A convenient, highly stereoselective, metal-free synthesis of chiral amines

Article abstract of DOI:10.1055/S-0029-1218541

A low cost, efficient, metal-free highly stereoselective reduction of ketimines to chiral amines was developed. Different imines bearing a very cheap and removable chiral auxiliary were reduced simply by trichlorosilane in the presence of N,N-dimethylformamide, often in quantitative yield and complete control of the absolute stereochemistry, to afford highly enantiomerically enriched amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218541

134
LETTER
A Convenient, Highly Stereoselective, Metal-Free Synthesis of Chiral Amines
A
S
tereoselect
t
ive Syn
e
thesis of
C
f
hiral
A
m
a
ines nia Guizzetti,*a Maurizio Benaglia,*a Cinzia Biaggi,a Giuseppe Celentanob
a
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy
Fax +39(0250)314159; E-mail: maurizio.benaglia@unimi.it
Dipartimento di Dipartimento di Scienze Molecolari Applicate ai Biosistemi, Università degli Studi di Milano,
Via Golgi 19, 20133, Milano, Italy
b
Received 6 October 2009
efficiency simply by addition of trichlorosilane in the
presence of an achiral Lewis base such as N,N-dimethyl-
formamide.
Abstract: A low cost, efficient, metal-free highly stereoselective
reduction of ketimines to chiral amines was developed. Different
imines bearing a very cheap and removable chiral auxiliary were re-
duced simply by trichlorosilane in the presence of N,N-dimethyl-
formamide, often in quantitative yield and complete control of the
absolute stereochemistry, to afford highly enantiomerically en-
riched amines.
During our studies on the organocatalytic reduction of
chiral ketimines8 it was found that a catalytic amount of
N,N-dimethylformamide was able to promote HSiCl3 ad-
dition with good stereoselectivity, although in low yield.
We decided to further investigate the reaction; not only
DMF (A) but also other achiral formamide derivatives
were employed, like N,N-diisopropylformamide (B), N,N-
dibenzylformamide (C), and N,N-dimethylacetamide (D).
In preliminary studies the reduction of imine (R)-1 was
performed at 0 °C in dichloromethane for 12 hours in the
presence of different equivalents of different Lewis bases
(Scheme 1).
Key words: imine reduction, Lewis base, trichlorosilane, chiral
auxiliary, chiral amine
The advent of organocatalysis over the last few years has
led to the discovery and development of new activation
modes and novel transformations, sometimes comple-
mentary to those established in the field of organometallic
catalysis.1 A paradigmatic example comes from the stere-
oselective carbon–nitrogen double-bond reduction; for
this fundamental transformation that generates a new ni-
trogen-bearing stereocenter, both organometallic catalytic
systems2 and organic catalysts3 have been recently devel-
oped. However, the search of inexpensive but highly effi-
cient procedures for imines reduction, with total control of
the absolute stereochemistry, is still very active. Among
the different possibilities, an attractive methodology ex-
ploits trichlorosilane as the reducing species that needs to
be activated by co-ordination with Lewis bases, such as
N,N-dimethylformamide, acetonitrile, and trialkylamines,
to generate a hexacoordinated hydridosilicate acting as
the actual reducing agent.4
Lewis bases A–D
HN
N
HN
1) HSiCl3, CH2Cl2,
0 °C, 12 h
2) NaHCO3
(R)-1
(R,R)-2
3
Me
N
Me
N
H
N
H
N
H
Me
Me
O
O
O
O
Already in 1999 in his pioneering works Matsumura re-
ported the use of N-formyl proline to promote enantio-
selective reduction of ketones and later of imines.5 Since
then several chiral activators for trichlorosilane-mediated
reduction have been developed.4,6 In the course of our
work on the topic7 very recently we have demonstrated
that it is possible to reach often a complete stereocontrol
in the ketoimines reduction by combining the use of a
proper catalyst with a very cheap, removable chiral auxil-
iary at the imine nitrogen.8
A
C
B
D
Scheme 1 Stereoselective reduction of chiral imine 1
A few selected results are collected in Table 1. All activa-
tors promoted the trichlorosilane addition often in quanti-
tative yield, besides N,N-dimethylacetamide that was less
effective also as stereochemical controller (Scheme 1).
