Scalable process for manufacturing trifluorosulfonamides

Abstract

Disclosed are methods of synthesizing fluorinated sulfonamides.

Description

[0001]MTV-22125 SCALABLE PROCESS FOR MANUFACTURING TRIFLUOROSULFONAMIDES RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 515,895, filed July 27, 2023; the contents of which are hereby incorporated by reference in their entirety. BACKGROUND The development of next-generation batteries capable of longer cycle lives, higher energy densities, and / or improved recyclability beyond traditional Li-ion are critically needed to realize a sustainable energy economy. New electrolytes will undoubtedly play a key role in this development, as the commonly used carbonate electrolytes in today’s lithium-ion batteries (e.g., carbonate solvents with LiPF6 salt) are often incompatible with emerging battery compositions. For example, lithium metal batteries (LMBs), which replace the graphite anode of traditional lithium-ion batteries with pure Li metal, hold great promise due to their high theoretical capacities and energy densities; however, realizing practical LIBs is challenging due to uncontrolled electrolyte decomposition, poor solid-electrolyte interface (SEI) formation, and lithium dendrite growth, which lead to performance degradation and, ultimately, failure of the battery that may be exothermic / catastrophic in nature. Fluorinated electrolyte solvents have emerged as high-performance alternatives to overcome these issues due to their increased electrochemical stability, ability to form stable electrode interfaces, and their low flammability. A particularly promising fluorinated electrolyte solvent is N,N- dimethyltrifluoromethanesulfonamide (DMTMSA). DMTMSA has shown outstanding promise in practical, high-voltage LMBs with NMC811 cathodes, enabling the formation of a stable SEI layers on both the cathode and anode surfaces, limited transition metal dissolution (which leads to cathode decomposition), and enabling specific capacities as high as 231 mAh g-1over 100 cycles. Additionally, DMTMSA was shown to be effective in LMBs with a lithium cobalt oxide cathode, enabling up to 89% capacity retention after 200 cycles at a high charging voltage of 4.55 VLi while carbonate electrolyte degraded to only 7% of its original capacity under the same conditions. Though DMTMSA is a promising electrolyte solvent ripe for further study, it is still not widely commercially available for purchase. Though the synthesis of DMTMSA has been reported on many different accounts, all previous reports require a 1 FH12238826.3 MTV-22125 combination of organic solvent, harsh temperatures (-78 °C), and / or the use of an autoclave. These requirements inherently limit the scalability, sustainability, and approachability of DMTMSA synthesis, which limits its potential. Accordingly, new methods for synthesizing DMTMSA and related solvents are required. SUMMARY In certain aspects, disclosed here is a practical and safe synthesis of DMTMSA, and related products, that is demonstrated on 155 g scale (1.3 L reaction volume) scale with common laboratory equipment. Water is used as the solvent and the reaction is cooled with an ice bath. A Process Mass Intensity (PMI) analysis of the optimized conditions resulted in a PMI of 9.1. A simple short-path distillation of the final aqueous phase enables 92% recovery of unreacted dimethylamine and a 52% decrease in waste generated in the process. The same synthetic methodology was used to synthesize four additional trifluoromethanesulfonamide solvents derived from water-miscible secondary amines. In one aspect, the present disclosure provides methods of synthesizing a compound having a structure represented by formula I, comprising combining in a reaction vessel a compound having a structure represented by formula A, or a salt thereof, and a compound having a structure represented by formula B, or a salt thereof: wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; or R1and R2combine with the intervening nitrogen atom to form a heterocyclyl; R3is fluoroalkyl; and 2 FH12238826.3 MTV-22125 X is -OS(O)2CF3, Cl, or F. BRIEF DESCRIPTION OF THE DRAWING FIG. 1 shows a retrosynthetic analysis of DMTMSA including possible starting materials. DETAILED DESCRIPTION Described is a practical, safe, and scalable synthesis of DMTMSA from commercially available triflic anhydride and 40% aqueous dimethylamine. No specialized equipment is needed, no organic solvent is required, and the reaction is well-controlled with ice-bath cooling. A yield of 92% was achieved at a scale of nearly 900 mmol (>150 g of DMTMSA). No organic waste streams are generated, and the optimized process has a PMI of about 9.1. Furthermore, 92% of the unreacted dimethylamine can be recycled into the process by a short-path distillation of the aqueous waste stream, resulting in a 52% decrease in waste generated in the process. A careful molar balance of the reaction revealed that 96% of the triflic anhydride is amidated to DMTMSA under the reaction conditions. The synthetic methodology was used to synthesize four other trifluoromethanesulfonamide solvents derived from the water-miscible amines dimethylamine, pyrrolidine, piperidine, and morpholine. In one aspect, the present disclosure provides methods of synthesizing a compound