A one-pot parallel reductive amination of aldehydes with heteroaromatic amines

Article abstract of DOI:10.1021/co5000568

A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl₂-TMSOAc (activating agents) and NaBH(OAc)₃ (reducing agent). A library of diverse secondary amines was easily prepared on a 50-300 mg scale.

Full text of DOI:10.1021/co5000568

Technology Note
pubs.acs.org/acscombsci
A One-Pot Parallel Reductive Amination of Aldehydes with
Heteroaromatic Amines
Andrey V. Bogolubsky,† Yurii S. Moroz,*,†,‡ Pavel K. Mykhailiuk,*,†,§ Dmitriy M. Panov,†
Sergey E. Pipko,‡ Anzhelika I. Konovets,†,∥ and Andrey Tolmachev†,‡
†Enamine Ltd., 23 Matrosova Street, Kyiv 01103, Ukraine
‡ChemBioCenter, Kyiv National Taras Shevchenko University, 61 Chervonotkatska Street, Kyiv 02094, Ukraine
§Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska Street, Kyiv 01601, Ukraine
∥The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov Street, Building 5, Kyiv 03187, Ukraine
S
* Supporting Information
ABSTRACT: A parallel reductive amination of heteroaro-
matic amines has been performed using a combination of
ZnCl2−TMSOAc (activating agents) and NaBH(OAc)3
(reducing agent). A library of diverse secondary amines was
easily prepared on a 50−300 mg scale.
KEYWORDS: heteroaromatic amines, reductive amination, trimethylsilyl acetate, one-pot approach, parallel synthesis
he reductive amination of carbonyl substrates (aldehydes or
ketones)1,2 has attracted considerable attention among
reductive amination. Gutierrez et al.18 proposed a one-pot
reductive amination approach employing a combination of a
Lewis acid, TiCl(OiPr)3, to facilitate the imine formation and
NaBH(OAc)3 as a reducing agent, which satisfies criterion (a) of
the parallel synthesis. However, this approach has drawbacks that
result in its incompatibility with criteria (b) and (c): an
exothermic reaction with gas evolution occurs during the
addition of NaBH(OAc)3 because of the interaction of the
reductant with a byproduct (HCl), and laborious workup is
required because of the amorphous precipitate of titanic acid
formed after hydrolysis of TiCl(OiPr)3.
T
other approaches toward secondary amines.3−7 The reductive
amination reaction consists of (i) formation of an imine from a
primary amine and a carbonyl substrate and (ii) reduction of the
imine with a suitable hydride source.8−15 There are two distinct
approaches for the reductive amination: the direct approach,
which uses the in situ-generated imine (Scheme 1), and the
Scheme 1. Direct Reductive Amination
We recently employed trimethylsilyl chloride (TMSCl)19 as a
promoter and a water scavenger in the reductive amination
reaction. However, similar to TiCl(OiPr)3, its application in
combination with NaBH(OAc)3 to the one-pot parallel synthesis
is limited because of the HCl release. We then chose
trimethylsilyl acetate (TMSOAc), resulting in AcOH as the
byproduct, which is compatible with NaBH(OAc)3. Initial
experiments, however, showed poor yields in reactions with
some substrates because of the low reactivity of TMSOAc.
Therefore, we added ZnCl2 as an additional promoter for the
reductive amination.12 The experimentally established optimal
amount of ZnCl2 (0.05 equiv) allowed for the effective imine
formation and had no effect on the purity of the final product.
Herein we report our results on the use of this combination of
reagents, a TMSOAc/ZnCl2 mixture and NaBH(OAc)3, in the
parallel reductive amination of aldehydes with heteroaromatic
amines.
indirect approach, which uses the previously isolated imine. The
direct approach allows for the quick generation of sets of amines
when the synthesis is conducted in a one-pot fashion and
therefore is widely utilized.
One of our projects was to apply the reductive amination
approach to a parallel synthesis of secondary amines derived
from aldehydes and heteroaromatic amines. The approach must
satisfy the following conditions of the parallel synthesis: (a) one-
pot procedure with a simple “in vial” setup; (b) stable,
compatible reagents that would allow the creation of highly
diverse sets of compounds and be easily separated from the
product; and (c) addition of the reagents without control of the
temperature.
Despite the fact that heteroaromatic amines are common
building blocks in the synthesis of drugs and agrochemicals16
(Figure 1), literature reports on reductive amination with these
amines are rare and nonsystematic.2,17,18 The amino group of
heteroaromatic amines, which is generally electron-deficient,
