, the reactant is a sulfonamide compound.

[0011] Additionally or alternatively, the N-trifluoromethyl product is an N-trifluoromethyl amide product.

[0012] Additionally or alternatively, the reactant is an amide compound.

[0013] Additionally or alternatively, the N-trifluoromethyl product is an N-trifluoromethyl amine product.

[0014] Additionally or alternatively, the reactant is an amine compound.

[0015] Additionally or alternatively, the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t- butyllithium.

[0016] Additionally or alternatively, the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

[0017] Additionally or alternatively, the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

[0018] Additionally or alternatively, the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

[0019] Additionally or alternatively, the dithiocarbamate compound is reacted with CH3I in dimethylformamide.

[0020] Additionally or alternatively, the dithiocarbamate compound is reacted with a mixture of pyridine and hydrogen fluoride at about -70°C.

[0021] Additionally or alternatively, more than 20 g of N-trifluoromethyl product is produced.

[0022] In another aspect, a method of producing an N-trifluoromethyl product having a formula ofis disclosed where Ri is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2- C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or heteroaryl group, where R2 is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group, and where L is CH2, CO, or SO2. The method includes deprotonating a reactant having an acidic N-H group with a base, reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate compound, and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

[0023] Additionally or alternatively, the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

[0024] Additionally or alternatively, the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t- butyllithium.

[0025] Additionally or alternatively, the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

[0026] Additionally or alternatively, the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

[0027] Additionally or alternatively, the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

[0028] Additionally or alternatively, more than 20 g of N-trifluoromethyl product is produced.

[0029] Further, a method of producing an N-trifluoromethyl product of a formula ofwhere L is CH2, CO, or SO2, where Y is CnHmX2n-ni (in which X is F, Cl, Br, or I, n is selected from 1 to 9, and m is selected from 0 to 2n) and where Z is CH2, CHX, or CX2 (where X is F, Cl, Br, or I). The method includes deprotonating a reactant having an acidic N-H group with a base, reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate intermediate, and reacting the dithiocarbamate intermediate with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

[0030] Additionally or alternatively, the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate intermediate are performed at or below room temperature.

[0031] Additionally or alternatively, the reactant has the formula:H

[0032] Additionally or alternatively, the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t- butyllithium.

[0033] Additionally or alternatively, the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

[0034] Additionally or alternatively, the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

[0035] Additionally or alternatively, the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

[0036] Additionally or alternatively, more than 20 g of N-trifluoromethyl product is produced.

[0037] In another aspect, a method of producing an N-trifluoromethyl product having a formula of CF3-NR1R2, where Ri is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or heteroaryl group and where R2 is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group. The method includes deprotonating a reactant having an acidic N-H group with a base, reacting the deprotonated reactant with carbondisulfide and then an alkylating reagent to form a dithiocarbamate compound, and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N- trifluoromethyl product.

[0038] Additionally or alternatively, the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

[0039] Additionally or alternatively, the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t- butyllithium.

[0040] Additionally or alternatively, the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

[0041] Additionally or alternatively, the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

[0042] Additionally or alternatively, the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

[0043] Additionally or alternatively, the dithiocarbamate compound is reacted with CH3I in dimethylformamide.

[0044] Additionally or alternatively, the dithiocarbamate compound is reacted with a mixture of pyridine and hydrogen fluoride at about -70°C.

[0045] Additionally or alternatively, more than 20 g of N-trifluoromethyl product is produced.

[0046] In addition, a compound having the formulais disclosed.DETAILED DESCRIPTION

[0047] Methods disclosed may be used for synthesizing N-CF3 compounds, including N-CF3 sulfonamides and analogues thereof, having any of the following formulae:and salts thereof, wherein Ri is a C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group; and R2 is a C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group.

[0048] The methods disclosed may also be used for synthesizing N-CF3 compounds having the following formulae:wherein Ri is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group; R2 is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2- C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or heteroaryl group; L is CH2, CO, or SO2; Y is CnHmX2n-ni (in which X is F, Cl, Br, or I, n is selected from 1 to 9, and m is selected from 0 to 2n); and Z is CH2, CHX, or CX2 (wherein X is F, Cl, Br, or I).

[0049] In addition, the compound N-methyl-N-(trifluoromethyl)methanesulfonamide is provided, having the formula H3CSO2N(CF3)(CH3) and shown below:and being prepared by any suitable process, including methods described herein.

[0050] In addition, the compound 2-(trifluoromethyl)isothiazolidine 1,1 -di oxi de is provided, having the formula HeCsSChN^CFs) and shown below:and being prepared by any suitable process, including methods described herein.

