One-Pot Synthesis of 1 H -Indazole-4,7-diols via Iodine(III)-Mediated [3+2] Cyclization in Water

Article abstract of DOI:10.1055/s-0035-1560596

An efficient route in one-pot to a new class of 1H-indazole-4,7-diols derivatives has been developed through [3+2] cycloadditive approach in water. The cycloaddition reaction was carried out via condensation of phenol and diazomethyl benzene intermediates

Full text of DOI:10.1055/s-0035-1560596

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
Y. Hou et al.
Letter
Synlett
One-Pot Synthesis of 1H-Indazole-4,7-diols via Iodine(III)-Mediat-
ed [3+2] Cyclization in Water
Yingwei Houa
Chao Caib
Guangli Yu*a,b
OH
R2
N
OH
PhI(OAc)2, H2O
one-pot
R1
R1
R2
N2
+
N
a Key Laboratory of Marine Drugs, Ministry of Education,
School of Medicine and Pharmacy, Ocean University of
China, Qingdao 266003, P. R. of China
H
OH
R1 = H, Me,
tetralol
R2 = Ph, MeC6H4,
ClC6H4, FPh,
18 examples
53–94% yield
glyu@ouc.edu.com
b Shandong Provincial Key Laboratory of Glycoscience and
Glycotechnology, Ocean University of China, Qingdao
266003, P. R. of China
i-PrC6H4, MeOC6H4,
AcNHC6H4, Py,
(CH2)3Ph
Received: 04.09.2015
Accepted after revision: 27.10.2015
Published online: 09.12.2015
lecular shape and electrostatic distribution have been de-
veloped as useful drugs for anti-inflammatory, 5-HT3 re-
ceptor antagonist and anticancer action (Figure 1,A).2–5 Lon-
idamine,4 an anticancer drug developed by Aigelini Italy,
was launched in 1988 for ovarian cancer patients, and pa-
zopanib6 is an angiogenesis inhibitor launched by GSK in
2009. Recently, as a tyrosine kinase inhibitor, axitinib7
launched by Pfizer in 2012 was reported with anti-ovarian
cancer activity. Niraparib,8 a drug candidate developed by
Tesaro, was on phase III research for ovarian and breast can-
cer. Indazoles and analogues are of great interest for biolog-
ical and pharmaceutical research. Although indazoles are
rare in nature, the natural products containing indazole nu-
cleus exhibited fascinating biological activities. Nigellicine,
nigellidine and nigeglanine isolated from the seeds of Nigel-
la sativa were reported as potent anticancer agents (Figure
1,B).9,10
DOI: 10.1055/s-0035-1560596; Art ID: st-2015-w0699-l
Abstract An efficient route in one-pot to a new class of 1H-indazole-
4,7-diols derivatives has been developed through [3+2] cycloadditive
approach in water. The cycloaddition reaction was carried out via con-
densation of phenol and diazomethyl benzene intermediates by taking
advantage of iodobenzene diacetate as an oxidant. Eighteen indazole
derivatives were successfully prepared by the established method.
Key words synthesis, 1H-indazole-4,7-diols derivatives, one pot, water
Indazole is a very important heterocyclic scaffold with a
wide range of biological activities including antifungal, β3-
adrenergic receptor agonist, dopamine D2 receptor antago-
nist, 5-HT3 receptor antagonist, 5-HT2 and 5-HT4 receptor
agonist, anti-inflammatory and anticancer activities.1 In
particular, the indazole derivatives due to their specific mo-
Cl
A
B
N
Cl
H
N
N
N
N
N
N
N
N
O
OH
N
O
N
O
S
NH2
N
nigellicine
OH
O
O
pazopanib
lonidamine
OH
H
O
N
Me
S
OH
H
NH
N
N
N
N
nigellidine
N
N
H
H2N
O
OH
N
nigeglanine
niraparib
axitinib
Figure 1 Indazole derivatives with bioactivities
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Y. Hou et al.
