N -Monomethylation of amines using paraformaldehyde and H2

Article abstract of DOI:10.1039/c7cc02314f

The selective N-monomethylation of amines is an important topic in fine chemical synthesis. Herein, for the first time, we described a selective N-monomethylation reaction of amines with paraformaldehyde and H₂ in the presence of a CuAlO_x catalyst. A variety of amines, including primary aromatic amines, benzylamine and cyclohexylamine, as well as secondary amines, have been shown to be compatible with this reaction.

Full text of DOI:10.1039/c7cc02314f

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. Wang, Y.
Huang, X. Dai and F. Shi, Chem. Commun., 2017, DOI: 10.1039/C7CC02314F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Volume 52 Number
1 4 January 2016 Pages 1–216
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
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 Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C7CC02314F
Journal Name
COMMUNICATION
N-Monomethylation of amines using paraformaldehyde and H2
Hongli Wang, Yongji Huang, Xingchao Dai and Feng Shi*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The selective N-monomethylation of amines is an improtant topic specific electrophililic methylating agents, such as MeOTf,
in fine chemical synthesis. Herein, for the first time, we described dimethyl phosphite, is a choice to circumvent this problem.5
a
selective N-monomethylation reaction of amines with Yebeutchou and Dalcanale also described the selective N-
paraformaldehyde and H2 in the presence of CuAlOx catalyst. A monomethylation of primary amine with excess of MeI via
variety of amines, including primary aromatic amines, host-guest sequestration.6 However, the formation of
benzylamine and cyclohexylamine, as well as secondary amines stoichiometric amounts of salt wastes makes such methods
are shown to be compatible with this reaction.
environmentally unfriendly.
In the past years, the utilization of methanol as
environmentally benign methylating agent based on the
‘‘hydrogen autotransfer process’’ was reported as a promising
alternative methylation strategy. In 1981, Grigg et al.
described rhodium-catalyzed selective N-monomethylation of
amine with methanol.7 Supercritical MeOH was also severed as
methylating agent for the selective N-monomethylation of
primary amines in the presence of acid-base bi-functional
catalysts.8 However, these protocols were limited to aliphatic
primary amines. Recently, the complementary N-
monomethylation of aniline with methanol in the presence of
iridium9 or ruthenium catalyst in basic media was
accomplished.10 An attractive strategy using CO2 and H2 in the
presence of ruthenium,11a palladium11b or copper catalyst11c
for N-monomethylation was reported, but suffers from high
pressure (35-100 bar) and temperature (150-160 °C) as well as
incompatibility with aliphatic primary amines. In addition, N-
monomethylation of primary arylamines was also realized in
the presence of a large amount of zeolites as catalysts when
DMC was used.12 However, the aliphatic primary amines were
shown to be inactive in these processes.
Secondary amines are important structural motifs whose
synthesis is one of the hottest topics in chemical industry.1 N-
methyl amines, in particular, are not only recognized as
fundamental building blocks in a broad range of biologically
active compounds, but also serve as key intermediates in the
preparation of pharmaceuticals, dyes and agrochemicals, etc.2
The traditional approaches for N-methylation of amines
frequently employ activated methyl compounds, such as
methyl iodide.1b However, generation of stoichiometric
amounts of wasteful (in)organic salts is prejudicial for these
protocols. Recently, methanol, carbon dioxide, dimethyl
carbonate (DMC) and formic acid have been presented as
green alternatives for the preparation of the N-methyl
amines.3 The reductive amination using formaldehyde in the
presence
of
suitable
reductant
(Eschweiler−Clarke
methylation) still prevails in industrial production of N-methyl
amines.4
Despite a series of nice results were achieved in the
synthesis of N-methyl amines, the selective N-
monomethylation of primary amines is still limited. This
limitation normally originates from the N-monomethyl amines
with higher reactivity than primary amines, so it is further
transformed into N,N-dimethyl amines. The applying of
Compared with above methods, only one example13 with
paraformaldehyde as methylating agent for the selective N-
monomethylation of primary amines has been reported. In
that elegant work, heterogeneous Pd/C was used as catalyst
and CaH2 served as reductant. However, the employment of
CaH2 as reductant significantly reduced the appeal of this
method in industrial application. In comparison with CaH2, H2
State Key Laboratory for Oxo Synthesis and Selective Oxidation,Centre for Green
Chemistry and Catalysis, Lanzhou Institute of Chemical Physics,Chinese Academy
of Sciences, No. 18, Tianshui Middle Road, Lanzhou,P. R. China. E-mail:
fshi@licp.cas.cn.
