An Effective Method for the Synthesis of 1,3-Dihydro-2H-indazoles via N-N Bond Formation

Article abstract of DOI:10.1002/adsc.201901331

The [4+1] cycloaddition reaction of bifunctional amino reagents has been achieved with in situ formed aza-ortho-quinone methides. Specifically, N-(tosyloxy)carbamates were used as an N1 synthon and bifunctional amino reagents for this transformation, which provides a metal-free, catalyst-free, and oxidant-free strategy to form nitrogen-nitrogen bonds. (Figure presented.).

Full text of DOI:10.1002/adsc.201901331

Title: An Effective Method for the Synthesis of 1,3-Dihydro-2H-
indazoles via N-N Bond Formation
Authors: Huawu Shao, Xiaoke Zhang, Yang Pan, Peng Liang,
Xiaofeng Ma, and Wei Jiao
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901331
Link to VoR: http://dx.doi.org/10.1002/adsc.201901331

10.1002/adsc.201901331
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Effective Method for the Synthesis of 1,3-Dihydro-2H-
indazoles via N-N Bond Formation
Xiaoke Zhanga,b,c, Yang Pana,b, Peng Lianga,b, Xiaofeng Maa,b, Wei Jiao*a and Huawu
Shao*a
a
Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
Fax: +028–82890288; E-mail: shaohw@cib.ac.cn; jiaowei@cib.ac.cn.
Zunyi Medical University, Zunyi, Guizhou, China
University of Chinese Academy of Sciences, China
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
1,2,3-triazoles.[3] Recently, Rh/Cu co-catalyzed C-H
Abstract. The [4+1] cycloaddition reaction of bifunctional
amino reagents has been achieved with in situ formed aza-
ortho-quinone methides. Specifically, N-tosyloxycarba-
mates were used as an N1 synthon and bifunctional amino
reagents for this transformation, which provides a metal-
free, catalyst-free, and oxidant-free strategy to form
nitrogen-nitrogen bonds.
amidation and N-N bond formation were reported by
Glorius and co-workers, which was an alternative
strategy to construct the N-N bond of 1H-Indazoles
(Scheme 1, eq 1).[4] SanMartin reported the
hypervalent iodine reagent PIFA could promote the
formation of a new N-N single bond obtaining
indazol-3-ones (Scheme 1, eq 2).[5] The N-N bond
formation could be achieved by other metals, such as
Ni and Ag.[6] Nevertheless, all these methods could
not avoid using heavy metals, high temperatures,
hypervalent iodine reagent oxidation, and long
reaction times. Some elegant metal-free strategies,
including anodic oxidation and aerobic oxidation,
have been recently reported by Baran and Ji,
respectively.[7] However, some substrates could not
tolerate the oxidizing condition, which limits the
application of these strategies (Figure 1). Therefore, it
is still highly desirable to explore and exploit a mild
method to form the N-N bond. In this article, we
wished to report a novel synthetic protocol that does
not rely on metal precise, catalysts, and oxidation to
form N-N bonds promoted by an inorganic base.
Keywords: bifunctional amino reagents; N1 synthon;
annulation; indazole.
Indazoles compounds are important members in
pharmaceutical sciences because of their myriad
biological activities; these compounds include anti-
cancer agents, protein kinase C-β and Rho kinase-
II inhibitors, potent 5-HT2 receptor agonists, highly
selective estrogen receptor β ligands and others
(Figure 1). [1] In consideration of these activities, a
variety of methods have been developed to
synthesize indazole derivatives. The N-N bond
formation is critical but very challenging strategy
that has attracted much attention.[2] Indeed, until
now, a large number of nitrogen-nitrogen bond
formation methods have been developed. For
example, Cu(OAc)2 could be used as a catalyst to
promote the cleavage of C-H bonds, and the
following N-N bond is formed to give
Ortho-quinone methides have been widely
employed in the [4+n] annulations to synthesize
heterocyclic compounds. For example, the [4+3]
annulations between aza-ortho-quinone methides, oxa
Glorius et al., ref 4
SanMartin et al., ref 5
Figure 1. Examples of biologically important molecules
containing indazoles motifs.
