Radical Addition of Hydrazones by α-Bromo Ketones to Prepare 1,3,5-Trisubstituted Pyrazoles via Visible Light Catalysis

Article abstract of DOI:10.1021/acs.joc.6b00992

A novel efficient tandem reaction of hydrazones and α-bromo ketones is reported for the preparation of 1,3,5-trisubstituted pyrazoles by visible light catalysis. In this system, the monosubstituted hydrazones show wonderful reaction activity with alkyl radicals, generated from α-bromo ketones. A radical addition followed by intramolecular cyclization affords the important pyrazole skeleton in good to excellent yields. This efficient strategy under mild conditions with wide group tolerance provides a potential approach to the 1,3,5-trisubstituted pyrazoles.

Full text of DOI:10.1021/acs.joc.6b00992

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Article
Radical Addition of Hydrazones by alpha-Bromo Ketones to
Prepare 1,3,5-Trisubstituted Pyrazoles via Visible Light Catalysis
Xiu-Wei Fan, Tao Lei, Chao Zhou, Qing-yuan Meng, Bin Chen, Chen-Ho Tung, and Li-Zhu Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00992 • Publication Date (Web): 30 Jun 2016
Downloaded from http://pubs.acs.org on July 1, 2016
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Radical Addition of Hydrazones by αꢀBromo Ketones to Prepare
1,3,5ꢀTrisubstituted Pyrazoles via Visible Light Catalysis
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XiuꢀWei Fan†, Tao Lei†, Chao Zhou, QingꢀYuan Meng, Bin Chen, ChenꢀHo Tung, and
LiꢀZhu Wu*
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Key Laboratory of Photochemical Conversion and Optoelectronic Materials,
Technical Institute of Physics and Chemistry & University of Chinese Academy of
Sciences, the Chinese Academy of Sciences, Beijing 100190, P. R. China
†These authors contributed equally to this work.
*Eꢀmail: lzwu@mail.ipc.ac.cn
ABSTRACT: A novel efficient tandem reaction of hydrazones and αꢀbromo ketones
is reported to prepare 1,3,5ꢀtrisubstituted pyrazoles by visible light catalysis. In this
system, the monosubstituted hydrazones show wonderful reaction activity with alkyl
radicals, generated from αꢀbromo ketones. A radical addition followed by
intramolecular cyclization affords the important pyrazole skeleton in good to excellent
yields. This efficient strategy with mild condition and wide group tolerance provides a
potential approach to the 1,3,5ꢀtrisubstituted pyrazoles.
INTRODUCTION
Visible light photoredox catalysis has attracted wide attention in organic
synthesis due to its low cost, easy availability and environmental friendliness.1
Particularly, it features a unique ability to facilitate radical/polar crossover
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reactions via single electron transfer. Following this strategy, many kinds of
covalent bonds such as C=O, C=C, CꢀX even CꢀH have been activated into relative
radical intermediates by photocatalysis,2 and numerous significant chemical
conversions have been realized including radical addition, dehydrogen cross
coupling and cyclic reaction.3 Recently, Zhu and Hashni independently reported
visibleꢀlight photoredox catalyzed aminyl radical/polar crossover reaction to CꢀH
difluoroalkylation of aldehydeꢀderived hydrazones.4 They proposed that the
generated CF2 radical addition to the C=N bond leads to the aminyl radical
intermediate and then proceeds singletꢀelectron oxidation and deprotonation to
obtain the product (Scheme 1a). In their work, the disubstituted groups on nitrogen
are essential for the successful conversion, or complex byproducts would be
obtained if there was only one substitution. Herein, we report that the hydrazones
that own monosubstituted group can react with αꢀbromo ketones to construct
pyrazoles in an efficient way (Scheme 1b).
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Scheme 1. Radical addition to carbonꢀnitrogen π bonds
Pyrazoles, with a wide range of biological activities and pharmacological
properties,5 are important structural motifs widely existing in nature products6 and
synthetic biologically active compounds such as Celebrex, 7,5f Viagra.8 In addition,
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pyrazoles can be used as ligands of metallic complexes for carbonꢀcarbon coupling
reaction.9 Traditional strategies for 1,3,5ꢀtrisubstituted pyrazoles synthesis include:
oxidative aromatization of 1,3,5ꢀtriaryl pyrazolines,10 cyclocondensation of
hydrazines with 1,3ꢀdicarbonyl compounds,11 intramolecular CꢀN coupling of
acetylenic and alkenyl hydrazones.12 Despite these great advances, the synthetic
processes suffer from the use of toxic, expensive reagents and harsh reaction
conditions. The strategy presented here is very attractive, because it shows the
good to excellent yields of 1,3,5ꢀtrisubstituted pyrazole in mild condition, short
reaction time and good function group tolerance.
