Trifluoromethylation and pentafluorophenylation of enamines

Article abstract of DOI:10.1007/s11172-007-0235-5

A reaction of enamines with Me₃SiCF₃ and Me ₃SiC₆F₅ in the presence of carboxylic acids leading to α-CF₃-and α-C₆F₅- substituted amines has been studied. 3-Cyanobenzoi

Full text of DOI:10.1007/s11172-007-0235-5

Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1522—1525, August, 2007
1522
Trifluoromethylation and pentafluorophenylation of enamines
A. D. Dilman,ꢀ V. V. Gorokhov, P. A. Belyakov, M. I. Struchkova, and V. A. Tartakovsky
N. 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
A reaction of enamines with Me3SiCF3 and Me3SiC6F5 in the presence of carboxylic acids
leading to αꢀCF3ꢀ and αꢀC6F5ꢀsubstituted amines has been studied. 3ꢀCyanobenzoic acid was
found to be the optimal promoter of these reactions.
Key words: silanes, iminium cations, pentacoordinate silicon, amines, enamines, organoꢀ
silicon compounds, organofluorine compounds.
Amines with fluorinated substituent at αꢀcarbon atom
are widely used in pharmaceutical industry and agroꢀ
chemistry.1,2 Recently, we started a systematic research
on the synthesis of these compounds, based on the reacꢀ
tion of fluorinated silanes with the in situ generated
iminium cations.3—7 As a particular example, a reaction of
pentafluorophenylation of enamines upon treatment with
MeSi(C6F5)3 and acetic acid was proposed4 (Scheme 1).
This method has a disadvantage of high cost of this
silyl reagent. The present study is aimed at a quest of
conditions for utilization of the less expensive fluorinated
organosilanes Me3SiCF3 and Me3SiC6F5.
The general mechanism of the process is given in
Scheme 2. In the first step, an equilibrium protonation of
enamine 1 by a carboxylic acid takes place to form iminium
cation 2 and a carboxylate anion. By interaction of the
carboxylate anion with silane, an anionic pentacoordinate
silicon intermediate 3 is generated (see Refs 8ꢀ10), from
which the fluorinated group is transferred to iminium catꢀ
ion 2. The reaction between cation 2 and complex 3,
accompanied by the formation of a new C—C bond, can
proceed either through the intermediate formation of carꢀ
banion species RF– or as a concerted process.11
Scheme 1
It should be noted that concentrations of electrophile
and nucleophile are defined by the opposite factors. Thus
an increase of RCO2H acid strength causes an increase of
R1 = Ph, R22 = (CH2)4, (CH2)5, R3 = H, Me
R1R3 = (CH2)4, (CH2)5
Scheme 2
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1466—1468, August, 2007.
1066ꢀ5285/07/5608ꢀ1522 © 2007 Springer Science+Business Media, Inc.

Trifluoromethylation of enamines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1523
iminium cation 2 concentration and, at the same time,
decreases basicity of the carboxylate anion necessary for
the formation of pentacoordinate silicon intermediate 3.
Moreover, the protonation of complex 3 by the carboxyꢀ
lic acid with the formation of RF—H can become a sigꢀ
nificant side process, resulting in unproductive consumpꢀ
tion of the fluorinated organosilane.
As it follows from the foregoing material, 3ꢀcyanoꢀ
benzoic acid is the most efficient promoter of the addition
of Me3SiCF3 to enamines. Under the optimal conditions,
a series of enamines has been involved into reaction of
trifluoromethylation with the use of Me3SiCF3 and pentaꢀ
fluorophenylation with the use of Me3SiC6F5 (Scheme 4).
A model reaction of enamine 1a with Me3SiCF3 was
investigated in the presence of various carboxylic acids.
