'One-pot' synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylates via lithium tert-butoxide-mediated sterically hindered Claisen condensation and Knorr reaction

Article abstract of DOI:10.1016/j.tet.2012.11.012

A concise 'one-pot' synthesis of a variety of 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylates has been developed in moderate to good yields with excellent regioselectivity. Less cost lithium tert-butoxide has been identified as a base for sterically hindered Claisen condensation to efficiently generate the labile 3-substituted 4-aryl-2,4-diketoesters. Furthermore, extensive studies lead to a 'one-pot' process by combination of the Claisen condensation and the Knorr reaction for the synthesis of highly valuable 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylates.

Full text of DOI:10.1016/j.tet.2012.11.012

Tetrahedron 69 (2013) 627e635
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
‘One-pot’ synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3-
carboxylates via lithium tert-butoxide-mediated sterically hindered
Claisen condensation and Knorr reaction
,b,
Jian-An Jiang a, Wei-Bin Huang a, Jiao-Jiao Zhai a, Hong-Wei Liu a, Qi Cai a, Liu-Xin Xu a, Wei Wang a
*
,
,
Ya-Fei Ji a
*
a School of Pharmacy, East China University of Science & Technology, Campus P.O. Box 363, 130 Meilong Road, Shanghai 200237, PR China
b Department of Chemistry & Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise ‘one-pot’ synthesis of a variety of 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylates has been
developed in moderate to good yields with excellent regioselectivity. Less cost lithium tert-butoxide has
been identified as a base for sterically hindered Claisen condensation to efficiently generate the labile
3-substituted 4-aryl-2,4-diketoesters. Furthermore, extensive studies lead to a ‘one-pot’ process by
combination of the Claisen condensation and the Knorr reaction for the synthesis of highly valuable
4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylates.
Received 14 September 2012
Received in revised form 27 October 2012
Accepted 2 November 2012
Available online 8 November 2012
Keywords:
Lithium tert-butoxide
Ó 2012 Elsevier Ltd. All rights reserved.
Sterically hindered Claisen condensation
3-Substituted 4-aryl-2,4-diketoesters
Knorr reaction
4-Substituted 1,5-diaryl-1H-pyrazole-3-
carboxylates
1. Introduction
a general and efficient approach to create 4-substituted 1,5-diaryl-
1H-pyrazole-3-carboxylates.
Pyrazoles have a rich chemistry with numerous applications.1e6
Of these, particularly interesting to medicinal chemists are highly
substituted pyrazoles, which constitute the core structures of clin-
ically used drugs, such as Celebrex,7 Viagra,8 and Rimonabant,9 as
well as many developing molecules across a wide spectrum of
therapeutic areas including anti-inflammation,10 analgesia,10b,11
anti-infection,12 and anti-cancer.13 These factors have assured
a continually increasing attention on the synthesis of functionalized
pyrazole derivatives and their biological explorations.10e14 Notably,
the recent discoveries in 4-substituted 1,5-diaryl-1H-pyrazole-3-
carboxylate derivatives as cannabinoid-1 (CB1) receptor antago-
There have been two prevalent strategies for constructing 4-
substituted 1,5-diaryl-1H-pyrazole-3-carboxylates deriving from
Knorr reaction15a,b,d,e,g,i and 1,3-dipolar cycloaddition of 2-chloro-2-
(2-aryl-hydrazono)acetates with 1-aryl-1-enamines.15l The Knorr
reaction involving a [3þ2]-cyclization between 3-substituted 4-
aryl-2,4-diketoesters and arylhydrazines has proven to be more ef-
fective in terms of convenience and versatility.15a,b,d,e,g,i,19 However,
the main limitation of this reaction relies on the use of non-readily
accessible 3-substituted 4-aryl-2,4-diketoesters. These versatile
2,4-diketoesters are also pivotal in the synthesis of pharmaceutically
significantheterocycles; yet theirmild and cost-effective synthesisis
rare. The most straightforward synthesis of 3-substituted 4-aryl-2,4-
diketoesters is the employment of the base-mediated Claisen con-
densation of alkylphenones with diethyl oxalate.15b,d,e,i,16b However,
the steric hindrance of the alkyl groups often leads to low chemical
yields in sodium ethoxide-mediated procedure (Scheme 1(a)).15b,16b
Therefore, a much stronger base lithium hexamethyldisilazide
(LiHMDS) has been frequently employed to effectively execute
a sterically hindered Claisen condensation (SHCC).15d,e,i Although
yields generally improve, the troublesome operation and high costof
nist,15 Ikb kinase or IKK-2) inhibitor,16a analgesic,16b and anti-
b (IKKb
inflammatory agent16b,c prompted us to explore a sustainable
chemistry-oriented synthesis17 tothe fullysubstituted 1H-pyrazole-
3-carboxylates. As our continuing efforts toward ‘one-pot’ synthesis
of functionalized heterocycles,18 in this context, we wish to report
* Corresponding authors. Tel./fax: þ86 21 6425 3314; e-mail addresses: wwang@
unm.edu (W. Wang), jyf@ecust.edu.cn (Y.-F. Ji).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.012

628
J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
of concomitants
3 and 4 to the well-studied retro-Claisen
reaction22 and a rare self-Claisen condensation process, respectively
(Scheme 3). Ethoxide anion attacking 40-carbonyl group of the re-
sultant 2 of the Claisen condensation triggers a retro-Claisen re-
action to yield 3 and 2-ketoester anion intermediates. Surprisingly,
the intermediates, not detected, were converted into 4 by a self-
Claisen condensation under the reaction conditions. These in-
vestigations suggest that a base not only plays an important role in
the product formation but also has a pronounced impact on stability
of product(s). Therefore, LiHMDS has often been used as a favorable
base in SHCC.15d,e,i We hypothesized that surrogates for sodium
ethoxide and LiHMDS might offer an opportunity to identify a suit-
able base for the preparation of 2 efficiently and sustainably.
Scheme 1. Base-mediated SHCC of alkylphenones with diethyl oxalate.
LiHMDS inevitably limit the procedure on large-scale preparation
(Scheme 1(b)).
Accordingly, development of a mild SHCC using robust and low
cost base for 3-substituted 4-aryl-2,4-diketoesters becomes es-
sential, but still remains a challenge. Toward this end, herein, we
wish to report a concise ‘one-pot’ procedure, which comprises
lithium tert-butoxide-mediated SHCC of alkylphenones with
diethyl oxalate, and subsequent Knorr reaction of the resulting 2,4-
diketoesters with arylhydrazines, to construct a wide range of fully
substituted 1H-pyrazole-3-carboxylates (Scheme 2). Notably, cy-
clization of the diketoesters generated in situ and arylhydrazines
effectively leads to the desired 1H-pyrazole-3-carboxylates in
moderate to good yields with excellent regioselectivity. The ready
availability of reactants, the employment of robust and cost-
effective lithium tert-butoxide,20 as well as high yields make this
procedure particularly appealing for synthesis of the pharmaceu-
tically relevant pyrazole compounds with highly structural di-
versity (alkyl, two or three aryl and carboxyl functionalities).
Scheme 3. A proposed reaction pathway for sodium ethoxide-mediated SHCC.
2.2. Substrate generality of the lithium tert-butoxide-medi-
ated SHCC
Scheme 2. A ‘one-pot’ procedure to construct fully substituted 1H-pyrazole-3-
carboxylates.