Letter
Synlett
Versatile synthetic methods have been reported for in-
dazoles to accelerate their applications in the pharmaceuti-
cal industry.11 Representative methods developed recently
are depicted in Scheme 1.12–18 Intramolecular cyclization
(Scheme 1, route 1)12 is mostly used for the construction of
indazole fragments; however, it commonly involves three
to four steps under harsh conditions as well as the use of
dangerous reagents such as hydrazine. Recently, Larock re-
ported13–15 the synthesis of indazoles by the [3+2] cycload-
dition with aryl hydrazones and arynes in situ (Scheme 1,
route 2) under mild conditions, which was a concise proto-
col but still using toxic solvents such as acetonitrile. The Ell-
man group at Yale university reported16 an attractive meth-
od for the synthesis of indazoles using [RhCp*Cl2]2 as the ef-
fective catalyst which is a relatively expensive metal
catalyst. Jiao and his co-workers at Peking university re-
ported a method using C–H activation for preparing inda-
zoles (Scheme 1, route 4).18 Ma’s group reported a new ap-
proach for the preparation of indazole derivatives using
copper(I) salt as catalyst in 2012 (Scheme 1, route 5).17 All
routes for the construction of indazoles are very effective,
but most of them require harsh conditions, metal catalysts,
or toxic solvents, etc.
An one-pot synthesis of benzo[d]isoxazole-4,7-diols us-
ing iodine(III)-mediated [3+2] cyclization has been report-
ed19 in Liu’s group. Iodobenzene diacetate [PhI(OAc)2, DIB],
one of the most important and commercially available rep-
resentatives of aryliodine(III) carboxylates, is a mild oxidiz-
ing agent used for various selective oxidative transforma-
tions of complex molecules.20 In this paper, a facile synthe-
sis of 1H-indazole-4,7-diol via iodobenzene diacetate
mediated [3+2] cycloaddition from phenol and diazomethyl
benzene in water is reported. The approach described here
is robust and avoids the use of dangerous and costly re-
agents, and water as the green solvent is more environ-
ment-friendly and safer.
2,3-Dimethylphenol (1a) and diazomethyl benzene (2a)
prepared according the literature21 were chosen as the re-
actants, and mixtures of acetonitrile and water were initial-
ly selected as solvents to investigate the proposed [3+2] cy-
cloaddition reaction (Table 1). The amount of iodobenzene
diacetate was determined as two equivalents based on the
mechanism of the reaction proposed in Scheme 2.15 Unfor-
tunately, acetonitrile mixed with water as solvents (Table 1,
entries 1–3) did not generate any anticipated new products
no matter what solvent ratio was employed. However, only
water as solvent supplied the desirable product 3aa in a
moderate yield of 66% (Table 1, entry 4). We screened reac-
tion times from 6–10 hours under aqueous conditions at
room temperature (Table 1, entries 4–6), but no significant
effect was observed. By raising the reaction temperature to
70 °C (Table 1 entry 8), the yields of 3aa were obviously in-
creased to 82%. Considering the solubility of different reac-
tants, we screened the reaction solutions under the mix-
tures of water with THF, DMF or DMSO (Table 1, entries 10–
12). By using water mixed with THF (Table 1, entry 12), 3aa
was obtained in the yield of 85%. Meanwhile, it was found
that the yields of 3aa achieved 91% and 92%, respectively,
with the addition of 1% (v/v) trifluoroacetic acid (Table 1,
entries 9 and 13), while the use of base, such as triethyl-
amine, obtained the opposed effect (Table 1, entry 14).
Once we obtained the optimal one-pot approach for the
iodine(III)-mediated [3+2] cyclization reaction, versatile in-
dazole derivatives were successfully synthesized according
to the following procedure.22 Compound 1a (1.0 mmol) in
OH
our work:
N2
R'
+
R
PhI(OAc)2
H2O, 70 °C
references reported:
H
R''
CuI
NH2
R1
N
4-hydroxy-L-proline
R2
heat
O
PhCONHNHAr
+
N
N
K2CO3
diaxone, 125 °C
X
Br
route 1
route 5
R3
R4
Ar
NH
OTf
+
N
AgSbF6
dioxane
(Cp*RuCl2)2
+
NaN3
R''''
H
TMS
N
H
route 2
route 4
O
N
+
N
R'''
H
route 3
Scheme 1 Synthetic methods of indazole derivatives
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Y. Hou et al.