[0051] The N-CF3 compounds may be used as or as part of electrolyte solvents, additives, polymer electrolytes, and polymer coating materials. In addition, the above compounds may be usedto synthesize organic compounds that have potential applications in the chemical, material, and pharmaceutical industries.

[0052] To synthesize these compounds, at a high level, starting materials with acidic N-H groups are converted into dithiocarbamates, and then these dithiocarbamates are fluorinated to obtain N-CF3 compounds using a combination of oxidants and fluorination reagents. The reagents used in these steps are readily available and have relatively low hazard levels. The reactions can be carried out under mild conditions, for example, at or below room temperature, and can be scaled-up since the reagents can be readily obtained in large quantities. High-purity yields can be obtained with simple purification processes. In some embodiments, the reactions can be run at a temperature of about 50°C or less, for example about 25°C or less, or in a range of about -10°C to about 35°, or in a range of about -5°C to about 30°C, or in a range of about 0°C to about 25°C, among others, which as can be seen in the examples will vary depending on the reaction stage, e.g., fluorination. In general, the reactions are exothermic, therefore, it is preferable to maintain reaction temperatures at or below 0°C. The reactions are preferably carried out within a range of temperatures, e.g., from -78°C (i.e., temperature of an acetone / dry ice bath) to 35°C. It will be understood that the ranges employed may depend on the particular reagents selected.

[0053] In certain embodiments, the starting materials may be secondary sulfonamides, amides, or amines, many of which are commercially available or can be readily synthesized from commercially available starting materials. Reagents may include sodium hydride, carbon disulfide, methyl iodide, pyridine hydrofluoride, and l,3-dibromo-5,5-dimethylhydantoin. As noted, reaction conditions are mild, and in many cases the reactions can be run at or below room temperature without external heating. The reactions can be scaled up to obtain relatively substantial amounts of product, e.g., more than 20 g, and may be scalable to obtain more than 1 kg or more of product. Higher or lower amounts may be obtained depending on the reactants used. For example, a particular type or strength of base may be required for certain reactants because of the different acidity of N-H bonds in each.

[0054] The synthesis scheme includes starting with reagents having acidic N-H structures that are converted to dithiocarbamates that are used to form N-trifluoromethyl compounds as shown in the sample reaction overviews, e.g., Schemes I-III below, in which the “A” compounds are startingreagents having acidic N-H groups, the “B” compounds are dithiocarbamate intermediaries, the “C” compounds are N-CF3 products, wherein Ri may be an alkyl-, aryl-, hetaryl-, N-, O-, or halogensubstituent, R2 may be a H-, alkyl-, aryl-, or hetaryl- substituent, and R3 may be an alkyl- substituent.Scheme IScheme III

[0055] In another embodiment, the starting reactant may be a compound with the formula shown below:in which Ri and R2 are independently selected from C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, heteroaryl, and L is CH2, CO, or SO2. Starting reactants may also be of the formula shown below:in which L is CH2, CO, or SO2, Y is CnHmX2n-ni (where X is F, Cl, Br, or I, n is selected from 1 to 9, and m is selected from 0 to 2n), and. Z is CH2, CHX, or CX2 (where X is selected from F, Cl, Br, or I).Example Synthesis I: N-methyl-N-(trifluoromethyl)methanesulfonamide

[0056] In an embodiment, N-methyl-N-(trifluoromethyl)methanesulfonamide may be produced as follows. A suspension of 2.7 g (67 mmol) of sodium hydride in mineral oil is added to a 50 mL solution containing 7 g (64 mmol) of the sulfonamide compound (e.g., Compound 1 in Reaction I overview shown below) in dimethylformamide (DMF) at 0°C, and this mixture is stirred for 30 minutes. (Stirring times and reaction times will vary depending on the reactants and condition. For example, for a weaker base or for a starting material having less acidic N-H bonds, longer reaction times may be needed. In general, a range of stirring times may be from 5 minutes to 8 hours.) After this step, 4.63 mL (77 mmol) of carbon disulfide is added dropwise, at which point the reaction mixture is warmed to room temperature, stirred for 4 hours, and then cooled to 0°C. (The temperatures used are based in part on how exothermic the reaction is, and the range for these reactions is preferably -78°C to 35°C.) Next, 10.9 g (77 mmol) of methyl iodide is added dropwise, and the mixture, with DMF as a solvent, is warmed back to room temperature. This reaction mixture is poured into 250 mL of water and the product is extracted using methyl tert-butyl ether. After evaporation of the solvent, 9.5 g of a dithiocarbamate compound (Compound 2 in Reaction I below) is obtained as a pale-yellow oil at a 75% yield. (In general, for the disclosed reactions the range of expected percent yield at this step may vary from 30% to 99%, depending on numerous factors including the starting reagents selected.)Reaction I2 3

