Copper-Promoted Oxidative Intramolecular C–H Amination of Hydrazones to Synthesize 1H-Indazoles and 1H-Pyrazoles Using a Cleavable Directing Group

Article abstract of DOI:10.1002/ejoc.201900947

A facile and efficient synthesis of 1H-indazoles and 1H-pyrazoles through a copper-promoted oxidative intramolecular C–H amination of hydrazones using a cleavable directing group was developed. This reaction is characterized by its mild conditions, operational simplicity, readily available reagents, and excellent yields. A tentative mechanism for Cu-mediated C–H oxidative amination was proposed.

Full text of DOI:10.1002/ejoc.201900947

A Journal of
Accepted Article
Title: Traceless Directing Group Assisted Copper-Promoted Oxidative
intramolecular C-H Amination of Hydrazones to Synthesis of 1H-
Indazoles or 1H-Pyrazoles
Authors: Guofu Zhang, Qiankun Fan, Yiyong Zhao, and Chengrong
Ding
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900947
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900947
Supported by

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
Traceless Directing Group Assisted Copper-Promoted Oxidative
intramolecular C-H Amination of Hydrazones to Synthesis of 1H-
Indazoles or 1H-Pyrazoles
Guofu Zhang,[a] Qiankun Fan, †[a] Yiyong Zhao, †[a] and Chengrong Ding*[a]
Dedication ((optional))
Abstract: A facile and efficient synthetic strategy for the 1H-
indazoles and 1H-pyrazoles via traceless directing group assisted
copper-promoted oxidative intramolecular C-H amination of
hydrazones was developed. This reaction is characterized by its mild
conditions, operational simplicity, readily available reagents and
was reported by Glorius, which involved Cu(OAc)2/[Cp*RhCl2]2
as a catalyst in AgSbF6/O2/DCE system at 110 oC (Scheme
1Ab).[16] However, these methods inevitably suffer from multiple
excellent yields.
A tentative mechanism for Cu-mediated C-H
oxidative amination was proposed.
Introduction
Nitrogen-containing heterocyclic compounds, due to their unique
properties, are widely used in medicine, dyes, pesticides and
other fields. [1] Significantly, 1H-indazoles and 1H-pyrazoles are
ubiquitous scaffolds in many compounds with a broad spectrum
of biological and pharmaceutical properties, including anti-
cancer,[2] antiviral,[3] antihypercholesterolemia,[4] antimicrobial,[5]
and so on. Some typical examples are outlined in Figure 1. In
the light of their prominent properties, preparation of the
indazole and pyrazole derivatives has been pursued for a long
time by synthetic organic chemists.
Figure 1. Representative biologically active 1H-indazoles and 1H-pyrazoles
Initially, the synthetic methods were mainly limited to
transition-metal-free processes include diazotization or
nitrosation of o-alkyl-substituted anilines,[6] and condensation of
2-halo or mesylate-substituted arylaldehydes or ketones with
hydrazines under fairly harsh conditions.[7] In terms of pyrazole
derivatives, an one-pot synthetic protocols were actualized by
condensation of ketones or aldehydes with hydrazines.[8] On the
basis of preliminary reports, a large number of methods for
synthesis of 1H-indazole and 1H-pyrazole derivatives have been
developed.[9] Unfortunately, many of these methods encounter
several blemishes, such as undesirable solvents,[10] specialized
reagents,[11] the preparation of potentially perilous diazo or azido
substrates or intermediates,[12] expensive starting materials, or
limited substrate scope, etc.