Letter
Synlett
Table 1 Screening Studies for Optimal Conditions
diazo employed, tetrahydronaphthol (1b) was found to give
good to excellent yields of anticipated products (Table 2,
entries 11–16). When there was only one substituent at the
2- or 3-position of phenol, two isomers of the 5- and 6-sub-
stituted indazoles were simultaneously produced (Table 2,
entry 18).
OH
OH
OH
H
N
PhI(OAc)2
N2
N
+
solvent
1.5 equiv
2a
1a
Table 2 Synthesis of 3-Substituted 1H-indazole-4,7-diols
3aa
OH
OH
Entry Solvent
Temp (°C) Time (h) Additive
Yield (%)a
H
R1
N
R1
R2
PhI(OAc)2
N
R3
1
2
MeCN–H2O (2:1)
25
25
25
25
25
25
50
70
70
70
70
70
70
70
6
6
none
none
none
66
N2
+
R2
H2O, 70 °C
1.5 equiv
MeCN–H2O (10:1)
MeCN–H2O (1:10)
H2O
R3
OH
3
6
1
2
3
4
6
Entry
1 R1, R2
2 R3
2a Ph
Product 3 Yield (%)a
5
H2O
8
69
1
2
1a Me, Me
3aa
3ab
3ac
3ad
3ae
3af
91
89
93
92
77
79
64
81
79
90
94
89
91
85
81
82
53
67
6
H2O
10
8
68
1a
2b 4-MeC6H4
7
H2O
75
3
1a
2c 4-i-PrC6H4
8
H2O
8
82
4
1a
2d 4-MeOC6H4
9
H2O
8
1% TFA
91
5
1a
2e 3-ClC6H4
10
11
12
13
14
H2O–DMF (10:1)
H2O–DMSO (10:1)
H2O–THF (10:1)
H2O–THF (10:1)
H2O–THF (10:1)
8
71
6
1a
2f 2,5-Cl2C6H3
8
61
7
1a
2g 4-FC6H4
3ag
3ah
3ai
8
85
8
1a
2h 4-AcNHC6H4
8
1% TFA
92
9
1a
2i 4-Py
8
1% Et3N
72
10
11
12
13
14
15
16
17
18
1a
2j (CH2)3Ph
3aj
a Yield after column chromatography.
1b -(CH2)4-
1b
2a
2c
2d
2e
2f
3ba
3bc
3bd
3be
3bf
3bi
12 mL of water with 1% v/v trifluoroacetic acid was first
treated with DIB (2.0 mmol) for 2 h at r.t. to form benzoqui-
none, and then 1.5 mmol of 2a was added at room tempera-
ture. The reaction was continued for eight hours at 70 °C,
and the desired product 3aa was obtained after the addi-
tion of 2.0 mmol of Na2S2O3 in 8 mL of water for overnight
at room temperature (Table 1, entry 9). Afterwards, the
scope of this reaction was systematically investigated on
the basis of our previous report. It was determined that our
protocol was suitable for versatile diazomethyl benzene
substrates (Table 2), and the corresponding products were
obtained in good to excellent yields. It was found that the
substituents of diazomethyl benzene contributed positive
effects to the yields of products (Table 2, entries 2–10). Al-
kyl and alkoxyl substitutions contributed to the high yields
up to 93% (Table 2, entries 2–4). Single or multiple chloro or
fluoro substitutions slightly or significantly decreased the
yields (Table 2, entries 5–7), while other electron-donating
groups, such as acetamido, presented a good yield (Table 2,
entry 8). Meanwhile, heteroaromatic diazomethyl such as
4-pyridyl yielded the anticipated compound in good yield
(Table 2, entry 9), as did the alkyl example (Table 2, entry
10). Phenol variabilities were next studied (Table 2, entries
11–18), and it was found that less alkyl substitution clearly
resulted in low yields. In spite of the different structures of
1b
1b
1b
1b
2i
1c H, H
1d Me, H
2a
2a
3ca
3da
a Yield after column chromatography.
Our proposed mechanism for the construction of inda-
zoles through [3+2] cycloaddition is depicted in Scheme 2.
