Trifluoromethylation of the amide group

Full text of DOI:10.1007/s11172-010-0039-x

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 484—486, February, 2009
484
Letters to the Editor
Trifluoromethylation of the amide group*
V. V. Levin,a M. A. Kozlov,b A. D. Dilman,a P. A. Belyakov,a M. I. Struchkova,a and V. A. Tartakovskya
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: dilman@ioc.ac.ru
bMoscow Chemical Lyceum,
4 Tamozhennyi pr., 109033 Moscow, Russian Federation
Amines containing an αꢀtrifluoromethyl substituent
N,Nꢀdialkyliminium cations react with Me3SiCF3 in the
presence of a fluoride or acetate anion.13 Here we propose
to use a cation generated in the Oꢀalkylation of a carꢀ
bamoyl group as an electrophile.14,15
constitute an important class of biologically active comꢀ
pounds.1—4 In particular, such a fragment is similar in
biological properties to an amide fragment.
Methylation of Nꢀbenzylpyrrolidone (1) with methyl
triflate in hot 1,2ꢀdichloroethane produces cation A, which
can be transformed into αꢀmethoxyꢀαꢀtrifluoromethyl
amine 2 by a reaction with Me3SiCF3 and KF in DMF
(Scheme 1).** Compound 2 should be stored at –25 °C
because of its low stability at room temperature.
Reduction of αꢀmethoxy amine 2 with NaBH4—
BF3•OEt2 gives 2ꢀtrifluoromethylpyrrolidine 3 in 87%
yield (Scheme 2). The methoxy group in amine 2 can
also be replaced by an aliphatic residue or a cyano
group in reactions with various Cꢀnucleophiles or triꢀ
methylsilyl cyanide to give the corresponding products
4a—d in good yields. It should be emphasized that
compound 4c contains adjacent quaternary C atoms,
Replacement of the oxo fragment in a peptide drug by
a trifluoromethyl group and a hydrogen atom can subꢀ
stantially enhance its therapeutic effect.1,2
Known general routes to CF3ꢀsubstituted amines inꢀ
volve nucleophilic addition to imines5—7 and fluorination
of amino acids.8,9 Below we describe a first example of the
straightforward transformation of amides into CF3ꢀconꢀ
taining amines.
Earlier,5,10—13 in a search for efficient ways of trifluoroꢀ
methylation of the C=N bond, we have shown that
** With dimethyl sulfate used to generate iminium salt A,
the reaction gives αꢀmethoxy amine 2 in 58% yield and a
byꢀproduct (supposedly, 1ꢀbenzylꢀ5ꢀtrifluoromethylꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀpyrrole) in 15% yield.
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 474—476, February, 2009.
1066ꢀ5285/09/5802ꢀ0484 © 2009 Springer Science+Business Media, Inc.

Trifluoromethylation of carboxamides
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
485
Scheme 1
Me3SiCF3 (332 μL, 2.25 mmol) and KF (109 mg, 1.88 mmol)
were added. The resulting suspension was stirred at 50 °C for
1 h, cooled to room temperature, quenched with saturated
aqueous Na2CO3 (0.5 mL), and stirred for 2 min. The mixture
was diluted with water (6 mL) and extracted with hexane—ether
(1 : 1, 3×5 mL). The combined extracts were filtered through
Na2SO4 and concentrated in vacuo. The residue was chromatoꢀ
graphed on silica gel with a hexane—EtOAc system (15 : 1) conꢀ
taining 0.5% NEt3 as an eluent. The yield of compound 2 was
311 mg (80%), a light yellow oil, Rf 0.20 (hexane—EtOAc, 6 : 1).
