Preparation of tri- and difluoromethylated amines from aldimines using (trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1021/ol061357w

Addition of a trifluoromethyl group into aldimines was accomplished using (trifluoromethyl)trimethylsilane with tetraalkylammonium fluorides as initiators, and the resulting adducts were converted to difluoromethylated imines in the presence of excess flu

Full text of DOI:10.1021/ol061357w

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3589-3592
Preparation of Tri- and
Difluoromethylated Amines from
Aldimines Using
(Trifluoromethyl)trimethylsilane
G. K. Surya Prakash,* Ryo Mogi, and George A. Olah
Loker Hydrocarbon Research Institute and Department of Chemistry,
UniVersity of Southern California, Los Angeles, California 90089-1661
gprakash@usc.edu
Received June 2, 2006
ABSTRACT
Addition of a trifluoromethyl group into aldimines was accomplished using (trifluoromethyl)trimethylsilane with tetraalkylammonium fluorides
as initiators, and the resulting adducts were converted to difluoromethylated imines in the presence of excess fluoride. The imines were
reduced to difluoromethylated amines using sodium borohydride.
Synthesis of tri- and difluoromethylated amines is important
because of their attractive properties in biological and
medicinal chemistry.1 One of the methods to synthesize
trifluoromethylated amines is by the addition of the CF3
moiety to imines. We have reported that (trifluoromethyl)-
trimethylsilane (TMSCF3) is an effective reagent for nucleo-
philic trifluoromethylation,2 and its applications have been
widely studied.3 However, in some studies, it was reported
that TMSCF3 does not work well for N-unactivated imines,
except in the case of reactive azirines,4 nitrones,5 and N-(tert-
butylsulfinyl)imines.6 In one study reported by Blazewski
et al., the addition of the CF3 group to N-unactivated imines
has been carried out using TMSCF3.7 They used TMS-
imidazole as an additive to trap the unstable intermediate
and obtained the trifluoromethylated amines only in moderate
yields. Yokoyama and Mochida have also reported the
nucleophilic addition of the CF3 moiety into N-unactivated
imines, using PhSCF3 and Et3GeNa.8
The introduction of the CF2H group into carbonyl com-
pounds with (difluoromethyl)dimethylphenylsilane (Me2PhSi-
CF2H) was reported by Hagiwara and Fuchikami.9 It was
difficult to break the Si-CF2H bond because of its shorter
bond length than that of the Si-CF3 bond, and the reactions
needed harsher conditions. However, no direct addition to
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, ReactiV-
ity, Application; Wiley-VCH: Weinheim, 2004. (b) Erickson, J. A.;
Mcloughlin, J. I. J. Org. Chem. 1995, 60, 1626. (c) Moore, W. R.;
Schatzman, G. L.; Jarvi, E. T.; Gross, R. S.; McCarthy, J. R. J. Am. Chem.
Soc. 1992, 114, 360. (d) Welch, J. T. The Effect of SelectiVe Fluorination
on ReactiVity in Organic and Bioorganic Chemistry; ACS Symposium Series
456; American Chemical Society: Washington, DC, 1991.
(2) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
1989, 111, 393.
(5) (a) Nelson, D. W.; Easley, R. A.; Pintea, B. N. V. Tetrahedron Lett.
1999, 40, 25. (b) Nelson, D. W.; Owen, J.; Hiraldo, D. J. Org. Chem. 2001,
66, 2572.
(6) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 40, 589. (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org.
Lett. 2001, 3, 2847. (c) Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc.
2002, 124, 6538.
(3) (a) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757. (b)
Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613. (c)Prakash, G.
K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123.
(7) Blazejewski, J.-C.; Anselmi, E.; Wilmshurst, M. P. Tetrahedron Lett.
1999, 40, 5475.
(4) Fe´lix, C. P.; Khatimi, N.; Laurent, A. J. Tetrahedron Lett. 1994, 35,
3303.