[0057] The dithiocarbamate compound is dissolved in 25 mL of dichloromethane (DCM) (e.g., 5 g of dithiocarbamate compound or 25 mmol) to which is added dropwise, preferably within a temperature range of -78°C to 35°C, such as at -70°C, to a mixture of 25 mL of Pyridine HF complex (30% pyridine, 70% hydrogen fluoride) and 21.6 g (75 mmol) of l,3-dibromo-5,5- dimethylhydantoin (DBDMH) in 75 mL of DCM. This mixture is then warmed to room temperature and stirred for 4 hours before being poured into crushed ice. (The stirring time and temperature mayvary based on the reactant, the oxidizing reagent, and the fluorination reagent. In general, a temperature range of -78°C to 35 °C may be used and stirring times may range from 2 minutes to 48 hours.) The mixture is then neutralized with K2CO3 and washed with 30 mL of water followed by 30 mL of IM aqueous HC1, and then again with 30 mL of water. After evaporation of the solvent, the residue is distilled with a column for rectification. Distillation may be conducted in a vacuum, such as from 0.01 torr up to standard pressure. In this example, 1.6 g of Compound 3 (in Reaction I shown above), i.e., N-methyl-N-(trifluoromethyl)methanesulfonamide (36% yield, which may vary from 10% to more than 90%), which has a boiling point of 76°C (40 mbar), was produced.Example Synthesis II: 2-(trifluoromethyl)isothiazolidine 1,1-dioxide1 2

[0058] In an embodiment, 2-(trifluoromethyl)isothiazolidine 1,1-dioxide may be produced from isothiazolidine, 1,1-dioxide (Compound 1 in the reaction sequence shown above) as follows. In step A, a sodium hydride suspension in mineral oil (20.8 g, 0.86 mol) was added to a solution of isothiazolidine, 1,1-dioxide (100 g, 0.83 mol) in dimethylformamide (500 mL) at 0°C. The mixture was stirred for 30 min and carbon disulfide (94 g, 1.24 mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for four hours and cooled to 0°C.Methyliodide (142 g, 1 mol) was added drop wise and the mixture was warmed to room temperature. The reaction mixture was poured into water (2 L) and the product was extracted with methyl tertbutyl ether. After evaporation, Compound 2 (174 g, 100% yield) was obtained as a pale-yellow low melt solid.

[0059] In step B, a solution of Compound 2 (69.7 g, 0.33 mol) in 250 mL of DCM was added dropwise at -70°C to a mixture of pyridine-HF complex (30% pyridine, 70% hydrogen fluoride) (330 mL) and l,3-dibromo-5,5-dimethylhydantoin (286 g, 1 mol) in DCM (1 L). This mixture was warmed to room temperature and stirred for four hours before it was poured into crushed ice. The mixture was neutralized with K2CO3 and washed with water, then with aqueous HC1, and then with water again. After evaporation of the solvent, the residue was distilled in vacuum with column forrectification, yielding 2-(trifluoromethyl)isothiazolidine 1,1 -di oxide (21 g, yield 33%), with a boiling point of 130 °C / 15 mbar.Example Synthesis III: Other N-Trifluoromethyl Compounds

[0060] Additional N-trifluoromethyl compounds may be synthesized based on the overall scheme described above. From starting materials described above, such as, for example:in which Ri and R2 are independently selected from C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, heteroaryl, and L is CH2, CO, or SO2 (designated as compound “Al” in Reaction II shown below) orin which L is CH2, CO, or SO2, Y is CnHmX2n-ni (where X is F, Cl, Br, or I, n is selected from 1 to 9, and m is selected from 0 to 2n), and. Z is CH2, CHX, or CX2 (where X is selected from F, Cl, Br, or I) (designated as compound “A2” in the Reaction III shown below), the reaction sequences shown in Reactions II and III along with the noted reagents and conditions can be used to synthesize N-CF3 compounds (e.g., Cl, C2).Reaction II1. base fluorination2. CS2regent3. alkylation oxidizing reagent reagent- ► - ► solvent, 0°C-rt solvent, -78°C-rtAl Bl ClReaction III1. base fluorination2. CS2regent3. alkylation oxidizing reagent reagent- ► - ► solven solvent, -78°C-rtt, 0°C-rtA2 B2 C2

[0061] In the first step, the starting reactant (e.g., Al or A2) is treated with a base. The base is selected based on the N-H proton acidity of the reactant, and may include sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, or t-butyllithium.