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RESULTS AND DICUSSION
We started our investigation by using (E)ꢀ1ꢀbenzylideneꢀ2ꢀphenylhydrazine
(1a) and αꢀbromoacetophenone (2a) as substrates (Table 1). Upon irradiation of 1a
(0.1 mmol), 2a (0.15 mmol), NaHCO3 (0.1 mmol) and Ir(ppy)3 (2 mol %) in 2 mL
DMSO with blue LEDs (λmax = 450 nm) under Ar atmosphere for 2 h, 80% yield of
3a was obtained (Table 1, entry 1). The good yield stimulated us to explore and
optimize the reaction conditions. Considering that DMSO is inconvenient in
workup, we screened other different solvents and found CH3CN as the best
medium for this conversion, which provide the target compound 3a in a 75% yield
(Table 1, entries 2ꢀ4). When NaHCO3 was replaced by K2CO3 and Na2CO3, the
yield became 71% and 80%, respectively (Table 1, entries 5ꢀ6). When the reaction
occurred in DMSO and Na2CO3, the product was achieved in 81% yield (Table 1,
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entry 7). Furthermore, the dosage of Na2CO3 and 2a were examined and found that
1 equivalent of Na2CO3 and 1.5 equivalent of 2a in the reaction could get the
7
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9
.
highest yield (Table 1, entries 8ꢀ11). However, Eosine and Ru(bpy)3Cl2 6H2O were
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inappropriate for this photoreaction (Table 1, entries 12ꢀ13), possibly due to
unfavorable redox potential1,13 of the two photocatalysts relative to substrate 2a.
Then different reaction concentrations were screened and found that 0.05 M of 1a
in the reaction is the best (Table 1, entries 14ꢀ15). Therefore, the optimized
reaction conditions were confirmed to be 0.1 mmol 1a, 0.15 mmol 2a, 1 equiv.
Na2CO3, and 2 mol% Ir(ppy)3 in 2 mL CH3CN with the irradiation of blue LEDs
under Ar atmosphere for 4 h.
Table 1. Optimization of the reaction conditiona
Ph
O
H
N
Br
N
N
2 mol% catalyst, h
Ph
N
Solvent, Base, rt, Ar, 4 h
Ph
1a
3a
2a
Entry
1c
Solvent
DMSO
Dioxane
Catalyst
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Eosine
Base (1eq)
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
Yield (%)b
80
51
<5
75
71
80
81
66
76
66
67
< 5
17
2
3
ClCH2CH2Cl
CH3CN
CH3CN
CH3CN
DMSO
4
5
6
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
7c
8d
9e
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10f
11g
12
13
.
Ru(bpy)3Cl2 6H2O
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14h
15i
16j
17
CH3CN
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
ꢀꢀꢀ
Na2CO3
70
77
0
CH3CN
CH3CN
CH3CN
Na2CO3
Na2CO3
Na2CO3
0
9
aReaction conditions: 0.1 mmol (E)ꢀ1ꢀbenzylideneꢀ2ꢀphenylhydrazine, 0.15 mmol
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αꢀbromoacetophenone, 2 mol% catalyst, and 1 equiv. base in 2 mL solvent irradiated by blue
b
1
LEDs under Ar for 4 h. Yields determined by H NMR using diphenylacetonitrile as an
c
d
e
internal standard. reaction time is 2 h. 0.5 equiv. of Na2CO3 was used. 2 equiv. of Na2CO3
f
g
h
was used. 1 equiv. of 2a was used. 2 equiv. of 2a was used. the reaction concentration is
0.025 M. i the reaction concentration is 0.1 M. in dark.
k
With the optimized reaction conditions in hand, we explored the scope of
hydrazones with αꢀbromoacetophenone as reaction partner, and the results were
summarized in Table 2. Various substituted benzylidene phenylhydrazones were
converted into the corresponding products in moderate to good yields. Comparison of
the yields of 3b, 3c and 3d indicated the slightly steric effect in phenyl group of R1
(Table 2, 3bꢀ3d). The different functional groups of pꢀsubstituted benzylidene showed
the electronic properties of the benzylidene phenylhydrazone substituents affected the
efficiency of the reaction (Table 2, 3eꢀ3j). The electronꢀwithdrawing substrates like F,
Cl and Br in phenyl group of R1 showed a higher reactivity than the electronꢀdonating
ones. Introducing CN group promoted the yield of relative product to 91%. When R1
was replaced by ester group, the reaction also has a good yield (Table 2, 3k). However,
the substitution of R2 decreased the reaction efficiency. The hydrazone with different
groups in phenyl group of R2 could generate corresponding products in a moderate
yields (Table 2, 3lꢀ3p). Satisfyingly, the Nꢀalkyl substituted hydrazine could get the
corresponding products in moderate yields as well (Table 2, 3qꢀ3r).
