Dichotomy of Atom-Economical Hydrogen-Free Reductive Amidation vs Exhaustive Reductive Amination

Article abstract of DOI:10.1021/acs.orglett.7b02821

Rh-catalyzed one-step reductive amidation of aldehydes has been developed. The protocol does not require an external hydrogen source and employs carbon monoxide as a deoxygenative agent. The direction of the reaction can be altered simply by changing the solvent: reaction in THF leads to amides, whereas methanol favors formation of tertiary amines.

Full text of DOI:10.1021/acs.orglett.7b02821

Letter
pubs.acs.org/OrgLett
Dichotomy of Atom-Economical Hydrogen-Free Reductive
Amidation vs Exhaustive Reductive Amination
Pavel N. Kolesnikov,† Dmitry L. Usanov,§ Karim M. Muratov,†,‡ and Denis Chusov*,†
†A.N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences, Vavilova St. 28, Moscow 119991,
Russian Federation
‡Dmitry Mendeleev University of Chemical Technology of Russia, Miusskaya Sq. 9, Moscow 125047, Russian Federation
S
* Supporting Information
ABSTRACT: Rh-catalyzed one-step reductive amidation of aldehydes has
been developed. The protocol does not require an external hydrogen
source and employs carbon monoxide as a deoxygenative agent. The
direction of the reaction can be altered simply by changing the solvent:
reaction in THF leads to amides, whereas methanol favors formation of
tertiary amines.
Table 1. Catalyst and Solvent Optimization for the
Preparation of Secondary Amides from Benzamide and p-
Fluorobenzaldehyde
mides are irreplaceable components of life, and therefore,
Athe development of amide bond formation methods has
received considerable attention over the past several decades.
The growing interest in biocatalysis and biological properties of
peptidomimetics, such as β-peptides, pseudopeptides, or
peptoids, further supports the importance of new convenient,
selective, and efficient ways to make amide bonds.1 Standard
protocols for amide synthesis commonly involve the use of
stoichiometric amounts of agents for the activation of
carboxylic acids, which is associated with additional costs,
greater amounts of chemical waste, increased toxicity, and
byproduct formation. It is therefore widely agreed that direct
catalytic methods without the need for stoichiometric reagents
comprise one of the greatest needs for the numerous research
fields relying on chemical synthesis of amide bonds.2,3
We have recently reported novel methods for atom-
economical and selective transformations of high synthetic
value.4 These include reductive alkylation, amination, and
pyrrolidine synthesis, all of which do not require an external
hydrogen source; instead, carbon monoxide can be efficiently
employed as a deoxygenative agent.5 We have shown that this
approach can be more selective than conventional reductive
protocols6 and can provide access to compounds which are
difficult to prepare otherwise.7 Herein, we report an expansion
of the concept to a fundamentally different type of chemistry
on the example of one-step Rh-catalyzed reductive amidation of
aldehydes without an external hydrogen source.
a
entry
catalyst
solvent
yield (%)
b
1
Rh2(OAc)4
CpRh(CO)I2
[Rh(CO)2Cl]2
[(cod)RhCl]2
RhCl3
THF
82
32
60
79
<5
13
21
35
40
39
41
45
41
45
56
60
75
b
b
b
b
2
THF
THF
THF
THF
3
4
5
6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
water
7
butanol-1
ethanol
8
9
methanol
solvent-free
MeCN
10
11
12
13
14
15
16
17
18
b
MeCN
Et2O
toluene
CH2Cl2
EtOAc
b
EtOAc
THF
50
a
b
Yields were determined by NMR with internal standard. Particularly
We began our studies with the model reaction between
benzamide and p-fluorobenzaldehyde (Table 1). Initially, a
number of rhodium metal complexes were screened, among
which rhodium(II) acetate showed the most promising catalytic
activity (Table 1, entries 1−5); other rhodium complexes
demonstrated inferior performance. We then tested a variety of
reaction media (including solvent-free conditions; Table 1,
entries 6−18). Conducting the reaction in dry THF and dry
ethyl acetate furnished the product in 82% and 75% yield,
dry solvents were used: 87 ppm of water in THF, 48 ppm of water in
EtOAc, 15 ppm of water in MeCN.
respectively. The effect of the reaction temperature was
substrate-dependent: for benzamide increasing the temperature
Received: September 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
led to higher yield; however, acetamide showed the opposite
trend with lower yields at the temperatures above 140 °C. With
the optimized conditions in hand, we proceeded to test a
representative range of substrates (Figure 1).
Scheme 1. Application of the Developed Methodology to the
