Simple and convenient synthesis of 3,5-bis-(trifluoromethyl)benzylamine via biomimetic 1,3-proton shift reaction

Article abstract of DOI:10.1016/j.jfluchem.2006.03.013

This paper describes an efficient, practical synthesis of 3,5-bis(trifluoromethyl)benzylamine via biomimetic transamination of 3,5-bis(trifluoromethyl)benzaldehyde with benzylamine. From a synthetic standpoint the reported procedure is highly operationall

Full text of DOI:10.1016/j.jfluchem.2006.03.013

Journal of Fluorine Chemistry 127 (2006) 889–893
www.elsevier.com/locate/fluor
Simple and convenient synthesis of 3,5-bis-(trifluoromethyl)benzylamine
via biomimetic 1,3-proton shift reaction
*
Vadim A. Soloshonok , Manabu Yasumoto
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Received 17 March 2006; received in revised form 22 March 2006; accepted 22 March 2006
Available online 2 May 2006
Abstract
This paper describes an efficient, practical synthesis of 3,5-bis(trifluoromethyl)benzylamine via biomimetic transamination of 3,5-bis(tri-
fluoromethyl)benzaldehyde with benzylamine. From a synthetic standpoint the reported procedure is highly operationally convenient and scalable
as it does not require any chromatographic purification of the intermediate products.
# 2006 Elsevier B.V. All rights reserved.
Keywords: 1,3-Proton shift reaction; Fluorine and compounds; Imines; Operationally convenient conditions; Biomimetic reductive methodology
1. Introduction
One of the most attractive features of this reaction is that it
does not require an external reducing reagent making use of the
intramolecular reduction/oxidation processes via a biomimetic
[7] base-catalyzed 1,3-proton shift (from 6 to 7). Moreover,
synthesis of starting Schiff bases 6 from benzylamine 4 and
carbonyl compounds 5, their isomerization to imines 7 as well as
hydrolysis of 7 can be conducted under convenient reaction
conditions and usually in high chemical yield. In overall, based
on the literature data [6,8], we envisioned that we can develop an
operationally convenient [9] and scalable method for preparation
of benzylamine 1. However, while this reaction was extensively
studied by our [6] and other [8] research groups, virtually all
examples reported in the literature deal with highly electrophilic
a-trifluoromethyl containing carbonyl compounds of type 5. In
this case, due to a strong electron-withdrawing effect of the
trifluoromethyl group, the equilibrium between Schiff bases 6
and 7 is completely shifted towards the latter, a more C–H acidic
isomer. Therefore our research aiming at the development of
alternative and more economical methods for preparation of
amine 1 hadan additional impetusin studying theapplicabilityof
this biomimetic transamination to new and much less electro-
philic substrates.
In the recent years, fluorine-containing amines gained a status
of privileged structural units in the rational design of pharma-
ceuticals and agrochemicals [1]. In particular, 3,5-bis-(trifluor-
omethyl)benzylamine (1) was demonstrated to be an essential
pharmacophore unit of various biologically active compounds.
Most notable examples are a series of non-peptide human NK1
receptor agonists and antagonists of general formulae 2 and 3,
respectively(Fig.1),recentlydevelopedbyseveralcompanies[2].
Current clinical investigations of a series of drug-candidates
possessing 3,5-bis-(trifluoromethyl)benzylamine 1 pharmaco-
phore, including types of compounds 2 and 3, stimulated
numerous research groups in academia and industry to search
for practical and scaleable methods for preparation of amine 1.
The literature methods for preparation of 3,5-bis-(trifluoro-
methyl)benzylamine 1 reported to date include direct amination
of the corresponding 3,5-bis-(trifluoromethyl)benzyl chloride
[3], reductions of 3,5-bis-(trifluoromethyl)benzonitrile [4] or
various protocols for reductive amination of 3,5-bis-(trifluor-
omethyl)benzaldehyde [5]. Taking into account the growing
demand for production of amine 1, we decided to explore
prospects for its preparation via biomimetic transamination
reaction [6], which represent a quite unusual, alternative
approach to conventional reductive methodology (Scheme 1).
2. Results and discussion
Based on the literature data [6,8], benzylamine 4 was
considered to be the best choice to serve as a reducing reagent
and a source of a nitrogen at the same time. Imine 14
(Scheme 2) was easily prepared in quantitative chemical yield
* Corresponding author. Tel.: +1 405 325 8279; fax: +1 405 325 6111.
E-mail address: vadim@ou.edu (V.A. Soloshonok).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.03.013

890
V.A. Soloshonok, M. Yasumoto / Journal of Fluorine Chemistry 127 (2006) 889–893
Fig. 1.
Scheme 1.
according to the recently published procedure [10] using
ZnCl2 as catalyst for the direct condensation of aldehyde 10
with benzylamine 11. Taking into account that virtually all
previously reported examples [6,8] of 1,3-proton shift reaction
were conducted in neat triethylamine (TEA) we started our
investigations using the same reaction conditions. To ensure
accuracy of the collected data, the outcome of the reactions
was controlled by both GC and NMR 19F. The results are
summarized in Table 1.
leading to 14/17 ratio of 15.3/84.7 (entry 3) and 14.8/85.2
(entry 4) after 1 and 2 days of the reaction, respectively.
Considering these data we assumed that, in about 1 day, the
reaction reached the thermodynamic equilibrium producing
close to 15/85 ratio of the imines 14/17 (k = 5.7).
Taking into account that our preliminary kinetic experiments
[11] indicated that this type of isomerization can be
significantly accelerated in a polar solvent, we conducted a
series of experiments to optimize the reaction condition for
isomerization of 14–17. In particular we have found that the
reaction conducted in acetonitrile proceeded with substantially
higher reaction rate. Thus, using acetonitrile as solvent and four
equivalents of TEA as base-catalyst, approximately 20/80 ratio
between 14 and 17 was detected after 1.5 h of the reaction time,
which is more than three times faster as compared with the
At an ambient temperature the reaction did not take place,
however, smooth and clean transformation of imine 14 to Schiff
base 17 was observed at 75 8C. Thus, after 1.5 h of the reaction
time about 25% of the starting 14 was transformed to product
17 (entry 1), and about 50% of the isomerization was detected
after 4.5 h (entry 2). Further reaction progress was rather slow
Scheme 2.

V.A. Soloshonok, M. Yasumoto / Journal of Fluorine Chemistry 127 (2006) 889–893
891
Table 1
Isomerization of imine 14 to Schiff base 17
Entry
Base
Solvent
Time
Ratio (S/P)
Yield (%)
1
2
TEA
TEA
1.5 h
4.5 h
1 d
75.4/24.6
45.7/54.3
15.3/84.7
14.8/85.2
20.3/79.7
15.2/84.8
15.0/85.0
13.6/86.4
16.2/83.8
16.3/83.7
15.4/84.6
15.2/84.8
98.4
97.6
97.3
97.7
97.9
96.9
94.3
79.1
99.4
99.4
97.3
69.7
TEA
TEA
3
TEA
TEA
4
TEA
TEA
2 d
5
TEA (4 equiv.)
TEA (4 equiv.)
TEA (4 equiv.)
TEA (4 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1.5 h
4.5 h
11 h
1 d
6
7
8
9
1.5 h
4.5 h
1 d
10
11
12
2 d
reaction conducted in TEA (entry 5 versus entry 1). Further
reaction progress led to the thermodynamic ratio of about 15/85
that was observed after 4.5 h (entries 6–8). Next, we conducted
a series of the reactions using different bases in the place of
TEA. We found that DBU, a much stronger base as compared
with TEA, was very efficient as a catalyst for this isomerization.
The optimum concentration of DBU was found to be about
10 mol%, as the higher concentrations led to formation of
byproduct and the lower amounts resulted in slower reaction
rates. Thus, based on the results obtained, we can conclude that
with application of DBU as a base, the thermodynamic
equilibrium between 14 and 17 was reached in less than 1.5 h
(entry 9) as longer reaction times (entries 10–12) gave virtually
the same ratio of the isomers.
to 19. Imine 16 was prepared using our ZnCl2-catalyzed
conditions and its isomerization was studied under the standard
conditions specified above. The results of the isomerization of
16–19 are summarized in Table 3.
First of all, this isomerization occurred at substantially
slower reaction rate as compared with that of reactions of
imines 14 and 15 (entries 1–4). Furthermore, these isomeriza-
tions were less clean as noticeable amount of fluorine-
containing byproducts was detected by 19F NMR. The
thermodynamic ratio between 16 and 19 was established after
5 days of the reaction and was found to be about 5.0/95.0,
respectively. In this regard it is interesting to note that the MeO-
group in para-position in imine 15 and the methyl group in
alpha-position in 16, had virtually the same affect on the
position of the thermodynamic equilibrium in the correspond-
ing base-catalyzed 1,3-proton shift reactions.