In the past decades, transition-metal catalysis has
increasingly became an indispensable protocols to generate N-
heterocyclic frameworks.[13] In these methods, the directing
groups are essential for acceleration and regioselective
control.[14] For instance, Bao and co-workers employed FeBr3 as
a catalyst in toluene/O2 system, in which arylhydrazones were
smoothly oxidized into desired substituted 1H-indazoles and 1H-
pyrazoles (Scheme 1Aa).[15] Another RhIII/CuII-cocatalyzed C−H
amidation and N−N bond formation to synthesis of 1H-indazoles
[a]
College of Chemical Engineering
Zhejiang University of Technology
Hangzhou 310014, P. R. China
E-mail: dingcr@zjut.edu.cn
Scheme 1. Synthesis of 1H-indazoles and 1H-pyrazoles via C-H amination
†
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
24[h]
25[i]
26[j]
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMSO
DMSO
DMSO
KOCN
KOCN
KOCN
NR
NR
43
steps including removal of directing groups after the reaction.[17]
Impressively, Shi group reported aryne reactions to prepare 1H-
indazoles using N-tosylhydrazones as inexpensive and eadily
available starting materials (Scheme 1B).[18] Recently, many
chemists has been developed using picolinamide as traceless
directing groups for C−H functionalization of organic
compounds.[19] The strategy using traceless directing group
which can be removed without additional steps is a much more
attractive alternative. Herein, we report an efficient traceless
[a] Reaction conditions: 1a (0.1 mmol), catalyst (0.1 mmol), bases (0.15 mmol)
in DMSO (1.0 ml) at 80oC under air for 9 h. [b] 60 oC. [c] 100 oC. [d] Under：N2.
[e] Under：O2. [f] DG-2. [g] DG-3. [h] DG-4. [i] DG-5. [j] DG-6. [k] Isolated yield.
atmosphere. To our delight, the desired product, 3-phenyl-1H-
indazole 2a, was isolated in 85% yield (entry 1). Encouraged by
this initial finding, further screening of reaction conditions was
performed. After exploring a series of catalysts (entries 1-7),
Cu(OAc)2 was found to be the most suitable acclereant for this
process, giving 2a in 92% yield (entry 4). Neither Co nor Fe
catalysts are effective in the catalysis with no target product 3-
phenyl-1H-indazole 2a formed. A control experiment confirmed
the necessity of the copper catalyst in the reaction (entry 8).
Subsequently, the effect of solvent on this oxidative
transformation was examined (entries 9-13). No desired
products were obtained, when the reaction was performed in t-
AmylOH or DCM. Among the examined bases, such as Na2CO3,
NaOCN, KOAc, and NaHCO3, KOCN exhibited higher efficiency
than other bases (entries 4, 14-17). Meanwhile, the factors of
temperature and reaction time all had significant influences to
the oxidative reaction (entries 18-19, and see SI). A decreased
yield was obtained when the reaction was carried out under O2
or N2 (entries 20-21). Finally, we have also investigated the
directing
group
assisted
copper-promoted
oxidative
intramolecular C-H amination of hydrazones to synthesis of 1H-
indazoles or 1H-pyrazoles.
Results and Discussion
To
optimize
the
experimental
conditions,
(diphenylmethylene)picolinohydrazide 1a was selected as the
model substrate and the detailed results are summarized in
Table 1. The probed reaction was carried out with Cu(OAc)2∙H2O
as the catalyst, and KOCN in DMSO at 80 oC under an air
Table 1. Reaction conditions optimization for 1H-Indazoles synthesis.[a]
directing
groups,
such
as
benzoyl,
hydrogen,
4-
toluenesulfonyl,[20] acetyl, diethyl phosphate,[21] which were gave
no apparent target molecule or low yield (entries 22-26). It is
worth noting that diethyl phosphate can cause phosphorus
contamination during post-treatment. Therefore, the optimal
reaction
conditions
were
found
to
include
N'-
(diphenylmethylene)picolinohydrazide 1a (1.0 equiv), Cu(OAc)2
o
(1.0 equiv), KOCN (1.5 equiv) in DMSO (1.0 ml) at 80 C under
air for 9 h.
With the optimized conditions in hand, several substrates
were applied to the reaction to test the generality and scope of
this method (Table 2). It was gratifying to observe that all
substrates tested could afford the desired products in moderate
to excellent yields under the standard reaction conditions.
