One-pot, expeditious and chromatography-free synthesis of new chromeno[4,3-e][1,3]oxazine derivatives catalyzed by reusable TiO2 nanopowder at room temperature

Article abstract of DOI:10.1016/j.tetlet.2014.04.099

An expeditious, one-pot, pseudo four-component coupling reaction between 3-hydroxy coumarin, formaldehyde, and amine catalyzed by reusable TiO ₂ nanopowder in ethanol at room temperature (25-28 °C) under stirring condition to synthesize the chromeno[4,3-e][1,3]oxazine derivatives has been described. A wide range of substrate variation, environmentally benign reaction procedure, easy work-up, chromatography free synthesis, and excellent yields with reusability of the catalyst make the methodology highly effective for the synthesis of chromeno[4,3-e][1,3]oxazine derivatives. To the best of our knowledge, this is the first Letter for the synthesis of chromeno[4,3-e][1,3] oxazines using 3-hydroxy coumarin.

Full text of DOI:10.1016/j.tetlet.2014.04.099

Accepted Manuscript
One-pot, expeditious and chromatography-free synthesis of new chromeno[4,3-
e][1,3]oxazine derivatives catalyzed by reusable TiO2 nanopowder at room
temperature
Animesh Mondal, Sunil Rana, Chhanda Mukhopadhyay
PII:
S0040-4039(14)00736-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.099
TETL 44561
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 March 2014
24 April 2014
25 April 2014
Please cite this article as: Mondal, A., Rana, S., Mukhopadhyay, C., One-pot, expeditious and chromatography-free
synthesis of new chromeno[4,3-e][1,3]oxazine derivatives catalyzed by reusable TiO2 nanopowder at room
temperature, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.099
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
One-pot, expeditious and chromatography-free
synthesis of new chromeno[4,3-e][1,3]oxazine
derivatives catalyzed by reusable TiO2
nanopowder at room temperature
Leave this area blank for abstract info.
Animesh Mondal , Sunil Rana , Chhanda Mukhopadhyay∗
2HCHO
R
(4a - 4q)
N
H2C CH2
O
OH
stiring(4-6h)
r.t (25-28°C)
nano
TiO2
O
O
EtOH
O
O
chromatography-
free
technique
R
NH2
Four new bonds (one C-C, one C-O and two C-N) are formed in a single operation in this pseudo four-component reaction.

1
Tetrahedron Letters
jou rn al h om ep a ge : www .e lsevier .com
One-pot, expeditious and chromatography-free synthesis of new chromeno[4,3-
e][1,3]oxazine derivatives catalyzed by reusable TiO2 nanopowder at room
temperature
Animesh Mondal, Sunil Rana, Chhanda Mukhopadhyay∗
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India..
E-mail: cmukhop@yahoo.co.in
ARTICLE INFO
ABSTRACT
Article history:
Received
An expeditious, one-pot, pseudo four-component coupling reaction between 3-hydroxy
coumarin, formaldehyde and amine catalyzed by reusable TiO2 nanopowder in ethanol at room
temperature (25-28°C) under stirring condition to synthesize the chromeno[4,3-e][1,3]oxazine
derivatives has been described. A wide range of substrate variation, environmentally benign
reaction procedure, easy work-up, chromatography free synthesis, excellent yields with
reusability of the catalyst make the methodology highly effective for the synthesis of
chromeno[4,3-e][1,3]oxazine derivatives. To the best of our knowledge, this is the first report
for the synthesis of chromeno[4,3-e][1,3]oxazines using 3-hydroxy coumarin.
Received in revised form
Accepted
Available online
Keywords:
Chromeno[4,3-e][1,3]oxazine derivatives
Multicomponent synthesis
TiO2 nanopowder
2009 Elsevier Ltd. All rights reserved
.
