N-TRIFLUORMETHYLCARBONYL COMPOUNDS AND METHODS FOR THEIR SYNTHESIS

Abstract

The present invention relates to the synthesis of N-trifluoromethylcarbonyl compounds starting from isothiocyanates, which can be converted into N-trifluoromethylcarbamoyl fluorides or similar compounds, which later on can be derivatized further to amides, ureas, carbamates, thiocarbamates and selenocarbamates.

Claims

1. A method for the synthesis of N-trifluoromcthylcarbonyl compounds having the structure R—N(CF.sub.3)CO—LG, whereby R is an organic moiety and LG is a leaving group, from isothiocyanates R—NCS, comprising the step of a) contacting the isothiocyanate R—NCS with AgF and an electrophilic C.sub.1-compound where the carbon is in the formal oxidation state (+IV).

2. The method according to claim 1, whereby the electrophilic C.sub.1-compound comprises a compound of the chemical structure LG.sup.1—CO-LG.sup.2 whereby LG.sup.1 and LG.sup.2 are independently from each other leaving groups.

3. The method according to claim 1, whereby the method is carried out in the presence of one or more additional fluoride compounds.

4. The method according to claim 1, whereby the molar ratio of AgF to isothiocyanate is ≥4.

5. The method according to claim 1, whereby the molar ratio of effective electrophilic C.sub.1 compound to isothiocyanate is ≥1.0 to ≤2.

6. The method according to claim 1, whereby the isothiocyanate R-NCS and/or the electrophilic C.sub.1-compound and/or the AgF are formed in situ during the course of the reaction.

7. The method according to claim 1, whereby AgOCF.sub.3 is used as a precursor for AgF and the electrophilic C.sub.1-compound.

8. A method for the synthesis of N-trifluoromcthyl amides comprising the step of contacting a compound R—N(CF.sub.3)CO-LG, whereby R is an organic moiety and LG is a leaving group, with an organometallic compound.

9. The method according to claim 8, whereby the organometallic compound is an organomagnesium compound, organolithium compound and/or an organozinc compound.

10. A method for the synthesis of N-trifluoromcthyl ureas, N-trifluoromcthyl carbamates, N-trifluoromcthyl thiocarbamates and/or N-trifluoromcthyl selenocarbamates comprising the step of contacting a compound R—N(CF.sub.3)CO— LG, whereby R is an organic moeity and LG is a leaving group, with an amine, alcohol, thiol or selenol.

11. The method according to claim 8, whereby the compound R— N(CF.sub.3)CO-LG is prepared from isothiocyanates R—NCS, by a method comprising the step of contacting the isothiocyanate R—NCS with AgF and an electrophilic C.sub.1-compound where the carbon is in the formal oxidation state (+IV).

12. Compounds of the structure R—N(CF.sub.3)—CO—X—R′ with R and R′ being organic moieties and X being S, O or Se.

13. The method according to claim 10, whereby the compound R—N(CF.sub.3)CO-LG is prepared from isothiocyanates R-NCS by a method comprising the step of contacting the isothiocyanate R—NCS with AgF and an electrophilic C.sub.1-compound where the carbon is in the formal oxidation state (+IV).

Description

[0063] Additional details, characteristics and advantages of the object of the invention are disclosed in the sub-claims and the following description of the respective examples—which in an exemplary fashion--show preferred embodiments according to the invention. Such embodiments do not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the present invention as claimed.

[0064] General Procedure for the Synthesis of N-trifluoromethylcarbamoyl Fluorides:

[0065] A 20 mL vial was charged with the isothiocyanate (2 mmol, 1 equiv.), silver fluoride (10 mmol, 5 equiv.) and triphosgene (237 mg, 0.8 mmol, 0.4 equiv.). Acetonitrile (10 mL) was added quickly and the vial was sealed (if the isothiocyanate was a liquid or an oil it was added as a solution in the solvent). The mixture was stirred at room temperature. Afterwards the crude mixture was added at once to Et.sub.2O (40 mL) and stirred for 10 minutes. The solid was filtered through celite and the solvents were then evaporated. The obtained crude material was dissolved in Et.sub.2O and filtered on a pad of celite again to remove the last traces of salt byproducts. The N-trifluoromethylcarbamoyl fluoride was then obtained in a technical grade purity ranging from 90 to 99%.