The reaction was carried out in DMF at 20 °C for 4 h
(Scheme 3).*
Scheme 4
Scheme 3
i. 1.5 equiv. Me3SiRF, 1 equiv. 3ꢀNCC6H4CO2H, DMF, 20 °C, 18 h
Enamine
RF
4
Yield of 4 (%)
CF3
4a
4b
77
60
(1a)
C6F5
i. 1.5 equiv. Me3SiCF3, 1 equiv. RCO2H, DMF, 20 °C, 4 h
CF3
4c
4d
66
78
(1b)
(1c)
R
pKa (RCO2H)
Yield 4a (%)
C6F5
Me
Ph
4.76
4.20
3.64
2.82
37
50
72
37
CF3
4e
4f
60
72
3ꢀNCC6H4
3,5ꢀ(O2N)2C6H3
C6F5
Both acetic and benzoic acids gave product 4a in 37
and 50% yield, respectively. The yield was considerably
higher in the presence of the stronger 3ꢀcyanobenzoic
acid (72%). However, the further increase in acidity by
the use of 3,5ꢀdinitrobenzoic acid led to a decrease in the
yield of amine 4a to 37%. Further optimization of the
reaction conditions with participation of 3ꢀcyanobenzoic
acid showed that by the prolongation of the reaction time
to 18 h, the yield of 4a can be raised up to 77%.
The observed influence of the carboxylic acid strength
on the effectivity of the reaction can be explained by the
assumption that, for the weaker acids, the formation of
iminium cation 2 is not complete, which results in the
protonation of pentacoordinate complex 3 by the remainꢀ
der of the acid. At the same time, for the stronger acids,
capable of exhausting themselves in protonation of enꢀ
amine, the Lewis basicity of carboxylate anion is not sufꢀ
ficient for the generation of the pentacoordinate silicon
intermediate.11
CF3
4g
4h
50
31
(1d)
(1e)
C6F5
CF3
4i
4j
51
49
C6F5
Enamines with pyrrolidine and piperidine moieties led
to the corresponding products in good yields. However,
substrates with morpholine fragment afforded amines 4g—j
in only 31—51% yield. The lower effectivity in the reacꢀ
tions with morpholine enamines can be attributed to the
electronꢀwithdrawing effect of oxygen atom, which deꢀ
stabilizes the iminium cation thus decreasing its equilibꢀ
rium concentration. The influence of oxygen atom is conꢀ
firmed both by pKa values for the conjugate acids of the
cyclic amines (morpholine, 8.36; piperidine, 11.22;
pyrrolidine, 11.27) and by the kinetic data on nucleophiꢀ
licity of enamines derived from the cyclic amines.14
In conclusion, the reactions of trifluoromethylation
and pentafluorophenylation of enamines were studied and
it was shown that 3ꢀcyanobenzoic acid was the optimal
promoter of the reaction. The use of Me3SiCF3 allows
one to obtain αꢀCF3ꢀsubstituted amines in 51—77% yield,
which are difficult to access by other methods. At the
same time, the product yields vary from 31 to 78% in the
reaction with Me3SiC6F5, which demonstrates the lower
* The literature data12,13 point to the fact that during nucleoꢀ
philic trifluoromethylation, carried out in strongly basic condiꢀ
tions or in the presence of fluoride anion, DMF can play the
role of mediator due to the formation of the anionic intermediꢀ
ate during the interaction with trifluoromethyl carbanion. Howꢀ
ever, it was also shown that, when the activation of Me3SiCF3
by carboxylic acid salts (RCO2M) occurs, the main function of
the solvent is reduced to the solvation of the metal ion.8,10

1524
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Dilman et al.
CCF3, JC,F = 23.0 Hz); 129.1 (q, CF3, JC,F = 292.1 Hz).
19F NMR, δ: –72.0 (CF3).
effectivity of this reagent in comparison with tris(pentaꢀ
fluorophenyl)silyl derivatives.4
1ꢀ(1ꢀPentafluorophenylcyclopentyl)pyrrolidine (4f) (see
Ref. 4). Chromatography with light petroleum—EtOAc, 25 : 1;
Rf 0.32 (light petroleum—EtOAc, 25 : 1). M.p. 89–91 °C
(MeOH).