Water, as a nucleophile, first attacked 1a, and then aided by
1.0 equivalents DIB to afford dihydroxybenzene A. It is be-
lieved that alcohol solvents such as methanol will induce
the ether linkage on A. Subsequently, an excess amount of
DIB (1.0 equiv) was continuously added for oxidation of
phenolic hydroxyl groups, and benzoquinone
B was
achieved in water. Ultimately, a [3+2] cycloaddition be-
tween 2a and B successfully occurred to afford anticipated
product 3aa.
In summary, we presented an efficient and environ-
ment-friendly method for the synthesis of 1H-indazole-4,7-
diols by iodine(III)-mediated [3+2] cycloaddition in water.
Versatile indazole derivatives were synthesized in moder-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Y. Hou et al.
Letter
Synlett
(3) Aapro, M. Oncologist 2004, 9, 673.
(4) Pelicano, H.; Martin, D. S.; Xu, R. H.; Huang, P. Oncogene 2006,
25, 4633.
(5) Ansari, A. S.; Kumar, Y.; Srivastava, S.; Lohiya, N. K. Contracep-
tion 1998, 57, 271.
(6) Jackson, A. L.; Eisenhauer, E. L.; Herzog, T. J. Expert Opin. Emerg-
ing Drugs 2015, 20, 331.
AcO
AcO
OH
I
Ph
Ph
I
O
OAc
OH
A
Ph
I
OH
(7) Damaraju, V. L.; Kuzma, M.; Mowles, D.; Cass, C. E.; Sawyer, M.
B. Mol. Cancer Ther. 2015, 14, 236.
2a
O
OAc
O
(8) Jones, P.; Wilcoxen, K.; Rowley, M.; Toniatti, C. J. Med. Chem.
2015, 58, 3302.
(9) Ali, Z.; Ferreira, D.; Carvalho, P.; Avery, M. A.; Khan, I. A. J. Nat.
Prod. 2008, 71, 1111.
N
N
OH
O
H
O
H
H
N
OH
(10) Randhawa, M. A.; Alghamdi, M. S. Am. J. Chin. Med. 2011, 39,
1075.
B
N
AcO
I
Ph
(11) (a) Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Tetrahedron 2006,
62, 7772. (b) Souers, A. J.; Gao, J.; Wodka, D.; Judd, A. S.;
Mulhern, M. M.; Napier, J. J.; Brune, M. E.; Bush, E. N.; Brodjan, S.
J.; Dayton, B. D.; Shapiro, R.; Hernandez, L. E.; Marsh, K. C.;
Sham, H. L.; Collins, C. A.; Kym, P. R. Bioorg. Med. Chem. Lett.
2005, 15, 2752. (c) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna,
M. R. J. Org. Chem. 2006, 71, 8166. (d) Qiu, G.; Su, J.; Feng, X.;
Wu, L.; Xu, W.; Hu, X. J. Heterocycl. Chem. 2004, 41, 601.
(e) Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G. E.;
Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez, P. A.;
Glen, R. C.; Goggin, M. C.; Hobbs, A. J.; Kling, M. R.; Liu, Q.;
Madge, D. J.; Meillerais, S.; Powell, K. L.; Reynolds, K.; Spacey, G.
D.; Stables, J. N.; Tatlock, M. A.; Wheeler, K. A.; Wishart, G.; Woo,
C.-K. J. Med. Chem. 2001, 44, 78. (f) Koga, N.; Koga, G.; Anselme,
J.-P. Tetrahedron 1972, 28, 4515. (g) Shoji, Y.; Hari, Y.; Aoyama, T.
Tetrahedron Lett. 2004, 45, 1769.
OH
OAc
1a
3aa
Scheme 2 Proposed mechanism of one-pot synthesis of 1H-indazole-
4,7-diols
ate to excellent yields by phenol and diazomethyl benzene
condensation in one pot. Further investigations to increase
the scope of this methodology and its applications are un-
der way in our research group.
Acknowledgment
This work was supported in part by China Postdoctoral Science Foun-
dation (2014M551967), NSFC-Shandong Joint Fund for Marine Sci-
ence Research Centers (U1406402) and National Science and
Technology Support Program of China (2013BAB01B02).
(12) Lukin, K. J. Org. Chem. 2006, 71, 8166.
(13) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10,
2409.
(14) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234.
(15) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77,
2279.
Supporting Information
(16) Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. J. Am. Chem.
Soc. 2013, 135, 7122.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560596.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(17) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552.
