Reductive amination agents: comparison of Na(CN)BH3 and Si-CBH

Article abstract of DOI:10.1016/j.tetlet.2009.09.076

Reductive amination is a chemical reaction commonly employed by organic chemists in academics and the pharmaceutical industry. In this reaction a carbonyl group is converted to an amine via an imine intermediate, the formation of which is rate limiting. A major reagent necessary for the completion of this reaction is a hydride source, commonly sodium cyanoborohydride (Na(CN)BH₃). The objective of this research was to compare the efficacy of Na(CN)BH₃ with silica-bound cyanoborohydride (Si-CBH) as hydride sources in reductive amination reactions. Work has shown that reactions employing Si-CBH as a hydride source showed significant improvement, exhibiting an average percent conversion 25% greater than reactions using Na(CN)BH₃.

Full text of DOI:10.1016/j.tetlet.2009.09.076

Tetrahedron Letters 50 (2009) 6658–6660
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Tetrahedron Letters
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Reductive amination agents: comparison of Na(CN)BH3 and Si-CBH
Paolo N. Grenga a, Brittany L. Sumbler a, François Beland b, Ronny Priefer a,
*
a Department of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
b SiliCycle Incorporated, Quebec City, QC, Canada G1P 4S6
a r t i c l e i n f o
a b s t r a c t
Article history:
Reductive amination is a chemical reaction commonly employed by organic chemists in academics and
the pharmaceutical industry. In this reaction a carbonyl group is converted to an amine via an imine
intermediate, the formation of which is rate limiting. A major reagent necessary for the completion of this
reaction is a hydride source, commonly sodium cyanoborohydride (Na(CN)BH3). The objective of this
research was to compare the efficacy of Na(CN)BH3 with silica-bound cyanoborohydride (Si-CBH) as
hydride sources in reductive amination reactions. Work has shown that reactions employing Si-CBH as
a hydride source showed significant improvement, exhibiting an average percent conversion 25% greater
than reactions using Na(CN)BH3.
Received 20 August 2009
Revised 10 September 2009
Accepted 13 September 2009
Available online 17 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Reductive amination, also referred to as reductive alkylation, is
one of the most important synthetic tools for the synthesis of
amines. Some noteworthy examples of its use are the syntheses of
delavirdine mesylate,1 valsartan,2 and amphetamine3 (Fig. 1) to
name a few. The typical reaction involves the coupling of an alde-
hyde or a ketone with an amine to initially yield a hydroxyamine,
which subsequently forms an imine upon dehydration. This imine
is then reduced to the substituted amine. The latter step can be per-
formedintwodifferentmethods: eitherhydrogenationorreduction.
Palladium, nickel, or platinum4–6 catalyst can be employed in hydro-
genation. Although this method is quite cost effective, there are lim-
itations with additional functional groups that may be present; in
particular, C@C, nitro, haloaromatic, etc.7,8
With reduction there tend to be less side products formed, how-
ever other issues are present. Various methods of performing this
reaction have been developed, including solvent-free microwave
reductive amination9 and biochemical techniques such as protein
immobilization.10 Common agents used are borohydride based;
some of which are NaBH4/Mg(ClO4)2,11 Zn(BH4)2/ZnCl2,12 Na(OAc)3
BH,13–15 and Na(CN)BH3,16,17 the latter of which has shown the most
use. Issues with this reagent are the toxicity of the sodium cyano-
borohydride, as well as the side products that are formed during
workup (HCN and NaCN).18 Additionally, reactions employing
Na(CN)BH3 are usually performed with acetic acid, which can be
problematic if acid labile groups are present. In an attempt to cir-
cumvent both the side product and acid sensitivity issues, we
explored solid-support bound cyanoborohydride as an alternate
source of hydride in reductive amination reactions. One such source
is SiliaBond cyanoborohydride (Si-CBH) available from SiliCycle Inc.
The cyanoborohydride is complexed to the quaternary ammonium
modified silica gel surface at a loading of 1.0 mmol/gram. For our
study we used a 1:2:2 ratio of carbonyl:amine:hydride.
Many combinations of carbonyls (0.1–0.25 g) and amines were
tested (Table 1) in order to demonstrate the effectiveness of Si-CBH
versus Na(CN)BH3. We chose very benign reaction conditions, that
is, room temperature, 24 h, in THF (10–25 mL). In order to obtain
product for comparison with GCMS from a Na(CN)BH3 reaction,
the mixtures were quenched with distilled water (10–25 mL),
extracted three times (10 mL) with ethyl acetate, washed with dis-
tilled water (10 mL), dried with MgSO4, filtered, and evaporated.
For reactions involving Si-CBH, however, the silica gel was simply
filtered off and concentrated under reduced pressure. Conversions
were obtained using GCMS.19 Figure 2 illustrates typical spectra
obtained. It can qualitatively be seen that the use of Si-CBH is supe-
rior to that of Na(CN)BH3 in the reductive amination reaction of
acetophenone with benzylamine.
Virtually every reaction performed had
a higher product
conversion percentage using Si-CBH (Table 1).20 With benzylamine
and benzaldehyde, an increase from 67.4% to 97.9% was observed
when Si-CBH was used in place of Na(CN)BH3. With benzylamine
and 3-pentanone, the difference in yield between the two hydride
sources used is even more pronounced. With Na(CN)BH3 no
product was observed after 24 h, and only 1.8% conversion after
48 h. In contrast, a conversion of 82.8% was observed after 24 h
when using Si-CBH. There were some reactions, such as those
involving n-hexylamine with benzaldehyde and heptaldehyde
with benzylamine which exhibited similar conversion percentages
(93.5 vs 99.8 and 95.5 vs 98.6%) when using Na(CN)BH3 and
Si-CBH, respectively. In addition, there were examples where no
or very little product was formed with either reagent. Extremely
low product conversions (commonly 0%) were noted for reactions
* Corresponding author. Tel.: +1 716 286 8261; fax: +1 716 286 8254.
E-mail address: rpriefer@niagara.edu (R. Priefer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.076