having a structure represented by formula I, comprising combining in a reaction vessel a compound having a structure represented by formula A, or a salt thereof, and a compound having a structure represented by formula B, or a salt thereof: wherein 3 FH12238826.3 MTV-22125 R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; or R1and R2combine with the intervening nitrogen atom to form a heterocyclyl; R3is fluoroalkyl; and X is -OS(O)2CF3, Cl, or F. In certain preferred embodiments, the method is performed in water. In certain embodiments, the compound represented by formula A is in an aqueous solution at a concentration of about 10% w / w, 20% w / w, 30% w / w, 40% w / w, 50%, w / w, or 60% w / w. In certain preferred embodiments, the compound represented by formula A is in an aqueous solution at a concentration of about 40% w / w. In certain embodiments, the compound represented by formula A is present at a molar ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1, as compared to the compound represented by formula B. In certain preferred embodiments, the compound represented by formula A is present at a molar ratio of about 5:1, as compared to the compound represented by formula B. In certain embodiments, the method is performed at about 0°C, about 5°C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C. In certain embodiments, the method is performed at about 10 °C or about 15 °C. In certain preferred embodiments, the method is performed at from about 10 °C to about 15 °C. In certain embodiments, the method comprises adding the compound having a structure represented by formula B to the compound of formula A. In certain embodiments, the adding the compound having a structure represented by formula B to the compound of formula A is performed at about 5°C. In certain preferred embodiments, the adding the compound having a structure represented by formula B to the compound of formula A is performed at about 0°C. In certain embodiments, X is -Cl. In certain embodiments, X is -F. In certain preferred embodiments, X is -OS(O)2CF3. In certain embodiments, R1is alkyl (e.g., methyl or ethyl). In certain embodiments, R2is alkyl (e.g., methyl or ethyl). In other embodiments, R1and R2combine with the intervening nitrogen atom to form a heterocyclyl (e.g., pyrrolidinyl, piperidinyl, or morpholinyl). In certain preferred embodiments, R3is trifluoromethyl. In certain embodiments, R1is ethyl; R2is ethyl; and R3is trifluoromethyl. In other embodiments, R1and R2combine with the intervening nitrogen atom to form pyrrolidinyl; and R3is trifluoromethyl. In yet other embodiments, R1and R2combine with the intervening nitrogen atom to form piperidinyl; and R3is trifluoromethyl. In yet other embodiments, R1and R2combine with the intervening nitrogen atom to form morpholinyl; and R3is trifluoromethyl. 4 FH12238826.3 MTV-22125 In certain embodiments, the method has a process mass intensity of about 7, about 8, about 9, about 10, or about 11. In certain embodiments, the method has a process mass intensity of about 9.1. In certain embodiments, the method has a yield of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. In certain embodiments, the method has a yield of about 60%. In certain embodiments, the method has a yield of about 75%. In certain embodiments, the method has a yield of about 80%. In certain preferred embodiments, the method further comprises an acidic workup. In certain embodiments, the compound having a structure represented by formula I is isolated via distillation (e.g., short path distillation). In another aspect, the present disclosure provides methods of synthesis of a N,N- dialkyltrifluoromethanesulfonamide solvent, the method comprising a. mixing 40% aqueous dialkylamine and water (1:1, v:v) at 0 °C; b. adding providing trifluoromethanesulfonic anhydride to the dialkylamine solution while mixing and maintaining the temperature at 10 - 15 °C; c. cooling the mixture to 0 °C while mixing; d. allowing aqueous and organic phases to separate; e. collecting the organic phase; and f. isolating the N,N-dialkyltrifluoromethanesulfonamide solvent. In certain embodiments, the dialkylamine is dimethylamine and N,N-dimethyltrifluoromethanesulfonamide (DMTMSA) solvent is synthesized. In certain embodiments, the dialkylamine is diethylamine and N,N-diethyltrifluoromethanesulfonamide solvent is synthesized. In certain embodiments, the dialkylamine is pyrrolidine, and pyrrolidinyltrifluoromethanesulfonamide solvent is synthesized. In certain embodiments, the dialkylamine is piperidine and piperidinyltrifluoromethanesulfonamide solvent is synthesized. In certain embodiments, the dialkylamine is morpholine and morpholinyltrifluoromethanesulfonamide solvent is synthesized. In certain embodiments, the N,N-dialkyltrifluoromethanesulfonamide solvent is isolated by distillation under vacuum. In certain embodiments, the product mass intensity is 9.1. 5 FH12238826.3 MTV-22125 Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry described herein, are those well-known and commonly used in the art. Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985). All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -OP(O)(O-alkyl)2or –CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to C1-C6 straight-chain alkyl groups or C1-C6 branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4straight-chain alkyl groups or C1-C46 FH12238826.3 MTV-22125 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1- hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4- octyl and the like. The “alkyl” group may be optionally substituted. The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc. The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbon atoms in the chain. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term “amido”, as used herein, refers to a group 7 FH12238826.3 MTV-22125 O R9N R10, wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group , wherein R9and R10independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more 8 FH12238826.3 MTV-22125 atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H- indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbonate” is art-recognized and refers to a group -OCO2-. The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H. The term “cycloalkyl” includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term “cycloalkyl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R100) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like. The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. 9 FH12238826.3 MTV-22125 The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group. The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. 10 FH12238826.3 MTV-22125 The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term “sulfate” is art-recognized and refers to the group –OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamido” is art-recognized and refers to the group represented by the general formulae 1R10 OR0 OS N orSO9N OR R9, wherein R9and R10independently represents hydrogen or hydrocarbyl. The term “sulfoxide” is art-recognized and refers to the group–S(O)-. The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group –S(O)2-. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is 11 FH12238826.3 MTV-22125 contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SR9or –SC(O)R9wherein R9represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term “urea” is art-recognized and may be represented by the general formula ,wherein R9and R10independently represent hydrogen or a hydrocarbyl. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts. Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. 12 FH12238826.3 MTV-22125 As used herein, the term “process mass intensity” refers to the ratio of the total mass of all materials consumed during the synthetic process (e.g., chemical reaction or reactions), including reagents, solvents, stationary phase and reactants divided by the amount of material produced and is used as a measure of the efficiency of a synthetic process. EXAMPLES The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention. Example 1: Exemplary Synthetic Methods An exemplary retrosynthetic analysis of DMTMSA is shown in FIG. 1. DMTMSA may be synthesized in a single step by the formation of the central N-S bond. This is achieved by directly triflating dimethylamine. Given that this reaction is facile and exothermic, the main challenge was to choose the appropriate dimethylamine source and triflating agent to maximize safety and efficiency. While there are a variety of commercially available triflating agents, a good choice for the purpose of this synthesis is triflic anhydride. While triflyl chloride and fluoride would afford a process with a greater atom economy, they are each more hazardous due to their increased volatility relative to triflic anhydride. Triflyl chloride is a volatile liquid with a boiling point just above room temperature (b.p. = 29 – 32 °C) and triflyl fluoride is a gas (b.p. = -25 °C), while triflic anhydride has a boiling point significantly higher at 82 °C. Furthermore, triflyl chloride (~$3 / g @ ≥100g) and triflyl fluoride ($7.50 / g @ 100g) are much more expensive compared to triflic anhydride ($1.10 / g @ 100g, <$0.50 / g @ ≥1kg). Other more exotic triflating agents exist, such as N-phenyltrifluoromethanesulfonimide or N-(5-Chloro-2- pyridyl)bis(trifluoromethanesulfonimide) (Comin’s reagent), but they are considered less attractive for this synthesis due to their high cost and increased molecular weight compared to triflic anhydride. The choice of dimethylamine source is also important. Gaseous anhydrous dimethylamine, solutions of dimethylamine in organic solvents, dimethylamine hydrochloride, and 40% aqueous dimethylamine were considered as feedstocks. Gaseous dimethylamine was not chosen due to the operational complexities involved with handling significant quantities of malodorous, toxic, flammable gases in a research laboratory setting. While organic solvent 13 FH12238826.3 MTV-22125 solutions of dimethylamine offer convenience, they necessitate large volumes of organic solvent (only 1–2 M solutions are commonly available) that must be purified from the product. Since DMTMSA has a boiling point of ~120 °C at atmospheric pressure, a relatively careful distillation would be required to separate it cleanly and quantitatively from a variety of organic solvents. While dimethylamine hydrochloride is readily available and extraordinarily cheap ($0.11 / g @ 1 kg), additional base would be required to deprotonate it for reaction with the triflating agent. We therefore did