Ruthenium-Catalyzed Synthesis of N-Methylated Amides using Methanol

Article abstract of DOI:10.1021/acs.orglett.9b01925

An efficient synthesis of N-methylated amides using methanol in the presence of a ruthenium(II) catalyst is realized. Notably, applying this process, tandem C-methylation and N-methylation were achieved to synthesize α-methyl N-methylated amides. In addition, several kinetic studies and control experiments with the plausible intermediates were performed to understand this novel protocol. Furthermore, detailed computational studies were carried out to understand the mechanism of this transformation.

Full text of DOI:10.1021/acs.orglett.9b01925

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium-Catalyzed Synthesis of N‑Methylated Amides using
Methanol
Bhaskar Paul, Dibyajyoti Panja, and Sabuj Kundu*
Department of Chemistry, Indian Institute of Technology, Kanpur, Uttar Pradesh 208016, India
S
* Supporting Information
ABSTRACT: An efficient synthesis of N-methylated amides
using methanol in the presence of a ruthenium(II) catalyst is
realized. Notably, applying this process, tandem C-methylation
and N-methylation were achieved to synthesize α-methyl N-
methylated amides. In addition, several kinetic studies and
control experiments with the plausible intermediates were
performed to understand this novel protocol. Furthermore,
detailed computational studies were carried out to understand
the mechanism of this transformation.
tilization of renewable feedstock to replace the hazardous
and waste-generating chemicals has drawn much
As a part of our continuing interest in the methanol
activation14 and the recent progress in the utilization of
methanol as a C1 building block,4,15 herein we report an
efficient and practically applicable Ru(II)-based catalytic
system for the synthesis of N-methylated amides using
methanol. To the best of our knowledge, this is the first
report for the atom economical and greener synthesis of N-
methylated amides using methanol (Scheme 1).
U
attention from chemists in the past few decades.1 In this
consequence, methanol is one of the attractive greener
alternatives, which annually produces almost 70 million tons
from several natural resources.2 Methanol is mostly utilized as
a raw material for the production of several fine chemicals as
well as fuels and a liquid hydrogen storage medium.3 In
addition, transition-metal-catalyzed construction of C−C
bonds and C−N bonds using methanol was recently developed
by several groups.4
Scheme 1. Different Methods for the Synthesis of N-
Methylated Amides
Sustainable replacement of the toxic methylation reagents
like methyl iodide, methyl triflate, dimethyl sulfate, or
formaldehyde with nontoxic and readily available reagents is
highly desirable.5 Recently, few protocols using carbon dioxide,
dialkylcarbonate, formic acid, and methanol were developed
for the methylation reactions.4a,6 Among them, methanol is a
more attractive and promising greener methylating reagent.4
Although, methylation of amines using methanol as an
alkylating reagent was extensively explored,4 to the best of
our knowledge, greener synthesis of N-methylated amides
using methanol is not reported yet. Using the long chain
alcohols, N-alkylation of amide was first conveyed by
Watanabe, and later on with aromatic alcohols, few reports
were immersed in literature.7
N-Methylated amides are present in various natural products
and pharmaceutically relevant compounds.8 In addition, N-
methylation of amide significantly alters the function of
proteins in biological systems.8b,9 For example, N-methylation
of histone in the chromatin scaffold plays a significant role in
gene regulation.10 Therefore, greener synthesis of N-methy-
lated amides is highly desirable. N-Methylation of amide can
be carried out using the borrowing hydrogen principle, which
discards the use of hazardous and waste-generating reagents.11
However, poor nucleophilicity of the amide12 and significantly
higher dehydrogenation energy of the methanol13 make this N-
methylation process challenging.
In the preliminary study, N-methylation of benzamide using
methanol was chosen as the benchmark reaction (Table 1).