P. N. Grenga et al. / Tetrahedron Letters 50 (2009) 6658–6660
CH3
HN
6659
H3C
CH3
H3C
O
H3C
N
N
N
N
CO2H
HN
N
N
NH2
H
H3C
N
N
O
S
O
O
N
H
Figure 1. Shown left to right: delavirdine mesylate, valsartan, and amphetamine.
Table 1
Combinations of ketones/aldehydes (0.1–0.25 g) and amines used in reductive amination reactions (1:2:2 carbonyl:amine:hydride source) stirring at rt for 24 h in THF (10–25 mL)
*
( ) indicates product percentages after 48 h.
[ ] indicates isolated yield from 24 h reactions.
*
involving acetophenone or p-methoxyacetophenone. Most likely
the initial nucleophilic attack of the amine onto the acetophenone
is compromised by steric hindrance. Similarly, the poor yield with
p-methoxyacetophenone can be attributed to steric as well as the
electron-donating methoxy group decreasing the electrophilicity
of the carbonyl carbon. Reactions between cyclohexylamine and
3-pentanone, as well as piperidine and 3-pentanone showed no
product conversion using Na(CN)BH3.

6660
P. N. Grenga et al. / Tetrahedron Letters 50 (2009) 6658–6660
Figure 2. Gas chromatography spectra for reductive amination of acetophenone and benzylamine using Na(CN)BH3 (left) or Si-CBH (right) as a hydride source.
The results depicted in Table 1 suggest that reductive amination
reactions performed were markedly more effective when using
Si-CBH as the hydride source. This suggests that the silica gel-based
reagent issuperiorto thetraditionalreagentandisa choicebettersui-
ted for reductive amination reactions in mild conditions.21 The differ-
ences in Si-CBH that give the compound its remarkable improvement
overthetraditionalhydridesourcearealsoofinterestforfutureinves-
tigation. There are two possible properties that may explain the supe-
riority of Si-CBH. Firstly, the structure of Si-CBH may provide pockets
to facilitate intermolecular collisions. This could indicate that the sil-
ica gel is acting as a Lewis acid hence catalyzing the formation of the
initial addition product. Alternatively, there may be residual H+ ions
on the silica gel, which would also catalyze the reaction.
Our results indicate that Si-CBH does perform much better in
benign reductive amination conditions. In addition to providing
superior conversions, acetic acid was not needed (eliminating is-
sues with acid labile groups), the workup required only a filtration
(decreasing amount of solvents used, as well as waste generated),
and HCN and NaCN should not be liberated during workup.
Although the cost of Si-CBH is higher than that of the traditional
Na(CN)BH3, its use may ultimately decrease overall expenditures
by minimizing man-hours, as well as solvent waste generation.
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Acknowledgments
5
l
20. Products were confirmed either by comparison with authentic material or by
using GCMS and/or NMR on purified product.
21. When acetic acid was added to the initial reaction both reactions were virtually
quantitative.
The authors thank the Niagara University Academic Center for
Integrated Science and the Rochester Academy of Science for their
financial support. P.N.G. would like to thank the Barbara S. Zimmer
Memorial Research Award for financial aid.