Table 2. Scope of substituted phenylhydrazonea
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N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
3c
, 63%
3d
, 71%
3a
, 81%
3b
, 67%
OCH3
F
Cl
N
N
N
N
N
N
N
N
Ph
Ph
Ph
3e
Ph
3f
, 60%
3h, 87%
, 69%
3g
, 81%
Br
CN
O
OEt
N
N
Ph
N
N
N
N
N
N
Ph
Ph
Ph
3j
, 91%
3i
, 82%
3l
, 65%
3k
, 54%
N
N
N
Ph
Ph
Ph
N
N
N
F
N
Ph
N
Br
3p
OCH3
, 79%
3m
, 67%
3o
, 72%
3n, 60%
N
Ph
N
N
N
Ph
b
3q
, 51%
3r
, 53%
aReaction conditions: 0.1 mmol (E)ꢀ1ꢀbenzylideneꢀ2ꢀphenylhydrazine, 0.15 mmol
αꢀbromoacetophenone, 2 mol% Ir(ppy)3, and 1 equiv. Na2CO3 in 2 mL CH3CN irradiated by blue
LEDs under Ar for 4 h. bOne pot reaction of methyldrazine sulphate, benzaldehyde and
αꢀbromoacetophenone. More details see Experimental Section.
Further experiments were performed to understand the reaction efficiency of
various αꢀbromo ketone derivatives (Table 3). A wide range of functional groups were
tolerated in this system. PꢀCH3, pꢀOCH3, pꢀF, pꢀCl, pꢀBr substituted
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αꢀbromoacetophenone and 2ꢀ(bromoacetyl) naphthalene could react with
(E)ꢀ1ꢀbenzylideneꢀ2ꢀphenylhydrazine to yield the products in moderate yields (Table
3, 3sꢀ3w, 3a’). Strong electronꢀwithdrawing group like pꢀCF3Ph and pꢀNO2Ph were
tolerated in this system (Table 3, 3vꢀ3y). To our surprise, the pꢀhydroxyl
αꢀbromoacetophenone could also react smoothly under the optimized condition to
yield the hydroxyl product in 50% yield (Table 3, 3z).
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Table 3. Scope of substituted αꢀbromo ketonea
Ph
H
O
2 mol% Ir(ppy)3, h
N
N
R3
N
Br
N
R3
CH3CN, Na2CO3, rt, Ar, 4 h
Ph
3
1
2a
aReaction conditions: 0.1 mmol (E)ꢀ1ꢀbenzylideneꢀ2ꢀphenylhydrazine, 0.15 mmol αꢀbromo
ketone, 2 mol% Ir(ppy)3, and 1 equiv. Na2CO3 in 2 mL CH3CN irradiated by blue LEDs under Ar
for 4 h.
Under optimized condition, the template reaction could get the product with
isolated yield of 81% at room temperature. When 2 equivalent 2,2,6,6ꢀtetramethyl
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piperidinꢀ1ꢀoxyl (TEMPO) was added, only 9% yield of target compound was
obtained (Scheme 2). Furthermore, an addition product 4a of acetophenone radical
and TEMPO was observed, with an isolated yield of 68%. This result demonstrated
that a radical procedure was involved in this system and the acetophenone radical
from 2a is the key intermediate.
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In order to elucidate more details about the reaction mechanism, the
spectroscopic experiments were carried out. UVꢀvis absorption spectra of these three
Ⅲ
compounds showed only Ir (ppy)3 could absorb visible light. When the photocatalyst
Ⅲ
Ir (ppy)3 was irradiated by the light of 405 nm, a strong emission in 529 nm was
Ⅲ
observed. Progressive addition of 1a or 2a into the solution of excited *Ir (ppy)3
demonstrated the quenching degree caused by 2a was much stronger than 1a (more
details see in SI). These results directly indicated the efficient interaction between 2a
Ⅲ
and excited Ir (ppy)3. According to the redox potential of 1a (Ered < −2.0 V vs. SCE
and Eox = 0.94 V vs. SCE), the electron transfer process between 1a and *Ir(ppy)3
(EIV/III* = −1.84 V vs. SCE, EIII*/II = 0.26 V)14 was less likely than that of 2a (Eox >1.6
V vs. SCE, Ered = −1.2 V vs. SCE).
Scheme 2. Control experiments
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On the basis of above results, a plausible mechanism was proposed in Scheme 3.
Under the irradiation of visible light, the photocatalyst Ir (ppy)3 is pumped to its
excited state *Ir (ppy)3. Then this excited species transfers one electron to 2a, which
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Ⅳ
+
leads to the generation of alkyl radical 2a• and Ir (ppy)3 . As a high electrophilic
specie, radical 2a• tends to react with the electronꢀrich hydrazine and produces the
Ⅳ
+
aminyl radical A. Further oxidation of A by Ir (ppy)3 affords intermediate B and
Ⅲ
regenerates Ir (ppy)3. To our delight, this intermediate B could further cyclize to
construct the pyrazole skeleton with mono Nꢀsubstituted hydrazone.
R3
R1
R3
intramolecular
cylization
O
HO
R2
N
N
N
R1
N
B
R2
C
Ir(ppy)3
-e-, -H+
R3
h
-H2O
O
H
*IIIIr(ppy)3
IVIr(ppy)3
+
N
R1
R2
N
R1
N
A
O
O
R3
Br
R3
R3
N
R2
H
R1
2a
Br
N
N
R2
2a
1a
3a
Scheme 3. Proposed mechanism
In conclusion, a novel oneꢀpot visible lightꢀpromoted singlet electron transfer
process has been developed for the facile synthesis of 1,3,5ꢀtrisubstituted pyrazoles
from easily accessible starting materials. The reaction has been demonstrated general
for a wide range of functional groups with electronꢀwithdrawing and
electronꢀdonating, such as nitro, nitrile and hydroxyl etc. in hydrazones and αꢀbromo
ketones. The good to excellent yields indicate the reaction potential of
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monosubstituted hydrazones in photocatalyzed radical addition. Such an approach
enriches photoredox reaction and represents a lower cost, milder, and greener process
for the synthesis of 1,3,5ꢀtrisubstituted pyrazoles.
