An easy synthesis of α-trifluoromethyl-amines from aldehydes or ketones using the Ruppert-Prakash reagent

Article abstract of DOI:10.1016/j.tetlet.2013.01.132

A small library of structurally diverse primary amines bearing a geminal CF₃ group was synthesized on a preparative scale. The synthesis starts with an aldehyde or ketone that reacts with benzylamine yielding the corresponding imine. The latter is then trifluoromethylated with Me ₃SiCF₃ under acidic conditions to give a benzylalkylamine. In the last step the Pd-mediated hydrogenation of the benzylalkylamines furnishes the title compounds. All synthetic steps are high-yielding; neither the isolation of the intermediates nor the chromatographic purification of the products is necessary.

Full text of DOI:10.1016/j.tetlet.2013.01.132

Tetrahedron Letters 54 (2013) 1897–1898
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An easy synthesis of a-trifluoromethyl-amines from aldehydes or ketones
using the Ruppert-Prakash reagent
Dmytro S. Radchenko a,b, Oleg M. Michurin a,b, Anton V. Chernykh a,c, Oleg Lukin d,
,
⇑
Pavel K. Mykhailiuk a,e,
⇑
a Enamine Ltd, Aleksandr Matrosov St. 23, 01103 Kiev, Ukraine
b The Institute of High Technologies, Kiev National Taras Shevchenko University, 4 Glushkov St., Building 5, 03187 Kiev, Ukraine
c Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska St. 5, 02660 Kiev, Ukraine
d ChemBioCenter, Kiev National Taras Shevchenko University, Volodymyrska St. 62, 01033 Kiev, Ukraine
e Department of Chemistry, Kiev National Taras Shevchenko University, Volodymyrska St. 64, 01033 Kiev, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A small library of structurally diverse primary amines bearing a geminal CF3 group was synthesized on a
preparative scale. The synthesis starts with an aldehyde or ketone that reacts with benzylamine yielding
the corresponding imine. The latter is then trifluoromethylated with Me3SiCF3 under acidic conditions to
give a benzylalkylamine. In the last step the Pd-mediated hydrogenation of the benzylalkylamines fur-
nishes the title compounds. All synthetic steps are high-yielding; neither the isolation of the intermedi-
ates nor the chromatographic purification of the products is necessary.
Received 17 December 2012
Revised 21 January 2013
Accepted 31 January 2013
Available online 6 February 2013
Keywords:
Trifluoromethylation
Amines
Ó 2013 Elsevier Ltd. All rights reserved.
Imines
Silicon
One-pot synthesis
Ph
Ph
F3C NH
Amines with a geminal trifluoromethyl group have attracted
considerable attention in biochemistry as they are metabolically
stable bioisosteres of the corresponding amides.1 The majority of
O
N
ii
i
iii
F3C NH2
R1
R2
R1
R2
R1
R2
R1
R2
available synthetic approaches to
a-trifluoromethylated amines
involves the use of trifluoromethyl-substituted imines.2 However,
the preparation of the latter often constitutes a synthetic challenge
on its own. An acid-catalyzed nucleophilic trifluoromethylation of
various imines with Me3SiCF3, described in a recent report by
Dilman and co-workers,3 provides a better alternative to the
1
2
3
4
a:
b:
c:
d:
e:
R1 = Me R2 = Et
R1 = R2 = Et
f:
g:
h:
i:
R =
1 = R2
aforementioned method.
A number of structurally diverse
secondary amines3 (including cyclic examples4) bearing a geminal
trifluoromethyl group were synthesized through this reaction. We
have recently expanded the scope of Dilman’s method to
CF3-functionalized primary amines by preparing two cyclobu-
tane-based amino acids through the catalytic de-benzylation of
the corresponding benzylalkylamine precursors.5 However, the
procedure involved chromatographic purification of the imine
and benzylalkylamine intermediates. In the present Letter, we re-
port an improved procedure giving an easy access to primary
amines possessing a geminal trifluoromethyl group from readily
available carbonyl compounds and benzylamine. As shown in
R1 = H R2
=
=
R1 = Me R2
=
1 = H R2
O
R
R
R
R1 = H R2 = t-Bu
1 = R2
1 = R2
=
=
R
1 = Me R2
=
j:
O
⇑
Corresponding authors. Tel.: +38 044 537 3218; fax: +38 044 537 3253.
E-mail addresses: oleg.lukin@univ.kiev.ua (O. Lukin), Pavel.Mykhailiuk@gmail.
Scheme 1. The preparation of primary amines possessing a geminal trifluoro-
methyl group. Reagents and conditions: (i) benzylamine, rt, (ii) Me3SiCF3, KHF2, TFA,
(iii) H2, 10% Pd/C.6
com (P.K. Mykhailiuk).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.132