Generally, the use of six mol equivalents of Lewis base al-
lowed to obtain amine (R,R)-2 in higher diastereoselectiv-
Now we wish to report that by working with the proper ex- ities, with N,N-dimethylformamide leading to the best
perimental conditions, the reduction of ketoimines de- result (99% yield, dr = 97:3, entry 2).
rived from (R)- or (S)-1-phenylethylamine may be
accomplished in very high chemical and stereochemical
With DMF having been identified as the Lewis base of
choice, a few experiments were dedicated to the individu-
ation of the best experimental conditions (Table 2).
SYNLETT 2010, No. 1, pp 0134–0136
Advanced online publication: 09.12.2009
DOI: 10.1055/s-0029-1218541; Art ID: G34209ST
x
x.
x
x.
2
0
1
0
At 0 °C in dichloromethane a variation of the amount of
DMF from 2 mol equivalents to 8 mol equivalents does
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Stereoselective Synthesis of Chiral Amines
135
Table 1 Different Lewis Bases in the Stereoselective Reduction of
(R,R)-1 with HSiCl3
DMF (6 equiv)
Entry Lewis base Lewis base (equiv) Yield (%)a dr of (R,R)-2/3b
1) CH2Cl2, –50 °C, 12 h
HSiCl3 (3 equiv)
2) NaHCO3
HN
N
1
2
3
4
5
6
7
A
A
B
B
C
C
D
2
6
2
6
2
6
2
99
99
99
99
99
99
95
95:5
R
R
97:3
(R)-4
(R)-5
(R)-6
(R)-7
(R)-8
(R,R)-9
R = 2-naphthyl
R = 4-MeOC6H4
R = 4-F3CC6H4
R = 2-thienyl
R = 2-i-Pr
(R,R)-10
(R,R)-11
(R,R)-12
(R,R)-13
89:11
90:10
91:9
Scheme 2 Stereoselective reduction of chiral imine 4–8
92:8
amines in quantitative yields, always maintaining an abso-
lute control of the stereoselectivity of the process
(Table 3).
87:13
a Reaction run at 0 °C, yields determined by 1H NMR and confirmed
after chromatographic purification.
Both aromatic and heteroaromatic alkyl ketimines can be
converted to the corresponding amines with great effi-
ciency and stereocontrol (entries 1–4, Table 3). It is worth
mentioning that amine 11 has been converted to 4-trifluo-
romethylphenylmethylamine by simple hydrogenation,12
thus demonstrating the feasibility of the approach for the
preparation of an enantiomerically pure primary amine.
b Diastereomeric excess determined by 1H NMR and confirmed by
HPLC (see Supporting Information).
not seem to influence the stereoselectivity decisively.
However, 6 mol equivalents of DMF and 3 mol equiva-
lents of HSiCl3 in CH2Cl2 seem to be the best combina-
tion. In other solvents, like toluene, acetonitrile, or
chloroform lower stereoselectivities were obtained. A de-
cisive improvement came from lowering the reaction tem-
perature; at –50 °C, after only 12 hours, the chiral amine
29 was obtained in 98% yield and basically as single dia-
stereomer.10
Imine 8 derived from methyl isobutyl ketone was also
readily reduced in >98% yield in the presence of N,N-di-
methylformamide at –50 °C (entry 5, Table 3). Chiral
amine 13, obtained as single isomer, represents a direct
precursor of (R)-isopropylmethylamine.13
The general applicability of the methodology was then in-
vestigated (Scheme 2).11 N-a-Methyl benzyl imines of
methyl aryl ketones of different electronic properties were
effectively reduced to the corresponding secondary
Table 3 Stereoselective Reduction of Chiral Imines
Entry
Imine
4
Product
9
Yield (%)a
drb
1
71
90
83
65
90
99
67
71
51
>99:1
91:9
99:1
>99:1
>99:1
98:2
98:2
91:9
88:12
Table 2 Stereoselective Reduction of Imine 1 Promoted by DMF–
HSiCl3
2
5
10
3
6
11
Entry Temp
(°C)
Lewis base Solvent
(equiv)
Yield
(%)a
dr of
(R,R)-2/3b
4
7
12
1
2
0
0
0.3
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeCN
CHCl3
91
99
99
99
99
99
72
99
90
95
98
94:6
95:5
94:6
93:7
97:3
96:4
94:6
87:13
95:5
94:6
>99:1
5
8
13
6c
7
14
14
16
16
15
3
0
4
15
4
0
5
8c
9
17
5
0
6
17
6
0
8
a Reaction run at 0 °C, yields determined by 1H NMR and confirmed
after chromatographic purification.