(8) Yokoyama, Y.; Mochida, K. Tetrahedron Lett. 1997, 38, 3443.
(9) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.
10.1021/ol061357w CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/11/2006

imines was reported. Recently, our group reported the intro-
duction of the CF2H group into alkyl halides (by nucleophilic
substitution) and carbonyl compounds (by addition) using
difluoromethyl phenyl sulfone or bromodifluoromethyl phen-
yl sulfone as a difluoromethyl anion equivalent.10a-c More
recently, Li and Hu have developed10d the addition of the
CF2H group into tert-butylsulfinylimines in high dia-
stereoselectivity. On the other hand, there are few methods
available to transform a CF3 group into a CF2H moiety.
Uneyama et al. reported defluorination from trifluoro-
methyl ketones to form difluoroenol silyl ethers by either
electrochemical reduction11 or reduction with Mg(0)12 in the
presence of TMSCl. We have optimized the reaction condi-
tions further, for successful transformation of difluoroenol
silyl ethers to difluoromethyl ketones.13 These reactions
have also been applied to trifluoromethylated imines14 and
arenes.15 Other methods to prepare difluoromethylenolates
include the reaction of trifluoromethyl ketones with dimeth-
yl-(phenyl)silyllithium16 and trifluoromethyl alcohols with
butyllithium.17 Furthermore, 1,1-bis(dimethylamino)-2,2,2-
trifluoroethane can be converted to N,N-dimethyldifluoro-
acetamide using n-butyllithium,18 and trifluoromethylated
pyridines can be converted to the corresponding difluoro-
methylated pyridines by 1,8-diazabicyclo[5,4,0]undece-7-ene
(DBU).19 Herein, we report a simple method for the
introduction of the CF3 moiety into imines using TMSCF3
and further conversion of the CF3 group to CF2H- via a
HF elimination and reduction sequence.
as a solvent (Table 1, entry 2) and also that tetramethylam-
monium fluoride (TMAF) could be used as an initiator (Table
1, entry 3). However, CsF did not work as an initiator (Table
1, entry 4) nor did fluorotriphenylsilane have any effect in
promoting the reaction (Table 1, entry 5). The use of the
tetraalkylammonium salts is important to accomplish the
reactions. In the case of imine 1b, TMS-protected intermedi-
ate 2b was stable enough to be isolated (Table 1, entries 6
and 7).
Subsequently, we applied the methodology to other imine
derivatives (Table 2). The reactions were carried out with 1
-
Table 2. Introduction of CF3 into Various Imines
1
R1
R2
TBAT (equiv)
3 (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
4-Me-Ph
4-MeO-Ph
4-Cl-Ph
4-F-Ph
4-Br-Ph
2,4-Cl2-Ph
2-F-Ph
2-Br-Ph
c-C6H11
t-Bu
Ph
4-MeO-Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.15
0.15
0.15
0.15
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
75
72
46
38
54
67
50
77
74
83
47
trace
10
11
12
1j
1k
1l
Ph
Ph
Ph
a Isolated yields.
The reaction of benzylideneaniline 1a with TMSCF3 was
carried out using tetrabutylammonium triphenyl-difluoro-
silicate (TBAT) in THF at room temperature. The formation
of trifluoromethylated amine 2a was confirmed by H and
19F NMR in high yield (Table 1, entry 1). The reactions were
(1 mmol), TMSCF3 (213 mg, 1.5 mmol), and TBAT in 5
mL of THF at room temperature for 1 h. Benzylideneanilines
without any substituent on the aryl rings or with halogens
on them showed moderate to good yields. However, electron-
donating substituents on R1 resulted in lower yields (Table
2, entries 3 and 4). Two kinds of aliphatic aldimines were
tested, and imine 1k gave trifluorinated amine 3k in moderate
yield (Table 2, entry 11); however, imine 1l did not work
well (Table 2, entry 12).
