Direct Synthesis of Benzo[f]indazoles from Sulfonyl Hydrazines and 1,3-Enynes by Copper-Catalyzed Annulation

Article abstract of DOI:10.1021/acs.orglett.8b03564

A novel and efficient strategy for the direct synthesis of benzo[f]indazoles via copper-catalyzed cascade reaction of sulfonyl hydrazides with 1,3-enynes under mild conditions has been developed. This method achieves the formation of two C-N bonds and one

Full text of DOI:10.1021/acs.orglett.8b03564

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Synthesis of Benzo[f ]indazoles from Sulfonyl Hydrazines and
1,3-Enynes by Copper-Catalyzed Annulation
Biao Yao, Tao Miao,*,† Pinhua Li,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A novel and efficient strategy for the direct synthesis of benzo[f]indazoles via copper-catalyzed cascade reaction
of sulfonyl hydrazides with 1,3-enynes under mild conditions has been developed. This method achieves the formation of two
C−N bonds and one C−C bond in one pot, providing a series of benzo[f ]indazoles in moderate to good yields with good
functional group tolerance and remarkable regioselectivity.
he indazole moiety is a privileged N-heterocyclic
structure in medicinal chemistry due to its pronounced
Scheme 2. Synthetic Routes to Benzo[f]indazoles
T
biological and therapeutic activities,1 and in particular, tricyclic
1H-benzoindazole plays an increasingly important role in drug
discovery.2 For example, benzo[f ]indazole I is the lead
compound for both antifungal and antibacterial activities,2a
and II, as an antiproliferative agent, has been chosen in
preclinical antitumor evaluation.2b Their analogue III, a
selective ligand of the human glucocorticoid receptor,2c
shows highly efficacious IL-6 inhibition (Scheme 1). In the
Scheme 1. Bioactive Benzoindazole Analogues
It is well-known that cascade cyclizations, particularly those
involving a radical process, are reliable and powerful synthetic
strategies for the straightforward construction of cyclic
molecules with unique chemical and biological importance.6
To date, the majority of work in this field has been focused on
the radical addition to unsaturated chemical bonds followed by
intramolecular cyclization to access cyclic skeletons.7 On the
other hand, 1,3-enynes are versatile building blocks for the
specific domino cyclization and have been widely applied in
numerous intriguing preparation via synergistic cascade
processes across CC and CC bonds of substrates in a
one-pot fashion.8 However, the radical cascade cyclization of
1,3-enynes is a particularly challenging transformation owing to
the inherent difficulty of controlling reaction reactivity and
regio- and chemo-selectivity. Herein, we wish to report a
copper-catalyzed synthesis of 1H-benzo[f ]indazoles from
past few decades, a number of impressive methods have been
reported for the construction of indazole frameworks,3 yet
synthetic protocols to benzo[f]indazole are severely scarce,
which have hampered their biomedical applications. Recently,
a synthetic reaction of 1,1-dialkylhydrazones with o-
(trimethylsilyl)naphthyl triflates via aryne annulation provided
a direct route to 1-alkylbenzo[f ]indazoles (Scheme 2a).4
Subsequently, the RhIII/CuII-cocatalyzed method for the
synthesis of 1H-indazoles through C−H amidation and N−
N bond formation was developed, generating the substituted
benzo[f ]indazole from naphthylimidate and organo azides
(Scheme 2b).5 However, some limitations including harsh
reaction conditions with high temperature, expensive starting
materials and catalysts, or limited substrate scope (naphthalene
derivatives) remain in the above methods. Therefore, the
development of novel and efficient method for the direct
synthesis of 1H-benzo[f ]indazoles with a variety of functional
groups under mild conditions is highly desirable.
Received: November 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03564
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
easily available sulfonyl hydrazides and (E)-2-benzylidene-4-
arylbut-3-ynals via a radical domino annulation in one pot. The
reaction proceeded smoothly to generate the corresponding
benzo[f ]indazoles in good yields with excellent selectivity
under mild conditions (Scheme 2c).
