Highly chemoselective reductive amination of carbonyl compounds promoted by InCl3/Et3SiH/MeOH system

Article abstract of DOI:10.1021/jo8016082

(Chemical Equation Presented) A new strategy has been developed for reductive amination of aldehydes and ketones with the InCV Et ₃SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our conditions. The reaction shows a first-order kinetics profile with respect to both InCl₃ and Et₃SiH. Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting species arising from InCl₃ and Et₃SiH in MeOH, which are important in deriving a mechanistic proposal. In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III) species which are presumably responsible for the gentle generation of indium hydride at room temperature. The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in the system being highly chemoselective.

Full text of DOI:10.1021/jo8016082

Highly Chemoselective Reductive Amination of Carbonyl
Compounds Promoted by InCl3/Et3SiH/MeOH System
On-Yi Lee, Ka-Lun Law, Chun-Yu Ho, and Dan Yang*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, People’s republic of China
yangdan@hku.hk
ReceiVed July 20, 2008
A new strategy has been developed for reductive amination of aldehydes and ketones with the InCl3/
Et3SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive
properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines.
Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our
conditions. The reaction shows a first-order kinetics profile with respect to both InCl3 and Et3SiH.
Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting
species arising from InCl3 and Et3SiH in MeOH, which are important in deriving a mechanistic proposal.
In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III)
species which are presumably responsible for the gentle generation of indium hydride at room temperature.
The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment
of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in
the system being highly chemoselective.
SCHEME 1
Introduction
Over the past decade, the growing use of catalytic indium(III)
halides in organic synthesis has attracted considerable attention.
With the advantage of indium(III) halides’ stability in air, their
combination with appropriate reducing agents has demonstrated
excellent degrees of chemoselective reducing activity toward
various functional groups. Extensive use of indium(III) halides
in different reaction types including selective double-bond
reduction,1 radical cyclization and radical addition,2 cleavage
of 2,3-epoxybromides,3 cyclization of enynes,4 Friedel-Crafts
alkylation,5 reduction of alkyl halides6 and aldehydes,7 reductive
aldol reaction,8 and other specific reactions9 has been reported.
Although indium(III) halides have been proven to be an
excellent catalyst for reduction, the application of the system
in iminium ion reduction has not yet been investigated. As
reductive amination10 is an important protocol in the construc-
tion of the carbon-nitrogen bond, we launch research on the
application of indium(III) halide as a catalyst in the area of
reductive amination.
(8) (a) Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem.,
Int. Ed. 2004, 43, 711. (b) Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A.
Synlett 2004, 1985.
(9) For other selected reactions involving indium(III) halides, see: (a) Yasuda,
M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 1414. (b)
Yamada, M.; Tanaka, K.; Araki, S.; Butsugan, Y. Tetrahedron Lett. 1995, 36,
3169. (c) Yamada, M.; Horie, T.; Kawai, M.; Yamamura, H.; Araki, S.
Tetrahedron 1997, 53, 15685. (d) Ranu, B. C.; Jana, U. J. Org. Chem. 1998,
63, 8212. (e) Miura, K.; Fujisawa, N.; Hosomi, A. J. Org. Chem. 2004, 69,
2427. (f) Onishi, Y.; Ogawa, D.; Yasuda, M.; Baba, A. J. Am. Chem. Soc. 2002,
124, 13690. (g) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M.
Org. Lett. 2005, 7, 1363. (h) Lu, J.; Ji, S-.J.; Teo, Y.-C.; Loh, T.-P. Org. Lett.
2005, 7, 159. (i) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int.
Ed. 2004, 43, 1414. (j) Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 2539. (k) Teo,
Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743.
(1) (a) Ranu, B. C.; Samanta, S. Tetrahedron 2003, 59, 7901. (b) Ranu, B. C.;
Samanta, S. J. Org. Chem. 2003, 68, 7130. (c) Ranu, B. C.; Samata, S.
Tetrahedron Lett. 2002, 43, 7405.
(2) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002,
124, 906.
(3) Ranu, B. C.; Banerjee, S.; Das, A. Tetrahedron Lett. 2004, 45, 8579.
(4) Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981.
(5) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39, 6291.
(6) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. Tetrahedron Lett. 2001, 42,
4661.
(7) Miyai, T.; Inoue, K.; Yasuda, M.; Shibata, I.; Baba, A. Tetrahedron Lett.
1998, 39, 1929.
(10) Baxter, E. W.; Reitz, A. B. In Organic Reactions; Overman, L. E., Ed.;
Wiley: Singapore, 2002; Vol. 59.
10.1021/jo8016082 CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8829–8837 8829

Lee et al.
TABLE 1. Solvent Screening for Reductive Aminationa
Organosilanes are mild and environmentally benign reducing
agents, which have applications in many kinds of reactions.11
In recent years, only a small number of studies in the literatures
have reported the use of organosilanes in reductive amination12-17
and demonstrated relative success in addressing some of the
inherent disadvantages of traditional reducing agents.18 Unfor-
tunately, they, too, suffer from their own drawbacks: the TFA/
Et3SiH12 system is not compatible with acid labile functional
groups; applicability of TiCl4/PHMS14 is restricted to aromatic
entry
solvent
MeOH
conv (%)b
yield (%)b
1
2
3
4
5
6
7
100
50
30
10
82
61
72
100
49
2
EtOH
i-PrOH
15
t-BuOH
CF3CH2OH
CH3NO2
MeCN
0
aldehydes; Bu2SnCl2/PhSiH3 is highly toxic; Ti(OiPr)4/
PMHS16 is water-sensitive; and IrCl3/Et3SiH17 is not compatible
with substrates containing double bonds.
47
12
13
Here we first report a study on mild and highly chemoselec-
tive reductive amination of carbonyl compounds with secondary
amine salts using a reducing system of triethylsilane in the
presence of indium(III) chloride, as shown in Scheme 1. InCl3/
Et3SiH generates [In-H] species in situ,4,6 which reduces
iminium ion in a chemoselective manner. This is the first method
that utilizes [In-H] in reducing iminium ion.
a All reactions were performed at room temperature for 24 h with 0.5
mmol of trans-cinnamaldehyde, 0.5 mmol of N-methylaniline·HCl salt,
0.1 equiv of indium(III) chloride, and 2.0 equiv of Et3SiH in 1.7 mL of
the indicated solvent. b Determined by 1H NMR with DMF as an
internal standard.
TABLE 2. Screening of In(III) Sources for Reductive Aminationa
Results and Discussion
I. Optimization of Reaction Conditions. Our studies began
with screening of various solvents for reductive amination
between trans-cinnamaldehyde and N-methylaniline·HCl salt.
We conducted the reactions by adding the corresponding
amine·HCl salt (0.5 mmol) to a stirred solution of carbonyl
substrate (0.5 mmol) in 1.7 mL of solvent at room temperature.
After being stirred for 1 h, Et3SiH (0.15 mL, 1.0 mmol) was
added to the reaction mixture via a syringe, followed by the
addition of InCl3 (10 mol %). The results are summarized in
Table 1.
