Microwave-promoted mono-N-alkylation of aromatic amines in water: A new efficient and green method for an old and problematic reaction

Article abstract of DOI:10.1039/b900750d

A greener improvement to direct mono-N-alkylation of aromatic amines by alkyl halides was achieved using microwave irradiation in water without any catalyst.

Full text of DOI:10.1039/b900750d

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www.rsc.org/greenchem | Green Chemistry
Microwave-promoted mono-N-alkylation of aromatic amines in water:
a new efficient and green method for an old and problematic reaction†
Giovanni Marzaro, Adriano Guiotto and Adriana Chilin*
Received 13th January 2009, Accepted 31st March 2009
First published as an Advance Article on the web 6th April 2009
DOI: 10.1039/b900750d
Table 1 Effects of time and temperature on N-benzylation of p-
A greener improvement to direct mono-N-alkylation of aro-
matic amines by alkyl halides was achieved using microwave
irradiation in water without any catalyst.
toluidinea
Selective synthesis of N-alkylanilines plays a crucial role in
organic chemistry due to the relevance of this type of amines
as raw materials, intermediates or final products in nearly every
field of the chemical industry.1 Even though many synthetic
methods were researched and reported in order to obtain mono-
or dialkylarylamines, the preparation of N-monoalkylated
derivatives via direct N-alkylation by alkyl halides is one of the
most frequently used procedures.2
Entry
Time/min
Temp/◦C
Yield (%)b
1
2
3
4
5
6
10
10
10
20
30
20
110
130
150
150
150
150
0
5
60
75
75
82c
Many recent efforts were made to make this synthesis eco-
friendlier: in this way, usual but hazardous volatile organic
solvents were replaced with water, using mild basic condi-
tions to reduce the amount of catalysts,3 and/or conventional
heating was substituted by microwave irradiation.4,5 All the
aqueous-mediated methods were efficient and successful but
they all needed catalysts and also long reaction times, if MAOS
(microwave-assisted organic synthesis) was not used. Moreover
the troublesome problem of polyalkylation was only partially
solved, working with a near equimolar ratio between arylamine
and alkyl halide.3
To make the direct N-alkylation of aromatic amines fully
green, possibly obtaining monoalkylation, we studied the pos-
sibility of carrying out the reaction with alkyl halide not only
using water as solvent, but moreover avoiding the use of any
catalyst, taking advantage of the MAOS technique.
As a basis of this study, a standard reaction between
p-toluidine6 and benzyl chloride was carried out in water
under microwave irradiation at various times and temperatures
(Table 1), using a monomode microwave reactor.
The alkylating reagent was initially added in a 1 : 1 ratio
of substrate/halide. The best yield of N-benzyl-p-toluidine
(75%) was achieved at 150 ◦C in 20 min (Table 1; entry 4):
this temperature lies in the lower part of the so-called near-
critical region of water7 and performing the reaction under
“superheated conditions” takes advantage of the favorable
changes of chemical and physical properties of water at high
temperatures and pressures.8
a Reaction conditions: p-toluidine (3 mmol) and benzyl chloride
(3 mmol) in water (1 ml) were irradiated in a monomode microwave
reactor. b Yield of isolated product. c Benzyl chloride: 6 mmol.
Different molar ratios of substrate/halide were also tested,
finding that doubling the halide concentration increased the
yield of monoalkylated toluidine up to 82% (Table 1; entry 6).
It is interesting to note that even with a three-fold excess of the
halide, only mono-N-alkylation occurred, without trace of the
dibenzylated product. In fact, the reaction mixture contained
only monoalkyltoluidine and unreacted starting compound.
On the contrary, the recently reported method of aqueous-
mediated alkylation with mild base needed a 1 : 1.1 molar ratio
to achieve mono-N-alkylation, but with a long reaction time and
with 10% of dialkylated product.4
Parallel experiments were also performed under thermal
heating. The reaction between p-toluidine and benzyl chloride
(1 : 2 molar ratio) in water was carried out in autoclave at
◦
150 C for 40 min,9 affording a complex reaction mixture
containing starting toluidine as the major product, mono-
and dialkyltoluidine as minor products, together with many
unidentified products. This finding indicated that microwave
irradiation provided higher conversion and selectivity compared
to conventional heating conditions.
We experimented with the same reaction also in the presence
of bases (Table 2; entries 1–4), with the catalysts frequently used
in similar procedures5,10 (Table 2; entries 5–6), and with organic
solvents (Table 2; entries 7–11).
