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EP3906230A1 - Fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds - Google Patents

Fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds

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Publication number
EP3906230A1
EP3906230A1 EP20701253.5A EP20701253A EP3906230A1 EP 3906230 A1 EP3906230 A1 EP 3906230A1 EP 20701253 A EP20701253 A EP 20701253A EP 3906230 A1 EP3906230 A1 EP 3906230A1
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nmr
mhz
mmol
chloroform
alkyl
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German (de)
French (fr)
Inventor
Matthew Hopkinson
Stefan DIX
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Freie Universitaet Berlin
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Freie Universitaet Berlin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • Fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds The present invention relates to fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds and methods for synthesizing them.
  • Fluoroalkyl groups in particular fluoroalkyl-containing thiol-groups, such as SCF 3 , are attracting increasing attention in medicinal chemistry as a substituent that when incorporated into pharmaceuticals and other biologically-active compounds, can improve their potency and bioavailability.
  • the SCF 3 group is one of the most lipophilic moieties available and can allow for an increase in the membrane permeability of drug targets.
  • Scheme 1 Selected examples of drug candidates containing SCF3 groups.
  • the synthesis of SCF3-containing molecules can be achieved using a number of different strategies.
  • a useful approach in the context of medicinal chemistry is direct trifluoromethylthiolation wherein the SCF3 moiety is attached directly as a whole intact group onto a target substrate.
  • These reactions can potentially be conducted on the same substrates used when installing other related groups (eg. CF 3 ) and thus are simple to incorporate into screening studies.
  • CF3X Cl, Br
  • F3CSSCF3 electrophilic trifluoromethylthiolation reactions.
  • R 2 , R 3 are in each case an alkyl, a cycloalkyl, an aryl, a heteroaryl, a halogen, a halogen substituted alkyl or both R 2 and R 3 are part of a cyclic system;
  • - X is S, O, Se, Te; preferably S, O, Se;
  • R 4 SO 3 - is R 4 SO 3 - with R 4 being H, C1-C10 alkyl, aryl, CaFbHc, in particular -OTf (CF 3 SO 3 - ), PhSO 3 - or p-Tos-; I-, Cl-, ClO 4 -, BF 4 -;
  • - a is 1-20, preferably 1-12, more preferably 1-8;
  • - c is 0-10, preferably 0-5, more preferably 0, 1, 2.
  • the compound of formulae (I) acts a source of nucleophilic -XC a F b H c , such as -SCF 3 . Unlike most existing species, this compound does not contain expensive metal cations and is purely organic in nature.
  • the compound of general formulae (I) is a solid that is easy to handle under ambient conditions and is bench-stable over extended periods.
  • R 1 is C1-C10 alkyl, preferably C1-C5 alkyl, more preferably C1-C3 alkyl.
  • R 1 is a methyl group (-CH3) or an ethyl group (-C2H5).
  • the moieties R 2 and R 3 are part of an aromatic system, preferably of a C6-C10 aryl ring, more preferably of a C6 aryl ring, which may be further substituted. This may comprise a non-substituted or substituted C6 aryl ring or non- substituted or substituted naphthyl ring.
  • the moieties have the following meaning: - R 1 is C1-C3 alkyl;
  • R 2 , R 3 are part of an unsubstituted or substituted C6 aryl ring or naphthyl ring, - X is S, O, Se;
  • R 4 being aryl or CaFbHc, in particular– OTf (CF3SO3-), p-Tos; Ph-SO3- ; or BF4-;
  • R 1 , X, Y, Z, a, b, c have one of the above meanings
  • R 5 is absent or a C1-C10 alkyl, a C1-C10 alkoxy, in particular C1-C5 alkoxy, or a halogen, in particular Cl or Br.
  • the present compound is of the general formulae (IIa)
  • R 1 is C1-C3 alkyl
  • R 5 is absent or C1-C5 alkoxy, or Cl.
  • X, Z, a, b, c have the above meanings.
  • the moiety is -XCaFb, as for example -XCF3, -XCF(CF3)2 or -XC8F17, in particular -SCF3, -SeCF3, -OCF3 or -SC8F17.
  • any perfluoralkyl moiety is suitable.
  • the moiety -XCaFbHc may be -XCF2H or -XCFH2, in particular - SCF2H or -SCFH2.
  • the moieties R 1 , R 2 , R 3 and R 5 can be non-substituted or further substituted.
  • substituted in particular in connection to alkyl, cycloalkyl, aryl or heteroaryl relates to the substitution of one or more atoms, usually H-atoms, by one or more of the following substituents: halogen, hydroxy, protected hydroxy, oxo, C 3 -C 10 -cycloalkyl, aryl, heteroaryl, naphthyl, imino, imido, isocyano, amino, protected amino, primary or secondary amino, heterocyclic ring, carbonate, imidazolyl, indolyl, pyrrolidinyl, C 1 -C 12 -alkoxy, C 1 -C 12 -acyl, C 1 -C 12 -acyloxy, nitro, nitroso, carboxy, ester, aldehyde, ketone,
  • R 1 , R 2 , R 3 , X, Y, Z, a, b, c have the above meanings.
  • a major advantage of the present compounds is their simple synthesis from relatively inexpensive precursor substrates.
  • G may be H, in particular in case of electrophilic or oxidative fluoroalkylation, or a leaving group such as a halogen, -XR (such as -SR, -SeR), -CN or others, in particular in case for nucleophilic fluoroalkylation.
  • a suitable starting material would be R-SH, R-S-S-R or R-Se-Se-R wherein R may be a benzothiazole or a benzoxazole.
  • the fluoroalkylating agent is selected from a group containing a compound of general formulae (VII) NaSO2CaFbHc wherein a, b and c have the above meanings.
  • a preferred variant of a fluoroalkylating agent is NaSO2CF3 (Langlois reagent). The reaction may be carried out under photoredox catalysis conditions.
  • At least one fluoroalkylating agent is selected from a group containing a compound of general formulae (VIII) Hal C a F b H c wherein Hal is I, Br, or Cl and wherein a, b, c have the above meanings.
  • a preferred variant of a fluoroalkylating agent of formulae (VIII) is IC a F b H c , such as ICF 3 or IC 8 F 17 .
  • the fluoroalkylating agent of formulae (VIII) is employed together with a suitable base (such as NaH or NaOH) under heating or irradiation with UVA light.
  • a suitable base such as NaH or NaOH
  • R-SH or R-SeH may be used as starting materials.
  • at least one alkylating agent selected from a group containing alkyl trifluoromethanesulfonate, alkyl iodide, trialkyl oxonium tetrafluoroborate, alkyl sulfate is employed for alkylating the intermediate compound of general formulae (VI).
  • the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto high value organic compounds, in particular pharmaceutical or agrochemical targets.
  • the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto alcohols, carboxylic acids or even alkyl halogenides, such as alkyl bromides.
  • alkyl bromides may react with the present compound in a silver-mediated reaction.
  • Example 1 Synthesis of 3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate) (BT-SCF3, Compound 1)
  • Compound 1 can bes prepared in two steps from the cheap starting material 2,2 ⁇ - dithiobis(benzothiazole) (MBTS) which is a bulk chemical used in the industrial vulcanisation of rubber.
  • MBTS 2,2 ⁇ - dithiobis(benzothiazole)
  • the trifluoromethyl group can be installed using the relatively inexpensive reagent NaSO 2 CF 3 (Langlois’ reagent) using published procedures leading to the intermediate compound.
  • This species is a stable, non-reactive heteroaromatic compound that can be readily purified without decomposition.
  • methylation of the ring nitrogen using methyl trifluoromethanesulfonate cleanly affords the reagent 1 which is obtained as a pure compound upon simple filtration.
  • the Langlois reagent is used as the CF 3 source, the two-step synthetic strategy towards compound 1 can be modified to enable even less expensive trifluoromethylthiolating reagents to be employed.
  • compound 1 can be prepared in two steps from the inexpensive industrial compound 2-mercaptobenzothiazole (MBT) using CF 3 I as a trifluoromethylating reagent in the presence a base and UV light irradiation.
  • MBT 2-mercaptobenzothiazole
  • CF 3 I a trifluoromethylating reagent
  • the procedure for this first step is described in Example 5 and the general procedure for the methylation in described in Example 8.
  • the same general approach for the first fluoroalkylation step can be used to prepare related compounds featuring longer perfluoroalkyl chains as described in Examples 3 and 11.
  • alternative strategies for the first step could be potentially realised.
  • nucleophilic trifluoromethylation of disulfides or other sulfur compounds has been reported using the least expensive and therefore most industrially-attractive CF3 source fluoroform (HCF3).
  • Compound 1 (BT-SCF 3 ) was employed in deoxytrifluoromethylthiolation reactions of aliphatic alcohols (Hopkinson, Chem. Eur. J. 2019, 25, 7635, see scheme 4a). This reaction is very useful as hydroxy groups are widespread in organic molecules and the ability to directly convert them into SCF 3 groups avoids the preparation of alkyl halide or pseudohalide precursors, reducing the overall number of synthetic steps required to prepare SCF 3 -containing molecules.
  • Example 14 In addition to acting as a reagent for deoxytrifluoromethylthiolation, compound 1 can also serve as a more general source of -SCF 3 upon addition of a suitable metal or ammonium salt activator. This could potentially be achieved catalytically; AgSCF 3 , for example, could be generated in situ upon activation of 1 with small amounts a soluble, inexpensive silver(I) salt such as Ag 2 O or AgNO 3 (see Scheme 4b).
  • Example 19 The general procedure for deoxytrifluoromethylselenylation of alcohols is described in Example 19.
  • An alternative method for the synthesis of Compound 5 uses ICF 3 as a trifluoromethylating reagent. This method is described in Example 20.
  • Example 5 General Procedure for the Trifluoromethylation of Mercaptobenzothiazoles
  • Mercaptobenzothiazole (1.0 eq) and NaOH (1.1 eq) were dissolved in MeCN/H 2 O (9:1, 0.5 M)
  • the Schlenk flask was closed and the mixture frozen by using a liquid nitrogen bath.
  • High vacuum was applied to the Schlenk flask and afterwards CF 3 I (2.0 eq) was condensed into the frozen mixture.
  • the nitrogen bath was removed, Argon was added until standard pressure was achieved and an empty balloon was attached to the Schlenk flask.
  • Example 6 General Procedure for the Trifluoromethylation of Mercaptobenzoxazoles
  • 1,2-Bis(benzo[d]thiazol-2-yl)diselane (0.8 eq, 3.2 mmol, 1.36 g) was suspended in degassed MeOH/THF (4:1, 40 mL) and NaBH4 (1.6 eq, 6.4 mmol, 0.24 g) was added portionwise under vigorous stirring at 0 °C. After 10 min degassed 1M HCl (80 mL) was added and the precipitate was washed with degassed H2O (3 x 50 mL).
  • Example 12 General Procedures for the Deoxytrifluoromethylthiolation reaction of Alcohols with BT-SCF 3 Method A: The primary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF 3 (250 mg, 0.625 mmol, 1.25 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr) 2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 1-2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method B The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (399 mg, 1.0 mmol, 2.0 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method C The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (133 mg, 0.33 mmol, one third of 2.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (174 mL, 1.00 mmol, 2.00 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (133 mg, 0.33 mmol) was added followed by a third portion (133 mg, 0.33 mmol) after an additional 20 minutes. The reaction was allowed to stir at rt for a further 80 minutes (total reaction time of 2 h) before being concentrated in vacuo and purified by column chromatography over silica gel.
  • Method D The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (200 mg, 0.50 mmol, one third of 3.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (261 mL, 1.5 mmol, 3.0 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (200 mg, 0.50 mmol) was added followed by a third portion (200 mg, 0.50 mmol) after an additional 20 minutes.
  • (4-(4-Methoxyphenyl)butyl)(trifluoromethyl)sulfane Prepared from 4-(4-methoxyphenyl)-1-butanol (88 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (89 mg, 0.34 mmol, 68%).
  • R f (n- pentane/CH 2 Cl 2 , 9:1): 0.29. 2-(((Trifluoromethyl)thio)methyl)isoindoline-1,3-dione
  • R f (n-pentane): 0.93. (4-Nitrobenzyl)(trifluoromethyl)sulfane
  • R f (n-pentane): 0.87. (Naphthalen-2-ylmethyl)(trifluoromethyl)sulfane
  • Example 16 Deoxydifluoroselenylation of Carboxylic Acids with BT-SeCF 2 H
  • n-Octanoic acid (1.0 eq, 0.5 mmol, 72.1 mg) and NaH (2 eq, 1.0 mmol, 24 mg) were suspended in dry THF (5.0 mL) and stirred for 15 min at 0 °C.
  • BT-SeCF2H (1.05 eq, 0.525 mmol, 225 mg) was added and the mixture was allowed to stir for another 2 h at rt. Afterwards, the mixture was quenched with sat. NH4Cl solution.
  • the organic phase was washed with H2O (1 x 5 mL), the aqueous phases were extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4 and concentrated in vacuo.
  • the crude product was purified by column chromatography (SiO2, Pentane). The product was obtained as a colourless oil (53 mg, 0.21 mmol, 42 %).
  • NEt(iPr) 2 70 mL, 0.40 mmol, 2.0 eq was then added dropwise and the reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method F The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF3 (112 mg, 0.250 mmol, 1.25 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
  • Method G The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF 3 (179 mg, 0.400 mmol, 2.00 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel. Characterization Data for Deoxytrifluoromethylselenylation Products (4-Nitrobenzyl)(trifluoromethyl)selane
  • Example 20 Alternative Method for the 3-Methyl-2-((trifluoromethyl)selanyl) benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SeCF3, Compound 5) Synthesis of 2-(trifluoromethyl)selenyl)benzo[d]thiazole Bis(benzothiazole)diselenide (4.20 g, 9.85 mmol, 0.50 eq) was suspended in methanol (100 mL, degassed using the freeze-pump-thaw technique) and THF (25 mL, degassed using the freeze-pump-thaw technique) in a 3-necked round-bottomed flask under argon and the mixture was cooled to 0 °C.
  • methanol 100 mL, degassed using the freeze-pump-thaw technique
  • THF 25 mL, degassed using the freeze-pump-thaw technique

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a compound of general formulae (I) and their use as reagents

Description

Fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds The present invention relates to fluorine-containing compounds for use as nucleophilic reagents for transferring functional groups onto high value organic compounds and methods for synthesizing them. Description Fluoroalkyl groups, in particular fluoroalkyl-containing thiol-groups, such as SCF3, are attracting increasing attention in medicinal chemistry as a substituent that when incorporated into pharmaceuticals and other biologically-active compounds, can improve their potency and bioavailability. In particular, the SCF3 group is one of the most lipophilic moieties available and can allow for an increase in the membrane permeability of drug targets. To date, several SCF3-containing pharmaceuticals have been introduced and medicinal chemistry programs now routinely investigate SCF3-substituted derivatives of potential drug candidates alongside those labelled with more traditional fluorinated (eg. trifluoromethyl, CF3) or non-fluorinated groups (scheme 1).
Scheme 1: Selected examples of drug candidates containing SCF3 groups. The synthesis of SCF3-containing molecules can be achieved using a number of different strategies. A useful approach in the context of medicinal chemistry is direct trifluoromethylthiolation wherein the SCF3 moiety is attached directly as a whole intact group onto a target substrate. These reactions can potentially be conducted on the same substrates used when installing other related groups (eg. CF3) and thus are simple to incorporate into screening studies. Until the last few years, there existed only a few known reagents such as the highly toxic and difficult to handle gaseous species SCF3X (X = Cl, Br) and F3CSSCF3 for electrophilic trifluoromethylthiolation reactions. In recent years, however, a number of bench-stable and easy-to-use electrophilic trifluoromethylthiolating reagents have been developed and, as a result, the use of the SCF3 group in research laboratories and in pharmaceutical development has increased dramatically (Scheme 2).
Scheme 2: Examples of trifluoromethylthiolating reagents. However, nucleophilic sources of SCF3 are limited to a relatively small number of stable metal or ammonium salts [M][SCF3] (M = eg. Ag, Cu, Me4N) which, in most cases, contain rather expensive metal cations. It is thus desirable to provide alternative nucleophilic sources for fluoroalkyl-containing thiol- groups, which do not require metal cations and are purely organic. Furthermore, nucleophilic sources of related fluoroalkyl-containing groups such as SCnF2n+1 (n > 1) or SCF2H are even more scarce due to the instability of simple metal salts with these anions. The incorporation of fluoroalkyl selenyl (eg. SeCF3) or fluoroalkoxy (eg. OCF3) groups into organic molecules would also benefit from the availability of new practical nucleophilic reagents. These objectives are solved by compounds as described in claim 1. Accordingly, a fluorine containing compound of the general formulae (I)
is provided, wherein - R1 is C1-C20 alkyl;
- R2, R3 are in each case an alkyl, a cycloalkyl, an aryl, a heteroaryl, a halogen, a halogen substituted alkyl or both R2 and R3 are part of a cyclic system;
- X is S, O, Se, Te; preferably S, O, Se;
- Y is S, O;
- Z- is R4SO3- with R4 being H, C1-C10 alkyl, aryl, CaFbHc, in particular -OTf (CF3SO3- ), PhSO3- or p-Tos-; I-, Cl-, ClO4-, BF4-;
- a is 1-20, preferably 1-12, more preferably 1-8;
- b is (2a+1) - c,
- c is 0-10, preferably 0-5, more preferably 0, 1, 2. Rather than acting as an electrophilic trifluoromethylthiolating reagent, the compound of formulae (I) acts a source of nucleophilic -XCaFbHc, such as -SCF3. Unlike most existing species, this compound does not contain expensive metal cations and is purely organic in nature. The compound of general formulae (I) is a solid that is easy to handle under ambient conditions and is bench-stable over extended periods. In an embodiment of the present compound moiety R1 is C1-C10 alkyl, preferably C1-C5 alkyl, more preferably C1-C3 alkyl. In a particular preferred embodiment moiety R1 is a methyl group (-CH3) or an ethyl group (-C2H5). In a further embodiment of the present compound the moieties R2 and R3 are part of an aromatic system, preferably of a C6-C10 aryl ring, more preferably of a C6 aryl ring, which may be further substituted. This may comprise a non-substituted or substituted C6 aryl ring or non- substituted or substituted naphthyl ring. In another embodiment of the present compound the moieties have the following meaning: - R1 is C1-C3 alkyl;
- R2, R3 are part of an unsubstituted or substituted C6 aryl ring or naphthyl ring, - X is S, O, Se;
- Y is S, O;
- Z- being R4 being aryl or CaFbHc, in particular– OTf (CF3SO3-), p-Tos; Ph-SO3- ; or BF4-;
- a is 1-8;
- b is (2a+1) - c;
- c is 0, 1, 2. In a further embodiment the present compound is of the general formulae (II)
wherein R1, X, Y, Z, a, b, c have one of the above meanings, and
wherein R5 is absent or a C1-C10 alkyl, a C1-C10 alkoxy, in particular C1-C5 alkoxy, or a halogen, in particular Cl or Br. In yet a further embodiment the present compound is of the general formulae (IIa)
(IIa) wherein R1, R5, X, Z, a, b, c have the above meanings. In still a further embodiment the present compound is of the general formulae (IIb)
wherein
- R1 is C1-C3 alkyl;
- R5 is absent or C1-C5 alkoxy, or Cl.
- X is S, O, Se;
- Y is S, O;
- Z- being– OTf (CF3SO - 3), p-Tos; Ph-SO3-; BF - 4;
- a is 1-8;
- b is (2a+1) - c;
- c is 0, 1, 2. In another embodiment the present compound is of the general formulae (III)
wherein R1, X, Y, Z, a, b, c have the above meanings. In yet a further embodiment the present compound is of the general formulae (IV)
wherein R1, X, Z, a, b, c have the above meanings. In still another embodiment the present compound is of the general formulae (IVa)
wherein X, Z, a, b, c have the above meanings. In a variant wherein c = 0 the moiety -XCaFbHc does not contain any hydrogen. In such a case the moiety is -XCaFb, as for example -XCF3, -XCF(CF3)2 or -XC8F17, in particular -SCF3, -SeCF3, -OCF3 or -SC8F17. However, any perfluoralkyl moiety is suitable. In variants wherein c = 1 or 2 the moiety -XCaFbHc may be -XCF2H or -XCFH2, in particular - SCF2H or -SCFH2. It is to be understood that the moieties R1, R2, R3 and R5 can be non-substituted or further substituted. Here the term“substituted”, in particular in connection to alkyl, cycloalkyl, aryl or heteroaryl relates to the substitution of one or more atoms, usually H-atoms, by one or more of the following substituents: halogen, hydroxy, protected hydroxy, oxo, C3-C10-cycloalkyl, aryl, heteroaryl, naphthyl, imino, imido, isocyano, amino, protected amino, primary or secondary amino, heterocyclic ring, carbonate, imidazolyl, indolyl, pyrrolidinyl, C1-C12-alkoxy, C1-C12-acyl, C1-C12-acyloxy, nitro, nitroso, carboxy, ester, aldehyde, ketone, sulfonic acid, sulfinic acid, thiocarbonyl, phosphate, phosphonate, boronate, carbamoyl, carboxamide, N-(C1-C12- alkyl)carboxamide, N,N-Di(C1-C12-alkyl)carboxamide, cyano, alkylsulfonylamino, arylsulfonylamino, arylsulfonyl, alkylsulfinyl, arylsulfinyl, thiol, C1-C10-alkylthio, arylthiol, C1-C12- (per)fluoroalkyl and C1-C10-alkylsulfonyl. The substituted groups can be once or twice substituted with same or different substituents. The alkyl moieties may also comprise one or multiple double bonds. Preferred embodiments of the present compound include:
wherein Z- is any of the above, preferably -OTf or BF - 4 It is to be understood that a methylsulfate salt of compound 3 is disclaimed. The present compound is obtained in a process comprising the following steps: - providing a compound of general formulae (V)
wherein G is H or a suitable leaving group as starting material; - reacting the compound of general formulae (V) with at least one fluoroalkylating agent thereby providing an intermediate compound of general formulae (VI)
- alkylating the ring nitrogen of general formulae (VI) thereby providing the compound of general formulae (I)
wherein R1, R2, R3, X, Y, Z, a, b, c have the above meanings. A major advantage of the present compounds is their simple synthesis from relatively inexpensive precursor substrates. As mentioned G may be H, in particular in case of electrophilic or oxidative fluoroalkylation, or a leaving group such as a halogen, -XR (such as -SR, -SeR), -CN or others, in particular in case for nucleophilic fluoroalkylation. For example a suitable starting material would be R-SH, R-S-S-R or R-Se-Se-R wherein R may be a benzothiazole or a benzoxazole. In an embodiment of the present process the fluoroalkylating agent is selected from a group containing a compound of general formulae (VII) NaSO2CaFbHc wherein a, b and c have the above meanings. A preferred variant of a fluoroalkylating agent is NaSO2CF3 (Langlois reagent). The reaction may be carried out under photoredox catalysis conditions. The reaction of compound (V) with at least one fluoroalkylating agent of general formulae (VII) may be carried in the presence of an oxidizing agent such as K2S2O8 or a photocatalyst, such as 9-mesityl-10-methylacridinium perchlorate or [Ir(dF(CF3)ppy)(dtbbpy]PF6 (dF(CF3)ppy = 2- (2,4-difluorophenyl)-5-(trifluoromethyl)pyridine, dtbbpy = 4,4ʹ-di-tert-butyl-2,2ʹ-biyridine). In the latter case R-S-S-R or R-Se-Se-R may be used as starting materials and photoredox conditions such as blue light irradiation may be applied. In another embodiment of the present process at least one fluoroalkylating agent is selected from a group containing a compound of general formulae (VIII) Hal CaFbHc wherein Hal is I, Br, or Cl and wherein a, b, c have the above meanings. A preferred variant of a fluoroalkylating agent of formulae (VIII) is ICaFbHc, such as ICF3 or IC8F17. The fluoroalkylating agent of formulae (VIII) is employed together with a suitable base (such as NaH or NaOH) under heating or irradiation with UVA light. In these cases, R-SH or R-SeH may be used as starting materials. In another embodiment of the present process at least one alkylating agent selected from a group containing alkyl trifluoromethanesulfonate, alkyl iodide, trialkyl oxonium tetrafluoroborate, alkyl sulfate is employed for alkylating the intermediate compound of general formulae (VI). As pointed out above, the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto high value organic compounds, in particular pharmaceutical or agrochemical targets. For example, the present compound can be used as a nucleophilic reagent for transferring a fluorine-containing functional group onto alcohols, carboxylic acids or even alkyl halogenides, such as alkyl bromides. In one variant alkyl bromides may react with the present compound in a silver-mediated reaction. The invention is explained in more detail by means of the following examples. Example 1: Synthesis of 3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate) (BT-SCF3, Compound 1) Compound 1 can bes prepared in two steps from the cheap starting material 2,2¢- dithiobis(benzothiazole) (MBTS) which is a bulk chemical used in the industrial vulcanisation of rubber.
The trifluoromethyl group can be installed using the relatively inexpensive reagent NaSO2CF3 (Langlois’ reagent) using published procedures leading to the intermediate compound. This species is a stable, non-reactive heteroaromatic compound that can be readily purified without decomposition. In a second step, methylation of the ring nitrogen using methyl trifluoromethanesulfonate cleanly affords the reagent 1 which is obtained as a pure compound upon simple filtration. Although the Langlois reagent is used as the CF3 source, the two-step synthetic strategy towards compound 1 can be modified to enable even less expensive trifluoromethylthiolating reagents to be employed. For example, compound 1 can be prepared in two steps from the inexpensive industrial compound 2-mercaptobenzothiazole (MBT) using CF3I as a trifluoromethylating reagent in the presence a base and UV light irradiation. The procedure for this first step is described in Example 5 and the general procedure for the methylation in described in Example 8. The same general approach for the first fluoroalkylation step can be used to prepare related compounds featuring longer perfluoroalkyl chains as described in Examples 3 and 11. Furthermore alternative strategies for the first step could be potentially realised. In particular, nucleophilic trifluoromethylation of disulfides or other sulfur compounds has been reported using the least expensive and therefore most industrially-attractive CF3 source fluoroform (HCF3).
Analytical data: 1H NMR (400 MHz, Acetonitrile-d3) d = 8.40 (d, J=8.0, 1H, HAr), 8.28 (d, J=8.6, 1H, HAr), 8.05 (t, J=8.0, 1H, HAr), 7.97 (t, J=7.9, 1H, HAr), 4.45 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -39.3 (SCF3), -79.3 (S(O)2CF3).13C NMR (151 MHz,
Acetonitrile-d3) d = 160.6 (Cq), 143.8 (Cq), 134.1 (Cq), 132.4 (CH), 131.5 (CH), 127.7 (q, J=314, SCF3), 125.2 (CH), 122.0 (q, J=321, S(O)2CF3), 119.4 (CH), 40.0 (CH3).HRMS (ESI): m/z calculated for [C9H7F3NS2]+ ([M-(SO3CF3)]+): 249.9967, measured: 249.9955. IR (ATR): n (cm-1): 3086, 1664, 1578, 1490, 1476, 1462, 1433, 1382, 1279, 1266, 1240, 1227, 1196, 1173, 1161, 1150, 1108, 1092, 1050, 1026, 998, 814, 760, 722, 714, 688. Example 2
Compound 1 (BT-SCF3) was employed in deoxytrifluoromethylthiolation reactions of aliphatic alcohols (Hopkinson, Chem. Eur. J. 2019, 25, 7635, see scheme 4a). This reaction is very useful as hydroxy groups are widespread in organic molecules and the ability to directly convert them into SCF3 groups avoids the preparation of alkyl halide or pseudohalide precursors, reducing the overall number of synthetic steps required to prepare SCF3-containing molecules. Existing published methods for conducting this reaction use super-stoichiometric amounts of expensive AgSCF3, CuSCF3 or electrophilic trifluoromethylthiolating reagents in combination with excess Lewis acid or tetrabutylammonium iodide activators (Qing, Angew. Chem. Int. Ed. 2015; Rueping, Chem. Eur. J.2014; Billard, Eur. J. Org. Chem. 2016; Magnier, Eur. J. Org. Chem.2017). Most methods also require high reaction temperatures. By contrast, the same process can be achieved using only a slight excess of metal-free compound 1 (1.25 equivalents) in acetonitrile (0.5 M) at room temperature with just 2 equivalents of an organic amine base (such as di(isopropyl)ethyl amine). The procedure for the deoxytrifluoromethylthiolation of alcohols using compound 1 is described in Example 12. Related reactions using derivatives of compound 1 is described in Example 13. Compound 1 can also be employed in deoxytrifluoromethylthiolation reactions of carboxylic acids affording trifluoromethylthioesters. The synthesis of these products is typically achieved using acid chloride substrates and there exists to the best of our knowledge only one recent report for the direct conversion of readily available carboxylic acids (Hu, Chem. Sci.2019). The procedure for this reaction is described in Example 14. In addition to acting as a reagent for deoxytrifluoromethylthiolation, compound 1 can also serve as a more general source of -SCF3 upon addition of a suitable metal or ammonium salt activator. This could potentially be achieved catalytically; AgSCF3, for example, could be generated in situ upon activation of 1 with small amounts a soluble, inexpensive silver(I) salt such as Ag2O or AgNO3 (see Scheme 4b).
Scheme 4: a) Deoxytrifluoromethylthiolation of aliphatic alcohols using reagent 1: b) Catalytic generation of metal SCF3 salts from reagent 1. Example 3: Synthesis of 3-methyl-2-((perfluorooctyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SC8F17, Compound 2)
3-Methyl-2-((perfluorooctyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate was synthesized in two steps from 1-mercaptobenzothiazole. In the first step the C8F17 group was installed using a modified literature procedure employing the commercially-available perfluoroalkyl iodide IC8F17 and sodium hydride under irradiation with UVA light. N-Methylation using methyl trifluoromethanesulfonate was then conducted in analogy to the method used in Example 1. Analytical data: 1H NMR (400 MHz, Acetonitrile-d3) d = 8.40 (d, J=8.4, 1H, HAr), 8.29 (d, J=8.7, 1H, HAr), 8.07 (t, J=7.6, 1H, HAr), 7.99 (t, J=7.8, 1H, HAr), 4.47 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -79.3 (S(O)2CF3), -81.4 (t, J=10, CF3), -82.5 (t, J=14, SCF2), -118.4– -118.6 (m, CF2), -121.2– -121.5 (m, CF2), -121.8– -122.1 (m, CF2), -122.1– -122.3 (m, CF2), -122.9 – -123.1 (m, CF2), -126.4– -126.6 (m, CF2). HR-MS (ESI): m/z calculated for [C16H7F17NS2]+ ([M]+-SO3CF3): 599.9743, measured: 599.9730. IR (ATR): n (cm-1): 3101, 2361, 1576, 1490, 1461, 1435, 1370, 1328, 1281, 1251, 1200, 1149, 1134, 1097, 1054, 1031, 958, 930, 849, 816, 798, 768, 756, 741, 723, 714, 707, 655. Example 4: Synthesis of 3-methyl-2-((trifluoromethyl)selanyl)benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SeCF3, Compound 5)
3-Methyl-2-((trifluoromethyl)selanyl)benzo[d]thiazol-3-ium trifluoromethanesulfonate was synthesized in two steps from 1,2-bis(benzo[d]thiazol-2-yl)diselane. In the first step the CF3 group was installed under photoredox catalysis conditions using NaSO2CF3. N-Methylation using methyl trifluoromethanesulfonate was then conducted in analogy to the method used in Example 1. The reactivity exhibited by the selenium derivative (compound 5) is similar to the reactivity of compound 1 (Hopkinson, Chem. Eur. J. 2019, 25, 7635). The general procedure for deoxytrifluoromethylselenylation of alcohols is described in Example 19. An alternative method for the synthesis of Compound 5 uses ICF3 as a trifluoromethylating reagent. This method is described in Example 20. Analytical data: 1H NMR (400 MHz, Acetonitrile-d3) d = 8.37 (d, J=7.8, 1H, HAr), 8.27 (d, J=8.6, 1H, HAr), 8.01 (t, J=8.3, 7.9, 1H, HAr), 7.93 (t, J=7.9, 1H, HAr), 4.47 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -32.7 (SeCF3), -79.3 (S(O)2CF3).13C NMR (126 MHz, Acetonitrile-d3) d = 159.2 (Cq), 143.9 (Cq), 135.0 (Cq), 132.1 (CH), 131.1 (CH), 125.1 (CH), 122.7 (q, J=337, SeCF3), 122.0 (q, J=321, S(O)2CF3), 119.3 (CH), 41.4 (CH3). CHNS Elemental Analysis: calculated for C10H7F6NO3S2Se: C 26.92; H 1.58; N 3.14, S 14.37; measured: C 27.00, H 1.97, N 3.14, S 14.50. IR (ATR): n (cm-1): 3098, 3064, 1577, 1489, 1461, 1442, 1388, 1252, 1223, 1187, 1151, 1140, 1101, 1079, 1054, 1043, 1028, 987, 962, 802, 766, 741, 729, 712. Example 5: General Procedure for the Trifluoromethylation of Mercaptobenzothiazoles Mercaptobenzothiazole (1.0 eq) and NaOH (1.1 eq) were dissolved in MeCN/H2O (9:1, 0.5 M), the Schlenk flask was closed and the mixture frozen by using a liquid nitrogen bath. High vacuum was applied to the Schlenk flask and afterwards CF3I (2.0 eq) was condensed into the frozen mixture. The nitrogen bath was removed, Argon was added until standard pressure was achieved and an empty balloon was attached to the Schlenk flask. The frozen mixture was allowed to thaw by using a water bath and the mixture was stirred under irradiation from UVA LEDs (lmax = 365 nm) for 6 h. DCM and H2O were added to the mixture, the organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Pentane/DCM). 2-((trifluoromethyl)thio)benzo[d]thiazole Prepared using 5-chloro-2-mercapto-benzothiazole on a 5.00 mmol scale. White solid (0.94 g, 4.0 mmol, 80 %).1H NMR (400 MHz, Chloroform-d) d = 8.12 (d, J=8.1, 1H, HAr), 7.87 (d, J=7.9, 1H, HAr), 7.53 (t, J=7.5, 1H, HAr), 7.47 (t, J=7.5, 1H, HAr). 19F NMR (376 MHz, Chloroform-d) d = -40.7.13C NMR (101 MHz, Chloroform-d) d = 153.2, 151.9, 138.0, 128.3 (q, J=311), 127.1, 126.8, 124.3, 121.4. HRMS (EI): m/z calculated for
[C8H4F3NS2]+ ([M]+): 234.9732, measured: 234.9739. IR (ATR): n (cm-1): 3065, 1556, 1456, 1411, 1311, 1237, 1143, 1099, 1075, 1015, 988, 941, 852, 755, 726, 708, 676. Rf: (n-pentane/EtOAc, 20:1): 0.75. 5-chloro-2-((trifluoromethyl)thio)benzo[d]thiazole Prepared using 5-chloro-2-mercapto-benzothiazole on a 5.00 mmol scale. White solid (0.90 g, 3.34 mmol, 67 %).1H NMR (400 MHz, Chloroform-d) d = 8.06 (d, J=2.0, 1H, HAr), 7.80 (d, J=8.6, 1H, HAr), 7.42 (dd, J=8.6, 2.0, HAr), 19F NMR (376 MHz, Chloroform-d) d = -39.9.13C NMR (101 MHz, Chloroform-d) d = 154.1 (q, J=3), 153.8, 135.9, 133.3, 128.2 (q, J=311), 127.3, 123.9, 122.1. HRMS (EI): m/z calculated for [C8H3ClF3NS2]+ ([M]+): 268.9348, measured: 268.9348. 5-ethoxy-2-((trifluoromethyl)thio)benzo[d]thiazole Prepared using 5-ethoxy-2-mercapto-benzothiazole on a 5.00 mmol scale. White solid (0.63 g, 2.25 mmol, 45 %).1H NMR (400 MHz, Chloroform-d) d = 7.94 (d, J=9.0, 1H, HAr), 7.21 (d, J=2.5, 1H, HAr), 7.08 (dd, J=9.0, 2.5, 1H, HAr), 4.03 (q, J=7.0, 2H, CH2), 1.42 (t, J=7.0, 3H, CH3).19F NMR (376 MHz, Chloroform-d) d = -40.7.13C NMR (101 MHz, Chloroform-d) d = 158.3, 147.8, 147.4 (q, J=3.0), 140.0, 128.3 (q, J=311.1), 124.8, 117.4 , 103.7, 64.2, 14.7. HRMS (EI): m/z calculated for [C10H8F3NOS2]+ ([M]+): 278.9999, measured: 278.9983. Example 6: General Procedure for the Trifluoromethylation of Mercaptobenzoxazoles Mercaptobenzoxazole (1.0 eq) and NaH (3 eq, as 60% wt in mineral oil) were dissolved in dry MeCN (0.2 M), the Schlenk flask was closed and the mixture frozen using a liquid nitrogen bath. High vacuum was applied to the Schlenk flask and afterwards CF3I (2.0 eq) was condensed into the frozen mixture. The nitrogen bath was removed, Argon was added until standard pressure was achieved and an empty balloon was attached to the Schlenk flask. The frozen mixture was allowed to thaw by using an water bath and the mixture was stirred under irradiation from UVA LEDs (lmax = 365 nm) for 6 h. Remaining NaH was filtered off from the reaction and quenched. DCM and H2O were added to the mixture, the organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Pentane/DCM). 2-((trifluoromethyl)thio)benzo[d]oxazole Prepared using 2-mercapto-benzooxazole on a 5.00 mmol scale. Colourless liquid (0.30 g, 1.36 mmol, 27 %). 1H NMR (400 MHz, Chloroform-d) d = 7.79– 7.75 (m, 1H, HAr), 7.60– 7.55 (m, 1H, HAr), 7.45– 7.34 (m, 2H, HAr).19F NMR (376 MHz, Chloroform-d) d = -38.6.13C NMR (101 MHz, Chloroform-d) d = 152.89 (q, J=3), 152.51, 141.50, 127.81 (q, J=312), 126.60, 125.41, 120.61, 110.97. HRMS (EI): m/z calculated for [C8H4F3NOS]+ ([M]+): 218.9966, measured: 218.9978. Example 7: Synthesis of Difluoromethylated Benzothiazole derivatives Compounds featuring a CF2H group can be prepared using the same general sequence with installation of the CF2H moiety being achieved using HCF2OTf as a source of difluorocarbene. This approach has been previously reported using aromatic thiols as substrates (Hartwig, Angew. Chem. Int. Ed.2013, 52, 2092–2095).. Procedure for the Synthesis of 2-((difluoromethyl)selanyl)benzo[d]thiazole
1,2-Bis(benzo[d]thiazol-2-yl)diselane (0.8 eq, 3.2 mmol, 1.36 g) was suspended in degassed MeOH/THF (4:1, 40 mL) and NaBH4 (1.6 eq, 6.4 mmol, 0.24 g) was added portionwise under vigorous stirring at 0 °C. After 10 min degassed 1M HCl (80 mL) was added and the precipitate was washed with degassed H2O (3 x 50 mL). The solid was added to a degassed solution of 6M KOH (6 mL) and MeCN (6 mL), afterwards difluoromethyl trifluoromethanesulfonate (1 eq, 4.0 mmol, 0.8 g) was added to the mixture at 0 °C. The mixture was stirred for 15 min at 0 °C and was diluted with H2O (25 mL) and extracted with diethyl ether (100 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product is purified by column chromatography (SiO2, Pentane/DCM). Colourless solid (0.56 g, 2.12 mmol, 53 %). 1H NMR (400 MHz, Chloroform-d) d = 8.04 (d, J=8.8, 1H, HAr), 7.86 (d, J=6.4, 1H, HAr), 7.84 (t, J=54.5, 2H, CF2H), 7.49 (t, J=7.4, 1H, HAr), 7.40 (t, J=7.6, 1H, HAr).19F NMR (376 MHz, Chloroform-d) d = -90.11 (d, J=54). 13C NMR (101 MHz, Chloroform-d) d = 153.68 , 151.55 (t, J=4), 137.06 , 126.61 , 125.61 , 122.93 , 121.20 , 117.83 (t, J=291). HRMS (EI): m/z calculated for [C8H5F2NSSe]+ ([M]+): 264.9276, measured: 264.9296. Procedure for the Synthesis of 2-((difluoromethyl)thio)benzo[d]thiazole
2-Mercaptobenzothiazole (1.0 eq, 3.0 mmol, 0.5 g) was added to a solution of 6M KOH (6 mL) and MeCN (6 mL), afterwards difluoromethyl trifluoromethanesulfonate (3 eq, 9.0 mmol, 1.2 mL) was added to the mixture. The mixture was stirred for 2 min and was diluted with H2O (25 mL) and extracted with diethyl ether (3 x 10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Colourless solid (0.57 g, 2.6 mmol, 87 %). 1H NMR (400 MHz, Chloroform-d): d 8.01 (d, J = 8.2, 1H, HAr), 7.84 (d, J = 8.0, 1H, HAr), 7.65 (t, J = 56.3, 1H, CF2H), 7.49 (t, J = 8.0, 1H, HAr), 7.41 (t, J = 7.6, 1H).19F NMR (376 MHz, Chloroform-d): d -93.08 (d, J = 56). The Analytical data is in agreement to literature (Hu, Org. Lett.2010, 12, 1444-1447). Example 8: General Procedure for the Methylation of Tri- or Difluoromethylated Chalcogenated Heterocycles using Methyl trifluoromethanesulfonate
The (fluoroalkyl)chalcogen-substituted benzothiazole or benzoxazole (1.0 eq) was dissolved in dry CH2Cl2 (1.0 M) at rt. Methyl trifluoromethanesulfonate (3.0 eq) was added and the mixture was stirred overnight at rt. Et2O was added and the precipitated product was collected by filtration. 5-ethoxy-3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium
trifluoromethanesulfonate
Prepared using 5-ethoxy-2-((trifluoromethyl)thio)benzo[d]thiazole on a 0.61 mmol scale. White solid (245 mg, 0.55 mmol, 90 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.17 (d, J=9.5, 1H, HAr), 7.82 (d, J=2.5, 1H, HAr), 7.57 (dd, J=9.6, 2.5, 1H, HAr), 4.22 (q, J=7.0, 2H, CH2), 1.45 (t, J=7.0, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -39.8, -79.2. 13C NMR (101 MHz, Acetonitrile-d3) d = 161.7, 138.3, 136.9, 127.7 (q, J=314.9), 123.4, 122.0 (q, J=321.0), 120.5, 120.5, 118.4, 106.6, 66.3, 40.0, 14.7. HRMS (ESI): m/z calculated for [C11H14NO2S]+ ([M- SO3CF3 -SCF3 +OCH3]+): 224.0740, measured: 224.0743. 5-chloro-3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium
trifluoromethanesulfonate
Prepared using 5-chloro-2-((trifluoromethyl)thio)benzo[d]thiazole on a 0.85 mmol scale. White solid (325 mg, 0.75 mmol, 88 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.40– 8.36 (m, 2H, HAr), 7.95– 7.92 (m, 1H, HAr), 4.41 (s, 3H, CH3). 19F NMR (376 MHz, Acetonitrile-d3) d = - 39.1, -79.2.13C NMR (126 MHz, Acetonitrile-d3) d = 162.8, 144.6, 138.5, 132.7, 132.0, 127.6 (q, J=314), 126.6, 122.0 (q, J=321), 119.4, 40.3. HRMS (ESI): m/z calculated for [C9H9ClNOS]+ ([M-SO3CF3 -SCF3 +OCH3]+): 214.0088, measured: 214.0084. 3-methyl-2-((trifluoromethyl)thio)benzo[d]oxazol-3-ium trifluoromethanesulfonate (BO-SCF3)
Prepared using 2-((trifluoromethyl)thio)benzo[d]oxazole on a 0.91 mmol scale. White solid (70 mg, 0.18 mmol, 20 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.11– 7.99 (m, 2H, HAr), 7.96 – 7.83 (m, 2H, HAr), 7.27– 7.18 (m, 1H, HAr), 7.17– 7.03 (m, 1H, HAr), 4.19 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -35.1, -79.3. HRMS (ESI): m/z calculated for [C8H8NO2]+ ([M-SO3CF3 -SCF3 +OH]+): 150.0550, measured: 150.0555. 2-((difluoromethyl)selanyl)-3-methylbenzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SeCF2H)
Prepared using 2-((difluoromethyl)selanyl)benzo[d]thiazole on a 0.91 mmol scale. White solid (362 mg, 0.85 mmol, 93%).1H NMR (400 MHz, Acetonitrile-d3) d = 8.31 (d, J=8.5, 1H, HAr), 8.19 (d, J=8.6, 1H, HAr), 7.94 (t, J=8.1, 1H, HAr), 7.85 (t, J=7.2, 1H, HAr), 7.79 (t, J=52.4, 2H, CF2H), 4.34 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -79.2 , - 87.9 (d, J=52). 13C NMR (101 MHz, Acetonitrile-d3) d = 164.1, 143.8, 133.9, 131.4 , 130.2, 124.8, 122.0 (q, J=321), 118.6 (t, J=296), 118.5, 40.9. HRMS (ESI): m/z calculated for [C9H10NOS]+ ([M-SO3CF3 -SeCF3 +OCH3]+): 180.0478, measured: 180.0495. 2-((difluoromethyl)thio)-3-methylbenzo[d]thiazol-3-ium trifluoromethanesulfonate (BT- SCF2H)
Prepared using 2-((difluoromethyl)thio)benzo[d]thiazole on a 2.4 mmol scale. White solid (0.79 g, 2.0 mmol, 84%).1H NMR (400 MHz, Acetonitrile-d3) d = 8.28 (d, J = 8.3 Hz, 1H, HAr), 8.13 (d, J = 8.6 Hz, 1H, HAr), 7.95 (t, J = 7.9 Hz, 1H, HAr), 7.86 (t, J = 7.8 Hz, 1H, HAr), 7.52 (t, J = 53.4 Hz, 1H, CF2H), 4.26 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -79.28, -91.53 (d, J = 53 Hz).CHNS Analysis: Calculated for C10H8F5NO3S3 C: 31.50%; H: 2.11%; N: 3.67%; S: 25.22% , found to be C: 31.53% ; H: 2.12% ; N: 3.72% ; S: 25.12% Example 9: General Procedure for the Methylation of Trifluoromethylated Chalkogen Derivatives using Trimethyloxonium Tetrafluoroborate
The Chalkogen derivative (1.0 eq) was dissolved in dry CH2Cl2 (1.0 M) at rt. Trimethyloxonium Tetrafluoroborate (3.0 eq) was added and the mixture was stirred overnight at rt. The crude mixture was filtered and extracted with DCM. Et2O was added to the filtrate and the precipitated product was collected by filtration. 3-methyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium tetrafluoroborate
Prepared using 2-((trifluoromethyl)thio)benzo[d]thiazole on a 1.15 mmol scale. White solid (40 mg, 0.12 mmol, 10 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.39 (d, J=8.3, 1H, HAr), 8.28 (d, J=8.6, 1H, HAr), 8.05 (t, J=8.3, 1H, HAr), 7.97 (t, J=8.1, 1H, HAr), 4.45 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -39.1, -151.5. HRMS (ESI): m/z calculated for [C9H10NOS+]+ ([M-BF4 -SCF3 +OCH3]+): 180.0478, measured: 180.0478.
Example 10: General Procedure for the Ethylation of Trifluoromethylated Chalkogen Derivatives
The Chalkogen derivative (1.0 eq) was dissolved in dry CH2Cl2 (1.0 M) at rt. Ethyl trifluoromethanesulfonate (3.0 eq) was added and the mixture was stirred overnight at rt. Et2O was added and the precipitated product was collected by filtration. 3-ethyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate
Prepared using 2-((trifluoromethyl)thio)benzo[d]thiazole on a 1.15 mmol scale. White solid (230 mg, 0.56 mmol, 48 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.48– 8.28 (m, 2H, 8.14– 7.85 (m, 2H, 5.03 (q, J=7.5, 2H, CH2), 1.61 (t, J=7.5, 3H, CH3).
19F NMR (376 MHz, Acetonitrile-d3) d = -39.2, -79.2.13C NMR (126 MHz, Acetonitrile- d3) d = 160.3, 142.8, 134.8, 132.5, 131.4, 127.6 (J=314), 125.5, 122.1 (q, J=321), 119.2, 49.6, 14.5. HRMS (ESI): m/z calculated for [C10H12NOS]+ ([M-SO3CF3 -SCF3 +OCH3]+): 194.0634, measured: 194.0643. 5-ethoxy-3-ethyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium
trifluoromethanesulfonate
Prepared using 5-ethoxy-2-((trifluoromethyl)thio)benzo[d]thiazole on a 0.61 mmol scale. White solid (214 mg, 0.47 mmol, 77 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.22 (d, J=9.5, 1H, HAr), 7.84 (d, J=2.5, 1H, 7.56 (dd, J=9.5, 2.5, 4.98 (q, J=7.4, 2H, CH2), 4.23 (q, J=7.0, 2H, CH2), 1.58 (t, J=7.4, 3H, CH3), 1.45 (t, J=7.0, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -39.7, -79.2.13C NMR (126 MHz, Acetonitrile-d3) d = 161.6, 154.6, 137.6, 137.2, 127.7 (q, J=314), 123.5, 122.1 (q, J=321), 120.3, 106.9, 66.3, 49.5, 14.7, 14.6. HRMS (ESI): m/z calculated for [C12H16NO2S]+ ([M-SO3CF3 -SCF3 +OCH3]+): 238.0896, measured: 238.0902. 5-chloro-3-ethyl-2-((trifluoromethyl)thio)benzo[d]thiazol-3-ium
trifluoromethanesulfonate
Prepared using 5-chloro-2-((trifluoromethyl)thio)benzo[d]thiazole on a 0.85 mmol scale. White solid (63 mg, 0.14 mmol, 16 %).1H NMR (400 MHz, Acetonitrile-d3) d = 8.44– 8.34 (m, 2H, HAr), 7.93 (dd, J=8.9, 1.8, 1H, , 4.96 (q, J=7.4, 2H, CH2), 1.58 (t, J=7.4, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -39.0, -79.2. HRMS (ESI): m/z calculated for [C10H11ClNOS]+ ([M-SO3CF3 -SCF3 +OCH3]+): 228.0244, measured: 228.0247. Example 11: General Procedure for the Synthesis of BT-SRF Reagents (RF = perfluoroalkyl)
1st Step: Mercaptobenzothiazole (1.0 eq) was dissolved in DMF under argon. Sodium hydride (60% wt in mineral oil, 1.1 eq) was added and the mixture was stirred at rt for 30 min. The perfluoroalkyl iodide (1.2 eq) was then added and the mixture was stirred under irradiation from UVA LEDS (lmax = 365 nm) overnight. Water was added and the crude product was extracted with EtOAc (3×). The combined organic fractions were washed with water (3x), dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography over silica gel afforded the 2-((perfluoroalkyl)thio)benzo[d]thiazole intermediate.
2nd Step: The 2-((perfluoroalkyl)thio)benzo[d]thiazole intermediate (1.0 eq) was dissolved in CH2Cl2 at rt. Methyl trifluoromethanesulfonate (3.0 eq) was added and the mixture was stirred overnight at rt. Et2O was added and the precipitated 3-methyl-2- ((perfluoroalkyl)thio)benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SRF) salt was collected by filtration. 3-Methyl-2-((perfluoropropyl)thio)benzo[d]thiazol-3-ium Trifluoromethanesulfonate (BT-SC3F7)
Prepared using perfluoro-n-propyl iodide on an 8.40 mmol scale. Yield of first step = 70%, yield of 2nd step = 94%). Off-white solid (1.94 g, 5.53 mmol).
1H NMR (400 MHz, Acetonitrile-d3) d = 8.44 (d, J=8.3, 1H, HAr), 8.33 (d, J=8.7, 1H, HAr), 8.05 (ddd, J=8.6, 7.2, 1.2, 1H, HAr), 7.97 (ddd, J=8.3, 7.2, 1.1, 1H, HAr), 4.51 (s, 3H, CH3).19F NMR (376 MHz, Acetonitrile-d3) d = -79.2, -80.5 (t, J=9), -83.8 (q, J=10), -123.2. 13C NMR (151 MHz, Acetonitrile-d3) d = 158.7, 144.1, 134.7, 132.6, 131.8, 125.3, 122.0 (q, J=320), 119.7, 39.7 (CH2). Note: Three perfluoroalkyl 13C peaks are not observed. HRMS (ESI): m/z calculated for [C11H7F7NS2]+ ([M-SO3CF3]+): 349.9903, measured: 349.9922. 3-Methyl-2-((perfluoropropan-2-yl)thio)benzo[d]thiazol-3-ium
Trifluoromethanesulfonate (BT-SCF(CF3)2) Prepared using perfluoropropan-2-yl iodide on a 14.1 mmol scale. Yield of first step = 91%, yield of 2nd step = 83%). Off-white solid (3.73 g, 10.65 mmol).
1H NMR (400 MHz, Acetone-d6) d = 8.63 (dm, J=7.9, 1H, HAr), 8.57 (dm, J=8.6, 1H, HAr), 8.11 (m, 1H, HAr), 8.03 (m, 1H, HAr), 4.75 (s, 3H, CH3).19F NMR (376 MHz, Acetone-d6) d = -74.7 (d, J=11), -78.9, -154.7 (sept, J=11).13C NMR (151 MHz, Acetonitrile-d3) d = 158.5, 143.2, 134.8, 132.7, 131.9, 125.4, 122.0 (q, J=320), 119.7, 40.0 (CH2). Note: Two perfluoroalkyl 13C peaks are not observed. HRMS (ESI): m/z calculated for [C11H7F7NS2]+ ([M-SO3CF3]+): 349.9903, measured: 349.9923. Example 12: General Procedures for the Deoxytrifluoromethylthiolation reaction of Alcohols with BT-SCF3 Method A: The primary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (250 mg, 0.625 mmol, 1.25 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 1-2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
Method B: The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (399 mg, 1.0 mmol, 2.0 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (174 mL,1.0 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
Method C: The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (133 mg, 0.33 mmol, one third of 2.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (174 mL, 1.00 mmol, 2.00 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (133 mg, 0.33 mmol) was added followed by a third portion (133 mg, 0.33 mmol) after an additional 20 minutes. The reaction was allowed to stir at rt for a further 80 minutes (total reaction time of 2 h) before being concentrated in vacuo and purified by column chromatography over silica gel.
Method D: The secondary alcohol (0.50 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT- SCF3 (200 mg, 0.50 mmol, one third of 3.0 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (261 mL, 1.5 mmol, 3.0 eq) was added dropwise and the reaction mixture was stirred at rt. After 20 minutes, a second portion of BT-SCF3 (200 mg, 0.50 mmol) was added followed by a third portion (200 mg, 0.50 mmol) after an additional 20 minutes. The reaction was allowed to stir at rt for a further 80 minutes (total reaction time of 2 h) before being concentrated in vacuo and purified by column chromatography over silica gel. Characterization Data for Deoxytrifluoromethylthiolation Products: (4-Phenylbutyl)(trifluoromethyl)sulfane
Prepared from 4-phenyl-1-butanol (76 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (100 mg, 0.43 mmol, 85%).
1H NMR (600 MHz, Chloroform-d) d = 7.31 (tm, J=7.7, 2H, HAr), 7.23– 7.17 (m, 3H, HAr), 2.93 – 2.88 (m, 2H, CH2), 2.68– 2.63 (m, 2H, CH2), 1.79– 1.72 (m, 4H, CH2) 19F NMR (565 MHz, Chloroform-d) d = -41.1.13C NMR (151 MHz, Chloroform-d) d = 141.8 (Cq), 131.3 (q, J=306, CF3), 128.6 (CH), 128.5 (CH), 126.1 (CH), 35.3 (CH2), 30.3 (CH2), 29.9 (q, J=2, CH2), 29.1 (CH2). HRMS (EI): m/z calculated for [C11H13F3S]+ ([M]+): 234.0685, measured: 234.0690. IR (ATR): n (cm-1): 3063, 3028, 2927, 2857, 2360, 2342, 1733, 1687, 1604, 1496, 1454, 1309, 1271, 1245, 1218, 1148, 1103, 1031, 909, 806, 744, 698, 653. (3-phenylpropyl)(trifluoromethyl)sulfane
Prepared from 3-phenyl-1-propanol (68 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (81 mg, 0.37 mmol, 74%).
1H NMR (600 MHz, Chloroform-d) d = 7.31 (tm, J=7.5, 2H, HAr), 7.23 (tt, J=7.3, 2.0, 1H, HAr), 7.19 (dm, J=7.5, 2H, HAr), 2.89 (t, J=7.3, 2H, CH2), 2.75 (t, J=7.5, 2H, CH2), 2.04 (quin, J=7.5, 2H, CH2). 19F NMR (376 MHz, Chloroform-d) d = -41.8. 13C NMR (151 MHz, Chloroform-d) d = 140.6 (Cq), 131.3 (q, J=306, CF3), 128.7 (CH), 128.6 (CH), 126.4 (CH), 34.5 (CH2), 31.1 (CH2), 29.3 (q, J=2, CH2). HRMS (EI): m/z calculated for
[C10H11F3S]+ ([M]+): 220.0528, measured: 220.0520. IR (ATR): n (cm-1): 3064, 3029, 2928, 1604, 1496, 1454, 1422, 1290, 1099, 1030, 970, 909, 859, 742, 698. (5-Phenylpentyl)(trifluoromethyl)sulfane
Prepared from 5-phenyl-1-pentanol (84 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (91 mg, 0.37 mmol, 73%).
1H NMR (400 MHz, Chloroform-d) d = 7.32– 7.27 (m, 2H, HAr), 7.22– 7.16 (m, 3H, HAr), 2.88 (J=7.5, 2H, CH2), 2.63 (dd, J=7.8, 7.5, 2H, CH2), 1.78– 1.61 (m, 4H, CH2), 1.51– 1.40 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.1.13C NMR (101 MHz, Chloroform-d) d = 142.3 (Cq), 131.3 (q, J=306, CF3), 128.5 (CH), 128.5 (CH), 125.9 (CH), 35.8 (CH2), 30.9 (CH2), 29.9 (q, J=2, CH2), 29.5 (CH2), 28.2 (CH2). HRMS (EI): m/z calculated for [C12H15F3S]+ ([M]+): 248.0841, measured 248.0839. IR (ATR): n (cm-1): 3028, 2934, 2859, 1604, 1496, 1454, 1297, 1147, 1102, 1031, 913, 797, 746, 697. (2-(Naphthalen-1-yl)ethyl)(trifluoromethyl)sulfane
Prepared from 2-(naphthalen-1-yl)ethan-1-ol (86 mg, 0.50 mmol) using Method A and isolated as a colourless oil (95 mg, 0.37 mmol, 74%).
1H NMR (400 MHz, Chloroform-d) d = 8.00 (dm, J=8.2, 1H, HAr), 7.92 (dm, J=7.7, 1H, HAr), 7.82 (d, J=8.2, 1H, HAr), 7.62– 7.52 (m, 2H, HAr), 7.46 (dd, J= 8.2, 7.0, 1H, HAr), 7.39 (dm, J=7.1, 1H, HAr), 3.50 (dd, J=9.5, 6.4, 2H, CH2), 3.30– 3.25 (m, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.1.13C NMR (101 MHz, Chloroform-d) d = 136.0 (Cq), 134.1 (Cq), 131.5 (Cq), 131.4 (q, J=306, CF3), 129.2 (CH), 127.9 (CH), 126.9 (CH), 126.6 (CH), 125.9 (CH), 125.7 (CH), 123.1 (CH), 33.6 (CH2), 30.6 (q, J=2, CH2). HRMS (EI): m/z calculated for [C13H11F3S]+ ([M]+): 256.0528, measured 256.0536. IR (ATR): n (cm-1): 3061, 2941, 1598, 1510, 1458, 1395, 1233, 1217, 1097, 1044, 1018, 965, 853, 793, 774, 755, 732, 698, 660. (4-(4-Methoxyphenyl)butyl)(trifluoromethyl)sulfane Prepared from 4-(4-methoxyphenyl)-1-butanol (88 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (89 mg, 0.34 mmol, 68%).
1H NMR (600 MHz, Chloroform-d) d = 7.10 (dm, J=8.2, 2H, HAr), 6.85 (dm, J=8.2, 2H, HAr), 3.80 (s, 3H, CH3), 2.90 (t, J=6.9, 2H, CH2), 2.60 (t, J=7.0, 2H, CH2), 1.76– 1.68 (m, 4H, CH2). 19F NMR (565 MHz, Chloroform-d) d = -41.1.13C NMR (156 MHz, Chloroform-d) d = 158.0 (Cq), 133.9 (Cq), 131.3 (q, J=306, CF3), 129.4 (CH), 113.9 (CH), 55.4 (CH3), 34.4 (CH2), 30.6 (CH2), 29.9 (q, J=2, CH2), 29.01 (CH2). HRMS (EI): m/z calculated for [C12H15F3OS]+ ([M]+): 264.0790, measured: 264.0798. IR (ATR): n (cm-1): 2935, 2858, 2837, 1612, 1584, 1511, 1464, 1442, 1421, 1300, 1245, 1176, 1148, 1102, 1036, 930, 820, 809, 755, 697. Rf: (n- pentane/CH2Cl2, 9:1): 0.29. 2-(((Trifluoromethyl)thio)methyl)isoindoline-1,3-dione
Prepared from N-hydroxymethylphthalimide (72 mg, 0.50 mmol) using Method A and isolated as an orange solid (71 mg, 0.27 mmol, 54%).
1H NMR (400 MHz, Chloroform-d) d = 7.94– 7.88 (m, 2H, HAr), 7.80– 7.75 (m, 2H, HAr), 5.09 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -40.7.13C NMR (101 MHz, Chloroform- d) d = 166.4 (Cq), 134.7 (CH), 131.9 (Cq), 130.3 (q, J=308, CF3), 124.0 (CH), 36.5 (q, J=3, CH2). IR (ATR): n (cm-1): 3002, 2928, 1780, 1713, 1627, 1610, 1466, 1412, 1380, 1308, 1294, 1154, 1102, 972, 912, 829, 795, 756, 717, 697, 680. Decyl(trifluoromethyl)sulfane
Prepared from 1-decanol (96 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (107 mg, 0.44 mmol, 88%).
1H NMR (400 MHz, Chloroform-d) d = 2.87 (t, J=7.4, 2H, CH2SCF3), 1.74– 1.63 (m, 2H, CH2), 1.45– 1.34 (m, 2H, CH2), 1.33– 1.23 (m, 12H, CH2), 0.88 (t, J=7.0, 3H, CH3). 19F NMR (376 MHz, Chloroform-d) d = -42.0.13C NMR (101 MHz, Chloroform-d) d =
131.4 (q, J=306, SCF3), 32.1 (CH2), 30.0 (q, J=3, CH2), 29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.1 (CH2), 28.7 (CH2), 22.8 (CH2), 14.2 (CH3). IR (ATR): n (cm-1): 2925, 2855, 1466, 1150, 1108, 756, 721. Dodecyl(trifluoromethyl)sulfane
Prepared from 1-dodecanol (112 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (110 mg, 0.41 mmol, 81%).
1H NMR (400 MHz, Chloroform-d) d = 2.87 (t, J=7.4, 2H, CH2), 1.73– 1.64 (m, 2H, CH2), 1.44 – 1.35 (m, 2H, CH2), 1.34– 1.19 (m, 16H, CH2), 0.88 (t, J=6.8, 3H, CH3).19F NMR (376 MHz, Chloroform-d) d = -42.0.13C NMR (101 MHz, Chloroform-d) d = 131.3 (q, J=305, CF3), 32.0 (CH2), 30.0 (q, J=2, CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.0 (CH2), 28.6 (CH2), 22.8 (CH2), 14.2 (CH3) Note: two 13C peaks are not observed due to overlapping. HRMS (EI): m/z calculated for [C12H25S]+ ([M-CF3]+): 201.1671, measured 201.1693. Note: a molecular ion peak could not be identified by EI. IR (ATR): n (cm-1): 2924, 2854, 1466, 1378, 1299, 1151, 1110, 756, 721. Tetradecyl(trifluoromethyl)sulfane
Prepared from 1-tetradecanol (107 mg, 0.50 mmol) using Method A and isolated as a colourless liquid (116 mg, 0.39 mmol, 78%).
1H NMR (600 MHz, Chloroform-d) d = 2.87 (t, J=7.5, 2H, CH2), 1.69 (quin, J=7.5, 2H, CH2), 1.42– 1.36 (m, 2H, CH2), 1.34– 1.21 (m, 20H, CH2), 0.88 (t, J=7.0, 3H).19F NMR (565 MHz, Chloroform-d) d = -41.2.13C NMR (151 MHz, Chloroform-d) d = 134.6 (q, J=306, CF3), 32.1 (CH2), 30.0 (q, J=2, CH2), 29.9 (CH2), 29.8 (CH2), 29.8 (CH2), 29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.1 (CH2), 28.7 (CH2), 22.9 (CH2), 14.3 (CH3) Note: one 13C peak is not observed due to overlapping. CHNS Elemental Analysis: calculated for C15H29F3S: C 60.37; H 9.79; N 0.00, S 10.74; measured: C 60.39; H 9.28; N 0.00; S 10.76. IR (ATR): n (cm-1): 2923, 2854, 1466, 1378, 1308, 1151, 1110, 756, 721. Rf: (n-pentane): 0.93. (4-Nitrobenzyl)(trifluoromethyl)sulfane
Prepared from (4-nitrophenyl)methanol (77 mg, 0.50 mmol,) using Method A and isolated as a orange liquid (104 mg, 0.44 mmol, 88%).
1H NMR (400 MHz, Chloroform-d) d = 8.20 (dm, J=8.8, 2H, HAr), 7.53 (dm, J=8.8, 2H, HAr), 4.18 (s, 2H).19F NMR (376 MHz, Chloroform-d) d = -41.2.13C NMR (151 MHz, Chloroform- d) d = 147.7 (Cq), 143.2 (Cq), 130.4 (q, J=307, CF3), 129.9 (CH), 124.2 (CH), 33.6 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H6F3NO2S]+ ([M]+): 237.0066, measured 237.0070. IR (ATR): n (cm-1): 3113, 3083, 2946, 2859, 1931, 1684, 1602, 1519, 1495, 1424, 1344, 1257, 1203, 1095, 1015, 973, 890, 858, 820, 802, 755, 707. Methyl 4-(((trifluoromethyl)thio)methyl)benzoate
Prepared from methyl 4-(hydroxymethyl)benzoate (83 mg, 0.50 mmol) using Method A and isolated as a colourless liquid (118 mg, 0.47 mmol, 94%).
1H NMR (600 MHz, Chloroform-d) d = 8.02 (d, J=8.4, 2H, HAr), 7.41 (d, J=8.4, 2H, HAr), 4.13 (s, 2H, CH2), 3.91 (s, 3H, CH3).19F NMR (565 MHz, Chloroform-d) d = -41.4.13C NMR (151 MHz, Chloroform-d) d = 166.7 (Cq), 140.5 (Cq), 130.6 (q, J=307, CF3), 130.2 (CH), 130.0 (Cq), 129.0 (CH), 52.3 (CH3), 34.0 (q, J=3, CH2). HRMS (EI): m/z calculated for [C10H9F3O2S]+ ([M]+): 250.0270, measured: 250.0257. IR (ATR): n (cm-1): 2954, 1719, 1612, 1577, 1509, 1436, 1415, 1279, 1179, 1145, 1097, 1020, 966, 890, 860, 838, 797, 774, 756, 725, 713. (4-Bromobenzyl)(trifluoromethyl)sulfane
Prepared from (4-bromophenyl)methanol (94 mg, 0.50 mmol) using Method A and isolated as a colourless liquid (121 mg, 0.45 mmol, 89%).
1H NMR (600 MHz, Chloroform-d) d = 7.46 (d, J=8.4, 2H, HAr), 7.22 (d, J=8.4, 2H, HAr), 4.07 (s, 2H, CH2).19F NMR (565 MHz, Chloroform-d) d = -41.4.13C NMR (151 MHz, Chloroform- d) d = 134.4 (Cq), 132.2 (CH), 130.6 (q, J=308, CF3), 130.7 (CH), 122.2 (Cq), 33.8 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H6BrF3S]+ ([M]+): 269.9320, measured: 269.9326. IR (ATR): n (cm-1): 2928, 1592, 1488, 1441, 1421, 1403, 1254, 1144, 1098, 1070, 1011, 880, 828, 816, 804, 756, 741, 723, 681. (4-Iodobenzyl)(trifluoromethyl)sulfane Prepared from (4-iodophenyl)methanol (117 mg, 0.50 mmol) using Method A and isolated as a yellow liquid (91 mg, 0.29 mmol, 57%).
1H NMR (400 MHz, Chloroform-d) d = 7.67 (dm, J=8.5, 2H, HAr), 7.09 (dm, J=8.3, 2H, HAr), 4.04 (s, 2H, CH2). 19F NMR (376 MHz, Chloroform-d) d = -41.4. 13C NMR (101 MHz, Chloroform-d) d = 138.1 (CH), 135.0 (Cq), 130.6 (q, J=307, CF3), 130.9 (CH), 93.7 (Cq), 33.9 (q, J=2, CH2). HRMS (EI): m/z calculated for [C8H6F3IS]+ ([M]+): 317.9181, measured: 317.9165. IR (ATR): n (cm-1): 3031, 2924, 1901, 1588, 1484, 1420, 1398, 1253, 1201, 1096, 1060, 1008, 961, 945, 879, 824, 809, 755, 739, 721, 679. Methyl(4-(((trifluoromethyl)thio)methyl)phenyl)sulfane
Prepared from (4-(methylthio)phenyl)methanol (77 mg, 0.50 mmol) using Method A and isolated as an orange oil (107 mg, 0,45 mmol, 90%).
1H NMR (600 MHz, Chloroform-d) d = 7.26 (dm, J=8.5, 2H, HAr), 7.22 (dm, J=8.4, 2H, HAr), 4.08 (s, 2H, CH2), 2.47 (s, 3H, CH3).19F NMR (565 MHz, Chloroform-d) d = -41.4.13C NMR (151 MHz, Chloroform-d) d = 138.7 (Cq), 131.7 (Cq), 130.7 (q, J=308, CF3), 129.5 (CH), 126.8 (CH), 34.0 (q, J=3, CH2), 15.7 (CH3). HRMS (EI): m/z calculated for [C9H9F3S2]+ ([M]+): 238.0092, measured: 238.0103. IR (ATR): n (cm-1): 3024, 2985, 2923, 1682, 1600, 1494, 1439, 1405, 1254, 1143, 1092, 1016, 968, 957, 878, 826, 814, 755, 742, 727, 687. Rf: (n- pentane/CH2Cl2, 9:1): 0.55. ([1,1'-biphenyl]-4-ylmethyl)(trifluoromethyl)sulfane
Prepared from (1,1'-biphenyl-4-yl)methanol (92 mg, 0.50 mmol) using Method A and isolated as a white solid (89 mg, 0.33 mmol, 67%).
1H NMR (400 MHz, Chloroform-d) d = 7.63– 7.58 (m, 4H, , 7.50– 7.36 (m, 5H,
4.19 (s, 2H, CH2). 19F NMR (376 MHz, Chloroform-d) d = -41.4. 13C NMR (101 MHz, Chloroform-d) d = 141.1 (Cq), 140.5 (Cq), 134.1 (Cq), 130.9 (q, J=307, CF3), 129.5 (CH), 129.0 (CH), 127.7 (CH), 127.7 (CH), 127.2 (CH), 34.1 (q, J=2, CH2). HRMS (EI): m/z calculated for [C14H11F3S]+ ([M]+): 268.0528, measured: 268.0519. IR (ATR): n (cm-1): 3033, 2924, 1487, 1452, 1441, 1408, 1096, 1006, 844, 769, 755, 736, 714, 688. ((Perbromophenyl)methyl)(trifluoromethyl)sulfane
Prepared from (perbromophenyl)methanol (251 mg, 0.50 mmol) using Method A and isolated as a white solid (132 mg, 0.22 mmol, 45%).
1H NMR (400 MHz, Chloroform-d) d = 4.73 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -40.9. 13C NMR (101 MHz, Chloroform-d) d = 137.3 (Cq), 130.4 (q, J=307, CF3), 130.0 (Cq), 129.8 (Cq), 127.7 (Cq), 40.6 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H2Br5F3S]+ ([M]+): 581.5741, measured: 581.5741. IR (ATR): n (cm-1): 2923, 2853, 2223, 1514, 1460, 1416, 1405, 1337, 1322, 1307, 1271, 1256, 1229, 1213, 1189, 1164, 1148, 1098, 1061, 899, 866, 754, 702, 666. Rf: (n-pentane): 0.70. (2,4,6-Trichlorobenzyl)(trifluoromethyl)sulfane
Prepared from (2,4,6-trichlorophenyl)methanol (106 mg, 0.50 mmol) using Method A and isolated as a colourless liquid (135 mg, 0.46 mmol, 91%).
1H NMR (400 MHz, Chloroform-d) d = 7.36 (s, 2H, HAr), 4.39 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.4.13C NMR (151 MHz, Chloroform-d) d = 136.6 (Cq), 134.9 (Cq), 130.6 (Cq), 130.6 (q, J=307, CF3), 128.6 (CH), 29.3 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H4Cl3F3S]+ ([M]+): 293.9046, measured: 293.9025. IR (ATR): n (cm-1): 3083, 2927, 2853, 1729, 1579, 1550, 1441, 1420, 1391, 1376, 1257, 1236, 1207, 1157, 1099, 1072, 897, 874, 856, 811, 785, 755, 735, 679, 658. Rf: (n-pentane): 0.87. (Naphthalen-2-ylmethyl)(trifluoromethyl)sulfane
Prepared from naphthalen-2-ylmethanol (79 mg, 0.50 mmol) using Method A and isolated as a pale yellow solid (70 mg, 0.29 mmol, 58%).
1H NMR (400 MHz, Chloroform-d) d = 7.89– 7.79 (m, 4H, HAr), 7.56– 7.45 (m, 3H, HAr), 4.31 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.4.13C NMR (101 MHz, Chloroform- d) d = 133.4 (Cq), 133.0 (Cq), 132.5 (Cq), 130.9 (q, J=307, CF3), 128.9 (CH), 128.1 (CH), 127.9 (CH), 127.9 (CH), 126.7 (CH), 126.6 (CH), 126.5 (CH), 34.7 (q, J=3, CH2). HRMS (EI): m/z calculated for [C12H9F3S]+ ([M]+): 242.0372, measured: 242.0368. IR (ATR): n (cm-1): 3049, 2927, 1598, 1578, 1512, 1453, 1398, 1353, 1250, 1236, 1219, 1138, 1097, 1017, 970, 950, 882, 867, 799, 791, 773, 756, 740, 712. (Naphthalen-1-ylmethyl)(trifluoromethyl)sulfane
Prepared from naphthalen-1-ylmethanol (79 mg, 0.50 mmol) using Method A and isolated as a pale yellow oil (46 mg, 0.19 mmol, 38%).
1H NMR (400 MHz, Chloroform-d) d = 8.05 (d, J=8.4, 1H, HAr), 7.91 (dm, J=8.0, 1H, HAr), 7.85 (d, J=8.3, 1H, HAr), 7.61 (ddd, J=8.4, 6.9, 1.5, 1H, HAr), 7.58– 7.50 (m, 2H, HAr), 7.44 (dd, J=8.2, 7.0, 1H, HAr), 4.61 (s, 2H, CH2).19F NMR (376 MHz, Chloroform- d) d = -41.7.13C NMR (151 MHz, Chloroform-d) d = 134.1 (Cq), 131.9 (Cq), 130.9 (q, J=307, CF3), 130.2 (Cq), 129.4 (CH), 129.2 (CH), 128.2 (CH), 126.9 (CH), 126.3 (CH), 125.5 (CH), 123.3 (CH), 32.2 (q, J=3, CH2). HRMS (EI): m/z calculated for [C12H9F3S]+ ([M]+): 242.0372, measured: 242.0371. IR (ATR): n (cm-1): 3049, 2927, 1598, 1578, 1512, 1453, 1398, 1353, 1250, 1236, 1219, 1138, 1097, 1017, 970, 950, 882, 867, 799, 791, 773, 756, 740, 712. (3-Nitrobenzyl)(trifluoromethyl)sulfane
Prepared from (3-nitrophenyl)methanol (59 mL, 0.50 mmol) using Method A and isolated as a yellow liquid (105 mg, 0.44 mmol, 89%).
1H NMR (400 MHz, Chloroform-d) d = 8.24 (s, 1H, HAr), 8.18 (dm, J=8.2, 1H, HAr), 7.70 (d, J=8.0, 1H, HAr), 7.55 (t, J=8.0, 1H, HAr), 4.20 (s, 2H, CH2). 19F NMR (376 MHz, Chloroform-d) d = -41.2.13C NMR (101 MHz, Chloroform-d) d = 148.5 (Cq), 137.9 (Cq), 135.0 (CH), 130.4 (q, J=307, CF3), 130.0 (CH), 123.9 (CH), 123.1 (CH), 33.6 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H6F3NO2S]+ ([M]+): 237.0066, measured: 237.0067. IR (ATR): n (cm-1): 3060, 2927, 2846, 1596, 1571, 1475, 1428, 1253, 1202, 1099, 1072, 997, 910, 888, 868, 849, 785, 756, 733, 708, 682, 667. (3-Bromobenzyl)(trifluoromethyl)sulfane
Prepared from (3-bromophenyl)methanol (60 mL, 0.50 mmol) using Method A and isolated as a colourless liquid (113 mg, 0.42 mmol, 83%).
1H NMR (400 MHz, Chloroform-d) d = 7.51 (t, J=1.9, 1H, HAr), 7.44 (ddd, J=7.8, 2.0, 1.3, 1H, HAr), 7.28 (dt, J=7.7, 1.5, 1H, HAr), 7.22 (t, J=7.8, 1H, HAr), 4.07 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.4.13C NMR (101 MHz, Chloroform-d) d = 137.6 (Cq), 132.0 (CH), 131.3 (CH), 130.6 (q, J=307, CF3), 130.5 (CH), 127.6 (CH), 122.9 (Cq), 33.7 (q, J=3, CH2). HRMS (EI): m/z calculated for [C8H6BrF3S]+ ([M]+): 269.9320, measured: 269.9320. IR (ATR): n (cm-1): 3060, 2927, 2846, 1596, 1571, 1475, 1428, 1253, 1202, 1099, 1072, 997, 910, 888, 868, 849, 785, 756, 733, 708, 682, 667. (2-Bromo-5-fluorobenzyl)(trifluoromethyl)sulfane
Prepared from (2-bromo-5-fluorophenyl)methanol (103 mg, 0.50 mmol) using Method A and isolated as a colourless liquid (96 mg, 0.33 mmol, 67%).
1H NMR (400 MHz, Chloroform-d) d = 7.54 (dd, J=8.8, 5.3, 1H, HAr), 7.15 (dd, J=8.9, 3.0, 1H, 6.92 (ddd, J=8.7, 7.8, 3.9, 1H, HAr), 4.17 (s, 2H, CH2).19F NMR (376 MHz, Chloroform-d) d = -41.2 (SCF3), -113.7 (FAr).13C NMR (151 MHz, Chloroform-d) d = 162.0 (d, J=248, CqF), 137.4 (d, J=8, Cq), 134.5 (d, J=8, CH), 130.7 (q, J=307, CF3), 118.7 (Cq), 118.1 (d, J=24, CH), 117.1 (d, J=22, CH), 34.7 (qd, J=3, 2, CH2). HRMS (EI): m/z calculated for [C8H5BrF4S]+ ([M]+): 287.9231, measured: 287.9232. IR (ATR): n (cm- 1): 3079, 2924, 1605, 1583, 1469, 1440, 1409, 1274, 1254, 1237, 1146, 1098, 1032, 958, 899, 876, 862, 812, 775, 755, 742, 731, 679. (3-Phenylprop-2-yn-1-yl)(trifluoromethyl)sulfane
Prepared from 3-phenyl-2-propyn-1-ol (62 mL, 0.50 mmol) using Method A and isolated as a yellow liquid (72 mg, 0.33 mmol, 66%).
1H NMR (400 MHz, Chloroform-d) d = 7.48– 7.43 (m, 2H, HAr), 7.38– 7.30 (m, 3H, HAr), 3.90 (s, 2H, CH 19
2). F NMR (376 MHz, Chloroform-d) d = -42.6. 13C NMR (101 MHz, Chloroform-d) d = 131.9 (CH), 130.5 (q, J=308, CF3), 128.8 (CH), 128.5 (CH), 122.4 (Cq), 84.7 (Cq), 82.34 (Cq), 19.6 (q, J=3, CH2). HRMS (EI): m/z calculated for [C10H7F3S]+ ([M]+): 216.0215, measured: 216.0215. IR (ATR): n (cm-1): 3063, 2926, 1707, 1599, 1573, 1491, 1443, 1411, 1317, 1272, 1243, 1149, 1100, 1029, 1002, 981, 916, 885, 864, 754, 731, 714, 688. Dodecan-4-yl(trifluoromethyl)sulfane
Prepared from dodecan-4-ol (112.4 mL, 0.50 mmol) using Method B and isolated as a colourless liquid (83 mg of 1.96:1 mixture with dodecene regioisomers: calculated yield of dodecan-4-yl(trifluoromethyl)sulfane: 47%).
Only peaks corresponding to dodecan-4-yl(trifluoromethyl)sulfane reported: 1H NMR (400 MHz, Chloroform-d) d = 3.16 (pent, J=6.5, 1H, CH), 1.73– 1.55 (m, 4H, CH2), 1.52 – 1.21 (m, 14 H, CH2), 0.99– 0.86 (m, 6H, CH3).19F NMR (376 MHz, Chloroform-d) d = -39.1. 13C NMR (151 MHz, Chloroform-d) d = 131.6 (q, J=307, CF3), 46.6 (q, J=1, CH), 37.4 (CH2), 35.2 (CH2), 32.0 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 26.5 (CH2), 22.8 (CH2), 19.8 (CH2), 14.2 (CH3), 13.9 (CH3). (4-Phenylbutan-2-yl)(trifluoromethyl)sulfane
Prepared from 4-phenylbutan-2-ol (7b, 77.4 mL, 0.50 mmol) using Method C and isolated as a colourless liquid (61 mg, 0.26 mmol, 52%).
1H NMR (600 MHz, Chloroform-d) d = 7.31 (dd, J=7.3, 6.8, 2H, HAr), 7.24– 7.19 (m, 3H, HAr), 3.32 (sext, J=6.9, 1H, CH), 2.82– 2.73 (m, 2H, CH2), 2.02– 1.90 (m, 2H, CH2), 1.48 (d, J=6.9, 3H, CH3).19F NMR (565 MHz, Chloroform-d) d = -38.3.13C NMR (151 MHz, Chloroform-d) d = 141.0 (Cq), 131.3 (q, J=306, CF3), 128.7 (CH), 128.5 (CH), 126.3 (CH), 40.6 (CH), 38.6 (CH2), 32.9 (CH2), 22.6 (q, J=1, CH3). HRMS (EI): m/z calculated for [C11H13F3S]+ ([M]+): 234.0685, measured: 234.0685. IR (ATR): n (cm-1): 3029, 2931, 2863, 1604, 1496, 1455, 1383, 1297, 1247, 1145, 1100, 1031, 913, 822, 746, 698, 659. Benzhydryl(trifluoromethyl)sulfane
Prepared from diphenylmethanol (92 mg, 0.50 mmol) using Method D and isolated as a yellow liquid (74 mg, 0.28 mmol, 55%).
1H NMR (600 MHz, Chloroform-d) d = 7.43– 7.41 (m, 4H, HAr), 7.38– 7.34 (m, 4H, HAr), 7.31– 7.28 (m, 2H, HAr), 5.71 (s, 1H, CH).19F NMR (565 MHz, Chloroform-d) d = -40.7.13C NMR (151 MHz, Chloroform-d) d = 139.3 (Cq), 130.1 (q, J=308, CF3), 128.9 (CH), 128.3 (CH), 128.1 (CH), 53.6 (q, J=2, CH). HRMS (EI): m/z calculated for [C14H11F3S]+ ([M]+): 268.0528, measured: 268.0540. IR (ATR): n (cm-1): 3063, 3031, 1601, 1493, 1450, 1336, 1101, 1031, 1002, 967, 918, 826, 782, 746, 714, 693. Example 13: Deoxytrilfuoromethylthiolation of Alcohols with BT-SCF3 and BO- SCF3 derivatives.
4-Bromobenzyl alcohol (1.0 eq, 0.1 mmol, 18.7 mg) was dissolved together with BT- SCF3 or BO-SCF3 derivative (1.25 eq) in MeCN (0.5 mL) and DIPEA (2.0 eq, 0.2 mmol, 35 mmL) was added dropwise at 0 °C. After the mixture was stirred for 2 h at rt, the mixture was concentrated in vacuo. The crude product was redissolved in CDCl3 (0.75 mL) and Dibromomethane (7 mmL) was added as an internal standard. Table 1: Deoxytrifluoromethylthiolation of Alcohols with different BT-SCF3 or BO-SCF3 derivatives. Given yields are 1H-NMR-Yields, calculated using Dibromomethane as an internal standard. Example 14: Deoxytrifluoromethylthiolation of Carboxylic Acids with BT-SCF3
S-(trifluoromethyl) 4-methylbenzothioate BT-SCF3 (1.25 eq, 0.63 mmol, 250 mg) and NaH (60% in mineral oil, 3 eq, 1.5 mmol, 60 mg) were suspended in dry THF (7.5 mL) at -78 °C and 4-Methylbenzoic acid (1.0 eq, 0.5 mmol, 68.1 mg) was added dropwise to the mixture. The mixture was stirred for 30 min at -78 °C and was afterwards quenched with sat. NH4Cl solution. The organic phase was washed with H2O (3 x 20 mL), the aqueous phases were extracted with DCM (2 x 10 mL) and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Pentane/Ethyl acetate). The product was obtained as a colourless oil (82 mg, 0.37 mmol, 74 %). 1H NMR (400 MHz, Chloroform-d) d = 7.75 (d, J=8.3, 2H, HAr), 7.31 (d, J=7.9, 2H, HAr), 2.44 (s, 3H, CH3).19F NMR (376 MHz, Chloroform-d) d = -39.6. The analytical data is in agreement to the literature (Glorius ACS Catal.2018, 8, 7, 5842-5846). Example 15: Deoxydifluoromethylthiolation of Carboxylic Acids with BT-SCF2H
S-(difluoromethyl) octanethioate n-Octanoic Acid (1.0 eq, 0.5 mmol, 68.1 mg) and NaH (60% in mineral oil, 2 eq, 1.0 mmol, 60 mg) were suspended in dry THF (5.0 mL) and stirred for 1 h at rt. BT-SCF2H (2.0 eq, 1.0 mmol, 381 mg) was added and the mixture was allowed to stir for another 2 h at rt. Afterwards, the mixture was quenched with sat. NH4Cl solution. The organic phase was washed with H2O (3 x 20 mL), the aqueous phases were extracted with DCM (2 x 10 mL) and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Pentane). The product was obtained as a colourless oil (92 mg, 0.44 mmol, 87 %).
1H NMR (400 MHz, Chloroform-d) d = 7.30 (t, J=55.1, 1H, CF2H), 2.61 (t, J=7.5, 2H, CH2), 1.78– 1.60 (m, 2H, CH2), 1.38– 1.19 (m, 8H, CH2), 0.89 (t, J=7.0, 3H, CH3). 19F NMR (376 MHz, Chloroform-d) d = -100.1 (d, J=55). The analytical data is in agreement to the literature (Wang, Angew. Chem. Int. Ed.2018, 57, 1663-1667).
Example 16: Deoxydifluoroselenylation of Carboxylic Acids with BT-SeCF2H
Se-(difluoromethyl) octaneselenoate
n-Octanoic acid (1.0 eq, 0.5 mmol, 72.1 mg) and NaH (2 eq, 1.0 mmol, 24 mg) were suspended in dry THF (5.0 mL) and stirred for 15 min at 0 °C. BT-SeCF2H (1.05 eq, 0.525 mmol, 225 mg) was added and the mixture was allowed to stir for another 2 h at rt. Afterwards, the mixture was quenched with sat. NH4Cl solution. The organic phase was washed with H2O (1 x 5 mL), the aqueous phases were extracted with DCM (2 x 10 mL) and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Pentane). The product was obtained as a colourless oil (53 mg, 0.21 mmol, 42 %).
1H NMR (500 MHz, Chloroform-d) d = 7.43 (t, J=53.5, 1H, CF2H), 2.68 (t, J=7.5, 2H, CH2,), 1.71– 1.63 (m, 2H, CH2), 1.37– 1.22 (m, 8H, CH2), 0.90– 0.85 (m, 3H, CH3).19F NMR (376 MHz, Chloroform-d) d = -96.18 (d, J=54).13C NMR (126 MHz, Chloroform- d) d = 198.2 (t, J=3), 120.2 (t, J=283) 49.2 (t, J=3), 31.7, 29.0, 28.8, 25.0, 22.7, 14.2. Example 17: Silver-Mediated Perfluoromethylthiolation of Alkyl Bromides with BT-SRF Reagents (4-(tert-Butyl)benzyl)(perfluorooctoyl)sulfane
4-(tert)-Butyl benzyl bromide (46 mL, 0.25 mmol, 1.0 eq), BT-SC8F17 (234 mg, 0.313 mmol, 1.25 eq) and silver oxide (116 mg, 0.500 mmol, 2.00 eq) were stirred in MeCN overnight. The mixture was then filtered through Celite (eluent: CH2Cl2) and concentrated in vacuo. Purification by column chromatography over silica gel afforded the product as a white solid (120 mg, 0.20 mmol, 80%). 1H NMR (400 MHz, Chloroform-d) d = 7.38 (dm, J=8.4, 2H, HAr), 7.29 (dm, J=8.5, 2H, HAr), 4.17 (s, 2H, CH2), 1.32 (s, 9H, tBu).19F NMR (376 MHz, Chloroform-d) d = -80.7 (d, J=3), -87.5 (d, J=4), -119.6, -121.1, -121.7, -121.8, -122.6, -126.1. 13C NMR (151 MHz, Chloroform-d) d = 152.3, 131.4, 129.0, 126.1, 34.7, 32.8 (t, J=9), 31.4. Note: Eight fluoroalkyl 13C peaks were not observed. HRMS (EI): m/z calculated for [C19H15F17S]+ ([M]+): 598.0618, measured: 598.0648. Example 18: Deoxyperfluoroalkylthiolation of Alcohols with BT-SRF Reagents (4-(tert-Butyl)benzyl)(perfluoropropyl)sulfane
4-(tert)-Butyl benzyl alcohol (44 mL, 0.25 mmol, 1.0 eq) was dissolved in MeCN (1 mL), BT-SC3F7 (156 mg, 0.31 mmol, 1.25 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (87 mL, 0.50 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at rt. Purification by column chromatography over silica gel afforded the product as a colourless oil (60 mg, 0.17 mmol, 69%).
1H NMR (400 MHz, Chloroform-d) d = 7.39 (dm, J=8.4, 2H, HAr), 7.29 (dm, J=8.4, 2H, HAr), 4.17 (s, 2H, CH2), 1.33 (s, 9H, tBu).19F NMR (376 MHz, Chloroform-d) d = -80.0 (t, J=9), -88.3 (tq, J=9, 5), -124.0 (t, J=5).13C NMR (151 MHz, Chloroform-d) d = 151.4, 131.4, 129.0, 126.1, 34.8, 32.6 (m), 31.4. Note: Two fluoroalkyl 13C peaks were not observed. HRMS (EI): m/z calculated for [C14H15F7S]+ ([M]+): 348.0777, measured: 348.0780. Example 19: General Procedures for the Deoxytrifluoromethylselenylation reaction of Alcohols with BT-SeCF3 Method E: The benzylic or propargylic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF3 (112 mg, 0.250 mmol, 1.25 eq) was added and the reaction mixture was cooled to 0 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
Method F: The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF3 (112 mg, 0.250 mmol, 1.25 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel.
Method G: The aliphatic alcohol (0.20 mmol, 1.0 eq) was dissolved in MeCN (0.50 M), BT-SeCF3 (179 mg, 0.400 mmol, 2.00 eq) was added and the reaction mixture was cooled to -40 °C. NEt(iPr)2 (70 mL, 0.40 mmol, 2.0 eq) was then added dropwise and the reaction mixture was stirred for 2 h at -40 °C. The reaction mixture was concentrated in vacuo and purified by column chromatography over silica gel. Characterization Data for Deoxytrifluoromethylselenylation Products (4-Nitrobenzyl)(trifluoromethyl)selane
Prepared from (4-nitrophenyl)methanol (31 mg, 0.20 mmol) using Method E and isolated as a pale yellow liquid (50 mg, 0.18 mmol, 88%).
1H NMR (400 MHz, Chloroform-d) d = 8.19 (dm, J=8.7, 2H, HAr), 7.51 (dm, J=8.7, 2H, HAr), 4.28 (s, 2H). 19F NMR (376 MHz, Chloroform-d) d = -34.0.13C NMR (101 MHz, Chloroform-d) d = 147.5 (Cq), 144.4 (Cq), 130.1 (CH), 124.2 (CH), 122.5 (q, J=332, CF3), 28.1 (q, J=4, CH2). HRMS (EI): m/z calculated for [C8H6F3NO2Se]+ ([M]+): 284.9510, measured 284.9536. IR (ATR): n (cm-1): 3080, 2948, 2857, 1600, 1517, 1424, 1343, 1322, 1088, 1069, 1015, 973, 858, 798, 752, 738, 695. Methyl(4-(((trifluoromethyl)selanyl)methyl)phenyl)sulfane
Prepared from (4-(methylthio)phenyl)methanol (31 mg, 0.20 mmol) using Method E and isolated as a yellow liquid (43 mg, 0.15 mmol, 75%).
1H NMR (600 MHz, Chloroform-d) d = 7.26 (dt, J=8.4, 2.1, 2H, HAr), 7.21 (dt, J=8.4, 2.1, 2H, HAr), 4.22 (s, 2H), 2.48 (s, 3H). 19F NMR (565 MHz, Chloroform-d) d = -34.2.13C NMR (151 MHz, Chloroform-d) d = 138.4 (Cq), 132.8 (Cq), 129.6 (CH), 126.8 (CH), 123.0 (q, J=332, CF3), 28.9 (q, J=2, CH2), 15.7 (CH3). HRMS (EI): m/z calculated for [C9H9F3SSe]+ ([M]+): 285.9537, measured: 285.9545. IR (ATR): n (cm-1): 3022, 2984, 2922, 1599, 1493, 1438, 1404, 1325, 1275, 1222, 1198, 1087, 1069, 1015, 967, 957, 824, 811, 737, 719. Rf: (n-pentane/CH2Cl2, 9:1): 0.58. (4-Bromobenzyl)(trifluoromethyl)selane
Prepared from (4-bromophenyl)methanol (37 mg, 0.20 mmol,) using Method E and isolated as a yellow liquid (48 mg, 0.15 mmol, 76%).
1H NMR (600 MHz, Chloroform-d) d = 7.46 (dm, J=8.5, 2H, HAr), 7.22 (dm, J=8.5, 2H, HAr), 4.18 (s, 2H, CH2). 19F NMR (565 MHz, Chloroform-d) d = -34.2. 13C NMR (151 MHz, Chloroform-d) d = 135.5 (Cq), 132.2 (CH), 130.8 (CH), 122.8 (q, J=331, CF3), 121.9 (Cq), 28.5 (q, J=2, CH2). HRMS (EI): m/z calculated for [C8H6BrF3Se]+ ([M]+): 317.8765, measured: 317.8758. IR (ATR): n (cm-1): 3035, 2952, 1899, 1591, 1487, 1420, 1402, 1276, 1218, 1195, 1090, 1068, 1011, 959, 944, 826, 800, 738, 713, 663. Rf: (n- pentane): 0.70. Methyl 4-(((trifluoromethyl)selanyl)methyl)benzoate
Prepared from methyl 4-(hydroxymethyl)benzoate (33 mg, 0.20 mmol) using Method E and isolated as a colourless liquid (55 mg, 0.19 mmol, 93%).
1H NMR (600 MHz, Chloroform-d) d = 8.00 (dm, J=8.3, 2H, HAr), 7.40 (dm, J=8.3, 2H, HAr), 4.25 (s, 2H, CH2), 3.91 (s, 3H, CH3).19F NMR (565 MHz, Chloroform-d) d = -34.2. 13C NMR (151 MHz, Chloroform-d) d = 166.7 (Cq), 141.7 (Cq), 130.3 (CH), 129.7 (Cq), 129.1 (CH), 123.7 (q, J=331, CF3), 52.3 (CH3), 28.7 (q, J=2, CH2). HRMS (EI): m/z calculated for [C10H9F3O2Se]+ ([M]+): 297.9714, measured: 297.9712. IR (ATR): n (cm-1): 3000, 2953, 2845, 1931, 1717, 1611, 1576, 1509, 1436, 1415, 1367, 1313, 1278, 1223, 1194, 1181, 1088, 1069, 1019, 966, 863, 838, 811, 794, 768, 738, 703, 665. Rf: (n- pentane/CH2Cl2, 1:1): 0.48. (4-Phenylbutyl)(trifluoromethyl)selane
Prepared from 4-phenyl-1-butanol (31 mL, 0.20 mmol) using Method F and isolated as a colourless liquid (31 mg, 0.11 mmol, 55%). 1H NMR (400 MHz, Chloroform-d) d = 7.32– 7.26 (m, 2H, 7.22– 7.15 (m, 3H), 3.00 (t, J=7.3, 2H, CH2), 2.65 (t, J=7.3, 2H, CH2), 1.88– 1.70 (m, 4H). 19F NMR (565 MHz, Chloroform-d) d = -34.0.13C NMR (151 MHz, Chloroform-d) d = 141.9 (Cq), 128.5 (CH), 128.5 (CH), 126.1 (CH), 122.8 (q, J=330, CF3), 35.3 (CH2), 31.4 (CH2), 29.9 (CH2), 25.8 (q, J=1, CH2). HRMS (EI): m/z calculated for [C11H13F3Se]+ ([M]+): 282.0129, measured: 282.0141. IR (ATR): n (cm-1): 3028, 2927, 2856, 1604, 1496, 1454, 1254, 1224, 1198, 1092, 1030, 969, 908, 803, 737, 697. Rf: (n-pentane): 0.43. (3-Phenylprop-2-yn-1-yl)(trifluoromethyl)selane
Prepared from 3-phenyl-2-propyn-1-ol (26 mg, 0.20 mmol) using Method E and isolated as a colourless liquid (43 mg, 0.16 mmol, 82%).
1H NMR (600 MHz, Chloroform-d) d = 7.42– 7.40 (m, 2H, 7.32– 7.28 (m, 3H, HAr), 3.90 (s, 2H, CH2). 19F NMR (565 MHz, Chloroform-d) d = -34.5. 13C NMR (151 MHz, Chloroform-d) d = 131.8 (CH), 128.7 (CH), 128.5 (CH), 122.6 (q, J=332, CF3), 122.5 (Cq), 85.0 (Cq), 83.5 (Cq), 11.7 (q, J=3, CH2). IR (ATR): n (cm-1): 3060, 2929, 2190, 1664, 1598, 1491, 1443, 1408, 1318, 1271, 1200, 1119, 1090, 1070, 1030, 1002, 977, 916, 869, 843, 822, 755, 738, 712, 688, 669. (4-Phenylbutan-2-yl)(trifluoromethyl)selane
Prepared from 4-phenylbutan-2-ol (31 mL, 0.20 mmol, 1.0 eq) using Method G and isolated as a colourless liquid (25 mg, 0.088 mmol, 44%).
1H NMR (600 MHz, Chloroform-d) d = 7.30 (tm, J=7.6, 2H, , 7.23– 7.18 (m, 3H, 3.53 (sext, J=7.0, 1H, CH), 2.82– 2.72 (m, 2H, CH2), 2.12– 1.96 (m, 4H, CH2), 1.63 (d, J=7.0, CH3). 19F NMR (565 MHz, Chloroform-d) d = -31.9.13C NMR (151 MHz, Chloroform-d) d = 140.9 (Cq), 128.6 (CH), 128.5 (CH), 126.3 (CH), 123.2 (q, J=331, CF3), 39.5 (q, J=1), 39.3 (q, J=1), 33.8, 23.1 (q, J=1). HRMS (EI): m/z calculated for [C11H13F3Se]+ ([M]+): 282.0129, measured: 282.0120. IR (ATR): n (cm-1): 3029, 2925, 2858, 1604, 1496, 1454, 1382, 1260, 1233, 1213, 1092, 1031, 912, 818, 738, 697. Example 20: Alternative Method for the 3-Methyl-2-((trifluoromethyl)selanyl) benzo[d]thiazol-3-ium trifluoromethanesulfonate (BT-SeCF3, Compound 5) Synthesis of 2-(trifluoromethyl)selenyl)benzo[d]thiazole Bis(benzothiazole)diselenide (4.20 g, 9.85 mmol, 0.50 eq) was suspended in methanol (100 mL, degassed using the freeze-pump-thaw technique) and THF (25 mL, degassed using the freeze-pump-thaw technique) in a 3-necked round-bottomed flask under argon and the mixture was cooled to 0 °C. NaBH4 (745 mg, 19.7 mmol, 1 equiv) was added portionwise over 5 minutes and the mixture was stirred at 0 °C for an additional 10 minutes. HCl (1 M, aq., 100 mL, degassed by argon sparging) was added via cannula resulting in the formation of a grey precipitate. The mixture was then filtered under argon and the solid was washed with water (3 × 100 mL, degassed by argon sparging) and then dried under high vacuum for 30 minutes. Separately, a solution of CF3I in DMF was prepared by attaching a balloon of CF3I to a flask containing freeze-pump-thaw degassed DMF under N2. This solution (110 mL, containing 6.3 g, 32 mmol, 1.6 equiv. of CF3I) was transferred to the round-bottomed flask via cannula and the grey solid product was re-dissolved. The mixture was cooled to -40 °C and NaH (709 mg, 29.5 mmol, 1.50 equiv.) was added portionwise over 5 minutes. A balloon containing CF3I (14.2 g, 72.8 mmol, 3.70 equiv) was then attached and the mixture was stirred under irradiation from UVA LEDs (lmax = 365 nm) for 12 h during which time the reaction temperature reached ca. 40 °C. After completion of the reaction EtOAc (250 mL) and water (300 mL) were added and the layers separated. The organic phase was then washed with water (5 × 500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography over silica gel (eluent = n-pentane:DCM, 10:1) afforded 2-(trifluoromethyl)selenyl)benzo[d]thiazole as a white solid (2.95 g, 10.5 mmol, 53%). 1H NMR (600 MHz, Chloroform-d) d = 8.13 (ddd, J=8.2, 1.3, 0.6, 1H, 7.90 (ddd, J=8.1, 1.3, 0.7, 1H, , 7.53 (tm, J=7.7, 1H, 7.46 (tm, J=7.7, 1H, 19F NMR (376 MHz, Chloroform-d) d = -33.2.13C NMR (151 MHz, Chloroform-d) d = 153.8 (Cq), 147.6 (Cq), 138.5 (Cq), 126.9 (CH), 126.5 (CH), 124.0 (CH), 122.2 (q, J=335, CF3), 121.2 (CH). HRMS (EI): m/z calculated for [C8H4F3NSSe]+ ([M]+): 282.9176, measured: 282.9174. IR (ATR): n (cm-1): 3066, 2924, 1557, 1453, 1409, 1313, 1277, 1232, 1012, 858, 738, 707, 670. Rf: (n-pentane/CH2Cl2, 10:1): 0.20. Synthesis of 3-Methyl-2-((trifluoromethyl)selanyl)benzo[d]thiazol-3-ium
trifluoromethanesulfonate
2-(trifluoromethyl)selenyl)benzo[d]thiazole (1.0 eq, 10.5 mmol, 2.96 g) was dissolved in dry CH2Cl2 (0.10 M) and methyl trifluoromethanesulfonate (3.0 eq, 31.5 mmol , 3.45 mL) was added dropwise. The reaction mixture was stirred at rt for 24 h and the product was precipitated with diethyl ether. The suspension was then filtered, and the residue washed with diethyl ether (3 × 100 mL). After drying in vacuo, BT-SeCF3 was obtained as off-white solid (4.28 g, 9.59 mmol, 92%). 1H NMR (400 MHz, Acetonitrile-d3) d = 8.37 (d, J=7.8, 1H, HAr), 8.27 (d, J=8.6, 1H, HAr), 8.01 (t, J=8.3, 7.9, 1H, HAr), 7.93 (t, J=7.9, 1H, HAr), 4.47 (s, 3H, CH3). 19F NMR (376 MHz, Acetonitrile-d3) d = -32.7 (SeCF3), -79.3 (S(O)2CF3).13C NMR (126 MHz, Acetonitrile-d3) d = 159.2 (Cq), 143.9 (Cq), 135.0 (Cq), 132.1 (CH), 131.1 (CH), 125.1 (CH), 122.7 (q, J=337, SeCF3), 122.0 (q, J=321, S(O)2CF3), 119.3 (CH), 41.4 (CH3). CHNS Elemental Analysis: calculated for C10H7F6NO3S2Se: C 26.92; H 1.58; N 3.14, S 14.37; measured: C 27.00, H 1.97, N 3.14, S 14.50. IR (ATR): n (cm-1): 3098, 3064, 1577, 1489, 1461, 1442, 1388, 1252, 1223, 1187, 1151, 1140, 1101, 1079, 1054, 1043, 1028, 987, 962, 802, 766, 741, 729, 712.

Claims

Claims 1. A fluorine containing compound according to the general formulae (I)
wherein - R1 is C1-C20 alkyl;
- R2, R3 are in each case an alkyl, a cycloalkyl, an aryl, a heteroaryl, halogen, fluoroalkyl or both R2 and R3 are part of a cyclic system;
- X is S, O, Se, Te; preferably S, O, Se;
- Y is S, O;
- Z- is R4SO3- with R4 being H, C1-C10 alkyl, aryl, CaFbHc, in particular– OTf (CF3SO3- ), p-Tos; Ph-SO3-; or I-, Cl-, ClO4-, BF4-;
- a is 1-20, preferably 1-12, more preferably 1-8;
- b is (2a+1) - c;
- c is 0-10, preferably 0-5, more preferably 0, 1, 2.
2. Compound according to claim 1, characterized in that R1 is C1-C10 alkyl, preferably C1-C5 alkyl, more preferably C1-C3 alkyl.
3. Compound according to claim 1 or 2, characterized in that R2 and R3 are part of an aromatic system, preferably of a C6 aryl ring.
4. Compound according to one of the preceding claims, characterized in that
- R1 is C1-C3 alkyl;
- R2, R3 are part of a unsubstituted or substituted C6 aryl ring or naphthyl ring, - X is S, O, Se;
- Y is S, O;
- Z- is R4SO3- with being R4 being aryl, CaFbHc , in particular– OTf (CF3SO3-), p- Tos; Ph-SO3-; or BF4-; - a is 1-8;
- b is (2a+1) - c;
- c is 0, 1, 2.
5. Compound according to one of the preceding claims, characterized by the general formulae (II)
wherein R1, X, Y, Z, a, b, c have the above meanings, and
wherein R5 is absent or a C1-C10 alkyl, a C1-C10 alkoxy, in particular C1-C5 alkoxy, or a halogen, in particular Cl, Br.
6. Compound according to one of the preceding claims, characterized by the general formulae (IIa)
wherein R1, R5, X, Z, a, b, c have the above meanings.
7. Compound according to claim 6, characterized by the general formulae (IIb)
wherein
- R1 is C1-C3 alkyl;
- R5 is absent or C1-C5 alkoxy, or Cl, Br.
- X is S, O, Se; - Y is S, O;
- Z- being– OTf (CF3SO - 3), p-Tos; Ph-SO3-; BF - 4;
- a is 1-8;
- b is (2a+1) - c;
- c is 0, 1, 2.
8. Process for obtaining a compound according to one of the preceding claims, comprising the following steps: - providing a compound of general formulae (V)
wherein G is H or a leaving group as starting material; - reacting the compound of general formulae (V) with at least one fluoroalkylating agent thereby providing an intermediate compound of general formulae (VI)
- alkylation of the ring nitrogen of general formulae (VI) thereby providing the compound of general formulae (I)
wherein R1, R2, R3, X, Y, Z, a, b, c have the above meanings.
9. Process according to claim 8, characterized in that at least one fluoroalkylating agent is selected from a group containing a compound of general formulae (VII) NaSO2CaFbHc wherein a, b, c have the above meanings.
10. Process according to claim 8, characterized in that at least one fluoroalkylating agent is selected from a group containing a compound of general formulae (VIII) Hal CaFbHc wherein Hal is I, Br, or Cl and wherein a, b, c have the above meanings.
11. Process according to claim 8-10, characterized in that at least one alkylating agent selected from a group containing alkyl trifluoromethanesulfonate, alkyl iodide, alkyl sulfate is employed.
12. Use of a compound according to one of claims 1 - 7 as a nucleophilic reagent for transferring a fluorine-containing functional group onto high value organic compounds, in particular pharmaceutical and agrochemical targets.
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