We employed polar solvents to facilitate the dissolution of
starting materials as well as the formation of iminium ion. As
shown in Table 1, among the solvents tested, alcoholic solvents
were generally more efficient (up to 100% conversion, 100%
yield; entries 1-5) than polar aprotic solvents (up to 72%
conversion, <20% yield; entries 6 and 7). Notably, the best
entry
InX3
InF3
InCl3
InBr3
InI3
time (h)
conv (%)b
yield (%)b
1
2
3
4
5
6
72
24
12
18
12
72
100
100
100
100
100
0
57
99
73
79
In(OTf)3
-
72
n.d.c
a All reactions were performed at room temperature with 0.5 mmol of
trans-cinnamaldehyde, 0.5 mmol of N-methylaniline·HCl salt, 0.1 equiv
of indium(III) halide, and 2.0 equiv of Et3SiH in 1.7 mL of methanol.
b Determined by 1H NMR with DMF as an internal standard. c Not
determined.
conversion and yield were achieved with MeOH as the solvent
(100% conversion, 100% yield; entry 1). In addition, we found
that sterically more hindered alcohols as solvents are associated
with lower substrate conversion and yield (cf. entry 1 and entries
2-4).
(11) For reviews on the use of organosilanes as reducing agents, see: (a)
Chatgilialoglu, C. In Organosilanes in Radical Chemistry; Wiley-VCH: Chich-
ester, UK, 2004; Chapters 3 and 4. (b) Kursanov, D. N.; Parnes, Z. N.; Loim,
N. M. Synthesis 1974, 633. (c) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25,
188. For other references, see: (d) Ballestri, M.; Chatgilialoglu, C.; Guerra, M.;
Guerrini, A.; Lucarini, M.; Seconi, G. J. Chem. Soc., Perkin Trans. 2 1993,
421. (e) Chatgilialoglu, C.; Guerra, M.; Guerrini, A.; Seconi, G. J. Org. Chem.
1992, 57, 2427. (f) Kamal, A.; Rao, N. V.; Laxman, E. Tetrahedron Lett. 1997,
38, 6945. (g) Lesage, M.; Simoes, J. A. M.; Griller, D. J. Org. Chem. 1990, 55,
5413. (h) Doyle, M. P.; West, C. T. J. Org. Chem. 1975, 40, 3829. (i)
Chatilialoglu, C.; Ferreri, C.; Lucarini, M. J. Org. Chem. 1993, 58, 249.
(12) (a) Chen, B.-C.; Sundeen, J. E.; Guo, P.; Bednarz, M. S.; Zhao, R.
Tetrahedron Lett. 2001, 42, 1245. (b) Dube, D.; Scholte, A. A. Tetrahedron
Lett. 1999, 40, 2295. (c) Webb, R. R.; Barker, P. L.; Baier, M.; Reynolds, M. E.;
Robarge, K. D.; Blackburn, B. K.; Tischler, M. H.; Weese, K. J. Tetrahedron
Lett. 1994, 35, 2113.
Next, various In(III) sources were examined and the results
are summarized in Table 2. Among the In(III) sources tested, a
trend can be observed in the In(III) catalysts of different halide
counterions. InCl3 gave the highest yield (entry 2). InF3 was
ineffective, with which the reaction was complete after 3 days
in low yield (57%, entry 1). The reaction rate increased upon
going down the series from InF3 to InBr3 (cf. entries 1-3).
In(OTf)3 displayed similar performance as InBr3 and complete
conversion was achieved in 12 h in 72% yield (entry 5). No
reaction was found in the absence of In(III) species (entry 6).
We then investigated the effect of loading InCl3 and Et3SiH.
In our observations, the reaction rate increased proportionally
with increasing amount of InCl3 (Table 3, entries 1-4), which
resembles a first-order kinetics profile. In addition, a similar
resemblance of a first-order kinetics profile was also found with
respect to the amount of Et3SiH administered (Table 3, entries
5-7). In a study by Ishii and colleagues17 on the use of Ir(III)/
Et3SiH in reductive alkylation of secondary amines, it was
proposed that the hydrogen source comes from both silane and
water in an equimolar ratio. Thus, the required amount of silane
would be only half of the essential hydrogen atoms delivered.
Our experimental findings revealed a nonresemblance between
(13) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
(14) Miura, K.; Ootsuka, K.; Suda, S.; Nishikori, H.; Hosomi, A. Synlett
2001, 10, 1617.
(15) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
(16) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M. Synlett 2000, 11, 1655.
(17) Mizuta, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 2195.
(18) For reviews using 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, 91, 2897. (c) Hutchins, R. O.; Hutchins, M. K. ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
UK, 1991; Vol. 8, p 25. For reviews using sodium triacetoxyborohydride, see:
(d) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah,
R. D. J. Org. Chem. 1996, 61, 3849. (e) Abdel-Magid, A. F.; Maryanoff, C. A.;
Carson, K. G. Tetrahedron Lett. 1990, 31, 5595. Sodium cyanoborohydride
requires large quantities of excess amine. Moreover, the reagent is highly toxic
and cyanides are generated as byproducts after reaction. Sodium triacetoxyboro-
hydride is not compatible with aromatic and unsaturated ketones.
8830 J. Org. Chem. Vol. 73, No. 22, 2008

ReductiVe Amination of Carbonyl Compounds
TABLE 3. Effect of InCl3/Et3SiH Loading in the Reductive
Amination Systema
conv (%)b
yield (%)b c
,
entry
equiv of InCl3/Et3SiH
time (h)
1
2
3
4
5
6
7
8
9
1.0/2.0
0.5/2.0
0.25/2.0
0.1/2.0
0.1/3.0
0.1/1.5
0.1/1.0
0.1/0.5
0.1/0.2
3
6
12
24
18
36
48
72
>96
100
100
100
100
100
100
100
88
100
100
100
100
100
100
100
42
<5
n.d.d
a All reactions were performed at room temperature for the indicated
reaction time with 0.5 mmol of trans-cinnamaldehyde, 0.5 mmol of
N-methylaniline HCl salt, and the indicated amount of InCl3 and Et3SiH
in 1.7 mL of MeOH. b Determined by integrating 1H NMR spectra
relative to an internal standard (DMF). c Based on conversion. d Not
determined.
FIGURE 1. Investigation on the effect of water content on the reductive
amination reaction.
In(III)- and Ir(III)-catalyzed reductive amination, which was
confirmed by incomplete conversion observed for loadings of
Et3SiH below 1.0 equiv (entries 8 and 9). These experimental
observations provide an important clue to the reaction mechanism.
As hydride ion reacts with water rapidly, many of the hydride
reduction reactions require strict anhydrous conditions.18a-c,19
A strict anhydrous reaction system created extra demands on
reagent quality as well as reaction handling. As a logical
alternative, the use of nonwater-sensitive reducing agents would
confer an advantage. We have also noticed that a considerable
number of silane reactions occur in aqueous media,20,21 and that
water is generated in situ during the formation of iminium salt
in reductive amination. It would be interesting to investigate
the possibility of a MeOH/water cosolvent system. As shown
in Figure 1, we found that the reaction between trans-
cinnamaldehyde and N-methylaniline·HCl salt displayed sat-
isfactory conversion with a cosolvent system of up to 10% water
in MeOH. Further increase in water content led to reduction in
yield due to the reduced solubility of starting materials in water.
