Towards a practical br?nsted acid catalyzed and hantzsch ester mediated asymmetric reductive amination of ketones with benzylamine

Article abstract of DOI:10.1055/s-0030-1259003

We report the use of benzylamine as the amine component in Hantzsch ester mediated and chiral Br?nsted acid catalyzed enantioselective reductive aminations of ketones. The method is noteworthy because the benzyl group is easily removable, and amine product purification is achieved through Hantzsch ester oxidation product removal via basic hydrolysis.

Full text of DOI:10.1055/s-0030-1259003

2708
LETTER
Towards a Practical Brønsted Acid Catalyzed and Hantzsch Ester Mediated
Asymmetric Reductive Amination of Ketones with Benzylamine
A
symmetric Redu
i
A
j
minatio
a
n of
K
eton
y
es with Benzylami
N
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062982; E-mail: list@mpi-muelheim.mpg.de
Received 24 August 2010
phenanthrene- and anthracene-substituted phosphoric ac-
Abstract: We report the use of benzylamine as the amine compo-
nent in Hantzsch ester mediated and chiral Brønsted acid catalyzed
enantioselective reductive aminations of ketones. The method is
noteworthy because the benzyl group is easily removable, and
ids 4e and 4f emerged as the best catalysts. The highest
enantioselectivities were obtained with the 9-anthryl-
substituted phosphoric acid 4f, which provided amine
amine product purification is achieved through Hantzsch ester oxi- product 5a in 94:6 er.
dation product removal via basic hydrolysis.
The efficient removal of water formed during the reaction
Key words: benzylamine, Hantzsch ester, reductive amination,
organocatalysis, chiral amines, Brønsted acids
is important. While we have initially used molecular
sieves for this purpose, we later found that azeotropic re-
moval using a Dean–Stark trap under refluxing conditions
at reduced pressure (57 °C, 167 mbar) is quite effective
and practical as well.
The catalytic asymmetric reductive amination of carbonyl
compounds is not only an attractive strategy for carbon–
nitrogen bond-forming fragment couplings but potentially Table 1 Catalyst Screeninga
also a powerful approach to chiral primary amines.1 Re-
O
HN
Ph
cently, we have developed a Brønsted acid catalyzed
2 (1 equiv), 3 (1.4 equiv)
asymmetric reductive amination of ketones using
Hantzsch esters as hydride source, and 3,3¢-bis(2,4,6-tri-
isopropylphenyl)-1,1¢-binaphthyl-2,2¢-diyl hydrogen phos-
phate (TRIP) as Brønsted acid organocatalyst.2–4 Both
Rueping et al.3a and MacMillan et al.3b developed alterna-
tive variants and additional applications of these method-
ologies have appeared.3,5 Despite these advances,
however, such catalytic asymmetric reductive aminations
have been limited to aromatic amines, in particular p-ani-
sidine. While the so-introduced p-methoxyphenyl group
(PMP) can be easily removed under oxidative conditions
to release the corresponding primary amine, p-anisidine is
toxic, and the protecting group removal conditions are
rather challenging for large-scale and industrial applica-
tions.6,7 A possibly attractive alternative would be to use
benzylamine, which introduces an easily removable ben-
zyl protecting group. Here we report progress towards the
realization of this goal with a chiral Brønsted acid cata-
lyzed and Hantzsch ester mediated enantioselective re-
ductive amination of ketones using benzylamine as the
amine component.
4 (5 mol%), toluene, 57 °C
167 mbar, Dean–Stark reflux, 5 d
1a (3 equiv)
5a
Ar
H
H
EtO2C
CO2Et
O
O
O
H2N
Ph
P
OH
2
N
H
3
Ar
4a–f
Entry
Ar
4
Conv. (%)b erc
1
2
3
4
5
6
Ph
4a
4b
4c
4d
4e
4f
99
97
95
98
99
99
79:21
85:15
4-biphenyl
2,4,6-(i-Pr)3C6H2
3,5-(F3C)2C6H3
9-phenanthryl
9-anthryl
63:37
84:16
91:9
94:6
a Conditions: 0.5 mmol scale.
b From GC analysis.
In initial optimization studies, we found the use of ketone
1 (3 equiv), benzylamine 2 (1 equiv), Hantzsch ester 3
(1.4 equiv), and toluene as the solvent to furnish the de-
sired product 5 upon treatment with a chiral acid catalyst.
We have synthesized and screened chiral phosphoric acid
catalysts 4a–f for the enantioselective reductive amina-
tion of acetophenone (1a, Table 1). From this survey the
c From chiral HPLC analysis (see the Supporting Information).
With catalyst 4f we also examined other ketone substrates
for the enantioselective reductive amination with benzyl-
amine under optimized reaction conditions. As shown in
(Table 2), aromatic as well as aliphatic ketone substrates
can be successfully used (entries 1–4). Under preparative
conditions, acetophenone gave the corresponding amine
product 5a in high yield (96%) and enantioselectivity
(94:6 er).8 Subjecting other ketones to the reductive ami-
SYNLETT 2010, No. 18, pp 2708–2710
x
x
.x
x
.2
0
1
0
Advanced online publication: 14.10.2010
DOI: 10.1055/s-0030-1259003; Art ID: G26010ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Reductive Amination of Ketones with Benzylamine
2709
nation conditions generally gave the corresponding prod- the first recycle of the catalyst, and after re-adding the re-
ucts in lower enantioselectivity. For example, 4-chloro agents, the reaction goes to completion after five days to
acetophenone gave amine 5b in 85:15 er. Also, while ali- provide the product in 93% yield while maintaining the
phatic ketone substrates can be reductively aminated with same enantiomeric ratio (94:6). As expected, debenzyla-
benzylamine, the enantiomeric ratios are once again lower tion of product 5 can be easily be performed via a simple
(entries 3 and 4).
hydrogenolysis (H2, Pd/C). This unoptimized step fur-
nished the desired product in 77% yield.
Another general problem of Hantzsch ester mediated imi-
ne reductions and reductive aminations is that in addition
to the desired amine product, the corresponding Hantzsch
pyridine is produced and can be difficult to separate.
H
H
EtO2C
CO2Et
N
Table 2 Preliminary Substrate Scopea
H2N
Ph
H
O
EtO2C
CO2Et
NHBn
2 (1.0 equiv) 3 (1.4 equiv)
O
+
HN
Ph
2 (1 equiv), 3 (1.4 equiv)
4f (5 mol%), toluene
57 °C, 167 mbar,
Dean–Stark reflux, 5 d
Ph
Ph
N
R
1a
(3 equiv)
4f (5 mol%), toluene, 57 °C
167 mbar, Dean–Stark reflux, 5 d
5a
er = 96:4
R
1 (3 equiv)
5
+
4f (catalyst),
excess of 3 and 1a
recycle organic phase
Entry
5
Product
Yield (%)b erc
4f (catalyst),
excess of 3 and 1a
add 4 N HCl
HN
Ph
1
5a
96
89
94:6
EtO2C
CO2Et
NH2Bn
Cl–
+
Ph
N
HN
Ph
H+
Cl–
HN
Ph
aqueous phase
2
5b
85:15
5a
96%, er = 94:6
(pure product)
add KOH
CO2K
Cl
extract &
isolate
HN
Ph
Pd/C (10 mol%)
2 (1 atm)
3
5c
81
59
63:37
73:27
KO2C
H
MeOH, r.t., 24 h
N
NH2
discharge
aqueous
phase
HN
Ph
4d
5d
77%
a Conditions: 0.5 mmol scale.
b Isolated yield.
Scheme 1 Production purification and isolation by acid/base
workup.
c From chiral HPLC analysis (see the Supporting Information).
d Reaction time 7 d.
In summary, we demonstrate the use of benzylamine as
the amine component in the asymmetric Brønsted acid
catalyzed enantioselective reductive amination of ketones
using the Hantzsch ester as hydrogen source. Notable ad-
vantages of the present method include (1) its simplicity
and practicability, (2) product purification via removal of
Hantzsch pyridine by hydrolysis, and (3) the successful
recycle of the catalyst and excess of ketone and Hantzsch
ester without affecting the enantioselectivity. Despite
these advancements, further improvements on the scope,
enantioselectivity, and reactivity of this transformation
are clearly needed but also expected.
To further improve the practicality of our method, we
have therefore investigated the workup and purification
procedure towards an effective removal of this byproduct.
This was finally achieved in the following way
(Scheme 1): After completion of the reaction, the mixture
was treated with 4 N HCl, which removes both the amine
product 5a and the Hantzsch pyridine into the aqueous
phase by hydrochloride salt formation. In contrast, cata-
lyst 4f as well as excess ketone and Hantzsch ester re-
mains in the organic layer. Neutralizing the aqueous layer
with solid potassium hydroxide (KOH) and then adding
more KOH (8 equiv), results in the hydrolysis of the ester
groups of the Hantzsch pyridine to furnish the correspond-
ing water-soluble potassium carboxylate. Extraction with
ethyl acetate provides the pure chiral amine product 5a in
96% yield with the same enantiomeric ratio (94:6). Under
these optimized reaction conditions, it is possible to recy-
cle the catalyst and excess ketone and Hantzsch ester. In
General Procedure for the Phosphoric Acid Catalyzed Reduc-
tive Amination of Ketones
In a typical experiment a mixture of ketone 1 (1.5 mmol, 3.0 equiv),
benzylamine (2, 0.5 mmol, 1.0 equiv, 0.055 mL), Hantzsch ester 3
(0.7 mmol, 1.4 equiv, 0177 g), and phosphoric acid 4f (5 mol%,
0.025 mmol, 0.0175 g) in toluene (15 mL) were stirred at 57 °C
Synlett 2010, No. 18, 2708–2710 © Thieme Stuttgart · New York

2710
V. N. Wakchaure et al.
LETTER
examples of Lewis base catalyzed asymmetric imine
under Dean–Stark refluxing conditions at reduced pressure (167
mbar) for 5–7 d. The solvent was removed under reduced pressure
and purification of the crude by column chromatography on silica
gel afforded the pure amine 5. The er values were determined by us-
ing established HPLC techniques with chiral stationary phases.
reduction using silanes, see: (i) Iwasaki, F.; Onomura, O.;
Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura, Y.
Tetrahedron Lett. 2001, 42, 2525. (j) Malkov, A. V.;
Mariani, A.; MacDougall, K. N.; Kočovský, P. Org. Lett.
2004, 6, 2253. (k) Malkov, A. V.; Stoncius, S.; MacDougall,
K. N.; Mariani, A.; McGeoch, G. D.; Kočovský, P.
Tetrahedron 2006, 62, 264. (l) Wang, Z.; Ye, X.; Wei, S.;
Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 8, 999. (m) Pei,
D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal.
2008, 350, 619. (n) Wang, C.; Wu, X.; Zhou, L.; Sun, J.
Chem. Eur. J. 2008, 14, 8789. (o) Wu, P. C.; Wang, Z. Y.;
Cheng, M. N.; Zhou, L.; Sun, J. Tetrahedron 2008, 64,
11304. (p) Gautier, F.-M.; Jones, S.; Martin, S. J. Org.
Biomol. Chem. 2009, 7, 229. (q) Guizzetti, S.; Benaglia, M.;
Cozzi, F.; Rossi, S.; Celentano, G. Chirality 2009, 21, 233.
For structural and mechanistic studies, see: (r) Zhang, Z.;
Rooshenas, P.; Hausmann, H.; Schreiner, P. R. Synthesis
2009, 1531.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Wacker for partly funding this study. Generous support
by the Max-Planck-Society, the Deutsche Forschungsgemeinschaft
(Priority Program 1179 Organocatalysis), and the Fonds der
Chemischen Industrie is gratefully acknowledged.
References and Notes
(4) (a) Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta
2008, 41, 31. For pioneering studies on the use of chiral
phosphoric acid catalysts, see: (b) Akiyama, T.; Itoh, J.;
Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,
1566. (c) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356. For reviews, see: (d) Connon, S. J. Angew.
Chem. Int. Ed. 2006, 45, 3909. (e) Akiyama, T. Chem. Rev.
2007, 107, 5744. (f) Terada, M. Chem. Commun. 2008,
4097. Also see: (g) Guo, Q.-X.; Liu, H.; Guo, C.; Luo,
S.-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129,
3790. (h) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.;
Zhou, Q.-L. Angew. Chem. Int. Ed. 2007, 46, 5565. (i) Jiao,
P.; Nakashima, D.; Yamamoto, H. Angew. Chem. Int. Ed.
2008, 47, 2411.
(1) For a review on asymmetric reductive aminations, see:
(a) Tararov, V. I.; Börner, A. Synlett 2005, 203. For
reviews on catalytic asymmetric imine reductions, see:
(b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, Chap. 1. (c) Ohkuma, T.; Noyori, R. In
Comprehensive Asymmetric Catalysis, Suppl. 1; Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York,
2004, 43. (d) Nishiyama, H.; Itoh, K. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000. (e) Blaser, H.-U.; Buser, H.-P.; Jalett,
H.-P.; Pugin, B.; Spindler, F. Synlett 1999, 867.
(f) Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int. Ed.
2003, 42, 5472. (g) Williams, G. D.; Pike, R. A.; Wade, C.
E.; Wills, M. Org. Lett. 2003, 5, 4227. (h) Kadyrov, R.;
Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Börner, A.
J. Org. Chem. 2003, 68, 4067. (i) Chi, Y. X.; Zhou, Y. G.;
Zhang, X. M. J. Org. Chem. 2003, 68, 4120.
(5) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc.
2006, 128, 13074.
(6) (a) Sakai, T.; Korenaga, T.; Washio, N.; Nishio, Y.; Minami,
S.; Ema, T. Bull. Chem. Soc. Jpn. 2004, 77, 1001. (b) Hata,
S.; Iguchi, I.; Iwasawa, T.; Yamada, K.; Tomioka, K. Org.
Lett. 2004, 6, 1721. (c) Overman, L. E.; Owen, C. E.; Pavan,
M. P. Org. Lett. 2003, 5, 1809. (d) Chi, Y.; Zhou, Y.-G.;
Zhang, X. J. Org. Chem. 2003, 68, 4120. (e) Fustero, S.;
Garcia Soler, J.; Bartolomé, A.; Sanchez-Rosello, M. Org.
Lett. 2003, 5, 2707. (f) Fustero, S.; Bartolomé, A.; Sanz-
Cervera, J. F.; Sanchez-Rosello, M.; Soler, J. G.;
(2) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed.
2005, 44, 7424.
(3) For other organocatalytic asymmetric reductive aminations
and imine reductions, see: (a) Rueping, M.; Sugiono, E.;
Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7,
3781. (b) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 84. (c)Singh, S.; Batra,
U. K. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1989, 28, 1; please note that so far, we have been unable to
reproduce any of the enantioselectivities reported in this
paper . For organocatalytic asymmetric of a-imino ester
reductions, see: (d) Li, G.; Liang, Y.; Antilla, J. C. J. Am.
Chem. Soc. 2007, 129, 5830. (e) Kang, Q.; Zhao, Z.-A.;
You, S.-L. Adv. Synth. Catal. 2007, 349, 1657. For a
theoretical study, see: (f) Simón, L.; Goodman, J. M. J. Am.
Chem. Soc. 2008, 130, 8741. For a review, see: (g)Connon,
S. J. Org. Biomol. Chem. 2007, 5, 3407. For organo-
catalytic asymmetric enamide reductions, see: (h) Li, G.;
Antilla, J. C. Org. Lett. 2009, 11, 1075. For selected
Ramirez de Arellano, C.; Fuentes, A. S. Org. Lett. 2003, 5,
2523. (g) Córdova, A. Synlett 2003, 1651.
(7) (a) Verkade, J. M. M.; van Hermert, L. J. C.; Quaedflieg,
P. J. L. M.; Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T.
Tetrahedron Lett. 2006, 47, 8109. (b) Verkade, J. M. M.;
van Hermert, L. J. C.; Quaedflieg, P. J. L. M.; Schoemaker,
H. E.; Schürmann, M.; van Delft, F. L.; Rutjes, F. P. J. T.
Adv. Synth. Catal. 2007, 349, 1332.
(8) The absolute configuration of amine 5a was established via
comparing the HPLC chromatogram with authentic sample
of (S)-5a.
Synlett 2010, No. 18, 2708–2710 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.