A tandem strategy for the synthesis of 1H-benzo[g]indazoles and naphtho[2,1-d]isoxazoles from o-alkynylarene chalcones

Article abstract of DOI:10.1002/ejoc.201201576

o-Alkynylarene chalcones when treated with hydrazines and hydroxylamine in the presence of iodine gave 1H-benzo[g]indazoles and naphtho[2,1-d]isoxazoles, respectively. The transformations involve tandem oxidative cyclocondensation/ electrophilic hydroarylation. The methodology was applied to quinoline-based chalcones, which also afforded the corresponding quinoline-fused benzindazole and benzisoxazole. o-Alkynylarene chalcones undergo tandem oxidative cyclocondensation/electrophilic hydroarylation with arylhydrazines and hydroxylamine in the presence of iodine to afford 1H-benzo[g]indazoles and naphtho[2,1-d]isoxazoles, respectively. Copyright

Full text of DOI:10.1002/ejoc.201201576

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201576
A Tandem Strategy for the Synthesis of 1H-Benzo[g]indazoles and
Naphtho[2,1-d]isoxazoles from o-Alkynylarene Chalcones
Sikkandarkani Akbar[a] and Kannupal Srinivasan*[a]
Keywords: Synthetic methods / Domino reactions / Cyclization / Heterocycles / Iodine
o-Alkynylarene chalcones when treated with hydrazines and
hydroxylamine in the presence of iodine gave 1H-benzo-
[g]indazoles and naphtho[2,1-d]isoxazoles, respectively. The
transformations involve tandem oxidative cyclocondensa-
tion/electrophilic hydroarylation. The methodology was ap-
plied to quinoline-based chalcones, which also afforded the
corresponding quinoline-fused benzindazole and benzisox-
azole.
alkynylarenes 2 having pyrazole and isoxazole moieties in
the ortho position. This kind of hydroarylation is well
known in the realm of alkynylarenes and can be achieved
by using iodine reagents,[11] Brønsted acids,[12] or transition-
metal compounds.[13] Alkynylarenes 2 could in turn be pre-
pared by oxidative cyclocondensation of chalcones 1 with
hydrazine or hydroxylamine. Reagents such as 2,2-diphenyl-
1-picrylhydrazyl (DPPH),[14] air/DMSO,[15] iodine,[16] and
sulfur[17] are known to effect this type of oxidative cy-
clocondensation. It would be possible to couple both steps
in a tandem (or one-pot) manner if the proper choices of
reagent and reaction conditions are made.
Introduction
Indazole and benzisoxazole cores are found in a large
number of biologically active compounds,[1] including the
drugs/drug candidates granisetron,[2] adjudin,[3] gamenda-
zole,[4] zonisamide,[5] risperidone,[6] and paliperidone.[7]
Thus, it is not surprising that numerous methods have been
reported for the synthesis of these scaffolds.[8] In contrast,
only a limited number of reports are available for the syn-
thesis of their benzo-fused derivatives, viz., benzindazoles
and naphthisoxazoles.[9] This prompted us to develop a gen-
eralized synthetic method for these two classes of heterocy-
cles.
o-Alkynylarene chalcones 1 are versatile synthons, and
their synthetic potentials have been exploited for the con-
struction of certain carbo- and heterocyclic frameworks.[10]
We envisaged that chalcones 1 could be converted into
Results and Discussion
Starting chalcones 1 with various substitution patterns
benzo[g]indazoles (3) and naphtho[2,1-d]isoxazoles (4) in were prepared from the appropriate o-alkynylarene carbox-
two steps, as retrosynthetically proposed in Scheme 1. Ac- aldehydes and acetophenones by standard procedures. Io-
cordingly, heterocycles 3 and 4 could be obtained from in- dine was chosen as the reagent for carrying out the first
tramolecular electrophilic hydroarylation of intermediate oxidative cyclocondensation step, because it is also capable
Scheme 1. Retrosynthetic route to 1H-benzo[g]indazoles and naphtho[2,1-d]isoxazoles.
