New and practical synthesis of 1,4-dihydrobenzopyrano-pyrazoles

Article abstract of DOI:10.1016/S0040-4039(01)01328-4

A new method for the synthesis of 1,4-dihydrobenzopyranopyrazoles using bromovinyl hydrazones has been described involving a [3+2] intramolecular cycloaddition.

Full text of DOI:10.1016/S0040-4039(01)01328-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6599–6601
New and practical synthesis of 1,4-dihydrobenzopyrano-
pyrazoles†
S. Chandrasekhar,* G. Rajaiah and P. Srihari
Indian Institute of Chemical Technology, Hyderabad, India 500007
Received 25 May 2001; revised 12 July 2001; accepted 20 July 2001
Abstract—A new method for the synthesis of 1,4-dihydrobenzopyranopyrazoles using bromovinyl hydrazones has been described
involving a [3+2] intramolecular cycloaddition. © 2001 Elsevier Science Ltd. All rights reserved.
Hydrazones and derivatives of aldehydes have been
proven to be versatile starting materials viz., as a source
of deoxygenation exemplified by the Wolf–Kishner
reduction,1 vinyl anion equivalents in the Shapiro
reaction2 and also as precursors for diazo compounds.
This diversified behaviour of hydrazones and in partic-
ular, tosylhydrazones, prompted our group to look into
this functionality. Our efforts in this direction resulted
in a serendipitous discovery of alkylative fragmentation
of tosylhydrazones when there is a heteroatom a to the
tosylhydrazone functionality.3 To further exploit the
usefulness of this class of compounds, it was proposed
to examine, whether, under the influence of non nucle-
ophilic bases such as NaH, a dipole is generated which
could be further trapped with dipolarophiles
(intramolecular) to result in the formation of dihy-
Surprisingly, for the synthesis of this class of com-
pounds there are very limited procedures available5
which include photochemical cycloaddition.6
Br
Br
O
O
O
Br
N N Ts
NaH
N
N
N
N
H
H
O
N
N
H
(1)
In the initial study, o-hydroxy benzaldehyde was O-
alkylated with 2,3-dibromo-1-propene and then deriva-
tized as a tosylhydrazone. The substrate thus obtained
(entry 1, Table 1) was stirred in THF in the presence of
3 equiv. of NaH for 8 h to observe clean formation of
pyrazole derivative 1b in 90% isolated yield.
drobenzopyranopyrazoles
(Scheme 1).
and
quinolinopyrazoles
This class of compounds have excellent pharmacologi-
cal properties especially as antiallergic compounds.4
The findings in this direction are reported herein (Table
1).
In a second experiment, 4-methyl-2-formyl phenol was
prepared through alkylation with 2,3-dibromo-1-
propene and tosylhydrazone and subjected to
a
O
O
O
N
Br
NH
cycloaddition reaction and clean formation of the
cycloadduct was obtained in 86% yield. Mechanisti-
cally, it is anticipated that the initially formed diazo
compound7 (Eq. 1) undergoes a [3+2] cycloaddition
reaction followed by HBr elimination to yield the more
stable desired product. To further prove the generality
of the present protocol, various substituted aryl sub-
strates were prepared which include a chloroderivative
(entry 2), a p-methoxyphenol derivative (entry 4), the
benzyloxy derivative (entry 5), an isopropyl phenol
derivative (entry 6) and a naphthyl derivative (entry 7),
NaH, THF
rt
N
H
N
NNHTs
R
R
R
Scheme 1.
Keywords: benzopyrano pyrazoles; tosyl hydrazones; 2,3-dibromo-1-
propene.
* Corresponding address. Tel.: +91 40 7170512, fax: 7170512;
e-mail: srivaric@iict.ap.nic.in
†
IICT Communication No. 4811.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01328-4

