Facile synthesis of 1,1-gem-dialkylperfluoroalkylamines

Article abstract of DOI:10.1016/S0022-1139(02)00168-9

Tertiary 1,1-gem-dialkylperfluoroalkylamines were prepared by treatment of perfluoroalkylcarboxamides with alkylcerium chlorides, generated from cerium chloride and alkyllithium or alkyl Grignard reagents. The products were easily isolated as the hydrochl

Full text of DOI:10.1016/S0022-1139(02)00168-9

Journal of Fluorine Chemistry 117 (2002) 9±11
Facile synthesis of 1,1-gem-dialkylper¯uoroalkylamines
*
Nan Zhang , Semiramis Ayral-Kaloustian
Chemical Sciences, Wyeth Research, Pearl River, New York, NY 10965, USA
Received 7 June 2002; received in revised form 28 June 2002; accepted 1 July 2002
Abstract
Tertiary 1,1-gem-dialkylper¯uoroalkylamines were prepared by treatment of per¯uoroalkylcarboxamides with alkylcerium chlorides,
generated from cerium chloride and alkyllithium or alkyl Grignard reagents. The products were easily isolated as the hydrochloride salts.
Higher yields were obtained with alkyllithium than with alkyl Grignard reagents.
#
2002 Elsevier Science B.V. All rights reserved.
Keywords: 1,1-gem-Dialkylper¯uoroalkylamines; Per¯uoroalkylcarboxamides; Alkylcerium chlorides; bis-Alkylation
1
. Introduction
gem-dialkylper¯uoroalkylamines known in the literature
include 2-(per¯uorohexyl)-2-aminopropane and 2-(per¯uor-
ooctyl)-2-aminopropane, prepared by a radical chain
reaction followed by reduction [8], and 1,1-gem-diallylper-
¯uorooctylamines, obtained in low yield by reaction of per-
¯uoroalkyl nitriles with triallyltin ¯uoride [9]. Recent
developments in direct nucleophilic tri¯uoromethylation
(for a review, see [10]) with (tri¯uoromethyl)trimethylsilane
Fluorine-containing amines play an important role in
pharmaceutical and agricultural research due to their unique
biological and pharmacological properties (for reviews, see
[
1±3]). Synthesis of ¯uoroalkyl-amines has attracted great
attention (for reviews, see [2±4]). A practical synthesis of
uoroalkyl- and ¯uoroaryl-amines has been reported by
¯
Soloshonok, et al. [5] through a base-catalyzed [1,3] proton
shift reaction from ¯uoro-containing aldehydes or ketones
(TMSCF ) provide a general approach to various tri¯uro-
3
methyl-containing amine derivatives, including tri¯uoro-
methylaziridines [11], a-tri¯uoromethylated anilines [12],
etc. Now, we report a convenient, general synthesis of 1,1-
gem-dialkylper¯uoroalkylamines by reaction of per¯uoroalk-
ylcarboxamides with alkylcerium chlorides. The method is
complimentary to the approach reported by Soloshonok, et al.
(
or their hydrates). The method is general and ef®cient to
prepare primary and secondary ¯uoroalkyl- and ¯uoroaryl-
amines in which the carbon adjacent to the amine (C-1) has
one or two hydrogens.
[5] in product structural types.
2. Results and discussion
We were interested in preparing a series of tertiary 1,1-
gem-dialkylper¯uoroalkylamines in which the C-1 has no
hydrogen. The most simple analogue, 2,2,2-tri¯uoro-1,1-
dimethylethylamine, is known in the literature [6,7], pre-
pared in 35% yield by treatment of 2-aminoisobutyric
acid with sulfur tetra¯uoride in hydrogen ¯uoride at
It was reported that benzamides and thiobenzamides can
be dehydrated to benzonitriles and further converted into
tertiary carbinamines by treatment with methylcerium chlor-
ide generated from cerium chloride and methyllithium [13].
We extended this method to the synthesis of 1,1-gem-dia-
lkylper¯uoroalkylamines by reaction of per¯uoroalkylcar-
boxamides with alkylcerium chlorides generated from
cerium chloride and methyllithium or ethylmagnesium
chloride at À78 8C. After completion of the reaction, the
mixture was quenched with a small quantity of water. The
amine product was obtained together with reaction solvents
by distillation. Acidi®cation followed by removal of the
1
20 8C. The reaction conditions are harsh and the reagents
corrosive. Furthermore, the method is not generally applic-
able to synthesis of 1,1-gem-dialkylper¯uoroalkylamines
with other ¯uoroalkyl groups. Other examples of 1,1-
*
Corresponding author. Tel.: ‡1-845-602-3425; fax: ‡1-845-602-5561.
E-mail address: zhangn@wyeth.com (N. Zhang).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 6 8 - 9

10
N. Zhang, S. Ayral-Kaloustian / Journal of Fluorine Chemistry 117 (2002) 9±11
solvents provided the desired 1,1-gem-dialkylper¯uoroalk-
ylamines as the hydrochloride salts.
(30 mmol) in diethyl ether or ethylmagnesium chloride
(30 mmol) in THF was added dropwise. The mixture was
stirred at À78 8C for 30 min, and a solution of per¯uoroalk-
ylcarboxamide (6 mmol) in THF (10 ml) was added dropwise.
Stirring was continued at À78 8C for 1 h, and the reaction was
gradually warmed to room temperature. Water (0.5 ml) was
added, and the mixture was ®ltered through Celite. The ®ltrate
was transferred to a distillation apparatus. Distillation pro-
vided the amine together with reaction solvents (collected in a
cold trap). Hydrogen chloride gas was then bubbled through
this solution. Removal of the solvents gave the desired 1,1-
gem-dialkylper¯uoroalkylamine as a hydrochloride salt,
which was washed with a small amount of hexanes and dried.
a
Entry
Rf
RLi or RMgCl
Yield (%)
a
b
c
d
a
CF3
MeLi
MeLi
MeLi
EtMgCl
80
67
62
36
CF CF
3
2
CF CF CF
3
2
2
CF3
3.2.1. 2,2,2-Trifluoro-1,1-dimethylethylamine
hydrochloride (2a)
Isolated yields.
White crystals: mp > 200 8C (sublimed). IR (KBr): n 1053,
1172, 1401, 1533, 1600, 2578, 2800, 2854, 2904 cm . H
À1
1
As shown in the table earlier, good yields were obtained
with methylcerium chloride generated from methyllithium
NMR (400 MHz, CDCl ): d 1.66 (s, 6H, CH ), 9.23 (s, 3H,
3
3
1
3
(
entry a±c). However, treatment of 1a with ethylcerium
chloride generated from ethylmagnesium chloride provided
d in a much lower yield (entry d). The lower yield is
NH3). C NMR (100 MHz, CDCl ): d 20.0 (s, CH ), 56.9 (q,
3
3
19
J ˆ 26:6 Hz, C-1). F NMR (376.5 MHz, CDCl ): d À81.6
3
‡
2
(s, 3F, CF ). MS (electrospray, 20 eV) m/z: 128.1 (M ‡ H) .
3
probably due to low reactivity of Grignard reagents, since a
similarly low yield of 2a was obtained from the reaction of
Anal. calcd. for C H ClF N: C, 29.37; H, 5.55; N, 8.56.
4
9
3
Found: C, 29.34; H, 5.60; N, 8.69.
1
nesium chloride.
a with methylcerium chloride generated from methylmag-
3.2.2. 2,2,3,3,3-Pentafluoro-1,1-dimethylpropylamine
hydrochloride (2b)
In conclusion, we have developed a convenient, general
synthesis of 1,1-gem-dialkylper¯uoroalkylamines by reac-
tion of per¯uoroalkylcarboxamides with alkylcerium chlor-
ides. Using this method, we have prepared tertiary
per¯uoroalkylamines that are either unknown in the litera-
ture or were previously prepared in lower yield under much
harsher conditions. This approach is complimentary to the
base-catalyzed [1,3] proton shift reaction [5] in product
structural types.
Off-white crystals: mp > 200 8C (sublimed). IR (KBr): n
1013, 1147, 1210, 1529, 2800, 2854, 2926 cm . H NMR
À1
1
(400 MHz, CDCl ): d 1.75 (s, 6H, CH ), 9.29 (s, 3H, NH ).
3
3
3
1
3
C NMR (100 MHz, CDCl ): d 20.5 (s, CH ), 57.7 (q,
3
3
J ˆ 22:4 Hz, C-1), 113.6 (tq, J ˆ 262:2, 37.2 Hz, CF ),
2
1
9
118.6 (qt, J ˆ 287:2, 35.1 Hz, CF ).
F
NMR
3
(376.5 MHz, CDCl ): d À79.0 (s, 3F, CF ), À123.2 (s,
3
3
‡
2F, CF ). MS (electrospray, 20 eV) m/z: 178.1 (M ‡ H) .
2
Anal. calcd. for C H ClF N: C, 28.12; H, 4.25; N, 6.56.
5
9
5
Found: C, 28.04; H, 4.09; N, 6.70.
3
. Experimental
3.2.3. 2,2,3,3,4,4,4-Heptafluoro-1,1-dimethylbutylamine
hydrochloride (2c)
3
.1. General
Beige crystals: mp > 200 8C (sublimed). IR (KBr): n 914,
1121, 1184, 1221, 1591, 2574, 2800, 2942 cm . H NMR
À1
1
Melting points were determined in capilaries and not
13
corrected. IR spectra were obtained using a Nicolet-710
FT±IR spectrometer. H, 13C and 19F NMR spectra were
recorded with a Bruker Avance 400 spectrometer at 400, 100
and 376.5 MHz, respectively. Chemical shifts are quoted in
ppm from internal TMS for H and 13C and from external
C H F (d, À113.7 ppm) for 19F. Mass spectra were obtained
(400 MHz, CDCl ): d 1.70 (s, 6H, CH ), 8.93 (s, 3H, NH ). C
3
3
3
1
19
NMR (100 MHz, CDCl ): d 21.0 (s, CH ). F NMR
3
3
(376.5 MHz, CDCl ): d À81.2 (t, 3F, J ˆ 11:8 Hz, CF ),
3
3
À120.0 (d, 2F, J ˆ 9:2 Hz, CF ), À123.2 (m, 2F, CF ). MS
2
2
1
‡
(electrospray, 20 eV) m/z: 228.1 (M ‡ H) . Anal. calcd. for
C H ClF N: C, 27.34; H, 3.44; N, 5.31. Found: C, 27.47; H,
6
6
5
9
7
using a Micromass LCT mass spectrometer operating at
3.40; N, 5.32.
2
0 eV.
3.2.4. 2-Ethyl-2-(trifluoromethyl)butylamine
hydrochloride (2d)
3
.2. Typical procedure
White crystals: mp > 200 8C (sublimed). IR (KBr): n
À1
A suspension of anhydrous CeCl (30 mmol) in THF
3
1152, 1171, 1182, 1205, 1533, 2585, 2880, 2986 cm
.
1
(
60 ml) was stirred at room temperature for 1 h. The mixture
was cooled to À78 8C, and a solution of methyllithium
H NMR (400 MHz, CDCl ): d 1.13 (t, 6H, J ˆ 7:4 Hz,
13
3 2 3
3
CH ), 2.03 (m, 4H, CH ), 9.26 (s, 3H, NH ). C NMR