Generally, the oxidative amination reaction was uninfluenced by
the electronic properties of the substituents on the arene ring
(2a-2l). With respect to substrates bearing two identical groups
on the para positions of the aromatic rings gave only
corresponding products with 82-96 % yields (2b-2f). In the case
Yield/%k
85
20
<5
92
15
NR
NR
NR
NR
NR
98
60
NR
68
75
83
70
64
85
Entry
1
2
3
4
5
6
7
8
catalysts
Cu(OAc)2∙H2O
Cu2O
Solvents
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
t-AmylOH
DCM
Bases
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
Na2CO3
NaOCN
KOAc
NaHCO3
KOCN
KOCN
KOCN
KOCN
KOCN
KOCN
CuCl
of mono-substituted hydrazones (2g-2j),
a regioselectivity
Cu(OAc)2
Cu2(OH)2CO3
Co(acac)2
FeCl3
mixture was obtained in good yields (79%-92%). When 1k was
used as the substrate, (3, 6-diphenyl-1H-indazole) 2k could be
Table 2. Hydrzone scope in the synthesis of 1H- indazoles.[a][b]
No Cu
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
10
11
12
13
14
15
16
17
18[b]
19[c]
20[d]
21[e]
22[f]
23[g]
DMSO
DMF
EtOAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
41
86
NR
NR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
Table 3. Hydrzone scope in the synthesis of 1H-pyrazoles.[a][b]
[a] Reaction conditions: substrates (0.1 mmol), Cu(OAc)2 (0.1 mmol), KOCN
(0.15 mmol) in DMSO (1.0 ml) at 80 oC under air for 9 h. [b] Isolated yields.
isolated in 94% yield. Remarkably, the substrates containing
thienyl also showed good reactivity in this reaction to give the
product 2l in good yields.
Encouraged by the successful synthesis of 1H-indazoles, we
turned our attention to the preparation of 1H-pyrazole derivatives.
Nevertheless, the product 3, 5-diphenyl-1H-pyrazole (4a) was
only afforded in 77% isolated yield from substrate 3a, under
previously optimized reaction conditions. In order to obtain a
satisfactory yield, we further optimized the reaction conditions.
To our delight, after a varieties of optimization experiments,
substrate 3a under Cu(OAc)2 (0.5 equiv) and O2 atmosphere
was achieved 86% yield (see SI). With the optimal conditions
identified, we set about exploring the scope of this method with a
series of substrates (Table 3). Gratifying, the reaction was
effective for a wide scope of substrates, and a set of highly
functionalized pyrazole derivatives were synthesized. Notably,
the efficiency of this transformation was insignificantly affected
by the electronic properties of the substituents on the aryl rings
(4a-4p). The hydrazones with R2 bearing electron-donating (Me,
OMe) at different positions could easily be converted to the
corresponding pyrazole derivatives with 77~86% yields (4b-4c,
4i). Moreover, R2 bearing electron-withdrawing (F, Cl, Br, NO2,
CF3) at para or meta positions, also delivered the corresponding
products in good yields (4d-4h, 4j). It is noteworthy that the
derivatives bearing substituent groups, including naphthyl, furyl
and thienyl were also reacted smoothly, providing satisfying
yields of the desired pyrazoles (4k-4l, 4p). Additionly, the
variation of R1 was also possible, leading to target molecules in
gratifying yields (4m-4o).
[a] Reaction conditions: substrates (0.1 mmol), Cu(OAc)2 (0.05 mmol), KOCN
(0.15 mmol) in DMSO (1.0 ml) at 80 oC under O2 for 9 h. [b] Isolated yields.
To gain mechanistic insight into the catalytic system, control
experiment in the absence of Cu salt was carried out.
Regrettably, the reaction has no target product generation
(Scheme 2, eq. 1). Apparently, base is essential for this reaction,
as the reaction under no base participation only generated a
handful of desired product (20% yields for 2a) (Scheme 2, eq. 2).
Similarly, the reaction under N2 atmosphere was also found to
be deactivated, leading to lower yield (41% yield for 2a)
(Scheme 2, eq. 3). Subsequently, we tested radical scavenger
(TEMPO) under the optimized reaction conditions. The reaction
was uninhibited, but caused abated yields for target molecules
(83% yield for 2a), suggesting that a radical pathway might not
be the major process in this reaction (Scheme 2, eq. 4).
