Hydrogen bond catalyzed direct reductive amination of ketones

Article abstract of DOI:10.1021/ol053001a

A novel, biomimetic concept for the direct reductive animation of ketones is described that relies on selective imine activation by hydrogen bond formation. The mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bon

Full text of DOI:10.1021/ol053001a

ORGANIC
LETTERS
2006
Vol. 8, No. 4
741-744
Hydrogen Bond Catalyzed Direct
Reductive Amination of Ketones
Dirk Menche,* Jorma Hassfeld, Jun Li, Gerd Menche, Antje Ritter, and
Sven Rudolph
Gesellschaft fu¨r Biotechnologische Forschung mbH, Medzinische Chemie, Mascheroder
Weg 1, D-38124 Braunschweig, Germany
dme05@gbf.de
Received December 12, 2005
ABSTRACT
A novel, biomimetic concept for the direct reductive amination of ketones is described that relies on selective imine activation by hydrogen
bond formation. The mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bond donor and utilizes the
Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.
Chiral amines are key structural elements in a multitude of
biologically active natural products and pharmaceuticals
rendering their synthesis an objective of high priority from
the perspective of medicinal chemistry and organic synthe-
sis.1 Reductive amination of ketones, in which a mixture of
a carbonyl compound and an amine is treated with a reductant
in a “one-pot” fashion, is one of the most useful methods
for the preparation of secondary or tertiary amines and related
functional compounds; thus, a number of methods have been
developed to carry out this direct process.2,3 Known methods
such as the authentic procedure of Borch [NaBH3CN, pH
3-4]4 rely on Brønsted and Lewis acids to facilitate
formation of the intermediate imines and to activate these
CdN intermediates for a preferential reduction in the
presence of the carbonyl compound.2-4
Nevertheless, application of these protocols to sensitive,
acid-labile or polyfunctional substrates is limited. Further-
more, many of these procedures seem not to be adaptable to
asymmetric variants.2d,5 This renders the development of
novel catalytic concepts for a mild direct reductive amination
a very important research goal.
Herein, we report the first direct reductive amination of
ketones, which exclusively relies on hydrogen bonding for
imine activation. This completely acid-free reaction is
mediated by catalytic amounts of thiourea as a simple and
readily modifiable organocatalyst and uses the Hantzsch ester
for transfer hydrogenation. The general applicability of the
method for the synthesis of a wide variety of diverse amines
is demonstrated and the mechanistic background is studied.
(1) (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.
(2) For reviews, see: (a) Martens, J. Methods of Organic Chemistry
(Houben-Weyl); G. Thieme: New York, 1995; Vol. E21d, p 4199. (b)
Baxter, E. W.; Reitz, A. B. Organic Reactions; Wiley: New York, 2002;
Vol. 59, p 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.; Bo¨rner, A. AdV. Synth. Catal. 2004, 346, 561.
(3) More recent examples are described in the following: (a) Apodaca,
R.; Xiao, W. Org. Lett. 2001, 3, 1745. (b) Allegretti, M.; Berdini, V.;
Candida Cesra, 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. (d) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S.
Tetrahedron 2004, 60, 1463. (e) Itoh, T.; Nagata, K.; Miyazaki, M.;
Ishikawa, H.; Kurihara, A.; Ohsawa, A. Tetrahedron 2004, 60, 6649.
(4) (a) Borch, R. F.; Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996. (b)
Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93,
2897.
(5) (a) Blaser, H.-U.; Buser, H.-P.; Jalett, H. P.; Pugin, B.; Spindler, F.
Synlett 1999, 867. (b) Williams, G. D.; Pike, R. A.; Wade, C. E.; Wills, M.
Org. Lett. 2003, 5, 4227. (c) Kadyrov, R.; Riermeier, T. H. Angew. Chem.,
Int. Ed. 2003, 42, 5472.
10.1021/ol053001a CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/26/2006

