United States Patent (19) 11 Patent Number: 6,080,886 Lal Et Al

US00608088.6A United States Patent (19) 11 Patent Number: 6,080,886 Lal et al. (45) Date of Patent: Jun. 27, 2000

54 FLUORINATION WITH AMINOSULFUR Messina, et al., Aminosulfur Trifluorides: Relative Thermal TRIFLUORIDES Stability, Journal of Fluorine Chemistry, 43, (1989), pp. 137-143. 75 Inventors: Gauri Sankar Lal, Whitehall; Guido Peter Pez, Allentown, both of Pa. M. Hudlicky, Fluorination with Diethylaminosulfur Trifluo ride and Related AminofluoroSulfuranes, Organic Reaction, 73 Assignee: Air Products and Chemicals, Inc., vol. 35, (1988), pp. 513–553. Allentown, Pa. G. L. Hann, et al. Synthesis and Enantioselective Fluorode hydroxylation Reactions of 21 Appl. No.: 08/939,940 (S)-2-(Methoxymethyl(pyrrolidin-1-ylsulphur Trifluoride, 22 Filed: Sep. 29, 1997 the First Homochiral Aminofluorosulphurane, J. Chem. Sol., 51 Int. Cl." ...... C07C 17/013; CO7C 29/62 Chem. Commun. (1989) pp. 1650–1651. 52 U.S. Cl...... 560/227: 544/158; 546/248; J. Cochran, Laboratory, Explosions, Chemical and Engineer 548/562; 548/565; 548/570; 564/102; 568/437; ing News, (1979), vol. 57, No. 12, pp. 4 & 74. 568/821; 570/127; 570/144; 570/125 58 Field of Search ...... 564/102; 544/158; W. T. Middleton, Explosive Hazards with DAST, Chemical 546/248; 548/562, 565, 570; 570/142, 127, and Engineering News, (1979), vol. 57, No. 21, p. 43. 144, 175; 560/227; 568/437, 821 W. J. Middleton, et al., a,a-Difluoroarylacetic Acids: Prepa ration from (Diethylamino)sulfur Trifluoride and X-Oxary 56) References Cited lacetates, J. Org. Chem. (1980) 45, 2883-2887. U.S. PATENT DOCUMENTS

3,499,030 3/1970 Kuhle et al...... 260/551 Primary Examiner-Peter O'Sullivan 3,914.265 10/1975 Middleton ...... 260/397 3,976,691 8/1976 Middleton ...... 260/544 Attorney, Agent, or Firm-Geoffrey L. Chase FOREIGN PATENT DOCUMENTS 57 ABSTRACT 433136 12/1974 Russian Federation. A fluorination method of oxygen and halogen Sites with diaryl-, dialkoxyalkyl-, alkylalkoxyalkyl-, arylalkoxyalkyl OTHER PUBLICATIONS and cyclic aminoSulfur trifluorides fluorinating reagents is W. J. Middleton, New Fluorinating Reagents, Dialkylami disclosed. nosulfur Fluorides, J. Org. Chem., vol. 40, No. 5, (1975), pp. 574-578. 20 Claims, No Drawings 6,080,886 1 2 FLUORINATION WITH AMINOSULFUR carbonyl to gem-difluoride transformation is usually carried TRIFLUORIDES out at room temperature or higher. Numerous Structurally diverse aldehydes and ketones have been Successfully flu CROSS-REFERENCE TO RELATED orinated with DAST. These include acyclic, cyclic, and APPLICATIONS aromatic compounds. Elimination does occur to a certain Not applicable. extent when aldehydes and ketones are fluorinated and olefinic by-products are also observed in these instances. STATEMENT REGARDING FEDERALLY While the DAST compounds have shown versatility in SPONSORED RESEARCH OR DEVELOPMENT effecting deoxofluorinations, there are Several well recog nized limitations associated with their use. The compounds Not applicable. can decompose violently and while adequate for laboratory Synthesis, they are not practical for large Scale industrial use. BACKGROUND OF THE INVENTION In Some instances, undesirable by-products are formed dur The development of Safe, efficient, and Simple methods 15 ing the fluorination proceSS. Olefin elimination by-products for Selective incorporation of fluorine into organic com have been observed in the fluorination of Some alcohols. pounds has become a very important area of technology. Often, acid-catalyzed decomposition products are obtained. This is due to the fact that fluorine Strategically positioned The reagent's two step method used for their Synthesis at Sites of Synthetic drugs and agrochemical products Sig renders these relatively costly compositions only Suitable for nificantly modifies and enhances their biological activities. Small Scale Syntheses. The conversion of the C-O to the C-F bond, which is The DAST reagents are recognized as fluorinating referred to herein a deoxofluorination, represents a viable reagents in U.S. Pat. Nos. 3,914,265 and 3,976,691. method to produce Selectively fluorinated organic Additionally, Et-DAST and related compounds have been discussed in W. J. Middleton, New Fluorinating Reagents. compounds, but the low yields and hazards associated with 25 the current deoxofluorination reagents and processes Dialkylaminosulfur Fluorides, J. Org. Chem., Vol. 40, No. 5, Severely limit the application of this technique. (1975), pp 574-578. However, as reported by Messina, et al., Aminosulfur Trifluorides: Relative Thermal Stability, The introduction of fluorine into medicinal and agro Journal of Fluorine Chemistry, 43, (1989), pp 137-143, chemical products can profoundly alter their biological these compounds can be problematic fluorinating reagents properties. Fluorine mimics hydrogen with respect to Steric due to their tendency to undergo catastrophic decomposition requirements and contributes to an alteration of the elec tronic properties of the molecule. Increased lipophilicity and (explosion or detonation) on heating. See also reports on this oxidative and thermal stabilities have been observed in Such by J. Cochran, Laboratory Explosions, Chemical and Engi fluorine-containing compounds. neering News, (1979), vol. 57, No. 12, pp. 4 & 74; and W. 35 T. Middleton, Explosive Hazards with DAST, Chemical and In View of the importance of organofluorine compounds, Engineering News, (1979), vol. 57, No. 21, p. 43. Difficul efforts aimed at the development of Simple, Safe, and effi ties with major amounts of by-products in the fluorination cient methods for their Synthesis have escalated in recent reaction is also noted. See also M. Hudlicky, Fluorination years. The conversion of the carbon-oxygen to the carbon 40 with Diethylaminosulfur Trifluoride and Related fluorine bond by nucleophilic fluorinating Sources Aminofluorosulfuranes, Organic Reaction, Vol. 35, (1988), (deoxofluorination) represents one Such technique which has pp. 513–553. been widely used for the selective introduction of fluorine Further, Russian Inventor's Certificate No. 433,136 pub into organic compounds. A list of the deoxofluorination lished Dec. 15, 1974 discloses sulfur dialkyl(alkylaryl) methods practiced to date includes: nucleophilic Substitution 45 aminotrifluorides. via the fluoride anion; phenylsulfur trifluoride; fluoroalky lamines; Sulfur tetrafluoride; SeF; WF; difluorophospho G. L. Hann, et. al., in Synthesis and Enantioselective ranes and the dialkylaminosulfur trifluorides (DAST). The Fluoro dehydroxylation Reactions of (S)-2- most common reagent of this class is diethylaminoSulfur (Methoxymethyl)pyrrolidin-1-ylsulphur Trifluoride, the 50 First Homochiral Aminofluorosulphurane, J.Chem. Soc., trifluoride, Et-DAST or simply DAST. Chem. Commun. (1989) pp 1650–1651, disclosed the ami The DAST compounds have proven to be useful reagents nosulfur trifluorides, (S)-2-(methoxymethyl)pyrrolidin-1- for effecting deoxofluorinations. These reagents are conven ylsulphur trifluoride and N-morpholinosulphur trifluoride as tionally prepared by reaction of N-silyl derivatives of 2 fluorinating reagents for 2-(trimethylsiloxy)Octane. amines with SF. In contrast to SF, they are liquids which 55 The method and compositions of the present invention can be used at atmospheric pressure and at near ambient to overcome the drawbacks of the prior art fluorinating relatively low temperature (room temperature or below) for reagents, including DAST, by providing more thermally most applications. Deoxofluorination of alcohols and stable fluorine bearing compounds which have effective ketones are particularly facile and reactions can be carried 60 fluorinating capability with far less potential of Violent out in a variety of organic Solvents (e.g., CHCl, CFCl, decomposition and attendant high gaseous by-product glyme, diglyme, CH2Cl2, hydrocarbons, etc.). Most fluori evolvement, with Simpler and more efficient fluorinations, as nations of alcohols are done at -78 C. to room temperature. will be set forth in greater detail below. Various functional groups are tolerated including CN, BRIEF SUMMARY OF THE INVENTION CONR, COOR (where R is an alkyl group), and successful 65 fluorinations have been accomplished with primary, Second The present invention is a method for the fluorination of ary and tertiary (1,2,3) allylic and benzylic alcohols. The a compound using a fluorinating reagent comprising con 6,080,886 3 4 tacting the compound with the fluorinating reagent under Preferably, the composition used as the fluorinating conditions Sufficient to fluorinate the compound wherein the reagent has the Structure: fluorinating reagent is an aminoSulfur trifluoride composi tion having a structure with one or more: wherein R' are individually H, normal or branched SF alkyl Co or aryl Co and R" are Cao normal or branched alkyl. N Alternatively, the composition used as the fluorinating 1-(- SR)- reagent has the Structure: wherein m=1-5 and R' and R are: RORN(SF)ROR (1) when m=1, individually aryl or meta- or para wherein R and Rare individually C, to Co. in a normal or Substituted aryl radicals in which the meta- or para branched chain alkyl and R' and R are C-do normal or Substitution is Selected from the group consisting of 15 branched alkyl. normal and branched Co, trifluoromethyl, alkoxy, More preferably, the composition used as the fluorinating aryl Co., nitro, Sulfonic ester, N,N-dialkylamino and halogens, or reagent has the Structure: (2) when m=1, individually aryl radicals which are fused CHOCHCHN(SF)CHCHOCH, or linked to one another; or (3) when m=1, one of R' and R is an aryl radical and the Preferably the fluorination is conducted in the presence of other is an at least 5 member Saturated cyclic hydro a Solvent. carbon radical having Zero to three heteroatoms More preferably, Solvent is Selected from the group con Selected from the group consisting of oxygen, nitrogen Sisting of paraffins, halocarbons, ethers, nitriles, nitro com and mixtures thereof; or 25 pounds and mixtures thereof. (4) when m=1, one of R' and R is an aryl radical and the Preferably, the fluorination is conducted under anhydrous other is an at least 5 member Saturated cyclic hydro conditions. carbon radical having Zero to three heteroatoms Preferably, the fluorination is conducted at a temperature Selected from the group consisting of oxygen, nitrogen above the freezing point of said solvent and below the and mixtures thereof wherein Said cyclic hydrocarbon boiling point of Said Solvent. radical is fused to Said aryl radical; or Alternatively, when the compound is a ketone, the fluo (5) when m=1, together a cyclic ring having 2 to 10 rination is catalyzed with at least a catalytic amount of a carbon ring members and 1 heteroatom Selected from the group consisting of oxygen, nitrogen and alkylated Lewis acid. nitrogen wherein Said ring has 1 to 2 alkoxyalkyl 35 Preferably, the Lewis acid is selected from the group functionalities; or consisting of BF, Znl, TiCl, and mixtures thereof. (6) when m=1, together an unsaturated cyclic ring having Alternatively, when the compound is a ketone, at least a 2 to 4 carbon ring members and one to three heteroa catalytic amount of HF is added to the fluorination. toms Selected from the group consisting of oxygen, Preferably the alcohol is selected from the group consist nitrogen, protonated nitrogen and alkylated nitrogen 40 ing of monofunctional and poly functional primary, wherein Said ring has one to three functional groups Secondary, tertiary and Vinyl alcohols and mixtures thereof. Selected from hydrogen, normal and branched Co Preferably, the carboxylic acid is selected from the group alkyl, haloalkyl, alkoxy, aryl halogen, cyano, nitro and consisting of aliphatic, aromatic and heterocyclic carboxylic amino; or 45 acids and mixtures thereof. (7) when m=1, individually alkoxyalkyl radicals; or Preferably, the aldehyde is selected from the group con (8) when m=1, one of R and R is alkoxyalkyl and the Sisting of aliphatic, aromatic and heterocyclic aldehydes and other is Selected from the group consisting of alkyl and mixtures thereof. aryl radicals, or Preferably, the ketone is Selected from the group consist (9) when m=2-5, R is a single phenyl radical linked to 50 ing of aliphatic, aromatic and heterocyclic ketones and each-NSF radical and R is an aryl radical having C mixtures thereof. to Co., or (10) when m=2-5, R' and R are individually divalent Preferably, the carboxylic acid halide is selected from the aryl radicals of C to Co linked to adjacent -NSF group consisting of aliphatic, aromatic and heterocyclic radicals except R and Rare monovalent aryl radicals 55 carboxylic acid halides of chlorine, bromine and iodine and having C to Co where R' and R are linked to only mixtures thereof. one -NSF radical; or Preferably, the Sulfoxide is selected from the group con (11) when m=1, one of R and R is an aryl radical and Sisting of aliphatic, aromatic and heterocyclic Sulfoxides the other is an alkyl radical of Co. having adjacent hydrogen atoms and mixtures thereof. Preferably, the compound being fluorinated is selected 60 Preferably, the phosphonic acid is Selected from the group from the group consisting of alcohols, carboxylic acids, consisting of aliphatic, aromatic and heterocyclic phospho aldehydes, ketones, carboxylic acid halides, Sulfoxides, nic acids and mixtures thereof. phosphonic acids, Sulfinyl halides, Sulfonic acids, Preferably, the sulfinyl halide is selected from the group sulfonylhalides, silylhalides, silyl ethers of alcohols, 65 consisting of aliphatic, aromatic and heterocyclic Sulfinyl epoxides, phosphines, thiophosphines, Sulfides and mixtures halides of chlorine, bromine and iodine and mixtures thereof. thereof. 6,080,886 S 6 Preferably, the Sulfonic acid is selected from the group including: Diaryl Systems, alkoxyalkyl aminoSulfur trifluo consisting of aliphatic, aromatic and heterocyclic Sulfonic rides and arylalkylaminosulfur trifluorides. acids and mixtures thereof. Preferably, the Sulfonyl halide is selected from the group 1. Diaryl Compositions consisting of aliphatic, aromatic and heterocyclic Sulfonyl halides of chlorine, bromine and iodine and mixtures ArN(SF)Ar" thereof. Preferably, the silyl halide is selected from the group where Ar and Ar' are the same or different aryl groups (i.e., consisting of aliphatic, aromatic and heterocyclic silyl mixed compositions). The aryl groups can be mono or halides of chlorine, bromine and iodine and mixtures polynuclear, the latter encompassing isolated ring or fused thereof. ring groups and each contemplates Substituted aryl groups. Preferably, the silyl ether of alcohol is selected from the For example, when both groups are derived from benzene, group consisting of silyl ethers of primary, Secondary and the general formula is: tertiary alcohols and mixtures thereof. 15 Preferably, the epoxide is Selected from the group con SF Sisting of aliphatic, aromatic and heterocyclic epoxide and mixtures thereof. Preferably, the phosphine is Selected from the group consisting of aliphatic, aromatic and heterocyclic phos phines and mixtures thereof. Preferably, the thiophosphine is selected from the group consisting of aliphatic, aromatic and heterocyclic thiophoS a) R' and R represent one or more substituents (like or phines and mixtures thereof. different). Examples provided (Table 1) for R, R = H, Preferably, the sulfide is selected from the group consist 25 p-Cl, p-OCH, p-CH. These groups may be para or ing of aliphatic, aromatic and heterocyclic Sulfides with meta to the NSF group. R', R can additionally be OR adjacent hydrogens and mixtures thereof. (R=alkyl or aryl), Br, I, F, alkyl or aryl groups, CF, In a preferred embodiment, the present invention is a NO, SOR (R=alkyl or aryl), NR (R=alkyl or aryl). method for the fluorination of a compound using a fluori These groups may be ortho, meta or para to the NSF nating reagent comprising an aminoSulfur trifluoride com grOup. position comprising Synthesizing the aminoSulfur trifluoride b) Aryl naphthyl compositions (Table 1) composition with a secondary amine and SF and without isolating Said aminoSulfur trifluoride composition, fluorinat c) Fused or linked diaryl compositions, e.g., ing Said compound with Said aminoSulfur trifluoride com 35 position. (CH2)n Preferably, the synthesis is performed in the presence of a tertiary amine. N Preferably, the aminosulfur trifluoride is a dialkyl amino 40 sulfur trifluoride, more preferably, diethylaminosulfur trif SF luoride. FS Air n N 1 BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 45 Not Applicable F3S DETAILED DESCRIPTION OF THE N NS INVENTION / / Air Af FS A novel fluorination method using Several novel amino 50 sulfur trifluorides is presented in this invention. These compositions have been shown to be very efficient and n=2 or more useful for effecting deoxofluorination of alcohols and ketones. In addition, thermal analysis Studies indicate that 55 Arn N they should be much safer to use in the present fluorination -N method than the currently available dialkylaminosulfur tri FS 2 fluorides (DAST). The Simplicity of the method used for preparing the new aminoSulfur trifluorides, as described hereafter, combined 60 with their relative Safety in use in the present invention should make this fluorination method attractive for large Scale production of fluorinated products.