not consider it for this synthesis. Finally, 40% aqueous dimethylamine is even cheaper ($0.04 / g Me2NH @ 2.5 L solution) but contains a large amount of water that may react with the water-sensitive triflating agent in the reaction. Nonetheless, we envisioned the possibility of synthesizing DMTMSA by directly “quenching” triflic anhydride into concentrated aqueous solutions of dimethylamine due to the high nucleophilicity of dimethylamine compared to water, and the precedent for performing triflation reactions in water. Additionally, triflic anhydride is insoluble in water, and we hypothesized that the reaction’s biphasic nature would further increase the selectivity for amidation versus hydrolysis. To test this hypothesis, a small amount of triflic anhydride was added directly to 20 equivalents of 40% w / w aqueous dimethylamine solution at 0 °C. Upon warming to room temperature, a cloudy solution remained, which indicates that the presumably formed DMTMSA formed during the reaction is just above its solubility limit in the aqueous phase. The mixture was homogenized by adding DMSO, then an19F NMR spectrum (DMSO- d6) was collected. Only two singlets were present; one corresponding to DMTMSA and the other presumably the byproduct of the reaction, Me2NH2OTf. The ratio of DMTMSA:Me2NH2OTf was 1:1.25, indicating a roughly ~88% selectivity for amidation versus hydrolysis. Acidification with concentrated HCl (aq) led to nearly complete phase separation and facile isolation of the crude DMTMSA product. While such a procedure may be considered an ideal workup, the acidification step inherently requires the use of additional reagents and solvents, decreases the amount of potentially recyclable dimethylamine post-reaction, and causes another large exotherm that must be addressed with proper cooling at larger scales. Therefore, we explored a wider range of dimethylamine equivalents and concentrations to search for conditions that would offer both high selectivity for amidation and spontaneous DMTMSA phase-separation. Additionally, we included an organic cosolvent, the product DMTMSA itself, to dilute the triflic anhydride before addition to the reaction (Table 1, entries 1 – 5). This allowed for more careful and slow dispensing of the triflic anhydride for safety precautions, and we hypothesized that the selectivity for amidation may be increased due to the 14 FH12238826.3 MTV-22125 reaction having more biphasic character (reminiscent of Schotten-Baumann conditions). We note that the scale of each reaction was gradually increased only after a safe and successful reaction at the previous scale, and in every case, the addition rate was regulated to maintain a reaction temperature of <15 °C. Upon decreasing the number of equivalents of dimethylamine from 20 to 5 while maintaining the same initial concentration of 40% w / w (Table 1, entries 1-3), similar high amidation selectivity was maintained as evidenced by the crude yields; however, acidification was still required to promote full phase-separation in each case. Encouraged by the apparently high selectivity for amidation versus hydrolysis even at an excess of 5 equiv., we diluted the reaction two-fold to an initial dimethylamine concentration of 20% w / w (Entry 4) to assess whether the selectivity would be preserved at lower concentration. Under these conditions, high selectivity was maintained and the crude DMTMSA product phase-separated nearly completely without the need for an acid workup. Additionally, by diluting the reaction mass with more water, a high heat capacity solvent, the addition time was even shorter (17 min vs. 23 min) for a reaction at roughly 1.6x the scale of the previous non-diluted reaction. We continued to scale-up the reaction with these conditions (Entry 4) with only minor changes. Changing the manner with which the DMTMSA cosolvent was incorporated (i.e., adding it to the reaction vessel before neat triflic anhydride addition) (Table 1, entries 6- 8) did not affect the yields significantly, nor did lowering the initial dimethylamine concentration further to 16% w / w (Entry 7). Confident in our thermal management and familiarity with the reaction at large scales (Entry 8), in the final entry (Entry 9) we assessed whether an organic cosolvent was required for the reaction. It is advantageous to cut out any unnecessary starting materials / reagents / solvents in a synthesis for practical reasons and to decrease the environmental impact of the chemistry. Similar yields were observed when compared to the same reaction ran on a similar scale with DMTMSA cosolvent (Entry 8). This final reaction scale (~137-155 g) was identified as a good stopping point because this corresponds to an amount of product generated from a fresh 250 g bottle of Tf2O, and because any larger reaction vessel (1.3 L reaction volume, 3L flask) would be difficult to stir with magnetic stirring and unwieldy to cool with an ice bath. A careful and thorough molar balance of triflate-containing species was performed for Entry 9 to gravimetrically assess the selectivity for amidation (DMTMSA) versus hydrolysis (Me2NH2OTf). A total of 890.2 mmol of DMTMSA was recovered (872.7 mmol isolated product, 5.1 mmol in the distillation cold trap, and 12.4 mmol from the aqueous phase). Additionally, a total of 964.7 mmol