Living organisms employ organic dihydropyridine cofac-
tors such as nicotinamide adenine dinucleotide (NADH, 1,
Figure 1) in combination with enzyme catalysts for the direct
reductive amination of ketones.6 A salient feature of this and
the related vitamine B6 mediated amination is the activation
of the imine nitrogen by hydrogen bonds, as schematically
shown in 2. To mimic key features of this biosynthetic
pathway, assembly 3/4 was selected as a surrogate. Thus, in
a similar fashion, a dihydropyridine unit would act as a
reducing agent by hydride transfer and the imine should be
activated by intermolecular hydrogen bonding (viz. 4). The
“Hantzsch ester” 3 was selected as a readily available
replacement for NADH (1).
product. After optimizing conditions (number of equivalents,
solvent,13 temperature, drying agent, time), this reaction
proceeded essentially quantitatively (entry 4).
Table 1. Development of the Hydrogen Bond Catalyzed Direct
Reductive Amination
Figure 1. Delineation of a biomimetic concept.
While limited precedence in the literature has shown
imines to be reduced by 3, these reactions typically proceed
in low yield and require extended reaction times. Lewis acid
activation [Mg(II),7a SiO2,7b Al2O3,7b and Sc(OTf)37c] of the
imine significantly improves this result. Completely inde-
pendent from our approach, the groups of Rueping8 and List9
have very recently reported on the organocatalytic, asym-
metric hydrogenation of imines by 3 in the presence of chiral
Brønsted acids. These procedures have not been adapted to
a direct reductive amination.
To test our notion, whether a biomimetic H-bonding
activation may be used to accelerate this process in vitro
and in particular whether such an approach may be used for
a direct process, the reductive amination of acetophenone
(6) with equimolar amounts of p-anisidine (7)10 and the
Hantzsch ester was studied in the presence of mono- and
bidentate hydrogen bond donors (Table 1). While under a
variety of reaction conditions (solvent, temperature), no
transformation to 8 was observed (entry 1), equimolar
amounts of urea (5a, entry 2) and thiourea (5b, entry 3)11,12
proved to be promising additives giving amine 8 as the main
With the same efficiency, this transformation may also
be carried out with only catalytic quantities of thiourea.14
Notably, the amount of additive appears to have no signifi-
cant influence on the reaction rate (entries 5 and 6) indicating
that 5b is not participating in the rate determining step. Under
the same reaction conditions but without thiourea, no
formation of 8 was observed (entry 7), proving the crucial
influence of 5b as organocatalyst. This observation together
with the finding that the corresponding, separately prepared
ketimine (not shown) is only reduced in the presence of
thiourea and no reduction of the ketone was observed under
these conditions suggest a high selectivity of thiourea for
imine activation. Notably, this one-pot process appears to
(6) (a) John, R. O. In ComprehensiVe Biological Catalysis; Sinnot, M.,
Ed.; Academic Press: London, UK, 1998; Vol. 2, p 173. (b) Silverman, R.
B. The Organic Chemistry of Enzyme-Catalyzed Reactions; Academic
Press: London, UK, 2002; p 428.
(7) (a) Steevens, J. B.; Pandit, U.K. Tetrahedron 1983, 39, 1395. (b)
Fujii, M.; Aida, T.; Yoshihara, M.; Ohno, A. Bull. Chem. Soc. Jpn. 1989,
62, 3845. (c) 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.
(9) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005,
44, 47424.
(11) For a review and more recent examples on the use of urea and
analogues in organocatalysis, see: (a) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; VCH: Weinheim, Germany, 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.; Mu¨ller, T. N.; Lex, J. Angew. Chem., Int.
Ed. 2005, 44, 807.
(12) The higher yield with thiourea in comparison to 5a may be
rationalized by the stronger hydrogen bonds the former may form.
(13) Similar yields are obatined in benzene and dichloromethane, while
ethyl acetate, THF, MeOH, and CH3CN are less suitable.
(14) The amount of thiourea may be reduced to 3 mol % with only slight
decrease in the chemical yield.
(10) The PMP group is readily cleaved under oxidative conditions (CAN).
742
Org. Lett., Vol. 8, No. 4, 2006

