Nucleophilic fluoroalkylation of iminium salts

Article abstract of DOI:10.1016/j.tetlet.2008.03.043

Iminium cations generated by the coupling of aldehydes, N-trimethylsilylamines and TMSOTf or by the methylation of imines with MeOTf smoothly react with silanes of a general formula Me₃SiR_f (R_f = CF₃, CCl_2<

Full text of DOI:10.1016/j.tetlet.2008.03.043

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Tetrahedron Letters 49 (2008) 3108–3111
Nucleophilic fluoroalkylation of iminium salts
a
b
c
a,
*
Vitalij V. Levin , Mikhail A. Kozlov , Young-Hun Song , Alexander D. Dilman ,
Pavel A. Belyakov a, Marina I. Struchkova a, Vladimir A. Tartakovsky a
a N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky Prospect 47, Russia
b Moscow Chemical Lyceum, 111033 Moscow, Tamozhennyj Proezd, 4, Russia
c Korea Science Academy, 111 Baekyang Gwanmun Ro, Busanjin-Gu, Busan, Republic of Korea
Received 23 January 2008; revised 20 February 2008; accepted 7 March 2008
Available online 12 March 2008
Abstract
Iminium cations generated by the coupling of aldehydes, N-trimethylsilylamines and TMSOTf or by the methylation of imines with
MeOTf smoothly react with silanes of a general formula Me3SiRf (Rf = CF3, CCl2F, C6F5) to afford the corresponding tertiary amines
having a fluorinated substituent. The key step, involving C–C bond formation, is promoted by NaOAc or KF in DMF as a solvent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Iminium ions; Imines; Fluorinated silanes; Lewis bases
Amines containing a trifluoromethyl group1 or another
fluorinated substituent2 at the a-position have attracted
significant attention due to their diverse biological activity.
Recently, we proposed a new approach for the synthesis of
C6F5-substituted amines based on the transfer of a C6F5
group from silicon to iminium cations.3 This methodology
requires the use of sophisticated silanes (e.g., (C6F5)3-
SiX,3a–g C6F5SiF33h) in combination with mild Lewis bases.
However, the same approach cannot conveniently be used
for transferring trifluoromethyl or other fluorinated groups
owing to the difficulties in synthesizing the corresponding
silicon reagents.
At the same time, trifluoromethyltrimethylsilane,
Me3SiCF3, has found numerous applications4 for the tri-
fluoromethylation of carbonyl compounds5 and imines.6
During our studies of the reactions of enamines with differ-
ent silanes, we noted that reagents such as Me3SiCF3 and
Me3SiC6F5 were able to serve as a source of fluorinated
groups for the iminium cations, though the yields of the
desired products were moderate.7 Herein, we report a
R2
R3
O
N
Me3SiOTf
(a)
+
R1
SiMe3
R2
R1
R3
R2
R3
R2
R1
R3
Rf
N
Rf SiMe3
X
N
N
Me
Rf Si
Me Me
R1
R3
+
(b)
X
TfO
N
R2 OTf
X = OAc, F
R1
Scheme 1.
*
Corresponding author. Fax: +7 499 135 53 28.
E-mail address: adil25@mail.ru (A. D. Dilman).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.043

