A new route to 1,2,3-triazole fused benzooxazepine and benzodiazepine analogues through metal-free intramolecular azide-olefin oxidative cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2019.151164

A collection of 1,2,3-triazole fused benzooxazepine and benzodiazepine analogues was prepared by one pot azide substitution and intramolecular azide-olefin oxidative cycloaddition sequence under metal-free conditions.

Full text of DOI:10.1016/j.tetlet.2019.151164

Journal Pre-proofs
A New Route to 1,2,3-Triazole Fused Benzooxazepine and Benzodiazepine Analogues Through Metal-free Intramolecular
Azide-Olefin Oxidative Cycloaddition
D. Gangaprasad, J. Paul Raj, K. Karthikeyan, R. Rengasamy, M. Kesavan, M.
Vajjiravel, J. Elangovan
PII:
S0040-4039(19)30938-4
DOI:
https://doi.org/10.1016/j.tetlet.2019.151164
TETL 151164
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 July 2019
14 September 2019
16 September 2019
Please cite this article as: Gangaprasad, D., Paul Raj, J., Karthikeyan, K., Rengasamy, R., Kesavan, M., Vajjiravel,
A New Route to 1,2,3-Triazole Fused Benzooxazepine and Benzodiazepine Analogues Through Metal-free Intramolecular Azide-Olefin Oxidative
M., Elangovan, J.,
Cycloaddition
,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151164
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. 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.
©
2019 Published by Elsevier Ltd.

Graphical Abstract
A collection of 1,2,3-Triazole fused benzooxazepine and benzodiazepine analogues was prepared by one pot azide
substitution and intramolecular azide-olefin oxidative cycloaddition sequence under metal-free conditions.
A New Route to 1,2,3-Triazole Fused Benzooxazepine Leave this area blank for abstract info.
and Benzodiazepine Analogues Through Metal-free
Intramolecular Azide-Olefin Oxidative Cycloaddition
a
a
a
b
c
a,
Gangaprasad. D , Paul Raj. J , Karthikeyan. K , Rengasamy. R , Kesavan. M , Vajjiravel. M * and Elangovan.
b,
J *
R2
O
N
O
- Metal-free
- One-pot
- Easy accessibility of
starting materials
R2
N
NaN3
R1
N
Br
R1
X
DMF
X= O,NTs
X
Up to 92 % Yield
7 Compounds
1

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A New Route to 1,2,3-Triazole Fused Benzooxazepine and Benzodiazepine
Analogues Through Metal-free Intramolecular Azide-Olefin Oxidative
Cycloaddition
a
a
a
b
c
a,
Gangaprasad. D , Paul Raj. J , Karthikeyan. K , Rengasamy. R , Kesavan. M , Vajjiravel. M * and
Elangovan. J *
b,
a
Department of Chemistry, B. S. Abdur Rahman Crescent Institute of Science and Technology, Vandalur, Chennai - 600048, India. E-mail:chemvel@gmail.com
Department of Chemistry, Rajah Serfoji Government College, Thanjavore, Tamilnadu - 613005, India.
E-mail: elangoorganic@gmail.com
b
c
Interdisplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology, Kattankulathur 603203, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A collection of 1,2,3-Triazole fused benzooxazepine and benzodiazepine analogues was
prepared by one pot azide substitution and intramolecular azide-olefin oxidative cycloaddition
sequence under metal-free conditions.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Fused 1,2,3-triazole
Metal-free conditions
Benzooxazepine
Benzodiazepine
Oxidative Cycloaddition
8
Fused oxazepines have sprung into prominence due to their
activity. Compound (D) is a 1,2,3-triazole fused benzodiazepine
1
9
remarkable implications in biology and pharmacy including
skeleton and it has emerged as a protease inhibitor.
2
3
4
antipsychotic , anti-tumor and anti-inflammatory activities.
