Copper-catalyzed aerobic C(sp2)-H functionalization for C-N bond formation: Synthesis of pyrazoles and indazoles

Article abstract of DOI:10.1021/jo400162d

A simple, practical, and highly efficient synthesis of pyrazoles and indazoles via copper-catalyzed direct aerobic oxidative C(sp²)-H amination has been reported herein. This process tolerated a variety of functional groups under mild conditions. Further diversification of pyrazoles was also investigated, which provided its potential for drug discovery.

Full text of DOI:10.1021/jo400162d

Article
pubs.acs.org/joc
Copper-Catalyzed Aerobic C(sp2)−H Functionalization for C−N Bond
Formation: Synthesis of Pyrazoles and Indazoles
Xianwei Li, Li He, Huoji Chen, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A simple, practical, and highly efficient synthesis
of pyrazoles and indazoles via copper-catalyzed direct aerobic
oxidative C(sp2)−H amination has been reported herein. This
process tolerated a variety of functional groups under mild
conditions. Further diversification of pyrazoles was also
investigated, which provided its potential for drug discovery.
it is desirable to develop efficient methods with regard to green
chemistry, regioselectivities, and synthetic practice.
INTRODUCTION
■
The development for the rapid access to N-heterocycles with
complexity and diversity which stem from their wide
occurrence in nature and broad application in chemistry,
biology, and material sciences has attracted considerable
attention in the studies of chemical genetics.1 In this respect,
pyrazoles and indazoles are important synthetic targets in
biologically active molecules, synthetic drugs, and drug
candidates, (Scheme 1), and in addition, they can be used as
ligands for generating metallic complexes.2,3
Direct C−H bond amination without prefunctionalization of
simple starting materials to the corresponding organic
(pseudo)halides is a highly attractive synthetic strategy as an
atom-economic and environmentally benign method for C−N
bond formation.6 From a synthetic standpoint, a strategy
involving transition-metal-catalyzed C−H bond fuctionalization
followed by C−N bond formation represents one of the most
versatile and practical approaches for installing nitrogen
functional groups.7 For example, utilizing a directing group-
assisted C−H bond functionalization strategy to achieve C−X
bonds is a powerful and challenging area in organic synthesis.8
However, extra steps are required for the introduction and
removal of directing groups and limit its synthetic applications
(Scheme 2a).
Scheme 1. Pyrazole and Indazole Representative Biologically
Active Analogues
On the other hand, Cu/O2 catalytic systems that comprise
naturally occurring metalloenzyme copper and molecular
oxygen as the oxidant are notable bacause they often exhibit
exquisite substrate specificity as well as regioselectivity and/or
stereoselectivity and operate under mild conditions through
inherently “green” processes.9 Consequently, copper-catalyzed
a
Scheme 2
The importance of these heterocyclic moieties has prompted
the development of many practical synthetic routes to construct
their derivatives.4,5 However, traditional methods for their
derivatives often suffer from low regioseletivities, harsh reaction
conditions (stoichiometric strong base, high reaction temper-
ature), and the need for precious metal catalysts and
stoichiometric and environmentally unfriendly oxidants. Thus,
a
Key: (a) ortho-assisted C−H bond functionalization for the C−X
bond formation; (b) Cu-catalyzed aerobic oxidative C−X bond
formation. DG = directing group, X = Nu.
Received: January 24, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
aerobic oxidative C−H bond functionalization10 for the C−X
bond formation11 could provide an alternative route with its
versatility and green chemistry (Scheme 2b). As part of our
continuous efforts on copper-catalyzed aerobic oxygenation/
oxidation reactions,12 herein we report copper-catalyzed aerobic
amination of the C(sp2)−H bond for pyrazole and indazole
synthesis based on N-tosylhydrazone 1 and 3 derivatives. This
Cu-mediated aerobic oxidative transformation features great
efficiency, broad substrate scope, and good functional group
tolerance under mild conditions, and the use of molecular
oxygen (1 atm) as the sole oxidant made this strategy even
more practical and green.
reaction conditions were Cu(OAc)2 (10 mol %) and DABCO
(30 mol %) in DMSO at 100 °C with molecular oxygen (1
atm) as the oxidant.
Substrate Scope for the Synthesis of Pyrazoles. With
these optimized conditions in hand, we next explored the scope
and generality of the process, and the results are summarized in
Table 2. The scope of the process with respect to the hydrazine
a
Table 2. Synthesis of Pyrazole Derivatives
RESULTS AND DISCUSSION
■
We commenced our investigation by studying the conversion of
1 to the desired pyrazole 2 using a combination of a copper
catalyst together with 1 atm of O2 as the stoichiometric oxidant
(Table 1). Without additives, the transformation could proceed
a
Table 1. Optimization of Reaction Conditions
b
entry copper catalyst
additive
solvent
temp (°C) yield (%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
DCE
100
100
100
100
100
100
100
100
100
100
100
100
80
32
12
2
HOAc
3
K2CO3
65
4
Li2CO3
K2CO3
52
5
65
a
Standard reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (10 mol %),
6
pyridine
NEt3
37
b
DABCO (30 mol %), DMSO (2 mL), 100 °C, 12 h. The Ts group of
the substrate was dissociated in the reaction.
7
42
8
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
95 (92)
66
9
reactant was examined. In general, aromatic and aliphatic R3
under the optimized reaction conditions all form the
corresponding pyrazoles in excellent yields. Various electron-
donating and electron-accepting groups on aromatic R3
substrates were tolerated well in this reaction. These results
showed that electron-donating goups had more favorable
effects than electron-withdrawing goups. What’s more, the
process tolerated functional groups such as fluorides, chlorides,
bromides, nitriles, trifluoromethyls, carboxyls, sulfonamides,
and ethers and, therefore, should be applicable to late-stage
modifications of advanced intermediates. However, free NH2
group substituted substrates gave no desired products. Both
aromatic and aliphatic groups (Table 2, 2x, 2y) were tolerated
and furnished the target products in comparable yields.
Pyrazoles 2x and 2y were derived from β-ionone, which is
known as a starting material for the synthesis of vitamin A.
Interestingly, 3,5-diphenyl-1H-pyrazole (2p) was obtained
when R = Ts, which was different from what we observed in
product 2a. However, there was no prededent for this in situ
deprotection of the pyrrazole nitrogen. Bolotin and Larock had
reported similar observations.13 The deprotection of the Ts
group still proceeded even at lower reaction tempearture or
with other bases. We assumed that this result might be due to
the copper catalyst or the aromatic system (R1 = R2 = Ph) of
the obtained pyrazole products. Notably, heterocycle-substi-
tuted pyrazoles could also be obtained in high yields (Table 2,
2t−2w). We could also obtain 2z bearing a C−C double bond,
10
11
12
13
14
15
CuBr
49
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
75
68
DMSO
DMSO
DMSO
76
c
100
100
72
<10
a
Reaction conditions: 1 (0.2 mmol), Cu catalyst (0.02 mmol), additive
b
(0.06 mmol) in DMSO (2 mL), 100 °C, 12 h. Yield was determined
by GC analysis. Reaction was performed under air.
c
with low efficiency. When a Brønsted acid such as HOAc was
used as the additive, the yield deteriorated to 12% (entry 2).
Detailed examination of base as the additive suggested that the
use of 30 mol % of DABCO gave the best yield and provided
the optimized result (entry 8); other bases also gave moderate
yields (entries 3−7). We suspected that DABCO might act as
both base and ligand to facilitate the product formations. A
range of copper sources were evaluated, such as CuCl; CuBr
could also serve as the catalyst and led to the desired products
although with inferior results (entries 9 and 10). We also
optimized the solvent effect and found that DMSO gave the
superior results than toluene and DCE. Lowering the
temperature to 80 °C just led to a decrease in yield (entry
13). This process could also be performed under air
atmosphere (entry 14). Control experiments revealed that in
the absence of the copper source only trace amount of target
molecular 2 was detected (entry 15). Thus, the optimal
B
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Synthesis of Indazole Derivatives
a
Standard reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (10 mol %), DABCO (30 mol %), K2CO3 (1 equiv), DMSO (2 mL), 120 °C, 12 h.
a
Scheme 3. One-Pot Pyrazole Synthesis
a
Reaction conditions: (a) 1. MeOH (6 mL), reflux, 3 h; (b) Cu(OAc)2 (10 mol %), DABCO (30 mol %), DMSO (2 mL), O2 (1 atm), 100 °C, 10 h.
which could be further functionalized in various trans-
formations. The stereochemistry of the hydrazone CN double
bond did not influence the result of this reaction. Both cis- and
trans-type substrates 1 could afford the responding pyrazole
products, and we suspected that the (E)-1 isomerizes could
transform to (Z)-1 with the aid of DABCO at elevated
temperature.10i
The above results inspired us to further demonstrate the
synthetic application of our developed protocol into aromatic
C(sp2)−H amination for the synthesis of indazole derivatives.
The reaction was further optimized with the addition of 1 equiv
of K2CO3 into the system, and indazole derivatives were
obtained in good yields. With the optimized results, we
embarked on an investigation of the scope of this aromatic
C(sp2)−H amination.
provide ample opportunity for further synthetic manipulations.
The introduction of fluorine atoms or fluorine-containing
groups into heterocyclic rings has made possible the discovery
of new bioactive products.14 Trifluoromethylated arenes are
essential structural motifs in a great number of pharmaceuticals,
agrochemicals, and organic materials.15 The cyano group is a
versatile functional group that could serve as a coordinating
functional group and for versatile intermediates and valued
target pharmacophores.16 When two electronically unsym-
metrical aromatic groups were present in benzophenones, a
mixture of 75:25 to 65:35 isomers was observed for the
formation of 4m+4m′ to 4p+4p′, respectively. The regiose-
lectivity in the case of unsymmetric aryl groups was moderate,
and we surmised that electron-rich substrates were favored in
the insertion step and the steric factors might also affect the
regioselectivities.
Substrate Scope for the Synthesis of Indazoles. As is
depicted in Table 3, indazoles could be obtained smoothly with
good results. Moreover, functional groups, like F, Cl, CF3, and
CN were all well tolerated in this transformation. In general,
substrates 3 bearing electron-donating groups gave better yields
than electron-withdrawing groups. These functional groups
We then succeeded in performing the reaction on a larger
scale to demonstrate the practicability of the developed
methodology in a one-pot fashion (Scheme 3). By using this
procedure, pyrazole product 2a could be conveniently obtained
on a 5 mmol scale in yields similar to those for the pyrazole
C
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 4. Further Demonstration of the Synthetic Application of the Pyrazole Products
a
Reaction conditions: (1) 2c (0.5 mmol), NBS (0.6 mmol), CH2Cl2, 50 °C, 12 h, 70% (R = Me), 72% (R = Ph); (2) 5 (0.25 mmol), ethynylbenzene
(1.1equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N (2equiv), MeCN (2 mL), 70 °C, 4 h, 90%; (3) 5 (0.25 mmol), p-tolylboronic acid
(1.5equiv), Pd(PPh3)4 (10 mol %), PPh3 (20 mol %), K2CO3 (2.5equiv), tolunene/EtOH/H2O (20:5:1) 5 mL, 80 °C, 12 h, 85%; (4) 5 (0.25
mmol), tert-butyl isocyanide (0.30 mmol), PdCl2 (5 mol %), PPh3 (10 mol %), CsF (1.0equiv), and 0.2 mL of H2O in 1.5 mL of DMSO at 110 °C
for 12 h, 82%.
formation step only (e.g., 2a: 92% versus 85%, respectively).