Since the thermodynamic ratio between 14 and 17 is a
function of C–H acidity of the methylene protons in 14 and 17
[12], we attempted to effect the ratio between the isomers using
( p-methoxy)benzylamine 12. The corresponding imine 15 was
easily prepared using the same standard procedure we used for
synthesis of imine 14. The results of imine 15 isomerization to
Schiff base 18 are summarized in Table 2.
Using our optimized conditions (0.1 equiv. of DBU as a base
and MeCN as a solvent, at 75 8C) we were pleased to find that
the isomerization of p-methoxy-containing imine 15 to product
18 occurred at relatively high reaction rate (entry 1) and, most
importantly, with substantially improved, synthetically useful
thermodynamic ratio between imines 15 and 18, about 6–94
(entries 2 and 3), respectively.
Considering the data obtained one may agree that
application of ( p-methoxy)benzylamine 12 for transamination
of the aldehyde 10 gave the best synthetic result in this study.
However, from the stand point of the cost structure of the whole
synthetic process application of benzylamine looked more
advantageous [13], provided that we can develop a simple and
efficient procedure for preparation of a chemically pure target
amine 1 from the 15/85 mixture of imines 14 and 17,
respectively. After extensive experimentation we finally found
that the mixture of imines 14 and 17 can be hydrolyzed directly
after evaporation of acetonitrile and TEA to furnish a mixture
of hydrochloride salts of target amines 20 and 11 (Scheme 2).
Our attempts to prepare chemically pure amine 1 by crystal-
lization of thus obtained hydrochloride salts were unsuccessful
(Table 4, entry 1). Application of hydrobromic acid and
crystallization of the corresponding salts was also unsuccessful
Finally, we decided to explore the stereo-electronic effect of
the methyl group, inthe alpha-positiontotheSchiffbasefunction
in the starting imine 16, on the reaction rate and position of the
thermodynamic equilibrium in its base-catalyzed isomerization
Table 3
Isomerization of imine 16 to Schiff base 19
Table 2
Entry
Base
Solvent
Time
Ratio
(S/P)
Yield
(%)
Isomerization of imine 15 to Schiff base 18
Entry
Base
Solvent
Time
(h)
Ratio
(S/P)
Yield
(%)
1
2
3
4
5
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
MeCN
MeCN
MeCN
MeCN
MeCN
1.5 h
4.5 h
10 h
1 d
65.9/34.1
31.1/68.9
20.8/79.2
16.2/83.8
5.0/95.0
95.6
93.1
92.5
65.3
61.8
1
2
3
DBU (0.1 equiv.)
DBU (0.1 equiv.)
DBU (0.1 equiv.)
MeCN
MeCN
MeCN
1.5
4.5
19
9.1/90.9
6.4/93.7
5.9/94.1
98.4
98.7
99.0
5 d

892
V.A. Soloshonok, M. Yasumoto / Journal of Fluorine Chemistry 127 (2006) 889–893
Table 4
Crystallization of the mixture of 3,5-bis-(trifluoromethyl)benzylamine salt 20 and benzylamine salt 11
Entry
Acid
Solvent
Yield of 20 (%)
20/11
1
2
3
4
5
HCl
HBr
HBr
PTS
PTS
i-PrOH (3 mL/g) + n-hexane (5 mL/g)
i-PrOH (2 mL/g) + n-hexane (4 mL/g)
Ethyl acetate (2 mL/g)
53
39
2
79.1/20.9
74.9/25.1
51.0/ 49.0
100/0
i-PrOH (15 mL/g)
92
62
MeOH (3 mL/g) + toluene (3 mL/g)
100/0
(entries 2 and 3). Therefore, the hydrochloride salts 11 and 20
were then transformed to the corresponding free amines and
treated with various organic acids. The best result was obtained
with the salts derived from p-tolylsulfonic acid (PTS). In this
case, crystallization of the corresponding salts from i-propyl
alcohol allowed for precipitation of chemically pure PTS salts
of the target amine 20 in 92% chemical yield (entries 4 and 5).
Thus prepared salt of amine 20 with PTS can be stored and used
as a source of amine 1 for its transformation to desired
derivatives. Alternatively, amine 1 can be isolated as free base
by treatment of this salt with inorganic base in one easy step.