Department of Pharmaceutical Sciences, University of Padova, Via
Marzolo 5, I-35131, Padova, Italy. E-mail: adriana.chilin@unipd.it;
Fax: +39 0498275366; Tel: +39 0498275349
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all compounds. See DOI:
10.1039/b900750d
In all the aqueous mediated conditions the yields were lower
than that of the standard procedure, thus proving that the
presence of bases and/or catalysts negatively affected the course
and the yield of the reaction. Moreover, if organic solvents were
used instead of water, the reaction didn’t occur in the absence of
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Table 2 Effects of bases, catalysts and solvents on the N-benzylation
of p-toluidinea
Table 3 N-Alkylation of p-toluidine with different alkyl halidesa
Entry
Base
Catalyst
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
KOH
TEA
K2CO3
NaHCO3
—
—
—
—
—
—
—
—
—
—
—
KI
CuI
—
—
—
—
KI
H2O
H2O
H2O
H2O
H2O
H2O
DMF
DMSO
Dioxane
MeCN
MeCN
40
35
45
48
40
0
0
0
0
Entry
1
Alkyl halide
Product
Yield (%)b
85
2
3
88
73
10
11
0
10c
a Reaction conditions: p-toluidine (3 mmol) and benzyl chloride
(6 mmol) in water (1 ml) were irradiated at 150 ◦C for 20 min. b Yield of
isolated product. c Dialkylated compound was the major product.
4
5
6
7
68
66
90
85
bases and/or catalysts, and anyway the yields are very poor and
dialkylation occurred preferentially.
Now that optimised conditions had been established, the
reaction was attempted with a range of different alkyl halides.
With all halides, the alkylation was achieved with high yield and
selectivity (Table 3; entries 1–6), without trace of dialkylated
product11 and with no difference between bromo or iodoalkane
(Table 3; entries 1–2).
Only with a,w-dibromoalkanes selective mono-alkylation did
not occur. As already reported, although in slightly differ-
ent reaction conditions,12 with 1,4-dibromobutane a cyclo-
condensation took place via double N-alkylation of starting
aniline to obtain N-arylpyrrolidine (Table 3; entry 7).
With 1,2-dibromoethane intramolecular cyclization didn’t
occur, but two different alkylation products were obtained
(Table 3; entry 8): N,N¢-di-p-tolylethylenediamine, correspond-
ing to mono-alkylation for each bromine of the halide, and N,N¢-
di-p-tolylpiperazine, corresponding to a particular dialkylation
involving a second molecule of the halide. Even increasing
the excess of halide up to ten fold, the final yields and
the ratio between the two products remained practically the
same, together with the formation of by-products (detected by
HRMS).
8
20
20
a Reaction conditions: p-toluidine (3 mmol) and alkyl halide (6 mmol)
in water (1 ml) were irradiated at 150 ◦C for 20 min. b Yield of isolated
product.
Then the reaction was tested with different starting arylamines
and 2-chloro-N,N-dimethylethylamine hydrochloride as alkylat-
ing agent.
Activated anilines were well derivatized, as in the case of
o-anisidine (Table 4, entry 4), but if a strong deactivating group
was also present, as in the case of 2-methoxy-4-nitroaniline, the
yield was considerably reduced (Table 4, entry 5).
The N-alkylation of electron-poor anilines took place with
variable yields, from a low yield for 4-nitroaniline to a moderate
yield for 4-aminobenzoic acid (Table 4, entries 6–7), up to a
satisfactory yield for p-chloroaniline (Table 4, entry 8). Anyway
the reaction mixture contained only monoalkylarylamine and
unreacted starting product.
We chose this alkyl halide among the tested ones for its
interesting features. It allows easy functionalization of aro-
matic amines with a dialkylaminoalkyl chain, which is one
of the most common substituents in many pharmaceutical
products,13 and is usually obtained by substitution of aryl
halides and not by direct alkylation of arylamines.14 More-
over, it must be used as the hydrochloride to avoid aziri-
dinium formation and the hydrochloride is water soluble, so
optimal for our reaction conditions, but, on the contrary,
not useful with conventional organic solvents, as commonly
required.
Naphthylamines were also monoalkylated with very good
yields (Table 4, entries 9–10).
The results are summarised in Tables 4 and 5.
Aniline and toluidines were easily alkylated in good yields
(Table 4, entries 1–3).
Heteroaryl amines, such as 2-aminopyridine and 1-amino-
isoquinoline, didn’t react in this condition, probably owing to
their deactivation properties (Table 4, entries 11–12).
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Table 4 N-Alkylation of different arylaminesa
Table 5 N-Alkylation of hydroxyanilines and phenylenediaminesa
Entry
1
Alkyl halide
Product
Yield (%)b
45
Entry Arylamine
1
Yield (%)b Entry Arylamine
Yield (%)b
35
2
3
n.d.c
32
89
7
2
74
8
67
3
4
82
72
9
78
75
4
n.d.c
10
a Reaction conditions: arylamine (3 mmol) and 2-chloro-N,N -
dimethylethylamine hydrochloride (6 mmol) in water (1 ml) were
irradiated at 150 ◦C for 20 min. b Yield of isolated product. c Yield not
determined: structures identified by HRMS analysis.
5
6
20
10
11
12
—
—
Notes and references
1 A. S. Travis, in The Chemistry of Anilines, ed. Z. Rappoport, Wiley
& Sons, Chichester, 2007, 715–782; S. A. Lawrence, in Amines:
Synthesis, Properties and Applications, Cambridge University Press,
Cambridge, 2004.
2 R. N. Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57,
7785–7811; S. Narayanan and K. Deshpande, Appl. Catal., A, 2000,
199, 1–31; C. A. Olsen, H. Franzyk and J. W. Jaroszewski, Synthesis,
2005, 2631–2653.
a Reaction conditions: arylamine (3 mmol) and 2-chloro-N,N -
dimethylethylamine hydrochloride (6 mmol) in water (1 ml) were
irradiated at 150 ◦C for 20 min. b Yield of isolated product.
3 Y. Ju and R. S. Varma, Green Chem., 2004, 6, 219–221.
4 C. B. Singh, V. Kavala, A. K. Samal and B. K. Patel, Eur. J. Org.
Chem., 2007, 1369–1377.
5 J. L. Romera, J. M. Cid and A. A. Trabanco, Tetrahedron Lett., 2004,
45, 8797–8800.
6 Toluidine was used instead of aniline for handling and work-up
reasons, while reactivity remains almost the same for both the
derivatives. Aniline was also tested with benzyl bromide obtaining
the same results (see ESI)†.
7 D. Dallinger and O. Kappe, Chem. Rev., 2007, 107, 2563–2591.
8 J. An, L. Bagnell, T. Cablewski, C. R. Strauss and R. W. Trainor,
J. Org. Chem., 1997, 62, 2505–2511.
The reaction with hydroxyanilines was chemoselective achiev-
ing only the mono-N-alkyl derivatives (Table 5, entry 1–2), but
in the case of p-hydroxyaniline the product was easily oxidized to
the corresponding quinone (Table 5, entry 2). In a similar way,
with phenylenediamines only one amino group preferentially
reacted, although with moderate yield (Table 5, entry 3), and
with p-phenylenediamines only the corresponding quinoneimine
was formed (Table 5, entry 4).
In conclusion, we have set up a green way to mono-N-
alkylated aromatic amines under microwave irradiation. The
reaction was carried out in water at 150 ◦C with twice the
amount of the appropriate alkyl halide and without any catalyst.
This synthetic procedure works very well with a variety of
arylamines and in a satisfactory way also with deactivated
amines; it allows only mono-N-alkylated products to be ob-
tained and it is chemoselective in the presence of more than
one functional group. The reaction is efficient, rapid and clean.
Indeed, the described method could be a useful synthetic way
to achieve alkylarylamines avoiding the use of organic solvents
and catalysts or additives.
9 A stainless steel commercial miniautoclave was used: owing to
its thermal inertia, the reaction time was longer than that of the
microwave reaction.
10 I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004, 248,
2337–2364.
11 The reaction mixture contained only monoalkyltoluidine and unre-
acted starting material.
12 Y. Ju and R. S. Varma, Org. Lett., 2005, 7, 2409–2411.
13 Foye’s Principles of Medicinal Chemistry, ed. T. L. Lemke and
D. A. Williams, Lippincott Williams &, Wilkins, Philadelphia,
6th edn, 2007.
14 J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37, 2046–2067; S. F.
Nielsen, M. Larsen, T. Boesen, K. Schønning and H. Kromann,
J. Med. Chem., 2005, 48, 2667–2677.
776 | Green Chem., 2009, 11, 774–776
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The Royal Society of Chemistry 2009
©