of Me2NH2OTf was recovered (962.6 mmol from the 15 FH12238826.3 MTV-22125 aqueous phase, 2.1 mmol from the DMTMSA-rich phase). Combined, these values correspond to a 97.4% molar balance of triflate species, assuming the input triflic anhydride is 100% pure and 2 triflate-containing molecules are generated per anhydride. Moreover, the relative amounts of DMTMSA and Me2NH2OTf isolated suggest that 96% of the input triflic anhydride was amidated to form DMTMSA while the remaining 4% was hydrolyzed to ultimately form the salt byproduct Me2NH2OTf. Process mass intensity (PMI) is a useful and general metric to quickly gauge the sustainability and environmental impact of a synthetic step or route. The PMI of a process is simply the sum of the masses of all input materials (reagents, solvents, consumables, etc.) divided by the mass of the product. A Process Mass Intensity analysis of the optimized process yielded a PMI of 9.1, representing a mass-efficient process for the synthesis of DMTMSA. Furthermore, a simple distillation may be performed to recover and recycle the excess unreacted dimethylamine from the aqueous layer. The aqueous layer of Entry 9 was subjected to a short-path atmospheric pressure distillation, and the distillate was collected in two fractions of roughly equal volumes. Towards the end of the first fraction, the distillate became cloudy and a small amount of DMTMSA phase- separated from the first fraction upon standing. The second fraction was clear and colorless. HCl titration of the two fractions revealed that the first fraction contained 21.5% w / w dimethylamine and the second fraction contained <0.1% w / w. The dimethylamine concentration of the first fraction was corrected to 20% w / w by the addition of some of the second fraction, rendering it directly recyclable into the process. 92% of the unreacted dimethylamine was recovered, and the total mass of waste was reduced by 52%. The only waste products generated are Me2NH2OTf and nearly pure (<0.1% w / w Me2NH) water. Furthermore, the DMTMSA that co-distilled with this fraction was isolated by partitioning in a separatory funnel overnight, resulting in an extra 1.3% yield of crude DMTMSA that may also be recycled / recovered. To expand the scope of this reaction, the optimized conditions were used to synthesize other trifluoromethanesulfonamide solvents derived from other water-miscible secondary amines: diethylamine, pyrrolidine, piperidine, and morpholine. Each was synthesized on ~150 mmol scale. The same methodology used above for DMTMSA, entry 9, was used for each case except for morpholine, which required a higher nucleophile concentration (40% w / w) and acidification post-reaction due to its decreased nucleophilicity and high solubility in both the product and water, respectively. 16 FH12238826.3 MTV-22125 General trifluoromethanesulfonamide synthesis procedure: Optimized, scaled procedure: To a 250 mL pressure-equalized addition funnel was added an entire freshly opened 250g bottle of trifluoromethanesulfonic anhydride (268.4 g, 951.8 mmol, 1.0 equiv.), and this funnel was set aside while the reaction flask was prepared. The weight of the triflic anhydride bottle was measured before and after pouring to calculate the mass added to the funnel. A 3-liter three-neck flask was charged with a magnetic stir bar and suspended in a water / ice bath atop a magnetic stirrer.40% aqueous dimethylamine solution (603 mL, 4.76 mol, 5.0 equiv.) and deionized water added to the flask and stirred. A water- jacketed reflux condenser, a thermometer, and the triflic anyhydride-filled addition funnel were fitted into the necks of the flask. When the contents of the flask approached 0 °C, the slow addition of trifluoromethanesulfonic anhydride began. The addition rate and pot temperature are closely monitored and adjusted such that the flask contents remain between 10 - 15 °C for the entire duration of the reaction. A 76 min additional time was required, and the ice bath was drained and refreshed with more ice halfway through the addition. The reaction is stirred until the contents cool to 0 °C. Then the entire contents are transferred to a separatory funnel and allowed to phase-separate. The cloudy, dense DMTMSA-rich phase is collected, and the aqueous phase is drained and reserved. The DMTMSA-rich phase is re-added to the separatory funnel and allowed to fully phase-separate overnight. Finally, the crude DMTMSA is distilled under vacuum to afford pure DMTMSA (155 g, 886 mmol, 92% yield). 17 FH12238826.3 MTV-22125 Table 1: Exemplary optimization of reaction conditions a Triflic anhydride was diluted with 1 vol. of cosolvent (DMTMSA) before addition. b Cosolvent (1 vol. DMTMSA) was added to the reaction vessel before neat triflic anhydride addition. c Yield of crude, wet DMTMSA after initial phase-separation. d Yield of pure, vacuum-distilled DMTMSA. e Final, optimized conditions. Table 2: Exemplary trifluoromethanesulfonamide solvents synthesized with the disclosed methodology 18 FH12238826.3 MTV-22125 INCORPORATION BY REFERENCE All U.S. and PCT patent application publications and U.S. patents mentioned herein are hereby incorporated by reference in their entirety as if each individual patent application publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. 19 FH12238826.3

Claims

MTV-22125 CLAIMS What is claimed is:

1. A method of synthesizing a compound having a structure represented by formula I, comprising combining in a reaction vessel a compound having a structure represented by formula A, or a salt thereof, and a compound having a structure represented by formula B, or a salt thereof:wherein R1and R2are each independently alkyl, aryl, heteroaryl, cycloalkyl, aralkyl, or heteroaralkyl; or R1and R2combine with the intervening nitrogen atom to form a heterocyclyl; R3is fluoroalkyl; and X is -OS(O)2CF3, Cl, or F.

2. The method of claim 1, wherein the method is performed in water.

3. The method of claim 1, wherein the compound represented by formula A is in an aqueous solution at a concentration of about 10% w / w, 20% w / w, 30% w / w, 40% w / w, 50%, w / w, or 60% w / w.

4. The method of any one of claims 1-3, wherein the compound represented by formula A is in an aqueous solution at a concentration of about 40% w / w. 20 FH12238826.3MTV-22125 5. The method of any one of claims 1-4, wherein the compound represented by formula A is present at a molar ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1, as compared to the compound represented by formula B.

6. The method of any one of claims 1-4, wherein the compound represented by formula A is present at a molar ratio of about 5:1, as compared to the compound represented by formula B.

7. The method of any one of claims 1-6, wherein the method is performed at about 0°C, about 5°C, about 10 °C, about 15 °C, about 20 °C, or about 25 °C.