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
is
a clean, atom-economical and economic reductant.
Furthermore, products are prone to be isolated from the
reaction mixtures when H2 was released. Thus, the
development of selective N-monomethylation of amines with
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 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/C7CC02314F
COMMUNICATION
Journal Name
formaldehyde and H2 is highly desired. Nevertheless, the
activation of H2 usually needs high temperature, which makes
it difficult to realize selective N-monomethylation of amines.14
In on our previous work, CuAlOx displayed high reactivity and
selectivity for the N-monomethylaton of amines with CO2 and
H2.11c We envisioned that CuAlOx could possess better
reactivity and selectivity for the N-monomethylaton of amines
with paraformaldehyde and H2. Herein we describe for the first
time the selective synthesis of N-monomethyl amines with
paraformaldehdye and H2 in the presence of a simple CuAlOx
catalyst (Scheme 1).
Fig. 2 Fourier transform (FT) of Cu K-edge EXAFS: a) CuAlOx(2:8);b) CuAlOx(3:7);
c) CuAlOx(5:5); d) CuAlOx(7:3); e) CuAlOx(8:2); f) Cu; g) Cu2O; h) CuO.
Scheme 1 Selective reductive N-monomethylation of amines.
The catalyst used here was prepared by a co-precipitation
method via adding an aqueous solution of Na2CO3 into a
Cu(NO3)2 and Al(NO3)3 solution. The precipitates were washed
by deionized water, dried in air and reduced under H2 flow at
450 oC. A series of CuAlOx catalysts were obtained and
denoted as CuAlOx (m : n) (m : n = molar ratios of Cu and Al).
These catalysts were characterized by ICP-AES, BET surface
area analysis, XPS, XRD, EXAFS and TEM.
Fig. 3 TEM (a), HR-TEM (b), HAADF (c) and the line-scan EDS analysis (d) images
of the fresh CuAlOx (5 : 5) catalyst.
Table 1 The physicochemical properties of catalysts
Fig. 1a shows the Cu2p XPS spectra of fresh and used
CuAlOx (5 : 5). The XPS spectra of fresh CuAlOx (5 : 5) display
two main peaks at 932.8 and 952.6 eV that can be attributed
to Cu2p3/2 and Cu2p1/2 binding energies of Cu0 or Cu+. In order to
verify the valent state of copper species, CuLMM Auger spectra
were collected and are shown in Fig. 1b. A peak at 916.2 eV,
which can be attributed to Cu+, are observed.15 In addition, the
XRD diffraction patterns of the as-prepared catalysts
performed to further elucidate the structure of the catalysts
(see Fig. S3). The CuAlOx samples show diffraction peaks at
36.7°, 43.3°, 50.6°, 74.1°and 89.9°, which can be ascribed to
the diffraction peaks of Cu2O(111), Cu(111), (200), (220) and
(311). From the analysis of the XRD diffraction patterns, both
CuAlOx (2 : 8) and CuAlOx (3 : 7) samples display broad peaks
of Cu(111), which suggest the amorphous nature of these
catalysts. However, with the increasing of Cu : Al ratios in the
catalysts, sharper diffraction peaks of Cu(111) and Cu(200)
were observed in CuAlOx (5 : 5), CuAlOx (7 : 3), and CuAlOx (8 :
2). CuAlOx catalysts were further characterized by TEM and
HR-TEM, Fig. 3. The HR-TEM image confirmed the observations
from the XRD diffraction patterns in Fig. S3. The crystal lattices
of Cu(111) and Cu2O(111) can be observed clearly. The catalyst
sample used three times was also characterized by XPS and the
formation of Cu2O on the catalyst surface was observed, but
no Cu2O diffraction peak was seen from XRD diffraction
patterns. Considering that this is a reductive reaction and
according to the analytical results, we suppose that metallic
copper might be the active species for this reaction. The
Fourier transform (FT) of Cu K-edge EXAFS spectra of different
catalyst samples also support this perspective. Although some
Entry
Catalysts
Cua wt%
SAb (m2/g)
59.2
APSb (nm)
15.4
PVb (cm3/g)
0.46
1
2
CuAlOx (2 : 8)
CuAlOx (3 : 7)
CuAlOx (5 : 5)
CuAlOx (7 : 3)
CuAlOx (8 : 2)
17
27
57
82
83
b
85.9
7.0
0.30
3
58.7
9.5
0.28
4
52.4
10.0
0.27
5
36.3
15.5
0.26
a
Determined by ICP-AES. Determined by an IQ2 automated gas sorption
analyser. SA: BET surface area; APS: Average pore size; PV: Pore volume.