[0062] After treatment with the base, carbon disulfide is added to the reaction mixture and reacts with the deprotonated nitrogen of the reactant (Al or A2), which is then reacted with an alkylation reagent to form dithiocarbamate intermediaries (e.g., Bl and B2 in Reactions II and III respectively). The alkylation reagents may be C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, or C1-C6 alkyl trifluoromethanesulfonate.

[0063] Solvents for the first step may be selected from dimethylformamide, dichloromethane, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, tetrachloromethane, chloroform, 1, 1,2,2- tetrachloroethane, benzene, toluene, and xylene. The temperature of the mixture is preferably between 0°C and 22°C during these reactions, but could be carried out from the melting point up to the boiling point of the solvent, depending on the reactants.

[0064] Once formed, the dithiocarbamate intermediaries are extracted by pouring the reaction mixture into water and the intermediaries extracted using an organic solvent which is not water miscible, such as dichloromethane, ethyl acetate, diethyl ether, and methyl tert-butyl ether. After separation, that solvent is removed and the extracted intermediaries are dissolved in another solvent, such as dichloromethane or another suitable solvent including dimethylformamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, tetrachloromethane, chloroform, 1 , 1 ,2,2-tetrachloroethane, benzene, toluene, and xylene. At a temperature of about -78°C (or generally within a range of -78°C to 35°C), a fluorination reagent is added to the dithiocarbamate mixture. The fluorination reagent may be pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, or silver fluoride. An oxidizing reagent is also added, wherein the oxidizing reagent may be l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N- bromosuccinimide, N-iodosuccinimide, or nitrosonium tetrafluoroborate. This mixture may then be warmed to about 22°C (e.g., 0°C to 35 °C) and may be stirred for a sufficient amount of time to allow for the reactions to be completed (e.g., from about two minutes to 48 hours depending on the reaction conditions, solvent, and reagents). At this point, the N-CF3 compound (e.g., Cl and C2 in Reactions II and III respectively) may be extracted and purified. Yields may vary from 10% to more than 90%.

[0065] These synthetic methods do not require the use of highly toxic reagents (e.g., triphosgene), highly reactive reagents (e.g., l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2. 2]octane bis(tetrafluoroborate, sulfonyl bromide), and / or very expensive reagents (e.g., tetramethylammonium trifluoromethanethiolate, silver fluoride) that have been previously required for the synthesis of N-CF3 compounds, including N-CF3 sulfonamide and analogues thereof. Further, and in particular for N-trifluoromethyl sulfonamides, reactions between sulfonyl bromideand N-trifluoromethylamine are avoided (since N-trifluoromethylamine can be unstable) by using the N-trifluoromethylation of secondary sulfonamides.

[0066] The term “about” when used with a corresponding numeric value refers to ±20% of the numeric value, typically ±10% of the numeric value, often ±5% of the numeric value, and most often ±2% of the numeric value. In some embodiments, the term “about” can be taken as exactly indicating the actual numerical value.

[0067] Various modifications and additions can be made without departing from the spirit and scope of this disclosure. Features of each of the various embodiments described above may be combined with features of other described embodiments as appropriate in order to provide a multiplicity of feature combinations in associated new embodiments. Furthermore, while the foregoing describes a number of separate embodiments, what has been described herein is merely illustrative of the application of the principles of the present disclosure. Additionally, although particular methods herein may be illustrated and / or described as being performed in a specific order, the ordering is highly variable within ordinary skill to achieve aspects of the present disclosure. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this disclosure.

[0068] Exemplary embodiments have been disclosed above and illustrated in the accompanying drawings. It will be understood by those skilled in the art that various changes, omissions and additions may be made to that which is specifically disclosed herein without departing from the spirit and scope of the present disclosure.

Claims

What is claimed is:

1. A compound having the formula:

2. A method of producing an N-trifluoromethyl product having a formula of:wherein Ri is selected from the group of C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, and a heteroaryl group, and wherein R2 is selected from the group of C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3- C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, and a heteroaryl group, the method comprising: deprotonating a reactant having an acidic N-H group with a base; reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate compound; and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

3. The method of claim 2, wherein the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

4. The method of claim 2, wherein the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed in a temperature range of about 0°C to about 25°C.