1
Table 1. Modification of Reaction Conditions for the
-
Introduction of CF3 into Imines
Surprisingly, when the trifluoromethylation of 4-Cl de-
rivative 1e was carried out with 0.15 equiv of TBAT, the
(10) (a) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett.
2004, 6, 4315. (b) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur.
J. Org. Chem. 2005, 2218. (c) Prakash, G. K. S.; Wang, Y.; Hu, J.; Olah,
G. A. J. Fluorine Chem. 2005, 126, 1361. (d) Li, Y.; Hu, J. Angew. Chem.,
Int. Ed. 2005, 44, 5882.
(11) Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J. Org. Chem.
1999, 64, 6717.
(12) (a) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323. (b) Hata, H.; Kobayashi, T.; Amii, H.; Uneyama,
K.; Welch, J. T. Tetrahedron Lett. 2002, 43, 6099.
(13) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Fluorine Chem. 2001,
112, 357.
(14) (a) Uneyama, K.; Kato, T. Tetrahedron Lett. 1998, 39, 587. (b) Mae,
M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893. (c) Mae,
M.; Matsuura, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002, 43, 2069.
(15) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J. Org. Chem. 2001,
66, 7216.
1
R1
R2
F-
TBAT
TBAT
TMAF
CsF
solvent 2a (%) 3a (%)
1
2
3
4
5
6
7
1a Ph Ph
1a Ph Ph
1a Ph Ph
1a Ph Ph
1a Ph Ph
THF
92
-
DMF 75
-
THF
THF
THF
THF
THF
72
25
25
86 (59b)
(21)
12
-
11
-
CsF/Ph3SiF
1b Ph 4-MeO-Ph TBAT
1b Ph 4-MeO-Ph TMAF
(19)
a Yields were estimated by H NMR of reaction crudes. Isolated yields
1
after aqueous workup are shown in parentheses. b A mixture with Ph3SiF.
carried out with 1 (1 mmol) and F- sources (0.15 mmol) in
5 mL of solvent at room temperature for 1 h.
This is the first example of the introduction of the CF3
group into N-unactivated imines in a simple and straight-
forward manner. It was confirmed that DMF could be used
(16) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin Trans.
1, 1998, 1215.
(17) Qian, C.-P.; Nakai, T. Tetrahedron Lett. 1988, 29, 4119.
(18) Xu, Y.; Dolbier, W. R., Jr.; Rong, X. X. J. Org. Chem. 1997, 62,
1576.
(19) Lee, L. F.; Stikes, G. L.; Molyneaux, J. M.; Sing, Y. L.; Chupp, J.
P.; Woodard, S. S. J. Org. Chem. 1990, 55, 2872.
3590
Org. Lett., Vol. 8, No. 16, 2006

1
CF2H moiety was identified in the H and 19F NMR of the
crude product. We investigated this product carefully and
optimized the reaction conditions. Difluoromethyl imines 4e
were obtained as a 1:1 mixture of syn and anti isomers by
the reaction of 1e and TMSCF3 with 0.5 equiv of TMAF.
Some of the imine 4e was hydrolyzed to the corresponding
difluoromethyl ketone 5e during the workup and on purifica-
tion over silica gel column chromatography. The plausible
mechanism for the formation of difluoromethylated imine
is shown in Scheme 1. The elimination of HF from TMS-
Scheme 2
Scheme 1
gave difluoromethylated amines 8 in moderate to good yields
(Table 3). The reactions were carried out with 1 (1.0 mmol),
Table 3. Direct Preparation of Difluorinated Amines from
Imines
1
R1
R2
TMAF (equiv) 8 (%)a 3 (%)a
protected amine 2e can give rise to the difluoroenamine
intermediate 7e. Subsequently, the nucleophile (F-) can
attack the Si atom of the TMS group of 7e, and the resulting
species react with a proton to give the difluoromethylimine
4e or with unreacted starting material 1e to give the dimer
product 6e. The preparation of trimethylsilylated difluoro-
enamines, such as the intermediate 7e, was reported earlier
by Uneyama et al.14 They isolated the difluoroenamines and
investigated the reactions with some nucleophiles (PhLi,
ROH, F-) and electrophiles (H+, RCHO, R-I, PhSCl,
PhSeF). Under our reaction conditions, nucleophile F- is
already present in the reaction media; therefore, the conver-
sion of enamine 7e to difluoromethylimine 4e takes place
in situ.