Room temperature
Chromatography-free

2
In recent time, multicomponent reactions (MCRs) offer several
opportunities in academia, industry, organic and medicinal chemistry
for the generation of structural diversity, less toxic, eco-friendly and
combinatorial libraries.1 These one-pot, step economic reactions are
highly efficient as they avoid time consuming, costly purification
processes of the intermediates in addition to the protection and
deprotection steps, formation of several bonds in a single step
operation and manufacture of complex molecular architectures.2
Coumarins present in various vegetables show immense biological
activities like antibacterial, antifungal, antiviral, antitubercular,
antimalarial, anticoagulant, anti-inflammatory, anticancer and
antioxidant etc.3 An increasing number of coumarin compounds have
shown great potency in the treatment of various types of diseases.4 In
the present context, the chemistry of heterocyclic compounds have
increased to a wide range and also are essential to comfort the human
life. Most of the heterocyclic compounds which contain 1,3-oxazine
particle than other catalytic reagents. Thus, newer
methodologies are still required for structural diversity and
operational simplicity.
In this context, we present a new, one-pot, multicomponent
methodology for the synthesis of chromeno-[4,3-e][1,3]-oxazine
derivatives by the reaction of 3-hydroxycoumarin, formaldehyde
and amines catalyzed by reusable TiO2 nanopowder. As a
prototype, the reaction of 3-hydroxycoumarin, formaldehyde and
aniline (Scheme 1) was studied under different catalytic
conditions summarized in Table 1. In our search of an efficient
and environmentally benign catalyst, the preferred reaction was
conducted in the presence of various catalyst at room temperature
(25-28°C). At the beginning of investigation we considered
several basic and acidic catalysts to set up a standard reaction
condition. The experimental results showed that the reaction
proceeds favourably under acidic conditions. After that various
Lewis acids such as AcOH, H3PO4, FeCl3 and TiO2 nanopowder
were examined in the reaction. The results indicated that in
presence of TiO2 nanopowder this reaction gives fair conversion
and yield. In contrast to TiO2 nanopowder, when the reaction
switched to other catalysts the reaction offered very low yields
(Table 1, entries 2-8) and conveniently, when the reaction was
performed in the presence of 10 mol % of TiO2 nanopowder at
room temperature (25-28°C) for 6 h, the desired product 4a was
obtained with maximum yield (Table 1, entry 11). Although the
reaction afforded the desired product even in presence of
commercial TiO2 (Table 1, entry 9), the isolated yield was
comparatively lower than that with the synthesized
TiO2 nanopowder as the catalyst (Table 1, entry 10), Notably, in
the absence of the catalysts only trace amount of the product was
formed (matched by TLC) (Table 1, entry 1) after 15 h at room
temperature, which could not be separated in pure form.
moiety possess higher synthetic utility and act as
useful
intermediates for the variety of functional group interconversions.4-6
This 1,3-oxazine ring system is also useful for the photo induced ring
opening and thermal ring closing,7 in addition to the synthesis of
various type of drug sources that are reported.8 The heterocyclic
system of pyrano(chromeno)-[3,4-e][1,3]oxazine is promising both
in terms of synthetic and biological aspects. Chromeno[3,4-
e][1,3]oxazine type compounds are used as intermediates for the
synthesis of a macrolide antitumor antibiotic lankacidin C.9
A
number of chromeno[3,4-e][1,3]oxazines exhibit high bactericidal
and fungicidal actions.10 Chromeno[3,4-e][1,3]oxazine derivatives
are generally obtained by reactions of malonyl dichloride with
amides, nitriles and heterocumulenes.11 In addition, synthesis of
chromeno[3,4-e][1,3]oxazine is performed by condensation of 4-
hydroxycoumarins with azomethines and aldehydes.12
NO2
H2N
N
O
OMe
O
O
O
H
N
N
Br
CH3
H3C
C2H5O
O
N
OMe
MeO
CH3
MeO
CH3
Table 1: Screening of catalysts for the multicomponent
synthesis of chromeno-[4,3-e][1,3]oxazine derivatives*
O
CH3
N
Br
O
N
O
O
O
N
N
4a
NH2
O
O
N
OH
O
H2C
O
CH2
O
Catalyst (10 mol%)
CH3
+
2 HCHO
+
NO2
EtOH, r.t (25-28°C) stirring (4-6 h)
O
Br
O
Br
OH
O
Br
HO
Scheme 1
N
N
O
Entry
Catalyst(10 mol%)
Solvent Isolated
Time
NH2
NH2
Yield (%) (h)
1
-
AcOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
trace
55
49
34
24
53
36
48
82
92
92
91
88
15
Figure 1: Some biologically important [1-3]oxazine
derivatives.