Similarly fused diazepines also are bestowed with a wide
spectrum of applications.5 Figure 1 gives a glimpse on the
paramount importance of these molecules in biology by
displaying a few active molecules. Sintamil (A) was known to be
In continuation of our previous report on synthesis of 1,2,3-
triazoles by oxidative azide-olefin cycloadditions (OAOC) and
eliminative azide-olefin cycloadditions (EAOC),
10
we were
prompted to extend that approach to the synthesis of 1,2,3-
triazole fused oxazepines and diazepines. Our literature perusal
on these fused heterocycles revealed four precedented strategies
to access the triazole fused diazepines. Nevertheless, to the best
of our knowledge, no report is found on the synthesis of triazole
fused oxazepines. Martin et al. have reported the synthesis of
triazolefused diazepines by one pot synthesis involving reductive
amination, followed by a thermally induced, intramolecular
Huisgen cycloaddition (Scheme 1, Equation 1)11. Eycken’s group
has reported a protocol involving Cu-catalyzed azidation
followed by intramolecular Huisgen cycloaddition to access the
6
used as an antidepressant agent. Loxapine (B), a piperazine
substituted benzooxazepine skeleton is a drug administered for
7
the treatment of schizophrenia. Anthramycin (C), which is a
pyrrolobenzodiazepine antibiotic, is known for its antitumor
N
O
N
N
O2N
N
Cl
O
O
A
HCl
N
B
12
triazole fused benzodiazepines (Scheme 1, Equation 2).
N
N
N
Another elegant method was reported by Majumdar and co-
workers where tandem Ullmann type coupling and azide-alkyne
sequence was employed to prepare this family of molecules
(Scheme 1, Equation 3). Finally Sudhapriya et al have
developed a one-pot sequential diazotization, azidation and
OH
H
HO
H
HN
H3C
N
N
13
O
F
O
O
D
C
NH2
cycloaddition reactions to access this family of benzodiazepines
Figure 1. Some biologically important fused oxazepines and
diazepines.
14
(Scheme 1, Equation 4). However, no reports are found in the
synthesis of triazole fused benzooxazepines. As an alternative
attempt, herein we report a one-pot synthesis of 1,2,3-triazole
fused benzooxazepines and diazepines by sequential azidation

2
Tetrahedron
S.No
1
Solvent
Toluene
DMSO
DMF
Temperature
Time
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6h
Yield%[b]
45
56
78
53
48
42
32
49
47
46
52
67
79
60
77
79
and intramolecular oxidative azide-olefin cycloaddition
o
reactions (Scheme 1, Equation 5).
90 C
o
2
3
4
5
6
7
8
9
90 C
Precedents
o
N
N
90 C
o
N3
1. H2N
NaBH(OAc)3
, AcOH
2
H O
90 C
N
N
(
1)
2)
o
CHO
t-BuOH
THF
90 C
o
. Toluene, 100 o
90 C
2
C
o
CHCl
3
90 C
R1
o
MeOH
ACN
DCE
DMF
DMF
DMF
DMF
DMF
DMF
90 C
R2
N
(
o
1
5-Crown-5
R2
R3
90 C
N
NaN3, CuI
o
N
N
10
90 C
R1
R3
Br
Br
o
1
1
60 C
N
o
R
12
80 C
6h
6h
5h
7h
H
N
o
1
1
3
4
110-120 C
N
(3)
N3
R
DMF, K2CO3
o
90 C
+
N
CuI, 110 o
C
o
15
16
90 C
N
N
o
R1
90 C
8h
R1
N
R2
i) diazotization
ii) azidation
[a]
N
Olefin (1.0 mmol), sodium azide (2.0 mmol), were dissolved in (1.0 ml) solvent,
R2
R3
o
[b]
(4)
NH2
heated into 90 C at 6h under open atmosphere. Isolated yield.
iii) cycloaddition
N
R3
N
N
R2
Present work
Having established the optimized conditions (Table 1, entry 3)
for metal-free synthesis of 1,2,3-triazole fused benzooxazepines
and benzodiazepines, we extended that condition to various
substrates (Table 2).Various changes in the substitution on the
ketone side and the alkene side of the starting material were
meticulously examined. As shown in the optimization table,
ketone with an unsubstituted aryl group furnished the
O
N
O
R2
Br
N
NaN3
R1
N
(5)
R1
X
X= O,NTs
X
Scheme 1. Background of the synthesis of triazole fused
benzodiazepines.
benzooxazepine (2a) with 78% yield.
While introducing
substitution in the meta position of the aryl ring, methyl
substitution has shown almost similar efficacy while chloro
substitution has displayed a remarkable enhancement as stated
At the outset, we started our investigation, fixing the olefin (1a)
as model substrate for examination and optimization. Fixing the
o
temperature and time invariably as 90 C and 6.0 hours, we
Table 2 . Metal-free synthesis of triazole fused benzooxazepines and
benzodiazepines
carried out the reaction in various solvents. Initial attempt with
toluene as solvent resulted in a poor yield of product (Table 1,
entry 1). Little enhancement of yield was observed in DMSO
Br
CH3
Cl
(Table 1, entry 2). To our surprise, remarkable enhancement of
yield of the fused triazole (2a) was obtained when the reaction
was carried out in DMF (Table 1, entry 3). Water and tertiary
butanol were also found to be ineffective for this transformation
as the yield of the product decreased to 53% and 48 % (Table 1,
entry 4 and entry 5). Further decrease of the yield of the product
was obtained when THF was used as the solvent (Table 1, entry
N
N
O
O
N
N
N
N
O
O
N
N
N
N
N
N
O
O
O
O
2
a (78%)
2c (92%)
2d (90%)
6
). On the other hand, when we moved on to chloroform, the
2b (78%)
yield plummeted to 32% (Table 1, entry 7). Solvents such as
methanol, acetonitrile and dichloroethane also gave a poor yield
of 46-49%. (Table 1, entry 8-entry 10). From these above
observation, DMF was revealed as the best solvent. Fixing the
DMF as the solvent, the role of temperature was also
BnO
Ph
S
N
N
N
O
N
N
N
O
O
O
N
N
N
o
meticulously studied. As we raised the temperature from 60 C
N
N
N
o
to 80 C, consistent improvement of yield was noticed (Table 1,
O
entry 11 – entry 12). When the temperature was elevated to 110
O
O
O
o
o
C – 120 C, no pronounceable improvement was observed
2e (91%)
2f (89%)
2g (82%)
2h (78%)
o
(
Table 1, entry 13). Hence, we resolved to fix 90 C as the
temperature for this transformation. To study the role of time
variation, we tested the reaction by prolonging the reaction from
CH3
N
5
hours to 8 hours (Table 1, entries 14 – 16). Reaction for 5
N
N
N
N
O
O
N
O
O
N
N
N
hours, substantially decreased the yield of the product while 7
hours and 8 hours furnished almost equal yield to that of the
reaction carried out for 6 hours. Hence we decided to fix 6 hours
as the time duration for this protocol.
N
Br
N
N
H3C
N
O
Ts
70%)
O
O
2i (76%)
2j (85%)
2k
(84%)
2l (
CH3
Cl
n-Bu
N
N
Table 1. Optimization of one-pot azidation, intramolecular
N
O
O
O
N
N
[a]
N
N
N
N
N
OAOC.
O
O
N
N
N
N
N
Ph
N
N
N
Ts
N
N
N
Ts
Ts
O
O
N
Ts
m (75%)
Ts
2n (78%)
2o (85%)
2p (70%)
2q (72%)
N
2
NaN3
Ph
Br
Solvent
[
a]Olefin (1.0 mmol), sodium azide (2.0 mmol), were dissolved in (1.0 ml)
DMF, heated into 90 C at 6h under open atmosphere. [b] Isolated yield.