Fluorinating Reagents for the Present Method 65 The compositions useful in the present fluorination method are identified as follows by Several general classes, 6,080,886 7 8 -continued 2. Alkoxyalkylamine Compositions N 1. Air NN 21 SF Alkyln N 1 alkoxyalkyl

SF Furthermore, oligomeric or polymeric analogues may be Table 5 b) used in which aromatic units are linked via the nitrogen of alkoxyalkyl- 1. alkoxyalkyl the NSF group, Such as: N SF -(CH-CH)-(CH-CH); l. Table 5 15 Aryla N1. alkoxyalkyl

SF OCNSF Table 5 Alkyl=normal or branched Co. Alkoxyalkyl=(a) -R-O-R, where R is Co normal or branched alkyl and R is Co normal or branched alkyl or (b) -(R-O) where y = 0–6 and x = 1-1000 25 -R, where R is Co normal or branched alkyl and R is C- normal or branched alkyl and n=1-10. d) Alkoxyalkyl branched from ring compositions contain Oul, ing NSF SF FS SF (1 l, C(R)(R)nOR

d) Heteroatom (O.N) containing aromatic compositions 35 rocee (branched or fused) wherein R and Rare individually normal or branched alkyl Co., R., are individually H or normal or branched alkyl RN Co., m=1-10, n=1-10, and p=1-10. 40 SF e) Alkoxyalkyl branched heteroatom ring compositions containing NSF wherein R is an aryl radical of C to Co., n=1-5, R and R' are individually H or alkyl Co and X=Zero to three ring 45 element Substitutions at any available position on the ring of O or NR" where R'=H, normal or branched alkyl Co. s',