2
10
10
10
10
10
10
10
10
10
6
In general, most of the above-mentioned reactions occur at
3
Boric Acid
4N HCl
4N H3PO4
FeCl3
higher energetic reaction condition with low product yield,
longer reaction time and difficulties in work-up procedure. For
such reasons, we must need to search a better alternative route to
find a convenient and efficient method on the basis of green
approach over the reported methods, for the synthesis of
chromeno[4,3-e][1,3]oxazine derivatives. Another aspect towards
the synthesis of these derivatives is the choice of a suitable
catalyst. Recently, there is a consideration on the use and design
of environmentally friendly heterogeneous catalysts to reduce the
amount of toxic waste. Among them, nano scale metal oxides13
have been efficiently used as catalysts for organic
transformations.14-17The high reactivities of the nano catalyst
depend on large surface areas or unusually reactive morphologies
to a certain extent. Over the recent times, TiO2 and nanosize-TiO2
are being used as catalysts to promote the various type of organic
reactions.18-21 Therefore we consider the use of nano TiO2 in the
reaction due to the more efficiency and advantages of TiO2 nano
4
5
6
7
SiO2
8
Al2O3 (acidic)
9
CommercialTiO2(10) EtOH
TiO2nanopowder(10) EtOH
TiO2nanopowder(10) EtOH
TiO2nanopowder(15) EtOH
TiO2nanopowder (5) EtOH
10
11
12
13
10
10

3
Cl
N
14
15
16
17
18
TiO2nanopowder(10) MeOH
TiO2nanopowder(10) ACN
TiO2nanopowder(10) DMF
TiO2nanopowder(10) DCM
TiO2nanopowder(10) THF
55
65
50
40
70
6
6
6
6
6
2
3
4
6
4
85
93
91
O
O4b
O
Me
*3-hydroxy coumarin (1 mmol), formaldehyde (2.2 mmol),
aniline (1 mmol) and 5 mL ethanol were taken in a 25 mL round
bottomed flask. The resulting mixture was then stirred in the
presence of catalysts for the specified times as shown.
N
O
With these screening results in hand, we have investigated this
pseudo four-component reaction in various solvents like MeOH,
EtOH, ACN, DMF, DCM and THF. The best results were
obtained at room temperature (25-28°C) by stirring the reaction
mixture in EtOH with high yield of the product (Table 1, entry
10). Whereas other solvents presented very low yield compared
to desired product (Table 1, entries 14-17). Although THF gave
slightly higher yield but it was less than ethanol (Table 1, entry
18). Therefore in the presence of 10 mol % TiO2 nanopowder, 3-
hydroxycoumarin, formaldehyde and aniline (stoichiometric ratio
1:2.2:1) in ethanol were found to be the optimum conditions for
the maximum yield of the reaction.