Nevertheless, this result reveals the superiority of the InCl3/
Et3SiH system as a nonwater-sensitive reducing agent.
II. Reductive Amination of Various Carbonyl Compounds.
After gaining some initial insights about the reaction conditions,
we moved on to examine the reductive amination of trans-
cinnamaldehyde with various amine salts (Table 4). To achieve
higher catalytic efficiency, we increased the loading of InCl3
to 30 mol % and the reaction concentration to 0.5 M. Apart
fromN-methylaniline ·HClsalt,reactionswithaliphaticamine ·HCl
salts were also successful (entries 2-9).
Since most biologically interesting organic compounds con-
tain multiple functionalities, the reaction system will be valuable
if it demonstrates high chemoselectivity. We further tested the
system’s applicability with respect to different functional groups.
Morpholine·HCl salt reacted smoothly with trans-cinnamalde-
hyde to furnish 3c in 88% yield (entry 3), while the reaction
with proline methyl ester gave 3g in 80% yield (entry 7),
demonstrating the system’s compatibility with ether and ester
groups. Interestingly, reactions with 3-hydroxypiperidine and
prolinol gave products 3e and 3f, respectively, suggesting the
inertness of the OH functionality toward the reaction system
(entries 5 and 6). Notably, carboxylic acid was also compatible
with the system, as indoline-2-carboxylic acid gave product 3h
in 67% yield (entry 8). Furthermore, indoline-2-carboxylic acid
could be administered directly without preforming HCl salt
presumably because it contains a carboxylic acid group. Apart
from cyclic amines, acyclic dibenzylamine HCl salt was also
efficient in furnishing 3i in 80% yield (entry 9). The wide scope
of amines and excellent tolerance of functionalities underscore
the robustness and high value of the system in organic synthesis
applications in which a protecting group may well be redundant.
We next explored the reductive amination of different
carbonyl compounds with various amine ·HCl salts (Table 5).
The InCl3/Et3SiH/MeOH system was specific to 1,2-reduction.
Clean reactions in excellent yields (entries 1-4) were achievable
with a variety of substituted R,ꢀ-unsaturated aldehydes. Notably,
the reaction of methacrolein (1b), which contains an unsubsti-
tuted terminal double bond, proceeded smoothly with 3j as the
only detectable product in 95% yield, further highlighting the
remarkably chemoselective character of the system toward R,ꢀ-
unsaturated iminium ions. Reactions with aliphatic aldehydes
were also satisfactory in generating the products 3n-q (entries
5-8). In addition, the system could also be applied to less
reactive aromatic aldehydes. The reaction of 4-methyoxyben-
zaldehyde with various amine ·HCl salts proceeded efficiently
to afford benzylic tertiary amines 3r, 3s, and 3t (entries 9-11).
One aspect of the superiority of the InCl3/Et3SiH system is that
it is so highly compatible with acid labile double bonds that
neither hydrolysis nor reduction of olefin results. While many
existing reductive amination methods require strongly acidic
conditions12,18 or highly reactive catalysts17 by which the
structural integrity of isolated olefin is often destroyed, we have
demonstrated the intactness of such isolated double bonds under
the reaction system. The trisubstituted double bond in citral 1e
was not protonated, affording the product 3m (entry 4).
Furthermore, unlike transition metals, indium metal did not
(19) For reviews on the use of zinc borohydride in reduction, see: Ranu,
B. C. Synlett 1993, 885.
(20) Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc.
Jpn. 1997, 70, 2519.
(21) (a) Doyle, M. P.; West, C. T. J. Org. Chem. 1975, 40, 3821. (b) Doyle,
M. P.; West, C. T. J. Org. Chem. 1975, 40, 3835. (c) Doyle, M. P.; DeBruyn,
D. J.; Donnelly, S. J.; Kooistra, D. A.; Odubela, A. A.; West, C. T.; Zonnebelt,
S. M. J. Org. Chem. 1974, 39, 2740.
J. Org. Chem. Vol. 73, No. 22, 2008 8831

Lee et al.
TABLE 4. Reductive Amination with Various Amine Salts To
Give Tertiary Aminesa
TABLE 5. Reductive Amination with Various Aldehydes and
Amine·HCl Salts Promoted by the InCl3/Et3SiH/MeOH Systema
a All reactions were conducted at room temperature with 0.5 mmol of
trans-cinnamaldehyde, 0.5 mmol of amine·HCl salt, 0.3 equiv of InCl3,
and 2.0 equiv of Et3SiH in 1 mL of MeOH. b Determined by 1H NMR
with DMF as an internal standard. c Isolated yield. d The concentration
was 0.13 M owing to low solubility of starting materials. e Indole
2-carboxylic acid was directly used instead of its HCl salt.
promote reduction of isolated olefins. Thus, both cis- and trans-
disubstituted double bonds in substrates 1f and 1g, which
furnished the products 3n and 3o (entries 5 and 6), respectively,
were intact against reduction.
Apart from aldehydes, ketones were also found to undergo
reductive amination to give tertiary amines. Cyclic ketones
underwent reaction in the manner that more rigid cyclopentanone
1j and cyclohexanone 1k reacted faster to give the products 3u
and 3v (Table 5; entries 12 and 13), respectively, while the
reaction of cycloheptanone was less efficient (entry 14). The
trend in reactivity may be contributed by a higher steric shield
from adjacent hydrogen atoms to carbonyl group owing to a
more flexible ring structure upon increasing ring size. The rigid
2-indanone also presented excellent reactivity, furnishing product
a All reactions were conducted at room temperature for the indicated
reaction time with 0.5 mmol of carbonyl compound, 0.5 mmol of
amine·HCl salt, 0.3 equiv of InCl3, and 2.0 equiv of Et3SiH in 1 mL of
MeOH. b Determined by 1H NMR with DMF as an internal standard.
c Isolated yield.
3x (entry 15). Similarly, cyclopentanone also reacted with
1,2,3,4-tetrahydroquinoline·HCl salt to produce 3y (entry 16).
III. Mechanistic Studies. Although isolation of the inter-
mediates was not possible, it could be conjectured that indium
8832 J. Org. Chem. Vol. 73, No. 22, 2008

ReductiVe Amination of Carbonyl Compounds
FIGURE 2. 1H NMR studies on the reaction between InCl3 (0.15
mmol) and Et3SiH (1 mmol) in CD3OD (1 mL).
FIGURE 3. 13C NMR studies on the reaction between InCl3 (0.15
mmol) and Et3SiH (1 mmol) in CD3OD (1 mL).
hydride, formed by the combination of indium(III) chloride and
triethylsilane, is a likely candidate responsible for the reduction.