6600
S. Chandrasekhar et al. / Tetrahedron Letters 42 (2001) 6599–6601
Table 1. Conversion of vinyl bromide hydrazones to 1,4-dihydrobenzopyranopyrazoles
Producta
Substrate
Yields(%)b
90
Entry
a
b
O
O
Br
NNHTs
N
1
N
H
O
O
N
Br
Br
N
H
NNHTs
NNHTs
2
3
85
86
Cl
O
Cl
O
N
N
H
Me
O
Me
O
N
Br
NNHTs
N
H
4
5
84
83
82
OMe
O
OMe
O
Br
N
N
H
NNHTs
NNHTs
OBn
O
OBn
O
N
Br
6
7
N
H
N
HN
NNHTs
O
Br
81
O
O
O
Br
EtO
N
EtO
NNHTs
N
85
80
80
8
H
BocN
BocN
Br
N
NNHTs
N
9
H
O
F
O
F
N
Br
N
NNHTs
10
H
a Products characterized by 1H NMR, mass spectroscopy and IR spectroscopy
b Yields calculated after column chromatography
General procedure for cyclization of vinyl bromide hydra-
zone
which all responded well to the reaction protocol. Entry
9 demonstrated the formation of a quinolinopyrazole
derivative in 80% isolated yield.
To sodium hydride (35.2 mg, 1.46 mmol) in dry THF (8
mL) was added hydrazone 1a (200 mg, 0.48 mmol) at
0°C, and the reaction mixture was stirred for 12 h at
room temperature. After quenching the reaction mix-
ture with saturated ammonium chloride solution, the
reaction mixture was extracted with ethyl acetate, the
organic layer was washed with brine, dried over sodium
sulphate and concentrated under vacuum. The crude
In conclusion, a practical synthesis of 1,4-dihydroben-
zopyranopyrazoles and quinolinopyrazoles is demon-
strated, under practical conditions, which provide
access to a hitherto not easily accessible class of hetero-
cycles in excellent yields. Further work to prove the
mechanistic pathway and biological activity is currently
being investigated.

S. Chandrasekhar et al. / Tetrahedron Letters 42 (2001) 6599–6601
6601
material was chromatographed (silica gel 60–120 mesh,
ethyl acetate:hexane 4:6) to give the pure product 1b
75.5 mg (90% yield).
2. Shapiro, R. H. Org. React. 1976, 23, 1976.
3. (a) Chandrasekhar, S.; Reddy, M. V.; Takhi, M. Tetra-
hedron Lett. 1998, 39, 6535; (b) Chandrasekhar, S.;
Takhi, M.; Yadav, J. S. Tetrahedron Lett. 1995, 36, 307;
(c) Chandrasekhar, S.; Takhi, M.; Yadav, J. S. Tetra-
hedron Lett. 1995, 36, 5071; (d) Chandrasekhar, S.;
Mohapatra, S.; Takhi, M. Synlett 1996, 759; (e) Chan-
drasekhar, S.; Reddy, M. V.; Reddy, K. S.; Ramarao, C.
Tetrahedron Lett. 2000, 41, 2667; (f) Chandrasekhar, S.;
Reddy, M. V.; Rajaiah, G. Tetrahedron Lett. 2000, 41,
10131.
1
Spectroscopic data for compound 4b: H NMR (400
MHz, DMSO-d6): l 7.7 (s, 1H), 7.3 (s, 1H), 7.2 (d, 1H,
J=4.8 Hz), 6.6–6.8 (m, 2H), 5.2 (s, 2H), 3.8 (s, 3H).13C
NMR (400 MHz, DMSO-d6) 152.0, 146.0, 141.0, 121.6,
118.0, 115.7, 112.5, 109.2, 104.2, 61.3, 53.4. Mass: 217
(M+), 202, 176, 133. Anal. calcd for C11H10N2O2: C,
65.34, H, 4.98, N, 13.85 found C, 65.32, H, 4.96, N,
13.81; IR (KBr): 3427, 2935, 3120, 1124 cm−1.
4. Di Parsia, M. T.; Suarez, C.; Vitolo, M. J.; Marquez, V.
E.; Beyer, B.; Urbina, C.; Hurtado, I. J. Med. Chem.
1981, 24, 117.
Acknowledgements
5. (a) Meier, H.; Heimgartner, H. Helv. Chim. Acta. 1977,
60, 3035; (b) Schmitt, G.; Laude, B. Tetrahedron Lett.
1978, 39, 3727; (c) Shimizu, T.; Hayashi, Y.; Nagano, Y.;
Kazuhiro, T. Bull. Chem. Soc. Jpn. 1980, 53, 429; (d)
Dean, F. M.; Murray, S. J. Chem. Soc., Perkin Trans. 1
1975, 1706.
G.R. and P.S.H. thank CSIR, New Delhi for the
financial support in the form of a fellowship.
6. Padwa, A.; Nahm, S.; Sato, E. J. Org. Chem. 1978, 43,
1664.
References
7. (a) Kirmse, W.; Dietrich, H. Chem. Ber. 1967, 100, 2710;
(b) Shimizu, T.; Hayashi, Y.; Yamada, K.; Nishio, T.;
Teramura, K. Bull. Chem. Soc., Jpn. 1981, 54, 217.
1. Todd, D. Org. React. 1948, 4, 378 and references cited
therein.