O
O
4c
OCH3
N
O
4
O 4d
O
CH3
CH3
N
5
6
5
6
94
After the optimization of the reaction condition, we turned our
focus to the substrate scope and generality of the reaction. A
variety of amines were used (Table 2) under the optimized
conditions. It was found that, when we introduced aromatic
amines with electron-donating groups (like Me, OMe and
isopropyl) (Table 2, entries 3, 4, 5 and 8) at different positions of
the aromatic ring, it resulted in good to excellent yield of the
desired product, whereas groups with electron-withdrawing
nature (like Cl, Br and NO2) (Table 2, entries 2, 6 and 13) gave
slightly lower yield. Aliphatic amines like 1-aminomethyl
naphthalene and cyclohexyl amine (Table 2, entries 7 and 9) also
O
O
O
4e
Br
87
N
O
O
O
4f
reacted well.
Meanwhile, the substrate bearing a bulky
polycyclic aromatic group like 2-amino anthracene (Table 2,
entry 12) reacted well and gave the desired product 4l in 76%
yield. High product was also obtained when the reaction was
performed with polycyclic hetero aromatic (Table 2, entries 14-
17) amines.
N
7
8
9
5
6
6
92
79
82
O
O
O
4g
Table 2: TiO2 nanopowder catalyzed multicomponent
synthesis of chromeno-oxazine derivatives.
N
O
R
N
H2C
CH2
O
O
O
4h
OH
O
TiO2 nanopowder (10 mol%)
EtOH, r.t (25-28°C) stirring (4-6 h)
+
R NH2
+
2 HCHO
O
O
O
(4a-4q)
N
Scheme 2
O
Entry
Product
Time(h)
Isolated
Yield (%)
O
O
4i
CH3
N
N
10
6
90
1
6
92
O
O
O
O
4a
O
O
4j

4
CH3
2
6
6
6
6
6
6
6
6
6
91
91
89
86
84
84
82
80
70
3
N
11
6
88
4
O
5
O
O
4k
6
7
N
O
8
12
13
6
6
76
80
9
O
O
4l
NO2
10
N
The catalyst TiO2 nanopowder was synthesised by the
previously reported standard gel combustion method22. The
prepared catalyst was characterized by TEM, X-ray diffraction
and BET surface area determination. The rutile structure of TiO2
and characteristic peaks for the crystal planes (1 0 1), (0 0 4), (2 0
0), (1 0 5), (2 1 1), (2 0 4) (1 1 6), (2 2 0) and (2 1 5) are
confirmed from X-ray diffraction, which are in agreement with
the standard JCPDS value. The specific surface area of TiO2
nanopowder was calculated 69.51m2g-1 from nitrogen adsorption
isotherm study. The pore size of the crystals was predicted by HR
TEM analysis and all the above characterization data of TiO2 is
given in supplementary information.
O
O
O
4m
N
N
14
15
5
6
90
85
O
O
O
4n
4o
N
Moreover, all the compounds were purified by simple
recrystallization, even though the compounds were not subjected
to chromatography. After filtering the catalyst (sintered funnel)
from the reaction mixture, the solvent was pumped out by rotary
evaporation. The crude product was then purified directly by
recrystallization from ethyl alcohol-water mixture (5:1 v/v).
N
O
O
O
N
Structures of all the above synthesized chromeno[4,3-
1
e][1,3]oxazines derivatives were fully characterized by H and
N
13C NMR and IR spectra. The final structure was confirmed by an
X-ray crystallography study of a single crystal of the chromeno-
[4,3-e][1,3]oxazine 4c (Table 2, entry 3) which is given below in
Figure 2.
16
17
6
5
88
87
O
O
O
4p
4q
N
N
O
O
O
Additionally, we considered a standard reaction (Scheme 1) to
investigate the catalytic recycle experiment (Table 3). The
catalyst was easily recovered by the filtration throughout a sinter
funnel after completion of the reaction (checking TLC). Then it
was washed with EtOH for four times to remove any adhering
organic compound. It was next dried under vacuum followed by
drying in the oven completely. The catalyst (nano-TiO2) was
reused for the standard reaction for up to nine cycles without any
appreciable loss of activity and after that we have observed a
considerable amount of lowering of activity from 9th to 10th cycle.