5. The method of claim 2, wherein the N-trifluoromethyl product is an N-trifluoromethyl sulfonamide product.

6. The method of claim 2, wherein the N-trifluoromethyl product is N-methyl-N- (trifluoromethyl)methanesulfonamide.

7. The method of claim 2, wherein the reactant is a sulfonamide compound.

8. The method of claim 2, wherein the N-trifluoromethyl product is an N-trifluoromethyl amide product.

9. The method of claim 2, wherein the reactant is an amide compound.

10. The method of claim 2, wherein the N-trifluoromethyl product is an N-trifluoromethyl amine product.

11. The method of claim 2, wherein the reactant is an amine compound.

12. The method of claim 2, wherein the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t-butyllithium.

13. The method of claim 2, wherein the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

14. The method of claim 2, wherein the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

15. The method of claim 2, wherein the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

16. The method of claim 3, wherein the dithiocarbamate compound is reacted with CH3I in dimethylformamide.

17. The method of claim 16, wherein the dithiocarbamate compound is reacted with a mixture of pyridine and hydrogen fluoride at about -70°C.

18. The method of claim 2, wherein more than 20 g of N-trifluoromethyl product is produced.

19. A method of producing an N-trifluoromethyl product having a formula of:wherein Ri is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or heteroaryl group, wherein R2 is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or a heteroaryl group, and wherein L is CH2, CO, or SO2, the method comprising: deprotonating a reactant having an acidic N-H group with a base; reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate compound; and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

20. The method of claim 19, wherein the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

21. The method of claim 19, wherein the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t-butyllithium.

22. The method of claim 19, wherein the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

23. The method of claim 19, wherein the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

24. The method of claim 19, wherein the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

25. The method of claim 19, wherein more than 20 g of N-trifluoromethyl product is produced.

26. A method of producing an N-trifluoromethyl product of a formula of:wherein L is CH2, CO, or SO2, wherein Y is CnHmX2n-m (in which X is F, Cl, Br, or I, n is selected from 1 to 9, and m is selected from 0 to 2n) and wherein Z is CH2, CHX, or CX2 (where X is F, Cl, Br, or I), the method comprising: deprotonating a reactant having an acidic N-H group with a base; reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate intermediate; and reacting the dithiocarbamate intermediate with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

27. The method of claim 26, wherein the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate intermediate are performed at or below room temperature.

28. The method of claim 26, wherein the reactant has the formula:H29. The method of claim 26, wherein the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t-butyllithium.

30. The method of claim 26, wherein the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

31. The method of claim 26, wherein the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

32. The method of claim 26, wherein the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

33. The method of claim 26, wherein more than 20 g of N-trifluoromethyl product is produced.

34. A method of producing an N-trifluoromethyl product having a formula of CF3-NR1R2, wherein Ri is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3-C9 heterocycloalkyl, or heteroaryl group and wherein R2 is C1-C9 alkyl, C1-C9 haloalkyl, aryl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C3- C9 heterocycloalkyl, or a heteroaryl group, the method comprising: deprotonating a reactant having an acidic N-H group with a base; reacting the deprotonated reactant with carbon disulfide and then an alkylating reagent to form a dithiocarbamate compound; and reacting the dithiocarbamate compound with an oxidizing reagent and a fluorinating reagent to form the N-trifluoromethyl product.

35. The method of claim 34, wherein the deprotonating the reactant, reacting the deprotonated reactant, and reacting the dithiocarbamate compound are performed at or below room temperature.

36. The method of claim 34, wherein the base is selected from the group consisting of sodium hydride, lithium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium diisopropylamide, n-butyllithium, s-butyllithium, and t-butyllithium.

37. The method of claim 34, wherein the alkylating reagent is selected from the group consisting of C1-C6 alkyl iodide, C1-C6 alkyl bromide, C1-C6 alkyl chloride, C1-C6 alkyl toluenesulfonate, C1-C6 alkyl methanesulfonate, and C1-C6 alkyl trifluoromethanesulfonate.

38. The method of claim 34, wherein the oxidizing reagent is selected from the group consisting of l,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N- iodosuccinimide, and nitrosonium tetrafluoroborate.

39. The method of claim 34, wherein the fluorinating reagent is selected from the group consisting of pyridine hydrofluoride, tetrabutylammonium dihydrogen trifluoride, triethylamine trihydrofluoride, triethylamine pentahydrofluoride, triethylamine hexahydrofluoride, N- diisopropylethylamine trihydrofluoride, diethylaminosulfur trifluoride, potassium bifluoride, potassium fluoride, sodium fluoride, and silver fluoride.

40. The method of claim 34, wherein the dithiocarbamate compound is reacted with CH3I in dimethylformamide.

41. The method of claim 40, wherein the dithiocarbamate compound is reacted with a mixture of pyridine and hydrogen fluoride at about -70°C.

42. The method of claim 34, wherein more than 20 g of N-trifluoromethyl product is produced.

43. A compound having the formula:

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