Trifluoromethylation of enamines under acidic conditions

Article abstract of DOI:10.1016/j.tetlet.2009.03.187

A method for the trifluoromethylation of enamines using Me₃SiCF₃ leading to α-CF₃-substituted amines is described. The reaction is promoted by hydrofluoric acid generated from KHF₂ and either trifluoroacetic or

Full text of DOI:10.1016/j.tetlet.2009.03.187

Tetrahedron Letters 50 (2009) 2994–2997
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Trifluoromethylation of enamines under acidic conditions
*
Roman T. Gritsenko, Vitalij V. Levin, Alexander D. Dilman , Pavel A. Belyakov, Marina I. Struchkova,
Vladimir A. Tartakovsky
N.D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the trifluoromethylation of enamines using Me3SiCF3 leading to a-CF3-substituted amines is
Received 27 January 2009
Revised 17 March 2009
Accepted 27 March 2009
Available online 2 April 2009
described. The reaction is promoted by hydrofluoric acid generated from KHF2 and either trifluoroacetic
or triflic acid, and involves protonation of the enamine followed by transfer of the CF3-carbanion from the
silicon reagent to the cationic electrophile.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Enamines
Iminium ions
Trifluoromethylation
Amines bearing a trifluoromethyl group at the
a-position con-
KHF2 + HY
2HF + KY
stitute an important class of biologically active compounds.1
Among methods for the synthesis of these compounds,2 the ap-
proach based on the direct introduction of the CF3 group via nucle-
ophilic trifluoromethylation is arguably the most effective, owing
to the ready availability of electrophilic precursors with a C@N
bond.3–5 In the latter processes, the combination of trifluorometh-
yltrimethylsilane (Me3SiCF3, the Ruppert–Prakash reagent) and a
Lewis base serves as an equivalent of a trifluoromethyl carban-
ion.4–6
R2
R1
R2
R3
R2
R1
R2
N
N
2HF
Me3SiCF3
R3
R2
HF2
1
R2
R1
R2
R1
R2
R3
N
N
Me
F3C Si
Recently, we introduced a method for the nucleophilic trifluo-
romethylation of imines with Me3SiCF3 under acidic conditions,
where hydrofluoric acid, generated in situ, played the key role as
an activator.7 Herein we report the application of this methodology
F
– Me3SiF
– HF
F3C
R3
H
Me Me
F
2
for the trifluoromethylation of enamines leading to various
a-CF3-
Scheme 1.
substituted amines.8
The general mechanism of the reaction is shown in Scheme 1.
Hydrofluoric acid, which is generated in situ from potassium
hydrogen difluoride and a strong acid (TfOH or TFA), reversibly
protonates the enamine substrate 1 to give the iminium ion
and hydrodifluoride anion. Subsequent activation of the silane
followed by transfer of the CF3-group provides product 2.
According to this mechanism, the reaction should proceed faster
for enamines giving, upon protonation, more stable iminium
ions.
silicon reagent with the formation of trifluoromethane. Indeed,
earlier we tried to employ carboxylic acids of different
strengths, and even with the optimal conditions, the scope of
substrates was quite narrow and product yields were
moderate.9
Following our previous observations on reactions of imines,7 in
this work, we used two protocols for the trifluoromethylation of
enamines (Table 1). Method A, in which trifluoroacetic acid is used
to generate HF, is suitable for more reactive substrates, whereas
method B requiring expensive triflic acid and a larger excess of
the silane is more general and applicable for less reactive
enamines.
The use of HF is crucial, since it provides the optimal bal-
ance required for the activation of both the enamine and the si-
lane, and at the same time minimizing decomposition of the
* Corresponding author. Fax: +7 499 135 53 28.
E-mail address: adil25@mail.ru (A.D. Dilman).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.187

R. T. Gritsenko et al. / Tetrahedron Letters 50 (2009) 2994–2997
2995
Table 1
Trifluoromethylation of enamines 1
R2
R1
R2
R3
R2
R1
R2
R3
Me3SiCF3
acid, KHF2
Method Me3SiCF3
(eq.)
Acid
(eq.)
TFA (1.5) 1.0
KHF2
(eq.)
Solvent
MeCN
N
N
A
2.0
Solvent, r.t., 18 h
F3C
1
2
B
3.0
TfOH (1.6) 1.5 MeCN/3 eq. DMF
Entry
Substrate
Method
Product
Yield of 2,%a
O
Ph
N
1
1a
1b
A
A
2a
86
Ph
N
O
CF3
O
2b
2b
88
N
N
O
CF3
O
3b
1c
A
A
2c
71 (86)c
N
N
O
CF3
N
4
1d
2d
81
Ph
Ph
N
Ph
Ph
CF3
NEt2
CF3
NEt2
5
6
1e
1f
A
B
2e
2f
59
82
N
O
Ph OEt
N
O
7
8
A
B
71
87
F3C Ph
OEt
O
O
N
O
N
O
9
10
11
1g
B
B
B
2g
75
80
84
F3C Ph
Ph OEt
OEt
N
O
N
O
1h
1i
2h
2i
F3C
OMe
OMe
O
O
N
O
N
O
F3C
OMe
OMe
N
O
N
O
12
13
1j
A
B
2j
74
72
F3C
MeO
OMe
OMe
MeO
F3C
N
N
F3C
N
O
14
15
1k
A
B
2kd
78
90
CO2Et
CO2Et
OEt
88 : 12
(continued on next page)

