"One-poto" synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3- carboxylic acids via a MeONa/LiCl-mediated sterically hindered claisen condensation-Knorr reaction-hydrolysis sequence

Article abstract of DOI:10.1055/s-0032-1317668

A "one-poto" synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3- carboxylic acids was first reported in moderate to good yields. This concise procedure, featuring efficiency and green chemistry, was composed of MeONa/LiCl-mediated sterically hindered Claisen condensation, Knorr reaction and hydrolysis. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317668

LETTER
▌2965
letter
“One-Pot” Synthesis of 4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic
Acids via a MeONa/LiCl-Mediated Sterically Hindered Claisen
Condensation–Knorr Reaction–Hydrolysis Sequence
4-Substituted 1,5-diaryl-1H-pyrazole-3-carboxylic acids
Jian-An Jiang, Cai-Yan Du, Chun-Hui Gu, Ya-Fei Ji*
School of Pharmacy, East China University of Science & Technology, Campus P. O. Box 363, 130 Meilong Road, Shanghai 200237,
P. R. of China
Fax +86-21-64253314; E-mail: jyf@ecust.edu.cn
Received: 17.09.2012; Accepted after revision: 28.10.2012
followed by basic hydrolysis.2a,b,f,g,4 This classical prepa-
Abstract: A “one-pot” synthesis of 4-substituted 1,5-diaryl-1H-
ration inevitably requires the use of commercially un-
pyrazole-3-carboxylic acids was first reported in moderate to good
available 2,4-diketo esters, which are usually synthesized
yields. This concise procedure, featuring efficiency and green
from alkylphenones and diethyl oxalate by base-mediated
sterically hindered Claisen condensation (SHCC). How-
ever, the SHCC reaction often suffers from low chemical
yield in sodium ethoxide-mediated procedures,2a,4 or trou-
blesome and uneconomical operation in lithium hexa-
methyldisilazide (LiHMDS)-mediated procedures.2b,f,g
Hence, there remains an urgent need for conceptually sus-
tainable and versatile syntheses of 2,4-diketo esters as
well as the fully substituted pyrazoles from easily avail-
able reactants. Toward this end, we became interested in
the development of a mild SHCC using low-cost and ro-
bust base to efficiently generate the labile 2,4-diketo es-
ters on both bench and industrial scales.
chemistry, was composed of MeONa/LiCl-mediated sterically hin-
dered Claisen condensation, Knorr reaction and hydrolysis.
Key words: MeONa/LiCl, sterically hindered Claisen condensa-
tion, Knorr reaction, 4-substituted 1,5-diaryl-1H-pyrazole-3-car-
boxylic acids, “one-pot” synthesis
Among nitrogen-containing heterocycles, the pyrazole
motif is a common core component of numerous biologi-
cally active molecules.1 Notably, recent discoveries that
4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylate de-
rivatives can act as cannabinoid-1 (CB1) receptor antago-
nists,2 Iκβ kinase β (IKKβ or IKK-2) inhibitors,3
analgesics,4 and anti-inflammatory agents5 have attracted
increasing attention and have led to the development of
new syntheses of this class of compounds and further bio-
logical explorations.2–6 With this background, the precur-
sor 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylic
acids have been a particular focus; these are generally pre-
pared through application of the Knorr reaction of 3-sub-
stituted 4-aryl-2,4-diketo esters and arylhydrazines
Our group had found that the use of an alkoxide/LiCl sys-
tem could efficiently execute the SHCC of 4-chloropropi-
ophenone and diethyl oxalate to generate an intermediate
of Rimonabant, a listed CB1 receptor antagonist.7 Thus,
we formally turned our attention to the alkoxide/LiCl sys-
tem, as a potentially green and competent surrogate for so-
dium ethoxide and LiHMDS, for preparing the 2,4-diketo
esters efficiently and sustainably. Herein, we reported a
Li+
O
O
O–
O
R2
OEt
MeONa/LiCl
OEt
R1
+
R1
EtO
THF, r.t., 4 h
R2
O
O
enolated six-membered
cyclic lithium salts of 2
1
R2
R2
CO2Et
N
CO2H
NHNH2⋅HCl
R3
N
3
NaOH
H+
N
N
R1
R1
TFA, EtOH, reflux
R3
R3
4
Scheme 1 “One-pot” synthesis of 4-substituted 1,5-diaryl-1H-pyrazole-3-carboxylic acids
SYNLETT 2012, 23, 2965–2968
Advanced online publication: 28.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317668; Art ID: ST-2012-W0785-L
© Georg Thieme Verlag Stuttgart · New York

2966
J.-A. Jiang et al.