Scheme 1. Methods of the synthesis of indazoles
1
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
Previous work:
methylbenzenesulfonamide 1a and benzyl-N-
tosyloxycarbamate 2a as model substrates. We first
performed the reaction in MeCN using Cs2CO3 as a
base. To our delight, when the reaction mixture was
This work:
Figure 2. X-ray of 3a
3
H
R
N
3
metal-free
R
N
2
4
R
2
R
NHOTs
4
eq 4
R
N
1
R
Cl
oxidant-free
N1 synthons
1
R
R
Scheme 2. The cycloaddition of the ortho-quinone
methides
-diene precursors and N, N’-cyclic azomethine
imines, nitrones, α, β-unsaturated aldehydes, and
other 1,3-dipole synthons have been demonstrated by
Shi and others to construct the seven-membered
heterocycles (Scheme 2, eq 1).[8] Meanwhile,
dihydrocoumarins, tetrahydroxanthenes and other six-
membered heterocyclic skeletons could also be
achieved by [4+2] cycloaddition with the allenic
esters, 1,3 cyclohexanedione and other C2 synthons
(Scheme 2, eq 2).[9] Very recently, the [4+1]
annulations of 2-tosylalkylphenols and aza-ortho-
quinone methideprecursors with ylides including the
sulfur ylides, ammonium ylides and iodonium ylides
to synthesize the 2,3-dihydrobenzofurans, indoles and
indolines were also investigated.[10] In addition, the
reactions of ortho-quinone methides with pyridinium
Figure 3. X-ray of dimerization product of the aza-ortho-
quinone methides
stirred at room temperature for 8 h, the corresponding
1,3-dihydro-2H-indazole was isolated in 64% yields.
The structure of 3a was identified through NMR
analysis and confirmed by X-ray crystallographic
analysis (Figure 2).[15] In addition, a small amount of
dimerization
product
of
the
aza-ortho-
quinonemethides was also obtained (Figure 3).[16]
With the aim to improve the yield of 3a, various
bases were then screened. When the organic bases,
such as DBU and DABCO, were used for this
transformation, the cycloaddition product
Table 1. Optimization of the reaction conditions a
methylides
could provide
dihydroarenofuran
derivatives via [4+1] annulation reactions.[11]
Moreover, the 1,2-dicarbonyls were also used for
those [4+1] annulation reaction with the o-quinone
methides providing the dihydronaphthylfuran
(Scheme 2, eq 3).[12] However, to date, only C1
synthons were employed in the [4+1] annulation
reaction of ortho-quinone methides; the [4+1]-
annulations of ortho-quinone methides with N1
synthons had never been achieved in the
cycloaddition of ortho-quinone methide precursors.
Due to our continued interest in cycloaddition and
cyclization reactions,[13] we envisioned the [4+1]
cycloaddition between aza-ortho-quinone methides
and N-tosyloxy-carbamates,[14] which could provide a
metal-free, catalyst-free, and oxidant-free protocol to
form a new nitrogen-nitrogen bond affording 1,3-
dihydro-2H-indazoles derivatives (Scheme 2, eq 4).
With this consideration in mind, we initiated our
study by using N-(2-(chloromethyl) phenyl)-4-
Entry
1
2
3
4
5
6
7
8
Base
DBU
DABCO
Cs2CO3
KOH
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
DCM
CHCl3
MeOH
toluene
MeCN
MeCN
MeCN
Yield (%) b
45
41
64
61
68
76
91
49
55
LiOH
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
51
10
11
12
13
14
15
trace
42
79 c
77 d
60 e
2
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
a
Reaction conditions: 1a (0.48 mmol), 2a (0.4 mmol)
of
1,3-dihydro-2H-indazole
derivatives,
the
and base (1 mmol) were stirred at room temperature for
substitutes were varied on the N1 synthons and o-
chloromethyl sulfonamides. When these aza-ortho-
quinone methide precursors bearing electron-
withdrawing substituents (-Cl, -Br, and -F) were
tested, the transformations worked smoothly, and
b
c
8 h. Isolated yield based on 2a. Reaction was
performed at 0 oC. d Reaction was performed at -10 oC. e
Reaction was performed at 60 oC.
Table 2. Screen of the leaving group a
Table 3. Substrate scope of reaction a
Entry
Leaving group
Tosyloxy
Yield (%)
b
91
84
81
1
2
3
Nosyloxy
4-(Trifluoromethyl)-
benzenesulfonyloxy
Benzenesulfonyloxy
Mesyloxy
83
90
4
5
a Reaction conditions: 1a (0.48 mmol), 2 (0.4 mmol) and
base (1 mmol) were stirred in MeCN (4 mL) at room
temperature for 8 h. b Isolated yield based on 2.
was afforded in moderate yield (Table 1, entries 1-2).
In addition, the inorganic bases were also tested
(Table 1, entries 3-7). Among the screened inorganic
bases, K2CO3 was proven to be the best inorganic
base (Table 1, entry 7). Further optimization of the
reaction conditions by using different solvents did not
offer better results compared with MeCN (Table 1,
entries 8-12). Then, the reaction temperature was
changed; however, the yields could not be further
improved (Table 1, entries 13-15). The optimal
reaction conditions were obtained when 1a (1.2
equiv), 2a (1 equiv) and K2CO3 (2.5 equiv) in MeCN
for 8 h were employed with the complete conversion
of 2a.