V. V. Levin et al. / Tetrahedron Letters 49 (2008) 3108–3111
3109
convenient method for the transfer of CF3, C6F5 and
CCl2F groups from the readily available trimethylsilyl
reagents to iminium cations.8
Me3SiCF3, Makosza and co-workers reported the applica-
tion of potassium fluoride in dichloromethane in the pres-
ence of 0.3 equiv of Ph3SnF as a phase transfer catalyst.11
The applicability of acetate anions for the activation of
fluorinated silanes was first disclosed by Mukaiyama in
2005, and it was demonstrated that acetate anions may
work in the form of alkali salts (lithium, sodium and potas-
sium) only if DMF is used as a solvent.12 Consequently, for
the reaction of iminium salts with silanes we decided to test
alkali fluorides and acetates in DMF.
The generation of iminium triflates from aldehydes 1
and N-trimethylsilylpyrrolidine proceeded smoothly in
the presence of Me3SiOTf in dichloromethane.13 Next, a
change of solvent to DMF and the addition of the silane
and Lewis base afforded amines 2 (Table 1).
For the generation of iminium salts, two procedures were
exploited: the reaction of aldehydes with N-trimethylsilyl-
amines in the presence of Me3SiOTf (path a)9 and the alkyl-
ation of imines with a strong alkylating agent (path b)
(Scheme 1). For the activation of fluorinated silanes, acetate
and fluoride ions were used.10 The C–C bond forming event
is likely to occur in a tight ion pair consisting of the iminium
cation and a five-coordinate siliconate anion.3b
The selection of Lewis base deserves special comment.
Fluoride is the most efficient activator, which is frequently
used in the form of Bu4NF, Me4NF or Bu4NPh3SiF2.4,6
Since for the interaction of silanes with iminium ions a stoi-
chiometric amount of fluoride is required, we sought condi-
tions that made use of cheaper and more convenient
fluoride sources, such as alkali fluorides. Recently, for the
reaction of quinolinium and pyridinium salts with
Sodium acetate and potassium fluoride appeared to be
equally effective Lewis bases, though fluoride provided
higher yields for more reactive electrophilic iminium ions.
Thus, in the case of p-nitrobenzaldehyde, which forms a
Table 1
Interaction of aldehydes, N-trimethylsilylpyrrolidine and fluorinated silanesa
N
SiMe3
O
Rf
SiMe3
N
N
R
Me3SiOTf
R
Lewis base
DMF, r.t.
R
Rf
1
CH2Cl2, 0 ºC → r.t.
2
TfO
Timeb (h)
Entry
R
Rf
Lewis basec
2
Yield of 2d (%)
1
2
3
4
5
6
7
8e
9e
a
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
1a
1a
1a
1a
1b
1c
1c
CF3
CF3
CF3
C6F5
CCl2F
CCl3
CF3
CF3
CF3
1
1
1
1
1
1
1
18
18
NaOAc
KF
NaF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KF
2a
2a
2a
2b
2c
2d
2e
2f
78
76
—
62
90
72
70
28
68
p-MeOC6H4
p-O2NC6H4
p-O2NC6H4
2f
Unless stated otherwise, the generation of iminium ions was performed for 30 min, the ratio of reagents 1:amine:Me3SiOTf:RfSiMe3 = 1:1.2:1.2:1.5.
b
c
Time for the reaction of the iminium salt with the fluorinated silane.
For NaOAc, 2 equiv; for KF or NaF, 1.5 equiv.
Isolated yield.
d
e
Time for the generation of the iminium ion was 2 h.
O
NEt2
CCl2F
1. Me3SiOTf, CH2Cl2
30 min, r.t.
Me3Si NEt2
+
2. Me3SiCCl2F, AcONa
DMF, 1 h, r.t.
1a
3
92%
O
N
O
1. Me3SiOTf, CH2Cl2
1 h, r.t.
O
+
N
SiMe3
2. Me3SiCF3, KF
DMF, 18 h, r.t.
CF3
O2N
1c
O2N
4
35%
Scheme 2.

3110
V. V. Levin et al. / Tetrahedron Letters 49 (2008) 3108–3111
less stable cation, NaOAc and KF gave the desired amine
in 28% and 68% yields, respectively (entries 8 and 9). The
latter phenomenon may be associated with the stronger
affinity of fluorine to silicon. This method can be applied
for the synthesis of amines bearing CF3, C6F5, CCl2F
and CCl3 groups.14
N-Trimethylsilyl derivatives of diethylamine and mor-
pholine can also be used in the reaction with aldehydes
and fluorinated silanes (Scheme 2). The diminished yield
(35%) of product 4 obtained from p-nitrobenzaldehyde
and N-silylmorpholine is, apparently, due to the significant
electrophilicity of the intermediate iminium cation, which
O
1. Me3SiOTf, CH2Cl2
Ph
Me
Me
Rf
30 min, r.t.
N
N
+
+
2. Me3SiRf, Lewis base,
DMF, 2 h, r.t.
Ph
Rf
Ph
2g,h
5g,h
N
SiMe3
Rf = CF3, Lewis base = NaOAc
Rf = C6F5, Lewis base = NaOAc 72%
Rf = C6F5, Lewis base = KF
48%
12%
22%
32%
36%
Scheme 3.
Table 2
The synthesis of amines 7 from iminesa
R2
R2
Me
R2
Rf
Me
Rf
MeOTf, CH2Cl2
SiMe3
N
N
N
R1
—20 ºC → r.t.
R1
7
R1
NaOAc or KF
DMF, r.t.
TfO
6
Time 1
Time 2
Entry
1
Imine
6
Rf
Time 1
15 min
Time 2 (h)
Lewis baseb
NaOAc
Product
Yieldc (%)
64
N
OMe
6a
CF3
2
7a
S
N Bn
2
3
4
6b
6b
6b
CF3
CF3
C6F5
30 min
30 min
15 min
2
2
1.5
NaOAc
KF
NaOAc
7b
7b
7c
67
81
80
N Bn
5
6
7
6c
6c
6c
CF3
CCl2F
C6F5
15 min
15 min
15 min
1
1
1.5
NaOAc
NaOAc
NaOAc
7d
7e
7f
73
89
85
MeO
N Bn
8
9
6d
6d
CF3
CF3
30 min
30 min
1
1
NaOAc
KF
7g
7g
34
62
10
6e
CF3
30 min
1
KF
7h
77
N
Bn
Ph
Ph
N
11
12
6f
6f
CF3
CF3
30 min
30 min
1
1
NaOAc
KF
7i
7i
51
58
N
13
6g
CF3
18 h
2
KF
7j
67
OMe
N
14
15
a
6h
6h
CF3
C6F5
15 min
15 min
1
1
NaOAc
NaOAc
5g
5h
89
94
Me
Ratio of reagents 6:MeOTf:RfSiMe3 = 1:1.2:1.5.
For NaOAc, 2 equiv; for KF, 1.5 equiv.
Isolated yield.
b
c

V. V. Levin et al. / Tetrahedron Letters 49 (2008) 3108–3111
3111
517; (f) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Korlyukov, A. A.;
Struchkova, M. I.; Tartakovsky, V. A. Mendeleev Commun. 2007, 105;
(g) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Tetrahedron Lett. 2006, 47, 8959; (h) Dilman, A. D.;
Gorokhov, V. V.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V.
A. Tetrahedron Lett. 2006, 47, 6217.
may strongly bind fluoride anions in the form of
fluoroaminal.
An unexpected result was observed for the iminium cat-
ion derived from cinnamaldehyde and N-trimethylsilyl-
pyrrolidine (Scheme 3). In this case, besides the desired
amines 2g,h, dimethylamino derivatives 5g,h were obtained
in 12–32% yields. It is noteworthy that by using KF as the
Lewis base, the yield of the byproduct was nearly equal to
that of the desired pyrrolidine derivative.
In another approach to iminium salts, imines 6 were
treated with methyl triflate in dichloromethane. Subse-
quent change of the solvent to DMF and the addition of
the silane and Lewis base furnished fluorinated amines 7
(Table 2). As a rule, the products containing CF3, C6F5
and CCl2F groups were obtained in reasonable yields.15
Sodium acetate and potassium fluoride are effective acti-
vators for the reactions of non-enolizable substrates, such
as those derived from the aromatic and heteroaromatic
aldehydes, as well as pivalaldehyde. On the other hand,
for imines possessing a hydrogen atom adjacent to a
C@N bond, the use of potassium fluoride is preferable
(for example, compare entries 8 and 9).
4. For general reviews, 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.
5. For recent comprehensive studies, see: (a) Prakash, G. K. S.; Panja, C.;
Vaghoo, H.; Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.;
Mathew, T.; Olah, G. A. J. Org. Chem. 2006, 71, 6806; (b) Kawano,
Y.; Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 1133.
6. For recent papers, see: (a) Prakash, G. K. S.; Mogi, R.; Olah, G. A.
Org. Lett. 2006, 8, 3589; (b) 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.
7. Dilman, A. D.; Gorokhov, V. V.; Belyakov, P. A.; Struchkova, M. I.;
Tartakovsky, V. A. Russ. Chem. Bull. 2007, 56, 1522.
8. Me3SiCF3 and Me3SiC6F5 are commercially available. Me3SiCCl2F
can be easily made from Me3SiCl and FCCl3, see: Joste, R.; Ruppert,
I. J. Organomet. Chem. 1987, 329, 313.
9. (a) Schroth, W.; Jahn, U.; Stro¨hl, D. Chem. Ber. 1994, 127, 2013; (b)
Schroth, W.; Jahn, U. J. Prakt. Chem. 1998, 340, 287.
10. Though the interaction of a Lewis base with an iminium ion forming
the covalent semiaminal species can occur, this process is expected to
be reversible. (a) Bo¨hme, H.; Hilp, M. Chem. Ber. 1970, 103, 104; (b)
Knunyants, I. L.; Delyagina, N. I.; Igumnov, S. M. Izv. Akad. Nauk
SSSR Ser. Khim. 1981, 857 [Bull. Acad. Sci. USSR Div. Chem. Sci.
1981, 30, 637 (Engl. Transl.)].
11. Loska, R.; Majcher, M.; Makosza, M. J. Org. Chem. 2007, 72, 5574.
12. (a) Mukaiyama, T.; Kawano, Y.; Fujisawa, H. Chem. Lett. 2005, 34,
88; (b) Kawano, Y.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 2005,
34, 422; (c) Kawano, Y.; Mukaiyama, T. Chem. Lett. 2005, 34, 894;
(d) see also Ref. 5b.
In summary, we have reported a convenient method for
the synthesis of amines, bearing different fluorinated
groups at the a-carbon atom. The method is based on
the coupling of iminium salts with the readily available
fluorinated silicon reagents under mild conditions.
Acknowledgements
13. During this step the use of DMF is problematic, since it reacts with
TMSOTf leading to the silylium salt Me2NCHOSiMeþ3 OTfꢀ, see:
Bassindale, A. R.; Stout, T. Tetrahedron Lett. 1985, 26, 3403.
14. General procedure for the synthesis of amines 2: N-Trimethylsilylpyrr-
olidine (209 lL, 1.2 mmol) and TMSOTf (220 lL, 1.2 mmol) were
added successively to a solution of aldehyde 1 (1 mmol) in CH2Cl2
(2 mL) at 0 °C. The cooling bath was removed, the solution was
stirred for 30 min (for 1a,b) or 2 h (for 1c), and the solvent was
removed under vacuum. The residual salt was dissolved in DMF
(2 mL) followed by the successive addition of silane (1.5 mmol) and
Lewis base (NaOAc, 164 mg, 2.0 mmol or KF, 82 mg, 1.5 mmol). The
resulting suspension was stirred for the time indicated in Table 1. For
the work-up, saturated aqueous Na2CO3 (1 mL) was added dropwise,
the mixture was stirred for an additional two minutes, diluted with
water (10 mL) and extracted with ether/hexane (1:1, 3 ꢁ 5 mL). The
combined organic phase was filtered through Na2SO4, concentrated
under vacuum, and the crude product was chromatographed on a
silica gel eluting with hexanes/ethyl acetate.
15. General procedure for the synthesis of amines 7: Methyl triflate
(1.2 mmol, 136 lL) was added to a solution of imine 6 (1 mmol) in
CH2Cl2 (2 mL) at ꢀ20 °C. The cooling bath was removed, the
solution was stirred for the time indicated in Table 2, and the solvent
was removed under vacuum. The residual salt was dissolved in DMF
(2 mL) followed by the successive addition of silane (1.5 mmol) and
Lewis base (NaOAc, 164 mg, 2.0 mmol or KF, 82 mg, 1.5 mmol). The
resulting suspension was stirred for the time indicated in Table 2. For
the work-up, saturated aqueous Na2CO3 (1 mL) was added dropwise,
the mixture was stirred for an additional 2 min, then diluted with
water (10 mL) and extracted with ether/hexane (1:1, 3 ꢁ 5 mL). The
combined organic phase was filtered through Na2SO4, concentrated
under vacuum, and the crude product was chromatographed on a
silica gel eluting with hexanes/ethyl acetate.
This work was supported by the Ministry of Science
(Project MK-4483.2007.3), the Russian Academy of Sci-
ences (Program # 8), the Russian Foundation for Basic Re-
search (Project 08-03-00428) and the Russian Science
Support Foundation.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.043.
References and notes
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