S-benzyl isothiouronium chloride as a recoverable organocatalyst for the direct reductive amination of ketones with Hantzsch ester

Article abstract of DOI:10.1055/s-0031-1291125

The direct reductive amination of ketones using the Hantzsch ester in the presence of S-benzyl isothiouronium chloride as a recoverable organocatalyst is reported. A wide range of ketones as well as amines were found to give the expected products in moder

Full text of DOI:10.1055/s-0031-1291125

PAPER
▌1977
paper
S-Benzyl Isothiouronium Chloride as a Recoverable Organocatalyst for the
Direct Reductive Amination of Ketones with Hantzsch Ester
Quynh Pham Bao Nguyen, Taek Hyeon Kim*
School of Applied Chemical Engineering and Center for Functional Nano Fine Chemicals, College of Engineering,
Chonnam National University, Gwangju 500-757, Republic of Korea
Fax +82(62)5301889; E-mail: thkim@chonnam.ac.kr
Received: 05.03.2012; Accepted after revision: 17.04.2012
The development of acid- and metal-free catalysts still re-
Abstract: The direct reductive amination of ketones using the
mains a challenging task. The advent of organocatalysts
Hantzsch ester in the presence of S-benzyl isothiouronium chloride
has led to the discovery of new activation modes and nov-
as a recoverable organocatalyst is reported. A wide range of ketones
el transformations. Isothiouronium salts have been ex-
plored quite recently as a new class of hydrogen-bonding
subunit for the purpose of anion recognition.8 The isothio-
uronium group as an anion-binding site has several advan-
tages: (i) it enhances the NH acidity compared to the
corresponding thiourea, and (ii) the chemical modifica-
tion is readily varied using synthetic methods to make
several types of functional molecular systems.8f There-
fore, the isothiouronium salt might be expected to act as
an activator for the reductive amination of ketones
(Scheme 1).
as well as amines were found to give the expected products in mod-
erate to excellent yields.
Key words: S-benzyl isothiouronium chloride, reductive amina-
tion, ketones, amines, hydrogen bond
Reductive amination is one of the oldest, but most power-
ful and widely used methods of accessing different kinds
of amines, which are indispensable building blocks in nat-
ural products, pharmaceuticals, and agrochemicals.1 Pre-
vious reports indicate that there are two general
approaches to transforming ketones into amines. The first
is an indirect/stepwise method whereby the intermediate
ketimines are pre-formed and then reduced in an indepen-
dent step.2 This method is not straightforward because
some ketimines are unstable and difficult to isolate.3
Therefore, direct reductive amination, in which the ke-
tone, amine, and reducing agent are all present at the out-
set of the reaction, avoiding the isolation of ketimine
intermediate, is much more convenient and extremely at-
tractive. However, the choice of reducing agent is critical
to the success of the reaction, because the ketimine should
be reduced selectively in the presence of the ketone.4 In
previous reports, Hantzsch esters were shown to be pow-
erful biomimetic reductants, because they overcome some
of the problems encountered with traditional reductive re-
agents such as hydrogen gas/metal and metal hydrides, for
instance, their limitations in the case of sensitive, acid-la-
bile, or polyfunctional substrates.5d The reductive amina-
tion of ketones using Hantzsch esters has been developed
with effective catalysts such as the Lewis acid scandium
triflate Sc(OTf)3,5a,b binol phosphoric acid,5c,e,f and thio-
urea.5d Recently, we reported S-benzyl isothiouronium
chloride6 as a novel noncovalent organocatalyst for the di-
rect reductive amination of aldehydes using Hantzsch es-
ters.7 Herein, we wish to introduce the use of this system
in the direct reductive amination of ketones. A wide range
of ketones as well as amines were investigated, and the re-
cyclability of the S-benzyl isothiouronium chloride cata-
lyst is also described.
EtO2C
CO2Et
R2
N
H
O
H2N R3
R1
N
R3
+
R1
R2
H
5 Å MS
1
2
3
Cl–
S+
H2N
NH2
Scheme 1 The direct reductive amination of ketones using S-benzyl
isothiouronium chloride
Mechanistically, this reaction includes two steps: (i) the
first step is the equilibrium of the ketone and amine with
the ketimine; (ii) in the second step, due to the formation
of strong hydrogen bonds between the C=N moiety of the
ketimine intermediate and the isothiouronium moiety of
the catalyst, the reduction of the Hantzsch ester is expect-
ed to be accelerated (Scheme 2).5d
With this mind, our initial study began with the reaction
of acetophenone, p-anisidine, and the Hantzsch ester in
the presence of S-benzyl isothiouronium chloride as an or-
ganocatalyst (Table 1). To identify the hydrogen bond be-
tween the respective ketimine and S-benzyl
isothiouronium chloride catalyst, a 1H NMR spectropho-
tometric method was developed that involved monitoring
the changes in the spectra of the catalyst in the presence of
the excess ketimine (10 equiv) in DMSO-d6. The protons
of the -NH and -CH2Ph moieties of the S-benzyl isothio-
uronium chloride catalyst were shifted from δ = 9.37 to
9.45 ppm and from δ = 4.55 to 4.58 ppm, respectively,
SYNTHESIS 2012, 44, 1977–1982
Advanced online publication: 25.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291125; Art ID: SS-2012-F0232-OP
© Georg Thieme Verlag Stuttgart · New York

1978
Q. P. B. Nguyen, T. H. Kim
PAPER
O
H2N R3
R1
+
R1
R2
ketimines
N
1
2
R2
R3
Cl–
S+
H2N
H2N
R1
R2
EtO2C
CO2Et
N
R3
N
H
Cl–
S+
H2N
H2N
Cl–
S+
H2N
H2N
EtO2C
CO2Et
R1
R2
R3
NH
HN
R1
N
R3
R2
3
Scheme 2 Proposed mechanism of the hydrogen-bond catalyzed direct reductive amination of ketones using S-benzyl isothiouronium chloride
Table 1 Direct Reductive Amination of Ketones
EtO2C
CO2Et
O
N
H
NH2
N
H
OMe
+
(1.5 equiv)
MeO
5 Å MS
1a
2a
(1.5 equiv)
3a
(1 equiv)
Entry
Catalyst
Equiv
Solvent
Temp (°C)
Time (h)
Yield of 3a (%)
1
2
3
4
none
0
MeOH
70
70
r.t.
50
48
48
24
24
0
none
0
toluene
benzene
benzene
<5
75a
87b
Sc(OTf)3
0.1
0.1
phosphoric acid
S
5
6
0.1
0.1
toluene
MeOH
50
70
48
48
88c
0
H2N
H2N
NH2
NH2
S
Cl–
S+
S+
S+
7
8
9
0.1
0.1
toluene
MeOH
toluene
70
70
70
48
48
48
91 (0)d
73 (0)d
60
H2N
NH2
NH2
NH2
Cl–
H2N
Cl–
0.05
H2N
a Yield from ref.5b
b Yield from ref.5c
c Yield from ref.5d
d Yields in parentheses were obtained in the presence of excess tetrabutyl ammonium acetate (1.5 equiv).
Synthesis 2012, 44, 1977–1982
© Georg Thieme Verlag Stuttgart · New York

PAPER
S-Benzyl Isothiouronium Chloride for the Reductive Amination of Ketones
Table 2 Scope of Ketones
1979
showing the hydrogen bonding interaction between them.
However, upon adding excess acetophenone, the 1H NMR
spectra of the catalyst remained almost unchanged. With-
out S-benzyl isothiouronium chloride, no transformation
into the product 3a was observed (Table 1, entries 1 and
2). In addition, S-benzyl isothiouronium chloride was
completely inactive in the presence of excess tetrabutyl
ammonium acetate (TBAA), which could successfully
break the hydrogen bond between the S-benzyl isothio-
uronium chloride and ketimine due to the stronger coordi-
nation of the acetate anion with the isothiouronium moiety
(Table 1, entries 7 and 8).9,10 From these experimental
data, we concluded that this reaction relies exclusively on
hydrogen bonding activation by the S-benzyl isothio-
uronium catalyst.