Moreover, the fact that unsubstituted benzophenone hydrazine
could not afford the desired product (Table 1, entry 21), which
demonstrated that the C-N bond cleavage may not arise in the
initial stage. [21]
On the basis of preliminary mechanistic studies and the
relevant literature reports,[19b,22] a plausible reaction mechanism
is depicted in Scheme 3 with 1a as the model substrates. Initially,
the reaction proceeds with the coordination of Cu(OAc)2 with 1a
to form species A and release of
HOAc. Subsequently,
intermediate A further undergoes C−H activation and oxidation
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
Conclusions
to afford a six-membered intermediate B, which undergoes
reductive elimination to obtain the species C and Cu (I) species.
Finally, hydrolysis of intermediate C leads to the desired product
2a, might due to the activation of the amide group by the
coordination of Cu (I) species with intermediate C via N, O-
coordination. The Cu (I) species could be oxidized in the
presence of HOAc and O2 to regenerate Cu(OAc)2 for the next
catalytic cycle.
In conclusion, we have established a new synthetic method
for 1H-indazoles and 1H-pyrazoles via traceless directing group
assisted copper-promoted oxidative intramolecular C-H
amination of hydrazones. Using picolinamide as traceless
directing group and the inexpensive Cu salts as the oxidant, it
has been proved to be an efficient method for the direct
construction of N-heterocycles. In all cases, the easily handled
protocol proceeded with readily available reagents, good
functional-group compatibility. Additionally, the reaction system
could be carried out in moderate to excellent yields. Further
studies on this original approach are ongoing in our group.
Experimental Section
General procedure A for the synthesis of 1 or 3. To a solution of 2-
picolinic acid (12.3 g, 0.1 mol) in anhydrous ethanol (60 mL) was added
concentrated sulfuric acid (12 mL) at 0 oC. The mixture was refluxed for
12 h. Upon cooling to ambient temperature, the product was poured into
50 mL ice-water. The resulting solution was neutralized to pH=7-8 with a
solution of potassium carbonate. The precipitate was filtered and the
filtrate was extracted with ether (4×50 mL). After drying over magnesium
sulfate, the organic phases were evaporated to dryness under reduced
pressure. The unpurified ester can be used for next hydrazinolysis. A
mixture of above ester, 80% hydrazine hydrate (10 mL, 0.2 mol) and
ethanol (50 mL) was refluxed for 4 h. Then the solution was evaporated
to dryness, and the resulting white solid was recrystallized from
anhydrous ethanol to give pyridine-2-carbonylhydrazine as colorless
needles (10.7g, 78% for a two-step reaction).
To a stirred solution of substituted acetophenone (20 mmol) in methanol
(10 mL) was added dropwise a solution of NaOH (26 mmol) in methanol
( 20 mL). Fifteen minutes later, the resulting mixture was further treated
with substituted benzaldehydes (20 mmol) and stirred at room
temperature until the conversion was complete (disappearance of
substituted acetophenone, monitored by TLC). Then, the mixture was
poured into 100 mL H2O, and extracted with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel flash
chromatography(n-hexane/EtOAc:10:1) to give the desired α,β-
unsaturated ketones.
Scheme 2. Mechanistic studies
To
a solution of substituted benzophenones (or substituted α,β-
unsaturated ketones) (5 mmol), pyridine-2-carbonylhydrazine (5 mmol)
were dissolved in 10 mL anhydrous EtOH. After two drops TFA
(trifluoroacetic acid) was dropped, the mixture was stirred at reflux for 6-
12 h, and concentrated in vacuo. The residue was recrystallized in
anhydrous EtOH, and filtered to give the desired product 1 or 3.
General procedure for the synthesis of compounds 2 or 4.
To a mixture of 1 or 3 (0.1 mmol), Cu(OAc)2 (0.1 or 0.05mmol), KOCN
(0.15 mmol, 12.1 mg, 1.5 eq.) and DMSO (1.0 ml) in a 15 mL flask was
heated at 80oC under air or O2 for 9 hours. The reaction mixture was
cooled to room temperature and poured into 10 mL H2O, extracted with
20 mL EtOAc. The organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (n-hexane/EtOAc: 1:1 to 1:5) to
yield 2 (or 4) as a white (yellow) solid.