The contents of Cu in these catalysts were tested by ICP-AES,
and the copper loadings in CuAlOx increased from 17% to 83%
(Table 1, entries 1-5). Then, the surface areas and pore size
distributions of these catalysts were investigated by BET
surface area analysis. With the increasing of Cu : Al ratios, the
BET surface area of the CuAlOx catalysts increased first and
then decreased. However, the average pore size changed in
the opposite tendency. The CuAlOx (3 : 7) possessed the
highest BET surface area, i.e. 85.9 m2g-1, and smallest pore
volume, i.e. 7 nm (entry 2). The pore volume gradually
decreased as the Cu : Al ratios of the catalysts increased.
Fig. 1 Cu2p XPS spectra (a) and Auger CuLMM spectra (b) of the fresh and used
CuAlOx (5 : 5) catalyst.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C7CC02314F
Journal Name
COMMUNICATION
Table 3 Results of the N-monomethylation of primary aminesa
CuOx species were observed by XRD and XPS characterizations
from sample CuAlOx (5 : 5), almost no Cu-O coordination peak
can be observed from the Cu K-edge EXAFS spectra. Therefore,
only small amount of CuOx was formed in CuAlOx (5 : 5), and
the main copper species is metallic copper.
Entry
1
Substrate
Product
Yield(%)b
89
NH2
1a
3a
Next, the N-monomethylation reaction of aniline with
paraformaldehyde and H2 was chosen as the model reaction to
test the performance of these catalysts (Table 2, entries 1-5).
Clearly, with the increasing of Cu : Al ratios in the catalysts, the
reactivity and the selectivity for N-methylaniline were
improved and 94% conversion of aniline with 97% N-
methylaniline selectivity was achieved when CuAlOx (5 : 5) was
used as the catalyst (entry 3). However, both the conversion of
aniline and the selectivity for N-methyl aniline were slightly
decreased if the Cu : Al ratio was further increased. The impact
of the solvent over the reactivity and selectivity of this reaction
was further investigated, and it was discovered that THF
remained the optimal choice (see Table S1). Furthermore, if
the amount of CuAlOx (5 : 5) was reduced to 20 mg, it still
maintained good catalytic performance (entries 6-9). Finally,
97% aniline conversion and 93% N-methylaniline selectivity
were obtained when reducing the H2 pressure to 0.5 Mpa and
prolonging the reaction time to 9 h (entry 12). Unfortunately,
both conversion and selectivity were decreased if the reaction
temperature was decreased (see Table S1). Noteworthy, this
catalyst is easily recoverable by simple filtration, and it can be
reused directly without further treatment. To our delight, 98%
conversion of aniline with 91% N-methylaniline selectivity was
maintained when it was used at the 3rd run thus this catalyst
exhibits nice reusability.
2
3
85
84
1b
3b
Me
NH2
1c
3c
4
83
1d
3d
5
80
76
70
74
1e
3e
3f
6c
7c
8c
1f
1g
1h
3g
3h
9c
69
79
61
1i
1j
3i
3j
Table 2 Reaction conditions optimization for N-monomethylation of anilinea
10c
11c
1k
3k
12c
13d
14e
81
73
64
1l
3l
Sel.c (%)
Entry CuAlOx (m : n) Conv.b (%)
3a
76
87
97
91
91
98
696
89
77
94
95
4a
10
1
5a 6a 7a
1m
3m
1
2
(2 : 8), 50 mg
(3 : 7), 50 mg
(5 : 5), 50 mg
(7 : 3), 50 mg
(8 : 2), 50 mg
(5 : 5), 30 mg
(5 : 5), 20 mg
(5 : 5), 10 mg
(5 : 5), 5 mg
(5 : 5), 20 mg
(5 : 5), 20 mg
(5 : 5), 20 mg
80
78
13
10
--
--
2
--
--
--
--
--
--
--
2
3
94
3
--
--
1
1n
3n
4
90
9
--
5
90
8
--
15e
66
1o
6
91
2
--
--
--
3
3o
7
96
4
--
8
94
3
3
aamine (1.0 mmol), paraformaldehyde (1.2 mmol), CuAlOx (5 : 5) (20 mg), H2 (0.5
MPa), THF (3.0 mL), 120 °C,
paraformaldehyde (1.0 mmol), 140 °C. dGC-FID yield. eNMR yield.