be the first nucleophilic amination process of carbonyls in
general catalyzed by selective hydrogen bonding.11a
under the reaction conditions. It is only after hydrogen bond
activation by thiourea (5b) to give intermediate 26 that the
CdN moiety may be hydrogenated by the Hantzsch ester
(3) to produce amine adduct 28. For the catalytic cycle to
proceed, a transfer of thiourea from 28 to 25 is required to
give again complex 26 with concomitant liberation of the
product amine 29.
We then studied the general applicability of this procedure
for the synthesis of sterically, electronically, and functionally
diverse amines (9-22, Figure 2). In addition to p-anisidine
(7, formation of 8), also electron less rich and thus less
reactive amines add with the same efficiency (formation of
9-11). Electron deficient or hindered anilines are trans-
formed with preparatively useful yields to give 12 and 13.
Both aromatic (8-10, 12, 13) and aliphatic ketones (11, 14-
17) are accepted as substrates allowing a direct and high-
yielding access to substituted amines such as 8-17. More-
over, this protocol is applicable to the preparation of
substituted heteroaromatic amines, such as furans (18),
thiophenes (19), or pyridines (20).15 The broad applicability
and chemoselectivity of our method is further demonstrated
in the synthesis of amines 21 and 22. In comparison to
related, nondirect approaches, this tolerance of double bonds
and free acids is noteworthy.8,9
Figure 3. Proposed mechanism of the hydrogen bond catalyzed
direct reductive amination.
This mechanistic proposal is supported by ab initio
calculations (Gaussian 98, B3LYP: 6-31G* basis set)16 of
thiourea complexes of acetone (24, R1 ) R2 ) Me),
methylisopropylamine (29, R1 ) R2 ) Me), and the
respective ketimine (25, R1 ) R2 ) Me), which suggest that
the interactions with the imine (8.2 kcal/mol) are stronger
in comparison to the ones with the amine (4.3 kcal/mol) and
the ketone (6.1 kcal/mol).17,18
In summary, based on a novel biomimetic approach, we
have developed the first hydrogen bond catalyzed direct
reductive amination of ketones, which allows the convergent
and efficient synthesis of diverse amines. The mild and
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(17) The calculations suggest that thiourea forms two hydrogen bonds
to the ketimine and acetone, while only one such bond is formed to
methylisopropylamine. The formation of two hydrogen bonds to the imine
as depicted in 26 and only one such bond to the respective amine as
presented in 28 is in agreement with related calculations on aldimines and
amines by the group of Jacobsen.18 Calculated bond lengths for the crucial
hydrogen bonds of 26, with R1 ) R2 ) Me are 2.01 and 2.04 Å. NMR
spectroscopic experiments of 5b in [D6]benzene support these calculations
by showing downfield shifts of the thiourea N-H hydrogen atoms upon
addition of separately prepared imine.
Figure 2. Scope of the hydrogen bond catalyzed reaction for the
synthesis of diverse amines with the indicated yields.
Mechanistically, we assume that this reaction proceeds by
the pathway shown in Figure 3. The first steps should involve
an equilibrium of ketone 24 and amine 23 with ketimine
25, which might be rate determining. Imine 25 is not reduced
(18) Comparable calculations with aldimines and amines, however,
without consideration of the carbonyls, are described by: Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(15) For complete conversion the reaction was stirred in this special case
24 h at 50 °C and 48 h at 85 °C.
Org. Lett., Vol. 8, No. 4, 2006
743

nonacidic conditions together with the high chemoselectivity
of this protocol should enable applications to complex or
acid-sensitive substrates. Furthermore, the underlying cata-
lytic cycle and the modular structure of the organocatalyst
should allow the development of asymmetric variants19 and
adaption of our approach also to other direct procedures with
imines as reaction intermediates.
Acknowledgment. We thank the Fonds der Chemischen
Industrie (“Liebig-Stipendium” to D.M.) and the Deutsche
Forschungsgemeinsschaft (fellowships to J.L. and S.R.) for
financial support.
Supporting Information Available: Experimental de-
tails, spectral data, and copies of NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Preliminary results show that thiourea derivatives with chiral,
electron-withdrawing substituents on the nitrogens are particularly promising
for such an endeavor.
OL053001A
744
Org. Lett., Vol. 8, No. 4, 2006