This efficient and highly modular one-pot procedure
significantly increases the practicality and usefulness of this
new method.
Scheme 5. Mechanism Probing Experiments
Application To Further Functionalize the Obtained
Pyrazoles. To further demonstrate the synthetic application of
our developed protocol, we performed experiments using 2c as
the starting materials for the diversification of pyrazole
derivatives. The C−Ha bond of 2 could also be brominated
with NBS to 5, which could undergo Sonogashira and Suzuki−
Miyaura reactions to afford 6 and 7, respectively. These
analogues may have potential application in materials synthesis
(Scheme 4, eqs 1 and 2). We also performed amidation
reactions of 5 using our previous developed palladium-catalyzed
C−C coupling of aryl halides with isocyanides for the synthesis
of amides, which as we know, are potential precursors for the
synthesis of numerous natural products, potential pharmaceut-
icals, and bioactive polymers (Scheme 4, eq 3).17
Mechanistic Studies of the Synthesis of Pyrazoles and
Indazoles. To further elucidate the reaction mechanism, we
conducted several experiments by stiochiometric addition of an
electron-transfer scavenger (1, 4-dinitrobenzene), a radical
clock (diallyl ether), or radical inhibitor (hydroquinone,
TEMPO) to the Cu-catalyzed aerobic C−H amination process.
The reaction still proceeded smoothly to afford the desired
product with the addition of hydroquinone, TEMPO, or 1,4-
dinitrobenzene (Scheme 5). In addition, when 1.0 equiv of
diallyl ether was added to the standard conditions, no radical-
initiated cyclization product was observed. These results
suggest that radical process is not involved in this trans-
formation.18
In the light of these preliminary results, a catalytic cycle for
this transformation was hypothesized as shown in Scheme 6,
while further detailed elucidation should be indispensable.
Initially, the reaction of substrates 1 or 3 with Cu(OAc)2
presumably led to a Cu−N adduct A.11a,19 Intramolecular
electrophilic aromatic substitution with the nitrogen of the
Cu−N adduct A followed by aromatization via C would
provide the pyrazoles 2 or indazoles 4 with generation of
reduced copper species (Cun−2), which could be reoxidized by
O2 to achieve the catalytic cycle. Alternatively, formation of
metallacycle B by electronphilic metalation or a C−H bond
activation followed by reductive elimination20,21 and aromatiza-
tion gave the products 2 or 4.22
D
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
× 10 mL), and the organic layers were combined, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure.
The residue was separated by column chromatography to give the pure
products 2a−z and 4a−q.
Scheme 6. Proposed Catalytic Cycle
(Z)-4-Methyl-N′-((E)-4-phenylbut-3-en-2-ylidene)-
benzenesulfonohydrazide (1a): 1H NMR (400 MHz, DMSO-d6) δ =
10.55 (s, Br, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H),
7.38 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz,
1H), 7.01 (d, J = 14.8 Hz, 3H), 6.72 (d, J = 16.4 Hz, 1H), 2.34 (s, 3H),
2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 154.2, 143.2, 135.9,
133.8, 129.4, 128.7, 128.4, 128.3, 127.5, 126.9, 21.0, 12.3; MS (EI) m/
z 51, 75, 102, 116, 160, 237, 299, 314; HRMS calcd C17H18N2O2S,
[M+] 314.1089, found 314.1094.
(Z)-1-Phenyl-2-((E)-4-phenylbut-3-en-2-ylidene)hydrazine
(1b):.4g,h 1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J = 8.8 Hz, 2H),
7.40−7.35 (m, 6H), 7.22 (dd, J = 1.6 Hz, 7.2 Hz, 3H), 6.33 (s, 1H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 149.4, 143.6, 140.1,
130.7, 128.6, 128.3, 128.0, 127.0, 125.1, 107.7, 13.5; MS (EI) m/z 51,
77, 102, 116, 156, 192, 236.
(Z)-1-(4-Methoxyphenyl)-2-((E)-4-phenylbut-3-en-2-ylidene)-
hydrazine (1c): 1H NMR (400 MHz, CDCl3) δ = 7.29−7.20 (m, 2H),
6.85 (d, J = 8.8 Hz, 2H), 6.32 (s, 1H), 3.79 (s, 3H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ = 158.6, 149.0, 143.7, 133.5, 130.8, 128.6,
128.0, 126.6, 114.0, 107.2, 55.4, 13.6; MS (EI) m/z 64, 76, 116, 156,
192, 235, 266; HRMS calcd C17H18N2O [M+] 266.1419, found
266.1415.
4-((Z)-2-((E)-4-Phenylbut-3-en-2-ylidene)hydrazinyl)benzonitrile
(1d): 1H NMR (400 MHz, CDCl3) δ = 7.86 (d, J = 6.4 Hz, 2H), 7.62
(d, J = 8.0 Hz, 2H), 7.46−7.40 (m, 5H), 7.21 (d, J = 8.0 Hz, 3H), 6.62
(s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 155.3, 149.5,
145.4, 129.7, 129.4, 128.8, 128.1, 127.9, 126.5, 109.6, 21.7; MS (EI)
m/z 64, 75, 102, 157, 192, 218, 245, 261; HRMS calcd C17H15N3,
[M+] 261.1266, found 261.1269.
(Z)-1-(4-Fluorophenyl)-2-((E)-4-phenylbut-3-en-2-ylidene)-
hydrazine (1e): 1H NMR (400 MHz, CDCl3) δ = 7.91 (d, J = 8.4 Hz,
2H), 7.38 (d, J = 7.6 Hz, 3H), 7.31−7.26 (m, 7H), 7.23−7.20 (m,
2H), 6.97 (t, J = 8.4 Hz, 1H), 6.77 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ = 162.8, 160.4, 152.1, 144.5, 136.4, 133.0, 130.4, 128.8,
128.6, 128.5, 128.1, 127.1, 127.0, 125.9, 115.9, 115.7, 105.2; MS (EI)
m/z 64, 75, 102, 117, 155, 191, 235, 254; HRMS calcd C16H15FN2
[M+] 254.1219, found 254.1223.
(Z)-1-(4-Bromophenyl)-2-((E)-4-phenylbut-3-en-2-ylidene)-
hydrazine (1f): 1H NMR (400 MHz, CDCl3) δ = 7.42−7.37 (m, 1H),
7.33−7.29 (m, 3H), 7.25−7.22 (m, 3H), 7.18 (d, J = 8.8 Hz, 2H), 2.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ = 149.2, 144.9, 142.4, 131.6,
128.6, 127.6, 126.5, 125.8, 114.7, 110.5, 15.9; MS (EI) m/z 64, 75,
117, 155, 191, 234, 276, 314; HRMS calcd C16H15BrN2 [M+]
314.0419, found 314.0412.
CONCLUSION
■
In conclusion, we have developed a Cu-catalyzed aerobic
oxidative C(sp2)−H amination leading to pyrazoles and
indazoles, which are ubiquitous structural units in a number
of biological active compounds. This method is highly efficient
and exhibits a good functional group tolerance. Further
modification could be performed smoothly which showed its
potential in organic synthesis. It is noteworthy that this reaction
provides a highly attractive practical synthetic strategy for the
direct C−H amination that precludes the need for
prefunctionalized starting materials and the use of molecular
oxygen as the oxidant make the overall chemical transformation
sustainable and practical.
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out in 10 mL
tubes under air atmosphere. TLC was performed by using
commercially prepared 100−400 mesh silica gel plates (GF254) and
visualization was effected at 254 nm. All reagents were purchased as
reagent grade and used without further purification. Melting points
were measured with a micromelting point apparatus. 1H NMR spectra
were recorded at 400 MHz using TMS as an internal standard and 13C
NMR spectra at 100, using CDCl3. The chemical shifts are referenced
to signals at 7.24 and 77.0 ppm, respectively. IR spectra were obtained
either as potassium bromide pellets or as liquid films between two
potassium bromide pellets with an infrared Fourier spectrometer.
High-resolution mass spectra (ESI) were obtained with a LCMS−IT-
TOF mass spectrometer.
Typical Procedure for the Synthesis of Hydrazone. Ketones
(1.0equiv) and phenylhydrazines (1.05equiv) were mixed in MeOH or
toluene to stir at room temperature (AcOH was added if necessary).
After minutes, a lot of solid precipitated from the solution. After the
disappearance of the enones by TLC, the solid was collected by
filtration and washed with cooled MeOH. Then the solid was dissolved
in DCM, and the organic layer was washed with saturated aqueous
NaHCO3 and brine. The organic layer was dried with Na2SO4, filtered,
and evaporated to give the solid, which was further purification by
recrystallization in EtOAc/MeOH cosolvent system.
(Z)-1-(tert-Butyl)-2-((E)-4-phenylbut-3-en-2-ylidene)hydrazine
(1g): 1H NMR (400 MHz, CDCl3) δ = 7.39 (d, J = 7.2 Hz, 2H), 7.33−
7.32 (m, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 6.8 Hz, 1H), 5.09 (t,
J = 4.8 Hz, 3H), 2.16−2.11 (m, 3H), 1.29−1.24 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ = 146.8, 130.4, 128.4, 127.7, 126.8, 126.6, 109.9,
64.3, 27.3, 16.0; MS (EI) m/z 64, 79, 133, 159, 188, 216; HRMS calcd
C14H20N2 [M+] 216.1626, found 216.1633.
(E)-1-((E)-1,3-Diphenylallylidene)-2-phenylhydrazine (1h):4h 1H
NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 6.8 Hz, 2H), 7.37−7.06
(m, 13H), 6.79−6.78 (m, 1H), 5.25 (dd, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ = 146.7, 144.9, 142.6, 132.8, 128.6, 125.8, 119.1,
113.4; MS (EI) m/z 75, 147, 192, 243, 269, 298.
(E)-1-((E)-1,3-Diphenylallylidene)-2-(4-methoxyphenyl)hydrazine
(1i): 1H NMR (400 MHz, CDCl3) δ = 7.69 (d, J = 7.2 Hz, 2H), 7.38−
7.22 (m, 9H), 7.00 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 5.14
(dd, J = 8.4 Hz, 3.6 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 153.3, 146.3, 142.7, 139.7, 132.9, 129.1, 127.6, 125.7,
114.9, 114.4, 55.6; MS (EI) m/z 64, 77, 89, 167, 218, 269, 298, 328;
HRMS calcd C22H20N2O [M+] 328.1576, found 328.1584.