1H NMR (300 MHz), δ: 1.77—1.97 (m, 2 H); 2.18—2.32 (m,
2 H); 2.88—3.06 (m, 2 H) ((CH2)3); 3.42 (s, 3 H, OMe); 4.02
(d, 1 H, NCHAHB, J = 14.5 Hz); 4.11 (d, 1 H, PhCHAHB,
J = 14.5 Hz); 7.27—7.45 (m, 5 H, Ph). 13C NMR (75 MHz), δ:
21.5 (NCH2CH2); 29.6 (CH2); 49.7 (CH2); 50.3 (q, CH2,
J = 1.8 Hz); 51.0 (CH2); 95.2 (q, CCF3, J = 28.9 Hz); 125.1
(q, CF3, J = 289.9 Hz); 126.8 (CH); 127.8 (CH); 128.3 (CH);
139.5 (Ci). 19F NMR (282 MHz), δ: –79.3 (s, 3 F).
i. MeOTf, 1,2ꢀdichloroethane, 80 °C, 15 min;
ii. Me3SiCF3, KF, DMF, 50 °C, 1 h
Scheme 2
1ꢀBenzylꢀ2ꢀtrifluoromethylpyrrolidine (3). Sodium boroꢀ
hydride (29 mg, 0.75 mmol) and BF3•OEt2 (71 μL, 0.56 mmol)
were successively added to a solution of αꢀmethoxy amine 2
(130 mg, 0.5 mmol) in dioxane (1 mL). The resulting suspension
was stirred at 50 °C for 2 h, cooled to room temperature,
quenched with saturated aqueous Na2CO3 (0.5 mL), and stirred
for an additional 2 min. Then the mixture was diluted with water
(6 mL) and extracted with hexane—ether (1 : 1, 3×5 mL). The
combined extracts were filtered through Na2SO4 and concenꢀ
trated in vacuo. The residue was chromatographed on silica gel
with hexane—EtOAc (20 : 1) as an eluent, Rf 0.36. The yield
of compound 3 was 100 mg (87%), a colorless oil. Found (%):
C, 62.74; H, 6.09; N, 6.05. C12H114F3N (229.24). Calcuꢀ
lated (%): C, 62.87; H, 6.16; N, 6.11. H NMR (300 MHz), δ:
1.70—2.08 (m, 4 H, (CH2)2); 2.41 (td, 1 H, NCHAHB, J = 9.5 Hz,
J = 6.6 Hz); 3.00 (t, 1 H, NCHAHB, J = 7.5 Hz); 3.30 (qt, 1 H,
CHCF3, J = 7.3 Hz); 3.63 (d, 1 H, PhCHAHB, J = 13.3 Hz);
4.22 (d, 1 H, PhCHAHB, J = 13.3 Hz); 7.23—7.42 (m, 5 H, Ph).
13C NMR (75 MHz), δ: 24.3 (NCH2CH2); 26.4 (q, F3CCHCH2,
J = 1.8 Hz); 53.8 (NCH2CH2); 59.8 (q, CH2Ph, J = 1.1 Hz);
63.4 (q, CHCF3, J = 28.3 Hz); 127.0 (CH); 127.1 (q, CF3,
J = 280.3 Hz); 128.3 (CH); 128.6 (CH); 138.9 (Ci). 19F NMR
(282 MHz), δ: –76.8 (d, 3 F, J = 7.3 Hz).
Reactions of αꢀmethoxy amine 2 with Cꢀnucleophiles (general
procedure). Boron trifluoride etherate (95 μL, 0.75 mmol) was
added dropwise at –25 °C to a solution of αꢀmethoxy amine 2
(130 mg, 0.5 mmol) and an appropriate nucleophilic reagent
(0.75 mmol) in dichloromethane (1 mL). The reaction mixture
was stirred at –25 °C for 10 min and then at room temperature
for 1 h. Saturated aqueous Na2CO3 (0.5 mL) was added. The
mixture was stirred for an additional 2 min, diluted with water
(6 mL), and washed with hexane—ether (1 : 1, 3×5 mL). The
combined extracts were filtered through Na2SO4 and concenꢀ
trated in vacuo. The residue was chromatographed on silica gel.