O
EtO2C
CO2Et
R1
R2
1
N
H
(1 equiv)
+
R2
(1.5 equiv)
R1
N
OMe
H
NH2
Cl–
S+
3
MeO
H2N
NH2
2a
(1.5 equiv)
(0.1 equiv)
5 Å MS, 70 °C, toluene
Entry
Ketone 1
3
Time (h) Yield (%)a
O
The best yields for this reversible reaction were obtained
when a slight excess (1.5 equiv) of the amine and
Hantzsch ester were used with respect to the ketone (1
equiv) and 5 Å molecular sieves were used to remove the
water formed. Toluene was the most suitable solvent (Ta-
ble 1, entry 7);11 although this solvent did not dissolve the
S-benzyl isothiouronium chloride, it allowed the catalyst
to be easily separated from the reaction mixture and facil-
itated its recovery and reuse. Interestingly, whereas the
known thiourea catalyst did not work in protic methanol
solvent (Table 1, entry 6),5d the S-benzyl isothiouronium
chloride catalyst functioned well to give the required
product in 73% yield (Table 1, entry 8); thus, one advan-
tage of the use of isothiouronium over thiourea is that a
higher binding interaction could be achieved even in polar
protic solvents, as known in anion recognition.8 Com-
pared with the previously developed catalysts (Table 1,
entries 3, 4, and 5),5b–d S-benzyl isothiouronium chloride
was an effective metal- and acid-free catalyst for the re-
ductive amination of aldehydes7 and ketones, primarily
because of its high hydrogen-bond forming ability, which
allows it to function even in protic solvents, and because
of its easy recovery.
1
2
3a
3b
48
48
91
87
1a
1b
O
O
3
4
3c
48
72
65
45
Cl
1c
O
3d
O2N
1d
O
1e
S
5
6
3e
3f
72
48
73
80
With the optimized reaction conditions in hand, we inves-
tigated the scope and limitations of the organocatalytic re-
duction of a range of ketones with p-anisidine (Table 2).
The latter substrate was chosen because the p-methoxy-
phenyl group of this amine can be oxidatively removed
from the resulting secondary amine to produce a primary
amine, which renders the whole protocol more versatile.12
To our delight, for all of the ketones considered, including
aromatic, aliphatic, aliphatic cyclic, and heterocyclic ke-
tones, the expected products were obtained in moderate to
excellent yields. Aliphatic and cyclic aliphatic ketones
were the most reactive (Table 2, entry 7 and 8). The aro-
matic ketone with a nitro substituent, which might form a
hydrogen bond with the catalyst, furnished low yield (Ta-
ble 2, entry 4). Notably, no reduction of the nitro group
(Table 2, entry 4) or double bond (Table 2, entry 8) was
observed. The reactions proceeded in good yields even with
sterically hindered ketones (Table 2, entries 9, 10 and 11).
O
O
1f
O
7
8
3g
48
48
98
92
1g
1h
O
3h
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1977–1982

1980
Q. P. B. Nguyen, T. H. Kim
PAPER
Table 2 Scope of Ketones (continued)
Table 3 Scope of Amines
O
O
EtO2C
CO2Et
EtO2C
CO2Et
R1
R2
1
N
H
(1 equiv)
+
N
R2
1a
(1 equiv)
H
(1.5 equiv)
N
R3
(1.5 equiv)
H
R1
N
OMe
+
H
NH2
Cl–
S+
3
3
Cl–
H2N R3
S+
MeO
Entry
9
2
H2N
NH2
2a
(1.5 equiv)
H2N
(0.1 equiv)
5 Å MS, toluene
NH2
(1.5 equiv)
(0.1 equiv)
5 Å MS, 70 °C, toluene
Ketone 1
3
Time (h) Yield (%)a
r.t., 24 h, and then reflux
O
Entry Amine 2
3
Time (h)
72
Yield (%)
82 (70)a
NH2
3i
72
72
96
83
67
56a
1
3l
1i
2b
O
NH2
10
11
3j
3k
2
3m
96
81
Cl
1j
O
2c
NH2
3
3n
72
96
78
76
1k
2d
a Yield obtained at r.t. for 24 h and then at reflux temperature.