Initially, 4-toluenesulfonyl hydrazide (1a) and (E)-2-
benzylidene-4-phenylbut-3-ynal (2a) were selected as the
model substrates to optimize the reaction conditions (Table
1). To our delight, when the model reaction of 1a and 2a was
40−52% yields when PAA (peracetic acid), CHP (cumyl
hydroperoxide), and m-CPBA (3-chloroperbenzoic acid) were
employed as oxidants (Table 1, entries 14−16). However,
other oxidants including tert-butyl peroxybenzoate (TBPB), di-
tert-butyl peroxide (DTBP), dicumyl peroxide (DCP), and
H2O2 exhibited negative efficiency to the model reaction
(Table 1, entries 17−20). In addition, the reaction could not
work in an O2 atmosphere. It was found that CuI was not
involved in this reaction and still deposited at the bottom of
reaction tube (Table 1, entry 21). Furthermore, increasing the
amount of 1a to 1.5 equiv did not enhance the yield of 3a
(Table 1, entry 22). It is important to note that Cu catalyst and
TBHP showed a significant impact on the reaction, and no
desired product 3a was detected in the absence of either the
catalyst or oxidant (Table 1, entries 23 and 24).
a
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, we first
investigated the scope of sulfonyl hydrazides, and the results
are listed in Scheme 3. A variety of arylsulfonyl hydrazides with
b
entry
catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
oxidant
solvent
DCM
DCE
CHCl3
DMF
DMSO
toluene
1,4-dioxane
CH3CN
THF
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
yield (%)
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
PAA
55
79
60
32
23
45
18
trace
0
a,b
Scheme 3. Scope of Sulfonyl Hydrazides
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
55
64
67
40
52
47
0
CHP
m-CPBA
TBPB
DTBP
DCP
H2O2
O2
0
0
CuI
CuI
CuI
CuI
0
c
0
d
TBHP
TBHP
77
DCE
DCE
0
0
CuI
a
Reaction conditions: 4-toluenesulfonyl hydrazide (1a, 0.30 mmol),
(E)-2-benzylidene-4-phenylbut-3-ynal (2a, 0.25 mmol), Cu-catalyst
(10 mol %), oxidant (0.50 mmol), solvent (2.0 mL), 40 °C, N2, 5 h.
b
c
d
Isolated yield based on 2a. O2 balloon was used. 1a (1.5 equiv)
was used.
conducted in dichloromethane (DCM) under N2 atmosphere
at 40 °C for 5 h by using CuI as a catalyst and TBHP (70% in
water) as an oxidant, the cascade cyclization afforded product
9-phenyl-1-tosyl-1H-benzo[f ]indazole (3a) in 55% yield
(Table 1, entry 1). The structure of 3a was confirmed
unambiguously by X-ray crystal analysis.9 Further exploration
of a variety solvents indicated that 1,2-dichloroethane (DCE)
was the most efficient, and 79% yield of 3a was obtained
(Table 1, entry 2). Other solvents including CHCl3, DMF,
DMSO, toluene, and 1,4-dioxane were less effective and gave
3a in 18−60% yields (Table 1, entries 3−7). Solvents CH3CN,
THF, and methanol were not suitable, and the model reaction
was almost prohibited (Table 1, entries 8−10). Next, a range
of copper sources such as CuCl, CuBr, and Cu(OAc)2 were
evaluated, leading to the desired 3a with inferior results (Table
1, entries 11−13). Subsequently, the effect of the oxidants on
the model reaction was examined. Product 3a was isolated in
a
Reaction conditions: sulfonyl hydrazide (1, 0.30 mmol), 2a (0.25
mmol), CuI (10 mol %), TBHP (0.50 mmol), DCE (2.0 mL), 40 °C,
b
N2, 5 h. Isolated yield based on 2a.
an electron-donating group (MeO, Me, t-Bu) or an electron-
withdrawing group (F, Cl, Br, CF3, CN, Ph) on the aryl rings
reacted efficiently with 2a to give the corresponding products
3a−p in good yields. The sterically hindered o-methyl-
substituted benzenesulfonyl hydrazide was a suitable substrate
in this process, giving the corresponding product 3d in 65%
B
DOI: 10.1021/acs.orglett.8b03564
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Organic Letters
Letter
yield. Notably, arylsulfonyl hydrazides bearing a trifluorometh-
yl group (CF3), as a useful structural motif in biologically
active molecules,10 reacted with 2a to generate the anticipated
products 3k and 3l in good yields. High yields were obtained
with the bulkier 1,1′-biphenyl- and 2-naphthylsulfonyl
hydrazides as substrates. On the other hand, multisubstituted
arylsulfonyl hydrazides were also well tolerated in this
transformation, affording the products 3o and 3p in 70% and
84% yields, respectively. Furthermore, 2-thienylsulfonyl
hydrazide was also suitable for this protocol, which gave the
desired product 3q in 58% yield. Importantly, aliphatic sulfonyl
hydrazides, as a case study of n-butylsulfonyl hydrazide,
worked well with 2a, producing the product 3r in good yield.
However, when phenylhydrazine and benzhydrazide were
employed as starting materials to react with 2a under the
optimized conditions, no desired product was obtained.
We then turned our attention to explore the scope of 1,3-
enynes by reacting with a number of arylsulfonyl hydrazides,
and the results were shown in Scheme 4. This radical domino
removed by reduction to afford 4 in excellent yield, which can
be used for the further functionalization of the benzo[f ]-
indazoles (Supporting Information).