In summary, we have developed practical and efficient
synthesis of pure 3,5-bis(trifluoromethyl)benzylamine via
biomimetic transamination of 3,5-bis(trifluoromethyl)benzal-
dehyde with benzylamine. From a synthetic standpoint the
reported procedure is highly operationally convenient and
scalable as it does not require any chromatographic purification
of the intermediate products.
pressure to afford Schiff base 14 in quantitative yield. 1H NMR
4.89 (d, 2H, J = 1.2 Hz), 7.30–7.40 (m, 5H), 7.92 (s, 1H),
8.23(s, 2H), 8.45 (t, 1H, J = 1.2 Hz); 19F NMR d À63.43; 13C
NMR d 65.0, 123.1 (q, J = 273.2 Hz), 124.0 (quint, J = 3.8 Hz),
127.4, 128.1, 128.7, 132.1 (q, J = 33.8 Hz), 138.0, 138.2, 158.5;
HRMS(TOF)[M + H]+, calcd for [C16H11F6N + H]+: 332.0874,
found: 332.0778. Calculated for C16H11F6N: C, 58.01; H, 3.35;
F, 34.41; N, 4.23; found: C, 58.04; H, 3.36; F, 34.44; N, 4.22.
Schiff bases 15 and 16 were prepared in quantitative yield
using the same procedure.
Schiff base 15. 1H NMR d 3.81 (s, 3H), 4.81 (bs, 2H), 6.91 (d,
2H, J = 8.8 Hz), 7.26 (d, 2H, J = 8.8 Hz), 7.91 (s, 1H), 8.22 (s,
2H), 8.42 (bs, 1H); 19F NMR d À63.44; 13C NMR d 55.3, 64.4,
114.1, 123.1 (q, J = 273.1 Hz), 123.9 (quint, J = 3.8 Hz), 128.1,
129.4, 130.2, 138.1, 132.1 (q, J = 34.1 Hz), 158.1, 159.0;
HRMS(TOF)[M + H]+, calcd for [C17H13F6NO + H]+:
362.0980, found: 362.0807. Calculated for C17H13F6NO: C,
56.52; H, 3.63; F, 31.55; N, 3.88; found: C, 56.60; H, 3.70; F,
31.33; N, 4.91.
3. Experimental
Schiff base 16. 1H NMR d 1.62 (d, 3H, J = 6.6 Hz), 4.62 (q,
1H, J = 6.6 Hz), 7.25–7.44 (m, 5H), 7.91 (s, 1H), 8.22 (s, 2H),
8.42 (s, 1H); 19F NMR d À63.42; 13C NMR d 24.7, 69.9, 123.1
(q, J = 273.2 Hz), 123.8 (quint, J = 3.8 Hz), 126.6, 127.2,
128.1, 128.6, 132.0 (q, J = 33.8), 138.3, 144.2, 156.2;
3.1. General methods
Unless otherwise noted, all reagents and solvents were
obtained from commercial suppliers and used without further
purification. All the reactions were carried out under atmo-
sphere without any special caution to exclude air. Unless
indicated, 1H, 19F and 13C NMR spectra, were taken in CDCl3
solutions at 299.95, 282.24 and 75.42 MHz, respectively, on an
instrument in the University of Oklahoma NMR Spectroscopy
Laboratory. Chemical shifts refer to TMS (1H NMR and 19C
NMR) and fluorotrichloromethane (19F NMR) as the internal
standards. Yields refer to isolated yields of products of greater
HRMS(TOF)[M + Na],
calcd
for
[C17H13F6N + H]+:
346.1030, found: 346.0887. Calculated for C17H13F6N: C,
59.13; H, 3.79; F, 33.01; N, 4.06; found: C, 59.19; H, 3.75; F,
32.99; N, 4.01.
3.3. Procedure for preparation of Schiff base (17)
To the solution of Schiff base 14 (13.00 g, 39.2 mmol) and in
acetonitrile (39 mL), triethylamine (15.88 g, 157.0 mmol) was
added to the reaction mixture at r.t. The condenser was attached
to the reactor and the reaction mixture was heated at 75 8C for
6 h. Upon the completion of isomerization (monitored by gas
chromatograph), the solvent and triethylamine were removed
under reduced pressure. Schiff base 17 was purified by silica gel
1
than 95% purity as estimated by H NMR spectrometry. All
new compounds were characterized by 1H, 19F and 13C NMR,
by mass spectrometry and/or elemental analysis.
