Iodine-catalyzed aerobic oxidation of o-alkylazoarenes to 2H-indazoles

Article abstract of DOI:10.1016/j.tet.2017.01.035

An iodine-catalyzed aerobic-oxidative C-H functionalization of o-alkylazoarenes to afford 2H-indazoles has been developed. CuI was found to be an effective additive to accelerate the regeneration of iodine in the catalytic cycle. This catalytic system is suitable for both electron-rich and electron-deficient azoarenes and tolerates a variety of functional groups with high yields. A gram-scale reaction was successfully conducted, proving the scalability of this reaction.

Full text of DOI:10.1016/j.tet.2017.01.035

Accepted Manuscript
Iodine-catalyzed aerobic oxidation of o-alkylazoarenes to 2H-indazoles
Xiangli Yi, Chanjuan Xi
PII:
S0040-4020(17)30058-3
10.1016/j.tet.2017.01.035
TET 28405
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 December 2016
Revised Date: 12 January 2017
Accepted Date: 16 January 2017
Please cite this article as: Yi X, Xi C, Iodine-catalyzed aerobic oxidation of o-alkylazoarenes to 2H-
indazoles, Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.035.
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ACCEPTED MANUSCRIPT
Iodine-Catalyzed Aerobic Oxidation of o-Alkylazoarenes
to 2H-Indazoles
Xiangli Yia, and Chanjuan Xi*ab
aKey Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, China.
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China.
E-mail: cjxi@tsinghua.edu.cn.

ACCEPTED MANUSCRIPT
Iodine-Catalyzed Aerobic Oxidation of o-
Alkylazoarenes to 2H-Indazoles
Xiangli Yi1 and Chanjuan Xi*1,2
Address: 1Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, China and 2State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China.
Email: cjxi@tsinghua.edu.cn
Abstract
An iodine-catalyzed aerobic-oxidative C-H functionalization of o-alkylazoarenes to
afford 2H-indazoles has been developed. CuI was found to be an effective additive to
accelerate the regeneration of iodine in the catalytic cycle. This catalytic system is
suitable for both electron-rich and electron-deficient azoarenes and tolerates a variety
of functional groups with high yields. A gram-scale reaction was successfully
conducted, proving the scalability of this reaction.
Keywords
Iodine catalysis; sp3 C-H functionalization; Aerobic oxidation; 2H-Indazole.
Introduction
1

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2H-Indazole is an important skeleton of nitrogen-containing heterocycle present in
many biologically active compounds, including in natural products and
pharmaceuticals (Scheme 1).1 For example, molecule A as a poly(ADP-
ribose)polymerase inhibitor displays antiproliferation activity against BRCA-deficient
cancer cells.1a Compound B acts as a Liver-X-receptor agonist and thus is a drug for
cardiovascular diseases.1b Molecule D is a kind of antiparasitic drug.1d One traditional
approach
to
yield
2H-indazoles
is
reductive
cyclization
of
N-(o-
nitrobenzylidene)anilines2 or N-(2-aminobenzyl)anilines.3 Another way to prepare
2H-indazoles is via cross coupling reactions,4 such as palladium-catalyzed coupling
of 2-halophenyl acetylenes with hydrazines,4c and reaction of 2-chloromethylarylzinc
reagents with aryldiazonium salts.4e Among these methods leading to the 2H-
indazole derivatives, many of them suffer from complicated preparation of substrates
or using air sensitive organometallic reagents with poor functional tolerance.
Accordingly, development of facile and scalable routes to construct the 2H-indazoles
is still desirable.
Scheme 1: Several Bioactive 2H-Indazoles.
Recently, C-H functionalization strategy has been introduced to the synthesis of
2H-indazoles to make the reactions more step- and atom-economical. Several
protocols of sp2 C-H activation of azobenzenes by Pd,5 Rh,6 Re7 and Co8 with
incorporation of carbonyl compounds have been reported to afford the 2H-indazoles.
2

