A solvent-free and formalin-free Eschweiler-Clarke methylation for amines

Article abstract of DOI:10.1081/SCC-120002131

Primary and secondary amines are N-methylated by a mixture of paraformaldehyde and oxalic acid dihydrate in good to excellent yields. The reaction proceeds without involvement of organic solvents and toxic formalin. Reaction temperatures of 100°C are required for the decomposition of oxalic acid into the intermediate formic acid which acts as the actual reductant. The reaction conditions have been optimized, and the mechanism has been elucidated by means of deuteration experiments.

Full text of DOI:10.1081/SCC-120002131

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A SOLVENT-FREE AND FORMALIN-FREE ESCHWEILER-
CLARKE METHYLATION FOR AMINES
Thomas Rosenau a , Antje Potthast a , Jürgen Röhrling a , Andreas Hofinger a , Herbert
Sixta b & Paul Kosma a
a Institute of Chemistry, Christian-Doppler-Laboratory, University of Agricultural
Sciences, Muthgasse 18, A – 1190, Vienna, Austria
b R&D Lenzing AG, A – 4860, Lenzing, Austria
Published online: 16 Aug 2006.
To cite this article: Thomas Rosenau , Antje Potthast , Jürgen Röhrling , Andreas Hofinger , Herbert Sixta & Paul Kosma
(2002) A SOLVENT-FREE AND FORMALIN-FREE ESCHWEILER-CLARKE METHYLATION FOR AMINES, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:3, 457-466
To link to this article: http://dx.doi.org/10.1081/SCC-120002131
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SYNTHETIC COMMUNICATIONS, 32(3), 457–465 (2002)
A SOLVENT-FREE AND
FORMALIN-FREE ESCHWEILER-CLARKE
METHYLATION FOR AMINES
Thomas Rosenau,1 Antje Potthast,1 Jurgen Rohrling,1
Andreas Hofinger,1 Herbert Sixta,2 and Paul Kosma1,
*
1Institute of Chemistry, Christian-Doppler-Laboratory,
University of Agricultural Sciences, Vienna,
Muthgasse 18, A – 1190 Vienna, Austria
2R&D Lenzing AG, A – 4860 Lenzing, Austria
ABSTRACT
Primary and secondary amines are N-methylated by a mixture
of paraformaldehyde and oxalic acid dihydrate in good to
excellent yields. The reaction proceeds without involvement
of organic solvents and toxic formalin. Reaction temperatures
of 100ꢀC are required for the decomposition of oxalic acid
into the intermediate formic acid which acts as the actual
reductant. The reaction conditions have been optimized, and
the mechanism has been elucidated by means of deuteration
experiments.
*Corresponding author. Fax: þ 43 1 36006 6059; E-mail: pkosma@edv2.boku.ac.at
457
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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ROSENAU ET AL.
INTRODUCTION
N-Methylation of nucleophilic nitrogen in amines is a common
procedure in both lab-scale and bulk-scale organic synthesis. The use
of alkylating agents, such as methyl iodide or methyl tosylate, has
often the disadvantage of competing quaternization of the amine, so that
the Eschweiler-Clarke methylation procedure1,2 is applied instead. This
approach, in principle a variant of the well-known Leuckart-Wallach reac-
tion,3,4 uses aqueous formaldehyde solution (formalin) together with con-
centrated formic acid. The N-methylation is effected in two steps: formation
of N-(methylene)iminium cation intermediates via the N-hydroxymethyl
derivatives, and subsequent reduction by formic acid, which is oxidized to
carbon dioxide in turn.
Practical application of the Eschweiler-Clarke methylation follows a
well-established protocol that ensures its wide applicability. In this paper, a
N-methylation approach is presented, which differs from the conventional
practice and includes some distinct improvements over the existing method-
ology in terms of simplicity of the work-up and use of hazardous chemicals:
The use of toxic formaldehyde and organic solvents is avoided, and rather
time-consuming and tedious purification steps, such as column chromato-
graphy purification or steam distillation, which were hitherto required in
most cases, are not required.
RESULTS AND DISCUSSION
During our investigations on deoxygenative demethylations of
N-methylmorpholine-N-oxide (1),5 we observed that N-methylmorpholine
(2) was found in addition to the expected products morpholine (3) and
formaldehyde (4), if traces of oxalic acid (5) were present. Increasing the
amount of oxalic acid in the reaction mixture shifted the product distri-
bution towards higher yields of N-methylmorpholine. This was evidently
due to a reduction of intermediate N-(methylene)morpholinium cations
(6), so that the formation mechanism resembled a Leuckart-Wallach reac-
tion. This result was intriguing insofar as oxalic acid is well-known as a
reductant, but not as a cryptobase or hydride transfer reagent6 as needed for
these reductions to proceed.
Further experiments revealed that oxalic acid is indeed able to act as a
reductant in mixtures of primary amines or secondary amines and formalin,
albeit at elevated temperatures around 100ꢀC. The resulting N-methyl-
amines or N,N-dimethylamines, respectively, were obtained in rather low
yields below 10%, however. The use of solid paraformaldehyde (4a) instead

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ESCHWEILER-CLARKE METHYLATION FOR AMINES
459
of formalin provided a distinct improvement. The yields were significantly
increased, so that further optimization towards synthetic usability seemed to
be justified.
Finally, a clean methylation of secondary amines in yields above 90%
was achieved with an equimolar ratio of secondary amine and paraform-
aldehyde along with the fivefold molar amount of oxalic acid dihydrate (5a)
within one hour. The same good result was obtained for the bismethylation
of primary amines, now employing amine, 4a and 5a in the molar ratio
1 : 2 : 10. Carried out at 100–120ꢀC, the reaction is a solvent-free process
that proceeds in the molten state. The formaldehyde required is generated
in situ from paraformaldehyde by thermal or acid-catalyzed decomposition.
The primary product obtained is the corresponding ammonium oxa-
late. The free base can be conveniently obtained by treatment of the product
mixture with aqueous calcium hydroxide followed by extraction, or by
treatment with a suspension of calcium oxide in ethyl acetate or ethanol.
One advantage of the presented N-methylation procedure is the purity of the
amine obtained which is indicative of an almost complete absence of side
reactions. No quaternization of the amines was observed.
For optimization of the reaction conditions the system morpholine (3)/N-
methylmorpholine (2) was used. In preliminary experiments it was established
that an equimolar ratio between amine and paraformaldehyde (4a) was required
to avoid side reactions. Already a small excess of 10% 4a caused the formation
of a complex product mixture with severe discoloration of the reaction mixture