3.2. Procedure for preparation of Schiff base (14)
1
column chromatography (n-hexane:ethyl acetate = 20:1). H
To the solution of 3,5-bis(trifluoromethyl)benzaldehyde 10
(20.00 g, 82.6 mmol) and ZnCl2 (1.13 g, 8.3 mmol) in benzene
(43 mL), a benzene (40 mL) solution of benzylamine 11
(9.74 g, 90.9 mmol) was added at r.t. The solution was refluxed
with azeotropic removal of water for 1 day using a Dean-Stark
trap. The reaction mixture was washed with 1N NaOH, a
saturated aqueous solution of NH4Cl (three times) to remove an
excess of benzylamine. Solvent was removed under reduced
NMR d 4.91 (s, 1H), 7.45–7.49 (m, 3H), 7.79 (s, 1H), 7.80–7.83
(m, 2H), 7.84 (s, 2H), 8.47(s, 1H); 19F NMR d À63.30; 13C
NMR d 63.8, 120.9 (quint, J = 3.8 Hz), 123.4 (q, J = 272.4 Hz),
127.9, 128.4, 128.8, 131.3, 131.6 (q, J = 33.8 Hz), 135.6, 142.1,
163.4; HRMS(TOF)[M + H]+, calcd for [C16H11F6N + H]+:
332.0874, found: 332.0818. Calculated for C16H11F6N: C,
58.01; H, 3.35; F, 34.41; N, 4.23; found: C, 58.05; H, 3.44; F,
34.46; N, 4.17.

V.A. Soloshonok, M. Yasumoto / Journal of Fluorine Chemistry 127 (2006) 889–893
893
Schiff bases 18 and 19 were prepared under the same
conditions using DBU (0.1 equiv.) as a base instead of
triethylamine. Schiff bases 18 and 19 were unstable on silica
gel, they were partially hydrolyzed during purification.
Schiff base 18. 1H NMR d 3.86 (s, 3H), 4.87 (s, 2H), 6.96 (d,
2H, J = 8.8 Hz), 7.75 (d, 2H, J = 8.8 Hz), 7.78 (s, 1H), 7.82 (s,
2H), 8.39 (s, 1H); 19F NMR d À63.27; 13C NMR d 55.4, 63.7,
114.1, 120.8 (quint, J = 3.8 Hz), 123.4 (q, J = 272.3 Hz), 127.9,
128.5, 130.0, 131.6 (q, J = 33.0 Hz), 142.4, 162.1, 162.6;
HRMS(TOF)[M], calcd for [C17H14F6NO]: 362.0980, found:
362.1210. Calculated for C17H13F6NO: C, 56.52; H, 3.63; F,
31.55; N, 3.88; found: C, 56.48; H, 3.69; F, 31.33; N, 3.64.
Schiff base 19. 1H NMR d 2.39 (s, 3H), 4.78 (s, 2H), 7.43–
(m, 3H). Calculated for C9H7F6N: C, 44.46; H, 2.90; F, 46.88;
N, 5.76; found: C, 44.35; H, 2.94; F, 46.72; N, 5.71.
Acknowledgements
This work was supported by Department of Chemistry and
Biochemistry, University of Oklahoma. The authors gratefully
acknowledge generous financial support from Central Glass
Company (Tokyo, Japan) and Ajinomoto Company (Tokyo,
Japan).
References
7.47 (m, 5H), 7.79 (s, 1H), 7.97 (s, 2H); 19F NMR d À63.25; 13
C
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acetonitrile (39 mL), triethylamine (15.88 g, 157.0 mmol) was
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at r.t., and the solvents were removed under reduced pressure.
To the residue, i-propyl (244 mL) was added, the solution was
heated until the solid was dissolved. The solution was cooled to
r.t., PTS salt of 3,5-bis-(trifluoromethyl)benzylamine was
obtained by filtration after washing with n-hexane. The crystal
was dissolved with ethyl acetate, 3N NaOH was added until the
aqueous layer became pH-14. After separation of the organic
layer, the solvent was removed under reduced pressure to
give 3,5-bis-(trifluoromethyl)benzylamine 1 (>98% purity by
NMR). 1H NMR d 1.52 (bs, 2H), 4.03 (s, 2H), 7.73–7.95
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(c) T. Ono, V.P. Kukhar, V.A. Soloshonok, J. Org. Chem. 61 (1996) 6563–
6569;
(d) V.A. Soloshonok, T. Ono, J. Org. Chem. 62 (1997) 3030–3031;
(e) V.A. Soloshonok, T. Ono, I.V. Soloshonok, J. Org. Chem. 62 (1997)
7538–7539.
[13] ( p-Methoxy)benzylamine 12 is more than 10 times more expansive than
benzylamine.