(18) Zheng, Q.; Feng, P.; Liang, Y.; Jiao, N. Org. Lett. 2013, 15, 4262.
(19) Hou, Y.; Lu, S.; Liu, G. J. Org. Chem. 2013, 78, 8386.
(20) Wada, Y.; Harayama, Y.; Kamimura, D.; Yoshida, M.; Shibata, T.;
Fujiwara, F.; Morimoto, K.; Fujioka, H.; Kita, Y. Org. Biomol.
Chem. 2011, 9, 4959.
References and Notes
(1) (a) Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa, M.; Nakano, S.;
Morimoto, A.; Kasahara, K. I.; Tanaka, E.; Takada, Y.; Ohashi, S.;
Mori, M.; Shuto, S. J. Med. Chem. 2015, 58, 6048. (b) Marin, C.;
Ramirez-Macias, I.; Rosales, M. J.; Muro, B.; Reviriego, F.;
Navarro, P.; Aran, V. J.; Sanchez-Moreno, M. Acta Trop. 2015,
148, 170. (c) Balakrishnan, N.; Raj, J. S.; Kandakatla, N. Int. J.
Pharm. Pharm. Sci. 2015, 7, 295. (d) Reddy, M. T.; Reddy, V. H.;
Reddy, R. C. K.; Reddy, V. K.; Reddy, Y. V. R. Pharma Chem. 2014,
6, 411. (e) Yuan, T.; Nahar, P.; Sharma, M.; Liu, K.; Slitt, A.; Aisa,
H. A.; Seeram, N. P. J. Nat. Prod. 2014, 77, 2316. (f) Lebouvier, N.;
Pagniez, F.; Duflos, M.; Le Pape, P.; Na, Y. M.; Le Baut, G.; Le
Borgne, M. Bioorg. Med. Chem. Lett. 2007, 17, 3686. (g) Becker, D.
P.; Flynn, D. L.; Moormann, A. E.; Nosal, R.; Villamil, C. I.;
Loeffler, R.; Gullikson, G. W.; Moummi, C.; Yang, D. C. J. Med.
Chem. 2006, 49, 1125. (h) Harada, H.; Hirokawa, Y.; Suzuki, K.;
Hiyama, Y.; Oue, M.; Kawashima, H.; Kato, H.; Yoshida, N.;
Furutani, Y.; Kato, S. Chem. Pharm. Bull. 2005, 53, 184.
(i) Grundt, P.; Little Jane Husband, S.; Luedtke, R. R.; Taylor, M.;
Hauck Newman, A. Bioorg. Med. Chem. Lett. 2007, 17, 745.
(2) Uno, H.; Kurokawa, M.; Masuda, Y.; Nishimura, H. J. Med. Chem.
1979, 22, 180.
(21) Xavier, C. Org. Synth. 1986, 64, 207.
(22) Procedure of Preparing Compound 3ab
DIB (644 mg, 2.0 mmol) was added to a solution of compound
1a (112 mg, 1.0 mmol) in TFA (12 mL) and H2O (1%, v/v). After
the mixture was stirred for 2 h at r.t., compound 2b (198 mg, 1.5
mmol) was added. The resulting solution was stirred for
another 8 h at 70 °C. After the addition of Na2S2O3 (2.0 mmol) in
H2O (8 mL), the mixture was poured into brine (30 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layer
was washed with brine (2 × 50 mL) and dried over Na2SO4. After
evaporation of the solvent under reduced pressure, the residue
was purified by silica gel (MeOH–CH2Cl2, 1:100) to obtain the
product 3ab (238 mg, 89% yield). 1H NMR (500 MHz, acetone-
d6): δ = 8.49 (s, 1 H, OH), 7.80 (d, J = 8.2 Hz, 2 H, ArH), 7.29 (d,
J = 8.0 Hz, 2 H, ArH), 2.42 (s, 3 H, ArCH3), 2.36 (s, 6 H, ArCH3).
13C NMR (126 MHz, acetone-d6): δ = 170.94, 151.29, 145.24,
140.56, 130.94, 130.42, 130.32, 130.14, 129.32, 125.57, 21.84,
21.46. HRMS (ESI-TOF): m/z calcd for C16H17N2O2 [M + H]+:
269.1285; found: 269.1284.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D