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ROSENAU ET AL.
due to condensation processes. The molar ratio of amine and 4a was conse-
quently kept constant at 1/1 throughout the experiments.
The stoichiometric amount of oxalic acid (5) employed proved to be a
crucial issue in terms of conversion of the starting material and purity of the
methylated product. At a ratio below 1, relative to the amine 3 and para-
formaldehyde (4a), mainly unreacted starting amine besides small amounts
of the methylated amine were found. Formation of byproducts was not
observed. At increasing ratios up to 5, the product yield increased accord-
ingly up to about 80%. Interestingly, small amounts (<10%) of N-formyl-
morpholine (7) were found, traces of several unidentified reaction products,
in sum less than 3%, were also detected. The highest yield of byproduct 7
was obtained at a molar ratio 3/4a/5 ¼ 1/1/3. The occurrence of such for-
mylated compounds is a strong indication of the intermediate occurrence of
formic acid from the decomposition of oxalic acid. This is in complete
agreement with experimental and theoretical studies on the thermal decom-
position of oxalic acid.7,8
Experimental studies have firmly established that the major decompo-
sition products of pure oxalic acid over the temperature range 400–430 K
are equimolar quantities of formic acid and carbon dioxide7 if other reaction
routes, such as metal ion catalysis, catalysis by strong acids or decomposi-
tion at the walls of the reaction vessel, which lead to formation of equimolar
amounts of CO2, CO and water, can be excluded. High-level quantum
mechanical calculations8 indicate that this reaction is a bimolecular process:
in a first step oxalic acid fragments into carbon dioxide and dihydroxy-
carbene. In the rate determining step dihydroxycarbene reacts with oxalic
acid or water to be rearranged to formic acid. The unimolecular channel to
produce CO2, CO and water becomes more prominent only with increasing
temperature. At higher molar ratios, above 5, formation of both 7 and trace
byproducts was completely suppressed, but up to an eightfold excess of 5
conversion of 3 to the product was incomplete. A ratio of 1/1/10 reliably
allowed for a complete consumption of starting amine and neat N-methyla-
tion in quantitative or nearly-quantitative yields.
As oxalic acid (5) does not solely act as the reductant, but also as the
hydrogen donor in the system, oxalic acid dihydrate (5a), possessing hydrate
water as an additional proton source, was employed instead. With 5a as the
reductant, the amount of oxalic acid required could be reduced to 50 percent
without impairing yield or product purity. Hence, the optimum molar ratio
amine/paraformaldehyde (4a)/oxalic acid dihydrate (5a) employed was
1/1/5. This starting material composition was used throughout the methyla-
tion experiments on different amines and for all further mechanistic studies.
The reactions carried out and the corresponding conditions applied are
summarized in Table 1.

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461
Both oxalic acid (dihydrate) and paraformaldehyde are required to
cause N-methylation of the amines, only one single component shows no
effect. Paraformaldehyde proved to be inert towards the amine under the
applied reaction conditions. However, upon prolonged reaction times a
Table 1. Products and Reaction Conditions
Starting
Amine
Product Amine
(% Yield)
Ratio
Amine/4a/5
3
3
3
2 (8)a
1/2/1
1/1.1/1
1/1/0.2
1/1/0.5
1/1/1
1/1/2
1/1/3
1/1/4
2 (19)b
2 (12)
3
3
3
3
2 (18)
2 (22)
2 (49), 7 (5)
2 (67), 7 (9)
2 (76), 7 (7)
2 (81), 7 (2)
2 (80)
3
3
3
1/1/5
1/1/6
3
3
3
2 (97)
2 (quantitative)
2 (98)
1/1/8
1/1/10
1/1/4 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
1/1/5 (5a used)
3
3
3
3
2 (quantitative)
2 (20)c
2 (58)d
2a (98)e
2b (97)f
2g (0)
2h (2)
2i (26)
8 (93)
9 (quantitative)
10 (96)
11 (84)
3
3
3
3
2-Aminoethanol
Aniline
Ethylene diamine
HNMe2*HCl
aDiscoloration, complex mixture.
bDiscoloration, byproducts.
cReaction temperature 60ꢀC.
dReaction temperature 80ꢀC.
eDeuterated oxalic acid dihydrate ((COOD)2*2D2O) was used.
fDeuterated paraformaldehyde ((CD2O)n) was used.
gOxalic acid diethylester.
hOxalic acid diethylester þ2H2O.
iOxalic acid diethylester þ2H2O, morpholine hydrochloride.

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ROSENAU ET AL.
gradually increasing formation of chromophoric condensation products was
observed. Oxalic acid and amine produced the corresponding oxalate with-
out further reactions.
By addition of a-tocopherol or g-tocopherol, respectively, to the reac-
tion mixture it was shown that the formation of the N-methylated products
does not proceed according to a free radical process. Typical dimeric coup-
ling products of the tocopherols, which are a sensitive indicator of homo-
lytic processes,9,10 were not observed. The absence of those coupling
products in the reaction mixture allowed to reliably rule out the occurrence
of homolytic reactions during the N-methylation.
To establish the reaction mechanism, cross deuteration experiments
were employed. With deuterated oxalic acid dihydrate (5a-D) and para-
formaldehyde (4a), neat N-(monodeuteromethyl)morpholine (2a) was
obtained. Using perdeuterated paraformaldehyde (4a-D) and 5a, isotopi-
cally pure N-(dideuteromethyl)morpholine (2b) was produced, a 1/1 mixture
of 4a and 4a-D together with 5a afforded a 1/1 mixture of 2 and 2b.
Interestingly, the system oxalic acid dihydrate/paraformaldehyde does not
cause proton exchange at the methylene positions of HCHO, and can thus
be used for selective monodeutero-, bisdeutero-, or trideuteromethylation.
This constitutes an interesting synthetic application of the novel reaction
system, since in the system formic acid/formalin, conventionally used in
Eschweiler-Clarke procedures, the isotopic integrity of HCHO is impaired,
so that selective monodeuteromethylation or bisdeuteromethylation with
this system was hitherto difficult.
The labeling experiments demonstrated that the N-methylation reac-
tion proceeds via transfer of hydrogen to an intermediate which is
formed by the reaction between amine and formaldehyde, probably the
N-(hydroxymethyl)amine which is subsequently dehydrated in a proton-
catalyzed reaction to the corresponding N-(methylene)iminium derivative
(carbonium-iminium ion). The hydrogen transfer to this intermediate
occurs dieither directly as hydride, or in a sequence of a proton and two
electrons.

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ESCHWEILER-CLARKE METHYLATION FOR AMINES
463
With diethyl oxalate being used instead of oxalic acid dihydrate, no
reaction was observed. The same result was obtained with a mixture of
diethyl oxalate and two equivalents of water. This outcome proves the
role of oxalic acid dihydrate in the reaction system as both acidic catalyst
and hydrogen donor. With diethyl oxalate instead of 5a and amine hydro-
chloride instead of the free base, the methylated product was produced at
rather low yield, indicating that the ester had been partly hydrolyzed to
oxalic acid which acted as the reductant in turn.
EXPERIMENTAL
1H NMR spectra were recorded at 300 MHz, 13C NMR spectra at
75.47 MHz, with CDCl3 as the solvent and TMS as the internal standard
for amines, and D2O as the solvent with DSS as the internal standard for
aminium hydrochlorides. 13C peaks were assigned by means of HMQC and
HMBC spectra. Chemical shift values are given in ppm. Chemicals were
obtained from commercial sources or synthesized according to standard
procedures. Even though the N-methylamines obtained are standard sub-
stances, their NMR data are listed in the following since literature
values11,12 are inconsistent and difficult to compare.
General Procedure for the Methylation of
Primary or Secondary Amines
A flask was charged with primary amine (10 mmol), paraformaldehyde
(4a, 20 mmol) and oxalic acid dihydrate (5a, 0.1 mol) and briefly flushed
with nitrogen. In the case of secondary amines, 10 mmol of 4a and
50 mmol of 5a were used. For amines with multiple amino functions,
10 mmol of 4a and 50 mmol of 5a were applied per methyl group to be
introduced. The vessel was closed and heated to 100ꢀC for 1 h, and to
120ꢀC for 10 min. The reaction mixture was cooled to room temperature.
The white, crystalline mass obtained was crushed, and calcium oxide
(0.1 mol) suspended in 50 ml of ethanol was added. The mixture was stirred
vigorously for 30 min, solids were removed by filtration, and the solvent was
removed in vacuo to produce the pure amine.
For volatile amines, the crystalline reaction product was crushed and
dissolved in water (100 ml). The solution was adjusted to a pH of 10 by 10%
aqueous sodium hydroxide and twice extracted with ethyl acetate (10 ml).
The combined organic phases were dried over Na2SO4, the desiccant was
removed, and a 2 Msolution of hydrogen chloride in ethyl ether (8 ml) was

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ROSENAU ET AL.
added. The resulting precipitate, the corresponding aminium hydrochloride,
was separated by filtration, washed with ethyl acetate (5 ml) and liberated
from residual solvent in vacuo.
N-Methylmorpholine (2). M ¼ 101.14 g/mol, yield: 1.02 g (100%).
1H NM R:d 2.27 (s, 3H, N-CH3), 2.39 (t, 4H, N-CH2), 3.70 (t, 4H, O-CH2).
N-(Monodeuteromethyl)morpholine (2a). M ¼ 102.15 g/mol, yield:
1
1.00 g (98%). H NM R (D O): d 2.90 (t, 1H, N-CDH2), 3.21 (dt, 2H), 3.49
2
(dd, 2H), 3.82 (dt, 2H), 4.12 (dd, 2H). 13C NM R: d 43.6 (t, N-CDH2,
J ¼ 21.9 Hz), 53.6 (N-CH2), 64.3 (O-CH2).
N-(Bisdeuteromethyl)morpholine (2b). M ¼ 103.16 g/mol, yield: 1.00 g
1
(97%). H NM R (D O): d 2.92 (t, 1H, N-CD2H), 3.20 (dt, 2H), 3.49 (dd,
2
2H), 3.80 (dt, 2H), 4.12 (dd, 2H). 13C NM R: d 43.6 (pentett, N-CD2H,
J ¼ 21.9 Hz), 54.0 (N-CH2), 64.7 (O-CH2).
2-(Dimethylamino)-ethanol (8). M ¼ 89.13 g/mol, yield: 0.83 g (93%).
1H NM R:d 2.27 (s, 6H, N-(CH3)2), 2.46 (t, 2H, J ¼ 5.4 Hz, N-CH2), 3.61 (t,
2H, J ¼ 5.4 Hz, O-CH2). 13C NM R: d 45.6 (N-(CH3)2), 58.5 (N-CH2), 61.2
(O-CH2).
N,N-Dimethylaniline (9). M ¼ 121.18 g/mol, yield: 1.22 g (100%).
1H NM R: d 2.93 (s, 6H, N-(CH3)2), 6.63 (m, 3H, ArCH), 7.24 (m, 2H,
ArCH). 13C NM R: d 41.0 (N-CH3), 113.1 (C2, C6), 117.1 (C4), 129.5 (C3,
C5), 151.1 (C1).
N,N,N0,N0-Tetramethylethylene diamine (10). M ¼ 116.20 g/mol, yield:
1
1.11 g (96%). H NM R: d 2.18 (s, 12H, N-(CH3)2), 2.36 (s, 4H, N-CH2).
13C NM R: d 41.2 (N-(CH3)2), 57.7 (N-CH2).
Trimethylamine hydrochloride (11). M ¼ 95.57 g/mol, yield: 0.80 g
1
(84%). H NM R (D O): d 2.88 (s, 9H, N-(CH3)3). 13C NM R: d 42.4.
2
CONCLUSION
A mixture of paraformaldehyde and oxalic acid dihydrate in the molar
ratio 1/5 can be used for neat N-methylation of primary or secondary
amines, paraformaldehyde and amine must be employed in equimolar
ratios. As the reaction proceeds in the molten state, reaction temperatures
of 100–120ꢀC must be applied. No solvents are required, the toxic
formalin and concentrated formic acid, as used in the conventional
Eschweiler-Clarke methylation, are avoided. The methylated amines
are obtained in excellent to quantitative yields, no quaternization of
the amines is observed. Due to the elevated reaction temperatures necessary
and the acidity of the reaction medium, the procedure is not apt
for thermally labile or acid-sensitive amines. With either deuterated

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ESCHWEILER-CLARKE METHYLATION FOR AMINES
465
paraformaldehyde or deuterated oxalic acid a selective N-bisdeutero-
methylation, respectively N-monodeuteromethylation, of amines is possible
which could not be accomplished by the traditional Eschweiler-Clarke
procedures.
ACKNOWLEDGMENT
The authors are grateful to the Christian-Doppler-Forschungsge-
sellschaft, Vienna, Austria, and to Lenzing AG, Lenzing, Austria, for
financial support.
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Received in the USA March 19, 2001

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