Si-OSO3H catalyzed one-pot three-component synthesis of 1,3-oxazines

Article abstract of DOI:10.1007/s13738-014-0423-9

A simple and an efficient method for the synthesis of six membered nitrogen containing heterocyclic compounds - 1,3-oxazines from diethyl acetylene dicarboxylate, substituted anilines or amines and formaldehyde is reported. A versatile, economical and eco

Full text of DOI:10.1007/s13738-014-0423-9

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0423-9
ORIGINAL PAPER
Si-OSO3H catalyzed one-pot three-component synthesis
of 1,3-oxazines
•
S. Sudha M. A. Pasha
Received: 14 March 2013 / Accepted: 31 January 2014
Ó Iranian Chemical Society 2014
Abstract A simple and an efficient method for the syn-
thesis of six membered nitrogen containing heterocyclic
compounds—1,3-oxazines from diethyl acetylene dicar-
boxylate, substituted anilines or amines and formaldehyde
is reported. A versatile, economical and eco-friendly het-
erogeneous reagent silica sulfuric acid (Si-OSO3H) is used
as a catalyst for this reaction.
Multi-component reactions (MCRs) are defined as one-
pot reactions in which three or more substrates combine
either simultaneously or through a sequential procedure to
form products that contain significant portions of all the
reactants. MCRs are considered to be economical as the
number of reaction steps and waste production are reduced;
MCRs are best employed for diversity-oriented synthesis
[5–7]. Though there are reports on this MCR in the liter-
ature, [8–10] use of a heterogeneous catalyst for the syn-
thesis of this important six membered heterocyclic
molecule will be of greater advantage.
Keywords DEAD Á MCR Á Silica sulfuric acid Á
1,3-oxazines
Heterogeneous catalysts in organic synthesis offer
diverse applications, the solid acid catalysts compared to
their homogeneous counterparts have many advantages
such as ease in handling and environmental compatibility
[11, 12]. Silica sulfuric acid (Si-OSO3H) acts as a het-
erogeneous catalyst for MCRs in a much more profitable
manner because of its low cost, ease of preparation and
catalyst recycling; and catalytic amounts of nano silica
sulfuric acid has been used recently in the synthesis of
1,3,5-triarylbenzenes under microwave irradiation [13]
and in the one-pot multi-component reactions [14]. In
continuation of our work on the use of silica sulfuric acid
as catalyst in organic synthesis, [15, 16] herein, we report
the synthesis of 1,3-oxazines from diethylacetylene
dicarboxylate (DEAD), substituted anilines/amines and
formaldehyde in ethanol in the presence of catalytic
amounts of silica sulfuric acid at 26 °C as shown in the
Scheme 1.
Introduction
Oxazine and its derivatives are structurally important
motifs which possess a wide range of biological activities
including anti-tumor, analgesic, anti-convulsant, anti-
malarial, anti-anginal, anti-hypertensive and non-nucleo-
side reverse transcriptase inhibitor activities [1–3]. They
are also used as organic dyes with interesting photo-
physical and lasing properties [4]. The 1,3-oxazines are
generally constructed by hydroamination/Prins reaction/
cyclization/dehydration reactions.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0423-9) contains supplementary
material, which is available to authorized users.
Results and discussion
S. Sudha Á M. A. Pasha (&)
Department of Studies in Chemistry, Bangalore University,
Central College Campus, Bengaluru, India
e-mail: mafpasha@gmail.com
At the onset of this reaction, various Lewis acid catalysts
were tested, 1 mmol of DEAD and 1 mmol of aniline were
123