50 wherein R' and Rare individually normal or branched alkyl ( Co., R., are individually H, or normal or branched alkyl N M Co, m=1-10, n=1-10, and p=1-10, and X=a ring element SF substitution at any available position of the ring of O or NR where R'=H, normal or branched alkyl Co. 55 wherein R' and R=individually H or normal or branched alkyl Co. n=1-5 and X=Zero to three ring element Sub NY stitutions at any available position on the ring of O or NR where R=H, normal or branched alkyl Co. 60 ( . One of the aromatic ring groups attached to the N-SF where m=1-10, n=1-10, R and R=individually H, or group may be 5-membered or greater and contain heteroa normal or branched alkyl Co., R=normal or branched toms such as O(1-3) or N(1-3). The heteroatom-containing 65 alkyl Co and X=a ring element Substitution at any avail ring may be branched from the N-SF group or fused to the able position of the ring of O, NR' where R'-normal or other aromatic ring (Ar). branched alkyl Co. 6,080,886 9 10 3. Arylalkylaminosulfur trifluorides Only a small amount of product (<10% yield) was obtained N-methyl, N-phenyl aminosulfur trifluoride exemplifies in a reaction carried out at room temperature. this group. A Synthetic route to dialkyl and arylalkylaminoSulfur A preferred class of deoxofluorination reagents has the trifluorides described in Russian Inventor's Certificate No. general Structure: 433,136 was used in which a secondary (2) amine is reacted with SF in ethyl ether containing triethylamine for the preparation of Several novel diarylaminoSulfur trifluorides. wherein R' are individually H, normal or branched This simple one-step process (as opposed to the two-step alkyl Co or aryl Co and R" are normal or branched 1O method via a silyl amine) afforded a virtual quantitative Co. A more specific class of preferred deoxofluorination yield of products at temperatures ranging from -10° C. to reagents has the general Structure: room temperature. Table 1 Summarizes the diaryl composi tions which were prepared by this method. The procedure RORN(SF)ROR proved to be particularly useful for the preparation of wherein R and R are individually C, to Co normal or 15 diarylaminosulfur trifluorides bearing both electron with branched chain, R" are C-do normal or branched alkyl. drawing and electron donating groups at the para position of More Specifically the deoxofluorination reagent has the the aromatic rings. The sterically hindered N-phenyl-N- Specific Structure: naphthyl-amine was Successfully converted to the diary laminosulfur trifluoride at room temperature. However, the CHOCHCHN(SF)CHCHOCH, preparation of diarylaminoSulfur trifluorides bearing Sub For the purpose of this invention the following definitions Stituent groups at the ortho position of the aromatic ring are provided. Alkyl shall mean normal and branched carbon proved to be more difficult. None of the desired products radicals up to ten carbons. Aryl Shall mean Six and ten were obtained in reactions carried out at -10° C. or room member carbon rings having aromatic character. Fused aryl 25 temperature with either 2,2'-dimethyl-diphenylamine or shall mean aromatic rings containing two common carbon 2,2'-dimethoxy-diphenylamine. Instead only starting mate atoms. Linked aryl Shall mean aromatic rings joined together rial was recovered after several hours (3-24 h) of reaction by a bond from a carbon atom of one ring to a carbon atom time. The Steric hindrance imposed by the adjacent Substitu of another ring. Heteroatoms Shall mean oxygen and/or ent groups on the aromatic ring Seems to be significant in nitrogen in a carbon membered radical. Para-Substitution on these compositions. an aryl ring shall include H, p-Cl, p-OCH, p-CH, OR Aminosulfur trifluorides derived from relatively electron (R=alkyl Co or aryl Co-o), Br, I, F, alkyl Co or aryl deficient diarylamines were found to be relatively unstable. Co groups, NO, SOR (R=H, alkyl Co or aryl Co.), In an attempted preparation of 4,4'-dichloro-diphenyl ami NR (R=H, alkyl Co or aryl Co.). Alkoxyalkyl typically 35 nosulfur trifluoride, the amine was reacted with SF in ethyl means an oxygen bridging two alkyl groups, but it is also ether/triethylamine (EtO/TEA) at 0° C. After work-up a contemplated to include polyethers, such as: -O(-RO), R' light yellow solid was isolated. This solid product darkened where R and R' are C alkyl and n=1-10. considerably on Standing at room temperature (<1 h) form To develop thermally stable aminosulfur trifluorides for ing 4-chlorophenyl iminoSulfur difluoride as the principal the fluorination method of the present invention, the inven 40 decomposition product. tors considered compositions which would not produce The aminosulfur trifluoride is synthesized by reaction of gaseous by-products on decomposition. The production of a Secondary amine with SF in a non-aqueous Solvent that HF via abstraction of acidic protons in the vicinity of the will not react chemically with SF or the aminosulfur N-SF group by fluoride ion is believed to be one factor 45 trifluoride product. Examples include ethers, e.g., ethylether which contributes to the instability of the dialkylaminosulfur (EtO), tetrahydrofuran (THF), halogenated hydrocarbons, trifluorides. Consequently, compositions lacking Such pro e.g., CH2Cl2, freons, hydrocarbons, e.g., toluene, hexane, tons are attractive candidates for the present invention, tertiary amines, liquid SO and Supercritical CO. although compositions with Such protons can be useful. In The reaction can be carried out at temperatures ranging order to circumvent the thermal instability which results 50 from -90° C. or the freezing point of the solvent to the from molecular disproportionation of dialkylaminoSulfur boiling point of the Solvent. trifluoride, the inventors prepared compositions which poS The reaction mixture may be homogenous or heterog SeSS Sterically demanding groups attached to the N-SF COUS. function. Aminosulfur trifluorides with a highly electron 55 The secondary amine is represented by R'R''NH. deficient nitrogen bonded to the SF group are also appro R = alkyl (cyclic or non-cyclic, with or without priate Since molecular disproportionation will be leSS Sig heteroatoms), aryl, or alkoxyalkyl. R=alkyl (cyclic or non nificant in these compositions. cyclic, with or without heteroatoms), aryl or alkoxyalkyl. R' The diaryl, arylalkyl and alkoxyalkylaminosulfur trifluo may or may not be the same as R. rides fulfill most of the structural requirements for a ther 60 The tertiary amine is represented by RRR.N. R', Ror mally stable product for a fluorination method, Such as R = alkyl (cyclic or non-cyclic, with or without deoxofluorination. The preparation and reactions of these heteroatoms), or aryl. This includes tertiary amines which compositions are described below. contain the N-atom in a ring, e.g., N-methylpiperidine or in An attempted Synthesis of diphenylaminoSulfur trifluoride 65 a chain, e.g., triethylamine. It also includes tertiary amines by the conventional reaction route of the N-trimethylsilyl which contain the N-atom at a bridge-head, e.g., quinucli derivative of diphenylamine with SF proved to be difficult. dine or triethylene diamine and in fused rings, e.g., diazabi 6,080,886 11 12 cycloundecane (DBU). Compounds containing >1, tertiary The Substrate for fluorination may be an alcohol, an amine group in the molecule can also be used. The tertiary aldehyde, ketone, carboxylic acid, aryl or alkyl Sulfonic amine could also function as the reaction Solvent. Examples acid, aryl or alkyl phosphonic acid, acid chlorides, Silyl of specific amines employed for the synthesis of RNSF chlorides, silyl ethers, Sulfides, Sulfoxides, epoxides, phos reagents should also be effective for the in Situ proceSS 5 phines and thiophosphines. described below. Water or a low molecular weight alcohol (CHOH, No aminosulfur trifluoride product was obtained when CHOH, etc.) may be added to hydrolyze the intermediate pyridine or 3-methylpyridine was used instead of a tertiary Sulfinyl fluoride for disposal and to generate the Starting amine; however, more basic pyridines than the latter are Secondary amine. expected to be useful. The fluorinated product may be separated from the aque No aminosulfur trifluoride product was obtained when ous acidic mixture by extraction into a water immiscible NaF or CSF was used instead of a tertiary amine. Thus, its organic Solvent. utilization in the process beyond Simply acting as an HF The desired product may be distilled and thus isolated acceptor is an essential feature of the invention. from the crude reaction mixture.

TABLE 1.

Preparation of Diarylaminosulfur trifluorides from SF and Diarylamines

Product Starting Material Reaction Conditions (Yield)

H SF EtO, or THF, TEA SF N -10° C., 3 h N C 1. 2 (quantitative)

H EtO, or THF SF N -10° C., 3 h N

HC CH 3 HC CH 4 (quantitative)

H EtO, or THF SF N -10° C., 3 h N H3CO OCH Ol 5 H3CO OCH3 6 (quantitative)

H EtO, or THF SF N -10° C., 3 h N

7 C Ol C 8 (quantitative)

EtO, or THF SF H -10° C., 3 h N N

9 1O (quantitative) 6,080,886 13 14

TABLE 1-continued

Preparation of Diarwlaminosulfur trifluorides from SF and Diarwlamines

Product Starting Material Reaction Conditions (Yield) CH CH THF Starting material H -78°-RT, 3 h N

OCH Et2O, Starting material -78°-RT, 3 h H N

12 HCO

H EtO, N -78°-RT, 3 h

C Cl C 13 14

Saturated indoles (26, 28, Table 2) afford good yields of the corresponding aminosulfur trifluorides on reaction with TABLE 2-continued SF in EtO/TEA at -78 C. These compounds which appeared to be stable on initial preparation decomposed 35 Reaction of SF with heterocyclic amines in Et2O/TEA rapidly on Storage (<3 days). Product Starting material Reaction Conditions (yield) TABLE 2

Reaction of SF with heterocyclic amines in EtOTEA 40

Product Starting material Reaction Conditions (yield) O SF, EtO, TEA O

H SF, EtO, TEA Tarry reaction product. N -78° C. to -10° C. No SF derivative 45 -78° C. to -10° C. OC D N N / H 28 29 SF 24 quantitative 50 H SF, EtO, TEA Tarry reaction product. N -78° C. to -10° C. No SF derivative

25 55 Russian Inventor's Certificate No. 433,136 reported the preparation of N-ethyl-N-phenylaminosulfur trifluoride in H SF, EtO, TEA SF N -78° C. to -10° C. / 78% yield by reaction of N-ethyl-N-phenylamine with SF N in Et2O containing tertiary (3) amines. The present inven 60 tors confirmed these results and extended the method to the preparation of the N-methyl analog (Table 3). The arylalkyl 26 27 amines were much more reactive towards SF than the quantitative diarylamines and the reactions were completed at -78 C. with quantitative formation of products. The N-ethyl-N- phenyl aminosulfur trifluoride was not identified as a flu 6,080,886 15 16 orinating agent. However, the present inventors found that It has been further determined that dialkylaminosulfur this compound and related arylalkylaminoSulfur trifluorides trifluorides that contain an oxygen atom in the vicinity of the are very advantageous in deoxofluorination reactions, as Set SF group possess enhanced thermal Stability. The amino forth below. sulfur trifluorides with the highest reported decomposition temperatures are N-morpholinosulfur trifluoride and (S)-2- TABLE 3 (methoxyethyl) pyrrolidin-1-yl-sulfur trifluoride. The increased thermal Stability of these compounds may result Preparation of arylalkyl aminosulfur trifluorides from coordination of the electron-rich oxygen atom with Sulfur affording a conformationally rigid structure. Reaction Product However, the inventors found that (S)-2-(methoxyethyl) Starting material conditions (yield) pyrrolidin-1-yl-Sulfur trifluoride was a poor fluorinating H SF EtO, TEA SF reagent for deoxofluorination of cyclooctanol, as reported -78° C., 1 h 15 below, and N-morpholino Sulfurtrifluoride decomposes with NYCH, N YCH, the evolution of large quantities of gas (i.e., explosively). See Table 5.