9
h. bIsolated yields. cAmine (1.5 mmol),
9
93
2
13
2
6
2
10d
11e
12f
89
1
2
2
83
97(98g)
--
3
1
--
--
93(91g) 7(9g)
--
--
With the optimized conditions in hand, the scope of this
CuAlOx catalyzed selective N-monomethylation of different
primary amines was further investigated. As shown in Table 3,
the anilines with both electron-withdrawing and -donating
groups on the phenyl ring were well tolerated the current
conditions. Reductive amination of electron-rich methyl-, tert-
a1a (1.0 mmol), paraformaldehyde (1.2 mmol), CuAlOx (x mg), H2 (1.0 Mpa), THF
(3.0 mL), 120 oC, 5 h. bDetermined by GC-MS. cDetermined by GC-MS. H2 (0.5
d
Mpa). e H2 (0.2 Mpa). f H2 (0.5 Mpa), 9 h. g The catalyst was reused at the 3rd run.
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/C7CC02314F
COMMUNICATION
Journal Name
butyl-, and methoxy-substituted anilines proceeded smoothly This work was financially supported by the NSFC (21633013)
to provide the corresponding products in 76−89% yields (Table and Youth Innovation Promotion Association CAS.
3, entries 1-6). The anilines bearing electron-deficient groups,
such as halogen, ester, and cyano groups, provided the
Notes and references
corresponding products in 61-79% yields (entries 7-10). The
halogen groups in the products are useful handles for further
synthetic elaborations. As expected, 2-naphthalene amine also
underwent the N-monomethylation to give the desired
product in 81% yield (entries 12). It should be noted that
selective N-monomethylation of aliphatic primary amines
remains a challenge in this field. After improving the reaction
1
(a) A. Ricci, Amino Group Chemistry, From Synthesis to the
Life Sciences, Wiley-VCH, Weinheim, 2008; (b) R. N.
Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron 2001, 57
7785–7811.
,
2
3
D. Desaiah, S. L. N. Reddy, S. Z. Imam and S. F. Ali, Pure Appl.
Chem., 2000, 72, 1001–1006.
For recent review of DMC as methyl source, see: (a) P. Tundo
and M. Selva, Acc. Chem. Res., 2002, 35, 706–716; for recent
review of DMC and MeOH as methyl source, see: (b) M.
Selva and A. Perosa, Green Chem., 2008, 10, 457–464; for
recent review of CO2 as methyl source, see: (c) A. Tlili, X.
Frogneux, E. Blondiaux and T. Cantat, Angew. Chem., Int. Ed.,
2014, 53, 2543–2545; (d) J. Klankermayer, S. Wesselbaum, K.
conditions,
benzylamine,
cyclohexylamine
and
cyclopentylamine underwent successful N-monomethylation
to afford the aim products in 64-73% yields (entries 13-15).
Table 4 Results of the N-methylation of secondary amines a
Yield(%)b
79
Beydoun and W. Leitner, Angew. Chem., Int. Ed., 2016, 55
,
Entry
1c
Substrate
Product
7296–7343; for recent examples of HCOOH as methyl source,
see: (e) S. Savourey, G. Lefevre, J.-C. Berthet and T. Cantat,
Chem. Commun., 2014, 50, 14033−14036; (f) I. Sorribes, K.
Junge and M. Beller, Chem. - Eur. J., 2014, 20, 7878−7883.
(a) W. Eschweiler and B. Dtsch, Chem. Ges., 1905, 38, 880–
882; (b) H. T. Clarke, H. B. Gillespie and S. Z. Weisshaus, J.
Am. Chem. Soc., 1933, 55, 457–4587; (c) M. L. Moore, Org.
React., 1949, 5, 301–330; (d) E. Farkas and C. J. Sunman, J.