LETTER
MeONa/LiCl-mediated SHCC of alkylphenones 1 with esters10c and 2-unsubstituted 1,3-diketones,10a compound
diethyl oxalate to afford the corresponding enolated lithi- 2a is highly unstable. To avoid the need to isolate unstable
um salts of 3-substituted 4-aryl-2,4-diketo esters 2, which 2, we subsequently sought to combine the SHCC, the
were trapped in situ by arylhydrazine hydrochlorides 3 Knorr reaction, and the base-mediated hydrolysis into a
upon addition of stoichiometric trifluoroacetic acid (TFA) “one-pot” process. Extensive studies led to an optimal
in ethanol, followed by a sodium hydroxide mediated hy- process allowing a “one-pot” synthesis of highly valuable
drolysis in situ to create structurally diverse 4-substituted 4.11 First, a mixture of LiCl (2.5 equiv) and MeONa (1.5
1,5-diaryl-1H-pyrazole-3-carboxylic acids 4 in a “one- equiv) in THF was heated at reflux for three hours,12 to
pot” fashion (Scheme 1).
which was then added 1a (1.0 equiv) and diethyl oxalate
(1.3 equiv) and the reaction mixture was stirred for a fur-
ther three hours at room temperature. After removal of
THF, EtOH (solvent), TFA (2.0 equiv), and phenylhydra-
zine hydrochloride (3a; 1.0 equiv) were sequentially add-
ed to instigate the Knorr reaction of 2a and 3a, which was
conducted at reflux for 12 hours. Subsequent addition of
NaOH (4.0 equiv) to the reaction mixture and heating at
reflux for four hours gave 4aa in a good total yield of
73%. We realized that the use of an equimolar amount of
3a (versus 1a) was necessary to trap the freshly generated
2a almost completely. Another key factor for this “one-
pot” synthesis was direct introduction of NaOH to achieve
4 after completion of the Knorr reaction without any mod-
ification of the reaction mixture.
Our investigations began with the EtONa/LiCl-mediated
SHCC of propiophenone (1a; 1.0 equiv) and diethyl oxa-
late (1.3 equiv, Table 1). Interestingly, when the SHCC
was conducted with a pre-prepared mixture of EtONa (1.5
equiv) and LiCl (1.5 equiv) in tetrahydrofuran (THF) at
room temperature for three hours, the expected 3-methyl
4-phenyl-2,4-diketo ester (2a) was isolated only in 74%
yield, with two consistent contaminants being observed
(entry 1).8 The formation of unexpected contaminants
promoted us to further optimize the reaction conditions.
On increasing the amount of LiCl, the formation of unde-
sired contaminants could be suppressed (entries 2–4), and
the yield of 2a was increased to 90–91% by utilizing 2.5
or 3.0 equiv LiCl (entries 3 and 4). It was further observed
that the use of other alkoxides including t-BuOK and Me- Having established the “one-pot” procedure, we then
ONa also proved to be equally effective for this transfor- evaluated the generality of the approach with respect to
mation (entries 5 and 6), with the latter system being substrate 3 (Table 2). By varying the substituent(s) R3 of
preferable in terms of cost. These results suggested that 3, it became clear that electron-neutral 3a (entry 1) and
the presence of lithium could play a vital role in this electron-deficient 3b–d, bearing chlorine substituents on
SHCC to generate the enolated six-membered cyclic lith- the benzene ring, was slightly beneficial, giving the corre-
ium salts;2f,g the advantage of using lithium in the reaction sponding products 4ab–ad in yields of 74–76% (entries
could stem from the stronger affinity of lithium towards 2–4). We considered that the chlorine atom(s) could stabi-
oxygen compared with that of sodium and potassium.9
lize the hydrazinyl group, making the arylhydrazines
more stable under reflux conditions. In contrast, the “one-
pot” procedure gave the products 4af–ah in lower yields
of 70–72% with electron-rich substrates 3f–h bearing
electron-donating methyl group(s) on the benzene ring
It should also be mentioned that, similar to sterically hin-
dered 2-substituted 1,3-diketones,10e–h 2-substituted 3-
keto esters,10b,d,h as well as 3-unsubstituted 2,4-diketo
Table 1 The Investigation of Alkoxid/LiCl-Mediated SHCCa
Li+
O–
O
O
O
O
H+
OEt
OEt
diethyl oxalate
O
O
alkoxide/LiCl
THF, r.t.