3O 31 quantitative

H SF EtO, TEA SF The preparation of aminosulfur trifluorides by reaction of -78° C., 1 h 25 N N the amine with SF in EtO/TEA was successfully applied to YCH, YCH, the preparation of Several alkoxyalkylaminoSulfur trifluo rides (Table 4). These include compositions bearing one or

32 33 two methoxy groups. The reactions of the precursor amines quantitative with SF were quite rapid at -78 C. affording high yields of products.

TABLE 4 Preparation of alkoxyalkyl aminosulfur trifluorides Product Starting material Reaction conditions (Yield) H SF EtO, TEA SF Na -78° C., 1 h CH2CH2OMe N n CHCHOMe

34 35 quantitative

CHNHCHCHOMe SF EtO, TEA CHN(SF)CHCHOMe 36 -78° C., 1 h 37 quantitative

H SF-78° E.O.C., 1 TEAh SF N N

quantitative

MeOCHCH-NHCHCHOMe SF, EtO, TEA MeOCHCHN(SF)CHCHOMe 40 -78° C., 1 h 41 quantitative 6,080,886 17 18 Thermal analysis Studies of the newly Synthesized ami on decomposition are important indicators of the Safety in nosulfur trifluorides and dialkylaminosulfur trifluorides use of the compositions. (DAST) were performed on a Radex instrument, available Table 5 Summarizes the results of the Radex thermal from Systag of Switzerland. The instrument is similar to analysis Studies and provides a listing of decomposition ASTM E476-87. The instrument operates at a constant temperatures, preSSure gain and gas produced on two bases heating rate (0.5 to 2.0° C./min.) and measures heat flux into for the decomposition of diaryl, dialkyl, arylalkyl, and or out of a Sample, in the form of a temperature difference between Sample and inert reference and also the System's alkoxyalkylaminosulfur trifluorides (300 mg). Higher total internal pressure. This provides a measure of the onset 10 decomposition temperatures were recorded for the dialkyl of exothermic decomposition. The results of these Studies compositions. Among the newly Synthesized compositions, provide useful information about the relative thermal sta the alkoxyalkylaminosulfur trifluorides decomposed at bilities of these compositions. The decomposition tempera higher temperatures than the arylalkyl and diaryl composi ture and the quantity of gas (resultant gas pressure) produced tions.

TABLE 5 Thermal analysis of aminosulfur trifluorides by Radex Decomposi- Pressure Gain Gas tion Temp. On Decomposi- Produced Composition o C. tion (psia) (psia?m mol

EtNSF, 128 101 13 Me2NSF3 126 96.6 33

O 151 98.2 22

SF 68 8.9 3 Oro 2

SF 55 7.4 2

SF 87 23.3 8 ... O N Ol. 6

95 O O Cro 6,080,886 19 20

TABLE 5-continued

Thermal analwsis of aminosulfur trifluorides bw Radex Decomposi- Pressure Gain Gas tion Temp. On Decomposi- Produced Composition o C. tion (psia) (psia?m mol t 109 1O.O 3