4-((E)-2-((E)-1,3-Diphenylallylidene)hydrazinyl)benzonitrile (1j):
1H NMR (400 MHz, CDCl3) δ = 7.79−7.75 (m, 1H), 7.66−7.55
Typical Procedure for the Synthesis of Pyrazoles and
Indazoles. To a dried Schlenk tube was added successively a mixture
of hydrazone (0.2 mmol), Cu(OAc)2 (10 mol %, 3 mg), DABCO (30
mol %, 6 mg) (1 equiv of K2CO3 (32 mg) was also added for the
synthesis of indazoles), and 2 mL of DMSO. Then the mixture was
stirred at 100 °C (or 120 °C) for 12 h under 1 atm of O2. Upon
completion, the reaction mixture was washed by saturated NaCl
aqueous solution (2 × 10 mL) and then extracted with ethyl acetate (2
(m, 4H), 7.49 (d, J = 8.0 Hz, 2H), 7.34−7.32 (m, 5H), 7.10 (d, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 147.7, 147.5, 137.6, 133.6,
E
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
132.1, 129.9, 128.9, 128.4, 126.9, 120.0, 113.0, 101.9; MS (EI) m/z 75,
145, 196, 243, 298, 323; HRMS calcd C22H17N3 [M+] 323.1422, found
323.1426.
MHz, CDCl3) δ = 153.5, 143.5, 138.2, 130.9, 129.8, 128.6, 126.3,
125.2, 112.2, 107.7, 21.7; MS (EI) m/z 64, 152, 234, 281, 327, 343;
HRMS calcd C21H17N3S [M+] 343.1143, found 343.1147.
(E)-1-(4-Bromophenyl)-2-((E)-1,3-diphenylallylidene)hydrazine
(1k): 1H NMR (400 MHz, CDCl3) δ = 7.69 (d, J = 7.2 Hz, 2H), 7.38−
7.22 (m, 9H), 7.00 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 5.14
(dd, J = 8.4 Hz, 3.6 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 153.3, 146.3, 142.7, 139.7, 132.9, 129.1, 127.6, 125.7,
114.9, 114.4, 55.6; MS (EI) m/z 75, 145, 193, 218, 267, 298, 376;
HRMS calcd C21H17BrN2 [M+] 376.0575, found 376.0583.
(E)-1-((E)-1,3-Diphenylallylidene)-2-(4-(trifluoromethyl)phenyl)-
hydrazine (1l): 1H NMR (400 MHz, CDCl3) δ = 7.91 (d, J = 8.4 Hz,
2H), 7.38 (t, J = 7.2 Hz, 2H), 7.31−7.26 (m, 7H), 7.23−7.20 (m, 2H),
6.97 (t J = 8.4 Hz, 2H), 6.77(s, 1H); 13C NMR (100 MHz, CDCl3) δ
= 62.9, 160.4, 152.1, 144.5, 136.4, 130.4, 128.7, 128.5, 127.1, 125.9,
115.9, 115.7, 105.2; MS (EI) m/z 55, 146, 192, 218, 267, 289, 366;
HRMS calcd C22H17F3N2 [M+] 366.1344, found 366.1349.
(E)-1-(tert-Butyl)-2-((E)-1,3-diphenylallylidene)hydrazine (1m): 1H
NMR (400 MHz, CDCl3) δ = 7.59 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 8.4
Hz, 4H), 7.29 (dd, J = 8.0 Hz, 4.0 Hz, 5H), 1.14 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ = 148.1, 146.5, 145.2, 142.8, 134.8, 134.0, 133.5,
133.0, 132.5, 132.0, 128.7, 128.4, 127.5, 125.7, 125.5, 106.9, 64.1, 27.9;
MS (EI) m/z 55, 133, 192, 220, 278; HRMS calcd C19H22N2 [M+]
278.1783, found 278.1786.
(E)-1-(4-Bromophenyl)-2-((E)-3-(thiophene-2-yl)-1-(p-tolyl)-
allylidene)hydrazine (1v): 1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J
= 8.0 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.17−7.14 (m, 3H), 6.99 (d, J
= 8.4 Hz, 2H), 6.93 (d, J = 2.8 Hz, 1H), 6.88 (t, J = 8.4 Hz, 3H), 5.38
(dd, J = 2.8 Hz, 15.6 Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 148.3, 145.6, 144.2, 139.3, 131.7, 126.0, 125.1, 124.4,
115.4, 111.6, 21.5; MS (EI) m/z 64, 133, 212, 281, 318, 396; HRMS
calcd C20H17BrN2S [M+] 396.0296, found 396.0301.
(E)-1-(tert-Butyl)-2-((E)-3-(thiophene-2-yl)-1-(p-tolyl)allylidene)-
hydrazine (1w): 1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.0 Hz,
2H), 7.32−7.18 (m, 2H), 7.09 (d, J = 5.2 Hz, 3H), 7.05 (d, J = 7.6 Hz,
2H), 6.88 (d, J = 2.8 Hz, 1H), 6.84−6.82 (m, 1H), 4.84 (t, J = 2.8 Hz,
1H), 2.54 (s, 3H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ =
151.2, 145.1, 138.2, 129.1, 128.4, 128.2, 128.1, 126.5, 125.7, 125.6,
124.1, 123.0, 60.0, 27.4, 21.4; MS (EI) m/z 64, 133, 231, 282, 298;
HRMS calcd C18H22N2S [M+] 298.1504, found 298.1507.
(Z)-1-Phenyl-2-((E)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)but-3-en-
1
2-ylidene)hydrazine (1x): H NMR (400 MHz, CDCl3) δ = 7.50−
7.48 (m, 2H), 7.33−7.28 (m, 3H), 7.19−7.17 (m, 1H), 5.89 (d, J = 2.8
Hz, 1H), 2.40 (s, 3H), 2.02 (s, 2H), 1.71−1.62 (m, 2H), 1.47 (s, 2H),
1.01 (s, 3H), 0.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 154.3,
148.5, 141.2, 136.5, 131.1, 128.7, 126.3, 123.3, 108.8, 39.1, 32.0, 28.3,
191., 13.9; MS (EI) m/z 64, 133, 172, 199, 235, 267, 282; HRMS calcd
C19H26N2 [M+] 282.2096, found 282.2103.
4-((E)-2-((E)-1, 3-Diphen ylallylidene)hydrazinyl)-
benzenesulfonamide (1n):4c 1H NMR (400 MHz, CDCl3) δ = 7.78−
7.69 (m, 3H), 7.31−7.29 (m, 3H), 7.14−7.05 (m, 4H), 7.03−6.89 (m,
2H); 13C NMR (100 MHz, CDCl3) δ = 170.6, 155.7, 154.0, 143.4,
137.1, 135.4, 134.9, 128.3, 127.4, 116.9.
4-((Z)-2-((E)-4-(2,6,6-Trimethylcyclohex-1-en-1-yl)but-3-en-2-
ylidene)hydrazinyl)benzonitrile (1y): 1H NMR (400 MHz, CDCl3) δ
= 7.35 (d, J = 9.2 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 4.48 (dd, J = 9.2
Hz, 12.8 Hz, 1H), 3.29 (dd, J = 14.8 Hz, 18.4 Hz, 1H), 2.06 (s, 4H),
1.87−1.85 (m, 2H), 1.74 (s, 1H), 1.58−1.52 (m, 3H), 1.32−1.29 (d, J
= 9.2 Hz, 6H), 0.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 151.7,
147.7, 135.6, 133.0, 132.9, 131.8, 120.7, 112.9, 112.0, 98.8, 40.3, 34.6,
28.0, 19.2, 18.9, 15.8; MS (EI) m/z 64, 132, 198, 235, 282, 318, 360;
HRMS calcd C20H25N3 [M+] 307.2048, found 307.2054.
4-((E)-2-((E)-1,3-Diphenylallylidene)hydrazinyl)benzoic acid (1o):
1H NMR (400 MHz, CDCl3) δ = 7.78 (m, 3H), 7.31−7.29 (m, 3H),
7.14−7.05 (m, 4H), 7.03−6.89 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ = 166.4, 151.6, 144.2, 142.8, 130.0, 128.6, 128.4, 128.1,
125.4, 124.5, 109.9, 106.1; MS (EI) m/z 64, 77, 165, 192, 221, 298,
342; HRMS calcd C22H18N2O2 [M+] 342.1368, found 342.1371.
(E)-N′-((E)-1,3-Diphenylallylidene)-4-methylbenzenesulfonohy-
1
drazide (1p): H NMR (400 MHz, CDCl3) δ = 7.78−7.69 (m, 3H),
1-((1E,4E)-1,5-Diphenylpenta-1,4-dien-3-ylidene)-2-phenylhydra-
zine (1z):4h 1H NMR (400 MHz, CDCl3) δ = 7.77 (d, J = 8.0 Hz, 2H),
7.64−7.62 (m, 2H), 7.43−7.39 (m, 5H), 7.37−7.32 (m, 5H), 7.30−
7.25 (m, 4H), 6.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ = 151.9,
151.6, 141.1, 139.6, 139.3, 129.0, 128.6, 128.0, 122.5, 115.5, 104.6; MS
(EI) m/z 64, 155, 192, 298, 324.
7.31−7.29 (m, 3H), 6.92−6.89 (m, 2H), 2.18 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 171.0, 156.2, 154.4, 144.1, 143.9, 141.1, 135.3,
129.5, 128.2, 127.0, 117.3, 20.9; MS (EI) m/z 64, 133, 192, 222, 298,
376; HRMS calcd C22H20N2O2S [M+] 376.1245, found 376.1248.
4-((E)-2-((E)-3-(4-Chlorophenyl)-1-phenylallylidene)hydrazinyl)-
benzonitrile (1q):4f 1H NMR (400 MHz, CDCl3) δ = 7.53−7.44 (m,
5H), 7.29−7.18 (m, 7H), 7.03 (dd, J = 8.4 Hz, 2H), 6.80 (t, J = 7.2 Hz,
1H), 5.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 144.6, 144.5,
143.1, 142.9, 138.2, 137.1, 135.4, 133.9, 132.4, 129.7, 128.5, 127.8,
126.5, 120.5, 113.2; MS (EI) m/z 64, 101, 133, 167, 212, 298, 357.
(E)-1-(4-Bromophenyl)-2-((E)-3-(4-chlorophenyl)-1-
phenylallylidene)hydrazine (1r):4f 1H NMR (400 MHz, CDCl3) δ =
7.69 (d, J = 6.8 Hz, 2H), 7.37−7.18 (m, 10H), 6.89 (d, J = 7.2 Hz,
2H), 5.17 (dd, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ =
147.5, 143.5, 140.5, 133.6, 132.3, 131.8, 129.5, 128.7, 125.9, 115.0,
113.4; MS (EI) m/z 64, 101, 133, 212, 298, 314, 376, 410.
1-(Diphenylmethylene)-2-phenylhydrazine (3a):4f 1H NMR (400
MHz, CDCl3) δ = 7.57 (d, J = 6.8 Hz, 2H), 7.51 (t, J = 7.2 Hz, 2H),
7.45 (t, J = 7.6 Hz, 1H), 7.29−7.18 (m, 7H), 7.03 (d, J = 7.6 Hz, 2H),
6.80 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 144.8,
144.3, 138.6, 132.9, 129.9, 129.4, 129.3, 128.4, 128.2, 126.7, 120.2,
113.1; MS (EI) m/z 64, 167, 192, 215, 243, 272.
