Thiourea-catalyzed direct reductive amination of aldehydes

Article abstract of DOI:10.1055/s-2006-939052

A hydrogen-bond-catalyzed direct reductive amination of aldehydes is reported. The acid- and metal-free process uses thiourea as organocatalyst and the Hantzsch ester for transfer-hydrogenation and allows for the high-yielding synthesis of diverse amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939052

LETTER
841
Thiourea-Catalyzed Direct Reductive Amination of Aldehydes
T
hiourea-Catalyze
i
dDire
c
r
t
Reduc
k
A
minationof
A
M
ldehydes enche,* Fatih Arikan
Gesellschaft für Biotechnologische Forschung mbH, Medizinische Chemie, Mascheroder Weg 1, 38124 Braunschweig, Germany
Fax +49(531)6181461; E-mail: dme05@gbf.de
Received 20 January 2006
groups of Rueping,8 List9 and MacMillan10 have very re-
cently reported that this imine reduction by the Hantzsch
ester may also be catalyzed by phosphoric acids.
Abstract: A hydrogen-bond-catalyzed direct reductive amination
of aldehydes is reported. The acid- and metal-free process uses thio-
urea as organocatalyst and the Hantzsch ester for transfer-hydroge-
nation and allows for the high-yielding synthesis of diverse amines.
To test our notion, whether such a biomimetic amination
Key words: amines, reductions, organocatalysis, hydrogen bonds, may also be accelerated by hydrogen bonds, we studied
aminations
the reaction of benzaldehyde (1a, Table 1) with p-anisi-
dine (2a) and the Hantzsch ester in the presence of non-
acidic hydrogen-bond donors. Best results were obtained
with thiourea (4).11 After optimizing reaction condi-
The reductive amination presents one of the most power-
ful and widely utilized methods for the synthesis of
tions,12 the desired substituted amine 5a was obtained in
an essentially quantitative manner.13 This reaction re-
quires only catalytic amounts of the organocatalyst to pro-
ceed,14 suggesting a selective complexation of thiourea to
the imine in the presence of free amine and aldehyde.15 In
addition, no reduction of the aldehyde was observed under
the reaction conditions, which further corroborates a high
degree of selectivity of the organocatalyst and adds to the
efficiency of the protocol.
amines.1 The versatile coupling reaction enables a rapid
and general access to C–N bonds, a key structural feature
in natural products and pharmaceuticals.2 Particularly im-
portant are direct procedures, where the carbonyl compo-
nent is treated in a ‘one-pot’ fashion with the amine and a
reducing agent.1,3 Known procedures to carry out this
transformation rely on Brønsted and Lewis acids to facil-
itate the formation and selective reduction of the interme-
diate imines in the presence of the carbonyl.1,3 However,
application of these protocols to sensitive or polyfunction-
al substrates is limited, which renders the development of
mild and acid-free protocols an important research goal.
To evaluate the general applicability of this protocol,
various aromatic (1b–d) and aliphatic (1e,f) aldehydes
were submitted to the reaction conditions. In all cases, the
desired product amines (5b–f) were obtained in high
yields, without the need for further adaption of the
reaction conditions for specific substrates.16 Both elec-
tron-deficient (entry 2) as well as electron-rich aromatic
aldehydes (entry 3) are readily aminated. No reduction of
the nitro group (entry 2) was observed and free hydroxyls
are tolerated (entry 4). Aliphatic aldehydes react with the
same effectiveness (entries 5 and 6), regardless of whether
they are linear (1d) or a-branched (1e).
Herein, we report a novel method for the direct reductive
amination of aldehydes, which exclusively relies on
hydrogen bond catalysis. The completely acid-free
method utilizes thiourea as hydrogen bond donor and the
Hantzsch ester as hydride source. The procedure is of
broad applicability for the synthesis of diverse amines and
characterized by a high degree of functional group
tolerance.
As shown in Table 2, the method is also applicable to
various aromatic and heterocyclic amines (2b–g) allow-
ing an efficient access to the substituted products 5g–l
(Table 2).16 A broad spectrum of electronically and steri-
cally diverse amines is accepted. Furthermore, hydroxyls
(entry 3), nitro groups (entry 3) as well as ketones (entry
5) and carboxylic acids (entry 6) are tolerated, demon-
strating a high degree of functional group tolerance of our
protocol.
Biosynthetically, amines may be derived by reductive
amination of carbonyls by NADH-dependent transferases
or the vitamin B6 pathway.4 These pathways rely on hy-
drogen bonding to activate imines towards the hydride de-
livery. This prompted us to investigate, whether such
hydrogen bonding may also be used for a related process
in vitro.
In our biomimetic approach, the Hantzsch ester 3
(Table 1) was selected as a readily available mimic to the
enzymatic dihydropyridine cofactors. It has been shown
that the Hantzsch ester is not suitable for the direct reduc-
tion of imines.5 However, this reduction proceeds smooth-
ly in the presence of Lewis acids, such as Mg(II),5 SiO2,6
In summary, we have developed an organocatalytic direct
reductive amination of aldehydes, which relies on hydro-
gen bonding for imine activation. A mild and operational-
ly simple fragment coupling has been accomplished with
a wide range of aldehydes in combination with aryl and
heterocyclic amines. Expansion of the catalytic principle
to related procedures is underway.
6
Al2O3 or Sc(OTf)3.7 In the course of our studies, the
SYNLETT 2006, No. 6, pp 0841–0844
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939052; Art ID: G02306ST
© Georg Thieme Verlag Stuttgart · New York

842
D. Menche, F. Arikan
LETTER
Table 1 Thiourea-Catalyzed Direct Reductive Amination of Diverse Aldehydes
H
H
EtO2C
CO2Et
OMe
OMe
N
H
O
3
+
S
R
H
H2N
R
N
H
1a–f
2a
5a–f
H2N
NH2
4 (0.1 equiv)
5 Å MS, toluene, 70 °C
Entry
1
Aldehyde 1a–f
Product amine 5a––f
Yield (%)
93
OMe
OMe
OMe
O
H
N
H
1a
5a
O
OMe
H
2
3
93
93
N
H
O2N
O2N
1b
5b
O
H
N
H
OMe
OMe
1c
5c
O
OMe
O2N
H
O2N
4
5
6
73
82
83
N
H
HO
HO
1d
5d
O
n-octyl
H
n-octyl
N
H
1e
5e
O
OMe
H
N
H
1f
5f
Acknowledgment
References and Notes
Generous financial support by the Fonds der Chemischen Industrie
(‘Liebig-Stipendium’ to D.M., ‘Doktorandenstipendium’ to F.A.)
and the Deutsche Forschungsgemeinschaft (research stipend) is
most gratefully acknowledged. We thank Antje Ritter and Tatjana
Arnold for technical support.
(1) For reviews, see: (a) Martens, J. In Houben-Weyl, 4th ed.,
Vol. E21d; de Meijere, A., Ed.; Thieme: Stuttgart, 1995,
4199. (b) Baxter, E. W.; Reitz, A. B. Organic Reactions,
Vol. 59; Wiley: New York, 2002, 1. (c) Gomez, S.; Peters,
J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002, 344, 1037.
(d) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Fischer,
C.; Börner, A. Adv. Synth. Catal. 2004, 346, 561.
(e) Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric
Catalysis, 1st Suppl.; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: New York, 2004.
Synlett 2006, No. 6, 841–844 © Thieme Stuttgart · New York

LETTER
Thiourea-Catalyzed Direct Reductive Amination of Aldehydes
843
Table 2 Scope of Amines
O
R
see Table 1
H
N
H
R
+
H2N
1a
5g–l
2b–g
Entry
1
Amine 2b–g
Product amine 5g–l
Yield (%)
93
H2N
N
H
2b
5g
Cl
Cl
2
3
4
73
68
91
N
H
H2N
2c
5h
O2N
OH
O2N
OH
H2N
N
H
2d
5i
N
N
N
H
H2N
2e
5j
O
O
5
6
72
75
H2N
N
H
2f
5k
CO2H
CO2H
N
H
H2N
2g
5l
(2) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J.
Comb. Chem. 1999, 1, 55. (b) Henkel, T.; Brunne, R. M.;
Mueller, H.; Reichel, F. Angew. Chem. Int. Ed. 1999, 38,
643.
(7) Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett. 2002, 43, 3105.
(8) Rueping, M.; Sugioni, E.; Azap, C.; Theissmann, T.; Bolte,
M. Org. Lett. 2005, 7, 3781.
(3) For selected recent examples, see: (a) Gross, T.; Seayad, A.
M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4, 2055.
(b) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S.
Tetrahedron 2004, 60, 1463. (c) Itoh, T.; Nagata, K.;
Miyazaki, M.; Ishikawa, H.; Kurihara, A.; Ohsawa, A.
Tetrahedron 2004, 60, 6649.
(4) (a) John, R. O. In Comprehensive Biological Catalysis, Vol
2; Sinnot, M., Ed.; Academic Press: London, 1998, 173.
(b) Silverman, R. B. The Organic Chemistry of Enzyme-
Catalyzed Reactions; Academic Press: London, 2002, 428.
(5) Steevens, J. B.; Pandit, U. K. Tetrahedron 1983, 39, 1395.
(6) Fujii, M.; Aida, T.; Yoshihara, M.; Ohno, A. Bull. Chem.
Soc. Jpn. 1989, 62, 3845.
(9) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed.
2005, 44, 7424.
(10) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2006, 128, 84.
(11) For a review and recent examples on the use of urea and
analogues in organocatalysis, see: (a)Berkessel, A.;Gröger,
H. Asymmetric Organocatalysis; VCH: Weinheim, 2005.
(b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005,
44, 466. (c) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2005, 127, 8964. (d) Berkessel, A.; Cleemann, F.;
Mukherjee, S.; Müller, T. N.; Lex, J. Angew. Chem. Int. Ed.
2005, 44, 807. (e) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto,
Y. Synlett 2006, 137.
Synlett 2006, No. 6, 841–844 © Thieme Stuttgart · New York

844
D. Menche, F. Arikan
LETTER
(12) (a) Benzene and CH2Cl2 are as suitable as toluene, while
more polar solvents such as dioxane or THF are less
efficient. Protic solvents (e.g. MeOH) are of limited
applicability. (b) Upon extended reaction times, the
transformation may also be carried out at r.t.
(16) All new compounds had spectroscopic data in support of the
assigned structures.
Compound 5d: 1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3
H), 4.27 (s, 2 H), 6.56 (d, J = 9.04 Hz, 2 H), 6.76 (d, J = 9.04
Hz, 2 H), 7.12 (d, J = 8.48 Hz, 1 H), 7.60 (d, J = 10.74 Hz, 1
H), 8.10 (d, J = 2.26 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 47.95, 55.80, 114.37, 115.02, 120.26, 123.37, 132.45,
133.56, 136.76, 141.58, 152.66, 154.27. HRMS (ESI): m/z
calcd for C14H15N2O4 [M + H]+: 275.1032. Found: 275,1034.
Compound 5k: 1H NMR (300 MHz, CDCl3): d = 2.54 (s, 3
H), 4.21 (s, 1 H), 4.37 (s, 2 H), 6.71 (d, J = 4.14 Hz, 2 H),
6.82 (d, J = 3.96 Hz 2 H), 7.26–7.36 (m, 5 H). 13C NMR (75
MHz, CDCl3): d = 26.73, 48.31, 111.82, 118.01, 127.55,
128.77, 129.40, 138.27, 139.89, 148.29, 198.57. HRMS
(ESI): m/z calcd for C15H16NO [M + H]+: 226,1232. Found:
226,1233.
(13) General Procedure.
A solution of the aldehyde (1a–f, 2.20 mmol) and the amine
(2a–g, 2.00 mmol) in toluene (5 mL) is treated with the
Hantzsch ester (3, 608 mg, 2.40 mmol), thiourea (4, 15.2 mg,
0.200 mmol) and MS 5 Å (2.0 g). The mixture is stirred 24 h
at 70 °C under nitrogen. After filtration over Celite®, the
solvent is evaporated and the residue purified by flash
chromatography on silica gel using mixtures of PE and
EtOAc as eluants to give the product amines (5a–l) in pure
form.
(14) (a) The catalyst loading may be reduced to 1 mol% upon
extended reaction times (>48 h). (b) Under the same
reaction conditions but in the absence of thiourea, the
product amine is only obtained in low yields proving the
vital influence of the organocatalyst.
(15) This assumption is supported by previous calculations on
related thiourea complexes with aldimines and amines:
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012.
Compound 5l: 1H NMR (400 MHz, CDCl3): d = 3.52 (s, 2
H), 4.31 (s, 2 H), 6.60 (d, J = 8.65 Hz, 2 H), 7.07 (d, J = 8.65
Hz, 2 H), 7.26–7.34 (m, 5 H). 13C NMR (100 MHz, CDCl3):
d = 40.00, 48.47, 113.12, 122.18, 127.54, 128.69, 130.24,
139.24, 139.35, 147.43, 176.85. HRMS (ESI): m/z calcd for
C15H16NO2 [M + H]+: 242.1181. Found: 242.1178.
Synlett 2006, No. 6, 841–844 © Thieme Stuttgart · New York