NH2
4
3o
HO
The scope of amines was also examined with acetophe-
none (Table 3). Initially, the reaction was performed at
70 °C; however, with aniline this did not lead to a high
yield and increasing the temperature to reflux gave an
even poorer result. The yield was improved by first con-
ducting the reaction at room temperature for 24 hours and
then at reflux temperature (Table 3, entry 1). Under these
conditions, the reaction with aromatic amines containing
either an electron-withdrawing substituent (chloride) or
an electron-donating substituent (methyl and hydroxy),
proceeded smoothly to give good yields of the expected
products (Table 3, entries 2–4). In addition, a free hydroxy
group was tolerated under the reaction conditions (Table
3, entry 4). However, the heterocyclic amine 2f reacted
with more difficultly (Table 3, entry 5) and the aliphatic
amine was completely unreactive (Table 3, entry 6).
2e
5
6
3p
3q
96
96
55
0
N
NH2
2f
Me(CH2)7NH2
2g
a Yield in parenthesis was obtained at 70 °C.
In summary, S-benzyl isothiouronium chloride has been
successfully developed as a novel class of noncovalent or-
ganocatalyst for the direct reductive amination of ketones.
A wide range of ketones as well as amines were found to
give the expected products in moderate to excellent
Finally, a striking feature of this method was the recovery yields. The isothiouronium catalyst has certain valuable
of the S-benzyl isothiouronium chloride catalyst. Under characteristics such as high hydrogen-bonding propensity
heterogeneous reaction conditions, S-benzyl isothiouroni- and the ability to be recovered and reused. In addition, we
um chloride was easily recovered by simple filtration and expect that the isothiouronium organocatalyst should be
reused with no significant change in its efficiency (Table readily modifiable, allowing the development of chiral or-
4).
ganocatalysts for asymmetric syntheses that may even be
Synthesis 2012, 44, 1977–1982
© Georg Thieme Verlag Stuttgart · New York

PAPER
S-Benzyl Isothiouronium Chloride for the Reductive Amination of Ketones
1981
1H NMR (300 MHz, CDCl3): δ = 1.40 (d, J = 6.3 Hz, 3 H), 3.40 (br
s, 1 H), 4.31 (q, J = 6.3 Hz, 1 H), 6.33 (d, J = 8.0 Hz, 2 H), 6.50 (d,
J = 8.0 Hz, 2 H), 7.10–7.30 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 24.9, 54.4, 115.0, 116.1, 125.9,
126.8, 128.6, 141.6, 145.4, 147.6.
used in polar protic solvent systems. A chiral isothio-
uronium organocatalyst will be reported in due course.
Table 4 Recovery of the Catalyst
O
High-resolution mass spectroscopy did not produce a signal for the
molecular ion [M + H]+, but rather gave a signal at m/z 212.0888,
which corresponds to the fragment of the ketimine produced by ox-
idation of the amine under HRMS conditions.
EtO2C
CO2Et
N
H
1a
(1 equiv)
(1.5 equiv)
N
OMe
H
+
Acknowledgment
NH2
3a
Cl–
S+
This research was supported by the Sabbatical Research Program of
Chonnam National University, 2010. We wish to thank the Korea
Basic Science Institute, Gwangju for performing the LC-MS/MS
analysis.
MeO
H2N
NH2
2a
(0.1 equiv)
(1.5 equiv)
5 Å MS, 70 °C, toluene
Run
Yield of recovered catalyst (%)
Yield of 3a (%)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
1
2
3
4
80
81
78
80
91
86
88
85
References
(1) Tripathy, R. P.; Verna, S. S.; Pandey, J.; Tiwari, V. K. Curr.