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Methods of direct sp3 C-H functionalization of alkylazobenzenes leading to 2H-
indazoles are still limit.9 A stepwise bromination-cyclization procedure (Scheme 2,
route a) was reported, which potentially suffers from selectivity problem of
bromination in multiaralkyl-containing substrates.9a More recently, a stoichiometric
iodine-mediated procedure has been reported by our group (Scheme 2, route b).9c
From the point of sustainability and green chemistry, it is highly desired to use more
regenerative and abundant oxidant like O2 to fulfil this conversion.10 As a part of our
ongoing project on the construction of heterocycles,11 herein, we report an iodine-
catalyzed aerobic-oxidative reaction for construction of 2H-indazoles (Scheme 2, this
work). Besides the high efficiency and environmentally friendly nature of the reagents,
this reaction displays extensive substrate scope, excellent functional tolerance, and
good scalability.
Scheme 2: Cyclization of ortho-Alkylazobenzenes to 2H-Indazoles via sp3 C-H
Functionalization.
Results and Discussion
Based on the conditions for stoichiometric I2-mediated reaction,9c we first tried
reduced amount of I2 (20 mol%) and oxygen atmosphere (entry 1, Table 1), and the
product 2a was obtained in 43% yield, with 50% starting material remaining. This
result suggests that I2 can catalyze this conversion, yet the regeneration of I2 from I-
3

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might not be fast enough under this condition. Therefore, we tried to add several
metal salts, such as CuBr, CuI, CuCl2, FeBr2, MnCl2 (entry 2-6), as additive to
facilitate the oxidation of I-, and we found that addition of 10 mol% CuI led to 2a in
81% yield. Then, the solvent dichloroethane (DCE) was respectively replaced with
CHCl3, CH3CN, and toluene (entry 7-9), and toluene was found to behave better than
DCE for this reaction. During the reaction in toluene, we noticed that the solubility of
NaOAc was poor, so organic bases were tried (entry 10-11) and pyridine as base
was found to increase the yield to 96%. The amount of CuI could be reduced to 5
mol% (97% yield, entry 12), while reduction of I2 to 10 mol% led to a lower yield
(entry 13). Therefore, the optimized condition is shown in entry 12.
Table 1: Optimization Reaction Conditionsa.
20% I2
N
N
Mes
base, additive
N
N Mes
1a O2,120 oC, solvent, 12 h
2a
entry
1
base
yieldb/ %
solvent
DCE
additive
_
NaOAc (40%)
NaOAc (40%)
NaOAc (40%)
NaOAc (40%)
NaOAc (40%)
43
70
CuBr (10%)
CuI (10%)
DCE
DCE
2
3
81
59
4
5
6
7
8
CuCl2 (10%)
FeBr2 (10%)
DCE
DCE
55
47
70
60
MnCl2 (10%)
CuI (10%)
NaOAc (40%)
NaOAc (40%)
DCE
CHCl3
NaOAc (40%)
NaOAc (40%)
NEt3 (40%)
CH3CN
toluene
toluene
CuI (10%)
87
9
CuI (10%)
CuI (10%)
10
11
12
13d
27
96
CuI (10%)
CuI (5%)
CuI (10%)
toluene
toluene
toluene
pyridine (40%)
pyridine (40%)
pyridine (20%)
97, 93c
75
aReaction condition: 0.2 mmol 1a, 0.04 mmol I2, 0.08 mmol base, 1 mL solvent, 120
oC under O2 in sealed tube. bNMR yield. cIsolated yield. d10 mol% I2 was used.
With the optimal conditions in hand, the substrate scope was examined and
representative results are showed in Scheme 3. Replacing the bulky mesityl in 1a
4

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with phenyl furnished 5,7-dimethyl-2-phenyl-2H-indazole 2b in 92% yield. Then, para-
Substitution on the phenyl ring in 1b was changed from electron-donating to electron-
withdrawing group (OMe, H, Br and CN). The former three substrates (1c, 1d, and
1e) gave excellent yields (2c, 94%; 2d, 85% and 2e, 84% respectively), while 1f
required higher I2 load and longer reaction time to achieve moderate yield (2f, 58%).
Replacing one ortho-methyl in 1b with phenyl led to product 2g in 90% yield.
Substrates with ortho-bromo and -iodo group also afforded products in high yields
(2h+2i, 93%; 2i, 90%). It is noteworthy that when substrate 1h was treated, bromo
group is partially substituted by iodo group in the product (2h: 2i = 1: 0.13).
Then, the functional group tolerance on the other aryl group of azobenzene was
examined. Electron-withdrawing group like CN and CO2Me resulted in desired
products in high yield (2j, 95% and 2k, 83% respectively), while COMe substituent
led to product 2l in only 31% yield. To our delight, the crystal of 2j was suitable for
single crystal analysis, and its structure was fully characterized by X-ray diffraction
analysis, which unequivocally confirmed the 2-aryl-2H-indazole backbone of the
product.
Strong electron-donating group NMe2 could also be tolerated in this reaction
and afforded product 2m in 43% yield. Moreover, acetyl-protected indole was
tolerated and gave the product 2n in 42% yield. Interestingly, the radical-sensitive
phenol moiety didn’t show any prohibition and the corresponding product 2o was
obtained in 70% yield. Four substrates with ortho-methylene were tested. When 2,6-
diethylazobenzene 1p was used, the product 2p was also formed in 89% yield. 2-
Ethyl-6-methylazobenzene 1q furnished two separable products (2q, 75% yield and
2q', 17% yield), while 1r and 1s were selectively transformed into 3-substituted
products, respectively in 85% (2r) and 88% (2s) yield. As is consistent with our
5