With the optimized experimental conditions in
hand, the scope of the method was studied by varying
the leaving group. As shown in Table 2, a range of
leaving groups could be employed in the
transformation to give the desired cycloaddition
products in moderate to good yields. For instance,
when a mesyloxy group was used as the leaving
group (Table 2, entry 5), the corresponding
cycloaddition product was obtained in the same yield
(90%) as with the tosyloxy group (91%) (Table 2,
entry 1). However, the electron-deficient group
substituted on the leaving group, such as p-NO2 or p-
CF3 group in the benzene sulfonyl moiety, did not
have a beneficial effect on this transformation (Table
2, entries 2 and 3). Meanwhile, the reactivity could
not be improved when the benzenesulfonyloxygroup
was used (Table 2, entry 4).
a
Reaction conditions: 1 (0.48 mmol), 2 (0.4 mmol) and
base (1 mmol) were stirred in MeCN (4 mL) at room
temperature for 8 h. b Isolated yield based on 2.
the corresponding cycloaddition products were
produced in moderate to good yields (Table 3, 3b and
3e). In addition, this protocol was also amenable to
the sulfonamide substrates with electro-donating
group, such as methyl groups, which gave the product
in 80% yields (Table 3, 3g). In the presence of ether
groups on the aromatic ring, this transformation could
also obtain the cycloaddition product in a moderate
yield (Table 3, 3h). When the ether functional group
is on the 3 position of the aromatic ring, a deprotected
product is afforded (Table 3, 3i). The sulfonamide
containing a methyl or phenyl at the 2-chloroalkyl
group can also undergo [4+1] cycloaddition, and the
To further demonstrate the generality and
efficiency of our [4+1] strategy for the construction
3
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
substituted indazoles were obtained in 83% and 62%
yields (Table 3, 3j and 3k). Moreover, the mesyl and
the brosyl can also be used as the protecting groups
for this transformation; when those substrates were
subjected to the standard conditions, the correspond-
ing cycloaddition products were achieved in 61% and
75% yields, respectively (Table 3, 3l and 3m). In
addition, we found that the annulation was affected
when the tert-butyl-N-tosyloxycarbamate was used as
the N1 synthon with different substituted in the
benzenesulfonyl moiety (Table 3, 3f and 3n). The
main reason was likely due to solubility or chemical
stability. However, when 3n and 3q were compared,
it was found that the steric hindrances have a little
impact on this transformation. Additionally, these
cycloaddition between aza-ortho-quinone methides
and N-tosyloxycarbamates was then proposed. As
shown in Scheme 5, the aza-ortho-quinone methide
intermediate INT1 was generated, in situ, under the
base condition. Meanwhile, deprotonation of N-
tosyloxycarbamates by K2CO3 formed nucleophilic
nitrogen anion which attacked the intermediate INT1
via 1,4-addition to form a new nitrogen anion INT2.
Subsequently, intramolecular attacking of the
nitrogen anion INT2 to the electrophilic nitrogen
atom, followed by the departure of the leaving group,
afforded the 1,3-dihydro-2H-indazole derivatives.[17,
18]
To address the viability of the [4+1]
cycloaddition reaction in the synthesis of the indazole,
species of alky-N-tosyloxycarbamates have
a
remarkable effect on the annulation. For instance,
when the transformation occurred with 2,2,2-
trichloroethyl-N-tosyloxy-carbamate and ethyl-N-
tosyloxycarbamate as the nitrogen source, the desired
cycloaddition product was achieved in lower yields
(Table 3, 3a, 3o, and 3q), while the cyclohexyl
(tosyloxy) carbamate offered the cycloaddition
product in better yield (Table 3, 3p). Additionally, N-
(tosyloxy) benzene-sulfonamide was a suitable
substrate to this [4+1] cycloaddition reaction and
produced the desired product in 82% yields (Table 3,
3r).
Scheme 5. Proposed [4+1] cycloaddition mechanism
To further expand the [4+1] protocol, we screened
the reaction of benzyl-N-tosyloxycarbamate 2a and
heterocyclic azadiene (Scheme 3). Unfortunately, we
didn’t obtain the [4+1] cycloaddition products under
standard conditions.
Scheme 6. Deprotection of 3a and modification of
indazole
Scheme 3. Limitations of heterocyclic azadiene and N1
synthon 2a
we explored the efficient deportation condition of
protecting groups. Here, we found that the 3a with
KOH in MeCN efficiently cleaved the N-Ts and N-
Cbz, providing the indazole 3a-1 in 86%. Further
exploration of the nucleophilicity of the indazole
nitrogen, we found that methylation could be
performed on the indazole nitrogen, obtaining 3a-2
with the NaHMDS and MeI in THF. In addition,
different derivatization of the three positions of
indazole catalyzed by palladium were performed,
providing the alkenylation and arylation of
substituted indazoles 3a-3 and 3a-4 (Scheme 6).