Given the fact that LiHMDS functions as both a strong base and an
oxygenphilic reagent to bring about enolated six-membered cyclic
lithium salts15d,i based on stronger affinity of lithium with oxygen
than sodium and potassium,23 t-BuOLi should improve the effi-
ciency of SHCC. Indeed, desired 2a was exclusively obtained in
a yield of 95% under the optimized reaction conditions: 5.0 mmol
alkylphenones, 6.0 mmol diethyl oxalate, and 6.5 mmol t-BuOLi at
room temperature for 4 h (Table 2, entry 1). We then examined the
scope of the lithium tert-butoxide-mediated SHCC. It was found that
it serves as a general strategy for the preparation of structurally
diverse 3-substituted 4-aryl-2,4-diketoesters 2 (Table 2). The
electron-deficient propiophenones 1b and 1e with chlorine atom at
the para- or meta-position smoothly formed 2b and 2e in good
yields (82% and 86%, respectively, entries 2 and 5). The same trend
was observed for electron-rich 1c and 1d containing methyl or
methoxyl group on the benzene ring (85% and 84%, respectively,
entries 3 and 4).
2. Results and discussion
2.1. Investigation of sodium ethoxide-mediated SHCC
It is well known that the yield of sodium ethoxide-mediated
SHCC is low.15b,16b To shed new light on the nature of the sodium
ethoxide-mediated SHCC, we investigated three model reactions of
representative alkylphenones 1 and diethyl oxalate (Table 1), by
following the EtONa procedure described by Zhang and co-work-
ers.15b These reactions uniformly generated unexpected benzoates 3
and triketoesters 421 as major products, whereas the originally
desired 222 was obtained in low yields (20e38%). The results again
clearly showed that sodium ethoxide-mediated SHCC is difficult
to achieve 2 in yield at a useful level. We attributed the formation
Table 1
Sodium ethoxide-mediated SHCCa
A difficult challenge for the synthesis of 3-substituted 4-aryl-2,4-
diketoesters is the steric hindrance. The size of the substituents (R1)
at C2 position of alkylphenones has a significant influence on the
reaction. The studies have shown that the relatively smaller methyl
group could participate in the process smoothly (entry 1). We fur-
ther examined the influence of larger R1 of chain alkylphenones
1fei. It was found that the corresponding steric hindrance expressed
a powerful impact on reactionyields. For example, n-butyrophenone
(1f), n-valerophenone (1g) and isovalerophenone (1h) gave rise to
2f, 2g, and 2h in yields of 69%, 58%, and 52%, respectively (entries
6e8). What is more, for 2-phenyl-1-p-tolylethanone (1i) with bulky
phenyl group at C2 position, the sterically more hindered product 2i
Entry
R1
R2
2 (Yieldb)
3 (Yieldb)
4 (Yieldb)
1
2
3
Me
Et
n-Pr
H
H
H
2a (38%)
2f (23%)
2g (20%)
3a (45%)
3a (63%)
3a (62%)
4a (43%)
4f (62%)
4g (61%)
a
Reactions were performed in an oven-dried vial with alkylphenones
1
(5.0 mmol), diethyl oxalate (6.5 mmol), and sodium ethoxide (10.0 mmol) in
anhydrous ethanol (15 mL) at room temperature for 24 h.
b
Isolated yields via column chromatography.

J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
629
Table 2
nearly quantitative yields (entries 11e13). With regard to the par-
tially rigid aromatic cycloketones (e.g., 1-benzocyclopentanones, 1-
tetralones and 1-benzosuberones), the Claisen condensations could
be implemented with good yields even in the presence of EtONa.15a
It is reasonably understood that such stable cycloketone structures
of 2kem inherently suppress potential decomposition. Thus, we
concluded that the SHCC is more suitable for defining the con-
densation pattern of chain alkylphenones (except acetophenone).
In general, t-BuOLi instead of LiHMDS can equally efficiently ac-
complish SHCC for 2.
Substrate generality of lithium tert-butoxide-mediated SHCCa
Entry
1
1
2
Yieldb (%)
95
2.3. Further insight for the Knorr reaction
2
3
4
82
85
84
Having established an efficient protocol for 3-substituted 4-aryl-
2,4-diketoesters, we made our efforts on the construction of 4-
substituted 1,5-diaryl-1H-pyrazole-3-carboxylates 6 (1,5-isomers)
from freshly prepared 2 and arylhydrazines 5 via Knorr reaction
(Table 3). The diketoesters 2a, 2b, and 2f were converted into the
desired 1,5-isomers 6aa, 6ab, 6bd, and 6fa in the yields of 60e66%.
Meanwhile, N-arylhydrazones 7aa, 7ab, 7bd, and 7fa were obtained
in the yields of 24e31%. These facts support a mechanism starting at
the attack of arylhydrazines at more active 20-carbonyl group of 2
followed by an intramolecular dehydrating cyclization.24e26 With
the 1,5-isomer overwhelmingly exceeding 4-substituted-1,3-diaryl-
1H-pyrazole-5-carboxylate (1,3-isomer) in a 33/1 ratio detected by
1H NMR for 6ab (entry 2),27 indeed, the Knorr reactions fulfill ex-
cellent regioselectivity to 1,5-isomers. The previous report has un-
equivocally confirmed the proximity of the two aromatic rings in
the 1,5-isomer by a nuclear Overhauser effect (NOE) interaction.26
Furthermore, our 1H NMR spectra demonstrated that 7 were com-
posed of comparable E/Z-isomers, while Z-isomers were considered
impossible for intramolecular dehydrating cyclization.26
5
86
6
7
8
69
58
52
Table 3
Knorr reactions of some representative 2 and 5a
9
dc
10
11
12
98
97
96
Entry
R1
R2
R3
6 (Yieldb)
7 (Yieldb)
1
2
3
4
Me
Me
Me
Et
H
H
4-Cl
H
H
6aa (60%)
7aa (31%)
7ab (26%)
7bd (27%)
7fa (24%)
4-Cl
2,4-Cl2
H
6ab (65%, 33/1c)
6bd (66%)
6fa (61%)
a
Reactions were performed in an oven-dried vial with freshly prepared
3-substituted 4-aryl-2,4-diketoesters 2 (4.0 mmol) and arylhydrazines 5 (4.0 mmol)
in glacial acetic acid (8 mL) at reflux for 12 h.
b
Isolated yields via column chromatography.
c
Ratio of 1,5-isomer/1,3-isomer determined by 1H NMR.
13
97
A plausible mechanism (Scheme 4) for the formation of 6aa was
proposed. Initially, under acidic conditions, the reaction begins with
an attack of more nucleophilic NH2 of 5a at the more electrophilic
20-carbonyl group of 2a,25 or a conjugate addition of terminal ni-
trogen of 5a with the acid-promoted enolate of 2a,28 followed by
a rapid acid-catalyzed dehydration irreversibly to result in E/Z-7aa,
of which E-7aa having geometrically closeness of NH and 40-car-
bonyl group can be cyclized into 6aa. Meantime, acetic acid prob-
ably undertakes another role to convert noncyclizable Z-7aa into
cyclizable E-7aa via E/Z-enamine intermediates arising from an
acid-promoted double bond-migration. Accordingly, the regen-
erated E-7aa from Z-7aa was again transformed into 6aa. Therefore,
the yield of Knorr reaction largely depends on a conversion of
noncyclizable Z-7 into cyclizable E-7.
a
The reactions were performed in an oven-dried vial with alkylphenones 1
(5.0 mmol), diethyl oxalate (6.0 mmol), and t-BuOLi (6.5 mmol) in anhydrous THF
(15 mL) at room temperature for 4 h.
b
Isolated yields via column chromatography.
No product obtained for its instability.
c
is difficult to reach owing to its instability under the reaction
conditions (entry 9), albeit the product 2i could be observed with
TLC monitoring. Indeed, acetophenone (1j) with no substituent at C2
position gave enolated diketoesters 2j with nearly quantitative yield
(entry 10).