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former work,9c substrates with only one ortho-methyl, such as 2,4-
dimethylazobenzene (1t), are unreactive.
6

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Scheme 3: Scope of Substrates for Synthesis of 2H-Indazoles. Reaction condition:
0.2 mmol 1, 0.04 mmol I2, 0.01mmol CuI, 0.08 mmol pyridine, 1 mL toluene, 120 oC
under O2 for 12 h in sealed tube; 1H-NMR yields (%) and isolated yields (%, in
bracket) are displayed. a Reaction time: 6 h. b Reaction time: 24 h. c Reaction time:
24 h, 30 mol% I2, 60 mol% pyridine.
Iodine has been reported to mediate C-H functionalization of benzyl C-H in o-
alkylazoarenes to form 2H-indazoles via a radical chain mechanism.9c To elucidate
the process of this catalytic reaction, several additional experiments were conducted.
First, iodine was removed from the conditions (Eq. 1), and the reaction did not
proceed, which proves the central role of iodine in mediating the conversion of o-
alkylazoarenes. Then, pyridine hydroiodide was used in place of I2 and pyridine, and
products 2a was still obtained in 85% yield (Eq. 2), suggesting that I- can be oxidized
to I2 to mediate the reaction. When CuI was eliminated from the reaction, the product
2a was obtained in 55% yield in 12 h and 72% yield in 24 h (Eq. 3), and this
observation is consistent with the proposed role of CuI to facilitate the oxidation of I-
to I2 under oxygen.
Based on these results and reported literature,9c a possible reaction
mechanism has been proposed as shown in Scheme 4. First, azo substrate 1
associates with I2 to form compound 3. Then, iodine radical mediates homolysis of I–I
7

ACCEPTED MANUSCRIPT
bond in the compound 3 to give intermediate 4, which undergoes hydrogen transfer
and cyclization to a ord intermediate 6 via intermediate 5. Abstraction of a second
benzylic hydrogen by I2 achieves the product 2 with generation of pyridine
hydroiodide in the presence of pyridine. Finally, I2 is regenerated by aerobic oxidation
of pyridine hydroiodide with the assistance of CuI.
Scheme 4: Proposed Reaction Mechanism.
To further demonstrate the applicability of this procedure, a gram-scale reaction of
1b was run in schlenk tube (atmospheric pressure), using p-xylene as a solvent and
CuI (2 mol%). The product 2b was obtained in 89% isolated yield (Eq. 4). This trial
suggests that this reaction can be easily scaled up for synthesis of substantial
amount of 2-aryl-2H-indazoles.
Conclusion
An efficient iodine-catalyzed aerobic-oxidative C-H functionalization method
has been developed for the synthesis of 2H-indazoles from o-alkylazoarenes.
8

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Utilization of CuI as oxidation promotor successfully enabled the use of oxygen as
terminal oxidant and catalytic amount of iodine, which makes this reaction very
environmentally benign. Moreover, this reaction can tolerate a variety of functional
groups with high yields and can be easily amplified for gram-scale synthesis of 2H-
indazoles.
Experimental
General Procedure for Synthesis of Azobenzenes 1 (GP1): 2.2 mmol of aniline and
2.0 mmol nitrosobenzene were added into 20 mL acetic acid. The reaction mixture
was shielded form light and stirred at 30 oC for 2 days. After the reaction completed,
the mixture was diluted with 20 mL water and then extracted twice with 20 mL
petroleum ether (PE). The organic phase was washed with 20 mL NaHCO3 solution,
dried and evaporated. The obtained residual was separated by chromatography (PE-
DCM) to give the corresponding products (1b-1i, 1p, 1q and 1t). Additionally, 1a, 1r
and 1s was prepared via coupling reactions.9c Specific preparation procedures are
provided along with the characterization data in ESI.
General Procedure for I2-Catalyzed Synthesis of 2H-Indazoles 2 (GP2): A seal tube
(25 mL) was charged with 0.2 mmol azobenzene and 0.01 mmol CuI (1.9 mg) and
then vacuumized and refilled with O2. Subsequently, 0.04 mmol I2 (10.8 mg), 0.08
mmol pyridine (6 µL) and 1 mL toluene were added. The reaction vessel was heated
at 120 oC for 12 h. After the reaction completed, 0.5 mL 1 mol/L amonia solution and
3 drops of saturated Na2S2O3 solution was added and the mixture was extracted with
EA. Column seperation gives the corresponding 2H-indazoles.
Characterization data of unkown products are displayed below.
9