2ꢀAllylꢀ1ꢀbenzylꢀ2ꢀtrifluoromethylpyrrolidine (4a), an oil, Rf
0.15 (hexane). Found (%): C, 66.87; H, 6.80; N, 5.15. C15H18F3N
i. NaBH4, BF3•OEt2, dioxane, 50 °C, 2 h;
ii. BF3•OEt2, CH2Cl2, –25→20 °C, 1 h.
which is evidence for the efficiency of this method of
C—C bond formation.
1H, 13C, and 19F NMR spectra were recorded on Bruker
AMꢀ300 and Bruker ACꢀ200 instruments in CDCl3. Dichloroꢀ
ethane and dichloromethane were distilled over CaH2 immediꢀ
ately before use; DMF was distilled in vacuo over P2O5 and kept
over molecular sieves (4 Å). NꢀBenzylpyrrolidone was prepared
according to a known procedure.16 Boron trifluoride etherate
was purified by distillation in vacuo. The other commercial
reagents were used as purchased.
1
(269.31). Calculated (%): C, 66.90; H, 6.74; N, 5.20. H NMR
(300 MHz), δ: 1.61—1.88 (m, 2 H), 1.94—2.18 (m, 2 H)
((CH2)2); 2.45 (dd, 1 H, =CCHAHB, J = 14.5 Hz, J = 8.1 Hz);
2.66 (dd, 1 H, =CCHAHB, J = 14.5 Hz, J = 6.1 Hz); 2.70—2.82
(m, 2 H, NCH2); 3.87 (d, 1 H, PhCHAHB, J = 13.8 Hz); 4.00
(d, 1 H, PhCHAHB, J = 13.8 Hz); 5.13—5.32 (m, 2 H,
CH2=); 5.85—6.02 (m, 1 H, —CH=); 7.20—7.41 (m, 5 H, Ph).
1ꢀBenzylꢀ2ꢀmethoxyꢀ2ꢀtrifluoromethylpyrrolidine (2). Methyl
triflate (176 μL, 1.8 mmol) was added to a solution of Nꢀbenzylꢀ
pyrrolidone (263 mg, 1.5 mmol) in 1,2ꢀdichloroethane (1.5 mL).
The mixture was stirred at 80 °C for 15 min and concentrated
in vacuo. The residue was dissolved in DMF (2.5 mL) and then

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Levin et al.
13C NMR (75 MHz), δ: 22.1 (NCH2CH2); 31.2 (CH2); 35.7
(CH2); 51.6 (CH2); 52.2 (CH2); 67.2 (q, CCF3, J = 23.8 Hz);
119.0 (H2C=); 126.8 (CH); 128.0 (CH); 128.2 (CH); 128.6 (q,
CF3, J = 291.4 Hz); 132.8 (CH=CH2); 140.2 (Ci). 19F NMR
(282 MHz), δ: –75.0 (s, 3 F).
MKꢀ4483.2007.3), the Russian Foundation for Basic
Research (Project No. 08ꢀ03ꢀ00428), the Russian Acadꢀ
emy of Sciences (Program of the Presidium of the Russian
Academy of Sciences), and the Russian Science Support
Foundation.