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EXPERIMENTAL SECTION
General experimental procedure
1H and 13C NMR spectra were recorded with 400 MHz and 100 MHz NMR
instruments. Chemical shifts (δ, ppm) are given with tetramethylsilane (TMS) as an
internal standard. The coupling constants (J) were reported in hertz. Flash column
chromatography was performed over silica gel 200ꢀ300 mesh, and the eluent was a
mixture of ethyl acetate (EA) and petroleum ether (PE). High–resolution mass spectra
(HRMSꢀESI) were obtained on a QꢀTOF mass spectrometer. All the substituted
αꢀbromo ketones, benzaldehydes and phenylhydrazines hydrochloride salts were
purchased from commercial and used without further purification. All the substituted
phenylhydrazines obtained from neutralization reaction of corresponding
hydrochloride salts with sodium hydroxide in water and diethyl ether twoꢀphase
solution.
General Procedure for the Synthesis of Substituted Benzylidene
Phenylhydrazones 1. To a stirred solution of substituted phenylhydrazine (5.5 mmol)
in methanol (5 mL), benzaldehyde derivatives (5 mmol) were added dropwise. Then
stirring at room temperature until the conversion was complete (disappearance of
benzaldehydes, monitored by TLC). The solid was collected by filtration and washed
with cooled MeOH. Then dried to afford the product 1.
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General Procedure for the Synthesis of Pyrazoles. benzylidene phenylhydrazone
(0.1 mmol, 1 equiv.), αꢀbromo ketone (0.15 mmol, 1.5 equiv.), Na2CO3 (0.1 mmol, 1
equiv.) and Ir(ppy)3 (2 ꢁmol, 0.02 equiv.) were dissolved in CH3CN (2 mL) in a 10
mL pyrex tube equipped with a rubber septum and magnetic stir bar, and then the
argonꢀpurged solution was irradiated by blue LEDs (λmax = 450nm) at room
temperature for 4 h. The solvent was removed under reduced pressure after the
reaction was finished. Then the residue was purified by column chromatography on
silica gel eluting with ethyl acetate/petroleum ether to give the corresponding product.
The one pot synthesis of 3q: 0.1 mmol Methylhydrazine sulphate, 0.15 mmol
benzaldehyde, 2 equiv. Na2CO3 was dissolved in 1.5 mL CH3CN 10 mL in a pyrex
tube equipped with a rubber septum and magnetic stir bar. After the solution was
purged with argon and stirred for 1 h, the reaction solution was injected with 0.15
mmol αꢀbromoacetophenone in 0.5 mL CH3CN, and then irradiated by blue LEDs for
4 h.
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1,3,5-Triphenyl-1H-pyrazole (3a). Yield: 23.9 mg, 81%. White solid, m.p.
138ꢀ140 ℃. 1H NMR (400 MHz, CDCl3) δ = 7.96 (d, J = 7.7 Hz, 2H), 7.45 (t, J = 7.4
13
Hz, 2H), 7.42ꢀ7.29 (m, 11H), 6.85 (s, 1H). C NMR (100 MHz, CDCl3) δ = 152.0,
144.4, 140.2, 133.1, 130.6, 128.9, 128.8, 128.7, 128.5, 128.3, 128.0, 127.5, 125.9,
125.3, 105.2; HRMS (ESI) calcd. for C21H17N2 [M + H]+ 297.1386, found 297.1386.
1,5-Diphenyl-3-(p-tolyl)-1H-pyrazole (3b). Yield: 20.8 mg, 67%. White solid, m.p.
127ꢀ128 ℃. 1H NMR (400 MHz, CDCl3) δ = 7.82 (d, J = 7.6 Hz, 2H), 7.30 (m, 12H),
6.79 (s, 1H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 152.0, 144.3, 140.2, 137.8,
130.7, 130.2, 129.4, 128.9, 128.8, 128.5, 128.3, 127.4, 125.8, 125.3, 105.1, 21.3.
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HRMS (ESI) calcd. for C22H19N2 [M + H]+ 311.1543, found 311.1543.
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1,5-Diphenyl-3-(m-tolyl)-1H-pyrazole (3c). Yield: 19.5 mg, 63%. White solid, m.p.