Experimental
1
H, 13C, and 19F NMR spectra were recorded on a Bruker
4ꢀ(1ꢀTrifluoromethylcyclohexyl)morpholine (4g). Chromatoꢀ
graphy with light petroleum—EtOAc, 20 : 1, Rf 0.24 (light peꢀ
troleum—EtOAc, 10 : 1). B.p. 140—145 °C (bath temperature;
30 Torr). Found (%): C, 55.84; H, 7.75; N, 5.91. C11H18F3NO
(237.26). Calculated (%): C, 55.68; H, 7.65; N, 5.90. 1H NMR,
δ: 1.17—1.32 (m, 1 H); 1.38—1.62 (m, 6 H); 1.69—1.79 (m,
1 H); 1.94—2.03 (m, 2 H) ((CH2)5); 2.75—2.91 (m, 4 H,
CH2NCH2); 3.62—3.68 (m, 4 H, CH2OCH2). 13C NMR, δ:
19.5 (CH2); 25.5 (CH2); 26.9 (q, CH2, JC,F = 1.6 Hz); 46.1
(CH2NCH2); 60.8 (q, CCF3, JC,F = 22.0 Hz); 68.2 (q,
CH2OCH2, JC,F = 1.4 Hz); 128.5 (q, CF3, JC,F = 296.3 Hz).
19F NMR, δ: –74.1 (CF3).
4ꢀ(1ꢀPentafluorophenylcyclohexyl)morpholine (4h) (see
Ref. 4). Chromatography with light petroleum—EtOAc, 10 : 1;
Rf 0.12 (light petroleum—EtOAc, 15 : 1). M.p. 79—80 °C
(MeOH).
4ꢀ[3ꢀ(Trifluoromethyl)pentꢀ3ꢀyl]morpholine (4i). Chromaꢀ
tography with light petroleum—EtOAc, 20 : 1, Rf 0.30 (light
petroleum—EtOAc, 10 : 1). B.p. 130—135 °C (bath temperature;
30 Torr). Found (%): C, 53.58; H, 8.09; N, 6.08. C10H18F3NO
(225.25). Calculated (%): C, 53.32; H, 8.05; N, 6.22. 1H NMR,
δ: 0.94 (tq, 6 H, 2 CH3, J = 0.9 Hz, J = 7.5 Hz); 1.59—1.72 (m,
2 H, 2 CHAHB); 1.73—1.87 (m, 2 H, 2 CHAHB); 2.75—2.80 (m,
4 H, CH2NCH2); 3.60—3.65 (m, 4 H, CH2OCH2). 13C NMR,
δ: 7.4 (q, 2 CH3, JC,F = 1.6 Hz); 21.9 (q, 2 CH2, JC,F = 1.6 Hz);
AMꢀ300, Bruker WMꢀ250, or Bruker ACꢀ200 spectrometers in
CDCl3. Dimethylformamide was distilled in vacuo over P2O5
and kept over molecular sieves 4 Å. Enamines 1a—d 15 and 1e 16
and Me3SiC6F5 17,18 were obtained according to the known proꢀ
cedures, Me3SiCF3 was purchased from PiM Invest.
Trifluoromethylation and pentafluorophenylation of enamines
(general procedure). 3ꢀCyanobenzoic acid (147 mg, 1.0 mmol)
was added to a solution of the corresponding enamine 1
(1.0 mmol) and RFSiMe3 (1.5 mmol) in DMF (1 mL) at 20 °C
and this was kept for 18 h. Saturated aq. Na2CO3 (0.4 mL) was
added to the reaction mixture, which was kept for another 5 min
and then diluted with Et2O (10 mL). The resulting mixture was
placed into a separatory funnel and washed with water (10 mL).
The aqueous phase was extracted with Et2O (10 mL), the comꢀ
bined extracts were washed with water (10 mL), dried with
Na2SO4 and concentrated in vacuo. Compounds 4a,b,d,f—j were
isolated by column chromatography on SiO2 using mixtures of
light petroleum—EtOAc as the eluent. For compounds 4c,e, the
formed product was dissolved in light petroleum, washed with
water (3×10 mL), dried with Na2SO4, concentrated, and the
residue was distilled in vacuo.
