Catalyst-free N-methylation of amines using CO2

Article abstract of DOI:10.1039/c6cc09072a

Recently, utilizing CO₂ as a methylation reagent to construct functional chemicals has attracted significant attention. However, the conversion of CO₂ is still a challenge due to its inherent inertness. In this study, we have developed a catalyst-free N-methylation of amines to prepare numerous methylamines using CO₂ as a methyl source. By utilizing 2 eq. PhSiH₃ as the reductant, amines could undergo N-methylation under 1 atm of CO₂ in DMF at 90 °C. Aliphatic and aromatic amines were compatible, generating the desired products in up to 95% yield.

Full text of DOI:10.1039/c6cc09072a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Niu, L. Lu, R.
Shi, C. Chiang and A. Lei, Chem. Commun., 2016, DOI: 10.1039/C6CC09072A.
Volume 52 Number
1
4
January 2016 Pages 1–216
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
www.rsc.org/chemcomm
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C6CC09072A
Journal Name
COMMUNICATION
Catalyst-free N-Methylation of Amines Using CO2
a
a
a
a
a, b
Huiying Niu, Lijun Lu ,Renyi Shi , Chien-Wei Chiang* and Aiwen Lei*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Recently, utilizing CO
2
as a methylation reagent to construct Herein, we report a catalyst-free methylation of amines using CO
under mild conditions. This protocol realized the reduction of CO
2
2
functional chemicals has attracted much more attention. However,
the conversion of CO is still a challenge due to its inherent
inertness. In this work, we developed a catalyst-free methylation
of amines to prepare numerous methylamines, using CO as
methyl source. By utilizing the 2 eq. PhSiH as the reductant,
amines could be proceeded methylation under 1 atm CO in DMF
and coupled C–N bond without catalysts, providing a simple and
new way to perform the methylation reactions on several amines.
2
R1
H
R1
R1
2
N
hydrogen or hydrosilane
metal catalysts
N
N
N
+
CO
2
or
3
2
R2
R (H)
2
metal catalysts = Ru, Fe, Cu, Zn, Ni, Au, Cs
o
at 90 C. Aliphatic and aromatic amines were compatible,
generating the desired products in up to 95 % yield.
R1
H
R1
R1
hydrogen or hydrosilane
organocatalysts
N
N
+
CO
2
or
2
R2
R (H)
On the earth, most of the carbon exists in the form of carbon
dioxide and carbonates. Nowadays, excess consumption of
6 5 3
organocatalysts = NHCs, CDCs, B(C F ) , TBAF
This work:
fossil fuels leads to the increasing concentration of CO in the
2
R1
H
air, which aggravates greenhouse effect. Hence transforming
phenylsilane
R1
R
1
N
CO2
+
N
N
or
CO into fuels and valuable chemicals is an ideal way to fix this
2
2
R (H)
R2
1
greenhouse gas. Although CO is an economic and nontoxic C1
2
building block, the way of CO activation is still less due to its
2
Scheme 1 Previous works on methylation of amines
thermodynamic stability and kinetic inert, which calls for a
2
large driving force. Up to now, most of the previous works on
In the initial optimization investigations, we employed N-
methylaniline (1a) as model substrate, with 2 eq. of Ph SiH as
CO conversion suffer from highly reactive substrates or harsh
2
2
2
o
conditions, such as high pressure and temperature, limiting the
3
applications of these methods.
reductant under 1 atm CO in DMF at 90 C, the desired product 2a
2
can be obtained in 54% yield (Table 1, entry 1). Notably, we found
2
2 2 3
Therefore, develop more applications in CO activation is very that when Ph SiH was replaced to PhSiH , the generation of 2a can
important. Recently, the investigations of the inert CO molecule be improved to 81% yield (entry 2). However, we found that
2
converted with amines to generate formamide, formamidine and treatment of 1 eq. PhSiH will decrease the yield to 41% (entry 3), it
3
methylamine derivatives by different reductants have been means that PhSiH would be needed more than 1 eq. to complete
3
4
reported. Moreover, it’s worth noting that the methyl-substituted the reaction under whole process. In the control experiments,
amines represent core structures in drugs, natural products, dyes, without CO or PhSiH , the reaction could not be performed (entries
2
3
5
6
7
etc. In 2013, Beller et al. and Cantat et al. developed Ru- and Zn- 4 and 5). With this encouraged, solvent screens were evaluated as
catalyzed system converting CO and amines into various kinds of N- well. When toluene was employed as solvent, only trace amount of
2
methylated products in the presence of hydrosilanes. Subsequently, the desired product was detected (entry 6). Methylation did not
Cantat and co-workers reported the first metal-free methylation of reach in the presence of CH CN, and perform a relative low yield of
3
8
amines by using phosphorus base as catalyst. In recent years, in DMSO (entries 7 and 8). The yield of 2a was dropped significantly
6
, 9-13
o
methylation of amines with CO based on metal catalysts
organocatalysts
and in higher temperature such as 110 C (entry 11), which would be
have been developed as shown in Scheme 1. suggested the decomposition of 1a will be occurred in this reaction.
