Synthesis of substituted 1,3-oxazines using sulfamic acid as an efficient and eco-friendly catalyst

Article abstract of DOI:10.1002/jhet.489

Sulfamic acid catalyzed the synthesis of substituted 1,3-oxazines by one-pot three-component reaction of aniline, alkynoates, and formaldehyde in excellent yields. The catalyst possesses distinct advantages shows ease of handling, good yields, cleaner rea

Full text of DOI:10.1002/jhet.489

1386
Synthesis of Substituted 1,3-Oxazines Using Sulfamic Acid as an
Efficient and Eco-Friendly Catalyst
Vol 47
M. Damodiran and Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute,
Adyar, Chennai 600 020, Tamil Nadu
*E-mail: ptperumal@gmail.com
Received January 22, 2010
DOI 10.1002/jhet.489
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Sulfamic acid catalyzed the synthesis of substituted 1,3-oxazines by one-pot three-component reaction
of aniline, alkynoates, and formaldehyde in excellent yields. The catalyst possesses distinct advantages
shows ease of handling, good yields, cleaner reactions, nonhygroscopic, noncorrosive, and high activity.
Sulfamic acid is a green alternative for metal-containing acidic materials, which are toxic and deleteri-
ous for human health and environmental protection.
J. Heterocyclic Chem., 47, 1386 (2010).
INTRODUCTION
acid catalyzed organic transformations, as witnessed by
numerous reports published in the past years [4]. Subse-
quently, there are reports of sulfamic acid-catalyzed
tetrahydropyranylation of hydroxy compounds [5], ester-
ification of cyclic olefins with aliphatic acids under
solvent-free conditions [6], and transesterification of
b-ketoesters in ionic liquids [7], synthesis of quinoline
[8], sulfamic acid is recyclable, easy to handle owing to
its immiscibility with common organic solvents and it’s
intrinsic zwitter ionic property prompted us to explore
further applications of NH2SO3H as an acidic catalyst in
other carbon-heteroatom forming reactions.
The rapid assembly of molecular diversity is an im-
portant goal of synthetic organic chemistry and one of
the key paradigms of modern drug discovery. Domino
reactions, which result from the combination of multiple
transformations in a single pot, are highly efficient
means for the improvement of reaction efficiency [1].
Hence, domino reactions and multicomponent reactions
(MCRs) [2] involves three or more reactants in a single
reaction flask to generate a product incorporating most
of the atoms contained in the starting material. Because
of intrinsic atom economy, simpler procedure, equip-
ment, time, and energy saving MCRs are gaining much
importance in both academia and industry [3]. In dom-
ino reactions, each new bond delivers a reactive species,
which undergoes further steps without changing the
reaction conditions. The main advantage of this strategy
is that prefunctionalization of one or both coupling part-
ners are not required; this simplifies the preparation of
substrates, shortens the synthetic route, and therefore,
minimizes waste production.
The synthesis of 1,3-oxazines has attracted attention
in the past because of their potential as antibiotics [9],
antitumor [10], analgesics [11], and anticonvulsants
[12]. 1,3-Oxazines have generated great interest as anti-
psychotic agents and as possible effectors for serotonin
and dopamine receptors [13]. The ring-chain tautomeric
interconversion of N-unsubstituted 1,3-N-O-heterocycles
and the corresponding hydroxyalkylimines can often be
exploited advantageously in different areas of organic
synthesis. Hence, synthesis of these derivatives is of
considerable interest. The synthesis of dihydro-2H-1,3-
oxazines was reported using hydrochloric acid as cata-
lyst [14]. The disadvantage of this methodology is lon-
ger reaction time and hazardous acid catalyst. In a broad
program of developing efficient eco-friendly synthetic
method for pharmacologically important moieties, we
Sulfamic acid (NH2SO3H) has emerged as a substitute
for conventional acidic catalysts and is a dry, nonvola-
tile, nonhygroscopic, odorless, and white crystalline
solid with an outstanding stability. It possesses distinc-
tive catalytic features related to its zwitterionic nature
and displays an excellent activity over a vast array of
C
V
2010 HeteroCorporation

November 2010
Synthesis of Substituted 1,3-Oxazines Using Sulfamic Acid as an Efficient
and Eco-Friendly Catalyst
1387
Scheme 1. Sulfamic acid-catalyzed synthesis of substituted 1,3-oxa-
zines at room temperature.
Table 2
Solvent effect on the synthesis of substituted 1,3-oxazine 3a catalyzed
by sulfamic acid at room temperature.
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
EtOH/H2O (1:1)
EtOH
MeOH
3
12
12
12
12
12
12
80
70
50
50
trace
30
45
CH3CN
Toluene
CHCl3
DCM
explored an alternative procedure, which resulted in an
operationally efficient process. More recently we have
reported the synthesis of heterocyclic compounds pro-
moted by sulfamic acid [15]. In our ongoing efforts on
one-pot multicomponent synthesis [16] and organic syn-
thesis using solid acid catalysts [17], herein we report
the synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-
oxazines using sulfamic acid as catalyst. The reactions
proceeded in short reaction times. The catalytic activity
of sulfamic acid showed enhanced effect in 1:1 mixture
of ethanol and water.
Also it has been observed that 1:1 mixture of ethanol
and water is the best solvent for carrying out this reac-
tion using sulfamic acid (30 mol %) (Table 3). For reac-
tion of dimethyl acetylenedicarboxylate 2b, aniline 1a
and formaldehyde, similar yields were obtained (Table 3,
entries 1–7).
An evident electronic effect was observed on the
yields of the products (3a–n). The yield of the products
decreased when electron donating groups were present
on the phenyl ring. When diethyl acetylenedicarboxylate
was used, there was no change in yields (Table 3, entries
8–14).
RESULTS AND DISCUSSION
The reactions were carried out using aniline 1a (1
eq.), diethyl acetylenedicarboxylate 2a (1 eq.), and
formaldehyde (3 eq.) in the presence of 20 mol % sul-
famic acid in 1:1 mixture of ethanol and water (Scheme
1). It was found that all the reactions proceeded rapidly
and afforded the desired products in 70% yield. It was
also found that increasing the amount of sulfamic acid
(20–40 mol %.) increased the yield of the reaction. Fur-
ther, increasing the amount of sulfamic acid (40–60 mol
%) did not affect the rate of the reaction as well as
yield. We tried using different acid catalysts, such as
KClO4, Ce(SO4)2, Cd(OAc)2, tetrabutylammmoniumhy-
drogen suphate, and oxalic acid (Table 1) and found
that sulfamic acid is the most effective catalyst in terms
of reaction time as well as yield (80%) (Table 2),
whereas in presence of other catalysts formed the prod-
ucts with varying yields (0–40%).
CONCLUSIONS
We have developed a novel and highly efficient
method for the synthesis of 3,4,5-trisubstituted-1,3-oxa-
zine from alkynoates, amines, and formaldehyde with a
simple experimental workup procedure. Sulfamic acid
has proved to be an efficient catalyst and green alterna-
tive for metal-containing acidic materials, which are
toxic and deleterious for human health and environmen-
tal protection.
EXPERIMENTAL
Materials and methods. CDCl3 and DMSO-d6 was pur-
chased from Aldrich. IR measurements were done using Perkin
Elmer Spectrum RXI FT-IR. The 1H and 13C NMR were
recorded in CDCl3 with JEOL 500 MHz high resolution NMR
spectrometer. CDCl3 was used as the solvent for the NMR
spectral measurements and spectra were recorded in ppm with
TMS as internal standard. The mass spectra were recorded by
using an Electrospray Ionization method with Thermo Finni-
gan mass spectrometer and EI method with JEOL DX-303
mass spectrometer. Melting points were determined in capil-
lary tubes and were uncorrected. Analytical TLC was per-
formed on precoated plastic sheets of silica gel G/UV-254 of
0.2 mm thickness (Macherey-Nagel, Germany). Elemental
analysis data were recorded using a Thermo Finnigan FLASH
EA 1112 CHN analyzer.
Table 1
Screening of different catalysts on the synthesis of substituted
1,3-oxazine 3a at room temperature in EtOH/H2O (1:1).
Entry
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
NH2SO3H
KClO4
Oxalic acid
TBAHS
3
12
12
12
12
12
80
20
40
trace
Ce(SO4)2
Cd(OAc)2
trace
No product
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 3
Sulfamic acid-catalyzed synthesis of substituted 1,3-oxazines at room temperature.
Entry
1
Aniline (1)
Alkynoates (2)
Product (3)
Yield (%)a
80
2
3
4
5
2a
2a
2a
2a
82
85
80
72
6
2a
70
7
2a
82
(Continued)

Table 3
(Continued)
Entry
8
Aniline (1)
Alkynoates (2)
Product (3)
Yield (%)a
70
1a
9
10
11
12
1b
1c
1d
1e
2b
2b
2b
2b
78
80
80
76
13
1f
2b
70
14
1g
2b
85
a Isolated yield.

1390
M. Damodiran and P. T. Perumal
Vol 47
solid. mp 83–85ꢂC; IR (KBr): 3031, 2985, 1706, 1677, 1481,
Representative procedure for the synthesis of 3,4,5-tri-
1
915 cmꢁ1. H NMR d: 3.34 (s, 3H), 3.38 (s, 3H), 4.02 (d, 1H,
substituted-3,6-dihydro-2H-1,3-oxazines 3a–n. To a mixture
of diethyl acetylenedicarboxylate 2a (1 mmol) and aniline 1a
(1 mmol), ethanol (3 mL) was added. The mixture was stirred
at room temperature for 10 min. Subsequently, sulfamic acid
(30 mmol %) and formaldehyde (3.5 mmol) were added. Af-
ter 30 min, water (3 mL) was added and stirring was contin-
ued for 3 h. After completion of the reaction, the reaction
mixture was extracted with diethyl ether (3 ꢀ 15 mL) and
organic layer was separated and the combined extract was
dried with anhydrous Na2SO4. Solvent was removed, and the
residue was separated by column chromatography on silica
gel (Merck, 100–200 mesh), ethyl acetatepetroleum ether
(20:80) to obtain pure product 3a. 1H NMR, 13C NMR, IR,
and mass data of the products 3a–c, 3e, 3f, 3h–j, 3l, and
3m are in full agreement with those reported previously
(Ref. 14).
J ¼ 9.2 Hz), 4.41 (d, 1H, J ¼ 9.2 Hz), 4.52 (d, 1H, J ¼ 10.6
Hz), 4.79 (d, 1H, J ¼ 10.2 Hz), 7.00 (d, 1H, J ¼ 6.8 Hz), 7.55
(d, 1H, J ¼ 7.2 Hz), 7.89 (d, 1H, J ¼ 1.6 Hz); 13C NMR d:
47.8, 53.3, 55.6, 58.5, 71.9, 118.2, 127.1, 136.7, 156.9, 164.4,
194.0; ms (EI) m/z ¼ 390 (Mþ), 392 (Mþ2), 394 (Mþ4); Anal.
Calcd for C14H13BrClNO5: C 43.05, H 3.35, N 3.59. Found: C
43.10, H 3.32, N, 3.61.
Acknowledgment. One of the authors M.D. thanks CSIR (New
Delhi) for the award of Senior Research Fellowship.
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.
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November 2010
Synthesis of Substituted 1,3-Oxazines Using Sulfamic Acid as an Efficient
and Eco-Friendly Catalyst
1391
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