SF 91 9.9 3 O NYCH,

SF 66 O O O N SCHCH-OMe

CHN(SF)CHCHOMe 104 1.5 O 37

SF 116 16.5 5

MeOCHCHN(SF)CHCHOMe 108 O O 41

A comparison of the pressure gain on decomposition 45 chlorophenyl-N-phenylaminosulfur trifluoride and the indicates that the dialkylaminoSulfur trifluorides produced a alkoxyalkylaminosulfur trifluorides should be especially Significantly larger quantity of gas as compared to the other Suitable for Scale-up and large Scale use. compositions. Most of the diaryl compositions produced a NMR spectra were obtained on a Bruker CP-300FT relatively Small quantity of gas. However, N-4- spectrometer operating at 282.4 MHz ('F), 300.13 MHz chlorophenyl-N-phenylaminosulfur trifluoride was found to 50 (H). Chemical shifts were referenced to neat CFCl('F) be remarkably stable in this regard producing no gas on and CHCl(H). decomposition. The arylalkyl compositions produced Some G.C.M.S. Spectra were recorded on a HP 5890 Series 11 gas on decomposition, but the alkoxyalkylaminoSulfur trif G.C. and 5972 series mass selective detector with a HP-1 luorides evolved essentially no gas at the conditions of these 55 column. tests. However, the most Significant factor demonstrated by All compositions in Subparagraphs (1) through (10) of the the data in Table 7 is the amount of gas produced per mmol Summary of the Invention are novel. There is one example of deoxofluorination reagent tested. This is a measure of the in the literature of a composition that exemplifies Subpara potential for dangerous results based upon explosion of the graph (11): N-ethyl-N-phenyl aminosulfurtrifluoride. It was reagent for a normalized amount of each reagent for com 60 prepared by L. N. Markovskii, et al (USSR patent, 1974, parison purposes. The reagents of the present invention No(II) 433136), but it was never used, or suggested for use, showed Significant improvement over the prior art compo as a fluorinating agent. Other members of this class (e.g., the Sitions. N-methyl-N-phenyl analog) were prepared and used. (S)-2- These results indicate that the novel aminosulfur trifluo 65 (methoxymethyl) pyrrolidin-1-yl-sulfur trifluoride rides prepared should be much Safer to use than the previ (compound 39 in Table 5) was reported in the literature. It ously known DAST compounds. The more stable N-4- was only employed in the fluorination of silylethers. No 6,080,886 21 22 indication or Suggestion was given that the compound butylcyclohexanone was obtained. The remainder, (33%) should be generally useful for the replacement of certain consisted of many other fluorinated by-products including oxygen atoms in organic compounds, i.e., for the deoxo the vinyl fluoride: 1-t-butyl-4-fluoro-3-cyclohexene. Data fluorination of alcohols, ketones, aldehydes, etc. In fact, in for the same ketone fluorination reaction conducted with the experimental work of the present invention, the deox compounds of Subparagraphs (1) to (11) are presented in ofluorination of alcohols by this compound afforded much Table 7. For all these compounds, the only products seen (by less yield than is obtained by fluorination using our new NMR) are the 1,1-difluoro-4-t-butylcyclohexane and the compositions of aminoSulfurtrifluorides. For example, only Vinyl fluoride compound. The reactions were remarkably a 17% yield of cyclooctyl fluoride was obtained on fluori (and Surprisingly) clean. The desired difluoro compound is nation of cyclooctanol with compound 39. In contrast yields always produced in a higher yield than was seen for DAST, in excess of 70% were obtained on fluorination of cyclooc the remainder being only the vinyl fluoride. The difluoro to tanol with the novel aminosulfur trifluorides under the same Vinyl Fluoride ratio, e.g., 96:4 for PhNSF cited in Table 7, reaction conditions. It is expected that the fluorination of a is thus equivalent to a 96% yield of the required difluoro silyl ether (which proceeds via the formation of a reactive 15 product). oxygen anion, R-O) will be more facile than reaction of Synthesis of the novel and more stable fluorinating the corresponding alcohol ROH with the -SF compound. reagent compositions used in the fluorination method of the The known N,N-dialkylaminosulfurtrifluorides, RNSF, present invention will now be set forth with regard to the (e.g., (CH)SF (DAST), and including those which con following examples. tain O as a heteroatom Such as N-morpholino Sulfur trifluoride, as well as the, bis(N,N-dialkylamino)-sulfur EXAMPLE 1. difluorides, are well known, useful reagents for effecting the replacement of certain oxygen and halogen (Cl, Br, I) atoms Synthesis of Aminosulfur Trifluorides in various classes of organic compounds with fluorine. The 25 A 3-neck, 250 mL round-bottom flask was equipped with present inventors have found that the aminosulfur trifluoride a magnetic stirring bar, a Na inlet tube attached to dry ice compounds of Subparagraphs (1) to (11) are generally safer condenser, a SF gas inlet tube connected to a metal vacuum to use, and can perform the oxygen and halogen replacement line manifold and a pressure equalized dropping funnel. The chemistry with Significant improvements in reaction Selec solvent (EtO or THF, 75 mL) was introduced into the flask tivity and yield of the desired fluoro product. via the dropping funnel and a 2 amine, corresponding to the All compositions under Subparagraphs (1) to (11) of the products as specified below (25.0 mmol), dissolved in the Summary of the Invention, are safer to use than the solvent (EtO or THF, 25 mL) and triethylamine (3.50 mL, dialkylaminosulfurtrifluorides, on the basis of quantifiable 25.0 mmol) were added to the dropping funnel. The con thermal decomposition criteria, set forth in Table 5. These 35 denser was cooled to -78 C. with dry ice/acetone and the are: onset temperature of Self-heating, and rate and extent of Solvent was cooled in like manner. A 1 liter ballast in the preSSure increase, as measured by RadeX instrumentation, manifold was filled with SF from a metal cylinder to and in Some cases by accelerated rate calorimetry (ARC) produce a pressure of 18 psia and SF (13 psia, 37 mmol) measurements. It is believed that the most discerning crite was introduced into the flask. The residual SF in the ballast rion for Safety in use is the pressure gain of volatiles upon 40 was pumped through a Soda-lime trap. The Solution of 2 decomposition, which may be qualitatively related to poten amine in EtO/TEA was then added dropwise to the SF tial explosivity. Note that the dialkylaminosulfur-trifluorides solution and stirred. The -78 C. bath was replaced by a (first 3 entries in Table 5) have far larger values of pressure -10° C. bath and the mixture was stirred for 3 h. After gained, as compared to compounds in Subparagraphs (1) to 45 cooling to -78. C., excess SF was pumped out of the (11). Solution through a Soda-lime trap and the Solution was In general, with compounds of Subparagraphs (1) to (11), brought to room temperature. When EtO was used as higher yields and Selectivities to the desired fluoroproducts Solvent, an H-tube was attached to the flask and the solvent were realized, for alcohol and ketone Substrates, as com decanted into one arm of the H-tube. This was followed by pared to those realizable under the same conditions with the 50 filtration of the solution to remove precipitated TEAHF. dialkylaminosulfurtrifluorides. The filtrate was then evaporated in-vacuo. After the solvent For the fluorination of cyclooctanol (a model alcohol) was completely removed, the H-tube was taken into a with DAST, W. M. Middleton reported, for the formation of dry-box and the product was transferred to a Teflon bottle. cyclooctyl fluoride, a yield of 70% and 30% of a cyclooctene 55 When THF was used as solvent, an in-vacuo evaporation of elimination product. (Ref. J. Org. Chem. 40, 574 (1975)). the Solvent was first carried out and the residue was redis The data of the present invention on this reaction of solved into EtO and further processed as above H and 'F cyclooctanol, done under the same conditions, is in Table 6. NMR of samples were done in teflon NMR tubes. For diphenylaminosulfurtrifluoride (first entry in Table), the The following compositions were obtained via this pro yield and selectivity are comparable to those of DAST. 60 cedure: diphenylaminosulfur trifluoride (2), H NMR However, all the other reagents defined in Subparagrahs (1) (CDC1)8 7.5-7.3 (m, 10H), 'F NMR (CDC1)ö 69.5 (d. to (11) of the Summary of the Invention offer significantly 2F), 31 (t, 1F)4,4'-dimethyl-diphenylamino-sulfur trifluo higher yields of the desired fluoro products, and higher ride (4) "H NMR (CDC1)8 7.35–7.10 (m, 8H), 2.35 (s, Selectivities (less elimination products). 65 6H)'F NMR (CDC1)ö 68.25 (d. 2F), 32.0 (t, 1 F)4,4'- For the fluorination of 4-t-butylcyclohexanone, a model dimethoxy-diphenylaminosulfur trifluoride (6)''H NMR ketone, with DAST a 67% yield of 1,1-difluoro-4-t- (CDC1)8 7.25 (d, 4H), 7.35 (d, 4H), 3.8 (s, 6H)'F NMR 6,080,886 23 24 (CDC1)ö 68.5 (s, br, 2F), 31.75 (s, br, 1F)N-4- Fluorination of the 3alcohol, ethyl-2-hydroxybutyrate chlorophenyl-N-phenylaminosulfurtrifluoride (8)"H NMR with Ph(Me)NSF afforded a 90% yield of ethyl-2- (CDC1)8 7.5-7.25 (m,9H), 'F NMR (CDC1)870 (d. 2F), fluorobutyrate. Similar results were obtained with bis 31 (t, 1F).N-naphthyl-N-phenyl-aminosulfur trifluoride (10) methoxyethyl aminosulfur trifluoride. With the 3alcohol, "H NMR (CDC1)88.4 (d. 0.66H), 8.15 (d, 0.34H), 7.9-6.8 acetone cyanohydrin a 66% yield of 2-fluoro-2- (m, 11H), 'F NMR (CDC1)ö 71, 66.5 (2(d) 0.66F), 70, methylpropionitrile was obtained on reaction with PhOMe) 67.5 (2(d), 134F) 33 (t, 1F).Indolineaminosulfur trifluoride NSF. (27)"H NMR (CDC1)ö 7.4 (d. 1H), 7.2 (dd, 2H), 7.0 (d. Aldehydes and ketones react with the aminosulfur trif 1H), 4.3 (t, 2H), 3.1 (t, 2H)'F NMR (CDC1)ö 60 (br, s, luorides to effect a replacement of the oxygen atom by two 2F), 20 (br, s, 1F)3,4-dihydro-2H-1,4-benzoxazinesulfur fluorine atoms. For example benzaldehyde reacted with trifluoride (29)H NMR (CDC1)8 7.3–7.1 (m, 2H), 6.8-7.1 either PhNSF, or (MeO CHCH)NSF to produce benzal (m, 2H), 4.5-4.3 (t, 2H), 4.2–3.9 (t, 2H)'F NMR (CDC1)ö fluoride (PhCHF) in quantitative yields. The dialdehyde, 63 (br, S, 2F) 11 (br, s, 1F). N-methyl-N-phenylaminosulfur terephthaldehyde reacted with PhOMe)NSF to afford a 95% trifluoride (31)H NMR (CDC1)ö 7.5-7.3 (m,3H), 7.3–7.0 15 yield of 1,1,4,4-tetrafluoro-p-xylene.after 16 h at room (m, 2H) 3.4 (s, 3H) 'F NMR (CDC1)& 64 (2F)ö 26 temperature in CHC1. This product was obtained in 98% (1F)*N-ethyl-N-phenyl aminosulfur trifluoride (33)-N-2- yield on reaction with (MeOCH2CH)NSF in refluxing methoxyethyl-N-phenylaminosulfur trifluoride (35) "H CH2Cl after 5 h while an 86% yield was obtained on NMR (CDC1)8 7.5-7.35 (m, 3H), 7.35-7.20 (m, 2H), reaction with PhOMe)NSF in CHCl at room temperature 4.1–3.9 (m, 2H), 3.7–3.5 (m, 2H), 3.30 (s, 3H) 'F NMR after 69 h. (CDC1)ö 63 (br, s, 2F), 31.5 (br, s, 1F)-N-2-methoxyethyl Other ketones also afforded the corresponding gem N-methylaminosulfur trifluoride (37). H NMR (CDC1)ö difluoro product on reaction with the aminosulfur trifluo 3.8-3.3 (m, 4H), 3.15 (s, 3H), 2.95 (s, 3H) 'F NMR rides. For example 4-carboethoxy cyclohexanone react with (CDC1) & 56 (s, br, 2F), 23 (s, br, 1F) (S)-2- 25 Ph(Me)NSF and N-4-chlorophenyl-N-phenyl aminosulfur (methoxymethyl) pyrrolidin-1-ylsulfur trifluoride (39) 'bis trifluoride to produce 1-carbo ethoxy-4, 4 (2-methoxyethyl)aminosulfur trifluoride (41) H NMR diflurocyclohexanone in CHCl in 70% and 95% yields (CDC1) & 3.5 (t, 4H), 3.15 (t, 4H), 3.05 (s, 6H) 'F NMR respectively. Also a 30% yield of difluorocyclooctane was (CDC1)ö 55 (s, br, 2F) 28 (s, br. 1 F). obtained on reaction of cyclooctanone with PhNSF at Present Fluorination Method with Novel room temperature after 7 days in CHCl2. Aminosulfur Trifluorides When the compound is a ketone, at least a catalytic The fluorination reactions of target compounds with the amount of HF can be added to the fluorination. The HF may aminoSulfur trifluorides are conducted by charging the reac 35 be added as the neat liquid or gas or as an adduct with a base, tion vessel with the Substrate first then adding the amino as with HFpyridine. Sulfurtrifluoride or charging the vessel first with the amino Carboxylic acids react with aminosulfur trifluorides to sulfur trifluoride then adding the substrate. Alternatively, produce carboxylic acid fluorides. For example benzoic acid both may be charged Simultaneously. Solvents may or may reacts with PhNSF to produce benzoyl fluoride in quan not be used. Solvents include materials which will not react 40 titative yield. with the aminosulfur trifluoride or Substrate. These include Carboxylic acid chlorides react with aminosulfur trifluo hydrocarbons e.g. hexane, halocarbons e.g., CHCl, ethers, rides to produce acid fluorides. For example (MeOCH2CH) Such as diethyl ethe,r nitriles, Such as acetonitrile, nitro NSF react with benzoic acid to generate benzoyl fluoride compounds e.g. nitromethane. 45 in quantitative yield. The fluorination reactions are usually conducted under Sulfoxides react with aminosulfur trifluorides to afford anhydrous conditions in metal, glass, plastic or ceramic a-fluorosulfides. For example phenyl methyl Sulfoxide gave vessels. The fluorination reaction temperature is conducted fluoromethyl phenyl sulfide in 70% yield on reaction with at any temperature between the freezing point of the Solvent (MeOCHCH-)-NSF. and the boiling point of the solvent. Pressure is usually not 50 Epoxides react with aminosulfur trifluorides to produce necessary and reactions are mostly carried out at ambient or the corresponding vicinal difluoride. For example cyclohex autogeneous preSSure. ene oxide reacts with bis(2-methoxyethyl)aminosulfur trif The fluorination products can be separated from the luoride in. CH2Cl containing a catalytic quantity of HF to reaction mixture and then purified by Standard methods 55 afford 1,2-difluorocyclohexane in 33% yield. including distillation, chromatography, Solvent extraction It was found that the deoxofluorination of ketones by and recrystallization. Ph(Me)NSF are considerably accelarated in the presence of In general, with the aminoSulfurtrifluoride compositions Lewis acids as catalysts. No Such rate increase was observed of the present invention higher yields and Selectivities to the with EtNSF (prior art DAST). For example in the synthe desired fluoroproducts were realized, for alcohol and ketone 60 sis of 1-t-butyl-4,4-difluorocyclohexane from 4-t- Substrates, as compared to those realizable under the same butylcyclohexanone and PhOMe)NSF a quantitative yield conditions with the dialkylaminosulfurtrifluorides. was obtained in the presence of 0.1 equivalent of BF.OEt Fluorination of the 1 alcohol, phenethanol was also easily after 16 h. In the absence of BF.OEt the reaction took 69 accomplished. For example reaction of this compound with 65 h for complete conversion of the Starting material to product. PhNSF and (MeOCHCH-)-NSF produce phenethyl A similar accelaration of this reaction was observed with fluoride in 60 and 68% yield respectively. Znland TiCl. No increase in rate with added Lewis acids 6,080,886 25 26 was observed when the fluorination of 4-t- The reaction mixture may be homogenous or heterog butylcyclohexanone was carried out with EtNSF (prior art COUS. DAST). These results indicate that Ph(Me)NSF may be useful for fluorinating unreactive ketones. The secondary amine is represented by R'R''NH. R = alkyl (cyclic or non-cyclic, with or without In an examplary fluorination of the present invention, heteroatoms), aryl, or alkoxyalkyl. R=alkyl (cyclic or non deoxofluorination of cyclooctanol with diarylaminoSulfur cyclic, with or without heteroatoms), aryl or alkoxyalkyl. trifluorides proceeds rapidly at -78 C. in CHCl to pro 1O R may or may not be the same as R. duce cyclooctylfluoride and cyclooctene with the former predominating (Table 6). Differing ratios of fluoride to olefin were observed with the various aromatic Substituted trifluo rides. The sterically hindered N-naphthyl-N- The tertiary amine is represented by RRR.N. R', Ror 15 R = alkyl (cyclic or non-cyclic, with or without phenylaminoSulfur trifluoride reacted quite slowly affording heteroatoms), or aryl. This includes tertiary amines which only a 10% conversion of Starting material to products after contain the N-atom in a ring, e.g., N-methylpiperidine or in 16 hat room temperature. A rapid conversion to the monof a chain, e.g., triethylamine. It also includes tertiary amines luoride was obtained with N-methyl-N-phenylaminosulfur which contain the N-atom at a bridge-head, e.g., quinucli trifluoride. Among the alkoxyalkyl compositions 35-41 dine or triethylene diamine and in fused rings, e.g., diazabi (Table 4), the phenyl substituted aminosulfur trifluoride (35) cycloundecane (DBU). Compounds containing >1, tertiary proved to be the most reactive affording fluorination at -78 amine group in the molecule can also be used. The tertiary C. in 1 h as compared to the methyl and bisalkoxyalkyl amine could also function as the reaction Solvent. Examples compositions (37, 41, respectively) which required longer 25 of specific amines employed for the synthesis of RNSF reaction times (-3 hr) at -78° C. to effect the same conver reagents should also be effective for the in Situ process SO. described below.

