Ruthenium-Catalyzed Methylation of Amines with Paraformaldehyde in Water under Mild Conditions

Article abstract of DOI:10.1002/cssc.201600824

Methylated amines are highly important for a variety of pharmaceutical and agrochemical applications. Existing routes for their formation result in the production of large amounts of waste or require high reaction temperatures, both of which impact the ecological and economical footprint of the methodologies. Herein, we report the ruthenium-catalyzed reductive methylation of a range of aliphatic amines, using paraformaldehyde as both substrate and hydrogen source, in combination with water. This reaction proceeds under mild aqueous reaction conditions. Additionally the use of a secondary phase for catalyst retention and recycling has been investigated with promising results.

Full text of DOI:10.1002/cssc.201600824

DOI: 10.1002/cssc.201600824
Communications
Ruthenium-Catalyzed Methylation of Amines with
Paraformaldehyde in Water under Mild Conditions
Dominic van der Waals, Leo. E. Heim, Christian Gedig, Fabian Herbrik, Simona Vallazza, and
[a]
Martin H. G. Prechtl*
Methylated amines are highly important for a variety of phar-
maceutical and agrochemical applications. Existing routes for
their formation result in the production of large amounts of
waste or require high reaction temperatures, both of which
impact the ecological and economical footprint of the method-
ologies. Herein, we report the ruthenium-catalyzed reductive
methylation of a range of aliphatic amines, using paraformal-
dehyde as both substrate and hydrogen source, in combina-
tion with water. This reaction proceeds under mild aqueous re-
action conditions. Additionally the use of a secondary phase
for catalyst retention and recycling has been investigated with
promising results.
scope was, however, noted to be limited, and reaction temper-
atures of 1508C were required. Similarly, the classical amine
[11]
methylation Eschweiler–Clarke reaction,
which needs an
excess of both formic acid and formaldehyde, requires high
temperatures, 120–1608C, with long reaction times and results
[6]
in the formation of various side products. In these reactions,
the formaldehyde is believed to condense with the amine,
with the resulting imine becoming reduced by the formic acid.
The use of a metal catalyst to directly hydrogenate the imine
intermediate or substrate has been reported to negate the
need for the formic acid; many, primarily noble metal, catalysts
[12–14]
have been reported for this methodology.
Our interest in formaldehyde as a C building block originat-
1
ed from the recent publications whereby aqueous formalde-
Methylamines are ubiquitous in both natural products as well
as throughout synthetic organic molecules. Key examples in-
hyde solutions were shown to liberate H in the presence of
2
[15–17]
a
robust ruthenium catalyst, [Ru(p-cymene)Cl ] .
This
2
2
[
1,2]
clude their use in drug molecules as well as their occurrence
mechanism was thought to proceed through the dehydrogen-
ation of methanediol, the favourable product formed upon
formaldehyde hydration, to formic acid. Further work showed
that formaldehyde could be trapped as an intermediate in the
catalytic reforming of paraformaldehyde (pFA) in aqueous solu-
[
3–5]
within natural molecules such as neurotransmitters.
One existing method for the methylation of amines involves
the use of a methylating agents, which, whilst effective, can
[6]
result in over-methylation to yield quaternary amine salts.
[18]
Alternative single-carbon sources have also been investigated.
A recent seminal publication by Leitner et al. reports the use of
CO as the C source for the methylation of anilinic amines
tions to yield methanol. It was speculated that the use of
a nucleophilic substrate, such as an amine, could attack the
formaldehyde intermediate yielding an iminium cation and
then undergo subsequent reduction to lead to a single sub-
strate acting as both the carbon and hydrogen source in the
methylation of amines for synthetic applications (Scheme 1).
The high importance of formaldehyde as a chemical reagent
for current and future technologies is reflected in more than
2
1
using a ruthenium catalyst. The proposed mechanism is be-
lieved to proceed through the formation of a formamide fol-
[
7]
lowed by subsequent reduction. This work was built upon in
a later publication detailing the reductive methylation of
[
8]
imines. Beller et al. reported an alternative ruthenium system
with an expanded substrate scope that included aliphatic
50 industrial processes in which formaldehyde plays a key role
[
9]
[15,19–21]
amines. Formic acid has been reported as a C source in the
for the manufacture of products used in daily life.
