Rapid and convenient synthesis of N-arylmorpholines under microwave irradiation

Article abstract of DOI:10.1002/jhet.1710

A series of N-arylmorpholines 1a-1n was obtained by cyclocondensation of arylamines and diethylene glycol dimesylate under microwave irradiation in an aqueous potassium carbonate medium. The reaction is rapid and convenient, and a variety of functional groups are tolerated in the process.

Full text of DOI:10.1002/jhet.1710

July 2013
Rapid and Convenient Synthesis of N-Arylmorpholines under
Microwave Irradiation
995
Hong Bo Li,* Wu Liang, Chang Peng Ma, Yong Mao Kai, Lei Li, and Yong Gang Zhang
School of Material Science and Engineering, Southwest University of Science and Technology, Mianyang, Sichuan,
People’s Republic of China
*
E-mail: li-honggg@163.com
Received February 5, 2012
DOI 10.1002/jhet.1710
Published online 2 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
MW
NH2
N
O
Ar
+
o
Ar
MsO
OMs
K CO /H O,100 C
2 3 2
1a ~ 1n
A series of N-arylmorpholines 1a–1n was obtained by cyclocondensation of arylamines and diethylene
glycol dimesylate under microwave irradiation in an aqueous potassium carbonate medium. The reaction
is rapid and convenient, and a variety of functional groups are tolerated in the process.
J. Heterocyclic Chem. 50, 995 (2013).
INTRODUCTION
mildly basic aqueous media (Scheme 1). This method is
attractive for several reasons: (i) it proceeds faster and gives
moderate to good yield; (ii) it does not need any catalyst or
other additives; (iii) it offers experimental simplicity and
does not require an inert atmosphere and anhydrous solvents;
Morpholine derivatives, as a large class of N-heterocycle
compound, have attracted considerable attention owing to
their functionality in pharmaceutical chemistry, material
chemistry, and synthetic organic chemistry [1]. During
the past several decades, much effort has been devoted
to develop an efficient method for the synthesis of
N-arylmorpholines [2–6]. Among the most common way
is by the cross-coupling reaction of morpholine with several
arylating agents such as aryl halides [4], aryl triflates
(iv) it is applicable to various arylamines; at the same time,
water is abundant, cheap, and an environmentally benign
solvent. In recent years, the combination of these two
prominent green chemistry principles, “microwaves” and
“
water”, has become very popular and has received
substantial interest [11].
(
tosylates/mesylates) [5], or arylboronic acids [6]. Although
these methods are highly effective, these reported methods
usually require (1) specially designed ligands or stoichiomet-
ric amounts of catalysts/reagents, (2) anhydrous solvents and
an inert atmosphere and (3) high temperature or long reaction
time. Furthermore, some of them suffer from a relatively
narrow scope of substrates, especially for arylating agents.
Particularly, the use of transition metals leads to generation
of waste and has a number of hazards associated with it [7].
Microwave-assisted organic synthesis is a quickly growing
technology in synthetic organic chemistry. This method can
accelerate a variety of synthetic transformations via time-
saving and energy-saving protocols [8] and has been success-
fully used in the synthesis of heterocyclic compounds [9].
Recently, some studies realized the N-arylmorpholines
through the cross-coupling reaction of morpholine and aryl
halides or arylboronic acids with the microwave-assisted
organic synthesis technique [10]. Although these results
are encouraging, there is much room for improvement.
For example, these methods require ligand-free metal
catalyst, organic solvent and base, or materials unavailable
readily. In this paper, we wish to report the facile preparation
of N-arylmorpholines via the microwave-assisted cyclocon-
desation of arylamines with diethylene glycol dimesylate in
RESULTS AND DISCUSSION
Initially, we found that the N-cyclocondensation of
aniline using diethylene glycol dimesylate could occur in
the presence of K CO in a polar solvent under microwave
2
3
irradiation. To choose the most appropriate medium in this
heterocyclization reaction, we screened typical reaction
parameters including base, solvents, and reaction times
by using aniline (20 mmol) and diethylene glycol dimesylate
(26 mmol) as model substrates, and the results are summa-
rized in Table 1. The reaction did not occur without a base
(entry 1). But the strong inorganic base of NaOH would
accelerate the hydrolysis of dimesylate to result in a
poor yield (28%, entry 2). Other bases, such as Na CO ,
2
3
K PO , Et N, and pyridine (C H N), did not improve
3
4
3
5 5
the yield effectively compared with K CO (entries 4–7).
2
3
Moreover, using of DMF and DMSO as solvent gave
rise to side reactions and afforded low product yields
(entries 8–9). As for the insolubility of K CO in dioxane,
2
3
the reaction in dioxane also afforded low product yield
(32%, entry 10). Therefore, water as a good absorber for
microwave energy should be the best reaction medium
for this reaction. Furthermore, a considerable yield of
©
2013 HeteroCorporation

