Microwave-accelerated reductive amination between ketones and ammonium acetate

Article abstract of DOI:10.1016/j.tetlet.2010.07.156

A new procedure for reductive amination between ketones and ammonium acetate has been developed to access a variety of primary amines. This protocol takes advantage of microwave heating to significantly accelerate the reaction and offers a convenient and effective method to access some interesting amines. This new procedure compares favorably to previously reported approaches in terms of practicality, efficiency, and functional group compatibility.

Full text of DOI:10.1016/j.tetlet.2010.07.156

Tetrahedron Letters 51 (2010) 5210–5212
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Tetrahedron Letters
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Microwave-accelerated reductive amination between ketones
and ammonium acetate
*
Li Dong , Saadat Aleem, Cynthia A. Fink
Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new procedure for reductive amination between ketones and ammonium acetate has been developed
to access a variety of primary amines. This protocol takes advantage of microwave heating to significantly
accelerate the reaction and offers a convenient and effective method to access some interesting amines.
This new procedure compares favorably to previously reported approaches in terms of practicality, effi-
ciency, and functional group compatibility.
Received 12 July 2010
Revised 26 July 2010
Accepted 27 July 2010
Available online 2 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
importantly, the competing reaction involving the resulting primary
amine and the starting ketone. We believed that a large excess of
As part of our work to investigate the SAR of a lead series for a
medicinal chemistry project, we required several racemic, con-
formationally restricted benzyl amine derivatives (Fig. 1). Since
many of them were not commercially available, we needed to
identify a general and efficient way to access these compounds.
Although the synthesis of secondary and tertiary amines by reduc-
tive amination reactions of carbonyl compounds has been widely
utilized, the preparation of primary amines using analogous meth-
ods is not as straightforward.1 Previous reports indicate that there
are two general approaches to synthesize these compounds using
this methodology. In the first, a discrete intermediate imine or
oxime is formed followed by a separate reduction step utilizing
Pd/H2, LiAlH4, or Na.2 Although this two-step approach generally
affords a good yield of the desired product, there is the potential
for functional group incompatibility due to the harsh reducing con-
ditions. Alternatively, the direct reductive amination reactions of
1-indanone and 1-tetralone to access primary amines require
either NH3 and Raney Ni at high pressure3 or a low-yielding condi-
tion of NH4OAc and NaCNBH3.4 As none of these alternatives
seemed attractive, we were determined to identify a more efficient
and straightforward approach to prepare these useful structural
motifs.
NH4OAc would be necessary to suppress this side reaction.
In recent years, microwave-assisted reactions have gained
increasing popularity due to their unique reaction profiles and
impressive capability and versatility.5 In fact, since the 1990s, sci-
entists have used this new tool to improve yields, shorten reaction
time, and achieve cleaner reductive amination reactions.6 Due to
the known pronounced acceleration achieved with microwave
heating, we decided to use this method to promote our reactions.
2. Results and discussion
The initial screening of reaction conditions is summarized in Ta-
ble 1. Reaction of 4-bromo-2,3-dihydro-1H-inden-1-one (1) with
15.0 equiv of NH4OAc and 1.2 equiv of NaCNBH3 in methanol at
90 °C for 2 min failed to give any significant quantities of the antic-
ipated product, affording mostly recovered starting material.
Increasing the reaction time to 5 min did not improve the conver-
sion (entry 2). Using ethanol as the solvent allowed us to explore
how higher temperatures would affect the reaction. At 130 °C,
the reaction proceeded smoothly to give 76% yield of the desired
amine in just 2 min. Encouraged by this result, a lower amount
of NH4OAc (10.0 equiv) as well as higher temperature and shorter
reaction time was attempted. Unfortunately, reaction yields suf-
fered in these cases (entries 4 and 5). It is also worth noting that
in all examples, side product 3 was not detected by LC–MS in the
crude mixture.
One objective of this research was to maintain many advantages
of reductive amination reactions such as broad scope, versatility,
and ease of operation. Toward this end, we first selected NaCNBH3
as the reducing agent while deciding that NH4OAc was a practical
choice as the ammonia source. Early on, we were aware of the chal-
lenges of these conditions including low reactivity of aryl ketone
substrates, instability of ammonium acetate under heat, and more
NH2
R
n = 0,1,2
* Corresponding author. Tel.: +1 908 740 4711; fax: +1 908 740 3705.
E-mail address: li.dong@spcorp.com (L. Dong).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.156

L. Dong et al. / Tetrahedron Letters 51 (2010) 5210–5212
5211
Table 1
Microwave-accelerated reductive amination of ketone 1 and ammonium acetatea
O
NH2
HN
NH4OAc (15 eq.),
NaCNBH3 (1.2 eq.)
+
Br
mircrowave
2
1
3
Br
Br
Br
130 oC, 2 min
Entry
NH4OAc (equiv)
Solvent
Temperature (°C)
Time (min)
Yield (2)b (%)
1
2
3
4
5
15.0
15.0
15.0
10.0
15.0
MeOH
MeOH
EtOH
EtOH
EtOH
90
90
130
130
160
2
5
2
2
<5
<5
76
62
40
1.5
a
NaCNBH3 (1.2 equiv), solvent (1.2 mL), ketone 1 (100 mg).
Yield based on LC–MS for entries 1 and 2, isolated yields for entries 3–5 (purified by prep-HPLC).
b
Two more experiments were carried out before we decided the
With the optimized conditions in hand, we then investigated
the substrate scope of this new protocol. We exposed a variety of
ketones to the microwave-accelerated reductive amination condi-
tions and the results are summarized in Table 2. In most cases, LC–
MS analysis of the crude reaction mixtures indicated that the reac-
optimal conditions. First, the conventional thermal conditions
were compared to microwave heating used in the above studies.
When the reaction was heated in a sealed tube at 90 °C for 10 h,
we received only 41% isolated yield of the desired product with
complete consumption of ketone 1. The major side product under
this reaction condition was compound 3. Furthermore,
Na(OAc)3BH was used as the alternative reducing agent and sur-
prisingly, this change caused a complete reversal of the reaction
profile as only compound 3 was obtained in 72% yield using the
otherwise same conditions.
tions proceeded cleanly. Reaction with acetophenone gave
a-
methyl benzylamine in modest yield, reflecting the difficulty in
handling compounds of low molecular weight and good water sol-
ubility (entry 1). The reaction was tolerant of different ring sizes
including 5-, 6-, and 7-membered rings, and also proceeded in
the presence of steric hindrance flanking the aromatic ring (entries
2–4 and 6). However, electron-donating groups such as methoxy
on the aromatic ring led to diminished yield of the desired prod-
uct.7 Heteroatoms were tolerated on the neighboring aromatic ring
or as part of a ring containing the ketone (entries 7 and 8). Finally,
both diaryl and alkyl ketones are suitable substrates for this meth-
odology (entries 9 and 10). Unlike other examples, in the case of
entry 10, a small amount (<10%) of bisalkylated product similar
to 3 was also isolated. Not surprisingly, base-sensitive b-tetralone
is not a suitable substrate for this reductive amination procedure
as only an intractable mixture was obtained.
Table 2
Reactions of various ketones
Entry
1
Substrate
Yield (%)
68
O
O
Br
2
3
4
5
81
76
83
66
O
3. Conclusions
In conclusion, a convenient and efficient reductive amination
protocol for the preparation of primary amines was developed uti-
lizing microwave heating. A variety of ketones reacted with NH4OAc
and NaCNBH3 under these conditions to afford the desired primary
amine rapidly and in good yield. We believe that this improved pro-
cedure will be valuable in the preparation of many biologicallyinter-
esting molecules containing primary amine functionalities.
Br
Br
O
O
OMe
O
4. Experimental
6
7
88
95
Ammonium acetate (513.5 mg, 6.66 mmol) and sodium cyano-
borohydride (33.5 mg, 0.533 mmol) were added to a solution of
6-bromochroman-4-one (100 mg, 0.444 mmol) in EtOH (1 mL) in
a 2 mL microwave vial. The mixture was stirred and heated at
130 °C for 2 min in a microwave reactor (Biotage InitiatorÒ). The
reaction mixture was concentrated to remove most of the EtOH,
treated with 2 N NaOH until pH >10, and extracted with EtOAc
(2 Â 10 mL). The organic phase was dried (Na2SO4), filtered, and
concentrated under reduced pressure to give crude product which
was usually more than 90% pure (LC–MS). An analytical sample
was obtained by prep HPLC as a formate salt. 1H NMR (CD3OD,
400 MHz, ppm): d = 2.13 (m, 1H), 2.35 (m, 1H), 4.31 (m, 2H), 4.56
(m, 1H), 6.87 (d, J = 6.8 Hz, 1H), 7.56 (dd, J = 2.0, 6.8 Hz, 1H), 7.62
(m, 1H), 8.62 (s, 1H).
O
O
Br
O
N
8
9
78
85
O
10
11
83
Ph
Br
O
O
Complex mixture

5212
L. Dong et al. / Tetrahedron Letters 51 (2010) 5210–5212
Org. Chem. 2006, 71, 4130–4140; (e) Meng, Y.-Q.; Wang, Z.; Cheng, M.-S.
Acknowledgment
Zhonggui Xinyao Zazhi 2003, 12, 457–458.
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Chambournier, G.; Hsu, M. C.-P.; Leanna, R. M.; Cink, R. D. U.S. Patent
200,82,87,676, 2008.
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Huang, C.; Zou, A.; Yu, W. Bioorg. Med. Chem. Lett. 2007, 17, 2849–2853.
5. Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
9283.
We thank Dr. G. Greg Zipp for his generous assistance in prep-
aration of this Letter.
References and notes
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7. No starting material was isolated after the reaction. Unidentified side products
were formed with this substrate.