The
1
direct methylation of a range of primary and secondary aro-
product variety covers processed wood, paints, cosmetics,
resins, polymers, adhesives besides many others. Formalde-
hyde is usually processed in the liquid and even aqueous
phase. All these industries merge to a multi-billion-dollar
market based on more than 30 mega tons per year of formal-
[
10]
matic amines as recently reported by Cantat et al. In analogy
to CO protocols, a ruthenium triphos catalyst with triflimide
2
additive has been used to activate formic acid instead of CO2.
It has been proposed that the reaction proceeds through
a mechanism involving the formation of a formamide inter-
mediate with subsequent reduction. The reaction substrate
[15,19–21]
dehyde as building block and cross-linker.
Currently,
>35% of the world methanol production is converted into
formaldehyde, which turns formaldehyde into the number one
product directly derived from methanol. In this context, it is
feasible to find further processes using paraformaldehyde
owing to its safe handling, availability and the fact that it can
be derived from biomass (currently via syngas and methanol
synthesis); this will turn paraformaldehyde into a bulk reagent
[a] Dr. D. van der Waals, L. E. Heim, C. Gedig, F. Herbrik, S. Vallazza,
Dr. M. H. G. Prechtl
Department Chemie
Universitꢀt zu Kçln
Greinstrasse 4-6, 50939 Cologne (Germany)
E-mail: martin.prechtl@uni-koeln.de
Homepage: www.catalysislab.de
available from renewable sources in future biomass- and C -
1
[15–17,19–21]
based industries.
Additionally, there are processes
Supporting Information for this article can be found under http://
dx.doi.org/10.1002/cssc.201600824.
under development to decompose residual formaldehyde from
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industrial wastewater; therefore, aqueous-phase processes
using formaldehyde may turn even greener in the near
We herein report the use of arene ruthenium halide catalysts
for the methylation of a range of primary and secondary
amines with pFA under mild reaction conditions in short reac-
tion times. Initial investigations employed benzylamine as the
exemplary substrate and the reaction parameters were opti-
mised using the commercially available [Ru(p-cymene)Cl ] cat-
[
15]
future.
Table 1. Optimisation of reaction parameters for methylation reactions.
2
2
alyst as shown in Table 1.
Whilst increases in temperature and catalyst loadings were
noted to be favourable for methylation, it was seen that reac-
tions at 608C with low catalyst loadings of 0.5 mol% gave ac-
ceptable conversions provided a 2:5 ratio of pFA per NÀH
group was used. An excess of pFA is required as some is lost
to the competing reactions of dehydrogenation and methanol
reformation. It was noted that higher reaction concentrations
led to higher conversions (entries 7 and 8).
[
a]
[b]
Entry
T
Cat.
[mol%]
Amine/pFA
Conv.
[%]
[
8C]
1
2
3
4
5
6
7
8
9
50
60
70
70
60
60
70
60
60
0.5
0.5
0.5
2
0.5
2
0.5
0.5
0.5
1:3
1:3
1:3
1:3
1:5
1:5
1:10
1:5
1:5
6
40
55
58
85
95
>99
91
Taking the optimised reaction parameters, the use of
a range of similar ruthenium catalysts was investigated. Table 2
shows that whilst alternative halide bridging anions, such as
iodide and bromide, were compatible to the reaction with
iodide showing quantitative conversion, the use of others such
as the thiocyanate-bridged catalyst gave almost no conversion.
Similarly, the replacement of the ruthenium catalyst with the
osmium analogue (entry 3) gave low conversions.
61
[
a] Reactions were run on a 2 mmol (1m) scale of benzylamine, except
entries 8 (2m) and 9 (0.5m). [b] Conversions were determined by analysis
1
of the H NMR spectra.