In contrast, benzocyclohexanones 1kem displayed excellent
outcomes for the formation of enolated diketoesters 2kem in

630
J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
Table 4
Substrate generality of the ‘one-pot’ procedure
Entrya
1
1
5
6
Ratiob (1,5-/1,3-)
Nod
Yieldc (%)
75
1a
6aa
2
3
1a
1a
6ab
6ac
33/1
No
76
78
4
5
1a
1a
6ad
6ae
18/1
No
78
60
Scheme 4. A plausible mechanism for the Knorr reaction.
6
7
1a
1a
6af
14/1
No
77
77
2.4. Optimization of the Knorr reaction and exploration of
‘one-pot’ procedure
6ag
To further improve efficiency of the Knorr reaction, materials 2a
and 5a were chosen to explore optimum conditions for the prep-
aration of 6aa. Control experiments revealed that the desired 6aa
was achieved in a higher yield of 76% (vs 60%, Table 3, entry 1) when
2a reacted with equimolar 5a in glacial acetic acid at reflux for 8 h,
followed by a treatment of 2.0 equiv of acetyl chloride for another
8 h. On the one hand, the addition of acetyl chloride would use up
all water generated in the reaction to facilitate the formation of 6aa.
On the other hand, it is likely that the resulting hydrogen chloride
further propels Z-7aa into E-7aa to increase the yield of 6aa.
Nonetheless, the isolation of unstable 2 still brings about some
disadvantages to decrease the applicability of the Knorr reaction.
With the insights to the SHCC and Knorr reaction in mind, we
sought to combine two descrete reaction steps into a ‘one-pot’
fashion. Thus, we achieved an optimized ‘one-pot’ procedure in
terms of the model reaction for 6aa. The reaction of 1a (1.0 equiv),
diethyl oxalate (1.2 equiv) and t-BuOLi (1.3 equiv) was performed in
THF at room temperature for 4 h to completely transform 1a into
the lithium salt of 2a. Upon removal of THF, glacial acetic acid, and
5a (1.0 equiv) were added to carry out the following condensation
of 2a and 5a at reflux for 8 h. Then, addition of 2.0 equiv of acetyl
chloride, the reaction proceeded another 8 h in order at reflux. Fi-
nally, the desired 6aa was obtained in 75% yield, indicating a fa-
vorable increase by comparison with the total yield of 72% for the
discrete steps (95% (Table 2, entry 1)ꢀ76%).
8
9
1a
1a
6ah
6ai
22/1
No
76
51
10
11
12
13
14
1a
1a
1a
1a
1a
6aj
No
No
No
No
No
72
73
73
67
72
6ak
6al
6am
6an
15
16
17
18
19
20
21
22
1b
1c
1d
1e
1f
1g
1h
1i
5a
5a
5a
5a
5a
5a
5a
5a
6ba
6ca
6da
6ea
6fa
6ga
6ha
6ia
No
No
No
No
No
No
No
No
62
69
71
67
61
52
48
47
2.5. Substrate generality of the ‘one-pot’ procedure for 4-
substituted 1,5-diaryl-1H-pyrazole-3-carboxylates 6
With the established ‘one-pot’ procedure in hand, we in-
vestigated the scope for the synthesis of 6 with commercially
available 1 and 5 (Table 4). First, compounds 5aen bearing various
electronic properties of substituents at benzene ring were used to

J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
631
Table 4 (continued )
reaction. The cost-effective process possesses two notable features:
(i) the use of inexpensive, robust, safe, and easier-to-handle t-BuOLi
in place of LiHMDS to conduct SHCC reaction; (ii) no need to isolate
intractable 2 to achieve the valuable pyrazole compounds in a ‘one-
pot’ manner. The synthetic versatility and pharmaceutical impor-
tance of 2 and 6 greatly highlight the usefulness of this methodology.
We believe that this operationally simple protocol holds application
potential in the field of organic synthesis and medicinal chemistry.
Entrya
1
5
6
Ratiob (1,5-/1,3-)
Yieldc (%)
23
24
25
26
1j
1k
1l
5a
5a
5f
6ja
6ka
6lf
No
No
No
No
91
90
87
92
1m
5a
6ma
a
Reactions were performed in an oven-dried vial with alkylphenones
1
(5.0 mmol), diethyl oxalate (6.0 mmol), t-BuOLi (6.5 mmol), arylhydrazines 5
(5.0 mmol), anhydrous THF (15 mL), glacial acetic acid (10 mL), and then acetyl
chloride (10 mmol) following the typical ‘one-pot’ procedure.
4. Experimental section
4.1. General methods
b
Ratios of 1,5-/1,3-isomer determined by 1H NMR.
Isolated yields via column chromatography.
No 1,3-isomer observed.
c
d
evaluate the generality of arylhydrazines (entries 1e14). Compared
to electron-neutral 5a, a feebly beneficial influence of 5bed and
5feh on chemical outcomes was generally displayed with the
yields of 76e78% for 6abead and 6afeah (entries 2e4, 6e8) by
changing the nature and number of electron-withdrawing sub-
stituent with chlorine, fluorine or nitro group(s). However, aryl-
hydrazines bearing electron-donating methyl or ethyl group(s) on
benzene ring conversely gave the products 6ajeal and 6an in
slightly low yields of 72e73% (entries 10e12 and 14). It should be
also noted that, despite of the electronic effect of substituents, the
di-ortho-substituted steric hindrance of 5e and 5m delivers a strong
impact on the products 6ae and 6am in low yields of 60% and 67%,
respectively (entries 5 and 13). Furthermore, the reduced yield of
51% for 6ai appeared in the case of 5i with nitro group at ortho-
position (entry 9). We reasoned that the conceivable intramolecular
NH/O2N hydrogen bond as well as decreased nucleophilicity of NH
by NO2 block the cyclization in the Knorr reaction.29 Again it is
suggested that the influence on the efficiency of the ‘one-pot’
procedure might be more expected from steric effect.
On the basis of the aforementioned substrate generality of the
lithium tert-butoxide-mediated SHCC (Table 2), a variety of alkyl-
phenones were again investigated to evaluate the scope of 1 in the
‘one-pot’ procedure (Table 4, entries 15e26). In comparison with 1a
(entry 1), the substituted propiophenones 1bee with electron-
withdrawing or electron-donating group at benzene ring all reac-
ted smoothly to provide 6baeea in respected yields of 62e71%
(entries 15e18). Again we witnessed the steric effect associated
with C2 position of chain alkylphenones. For instance, chain
alkylphenones 1fei afforded the corresponding 6fa, 6ga, 6ha, and
6ia, in relatively lower yields of 61%, 52%, 48%, and 47%, respectively
(entries 19e22). However, it should be noted that the ‘one-pot’
procedure can achieve sterically overcrowded 1,4,5-triaryl-1H-
pyrazole-3-carboxylate 6ia (entry 22), which would be inaccessible
by discrete protocol due to the inaccessibility of precursor 2i (Table
2, entry 9). In addition, very high yields were obtained with ace-
tophenone (1j) and benzocyclohexanones 1kem in the ‘one-pot’
process (Table 4, entries 23e26, 91%, 90%, 87%, and 92%, re-
spectively) based on the excellent results of the above stepwise
approach (Table 2, entries 10e13, 2jem). Finally, critically the ‘one-
pot’ procedure offered excellent regioselectivity to the desired 6
without 1,3-isomer observed in most of cases. High regioselectivity
(33/1, 18/1, 14/1, and 22/1 of 1,5-/1,3-isomer ratios detected by 1H
NMR, respectively) for 6ab, 6ad, 6af, and 6ah was also observed
(Table 4, entries 2, 4, 6, and 8).
Unless otherwise indicated, all reagents were obtained from
commercial sources and used as received without further purifi-
cation. All reactions were carried out in oven-dried glassware and
monitored by thin layer chromatography (TLC, pre-coated silica gel
ꢀ
plates containing HF254). All solvents were only dried over 4 A
molecular sieves. Reaction products were purified by silica gel
column chromatography with elution of petroleum ether/ethyl
acetate. Melting points were determined using an open capillaries
and uncorrected. NMR spectra were determined on Bruker AV400
in CDCl3 with TMS as internal standard for 1H NMR (400 MHz) and
13C NMR (100 MHz), respectively. MS were recorded on Micromass
GCTTM gas chromatograph-mass spectrometer. HRMS were carried
out on a QSTAR Pulsar I LC/TOF MS mass spectrometer and
Micromass GCTTM gas chromatograph-mass spectrometer.
4.2. General ‘one-pot’ procedure for the preparation of ethyl 4-
substituted 1,5-diaryl-1H-pyrazole-3-carboxylates 6 (Table 4)
An oven-dried vial equipped with a stir bar was charged with
a mixture of lithium tert-butoxide (0.52 g, 6.5 mmol) and diethyl
oxalate (0.88 g, 6.0 mmol) in anhydrous THF (10 mL), and the
mixture was then stirred at 0 ꢁC under a nitrogen atmosphere. Ten
minutes later, a solution of alkylphenones 1 (5.0 mmol) in anhy-
drous THF (5 mL) was added dropwise to the mixture, and the
resulting mixture was allowed to stir at room temperature for 4 h.
After completion of the reaction as monitored by TLC, the mixture
was concentrated to remove THF giving a residual. Glacial acetic
acid (10 mL) and arylhydrazines 5 (5.0 mmol) were added to the
residual at room temperature, followed by reflux for 8 h. Then to
the reaction solution was added acetyl chloride (0.78 g, 10.0 mmol),
and stirred at reflux for another 8 h. Next, the solution was con-
centrated in vacuo to remove glacial acetic acid affording a residual,
to which were added water (10 mL) and methylene chloride
(15 mL) to make the solution partitioned into organic and aqueous
layers. The aqueous layer was extracted with methylene chloride
(10 mLꢀ2). Finally, the combined organic phase was washed with
water (20 mLꢀ2), dried over anhydrous sodium sulfate, and con-
centrated to give a crude oil, which was purified by column chro-
matography (200e300 mesh silica gel, petroleum ether/ethyl
acetate 10:1) to offer the corresponding 6.
4.2.1. Ethyl 1,5-diphenyl-4-methyl-1H-pyrazole-3-carboxylate
(6aa).30 Yellow solid, 1.15 g (75% yield), mp 104e106 ꢁC (lit.30 mp
105e106 ꢁC); 1H NMR (400 MHz, CDCl3, ppm):
d 7.38e7.35 (m, 3H),
7.30e7.22 (m, 5H), 7.17e7.14 (m, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.33 (s,
3. Summary
3H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.2,
142.2, 142.1, 139.6, 130.1 (2C), 129.6, 128.8 (2C), 128.6, 128.5 (2C),
127.8, 125.4 (2C), 119.9, 60.8, 14.5, 9.7; MS (EI): m/z (%)¼306.1 (93)
[Mþ], 260.1 (53), 233.1 (100), 180.1 (50), 77.0 (24); HRMS (ESI): m/z
[MþHþ] calcd for C19H19N2O2 307.1447, found 307.1442.
In summary, a concise ‘one-pot’ synthesis of synthetically and
biologically important 4-substituted 1,5-diaryl-1H-pyrazole-3-
carboxylates 6 has been developed in moderate to good yields
with excellent regioselectivity from readily available diethyl oxalate,
alkylphenones 1 and arylhydrazines 5. The procedure involves
a newly expounded SHCC reaction and subsequent optimized Knorr
4.2.2. Ethyl 1-(4-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-
carboxylate (6ab). Yellow powder, 0.88
g (65% yield), mp

632
J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
69e71 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
7.40e7.36 (m, 3H),
(2C), 124.4 (2C), 121.1, 61.2, 14.4, 9.6; MS (EI): m/z (%)¼351.1 (72)
7.23 (d, J¼8.8 Hz, 2H), 7.19 (d, J¼8.8 Hz, 2H), 7.17e7.12 (m, 2H), 4.46
[Mþ], 305.1 (100), 277.1 (42), 225.1 (57), 179.1 (21); HRMS (EI): m/z
(q, J¼7.2 Hz, 2H), 4.46 (q, J¼7.2 Hz, 0.06H, as 1,3-isomer), 2.31 (s,
[Mþ] calcd for C19H17N3O4 351.1219, found 351.1217.
3H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.1,
142.5, 142.1, 138.1, 133.6, 130.1 (2C), 129.3, 128.9 (2C), 128.8, 128.7
(2C), 126.4 (2C), 120.1, 60.9, 14.5, 9.7; MS (EI): m/z (%)¼340.1 (100)
[Mþ], 294.1 (78), 267.1 (96), 231.1 (43), 214.0 (62), 111.0 (21); HRMS
(ESI): m/z [MþHþ] calcd for C19H18ClN2O2 341.1057, found 341.1055;
m/z [MþNaþ] calcd for C19H17ClN2NaO2 363.0876, found 363.0877;
m/z [MþKþ] calcd for C19H17ClN2KO2 379.0616, found 379.0612.
4.2.8. Ethyl 4-methyl-1-(3-nitrophenyl)-5-phenyl-1H-pyrazole-3-
carboxylate (6ah). Yellow powder, 1.33
g
(76% yield), mp
8.18 (t, J¼2.0 Hz,
118e120 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
1H), 8.13 (dd, J¼1.2, 8.4 Hz, 1H), 7.57 (d, J¼8.0 Hz, 1H), 7.46 (d,
J¼8.0 Hz, 1H), 7.43e7.38 (m, 3H), 7.20e7.15 (m, 2H), 4.48 (q,
J¼7.2 Hz, 2H), 4.29 (q, J¼7.2 Hz, 0.09H, as 1,3-isomer), 2.32 (s, 3H),
1.46 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 162.8,
4.2.3. Ethyl 1-(3-chlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-
148.3, 143.3, 142.4, 140.4, 130.5, 130.0 (2C), 129.6, 129.3, 129.1 (2C),
128.8, 122.3, 120.7, 120.1, 61.1, 14.4, 9.6; MS (EI): m/z (%)¼351.1 (71)
[Mþ], 305.1 (100), 277.1 (31), 225.1 (50), 179.1 (11); HRMS (EI): m/z
[Mþ] calcd for C19H17N3O4 351.1219, found: 351.1214.
carboxylate (6ac). Yellow powder, 1.33
g
d
(78% yield), mp
78e79 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
7.41 (t, J¼2.0 Hz, 1H),
7.40e7.35 (m, 3H), 7.24 (d, J¼8.4 Hz, 1H), 7.18e7.12 (m, 3H), 7.02 (d,
J¼8.0 Hz, 1H), 4.47 (q, J¼7.2 Hz, 2H), 2.31 (s, 3H), 1.44 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3, ppm):
d
163.0, 142.6, 142.2, 140.5,
4.2.9. Ethyl 1-(2,4-dinitrophenyl)-4-methyl-5-phenyl-1H-pyrazole-
3-carboxylate (6ai). Red powder,1.01 g (51% yield), mp 128e131 ꢁC;
134.6, 130.0 (2C), 129.6, 129.2, 128.9, 128.8 (2C), 127.9, 125.5, 123.3,
120.2, 60.9, 14.5, 9.7; MS (EI): m/z (%)¼340.1 (100) [Mþ], 294.1 (85),
267.1 (74), 231.1 (46), 214.0 (57), 111.0 (19); HRMS (ESI): m/z
[MþHþ] calcd for C19H18ClN2O2 341.1057, found 341.1053; m/z
[MþKþ] calcd for C19H17ClKN2O2 379.0616, found: 379.0611.
1H NMR (400 MHz, CDCl3, ppm):
d
8.71 (d, J¼2.4 Hz, 1H), 8.40 (dd,
J¼8.8, 2.4 Hz, 1H), 7.57 (d, J¼8.4 Hz, 1H), 7.43e7.35 (m, 3H), 7.14 (dd,
J¼8.0, 1.6 Hz, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.35 (s, 3H), 1.43 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 162.3,146.7,145.2,
144.8, 143.5, 137.8, 130.7, 129.9 (2C), 129.6, 129.2 (2C), 127.5, 127.4,
120.9, 120.6, 61.3, 14.4, 9.6; MS (EI): m/z (%)¼396.1 (58) [Mþ], 379.1
(13), 350.1 (100), 229.1 (15), 105.0 (40); HRMS (ESI): m/z [MþHþ]
calcd for C19H17N4O6 397.1148, found 397.1154; m/z [MþNaþ] calcd
for C19H16N4NaO6 419.0968, found 419.0964; m/z [MþKþ] calcd for
C19H16KN4O6 435.0707, found: 435.0713.
4.2.4. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-
3-carboxylate (6ad).31 Yellow powder, 1.46 g (78% yield), mp
90e92 ꢁC (lit.31 80e82 ꢁC); 1H NMR (400 MHz, CDCl3, ppm):
d 7.37
(d, J¼2.0 Hz, 1H), 7.35e7.30 (m, 4H), 7.26e7.24 (m, 1H), 7.16e7.12
(m, 2H), 4.46 (q, J¼7.2 Hz, 2H), 4.36 (q, J¼7.2 Hz, 0.11H, as 1,3-
isomer), 2.35 (s, 3H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3, ppm):
d
162.9, 144.1, 142.9, 136.2, 135.8, 133.2, 130.8, 130.0,
4.2.10. Ethyl 4-methyl-5-phenyl-1-p-tolyl-1H-pyrazole-3-carboxyl-
129.7 (2C), 128.7, 128.6, 128.5 (2C), 127.6, 119.0, 60.9, 14.5, 9.7; MS
(EI): m/z (%)¼374.1 (100) [Mþ], 328.0 (87), 301.0 (86), 267.1 (94),
248.0 (80), 77.0 (24); HRMS (ESI): m/z [MþHþ] calcd for
C19H17Cl2N2O2 375.0667, found 375.0670; m/z [MþNaþ] calcd for
C19H16Cl2N2NaO2 397.0487, found 397.0483.
ate (6aj). Yellow powder, 1.15 g (72% yield), mp 73e76 ꢁC; 1H NMR
(400 MHz, CDCl3, ppm): d 7.37e7.31 (m, 3H), 7.17e7.10 (m, 4H), 7.06
(d, J¼8.4 Hz, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.32 (s, 3H), 2.31 (s, 3H),
1.43 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.3,
142.1, 141.9, 137.7, 137.2, 130.1 (2C), 129.7, 129.3 (2C), 128.5 (2C),
128.4, 125.2 (2C), 119.7, 60.7, 21.1, 14.5, 9.7; MS (EI): m/z (%)¼320.2
(83) [Mþ], 274.1 (36), 247.1 (100), 194.1 (35), 145.1 (6), 91.1 (13);
HRMS (ESI): m/z [MþHþ] calcd for C20H21N2O2 321.1603, found
321.1601; m/z [MþNaþ] calcd for C20H20N2NaO2 343.1422, found
343.1437; m/z [MþKþ] calcd for C20H20KN2O2 359.1162, found
359.1166.
4.2.5. Ethyl
azole-3-carboxylate (6ae). Yellow powder, 1.23 g (60% yield), mp
72e74 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
7.37e7.31 (m, 5H),
4-methyl-5-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyr-
d
7.25e7.21 (m, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.34 (s, 3H), 1.43 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 161.6,143.2,142.4,
135.0,134.6 (2C),133.3,128.0 (2C),127.9,127.3 (2C),127.2 (2C),127.1,
117.7, 59.7, 13.3, 8.5; MS (EI): m/z (%)¼408.0 (57) [Mþ], 364.0 (58),
336.0 (55), 301.0 (100), 282.0 (54), 77.0 (19); HRMS (ESI): m/z
[MþHþ] calcd for C19H16Cl3N2O2 409.0277, found 409.0279; m/z
[MþNaþ] calcd for C19H15Cl3N2NaO2 431.0097, found 431.0100.
4.2.11. Ethyl
azole-3-carboxylate (6ak). Yellow powder, 1.22 g (73% yield), mp
88e90 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
7.31e7.25 (m, 3H),
1-(2,4-dimethylphenyl)-4-methyl-5-phenyl-1H-pyr-
d
7.15e7.09 (m, 3H), 6.94 (d, J¼11.2 Hz, 2H), 4.45 (q, J¼7.2 Hz, 2H),
2.36 (s, 3H), 2.29 (s, 3H), 1.88 (s, 3H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR
4.2.6. Ethyl 1-(4-fluorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-
(100 MHz, CDCl3, ppm): d 163.4, 143.4, 141.7, 139.0, 136.4, 135.0,
carboxylate (6af). White powder, 1.25
g
(77% yield), mp
131.3, 129.7 (2C), 129.3, 128.3 (2C), 128.3, 128.0, 126.9, 118.5, 60.7,
21.1, 17.5, 14.5, 9.9; MS (EI): m/z (%)¼334.2 (100) [Mþ], 289.1 (22),
259.1 (90); HRMS (EI): m/z [Mþ] calcd for C21H22N2O2 334.1681,
found: 334.1682.
96e98 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
7.36 (t, J¼3.2 Hz, 3H),
7.25e7.20 (m, 2H), 7.16e7.12 (m, 2H), 6.97 (t, J¼8.4 Hz, 2H), 4.46 (q,
J¼7.2 Hz, 2H), 4.42 (q, J¼7.2 Hz, 0.14H, as 1,3-isomer), 2.32 (s, 3H),
1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.1,161.8
(d, JCeF¼246.6 Hz), 142.3, 142.2, 135.8 (d, JCeF¼3.1 Hz), 130.1 (2C),
129.3, 128.7, 128.7 (2C), 127.2 (d, JCeF¼8.6 Hz, 2C), 119.9, 115.7 (d,
JCeF¼22.8 Hz, 2C), 60.8, 14.5, 9.7; MS (EI): m/z (%)¼324.1 (100) [Mþ],
278.1 (66), 251.1 (86),198.1 (64), 95.0 (15); HRMS (ESI): m/z [MþHþ]
calcd for C19H18FN2O2 325.1352, found 325.1350; m/z [MþNaþ]
calcd for C19H17FN2NaO2 347.1172, found 347.1164.
4.2.12. Ethyl
azole-3-carboxylate (6al). Yellow powder, 1.22 g (73% yield), mp
68e70 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
7.31e7.25 (m, 3H),
1-(2,5-dimethylphenyl)-4-methyl-5-phenyl-1H-pyr-
d
7.15e7.09 (m, 3H), 7.05 (d, J¼8.0 Hz, 1H), 6.98 (d, J¼8.0 Hz, 1H), 4.45
(q, J¼7.2 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H), 1.43 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.3, 143.3,141.8,
138.6, 136.1, 131.9, 130.4, 129.9, 129.6 (2C), 129.2, 128.7, 128.3 (3C),
118.5, 60.7, 20.7, 17.1, 14.5, 9.9; MS (EI): m/z (%)¼334.2 (100) [Mþ],
289.1 (21), 259.1 (92); HRMS (EI): m/z [Mþ] calcd for C21H22N2O2
334.1681, found 334.1677.
4.2.7. Ethyl 4-methyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-
carboxylate (6ag). Yellow powder, 1.35
g
(77% yield), mp
8.16e8.11 (m, 2H),
136e138 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
7.46e7.40 (m, 5H), 7.19e7.15 (m, 2H), 4.47 (q, J¼7.2 Hz, 2H), 2.30 (s,
3H), 1.44 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d
162.7,
4.2.13. Ethyl
1-(2,6-dimethylphenyl)-4-methyl-5-phenyl-1H-pyr-
146.3, 144.3, 143.7, 142.4, 130.0 (2C), 129.3, 129.1 (2C), 129.0, 125.1
azole-3-carboxylate (6am). Yellow powder, 1.12 g (67% yield), mp

J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
633
94e96 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
7.31e7.25 (m, 3H),
[MþHþ] calcd for C19H18ClN2O2 341.1057, found 341.1052; m/z
[MþNaþ] calcd for C19H17ClN2NaO2 363.0876, found 363.0877; m/z
[MþKþ] calcd for C19H17ClKN2O2 379.0616, found: 379.0606.
7.14 (t, J¼7.6 Hz, 1H), 7.11e7.06 (m, 2H), 6.99 (d, J¼7.6 Hz, 2H), 4.45
(q, J¼7.2 Hz, 2H), 2.40 (s, 3H), 1.95 (s, 6H), 1.43 (t, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm): d 163.4, 143.1, 142.0, 138.0, 136.2 (2C),
129.1, 129.1 (2C), 129.0, 128.4, 128.3 (2C), 128.0 (2C), 118.4, 60.7, 17.8
(2C), 14.5, 10.1; MS (EI): m/z (%)¼334.2 (100) [Mþ], 289.1 (37), 259.1
(81); HRMS (EI): m/z [Mþ] calcd for C21H22N2O2 334.1681, found
334.1675.
4.2.19. Ethyl 1,5-diphenyl-4-ethyl-1H-pyrazole-3-carboxylate
(6fa).33 Yellow powder, 0.78 g (61% yield), mp 78e79 ꢁC; 1H NMR
(400 MHz, CDCl3, ppm):
d 7.39e7.32 (m, 3H), 7.30e7.22 (m, 5H),
7.20e7.13 (m, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.73 (q, J¼7.6 Hz, 2H), 1.44
(t, J¼7.2 Hz, 3H), 1.19 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3,
4.2.14. Ethyl 1-(2-ethylphenyl)-4-methyl-5-phenyl-1H-pyrazole-3-
ppm): d 163.0, 141.9, 141.6, 139.5, 130.1 (2C), 129.7, 128.7 (2C),
carboxylate (6an). Yellow powder, 1.20 g (72% yield); 1H NMR
128.64, 128.60 (2C), 127.8, 126.5, 125.4 (2C), 60.8, 17.3, 15.8, 14.4; MS
(EI): m/z (%)¼320.2 (56) [Mþ], 274.1 (100), 245.1 (70), 231.1 (23),
180.1 (58), 77.0 (26); HRMS (ESI): m/z [MþHþ] calcd for C20H21N2O2
321.1603, found 321.1606.
(400 MHz, CDCl3, ppm):
d
7.32e7.25 (m, 4H), 7.20 (d, J¼7.6 Hz, 2H),
7.17 (d, J¼8.0 Hz, 1H), 7.14e7.09 (m, 2H), 4.45 (q, J¼7.2 Hz, 2H), 2.38
(s, 3H), 2.26 (q, J¼7.6 Hz, 2H), 143 (t, J¼7.2 Hz, 3H), 0.97 (t, J¼7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.3, 143.4, 141.7, 141.0,
138.3, 129.8 (2C), 129.3, 129.1, 128.9, 128.4, 128.3, 128.3 (2C), 126.1,
118.6, 60.7, 23.7, 14.5, 13.8, 9.9; MS (EI): m/z (%)¼334.2 (100) [Mþ],
305.1 (40), 259.1 (55), 245.1 (54), 206.1 (25); HRMS (EI): m/z [Mþ]
calcd for C21H22N2O2 334.1681, found 334.1682.
4.2.20. Ethyl 1,5-diphenyl-4-propyl-1H-pyrazole-3-carboxylate
(6ga). Yellow powder, 0.87 g (52%), mp 44e46 ꢁC; 1H NMR
(400 MHz, CDCl3, ppm):
d 7.38e7.34 (m, 3H), 7.30e7.24 (m, 5H),
7.19e7.15 (m, 2H), 4.47 ( q, J¼7.2 Hz, 2H), 2.70 (quint, J¼7.6, 5.6 Hz,
2H), 1.63e1.54 (m, 2H), 1.45 (t, J¼7.2 Hz, 3H), 0.89 (t, J¼7.2 Hz, 3H);
4.2.15. Ethyl 5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-
13C NMR (100 MHz, CDCl3, ppm):
d 163.0, 142.2, 141.8, 139.6, 130.1
carboxylate (6ba). Yellow powder, 1.05
g
(62% yield), mp
(2C), 129.9, 128.7 (2C), 128.7, 128.6 (2C), 127.7, 125.3 (2C), 125.0,
60.8, 25.9, 24.5, 14.4, 14.2; MS (EI): m/z (%)¼334.2 (55) [Mþ], 305.1
(64), 288.1 (100), 259.1 (68), 180.1 (34), 77.0 (19); HRMS (ESI): m/z
[MþNaþ] calcd for C21H22N2NaO2 357.1579, found 357.1578; m/z
[MþKþ] calcd for C21H22KN2O2 373.1318, found 373.1328.
94e96 ꢁC 7.30 (dd, J¼5.2, 2.0 Hz, 3H), 7.25e7.20 (m, 2H), 7.08 (d,
J¼8.8 Hz, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.31 (s, 3H), 1.43 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.1, 142.3, 140.9, 139.4,
134.7,131.3 (2C),128.9 (4C), 128.1,128.0, 125.4 (2C), 120.0, 60.8, 14.5,
9.7; MS (EI): m/z (%)¼340.1 (100) [Mþ], 294.1 (69), 267.1 (93), 214.1
(52), 77.0 (35); HRMS (ESI): m/z [MþHþ] calcd for C19H18ClN2O2
341.1057, found 341.1058; m/z [MþNaþ] calcd for C19H17ClN2NaO2
363.0876, found 363.0883; m/z [MþKþ] calcd for C19H17ClKN2O2
379.0616, found 379.0626.
4.2.21. Ethyl 4-isopropyl-1,5-diphenyl-1H-pyrazole-3-carboxylate
(6ha). Yellow oil, 0.80 g (48%); 1H NMR (400 MHz, CDCl3, ppm):
7.36e7.33 (m, 3H), 7.25e7.20 (m, 5H), 7.19e7.15 (m, 2H), 4.46 (q,
J¼7.2 Hz, 2H), 3.26 (quint, J¼7.2 Hz, 1H), 1.45 (t, J¼7.2 Hz, 3H), 1.27
(d, J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.2, 141.7,
4.2.16. Ethyl 4-methyl-1-phenyl-5-p-tolyl-1H-pyrazole-3-carboxyl-
141.3, 139.5, 130.7 (2C), 130.5, 130.1, 128.7, 128.6 (2C), 128.4 (2C),
127.7, 125.5 (2C), 60.9, 24.7, 22.3 (2C), 14.4; MS (EI): m/z (%)¼334.2
(42) [Mþ], 305.1 (16), 288.1 (91), 259.1 (100), 245.1 (39), 77.0 (21);
HRMS (EI): m/z [Mþ] calcd for C21H22N2O2 334.1681, found
334.1678.
ate (6ca). Yellow powder, 1.10 g (69% yield), mp 95e97 ꢁC; 1H NMR
(400 MHz, CDCl3, ppm):
d
7.29e7.22 (m, 5H), 7.15 (d, J¼8.0 Hz, 2H),
7.03 (d, J¼8.0 Hz, 2H), 4.46 (q, J¼7.2 Hz, 2H), 2.36 (s, 3H), 2.31 (s,
3H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 163.3,
142.2, 142.1, 139.7, 138.5, 129.9 (2C), 129.3 (2C), 128.7 (2C), 127.7,
126.6, 125.4 (2C), 119.7, 60.7, 21.3, 14.5, 9.7; MS (EI): m/z (%)¼320.2
(94) [Mþ], 274.1 (44), 247.1 (100), 194.1 (52), 77.0 (15); HRMS (ESI):
m/z [MþHþ] calcd for C20H21N2O2 321.1603, found 321.1601; m/z
[MþNaþ] calcd for C20H20N2NaO2 343.1422, found 343.1423; m/z
[MþKþ] calcd for C20H20KN2O2 359.1162, found 359.1162.