8. The method of any one of claims 1-6, wherein the method is performed at about 10 °C or about 15 °C.

9. The method of any one of claims 1-6, wherein the method is performed at from about 10 °C to about 15 °C.

10. The method of any one of claims 1-9, wherein the method comprises adding the compound having a structure represented by formula B to the compound of formula A.

11. The method of claim 10, wherein the adding the compound having a structure represented by formula B to the compound of formula A is performed at about 0°C.

12. The method of claim 10, wherein the adding the compound having a structure represented by formula B to the compound of formula A is performed at about 5°C.

13. The method of any one of claims 1-12, wherein X is -OS(O)2CF3.

14. The method of any one of claims 1-12, wherein X is -Cl.

15. The method of any one of claims 1-12, wherein X is -F.

16. The method of any one of claims 1-15, wherein R1is alkyl (e.g., methyl or ethyl). 21 FH12238826.3MTV-22125 17. The method of any one of claims 1-16, wherein R2is alkyl (e.g., methyl or ethyl).

18. The method of any one of claims 1-17, wherein R1and R2combine with the intervening nitrogen atom to form a heterocyclyl (e.g., pyrrolidinyl, piperidinyl, or morpholinyl).

19. The method of any one of claims 1-18, wherein R3is trifluoromethyl.

20. The method of any one of claims 1-19, wherein: R1is ethyl; R2is ethyl; and R3is trifluoromethyl.

21. The method of any one of claims 1-19, wherein: R1and R2combine with the intervening nitrogen atom to form pyrrolidinyl; and R3is trifluoromethyl.

22. The method of any one of claims 1-19, wherein: R1and R2combine with the intervening nitrogen atom to form piperidinyl; and R3is trifluoromethyl.

23. The method of any one of claims 1-19, wherein: R1and R2combine with the intervening nitrogen atom to form morpholinyl; and R3is trifluoromethyl.

24. The method of any one of claims 1-23, wherein the method has a process mass intensity of about 7, about 8, about 9, about 10, or about 11.

25. The method of any one of claims 1-23, wherein the method has a process mass intensity of about 9.

1.

26. The method of any one of claims 1-25, wherein the method has a yield of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.

27. The method of any one of claims 1-25, wherein the method has a yield of about 60%.

28. The method of any one of claims 1-25, wherein the method has a yield of about 75%.

29. The method of any one of claims 1-25, wherein the method has a yield of about 80%. 22 FH12238826.3MTV-22125 30. The method of any one of claims 1-29, wherein the method further comprises an acidic workup.

31. The method of any one of claims 1-30, wherein the compound having a structure represented by formula I is isolated via distillation (e.g., short path distillation).

32. A method of synthesis of a N,N-dialkyltrifluoromethanesulfonamide solvent, the method comprising g. mixing 40% aqueous dialkylamine and water (1:1, v:v) at 0 °C; h. adding providing trifluoromethanesulfonic anhydride to the dialkylamine solution while mixing and maintaining the temperature at 10 - 15 °C; i. cooling the mixture to 0 °C while mixing; j. allowing aqueous and organic phases to separate; k. collecting the organic phase; and l. isolating the N,N-dialkyltrifluoromethanesulfonamide solvent.

33. The method of claim 31, wherein the dialkylamine is dimethylamine and N,N-dimethyltrifluoromethanesulfonamide (DMTMSA) solvent is synthesized.

34. The method of claim 31, wherein the dialkylamine is diethylamine and N,N-diethyltrifluoromethanesulfonamide solvent is synthesized.

35. The method of claim 31, wherein the dialkylamine is pyrrolidine, and pyrrolidinyltrifluoromethanesulfonamide solvent is synthesized.

36. The method of claim 31, wherein the dialkylamine is piperidine and piperidinyltrifluoromethanesulfonamide solvent is synthesized.

37. The method of claim 31, wherein the dialkylamine is morpholine and morpholinyltrifluoromethanesulfonamide solvent is synthesized.

38. The method of any of claims 31-36, wherein the N,N- dialkyltrifluoromethanesulfonamide solvent is isolated by distillation under vacuum.

39. The method of any of claims 31-37, wherein the product mass intensity is 9.

1. 23 FH12238826.3