1a
2a
six-membered cyclic
lithium salt of 2a
Entry
Alkoxide
LiCl (n equiv to 1a)
Yield (%)b
1
2
3
4
5
6
EtONa
EtONa
EtONa
EtONa
t-BuOK
MeONa
1.5
2.0
2.5
3.0
2.5
2.5
74
83
90
91
90
90
a Performed with LiCl (n equiv), alkoxide (7.5 mmol), anhydrous THF (15 mL) at reflux for 3 h, then 1a (5.0 mmol), diethyl oxalate (6.5 mmol)
at room temperature for 3 h.
b Isolated yields.
Synlett 2012, 23, 2965–2968
© Georg Thieme Verlag Stuttgart · New York

LETTER
4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic acids
2967
(entries 6–8). This weakly detrimental effect was pre- To test the limits of the procedure further, we synthesized
sumed to result from the increased oxidizability caused by more sterically challenging substrates 4 containing larger
the electron-donating group(s) for the hydrazinyl group. It R2 groups, which would be expected to be obtained with
should be noted that, irrespective of the electronic proper- poor efficiency through the discrete protocol due to the
ties of R3, the di-ortho-substituted steric hindrance of 3e extreme instability of the corresponding precursors 2. By
and 3i had a remarkable impact on the yield of products using n-butyrophenone (1i) and n-valerophenone (1j), as
4ae and 4ai, with relatively low yields of 65 and 60%, re- well as 2-phenyl-1-(p-tolyl)ethanone (1k), we were
spectively (entries 5 and 9). Thus, steric effects would be pleased to obtain 4id–kd in respectable yields of 62, 56,
expected to significantly influence the efficiency of the and 45%, respectively (Table 3, entries 8–10).
“one-pot” procedure. As expected, isopropylhydrazine
Table 3 The Generality of Alkylphenones 1a
hydrochloride gave a good yield in the “one-pot” proce-
dure as a representative alkylhydrazine (3j; entry 10), fur-
ther demonstrating the utility and scope of this
methodology.
1. diethyl oxalate
MeONa/LiCl, THF, r.t.
Cl
NHNH2•HCl
2.
Table 2 The Generality of Arylhydrazine Hydrochlorides 3a
R2
CO2H
3d
O
Cl
1. diethyl oxalate
MeONa/LiCl, THF, r.t.
R2
TFA, EtOH, reflux
N
N
R1
R1
NHNH2⋅HCl
3. NaOH
4. H+
2.
Cl
R3
CO2H
1
3
O
EtOH, TFA, reflux
N
N
Cl
3. NaOH
4. H+
4
1a
Entry
1 (R1/R2)
Product Yield (%)b
R3
4
1
2
1b (R1 = 4-MeO, R2 = Me)
1c (R1 = 4-Me, R2 = Me)
1d (R1 = 2,4-Me2, R2 = Me)
1e (R1 = 4-Cl, R2 = Me)
1f (R1 = 2,4-Cl2, R2 = Me)
1g (R1 = 4-Br, R2 = Me)
1h (R1 = 2-F, R2 = Me)
1i (R1 = H, R2 = Et)
4bd
4cd
4dd
4ed
4fd
4gd
4hd
4id
70
72
70
72
67
70
66
62
56
45
Entry
3 (R3)
Product
Yield (%)b
1
2
3a (R3 = H)
4aa
4ab
4ac
4ad
4ae
4af
73
74
74
76
65
72
70
72
60
79
3
3b (R3 = 3-Cl)
4
3
3c (R3 = 4-Cl)
5
4
3d (R3 = 2,4-Cl2)
3e (R3 = 2,4,6- Cl3)
3f (R3 = 4-Me)
6
7
5
8
6
1j (R1 = H, R2 = n-Pr)
4jd
4kd
7
3g (R3 = 2,4-Me2)
3h (R3 = 2,5- Me2)
3i (R3 = 2,6-Me2)
3j = i-PrNHNH2HCl
4ag
4ah
4ai
9
10
1k (R1 = 4-Me, R2 = Ph)
8
a Performed with LiCl (12.5 mmol), MeONa (7.5 mmol), anhydrous
THF (15 mL), 1 (5.0 mmol), diethyl oxalate (6.5 mmo), anhydrous
EtOH (15 mL), TFA (10.0 mmol), 3d (5.0 mmol) and NaOH (20.0
mmol) following the typical “one-pot” procedure.11
b Isolated yields.