Org. Chem. 2008, 12, 1093.
(2) For the reduction of ketimines, see: (a) Rueping, M.; Azap,
C.; Sugiono, E.; Theissmann, T. Synlett 2005, 2367.
(b) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J.
Org. Lett. 2006, 8, 999. (c) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-
Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886.
(d) Cheemala, M. N.; Knochel, P. Org. Lett. 2007, 9, 3089.
(e) Li, W.; Hou, G.; Chang, M.; Zhang, X. Adv. Synth. Catal.
2009, 351, 3123. (f) Malkov, A. V.; Vrankova, K.; Stoncius,
S.; Kocovsky, P. J. Org. Chem. 2009, 74, 5839. (g) Che, J.;
Lam, Y. Adv. Synth. Catal. 2010, 352, 1752.
All reagents and solvents were obtained from commercial suppliers
and were used without further purification. All air- and/or moisture-
sensitive reactions were carried out under an argon atmosphere. The
products were purified by using flash column chromatography.
TLC was developed on Merck silica gel 60 F254 aluminum sheets.
1H and 13C NMR spectra were recorded on a Bruker AMX300 spec-
trometer operating at 300 and 75 MHz, respectively, using CDCl3
as solvent. HRMS were measured with a Micromass Q-TOF instru-
ment (ES+ ion mode).
(3) Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty,
R. R. Adv. Synth. Catal. 2006, 348, 1289.
(4) For the direct reductive amination of ketones, see: (a) Abdel-
Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849. (b) Apodaca, R.;
Xiao, W. Org. Lett. 2001, 3, 1745. (c) Sato, S.; Sakamoto,
T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60,
7899. (d) Bailey, H. V.; Heaton, W.; Vicker, N.; Potter, B.
V. L. Synlett 2006, 2444. (e) Salmi, C.; Loncle, C.;
Letourneux, Y.; Brunel, J. M. Tetrahedron 2008, 64, 4453.
(f) Rubio-Perez, L.; Perez-Flores, F. J.; Sharma, P.; Velasco,
L.; Cabrera, A. Org. Lett. 2009, 11, 265. (g) Li, C.; Villa-
Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2009, 131, 6967.
(h) Wang, C.; Pettman, A.; Bacsa, J.; Xiao, J. Angew. Chem.
Int. Ed. 2010, 49, 7548.
(5) (a) Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.;
Ohsawa, A. Tetrahedron Lett. 2002, 43, 3105. (b) Itoh, T.;
Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara, A.;
Ohsawa, A. Tetrahedron 2004, 60, 6649. (c) Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 84. (d) Menche, D.; Hassfeld, J.; Li, J.;
Menche, G.; Ritter, A.; Rudolph, S. Org. Lett. 2006, 8, 741.
(e) Wakchaure, V. N.; Zhou, J.; Hoffmann, S.; List, B.
Angew. Chem. Int. Ed. 2010, 49, 4612. (f) Wakchaure, V.
N.; Nicoletti, M.; Ratjen, L.; List, B. Synlett 2010, 2708.
(6) S-Benzyl isothiouronium chloride is commercially
available.
Direct Reductive Amination of Ketones; General Procedure
A solution of ketone 1 (0.54 mmol, 1 equiv) and amine 2 (1.5 equiv)
in toluene (4 mL) was treated with the Hantzsch ester (1.5 equiv),
S-benzyl isothiouronium chloride (0.1 equiv) and 5 Å MS (1 g). The
reaction mixture was stirred either at 70 °C or first at r.t. for 24 h
and then heated at reflux. Upon the completion of the reaction, the
mixture was filtered and washed several times with CH2Cl2. The fil-
trate was evaporated and then purified by flash column chromatog-
raphy to obtain the pure amine 3. The residue in the filter was
washed several more times with MeOH and the filtrate was evapo-
rated to recover the S-benzyl isothiouronium chloride catalyst. All
amines except 3m and 3o were characterized by comparison with
reported spectroscopic data.