1-(Diphenylmethylene)-2-(4-methoxyphenyl)hydrazine (3b):.5d,g
1H NMR (400 MHz, CDCl3) δ = 8.06−8.01 (m, 4H), 7.65−7.62
(m, 4H), 7.50 (t, J = 6.8 Hz, 2H), 7.39 (t, J = 6.8 Hz, 2H), 7.25−7.20
(dd, J = 7.6 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ = 158.6, 145.6, 140.7, 133.4, 127.0, 121.6, 114.7,
110.6, 55.7; MS (EI) m/z 64, 167, 192, 223, 245, 302.
(E)-1-tert-Butyl-2-((E)-3-(thiophene-2-yl)-1-p-tolylallylidene)-
hydrazine (1s): 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 7.6 Hz,
2H), 7.39−7.30 (m, 6H), 7.27−7.22 (m, 5H), 6.92 (d, J = 8.4 Hz,
2H), 5.21 (dd, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ =
147.4, 143.7, 142.0, 131.7, 129.3, 128.9, 128.6, 127.8, 125.8, 115.0,
111.1; MS (EI) m/z 64, 103, 191, 219, 253, 298, 312; HRMS calcd
C18H22N2S [M+] 298.1504, found 298.1507.
(E)-1-Phenyl-2-((E)-3-(thiophene-2-yl)-1-(p-tolyl)allylidene)-
hydrazine (1t): 1H NMR (400 MHz, CDCl3) δ = 7.78 (d, J = 8.0 Hz,
2H), 7.45−7.33 (m, 6H), 7.25−7.20 (m, 3H), 6.91 (t, J = 4.0 Hz, 1H),
6.82−6.81 (m, 2H), 6.77 (s, 1H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 153.2, 143.3, 137.9, 133.1, 129.3, 128.3, 127.6, 125.9,
124.9, 111.1, 107.4, 21.5; MS (EI) m/z 64, 115, 198, 234, 282, 318;
HRMS calcd C20H18N2S [M+] 318.1191, found 318.1195.
1-(Diphenylmethylene)-2-(4-fluorophenyl)hydrazine (3c):.5f,g 1H
NMR (400 MHz, CDCl3) δ = 7.55−7.42 (m, 5H), 7.28−7.16 (m,
3H), 7.06−6.99 (m, 2H), 6.82−6.78 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ = 144.4, 142.8, 138.0, 136.9, 135.2, 133.7, 132.2, 130.0,
129.4, 129.0, 128.2, 127.6, 126.4, 120.3, 113.0; MS (EI) m/z 64, 133,
212, 265, 290.
1-(Diphenylmethylene)-2-(4-(trifluoromethyl)phenyl)hydrazine
1
(3d): H NMR (400 MHz, CDCl3) δ = 7.81 (s, 1H), 7.76−7.75 (m,
2H), 7.70−7.61 (m, 5H), 7.44−7.41 (m, 5H), 7.20 (d, J = 7.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 147.4, 146.4, 138.2, 128.7,
126.7, 121.8, 121.5, 112.6; MS (EI) m/z 64, 133, 192, 235, 317, 340;
HRMS calcd C20H15F3N2 [M+] 340.1187, found 340.1194.
1
1-(2,4-Dichlorophenyl)-2-(diphenylmethylene)hydrazine (3e): H
4-((E)-2-((E)-3-(Thiophene-2-yl)-1-(p-tolyl)allylidene)hydrazinyl)-
1
NMR (400 MHz, CDCl3) δ = 8.17 (d, J = 8.8 Hz, 2H), 7.83−7.75 (m,
3H), 7.69−7.60 (m, 3H), 7.46−7.44 (m, 5H), 7.34−7.30 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 147.3, 139.5, 138.0, 137.9, 132.6, 132.5,
benzonitrile (1u): H NMR (400 MHz, CDCl3) δ = 7.78 (d, J = 8.0
Hz, 2H), 7.43−7.33 (m, 6H), 7.25−7.20 (m, 3H), 6.91 (dd, J = 7.6
Hz, 1.2 Hz, 1H), 6.82−6.81 (m, 2H), 2.36 (s, 3H); 13C NMR (100
F
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
129.9, 129.7, 128.9, 128.5, 128.2, 127.0, 124.1, 117.7, 114.9; MS (EI)
m/z 64, 133, 215, 269, 304, 340; HRMS calcd C19H14Cl2N2 [M+]
340.0534, found 340.0522.
(Z)-4-(2-((4-Chlorophenyl)(phenyl)methylene)hydrazinyl)-
1
benzonitrile (3p): H NMR (400 MHz, CDCl3) δ = 8.02−8.00 (m,
2H), 7.92 (t, J = 8.8 Hz, 3H), 7.74−7.71 (m, 2.4H), 7.51 (d, J = 7.2
Hz, 1.7H), 7.45−7.41 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.24−7.21
(m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 2.50 (s, 2H), 2.43 (s, 1.5H); 13C
NMR (100 MHz, CDCl3) δ = 162.5, 160.1, 146.4, 146.1, 133.4, 129.0,
127.8, 125.0, 123.2, 121.4, 116.3, 110.4, 110.0, 22.1, 21.5; MS (EI) m/
z 64, 222, 298, 331; HRMS calcd C20H14ClN3 [M+] 331.0876, found
331.0882.
4-(2-(Diphenylmethylene)hydrazinyl)benzonitrile (3f):5e 1H NMR
(400 MHz, CDCl3) δ = 7.79−7.75 (m, 1H), 7.66−7.55 (m, 4H), 7.49
(d, J = 8.0 Hz, 2H), 7.34−7.32 (m, 5H), 7.10 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ = 147.7, 147.5, 137.6, 133.6, 132.1, 129.9,
128.9, 128.4, 126.9, 120.0, 113.0, 101.9; MS (EI) m/z 64, 133, 263,
297.
1-(Di-p-tolylmethylene)-2-phenylhydrazine (3g):4f 1H NMR (400
MHz, CDCl3) δ = 7.94 (dd, J = 9.2 Hz, 8.0 Hz, 1H), 7.83 (d, J = 8.0
Hz, 1H), 7.73−7.69 (m, 2H), 7.54−7.47 (m, 2H), 7.46−7.37 (m, 3H),
7.32−7.26 (m, 2H), 2.61−2.51 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ = 145.0, 144.6, 139.2, 129.9, 129.2, 126.7, 120.1, 113.2, 21.6,
21.5; MS (EI) m/z 64, 185, 206, 269, 300.
3-Methyl-5-phenyl-1-tosyl-1H-pyrazole (2a): 56.7 mg, 92% yield;
yellow oil; 1H NMR (400 MHz, CDCl3) δ = 7.54 (d, J = 8.0 Hz, 2H),
7.46−7.36 (m, 5H), 7.20 (d, J = 8.4 Hz, 2H), 6.11 (s, 1H), 2.38 (s,
3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 153.9, 148.9,
145.1, 134.9, 129.6, 129.3, 127.9, 127.7, 12.8, 112.7, 21.7, 13.9; MS
(EI) m/z 51, 75, 102, 116, 158, 236, 298, 312; HRMS calcd
C17H16N2O2S [M+] 312.0933, found 312.0929.
1
4-(2-(Di-p-tolylmethylene)hydrazinyl)benzonitrile (3h): H NMR
3-Methyl-1,5-diphenyl-1H-pyrazole (2b):4d 42.5 mg, 91% yield;
slightly yellow solid; mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ
= 7.16−7.09 (m, J = 8.0 Hz, 10H), 6.18 (s, 1H), 2.26 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ = 149.5, 143.7, 140.2, 130.8, 128.9, 128.7,
128.5, 128.1, 127.1, 125.2, 107.8, 13.7; MS (EI) m/z 51, 75, 102, 116,
155, 190, 234.
(400 MHz, CDCl3) δ = 8.17 (d, J = 8.8 Hz, 2H), 7.83−7.75 (m, 3H),
7.69−7.60 (m, 3H), 7.46−7.44 (m, 5H), 7.34−7.30 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 147.8, 144.1, 140.7, 138.9, 138.6, 133.6,
129.9, 129.8, 127.8, 125.0, 122.5, 122.0, 121.8, 118.9, 110.5, 108.9,
22.3, 21.6; MS (EI) m/z 64, 133, 205, 297, 325; HRMS calcd
C22H19N3 [M+] 325.1579, found 325.1586.
1-(4-Methoxyphenyl)-3-methyl-5-phenyl-1H-pyrazole (2c): 47.0
1-(Di-p-tolylmethylene)-2-(4-(trifluoromethyl)phenyl)hydrazine
(3i): 1H NMR (400 MHz, CDCl3) δ = 7.63 (s, 1H), 7.45 (dd, J = 8.0
Hz, 4H), 7.33 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.07 (dd, J
= 8.0 Hz, 4H), 2.42 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 147.4, 146.8, 139.5, 138.6, 135.6, 128.9, 126.9, 126.6,
126.5, 112.4, 21.4, 21.3; MS (EI) m/z 64, 133, 192, 248, 298, 338, 352,
368; HRMS calcd C22H19F3N2 [M+] 368.1500, found 368.1512.
1-(Bis(4-fluorophenyl)methylene)-2-phenylhydrazine (3j):4f 1H
NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 2.0 Hz, 1H), 7.56−7.49
(m, 4H), 7.33−7.31 (m, 4H), 7.10 (d, J = 8.4 Hz, 2H), 7.03 (t, J = 8.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 164.6, 162.1, 147.6, 145.5,
133.8, 133.7, 131.1, 128.7, 127.7, 119.9, 117.4, 117.2, 115.5, 115.3,
113.0, 102.2; MS (EI) m/z 64, 133, 185, 212, 247, 288, 308.
4-(2-(Bis(4-fluorophenyl)methylene)hydrazinyl)benzonitrile (3k):
1H NMR (400 MHz, CDCl3) δ = 7.37−7.33 (m, 3H), 7.13−7.09
1
mg, 89% yield; yellow oil; H NMR (400 MHz, CDCl3) δ = 7.22−
7.16 (m, 3 H), 7.81−7.73 (m, 7 H), 6.79 (m, 2H), 6.27 (s, 1 H), 3.72
(s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 158.6, 149.0,
143.7, 130.8, 128.6, 128.4, 128.0, 126.6, 114.0, 107.2, 55.3, 13.5; MS
(EI) m/z 75, 116, 155, 190, 234, 264; HRMS calcd C17H16N2O [M+]
264.1263, found 264.1258.
4-(3-Methyl-5-phenyl-1H-pyrazol-1-yl)benzonitrile (2d:). 47.1 mg,
1
91% yield; yellow oil; H NMR (400 MHz, CDCl3) δ = 7.41 (d, J =
8.4 Hz, 2H), 7.28−7.22 (m, 5H), 7.12 (s, 2H), 6.22 (s, 1H), 2.26 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 150.7, 143.9, 143.3, 132.7,
130.3, 128.8, 128.7, 128.6, 124.4, 118.2, 109.8, 109.6, 13.6; MS (EI)
m/z 75, 102, 155, 190, 217, 243, 259; HRMS calcd C17H13N3, [M+]
259.1110, found 259.1106.
1-(4-Fluorophenyl)-3-methyl-5-phenyl-1H-pyrazole (2e): 42.8 mg,
85% yield; slightly yellow oil; 1H NMR (400 MHz, CDCl3) δ = 7.23−
7.16 (m, 7H), 6.96−6.92 (m, 2H), 6.79 (m, 2H), 6.27 (s, 1H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 162.6, 160.2, 149.5, 143.8,
136.4, 128.6, 128.2, 115.8, 115.6, 107.8, 60.3, 13.5; MS (EI) m/z 51,
75, 102, 116, 155, 190, 234, 252; HRMS calcd C16H13FN2, [M+]
252.1063, found 252.1060.
1-(4-Bromophenyl)-3-methyl-5-phenyl-1H-pyrazole (2f): 54.2 mg,
87% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ = 7.26−7.19 (m,
10H), 6.28 (s,1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
149.4, 143.7, 140.2, 130.8, 128.8, 127.1, 125.1, 107.8, 13.6; MS (EI)
m/z 75, 116, 155, 190, 234, 312; HRMS calcd C16H13BrN2 [M+]
312.0262, found 312.0259.
(m, 5H), 6.80 (dd, J = 8.8 Hz, 4H), 7.10 (d, J = 8.4 Hz, 2H), 7.03 (t, J
= 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 171.0, 164.4, 161.9,
143.7, 142.9, 132.0, 131.2, 128.2, 117.2, 117.0, 115.4, 115.1, 114.7,
112.0; MS (EI) m/z 64, 187, 210, 298, 333; HRMS calcd C20H13F2N3
[M+] 333.1078, found 333.1086.
1-(Bis(4-fluorophenyl)methylene)-2-(4-fluorophenyl)hydrazine
1
(3l): H NMR (400 MHz, CDCl3) δ = 7.89 (s, 1H), 7.56−7.48 (m,
3H), 7.28−7.20 (m, 4H), 7.10 (d, J = 12.0 Hz, 2H), 6.96 (t, J = 8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ = 164.5, 162.0, 145.1, 139.2,
130.9, 128.5, 124.2, 117.3, 117.0, 115.5, 115.3, 114.8; MS (EI) m/z 64,
156, 229, 252, 293, 305, 324; HRMS calcd C19H13F3N2 [M+]
326.1031, found 326.1042.
1-(tert-Butyl)-3-methyl-5-phenyl-1H-pyrazole (2g): 35.1 mg, 82%
yield; colorless oil; 1H NMR (400 MHz, CDCl3) δ = 7.38−7.33 (m, 5
H), 5.92 (s, 1 H), 2.29 (s, 3H), 1.44 (s, 9 H); 13C NMR (100 MHz,
CDCl3) δ = 145.2, 143.5, 134.7, 130.4, 128.2, 127.7, 109.0, 60.6, 31.3,
13.5; MS (EI) m/z 63, 79, 127, 158, 214; HRMS calcd C14H18N2 [M+]
214.1470, found 214.147066.
(Z)-1-((4-Chlorophenyl)(phenyl)methylene)-2-(4-fluorophenyl)-
1
hydrazine (3m): H NMR (400 MHz, CDCl3) δ = 8.04−7.96 (m,
2H), 7.78−7.66 (m, 4H), 7.53−7.43 (m, 3H), 7.32−7.22 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ = 162.6, 160.1, 146.3, 140.6, 129.0, 127.9,
124.9, 121.8, 116.4, 110.5; MS (EI) m/z 64, 117, 192, 215, 286;
HRMS calcd C19H14ClFN2 [M+] 324.0830, found 324.0837.
(Z)-1-((4-Chlorophenyl)(phenyl)methylene)-2-phenylhydrazine
(3n):4f 1H NMR (400 MHz, CDCl3) δ = 8.28 (d, J = 7.2 Hz, 1H), 8.19
(d, J = 8.4 Hz, 1H), 7.943 (d, J = 8.8 Hz, 2H), 7.84 (m, 1H), 7.71−
7.57 (m, 5H), 7.52−7.44 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ = 145.8, 139.9, 129.2, 127.5, 126.3, 122.6, 121.3,
110.4; MS (EI) m/z 75, 167, 241, 297, 306.
1,3,5-Triphenyl-1H-pyrazole (2h):4d 53.2 mg, 90% yield; white
solid; mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ = 7.97 (d, J =
8.0 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.42−7.32 (m, 11H), 6.86 (s,
1H); 13C NMR (100 MHz, CDCl3) δ = 152.0, 144.5, 140.2, 133.1,
130.6, 1299.0, 128.7, 128.5, 128.4, 128.1, 127.5, 125.9, 125.4, 105.3;
MS (EI) m/z 77, 147, 192, 241, 267, 296.
1-Phenyl-2-(phenyl(p-tolyl)methylene)hydrazine (3o): 1H NMR
(400 MHz, CDCl3) δ = 8.02−8.00 (m, 2H), 7.92 (t, J = 8.8 Hz, 3H),
7.74−7.71 (m, 2.4H), 7.51 (d, J = 7.2 Hz, 1.7H), 7.45−7.41 (m, 2H),
7.32 (d, J = 8.0 Hz, 1H), 7.24−7.21 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H),
2.50 (s, 2H), 2.43 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ = 162.5,
160.1, 146.4, 146.1, 133.4, 129.0, 127.8, 125.0, 123.2, 121.4, 116.3,
110.4, 110.0, 22.1, 21.5; MS (EI) m/z 64, 117, 215, 290, 324; HRMS
calcd C20H18N2 [M+] 286.1470, found 286.1482.
1-(4-Methoxyphenyl)-3,5-diphenyl-1H-pyrazole (2i): 59.3 mg,
91% yield; colorless solid, mp 128−130 °C; H NMR (400 MHz,
1
CDCl3) δ = 7.92 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.30−
7.24 (m, 7H), 6.80 (t, J = 8.8 Hz, 3H), 3.70 (s, 3H); 13C NMR (100
MHz, CDCl3) δ = 158.9, 151.7, 144.4, 133.5, 133.3, 130.7, 128.8,
128.3, 128.0, 126.8, 125.9, 114.2, 104.7, 55.5; MS (EI) m/z 77, 89,
165, 218, 267, 296, 326; HRMS calcd C22H18N2O [M+] 326.1419,
found 326.1416.
G
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4-(3,5-Diphenyl-1H-pyrazol-1-yl)benzonitrile (2j): 57.1 mg, 89%
yield; colorless oil; H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.6
6.84−6.78 (m, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
152.1, 140.1, 138.2, 137.9, 130.2, 129.1, 127.5, 126.7, 125.9, 105.0,
21.5; MS (EI) m/z 51, 115, 198, 255, 281, 316; HRMS calcd
C20H16N2S [M+] 316.1034, found 316.1031.
4-(5-(Thiophene-2-yl)-3-(p-tolyl)-1H-pyrazol-1-yl)benzonitrile
(2u:). 62.0 mg, 91% yield; dark purple oil; 1H NMR (400 MHz,
CDCl3) δ = 7.76 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.52 (d,
J = 8.4 Hz, 2H),7.36 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.00
(t, J = 4.0 Hz, 2H), 6.88 (d, J = 2.8 Hz, 1H), 6.82 (s, 2H), 2.36 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 153.1, 143.2, 138.5, 137.9,
133.0, 132.9, 129.5, 129.2, 128.2, 127.5, 125.9, 125.3, 124.9, 110.9,
107.4, 21.4; MS (EI) m/z 77, 152, 231, 281, 326, 341; HRMS calcd
C21H15N3S, [M+] 341.0987, found 341.0983.
1-(4-Bromophenyl)-5-(thiophene-2-yl)-3-(p-tolyl)-1H-pyrazole
(2v): 69.3 mg, 88% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ =
7.75 (d, J = 7.0 Hz, 1H), 7.48 (dd, J = 5.6 Hz, 37.6 Hz, 2H), 7.25−7.09
(m, 5H), 6.97−6.77 (m, 4H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 152.4, 148.3, 145.6, 138.1, 129.5, 127.0, 111.7, 105.7, 21.6;
MS (EI) m/z 77, 152, 211, 281, 316, 394; HRMS calcd C20H15BrN2S
[M+] 394.0139, found 394.0136.
1-tert-Butyl-5-(thiophene-2-yl)-3-(p-tolyl)-1H-pyrazole (2w): 48.5
mg, 82% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ = 7.97 (d, J
= 8.0 Hz, 2H), 7.53 (d, J = 5.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.29
(d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 2.54 (s,
3H), 1.80 (s, 9H); 13C NMR (100 MHz, CDCl3) δ = 148.1, 137.0,
135.7, 133.9, 131.3, 129.5, 127.3, 126.9, 125.7, 108.9, 61.8, 31.1, 21.5;
MS (EI) m/z 65, 91, 130, 197, 211, 281, 296; HRMS calcd C18H20N2S
[M+] 296.1347, found 296.1343.
1
Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.51−7.44 (m, 4H), 7.41−7.38 (m,
4H), 7.30 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ =
153.1, 144.8, 143.4, 132.9, 132.4, 128.5, 125.9, 124.8, 110.4, 106.9; MS
(EI) m/z 77, 145, 218, 241, 296, 321; HRMS calcd C22H15N3 [M+]
321.1266, found 321.1262.
1-(4-Bromophenyl)-3,5-diphenyl-1H-pyrazole (2k): 62.0 mg, 83%
yield; light yellow solid; mp 133−135 °C; 1H NMR (400 MHz,
CDCl3) δ = 7.88 (d, J = 7.2 Hz, 2H), 7.38−7.34 (m, 4H), 7.29−7.24
(m, 4H), 7.21−7.15 (m, 4H), 6.74 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ = 152.4, 144.5, 139.3, 128.9, 128.8, 128.7, 128.3, 126.7,
126.0, 121.0, 105.8; MS (EI) m/z 77, 165, 192, 218, 267, 296, 374;
HRMS calcd C21H15BrN2 [M+] 374.0419, found 374.0416.
3,5-Diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (2l): 61.9
1
mg, 85% yield; yellow solid; mp 139−141 °C; H NMR (400 MHz,
CDCl3) δ = 7.90 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.42−
7.36 (m, 4H), 7.31−7.19 (m, 6H), 6.76 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ = 152.8, 144.7, 143.0, 132.8, 128.9, 128.4, 126.1, 126.0,
125.9, 124.8, 106.4; MS (EI) m/z 77, 146, 165, 192, 218, 267, 288,
364; HRMS calcd C22H15F3N2 [M+] 364.1187, found 364.1184.
1-(tert-Butyl)-3,5-diphenyl-1H-pyrazole (2m): 50.2 mg, 91% yield;
1
colorless oil; H NMR (400 MHz, CDCl3) δ = 7.74−7.72 (m, 2H),
7.25−7.22 (m, 7H), 7.12 (t, J = 7.2 Hz, 1H), 1.38 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ = 146.7, 142.9, 133.3, 132.9, 129.4, 127.3, 126.1,
124.4, 105.4, 60.3, 30.1; MS (EI) m/z 64, 133, 192, 220, 276; HRMS
calcd C19H20N2 [M+] 276.1628, found 276.1624.
