An approach toward the syntheses of triazolo benzoxazines, triazolo quinoxalines, triazolo benzodiazepines, triazolo benzoxazepines, and triazolo benzothiazines via a simple and convenient protocol using basic alumina as solid support

Article abstract of DOI:10.1016/j.tetlet.2014.02.080

A microwave assisted green protocol for the syntheses of triazole fused benzoxazines, benzoxazepines, quinoxalines, and benzothiazines was investigated using basic alumina as solid support. The one-pot reaction was carried out using Cu(phen)(PPh₃)Br as a catalyst. The protocol did not require the use of any additional ligands, base or the use of expensive and toxic palladiums.

Full text of DOI:10.1016/j.tetlet.2014.02.080

Tetrahedron Letters 55 (2014) 2261–2265
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An approach toward the syntheses of triazolo benzoxazines, triazolo
quinoxalines, triazolo benzodiazepines, triazolo benzoxazepines,
and triazolo benzothiazines via a simple and convenient protocol
using basic alumina as solid support
⇑
Nivedita Chatterjee, Swarbhanu Sarkar, Rammyani Pal, Asish Kumar Sen
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave assisted green protocol for the syntheses of triazole fused benzoxazines, benzoxazepines,
quinoxalines, and benzothiazines was investigated using basic alumina as solid support. The one-pot
reaction was carried out using Cu(phen)(PPh3)Br as a catalyst. The protocol did not require the use of
any additional ligands, base or the use of expensive and toxic palladiums.
Received 10 December 2013
Revised 20 February 2014
Accepted 23 February 2014
Available online 1 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Triazolo benzoxazines
Triazolo benzoxazepines
Triazolo benzodiazepines
Triazolo quinoxalines
Triazolo benzothiazines
Domino one-pot reaction
Organic reactions performed under non-traditional reaction
conditions by using inexpensive and recyclable mineral supports
have attracted great attention in recent years primarily due to
the growing environmental concerns.1–3 The application of solid
supports in a microwave-assisted reaction eliminates the use of
solvents and the necessity of rigorous reaction conditions.4
Besides, the homogenous dispersion of the active sites, simpler
work-up procedure etc. makes the solid-supported reactions more
useful than the conventional solution phase synthesis.5 The use of
solid support in a microwave-accelerated reaction also enables the
reaction to execute at atmospheric pressure and thus it can be uti-
lized for large scale synthesis of various organic compounds.6,7
Triazole fused benzoxazines showed a broad range of biological
activities8 and have wide clinical applications9 (e.g., estazolam,
alprazolam, etc.). 1,4-Benzoxazines or their modified scaffolds are
present in a number of bioactive natural products,10 as well as, in
many medicinally significant compounds11 (e.g., levofloxacin). Fur-
thermore, there are many triazole fused 2,3-dihydro-1,4-benzoxa-
zines12 which have shown therapeutic potential based on in vitro
and molecular modeling studies.13 Similarly, 1,4-benzothiazines
have also shown a wide range of pharmacological properties
including anti-allergic, anti-aldoso-reductase, antifungal, anti-
rheumatic, immunostimulating, vasorelaxant, anti-arrhythmic,
anti-hypertensive, neuroprotective, and cytotoxic activities.14
1,4-/1,5-Benzodiazepines or benzoxazepines also have been well
recognized for their wide array of biological activities, such as
anti-insectant, antitumor, fibrinogenic receptor antagonist, human
neurokinin NK1 receptors, muscarinic receptor ligands etc.15
A
number of triazoloquinoxaline derivatives can act as human A3
(hA3) adenosine receptor (AR) antagonists. Receptor-based SAR
analysis also highlighted the versatility of the triazoloquinoxaline
scaffold as potent and selective hA3 AR antagonists.16 In addition
1,2,3-triazole derivatives showed strong antibacterial17–19 and
antifungal20,21 properties.
Due to the varied biological activities of these heterocyclic scaf-
folds, several sequential and one-pot synthetic routes involving
domino Sonogashira-azide–alkyne cycloaddition reactions in the
presence of various transition-metal catalysts have been
reported.22a,22b Chowdhury et al. had carried out the synthesis of
triazolo-benzoxazines using Pd(OAc)2/PPh3/CuI/K2CO3 in DMF at
100 °C.22c These methodologies are no doubt quite efficient but
may require both palladium and copper salts as catalysts and were
carried out at elevated temperature. We have modified this
⇑
Corresponding author. Tel.: +91 33 24995806; fax: +91 33 24735197.
E-mail addresses: asishksen@yahoo.com, aksen@iicb.res.in (A.K. Sen).
http://dx.doi.org/10.1016/j.tetlet.2014.02.080
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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N. Chatterjee et al. / Tetrahedron Letters 55 (2014) 2261–2265
reaction using microwave heating, basic alumina as solid support
and base, and aryl imidazol-1-yl-sulfonate as oxygen based
