N,N-dimethylation of nitro-eugenol to its new 4-allyl-2-(dimethylamino)-6-methoxyphenol via Eschweiler-Clarke methylation reaction

Article abstract of DOI:10.14233/ajchem.2017.20339

Eugenol is a main constituent of essential oil and can be extracted and isolated from clove (Syzygium aromaticum). Eugenol has widely biological activities such as antiseptic and anesthetic. Eugenol can be used as a fine chemical for further synthesis of new or novel compounds. The main aim of this research was to develop new or novel compounds with potential biological activity such as 4-allyl-2-(dimethylamino)-6-methoxyphenol from eugenol (1). Derivatization of eugenol to its nitro derivative (2) can be achieved by treated with ammonium nitrate and potassium bisulphate. One-pot synthesis method via the Eschweiler-Clarke methylation of nitroeugenol using formaldehyde, formic acid, Zn catalyst, gave the N,N-dimethylation of nitro moiety. The result was then analyzed by GC-MS and NMR. The GC-MS analyses showed peak with m/z of 207 (59.51 %) and consistent with the molecular formula C₁₂H₁₇O₂N. The ¹ H NMR was in accordance with the proposed structure which showed 17 protons corresponded to 4-allyl-2-(dimethylamino)-6-methoxyphenol (3).

Full text of DOI:10.14233/ajchem.2017.20339

Asian Journal of Chemistry; Vol. 29, No. 4 (2017), 867-869
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20339
N,N-Dimethylation of Nitro-eugenol to its New 4-Allyl-2-(dimethylamino)-6-methoxyphenol
via Eschweiler–Clarke Methylation Reaction
*
I.M. SUDARMA , A.R. SATRIANI and M.G. DARMAYANTI
Department of Chemistry, Faculty of Mathematic and Natural Science, University of Mataram, Jl. Majapahit 62 Mataram 83125, Indonesia
*Corresponding author: Fax: +62 370 648508; Tel: +62 370 646506; E-mail: sud_arma@yahoo.co.id
Received: 11 October 2016; Accepted: 27 December 2016; Published online: 31 January 2017;
AJC-18261
Eugenol is a main constituent of essential oil and can be extracted and isolated from clove (Syzygium aromaticum). Eugenol has widely
biological activities such as antiseptic and anesthetic. Eugenol can be used as a fine chemical for further synthesis of new or novel
compounds. The main aim of this research was to develop new or novel compounds with potential biological activity such as 4-allyl-2-
(
dimethylamino)-6-methoxyphenol from eugenol (1). Derivatization of eugenol to its nitro derivative (2) can be achieved by treated
with ammonium nitrate and potassium bisulphate. One-pot synthesis method via the Eschweiler–Clarke methylation of nitroeugenol
using formaldehyde, formic acid, Zn catalyst, gave the N,N-dimethylation of nitro moiety. The result was then analyzed by GC-MS and
1
NMR. The GC-MS analyses showed peak with m/z of 207 (59.51 %) and consistent with the molecular formula C12
H
17
O
2
N. The H NMR
was in accordance with the proposed structure which showed 17 protons corresponded to 4-allyl-2-(dimethylamino)-6-methoxyphenol
3).
(
Keywords: Nitro-eugenol, One-pot synthesis, Eschweiler–Clarke methylation, Schiff base.
The Eschweiler–Clarke methylation is a chemical reaction
INTRODUCTION
whereby a primary (or secondary) amine is methylated using
excess formic acid and formaldehyde according to the following
reaction:
It has been reported that eugenol was isolated from clove
Syzygium aromaticum) can be used as a fine chemical for
(
further synthesis of new or novel compounds [1-5]. In conti-
nuation of our work on chemical transformation of eugenol,
method of N,N-dimethylation of nitroeugenol (4-allyl-2-
methoxy-6-nitrophenol) using formaldehyde catalyzed with
zinc powder and formic acid was performed. This synthesis
involved direct reduction of nitro-eugenol compound without
isolating the intermediate of primary amine and make the
synthesis is more efficient compare to the normal synthesis of
amine.
Common methods for preparation of methylated amines
include nucleophilic attack of methylating reagents, for example,
methyl iodide or dimethyl sulfate, or methylation with formalde-
hyde in the presence of a reducing reagent, for example, formic
acid, metal hydrides or hydrogen gas and nitro compounds.
The aromatic nitro compounds could be transformed into dimethyl
amines directly in the presence of a simple iron catalyst without
ligand [6]. The N-methylation of amines and nitro compounds
CH3
HCOOH (Excess)
R
NH2
R N
CH O (Excess)
2
CH3
It is named for the German chemist Wilhelm Eschweiler
1860-1936) and the British chemist Hans Thacher Clarke
1887-1972) [8].
(
(
A facile synthesis of N,N-dimethylanilines from primary
aromatic amines and dimethyl carbonate has been achieved
for the first time in the presence of diphenylammonium triflate.
N,N-dimethylanilines were selectively obtained in high yields
[9]. A series of TiO
2
supported nano-Pd catalysts (Pd/TiO )
2
were prepared and used for the N,N-dimethylation of different
amines and nitro compounds with methanol under UV irradia-
tion at room temperature [10].
EXPERIMENTAL
with CO
2
/H can be realized with up to 97 % yield under rela-
2
tively mild reaction conditions. N-Formylation becomes the
main reaction if the reaction was performed under milder condi-
Unless otherwise stated, all chemical reagents were pur-
chased with the highest commercially available purity (Merck
and Sigma). The materials used were: dried clove buds, distilled
tions or using Pd/ZnZrO as the catalyst [7].
x

868 Sudarma et al.
Asian J. Chem.
water, dichloromethane (DCM), sodium hydroxide, anhydrous
sodium sulphate, n-hexane, acetonitrile, ammonium nitrate,
potassium bisulphate, ethanol, formaldehyde, formic acid, zinc
powder, methanol and silica gel 60 mesh.
with rotary evaporator to obtain the liquor, which then was
tested with TLC. Compounds in liquor were separated by using
column chromatography with eluents as follow: n-hexane 100 %,
n-hexane:dichloromethane (1:1) and dichloromethane 100 %.
Fractions obtained then were identified by TLC. Fractions with
the same spot were combined and evaporated. The result then
tested for purity with TLC.
Synthesis of amine [12]: A mixture of nitroeugenol (0.72
mmol), formaldehyde (0.72 mmol) and Zn powder (7.32
mmol) was dissolved in 25 mL of ethanol. Formic acid (4.5
mmol) was then added to the mixture. Reaction was heated at
General procedure:
Preparation of cloves: Dried clove buds were ground
into fine particles for extraction.
Cloves extraction: Extraction of cloves was done by
using Sudarma et al. method [1].Approximately 250 g of clove
powder were macerated with 1,750 mL dichloromethane and
stored away from light for 2 × 24 h. The result then filtered
and the filtrate was collected. The filtrate was evaporated with
rotary evaporator to obtain the extract.Afterwards, the solvent-
free extract was weighed and tested with thin layer chromato-
graphy (TLC).
6
5 °C for approximately 4.5 h and filtered while hot. Filtrate
was extracted with dichloromethane (3 × 25 mL) and the
organic phases were combined, which then dried with Na SO
2
4
.
Mixture was filtered and evaporated.Afterwards, the obtained
product was analyzed by using GC-MS.
Eugenol isolation: Clove oil (5 g) were dissolved in
dichloromethane (15 mL). The mixture was added with NaOH
RESULTS AND DISCUSSION
(
1.22 g), which had been dissolved with H O (9.15 mL). Mixture
2
Herein, we reported derivatization of eugenol isolated from
clove (Syzygium aromaticum) to its new N,N-dimethylamino
derivative via Eschweiler-Clarke methylation of nitro-eugenol.
Eschweiler-Clarke methylation normally used a primary (or
secondary) amine, aldehyde and formic acid, but in this one
pot synthesis the nitro compound (nitro-eugenol) was used
instead of amine compound and make this method more efficient
because one step reaction was eliminated.
was stirred with magnetic stirrer for 15 min in room tempe-
rature. Two layers were formed where the water phase in the
top layer was separated from the organic phase in the bottom
layer. The water phase that contains eugenol salt was acidified
with concentrated HCl to pH 3. The bottom layer (A) was
then separated from the top layer with separation funnel. The
remaining top layer then extracted with 15 mL dichloro-
methane and the bottom layer (B) was collected and combined
with the previous bottom layer (A). The extraction with dichloro-
methane was done three times. The mixture was washed with
water to neutral pH. The bottom layer (crude eugenol) was
One pot reaction of nitro-eugenol (2) and formaldehyde,
formic acid and zinc catalyst expected to afford Schiff base
(
2b), in fact this compound was not present and fortunately
unexpected of N,N-dimethyl amine derivative or 4-allyl-2-
dimethylamino)-6-methoxyphenol (3) was formed due to
further reaction occurred on Schiff base moiety or imine of
d by formic acid. The formic acid acts as a source of hydride
collected and added with anhydrous Na
2
SO . The crude eugenol
4
(
then filtered with dichloromethane:n-hexane (1:1) mixture and
evaporated with rotary evaporator.
Nitration of eugenol [11]: Eugenol (1.6 g) was dissolved
in acetonitrile (20 mL) and stirred with magnetic stirrer.
2
and reduces the imine to a secondary amine and the second
methylation occurred on secondary amine to form final products
Solution of NH
4
NO
3
(1.4 g) and KHSO (0.64 g) was added to
4
(
3) (Scheme-I).
the mixture. Mixture then refluxed for 5 h and filtered with
filter paper to obtain the filtrate (A). The remaining precipitation
was washed by acetonitrile (20 mL) and filtrate (B) was obtained,
which then combined with (A). Afterwards, filtrate was dried
GC-MS analyses of one pot reaction of nitro-eugenol with
formaldehyde and formic acid gave eugenol (25.02 %),
unreacted nitro-eugenol (5.13 %) and N,N-dimethylamino
derivative (59.51 %) (Fig. 1).
with anhydrous Na
2
SO
4
and filtered. Filtrate was evaporated
HO
Isolation
Clove Oil
MeO
CH2
Eugenol (1)
NH NO /KHSO
4
3
4
CH2
H C
CH3
NO2
3
N
N
CH O, HCOOH HO
HO
CH O, HCOOH
2
2
HO
MeO
Zn
Zn
MeO
CH2
MeO
CH2
CH2
(2)
(
2b)
(3)
Scheme-I: Synthesis of new N,N-dimethylamino derivative (3) from eugenol (1)

Vol. 29, No. 4 (2017)
N,N-Dimethylation of Nitro-eugenol to its New 4-Allyl-2-(dimethylamino)-6-methoxyphenol 869
CH2
N
NH2
NO2
HO
HO
CH O
2
HO
Zn/HCOOH
-
H O
2
MeO
MeO
MeO
(
2b)
(
2a)
(
2)
O
H
H
O
O
_
H C
CH3
H C
CH3
+
3
2
CH3
H
CH2
+
H
O
N
N
HN
N
HO
HO
-
CO2
O
HO
HO
-CO2
MeO
MeO
_
MeO
MeO
(
3)
H
O
(2e)
(2c)
(
2d)
Scheme-II: Formation of 4-allyl-2-(dimethylamino)-6-methoxyphenol (3)
reacted nitro eugenol (3). The occurance of the products was due
to elimination of amino group by acid. This acid could be reacted
with amino group through nucleophilic substitution reaction.
Conclusion
Nitro-eugenol prepared from nitration of eugenol could be
transformed to 4-allyl-2-(dimethylamino)-6-methoxyphenol
via the Eschweiler–Clarke methylation in moderate yield.
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
min
ACKNOWLEDGEMENTS
Fig. 1. GC-MS analysis the reaction of nitro-eugenol with formaldehyde,
formic acid and Zn catalyst
The authors thank Indonesian Ministry of Research,
Technology and Higher Education (Kementerian Riset,Teknologi,
dan Pendidikan Tinggi) for financial support.
The GC-MS analysis showed peak 3 as a major N,N-
dimethylamino derivative which has molecular ion at m/z 207
corresponding to the molecular formula C12
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2
was further reduced to the final product 4-allyl-2-(dimethyl-
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