Alkyl formates as reagents for reductive amination of carbonyl compounds

Article abstract of DOI:10.1016/j.mencom.2020.01.037

Alkyl formates in the presence of basic additives can serve as a reagent in the direct reductive amination of carbonyl compounds. The developed procedure can be applied to various aldehydes and ketones with electron donating and electron withdrawing groups.

Full text of DOI:10.1016/j.mencom.2020.01.037

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 112–113
Alkyl formates as reagents for reductive amination of carbonyl compounds
Oleg I. Afanasyev,a Ilia Cherkashchenko,b Anton Kuznetsov,c Fedor Kliuev,c Sergey Semenov,c
Olga Chusova,d Gleb Denisova and Denis Chusov*a,e
a A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: chusov@ineos.ac.ru
b Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation
c V. I. Chuikov Moscow South-Eastern School, 109457 Moscow, Russian Federation
d Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russian Federation
e G. V. Plekhanov Russian University of Economics, 117997 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2020.01.037
Alkyl formates in the presence of basic additives can serve as
R1
R2
R4
R3
a reagent in the direct reductive amination of carbonyl
compounds. The developed procedure can be applied to
various aldehydes and ketones with electron donating and
electron withdrawing groups.
O
HCO2Me
H
N
+
N
R1
R2
R3
R4
1% RhCl3, NaOAc
Keywords: reduction, reductive amination, formic acid esters, carbon monoxide surrogates, rhodium.
Reductive amination plays a key role in pharmaceutical and
medicinal chemistry owing to its synthetic merits and ubiquitous
presence of amines among biologically active compounds.
Nitrogen-containing compounds play an important role in
different fields of chemistry.1–3 Various reducing agents for the
reductive amination are known.4–8 The main problem of common
reducing agents is a balance between activity and selectivity. For
example, one of the most selective reagents, namely, sodium
triacetoxyborohydride, can reduce starting carbonyl compounds
to alcohols, thus lowering the yield of the target amines.8
New selective and active reducing agents for the reductive
amination are of a great importance for chemists. Reductive
amination without an external hydrogen source was developed
recently.9,10 Carbon monoxide is typically used as an oxygen
scavenger, allowing one to synthesize amines with a high
functional group tolerance.11–13 The employment of carbon
monoxide is convenient and desirable for industrial scale, but it
is limited in laboratories because of the necessity of cylinder
with CO. A number of compounds can serve as carbon monoxide
surrogates14–16 or precursors for different processes, such as
carbonylation or reduction.14,17–19 Alkyl formates are a good
example of a CO-releasing molecules14,20–26 since they are
nontoxic, cheap, readily available and non-corrosive compared
with formic acid.
In this work we have developed a convenient and available
procedure for the reductive amination using formates as
reducing agents. Carbon monoxide can be generated from alkyl
and aryl formates in the presence of a base and a metal catalyst.
Various parameters influencing the reaction outcome were
tested, including catalyst, temperature, solvent additives,
Me
R1
H
R2
R3
O
Me
i
N
Me
+
R1 NH2
+
N
R2
R3
2a–c
4-MeOC6H4
3a–d
1a,b
3'd (5%)
a R1 = 4-MeOC6H4 a R2 = 4-MeC6H4, R3 = H
b R1 = 4-EtO2CC6H4 b R2 = 4-ClC6H4, R3 = H
c R2 = R3 = Me
3
R1
R2
R3
Yield (%)
4-MeOC6H4 4-MeC6H4
4-MeOC6H4 4-ClC6H4
4-EtO2CC6H4 4-MeC6H4
4-MeOC6H4 Me
H
H
H
Me
67
54
66
62
a
b
c
d
H
H
H
N
O
H2N
NH2
N
N
H2N
+
+
p-Tol
p-Tol
p-Tol
H
p-Tol
S
S
S
O
O
O
O
O
O
4
5a (37%)
5b (18%)
Scheme 1 Reagents and conditions: i, 1 or 4, 2 (1 equiv. or 2.2 equiv. for 4 + 2a or 10 equiv. for 2c), RhCl3 (1 mol%), HCO2Me (10 equiv.), NaOAc
(15 equiv.), MeOH (or EtOH for 1b), H2O, 160 °C, 24 h.
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 112–113
reaction atmosphere and the formate structure (HCOOBui,
support by RUDN ‘5-100’program. NMR studies were supported
by the Ministry of Science and Higher Education of the Russian
Federation and were carried out using the equipment of Center
for Molecular Composition Studies of A. N. Nesmeyanov
Institute of Organoelement Compounds, Russian Academy of
Sciences.
HCOOBn, HCOOMe). The detailed optimization data is
provided in the Online Supplementary Materials. As a result, the
combination of methyl formate in the presence of 10 equiv.
sodium acetate or sodium hydrogen carbonate and 1 mol% of
rhodium(iii) chloride as a catalyst at 160 °C under nitrogen
atmosphere was found to be optimal. With these conditions in
hands, we investigated the substrate scope (Scheme 1). Aromatic
amines with both electron donating and electron withdrawing
groups were benzylated in the yields around 70% (3a and 3c).
Electron withdrawing chlorine atom in aldehyde 2b led to
decrease in the yield of product 3b due to elevated reduction rate
of this aldehyde into 4-chlorobenzyl alcohol. Acetone 2c could
be used for the preparation of N-isopropylamine derivative 3d,
however, N-isopropyl-N-methyl derivative 3'd was also formed.
This fact reveals the possibility of N-methylation by methanol in
the presence of the metal catalyst. Starting from diamine 4, a
mixture of mono- and dialkylation products 5a,b was generated
(see Scheme 1). Although yields are moderate, the developed
procedure is tolerant to reducible functional groups such as
sulfone. For example, aromatic chlorides can be easily reduced
with molecular hydrogen,8,27 but the chlorine atom persists under
the developed conditions.
The suggested procedure was found to be suitable for
N-methylation of amines by formaldehyde (Scheme 2). Anilines
with electron donating groups (1a, 7a) and electron withdrawing
groups (1b, 7b) were dimethylated in good to quantitative yields.
When diphenylamine 9 was used as a substrate, along with
product 10, the comparable amount of compound 10' was
detected, whose formation can be rationalized considering the
phenol-formaldehyde type condensation. However, no conden-
sation of this type was observed for substituted anilines, which
may be accounted for the inductive effect of methoxy group.
In conclusion, the new procedure for the reductive amination
comprising alkyl formates as reducing agents has been developed.
It does not require corrosive or complex reagents. The limitations
of the method were examined and the optimal conditions were
found.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.01.037.
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2
Z
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8a,b
a Z = O (76%)
b Z = SO2 (99%)
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Me
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H
i
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+
+
Ph
Ph
Ph
Ph
9
10 (32%)
10' (30%)
Scheme 2 Reagents and conditions: i, RhCl3 (1 mol%), CH2O
(12–20 equiv.), HCO2Me (10 equiv.), NaOAc (15 equiv.), MeOH (or EtOH
for 1b), H2O, 160 °C, 24 h.
Received: 2nd August 2019; Com. 19/6005
– 113 –