EXAMPLE 2 No aminosulfur trifluoride product was obtained when pyridine or 3-methylpyridine was used instead of a tertiary amine; however, more basic pyridines than the latter are expected to be useful. Reaction of Cyclooctanol with the New 35 Aminosulfur Trifluorides No aminosulfur trifluoride product was obtained when A Solution of cyclooctanol (128 mg, 1 mmol) in CH2Cl2 NaF or CSF was used instead of a tertiary amine. Thus, its (3.0 mL) was added to a solution of aminosulfur trifluoride 40 utilization in the process beyond Simply acting as an HF per Table 8 (1 mmol) in CHCl (2.0 mL) at -78° C. under acceptor is an essential feature of the invention. N in a 3-neck flask equipped with N inlet, Septum, and a magnetic Stirring bar. The reaction was monitored by G.C.M.S. for disappearance of the starting material. On 45 The Substrate for fluorination may be an alcohol, an completion, the mixture was poured into satd. NaHCO (25 aldehyde, ketone, carboxylic acid, aryl or alkyl Sulfonic mL) and after CO2 evolution ceased, it was extracted into acid, aryl or alkyl phosphonic acid, acid chlorides, Silyl CHCl (3x15 mL), dried (NaSO), filtered and evaporated chlorides, silyl ethers, Sulfides, Sulfoxides, epoxides, phos phines and thiophosphines. in vacuo to obtain the product as a mixture of cyclooctyl 50 fluoride and cyclooctene. Flash chromatography on Silica gel in hexane afforded the pure products. Water or a low molecular weight alcohol (CHOH, CHOH, etc.) may be added to hydrolyze the intermediate The aminosulfur trifluoride is synthesized by reaction of 55 Sulfinyl fluoride for disposal and to generate the Starting a Secondary amine with SF in a non-aqueous Solvent that Secondary amine. will not react chemically with SF or the aminosulfur trifluoride product. Examples include ethers, e.g., ethylether (EtO), tetrahydrofuran (THF), halogenated hydrocarbons, 60 The fluorinated product may be separated from the aque e.g., CH2Cl2, freons, hydrocarbons, e.g., toluene, hexane, ous acidic mixture by extraction into a water immiscible tertiary amines, liquid SO and Supercritical CO. organic Solvent.

The reaction can be carried out at temperatures ranging 65 from -90° C. or the freezing point of the solvent to the The desired product may be distilled and thus isolated boiling point of the Solvent. from the crude reaction mixture. 6,080,886 27 28

TABLE 6

Deoxofluorination of cyclooctanol

OH F RNSF He- --

Ratio of cyclooctyl fluoride/ Aminosulfur trifluoride Reaction conditions cycloctene

SF CHCl2, -78° C. 70:30 1 h. N

SF CHCl2, -78° C. 90:10 1 h.

HC CH 4

SF CHCl, -78° C. 76:24 1 h.

H3CO 1 C Ol OCH 6

SF CHCl2, -78° C. 94.6 1 h.

N N

Cl 8

SF CHCl2, RT 16 h, 10% N conversion

SF CHCl2, -78° C. 99.1 1 h. N YCH,

31 6,080,886 29 30

TABLE 6-continued Deoxofluorination of cyclooctanol

OH RNSF He O.O Ratio of cyclooctyl fluoride/ Aminosulfur trifluoride Reaction conditions cycloctene SF CHCl2, -78° C. 90:10 1 h. N YCHCH-OMe

35 CHN(SF)CHCHOMe CHCl2, -78° C. 85:15 37 3 h. MeOCHCHN(SF)CHCHOMe CHCl, -78° C. 85:15 41 3 h. SF CHCl2, -78° C. 17:6 8 h. (rowN 39

(CHS)NSF CCIF 70:30

35 In contrast to the Superior deoxofluorination of cyclooc nounced with the alkoxyalkyl aminosulfur trifluorides 37 tanol for the reagents reported in Table 6, (S)-2- and 41. A reasonable reaction time (40 h) for complete (methoxyethyl) pyrrolidin-1-yl-sulfur trifluoride was a poor fluorination of the ketone with bis(methoxyethyl deoxofluorination reagent for cyclooctanol. In a reaction 40 aminosulfur trifluoride (41) was obtained when the reaction carried out at -78°C. in CHCl for 8 h only 17% cyclooctyl was carried out at 40 C. fluoride was produced and 6% cyclooctene, as determined by nuclear magnetic resonance.

45 EXAMPLE 3

Reaction of 4-t-Butylcyclohexanone with Table 6 Summarizes the results obtained on fluorination of Aminosulfur Trifluorides 4-t-butyl cyclohexanone with the aminosulfur trifluorides. 50 All of the compositions examined except N-naphthyl-N- phenylaminoSulfur trifluoride converted the ketone to a A solution of 4-t-butylcyclohexanone (1.0 mmol) in mixture of 4-t-butyl-difluorocyclohexane and 4-t-butyl-1- CHCl (3.0 mL) contained in a 25 mL teflon vessel fluorocyclohexene, with the former predominating. The 55 equipped with a Swagelok Stopper, N inlet tube, and Stirring fluorination of this ketone was much slower than observed bar was treated with a solution of aminosulfur trifluoride per for the fluorination of cyclooctanol. A complete conversion Table 9 (1.8 mmol) in CHCl (2.0 mL) at room temperature. to the fluorinated products required Several days at room EtOH (11 mg, 14 uL, 0.2 mmol) was added and the mixture temperature in CH2Cl2. However, addition of a catalytic 60 was stirred at room temperature. The progress of the reaction amount of HF (generated in-situ from EtOH) accelerated the was monitored by a G.C.M.S. On completion, the solution rate of reaction considerably. The reaction time was reduced was poured into satd. NaHCO and after CO evolution from several days to ~16 h when the diaryl, arylalkyl, and ceased, it was extracted into CHCl (3x15 mL), dried N-methoxyethyl-N-phenylaminosulfur trifluorides were 65 (Na2SO), filtered, and evaporated in vacuo to afford a reacted with 4-t-butylcyclohexanone in the presence of HF. mixture of 4-t-butyl-difluorocyclohexane and 4-t-butyl-1- The effect of HF on reaction rate was, however, less pro fluorocyclohexene. 6,080,886 31 32

TABLE 7

Deoxofluorination of 4-t-butylcyclohexanone

OH F RNSF He- --

Ratio of cyclooctyl fluoride/ Aminosulfur trifluoride Reaction conditions cycloctene

SF CHCl2, -78° C. 70:30 1 h. N

SF CHCl2, -78° C. 90:10 1 h.

HC CH 4

SF CHCl, -78° C. 76:24 1 h.

H3CO 1 C Ol OCH 6

SF CHCl2, -78° C. 94.6 1 h.