Scheme 3. Mechanistic hypothesis
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
Chem. 2001, 66, 6787; g) S. T. Heller, S. R. Natarajan, Org. Lett. 2006,
8, 2675; h) O. Dirat, A. Clipson, J. M. Elliott, S. Garrett, A. B. Jones, M.
Reader, D. Shaw, Tetrahedron Lett. 2006, 47, 1729.
Acknowledgments
We acknowledge financial support from the National Natural
Science Foundation of China (no. 20702051), the Natural
Science Foundation of Zhejiang Province (LY13B020017).
[9]
a) Z. -J. Liu, F. -S. Shi, P. D. G. Martinez, C. Raminelli, R. C . Larock, J.
Org. Chem. 2008, 73, 219; b) T. Jin, Y. Yamamoto. Angew. Chem. Int.
Ed. 2007, 46, 3323; c) C. Spiteri, S. Keeling, J. E. Moses, Org. Lett.
2010, 12, 3368; d) G. -H Chen, M. -L. Hu, Y. -G. Peng, J. Org. Chem.
2018, 83, 1591; e) F. -H. Yi, W. -J. Zhao, Z. -K. Wang, X. -H. Bi, Org.
Lett. 2019, 21, 3158; f) S. Panda, N. Pradhan, D. Manna, ACS Comb.
Sci. 2018, 20, 573.
Keywords: traceless directing group • C-H amination •
indazoles • pyrazoles • C-H activation
[10] a) Q. -R. Chen, F. Yao, L. Yin, M. -Z. Cai, Organomet. Chem. 2016,
804, 108; b) J. -L. Zhao, J. Qiu, X. -F. Gou, C. -W. Hua, B. Chen, Chin.
J. Catal. 2016, 37, 571; c) K. Alex, A. Tillack, N. Schwarz, M. Beller,
Org. Lett. 2008, 10, 2377; e) M. Zora, A. Kivrak, J. Org. Chem. 2011,
76, 9379.
[1]
a) J. A. Joule, K. Mills, Heterocyclic Chemistry 2000; b) A. Schmidt, A.
Beutler, B. Snovydovych, Eur. J. Org. Chem. 2008, 4073; c) A. A.
Bekhit, A. Hymete, A. E. A. Bekhit, A. Damtew, H. Y. Aboul-Enein, Mini-
Rev. Med. Chem. 2010, 10, 1014; d) D. D. Gaikwad, A. D. Chapolikar, C.
G. Devkate, K. D. Warad, A. P. Tayade, R. P. Pawar, A. J. Domb, Eur.
J. Med. Chem. 2015, 90, 707; e) Q. Zhang, M. Tang, Org. Lett. 2019,
21, 1917.
[11] a) P. K. Mykhailiuk, Beilstein. J. Org. Chem. 2015, 11, 16; b) J. D.
Kirkham, S. J. Edeson, S. Stokes, J. P. A. Harrity, Org. Lett. 2012, 14,
5354; c) S. Caron, E. Vazquez, Synthesis 1999, 4, 588.
[2]
[3]
a) M. De Lena, V. Lorusso, A. Latorre, G. Fanizza, G. Gargano, L.
Caorusso, M. Guida, A. Catino, E. Crucitta, D. Sambiasi, A. Mazzei,
Eur J. Cancer. 2001, 37, 364; b) A. V. Dolzhenko, W. K. Chui,
Hetrocycles 2008, 75, 1575.
[12] a) G. -L. Zhang, H. -C. Ni, W. -T. Chen, J. -A. Shao, H. -L. Liu, B. -H.
Chen, Y. -P. Yu, Org. Lett. 2013, 15, 5967; b) Y. Yu, W. Huang, Y. Chen,
B. -J. Gao, W. -Q. Wu, H. -F. Jiang, Green Chem. 2016, 18, 6445; c) .
ar ovi , . D. o sovic. Green Chem. 2015, 17, 842; d) V. K.