N. Zhang, S. Ayral-Kaloustian / Journal of Fluorine Chemistry 117 (2002) 9±11
11
[
2] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991, pp. 7±86.
(
100 MHz, CDCl ): d 7.3 (s, CH ), 24.2 (s, CH ), 62.7 (q,
3
3
2
1
9
J ˆ 27:1 Hz, C-1), 125.1 (q, J ˆ 284 Hz, CF ). F NMR
3
[
[
3] J.T. Welch, Tetrahedron 43 (1987) 3123.
4] G.A. Olah, R.D. Chambers, G.K.S. Prakash, Synthetic Fluorine
Chemistry, Wiley, New York, 1992.
(
376.5 MHz, CDCl ): d À75.2 (s, 3F, CF ). MS (electro-
‡
3
3
spray, 20 eV) m/z: 156.1 (M ‡ H) . Anal. calcd. for
C H ClF N: C, 37.61; H, 6.84; N, 7.31. Found: C,
3
[5] V.A. Soloshonok, A.G. Kirilenko, V.P. Kukhar, G. Resnati, Tetra-
hedron Lett. 35 (1994) 3119.
6
13
3
7.58; H, 6.65; N, 7.14.
[
[
6] M.S. Raasch, J. Org. Chem. 27 (1962) 1406.
7] J.M. Cox, J.M. Clough, N.J. Barnes, D.P.J. Pearson, I.R. Matthews,
S.K. Vohra, S.C. Smith, G. Mitchell, R.A. Barber, R.S. Ellis, D.W.
Langton, K.J. Gillen, G. Hatter, A.M. Kozakiewicz, D.P. Bacon, P.
Bellini, PCT Int. Appl. WO 9533719 (1995).
Acknowledgements
The authors wish to thank the Discovery Analytical
Chemistry Department at Wyeth Research for collection
and interpretation of the analytical data.
[
[
8] A.E. Feiring, J. Org. Chem. 48 (1983) 347.
9] W.A. Nugent, B.E. Smart, J. Organomet. Chem. 256 (1983) C9.
[10] G.K.S. Prakash, M. Mandal, J. Fluorine Chem. 112 (2001) 123 and
references therein.
[
11] C.P. F e lix, N. Khatimi, A.J. Laurent, Tetrahedron Lett. 35 (1994)
303.
References
3
[
12] J.-C. Blazejewski, E. Anselmi, M.P. Wilmshurst, Tetrahedron Lett.
40 (1999) 5475.
[1] J.T. Welch, Selective Fluorination in Organic and Bioorganic
Chemistry, American Chemical Society, Washington, DC, 1991
[13] D.J. Calderwood, R.V. Davies, P. Rafferty, H.L. Twigger, H.M.
Whelan, Tetrahedron Lett. 38 (1997) 1241.
(Chapters 9, 11 and 13).