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88ꢀ90 ℃. H NMR (400 MHz, CDCl3) δ = 7.80 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H),
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7.40ꢀ7.26 (m, 11H), 7.17 (d, J = 7.5 Hz, 1H) 6.83 (s, 1H), 2.43 (s, 3H). 13C NMR (100
MHz, CDCl3) δ = 152.1, 144.4, 140.2, 138.3, 132.9, 130.64, 128.9, 128.84, 128.78,
128.6, 128.5, 128.3, 127.5, 126.5, 125.4, 123.1, 105.3, 21.5. HRMS (ESI) calcd. for
C22H19N2 [M + H]+ 311.1543, found 311.1542.
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1,5-Diphenyl-3-(o-tolyl)-1H-pyrazole (3d). Yield: 21.9 mg, 71%. Colorless oil. H
NMR (400 MHz, CDCl3) δ = 7.71 (t, J = 3.8 Hz, 1H), 7.42ꢀ7.27 (m, 13H), 6.69 (s,
1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 152.4, 143.4, 140.1, 136.2, 132.8,
130.9, 130.7, 129.4, 128.9, 128.8, 128.5, 128.3, 127.9, 127.3, 125.9, 125.2, 108.3,
21.4. HRMS (ESI) calcd. for C22H19N2 [M + H]+ 311.1543, found 311.1543.
3-(4-Isopropylphenyl)-1,5-diphenyl-1H-pyrazole (3e). Yield: 23.3 mg, 69%.
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White solid. m.p. 101ꢀ102 ℃. H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 7.4 Hz,
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2H), 7.43ꢀ7.27 (m, 12H), 6.80 (s, 1H), 2.95 (m, 1H), 1.30 (s, 3H), 1.29 (s, 3H). C
NMR (100 MHz, CDCl3) δ = 152.1, 148.8, 144.3, 140.2, 130.7, 130.6, 128.9, 128.8,
128.5, 128.3, 127.4, 126.7, 125.9, 125.3, 105.1, 34.0, 24.0. HRMS (ESI) calcd. for
C24H23N2 [M + H]+ 339.1856, found 339.1856.
3-(4-Methoxyphenyl)-1,5-diphenyl-1H-pyrazole (3f). Yield: 19.7 mg, 60%. White
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solid, m.p. 143ꢀ144 ℃. H NMR (400 MHz, CDCl3) δ = 7.86 (d, J = 8.0 Hz, 2H),
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7.39–7.26 (m, 10H), 6.97 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 3.85 (s, 3H). C NMR
(100 MHz, CDCl3) δ = 159.7, 151.8, 144.4, 140.1, 130.6, 128.9, 128.8, 128.5, 128.3,
127.4, 127.2, 125.7, 125.3, 114.1, 104.8, 55.3. HRMS (ESI) calcd. for C22H19N2O [M
+ H]+ 327.1492, found 327.1491.
3-(4-Fluorophenyl)-1,5-diphenyl-1H-pyrazole (3g). Yield: 25.4 mg, 81%. White
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solid, m.p. 143ꢀ144 ℃. H NMR (400 MHz, CDCl3) δ = 7.90 (t, J = 6.72 Hz, 2H),
7.40ꢀ7.27 (m, 10H), 7.12 (t, J = 8.2 Hz, 2H), 6.78 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ = 162. 8 (d, J = 246.6 Hz), 151.1, 144.6, 140.1, 130.5, 129.3 (d, J = 3.2 Hz),
129.0, 128.7, 128.5, 128.4, 127.5 (d, J = 8.0 Hz), 127.5, 125.3, 115.6 (d, J = 21.6 Hz),
105.0. HRMS (ESI) calcd. for C21H16FN2 [M + H]+ 315.1292, found 315.1292.
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3-(4-Chlorophenyl)-1,5-diphenyl-1H-pyrazole (3h). Yield: 28.9 mg, 87%. White
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solid, m.p. 138ꢀ139 ℃. H NMR (400 MHz, CDCl3) δ = 7.86 (d, J = 7.6 Hz, 2H),
7.42ꢀ7.24 (m, 12H), 6.79 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 150.9, 144.6,
140.0, 133.8, 131.6, 130.4, 129.0, 128.8, 128.7, 128.5, 128.4, 127.6, 127.1, 125.3,
105.1. HRMS (ESI) calcd. for C21H16ClN2 [M + H]+ 331.0997, found 331.0996.
3-(4-Bromophenyl)-1,5-diphenyl-1H-pyrazole (3i). Yield: 30.8 mg, 82%. White
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solid, m.p. 152ꢀ154 ℃. H NMR (400 MHz, CDCl3) δ = 7.79 (d, J = 8.1 Hz, 2H),
7.54 (d, J = 8.1 Hz, 2H), 7.37ꢀ7.24 (m, 10H), 6.79 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ = 150.9, 144.7, 140.0, 132.1, 131.8, 130.4, 129.0, 128.8, 128.54, 128.45,
127.6, 127.4, 125.3, 122.0, 105.1. HRMS (ESI) calcd. for C21H16BrN2 [M + H]+
375.0491, found 375.0490.