7
0
6
b Diastereomeric excess determined by 1H NMR and confirmed by
HPLC (see Supporting Information).
8
0
6
c Reaction run at 0 °C.
9
0
6
10
11
–20
–50
6
CH2Cl2
CH2Cl2
The procedure was successfully employed in the prepara-
tion of other chiral secondary amines of C2 symmetry. For
example, the reduction of (R)-N-1-b-naphthyl ethyl imine
of 2-acetonaphthone 14 with trichlorosilane was accom-
plished (Scheme 3). In this case amine 15 was obtained al-
ready at 0 °C in quantitative yield and 98:2 stereoisomeric
6
a Reaction run at 0 °C, yields determined by 1H NMR and confirmed
after chromatographic purification.
b Diastereomeric excess determined by 1H NMR and confirmed by
HPLC (see Supporting Information).
Synlett 2010, No. 1, 134–136 © Thieme Stuttgart · New York

136
S. Guizzetti et al.
LETTER
(2) (a) Blaser, H.-U.; Pugin, B.; Spindler, F.; Thommen, M. Acc.
Chem. Res. 2007, 40, 1240; and references cited therein .
See also: (b) Kadyrov, R.; Riermeier, T. H. Angew. Chem.
Int. Ed. 2003, 42, 5472. (c) Li, C.; Villa-Marcos, B.; Xiao, J.
J. Am. Chem. Soc. 2009, 131, 6967.
ratio; running the reaction at lower temperature did not
improve the stereoselectivity (entries 6 and 7, Table 3).
Finally, as further demonstration of the versatility of the
methodology, the addition of trichlorosilane to imine 16,
derived from reaction of 2-methoxyacetophenone and
(R)-1-phenylethylamine, was studied (Scheme 3). The re-
duction at 0 °C after only 12 hours afforded the 1,2-meth-
oxyamino derivative 17 in 71% yield and 91:9
diastereomeric ratio (entry 8, Table 3).14 Also for this
transformation a lower reaction temperature did not mod-
ify significantly the stereochemical result.
(3) Ouellet, S. G.; Walji, A.; MacMillan, D. W. C. Acc. Chem.
Res. 2007, 40, 1327; and references cited therein.
(4) Reviews: (a) Benaglia, M.; Guizzetti, S.; Pignataro, L.
Coord. Chem. Rev. 2008, 252, 492. (b) Denmark, S. E.;
Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47, 1560.
(5) (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 1999, 40, 7507.
(b) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.;
Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525.
(6) For two recent contributions about the enantioselective
synthesis of b-amino acids involving the use of trichloro-
silane, see: (a) Malkov, A. V.; Stoncius, S.; Vrankova, K.;
Arndt, M.; Kocovsky, P. Chem. Eur. J. 2008, 14, 8082.
(b) Zheng, H.-J.; Chen, W.-B.; Wu, Z.-J.; Deng, J.-G.; Lin,
W.-Q.; Yuan, W.-C.; Zhang, X.-M. Chem. Eur. J. 2008, 14,
9864; and references cited therein . For a recent contribu-
tion in the field, see: (c) Malkov, A. V.; Figlus, M.; Prestly,
M. R.; Rabami, G.; Cooke, G.; Kocovsky, P. Chem. Eur. J.
2009, 15, 9651.