J IRAN CHEM SOC
O
O
Table 2 Optimization of Si-OSO3H load for the reaction
COOEt
COOEt
Et
Et
Si-OSO3H
Yielda (%)
O
O
O
Sl. No
Catalyst (mg)
+
HCHO
RNH2
+
EtOH, 26 °C
N
R
1
2
3
4
a
200
100
50
40
75
50
40
R= Phenyl, aryl, cyclohexyl
Scheme 1 One-pot three-component synthesis of 1,3-oxazines
25
Isolated yield
Table 1 Optimization of catalyst for the one-pot, three-component
synthesis of 1,3-oxazine
reactions containing electron donating and electron with-
drawing anilines proceeded with the same ease to give the
corresponding products in high yield. We expect the
reaction to proceed by the hydroamination of amine (2)
with DEAD (1) to give intermediate I which may then react
with two molecules of formaldehyde (3) to give the desired
product (4) as shown the Scheme 2.
Sl. No
Catalyst
Yields (%)
1
2
3
4
5
6
Zinc chloridea
Zinc bromidea
Lithium perchloratea
Ceric ammonium nitratea
Cuprous Chloridea
15
20
15
40
20
70
After the completion of the reaction, the catalyst was
filtered, washed with minimum quantity of ethanol and
dried at 100 °C for about 3 h, this was then used for the
next reaction. To check the reproducibility of silica sulfuric
acid, the standard reaction was carried out using the
recovered catalyst and it can be seen from Graph 1 that,
the catalyst can be used for nearly thrice without the loss of
its activity.
Silica sulfuric acid (Si-OSO3H)b
Reaction condition: standard conditions as given in general procedure
for a time period not more than 7 h
a
10 mol %
b
100 mg
taken in ethanol (3 mL), to this 3.5 mmol of formaldehyde
was added, and stirred at 26 °C for about 10 h. The reac-
tion was considered as the standard reaction for the opti-
mization of the catalyst, and the results of catalyst
optimization are presented in the Table 1. It is clear from
this Table that, silica sulfuric acid is a better catalyst for
this reaction. After finding out the suitable catalyst for our
reaction, we then studied the quantity of catalyst required
to carry out the reaction i.e., the catalyst loading was tested
and 100 mg of the catalyst was sufficient to catalyze the
reaction and excessive loading was found to be futile
(Table 2). Encouraged by these finding we continued to
explore the reaction with various amines.
Experimental section
Synthesis
DEAD (1 mmol) and aniline (1 mmol) were taken in a RB
flask containing ethanol (3 mL), and stirred for 10 min, to
this formaldehyde (3.5 mmol) and Si-OSO3H (100 mg)
were added and stirring was continued till the formation of
the product at 26 °C (TLC, 5–7 h). After the completion of
the reaction, the solid catalyst was filtered and was washed
with ethanol (5 9 3 mL) and dried at 100 °C for about 3 h
and reused. All the organic portions were combined and
evaporated to get the crude product, which was then
purified by silica gel column chromatography.
A series of aromatic amines were tested with DEAD and
formaldehyde to get the corresponding 1,3-oxazines in
good yield, the reaction proceeded smoothly with aliphatic
amine like cyclohexyl amine and aromatic amines bearing
electron releasing and electron withdrawing groups. The
small library of 1,3-oxazines thus synthesized is presented
in Table 3. The substituents present on the phenyl ring did
not impart much on the rate of the reaction; all the
Synthesis of the catalyst
The catalyst silica sulfuric acid was prepared by known
methods as shown in the Scheme 3 [13–15].
123