4-(1,5-Diphenyl-1H-pyrazol-3-yl)benzonitrile (3j). Yield: 29.1 mg, 91%. Light
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yellow solid, m.p. 168ꢀ170 ℃. H NMR (400 MHz, CDCl3) δ = 8.02 (d, J = 7.7 Hz,
2H), 7.70 (d, J = 7.7 Hz, 2H), 7.39ꢀ7.31 (m, 8H), 7.28ꢀ7.24 (m, 2H), 6.86 (s, 1H). 13C
NMR (100 MHz, CDCl3) δ = 150.0, 145.0, 139.8, 137.5, 132.6, 130.1, 129.1, 128.8,
128.7, 128.6, 127.9, 126.2, 125.3, 119.1, 111.2, 105.6. HRMS (ESI) calcd. for
C22H16N3 [M + H]+ 322.1339, found 322.1337.
Ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate (3k). Yield: 15.8 mg, 54%. Yellow
oil. 1H NMR (400 MHz, CDCl3) δ = 7.38ꢀ7.27 (m, 8H), 7.21 (d, J = 7.4 Hz, 2H), 7.05
(s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ = 162.5, 144.7, 144.4 139.6, 129.6, 129.0, 128.8, 128.7, 128.6, 128.3, 125.8, 109.9,
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61.1, 14.4. HRMS (ESI) calcd. for C18H17N2O2 [M + H]+ 293.1285, found 293.1285.
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3,5-Diphenyl-1-(p-tolyl)-1H-pyrazole (3l). Yield: 20.3 mg, 65%. Colorless oil. H
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NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H),
7.36ꢀ7.23 (m, 8H), 7.14 (d, J = 7.7 Hz, 2H), 6.81 (s, 1H), 2.36 (s, 3H). 13C NMR (100
MHz, CDCl3) δ = 151.7, 144.3, 137.7, 137.4, 133.1, 130.7, 129.5, 128.7, 128.6, 128.5,
128.2, 128.0, 125.8, 125.2, 104.9, 21.1. HRMS (ESI) calcd. for C22H19N2 [M + H]+
311.1543, found 311.1543.
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3,5-Diphenyl-1-(m-tolyl)-1H-pyrazole (3m). Yield: 20.9 mg, 67%. White solid, m.p.
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72ꢀ73 ℃. H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.4
Hz, 2H), 7.34 (m, 7H), 7.20 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.05 (d, J =
7.8 Hz, 1H), 6.83 (s, 1H), 2.34 (d, J = 11.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ =
151.9, 144.4, 140.1, 139.1, 133.1, 130.7, 128.7, 128.64, 128.55, 128.4, 128.27, 128.25,
128.0, 126.0, 125.9, 122.5, 105.1, 21.4. HRMS (ESI) calcd. for C22H19N2 [M + H]+
311.1543, found 311.1543.
1-(4-Methoxyphenyl)-3,5-diphenyl-1H-pyrazole (3n). Yield: 19.6 mg, 60%. White
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solid, m.p. 109ꢀ111 ℃. H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.6 Hz, 2H),
7.43 (t, J = 7.4 Hz, 2H), 7.37ꢀ7.27 (m, 8H), 6.87 (d, J = 7.6 Hz, 2H), 6.82 (s, 1H),
3.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 158.9, 151.6, 144.4, 133.4, 133.1,
130.6, 128.7, 128.6, 128.5, 128.2, 127.9, 126.8, 125.8, 114.1, 104.7, 55.5. HRMS
(ESI) calcd. for C22H19N2O [M + H]+ 327.1492, found 327.1492.
1-(4-Fluorophenyl)-3,5-diphenyl-1H-pyrazole (3o). Yield: 22.3 mg, 72%. Light
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yellow solid, m.p. 107ꢀ108 ℃. H NMR (400 MHz, CDCl3) δ = 7.91 (d, J = 7.7 Hz,
2H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (m, 6H), 7.29ꢀ7.23 (m, 2H), 7.04 (t, J = 7.9 Hz,
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2H), 6.82 (s, 1H). C NMR (100 MHz, CDCl3) δ = 161.7 (d, J = 247.5 Hz), 152.1,
144.5, 136.3 (d, J = 3.0 Hz), 132.9, 130.4, 128.8, 128.7, 128.6, 128.5, 128.1, 127.1 (d,
J = 8.6 Hz), 125.8, 115.8 (d, J = 22.9 Hz), 105.2. HRMS (ESI) calcd. for C21H16FN2
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[M + H]+ 315.1292, found 315.1291.
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1-(4-Bromophenyl)-3,5-diphenyl-1H-pyrazole (3p). Yield: 29.5 mg, 79%. White
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solid, m.p. 100ꢀ101 ℃. H NMR (400 MHz, CDCl3) δ = 7.83 (d, J = 7.6 Hz, 2H),
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7.36 (m, 4H), 7.27 (m, 4H), 7.18 (m, 4H), 6.73 (s, 1H). 13C NMR (100 MHz, CDCl3)
δ = 152.3, 144.5, 139.2, 132.8, 132.0, 130.3, 128.8, 128.72, 128.69, 128.6, 128.2,
126.6, 125.9, 121.0, 105.7. HRMS (ESI) calcd. for C21H16BrN2 [M + H]+ 375.0491,
found 375.0490.