Org. Chem., 1985, 50, 1110–1112; (d) J. R. Harding, J. R.
Jones, S. Y. Lu and R. Wood, Tetrahedron Lett., 2002, 43
9487–9488.
1p
3p
4
5
2
99
1q
3q
3c
4c
5
88
75
99
1r
1s
3r
3s
,
,
(a) S. K. Kundu, K. Mitra and A. Majee, RSC Adv., 2013,
3
8649–8651; (b) T. Lebleu, X. Ma, J. Maddaluno and J. Legros,
Chem. Commun., 2014, 50, 1836–1838; (c) T. Lebleu, J.
1t
3t
Maddaluno and J. Legros, Org. Chem. Front., 2015, 2, 324–
327.
R. M. Yebeutchou and E. Dalcanale, J. Am. Chem. Soc., 2009,
131, 2452–2453.
6
99
67
1u
6
7
8
3u
R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N.
Tongpenyai, J. Chem. Soc., Chem. Commun., 1981, 611–612.
(a) T. Oku and T. Ikariya, Angew. Chem., Int. Ed., 2002, 41
7c
1v
3v
,
3476–3479; (b) T. Oku, Y. Arita, H. Tsuneki, T. Ikariya, J. Am.
Chem. Soc., 2004, 126, 7368–7377.
(a) F. Li, J. Xie, H. Shan, C. Sun and L. Chen, RSC Adv., 2012, 2,
aamine (1.0 mmol), paraformaldehyde (1.5 mmol), CuAlOx (5 : 5) (20 mg), H2 (0.5
MPa), THF (3.0 mL), 120 °C, 9 h. bIsolated yields. c140 °C.
9
8645–8652; (b) J. Campos, L. S. Sharninghausen, M. G.
Manas and R. H. Crabtree, Inorg. Chem., 2015, 54, 5079–
5084.
Next, we further investigated the N-methylation of different
secondary amines. Cyclic secondary amines, such as
morpholine and piperazine, were converted into desired
products in 79% and 99% yields, respectively (Table 4, entries
1-2). In addition, dialkylamines were also compatible with this
catalyst system, affording the corresponding products in good
to excellent yields, too (entries 3-6). Furthermore, N-
methylaniline can also be transformed into N,N-
dimethylaniline with good yield (entry 7).
10 (a) S. Naskar and M. Bhattacharjee, Tetrahedron Lett., 2007,
48, 3367–3370; (b) T. T. Dang, B. Ramalingam and A. M.
Seayad, ACS Catal., 2015, 5, 4082–4088.
11 (a) Y. Li, I. Sorribes, T. Yan, K. Junge and M. Beller, Angew.
Chem., Int. Ed., 2013, 52, 12156–12160; (b) X. Cui, Y. Zhang,
Y. Deng and F. Shi, Chem. Commun., 2014, 50, 13521–13524;
(c) X. Cui, X. Dai, Y. Zhang, Y. Deng and F. Shi, Chem. Sci.,
2014,
12 (a) M. Selva, P. Tundo and A. Perosa, J. Org. Chem., 2001, 66
5, 649–655.
,
In conclusion, we have developed a simple CuAlOx catalyst
system for the selective N-monomethylation reaction of
677-680; (b) M. Selva, P. Tundo and T. Foccardi, J. Org.
Chem., 2005, 70, 2476−2485.
primary amines with paraformaldehyde and H2. This work 13 C. Guyon, M.-C. Duclos, E. Métay and M. Lemaire,
Tetrahedron Lett., 2016, 57, 3002–3005.
offers a clean and economic methodology for the selective
synthesis of N-monomethyl amines. Further investigation of
selective N-monomethylation of the long-chain primary alkyl
amines is underway in our laboratory.
14 (a) S. Nishimura, Handbook of Heterogeneous Catalytic
Hydrogenation for Organic Synthesis, Wiley, New York, 2001;
(b) X. Ge, C. Luo, C. Qian, Z. Yu and X. Chen, RSC Adv., 2014, 4,
43195–43203.
15 (a) A. Galtayries and J.-P. Bonnelle, Surf. Interface Anal., 1995,
23, 171-179; (b) J. P. Espinós, J. Morales, A. Barranco, A.
Caballero, J. P. Holgado and A. R. González-Elipe, J. Phys.
Chem. B 2002, 106, 6921-6929.
Acknowledgements
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins