An expedient entry to fused [1,2,5]-triazepine derivatives: Extension to fused [1,2,5]-oxadiazine derivatives, a new class of seven-membered heterocycles

Article abstract of DOI:10.1055/s-0029-1217178

This document describes an efficient synthesis of fused indole containing tricyclic [1,2,5]-triazepine derivatives from 2-cyanomethyl indole in two simple and convenient steps. This new methodology allows us to synthesize a variety of substituted [1,2,5]-

Full text of DOI:10.1055/s-0029-1217178

LETTER
1463
An Expedient Entry to Fused [1,2,5]-Triazepine Derivatives: Extension to
Fused [1,2,5]-Oxadiazine Derivatives, a New Class of Seven-Membered
Heterocycles1
E
xpedient Entry to
a
F
used [1,2
d
,5]-Triazepin
e
e
D
erivatives Srinivas Reddy,a,b Prataprao Anil Kumar,a Ramasamy Vijaya Anand,a Kaga Mukkanti,b Padi Pratap Reddy*a
a
Research & Development, Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Bachupally, Ranga Reddy
District 500072, Andhra Pradesh, India
E-mail: prataprp@drreddys.com
b
Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, Andhra Pradesh, India
Received 6 January 2009
rivatives annulated with other heterocycles. Indole nucle-
us is found in several biologically active molecules,8 thus
many research groups were motivated to explore the func-
tionalization of indoles and study their pharmacological
Abstract: This document describes an efficient synthesis of fused
indole containing tricyclic [1,2,5]-triazepine derivatives from 2-
cyanomethyl indole in two simple and convenient steps. This new
methodology allows us to synthesize a variety of substituted [1,2,5]-
triazepine derivatives in excellent yields. Further exploration of this effects.9
methodology using 2-cyanomethyl indole and hydroxylamine di-
We describe, herein, a new and efficient route to the syn-
rected us to access a new class of seven-membered fused [1,2,5]-ox-
adiazine derivatives in good to excellent yields.
thesis of fused indole containing [1,2,5]-triazepine sys-
tems starting from readily accessible 1H-indole-2-
carbonitrile (5)10 in two straightforward steps. As a repre-
sentative example, 1H-indole-2-carbonitrile (5) was treat-
ed with p-methoxyphenacyl bromide (6) in the presence
of potassium carbonate and catalytic amount of tetrabutyl-
ammonium iodide (TBAI) in acetone at reflux tempera-
ture to provide N-alkylated 1H-indole-2-carbonitrile 7a in
78% yield. The next stage was cyclization reaction, where
7a was treated with hydrazine hydrate at reflux tempera-
ture to provide fused indole containing [1,2,5]-triazepine
derivative 8a in 86% yield (Scheme 1). Using the above
mentioned standard protocol, 1H-indole-2-carbonitrile 5
was converted into a variety of N-alkylated 1H-indole-2-
carbonitrile derivatives 7b–f11 followed by [1,2,5]-triaz-
epine derivatives 8b–f12 in an efficient manner with good
to excellent yields (Table 1). All the new compounds were
completely characterized by standard analytical tech-
niques.
Key words: heterocycles, indoles, fused-ring systems, [1,2,5]-tri-
azepines, [1,2,5]-oxadiazines
In recent years, it has been demonstrated that several seven-
membered heterocyclic compounds show important bio-
logical deeds.2 Among seven-membered heterocycles, di-
azepines and triazepines have attracted a great extent of
attention as precursors in the synthesis of annulated
heterocyclic systems of potential pharmacological activi-
ties.3 Recently, Sui and co-workers have revealed that
[1,2,5]-triazepine derivatives 1 and 2 could be used as
neurotropic agents for the treatment of Parkinson’s and
Alzheimer’s diseases (Figure 1).4 Gani’s group has
proved that proline-fused [1,2,5]-triazepine derivatives 3
and 4 are potential conformational mimics for cis-peptidyl
prolinamides (Figure 1).5
O
O
O
H2N
NH
N
CN
NH
N
N
N
NH
N
S
O
N
N
NH
NH
R2 R1
O
N
(ii)
(i)
S
CN
O
O
86%
78%
N
H
3 R1 = R2 = H
1
2
4 R1 = H, R2 = Me
R
R
7a (R = OMe)
8a (R = OMe)
Figure 1
5
Scheme 1 Synthesis of [1,2,5]-triazepine derivative 8a. Reagents
and conditions: (i) 6, K2CO3, TBAI (cat.), acetone, D (ii) hydrazine
hydrate, D.
Though the synthesis of seven-membered [1,2,4]-triaz-
epine derivatives is well precedented in the literature,6
few reports are known for [1,2,5]-triazepine systems.7 As
a part of our ongoing research work on indole derivatives,
we became interested in the synthesis of a few indole de-
The success in the synthesis of fused indole containing
seven-membered [1,2,5]-triazepine derivatives triggered
us to explore this methodology further by using different
reagents instead of hydrazine hydrate in the second stage.
In this regard, hydroxylamine hydrochloride was chosen
as the reagent of choice.
SYNLETT 2009, No. 9, pp 1463–1465
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x.
x
x.
2
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Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217178; Art ID: D00509ST
© Georg Thieme Verlag Stuttgart · New York

1464
G. S. Reddy et al.
LETTER
As expected, the reaction of 7a with hydroxylamine
hydrochloride and sodium carbonate in methanol at reflux
temperature furnished a new class of seven-membered
[1,2,5]-oxadiazine derivative 9a in 81% yield (Scheme 2).
IR spectrum of 9a displayed imine NH (3401 cm–1) and
C=N (1628 cm–1) absorptions and the structure of 9a was
Table 1 Synthesis of N-Alkylated 1H-Indole-2-carbonitrile Inter-
mediates 7b–f and [1,2,5]-Triazepine Derivatives 8b–f
Entry
R
Intermediate Yield (%)a Product Yield (%)b
1
2
3
4
5
H
7b
7c
7d
7e
7f
70
75
76
68
64
8b
8c
8d
8e
8f
86
84
81
78
82
Me
Et
1
further confirmed by mass spectrometric and H NMR
and 13C NMR spectroscopic techniques. To date, to the
best of our knowledge, no literature precedent is available
for the synthesis of seven-membered [1,2,5]-oxadiazepine
derivatives. We believe that these new seven-membered
[1,2,5]-oxadiazine systems might potentially show equal
or better pharmacological actions when compared with
six-membered [1,2,4]- and [1,2,5]-oxadiazine derivatives.
SMe
i-Bu
a Isolated yield of the intermediate.
b Isolated yield of the product.
To explore the versatility of this methodology, hydroxyl-
amine hydrochloride was treated with a variety of N-alky-
lated 1H-indole-2-carbonitrile derivatives 7b–f18 and the
results are summarized in Table 2. All the fused indole
containing [1,2,5]-oxadiazine derivatives 9b–f were iso-
lated as stable crystalline materials, and were thoroughly
characterized by standard spectroscopic techniques.
HN
CN
O
N
O
NH
(i)
N
88%
R
R
A plausible mechanism for the formation of 8a and 9a is
represented in Scheme 3, where 7, on reaction with hydra-
zine hydrate and hydroxylamine hydrochloride, provides
hydrazone derivative 10 and oxime derivative 11, respec-
tively. Intramolecular cyclization of 10 affords a seven-
membered heterocycle 12, which further isomerizes to 14.
Finally, 14 tautomerizes to [1,2,5]-triazepine derivative
8a.
7a (R = OMe)
9a (R = OMe)
Scheme 2 Reaction of 7a with NH2OH·HCl. Reagents and condi-
tions: (i) NH2OH·HCl, Na2CO3, MeOH, reflux.
Table 2 Synthesis of [1,2,5]-Oxadiazine Derivatives 9b–f
Entry
R
Substrate
Product
9b
Yield (%)a
1
2
3
4
5
H
7b
7c
7d
7e
7f
88
77
84
72
80
Similarly, in the case of 11, intramolecular cyclization
generates a seven-membered intermediate 13, which im-
mediately isomerizes to [1,2,5]-oxadiazine derivative 9a.
Me
Et
9c
9d
In conclusion, we have developed a novel and efficient
route to the synthesis of indole-annulated seven-mem-
bered [1,2,5]-triazepine derivatives from 1H-indole-2-
carbonitrile in two simple steps. By extending this meth-
odology, we were able to prepare a new class of indole-
annulated [1,2,5]-oxadiazine derivatives in excellent
yields. Further exploration using N-substituted hydrazine
and hydroxylamine analogues are currently in progress.
SMe
i-Bu
9e
9f
a Isolated yield of the product.
We anticipated that the reaction of hydroxylamine hydro-
chloride with 7a under basic conditions would perhaps
lead to a new class of seven-membered fused [1,2,5]-oxa-
diazine system, which would have potential pharmacolog-
ical properties. Six-membered [1,2,4]-oxadiazine13 and
[1,2,5]-oxadiazine14 derivatives are recognized as useful
heterocycles and could be used as bactericides,15 fungi-
cides,15 nitric oxide synthase inhibitors,16 and peripheral
vasodilators.17
Acknowledgment
We greatly appreciate the supportive environment encouraged at
Dr. Reddy’s Laboratories Ltd. We are thankful to the Intellectual
Property Management, the NMR group of Dr. Reddy’s Research
H
N
HN
N
H2N
N
CN
••
••
N
X
X
X
N
••
O
N
XH
N
NH
NH
N
N
H
OMe
OMe
OMe
OMe
OMe
10 X = NH
11 X = O
12 X = NH
13 X = O
14 X = NH
9a X = O
7a
8a X = N
Scheme 3 Proposed reaction mechanism
Synlett 2009, No. 9, 1463–1465 © Thieme Stuttgart · New York

LETTER
Expedient Entry to Fused [1,2,5]-Triazepine Derivatives
1465
Foundation and the analytical group of Integrated Product Develop-
ment Organization for their generous support.
(s, 3 H, OMe), 6.05 (s, 2 H, NCH2), 7.15 (d, J = 8.4 Hz, 2 H,
Ar), 7.21 (t, J = 7.6 Hz, 1 H, Ar), 7.37 (t, J = 8.4 Hz, 1 H,
Ar), 7.52 (s, 1 H, indole CH), 7.62 (d, J = 8.8 Hz, 1 H, Ar),
7.73 (d, J = 8.4 Hz, 1 H, Ar), 8.13 (d, J = 8.4 Hz, 2 H, Ar).
13C NMR (50 MHz, DMSO-d6): d = 50.5, 55.6, 109.9, 110.5,
113.4, 113.7, 114.2, 121.6, 122.5, 126.1, 126.2, 127.1,
130.4, 138.1, 164.4, 189.6. HRMS (ES): m/z calcd for
C18H15N2O2 [M + 1]: 291.1134; found: 291.1121.
(12) [1,2,5]-Triazepine Derivative 8a; Typical Procedure
A solution of 7a (10.2 g, 0.035 mol) in hydrazine hydrate (50
mL) was refluxed for 2 h. It was cooled to r.t. and filtered to
give compound 8a as a solid. Yield: 9.2 g (86%); mp 258–
260 °C. FT IR (KBr): 3164, 3293, 3053, 1638 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 3.81 (s, 3 H, OMe), 7.04 (d, J =
8.8 Hz, 2 H, Ar), 7.27 (s, 1 H, indole CH), 7.30 (t, J = 8.0 Hz,
1 H, Ar), 7.40 (t, J = 8.0 Hz, 1 H, Ar), 7.73 (d, J = 8.8 Hz, 2
H, Ar), 7.82 (d, J = 8.0 Hz, 1 H, Ar), 8.14 (s, 1 H, NCH=C),
8.20 (d, J = 8.8 Hz, 1 H, Ar), 10.99 (br s, 1 H, NH). 13C NMR
(50 MHz): d = 55.3, 101.1, 102.7, 112.1, 114.0, 122.0, 122.3,
123.5, 124.4, 124.5, 126.8, 126.9, 127.3, 132.2, 157.3,
159.4. HRMS (ES): m/z calcd for C18H17N4O [M + 1]:
305.1402; found: 305.1403.
(13) (a) Cho, S. Y.; Kang, S. K.; Ahn, J. H.; Ha, J. D.; Choi, J.-K.
Tetrahedron Lett. 2006, 47, 9029. (b) Srivastava, R. M.;
de Morais, L. P. F.; de Melo Souto, S. C.; Carpenter, G. B.;
de Carvalho, L. T. Tetrahedron Lett. 2006, 47, 3173.
(c) Tabei, K.; Kawashima, E.; Takada, T.; Kato, T. Chem.
Pharm. Bull. 1982, 30, 3987.
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C. S.; Schambony, S.; McArdle, P.; Cunningham, D. J.
Chem. Soc., Perkin Trans. 1 1997, 1047.
References and notes
(1) IPD communication number: DRL-IPDO-IPM-00176.
(2) (a) Eicher, T.; Hauptmann, S. The Chemistry of
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(d) Itto, M. Y. A.; Hasnaoui, A.; Riahi, A.; Lavergne, J.-P.
Tetrahedron Lett. 1997, 38, 2087. (e) Quan, H.-J.;
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S.; Komada, F.; Saito, S. Chem. Pharm. Bull. 2006, 54, 73.
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Trans. 1 1997, 2297.
(6) (a) Seebacher, W.; Michl, G.; Weis, A. Tetrahedron Lett.
2002, 43, 7481. (b) Rezessy, B.; Zubocics, Z.; Kovacs, J.;
Toth, G. Tetrahedron 1999, 55, 5909. (c) Adamo, M. F. A.;
Baldwin, J. E.; Adlington, R. M. J. Org. Chem. 2005, 70,
3307; and references cited therein.
