ACS Catalysis
Page 4 of 6
However, formation of the 2a was accelerated near the end of the
ACKNOWLEDGMENT
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4
5
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reaction. This advocated that the coordination of nitrile to the cata-
lyst played a significant role; as the concentration of the nitrile was
higher at beginning of the reaction it hindered the methanol dehy-
drogenation as well as the approach of other molecules to the metal
center which was further confirmed by carring out several
experiments in presence of coordinating and non-coordinating
solvents with methanol (1:1 ratio; SI, Table S6). Kinetic studies
also disclosed the inverse first-order dependence on nitrile concen-
tration (SI, Figure S5).
We are grateful to the Science and Engineering Research Board
(SERB), India, Council of Scientific & Industrial Research (CSIR)
and Indian Institute of Technology Kanpur for financial support.
B.P., K.C. thank UGC India, S.S. thank CSIR India and DP thank
IITK for fellowship. The authors sincerely thank Professor Gourab
Kanti Das for helpful and insightful discussions regarding DFT cal-
culations.
REFERENCES
9
To understand the mechanism of this process more clearly, a
detailed DFT studies were carried out (Figure 2).16 Initially, com-
plex 1b was transformed to the methoxy complex I1 through the
base promoted ligand substitution reaction from which dissociation
of benzonitrile generated the penta-coordinated species I2. Substi-
tution of one PPh3 ligand by benzonitrile from the complex 1b was
confirmed by 31P NMR spectroscopy and ESI-MS analysis (SI,
page 18). Next β-H elimination via TS1 afforded the ruthenium hy-
dride species I3 which was further converted to I4 by the replace-
ment of formaldehyde with benzonitrile. In this process activation
energy (Ea) for methanol dehydrogenation was 6.78 kcal/mol.
Next, benzonitrile was inserted to the Ru-H through a four member
transition state TS2 with energy barrier of 4.32 kcal/mol and gen-
erated intermediate I5. Then, I5 was converted to the imine coor-
dinated intermediate I6 by alcoholysis followed by β-H elimina-
tion. Afterwards, imine was hydrogenated to benzyl amine through
TS3 following the similar process. Next, coupling of benzyl amine
with formaldehyde followed by hydrogenation via TS4 delivered
the N-methylbenzyl amine and subsequently it was converted to the
final N,N-dimethylbenzylamine product following another cata-
lytic cycle. Nevertheless, hydrogenation of phenylmethanimine
and N-methelene-1-phenylmethanamine through TS3 and TS4 re-
quired lower activation energy i.e. 2.95 kcal/mol and 3.68 kcal/mol
respectively. In this process overall energy barrier was 20.65
kcal/mol to generate the N-methylated amine from benzonitrile and
methanol.
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In summary, an efficient and sustainable methodology for the
tandem conversion of various nitriles to the corresponding N,N-
dimethyl amines using methanol as a greener methylating reagent
was developed. Furthermore, transformation of challenging ali-
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lished. Notably, various β-methyl N,N-dimethylated amines were
synthesized from benzyl nitriles by incorporating multiple methyl
groups using methanol following the tandem C-methylation as well
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also established by the preparative scale synthesis of different N,N-
dimethyl amines and antialergic drug pheniramine. In addition,
several mechanistic investigations and detailed DFT calculations
were carried out to understand this protocol.
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ASSOCIATED CONTENT
Supporting Information
General procedure for the N-methylation experiments, preparative
scale reaction, optimization details, CIF data, computational stud-
ies, characterization data and NMR spectra of the products are
available. This material is available free of charge via the Internet
AUTHOR INFORMATION
Corresponding Author
*Email: sabuj@iitk.ac.in
Notes
The authors declare no competing financial interest.
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