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5-Bromo-7-methyl-2-phenyl-2H-indazole (2e): synthesized via GP2; white solid
o
1
(46.1 mg, 80% isolated yield); M.p. 139-141 C; Rf: 0.45 (PE: EA=10:1); H NMR
(400 MHz, CDCl3): δ 8.63 (s, 1H), 8.25 - 8.21 (m, 2H), 8.03 (dd, J = 1.5, 0.6 Hz, 1H),
13
7.89 - 7.84 (m, 2H), 7.77 - 7.72 (m, 1H), 7.51 - 7.49 (m, 1H), 3.00 (s, 3H); C NMR
(100 MHz, CDCl3): δ 148.8, 140.5, 130.5, 129.7, 129.2, 128.2, 123.6, 121.2, 120.1,
119.9, 116.2, 17.0; GC-MS: 286; HRMS (ESI positive mode) calcd for C14H11BrN2+H+
287.0178, found 287.0175.
4-(5,7-Dimethyl-2H-indazol-2-yl)benzonitrile (2j): synthesized via GP2; white
o
1
crystal (43.4 mg, 88% isolated yield); M.p. 176-177 C; Rf: 0.20 (PE: EA=4:1); H
NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.03 - 7.99 (m, 2H), 7.77 - 7.72 (m, 2H), 7.22
(s, 1H), 6.93 (s, 1H), 2.61 (s, 3H), 2.38 (d, J = 0.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 150.0, 143.6, 133.6, 133.2, 129.8, 127.9, 123.5, 120.6, 119.5, 118.4,
115.8, 110.6, 21.9, 17.0; GC-MS: 247; HRMS (ESI positive mode) calcd for
C16H13N3+H+ 248.1182, found 248.1180.
Methyl 4-(5,7-dimethyl-2H-indazol-2-yl)benzoate (2k): synthesized via GP2; white
solid (43.4 mg, 78% isolated yield); M.p. 150-152 oC; Rf: 0.26 (PE: EA=4:1); 1H NMR
(400 MHz, CDCl3): δ 8.29 (s, 1H), 8.21 - 8.14 (m, 2H), 8.02 - 7.97 (m, 2H), 7.23 (s,
1H), 6.93 (d, J = 1.1 Hz, 1H), 3.95 (s, 3H), 2.64 (s, 3H), 2.38 (d, J = 0.8 Hz, 4H); 13C
NMR (100 MHz, CDCl3): δ 166.4, 149.8, 144.0, 132.8, 131.2, 129.5, 128.9, 127.9,
123.3, 120.1, 119.7, 115.8, 52.4, 22.0, 17.1; GC-MS: 280; HRMS (ESI positive mode)
calcd for C17H16N2O2+H+ 281.1285, found 281.1280.
1-(4-(5,7-Dimethyl-2H-indazol-2-yl)phenyl)ethanone (2l): synthesized via modified
GP2 (24 h); white solid (14.1 mg, 27% isolated yield); M.p. 167-169 oC; Rf: 0.42 (PE:
EA = 4:1); 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 0.5 Hz, 1H), 8.09 (d, J = 8.1 Hz,
13
2H), 8.04 - 8.00 (m, 2H), 7.24 (s, 1H), 6.93 (s, 1H), 2.64 (m, 6H), 2.38 (s, 3H); C
NMR (100 MHz, CDCl3): δ 197.0, 149.9, 144.0, 135.7, 132.9, 130.0, 129.6, 127.9,
10