[a] School of Chemistry, Bharathidasan University,
Tiruchirappalli 620024, Tamil Nadu, India
Fax: +91-431-2407043
of bringing about the next hydroarylation step, and hence,
the one-pot synthesis of the target heterocycles would be
possible. Thus, an equimolar mixture of chalcone 1a and
phenyl hydrazine was heated under reflux in the presence
of iodine (1.2 equiv.) in AcOH. Astonishingly, instead of
expected alkynylarene 2a, the final product, benzindazole
E-mail: srinivasank@bdu.ac.in
Homepage: www.bdu.ac.in/schools/chemistry/
chemistry/dr_k_srinivasan.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201576.
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3a (E = H), was directly isolated in 65% yield after column dichloromethane (DCM) did not give any trace amounts of
chromatography (Scheme 2). This implied that intermediate 3a. Thus, we stuck to the original conditions in spite of the
alkynylarene 2a formed in the first step underwent further moderate yield and set out to investigate the scope of the
electrophilic hydroarylation caused by AcOH (also by the reaction.
co-product HI) to give benzindazole 3a. Thus, both oxidat-
ive cyclocondensation and electrophilic hydroarylation had
taken place in a tandem manner to give the final product.
Other o-alkynylarene chalcones 1b–d bearing OMe and
Br substituents at different positions all reacted smoothly
with phenyl/4-bromophenyl hydrazines under the prevailing
conditions to afford corresponding benzo[g]indazoles 3b–
f in yields ranging from 60 to 73% (Table 1, entries 2–6).
However, chalcone 1e having a NO2 substituent on the Ar
ring did not provide expected benzindazole 3g (Table 1, en-
try 7; the reaction stopped at the initial hydrazone stage).
Chalcone 1f, which bears no substituent on the aryl rings,
also afforded corresponding benzindazole 3h in 68% yield
(Table 1, entry 8). Chalcone 1g, which has an alkyl-yne unit,
was also tested; however, corresponding benzindazole 3i
could not be obtained in pure form, as it decomposed read-
ily (Table 1, entry 9). Chalcone 1a was also treated with hy-
drazine hydrate to furnish benzindazole 3j in 67% yield
(Table 1, entry 10). The products were all characterized by
various spectroscopic techniques, and for product 3h, the
structure was unequivocally confirmed by single-crystal X-
ray analysis (Figure 1).
Scheme 2. Formation of benzindazole 3a by tandem oxidative cy-
clocondensation/electrophilic hydroarylation.
To support the involvement of tandem oxidative cy-
No iodine-incorporated benzindazole (E = I) could be clocondensation/electrophilic hydroarylation reactions in
observed, even when up to 10 equiv. of iodine were used in the methodology, we performed the following experiments
the reaction (obviously, H+ wins over I+ as the electrophile). (Scheme 3). Intermediate (o-alkynylaryl)pyrazole 2e was
When other iodinating agents such as NIS and PhI- synthesized separately by subjecting chalcone 1d to cy-
(OAc)2 were used, the first step itself was problematic, and clocondensation with phenylhydrazine and then oxidizing
the corresponding nonaromatized cyclocondensation prod- the resulting pyrazoline by using 2,3-dichloro-5,6-dicyano-
uct (pyrazoline) was obtained instead of 2a. When MeOH 1,4-benzoquinone (DDQ). When 2e was heated under re-
(or EtOH) was used as the solvent, final product 3a was flux in AcOH for 2 h, benzindazole 3e was produced in
obtained in about 40% yield. The formation of 3a in the 68% yield, whereas upon treatment with iodine in DCM at
absence of AcOH indicates that the second hydroarylation room temperature for 8 h, it afforded iodobenzindazole 5 in
step is triggered by the HI co-product that was formed dur- 85% yield. These reactions clearly demonstrate that 2e was
ing the first oxidative cyclocondensation step. Other sol- indeed formed as an intermediate in the course of the syn-
vents such as DMF, MeCN, 1,2-dichloroethane (DCE), and thesis.
Table 1. Synthesis of benzo[g]indazoles 3a–j.
Entry
Chalcone
R1
R2
Ar
R3
Product, yield [%][a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1d
1d
1e
1f
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
Ph
4-BrC6H4
Ph
Ph
3a, 65
3b, 60
3c, 73
3d, 61
3e, 64
3f, 60
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
4-BrC6H4
4-O2NC6H4
Ph
[b]
[b]
3g, n.r.[c]
3h, 68
3i, –[d]
3j, 67
1g
1a
MeO
MeO
nBu
Ph
Ph
Ph
Ph
10
H[e]
[a] Isolated yield. [b] Used as its hydrochloride salt (NaOAc was also included to neutralize the salt). [c] No reaction. [d] Product 3i could
not be obtained in pure form. [e] Used as its hydrate.