Unfortunately, in the presence of NaOMe, a significant amount
of methyl benzoate (2a′) was formed in this transformation in
methanol (entry 1). After that, we turned our focus to the
amount of nucleophilic solvent methanol, as it favored the
ester formation at higher temperatures under basic con-
ditions.12,16 Using a lower proportion of methanol in the
presence of a nonpolar solvent toluene (1:9, v/v), selectivity of
the N-methylated amide was increased considerably (entry 3).
Next, various solvent ratios (entries 4−6), Ru(II) complexes
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01925
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Selected Data for the Optimization
Scheme 2. Substrate Scope for the N-Methylation of
Amide
a
yield
(2a)
(%)
yield
(2a′)
(%)
[Ru]
entry (mol %)
base
(equiv)
MeOH: time conv.
Toluene (h)
(%)
1
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
2 (5)
3 (5)
4 (5)
5 (5)
6 (5)
7 (5)
8 (5)
9 (5)
NaOMe
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
Cs2CO3
(1)
1:0
1:0
1:9
1:6
1:4
1:3
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:5
24
24
24
24
24
24
12
12
12
12
12
12
12
12
12
24
80
38
42
22
44
91
87
85
54
41
39
38
48
37
70
19
92
42
20
5
2
62
27
49
99
99
90
62
48
52
51
66
48
75
23
97
3
4
5
5
8
6
12
5
7
8
8
9
7
10
11
12
13
14
15
16
13
13
18
11
5
4
a
Reaction conditions: Amide (0.5 mmol), methanol/toluene (3 mL,
b
c
1:5, v/v), isolated yield. 3 mol % of cat. 1 at 150 °C. With 3 mol %
cat. 1. 5 mol % cat. 1 was used. 4-Formylbenzamide was used.
1 (1.5) Cs2CO3
5
d
e
(0.75)
a
Reaction conditions: Benzamide (0.5 mmol), methanol/toluene (3
mL), GC yield.
process, substituted amides were smoothly transformed to the
desired methylated amide up to 82% yield (2x−z).
(entries 7−15), bases, and solvents were screened (see SI,
Table S1−S7). Finally, it was observed that 1.5 mol % of
complex 1 in the presence of 0.75 equiv of Cs2CO3 was
sufficient to furnish the N-methyl benzamide (2a) in 92% yield
at 140 °C using methanol/toluene (1:5; v/v) within 24 h
(Table 1, entry 16).
Afterward, to evaluate the general applicability of this novel
protocol, methylation of a wide range of amides was carried
out using these optimized conditions, which are summarized in
the Scheme 2. Several amides bearing both the electron-
donating and electron-withdrawing groups afforded the desired
N-methylated amides efficiently (2b-k). In addition, di- or
poly-substituted amides provided the corresponding N-
methylated amides up to 84% yield (2m−o). Applying this
protocol, challenging heteronuclei-containing amides and
aliphatic amides also smoothly transformed to the respective
methylated products in 62−87% yields (2p−w). Incorporation
of multiple methyl group to the amide molecule is a highly
challenging process. Applying this simple protocol, tandem C-
methylation and N-methylation were achieved for the benzyl
amides (Scheme 2). It is worth noting that, using this greener
To check the sustainability of this protocol, the green
chemistry metrics17 were evaluated for the N-methylation of 4-
heptoxy benzamide (2.5 g) using methanol (see SI). This
transformation disclosed an E-factor of 5.46, 92% atom
economy, 75.44% atom efficiency, 100% carbon efficiency,
and 75.6% reaction mass efficiency. These results conveyed the
novelty and the sustainability of this greener process.
To understand the challenges associated with the incorpo-
ration of multiple methyl groups, a time-dependent product
distribution with 4-aminobenzamide and 2-phenylacetamide
was carried out (Scheme 3). Following the optimized reaction
conditions, >90% yields of the 4-(methylamino)benzamide
(3A) and 2-phenylpropanamide (3B) were observed within 12
h, whereas the yields of the corresponding N-methylated
amides were only 6−8%. To acquire the satisfactory yields of
these N-methylated amides (3A′ and 3B′), a longer reaction
time (36−48 h) was essential. This result clearly showed that
C-methylation and amine N-methylation were significantly
faster than the amide N-methylation under the similar reaction
conditions.
B
DOI: 10.1021/acs.orglett.9b01925
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Organic Letters
Letter
N-methylene benzamide hydrogenation was low (Figure 2,
ΔG⧧ = 0.73 kcal/mol). This result revealed that under the
optimized conditions, formation of [RuII−H] and the insertion
of olefin/imine to this metal hydride were relatively faster than
the N-methylation of the amide. Relatively easier hydro-
genation of olefin suggested that either the condensation
between the amide with the in situ generated formaldehyde
followed by dehydration to the imine or the alcoholysis of the
N-methyl amide bound intermediate (I5N) was slower.
Reaction of benzamide and the intermediate N-
(hydroxymethyl)benzamide with CD3OD under the standard
reaction conditions afforded the corresponding deuterium
incorporated N-methylated products (Scheme 4A,B). This
result confirmed that the methanol acted as both a C1 source
and hydrogen donor.
Scheme 3. Competitive Methylation Processes during the
N-Methylation of Amide
Scheme 4. Reaction with CD3OD
Next we focused on the mechanistic investigation of this
catalytic process. To check the induction period for the
formation of active [RuII−H] through the methanol dehydro-
genation and the relative rate of the hydrogenation of the
olefin or N-methylene amide, a time-dependent product
distribution experiment was carried out with cinnamamide
(Figure 1).
Methylation reaction of benzamide using CH3OH and
CD3OD disclosed a kH/kD of 5.86 (Scheme 4C). This result
specified that the C−H bond breaking of methanol is
kinetically important in this process. Additionally, competitive
reactions18 using a mixture of CH3OH and CD3OD (1:1)
showed the formation of N-methyl benzamide (2a) as a major
product compared to the other deuterated analogues (2a1−a3)
(Scheme 4D). This observation further confirmed that the
methylation reaction was much faster with CH3OH compared
to CD3OD. In this study, the kinetic isotope effect (KIE) was
calculated based on the yield of the N-methyl benzamide
product. A slightly higher value of KIE suggested that in this
multistep tandem transformation, along with the C−H bond
Figure 1. Olefin hydrogenation vs reductive N-methylation.
The olefin reduced product C was formed in 16% and 99%
yields within 10 min and 1 h, respectively. The formation of N-
methylated amide (C′) was very slow, where 74% yield was
observed after 36 h. In addition, the activation barrier for the
Figure 2. Computed reaction pathway for the methanol dehydrogenation and imine hydrogenation.
C
DOI: 10.1021/acs.orglett.9b01925
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Organic Letters
Letter
activation of methanol, other steps might also contribute to the
KIE, such as the alcoholysis step.19 However, further
mechanistic investigation is essential to validate this hypothesis
and is currently underway in our laboratory.
In order to gain more information regarding the reaction
mechanism, a complete theoretical study was performed for
this N-methylation process (Figures 2 and 3). This trans-
formation consists of mainly three steps: (a) methanol
dehydrogenation, (b) insertion of the N-methyleneamide
moiety in the metal hydride, and (c) alcoholysis of the N-
methyl amide bound intermediate.
experiments and kinetic studies were performed to understand
this process. Kinetic studies revealed that the C-methylation
and amine N-methylation were significantly faster than the
amide N-methylation. Additionally, it was observed that the
formation of [RuII−H] and the insertion of olefin in this metal
hydride were relatively faster than the N-methylation of the
amide. Moreover, detailed DFT studies were carried out to
understand the mechanism of this transformation more clearly.
ASSOCIATED CONTENT
■
S
* Supporting Information
For the methanol dehydrogenation initially, complex 1 was
transformed to the methoxy complex I1 through the base-
promoted ligand substitution reaction (Figure 2). Then, for the
β-hydride elimination, one of the PPh3 was dissociated from
the metal center to generate the five coordinated species I2.
Afterward, I2 was transformed to the Ru−H species (I3)
through TS1 with an activation barrier of 6.1 kcal mol−1.
Coupling the resulting formaldehyde with benzamide followed
by dehydration produced the N-methylenebenzamide. After-
ward, insertion of this imine in the Ru−H species followed by
methanolysis resulted the final N-methylated product. For the
insertion of the N-methylenebenzamide in the ruthenium
hydride, two probable pathways were considered depending on
the coordination of the ‘N’ or ‘O’ atom of the N-
methylenebenzamide to the ruthenium center (I4N and I4O).
The imine coordinated through the ‘N’ atom had an
activation energy barrier of 0.73 kcal mol−1 for the insertion
step which followed a four-membered TS (TS2N). However,
for the ‘O’ coordinated route, insertion was transpired via a six-
membered TS2O with an activation energy barrier of 4.99 kcal
mol−1. Due to a significantly lower energy barrier, the ‘N’ atom
coordinated pathway was more favored over the ‘O’ atom
coordinated route. Insertion of the N-methylenebenzamide to
the metal hydride formed the intermediate I5N to which one
methanol molecule was coordinated to generate the
intermediate I6 (Figure 3). Afterward, alcoholysis through a
four-membered transition state (TS3) with an activation
barrier of 11.11 kcal/mol produced the desired N-methylated
amide.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01925.
General procedure for the N-methylation experiments,
green chemistry metrics, optimization details, computa-
tional details, characterization data, and NMR spectra of
the products are available (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sabuj@iitk.ac.in
ORCID
Sabuj Kundu: 0000-0002-4227-294X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Science and Engineering Research Board
(SERB), India, Council of Scientific and Industrial Research
(CSIR), India and Indian Institute of Technology Kanpur for
financial support. B.P. thanks UGC India and D.P. thanks IITK
for fellowships. The authors sincerely thank Professor Gourab
Kanti Das, Visva Bharati University, and Professor Nisanth N.
Nair, IIT Kanpur, for helpful discussions regarding DFT
calculations.
REFERENCES
■
In summary, an efficient protocol for the selective synthesis
of N-methylated amides using methanol was developed.
Interestingly, tandem C-methylation as well as N-methylation
were achieved with the benzyl amides. Several control
(1) (a) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437. (b) Wang, L.-
M.; Morioka, Y.; Jenkinson, K.; Wheatley, A. E. H.; Saito, S.; Naka, H.
Sci. Rep. 2018, 8, 6931.
(2) Palo, D. R.; Dagle, R. A.; Holladay, J. D. Chem. Rev. 2007, 107,
3992.
(3) Olah, G. A. Angew. Chem., Int. Ed. 2005, 44, 2636.
(4) (a) Natte, K.; Neumann, H.; Beller, M.; Jagadeesh, R. V. Angew.
Chem., Int. Ed. 2017, 56, 6384. (b) Chen, Y. Chem. - Eur. J. 2019, 25,
3405.
(5) (a) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am.
Chem. Soc. 2015, 137, 531. (b) Li, J. J. Name Reactions: A Collection of
Detailed Reaction Mechanisms, Springer: Berlin, 2009, 210.
̀
(6) (a) Tundo, P.; Musolino, M.; Arico, F. Green Chem. 2018, 20,
28. (b) Fang, C.; Lu, C.; Liu, M.; Zhu, Y.; Fu, Y.; Lin, B.-L. ACS Catal.
2016, 6, 7876.
(7) (a) Watanabe, Y.; Ohta, T.; Tsuji, Y. Bull. Chem. Soc. Jpn. 1983,
56, 2647. (b) Apsunde, T. D.; Trudell, M. L. Synthesis 2014, 46, 230.
(c) Kerdphon, S.; Quan, X.; Parihar, V. S.; Andersson, P. G. J. Org.
Chem. 2015, 80, 11529. (d) Choo, G. C. Y.; Miyamura, H.;
Kobayashi, S. Chem. Sci. 2015, 6, 1719. (e) Das, J.; Banerjee, D. J. Org.
Chem. 2018, 83, 3378. (f) Jenner, G. J. Mol. Catal. 1989, 55, 241.
