A green-chemistry approach for the efficient synthesis of triazolo benzoxazepines or triazolo benzodiazepines in aqueous micellar system

Article abstract of DOI:10.1016/j.tetlet.2014.01.047

A convenient route for the synthesis of triazole fused benzoxazepines or benzodiazepines in aqueous micellar medium has been described. The two step one-pot synthesis involves Sonogashira reaction of prop-2-ynyl 2-azidobenzoates and aryl iodides followed by intramolecular azide-alkyne cyclization using Pd(CH₃CN)₂Cl₂ as catalyst and ethanedial,1,2-bis(2-methyl-2-phenylhydrazone) as ligand, under atmospheric condition. The method excludes the use of copper salts as catalyst as well as hazardous organic solvents.

Full text of DOI:10.1016/j.tetlet.2014.01.047

Accepted Manuscript
A green-chemistry approach for the efficient synthesis of triazolo benzoxaze-
pines or triazolo benzodiazepines in aqueous micellar system
Rammyani Pal, Swarbhanu Sarkar, Nivedita Chatterjee, Asish Kumar Sen
PII:
S0040-4039(14)00080-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.047
TETL 44079
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2013
10 January 2014
13 January 2014
Please cite this article as: Pal, R., Sarkar, S., Chatterjee, N., Sen, A.K., A green-chemistry approach for the efficient
synthesis of triazolo benzoxazepines or triazolo benzodiazepines in aqueous micellar system, Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.047
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GRAPHICAL ABSTRACT
A green-chemistry approach for the efficient synthesis of triazolo
benzoxazepines or triazolo benzodiazepines in aqueous micellar system
Rammyani Pal, Swarbhanu Sarkar, Nivedita Chatterjee, Asish Kumar Sen*
N3
O
O
O
Ph
H2O, 80 oC
Ph
Ar-I
O
N
N N
N
N
Ligand
Base
CH3
H3C
N
N
Ligand
Ar
Pd(CH3CN)2Cl2

A green-chemistry approach for the efficient synthesis of triazolo
benzoxazepines or triazolo benzodiazepines in aqueous micellar system
Rammyani Pal, Swarbhanu Sarkar, Nivedita Chatterjee, Asish Kumar Sen*
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Jadavpur, Kolkata-700 032, India.
*Corresponding author. Fax: +91 33 24735197; Tel: +91 33 24995806.
E-Mail: asishksen@yahoo.com; aksen@iicb.res.in (A. K. Sen)
Abstract: A convenient route for the synthesis of triazole fused benzoxazepines or
benzodiazepines in aqueous micellar medium has been described. The two step one-pot synthesis
involves Sonogashira reaction of prop-2-ynyl 2-azidobenzoates and aryl iodides followed by
intramolecular azide-alkyne cyclization using Pd(CH3CN)2Cl2 as catalyst and ethanedial,1,2-bis(2-
methyl-2-phenylhydrazone) as ligand, under atmospheric condition. The method excludes the use
of copper salts as catalyst as well as hazardous organic solvents.
Keywords: Domino reaction; Sonogashira, Intramolecular azide-alkyne cyclization; Reaction in
water.
Recent challenges for the synthetic organic chemists encompass the development of new
methods that afford structurally unique products from relatively simple starting materials in
environmentally benign and cost effective manner.1 Towards this endeavour, tandem reactions
where several transformations can be executed in a single reaction vessel, in aqueous medium,
have been evolved.2 Organic reactions in aqueous medium have found widespread applications and
now has become one of the frontier areas of modern research. But, the limited solubility of organic
compounds in water restricts its extensive applications in organic transformations. However, it can
be overcome through the application of various ionic or nonionic surfactants.3 It accumulates
precursor molecules within its small cavity either by internalization due to hydrophobic effect or
by counter ion binding due to electrostatic interactions. Thus surfactants often influence reaction
mechanism and consequently significant difference in the reaction parameters can be observed
with respect to homogeneous catalysis.4
Nitrogen or oxygen rich heterocycles being the integral part of many drugs or therapeutic
agents, the development of new protocols for the synthesis of nitrogen or oxygen-rich medium-
sized heterocyclic rings is always of high demand.5 Benzodiazepines are known to be anti-
insectan,6b antitumor agents,6c muscarinic receptor ligands,6d fibrinogenic receptor antagonist,6e

human neurokininNK1 receptors.6f Benzoxazepines are also known as interleukin-2 inhibitors,6g
apoptotic agents having therapeutic potential in both ex vivo chemotherapy-refractory patient
samples and in vivo murine carcinoma models,6h antitumor agents6i etc. Studies revealed that
structural modification of benzodiazepines or benzoxazepines with fused imidazoles, oxazoles,
triazoles or tetrazoles may increase its therapeutic potential.7 So many procedures have been
developed towards the synthesis of these scaffolds.8 However, the reactions often required the
involvement of either more than single step, drastic reaction conditions or the use of organic
solvents.
Palladium or copper salts or a combination of both have been established to be efficient
catalysts for C-C or C-N bond forming reaction and also widely used for inter and intramolecular
azide-alkyne cycloadditions.9 The most common catalytic system used in such reactions are mainly
PdCl2(PPh3)2, Pd(PPh3)4, Pd-C, Pd(OAc)2, Pd(OAc)2/PPh3 with CuI as co-catalyst. However, use
of only copper or palladium salts in such cross coupling reactions involves the use of phosphine
ligands or amines with tetra-butyl ammonium salts as activator.10 Generally these reactions are
carried out under completely inert atmosphere as phosphines and many copper complexes are
sensitive to moisture. However executions of such reactions in aqueous medium are also reported
in the literature.11 Herein we describe a green protocol in aqueous micellar medium where domino
Sonogashira-azide alkyne cyclization reaction has been used for the synthesis of triazole
benzoxazepines or benzodiazepines using Pd(CH3CN)2Cl2 as catalyst. The method allows domino
Sonogashira coupling-intramolecular azide-alkyne cyclization process under normal atmospheric
conditions using ethanedial,1,2-bis(2-methyl-2-phenylhydrazone) (1b) as ligand (Figure 1).2f,12
A
library of triazole benzoxazepines or benzodiazepines have been synthesized in high yield. The
novelty of the methodology lies in its eco-friendly operation, short reaction time and excellent
yield.
We envisaged using prop-2-ynyl ester or amides of 2-azidobenzoic acid (2a-b) and various
aryl halides (3a-j) that were subsequently used in the two-step, one-pot synthesis of 3-aryl 1,2,3-
triazolo benzoxazepines or benzodiazepines. Initially we chose prop-2-ynyl 2-azidobenzoates (2a)
and phenyliodide (3a) as model reactants to standardize the optimal condition for the synthesis of
3-phenyl-[1,2,3]triazolo[1,5-a][4,1]benzoxazepines (4a) and investigated the feasibility of
Sonogashira coupling-cyclization domino strategy in aqueous micellar medium (CTAB was used
as surfactant in this initial study) using Pd(CH3CN)2Cl2 (2.5 mol%) as the source of palladium in
the absence of any copper salts as co-catalyst (Scheme 1). The effect of different ligands (Figure 1)

was established. Among the ligands employed in the reaction, water-soluble ligand GUAPHOS
(1a) produced 53% of the product. The use of bis-hydrazone ligand N,N’-(1,2-
ethanediylidene)bishexahydro-1H-azepin-1-amine 1c, with a seven membered ring was not found
to be very effective. Similar results were also obtained with 1d, 1e and 1f (gave either poor or
moderate yield). The use of ligand 1b led to excellent yield of 82% for this reaction. The effect of
other palladium salts (PdCl2, Pd/C-PPh3, Pd(dba)2, Pd(PPh3)4, Na2PdCl4, Pd(dtbpf)Cl2, Pd2(dba)3)
were also investigated. It was found that Pd(CH3CN)2Cl2 gave the best result. An increase in the
amount of catalyst did not increase the overall yield significantly.
O
N3
O
I
Pd(CH3CN)2Cl2
O
N
O
Surfactant, H2O, 80 oC
Base, Ligand
N
N
2a
3a
4a
Scheme 1. Synthesis of 4a in aqueous micellar medium
Me2N
NH
NH2Cl
NMe2
ClH2N
Ph
N N
CH3
Ph
N N
H3C
N
P
H
N N
N N
HN
Me2N
1c
1b
NH2Cl
1a
PCy2
OMe
N N
N
MeO
N N
N N
1d
1f
1e
Figure 1. Various ligands used in the study
The effect of different micelles was investigated next and the results are summarized in Table
1. In the absence of any surfactant no significant amount of product was formed even after 24 h
under normal atmospheric condition. But a change in reaction yield was noticed when surfactants
was introduced in the reaction medium. Use of cetyltrimethylammonium bromide (CTAB, 50 mM)

gave a low yield (29%; Table 1, entry 1) of 4a at 80 °C within 40 min. The yield of the product
varied with the amount of the surfactant used. When the amount of CTAB was increased to 80
mM, 4a was obtained in excellent yield (82%, Table 1, entry 4). Further increase in the amount of
CTAB (90mM, Table 1, entry 5) did not produce better result. This result was compared with other
surfactants at 80 mM concentration. Tetradecyltrimethylammonium bromide (TTAB) produced
76% (Table 1, entry 6) whereas sodium dodecylsulfate (SDS) produced 62% (Table 1, entry 7).
The use of nonionic surface-active agents (Table 1, entry 8-11) such as PTS (polyoxyethanyl-α-
tocopheryl sebacate), PSS (polyoxyethanyl-sitosteryl sebacate) or TPGS (α-tocopherol
polyethylene glycol succinate) were almost equally reactive compared to ionic surfactants.
TritonX-114 (70%) however was less effective.
i
The effects of different organic bases, viz. Pr2EtN (N,N-diisopropylethylamine), DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), TMEDA (Tetramethylethylenediamine), DABCO (1,4-
i
diazabicyclo[2.2.2]octane), Et3N (triethylamine) were also envisaged (Table 2). Pr2EtN emerged
as the most effective base when employed in 3.0 molar equivalent and afforded the product in
maximum yield.
Table 1. Effect of different surfactants on the yield of triazolo[1,5-a][4,1]benzoxazepines 4aa
Entry
Surfactant
CTAB
CTAB
CTAB
CTAB
CTAB
TTAB
SDS
Concentration (mM)
Yieldb (%)
1
50
29
37
70
82
82
76
62
70
77
74
75
2
60
3
70
4
80
5
90
6
80
7
80
8
Triton X-114
PTS
80
9
15 wt %
15 wt %
15 wt %
10
11
PSS
TPGS
aAll reactions were performed using 2a and 3a in water at 80 °C for 40 min under normal
i
atmospheric condition; catalyst used Pd(CH3CN)2Cl2 (2.5 mol%), ligand 1b (5.0 mol%), Pr2EtN
(3.0 equiv.).

bYield of isolated pure product.
Table 2. Effect of different bases on the yield of triazolo[1,5-a][4,1]benzoxazepines 4aa
Entry
Base
Amount (equiv.)
Yieldb (%)
1
2
3
4
5
6
7
iPr2EtN
iPr2EtN
iPr2EtN
TMEDA
Et3N
2.5
3.0
3.5
3.0
3.0
3.0
3.0
76
82
82
70
67
62
65
DABCO
DBU
aAll the reactions were performed using 2a and 3a in water at 80 °C for 40 min under normal
atmospheric condition in presence of CTAB (80 mM), Pd(CH3CN)2Cl2 (2.5 mol%) and ligand 1b
(5.0 mol%).
bYield of isolated pure product.
The scope and generality of this approach was then investigated. Various aryl or heteroaryl
iodides were used in our study. Benzoxazepines or benzodiazepines were obtained in good yield
(Table 3). All new products were characterized by NMR and MS spectroscopy. The protocol was
found to be useful with aryl bromides also; it gave equally good result when employed in our
domino strategy (Table 3, entry 11). Formation of Glaser type homocoupling products13 could be
avoided as copper (I) was not used as catalyst in this methodology. No acyclic Sonogashira
products were observed in any cases.
Table 3 Reactions of prop-2-ynyl 2-azidobenzoates (2a-b) and aryl iodides (3a-j) leading to
triazolo benzoxazepines or benzodiazepines (4a-j) in aqueous medium
Entrya Alkynes
Aryl iodides
Product
Yieldb(%) Ref.
O
O
I
O
R1
R5
R4
O
R1
R2
R3
N
N
R2
N3
R3
N
2a
R5
R4
3a: R1 = R2 = R3 = R4 = R5 = H
4a: R1 = R2 = R3 = R4 = R5 = H 82
8a
1
2a
3b: R1 = OMe; R2 = R3 = R4 = R5 =
4b: R1 = OMe; R2 = R3 = R4 =
R5 = H
2
81
-
2a
H

4c: R2 = CF3; R1= R3= R4 = R5
3
4
3c: R2 = CF3; R1= R3= R4 = R5 = H
90
-
-
2a
2a
= H
4d: R2 = R4 = CF3; R1= R3= R5 88
3d: R2 = R4 = CF3; R1= R3= R5 = H
= H
O
I
O
5
6
7
79
-
2a
2a
N
N
N
N
N
3e
4e
O
O
I
78
-
S
N
N
S
3f
N
4f
O
O
I
Me
Me
Me
Me
N
Me
N
8b
80
N
N
N3
N
2b
2b
3g
3e
4g
4h
O
N
8b
8b
8
9
83
74
N
N
N
N
O
N
F
I
2b
N
N
3h
3b
N
F
4i
O
N
OMe
8b
8a
10
11
76
68
2b
2a
N
N
N
4j
Br
4a
3i
aAll reactions were performed using 2a-b (1 equiv.), 3a-j (1.5 equiv.) Pd(CH3CN)2Cl2 (2.5 mol
%), ligand 1b (5.0 mol %), CTAB (4mmol) in water (50 mL) at 80 °C for 30-40 min under normal
atmospheric condition in presence of iPr2EtN (3.0 equiv.).
bYield of isolated pure product.

In summary, we have developed an efficient and environmentally benign process for the easy
and fast synthesis of triazolo benzoxazepines and benzodiazepines in aqueous micellar medium.14-
15
It was demonstrated that ethanedial,1,2-bis(2-methyl-2-phenylhydrazone) arose as an useful
ligand for this domino strategy. The method does not require the use of copper as co-catalyst and
organic solvents. The green reaction condition and excellent yields of products make the protocol a
convenient and alternate route for the preparation of triazole fused benzoxazepines or
benzodiazepines.
Acknowledgment
The authors express their gratitude to the Director, IICB for laboratory facilities, the Council
of Scientific and Industrial Research (CSIR) for providing the funding and fellowships to R.P.,
S.S. and N.C.
Supplementary data
Supplementary data (1H and C NMR spectra of all new compounds) associated with this article
13
can be found in the online version, at doi…...
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14. General reaction procedure for the synthesis of triazolo benzodiazepines or benzoxazepines:
In a round-bottomed flask filled with 50 mL of water, prop-2-ynyl-2-azidobenzoates (2a-b,
1.0 equiv.), aryl halides (3a-j, 1.5 equiv.), Pd(CH3CN)2Cl2 (2.5 mol%), ligand 1b (5 mol%),
iPr2EtN (3.0 equiv.) were stirred vigorously under sonication at 80 °C for 30-40 min under
atmospheric condition in presence of CTAB (4 mmol). When TLC indicated completion of
the reaction, the mixture was extracted with ethyl acetate (3 x 25 mL) and washed thoroughly
with water. Column chromatography [silica gel (60-120), petroleum ether:ethyl acetate (5:1)
as eluent] produced pure products (4a-j).

1
15. Spectral data of compound 4f : H NMR (CDCl3, 300 MHz): δ = 5.44 (s, 2H), 7.18-7.20 (m,
1H), 7.47 (d, J = 5.1 Hz, 1H), 7.51 (dd, J = 0.9, 3.6 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.83-
7.86 (m, 1H), 8.14-8.18 (m, 2H) ppm; NMR (CDCl3, 75 MHz): δ = 57.12, 122.40, 122.70,
126.34, 126.93, 127.75, 128.02, 129.62, 130.55, 133.16, 134.12, 134.97, 140.59, 166.60
ppm; HRMS (ESI): m/z calcd for C14H9N3O2S [M + Na]+: 306.0313; found 306.0319.