Compound 3m
Yield: 101 mg (81%); yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.42 (d, J = 6.2 Hz, 3 H), 4.01 (br
s, 1 H), 4.38 (q, J = 6.2 Hz, 1 H), 6.20–7.30 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 24.7, 53.4, 111.5, 113.1, 117.2,
125.8, 127.1, 128.7, 130.1, 134.8, 144.6, 148.4.
High-resolution mass spectroscopy did not produce a signal for the
molecular ion [M + H]+, but rather gave a signal at m/z 230.0375,
which corresponds to the fragment of the ketimine produced by ox-
idation of the amine under HRMS conditions.
(7) Nguyen, Q. P. B.; Kim, T. H. Tetrahedron Lett. 2011, 52,
5004.
(8) For studies on the hydrogen bond in isothiouronium
compounds, see: (a) Yeo, W. S.; Hong, J. I. Tetrahedron
Compound 3o
Yield: 88 mg (76%); yellow oil.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1977–1982

1982
Q. P. B. Nguyen, T. H. Kim
PAPER
Lett. 1998, 39, 3769. (b) Yeo, W. S.; Hong, J. I. Tetrahedron
Lett. 1998, 39, 8137. (c) Kubo, Y.; Tsukahara, M.; Ishihara,
S.; Tokita, S. Chem. Commun. 2000, 653. (d) Nishizawa, S.;
Cui, Y. Y.; Minagawa, M.; Morita, K.; Kato, Y.; Taniguchi,
S.; Kato, R.; Teramae, N. J. Chem. Soc., Perkin Trans. 2
2002, 866. (e) Kubo, Y.; Ishihara, S.; Tsukahara, M.; Tokita,
S. J. Chem. Soc., Perkin Trans. 2 2002, 1455. (f) Kubo, Y.;
Kato, M.; Misawa, Y.; Tokita, S. Tetrahedron Lett. 2004, 45,
3769. (g) Kato, R.; Cui, Y.-Y.; Nishizawa, S.; Yokobori, T.;
Teramae, N. Tetrahedron Lett. 2004, 45, 4273. (h) Seong, H.
R.; Kim, D.-S.; Kim, S.-G.; Choi, H.-J.; Ahn, K. H.
(l) Nguyen, Q. P. B.; Kim, T. H. Bull. Korean Chem. Soc.
2010, 31, 712.
(9) For an example of eliminating the hydrogen bond in the
presence of TBAA, see: Maher, D. J.; Connon, S. J.
Tetrahedron Lett. 2004, 45, 1301.
(10) By monitoring the 1H NMR spectra of the catalyst, it was
found that the proton of the -NH moieties of the S-benzyl
isothiouronium chloride catalyst disappeared in the presence
of excess TBAA, showing the strong interaction between the
catalyst and the acetate anion; see the Supporting
Information for the 1H NMR spectra.
Tetrahedron Lett. 2004, 45, 723. (i) Kubo, Y.; Sayaka, U.;
Kemmochi, Y.; Okubo, T. Tetrahedron Lett. 2005, 46, 4369.
(j) Minami, T.; Kaneko, K.; Nagasaki, T.; Kubo, Y.
(11) The S-benzyl isothiouronium chloride catalyst is soluble in
methanol and ethanol, but insoluble in CH2Cl2, THF,
dioxane, benzene, and toluene.
Tetrahedron Lett. 2008, 49, 432. (k) Nguyen, Q. P. B.; Kim,
J. N.; Kim, T. H. Bull. Korean Chem. Soc. 2009, 30, 2093.
(12) Malkov, A. V.; Vrankova, K.; Stoncius, S.; Kocovsky, P.
J. Org. Chem. 2009, 74, 5839.
Synthesis 2012, 44, 1977–1982
© Georg Thieme Verlag Stuttgart · New York