Further reactions with the three best catalysts; [Ru(tolu-
ene)Cl ] , [Ru(p-cymene)Cl ] and [Ru(p-cymene)I ] , over a short-
2
2
2 2
2 2
er reaction time of 1 h led to conversions of 41%, 61% and
6%, respectively. Having determined that [Ru(p-cymene)I2]2
Table 2. Catalyst screen for the methylation of benzylamine.
7
was the optimum catalyst, we proceeded to investigate the
substrate scope available to the reaction. Table 3 shows
a range of amines that could be methylated. With the excep-
tion of entry 5, all of the reactions proceeded in good-to-quan-
titative conversions and it can be seen that both primary and
secondary amines, including cyclic and acyclic examples, were
susceptible to methylation under the reaction conditions.
Having demonstrated wide substrate scope availability, we de-
cided to test the limitations of the reaction methodology. Chal-
lenging nitrogen nucleophiles such as sulfonamides and
amides were investigated although no conversion to either the
corresponding methylated or formylated products was ob-
served even after 24 h under the reaction conditions; this is
presumed to be due to lack of nucleophilicity required to form
[
a,b]
Entry Metal Arene
X
Conv.
%]
[
1
2
3
4
5
6
7
8
Ru
Ru
Os
Ru
Ru
Ru
Ru
Ru
toluene
benzene
Cl
Cl
Cl
Br
SCN
I
>99
56
10
86
10
>99
77
83
p-cymene
benzene
p-cymene
p-cymene
2-phenoxyethanol
Cl
1-phenethyl-2,3,-dimethyl-imidazolium Cl
chloride
[
a] Reactions run on a 2 mmol scale with 5 equiv. of pFA. [b] Conversions
1
determined by analysis of the H NMR spectra.
Table 3. Amine methylation substrate scope.
[
a]
Entry
Amine
Product amine
Equiv. pFA
Isolated yield
%]
[
1
2
3
4
5
6
7
cyclohexylamine
benzylamine
morpholine
phenethylamine
5-amino-1-pentanol
piperidine
N,N-dimethyl cyclohexylamine
N,N-dimethyl benzylamine
N-methyl morpholine
N,N-dimethyl phenethylamine
N,N-dimethyl 5-amino-1-pentanol
N-methyl piperidine
5
5
2.5
5
5
78
80
89
86
73
95
97
2.5
2.5
dibutylamine
N-methyl dibutylamine
[a] Reactions run on a 2 mmol scale.
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the imine intermediate. Investigated anilines formed only in-
tractable mixtures thought to be caused by polymerisation,
and carbon nucleophiles showed no detectable methylation or
formylation (Supporting Information, Table 2).
optimisation despite it not showing the highest levels of meth-
ylation.
Retaining the use of the imidazolium ruthenium catalyst, op-
timisation of the biphasic system was carried out (Table 4).
These results indicate that again the use of an excess of pFA is
required with a 2:5 optimum ratio for each free NÀH group to
be methylated. It was encouraging to note that the use of low
catalyst loadings was possible without a corresponding decline
in the conversions.
Having seen that methylated products were formed rather
than the formamide products seen through similar methodolo-
[
22]
gies, the presence of a formamide intermediate, which could
undergo subsequent reduction to the methylated product,
1
13
was looked for in both the H and C NMR spectra. No corre-
sponding peaks were seen, suggesting that this is not a reac-
tion intermediate; this conclusion was further corroborated by
submitting test amides, namely dimethyl formamide and ben-
zamide, to the reaction conditions with no reduction seen in
Table 4. Reaction parameter optimisation for biphasic methylations.
1
13
either case. Further H and C NMR analysis was conducted
with initial build-up of the monomethylated product followed
by subsequent decrease as conversion to the dimethylated
[a]
Entry
Equiv. pFA
Catalyst
[mol%]
T
[8C]
t
[h]
Conv.
[%]
1
product swiftly occurred, as determined by H NMR analysis
13
(
Supporting Information, Figure 1). C NMR spectroscopy was
1
2
3
4
5
6
7
8
1.33
2
3
5
5
5
5
5
1.0
1.0
1.0
1.0
0.25
0.5
1.0
2.0
80
80
80
80
90
90
90
90
16
16
16
16
2
2
2
2
13
20
25
38
32
37
35
42
used to identify reaction intermediates present shortly after ini-
tiation of the reaction. As expected, signals corresponding to
both the mono- and dimethylated product were present as
was a signal indicative of the proposed Mannich-type imine in-
[
23]
termediate. This has led to the proposed reaction mecha-
nism (Scheme 1) detailing the bifunctional use of formalde-
hyde as both substrate and reducing agent, in the hydrated
[
a] Reactions run on a 2 mmol scale, 0.5 mL H
2
O and 2 mL heptane used
[
18]
form of methanediol in our ongoing research.
as solvent with [Ru(arene)Cl
lium chloride).
2 2
] (arene: 1-phenethyl-2,3,-dimethyl-imidazo-
Interestingly, the reduction of the reaction temperature led
to greater conversions; however, below 508C there was
a sharp decrease in activity. This was attributed both to avoid-
ing competitive reaction pathways, such as dehydrogenation
of aqueous formaldehyde, that were expedited by high tem-
peratures as well as circumventing the entropically favourable
hydrolysis of the proposed imine intermediate at the higher
temperatures. Having optimised the reaction conditions at
Scheme 1. Possible pathway for amine methylation with pFA.
508C, a screen of potential ruthenium catalysts was conducted
for the biphasic reaction (Table 5).
With the optimised system in hand, a substrate scope for
amines was undertaken as shown in Table 6. The use of simple,
low boiling amines was also investigated. For these substrates
an alternative method for isolation was required; thus, ethereal
HCl was applied to generate the hydrochloride salts, which led
to the high yields recorded in entries 6–9 in Table 6. As with
the monophasic reaction system, a range of primary and sec-
ondary amines could be isolated in good-to-excellent yields.
In consequence of the successful biphasic reactions and the
ability to retain the catalyst in the aqueous phase, this system
was further investigated. Dibutylamine was chosen as the ex-
emplary substrate for methylation and was submitted to a set
of recycling experiments, the results of which are reported in
Figure 1 below and SI-Figure 2 in the Supporting Information.
It is apparent that the turnover numbers remain high for each
of the recycling steps with little reduction in efficiency. Notably,
the addition of a phosphate buffer helped to stabilise the cata-
lyst over repeated use.
Having shown that the reaction could be conducted in
a monophasic system, leading to high yielding methylation of
amines, it was postulated that the methodology might be ex-
panded to allow for a biphasic system; this could enable cata-
lyst separation and reuse. As arene ruthenium catalysts show
high affinity for the aqueous phase, it was decided to investi-
gate the potential for conducting biphasic methylation reac-
tions with retention of the catalyst in the aqueous phase. To
ensure a high aqueous solubility of the ruthenium catalyst,
a ruthenium catalyst with a charged imidazolium functionality
[18,24]
attached as part of the aryl group was investigated.
The
results, shown in Table 1 in the Supporting Information, dem-
onstrate compatibility of the methylation of benzylamine with
a range of organic solvents, from the highly polar to the highly
hydrophobic. It was evident that the water/heptane biphasic
mixture visibly showed the least leaching of the catalyst into
the organic phase; hence, this system was taken forward for
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In conclusion, we have herein reported simple, mild and effi-
cient mono- and biphasic methodologies for the methylation
of a wide variety of aliphatic amines. Low catalyst loadings and
short reaction times for the aqueous monophasic reaction en-
hance its green credentials whilst the use of a secondary
phase allows for good levels of catalyst retention. Methods for
the immobilisation of the optimised catalysts upon a secondary
solid phase are ongoing.
Table 5. Catalyst screen for the biphasic methylation of benzylamine.
[
a]
Entry Arene
Halogen Conv.
%]
[
1
2
3
4
5
6
7
p-cymene
toluene
2-phenoxyethanol
benzene
p-cymene
Cl
Cl
Cl
Br
I
90
53
39
29
78
43
52
Experimental Section
1-phenethyl-2,3,-dimethyl-imidazolium chloride Cl
N,N,N-triethyl-phenethyl ammonium mesolate Cl
Exemplary monophasic reaction: Into a screw-neck vial, [Ru(p-cym-
ene)I ] (9.8 mg; 0.01 mmol, 0.5 mol%) and pFA (300 mg; 10 mmol)
2
2
[
a] Reactions run on a 2 mmol scale with 5 equiv. of pFA. Conversions de-
were added. Water (1.0 mL) was added, which was followed by ad-
dition of benzylamine (2 mmol; 218 mL); the vial was closed and
then placed into a preheated aluminium block at 608C and stirred
for 2 h. After this time, the vial was cooled to room temperature
and NaOH solution (2 mL, 2m) was added; the aqueous phase was
washed three times with 10 mL dichloromethane. Organic fractions
were combined, dried over MgSO and Al O and solvent was re-
1
termined by analysis of the H NMR spectra. Hexane used rather than
heptane simply for practical convenience.
4
2
3
Table 6. Substrate screen for biphasic methylations.
duced in vacuo to yield the desired amine.
Exemplary biphasic reaction: Into a screw-neck vial, [Ru(p-cyme-
ne)Cl ] (6.1 mg; 0.01 mmol, 0.5 mol%) and pFA (300 mg; 10 mmol)
2
2
were added. Hexane (2 mL) and water (0.5 mL) were added, which
was followed by addition of benzylamine (2 mmol; 218 mL); the
vial was closed and then placed into a preheated aluminium block
at 508C and stirred for 5 h. After this time, the vial was cooled to
room temperature, neutralised and separated as per the monopha-
sic system (see above).
[
a]
Entry
Amine
Equiv. pFA
Isolated yield
%]
[
1
2
3
4
5
6
7
8
9
cyclohexylamine
benzylamine
phenethylamine
dibutylamine
octylamine
5
5
5
2.5
5
2.5
5
5
88
83
93
87
98
83
83
77
71
Recycling experiment protocol: [Ru(p-cymene)Cl2]2 (6.1 mg,
0.01 mmol, 0.5 mol%) and pFA (150 mg; 5 mmol) were added to
a screw-cap vial, which was followed by addition of hexane (2 mL),
water (0.5 mL) and dibutylamine (340 mL; 2 mmol). After sealing
and heating at 508C for 5 h, the organic layer was extracted and
solvents were removed in vacuo. The residue was analysed by
[
[
[
[
b]
b]
b]
b]
diethylamine
isobutylamine
tert-butylamine
diisopropylamine
2.5
[
a] Reactions run on a 2 mmol scale. [b] Isolated yield determined by
1
H NMR spectroscopy. For each cycle, hexane (2 mL ), dibutylamine
comparison of isolated HCl salt against a 1,4-dioxane standard.
(340 mL; 2 mmol) and pFA (150 mg; 5 mmol) were recharged into
the reaction vial containing the ruthenium catalysts in the aqueous
phase.
Acknowledgements
We gratefully acknowledge financial support provided by the
Ministerium fꢁr Innovation, Wissenschaft und Forschung (NRW-
returnee award 2009 to M.H.G.P.), the Deutsche Forschungsge-
meinschaft (Heisenberg-Program), the Ernst-Haage-Stiftung (Max-
Planck Society) and the Alexander-von-Humboldt Foundation
(
Connect! program). Moreover, the authors acknowledge H. G.
Schmalz for access to GC–MS analysis and J. Deska for discus-
sion.
Keywords: amination · homogeneous catalysis · methylation ·
paraformaldehyde · ruthenium
[
1] A. Kimishima, H. Umihara, A. Mizoguchi, S. Yokoshima, T. Fukuyama,
Org. Lett. 2014, 16, 6244–6247.
[
2] P. J. Dunn, S. Galvin, K. Hettenbach, Green Chem. 2004, 6, 43–48.
Figure 1. Biphasic catalyst recycling experiments.
[3] K. J. Broadley, Pharmacol. Ther. 2010, 125, 363–375.
&
ChemSusChem 2016, 9, 1 – 6
www.chemsuschem.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communications
[
4] K. Yamasaki, T. Tamaki, S. Uzawa, U. Sankawa, S. Shibata, Phytochemistry
[16] L. E. Heim, D. Thiel, C. Gedig, J. Deska, M. H. G. Prechtl, Angew. Chem.
Int. Ed. 2015, 54, 10308–10312; Angew. Chem. 2015, 127, 10447–10451.
[17] L. E. Heim, N. E. Schlçrer, J. H. Choi, M. H. G. Prechtl, Nat. Commun.
2014, 5, 3621.
[18] D. Van der Waals, L. E. Heim, S. Vallazza, C. Gedig, J. Deska, M. H. G.
Prechtl, Chem. Eur. J. 2016, 22, 11568–11573.
[19] A. M. Bahmanpour, A. Hoadley, S. H. Mushrif, A. Tanksale, ACS Sustaina-
ble Chem. Eng. 2016, 4, 3970–3977.
[20] A. M. Bahmanpour, A. Hoadley, A. Tanksale, Green Chem. 2015, 17,
3500–3507.
[21] A. M. Bahmanpour, A. Hoadley, A. Tanksale, Rev. Chem. Eng. 2014, 30,
583–604.
[22] O. Saidi, M. J. Bamford, A. J. Blacker, J. Lynch, S. P. Marsden, P. Plucinski,
R. J. Watson, J. M. J. Williams, Tetrahedron Lett. 2010, 51, 5804–5806.
[23] R. A. da Silva, I. H. S. Estevam, L. W. Bieber, Tetrahedron Lett. 2007, 48,
7680–7682.
1973, 12, 2877–2882.
[
[
[
5] C. A. Faler, M. M. Joullie, Org. Lett. 2007, 9, 1987–1990.
6] S. H. Pine, B. L. Sanchez, J. Org. Chem. 1971, 36, 829–832.
7] K. Beydoun, T. vom Stein, J. Klankermayer, W. Leitner, Angew. Chem. Int.
Ed. 2013, 52, 9554–9557; Angew. Chem. 2013, 125, 9733–9736.
8] K. Beydoun, G. Ghattas, K. Thenert, J. Klankermayer, W. Leitner, Angew.
Chem. Int. Ed. 2014, 53, 11010–11014; Angew. Chem. 2014, 126, 11190–
[
[
1
1194.
9] Y. H. Li, I. Sorribes, T. Yan, K. Junge, M. Beller, Angew. Chem. Int. Ed.
013, 52, 12156–12160; Angew. Chem. 2013, 125, 12378–12382.
10] S. Savourey, G. Lefevre, J. C. Berthet, T. Cantat, Chem. Commun. 2014,
0, 14033–14036.
2
[
5
[
[
11] W. Eschweiler, Ber. Dtsch. Chem. Ges. 1905, 38, 880–882.
12] S. Burling, M. K. Whittlesey, J. M. J. Williams, Adv. Synth. Catal. 2005, 347,
591–594.
[
[
13] Y. N. C. Chan, J. A. Osborn, J. Am. Chem. Soc. 1990, 112, 9400–9401.
14] M. Albrecht, R. H. Crabtree, J. Mata, E. Peris, Chem. Commun. 2002, 32–
[24] T. J. Geldbach, P. J. Dyson, J. Am. Chem. Soc. 2004, 126, 8114–8115.
3
3.
15] L. E. Heim, S. Vallazza, D. van der Waals, M. H. G. Prechtl, Green Chem.
016, 18, 1469–1474.
[
Received: June 19, 2016
2
Published online on && &&, 0000
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COMMUNICATIONS
D. van der Waals, L. E. Heim, C. Gedig,
F. Herbrik, S. Vallazza, M. H. G. Prechtl*
Paraformaldehyde can do it easily:
Methylated molecules are highly impor-
tant for a variety of applications. Exist-
ing routes for their formation result in
the production of large amounts of
waste or require high reaction tempera-
tures. To solve this, a simple methylation
of aliphatic amines with paraformalde-
hyde in a biphasic reaction consisting of
water and organic solvent is presented.
The ruthenium catalyst is immobilized
in the aqueous phase and suitable for
recycling.
&& – &&
Ruthenium-Catalyzed Methylation of
Amines with Paraformaldehyde in
Water under Mild Conditions
&
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