Secondary amine formation from reductive amination of carbonyl compounds promoted by lewis acid using the InCl3ZEt3SiH system

Article abstract of DOI:10.1021/ol901111g

A robust and reliable method has been developed for reductive amination of primary amines with various aldehydes and ketones using Zn(ClO₄) ₂.6H₂0 as a catalyst. [In-H] generated in situ via a combination of InCl₃ and Et₃SiH is employed as an effective reducing system. A variety of secondary amines can be synthesized in a one-pot procedure in excellent yields.

Full text of DOI:10.1021/ol901111g

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3302-3305
Secondary Amine Formation from
Reductive Amination of Carbonyl
Compounds Promoted by Lewis Acid
Using the InCl3/Et3SiH System
On-Yi Lee, Ka-Lun Law, and Dan Yang*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, P.R. China
yangdan@hku.hk
Received May 20, 2009
ABSTRACT
A robust and reliable method has been developed for reductive amination of primary amines with various aldehydes and ketones using
Zn(ClO4)2·6H2O as a catalyst. [In-H] generated in situ via a combination of InCl3 and Et3SiH is employed as an effective reducing system. A
variety of secondary amines can be synthesized in a one-pot procedure in excellent yields.
Secondary amines constitute an important class of chemical
compounds that has a prodigious potential for industrial,1
pharmaceutical,2 and agrochemical3 applications. For the syn-
thesis of secondary amines,4 methods involving reductive
amination of carbonyl compounds remain the simplest approach.
However, overalkylation of amines (in particular, with alde-
hydes), a commonly encountered problem with this approach,
has been widely reported in the literature.5 In practice, conditions
including catalytic hydrogenation6 and reduction of imine
intermediates by NaBH3CN7 are frequently employed. Unfor-
tunately, the utility of these has been limited by a number of
unfavorable factors: specifically, hydrogenation is not compat-
ible with olefinic functional groups, while the use of the highly
toxic NaBH3CN generates many safety and environmental
issues. Recently, alternative reagents including NaBH(OAc)3
have been developed for this purpose.5,8
However, the utility of those reagents in reductive ami-
nation has not yet been fully covered. Although some indirect
methods for synthesis from alkynes9 have also been reported,
these entail extra experimental procedures, which are not
preferred in synthetic chemistry.10,11 To extend the scope
(6) (a) Rylander, R. N. Catalytic hydrogenation in organic synthesis;
Academic Press: New York, 1979; p 165. For modification of Leuckart’s
synthesis of primary amines from ketones using HCOONH4 and Pd-C,
see: (b) Allegretti, M.; Berdini, V.; Candida, C. M.; Curti, R.; Nicolini, L.;
Topai, A. Tetrahedron Lett. 2001, 42, 4257. (c) Gross, T.; Seayad, A. M.;
Ahmad, M.; Beller, M. Org. Lett. 2002, 4, 2055, and references cited therein.
(1) Gibson, M. S. In The Chemistry of the Amino Group; Patai, S., Ed.;
Wiley-Interscience: New York, 1968; p 61.
(2) Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112.
(3) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805.
(d) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977.
(7) For reviews on the use of sodium cyanoborohydride, see: (a) Lane,
C. F. Synthesis 1975, 135. (b) Borch, R. F.; Bernstein, M. D.; Durst, H. D.
J. Am. Chem. Soc. 1971, 93, 2897. (c) Hutchins, R. O.; Hutchins, M. K. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
(4) For reviews on secondary amine formation, see: (a) Salvatore, R. N.;
Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785. (b) Seayad, J.;
Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth. Catal. 2002, 344, 795.
(c) Gomez, S.; Peters, J. A.; Maschmeyer, T. AdV. Synth. Catal. 2002, 344,
1037.
Press: Oxford, 1991; Vol. 8, p 25
.
(8) For reviews on the use of sodium triacetoxyborohydride, see: (a)
Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.
1990, 31, 5595. (b) Abdel-Magid, A. F.; Maryanoff, C. A. Synlett 1990,
(5) (a) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry;
Wiley: New York, 2001; p 1187, and references cited therein. (b) Abdel-
Majid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shath, R. J.
Org. Chem. 1996, 61, 3849. (c) Borch, R. F.; Durst, H. D. J. Am. Chem.
Soc. 1969, 91, 3996.
537
.
(9) Heutling, A.; Pohlki, F.; Bytschkov, I.; Doye, S. Angew. Chem., Int.
Ed. 2005, 44, 2951.
10.1021/ol901111g CCC: $40.75
Published on Web 07/10/2009
 2009 American Chemical Society

and improve the selectivity of reductive amination reactions,
several other reagents have been developed.12
Table 1. Effects of Lewis Acids on Reductive Amination
We reported the InCl3/Et3SiH/MeOH system13 as a highly
chemoselective, mild reducing agent that can be used in
reductive amination reactions to afford tertiary amines. Extend-
ing our scope to secondary amine formation, we observed the
formation of overalkylation products as major product between
trans-cinnamaldehydes and benzylamine HCl salts (eq 1). On
the other hand, replacing benzylamine HCl salts with benzy-
lamines failed to produce the desired product (eq 2). To address
the problem, we employed Lewis acid, as catalysts in reductive
amination.14 In Scheme 1, an imine intermediate is predomi-
Reactionsa
entry
Lewis acid
yield (%)b
1
2
3
4
5
6c
Zn(OTf)2
85
Zn(ClO4)2·6H2O
FeSO4·7H2O
Fe(ClO4)2·xH2O
-
100
78
73
nrd
nrd
Zn(ClO4)2·6H2O
a Unless otherwise indicated, all reactions were carried out in MeOH at
room temperature using 0.5 mmol of 1a, 0.5 mmol of 2a, 0.3 equiv of
InCl3, 0.5 equiv of Lewis acid, and 2 equiv of Et3SiH. b Yields were
determined by 1H NMR using DMF as an internal standard. c No InCl3
was added. d No reaction.
Scheme 1
.
Concept of Lewis Acid-Promoted Reductive
Amination Reaction
that the system has its advantage upon water allowance as
reported by our group.13 Notably, no reaction was found in
the absence of Lewis acid (entry 5), suggesting the necessity
of Lewis acid activation. Most importantly, no conversion
of substrate was found in the absence of InCl3 (entry 6),
which confirms that In(III) was responsible for the reduction
via in situ generated [In-H] species and that it did not act
as a Lewis acid in catalyzing reductive amination.
nantly formed between the carbonyl compound and primary
amine, and its reactivity toward reduction could be enhanced
by binding to a Lewis acid.
We then explored reductive amination reactions of alde-
hydes with primary amines, as illustrated in Table 2. A wide
scope of small to bulky primary amines including benzylic,
allylic, aliphatic, cyclic, and aryl amines were successfully
tested. Reductive amination reaction with 4-methoxybenzal-
dehyde to produce secondary amines was observed in
excellent to quantitative yields (entries 1-5). Reactions of
less electron-rich benzaldehyde and p-tolualdehyde with
benzylamine could also proceed smoothly (entries 6 and 7).
Heteroaromatic aldehydes (for example, 2-furaldehyde)
resulted in efficient reaction (entry 8). Apart from aromatic
aldehydes, a number of unsaturated aldehydes were also
We started off by screening various Lewis acids for reductive
amination between 4-methoxybenzaldehyde (1a) and benzyl-
amine (2a). The reaction was carried out with a 1:1 ratio of
aldehyde and amine in the presence of 0.5 equiv of Lewis acid,15
0.3 equiv of InCl3, and 2.0 equiv of Et3SiH in MeOH at room
temperature. Organosilanes12f,g,16,17 were used in the reactions
for their mild reducing ability, low toxicity, and low
environmental impact. We focused on screening Lewis acids
derived from the transition metal series18 and found that
Fe(II) and Zn(II) complexes gave the best results (Table 1).
Among these, quantitative yield was achieved with
Zn(ClO4)2·6H2O (entry 2). Other hydrated Lewis acids such
as FeSO4·7H2O and Fe(ClO4)2·xH2O could also catalyze the
reactions effectively (78% and 73% yields, respectively;
entries 3 and 4). This finding provided corroborative evidence
(12) Recent examples of reductive amination in secondary amine
synthesis by various reagents. For Ti(OiPr)4-polymethylhydrosiloxane, see:
(a) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 1655. For
((EBTHI)TiF2)-polymethylhydrosiloxane, see: (b) Hansen, M. C.; Buchwald,
S. L. Org. Lett. 2000, 2, 713. For Bu2SnClH and Bu2SnIH, see: (c) Shibata,
I.; Suwa, T.; Sugiyama, E.; Baba, A. Synlett 1998, 1081. (d) Suwa, T.;
Sugiyama, E.; Shibata, I; Baba, A. Synthesis 2000, 789. (e) Shibata, I.;
Moriuchi-Kawakami, T.; Tanizawa, D.; Suwa, T.; Sugiyama, E.; Matsusda,
H.; Baba, A. J. Org. Chem. 1998, 63, 383. For PhMe2SiH-B(C6F5)3, see:
(f) Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. Org. Lett. 2000,
2, 3921For Zn(BH4)2-silica gel, see: (g) Ranu, B. C.; Majee, A.; Sarkar, A.
J. Org. Chem. 1998, 63, 370. For NiCl2-NaBH4, see: (h) Saxena, I.; Borah,
R.; Sarma, J. C. J. Chem. Soc., Perkin Trans. 1 2000, 503. For decaborane,
see: (i) Bae, J.-W.; Lee, S.-H.; Cho, Y.-J.; Yoon, C.-M. J. Chem. Soc.,
Perkin Trans. 1 2000, 145. For R-picoline-borane, see: (j) Sato, S.;
Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60, 7899.
(13) Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008,
73, 8829.
(10) (a) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett. 1994,
539. (b) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53, 15787.
(c) Salvatore, R. N.; Shin, S. I.; Nagle, A. S.; Jung, K. W. J. Org. Chem.
2001, 66, 1035.
(14) For examples of the use of Lewis acids in amine synthesis, see:
(a) Phanstiel, IV, O.; Wang, Q. X.; Powell, D. H.; Ospina, M. P.; Lesson,
B. A. J. Org. Chem. 1999, 64, 803. (b) Bar-Haim, G.; Kol, M. Tetrahedron
Lett. 1998, 39, 2643. (c) Miura, K.; Ootsuka, K.; Suda, S.; Nishikori, H.;
Hosomi, A. Synlett 2001, 10, 1617. (d) Chi, Y.-X.; Zhou, Y.-G.; Zhang, X.
J. Org. Chem. 2003, 68, 4120.
(11) For recent examples of secondary amine synthesis, see: (a) Fujita,
K,-I.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003, 44, 2687.
(b) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977. (c) Yu, Y.;
Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631. (d) Fujita, K.-I.; Li,
Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003, 44, 2687.
(15) When the Lewis acid loading was reduced to 0.3 equiv or lower,
poor conversion and product yield were observed.
Org. Lett., Vol. 11, No. 15, 2009
3303

Table 2. Reductive Amination of Aldehydes with Primary
Table 3. Lewis Acid-Promoted Reductive Amination of Ketones
Aminesa
with Primary Aminesa
a Unless otherwise indicated, all reactions were carried out in MeOH
(1 mL) at room temperature using 0.5 mmol of ketone. 0.5 mmol of primany
amine, 0.3 equiv of InCl3, 0.5 equiv of Zn(ClO4)2·6H2O, and 2 equiv of
a Unless otherwise indicated, all reactions were carried out in MeOH
(1 mL) at room temperature using 0.5 mmol of aldehyde, 0.5 mmol of
primany amine, 0.3 equiv of InCl3, 0.5 equiv of Zn(ClO4)2·6H2O, and 2
equiv of Et3SiH for 24 h. b Yields were determined by 1H NMR using DMF
as an internal standard. c Isolated yield in parentheses. d The Z:E ratio is in
parentheses.
b
1
Et3SiH for 24 h. Yields were determined by H NMR using DMF as an
internal standard. c Isolated yield in parentheses. d Yield based on 84%
conversion. e The HCl salts were prepared.
ketones to form the imine intermediate. Reactions of ben-
zylamine with various aliphatic cyclic ketones were highly
efficient, affording products in high to quantitative yields
(entries 1-4). In contrast, aromatic ketones displayed lower
reactivity, and the reaction between 1-indanone and benzyl-
amine thus proceeded slowly with only 84% conversion
(entry 5). Apart from benzylamine, other types of amines
also exhibited excellent reactivity toward ketones (entries
7-10). In addition, the simple aliphatic ketone 1n also
delivered promising results (entries 6, 11, and 12). Again,
no overalkylation products were detected, indicating good
chemoselectivity of the reaction system.
examined, including R,ꢀ-unsaturated aldehydes (entries
9-13). The observation of minor Z-product in entries 9-11
revealed partial double bond isomerization may occur during
the reduction process.19 Saturated aldehyde 1g reacted
smoothly with benzylamine to afford product in 75% yield
(entry 14). Most importantly, none of the entries gave
overalkylation products, suggesting that the system is highly
effective with various sizes of amines.
We next explored the reactions involving different ketones
(1h-n), and the results are summarized in Table 3. The
reactivity of the system depends on the ability of different
3304
Org. Lett., Vol. 11, No. 15, 2009

We believe that the Lewis acids play an important part in
activating the imine intermediate toward reduction. To gain
insights into the role of Lewis acids, we conducted control
experiments for illustration.
4 was isolated and subjected to reduction by InCl3/Et3SiH
in MeOH. It can be inferred that Lewis acid is necessary for
promoting successful reductions. Thus, no conversion of
imine 4 occurred in the absence of Zn(ClO4)2·6H2O (eq 7),
whereas 56% yield of 3a was obtained with the addition of
the Lewis acid (eq 8). The results also strongly suggest that
Zn(ClO4)2·6H2O can serve as a Lewis acid to activate imine,
which enhanced the electrophilicity of the CdN group for
hydride delivery.
First, we investigated if there is any effect of Lewis acid
Zn(ClO4)2·6H2O on the equilibrium among aldehyde, amine,
and imine. The studies on imine formation between 4-meth-
oxybenzaldehyde and benzylamine were compared. Surpris-
ingly, the addition of Zn(ClO4)2·6H2O resulted in an equilibrium
with 40% of imine formation (eq 3). On the other hand, 99%
of imine was formed in the absence of Zn(ClO4)2·6H2O (eq 4).
The equilibrium was further supported by the reverse experi-
ment described in eqs 5 and 6. Upon addition of
Zn(ClO4)2·6H2O to imine 4, a shift in the equilibrium occurred
in the backward reaction, giving 65% 4-methoxybenzaldehyde
and 35% imine, a ratio similar to that between aldehyde and
amine as starting materials. These results implied that
Zn(ClO4)2·6H2O altered the equilibrium position in the imine
formation process; however, it did not directly relate to the
enhanced reactivity observed in reactions.
In conclusion, we have developed a new method of wide
scope for Lewis acid-promoted reductive amination to give
secondary amines using an InCl3/Et3SiH/MeOH system. With
this robust system, both aldehydes and ketones can be
applied. In addition, the system has a number of advantages
in terms of convenience, low toxicity, and nonwater sensitiv-
ity. We have further demonstrated that the role of Lewis acids
in the direct reductive amination reaction is to activate the
in situ generated imine toward reduction. Asymmetric
reductive amination of ketones and amines constitutes
another promising area for future investigation.
Acknowledgment. This work was supported by The
University of Hong Kong and the Hong Kong Research
Grants Council.
Supporting Information Available: Experimental pro-
cedures and spectral data for 3a-z and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901111G
(16) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
(17) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 1655.
(18) No desired product was observed with Lewis acids CuBr, CuBr2,
Cu(OTf)2, Fe(NO3)3·9H2O, Fe(acac)3, Zn(OAc)2, ZnCl2, ZnI2, Ni(acac)2, and
Ni(ClO4)2·6H2O.
(19) No partial double bond isomerization was observed when 1e and
the Lewis acid were stirred with or without amine, suggesting that the partial
double bond isomerization is unlikely to be caused by the Lewis acid itself.
Additionally, we investigated the effect of Lewis acid on
the reactivity of the reduction system. The imine intermediate
Org. Lett., Vol. 11, No. 15, 2009
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