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1-methyl-3,5-diphenyl-1H-pyrazole (3q). Yield: 11.9 mg, 51%. Colorless oil. H
NMR (400 MHz, CDCl3) δ = 7.83 (d, J = 7.7 Hz, 2H), 7.51 – 7.43 (m, 5H), 7.41 (t, J
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= 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.61 (s, 1H), 3.93 (s, 3H). C NMR (100
MHz, CDCl3) δ = 150.5, 145.1, 133.3, 130.6, 128.8, 128.7, 128.63, 128.59, 127.7,
125.6, 103.3, 37.6. HRMS (ESI) calcd. for C16H15N2 [M + H]+ 235.1230, found
235.1226.
1-(Tert-butyl)-3,5-diphenyl-1H-pyrazole (3r). Yield: 14.7 mg, 53%. White solid,
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m.p. 110ꢀ112 ℃. H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 7.8 Hz, 2H), 7.45 –
7.33 (m, 8H), 7.27 (t, J = 6.4 Hz, 1H), 6.45 (s, 1H), 1.51 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ = 147.8, 144.0, 134.4, 134.0, 130.5, 128.5, 128.4, 127.8, 127.2, 125.5, 106.5,
61.5, 31.2. HRMS (ESI) calcd. for C19H21N2 [M + H]+ 277.1700, found 277.1700.
1,3-Diphenyl-5-(p-tolyl)-1H-pyrazole (3s). Yield: 22.8 mg, 73%. Yellow solid, m.p.
113ꢀ115 ℃. 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 7.5 Hz, 2H), 7.38 (m, 8H),
7.19 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.81 (s, 1H), 2.37 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ = 151.9, 144.5, 140.3, 138.3, 133.1, 129.2, 128.9, 128.7, 128.0,
127.7, 127.4, 125.9, 125.4, 105.0, 21.3. HRMS (ESI) calcd. for C22H19N2 [M + H]+
311.1542, found 311.1543.
5-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole (3t). Yield: 26.8 mg, 82%. White
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solid, m.p. 77ꢀ78 ℃. 1H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 7.7 Hz, 2H), 7.38
(m, 8H), 7.21 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.77 (s, 1H), 3.82 (s, 3H).
13C NMR (100 MHz, CDCl3) δ = 159.7, 151.9, 144.3, 140.2, 133.1, 130.1, 128.9,
128.6, 128.0, 127.4, 125.9, 125.4, 123.0, 114.0, 104.7, 55.3. HRMS (ESI) calcd. for
C22H19N2O [M + H]+ 327.1492, found 327.1492.
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5-(4-Fluorophenyl)-1,3-diphenyl-1H-pyrazole (3u). Yield: 20.5 mg, 65%. Yellow
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solid, m.p. 144ꢀ146 ℃. H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.5 Hz, 2H),
7.43 (t, J = 7.4 Hz, 2H), 7.38ꢀ7.30 (m, 6H), 7.24 (t, J = 6.3 Hz, 2H), 7.01 (t, J = 8.2
Hz, 2H), 6.79 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 162.7 (d, J = 248.8 Hz),
152.0, 143.4, 140.0, 133.0, 130.6 (d, J = 8.2 Hz), 129.0, 128.7, 128.1, 127.6, 126.8 (d,
J = 3.4 Hz), 125.8, 125.3, 115.6 (d, J = 21.7 Hz), 105.2. HRMS (ESI) calcd. for
C21H16FN2 [M + H]+ 315.1292, found 315.1292.
5-(4-Chlorophenyl)-1,3-diphenyl-1H-pyrazole (3v). Yield: 26.8 mg, 81%. White
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solid, m.p. 103ꢀ105 ℃. H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.7 Hz, 2H),
7.44 (t, J = 7.3 Hz, 2H), 7.41ꢀ7.28 (m, 8H), 7.21 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H). 13C
NMR (100 MHz, CDCl3) δ = 152.1, 143.2, 139.9, 134.4, 132.9, 130.0, 129.08, 129.05,
128.8, 128.7, 128.1, 127.7, 125.9, 125.4, 105.3. HRMS (ESI) calcd. for C21H16ClN2
[M + H]+ 331.0997, found 331.0997.
5-(4-Bromophenyl)-1,3-diphenyl-1H-pyrazole (3w). Yield: 27.7 mg, 74%. Yellow
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solid, m.p. 129ꢀ131 ℃. H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 7.6 Hz, 2H),
7.40 (m, 10H), 7.15 (d, J = 7.9 Hz, 2H), 6.83 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
= 152.1, 143.2, 139.9, 132.8, 131.8, 130.2, 129.5, 129.1, 128.7, 128.1, 127.7, 125.9,
125.4, 122.6, 105.3. HRMS (ESI) calcd. for C21H16BrN2 [M + H]+ 375.0491, found
375.0492.