O
O
o
2a
1a

3
from the yield of the products 2b and 2c. On the other hand,
while considering the para substitutions, bromo and benzyloxy
substitutuions excelled to ensure excellent yield of the
benzooxazepines 2d and 2e. A thiophene ring on the ketone side
exhibited a similar effect as evident from the yield of the product
Upadhyaya, P.; Eur. J. Med. Chem., 1986, 21, 21.
7
8
.
.
Liao, Y.; Venhuis, B. J.; Rodenhuis, N.; Timmerman, W.; Wikstrom,
H.; J. Med. Chem., 1999, 42, 2235-2244.
(a) Leimgruber, W.; Stefanovic, V.; Schenker, F.; Karr, A.; Berger, J.;
J. Am. Chem. Soc. 1965, 87, 5791-5793 (b) Leimgruber, W.; Batcho,
A. D.; Schenker, F.; Karr, A.; Berger, J.; J. Am. Chem. Soc. 1965, 87,
2
f. On the other hand, significant retardation in the efficiency of
this protocol was observed when biphenyl system is present in
the ketone side as evident from the decrease of yield of 2g.
Furthermore, when aliphatic substitution was on the ketone side
as reflected from the lower of yields of the products 2h and 2i.
Substitution on the aryl ring on the olefin side of the starting
material also was carefully examined. Methyl and bromo
substitutions were examined and it was perceived that both were
equally forwarded this transformation as reflected from the
similar yields of the products 2j and 2k. Similarly,
benzodiazepines also were synthesized in this approach.
Benzodiazepine (2l) was prepared in 70% yield which is slightly
less than the yield of its oxygen analogue 2a. Unlike 2b and 2c,
the methyl and chloro substitutions on the phenyl ring of the
ketone part of the starting material, exhibit almost similar effect
as testified from the yields of 2m and 2n. In the case of aliphatic
substitution on the ketone part, cyclopropyl group was perceived
to be more effective than n-butyl and methyl groups since the
yield of 2o is greater than 2p and 2q.
5
791-5793.
9.
(a) Sharpless, K. B.; Manetsch, R.; Expert. Opin. Drug Discovery.,
2006, 1, 525-538; (b) Mohapatra, D. M.; Maity, P. K.; Shabab, M.;
Khan, M. I.; Bioorg. Med. Chem. Lett., 2009, 19, 5241-5245.
1
0. (a) Gangaprasad, D.; Paul Raj, J.; Kiranmye, T.; Sadik, S. S.;
Elangovan, J.; RSC Adv. 2015, 5, 63473-63477; (b) Gangaprasad, D.;
Paul Raj, J.; Kiranmye, T.; Sasikala, R.; Karthikeyan, K.; Kutti Rani
S.; Elangovan, J.; Tet. Lett. 2016, 57, 3105-3108; (c) Gangaprasad, D.;
Paul Raj, J.; Kiranmye, T.; Karthikeyan, K.; Elangovan, J.; Eur. J.
Org. Chem. 2016, 34, 5642-5646; (e) Gangaprasad, D.; Paul Raj, J.;
Karthikeyan, K.; Rengasamy, R.; Elangovan, J.; Adv. Synth. Catal.
2018, 360, 4485-4490.
11. Donald, J. R.; Martin, S. F.; Org. Lett., 2011, 13, 852-855.
2. Hooyberghs, G.; Coster, H. D.; Vachhani, D. D.; Ermolat’ev, D. S.;
Van der Eycken, E. V.; Tetrahedron., 2013, 69, 4331-4337.
3. Majumdar, K. C.; Ganai, S.; Tetrahedron Lett., 2013, 54, 6192-6195.
4. Sudhapriya, N.; Nandakumar, A.; Arun, Y.; Perumal, P. T.;
Balachandran, C.; Emi, N.; RSC Advances., 2015, 5, 66260-66270.
5. Wang, T.; Guo, Z.; Curr. Med. Chem. 2006, 13, 525-537.
1
1
1
A new protocol to access 1,2,3-triazole fused benzooxazepine
and benzodiazepine analogues was developed by intramolecular
azide-olefin oxidative cycloaddition. This method differs from its
predecessors owing to the following attributes. 1. This method
involves azide-olefin cycloaddition to construct the 1,2,3-triazole
moiety while the other methods use azide-alkyne cycloaddition
approach. It is worth mentioning that the alkenes are
commercially and synthetically more viable than alkynes. 2. This
method becomes versatile because this can be used to access both
triazole fused benzooxazepine and benzodiazepine moieties
while other methods can be used to achieve only triazole fused
benzodiazepines. 3. This method also holds the advantage of
copper-free condition owing to the cytotoxicity of copper
1
Highlights
 A collection of 1,2,3-triazole fused
benzooxazepine and benzodiazepine
analogues was prepared
 Using one pot azide substitution and
intramolecular azide-olefin oxidative
1
5
catalysts. 4. The azide substitution and oxidative azide-olefin
cycloaddition steps take place consecutively in one-pot. Hence
this method can prove to be a promising alternative to the
existing methods to access this family of 1,2,3-triazole fused
benzooxazepines and benzodiazepines
References and notes
cycloaddition sequence under metal-free
conditions.
1
(a) MiKi, T.; Kori, M.; Mabuchi, H.; Tozawa, R.; Nishimotos, T.;
Sugiyama, Y.; Teshima, K.; Yukimasa, H.; J. Med. Chem., 2002, 45,

Conditions are grabs the advantage of
copper-free condition owing to the
cytotoxicity of copper catalysts.
4
7
571-4580; (b) Bihel, F.; Kraus, J. L.; Org. Biomol. Chem., 2003, 1,
93-799; (c) Merluzzi, V. J.; Hargrave, K. D.; Labadia, M.; Grozinger,
K.; Skoog, M.; Wu, J. C.; Shih, C. K.; Eckner, K.; Hattox, S.; Adams,
J.; Rosenthal, A. S.; Faanes, R.; Eckner, R. J.; Koup, R. A.; Sullivan, J.
L.; Science, 1990, 250, 1411-1413; (d) Smits, R. A.; Lim, H. D.;
Stegink, B.; Bakker, R. A.; de Esch, I. J. P.; Leurs, R.; J. Med. Chem.,
2
006, 49, 4512-4516; (e) Liao, Y.; Venhuis, B. J.; Rodenhuis, N.;
Timmerman, W.; Wikstrom, H.; Meier, E.; Bartoszyk, G. D.;
Bottcher, H.; Seyfried, C. A.; Sundell, S.; J. Med. Chem., 1999, 42,
2
235-2244.
2
3
Liao, Y.; Venhuis, B. J.; Rodenhuis, N.; Timmerman, W.; Wikström,
H.; J. Med. Chem., 1999, 42, 2235-2244.
Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.;
Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao,
M.; Garattini, E.; ACS Med. Chem. Lett., 2010, 1, 411-415.
Chakrabarti, J. K.; Hicks, T. A.; Eur. J. Med. Chem., 1987, 22, 161-
.
4
5
.
.
1
63.
(a) Thurston, D. E.; Jones, G. B.; Davis, M. E.; J. Chem. Soc., Chem.
Commun. 1990, 0, 874-876. (b) Basolo, L.; Beccalli, E. M.; Borsini,
E.; Broggini, G.; Khansaa, M.; Rigamonti, M.; Eur. J. Org. Chem.
2
010, 1694. (c) Markandeya, N.; Shankaraiah, N.; Reddy, C. S.;
Santos, L. S.; Kamal, A.; Tetrahedron Asymmetry 2010, 21, 2625-
2
2
8
630. (d) Antonow, D.; Thurston, D. E.; Chem. Rev. 2011, 111, 2815-
864. (e) Mitra, S.; Darira, H.; Chattopadhyay, P.; Synthesis 2013, 45,
5-92.
6
.
Nagarajan, K.; David, J.; Kulkarni, Y. S.; Hendi, S. B.; Shenoy, S. J.;