[0066] Using this general procedure, the following compounds 1 to 30 were synthesized:

##STR00001## ##STR00002##

[0067] Exemplarily the Synthesis of Compound 1 is Described in More Detail:

[0068] [1,1′-Biphenyf]-4-yl-N-trifluoromethylcarbamoyl fluoride 1: The title compound was obtained as a white solid after 15 h in 98% yield (555 mg) using 4-isothiocyanato-1,1′-biphenyl (423 mg) following the general procedure for N-trifluoromethylcarbamoyl fluorides. M.p.: 94-96° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71-7.64 (m, 2H), 7.61-7.54 (m, 2H), 7.50-7.43 (m, 2H), 7.43-7.34 (m, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ-2.6 (brs, 1F), −56.2 (brs, 3F). .sup.13C NMR (151 MHz, CDCl.sub.3) δ143.6, 142.1 (d, J=300.8 Hz), 139.4, 132.0, 129.0, 128.6, 128.6, 128.2, 127.3, 119.2 (q, J=264.8 Hz). MS (70eV, EI): m/z (%): 283 (100) [M+], 172 (19), 69 (5). HRMS (EI) calculated for C.sub.14H.sub.9ONF.sub.3: 264.06308 [M-F].sup.+, Found: 264.06302.

[0069] General Procedure for the Synthesis of Amides:

[0070] A 4 mL vial was charged with the N-trifluoromethylcarbamoyl fluoride (0.2 mmol, 1 equiv.), toluene (1.5 mL) and placed into a water bath at room temperature. The corresponding Grignard reagent (0.24 mmol, 1.2 equiv.) was subsequently added to the solution. The reaction mixture was stirred for 10 minutes at room temperature. Saturated aqueous ammonium chloride solution (1.5 mL) was then added. The phases were separated and the aqueous phase was further extracted with EtOAc (2×), dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained crude material was then purified by column chromatography.

[0071] Using this general procedure the compounds 31 to 44 were synthesized:

##STR00003##

[0072] Exemplarily the Synthesis of Compound 38 is Described in Detail:

[0073] 2-Chloro-5-(N-(trifluoromethyl) thiophene-2-carboxamido)phenyl trifluoromethanesulfonate 38 : The title compound was obtained as a colorless oil in 97% yield (88 mg) using 2-chloro-5-((fluorocarbonyl)(trifluoromethyl)amino)phenyl trifluoromethanesulfonate 11 (78 mg) with 2-thienylmagnesium bromide (240 μL, 1.0M in THF) after column chromatography on silica gel with EtOAc/hexane (5/95, R.sub.f=0.20). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.60 (dd, J=8.6, 1.0 Hz, 1H), 7.50 (dd, J=5.0, 1.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.6, 2.4 Hz, 1H), 7.25-7.23 (m, 1H), 6.92 (ddd, J=5.0, 3.9, 1.0 Hz, 1H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ-56.5 (s, 3F), −73.2 (s, 3F). .sup.13C NMR (151 MHz, CDCl.sub.3) δ 161.5, 145.8, 135.5, 135.3, 134.7, 134.1, 132.1, 131.2, 129.9, 127.5, 125.7, 119.8 (q, J=265.8 Hz), 118.5 (q, J=320.9 Hz). HRMS (ESI) calculated for C.sub.13H.sub.6O.sub.4N.sup.35ClF.sub.6Na.sup.32S.sub.2: 475.92232 [M+Na].sup.+, Found: 475.92151.