1,3-Diphenyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (3x). Yield: 21.3 mg,
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58%. White solid, m.p. 154ꢀ156 ℃. 1H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 7.7
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Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.49ꢀ7.34 (m, 10H), 6.89 (s, 1H). C NMR (100
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MHz, CDCl3) δ = 152.2, 142.9, 139.7, 134.0, 132.7, 130.3 (q, J = 32.4 Hz), 129.2,
128.9, 128.7, 128.3, 127.9, 125.9, 125.5 (q, J = 19.0 Hz), 125.4, 123.9 (q, J = 272.2
Hz), 105.8. HRMS (ESI) calcd. for C22H16F3N2 [M + H]+ 365.1260, found 365.1259.
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5-(4-Nitrophenyl)-1,3-diphenyl-1H-pyrazole (3y). Yield: 21.8 mg, 64%. White
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solid. m.p. 136ꢀ137 ℃. H NMR (400 MHz, CDCl3) δ = 8.18 (d, J = 7.8 Hz, 2H),
7.92 (d, J = 7.6 Hz, 2H), 7.49ꢀ7.33 (m, 10H), 6.95 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ = 152.4, 147.3, 142.0, 139.6, 136.7, 132.5, 129.33, 129.27, 128.8, 128.4,
128.2, 125.8, 125.5, 123.8, 106.3. HRMS (ESI) calcd. for C21H16N3O2 [M + H]+
342.1237, found 342.1237.
4-(1,3-Diphenyl-1H-pyrazol-5-yl)phenol (3z). Yield: 15.5 mg, 50%. White solid.
m.p. 221ꢀ223 ℃. 1H NMR (400 MHz, Acetoneꢀd6) δ = 8.62 (s, 1H), 7.93 (d, J = 7.6
Hz, 2H), 7.43ꢀ7.27 (m, 8H), 7.13 (d, J = 7.4 Hz, 2H), 6.89 (s, 1H), 6.80 (d, J = 7.5 Hz,
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2H). C NMR (100 MHz, d6ꢀAcetone) δ = 157.7, 151.3, 144.6, 140.7, 133.6, 130.1,
128.8, 128.5, 127.7, 127.2, 125.5, 125.1, 121.9, 115.4, 104.4. HRMS (ESI) calcd. for
C21H17N2O [M + H]+ 313.1335, found 313.1335.
5-(Naphthalen-2-yl)-1,3-diphenyl-1H-pyrazole (3a’). Yield: 27.8 mg, 80%. White
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solid. m.p. 102ꢀ103 ℃. H NMR (400 MHz, CDCl3) δ = 7.98 (d, J = 7.6 Hz, 2H),
7.88ꢀ7.74 (m, 4H), 7.54ꢀ7.41 (m, 6H), 7.34 (m, 5H), 6.95 (s, 1H). 13C NMR (100
MHz, CDCl3) δ = 152.1, 144.4, 140.2, 133.1, 133.0, 132.9, 129.0, 128.7, 128.2,
128.10, 128.06, 128.01, 127.98, 127.7, 127.5, 126.7, 126.6, 126.3, 125.9, 125.3, 105.6.
HRMS (ESI) calcd. for C25H19N2 [M + H]+, 347.1543, found 347.1543.
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5-methyl-1,3-diphenyl-1H-pyrazole (3b’). Yield: 16.8 mg, 72%. Colorless oil. H
NMR (400 MHz, CDCl3) δ = 7.93 – 7.84 (m, 2H), 7.57 ꢀ 7.46 (m, 4H), 7.40 (q, J =
7.6 Hz, 3H), 7.32 (t, J = 7.3 Hz, 1H), 6.54 (s, 1H), 2.39 (s, 3H). 13C NMR (100 MHz,
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CDCl3) δ = 151.7, 140.23, 140.18, 133.6, 129.2, 128.6, 127.8, 127.7, 125.9, 125.1,
104.5, 12.6. HRMS (ESI) calcd. for C16H15N2 [M + H]+, 235.1230, found 235.1233.
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1-Phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (4a). Yield: 17.3 mg,
68%. Colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 7.6 Hz, 2H), 7.56 (t,
J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 5.12 (s, 2H), 1.57 (dd, J = 19.5, 7.8 Hz, 1H),
1.52 – 1.44 (m, 4H), 1.37 – 1.30 (m, 1H), 1.19 (m, 12H). 13C NMR (100 MHz, CDCl3)
δ = 195.8, 135.5, 133.2, 128.6, 128.0, 81.4, 60.2, 39.8, 32.8, 20.3, 17.1. HRMS (ESI)
calcd. for C17H26NO2 [M + H]+ 276.1958, found 276.1957.
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SUPPORTING INFORMATION
1
Copies of H and 13C NMR spectra for all products, the UVꢀvis absorption spectra of
Ir(ppy)3, 1a and 2a and steady state emission quenching spectra of excited *Ir(ppy)3
by 1a or 2a. This material is available free of charge via the internet at
http://pubs.acs.org.
ACKNOWLEDGMENTS
We are grateful for financial support from the Ministry of Science and Technology of
China (2013CB834804 and 2013CB834505), the National Natural Science
Foundation of China (21390404, 91427303, and 21402217), Strategic Priority
Research Program of the Chinese Academy of Science (XDB17030200), and the
Chinese Academy of Sciences.
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