4-(3,5-Diphenyl-1H-pyrazol-1-yl)benzenesulfonamide (2n): 54.2
1
3-Methyl-1-phenyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)-1H-pyr-
mg, 87% yield; white solid; mp 158−161 °C; H NMR (400 MHz,
1
azole (2x): 48.7 mg, 87% yield; slightly yellow oil; H NMR (400
CDCl3) δ = 7.99 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.55 (d,
J = 8.4 Hz, 3H), 7.48 (d, J = 7.6 Hz, 2H), 7.43−7.41 (m, 3H), 7.37−
7.35 (m, 2H), 7.20 (s, 1H); 13C NMR (100 MHz, CDCl3) δ = 151.8,
144.4, 142.7, 142.0, 132.3, 129.7, 128.8, 128.6, 128.3, 127.0, 126.7,
125.5, 125.0, 113.4, 106.4.
MHz, CDCl3) δ = 7.46 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H),
7.17 (t, J = 6.8 Hz,1H), 5.88 (s, 1H), 2.32 (s, 3H), 2.01 (t, J = 6.4 Hz,
2H), 1.49−1.36 (m, 6H), 0.99 (s, 3H), 0.93 (d, J = 7.2 Hz, 1H), 0.49
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.3, 141.6, 136.2, 130.8,
128.4, 126.0, 123.1, 108.6, 38.8, 34.9, 31.7, 29.2, 28.0, 18.9, 13.6; MS
(EI) m/z 65, 77, 117, 170, 197, 235, 265, 280; HRMS calcd C19H24N2
[M+] 280.1940, found 280.1936.
4-(3,5-Diphenyl-1H-pyrazol-1-yl)benzoic acid (2o): 57.1 mg, 84%
yield; white solid; mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ =
8.00 (s, 4H), 7.48−7.35 (m, 10H), 7.20 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ = 166.6, 151.7, 144.3, 143.0, 130.2, 129.5, 128.7, 128.5,
128.2, 125.5, 124.6, 110.0, 106.2; MS (EI) m/z 77, 165, 192, 220, 296,
340; HRMS calcd C22H16N2O2 [M+] 340.1212, found 340.1207.
3,5-Diphenyl-1H-pyrazole (2p):4e 37.8 mg, 86% yield; slightly
yellow solid; mp 135−137 °C; 1H NMR (400 MHz, CDCl3) δ = 9.87
(br. s, 1H), 7.72−7.70 (d, J = 6.8 Hz, 4H), 7.38−7.29 (m, 6H), 6.82 (s,
1H); 13C NMR (100 MHz, CDCl3) δ = 148.8, 131.3, 128.8, 128.2,
125.6, 100.1; MS (EI) m/z 77, 101, 133, 165, 192, 220.
4-(5-(4-Chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzonitrile
(2q): 62.4 mg, 88%; yellow oil; 1H NMR (400 MHz, CDCl3) δ = 7.88
(d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.44−7.32 (m, 7H), 7.17
(d, J = 7.6 Hz, 2H), 6.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ =
153.2, 143.5, 143.1, 135.2, 132.3, 130.0, 128.5, 125.9, 124.9, 118.2,
110.7, 107.0; MS (EI) m/z 101, 133, 165, 192, 296, 355; HRMS calcd
C22H14ClN3 [M+] 355.0876, found 355.0872.
1-(4-Bromophenyl)-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-
1
yl)-1H-pyrazole (2y): 61.5 mg, 86% yield; yellow oil; H NMR (400
MHz, CDCl3) δ = 7.39−7.35 (m, 2H), 7.31 (d, J = 8.8 Hz, 2H), 5.82
(s, 1H), 2.25 (s, 3H), 1.96 (t, J = 6.4 Hz, 2H), 1.67−1.53 (m, 2H),
1.46−1.41 (m, 1H), 1.37−1.35 (m, 4H), 0.96 (s, 3H), 0.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ = 148.9. 142.6, 136.7, 126.8, 124.2,
119.5, 109.1, 38.9, 35.0, 31.8, 29.2, 28.2, 18.9, 13.7; MS (EI) m/z 77,
154, 197, 223, 280, 316, 358; HRMS calcd C19H23BrN2 [M+]
358.1045, found 358.1041.
(E)-1,5-Diphenyl-3-styryl-1H-pyrazole (2z): 51.6 mg, 81% yield;
white solid; mp 143−145 °C; 1H NMR (400 MHz, CDCl3) δ = 7.98−
7.96 (d, J = 8.0 Hz, 2H), 7.48−7.44 (d, J = 7.2 Hz, 1H), 7.42−7.32 (m,
11H), 6.86(s, 1H); 13C NMR (100 MHz, CDCl3) δ = 152.0, 144.5,
140.2, 133.1, 130.6, 129.0, 128.7, 128.5, 128.4, 128.1, 127.5, 125.9,
125.4, 105.3; MS (EI) m/z 75, 155, 190, 246, 322; HRMS calcd
C23H18N2 [M+] 322.1470, found 322.1467.
1-(4-Bromophenyl)-5-(4-chlorophenyl)-3-phenyl-1H-pyrazole
1,3-Diphenyl-1H-indazole (4a):5b 45.3 mg, 84%; yellow solid; mp
136−138 °C; 1H NMR (400 MHz, CDCl3) δ = 8.08 (dd, J = 4.0 Hz,
16.0 Hz, 3H), 7.81 (t, J = 8.0 Hz, 3 H), 7.55 (dd, J = 7.6 Hz, 15.6 Hz,
4H), 7.46 (dd, J = 8.8 Hz, 16.4 Hz, 2 H), 7.39 (t, J = 8.4 Hz, 1H), 7.30
(t, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 146.1, 140.4,
140.2, 133.3, 130.1, 129.5, 128.9, 127.8, 127.1, 126.7, 123.2, 123.0,
122.0, 121.6, 110.7; MS (EI) m/z 77, 115, 167, 192, 215, 241, 270.
1-(4-Methoxyphenyl)-3-phenyl-1H-indazole (4b): 492. mg, 82%;
yellow solid, mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ = 8.04
(t, J = 8.8 Hz, 3H), 7.51 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H),
7.22 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ = 158.5, 145.6, 140.7, 128.2, 124.8, 121.5,
114.7, 110.5, 55.6; MS (EI) m/z 77, 115, 167, 192, 215, 241, 300;
HRMS calcd C20H16N2O [M+] 300.1263, found 300.1259.
1
(2r): 69.3 mg, 85% yield; yellow solid; mp 147−149 °C; H NMR
(400 MHz, CDCl3) δ = 7.89 (d, J = 7.2 Hz, 2H), 7.47−7.40 (m, 4H),
7.36−7.29 (m, 3H), 7.23−7.17 (m, 4H), 6.78 (s, 1H); 13C NMR (100
MHz, CDCl3) δ = 152.4, 143.2, 138.9, 134.7, 132.7, 132.2, 128.8,
128.3, 126.6, 125.8, 121.3, 105.8; MS (EI) m/z 77, 101, 133, 192, 220,
296, 330, 374, 408; HRMS calcd C21H14BrClN2 [M+] 408.0029, found
408.0026.
1-(tert-Butyl)-5-(4-chlorophenyl)-3-phenyl-1H-pyrazole (2s): 50.8
1
mg, 82% yield; slightly yellow oil; H NMR (400 MHz, CDCl3) δ =
7.82 (d, J = 8.4 Hz, 2H), 7.38−7.27 (m, 7H), 6.43 (s, 3H), 1.49 (s,
9H); 13C NMR (100 MHz, CDCl3) δ = 148.0, 142.7, 131.8, 129.6,
128.6, 127.4, 125.5, 106.7, 61.6, 31.3; MS (EI) m/z 77, 103, 191, 219,
253, 297, 310; HRMS calcd C19H19ClN2 [M+] 310.1237, found
310.1233.
1-Phenyl-5-(thiophene-2-yl)-3-(p-tolyl)-1H-pyrazole (2t): 58.1 mg,
92% yield; black oil; 1H NMR (400 MHz, CDCl3) δ = 7.78 (d, J = 7.6
Hz, 2H), 7.58 (dd, J = 6.8 Hz, 33.2 Hz, 5H), 7.19−7.15 (m, 3H),
1-(4-Fluorophenyl)-3-phenyl-1H-indazole (4c): 49.5 mg, 86%;
yellow solid, mp 142−144 °C; H NMR (400 MHz, CDCl3) δ =
8.05 (dd, J = 4.0 Hz, 22.0 Hz, 3H), 7.81−7.73 (m, 2H), 7.69 (d, J = 4.0
1
H
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H), 7.60−7.49(m, 2H), 7.48−7.41 (m, 2H), 7.31−7.22 (m, 3H);
13C NMR (100 MHz, CDCl3) δ = 162.5, 160.0, 146.2, 140.5, 136.3,
133.1, 132.4, 128.9, 128.3, 127.3, 124.8, 123.1, 122.0, 121.7, 116.5,
116.2, 110.4; MS (EI) m/z 63, 77, 95, 157, 184, 210, 267, 288; HRMS
calcd C19H13FN2 [M+] 288.1063, found 288.1058.
122.0, 120.7, 118.4, 116.2, 116.0, 112.7, 112.4, 109.7; MS (EI) m/z 77,
95, 149, 185, 208, 295, 331; HRMS calcd C20H11F2N3 [M+] 331.0921,
found 331.0918.
6-Fluoro-1,3-bis(4-fluorophenyl)-1H-indazole (4l): 40.1 mg, 62%
yield; yellow solid; mp 170−172 °C; 1H NMR (400 MHz, CDCl3) δ =
8.01−7.94 (m, 5H), 7.86 (d, J = 8.8 Hz, 2H), 7.51 (dd, J = 0.4 Hz, 9.2
Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.14 (dt, J = 2.0 Hz, 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ = 164.3, 164.0, 162.6, 161.8, 160.2,
145.5, 140.8, 135.8, 132.5, 128.8, 122.8, 119.7, 115.5, 111.9, 111.7,
96.5, 96.2; MS (EI) m/z 69, 95, 121, 162, 202, 229, 251, 291, 303, 324;
HRMS calcd C19H11F3N2 [M+] 324.0874, found 324.0871.
6-Methyl-1,3-diphenyl-1H-indazole + 1-phenyl-3-(p-tolyl)-1H-in-
dazole (4m+4m′): 44.3 mg, 78% yield; yellow solid; mp 143−145 °C;
1H NMR (400 MHz, CDCl3) δ = 8.01 (dd, J = 8.4 Hz, 17.0 Hz, 3H),
7.90 (t, J = 8.8 Hz, 2.76H), 7.72−7.63 (m, 4.76H), 7.49 (t, J = 7.2 Hz,
2.3H), 7.40 (dd, J = 6.4 Hz, 3.3H), 7.30 (d, J = 8.0 Hz, 1.8H), 7.24−
7.18 (m, 4.7H), 7.08 (d, J = 8.4 Hz, 1.6H), 2.48 (s, 3H), 2.41 (s,
2.2H); 13C NMR (100 MHz, CDCl3) δ = 162.4, 160.0, 146.3, 146.0,
138.3, 133.3, 128.8, 127.7, 124.9, 123.1, 121.2, 116.2, 110.3, 109.8,
22.0, 21.4; MS (EI) m/z 77, 115, 167, 192, 215, 284; HRMS calcd
C20H16N2 [M+] 284.1313, found 284.1310.