1898
D. S. Radchenko et al. / Tetrahedron Letters 54 (2013) 1897–1898
Scheme 1, the reaction of carbonyl compounds 1 with benzylamine
readily gave imines 2. The latter undergo an addition of Me3SiCF3
to yield benzylalkylamine 3.
Notably, the two reaction steps can be carried out in one pot
since the preparation of intermediate 2 only requires evaporation
of the solvent and drying in vacuum.
References and notes
1. (a) Faraci, W. S.; Walsh, C. T. Biochemistry 1989, 28, 431–437; (b) Volonterio, A.;
Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruché, L.; Colombo, G.; Malpezzi, L.;
Mazzini, S.; Meille, S. V.; Meli, M.; de Arellano, C. R.; Zanda, M. Chem. Eur. J. 2003,
9, 4510–4522; (c) Grunewald, G. L.; Lu, J.; Criscione, K. R.; Okoro, C. O. Bioorg.
Med. Chem. Lett. 2005, 15, 5319–5323; (d) Sani, M.; Volonterio, A.; Zanda, M.
ChemMedChem 2007, 2, 1693–1700.
The work-up after the second synthetic step was also straight-
forward (see SI for details). The crude benzylalkylamines 3 were
then subjected to a Pd-mediated hydrogenolysis resulting in
gem-trifluoromethylamines 4. Compounds 4 were easily purified
by recrystallization of their hydrochloride salts from acetonitrile.
1H, 13C, 19F NMR, LC–MS, and elemental analyses data of com-
pounds 4 confirmed their structures and high purity. The possibil-
ity to combine the two-step preparation of benzylalkylamines in
one-pot along with no need for chromatographic purification of
both the intermediates and the products make the described ap-
proach to these amines with a geminal trifluoromethyl group ex-
tremely straightforward. Multigram amounts of the target
amines can be easily synthesized via this approach.
2. (a) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem. Soc. Rev. 2005, 34,
562–572; (b) Hughes, G.; Devine, P. N.; Naber, J. R.; O’Shea, P. D.; Foster, B. S.;
McKay, D. J.; Volante, R. P. Angew. Chem., Int. Ed. 2007, 46, 1839–1842; (c)
Dilman, A. D.; Levin, V. V. Eur. J. Org. Chem. 2011, 831–841.
3. Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A.
Eur. J. Org. Chem. 2008, 5226–5230.
4. Shevchenko, N. E.; Vlasov, K.; Nenajdenko, V. G.; Röschenthaler, G.-V.
Tetrahedron 2011, 67, 69–74.
5. Tkachenko, A. N.; Radchenko, D. S.; Mykhailiuk, P. K.; Shishkin, O. V.; Tolmachev,
A. A.; Komarov, I. V. Synthesis 2012, 44, 903–908.
6. In a typical reaction 0.243 mol of Ruppert-Prakash reagent was combined with
0.162 mol of freshly prepared imine 2 dissolved in CH3CN/DMF (10:1) in the
presence of a slight molar excess of TFA and a catalytic amount of KHF2 at 0 °C.
After 12 h of stirring at ambient temperature the mixture was triturated with
saturated aqueous Na2CO3, diluted with H2O and then extracted several times
with EtOAc. Evaporation of the solvent resulted in crude benzylalkylamine 3
which was further purified by transformation into its hydrochloride salt
followed by recrystallization from acetonitrile. Benzylalkylamine
successfully de-benzylated through hydrogenation over Pd/C at 50 bar. For full
experimental details see SI.
3 was
Acknowledgment
We thank Dr. A. D. Dilman for helpful discussions.
Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.01.132.