(7) (a) Saveleva, E. A.; Rozin, Y. A.; Kodess, M. I.; Meervelt,
L. V.; Dehaen, W.; Morzherin, Y. Y.; Bakulev, V. A.
Tetrahedron 2004, 60, 5367. (b) Zaleska, B.; Trzewik, B.;
Grochowski, J.; Serda, P. Synthesis 2003, 2559.
(c) Katritzky, A. R.; Fan, W.-Q.; Greenhill, J. V. J. Org.
Chem. 1991, 56, 1299. (d) Lenman, M. M.; Lewis, A.; Gani,
D. J. Chem. Soc., Perkin Trans. 1 1997, 2297. (e) Bouteau,
B.; Imbs, J.-L.; Lancelot, J.-C.; Barthelmebs, M.; Robba, M.
Chem. Pharm. Bull. 1991, 39, 81. (f) Kirchner, E.;
Bretschneider, H. Monatsh. Chem. 1971, 102, 162.
(8) Scott, A. I. Acc. Chem. Rev. 1970, 3, 151.
(9) (a) Flynn, B. L.; Hamel, E.; Junk, M. K. J. Med. Chem. 2002,
45, 2670. (b) Chao, W.-R.; Yean, D.; Amin, K.; Green, C.;
Jong, L. J. Med. Chem. 2007, 50, 3412. (c) Breslin, H. J.;
Miskowski, T. A.; Kukla, M. J.; Leister, W. H.; Winter, H.
L. D.; Gauthier, D. A.; Somers, M. V. F.; Peeters, D. C. G.;
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(18) [1,2,5]-Oxadiazine Derivative 9a; Typical Procedure
A mixture of 7a (18.0 g, 0.062 mol), HONH2·HCl (13.0 g,
0.187 mol) and Na2CO3 (19.8 g, 0.187 mol) in MeOH (100
mL) was refluxed for 30 min. The reaction mixture was
quenched with ice-water and filtered. The crude product thus
obtained was recrystallized from MeOH–acetone mixture to
provide pure 9a. Yield: 16.6 g (88%); mp 220–222 °C. FT
IR: 3403, 1629 cm–1. 1H NMR (400 MHz, DMSO-d6): d =
3.81 (s, 3 H, OMe), 6.87 (s, 1 H, indole CH), 7.05 (d, J = 8.8
Hz, 2 H, Ar), 7.18 (t, J = 7.2 Hz, 1 H, Ar), 7.27 (t, J = 7.2 Hz,
1 H, Ar), 7.63 (s, 1 H, NCH=C), 7.63–7,68 (m, 1 H, Ar), 7.67
(d, J = 8.4 Hz, 2 H, Ar), 7.99 (d, J = 8.4 Hz, 1 H, Ar), 8.29
(s, 1 H, NH), 10.37 (s, 1 H, =NH). 13C NMR (50 MHz,
DMSO-d6): d = 55.3, 96.0, 99.3, 110.7, 114.2, 120.8, 121.5,
122.1, 123.6, 124.4, 125.3, 126.4, 127.7, 132.4, 140.4,
159.4. HRMS (ES): m/z calcd for C18H16N3O2 [M + 1]:
306.1243; found: 305.1234.
(11) 1-[2-(4-Methoxyphenyl)-2-oxoethyl]-1H-indole-2-
carbonitrile (7a); Typical Procedure
To a solution of 1H-indole-2-carbonitrile (5; 10.0 g, 0.07
mol) in acetone (100 mL) were added p-methoxyphenacyl
bromide (6; 17.6 g, 0.077 mol) and anhyd K2CO3 (38.6 g,
0.28 mol) followed by TBAI (0.37 g, 0.001 mol) and the
resulting mixture was stirred at reflux temperature for 2 h.
Acetone was removed under vacuum and the residue was
quenched with H2O and filtered. The crude product 7a was
then recrystallized from MeOH to give the pure product as a
solid. Yield: 16.0 g (78%); mp 126 °C. FT IR (KBr): 2223,
1682, 1602 cm–1. 1H NMR (400 MHz, DMSO-d6): d = 3.89
Synlett 2009, No. 9, 1463–1465 © Thieme Stuttgart · New York

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