electrophile.
alines, triazolo benzodiazepines, triazolo benzoxazepines, and
triazolo benzothiazines involving various azido alkynes (2a–f)
and aryl imidazol-1-yl-sulfonate as oxygenated electrophilic com-
pounds (3a–e) with basic alumina as a solid support using only
Cu(phen)(PPh3)Br (1h) as a catalyst under microwave irradiation
(100 °C, 250 W). In all cases the products were obtained in high
yield. The use of solid support serves dual role; it eliminates the
use of hazardous and costly Pd-catalyst and also restricts the use
of organic solvents. The new protocol does not require additional
base and can be carried out efficiently in a short time.
We used 2a and 3a to synthesize triazole fused benzoxazine 4a
for the initial studies. Our first objective was to develop the opti-
mal condition for the one-pot reaction under solid support without
using Pd salts. Systematic studies of the reaction conditions in the
presence of copper(I) catalysts23b,26 (Fig. 1) and various solid sup-
ports (basic alumina, TiO2, MgO) revealed that basic alumina pro-
vided better yield (Table 1), even in the absence of any added
base (triethyl amine or DBU). Copper(I) iodide or bromide (1a–b),
yielded [1,2,3]triazolo[5,1-c][1,4]benzoxazines (4a) in 61% and
58%, respectively, (Table 1, entry 5 & 6), whereas, the use of cata-
lysts 1c and 1d gave yields of 54% and 57% (Table 1, entry 7 & 8).
Similar observations were noted for thio-copper complexes (1e–
g) (Table 1, entry 9–11). Use of catalyst 1h was found to be very
effective for the reaction with an excellent yield of 77% (Table 1,
entry 12). No additional base was required as basic alumina acts
as base and also as solid support.
To evaluate the effect of microwave irradiation in comparison
with conventional reaction conditions, a pre-heated oil-bath was
used as heat source. Reaction in an oil bath of the same reactants
2a, 3a, and catalyst 1h gave 4a in significantly lower yield (60%).
This clearly indicates that the effect of microwave is not purely
thermal. It could be expected that the application of microwave
irradiation causes easy excitation of electronic energy levels and
thus leads to better yield.
To establish the scope and generality of this approach, reaction
of various aryl imidazol-1-yl-sulfonates (3a–e) was carried out fol-
lowing the same reaction condition. The results are summarized in
Table 2. It was observed that a wide variety of aryl imidazol-1-yl-
sulfonates possessing different functional groups reacted success-
fully. All the products were characterized by spectral and analytical
methods. To ensure the recyclability of the solid support, the resi-
due was washed thoroughly with acetone and water, calcined at
Microwave heating at controlled temperature and pressure may
considerably reduce reaction time without promoting any side
reactions.23 Solid support like alumina, possesses excellent ability
to absorb the organic compounds on their surface, and transmits
microwave irradiation without absorbing or restricting it. Litera-
ture also revealed that the basic oxides, like alumina, serve as a
suitable alternative for palladium catalyzed heteroannulation reac-
tions due to its role as a base and the presence of oxide ion in the
solid framework.24 Oxygen based electrophiles25a,25b have also at-
tracted attention of the synthetic organic chemists, due to their
high stability and easy accessibility through functional group inter-
conversion from readily available hydroxylated compounds. These
prompted us to explore an efficient yet simple and one-pot green
protocol using basic alumina and microwave irradiation with aryl
imidazol-1-yl-sulfonate as electrophile. Herein, we describe
(Scheme 1) the synthesis of triazolo benzoxazines, triazolo quinox-
X
X
Ar-OSO2Imidazol-1-yl (3a-e)
N3
Basicalumina, Cu(phen)(PPh3)Br
M.W, 15-20min, 100°C
N
Ar
N
N
2a X = O, 2b X = COO
2c X = NAc, 2d X = NPh
2e X = S, 2f X = CONH
4a-j
Scheme 1. One-pot reaction under microwave irradiation using basic alumina as
solid support.
Cu-X
[Cu(MeCN)2(PPh3)2]Cl [Cu(CH3CN)4]PF6
1c
1d
N
Cu
S
1a X=I
1b X=Br
1e
N
N
N
N
Cu
Cu
S
S
Cu
Ph3P
Br
1f
1g
1h
Figure 1. Copper catalysts used in the study.
Table 1
Optimization of Cu(I) catalysts on various solid supports and bases
Entrya
Solid support
Catalyst used
Catalyst (mol %)
Time (min)
Yieldb (%)
A. Without additional base
1
2
3
4
4
5
6
7
8
9
10
11
12
TiO2
TiO2
TiO2
TiO2
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2.0
2.5
2.5
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
10
10
15
15
15
15
15
15
15
15
15
15
15
27
30
30
30
36
61
58
54
57
54
48
57
77
MgO
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
1g
1h
B. With Et3N as additional base
13
Basic alumina
1h
1h
2.5
2.5
15
15
77
75
C. With DBU as additional base
14
Basic alumina
a
All reactions were performed using 1-azido-2-(prop-2-ynyloxy)benzene (2a, 1 equiv) and arylimidazol-1-yl-sulfonate (3a, 1.2 equiv), with copper catalysts (1a–h) under
microwave irradiation (250 W, 100 °C).
b
Isolation of pure product, 4a.