1
2
3
4
5
6
7
8
9
1a Ph
1b Ph
1e 4-Cl-Ph
1f 4-F-Ph
1g 4-Br-Ph
Ph
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
0.5
0.5
62
37
78
79
63
58
35
trace
0
-
-
-
-
-
6
23
46
34
23b
4-MeO-Ph
Ph
Ph
Ph
1h 2,4-Cl2-Ph Ph
1i 2-F-Ph
1j 2-Br-Ph
1k c-C6H11
Ph
Ph
Ph
Ph
10 1l t-Bu
0
a Isolated yields. b (CH3)3CCH2NHPh, which was the reduction product
of 1l, was also obtained in 26% yield.
TMSCF3 (213 mg, 1.5 mmol), and TMAF in 5 mL of THF
at room temperature for 1 h, followed by treatment with
NaBH4 (757 mg, 20 mmol) in 10 mL of EtOH at room
temperature for 1 h.
In the case of 2-substituted phenyl imines such as 1i and
1j, the conversion of the CF3 group into the CF2H moiety
was suppressed even with 1.0 equiv of TMAF, and trifluo-
romethylated amines 3i and 3j were recovered (Table 3,
entries 7 and 8). We also attempted to extend this reaction
to aliphatic imines; however, the conversion to the CF2H
amine did not occur with these substrates (Table 3, entries
9 and 10).
In summary, TMSCF3 can be used for the introduction of
the CF3 moiety into N-unactivated imines using tetraalkyl-
ammonium fluorides as initiators. The reaction can be carried
out at ambient temperature, is easy to handle, and gives the
trifluoromethylated amines in moderate to good yields.
Furthermore, difluoromethylated amines can be prepared
The elimination of HF from 2e needs a base, and the actual
species which is acting as a base in the reaction medium
must be F-. To confirm the reaction pathway, we studied
some reactions as shown in Scheme 2. The reaction of imine
1e with TMSCF3 using 0.05 equiv of TBAT was carried out
in THF at room temperature for 0.5 h, followed by the
addition of 1.0 equiv of triethylamine. The mixture was
stirred for another 0.5 h. The formation of the CF2H- moiety
1
was confirmed by H and 19F NMR. On the other hand,
treatment of trifluoromethylated amine 3e with 0.5 equiv of
TMAF or 1.0 equiv of triethylamine resulted in no reaction.
According to these results, the actual species, which is
converted to difluoroenamine 7, is not free amine 4 but the
TMS-protected amine 2.
It was difficult to isolate difluoroimines 4 in high yield
because of their reactivity toward water and silica gel.
Therefore, we directly reduced the intermediate imines to
the corresponding difluoromethylamines by NaBH4. This
Org. Lett., Vol. 8, No. 16, 2006
3591

directly from imines and TMSCF3 using half a molar amount
of TMAF, followed by the reduction with NaBH4. The
mechanism involves the elimination of HF from TMS-
protected trifluoromethylated amines to provide the difluo-
romethylimine intermediate (through the difluoromethyl
enamine), which is reduced by sodium borohydride to the
difluoromethylated amine product.
edged. R. Mogi thanks Kanto Denka Kogyo Co., Ltd. for
the financial support and sponsorship.
Supporting Information Available: General experimen-
tal paragraph; experimental procedures for the preparation
of 3 and 8; 1H, 19F, 13C NMR and mass characterization data
of the isolated products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support of our work in part by the
Loker Hydrocarbon Research Institute is gratefully acknowl-
OL061357W
3592
Org. Lett., Vol. 8, No. 16, 2006