N N

Cl 8

SF CHCl2, RT 16 h, 10% N conversion

SF CHCl2, -78° C. 99.1 1 h. N YCH,

31 6,080,886 33 34

TABLE 7-continued Deoxofluorination of 4-t-butylcyclohexanone

OH F RNSF He- --

Ratio of cyclooctyl fluoride/ Aminosulfur trifluoride Reaction conditions cycloctene SF CHCl2, -78° C. 90:10 1 h. N YCHCH-OMe

35 CHN(SF)CHCHOMe CHCl2, -78° C. 85:15 37 3 h. MeOCHCHN(SF)CHCHOMe CHCl, -78° C. 85:15 41 3 h. SF CHCl2, -78° C. 17:6 8 h. (rowN 39

(CHS)NSF CCIF 70:30

35 A convenient and economically attractive method for -continued deoxofluorination of the alcohol (cyclooctanol) and ketone Fluorinated Substrate + HF + H2SO3 (4-t-butylcyclohexanone) was achieved by conducting the Step 4 Separation of Product reaction in the medium used for preparation of the reagent, 40 i.e., without isolating the aminoSulfur trifluoride. Fluorinated Product

Schematic representation of the in-situ fluorination pro 45 CCSS EXAMPLE 4

Deoxofluorination Conducted In-Situ without Isolation of Aminosulfur Trifluoride 50 SF4, Solvent A solution of diphenylamine (25 mmol) in THF (25 mL) Step 1 Tertiary Amine containing triethylamine (3.48 mL, 25 mmol) was added dropwise to a solution of SF (37 mmol) in THF (75 mL) contained in a 3-neck flask equipped with a Stirring bar, N. 55 inlet tube, dry ice condenser, and SF inlet tube (as described Substrate for fluorination, above) at -78°C. The mixture was brought to -10° C. and Step 2 e.g. alcohol, aldehyde, ketone kept for 3 h. It was again cooled to -78 C. and excess SF was removed in-vacuo. The mixture was then treated with a THF (10 mL) solution of cyclooctanol (3.20g, 25.0 mmol) Fluorinated Substrate + (R')(R)NSOF + 60 and stirred at -78 C. for 1 h. The reaction was quenched (R)(R)NH with 5 mL HO and the solvents were evaporated in-vacuo, treated with satd. NaHCO (200 mL), extracted into EtOAc, Step 3 H2O dried (MgSO), filtered, and evaporated in-vacuo to obtain 65 the product as a mixture of cyclooctyl fluoride and cyclooctene (70:30 ratio). 6,080,886 35 36 EXAMPLE 5 phenylaminosulfur trifluoride (292 mg, 1.5 mmol) at -78 A solution of diphenylaminosulfur trifluoride (25 mmol) C.; under N2, then brought to room temperature and Stirred in THF (100 mL) prepared as above was treated with a THF for 16 h. After work-up and purification as above 2-fluoro solution (10 mL) of 4-t-butylcyclohexanone (3.85g, 25 2-methylpropionitrile (59 mg, 90%) was obtained. H NMR mmol) at room temperature and Stirred for 7 days. After in (CDC1) d 1.75 (d. 6H), 'F (CDC1) d -138 (1 F). work-up as described for the alcohol above, a product was EXAMPLE 11 obtained which was a mixture of 4-t-butyl difluorocyclohexane and 4-t-butyl-1-fluorocyclohexene Fluorination of 4-carboethoxycyclohexanone (96:4 ratio). 1O A Solution of 4-carboethoxycyclohexanone (170 mg, 1 Additional examples of the fluorination method of the mmol) in CHCl (5.0 mL) was added to N-methyl-N- present invention with various target compounds to be phenylaminosulfur trifluoride (390 mg, 2.0 mmol) at -78 fluorinated are set forth below. C.; under N2, then brought to room temperature and Stirred for 16 h. After work-up and purification as above EXAMPLE 6 15 1-carboethoxy-4,4-difluorocyclohexanone (134 mg, 70%) Fluorination of phenethanol was obtained. "H NMR in CDC1 d5.3–5.1 (m, 1H), 4.34.0 (q, 2H), 2.7-1.6 (m, 8H), 1.25 (t, 3H). 'F (CDC1) d -94 A Solution of phenethanol (122 mg, 1 mmol) in CH2Cl2 (1F, dd) -100.5 (dd, 1F). (5.0 mL) was added to diphenylaminosulfur trifluoride (308 mg, 1.2 mmol) at -78 C.; under N; then brought to room EXAMPLE 12 temperature and Stirred for 16 h. After work-up and purifi A Solution of 4-carboethoxycyclohexanone (170 mg, 1 cation as above phenethyl fluoride (75 mg, 60%) was mmol) in CHCl (5.0 mL) was added to N-phenyl-N-4- obtained. "H NMR in CDC1, d 7.7–7.4 (d. 2H), 7.3–7.1 (t, chlorophenyl aminosulfur trifluoride (584 mg, 2.0 mmol) at 2H), 7.1-7.0 (t, 1H). 'F (CDC1) d -215 (2F). 25 -78° C.; under N; then brought to room temperature and stirred for 16 h. After work-up and purification as above EXAMPLE 7 1-carboethoxy-4,4-difluorocyclohexanone (134 mg, 70%) Fluorination of phenethanol was obtained. "H NMR in CDCld 5.3–5.1 (m, 1H), 4.3-4.0 A Solution of phenethanol (122 mg, 1 mmol) in CH2Cl2 (q, 2H), 2.7-1.6 (m, 8H), 1.25 (t, 3H). 'F (CDC1) d -94 (5.0 mL) was added to bismethoxyethyl aminosulfur trif (1F, dd) -100.5 (dd, 1F). luoride (265 mg, 1.2 mmol) at -78° C.; under N; then EXAMPLE 13 brought to room temperature and stirred for 16 h. After Fluorination of cyclooctanone work-up and purification as above phenethyl fluoride (85 35 mg, 68%) was obtained. "H NMR in CDCld 7.7–7.4 (d. A solution of cyclooctanone (3.20g, 25 mmol) in CHCl 2H), 7.3–7.1 (t, 2H), 7.1-7.0 (t, 1H). 'F (CDC1) d -215 (5.0 mL) was added to diphenylaminosulfur trifluoride (6.43 (2F). g, 25 mmol) at-room temperature under N, and stirred for 7 days. After work-up as above difluorcyclooctanone was EXAMPLE 8 40 obtained in 30% yield (by g.c.) 'F (CDC1) d -99.5 (2F). Fluorination of ethyl-2-hydroxybutyrate EXAMPLE 1.4 A solution of ethyl-2-hydroxybutyrate (397 mg, 3 mmol) in CHCl (5.0 mL) was added to N-methyl-N- Fluorination of benzaldehyde phenylaminosulfur trifluoride (877 mg, 4.5 mmol) at -78 45 A solution of benzaldehyde (106 mg, 1 mmol) in CHCl C.; under N and stirred for 16 h. After work-up and (5.0 mL) was added to diphenyl aminosulfur trifluoride (386 purification as above ethyl-2-fluorobutyrate (362 mg, 90%) mg, 1.0 mmol) at -78 C.; under N; then brought to room was obtained. "H NMR in CDCld 4.3-4.1 (q, 2H), 1.55 (d. temperature and Stirred for 16 h. After work-up and purifi 6H), 1.3–1.1 (t, 3H). 'F (CDC1) d -148 (1F). cation as above benzal fluoride (128 mg, quantitative yield) 50 was obtained. "H NMR in CDCld 7.65 (d. 2H), 7.4 (t, 1H), EXAMPLE 9 7.3 (t, 2H), 'F (CDC1) d -110 (2F). Fluorination of ethyl-2-hydroxybutyrate EXAMPLE 1.5 A solution of ethyl-2-hydroxybutyrate (397 mg, 3 mmol) A solution of benzaldehyde (106 mg, 1 mmol) in CHCl in CHCl (5.0 mL) was added to bis(methoxyethyl) 55 (5.0 mL) was added to bis(methoxyethyl)aminosulfur trif aminosulfur trifluoride (994 mg, 4.5 mmol) at -78 C.; luoride (332 mg, 1.5 mmol ) at -78 C.; under N; then under N and stirred for 16 h. After work-up and purification brought to room temperature and stirred for 16 h. After as above ethyl-2-fluorobutyrate (362 mg, 90%) was work-up and purification as above benzal fluoride (128 mg, obtained. "H NMR in CDCld 4.3-4.1 (q, 2H), 1.55 (d. 6H), 60 quantitative yield) was obtained. "H NMR in CDCld 7.65 1.3–1.1 (t, 3H). 'F (CDC1) d-148 (1F). (d. 2H), 7.4 (t, 1H), 7.3 (t, 2H), 'F (CDC) d-110 (2F). EXAMPLE 10 EXAMPLE 16 Fluorination of benzoic acid Fluorination of acetone cyanohydrin 65 A Solution of acetone cyanohydrin (87 mg, 1 mmol) in A Solution of benzoic acid (122 mg, 1 mmol) in CH2Cl2 CHC1 (10.0 mL) was added to N-methyl-N- (5.0 mL) was added to diphenylaminosulfur trifluoride (771 6,080,886 37 38 mg, 3.0 mmol ) under N and stirred for 16 h at room (b) Fluorination with N-ethyl-N-phenylaminosulfur temperature. After work-up as above benzoyl fluoride (124 trifluoride mg, quantitative yield) was obtained. The product was A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) identified by g.c.m.s. M=124 5 in CHCl (10.0 mL) was added to N-ethyl-N- EXAMPLE 1.7 phenylaminosulfur trifluoride (627 mg, 3.0 mmol) at room temperature under N. BF.OEt (100 mL) was added and Fluorination of benzoyl chloride the mixture was stirred for 6 h at room temperature. The A solution of benzoyl chloride (141 mg, 1 mmol) in mixture was washed with Saturated NaHCO, dried CHCl (5.0 mL) was added to bis(methoxyethyl) (Na2SO4), filtered and evaporated in vacuo. Proton and aminosulfur trifluoride (567 mg, 3.0 mmol) under N and Fluorine NMR with 4-fluoroanisole (2 mmol) as internal Stirred for 16 hat room temperature. After work-up as above standard showed that a 99% yield of 1,1-difluoro-4-t- benzoyl fluoride (124 mg, quantitative yield) was obtained. butylcyclohexane was obtained. The product was identified by g.c.m.S. M=24 15 EXAMPLE 21 EXAMPLE 1.8 Catalysis of fluorination by Lewis acids using N Fluorination of phenyl methylsulfoxide methyl-N-phenylaminosulfurtrifluoride. A solution of methyl phenyl sulfoxide (140 mg, 1 mmol) a comparisonp in CHCl (5.0 mL) was added to bis(methoxyethyl) aminosulfur trifluoride (332 mg, 1.5 mmol) under N and (a) Fluorination of 4-t-butylcyclohexanone without Stirred for 16 hat room temperature. After work-up as above Lewis acid catalyst fluoromethyl phenyl sulfide (70% yield as determined by 25 A reaction of 4-t-butylcyclohexanone (2 mmol) with NMR) was obtained. H NMR (CDC1) d 7.5-7.0 (m, 5H), N-methyl-N-phenylaminosulfur trifluoride (3.0 mmol) in 3.3 (d. 2H), 19F CHCl (10 mL) at room temperature gave a 99% conver NMR (CDC1) d-183 (1 F). sion to 1,1-difluoro-4-t-butylcyclohexane after 69 h. as EXAMPLE 1.9 determined by NMR (4-fluoroanisole as internal standard) Fluorination of cyclohexene oxide. (b) With BF.OEt as catalyst 20 mmol of cyclohexene oxide and 24 mmol of Deoxof A reaction of 4-t-butylcyclohexanone (2 mmol) with luor were charged to a 100 mL three neck, round bottom N-methyl-N-phenylaminosulfur trifluoride (3.0 mmol) in flask equipped with a stir bar, a condenser, a glass Stopper, 35 CHCl (10 mL) containing BF.OEt (0.3 mmol) at room a gas inlet adapter and a Septum. 4 mmol of ethanol was temperature gave a 99% conversion to 1,1-difluoro-4-t- added to generate HF in-situ. The flask was heated to 60-70 butylcyclohexane after 6 h. as determined by NMR C. for 30 h under N2. The reaction mixture was diluted in (4-fluoroanisole as internal Standard) chloroform washed with Saturated bicarbonate, dried 40 Na2SO4), filtered and evaporated in vacuo. GC-MS indi (c) With Znl as catalyst cated >95% conversion of the starting material to products. A reaction of 4-t-butylcyclohexanone (2 mmol) with Two major products were observed in the 'F NMR. A N-methyl-N-phenylaminosulfur trifluoride (3.0 mmol) in multiplet was observed at -193 ppm and another multiplet CHCl (10 mL) containing Znl (0.3 mmol) at room at -182 ppm. These signals agree with literature values for 45 temperature gave a 67% conversion to 1,1-difluoro-4-t- 1.2 difluorocyclohexane and bis (fluorocyclohexyl) ether butylcyclohexane after 3 h. as determined by NMR respectively. Integration of peaks indicate a product ratio of (4-fluoroanisole as internal Standard) 1:2 difluoride/difluoroether (d) With TiCl, as catalyst EXAMPLE 2.0 50 A reaction of 4-t-butylcyclohexanone (2 mmol) with Fluorination of 4-t-butylcyclohexanone by N-methyl-N-phenylaminosulfur trifluoride (3.0 mmol) in diethylaminosulfur trifluoride(DAST) and N-ethyl CHCl (10 mL) containing TiCl, (0.3 mmol) at room N-phenylaminosulfur trifluoride (a comparison). temperature gave a 67% conversion to 1,1-difluoro-4-t- 55 (a) Fluorination with DAST butylcyclohexane after 3 h. as determined by NMR A solution of 4-t-butylcyclohexanone (308 mg, 2.0 mmol) (4-fluoroanisole as internal Standard). in CHCl (10.0 mL) was added to diethylaminosulfur EXAMPLE 22 trifluoride (483 mg, 3.0 mmol) at room temperature under N. BFOEt (100 mL) was added and the mixture was 60 Reaction of diethylaminosulfur trifluoride with 4-t- stirred for 6 hat room temperature. The mixture was washed butylcyclohexanone (with and without Lewis acids) with saturated NaHCO, dried (Na2SO), filtered and evapo rated in vacuo. Proton and Fluorine NMR with (a) Without Lewis acid 4-fluoroanisole (2 mmol) as internal Standard showed that a 65 A reaction of 4-t-butylcyclohexanone (2 mmol) with 67% yield of 1,1-difluoro-4-t-butylcyclohexane was diethylaminosulfur trifluoride (3.0 mmol) in CHCl (10 obtained. mL) at room temperature gave a 99% conversion of starting 6,080,886 39 40 material to products and a 67% yield of 1,1-difluoro-4-t- butylcyclohexane after 6 h.as determined by NMR SF (4-fluoroanisole as internal Standard). N (b) With BF.OEt as catalyst 1-(- SR)- A reaction of 4-t-butylcyclohexanone (2 mmol) with diethylaminosulfur trifluoride (3.0 mmol) in CHCl (10 wherein m=1-5 and R' and R are: mL) containing BF3.OEt2 (0.3 mmol) at room temperature (1) when m=1, one of R and R is an aryl radical and the other is an at least 5 member Saturated cyclic hydro gave a 99% conversion of Starting material to products and 1O carbon radical having one to three heteroatoms Selected a 67% yield of 1,1-difluoro-4-t-butylcyclohexane after 6 h.as from the group consisting of oxygen; or determined by NMR (4-fluoroanisole as internal standard). (2) when m=1, one of R and R is an aryl radical and the (c) With Znl as catalyst other is an at least 5 member Saturated cyclic hydro 15 carbon radical having one to three heteroatoms Selected A reaction of 4-t-butylcyclohexanone (2 mmol) with from the group consisting of oxygen wherein Said diethylaminosulfur trifluoride (3.0 mmol) in CHCl (10 cyclic hydrocarbon radical is fused to Said aryl radical; mL) containing Znl2 (0.3 mmol) at room temperature gave O a 99% conversion of starting material to products and a 67% (3) when m=1, R' and Ran together a cyclic ring having yield of 1,1-difluoro-4-t-butylcyclohexane after 6 h.as deter 2 to 10 carbon ring members and 1 heteroatom Selected from the group consisting of oxygen, nitrogen and mined by NMR (4-fluoroanisole as internal standard). alkylated nitrogen wherein Said ring has 1 to 2 alkoxy (d) With TiCl, as catalyst alkyl functionalities; or (4) when m=1, R and Ran together an unsaturated A reaction of 44-butylcyclohexanone (2 mmol) with 25 cyclic ring having 2 to 4 carbon ring members and one diethylaminosulfur trifluoride (3.0 mmol) in CHCl (10 to three heteroatoms Selected from the group consisting mL) containing TiCl, (0.3 mmol) at room temperature gave of oxygen, nitrogen, protonated nitrogen and alkylated a 99% conversion of starting material to products and a 67% nitrogen wherein Said ring has one to three functional yield of 1,1-difluoro-4-t-butylcyclohexane after 6 h.as deter groups of alkoxy; or mined by NMR (4-fluoroanisole as internal standard). (5) when m=1, individually alkoxyalkyl radicals; or The present invention provides a high yielding, preferably (6) when m=1, one of R and R is alkoxyalkyl and the one-step, process for the preparation of a number of classes other is Selected from the group consisting of alkyl and of novel aminosulfur trifluoride compounds. These novel aryl radicals, or. aminosulfur trifluoride compounds have been shown to have 35 2. The method of claim 1 wherein said compound is unique performance for effecting deoxofluorination of alco Selected from the group consisting of alcohols, and mixtures hols and ketones as demonstrated by the presently reported thereof. thermal analysis Studies indicating that they are Safer to use 3. The method of claim 1 wherein said composition has than the currently available dialkylaminosulfur trifluorides the Structure: (DAST), see the data in Table 7 for gas pressure generated 40 per millimole of reagent decomposed, and more effective at fluorinating alcohols than (S)-2-(methoxyethyl) pyrrolidin wherein R' are individually H, normal or branched 1-yl sulfur trifluoride, see Table for the efficiency of fluo alkyl Co or aryl Co and R" are Cao normal or rination showing poor fluorination by the latter compound in 45 branched alkyl. contrast to the compounds of the present invention. 4. The method of claim 3 wherein said composition has The Simplicity of the method used for preparing the new the Structure: aminosulfur trifluorides combined with their safety and RORN(SF)ROR Simplicity in use should make these compounds attractive 50 wherein Rand Rare individually C, to Co. in a normal or for large Scale commercial production and use, providing branched chain alkyl and R' and R are Co normal or unexpected improvement in fluorination technology in con branched alkyl. trast to the industry avoidance of DAST for such fluorina 5. The method of claim 3 wherein said composition has tions. the Structure: The present invention has been set forth with regard to 55 several preferred embodiments, but the full scope of the CHOCHCHN(SF)CHCHOCHs. present invention should be ascertained from the claims 6. The method of claim 1 wherein said fluorination is which follow. conducted in the presence of a Solvent. We claim: 7. The method of claim 6 wherein said solvent is selected 1. A method for the fluorination of a compound selected 60 from the group consisting of paraffins, halocarbons, ethers, from the group consisting of alcohols, aldehydes, ketones, nitriles, nitro compounds and mixtures thereof. epoxides and mixtures thereof using a fluorinating reagent 8. The method of claim 1 wherein the fluorination is comprising contacting Said compound with Said fluorinating conducted under anhydrous conditions. reagent under conditions Sufficient to fluorinate Said com 65 9. The method of claim 6 wherein said fluorination is pound wherein Said fluorinating reagent is an aminoSulfur conducted at a temperature above the freezing point of Said trifluoride composition having a structure with one or more: solvent and below the boiling point of said solvent. 6,080,886 41 42 10. The method of claim 1 wherein said compound is a 16. The method of claim 1 comprising Synthesizing Said ketone and the fluorination is catalyzed with at least a aminoSulfur trifluoride composition from a Secondary amine catalytic amount of a Lewis acid. and SF in a reaction media and without isolating Said 11. The method of claim 10 wherein said Lewis acid is aminoSulfur trifluoride composition, fluorinating Said com Selected from the group consisting of BF, Znl, TiCl, and 5 pound with Said aminoSulfur trifluoride composition by mixtures thereof. contact of Said compound with Said aminoSulfur trifluoride 12. The method of claim 1 wherein said compound is a in Said reaction media. ketone and at least a catalytic amount of HF is added to Said 17. The method of claim 16 wherein a tertiary amine is fluorination. present during the Synthesizing of Said aminoSulfur trifluo 13. The method of claim 2 wherein said alcohol is selected ride. from the group consisting of monofunctional and polyfunc tional primary, Secondary, tertiary and Vinyl alcohols and 18. The method of claim 17 wherein a solvent is present mixtures thereof. during the Synthesizing of Said aminoSulfur trifluoride. 14. The method of claim 1 wherein said aldehyde is 15 19. The method of claim 16 wherein said aminosulfur Selected from the group consisting of aliphatic, aromatic and trifluoride is a dialkyl aminosulfur trifluoride. heterocyclic aldehydes and mixtures thereof. 20. The method of claim 19 wherein said dialkyl amino 15. The method of claim 1 wherein said ketone is selected sulfur trifluoride is diethylaminosulfur trifluoride. from the group consisting of aliphatic, aromatic and hetero cyclic ketones and mixtures thereof.