It is noteworthy that this [4+1] cycloaddition
reaction could be employed on a gram-scale
experiment. Thus, treated N-(2-(chloromethyl)-
phenyl)-4-methylbenzene-sulfonamide 1a and N-
tosyloxycarbamates 2a with K2CO3 under optimal
reaction condition afforded 3a (1.16 g) in 90% yields
(Scheme 4).
In summary, a new synthetic protocol to form N-N
bonds promoted by an inorganic base was developed
that does not rely on precise metal, catalysts and
oxidation. N-tosyloxycarbamates were used as an N1
synthon for this transformation, in the beginning of
the reaction, and worked as a nucleophile that
Scheme 4. Gram-scale experiment
A plausible mechanism for the formation of
these 1,3-dihydro-2H-indazole derivatives via [4+1]
4
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
attacked the in situ-formed aza-ortho-quinone
methide intermediate, followed by an electrophilic
trapping of the nitrogen anion to produce the
annulation products. Further investigation of the
scope and applications of this reaction are in
progress.
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Experimental Section
[8] For some selected examples about the cycloadditions
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a) J. Izquierdo, A. Orue, K. A. Scheidt, J. Am. Chem.
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Zhao, C. Y. Bian, J. Chen, R. W. Chen, F. Shi, Chem.
Commun. 2017, 53, 2768-2771; e) X. K. Zhang, Y. Pan,
X. F. Ma, W. Jiao, H. W. Shao, Adv. Synth. Catal. 2018,
360, 3015-3019.
[9] For some selected examples about the cycloadditions
between ortho-quinone methides and C2 synthons, see:
a) A. Lee, K. A. Scheidt, Chem. Commun. 2015, 51,
3407-3410; b) C. C. Hsiao, H. H. Liao, M. Rueping,
Angew. Chem. Int. Ed. 2014, 53, 13258-13263; c) O.
El-Sepelgy, S. Haseloff, S. K. Alamsetti, C. Schneider,
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Green, E. R. Brown, T. R. R. Pettus, Org. Lett. 2012,
14, 2929-2931; e) B. Wu, Z. Y. Yu, X. Gao, Y. Lan, Y.
G. Zhou, Angew. Chem. Int. Ed. 2017, 56, 4006-4010;
f) P. Chen, K. Wang, W. G. Guo, X. H. Liu, Y. Liu, C.
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[10] For some selected examples about the cycloadditions
between ortho-quinone methides and ylides, see: a) Q.
Q. Yang, C. Xiao, L. Q. Lu, J. An, F. Tan, B. J. Li, W. J.
Xiao, Angew. Chem. Int. Ed. 2012, 51, 9137-9140; b)
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Zhou, Chem. Commun. 2013, 49, 1660-1662; c) N.
Meisinger, L. Roiser, U. Monkowius, M.
Himmelsbach, R. Robiette, M. Waser, Chem.–Eur. J.
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54, 6049-6052.
General experimental [4+1] reaction procedure: To a
stirred solution of the o-chloromethyl arylsulfonamide
compounds 1 (0.48 mmol) and K2CO3 (1 mmol) in MeCN
(4 mL) at room temperature, N1 synthons 2 (0.4 mmol)
were added. After the reaction was complete, as indicated
by the TLC, the mixture was concentrated in vacuo, and
the crude product was purified by flash chromatography,
eluting with petroleum ether/ethyl acetate (15:1) to afford
the products 3.
Acknowledgements
This work was supported by the National Science Foundation of
China (21772192 and 21372215), Biological Resources
Programme, Chinese Academy of Sciences (KFJ-BRP-008) and
the Project of Discovery, Evaluation and Transformation of
Active Natural Compounds, Strategic Biological Resources
Service Network Programme of Chinese Academy of Sciences
(ZSTH-006).
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201901331
Advanced Synthesis & Catalysis
COMMUNICATION
An Effective Method for the Synthesis of 1,3-
Dihydro-2H-indazoles via N-N Bond Formation
R3
H
N
R3
Cl
R4 NHOTs
Adv. Synth. Catal. Year, Volume, Page – Page
N
metal-free
R2
R2
N
R4
N1 synthons
oxidant-free
Xiaoke Zhanga,b,c, Yang Pana,b, Peng Lianga,b, Xiaofeng
Maa,b, Wei Jiao*a and Huawu Shao*a
R1
R1
7
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