4.2.22. Ethyl 1,4-diphenyl-5-p-tolyl-1H-pyrazole-3-carboxylate
(6ia). White powder, 0.90 g (47% yield), mp 112e114 ꢁC; 1H NMR
(400 MHz, CDCl3, ppm): d 7.31 (s, 5H), 7.28e7.25 (m, 3H), 7.24e7.22
(m, 2H), 6.97 (d, J¼8.0 Hz, 2H), 6.86 (d, J¼8.0 Hz, 2H), 4.33 (q,
J¼7.2 Hz, 2H), 2.27 (s, 3H), 1.26 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3, ppm):
d 162.6, 142.3, 141.6, 139.6, 138.4, 132.0, 130.7 (2C),
4.2.17. Ethyl 5-(4-methoxyphenyl)-4-methyl-1-phenyl-1H-pyrazole-
3-carboxylate (6da).32 Yellow powder, 1.19 g (71% yield), mp
156e158 ꢁC (lit.32 148e150 ꢁC); 1H NMR (400 MHz, CDCl3, ppm):
130.2 (2C), 129.0 (2C), 128.8 (2C), 128.0, 127.6 (2C), 127.0, 125.9,
125.7 (2C),124.7, 60.9, 21.3,14.2; MS (EI): m/z (%)¼382.2 (100) [Mþ],
337.1 (16), 309.1 (44), 194.1 (39), 77.0 (7); HRMS (ESI): m/z [MþHþ]
calcd for C25H23N2O2 383.1760, found 383.1754.
d
7.31e7.23 (m, 5H), 7.07 (d, J¼8.8 Hz, 2H), 6.87 (d, J¼8.8 Hz, 2H),
4.46 (q, J¼7.2 Hz, 2H), 3.81 (s, 3H), 2.31 (s, 3H), 1.43 (t, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3, ppm):
163.3, 159.6, 142.1, 142.0, 139.7,
d
4.2.23. Ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate (6ja). Yellow
powder, 1.33 g (91%), mp 82e84 ꢁC; 1H NMR (400 MHz, CDCl3,
ppm): 7.38e7.28 (m, 8H), 7.23e7.20 (m, 2H), 7.05 (s, 1H), 4.46 (q,
J¼7.2 Hz, 2H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
131.4 (2C), 128.7 (2C), 127.7, 125.4 (2C), 121.7, 119.6, 114.1 (2C), 60.8,
55.2, 14.5, 9.8; MS (EI): m/z (%)¼336.1 (100) [Mþ], 290.1 (30), 263.1
(62), 210.1 (44), 77.0 (12); HRMS (ESI): m/z [MþHþ] calcd for
C20H21N2O3 337.1552, found 337.1551; m/z [MþNaþ] calcd for
C20H20N2NaO3 359.1372, found 359.1371; m/z [MþKþ] calcd for
C20H20KN2O3 375.1111, found 375.1127.
ppm):
d 162.4, 144.6, 144.3, 139.5, 129.5, 128.9 (2C), 128.7 (2C),
128.69, 128.6 (2C), 128.3, 125.7 (2C), 109.9, 61.1, 14.4; MS (EI): m/z
(%)¼292.1 (81) [Mþ], 247.1 (54), 220.1 (100), 193.1 (16), 180.1 (18),
77.0 (19); HRMS (EI): m/z [Mþ] calcd for C21H22N2O2 292.1212,
found 292.1210.
4.2.18. Ethyl 5-(3-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-
carboxylate (6ea). Yellow powder, 1.14
g
d
(67% yield), mp
7.35e7.31 (m, 2H),
96e98 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
4.2.24. Ethyl 1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-
7.31e7.28 (m, 2H), 7.26e7.23 (m, 3H), 7.19 (d, J¼1.6 Hz, 1H), 7.00 (d,
carboxylate (6ka).31 Brown powder, 1.43
g
(90% yield), mp
J¼7.6 Hz, 1H), 4.46 (q, J¼7.2 Hz, 2H), 2.33 (s, 3H), 1.44 (t, J¼7.2 Hz,
154e156 ꢁC (lit.31 152e154 ꢁC); 1H NMR (400 MHz, CDCl3, ppm):
3H); 13C NMR (100 MHz, CDCl3, ppm):
d
163.0, 142.3, 140.6, 139.2,
d
7.55e7.51 (m, 2H), 7.51e7.46 (m, 3H), 7.30 (d, J¼7.2 Hz, 1H), 7.17 (t,
134.5, 131.3, 129.9, 129.8, 128.9 (2C), 128.8, 128.3, 128.1, 125.4 (2C),
120.2, 60.9, 14.5, 9.7; MS (EI): m/z (%)¼340.1 (95) [Mþ], 294.1 (76),
267.1 (100), 231.1 (23), 214.0 (48), 77.0 (31); HRMS (ESI): m/z
J¼7.6 Hz, 1H), 6.98 (t, J¼7.2 Hz, 1H), 6.74 (d, J¼7.6 Hz, 1H), 4.45 (q,
J¼7.2 Hz, 2H), 3.12e3.07 (m, 2H), 3.03e2.99 (m, 2H), 1.43 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
d 162.9, 140.4,

634
J.-A. Jiang et al. / Tetrahedron 69 (2013) 627e635
5. For a selected example on pyrazoles as UV stabilizers, see: Catalan, J.; Fabero, F.;
Claramunt, R. M.; Maria, M. D. S.; Foces-Foces, M. C.; Cano, F. H.; Martinez-Ripoll,
M.; Elguero, J.; Sastre, R. J. Am. Chem. Soc. 1992, 114, 5039e5048.
6. For recent examples on pyrazoles as units in supramolecular entities, see: (a)
Gemming, S.; Schreiber, M.; Thiel, W.; Heine, T.; Seifert, G.; Avelino de Abreu,
H.; Anderson Duarte, H. J. Lumin. 2004, 108, 143e147; (b) Maeda, H.; Ito, Y.;
Kusunose, Y.; Nakanishi, T. Chem. Commun. 2007, 1136e1138; (c) Sachse, A.;
Penkova, L.; Noel, G.; Dechert, S.; Varzatskii, O. A.; Fritsky, I. O.; Meyer, F.
Synthesis 2008, 800e806.
7. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J.
Med. Chem. 1997, 40, 1347e1365.
140.2, 139.6, 137.4, 129.4 (2C), 129.1, 128.7, 128.0, 126.3, 126.2, 126.1,
122.9 (2C), 122.9, 60.9, 30.1, 20.1, 14.5; MS (EI): m/z (%)¼318.1 (35)
[Mþ], 271.1 (23), 245.1 (100); HRMS (ESI): m/z [MþHþ] calcd for
C20H19N2O2 319.1447, found 319.1445.
4.2.25. Ethyl 1-(4-fluorophenyl)-8-nitro-4,5-dihydro-1H-benzo[g]in-
dazole-3-carboxylate (6lf). Brown powder, 1.66 g (87% yield), mp
194e196 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
d
8.02 (dd, J¼8.4,
2.4 Hz, 1H), 7.55 (d, J¼2.4 Hz, 1H), 7.54e7.48 (m, 2H), 7.46 (d,
J¼8.4 Hz, 1H), 7.26e7.22 (m, 2H), 4.45 (q, J¼7.2 Hz, 2H), 3.17e3.08
(m, 4H), 1.42 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm):
8. Terrett, N. K.; A. Bell, S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6,
1819e1824.
d
163.1 (d, JCeF¼249.6 Hz), 162.4, 146.7, 144.5, 140.5, 137.9, 135.6 (d,
JCeF¼3.1 Hz), 129.6, 128.0 (d, JCeF¼8.9 Hz, 2C), 127.1, 123.5, 122.7,
117.3, 116.9 (d, JCeF¼22.8 Hz, 2C), 61.18, 30.21, 19.57, 14.42; MS (EI):
m/z (%)¼381.1 (51) [Mþ], 335.1 (54), 308.1 (100), 262.1 (24); HRMS
(ESI): m/z [MþHþ] calcd for C20H17FN3O4 382.1203, found 382.1202.
9. Barth, F.; Rinaldi-Carmona, M. Curr. Med. Chem. 1999, 6, 745e755.
10. (a) Sui, Z.; Guan, J.; Ferro, M. P.; McCoy, K.; Wachter, M. P.; Murray, W. V.; Singer,
M.; Steber, M.; Ritchie, D. M.; Argentieri, D. C. Bioorg. Med. Chem. Lett. 2000, 10,
601e604; (b) Bekhit, A. A.; Abdel-Aziem, T. Bioorg. Med. Chem. 2004, 12,
1935e1945; (c) Selvam, C.; Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K.
Bioorg. Med. Chem. Lett. 2005, 15, 1793e1797.
11. Katoch-Rouse, R.; L. Pavlova, A.; Caulder, T.; Hoffman, A. F.; Mukhin, A. G.; Horti,
4.2.26. Ethyl 8-methoxy-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-
A. G. J. Med. Chem. 2003, 46, 642e645.
3-carboxylate (6ma). Brown powder, 1.18
g
d
(85% yield), mp
7.56e7.45 (m, 5H),
12. Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.; Ueda, T.; Terauchi,
H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi, J.-I. Bioorg. Med. Chem. 2004,
12, 5515e5524.
13. (a) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43,
4934e4947; (b) Stauffer, S. R.; Huang, Y.; Coletta, C. J.; Tedesco, R.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. 2001, 9, 141e150.
134e136 ꢁC; 1H NMR (400 MHz, CDCl3, ppm):
7.19 (d, J¼8.4 Hz, 1H), 6.71 (dd, J¼8.4, 2.8 Hz, 1H), 6.27 (d, J¼2.8 Hz,
1H), 4.45 (d, J¼7.2 Hz, 2H), 3.44 (s, 3H), 3.07 (t, J¼7.2 Hz, 2H), 2.94 (t,
J¼7.2 Hz, 2H), 1.42 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
ppm):
d 162.9, 157.8, 140.2, 140.2, 139.6, 129.5, 129.4 (2C), 129.3,
14. For recent pyrazole syntheses, see, e.g.: (a) Martin, R.; Rivero, M. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 7079e7082; (b) Bagley, M. C.; Lubinu, M. C.;
Mason, C. Synlett 2007, 704e708; (c) Dang, T. T.; Dang, T. T.; Fischer, C.; Gorls,
H.; Langer, P. Tetrahedron 2008, 64, 2207e2215; (d) Liu, H.-L.; Jiang, H.-F.;
Zhang, M.; Yao, W.-J.; Zhu, Q.-H.; Tang, Z. Tetrahedron Lett. 2008, 49,
3805e3809; (e) Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008, 10,
1691e1694; (f) Deng, X.; Mani, N. S. Org. Lett. 2008, 10, 1307e1310; (g) Deng, X.;
Mani, N. S. J. Org. Chem. 2008, 73, 2412e2415; (h) Wu, X.-F.; Neumann, H.;
Beller, M. Chem.dEur. J. 2010, 16, 12104e12107; (i) Dadiboyena, S.; Valente, E. J.;
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Sparks, T. C.; Fettiger, J. C.; Kurth, M. J. J. Comb. Chem. 2010, 12, 129e136; (k)
Janin, Y. L. Mini-Rev. Org. Chem. 2010, 7, 314e323; (l) Chandanshive, J. Z.; Bonini,
B. F.; Gentili, D.; Fochi, M.; Bernardi, L.; Franchini, M. C. Eur. J. Org. Chem. 2010,
6440e6447; (m) Li, Y.; Hong, D.; Lu, P.; Wang, Y. Tetrahedron Lett. 2011, 52,
126.8, 126.5 (2C), 126.2, 123.1, 113.8, 108.4, 60.9, 54.9, 29.2, 20.4,
14.5; MS (EI): m/z (%)¼348.1 (53) [Mþ], 301.1 (35), 275.1 (100), 232.1
(13); HRMS (ESI): m/z [MþHþ] calcd for C21H21N2O3 349.1552,
found: 349.1551.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (Project No. 21176074) for financial support.
Supplementary data
€
4161e4163; (n) Willy, B.; Muller, T. J. J. Org. Lett. 2011, 13, 2082e2085; (o) Wu,
X.-F.; Neumann, H.; Beller, M. Eur. J. Org. Chem. 2011, 4919e4924; (p) Vazquez,
€
N.; Gomez-Vallejo, V.; Llop, J. Tetrahedron Lett. 2012, 53, 4743e4746; (q) Ruger,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.11.012.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
€
A. J.; Nieger, M.; Brase, S. Tetrahedron 2012, 68, 8823e8829.
15. For selected examples, see: (a) Murineddu, G.; Lazzari, P.; Ruiu, S.; Sanna, A.;
Loriga, G.; Manca, I.; Falzoi, M.; Dessi, C.; Curzu, M. M.; Chelucci, G.; Pani, R. L.;
Pinna, G. A. J. Med. Chem. 2006, 49, 7502e7512; (b) Zhang, Y.; Burgess, J. P.;
Brackeen, M.; Gilliam, A.; Mascarella, S. W.; Page, K.; Seltzman, H. H.; Thomas,
B. F. J. Med. Chem. 2008, 51, 3526e3539; (c) Dow, R. L.; Carpino, P. A.; Hadcock,
J. R.; Black, S. C.; Iredale, P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.;
Griffith, D. A.; Scott, D. O.; O’Connor, R. E.; Nduaka, C. I. J. Med. Chem. 2009, 52,
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J. Org. Lett. 2009, 11, 4760e4763; (e) Wu, C.-H.; Hung, M.-S.; Song, J.-S.; Yeh,
T.-K.; Chou, M.-C.; Chu, C.-M.; Jan, J.-J.; Hsieh, M.-T.; Tseng, S.-L.; Chang, C.-P.;
Hsieh, W.-P.; Lin, Y.; Yeh, Y.-N.; Chung, W.-L.; Kuo, C.-W.; Lin, C.-Y.; Shy, H.-S.;
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2009, 52, 234e237; (g) Szabo, G.; Varga, B.; Payer-Lengyel, D.; Szemzo, A.;
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I.; Fischer, J. J. Med. Chem. 2009, 52, 4329e4337; (h) Seo, H. J.; Kim, M. J.; Lee, S.
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