1ꢀBenzylꢀ2ꢀphenacylꢀ2ꢀtrifluoromethylpyrrolidine (4b),
an oil, Rf 0.31 (hexane—EtOAc, 25 : 1). Found (%): C, 69.21;
H, 5.76; N, 3.99. C20H20F3NO (347.37). Calculated (%):
References
1
C, 69.15; H, 5.80; N, 4.03. H NMR (300 MHz), δ: 1.78—1.93
(m, 2 H); 2.23 (ddd, 1 H, J = 13.2 Hz, J = 7.0 Hz, J = 4.9 Hz);
2.49 (dtd, 1 H, J = 18.3 Hz, J = 9.1 Hz, J = 0.8 Hz); 2.80—2.90
(m, 1 H); 2.95 (q, 1 H, J = 7.7 Hz) ((CH2)3); 3.42—3.57 (m,
2 H, CH2CO); 3.75 (d, 1 H, PhCHAHB, J = 13.6 Hz); 3.99 (d,
1 H, PhCHAHB, J = 13.6 Hz); 7.17—7.32 (m, 5 H, PhCH2);
7.46—7.55 (m, 2 H, PhCO); 7.61 (tt, 1 H, PhCO, J = 7.3 Hz,
J = 2.4 Hz); 7.98—8.04 (m, 2 H, PhCO). 13C NMR (75 MHz),
δ: 22.7 (NCH2CH2); 32.1 (CH2); 37.4 (CH2); 52.1 (CH2); 53.0
(CH2); 67.4 (q, CCF3, J = 26.0 Hz); 126.7 (CH); 127.9 (CH);
128.0 (CH); 128.0 (q, CF3, J = 288.6 Hz); 128.2 (CH); 128.7
(CH); 133.3 (CH); 137.7 (Ci); 140.0 (Ci); 196.9 (C=O).
19F NMR (282 MHz), δ: –78.2 (s, 3 F).
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Methyl
2ꢀ(1ꢀbenzylꢀ2ꢀtrifluoromethylpyrrolidinꢀ2ꢀyl)ꢀ
2ꢀmethylpropionate (4c), Rf 0.10 (hexane—EtOAc, 30 : 1),
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(s, 3 H, CMeAMeB); 1.59—1.81 (m, 2 H); 1.98—2.14 (m, 1 H);
2.45—2.59 (m, 1 H); 2.72 (dd, 1 H, J = 13.9 Hz, J = 7.7 Hz);
2.95—3.06 (m, 1 H) ((CH2)3); 3.64—3.75 (m, 4 H, PhCHAHB
+ CO2Me); 4.51 (d, 1 H, PhCHAHB, J = 14.7 Hz); 7.21—7.45
(m, 5 H, Ph). 13C NMR (75 MHz), δ: 22.7 (q, CMeAMeB,
J = 2.4 Hz); 23.3 (NCH2CH2); 23.5 (q, CMeAMeB, J = 1.5 Hz);
32.5 (q, CH2, J = 2.2 Hz); 49.3 (CH2); 52.0 (CH2); 53.9 (CH2);
55.0 (q, CH2, J = 2.4 Hz); 72.4 (q, CCF3, J = 22.3 Hz); 126.8
(CH); 127.5 (CH); 128.4 (CH); 129.0 (q, CF3, J = 294.5 Hz);
140.4 (q, Ci, J = 1.4 Hz); 175.9 (C=O). 19F NMR (282 MHz),
δ: –65.3 (s, 3 F).
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an oil, Rf 0.25 (hexane—EtOAc, 15 : 1). Found (%): C, 61.27;
H, 5.14; N, 10.87. C13H13F3N2 (254.25). Calculated (%):
C, 61.41; H, 5.15; N, 11.02. 1H NMR (300 MHz), δ: 1.83—2.03
(m, 2 H); 2.43—2.65 (m, 3 H); 3.03—3.16 (m, 1 H) ((CH2)3);
3.68 (d, 1 H, PhCHAHB, J = 13.2 Hz); 4.35 (d, 1 H, PhCHAHB,
J = 13.2 Hz); 7.28—7.44 (m, 5 H, Ph). 13C NMR (75 MHz), δ:
23.4 (NCH2CH2); 34.8 (q, CH2CCF3, J = 1.0 Hz); 52.7 (CH2);
56.2 (q, CH2); 66.3 (q, CCF3, J = 31.3 Hz); 114.8 (CN); 123.6
(q, J = 283.1 Hz); 127.5 (CH); 128.2 (CH); 128.5 (CH); 137.6
(Ci). 19F NMR (282 MHz), δ: –77.2 (s, 3 F).
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This work was financially supported by the Council on
Grants of the President of the Russian Federation (Proꢀ
gram for State Support of Young Ph.D. Scientists, Grant
Received November 18, 2008;
in revised form January 20, 2009