To gain insight into the reaction mechanism, some control
experiments were conducted, as shown in Scheme 5. First,
Scheme 5. Control Experiments
a,b
Scheme 4. Scope of 1,3-Enynes
when 1a was treated with 2a in DCE at 40 °C in the absence of
catalyst and oxidant for 5 h, a condensation product hydrazone
(A) was formed in 92% yield (Scheme 5a). In a further
experiment, hydrazone (A) was subjected the reaction under
the standard conditions, affording 3a in 85% yield (Scheme
5b). Meanwhile, the reaction of obtained A by using
Cu(OAc)2 as catalyst in the O2 generated 3a in 65% yield
(Scheme 5c). Nevertheless, no desired 3a was obtained when a
well-known radical scavenger, TEMPO (2,2,6,6-tetramethylpi-
peridine-1-oxyl, 2.0 equiv), was added in the reaction system of
A (Scheme 5d). Furthermore, when BHT (butylated
hydroxytoluene, 2.0 equiv) was added to the reaction of A,
the yield of 3a was decreased to 18%. More importantly, a
possible vinyl radical formed in situ were trapped by BHT
through the formation of radical adduct 5, which was
determined by HPLC−HRMS analysis (Scheme 5e, and
Supporting Information). The above observations clearly
suggest that a Cu(II) initiated radical pathway was involved
in the reaction.
On the basis of control experiments and previous literature
survey,7,8,11 a plausible mechanism is proposed in Scheme 6.
Initially, a hydrazone A was formed from the condensation of
1a and 2a. Then the intramolecular aminocupration of A
occurred upon alkyne activation by a copper(II) via
intermediate B to form vinylcopper complex C. Subsequently,
a
Reaction conditions: arylsulfonyl hydrazide (1, 0.30 mmol), 1,3-
enyne (2, 0.25 mmol), CuI (10 mol %), TBHP (0.50 mmol), DCE
b
(2.0 mL), 40 °C, N2, 5 h. Isolated yield based on 2.
reaction was not sensitive to the nature of the substituted
group on the 1,3-enyne moiety, as evidenced by the moderate
to good yields of 3s−ag. It is noteworthy that halogen and
dimethylamino substituents on the benzylidene moiety were
tolerated, thus facilitating further modifications toward the
synthesis of structural diverse benzo[f ]indazoles. In particular,
this transformation was not limited to phenyl 1,3-enynes; other
aromatic ring and aliphatic substituents, e.g., thienyl, cyclo-
propyl, and propyl, could also be compatible to afford the
expected benzo[f]indazoles (3ah, 3ai, and 3aj) in 76%, 74%,
and 64% yields, respectively.
Scheme 6. Proposed Mechanism
The developed radical annulation could be performed on a
gram scale, giving 3a in 72% yield (Supporting Information).
In addition, the N-sulfonyl group of 3a could be easily
C
DOI: 10.1021/acs.orglett.8b03564
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Organic Letters
Letter
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In summary, we have developed a facile and efficient method
for the synthesis of substituted benzo[f]indazoles from easily
available sulfonyl hydrazides and (E)-2-benzylidene-4-arylbut-
3-ynals through copper-catalyzed two C−N bonds and one C−
C bond formation in one pot. Mechanistic investigation to
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were obtained in moderate to high yields with good functional
group tolerance under mild reaction conditions. Further scope
and mechanism studies of the reaction are currently in progress
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03564.
■
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Full experimental details and characterization data for all
products (PDF)
Accession Codes
CCDC 1874385 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
́
(f) Fuentes, N.; Kong, W.; Fernandez-Sanchez, L.; Merino, E.;
Nevado, C. J. Am. Chem. Soc. 2015, 137, 964. (g) Liu, F.; Wang, J.-Y.;
Zhou, P.; Li, G.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Angew. Chem., Int. Ed.
2017, 56, 15570.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: taomiaochem@163.com.
*E-mail: leiwang88@hotmail.com.
ORCID
(8) For selective examples, see: (a) O’Connor, J. M.; Friese, S. J.;
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̂
Lei Wang: 0000-0001-6580-7671
Notes
́
Lett. 2011, 13, 6390. (e) Aguilar, E.; Sanz, R.; Fernandez-Rodríguez,
The authors declare no competing financial interest.
M. A.; García-García, P. Chem. Rev. 2016, 116, 8256. (f) Barday, M.;
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21772062, 21602072, 21572078) and
the National Science Foundation of Anhui Education Depart-
ment (KJ2016A643) for financial support of this work.
(9) X-Ray crystal structure of 3a.
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