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123.4, 120.3, 119.8, 115.8, 26.8, 22.0 17.1; GC-MS: 264; HRMS (ESI positive mode)
calcd for C17H16N2O+H+ 265.1335, found 265.1332.
4-(5,7-Dimethyl-2H-indazol-2-yl)-N,N-dimethylaniline (2m): synthesized via
modified GP2 (30% I2, 24 h); yellowish solid (17.0 mg, 32% isolated yield); M.p. 164-
165 oC; Rf: 0.40 (PE: EA=4:1); 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.72 (d, J
= 9.0 Hz, 2H), 7.26 (s, 1H), 6.91 (s, 1H), 6.82 (d, J = 6.7 Hz, 2H), 3.02 (s, 6H), 2.65
(s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 148.9, 131.6, 128.3, 127.5,
122.8, 122.4, 119.6, 115.7, 112.9, 40.9, 21.9, 17.3; GC-MS: 265; HRMS (ESI positive
mode) calcd for C17H19N3+H+ 266.1652, found 266.1655.
1-(3-(5,7-Dimethyl-2H-indazol-2-yl)-1H-indol-1-yl)ethanone (2n): synthesized via
modified GP2 (30% I2, 24 h); yellowish solid (16.9 mg, 28% isolated yield); M.p. 158-
1
159oC; Rf: 0.27 (PE: EA = 4:1); H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 8.2 Hz,
1H), 8.30 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.51 - 7.44 (m, 1H), 7.41 (td,
J = 7.9, 1.0 Hz, 1H), 7.30 (s, 1H), 6.98 (s, 1H), 2.71 (s, 3H), 2.67 (s, 3H), 2.42 (s,
13
3H); C NMR (100 MHz, CDCl3): δ 168.8, 148.9, 135.1, 132.5, 129.2, 127.4, 126.7,
125.2, 124.7, 123.9, 122.6, 122.0, 119.4, 117.4, 117.1, 115.7, 24.2, 22.0, 17.3;
HRMS (ESI positive mode) calcd for C19H17N3O+H+ 304.1444, found 304.1446.
4-(5,7-Dimethyl-2H-indazol-2-yl)phenol (2o): synthesized via modified GP2 (30%
I2, 24 h); yellowish solid (25.7 mg, 54% isolated yield); M.p. 196-198 oC; Rf: 0.16 (PE:
EA=4:1); 1H NMR (400 MHz, ACETONE-D6): δ 8.76 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H),
7.88 (dd, J = 8.8, 1.4 Hz, 2H), 7.27 (s, 1H), 7.01 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H),
2.56 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, ACETONE-D6): δ 157.9, 149.6,
134.5, 132.1, 128.9, 128.0, 123.9, 122.7, 120.4, 116.9, 116.8, 21.9, 17.2; HRMS (ESI
positive mode) calcd for C15H14N2O+H+ 239.1179, found 239.1178.
7-Ethyl-3-methyl-2-phenyl-2H-indazole (2p): synthesized via GP2; colorless oil
(39.3 mg, 83% isolated yield); Rf: 0.32 (PE: EA=10:1); 1H NMR (400 MHz, CDCl3): δ
11

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7.60 - 7.51 (m, 4H), 7.51 - 7.46 (m, 2H), 7.13 (dd, J = 6.7, 0.8 Hz, 1H), 7.05 (dd, J =
13
8.3, 6.7 Hz, 1H), 3.11 (q, J = 7.5 Hz, 2H), 2.63 (s, 3H), 1.44 (t, J = 7.5 Hz, 3H); C
NMR (100 MHz, CDCl3): δ 148.4, 140.2, 133.8, 132.2, 129.3, 128.7, 126.1, 123.7,
121.6, 121.4, 117.5, 24.4, 14.0, 11.3; GC-MS: 236; HRMS (ESI positive mode) calcd
for C16H16N2+H+ 237.1386, found 237.1385.
Gram scale procedure: 6.0 mmol 1b (1.34 g) and 0.12 mmol CuI (22.8 mg) was
added to a 50 mL schlenk tube. Then, 1.2 mmol I2 (0.30 g), 2.4 mmol pyridine (193
µL) and 10 mL p-xylene were in turn added to the tube. The reaction was conducted
o
under oxygen atmosphere at 120 C for 24 h. 2 mL 1 mol/L amonia solution and 0.5
mL saturated Na2S2O3 solution was added to the reaction mixture after cooling down.
Column seperation afforded 1.18 g 2b (89% isolated yield).
Supporting Information
Supporting information text: Containing detailed experimental procedures,
1
characterization data of known products and some substrates, H- and 13C- NMR
spectra of all products.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(21272132 and 21472106) and the National Key Basic Research Program of China
(973 program) (2012CB933402). We thank Prof. Chao Chen and Prof. Lei Jiao (in
Tsinghua University) for giving advices to this work.
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