2996
R. T. Gritsenko et al. / Tetrahedron Letters 50 (2009) 2994–2997
Table 1 (continued)
Entry
Substrate
Method
Product
Yield of 2,%a
16
17
1l
A
B
2l
36
55
Bn
Bn
NH
O
NH
O
F3C
OMe
OMe
a
Isolated yield.
Reaction time 6 h.
b
c
Yield is denoted in parentheses determined by NMR, the losses upon isolation are due to the volatility of the product.
The relative configurations were determined by 2D-NOESY experiments.
d
Enamines 1a–e derived from ketones and aldehydes gave
trifluoromethylated products 2a–e in good yields according to
method A (entries 1–5). The substrates 1f–k bearing an ester
group at the b-position also took part in the trifluoromethyla-
tion reaction affording products 2f–k, though in order to ob-
OEt
N
O
Bn
H
O
N
O
N
H
OMe
O
tain good yields, method
B should be used. The decreased
1l
1m
1n
reactivity of enamines 1f–k compared to that of enamines
1a–e is likely to be associated with the presence of the ester
group, which makes the formation of an iminium ion less
favorable. Thus, the protonation of ester-substituted enamines
can form cations 3–5 which exist in equilibrium, and subse-
quent reaction of either of these species can give the desired
product (Scheme 2).
Trifluoromethylation of substrate 1l containing an N–H frag-
ment gave the desired product 2l in moderate yields of 36–
55% (entries 16–17). Probably, the diminished reactivity of 1l
is due to the presence of an intramolecular hydrogen bond,
which imparts additional stability to the enamine and decreases
its basicity (Fig. 1). In this regard, we were surprised to find, that
the cyclic enamine 1m having a fixed anti arrangement of the
N–H and ester moieties, proved to be completely unreactive.
Compound 1n also did not undergo trifluoromethylation, even
under the conditions of method B. The latter observations sug-
gest that a cis-arrangement of amino and ester fragments may
be necessary for the reaction to proceed, presumably owing to
formation of a cyclic cationic intermediate species 5 stabilized
by a hydrogen bond.
Figure 1.
Me3SiCF3
MeO2C
CO2Me
TfOH, KHF2
N
OMe
MeCN/DMF, r.t.
O
CO2Me
1o
6 (46%)
Scheme 3.
In summary, a new method for the trifluoromethylation of en-
amines using the Ruppert–Prakash reagent has been described.11,12
The method gives high yields of products for reactions of conven-
tional enamines, as well as for enamines substituted with an ester
group. The key feature of the reaction is the transfer of a trifluoro-
methyl carbanion to the electrophilic species generated from en-
amines under acidic conditions.
In the reaction of substrate 1o containing an
a-hydrogen
atom at the enamine double bond, the trimethyl ester of ben-
zene-1,3,5-tricarboxylic acid 6 was obtained exclusively, while
the product of trifluoromethylation was detected only in a trace
amount (Scheme 3). The formation of 6 can be readily explained
by the increased reactivity of the sterically unhindered iminium
cation that interacts with enamine 1o, leading to trimerization
and aromatization.10
Acknowledgments
This work was supported by the Russian Academy of Sciences
(Program # 18), Ministry of Science, Russian Foundation for Basic
Research (Project 08-03-00428), and the Russian Science Support
Foundation.
R2
N
OH
R1 OMe
R2
R2
N
R2
R1
R2
4
R2
R1
R2
N
O
O
"CF3
"
R2
H
N
O
R1 OMe
OMe
OMe
F3C
3
R2
N
R2
H
O
R1
OMe
5
Scheme 2.

R. T. Gritsenko et al. / Tetrahedron Letters 50 (2009) 2994–2997
2997
Chem. 2008, 73, 5643; (c) Levin, V. V.; Kozlov, M. A.; Song, Y.-H.; Dilman, A.
D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett.
2008, 49, 3108.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.187.
6. For reviews on the chemistry of Me3SiCF3, see: (a) Prakash, G. K. S.; Yudin, A. K.
Chem. Rev. 1997, 97, 757; (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123; (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
7. Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Eur. J. Org. Chem. 2008, 5226.
References and notes
8. For the pentafluorophenylation of enamines with (C6F5)3SiX reagents, see: (a)
Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Synthesis 2006, 447; (b) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Korlyukov, A.
A.; Struchkova, M. I.; Tartakovsky, V. A. Mendeleev Commun. 2007, 105.
9. Dilman, A. D.; Gorokhov, V. V.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky,
A. D. Russ. Chem. Bull. 2007, 56, 1522.
10. In a reference experiment, when enamine 1o was treated with KHF2/TfOH in
MeCN/DMF, compound 6 was obtained in 48% yield. Similar acid-catalyzed
trimerization of 3-dialkylaminoacrylic esters to benzenetricarboxylic esters
has been described, see: Al-Saleh, B.; Makhseed, S.; Hassaneen, H. M. E.;
Elnagdi, M. H. Synthesis 2006, 59.
1. (a) Sani, M.; Volonterio, A.; Zanda, M. Chem. Med. Chem. 2007, 2, 1693;
(b) Leger, S.; Bayly, C. I.; Black, W. C.; Desmarais, S.; Falgueyret, J.-P.;
Masse, F.; Percival, M. D.; Truchon, J.-F. Bioorg. Med. Chem. Lett. 2007,
17, 4328; (c) Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Criscione, K. R. J.
Med. Chem. 1999, 42, 3315; (d) Faraci, W. S.; Walsh, C. T. Biochemistry
1989, 28, 431.
2. For methods based on addition to trifluoroacetaldehyde derivatives, see: (a)
Langlois, B. R.; Billard, T. Synthesis 2003, 185; (b) Bégué, J.-P.; Bonnet-Delpon,
D.; Crousse, B.; Legros, J. Chem. Soc. Rev. 2005, 34, 562; (c) Xu, Y.; Dolbier, W. R.
J. Org. Chem. 2000, 65, 2134.
11. All reactions were performed in conventional glass vessels. No deterioration of
reaction flasks, even after prolonged use, was noted. Presumably, HF formed
in situ reacts faster with the silicon reagent than with the glass surface.
3. (a) Xu, W.; Dolbier, W. R., Jr J. Org. Chem. 2005, 70, 4741; (b) Pooput,
C.,
; Dolbier, W. R., Jr; Medebielle, M. J. Org. Chem. 2006, 71, 3564; (c)
Motherwell, W. B.; Storey, L. J. J. Fluorine Chem. 2005, 126, 489; (d)
Yokoyama, Y.; Mochida, K. Tetrahedron Lett. 1997, 38, 3443; (e) Langlois,
B. R.; Billard, T.; Roussel, S. J. Fluorine Chem. 2005, 126, 173; (f)
Langlois, B. R.; Billard, T. Synthesis 2003, 185; (g) Nowak, I.; Robins, M.
J. J. Org. Chem. 2007, 72, 2678; (h) Ma, J.-A.; Cahard, D. J. Fluorine Chem.
2007, 128, 975.
12. General procedures. Method A. Trifluoroacetic acid (116 lL, 1.5 mmol) was
added to a mixture of enamine (1 mmol) and KHF2 (78 mg, 1.0 mmol) in
acetonitrile (2 mL) at 0 °C, and the suspension was stirred for 5 min.
Me3SiCF3 (295 lL, 2.0 mmol) was added, the cooling bath was removed, and
the mixture was stirred for 18 h (or 6 h for enamines 1b,c) at room
temperature. For the work-up, saturated aqueous Na2CO3 (0.5 mL) was
added dropwise, the mixture was stirred for an additional two minutes,
diluted with water (7 mL) and extracted with ether/hexane (1:1, 3 Â 5 mL).
The combined organic phase was filtered through Na2SO4, concentrated
under vacuum, and the crude product was chromatographed on silica gel.
4. (a) Petrov, V. A. Tetrahedron Lett. 2000, 41, 6959; (b) Prakash, G. K. S.; Mandal,
M.; Olah, G. A. Synlett 2001, 77; (c) Prakash, G. K. S.; Mogi, R.; Olah, G. A. Org.
Lett. 2006, 8, 3589; (d) Kirij, N. V.; Babadzhanova, L. A.; Movchun, V. N.;
Yagupolskii, Y. L.; Tyrra, W.; Naumann, D.; Fischer, H. T. M.; Scherer, H. J.
Fluorine Chem. 2008, 129, 14; (e) Blazejewski, J.-C.; Anselmi, E.; Wilmshurst, M.
Tetrahedron Lett. 1999, 40, 5475; (f) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2006, 79, 1133.
5. For results from our group, see: (a) Dilman, A. D.; Arkhipov, D. E.; Levin, V.
V.; Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J.
Org. Chem. 2007, 72, 8604; (b) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org.
Method B. Triflic acid (142
enamine (1 mmol) and KHF2 (117 mg, 1.5 mmol) in acetonitrile (2 mL) and
DMF (232 L, 3 mmol) at 0 °C, and the suspension was stirred for 5 min.
Me3SiCF3 (443 L, 3.0 mmol) was added, the cooling bath was removed, and
lL, 1.6 mmol) was added to a mixture of
l
l
the mixture was stirred for 18 h at room temperature. The work-up was the
same as in method A.