DMF (6 equiv)
1) CH2Cl2, –20 °C, 12 h
HSiCl3 (3 equiv)
2) NaHCO3
HN
N
(R)-14
(R,R)-15
(7) (a) Guizzetti, S.; Benaglia, M.; Cozzi, F.; Rossi, S.;
Celentano, G. Chirality 2009, 21, 233. (b) Guizzetti, S.;
Benaglia, M. EP 2008/010079, 2008. (c) Guizzetti, S.;
Benaglia, M. EP 07023240.0, 2008. (d) Guizzetti, S.;
Benaglia, M.; Cozzi, F.; Annunziata, R. Tetrahedron 2009,
65, 6354.
DMF (6 equiv)
1) CH2Cl2, 0 °C, 12 h
HSiCl3 (3 equiv)
2) NaHCO3
HN
N
(8) Guizzetti, S.; Benaglia, M.; Rossi, S. Org. Lett. 2009, 11,
2928.
(9) See: Alexakis, A.; Gille, S.; Prian, F.; Rosset, S.; Ditrich, K.
Tetrahedron Lett. 2004, 45, 1449; and references cited
therein.
OMe
OMe
(R)-16
(R,S)-17
(10) By 1H NMR analysis on the crude reaction mixture and then
confirmed after purification only one product was detected;
HPLC analysis showed the presence of the other
Scheme 3 Stereoselective reduction of chiral imines 14 and 16
diastereomer to be <0.5%, see Supporting Information. For
a recent contribution on the analytical aspect, see: Claridge,
T. D. W.; Davies, S. G. M.; Polywka, E. C.; Roberts, P. M.;
Russell, A. J.; Savory, E. D.; Edward, D.; Smith, A. D. Org.
Lett. 2008, 10, 5433.
In conclusion, we have developed a very convenient, low
cost protocol for a highly stereoselective reduction of
ketimines15 bearing a very cheap and removable chiral
auxiliary, promoted by an achiral inexpensive Lewis base.
A very simple experimental procedure allows to obtain
the products often with very high diastereomeric excess.
(11) For the diastereoselective reduction of these chiral substrates
through hydrogenation with different catalytic systems, see:
Nugent, T. C.; El-Shazly, M.; Wachaure, V. N. J. Org.
Chem. 2008, 73, 1297; and references cited therein.
(12) (a) For selective debenzylation reactions, see: Kanai, M.;
Yasumoto, M.; Kuriyama, Y.; Inomiya, K.; Katsuhara, Y.;
Higashiyama, K.; Ishii, A. Org. Lett. 2003, 5, 1007. (b) In
our hands the deprotection required hydrogenation for 12 h
at 25 °C and 9.9 bar, with catalytic amounts of Pd/C.
(13) Wakchaure, V. N.; Mohanty, R. R.; Shaikh, A. J.; Nugent,
T. C. Eur. J. Org. Chem. 2007, 959.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. It includes
characterization of reaction products, 1H NMR spectra, and HPLC
chromatograms on chiral stationary phase of chiral amines.
Acknowledgment
(14) Chen, Z. Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3464.
(15) Typical Experimental Procedure for the Reduction of
Ketimines
This work was supported by MIUR: ‘Nuovi metodi catalitici stereo-
selettivi e sintesi stereoselettiva di molecole funzionali’.
To a stirred solution of the imine (1 mmol/equiv, for the
imine synthesis see Supporting Information) in CH2Cl2 (2
mL), DMF (6 mmol/equiv) was added. The mixture was then
cooled to –50 °C and HSiCl3 (3 mmol/equiv) was added
dropwise by means of a syringe. The reaction was quenched
by the addition of NaHCO3 sat. soln (2 mL). The mixture
was allowed to warm up to r.t. and H2O (2 mL) and CH2Cl2
(5 mL) were added. The organic phase was separated and the
combined organic phases were dried over Na2SO4, filtered,
and concentrated under vacuum to afford the crude product.
References and Notes
(1) Reviews: (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138. (b) Dondoni, A.; Massi, A. Angew. Chem.
Int. Ed. 2008, 47, 4638. (c) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed. 2008, 47,
6138.
Synlett 2010, No. 1, 134–136 © Thieme Stuttgart · New York

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