6-Chloro-1,3-diphenyl-1H-indazole 3-(4-chlorophenyl)-1-phenyl-
1H-indazole (4n+4n′): 45.6 mg, 75% yield; yellow solid; mp 138−140
°C; 1H NMR (400 MHz, CDCl3) δ = 8.26 (d, J = 7.2 Hz, 1.9H), 8.17
(d, J = 8.4 Hz, 1H), 7.94 (dd, J = 7.6 Hz, 18.8 Hz, 2.3H), 7.82 (d, J =
8.4 Hz, 1H), 7.68−7.53 (m, 5.2H), 7.51−7.40 (m, 2.8H), 7.34 (t, J =
7.6 Hz, 1.3H); 13C NMR (100 MHz, CDCl3) δ = 146.2, 140.5, 140.4,
133.6, 131.3, 130.2, 129.6, 128.8, 128.5, 128.0, 127.3, 126.9, 126.8,
123.4, 123.0, 122.2, 121.7, 110.9; MS (EI) m/z 77, 115, 139, 167, 192,
241, 304; HRMS calcd C19H13ClN2 [M+] 304.0767, found 304.0763.
6-Chloro-1-(4-fluorophenyl)-3-phenyl-1H-indazole + 3-(4-chlor-
ophenyl)-1-(4-fluorophenyl)-1H-indazole (4o+4o′): 50.2 mg, 78%
yield; yellow solid; mp 145−147 °C; 1H NMR (400 MHz, CDCl3) δ =
8.02 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 4.9H), 7.78−7.66 (m,
7.4H), 7.59−7.43 (m, 7.5H), 7.32−7.22 (m, 6.7H); 13C NMR (100
MHz, CDCl3) δ = 162.7, 162.6, 160.2, 160.1, 146.3, 145.0, 140.9,
140.5, 135.8, 133.8, 132.5, 131.5, 129.0, 128.7, 128.4, 127.4, 125.0,
124.9, 123.0, 122.6, 122.2, 121.6, 121.4, 116.6, 116.5, 116.4, 116.3,
110.5, 110.1; MS (EI) m/z 77, 115, 167, 192, 215, 241, 288, 322;
HRMS calcd C19H12ClFN2 [M+] 322.0673, found 322.0670.
4-(6-Chloro-3-phenyl-1H-indazol-1-yl)benzonitrile + 4-(3-(4-
chlorophenyl)-1H-indazol-1-yl)benzonitrile (4p+4p′):4f 51.3 mg,
78% yield; yellow solid; mp 127−129 °C; 1H NMR (400 MHz,
CDCl3) δ = 8.04 (d, J = 8.0 Hz, 1.33H), 7.97−7.93 (m, 7.26H), 7.91
(s, 1.24H), 7.85−7.81 (m, 5.37H), 7.57−7.47 (m, 6H), 7.36 (t, J = 7.6
Hz, 1H), 7.30 (d, J = 84 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ =
147.9, 146.6, 143.6, 143.2, 140.4, 140.0, 134.9, 134.6, 133.6, 131.9,
130.9, 129.1, 128.9, 128.1, 127.8, 123.9, 123.8, 123.0, 122.6, 122.1,
122.0, 121.8, 118.5, 118.4, 110.8, 110.6, 109.7, 109.4; MS (EI) m/z 77,
115, 139, 192, 215, 295, 329; HRMS calcd C20H12ClN3 [M+]
329.0720, found 329.0716.
4-Bromo-3-methyl-1,5-diphenyl-1H-pyrazole (5a): 109.2 mg, 70%
yield; yellow solid; mp 146−148 °C; 1H NMR (400 MHz, CDCl3) δ =
7.12−7.00 (m, 10H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
148.2, 140.5, 139.9, 129.8, 129.2, 128.7, 128.5, 127.1, 124.5, 97.0, 60.1,
12.5; MS (EI) m/z 51, 75, 116, 155, 190, 234, 312; HRMS calcd
C16H13BrN2 [M+] 312.0262, found 312.0258.
4-Bromo-1,3,5-triphenyl-1H-pyrazole (5b): 104.6 mg, 72% yield;
yellow solid; mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ = 8.02
(d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.2 Hz, 5H), 7.47−7.21 (m, 13H); 13C
NMR (100 MHz, CDCl3) δ = 149.8, 142.1, 139.9, 130.3, 129.1, 128.6,
128.4, 127.6, 124.9, 95.0; MS (EI) m/z 77, 89, 147, 165, 192, 218, 241,
267, 296, 374; HRMS calcd C21H15BrN2 [M+] 374.0419, found
374.0415.
3-Phenyl-1-(4-(trifluoromethyl)phenyl)-1H-indazole (4d):5c 48.6
1
mg, 72% yield; yellow solid; mp 145−147 °C; H NMR (400 MHz,
CDCl3) δ = 7.85 (t, J = 7.6 Hz, 5H), 7.70 (d, J = 8.4 Hz, 2H), 7.48 (s,
1H), 7.26 (d, J = 7.6 Hz, 2 H), 7.02 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H),
2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 147.1, 143.3, 140.7,
138.5, 138.1, 130.1, 129.6, 126.7, 126.6, 124.5, 122.0, 122.0, 121.5,
110.2, 22.1, 21.4; MS (EI) m/z 77, 145, 192, 235, 317, 338.
1-(2,4-Dichlorophenyl)-3-phenyl-1H-indazole (4e): 48.6 mg, 73%
yield; yellow solid; mp 146−148 °C; 1H NMR (400 MHz, CDCl3) δ =
7.96−7.92 (m, 3H), 7.67 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H),
7.36 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 7.25−7.19 (m, 3H), 7.08−7.03 (m,
1H); 13C NMR (100 MHz, CDCl3) δ = 164.4, 164.0, 161.9, 161.6,
145.8, 138.3, 128.7, 123.8, 116.1, 115.9, 112.1, 111.8, 96.7, 96.4; MS
(EI) m/z 77, 139, 192, 215, 269, 304, 338; HRMS calcd C19H12Cl2N2
[M+] 338.0378, found 338.0374.
4-(3-Phenyl-1H-indazol-1-yl)benzonitrile (4f): 41.3 mg, 70% yield;
yellow solid; mp 141−143 °C; 1H NMR (400 MHz, CDCl3) δ = 8.05
(dd, J = 4.0 Hz, 22.0 Hz, 3H), 7.81−7.73 (m, 2H), 7.69 (d, J = 4.0 Hz,
1H), 7.60−7.49 (m, 2H), 7.48−7.41 (m, 2H), 7.31−7.22 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ = 162.5, 160.0, 146.2, 140.5, 136.3, 133.1,
132.4, 128.9, 128.3, 127.3, 124.8, 123.1, 122.0, 121.7, 116.5, 116.2,
110.4; MS (EI) m/z 77, 115, 167, 192, 215, 269, 295; HRMS calcd
C20H13N3 [M+] 295.1110, found 295.1106.
6-Methyl-1-phenyl-3-(p-tolyl)-1H-indazole (4g):4f 51.2 mg, 86%
1
yield; yellow solid; mp 88−90 °C; H NMR (400 MHz, CDCl3) δ =
7.93 (dd, J = 2.0 Hz, 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.69 (d, J =
8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.33
(dd, J = 7.6 Hz, 14.6 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0
Hz, 1H), 2.46 (d, J = 32.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ =
146.0, 142.9, 140.3, 138.1, 137.5, 135.3, 130.2, 129.5, 128.9, 127.6,
126.5, 124.0,123.1, 121.4, 121.2, 110.1, 22.1, 21.4; MS (EI) m/z 65,
95, 116, 183, 205, 269, 298; HRMS calcd C21H18N2 [M+] 298.1470,
found 298.1466.
4-(6-Methyl-3-(p-tolyl)-1H-indazol-1-yl)benzonitrile (4h): 50.3 mg,
78% yield; yellow solid; mp 127−129 °C; 1H NMR (400 MHz,
CDCl3) δ = 7.95−7.89 (m, 5H), 7.78 (d, J = 7.6 Hz, 2H), 7.59 (s, 1H),
7.40 (d, J = 7.6 Hz, 2H), 7.15 (d, J = 8.4 Hz, 1H), 2.54 (s, 3H), 2.45
(s, 3H); 13C NMR (100 MHz, CDCl3) δ = 147.7, 143.9, 140.6, 138.8,
138.5, 133.5, 129.7, 129.6, 127.7, 124.8, 121.8, 118.7, 110.3, 108.7,
22.2, 21.4; MS (EI) m/z 65, 77, 91, 183, 205, 223, 295, 323; HRMS
calcd C22H17N3 [M+] 323.1423, found 323.1420.
6-Methyl-3-(p-tolyl)-1-(4-(trifluoromethyl)phenyl)-1H-indazole
(4i): 56.3 mg, 77% yield; yellow solid; mp 147−149 °C; 1H NMR (400
MHz, CDCl3) δ = 8.03−7.98 (m, 3H), 7.87 (d, J = 8.0 Hz, 2H), 7.74−
7.71 (m, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.42−7.38 (m, 2H), 2.38 (t, J =
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 147.2, 143.1, 140.2,
132.8, 129.0, 128.2, 127.9, 127.7, 126.6, 125.5, 123.8, 122.8, 122.6,
122.1, 121.9, 110.6; MS (EI) m/z 65, 77, 91, 145, 183, 223, 248, 282,
296, 336, 350, 366; HRMS calcd C22H17F3N2 [M+] 366.1344, found
366.1340.
6-Fluoro-3-(4-fluorophenyl)-1-phenyl-1H-indazole (4j):4f 50.1 mg,
82% yield; yellow solid; mp 169−170 °C; 1H NMR (400 MHz,
CDCl3) δ = 7.90−7.87 (m, 2H), 7.81−7.78 (m, 1H), 7.65 (d, J = 7.6
Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.2 Hz, 2H), 7.13 (t, J =
8.4 Hz, 2 H), 6.93 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
= 164.3, 163.9, 161.8, 161.4, 145.3, 140.7, 140.6, 139.7, 129.6, 129.5,
129.0, 127.0, 122.8, 122.7, 119.8, 116.0, 115.8, 111.8, 111.6, 96.8, 96.5
; MS (EI) m/z 57, 77, 95, 123, 185, 210, 245, 285, 306; HRMS calcd
C19H12F2N2 [M+] 306.0968, found 306.0965.