Modification of Piracetam
Figure 1. Investigation of the substrate scope for the Rh-catalyzed
preparation of amides. 1:1 ratio of reactants, 1 mol % Rh2(OAc)4,
THF, 30 bar CO, 140 °C, 22 h. Yields were determined by NMR with
internal standard. Isolated yields are shown in parentheses. (a) 160 °C.
(b) 1.5 equiv of the amide was used.
Figure 2. Investigation of the substrate scope for the Rh-catalyzed
preparation of tertiary amines. 3 equiv of aldehyde and 1 equiv of
acetamide were used, 0.5 mol % of Rh2(OAc)4, methanol, 30 bar CO,
130 °C, 22 h. Yields were determined by NMR with internal standard.
Isolated yields are shown in parentheses.
Good-to-excellent yields were observed for both electron-
rich and electron-deficient aromatic aldehydes with various
substitution patterns (1a−p). The benzyloxy moiety was shown
to be stable under the reaction conditions; products 1h and 1i
were isolated in 50% yield. Aliphatic amides worked as well as
aromatic ones; generally, aromatic amides furnished higher
yields at 160 °C, while aliphatic substrates reacted better at 140
°C.
We exemplified the practical significance of the developed
methodology by implementation thereof into a simple one-step
modification of a pharmaceutically important compound.
Piracetam 3 is the parent compounds of the racetam family
of drugs, which includes anticonvulsant (e.g., seletracetam,
brivaracetam, levetiracetam, etc.) and nootropic agents (e.g.,
oxiracetam, phenylpiracetam). Substitution at the amide moiety
is known to be useful for pharmaceutical activity (e.g.,
pramiracetam, fasoracetam, coluracetam). Our protocol allows
convenient N-functionalization of piracetam to obtain com-
pound 4 in 70% yield (Scheme 1).
We found that switching to 3:1 aldehyde/amide ratio and
changing the solvent from THF to methanol leads to formation
of symmetric tertiary amines. These compounds can be very
useful as extractants8 or ligands for catalytic processes;9
however, they are rarely prepared directly from aldehydes.
Previous reports10 required the use of borohydride reductants
and sometimes strictly anhydrous conditions.11 We obtained
good yields for the products with various functional groups
(Figure 2). On the contrary, o-/p-alkoxy-substituted aldehydes
showed poor results. Whereas the central nitrogen atom
naturally comes from the starting amide, at the moment we still
have somewhat limited understanding of the mechanistic details
of this unusual process. Further studies in this direction are
currently ongoing and will be reported in due course. A
plausible mechanistic scenario is shown in Figure 3. This
scheme is consistent with all our previous observations4a and
experiments with deuterium labeling: when methanol-d4 was
employed in the reaction between p-tolualdehyde and
benzamide, methyl-d3 benzoate was detected as a product
(see the Supporting Information).
In summary, we developed a highly efficient method for one-
step preparation of secondary amides from a variety of
aldehydes and primary amides. The reaction does not require
an external hydrogen source and employs carbon monoxide as a
deoxygenative agent, which renders our method more atom-
economical in comparison to existing synthetic alternatives.
The direction of the reaction can be changed to the synthesis of
symmetric tertiary amines simply by changing the solvent from
tetrahydrofuran to methanol. The synthetic utility of the
developed method was exemplified by modification of
piracetam, the parent member of a wide family of
pharmaceuticals.
B
DOI: 10.1021/acs.orglett.7b02821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02821.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chusov@ineos.ac.ru, denis.chusov@gmail.com.
ORCID
(6) Afanasyev, O. I.; Tsygankov, A. A.; Usanov, D. L.; Perekalin, D.
S.; Shvydkiy, N. V.; Maleev, V. I.; Kudinov, A. R.; Chusov, D. ACS
Catal. 2016, 6 (3), 2043.
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V.; Nelyubina, Y. V.; Chusov, D. Chem. Commun. 2016, 52, 1397.
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Hazard. Mater. 2009, 165, 886. (b) Rajesh, N.; Subramanian, M. S. J.
Hazard. Mater. 2006, B135, 74.
Denis Chusov: 0000-0001-6770-5484
Present Address
§(D.L.U.) Harvard University, Department of Chemistry and
Chemical Biology, 12 Oxford Street, Cambridge, MA 02138
(USA).
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by the Russian Science
Foundation (grant no. 16-13-10393). The contribution of the
Center for Molecule Composition Studies of INEOS RAS is
gratefully acknowledged.
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