Recently, Baba et al. proposed radical behavior of the InCl3/
Et3SiH system with Et3SiCl as an end species.4 In addition, in
their study of reductive aldol condensation,8 they proposed direct
transmetalation between InCl3 and Et3SiH in acetonitrile, which
generates reactive indium hydride species and Et3SiCl as a
byproduct. To make comparisons with our system, we carried
out a series of experiments to elucidate the underlying mechanism.
We scrutinized the indirect evidence for indium hydride
species by observing silane end species in NMR studies. First,
we conducted 1H NMR experiments to determine the silane end
species. InCl3 (0.15 mmol) was dissolved in 1 mL of CD3OD,
followed by the addition of 1 mmol of Et3SiH. Upon mixing of
1
the reagents, the H NMR spectrum was recorded at several
time intervals (0 min, 15 min, 25 min, 1.5 h, 2.5 h, 7 h, 11 h,
and 24 h) as shown in Figure 2.22 The H NMR data revealed
1
that the signals of Si-H at 3.64 ppm and the ethyl group at
0.99 (CH3) and 0.60 ppm (CH2) gradually decreased over a
period of 24 h, while a new set of peaks at 0.97 (CH3) and 0.62
ppm (CH2) developed. The coupling pattern of the CH2 unit of
the Et group gradually changed from a doublet of quartets to a
quartet. The above observations served as strong evidence for
the consumption of organosilane under the actions of InCl3. A
control experiment was carried out with InCl3 being replaced
by Sc(OTf)3, and Et3SiH was found to be inert. This provides
further support to the hypothetical existence of a transmetalation
process that involves the generation of indium hydride as an
FIGURE 4. 29Si NMR studies on the reaction between InCl3 (0.15
mmol) and Et3SiH (1 mmol) in CD3OD (1 mL).
We then turned our attention to investigating the fate of
triethylsilane by 13C NMR analysis, whose results are as shown
in Figure 3. Over a period of 24 h, the original peaks
corresponding to the Et group of triethylsilane at 8.5 (CH3) and
3.3 ppm (CH2) slowly disappeared, while two new peaks at 6.9
(CH3) and 4.9 ppm (CH2) gradually emerged. This suggests that
Et3SiH slowly reacted with InCl3 to give a stable species as the
final product.
The fate of triethylsilane was also probed by 29Si NMR
analysis, and the results are as shown in Figure 4. Over a period
of 48 h, the 29Si chemical shift changed from 0.48 ppm to a
more downfield value at 21.18 ppm. This indicates the disap-
pearance of the Si-H bond and the formation of a new bond
between silicon and a heteroatom.
1
active intermediate. The absence of an extra peak in H NMR
might be due to the low concentration of this active intermediate.
Furthermore, this suggests that the properties of InCl3/Et3SiH
in MeOH is different from that in MeCN as reported by Baba
et al.
(22) Field, L. D.; Messerle, B. A.; Rehr, M.; Soler, L. P.; Hambley, T. W.
Organometallics 2003, 22, 2387.
J. Org. Chem. Vol. 73, No. 22, 2008 8833

Lee et al.
SCHEME 2. Proposed Mechanism for the InCl3/Et3SiH/
MeOH System-Promoted Reductive Amination
FIGURE 5. Conversion upon time at different concentrations of 1a.
We initially suspected the end-species to be Et3SiCl as a result
of direct transmetalation. However, this was disproved in a
control experiment, in which the 13C NMR of Et3SiCl in CD3OD
in the presence of InCl3 displayed peaks at 7.2 and 7.3 ppm. In
view of the above, there could be different mechanistic pathways
which diverge between our system (in MeOH) and Baba et al.’s
system (in MeCN).
species by MeOH is necessary for the observed hydride
reactivity and chemoselectivity.
Proposed Mechanism. On the basis of the above experi-
mental results, a plausible reaction mechanism is proposed in
Scheme 2. Initially, InCl3 exchanges one Cl ligand with MeOH
to form the cationic [InCl2(MeOH)x]+ complex (I). Transmeta-
lation with Et3SiH results in the active indium hydride species
[InHCl2(MeOH)x-1] (II). At the same time, Et3SiOMe is
generated. We have ruled out the generation of Et3SiOMe from
Et3SiCl and MeOH based on the results of a previously
described NMR control experiment in which Et3SiCl was found
to be stable in the presence of InCl3 in CD3OD. This active
indium hydride complex then transfers the hydride to the in
situ generated iminium ion, formed between the carbonyl
compound and secondary amine ·HCl salt, to give an intermedi-
ate complex (III). Finally, the product tertiary amine is released
by MeOH displacement of III with the regeneration of
[InCl2(MeOH)x]+ complex (I) for another catalytic cycle.
Significance of Donor Solvent Stabilization. The existence
of a MeOH-coordinated indium hydride complex has never been
described in the literature. Therefore, its activity compared to
that of the naked indium-hydride complex remains poorly
characterized. The highly chemoselective behavior can be
accounted for by the formation of MeOH-coordinated In-H
complexes which provide a steric shield to the generated indium
hydride species. Consequently, this methanol stabilization effect
leads to more efficient hydride delivery to iminium ion.
We propose the end-species to be Et3SiOMe. In a paper
describing the preparation of Et3SiOMe from Et3SiH by Field
and Messerle,22 the chemical shifts of the ethyl group were
1
reported to be 0.99 (CH3) and 0.64 ppm (CH2) in H NMR
spectra and 7.3 (CH3) and 4.7 ppm (CH2) in 13C NMR spectra,
both taken in CDCl3. In addition, the reported chemical shift in
29Si NMR in CDCl3 is 20.92 ppm. Those chemical shift values
were similar to our findings, providing compelling evidence for
the formation of Et3SiOMe.
Investigation of the Amount of Methanol vs the Reaction
Rate. To acquire a better understanding of methanol participa-
tion, we varied the amount of methanol during our kinetic study
in rate. We performed our studies using trans-cinnamaldehyde
(0.5 mmol), N-methylaniline·HCl salt (0.5 mmol), 0.1 equiv
of InCl3, and 2 equiv of Et3SiH in various volumes of MeOH,
corresponding to 0.05 to 1 M substrate concentration, and
followed the reaction conversion for 48 h by 1H NMR.
Throughout the whole concentration range, all the starting
materials and reagents were completely soluble in MeOH. The
results shown in Figure 5 revealed that an initial increase in
substrate concentration up to 0.5 M resulted in a more rapid
reaction, which resembled the intermolecular reaction profile;
but further increase in substrate concentration caused retardation
of the reaction, probably due to the reduced amount of MeOH.
This provides strong evidence that MeOH participated in the
reaction, which is highly informative in the formulation of the
mechanistic proposal.
Observation of In(III) Complex Using ESI-MS Analysis. We
identified several In(III) complexes by ESI-MS analysis. After
mixing 0.5 mmol of InCl3 and 1.0 mmol of Et3SiH in 1.0 mL
of MeOH, the mixture was subjected to ESI-MS experimental
procedures. Similar results were obtained throughout the reaction
time (15 min to 48 h). Four species were observed as shown in
Figure 6. The major species had m/z at 249, and the three other
minor species at 185, 217, and 281, respectively. In addition,
an isotope pattern in a ratio of 9:6:1 was observed with 3 discrete
peaks each differing by 2 m/z units. This pattern corresponds
to the existence of 2 Cl atoms in each of the four observed
species. This finding highlights that the coordination of In(III)
Furthermore, this discovery is consistent with the results of
solvent screening described in Table 1. A more sterically
hindered alcohol results in less efficient chelation to the In(III)
ion, reflected by the relative lower yield (cf. Table 1; entries
1-4). The strong withdrawing CF3 group in CF3CH2OH inhibits
the donating ability of the oxygen atom, as revealed by the
relatively lower yield based on conversion compared to that
with EtOH as a solvent (cf. Table 1; entries 2 and 5).
Conclusion
In conclusion, we have developed an InCl3/Et3SiH/MeOH
system and explored its applications in reductive amination. We
have discovered the existence of stable methanol-coordinated
indium(III) species, which are presumably responsible for the
gentle generation of indium hydride at room temperature. The
system’s superiority is underscored by its mild reducing
8834 J. Org. Chem. Vol. 73, No. 22, 2008

ReductiVe Amination of Carbonyl Compounds
FIGURE 6. ESI-MS spectra of the reaction mixture of InCl3 and Et3SiH in MeOH.
7.38-7.36 (m, 2H), 7.32-7.26 (m, 2H), 7.23-7.20 (m, 1H), 6.50
properties, functional group compatibility, and high chemose-
lectivity, which are desirable for efficient amine synthesis.
(d, J ) 15.9 Hz, 1H), 6.31 (dt, J ) 15.9, 6.7 Hz, 1H), 3.12 (d, J
) 6.7 Hz, 2H), 2.43 (br s, 4H), 1.64-1.58 (m, 4H), 1.45 (br s,
2H); 13C NMR (75 MHz, CDCl3) δ 137.1, 132.6, 128.5, 127.4,
127.2, 126.3, 61.9, 54.6, 26.0, 24.3; IR (CH2Cl2) 3035, 2927, 2855,
1799, 1499, 1447 cm-1; LRMS (EI) 201 (M+, 100), 200 (77), 117
(46); HRMS (EI) calcd for C14H19N (M+) 201.1518, found
201.1504.
Experimental Section
Typical Procedure for Reductive Amination Catalyzed by the
InCl3/Et3SiH/MeOH System: Formation of 3a-y. To a stirred
solution of carbonyl substrate (0.5 mmol) in methanol (1.0 mL)
was added the corresponding amine ·HCl salt (0.5 mmol) at room
temperature. The mixture was stirred for 1 h. Et3SiH (0.15 mL,
1.0 mmol) was added by syringe and followed by InCl3 (33 mg,
0.15 mmol). The reaction was allowed to stir at room temperature
and was monitored by TLC. When the reaction was completed,
the mixture was quenched by saturated K2CO3 solution (1.0 mL).
The mixture was extracted with ethyl acetate (3 × 5.0 mL). The
combined organic layer was washed with brine (5.0 mL) and finally
was dried over Na2SO4. The crude product was purified by flash
column chromatography to afford product.
4-Cinnamylmorpholine (3c): analytical TLC (silica gel 60), 20%
EtOAc in n-hexane, Rf 0.54; 1H NMR (400 MHz, CDCl3) δ
7.38-7.36 (m, 2H), 7.32-7.28 (m, 2H), 7.26-7.22 (m, 1H), 6.53
(d, J ) 15.9 Hz, 1H), 6.25, (dt, J ) 15.9, 6.8 Hz, 1H), 3.73 (t, J
) 4.7 Hz, 4H), 3.15 (dd, J ) 6.8, 1.3 Hz, 2H), 2.50 (br s, 4H); 13
C
NMR (100 MHz, CDCl3) δ 137.1, 133.7, 128.9, 127.9, 126.6, 126.3,
67.3, 61.8, 54.0; IR (CH2Cl2) 3035, 2921, 2853, 1495, 1447 cm-1
;
LRMS (EI) 203 (M+, 81), 117 (65), 112 (100); HRMS (EI) calcd
for C13H17NO (M+) 203.1310, found 203.1304.
1-Cinnamylpiperidin-4-one (3d): analytical TLC (silica gel 60),
1
20% EtOAc in n-hexane, Rf 0.17; H NMR (300 MHz, CDCl3) δ
N-Cinnamyl-N-methylbenzenamine (3a): analytical TLC (silica
1
7.40-7.37 (m, 2H), 7.34-7.29 (m, 2H), 7.27-7.21 (m, 1H), 6.63
(d, J ) 15.9 Hz, 1H), 6.30 (dt, J ) 15.9, 6.7 Hz, 1H), 3.26 (d, J
) 6.7 Hz, 2H), 2.80 (t, J ) 6.0 Hz, 4H), 2.48 (t, J ) 6.0 Hz, 4H);
13C NMR (75 MHz, CDCl3) δ 208.9, 136.6, 133.3, 128.5, 127.6,
126.3, 126.2, 59.9, 52.9, 41.2; IR (CH2Cl2) 3035, 1911, 2811, 1705,
1588, 1482 cm-1; LRMS (EI) 215 (M+, 65), 124 (99), 117 (100);
HRMS (EI) calcd for C14H17NO (M+) 215.1310, found 215.1302.
1-Cinnamylpiperidin-3-ol (3e): analytical TLC (silica gel 60),
gel 60), 20% EtOAc in n-hexane, Rf 0.63; H NMR (400 MHz,
CDCl3) δ 7.36-7.34 (m, 2H), 7.32-7.28 (m, 2H), 7.27-7.21 (m,
3H), 6.78 (dd, J ) 8.8, 0.8 Hz, 2 H), 6.72 (td, J ) 7.3, 0.8 Hz,
1H), 6.51 (d, J ) 15.9 Hz, 1H), 6.25 (dt, J ) 15.9, 5.5 Hz, 1H),
4.08 (dd, J ) 5.5, 1.6 Hz, 2H), 3.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 149.9, 137.2, 131.6, 129.5, 128.9, 127.7, 126.6, 126.1,
116.9, 112.9, 55.2, 38.4; IR (CH2Cl2) 3025, 2925, 1673, 1597, 1485
cm-1; LRMS (EI) 223 (M+, 19), 120 (49), 117 (100); HRMS (EI)
calcd for C16H17N (M+) 223.1361, found 223.1360.
1
50% EtOAc in n-hexane, Rf 0.25; H NMR (300 MHz, CDCl3) δ
1-Cinnamylpiperidine (3b): analytical TLC (silica gel 60), 20%
7.39-7.20 (m, 5H), 6.50 (d, J ) 15.9 Hz, 1H), 6.24 (dt, J ) 15.9,
6.7 Hz, 1H), 3.84-3.81 (br m, 1H), 3.18 (d, J ) 6.7 Hz, 2H), 2.64
EtOAc in n-hexane, Rf 0.17; 1H NMR (400 MHz, CDCl3) δ
J. Org. Chem. Vol. 73, No. 22, 2008 8835

Lee et al.
(br s, 2H), 2.41 (br s, 3H), 1.82-1.68 (br m, 2H), 1.57-1.52 (br
m, 2H); 13C NMR (75 MHz, CDCl3) δ 136.8, 132.9, 128.5, 127.4,
126.6, 126.3, 66.4, 61.0, 60.4, 53.5, 32.0, 21.9; IR (CH2Cl2) 3432,
2936, 2803, 1643 cm-1; LRMS (EI) 217 (M+, 43), 126 (100), 117
(59), 114 (58); HRMS (EI) calcd for C14H19NO (M+) 217.1467,
found 217.1468.
N-Methyl-N-(3-methylbut-2-enyl)benzenamine (3l): analytical
TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.65; H NMR
1
(400 MHz, CDCl3) δ 7.24-7.20 (m, 2H), 6.74-6.67 (m, 3H), 5.20
(qt, J ) 6.4, 1.4 Hz, 1H), 3.88 (d, J ) 6.4 Hz, 2H), 2.88 (s, 3H),
1.71 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.1, 134.9, 129.4,
121.2, 116.7, 113.3, 50.8, 38.2, 26.0, 18.2; IR (CH2Cl2) 2954, 2907,
2867, 1599, 1506 cm-1; LRMS (EI) 175 (M+, 100), 153 (42), 145
(11); HRMS (EI) calcd for C12H17N (M+) 175.1361, found
175.1356.
(S)-(1-Cinnamylpyrrolidin-2-yl)methanol (3f): analytical TLC
1
(silica gel 60), 20% EtOAc in n-hexane, Rf 0.24; H NMR (400
MHz, CDCl3) δ 7.39-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.21
(m, 1H), 6.53 (d, J ) 15.9 Hz, 1H), 6.28 (ddd, J ) 15.9, 7.6, 7.6
Hz, 1H), 3.68 (dd, J ) 10.8, 3.7 Hz, 1H), 3.57 (ddd, J ) 13.6, 5.8,
1.5 Hz, 1H), 3.44 (dd, J ) 10.8, 2.7 Hz, 1H), 3.19-3.14 (m, 1H),
3.11 (ddd, J ) 13.6, 7.6, 1.0 Hz, 1H), 2.74-2.68 (m, 1H),
2.45-2.36 (m, 1H), 1.95-1.88 (m, 1H), 1.82-1.80 (m, 2H),
1.76-1.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 137.0, 132.1,
128.6, 127.5, 127.4, 126.3, 64.0, 62.1, 56.5, 54.4, 27.9, 22.7; IR
(CH2Cl2) 3690, 2929, 2856, 2362, 1609 cm-1; LRMS (EI) 186 (M+
N-(3,7-Dimethylocta-2,6-dienyl)-N-methylbenzenamine (3m): ana-
1
lytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.65; H
NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.75-6.67 (m,
3H), 5.20 (t, J ) 6.3 Hz, 1H), 5.05 (t, J ) 5.6 Hz, 1H), 3.88 (d, J
) 6.3 Hz, 2H), 2.87 (s, 3H), 2.12-1.99 (m, 4H), 1.71-1.58 (m,
9H); 13C NMR (75 MHz, CDCl3) δ 150.2, 138.5, 131.8, 129.4,
124.4, 122.1, 121.3, 116.8, 113.3, 50.8, 39.9, 38.2, 26.8, 26.1, 18.0,
16.6; IR (CH2Cl2) 2979, 2923, 2850, 1599, 1499, 1443, 1376 cm-1
;
- CH2OH, 52), 117 (100); HRMS (EI) calcd for C13H16N (M+
CH2OH) 186.1282, found 186.1285.
-
LRMS (EI) 243 (M+, 78), 186 (23), 107 (100); HRMS (EI) calcd
for C17H25N (M+) 243.1987, found 243.1988.
(S)-Methyl 1-cinnamylpyrrolidine-2-carboxylate (3g): analytical
(Z)-N-(Dec-4-enyl)-N-methylbenzenamine (3n): analytical TLC
1
TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.22; H NMR
1
(silica gel 60), 20% EtOAc in n-hexane, Rf 0.62; H NMR (300
(300 MHz, CDCl3) δ 7.37-7.35 (m, 2H), 7.32-7.27 (m, 2H),
7.24-7.19 (m, 1H), 6.51 (d, J ) 15.9 Hz, 1H), 6.32 (dt, J ) 15.9,
6.8 Hz, 1H), 3.64 (s, 3H), 3.43 (dd, J ) 13.1, 6.8 Hz, 1H), 3.31
(dd, J ) 13.1, 6.9 Hz, 1H), 3.25-3.16 (m, 2H), 2.40 (q, J ) 8.4
Hz, 1H), 2.22-2.11 (m, 1H), 1.98-1.89 (m, 2H), 1.86-1.79 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 136.8, 132.4, 128.4,
127.4, 126.8, 126.2, 65.4, 57.0, 53.7, 51.8, 29.5, 23.0; IR (CH2Cl2)
3031, 2948, 1731, 1632, 1486, 1433 cm-1; LRMS (EI) 245 (M+,
13), 186 (56), 117 (100); HRMS (EI) calcd for C15H19NO2 (M+)
245.1416, found 245.1423.
MHz, CDCl3) δ 7.25-7.19 (m, 2H), 6.70-6.64 (m, 3H), 5.41-5.36
(m, 2H), 3.30 (t, J ) 7.6 Hz, 2H), 2.92 (s, 3H), 2.10-1.98 (m,
4H), 1.63 (quintet, J ) 7.4 Hz, 2H), 1.29-1.37 (m, 6H), 0.89 (t, J
) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 149.4, 130.8, 129.1,
128.8, 115.9, 112.2, 52.3, 38.2, 31.5, 29.4, 27.2, 26.6, 24.7, 22.6,
14.1; IR (CH2Cl2) 2933, 2868, 1606, 1505, 1382 cm-1; LRMS (EI)
245 (M+, 20), 120 (100); HRMS (EI) calcd for C17H27N (M+)
245.2144, found 245.2141.
(E)-1-(Dec-4-enyl)piperidin-4-one (3o): analytical TLC (silica gel
60), 20% EtOAc in n-hexane, Rf 0.66; 1H NMR (300 MHz, CDCl3)
δ 5.49-5.34 (m, 2H), 2.74 (t, J ) 6.1 Hz, 4H), 2.47-2.42 (m,
6H), 2.11-1.94 (br m, 4H), 1.59 (quintet, J ) 7.5 Hz, 2H),
1.39-1.25 (br m, 6H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 209.3, 131.2, 129.4, 56.9, 53.2, 41.3, 32.5, 31.4,
30.4, 29.3, 27.3, 22.5, 14.1; IR (CH2Cl2) 2979, 2929, 2861, 1705,
1449, 1353 cm-1; LRMS (EI) 237 (M+, 1), 138 (12), 112 (100);
HRMS (EI) calcd for C15H27NO (M+) 237.2093, found 237.2087.
(S,E)-Methyl 1-(dec-4-enyl)pyrrolidine-2-carboxylate (3p): ana-
1-Cinnamylindoline-2-carboxylic acid (3h): analytical TLC
1
(silica gel 60), 50% EtOAc in n-hexane, Rf 0.32; H NMR (400
MHz, CD3OD + D2O) δ 7.36-7.22 (m, 5H), 7.19-7.09 (m, 2H),
6.78 (t, J ) 7.4 Hz, 1H), 6.70-6.60 (m, 2H), 6.22 (dt, J ) 15.8,
6.5 Hz, 1H), 4.18 (t, J ) 9.6 Hz, 1H), 4.16-4.05 (m, 1H), 3.94
(dd, J ) 15.6, 7.3 Hz, 1H), 3.31 (dd, J ) 16.3, 10.6 Hz, 1H), 3.02
(dd, J ) 16.0, 8.9 Hz, 1H); 13C NMR (100 MHz, CD2Cl2) δ 181.2,
153.3, 138.4, 134.1, 129.7, 129.5, 128.4 (2C), 127.4, 126.3, 125.0,
118.7, 108.5, 69.3, 50.8, 35.4; IR (CH2Cl2) 3472, 3019, 2925, 1713,
1603 cm-1; LRMS (EI) 233 (M+ - COOH, 44), 117 (100); HRMS
(EI) calcd for C17H15N (M+ - COOH) 233.1204, found 233.1208.
(E)-N,N-Dibenzyl-3-phenylprop-2-en-1-amine (3i): analytical
1
lytical TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.66; H
NMR (400 MHz, CDCl3) δ 5.43-5.33 (m, 2H), 3.72 (s, 3H),
3.21-3.16 (m, 1H), 3.13 (dd, J ) 8.9, 6.0 Hz, 1H), 2.68-2.61 (m,
1H), 2.41-2.29 (m, 2H), 2.17-2.05 (m, 1H), 2.03-1.86 (m, 6H),
1.81-1.76 (m, 1H), 1.55 (quintet, J ) 7.6 Hz, 2H), 1.35-1.23 (m,
6H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
175.2, 131.2, 129.8, 66.5, 55.1, 53.9, 52.1, 32.8, 31.7, 30.8, 29.7,
29.6, 28.8, 23.5, 22.8, 14.4; IR (CH2Cl2) 2933, 2860, 1745, 1470
cm-1; LRMS (EI) 209 (M+ - C2H2O2, 20), 208 (M+ - COOMe,
100); HRMS (EI) calcd for C14H26N (M+ - COOMe) 208.2065,
found 208.2062.
N-Hexyl-N-methylbenzenamine (3q): analytical TLC (silica gel
60), 20% EtOAc in n-hexane, Rf 0.66; 1H NMR (400 MHz, CDCl3)
δ 7.24-7.19 (m, 2H), 6.70-6.64 (m, 3H), 3.29 (t, J ) 7.5 Hz,
2H), 2.91 (s, 3H), 1.65-1.54 (m, 2H), 1.30 (br s, 6H), 0.89 (t, J )
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 149.7, 129.5, 116.1,
112.4, 53.2, 38.6, 32.1, 27.2, 27.0, 23.0, 14.4; IR (CH2Cl2) 2967,
2921, 2853, 1599, 1507, 1459, 1370 cm-1; LRMS (EI) 191 (M+,
15), 153 (13), 120 (100); HRMS (EI) calcd for C13H21N (M+)
191.1674, found 191.1673.
1
TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.60; H NMR
(400 MHz, CDCl3) δ 7.40-7.38 (m, 4H), 7.36-7.26 (m, 8H),
7.24-7.19 (m, 3H), 6.52 (d, J ) 15.9 Hz, 1H), 6.29 (dt, J ) 15.9,
6.5 Hz, 1H), 3.62 (br s, 4H), 3.21 (dd, J ) 6.5, 1.1 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 139.6, 137.2, 132.4, 128.8, 128.5, 128.2,
127.7, 127.3, 126.8, 126.2, 57.9, 55.7; IR (CH2Cl2) 3025, 2925,
2797, 1491, 1439 cm-1; LRMS (EI) 313 (M+, 27), 222 (100), 117
(58); HRMS (EI) calcd for C23H23N (M+) 313.1831, found
313.1832.
N-Methyl-N-(2-methylallyl)benzenamine (3j): analytical TLC
1
(silica gel 60), 20% EtOAc in n-hexane, Rf 0.65; H NMR (300
MHz, CDCl3) δ 7.25-7.18 (m, 2H), 6.70-6.65 (m, 3H), 4.84 (br
s, 1H), 4.80 (br s, 1H), 3.79 (s, 2H), 2.94 (s, 3 H), 1.53 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 150.0, 141.8, 129.4, 116.3, 112.4,
111.0, 59.1, 38.6, 20.4; IR (CH2Cl2) 2968, 2875, 1606, 1467, 1417
cm-1; LRMS (EI) 161 (M+, 16); HRMS (EI) calcd for C11H15N
(M+) 161.1204, found 161.1212.
(E)-N-Methyl-N-(2-methylbut-2-enyl)benzenamine (3k): analyti-
cal TLC (silica gel 60), 20% EtOAc in n-hexane, Rf 0.64; 1H NMR
(300 MHz, CDCl3) δ 7.23-7.17 (m, 2H), 6.74-6.64 (m, 3H),
5.34-5.28 (br m, 1H), 3.75 (s, 2H), 2.88 (s, 3H), 1.60 (s, 3H),
1.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 150.0, 131.8, 129.0,
119.3, 115.9, 112.0, 60.1, 37.8, 14.0, 13.1; IR (CH2Cl2) 3035, 2927,
1603, 1495, 1374 cm-1; LRMS (EI) 175 (M+, 61), 120 (100), 107
(52); HRMS (EI) calcd for C12H17N (M+) 175.1361, found
175.1363.
N-(4-Methoxybenzyl)-N-methylbenzenamine (3r): analytical TLC
1
(silica gel 60), 20% EtOAc in n-hexane, Rf 0.34; H NMR (300
MHz, CDCl3) δ 7.23-7.17 (m, 2H), 7.13 (d, J ) 8.7 Hz, 2H),
6.82 (d, J ) 8.7 Hz, 2H), 6.75-6.67 (m, 3H), 4.43 (s, 2H), 3.74
(s, 3H), 2.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 149.8,
130.8, 129.1, 127.9, 116.5, 113.9, 112.4, 56.0, 55.2, 38.2; IR
(CH2Cl2) 3049, 2933, 2837, 1601, 1510, 1467 cm-1; LRMS (EI)
227 (M+, 35), 121 (100); HRMS (EI) calcd for C15H17NO (M+)
227.1310, found 227.1306 (M+).
8836 J. Org. Chem. Vol. 73, No. 22, 2008

ReductiVe Amination of Carbonyl Compounds
4-(4-Methoxybenzyl)morpholine (3s): analytical TLC (silica gel
60), 50% EtOAc in n-hexane, Rf 0.30; 1H NMR (300 MHz, CDCl3)
δ 7.22 (d, J ) 8.6 Hz, 2H), 6.85 (d, J ) 8.6 Hz, 2H), 3.78 (s, 3H),
3.69 (t, J ) 4.6 Hz, 4H), 3.43 (s, 2H), 2.41 (t, J ) 4.6 Hz, 4H);
13C NMR (75 MHz, CDCl3) δ 159.1, 130.6, 130.0, 113.9, 67.3,
63.1, 55.5, 53.8; IR (CH2Cl2) 3017, 1961, 2867, 2805, 1611, 1511,
1455 cm-1; LRMS (EI) 207 (M+, 31), 121 (100); HRMS (EI) calcd
for C12H17NO2 (M+) 207.1259, found 207.1248.
N-Methyl-N-phenylcycloheptanamine (3w): analytical TLC (silica
gel 60), 20% EtOAc in n-hexane, Rf 0.48; H NMR (400 MHz,
1
CDCl3) δ 7.24-7.19 (m, 2H), 6.75 (d, J ) 8.1 Hz, 2H), 6.67 (t, J
) 7.2 Hz, 1H), 3.77 (tt, J ) 9.9, 3.6 Hz,1H), 2.75 (s, 3H),
1.93-1.79 (m, 2H), 1.78-1.69 (m, 2H), 1.67-1.59 (m, 4H),
1.58-1.43 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 150.4, 129.5,
116.5, 113.4, 60.1, 32.4, 31.7, 28.1, 26.0; IR (CH2Cl2) 3023, 2929,
2873, 1588, 1499 cm-1; LRMS (EI) 203 (M+, 31), 146 (100);
HRMS (EI) calcd for C14H21N (M+) 203.1674, found 203.1668.
N-Methyl-N-phenyl-2,3-dihydro-1H-inden-2-amine (3x): analyti-
cal TLC (silica gel 60), 50% EtOAc in n-hexane, Rf 0.30; 1H NMR
(400 MHz, CDCl3) δ 7.25-7.18 (m, 4H), 7.16-7.13 (m, 2H), 6.86
(d, J ) 8.0 Hz, 2H), 6.74 (t, J ) 7.3 Hz, 1H), 4.74 (quintet, J )
7.4 Hz, 1H), 3.15 (dd, J ) 16.2, 8.1 Hz, 2H), 3.02 (dd, J ) 16.2,
6.8 Hz, 2H), 2.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.8,
142.0, 129.5, 126.8, 124.8, 117.8, 114.8, 59.7, 36.3, 33.2; IR
(CH2Cl2) 3073, 3029, 2950, 2906, 1599, 1504 cm-1; LRMS (EI)
223 (M+, 100), 208 (12), 116 (15); HRMS (EI) calcd for C16H17N
(M+) 223.1361, found 223.1359.
(S)-Methyl 1-(4-methoxybenzyl)pyrrolidine-2-carboxylate (3t):
analytical TLC (silica gel 60), 50% EtOAc in n-hexane, Rf 0.44;
1H NMR (400 MHz, CDCl3) δ 7.24-7.21 (m, 2H), 6.86-6.82 (m,
2H), 3.80 (d, J ) 12.7 Hz, 1H), 3.79 (s, 3H), 3.65 (s, 3H), 3.52 (d,
J ) 12.7 Hz, 1H), 3.21 (dd, J ) 9.0, 6.5 Hz, 1H), 3.06-3.01 (m,
1H), 2.37 (q, J ) 8.7 Hz, 1H), 2.17-2.09 (m, 1H), 1.98-1.87 (m,
1H), 1.84-1.72 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.9,
159.0, 130.7, 130.6, 113.8, 65.4, 58.3, 55.5, 53.5, 52.0, 29.7, 23.2;
IR (CH2Cl2) 3046, 2956, 2834, 1734, 1605, 1511, 1443 cm-1
;
LRMS (EI) 249 (M+, 2), 190 (100); HRMS (EI) calcd for
C14H19NO3 (M+) 249.1365, found 249.1376.
1-Cyclopentyl-1,2,3,4-tetrahydroquinoline (3y): analytical TLC
N-Cyclopentyl-N-methylbenzenamine (3u): analytical TLC (silica
1
(silica gel 60), 20% EtOAc in n-hexane, Rf 0.38; H NMR (300
1
gel 60), 20% EtOAc in n-hexane, Rf 0.48; H NMR (300 MHz,
MHz, CDCl3) δ 7.03 (t, J ) 7.7 Hz, 1H), 6.91 (d, J ) 7.2 Hz,
1H), 6.70 (d, J ) 8.3 Hz, 1H), 6.53 (t, J ) 7.2 Hz, 1H), 4.17
(quintet, J ) 7.7 Hz, 1H), 3.16 (t, J ) 5.8 Hz, 2H), 2.71 (t, J )
6.4 Hz, 2H), 1.92-1.84 (m, 4H), 1.70-1.59 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 146.2, 128.9, 127.0, 123.2, 115.2, 111.0, 58.5,
CDCl3) δ 7.25-7.19 (m, 2H), 6.83-6.80 (d, J ) 8.0 Hz, 2H), 6.70
(t, J ) 7.2 Hz, 1H), 4.14 (quintet, J ) 7.9 Hz, 1H), 2.77 (s, 3H),
1.88-1.83 (m, 2H), 1.71-1.67 (m, 2H), 1.63-1.54 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 151.4, 129.3, 117.1, 114.4, 60.6, 32.9,
29.0, 24.7; IR (CH2Cl2) 2946, 2861, 1597, 1504 cm-1; LRMS (EI)
175 (M+, 36), 146 (100); HRMS (EI) calcd for C12H17N (M+)
175.1361, found 175.1359.
42.0, 28.4, 28.0, 24.1, 22.6; IR (CH2Cl2) 2956, 1605, 1501 cm-1
;
LRMS (EI) 201 (M+, 59), 172 (100); HRMS (EI) calcd for C14H19N
(M+) 201.1518, found 201.1517.
N-Cyclohexyl-N-methylbenzenamine (3v): analytical TLC (silica
1
gel 60), 20% EtOAc in n-hexane, Rf 0.47; H NMR (400 MHz,
Acknowledgment. This work was supported by The Uni-
CDCl3) δ 7.25-7.19 (m, 2H), 6.78 (d, J ) 8.1 Hz, 2H), 6.68 (t, J
) 7.2 Hz, 1H), 3.56 (tt, J ) 14.8, 3.4 Hz, 1H), 2.77 (s, 3H),
1.85-1.77 (m, 4H), 1.70-1.67 (m, 1H), 1.50-1.33 (m, 4H),
1.18-1.10 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 150.3, 129.2,
116.4, 113.3, 58.2, 31.3, 30.2, 26.4, 26.1; IR (CH2Cl2) 2946, 2861,
1597, 1504 cm-1; LRMS (EI) 189 (M+, 26), 146 (100), 132 (20);
HRMS (EI) calcd for C13H19N (M+) 189.1518, found 189.1517.
versity of Hong Kong and Hong Kong Research Grants Council.
Supporting Information Available: Spectral characterization
data for compounds 3a-y. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO8016082
J. Org. Chem. Vol. 73, No. 22, 2008 8837