Figure 2: ORTEP plot of the chromeno-oxazine 4c by the
single crystal X-ray diffraction (Table 2, entry 3) (CCDC
969794)
A proposed mechanistic route for the formation of the
products is exhibited in Scheme 3. At first, amination reaction
occurs between the activated formaldehyde (by coordination with
TiO2 nanoparticle) and amine (RNH2) followed by H2O
elimination provides imine intermediate “A” that is further
activated by TiO2. “A” is then attacked by 3-hydroxy coumarin to
form “B” which further reacts with formaldehyde and eliminate
H2O. Next cyclization occurs to form the final product.
Table 3: Recycling of the catalyst for the pseudo four-component
coupling reaction of 3-hydroxycoumarin, formaldehyde and
aniline (product 4a)
Run
1
Time (h)
6
Yield (%) (isolated)
92

5
Dömling, A. Chem. Rev. 2006, 106, 17; (c) Zhu, J.;
Activation of the formaldehyde through the weak interaction
between the lone pair electron of oxygen and Lewis acidic sites
(Ti4+) on the surface of TiO2 make it susceptible to nucleophilic
attack by amine as well as 3-hydroxy coumarin. The step in
which elimination of H2O takes place is also facilitated by Ti4+.
The size of the TiO2 particles is more important for synthesizing
the target product. The smaller size TiO2 particles are more
efficient for the reaction, because as the particles size decreases
surface area for the contact of the reactants increases.
Bienayme, H. Multicomponent Reactions; Wiley: Weinheim,
2005; (d) D'Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev.
2007, 36, 1095; (e) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc.
Chem. Res. 2009, 42, 367; (f) Zhou, L.; Bohle, D. S.; Jiang,
H. F.; Li, C. J. Synlett. 2009, 937; (g) Kupchan, S. M.;
Komoda, Y.; Court, W. A.; Thomas, G. J.; Smith, R. M.;
Karim, A.; Gilmore, C. J.; Haltivanger, R. C.; Bryan, R. F. J.
Am. Chem. Soc. 1972, 94, 1354; (h) Trost, B. M. Science.
1991, 254, 1471-1477.; (i) Sheldon, R. A. Pure Appl. Chem.
2000, 72, 1233-1246.
R
(2)
(3)
(a) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259; (b)
Soleimani, E.; Zainali, M. J. Org. Chem. 2011, 76, 10306-
10311.
G. A. Kuznetsova, Natural Coumarins and Furocoumarins
[in Russian], Nauka, Leningrad (1967), 248 pp.
N
H2C
O
CH2
O
H
H
O
O
nano
TiO2
nano
TiO2
R
2
(4)
(5)
(6)
(7)
Meyers, A. I.; Smith, E. M. J. Org. Chem. 1972, 37, 4289.
Mayers, A. I.; Malone, G. R. J. Org. Chem. 1974, 39, 618.
Shing, O. V.; Han, H. Tetrahedron Lett. 2007, 48, 2345.
Tomasulo, M.; Sortino, S.; Raymo, F. M. Org. Lett. 2005,
7,1109
Zuhal, T.; Emel, P.; Adem, K. Molecules. 2007, 12, 345
(a) Kende, A.S., Koch, K., Dorey, G., Kaldor, I., Liu, K., J.
Am. Chem. Soc., 1993, 115, 9842; (b) Kende, A.S., Liu, K.,
Kaldor, I., Dorey, G., Koch, K., J. Am. Chem. Soc., 1995, 117,
8258.
H
H
R
N
O
H
nano
TiO2
H2C
O
H
H
O
nano
H
H
TiO2
O
O
(8)
(9)
nano
R
NH2
H2O
TiO2
H2O
H
H
R
N
O
nano
TiO2
H
H
H2C
O
H
(B)
N
O
(10) Nagesam, M., Raju, K.M., Raju, M. S., J. Ind. Chem. Soc.,
1992, 69, 592.
nano
TiO2
(A)
R
H
H
O
(11) (a) Ziegler, E.; Meinde, H., Monatsh. Chem., 1964, 95, 1318;
(b) Davis, S. J.; Elvidge, J. A., J. Chem. Soc., 1962, 3553.
(12) Dike, S.V.; Merchant, J. R., Tetrahedron Lett., 1978, 3607.
(13) Klabunde, K. J.; Mulukutla, R. Nanoscale Materials in
Chemistry; Wiley Interscience: New York, 2001; Chap 7, p.
223.
(14) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.;
Mahender, K. J. Am. Chem. Soc. 2004, 126, 3396–3397.
(15) Choudary, B. M.; Mulukutla, R. S.; Klabunde, K. J. J. Am.
Chem. Soc. 2003, 125, 2020–2021.
(16) Sarvari, M. H.; Sharghi, H. J. Org. Chem. 2004, 69, 6953–
6956.
(17) Kantam, M. L.; Kumar, K. B. S.; Sridhar, C. Adv. Synth.
Catal. 2005, 347, 1212–214.
(18) Su, K. M.; Li, Z. H.; Cheng, B. W.; Liao, K.; Shen, D. X.;
Wang, Y. F. J. Mol. Catal. A: Chem. 2010, 315, 60–68.
(19) Yan, X. M.; Mei, P.; Lei, J. H.; Mi, Y. Z.; Xiong, L.; Guo, L.
P. J. Mol. Catal. A: Chem. 2009, 304, 52–57.
(20) Ohno, T.; Tsubota, T.; Kakiuchi, K.; Miyayama, S.; Sayama,
K. J. Mol. Catal. A: Chem. 2006, 245, 47–54.
N
H
O
OH
H
R
OH
O
O
O
O
Scheme 3: A probable mechanistic pathway for the
synthesis of chromeno-oxazine derivatives through
recycling of TiO2 nano particle.
In summary, we have described the utility of nanopowder
TiO2 in synthesizing the chromeno-oxazine derivatives in good to
excellent yields. These are the first reported compounds in which
two new C-N bonds, one C-O bond and one new C-C bond are
formed in a single operation by the pseudo four-component
coupling reaction. This study presents simple, efficient and one-
pot multicomponent protocol, which provides several
advantages such as short reaction times, high yields, easy
working up, chromatography-free technique, catalyst recovery
and reusability are other highlights of this work.
Supplementary data: The data of experimental details,
catalyst TiO2, characterization and spectroscopic report of all
compounds along with 1H, 13C NMR and IR are given in the
Supplementary section.
(21) (a) Gandhe, A. R.; Fernandes, J. B.; Varma, S.; Gupta, N. M.
J. Mol. Catal. A: Chem. 2005, 238, 63–71; (b) Gandhe, A. R.;
Naik, S. P.; Kakodkar, S. B.; Fernandes, J. B. Catal. Commun.
2006, 7, 285–288.
(22) (a) Chen, X.; Wu, H.; Wang, S.; Huang, S. Synthetic
Communications.2012, 42, 2440-2452. (b) Sedghi, A.;
Baghshahi, S.; Nouri, R.Na*.; Barkhordari, M.; Dig. J. Nano.
Bios., 2011, 6, 1457-1462.
Acknowledgment
One of the authors (AM) thanks the University Grants
Commission (UGC), New Delhi, for his fellowship (JRF). We
thank the CAS Instrumentation Facility, Department of
Chemistry, University of Calcutta for spectral data.
Click here to remove instruction text...
References
(1)
(a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S.
D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123; (b)

6
1. Highly
efficient
multicomponent
chromatography-free synthesis
2. Wide range of amines including aromatic,
polyaromatic, alicyclic, aliphatic utilised
3. Catalyst reusability decreases the amount of
toxic wastes in the environment
4. Green,
methodology
environmentally
benign