often affords poor yields of the intermediate imines in direct
We selected 10 aldehydes (Figure 2) and 20 amines (Figure 3)
from our internal database to test the proposed combination. For
Received: April 8, 2014
Revised: June 16, 2014
Published: June 23, 2014
© 2014 American Chemical Society
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Figure 1. Agrochemicals and drugs bearing heteroaromatic amine moieties.20,21
Figure 2. Aldehydes tested in the study (chemset 1).
Figure 3. Amines tested in the study (chemset 2).
the aldehydes, we chose benzaldehyde and five of its derivatives
along with four heteroaromatic aldehydes. For the amines, we
selected nine five-membered ring and 11 six-membered ring
heteroaromatic substrates with electron-donating groups
(EDGs) or electron-withdrawing groups (EWGs) on the ring.
Then we conducted the parallel reductive amination, preparing a
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Table 1. Synthesized Secondary Amines (Chemset 3)
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Table 1. continued
a
Isolated yields.
40-member library of the secondary amines (Table 1). Our aim
was to synthesize a diverse set of amines that completely satisfied
the purpose of the work, but not all possible variants.
In the imine formation step, a dimethylformamide solution of
aldehyde 1, amine 2, and the TMSOAc/ZnCl2 mixture was
heated at 100 °C for 8 h (Scheme 2). In the reduction step,
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Scheme 2. Parallel Synthesis Approach to the Reductive Amination with Heteroaromatic Amines
NaBH(OAc)3 was added in one portion, and the reaction was
conducted at room temperature for 72 h. After the subsequent
simple workup, the crude product 3 was isolated and analyzed by
LC−MS analysis to check the initial purity (Figures S1−S40 in
the Supporting Information). The LC−MS analysis revealed that
∼50% of the samples had purities of >90%, 30% had purities of
>80%, and ∼20% had purities of 45−80%. The impurities were
identified as starting materials (Figures S2, S9, and S12),
intermediate imines (Figures S2, S12, and S19), and products of
overalkylation (Figures S24, S31, and S32). Overall, only 50% of
the samples required additional purification to obtain com-
pounds with >95% purity; purification was performed by flash
chromatography. Final yields of 20−96% were achieved (Table
1). The identities and purities of the obtained secondary amines
3 were confirmed by 1H and 13C NMR spectroscopy and LC−
MS analysis. The experimental data showed that the reaction
proceeded in low yields for amines that were deactivated (e.g.,
[1,2,4]triazolo[4,3-a]pyridine-3-amine, entries 11 and 12; 5-
methanesulfonyl-1,3-benzothiazol-2-amine, entries 15 and 16;
and 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-amine, entries
39 and 40) or had a sterically hindered amino group (e.g., 3-
methylpyridin-2-amine, entries 19 and 20, and 2-methylpyridin-
3-amine, entries 31 and 32). The ester functionality of methyl 5-
aminopyridine-3-carboxylate (entries 33 and 34) was tolerated
under the reaction conditions.
amine (0.7 mmol), an aldehyde (0.7 mmol), and TMSOAc (2.1
mmol) was added 0.25 mL of a 2% solution of ZnCl2 in DMF.
The vial was heated at 100 °C for 8 h and allowed to cool to room
temperature. Then NaBH(OAc)3 (1.4 mmol) was added, and
the mixture was kept at room temperature for 72 h with
occasional shaking. After subsequent sonication at 50−55 °C, the
mixture was treated with 1 mL of 10% KOH solution followed by
the addition of 7 mL of water. The product was extracted with 3
mL of CHCl3, and the organic phase was washed with water (2 ×
7 mL) and evaporated. Compounds with purity below 95% were
subjected to further purification by flash chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
LC−MS data for crude mixtures and spectral data for the selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: ysmoroz@mail.enamine.net.
*E-mail: Pavel.Mykhailiuk@mail.enamine.net; Pavel.
Mykhailiuk@gmail.com.
Notes
In conclusion, we have demonstrated a highly efficient
approach for the parallel reductive amination of aldehydes with
heteroaromatic amines utilizing the combination of a TMSOAc/
ZnCl2 mixture and NaBH(OAc)3. The approach is based on a
simple one-pot procedure and allows for the quick generation of
a library of secondary amines in quantities suitable for
preliminary biological studies.
The authors declare no competing financial interest.
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