4-(6-Fluoro-3-(4-fluorophenyl)-1H-indazol-1-yl)benzonitrile (4k):
48.9 mg, 74% yield; yellow solid; mp 172−174 °C; H NMR (400
MHz, CDCl3) δ = 8.01−7.94 (m, 5H), 7.86 (d, J = 8.8 Hz, 2H), 7.51
(dd, J = 0.4 Hz, 9.2 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.14 (dt, J = 2.0
Hz, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 164.6, 164.3,
162.1, 161.8, 147.1, 143.3, 140.4, 140.3, 133.7, 129.6, 128.2, 123.4,
3-Methyl-1,5-diphenyl-4-(phenylethynyl)-1H-pyrazole (6): 150.3
1
1
mg, 90% yield; yellow solid; mp 143−145 °C; H NMR (400 MHz,
CDCl3) δ = 7.46−7.41 (m, 4H), 7.36−7.27 (m, 11H); 13C NMR (100
MHz, CDCl3) δ = 151.9, 144.3, 139.8, 131.3, 128.6, 127.5, 125.2,
123.8, 104.2, 93.2, 81.6, 12.7; MS (EI) m/z 51, 75, 102, 155, 190, 234,
334; HRMS calcd C24H18N2 [M+] 334.1470, found 334.1466.
I
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N-tert-Butyl-3-methyl-1,5-diphenyl-1H-pyrazole-4-carboxamide
2333−2343. (g) Mauger, C.; Mignani, G. Adv. Synth. Catal. 2005, 347,
773−782. (h) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.;
Hiroya, K. Org. Lett. 2007, 9, 2931−2934.
(6) For recent reviews on C−N bond formations, see: (a) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174−238.
(b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27−50. (c) Cho,
S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068−
5083.
(7) Selected recent reviews for C−H functionalization: (a) Wencel-
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740−4761. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624−655. (c) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem.
Rev. 2011, 111, 1780−1824. (d) Acc. Chem. Res. 2012, Issue 6, 777−
958. (e) For a specific review on C(sp2)−H functionalization, see:
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174−
238.
(8) For selected reviews on chelation-assisted C−H functionalization,
see: (a) Engle, K. M.; Mei, T. S.; Wasa, M.; Yu, J. Q. Acc. Chem., Res.
2012, 45, 788−802. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2012, 45, 814−825. (c) Hartwig, J. F. Acc.
Chem. Res. 2008, 41, 1534−1544. (d) Surry, D. S.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 6338−6361.
1
(7): 141.5 mg, 85% yield; yellow solid; mp 149−151 °C; H NMR
(400 MHz, CDCl3) δ = 7.43−7.39 (m, 3H), 7.30−7.28 (m, 5H),
7.25−7.22 (m, 2H), 2.59 (s, 3H), 1.14 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ = 163.2, 150.8, 141.5, 139.3, 128.8, 127.5, 125.1, 116.8, 51.0,
28.6, 13.6; MS (EI) m/z 75, 102, 155, 190, 234, 333; HRMS calcd
C21H23N3O [M+] 333.1841, found 333.1837.
1,3,5-triphenyl-4-(p-tolyl)-1H-pyrazole (8): 158.3 mg, 82% yield;
yellow solid; mp 148−150 °C; 1H NMR (400 MHz, CDCl3) δ = 7.71
(s, 2H), 7.45−7.13 (m, 17H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 150.3, 141.4, 140.2, 136.3, 133.4, 130.6, 128.4, 127.3,
125.9, 125.4, 21.4; MS (EI) m/z 77, 139, 190, 263, 307, 355, 370, 386;
HRMS calcd C28H22N2 [M+] 386.1783, found 386.1780.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
■
(9) For recent reviews on copper−dioxygene systemes, see:
(a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int.
Ed. 2011, 50, 11062−11087. (b) Zhang, C.; Tang, C.; Jiao, N. Chem.
Soc. Rev. 2012, 41, 3464−3484.
Notes
The authors declare no competing financial interest.
(10) For selective reports on copper-catalyzed aerobic oxidative
transformation, see: (a) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J.
Q. J. Am. Chem. Soc. 2006, 128, 6790−679. (b) Tian, J. S.; Loh, T. P.
Angew. Chem., Int. Ed. 2010, 49, 8417−8420. (c) Do, H. Q.; Daugulis,
O. J. Am. Chem. Soc. 2009, 131, 17052−17053. (d) Wang, Y. F.; Zhu,
X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 3679−3682. (e) Matsuyama,
N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
2358−2361. (f) Wang, Z. Q.; Zhang, W. W.; Gong, L. B.; Tang, R. Y.;
Yang, X. H.; Liu, Y.; Li, J. H. Angew. Chem., Int. Ed. 2011, 50, 8968−
8973. (g) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed.
2011, 50, 11088−11092. (h) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu,
J.; Yi, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 4666−4670.
(i) Wendlandt, A. E.; Stahl, S. S. Org. Biomol. Chem. 2012, 10, 3866−
3870.
(11) For selected examples of copper-catalyzed aerobic oxidative C−
N bond formations: (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 1932−1934. (b) Hamada, T.; Ye, X.; Stahl, S. S. J. Am.
Chem. Soc. 2008, 130, 833−835. (c) Zhang, C.; Jiao, N. J. Am. Chem.
Soc. 2010, 132, 28−29. (d) Wang, Y. F.; Zhu, X.; Chiba, S. J. Am.
Chem. Soc. 2012, 134, 3679−3682. (e) Wang, X.; Jin, Y.; Zhao, Y.;
Zhu, L.; Fu., H. Org. Lett. 2012, 14, 452−455. (f) Lu, J.; Jin, Y.; Liu,
H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 3694−3697. (g) Zhang, Y.;
Patel, S.; Mainolfi, N. Chem. Sci. 2012, 3, 3196−3199. (h) Armstrong,
A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49, 2282. (i) John, A.;
Nicholas, K. M. J. Org. Chem. 2011, 76, 4158−4162. (j) Saha, P.;
Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 8719. (k) Wang, H.; Wang, Y.; Liang, D.; Liu, L.;
Zhang, J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678−5681.
(12) (a) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H.
Chem. Sci. 2012, 3, 3463−3467. (b) Jiang, H.; Li, X.; Pan, X.; Zhou, P.
Pure Appl. Chem. 2012, 84, 553−559. (c) Yuan, G.; Zheng, J.; G, X.;
Li, X.; Huang, L.; Chen, H.; Jiang, H. Chem. Commun. 2012, 48,
7513−7515. (d) Huang, L.; Jiang, H.; Qi, C.; Liu, X. J. Am. Chem. Soc.
2010, 132, 17652−17654.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (20932002 and 21172076), National Basic Research
Program of China (973 Program) (2011CB808600), and
Changjiang Scholars and Innovation Team Project of Ministry
of Education and Guangdong Natural Science Foundation
(10351064101000000) for financial support.
REFERENCES
■
(1) (a) Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Pergamon:
Oxford, 2008. (b) Ricci, A. Amino Group Chemistry: From Synthesis to
the Life Sciences; Willey-VCH: Weinheim, 2008.
(2) For general reviews on medical application of pyrazoles, see:
Dolzhenko, A. V.; Dolzhenko, A. V.; Chui, W. K. Heterocycles 2008, 75,
1575−1622.
(3) (a) Wrobleski, S. T.; Chen, P.; Hynes, J., Jr.; Lin, S.; Norris, D. J.;
Pandit, C. R.; Spergel, S.; Wu, H.; Tokarski, J. S.; Chen, X.; Gil-looly,
K. M.; Kiener, P. A.; McIntyre, K. W.; Patil-Koota, V.; Shuster, D. J.;
Turk, L. A.; Yang, G.; Leftheris, K. J. Med. Chem. 2003, 46, 2110−
2116. (b) Magano, J.; Waldo, M.; Greene, D.; Nord, E. Org. Process
Res. Dev. 2008, 12, 877−883.
(4) For selective examples on pyrazole synthesis, see, e.g.: (a) Liu, H.
L.; Jiang, H. F.; Zhang, M.; Yao, W. J.; Zhu, Q. H.; Tang, Z.
Tetrahedron Lett. 2008, 49, 3805−3809. (b) Zora, M.; Kivrak, A. J. Org.
Chem. 2011, 76, 9379−9390. (c) Hu, J.; Chen, S.; Sun, Y.; Yang, J.;
Rao, Y. Org. Lett. 2012, 14, 5030−5033. (d) Wen, J.; Fu, Y.; Zhang, R.
Y.; Zhang, J.; Chen, S. Y.; Yu, X. Q. Tetrahedron 2011, 67, 9618−9621.
(e) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 7079−7082. (f) Zhang, T.; Bao, W. J. Org. Chem. 2013, 78,
1317−1322. (g) Kovelesky, A. C.; Shine, H. J. J. Org. Chem. 1988, 53,
1973−1979. (h) Shah, J. N.; Shah, C. K. J. Org. Chem. 1978, 43, 1266−
1267.
(5) (a) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R.
C. J. Org. Chem. 2008, 73, 219−226. (b) Xiong, X.; Jiang, Y.; Ma, D.
Org. Lett. 2012, 14, 2552−2555. (c) Qi, X.; Ready, J. M. Angew. Chem.,
Int. Ed. 2007, 46, 3242−3244. (d) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2090−2093. (e) Huang, X.; Anderson, K. W.; Zim, D.; Jiang,
L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653−
6655. (f) Schmidt, A. M.; Eilbracht, P. Org. Biomol. Chem. 2005, 3,
(13) (a) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem.
2010, 75, 3900−3903. (b) Kadnikov, D. V.; Larock, R. C. J. Org. Chem.
2004, 69, 6772−6780.
(14) (a) Bioorganic and Medicinal Chemistry of Fluorine; Begue, J.-P.,
Bonnet-Delpon, D., Eds; Wiley: Hoboken, 2008. (b) Fluorine in
Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-
Blackwell: Chichester, 2009.
(15) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320−330.
J
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(16) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999; pp 1949 −1950, 1955, 1983−1985.
(b) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597−606. (c) Leow, D.;
Li, G.; Mei, T. S.; Yu, J. Q. Nature 2012, 486, 518−522.
(17) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett. 2011,
13, 1028−1031.
(18) Qi, Q.; Shen, Q.; Lu, L. J. Am. Chem. Soc. 2012, 134, 6548−
6551.
(19) (a) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans. 1
1997, 2319−2328. (b) Ramsden, C. A.; Rose, H. L. J. Chem. Soc.,
Perkin Trans. 1 1995, 615−620.
(20) (a) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272−4277.
(b) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org. Lett. 2011, 13,
1194−1197. (c) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12,
3682−3685. (d) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem.,
Int. Ed. 2010, 49, 7790−7794.
(21) For reports on reductive elimination of N-arylamines or N-
arylimines from the putative aminyl or iminyl copper (III) species, see:
(a) Zhou, W.; Liu, Y.; Yang, Y.; Deng, G. J. Chem. Commun. 2012, 48,
10678−10680. (b) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9,
1947−1950. (c) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org. Lett.
2011, 13, 1194−1197.
(22) Cacci reported a similar Cu-catalyzed intramolecular C(sp2)−H
amination leading to 2-quinolinones under an air atmosphere:
(a) Berrino, R.; Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Org. Chem.
2012, 77, 2537−2542. For a recent review on copper-catalyzed C−N
bond formations, see: (b) Beletskaya, I. P.; Cheprakov, A. V.
Organometallics 2012, 31, 7753−7808.
K
dx.doi.org/10.1021/jo400162d | J. Org. Chem. XXXX, XXX, XXX−XXX