Aggarwal, J. de Vicente, R. V. Bonnert, J. Org. Chem. 2003, 68, 5381.
[13] a) M. -S. Gao, X. -J. Liu, X. -Y. Wang, Q. Cai, K. Ding, Chin. J. Chem.
2011, 29, 1199; b) X. -D. Xiong, Y. -W. Jiang, D. -W. Ma, Org. Lett.
2012, 14, 2552; c) C. -L. Sun, B. -J. Li, Z.-J. Shi, Chem. Rev. 2011,
111, 1293; d) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 2011,
50, 3362; e) D. -B. Zhao, J. -S. You, C. -W. Hu, Chem. Eur. J. 2011, 17,
5466; f) J. Yamaguchi, A. D. Yamaguchi, K. Itami. Angew. Chem . Int.
Ed. 2012, 51, 8960; g) B. -J. Li, Z. -J. Shi, Chem. Soc. Rev. 2012, 41,
5588; h) K. N. Tu, S. Kim, S. A, Blum, Org. Lett. 2019, 21, 1283; i) L. Li,
H. Wang, S. -J. Yu, X. -F. Yang, X. –W. Li, Org. Lett. 2016, 18, 3662; j)
C. Wiethan, C. M. Lavoie, A. Borzenko, J. S. K. Clark, H. G. Bonacorso,
M. Stradiotto, Org. Biomol. Chem. 2017, 15, 5062.
a) . D. Rodgers, B. L. Johnson, H. Wang, R. A. Greenberg, S. Erickson-
Viitanen, R. M. Klabe, B. C. Cordova, M. M. Rayner, G. N. Lam, C.-H.
Chang, Bioorg. Med. Chem. Lett, 1996, 6, 2919; b) J. -H. Sun, C. A.
Teleha, J. -S. Yan, J. D. Rodgers, D. A. Nugiel, J. Org. Chem. 1997, 62,
5627.
[4]
[5]
J. A. Pfefferkorn, C. Choi, S. D. Larsen, B. Auerbach, R. Hutchings, W.
Park, V. Askew, L. Dillon, J. C. Hanselman, Z. -W. Lin, G. -H. Lu, A.
Robertson, C. Sekerke, M. S. Harris, A. Pavlovsky, G. Bainbridge, N.
Caspers, M. Kowala, B. D. Tait, J. Med. Chem. 2008, 51, 31.
a) X. -M. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S. Margosiak, V.
Nikulin, J. Levin, K. G. Sprankle, M. E. Tedder, R. Almassy, K. Appelt,
K. M. Yager, J. Med. Chem. 2003, 46, 5663; b) A. Tanitame, Y.
Oyamada, K. Ofuji, M. Fujimoto, N. Iwai, Y. Hiyama, K. Suzuki, H. Ito, H.
Terauchi, M. Kawasaki, K. Nagai, M. Wachi, J. Yamagishi, J. Med.
Chem. 2004, 47, 3693; c) T. S. Haque, S. Tadesse, J. Marcinkeviciene,
M. J. Rogers, C. Sizemore, L. M. Kopcho, K. Amsler, L. D. Ecret, D. -L.
Zhan, F. Hobbs, A. Slee, G. L. Trainor, A. M. Stern, R. A. Copel, A. P.
Combs, J. Med. Chem. 2002, 45, 4669.
[14] a) H. M. L. Davies, D. Morton, J. Org. Chem. 2016, 81, 343; b) G.
Rousseau, B. Breit, Angew. Chem. Int. Ed. 2011, 50, 2450.
[15] T. -S. Zhang, W. -L. Bao, J. Org. Chem. 2013, 78, 1317.
[16] D. -G. Yu, M. Suri, F. Glorius, J. Am. Chem. Soc. 2013, 135, 8802.
[17] J. -T. Hu, H. -C. Xu, P. -J. Nie, X. -B. Xie, Z. –X. Nie, Y. Rao, Chem
. Eur. J. 2014, 20, 3932.
[6] a) P. Jacobson, L. Huber, B. Dtsch. Chem. Ges. 1908, 41, 660; b) W.