1ꢀ(1ꢀPhenylꢀ1ꢀtrifluoromethylpropꢀ1ꢀyl)pyrrolidine (4a).
Chromatography with light petroleum—EtOAc, 30 : 1, Rf 0.71
(light petroleum—EtOAc, 10 : 1). B.p. 150—155 °C (bath temꢀ
perature; 25 Torr). Found (%): C, 65.31; H, 7.08; N, 5.26.
47.1 (q, CH2NCH2, JC,F = 1.6 Hz); 64.0 (q, CF3, JC,F
=
20.9 Hz); 68.2 (q, CH2OCH2, JC,F = 1.1 Hz); 129.0 (q, CF3,
C
14H18F3N (257.29). Calculated (%): C, 65.35; H, 7.05; N, 5.44.
JC,F = 297.4 Hz). 19F NMR, δ: –69.5 (CF3).
1H NMR, δ: 0.75 (t, 3 H, CH3, J = 7.4 Hz); 1.76–1.85 (m, 4 H,
CH2CH2); 1.93—2.23 (m, 2 H, CH2CH3); 2.84—2.97 (m, 4 H,
CH2NCH2); 7.28—7.45 (m, 3 H), and 7.58 (d, 2 H, J = 7.9 Hz)
(Ph). 13C NMR, δ: 8.5 (CH3); 23.9 (CH2CH2); 28.6 (CH2CH3);
46.3 (CH2NCH2); 68.9 (q, CCF3, JC,F = 22.1 Hz); 127.3 (CHPh);
127.5 (q, CHPh, JC,F = 2.6 Hz); 127.9 (CHPh); 129.6 (q, CF3,
JC,F = 298.9 Hz); 138.3 (ipsoꢀCPh). 19F NMR, δ: –65.2 (CF3).
1ꢀ(1ꢀPhenylꢀ1ꢀpentafluorophenylpropꢀ1ꢀyl)pyrrolidine (4b)
(see Ref. 4). Chromatography with light petroleum—EtOAc,
40 : 1; Rf 0.45 (light petroleum—EtOAc, 25 : 1).
4ꢀ[3ꢀ(Pentafluorophenyl)pentꢀ3ꢀyl]morpholine (4j) (see
Ref. 4). Chromatography with light petroleum—EtOAc, 15 : 1;
Rf 0.24 (light petroleum—EtOAc, 15 : 1).
This work was financially supported by the Ministry
of Science and Education (State Program for the Support
of Young Philosophy Doctors, Grant MK4483.2007.3)
and the Russian Academy of Sciences (the Presidium of
RAS Program No. 8).
1ꢀ(1ꢀTrifluoromethylcyclohexyl)pyrrolidine (4c). B.p.
125—130 °C (bath temperature; 25 Torr). Found (%): C, 59.63;
H, 8.45; N, 6.52. C11H18F3N (221.26). Calculated (%): C, 59.71;
References
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H, 8.20; N, 6.33. H NMR, δ: 1.10—1.30 (m, 1 H); 1.37—1.59
(m, 6 H); 1.61—1.80 (m, 5 H); 1.90—2.04 (m, 2 H) (7CH2);
2.81—2.95 (m, 4 H, CH2NCH2). 13C NMR, δ: 20.4 (CH2); 24.4
(CH2); 25.3 (CH2); 28.4 (q, CH2, JC,F = 1.6 Hz); 44.4 (q,
CH2NCH2, JC,F = 1.6 Hz); 59.7 (q, CCF3, JC,F = 21.5 Hz);
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1ꢀ(1ꢀPentafluorophenylcyclohexyl)pyrrolidine (4d) (see
Ref. 4). Chromatography with light petroleum—EtOAc, 15 : 1;
Rf 0.17 (light petroleum—EtOAc, 25 : 1).
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Reseived November 29, 2006;
in revised form April 11, 2007