(8) (a) Chatterjee, J.; Gilon, C.; Hoffman, A.; Kessler, H. Acc. Chem.
Res. 2008, 41, 1331. (b) Barreiro, E. J.; Ku
M. Chem. Rev. 2011, 111, 5215.
̈
mmerle, A. E.; Fraga, C. A.
Figure 3. Computed reaction mechanism for the alcoholysis.
D
DOI: 10.1021/acs.orglett.9b01925
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Chatterjee, J.; Rechenmacher, F.; Kessler, H. Angew. Chem.,
Int. Ed. 2013, 52, 254. (b) Ginnings, P. M.; Baum, R. J. Am. Chem.
Soc. 1937, 59, 1111.
(10) Kouzarides, T. Cell 2007, 128, 693.
(11) (a) Bernardi, L.; de Castiglione, R.; Scarponi, U. J. Chem. Soc.,
Chem. Commun. 1975, 320. (b) Li, Z.-l.; Cai, C. Org. Chem. Front.
2017, 4, 2207. (c) Xia, Q.; Liu, X.; Zhang, Y.; Chen, C.; Chen, W.
Org. Lett. 2013, 15, 3326.
(12) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.;
Yang, Y.-F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79.
(13) Moran, J.; Preetz, A.; Mesch, R. A.; Krische, M. J. Nat. Chem.
2011, 3, 287.
(14) (a) Paul, B.; Shee, S.; Chakrabarti, K.; Kundu, S. ChemSusChem
2017, 10, 2370. (b) Chakrabarti, K.; Maji, M.; Panja, D.; Paul, B.;
Shee, S.; Das, G. K.; Kundu, S. Org. Lett. 2017, 19, 4750.
(c) Chakrabarti, K.; Mishra, A.; Panja, D.; Paul, B.; Kundu, S.
Green Chem. 2018, 20, 3339. (d) Paul, B.; Shee, S.; Panja, D.;
Chakrabarti, K.; Kundu, S. ACS Catal. 2018, 8, 2890. (e) Maji, M.;
Chakrabarti, K.; Paul, B.; Roy, B. C.; Kundu, S. Adv. Synth. Catal.
2018, 360, 722. (f) Roy, B. C.; Debnath, S.; Chakrabarti, K.; Paul, B.;
Maji, M.; Kundu, S. Org. Chem. Front. 2018, 5, 1008.
(15) (a) Chan, L. K. M.; Poole, D. L.; Shen, D.; Healy, M. P.;
Donohoe, T. J. Angew. Chem., Int. Ed. 2014, 53, 761. (b) Ogawa, S.;
Obora, Y. Chem. Commun. 2014, 50, 2491. (c) Elangovan, S.;
Neumann, J.; Sortais, J.-B.; Junge, K.; Darcel, C.; Beller, M. Nat.
Commun. 2016, 7, 12641. (d) Liu, Z.; Yang, Z.; Yu, X.; Zhang, H.; Yu,
B.; Zhao, Y.; Liu, Z. Org. Lett. 2017, 19, 5228. (e) Polidano, K.; Allen,
B. D. W.; Williams, J. M. J.; Morrill, L. C. ACS Catal. 2018, 8, 6440.
(16) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.; The
Amide Linkage: Structural Significance in Chemistry, Biochemistry, and
Materials Science, Wiley, 2003.
(17) Ragupathi, A.; Charpe, V. P.; Sagadevan, A.; Hwang, K. C. Adv.
Synth. Catal. 2017, 359, 1138.
(18) Wei, D.; Sadek, O.; Dorcet, V.; Roisnel, T.; Darcel, C.; Gras, E.;
Clot, E.; Sortais, J.-B. J. Catal. 2018, 366, 300.
(19) Casey, C. P.; Johnson, J. B. J. Org. Chem. 2003, 68, 1998.
E
DOI: 10.1021/acs.orglett.9b01925
Org. Lett. XXXX, XXX, XXX−XXX