Stadlbauer. Sci. Synth. 2002, 12, 227; c) T. Yoshida, N. Matsuura, K.
Yamamoto, M. Doi, K. Shimada, T. Morie, S. Kato, Heterocycles 1996,
43, 2701.
[18] P. Li, C. -R. Wu, J. -J Zhao, D. C. Rogness, F. Shi, J. Org. Chem. 2012,
77, 3149.
[19] a) C. -S. Kuai, L. -H. Wang, B. -B. Li, Z. -H. Yang, X. -L. Cui, Org. Lett.
2017, 19, 2102; b) F. Ling, C. -R. Ai, Y. -P. Lv, W. -H. Zhong, Adv.
Synth. Catal. 2017, 359, 3707; c) F. Ling, C. -W. Zhang, C.-R. Ai, Y. -P.
Lv, W. -H. Zhong, J. Org. Chem. 2018, 83, 5698.
[7]
a) A. Y. Lebedev, A. S. Khartulyari, A. Z. Voskoboynikov, J. Org. Chem.
2005, 70, 596; b) K. Inamoto, M. Katsuno, T. Yoshino, Y. Arai, K.
Hiroya, T. Sakamoto, Tetrahedron 2007, 63, 2695; c) R. Liu, Y. -M.
Zhu, L. -N. Qin, S. -J. Ji, Synth. Commun. 2008, 38, 249; d) I. Thomé, C.
Besson, T. Kleine, C. Bolm, Angew. Chem. Int. Ed. 2013, 52, 7509.
a) W. -W Jin, H. -F Yu, Z. -K Yu, Tetrahedron Lett. 2011, 52, 5884; b)
P. Liu, Y. –M. Pan, Y.-L. Xu, H. -S Wang, Org. Biomol. Chem. 2012, 10,
4696; c) S. -H. Guo, J. -L. Wang, D. -Q. Guo, X. -Y. Zhang, X. -S. Fan,
RSC Adv. 2012, 2, 3772; d) F. Gosselin, P. D. O’Shea, R. A. Webster,
R. A. Reamer, R. D. Tillyer, E. J. J. Grabowski, Synlett 2006, 19, 3267;
e) Y. R. Huang, J. A. Katzenellenbogen, Org. Lett. 2000, 2, 2833; f) A.
R. Katritzky, M. Wang, S. Zhang, M. V. Voronkov, P. J. Steel, J. Org.
[20] a) T. Zhang, Y. -G. Meng, J.-Y. Lu, Y. -T. Yang, G. –Q. Li, C. -Y. Zhu,
Adv. Synth. Catal. 2018, 360, 3063; b）Q. Zhang , M. Tang, Org. Lett.
2019, 21, 1917-1920; c) K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto,
K. Hiroya, Org. Lett. 2007, 9, 2931.
[8]
[21] Z. -W. Ding, Q. -T. Tan, B. -X. Liu, K. Zhang, B. Xu, Acta Chim. Sinica.
2015, 73, 1302.
[22] a) C. -Y. Chen, G. -R. Tang, F. -X. He, Z. -B. Wang, H. -L. Jing, R.
Fsser, Org. Lett. 2016, 18, 1690; b) D. -G. Yu, M. Suri, F. Glorius, J.
Am. Chem. Soc. 2013, 135, 8802.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900947
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Traceless directing group
Guofu Zhang, Qiankun Fan, † Yiyong
Zhao, † and Chengrong Ding*
Page No. – Page No.
Traceless Directing Group Assisted
Copper-Promoted Oxidative
intramolecular C-H Amination of
Hydrazones to Synthesis of 1H-
Indazoles or 1H-Pyrazoles
A facile and efficient synthetic strategy for the 1H-indazoles and 1H-pyrazoles via traceless directing group assisted copper-promoted
oxidative intramolecular C-H amination of hydrazones was developed. This reaction is characterized by its mild conditions,
operational simplicity, readily available reagents and excellent yields. A tentative mechanism for Cu-mediated C-H oxidative
amination was proposed.
This article is protected by copyright. All rights reserved.