9
10
4ajc
a Performed with LiCl (12.5 mmol), MeONa (7.5 mmol), anhydrous
THF (15 mL), 1a (5.0 mmol), diethyl oxalate (6.5 mmo), anhydrous
EtOH (15 mL), TFA (10.0 mmol), 3 (5.0 mmol) and NaOH (20.0 mmol)
following the typical “one-pot” procedure.11
In summary, we have developed an efficient “one-pot”
synthesis of highly valuable 4 from readily available reac-
tants. This procedure, featuring green chemistry, was
based on a MeONa/LiCl-mediated sterically hindered
Claisen condensation/Knorr reaction/hydrolysis se-
quence. The low cost of the reagents MeONa and LiCl,
good tolerance, and simple operation render the procedure
particularly appealing for sustainable chemistry-oriented
synthesis. The synthetic versatility of 2 and pharmaceuti-
cal importance of 4 underline the usefulness of this meth-
odology. Studies are in progress to broaden the field of
b Isolated yields.
c N-substituent as isopropyl group in the structure of 4aj.
We then investigated the effect of substituents R1 and R2
of 1 by using 3d as a representative in the “one-pot” pro-
cedure (Table 3). The substituent(s) R1 could include not
only electron-donating group(s) (1b–d) but also electron-
withdrawing group(s) (1e–h), giving the corresponding
products 4bd–hd in good yields (66–72%; entries 1–7).
Indeed, the best result was obtained for 4aa with electron-
neutral 1a (Table 2, entry 4).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2965–2968

2968
J.-A. Jiang et al.
LETTER
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Acknowledgment
The authors thank the National Natural Science Foundation of Chi-
na (Project No. 21176074) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(8) Two contaminants were detected: ethyl benzoate and ethyl
2-hydroxy-3-methyl-4,5-dioxohept-2-enoate, which were
presumed to be byproducts derived from 2a.
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(11) Typical “one-pot” procedure for 4: An oven-dried vial
was charged with LiCl (0.53 g, 12.5 mmol) and MeONa
(0.41 g, 7.5 mmol) in anhydrous THF (15 mL). The mixture
was stirred and heated at reflux for 3 h and then cooled to
0 °C, and alkylphenone 1 (5.0 mmol) and diethyl oxalate
(0.95 g, 6.5 mmol) were added. The resulting mixture was
stirred at r.t. for 3 h and then concentrated to remove THF.
Anhydrous EtOH (15 mL), TFA (1.14 g, 10.0 mmol) and
arylhydrazine hydrochloride 3 (5.0 mmol) were added at r.t.,
and the mixture was heated to reflux for 12 h. A solution of
NaOH (0.8 g, 20.0 mmol) in H2O (2 mL) was then added to
the reaction solution, which was stirred and heated to reflux
for a further 4 h. The solution was then concentrated in
vacuo to remove EtOH, affording a residue, to which was
added H2O (15 mL), CH2Cl2 (15 mL), and 10% HCl (ca.
10 mL) until pH 3–4 to make the solution partition into
organic and aqueous layers. The aqueous layer was extracted
with CH2Cl2 (2 × 10 mL) and the combined organic phase
was washed with H2O (2 × 20 mL), dried over anhydrous
sodium sulfate, and concentrated to give the crude product,
which was purified by recrystallization (petroleum ether–
EtOAc, 5:1 v/v; 6 mL) to give the corresponding product 4.
Representative compound 4aa: yellow solid; Yield: 1.01 g
(73%); mp 158–160 °C. 1H NMR (400 MHz, CDCl3): δ =
7.45–7.37 (m, 3 H), 7.37–7.25 (m, 5 H), 7.25–7.15 (m, 2 H),
2.38 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 165.4, 142.8,
141.2, 139.4, 130.1 (2C), 129.3, 128.9 (2C), 128.7, 128.6
(2C), 128.1, 125.2 (2C), 120.3, 9.6; HRMS (ESI): m/z [M –
H+] calcd for C17H13N2O2: 277.0977; found: 277.0974.
(12) When the mixture of LiCl and MeONa was used directly, the
SHCC of 1a with diethyl oxalate gave unsatisfactory results.
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Synlett 2012, 23, 2965–2968
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