J IRAN CHEM SOC
Table 3 Si-OSO3H catalyzed
synthesis of 1,3-oxazines
Sl.
No.
Aniline/amine
Product (4)
Yieldb
(%)
M.pc (°C)
235
(2)
EtOOC
N
COOEt
NH2
75
70
75
a
b
c
O
EtOOC
COOEt
NH2
189–192
195–200
MeO
H3C
N
MeO
O
EtOOC
COOEt
NH2
N
O
H3C
EtOOC
N
COOEt
NH2
72
70
70
245–249
199–203
189–192
d
e
f
O2N
O2N
O
EtOOC
COOEt
NH2
N
O
All reactions were performed
using DEAD (1 mmol), amine
(1 mmol), formaldehyde
(3.5 mmol) and silica sulfuric
acid (100 mg) in ethanol (3 mL)
EtOOC
N
COOEt
NH2
Br
a
O
Br
Isolated yield; all the
synthesized compounds are
known, and physical properties
agree with the reported values.
Mass spectral data of all the
products match with the
reported data
EtOOC
COOEt
NH2
OMe
65
170
N
g
O
b
Observed melting points
comply with the literature
Melting point [10–12]
OMe
Scheme 2 Proposed pathway
for the formation of oxazines
EtOOC
EtOOC
H
NH2
COOEt
EtOOC
EtOOC
O
2HCHO (3)
+
NH
N
Prins reaction/
cyclization/
dehydration
Hydroamination
COOEt
R1
R1
R1
1
2
I
4
123

J IRAN CHEM SOC
Acknowledgments The authors are grateful to the University
Grants Commission, INDIA for the financial support through the
major research project [UGC No. F. No. 37-71/2009 (SR)].
100
80
60
40
20
0
References
1. A. Krantz, R.W. Spencer, T.F. Tam, T.J. Liak, L.J. Copp, E.M.
Thomas, S.P. Rafferty, J. Med. Chem. 33, 464 (1990)
2. P.W. Hsieh, F.R. Chang, C.H. Chang, P.W. Cheng, L.C. Chiang,
F.L. Zeng, H.K. Lin, Y.C. Wu, Bioorg. Med. Chem. Lett. 14,
4751 (2004)
1
2
3
4
5
No. of cycles
Graph 1 Reusability of Si-OSO3H
3. G.Y. Lesher, A.R. Surrey, J. Am. Chem. Soc. 77, 636 (1955)
4. Y. Prostota, P.J. Coelho, J. Pinaband, J. Seixas, Photochem.
Photobiol. Sci. 10, 1346 (2011)
5. J. Zhu, Eur. J. Org. Chem. 7, 1133 (2003)
¨
6. A. Domling, Chem. Rev. 106, 17 (2006)
7. B.M. Trost, Angew. Chem. Int. Ed. 34, 259 (1995)
8. H. Cao, F.J. Huan, R.Q. Chao, J.Y. Wen, J.C. Huo, Tetra. Lett.
50, 1209 (2009)
9. F. Epifano, C. Pelucchini, O. Rosati, S. Genovese, M. Curini,
Catal. Lett. 141, 844 (2011)
10. M. Damodiran, P.T. Perumal, J. Het, J. Chem. 47, 1386 (2010)
11. D. Minoo, P. Salehi, B. Mostafa, A.Z. Mohammad, A. Maria, H.
Sedigheh, Catal. Commun. 9, 785 (2008)
O
O
O
26 °C
+
HCl
O
O
Si OH
Si OSO3H
+
ClSO3H
O
Scheme 3 Synthesis of silica sulfuric acid catalyst from chlorosul-
fonic acid and silica gel
12. R.S. Hamid, G. Majid, F. Mostafa, App. Catal. A. Gen. 345, 128
(2008)
13. R. Ghanbaripour, I. Mohammadpoor-Baltork, M. Moghadam,
A.R. Khosropour, S. Tangestaninejad, V. Mirkhani, J. Iran.
Chem. Soc. 9, 791 (2012)
14. A. Khazaei, M.A. Zolfigol, M. Mokhlesi, R. Rostamian, J. Iran.
Chem. Soc. 10, 1297 (2013)
15. D. Bandita, M.A. Pasha, Chin. J. Catal. 32, 1180 (2011)
16. D. Bandita, M.A. Pasha, Phosphorus Sulfur Silicon 186, 171
(2011)
Conclusion
To summarize, silica sulfuric acid acts as a versatile,
reusable heterogeneous catalyst for the present one-pot
three-component reaction of DEAD, an amine/aniline and
formaldehyde to give biologically important 1,3-oxazines
in high yields.
123