N. Chatterjee et al. / Tetrahedron Letters 55 (2014) 2261–2265
2263
Table 2
Basic alumina supported reactions of aryl imidazol-1-yl-sulfonates (3a–e) with various azido alkynes (2a–f) leading to triazole fused derivatives (4a–j)
Entrya
Azide
Arylimidazol-1-yl-sulfonates
Product
Yield (%)b
Ref.
X
OSO2Im
O
R5
R1
R2
N3
2a: X = O
N
N
: R1 = R2 = R3 = R4 = R5 = H
1
77
22c
N
4a
2a: X = O
R4
R3
O
N
CH3
2
3
2a
2a
3b: R1 = R2 = R4 = R5 = H; R3 = CH3
3c: R1 = R2 = R4 = R5 = H; R3 = OMe
82
81
22c
22c
N
N
N
4b
O
OMe
N
N
4c
O
O
4
5
2b: X = COO
3a
72
84
21b
25c
N
N
N
4d
OSO2Im
O
O
3d
2b
N
3d
N
N
N
N
4e
Ac
N
6
7
2c: X = NAc
3a
67
64
27a
22c
N
N
N
4f
OSO2Im
O
N
N
2a
N
N
N
3d
4g
N
N
8
9
2d: X = NPh
2e: X = S
2b
3a
66
58
62
27a
N
N
4h
S
N
N
3a
28
N
4i
O
O
CF3
N
N
10
3e: R2 = R4 = CF3; R1 = R3 = R5 = H
25c
N
CF3
4j
a
Reactions were performed using (2a–f) (1.0 equiv), basic alumina (500 mg–1 gm), (3a–e) (1.2 equiv), 1h (2.5 mol %), under microwave irradiation (250 W, 100 °C) for 15–
20 min.
b
Isolated yield (some losses during purification were unavoidable in certain cases).
150 °C, and the material was reused three times without any
It is interesting to note that the new protocol was successfully
noticeable change in the yield of the products (data not shown).
employed for the synthesis of fused benzodiazepines 4k using

2264
N. Chatterjee et al. / Tetrahedron Letters 55 (2014) 2261–2265
O
Acknowledgments
O
NH
Ph-OSO2Im
NH
The authors express their gratitude to the Director, IICB for
Basic alumina
Cu(phen)(PPh3)Br
Microwave irradiation,
15 min.
N
N
N3
2f
laboratory facilities, the Council of Scientific and Industrial
Research (CSIR) for providing the funding and fellowships to N.C,
S.S and R.P. The authors gratefully acknowledge Dr. T. Sarkar, Mr.
E. Padmanaban and Mr. K. Sarkar for recording NMR and ESI-MS.
N
4k
Scheme 2. Synthesis of fused benzodiazepines 4k from 2-azido-N-(3-phenylprop-
2-ynyl)benzamide (2f).
Supplementary data
Supplementary data (1H and 13C NMR spectra of all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.080.
2-azido-N-(3-phenylprop-2-ynyl)benzamide (2f), where nitrogen
atom of the amide backbone is unprotected (Scheme 2). Similar
cyclization reactions have been reported earlier where nitrogen
was suitably protected.27a Under the new reaction condition, the
compound was produced in good yield (63%). No by-products
resulting from endo- or exo-cyclization due to the presence of NH
and alkyne functionality in immediate vicinity were observed.
To establish the pathway we carried out the reaction with com-
pounds 2b and 3a and tried to isolate the intermediate products [I
(path A) and II (path B), Scheme 3], but without success. This could
be due to rapid formation of the final product 4d under microwave
irradiation in the presence of basic alumina as solid support. When
the reaction was carried out stepwise and in the absence of electro-
phile (path B, Scheme 3), the intermediate II21b could be isolated.
Subsequent addition of the electrophile in the same reaction vessel
under the same reaction condition afforded the final product 4d.
Recently, Benton et al.27b have shown that a similar type of reac-
tion using Cu(I), base, and solvent at elevated temperature pro-
ceeds via cycloaddition followed by C–H arylation (path B). Since,
Path A and Path B utilize different reagents and keeping in mind
that Sonogashira reaction cannot take place in the absence of elec-
trophile, the exact pathway could not be ascertained.
In summary, we have demonstrated an efficient, economical,
environmentally benign, and rapid process for the synthesis of tri-
azole fused benzoxazines, benzothiazines, benzodiazepines, ben-
zoxazepines, and quinoxalines. The method eliminates the use of
hazardous and expensive palladium salts, additional ligands. No
additional base and solvent are required as basic alumina acts as
solid support and base. The exact reaction mechanism could not
be ascertained, as no intermediate compound could be isolated.
Cu(phen)(PPh3)Br is used as the only catalyst and plays a dual role
in cycloaddition reaction and activation of C–H bond. Moreover,
application of microwave reduces the time of the reaction consid-
erably with improved yield of the product. The uniqueness of the
methodology lies in its eco-friendly operation, reusability of the
solid support, and excellent yield.
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O
Basic alumina,
Cu(phen)(PPh3)Br
O
Ph-OSO2Imidazol-1-yl (3a)
N3
M.W, 15-20 min, 100 o
C
O
O
Ph
I
PATH A
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Basic alumina,
3a
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)
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PATH B
Scheme 3. Possible pathways for the formation of the product 4d.

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