[0074] General Procedure for the Synthesis of Ureas:

[0075] A 4 mL vial was charged with the N-trifluoromethylcarbamoyl fluoride (0.2 mmol, 1 equiv.) and CH.sub.2Cl.sub.2 (1.5 mL). The corresponding amine (0.24 mmol, 1.2 equiv.), Hunig's base (42 μL, 0.24 mmol, 1.2 equiv.) and DMAP (2 mg, 0.02 mmol, 0.1 equiv.) were subsequently added to the solution. The reaction mixture was stirred for 15 h at room temperature. Hexane (1 mL) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

[0076] Stability Investigation of Compound 45

[0077] To challenge the stability of N—CF.sub.3 amides, we subjected amide 45 to a solution of 0.5 M HCl and also 0.5 M NaOH at 50° C. for 15 h (in 50:50 THF/H.sub.2O) and observed essentially no decomposition, whereas the corresponding N—Me and N—H analogues showed decomposition. This suggests that many N-trifluoromethyl amides are more stable than their ‘conventional’ amide counterparts.

[0078] General Procedure for the Synthesis of Carbamates:

[0079] A 4 mL vial was charged with the N-trifluoromethylcarbamoyl fluoride (0.2 mmol, 1 equiv.) and CH.sub.2Cl.sub.2 (1.5 mL). The corresponding alcohol (0.24 mmol, 1.2 equiv.), Hunig's base (42 μL, 0.24 mmol, 1.2 equiv.) and DMAP (2 mg, 0.02 mmol, 0.1 equiv.) were subsequently added to the solution. The reaction mixture was stirred for 15 h at room temperature. Hexane (1 mL) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

[0080] General Procedure for the Synthesis of Thiocarbamates and Selenocarbamates:

[0081] A 4 mL vial was charged with the N-trifluoromethylcarbamoyl fluoride (0.2 mmol, 1 equiv.) and THF (1.5 mL). The corresponding sodium thiolate or selenolate (0.24 mmol, 1.2 equiv.) was subsequently added to the solution. The reaction mixture was stirred for 1 h at room temperature. Hexane (1 mL) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

[0082] Using the above general methods, the following compounds 46 to 74 were synthesized:

##STR00004## ##STR00005## ##STR00006##

[0083] Exemplarily the Synthesis of Compound 46 is Described in Greater Detail:

[0084] Methyl (S)-3-(3-(4-bromo-2-chlorophenyl) -3-(trifluoromethyl)ureido)-4-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoate 46 : The title compound was obtained as a colorless oil in 71% yield (87 mg) using (4-bromo-2-chlorophenyl)-N-trifluoromethylcarbamoyl fluoride 19 (64 mg) with methyl (S)-3-amino-4-(((S)-1-methoxy- 1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoate hydrochloride [aspartame-OMe.HCl] (83 mg) in presence of N,N diisopropylethylamine [Hunig's base] (77 μL, 0.44 mmol, 2.2 equiv.) after column chromatography on silica gel with EtOAc/hexane (40/60, R.sub.f=0.38). [α].sub.D=+40.2 (c=0.600, CHCl.sub.3, 26° C.). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.29-7.25 (m, 3H), 7.17 (d, J=8.5 Hz, 1H), 7.07 (dd, J=6.6, 2.9 Hz, 2H), 6.93 (d, J=7.6 Hz, 1H), 6.04 (s, 1H), 4.80-4.59 (m, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.10 (dd, J=14.0, 5.3 Hz, 1H), 3.04-2.95 (m, 2H), 2.55 (dd, J=17.3, 7.0 Hz, 1H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ-53.6. .sup.13C NMR (151 MHz, CDCl.sub.3) δ 172.6, 171.2, 169.5, 151.4, 136.0, 135.5, 133.9, 132.7, 132.0, 130.9, 129.2, 128.6, 127.1, 125.1, 119.6 (q, J=262.5 Hz), 53.7, 52.4, 52.2, 49.9, 37.5, 35.5. HRMS (ESI) calculated for C.sub.23H.sub.22.sup.79Br.sup.35ClF.sub.3N.sub.3NaO.sub.6: 630.02248 [M+Na].sup.+, Found: 630.02124.

[0085] The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the foregoing description is by way of example only and is not intended as limiting. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.