In addition, the ratio of CO /N in 1/1 would not affect the
reactivity, which showed a good tolerance in low concentration of
CO (entry 13).
2
8
, 14-16
2
2
2
[
a]
Table 1 Optimization of reaction conditions
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2016, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C6CC09072A
COMMUNICATION
Journal Name
2
Product
N
Yield (%) [b]
80%
2
Product
Yield (%) [b]
47%
N
2
a
b
c
2k
[
a]
Entry Variation from "standard conditions" Yield%
N
N
N
2
2
70%
49%
2l
34%
59%
1
2
3
4
5
6
7
8
9
1
Ph
2
SiH
2
instead of PhSiH
3
54
81(80)
41
0
[
c]
-
N
2m
1.0 equiv. PhSiH
No CO
No PhSiH
Toluene instead of DMF
CH CN instead of DMF
3
O N
2
N
2
N
N
2
2
d
e
45%
80%
2n
2o
34%
O
3
0
trace
0
N
N
95% [c]
N
3
N
DMSO instead of DMF
DEF instead of DMF
45
61
77
26
32
81
2
f
95%
2p
70% [c]
o
o
0
60 C instead of 90 C
N
N
2
2
g
h
88%
87%
77%
2q
2r
60%
69%
38%
o
o
O
11
110 C instead of 90 C
1
1
2
3
CO
CO
2
2
/N
/N
2
2
= 1/ 7
= 1/ 1
N
N
EtOOC
N
[
a] Sandard reaction conditions: 1a (0.5 mmol), phenylsilane (1.0 mmol), DMF
N
2
i
2s
o
(
2
3.0 mL), CO (1 atm), 90 C, 24 h. [b] Yield determined by by GC-MS using
biphenyl as an internal standard. [c] The isolated yield is given in parentheses.
N
N
With the optimized conditions in hand, we further considered the
scope of this methylation with various amines (Table 2). We firstly
investigated the para-methyl substituent on the benzene moiety,
2j
73%
2t
58%
showed no obvious influence on the reaction outcome (2b). [a] 1 (0.5 mmol), phenylsilane (2 eq. to amine moiety), DMF (3.0 mL), CO
2
(1 atm),
o
1
9
0 C, 24 h. [b] Yield of isolated product. [c] Yield determined by H-NMR using
Additionally, both electro-donating and -withdrawing groups were
tolerated affording the expected products in moderate yields (2c
and 2d). When secondary amines substituted with alkyl groups,
such as isopropyl, cycloalkyl, and cyclic amines were used as
substrates, the desired products were obtained in 73-95% yield (2e-
j). Moreover, primary amine was compatible with the reaction
conditions as well, albeit dimethylated product was obtained in 47%
yield (2k). Furthermore, diphenylamine could undergo this
dibromomethane as an internal standard.
As a proof of the versatility and applicability of the presented
methodology, this reaction could be run on gram scale (Scheme 2).
The desired product 2a was obtained in 60% yield (0.75 g) by using
2
eq. PhSiH in 50 mL DMF (See in the Supporting Information).
3
methylation, 34% yield of the desired 2l can be gained.
A
heterocyclic compound, 2-methylaminopyridine was also amenable
to this protocol (2n). Encouraged by the above results, we then
explored the aliphatic amines. To our delight, the expected
reactions occurred smoothly with satisfying yields (2o and 2p).
Moreover, this methylation reaction can tolerant the oxidizing
groups (2q-t) as well.
Scheme 2 Gram scale reaction
To gain some preliminary insight into the reaction mechanism,
several control experiments were carried out under the standard
conditions (Scheme 3). Some previous works suggested
[
a]
13,16
Table 2 Methylation of amines with CO
2
and phenylsilane
that the
formation of formamide could be the main intermediates in both
metal catalyst and organocatalyst introduced methylation reaction
system. Yet, in our catalyst-free case, we only got the starting
reactant quantitatively when N-methyl-N-phenylformamide (3a)
was used as the substrate in CO or N atmosphere, indicating that
2
2
the reaction was not through formamide as the intermediate in our
case.
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Please dC oh ne omt Ca do j um s mt margins
View Article Online
DOI: 10.1039/C6CC09072A
Journal Name
COMMUNICATION
A
B
Scheme 3 Preliminary mechanistic studies
A possible reaction pathway was proposed in Scheme 4. Firstly,
phenylsilane was converted into formoxysilane in CO
atmosphere. Then with the additional PhSiH was introduced, A
A
2
163 ppm
55 ppm
3
tended to form the bis(silyl)acetal intermediate. Subsequently,
intermediate B went through a deoxygenative reduction coupling in
the presence of PhSiH
accompany with the silyl ether was released. Thus, the reduction of
CO to a silyl methoxide intermediate proceeded in a three-step
process which was also suggested by Zhang et al. and Wang et Figure. 1 C-NMR spectrum of a) PhSiH
3
to afford the silyl methoxide intermediate C
2
1
3
6
3
in d -DMSO, b) the
1
7,18
6
al.
was used, the activity of Si-H bond and the solubility of CO
Moreover, when a highly polar aprotic solvent, such as DMF, reaction of CO
2
with PhSiH
3
in d -DMSO
2
could be
1
9
13
promoted through solvation and polarization. Finally, the resulting
2
Meanwhile, CO -labelled experiment has been conducted with
1
3
methyl group on the silyl methoxide was attacked nucleophilically N-methylaniline (Scheme 5). The corresponding
C-labelled
by amine (1a) to furnish the desired methylamine.
methylation product was characterized by EI-MS and isolated in 63%
yield. With this evidence, we can directly demonstrate the carbon
source was provided from CO
Information).
2
.
(See in the Supporting
13CH3
NH
2.0 equiv. PhSiH3
.0 mL DMF, 90 oC, 24 h
13CO2
N
3
6
3% yield
0.5 mmol
MS (EI): m/z =122
Scheme 5 Labelling experiment
Conclusions
Scheme 4 Proposed mechanism
In conclusion, we have developed a catalyst-free protocol for the
methylation of N-H bond by using CO as a C1 building block under
1
3
2
Thus, in order to prove the intervening route of this reaction, C-
mild conditions. In this simple system, a variety of aromatic and
aliphatic, secondary and primary amines could be directly converted
into desired methylated products in moderate to good yields.
Further studies will be focused on the mechanistic investigation.
The exploration on the applications of this system is currently in
progress and will be reported in due course.
NMR spectra were exploited (See the Supporting Information).
6
Interestingly, as PhSiH
atmosphere of CO after 1 h
could be indicated that formoxysilane intermediates, (OCHO-)
3
was dissolved in d -DMSO under an
2
,
an 163 ppm peak was found, which
n
SiH3-
13,20
n
Ph(A)
ppm of (CH3O-)
could suggest the reaction would be through the conversion of CO
was formed in this reaction. Additionally, a peak at 55
n
SiH3-nPh (B) was observed, with this result, we
2
Acknowledgement
1
7
to (CH3O-)
n
SiH3-nPh (Fig. 1). And when we used PhSi(OMe)
3
instead of PhSiH3 and CO , the methylated product was also This work was supported by the National Natural Science
2
detected.
Foundation of China (21390400, 21520102003, 21272180,
1302148), the Hubei Province Natural Science Foundation of China
2013CFA081), the Research Fund for the Doctoral Program of
2
(
Higher Education of China (20120141130002), and the Ministry of
Science and Technology of China (2012YQ120060). The Program
of Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
Notes and references
1
.
(a) D. M. D'Alessandro, B. Smit and J. R. Long, Angew. Chem. Int.
Ed., 2010, 49, 6058-6082; (b) M. Aresta, A. Dibenedetto and A.
Angelini, Chem. Rev., 2014, 114, 1709-1742; (c) T. Sakakura, J.-C.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C6CC09072A
COMMUNICATION
Journal Name
Choi and H. Yasuda, Chem. Rev., 2007, 107, 2365-2387; (d) K.
Huang, C.-L. Sun and Z.-J. Shi, Chem. Soc. Rev., 2011, 40, 2435-
2
3
452; (e) S. N. Riduan and Y. Zhang, Dalton Trans., 2010, 39,
347-3357; (f) Q. Liu, L. Wu, R. Jackstell and M. Beller, Nat.
Commun., 2015, 6, 5933.
2
.
.
M. Cokoja, C. Bruckmeier, B. Rieger, W. A. Herrmann and F. E.
Kühn, Angew. Chem. Int. Ed., 2011, 50, 8510-8537.
(a) A.-H. Liu, B. Yu and L.-N. He, Greenhouse Gases Sci. Technol.,
3
2
3
015, 5, 17-33; (b) X. Cai and B. Xie, Synthesis, 2013, 45, 3305-
324.
4.
(a) L. C. Grabow and M. Mavrikakis, ACS Catal., 2011, 1, 365-
84; (b) S. Wesselbaum, T. vom Stein, J. Klankermayer and W.
3
Leitner, Angew. Chem. Int. Ed., 2012, 51, 7499-7502; (c) A. Tlili,
E. Blondiaux, X. Frogneux and T. Cantat, Green Chem., 2015, 17,
1
2
57-168; (d) C. A. Huff and M. S. Sanford, J. Am. Chem. Soc.,
011, 133, 18122-18125; (e) N. M. Rezayee, C. A. Huff and M. S.
Sanford, J. Am. Chem. Soc., 2015, 137, 1028-1031; (f) S. Moret,
P. J. Dyson and G. Laurenczy, Nat. Commun., 2014, 5, 4017.
(a) S. Ding and N. Jiao, Angewandte Chemie, 2012, 124, 9360-
5
.
.
9
371; (b) J. M. Adams and S. Cory, Nature, 1975, 255, 28-33; (c)
D. Dominissini, S. Moshitch-Moshkovitz, S. Schwartz, M.
Salmon-Divon, L. Ungar, S. Osenberg, K. Cesarkas, J. Jacob-
Hirsch, N. Amariglio, M. Kupiec, R. Sorek and G. Rechavi,
Nature, 2012, 485, 201-206.
(a) Y. Li, I. Sorribes, T. Yan, K. Junge and M. Beller, Angew. Chem.
Int. Ed., 2013, 52, 12156-12160; (b) Y. Li, X. Fang, K. Junge and
M. Beller, Angew. Chem. Int. Ed., 2013, 52, 9568-9571.
O. Jacquet, X. Frogneux, C. Das Neves Gomes and T. Cantat,
Chem. Sci., 2013, 4, 2127-2131.
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
.
.
.
E. Blondiaux, J. Pouessel and T. Cantat, Angew. Chem. Int. Ed.,
2
014, 53, 12186-12190.
X. Frogneux, O. Jacquet and T. Cantat, Catal. Sci. Technol., 2014,
, 1529-1533.
4
0. O. Santoro, F. Lazreg, Y. Minenkov, L. Cavallo and C. S. J. Cazin,
Dalton Trans., 2015, 44, 18138-18144.
1. L. González-Sebastián, M. Flores-Alamo and J. J. García,
Organometallics, 2015, 34, 763-769.
2. X.-L. Du, G. Tang, H.-L. Bao, Z. Jiang, X.-H. Zhong, D. S. Su and J.-
Q. Wang, ChemSusChem, 2015, 8, 3489-3496.
3. C. Fang, C. Lu, M. Liu, Y. Zhu, Y. Fu and B.-L. Lin, ACS Catal.,
2
016, 6, 7876-7881.
4. S. Das, F. D. Bobbink, G. Laurenczy and P. J. Dyson, Angew.
Chem. Int. Ed., 2014, 53, 12876-12879.
5. Z. Yang, B. Yu, H. Zhang, Y. Zhao, G. Ji, Z. Ma, X. Gao and Z. Liu,
Green Chem., 2015, 17, 4189-4193.
6. X.-F. Liu, R. Ma, C. Qiao, H. Cao and L.-N. He, Chem. Eur. J.,
2
016, 22, 16489-16493.
7. S. N. Riduan, J. Y. Ying and Y. Zhang, ChemCatChem, 2013, 5,
490-1496.
8. F. Huang, G. Lu, L. Zhao, H. Li and Z.-X. Wang, J. Am. Chem. Soc.,
010, 132, 12388-12396.
9. H. Lv, Q. Xing, C. Yue, Z. Lei and F. Li, Chem. Commun., 2016, 52,
545-6548.
0. A. Jansen, H. Görls and S. Pitter, Organometallics, 2000, 19,
35-138.
1
2
6
1
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins