Reductive amination of ketones: Novel one-step transfer hydrogenations in batch and continuous-flow mode

Article abstract of DOI:10.1016/j.tetlet.2011.01.062

Various ketones were efficiently transformed into the corresponding amines using ammonium formate in the presence of Zn dust or 10% Pd/C. The low-cost Zn dust method proved to be effective in amine formation from carbonyl groups at the benzylic side-chain position of aromatic systems, whereas 10% Pd/C was an efficient catalyst in the reductive aminations of carbonyl groups non-conjugated with any π-system. The 10% Pd/C-catalyzed reductions were performed more effectively in a continuous-flow X-Cube reactor than in the batch system.

Full text of DOI:10.1016/j.tetlet.2011.01.062

Tetrahedron Letters 52 (2011) 1310–1312
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive amination of ketones: novel one-step transfer hydrogenations
in batch and continuous-flow mode
Péter Falus a, Zoltán Boros a, Gábor Hornyánszky a, József Nagy a, Ferenc Darvas b, László Ürge c,
László Poppe a,
⇑
a Department for Organic Chemistry and Technology, Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, Budapest University of Technology and Economics,
Müegyetem rkp. 3., H-1111 Budapest, Hungary
b Department of Cellular Biology and Pharmacology, Herbert Weinheim College of Medicine, Florida International University, 11200 S.W. 8th Street, Miami, FL 33199, USA
c ThalesNano Inc., Graphisoft Park, Záhony u. 7., H-1031 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Various ketones were efficiently transformed into the corresponding amines using ammonium formate in
the presence of Zn dust or 10% Pd/C. The low-cost Zn dust method proved to be effective in amine forma-
tion from carbonyl groups at the benzylic side-chain position of aromatic systems, whereas 10% Pd/C was
an efficient catalyst in the reductive aminations of carbonyl groups non-conjugated with any p-system.
The 10% Pd/C-catalyzed reductions were performed more effectively in a continuous-flow X-Cube reactor
Received 26 November 2010
Revised 21 December 2010
Accepted 14 January 2011
Available online 20 January 2011
than in the batch system.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Ketone
Amine
Ammonium formate
Zinc dust
Palladium on charcoal
Continuous-flow reductive amination
Amines are indispensable building blocks in numerous drugs,1,2
pesticides3, and color pigments.4 Thus, development of general and
efficient methods to prepare amino compounds is still required.
One of the most convenient methods to synthesize amines is the
reductive amination of carbonyl compounds.5 The classical Leuck-
art–Wallach (LW)6 reaction is clean and very simple, but it has sev-
eral drawbacks such as the requirement of harsh conditions,
formation of N-formyl derivatives, and the difficulty of selective
synthesis of primary amines from ammonia.
NH3 or other ammonia source.17 Sometimes, these processes result
in various side reactions such as formation of alcohols, Schiff-
bases, imines, and bis-amines.15
Amines can be formed stereoselectively by employing chiral
complexes18–21 or enzymes.22,23 In many cases, however, cost,
recyclability or environmental issues make such methods unsuit-
able for large scale production.
As the formation of oximes from carbonyl compounds is a well
established process,12,24 and that amines can be prepared by
reduction of oximes with LiAlH4,25 or by various metals such as
Zn26–28 or Mg,29 the combination of these two methods can pro-
vide a synthetic pathway to amines from ketones.
Nowadays, reductive transformations of ketones into amines
are performed in the presence of catalysts. A wide range of me-
tal-containing catalysts, usually as metal complexes, such as
Pd,7–9 Ir,10 Rh,10 Ru,10 and Ti11 are utilized in these processes.
Although some of these catalysts are widely used, they have limi-
tations with regard to chemoselectivity, recyclability, safety, and
costs.
Metals or metal-containing catalysts can be applied for reduc-
tive aminations with various reducing agents.5 In these processes,
molecular hydrogen,13–16,18 metal hydrides such as NaBH4
or
11,30
NaBH3CN,31 or various transfer hydrogenating agents such as Han-
tzsch esters19 can serve as the reducing agents. In addition, reduc-
tive amination of ketones requires a nitrogen source such as
Metals (Na,12 Ni,13 Raney-Ni,14 Pd,15 Pt16 or Ru15), or metals on
activated charcoal (Pd/C,15 Ru/C15) are also used in reductive amin-
ations of ketones. In these cases, either the metal is dissolved in a
protic solvent in the presence of an ammonia source, or the metal
serves as the catalyst under an H2 atmosphere in the presence of
ammonia,13–16,20,32 ammonium salts (NH4Cl,15,16,30 NH4OAc31),
L-
alanine22,23 or isopropylamine.23a,b
Ammonium formate is an inexpensive, non-toxic, and environ-
mentally safe reagent, and could serve as both the nitrogen source
and the transfer hydrogenating agent simultaneously.7,8,10,20,21
Ammonium formate was successfully applied previously in metal
⇑
Corresponding author. Tel.: +36 1 463 3299; fax: +36 1 463 3697.
E-mail address: poppe@mail.bme.hu (L. Poppe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.062

P. Falus et al. / Tetrahedron Letters 52 (2011) 1310–1312
1311
complex catalyzed10,20,21 or Pd/C-catalyzed7,8 reductive aminations
of ketones.
The development of novel synthetic techniques influences not
Method A
O
H2NOH.HCl
HCOONH4, MeOH
NH2
R1 R2
NOH
R1 R2
Zn dust
R1 R2
only the large scale production of pharmaceuticals, fine chemicals,
and agrochemicals but also provides efficient methods for research
laboratories to be able to prepare increased numbers of com-
pounds. Despite the strong trend for automation, the majority of
amine chemistry at the research phase is still carried out in
batches, whereas flow processes are restricted to production pro-
cesses.2,5 Consequently, exploitation of the main advantages of
the flow approach in the discovery phase, such as facile automa-
tion, reproducibility, safety, and process reliability, has gained sig-
nificant interest.33
reflux, 5 h
1a-i
2e-i
Method B
HCOONH4, Zn dust
MeOH, reflux, 5 h
1a-i
2e-i
2a-i
Method C
HCOONH4, 10% Pd/C
MeOH, RT, 16 h
1a-i
In this Letter, the reductive amination of ketones was investi-
gated with ammonium formate and various metals/metal catalysts
in one-pot and one-step reactions using both batch and continu-
ous-flow methods.
Method D
T
HCOONH4
The two-step production of oximes from ketones and their
reductive transformation into amines are well known.24–29
Although simple metal-promoted transfer hydrogenations of oxi-
mes using ammonium formate and Zn26 or Mg29 in methanol have
been developed, the oxime formation and reduction steps have not
been combined into a one-pot process. Since oxime reduction with
HCOONH4 and Zn in methanol26 proved to be reproducible and
effective, we first investigated a one-pot method using these re-
agents for different aliphatic, cycloaliphatic, and aromatic ketones
1a–i. Thus, ketones 1a–i were treated with H2NOHÁHCl, HCOONH4,
and Zn dust in methanol under reflux until disappearance of the
starting ketones by TLC (Method A, Fig. 1 and Table 1). The one-
O
NH2
R1 R2
2a-d
R1 R2
p
10% Pd/C filled reactor
1a-d
MeOH
O
O
O
1a
1b
1c
1f
O
O
step reductive amination of ketones with the carbonyl group
a to
O
the aromatic ring yielded the desired amines in moderate to good
yields (2e–i, Method A in Table 1). On the other hand, aliphatic and
cycloaliphatic ketones (1a–d) could not be aminated under these
conditions (Method A, Table 1).
1d
1e
The one-pot process (Method A, Fig. 1 and Table 1) may not
necessarily proceed via an oxime intermediate if the imine
formed from ammonium formate could be reduced. Therefore,
we omitted toxic H2NOHÁHCl, and studied the formation of 1-
O
O
O
phenylethylamine (2g) from acetophenone (1g) as
a model
experiment to test if using only HCOONH4 in the presence of
various metals or metal catalysts was a viable method. Prelimin-
ary screens were carried out in methanol (with 6 equiv of
HCOONH4), or in methanol–water 9:1 mixture (with 10 equiv
of HCOONH4) at room temperature (16 h) or under reflux (5 h).
While Raney-Ni, Mg dust, and Cu dust were not effective under
either conditions, Zn dust and 10% Pd/C proved to be effective in
reductive aminations under certain conditions. Zn dust promoted
reactions did not occur at room temperature, whereas at reflux,
1-phenylethylamine (2g) was produced in 60–71% yields (the
highest yield was observed when the solvent was pure metha-
nol). In the 10% Pd/C-catalyzed reactions, room temperature
was sufficient to reduce acetophenone (1g). Besides formation
of the desired amine 2g in 17% yield, an almost 1:1 mixture of
racemic and meso bis(1-phenylethylamine) as undesired side
products was isolated (50%).34 The yield of amine 2g and the
side products were virtually unaffected by the presence of water
(10%) and a larger excess of HCOONH4 (10 equiv) in methanol.
Following these model experiments, one-step reductive amina-
tions with the two most promising systems (Zn dust and 10% Pd/C)
were performed with all the ketones 1a–i. The Zn dust promoted
reactions were carried out in methanol under reflux (Method B,
Fig. 1 and Table 1), whereas the 10% Pd/C-catalyzed processes were
performed at room temperature (Method C, Fig. 1 and Table 1). The
two methods were found to be complementary, because the Zn
dust promoted reactions (Method B, Fig. 1 and Table 1) of ketones
with the carbonyl group at the benzylic position of an aromatic
1g
1h
1i
Figure 1. Reductive aminations of ketones 1a–i.
Table 1
Reductive aminations of ketones 1a–i with ammonium formate in methanol
Ketone
Yield of amine 2a–i (%)
Method A
Method B
Method C
Method Da
b
b
b
b
b
b
b
b
1a
1b
1c
1d
1e
1f
1g
1h
1i
52
60
38
64
5
11
17
<5
20
53
68
41
67
c
69
51
36
40
64
71
56
71
37
68
c
c
c
c
a
Reaction in a packed-bed continuous-flow reactor at 40 °C and at 0.2 ml/min
flow rate.
b
No product formation was observed by TLC.
c
Not tested.
side chain, 1e–i, resulted in smooth formation of the corresponding
amines 2e–i in moderate to good yields (37–71%, see Method B in
Table 1), while the 10% Pd/C-catalyzed reactions (Method C, Fig. 1
and Table 1) were more suitable to convert aliphatic and cycloali-

1312
P. Falus et al. / Tetrahedron Letters 52 (2011) 1310–1312
phatic ketones 1a–d into the corresponding amines 2a–d (in 38–
64% yields). On the other hand, Zn dust was not effective for the
transformation of aliphatic and cycloaliphatic ketones 1a–d (see
Method B in Table 1), while 10% Pd/C-catalysis resulted in signifi-
cant formation of side products (mostly bisalkylated-amines),
thereby decreasing the yields of the desired amines 2e–i (see
Method C in Table 1).
Supplementary data
Supplementary data (experimental details) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.01.062.
References and notes
We also investigated the application of these methods for the
reductive amination of ketones in continuous-flow systems using
the X-Cube flow reactor. Since various Zn-salts were formed and
precipitated during the Zn dust promoted reductive aminations
(Methods A and B, Fig. 1 and Table 1), these methods were
not appropriate for the continuous-flow system. As the reaction
mixture remains homogeneous with the 10% Pd/C-catalyst
(Method C, Fig. 1 and Table 1), reductive aminations of aliphatic
and cycloaliphatic ketones 1a–d were carried with the continu-
ous-flow system using a packed-bed column containing 10%
Pd/C (Method D, Fig. 1 and Table 1: 6 equiv of HCOONH4 and
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Acknowledgments
This research was supported by the Hungarian National Office
for Research and Technology (NKFP-07-A2 FLOWREAC). This
work is also related to the scientific program of ‘Development
of quality-oriented and harmonized R+D+I strategy and functional
model at BME’ (TÁMOP-4.2.1/B-09/1/KMR-2010-0002), supported
by the New Hungary Development Plan. The authors thank Dr. A.
Tomin for discussions and her help in the preparation of this
Letter.
34. 1H NMR (500 MHz, CDCl3, d ppm): 1.24 (d, J = 6.5 Hz, 3H, –CH3: meso); 1.32 (d,
J = 6.5 Hz, 3H, –CH3: rac), 1.52 (br s, 4H, NH2, meso and rac); 3.47 (q, J = 6.5 Hz,
1H, –CH: meso), 3.74 (q, J = 6.5 Hz, 1H, –CH: rac), 7.15–7.35 (m, 10H, Ar-H:
meso and rac); [Lit. 1H NMR: Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, L. Org.
Lett. 2008, 10, 181].