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Tandem Reactions of o-Alkynylarene Chalcones
Table 2. Synthesis of naphthisoxazoles 4a–g.
Entry Chalcone R1
R2
Ph
Ar
Ph
Product,
yield [%][a]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
MeO
MeO
MeO
MeO
MeO
H
4a, 54
4b, 52
4-MeOC6H4 Ph
4-MeOC6H4 4-MeOC6H4 4c, 57
4-MeOC6H4 4-BrC6H4 4d, 59
4-MeOC6H4 4-O2NC6H4 4e, n.r.[b]
Ph
nBu
Ph
Ph
4f, –[c]
4g, 59
1g
MeO
[a] Isolated yield. [b] No reaction. [c] Product 4f could not be iso-
lated in pure form.
Figure 1. ORTEP plot of the crystal structure of 3h.
Scheme 4. Synthesis of quinoline-fused benzindazole 7 and benz-
isoxazole 8.
Conclusions
Scheme 3. Synthesis of intermediate 2e and its reactions.
We have developed an iodine-mediated tandem method
for the facile synthesis of 1H-benzo[g]indazoles and
naphtho[2,1-d]isoxazoles from o-alkynylarene chalcones.
When treated with arylhydrazine/hydrazine/hydroxylamine,
these chalcones underwent oxidative cyclocondensation to
yield o-alkynylarylpyrazoles/oxazoles as intermediates,
which underwent electrophilic hydroarylation to afford the
benzindazoles and naphthisoxazoles. The methodology
could be extended to the synthesis of hybrid heterocycles
such as quinoline-fused benzindazoles and benzisoxazoles.
Work is in progress to explore other possibilities of this
methodology.
Next, we turned our attention to the synthesis of analo-
gous naphtho[2,1-d]isoxazoles from o-alkynylarene chalc-
ones. When chalcones 1a–d were heated under reflux with
hydroxylamine in the presence of iodine in AcOH (NaOAc
was included to neutralize the hydroxylamine hydro-
chloride), respective naphthisoxazoles 4a–d were isolated in
52–59% yields (Table 2, entries 1–4). Chalcone 1e having a
NO2 substituent on the Ar ring did not afford naphthisox-
azole 4e (Table 2, entry 5). We were not able to isolate
naphthisoxazole 4f in pure form from the reaction of un-
substituted chalcone 1f (Table 2, entry 6). Chalcone 1g hav-
ing an alkyl-yne unit furnished respective naphthisoxazole
4g in 59% yield (Table 2, entry 7). The yields of the naph-
thisoxazoles produced are generally lower by about 10%
relative to those of the benzindazoles.
Finally, we extended our methodology to quinoline-
based chalcone 6. When treated with phenylhydrazine and
hydroxylamine, chalcone 6 also smoothly underwent the
tandem oxidative cyclocondensation/electrophilic hydro-
arylation sequence to give quinoline-fused benzindazole 7
and benzisoxazole 8 in 58 and 55% yield, respectively
(Scheme 4).
Experimental Section
General Procedure for the Synthesis of 1H-Benzo[g]indazoles and
Naphtho[2,1-d]isoxazoles: To a solution of o-alkynylarene chalcone
(0.25 mmol) in acetic acid (3 mL) was added iodine (0.3 mmol) and
phenylhydrazine, p-bromophenylhydrazine hydrochloride, hydraz-
ine hydrate, or hydroxylamine hydrochloride (0.3 mmol) [when p-
bromophenylhydrazine hydrochloride or hydroxylamine hydrochlo-
ride was used, NaOAc (0.3 mmol) was also included to neutralize
the hydrochloride salt]. The reaction mixture was heated under re-
flux for 8 h, then cooled to room temperature, diluted with water,
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S. Akbar, K. Srinivasan
SHORT COMMUNICATION
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CCDC-911852 (for 3h) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Acknowledgments
The authors thank the Department of Science and Technology
(DST), India and the Council of Scientific and Industrial Research
(CSIR), India for financial support, DST-FIST for instrumentation
facilities at the School of Chemistry, Bharathidasan University and
Dr. N. Sampath (Sastra University) for X-ray structure determi-
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Received: November 23, 2012
Published Online: February 4, 2013
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