9
96
H. B. Li, W. Liang, C. P. Ma, Y. M. Kai, L. Li, and Y. G. Zhang
Vol 50
Scheme 1. Microwave-assisted synthesis of N-arylmorpholines.
reaction proceeded readily in the absence of phase-transfer
reagents. Compared with the conventional thermal condi-
tions, the hydrolysis of dimesylate to alcohols was
substantially suppressed, and reactive functional groups
O
MW
2
CO /H O,100 C
NH
2
O
N
Ar
+
MsO
OMs
K
o
Ar
2
3
1
(
carbonyl, ester, and amine) remained unaffected under
these mild reaction conditions. The experimental observa-
tions are consistent with the mechanism proposed in
Scheme 2. As the magnitude of heating by microwaves
depends on the dielectric properties of the molecules,
the greater the polarity of the reacting species, the more
efficient is the absorbance of the microwave energy.
Consequently, acceleration of the reaction by microwaves
has been attributed to a greater stabilization of the charged
intermediates 2 and 3 by the dipole–dipole interaction
with the microwave electric field when compared with
the less polar ground state (arylamine).
8
0% was obtained in 60 min; longer reaction time was unable
to promote the reaction effectively (entries 3 and 11–12).
Using the optimized conditions in hand, we subjected
a series of arylamines to the N-heterocyclization with
diethylene glycol dimesylate to explore the generality and
scope of the process. As shown in Table 2, we were
pleased to find that this method was applicable to a broad
substrate scope on arylamines. The results indicated that
this reaction conditions were sufficiently mild to tolerate
some functional groups in aniline such as carbonyl, ester,
and amine (entries 7–8 and 11), which are easily trans-
formed in the reaction under conventional heating in an
alkaline reaction medium [12]. This feature rendered the
reaction even more practically useful to construct the
N-arylmorpholine moiety without tedious functional group
protection/deprotection procedures. Aniline and p-toluidine
were easily cyclocondensed in good yields (entries 1–2).
Activated anilines were well derivatized (entries 3 and 9–10).
A weak electron-withdrawing substituent of chlorine did
not considerably affect the yield (entries 4–6). But if a strong
deactivating group of nitro or cyano was present, the yield
was rapidly reduced (entries 12–13). a-Naphthylamine was
also converted to the corresponding product with a good
yield (entry 14).
In summary, we have developed a green way to
synthesize N-arylmorpholine under microwave irradiation.
The reaction was carried out in an aqueous potassium
ꢀ
carbonate medium at 100 C with a slight excess of diethy-
lene glycol dimesylate (1.3 equiv) without any phase-transfer
or transition-metal catalyst. Particularly, valuable features of
this method included the short reaction time, high yield and
broad arylamine scope, as well as convenient operation.
Efforts to expand the scope of the method in combination
with application to the synthesis of pharmaceutical molecules
are ongoing in our laboratory.
EXPERIMENTAL
Although the reaction mixture could be regarded as
a multiphase system, as neither reactant was soluble in
the aqueous K CO medium, the microwave-assisted
Melting points were determined on a Yanaco MP-500 micromelt-
ing point apparatus (Yanaco, Kyoto, Japan) and are uncorrected.
IR spectra were recorded on a Nicolet-1705X IR spectrometer
2
3
Table 1
Optimization of the reaction of aniline with diethylene glycol dimesylate.
a
b
Entry
Base
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
—
NaOH
H
H
H
H
H
H
H
2
2
2
2
2
2
2
O
O
O
O
O
O
O
60
60
60
60
60
60
60
60
60
60
40
80
0
28
80
67
72
44
58
63
66
32
72
81
K
2
CO
CO
PO
3
Na
2
3
K
3
4
Et
3
N
C
5
H
5
N
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
DMF
DMSO
Dioxane
10
11
12
H
H
2
O
O
2
a
ꢀ
Reaction conditions: aniline (20 mmol), diethylene glycol dimesylate (26 mmol), base (26 mmol) in solvent (40mL) at 100 C under MW irradiation (200W).
Isolated yield based on aniline.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Microwave-assisted Synthesis of N-Arylmorpholines
997
Table 2
a,b
Microwave-assisted synthesis of N-arylmorpholines.
c
c
Entry
1
Arylamine
Product
Yield (%)
Entry
8
Arylamine
Product
Yield (%)
1a
80
1h
51
d
2
3
4
1b
1c
1d
82
88
65
9
10
11
1i
1j
87
d
86
1k
72
5
1e
75
12
1l
10
13
6
7
1f
77
64
13
14
1m
1n
d
1g
63
a
Reaction conditions: arylamine (20 mmol), diethylene glycol dimesylate (26 mmol), K
2
CO
3
(26 mmol) in water (40 mL) under MW irradiation (200 W) at
ꢀ
1
00 C for 60 min.
b
c
1
The H-NMR spectra of all products are in accord with the literature.
Isolated yield based on arylamine.
d
Unknown compounds.
Scheme 2. Possible reaction pathway.
MsO
O
MsO
H
MsO
OMs
MW
O
H
O
H
O
O
MW
Base
N
Base
N
H
N
Ar
Ar
N
Ar
-HOMs Ar
-HOMs
NH2
Ar
OMs
OMs
2
3
1
1
(
Thermo Nicolet, Madison, WI, USA ). H-NMR spectra were
(XH-MC-1, Beijing Xianghu Science and Technology Development
Co. Ltd., Beijing, China). All of the reagents and solvents were
obtained commercially and used without further purification.
acquired on a Bruker AV-300 MHz spectrometer (Bruker AG, Fael-
landen, Switzerland) in CDCl using Me Si as internal standard.
3
4
Mass spectra were obtained on a Finnigan MAT 4510 spectrometer
Finnigan MAT, San Jose, CA, USA). Elemental analyses were de-
termined on a Carlo Erba-1106 elemental analyzer (Carlo Erba,
Milan, Italy). Reactions were performed in a microwave reactor
General procedure for preparation by microwave
irradiation. A mixture of arylamine (20.0 mmol), diethylene
glycol dimesylate (26.0 mmol), and potassium carbonate
(26.0 mmol) in water (40 mL) was placed into a three-necked
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

9
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H. B. Li, W. Liang, C. P. Ma, Y. M. Kai, L. Li, and Y. G. Zhang
Vol 50
flask in a microwave reactor equipped with a temperature sensor
and a reflux condenser; then, the mixture was stirred and
irradiated for 60 min (200 W) at 100 C. After completion of the
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1
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ꢀ
mp 83–84 C; H-NMR(CDCl ) d 6.72 (d, 1H), 6.54 (d, 1H), 6.34
3
[5] Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc
(
4
dd, 1H), 5.90 (s, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.03 (t, J = 4.8 Hz,
H); IR (KBr) no NH band. MS (m/z): 207(M ). Anal. Calcd for
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C H13NO
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6
.47; N, 6.65.
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ꢀ
1
mp 81–82 C; H-NMR(CDCl ) d 6.77–6.80 (m, 1H), 6.43–6.46
3
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C, 65.29; H, 6.94; N, 6.12.
H
15NO
3
: C, 65.14; H, 6.83; N, 6.33. Found:
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1
H-NMR(CDCl
3
) d 8.23–8.28 (m, 1H), 7.83–7.88 (m, 1H),
7
.41–7.61 (m, 4H), 7.15 (d, 1H), 4.01 (t, J = 4.8 Hz, 4H), 3.14
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(
t, J = 4.8 Hz, 4H); IR (KBr) no NH band. MS (m/z): 213(M ).
1407.
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1
4
15
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1
Acknowledgments. Financial support by Youth Innovation
Research Team of Sichuan for Carbon Nanomaterials (No.
[
[
3
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[
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet