Copper-catalyzed acylation of pyrazolones with aldehydes to afford 4-acylpyrazolones

Article abstract of DOI:10.1039/c9ob01486a

Copper-catalyzed direct acylation of the alkenyl C-H bond in 1,2-dihydro-3H-pyrazol-3-ones has been developed, affording a series of 4-acylpyrazolones in moderate to good yields. Notably, this protocol involves readily accessible substrates and reagents, which have good functional group tolerance leading to pyrazolone derivatives under mild reaction conditions.

Full text of DOI:10.1039/c9ob01486a

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DOI: 10.1039/C9OB01486A
ARTICLE
Copper-Catalyzed Acylation of Pyrazolones with Aldehydes
toward 4-Acylpyrazolones
Received 00th January 20xx,
Accepted 00th January 20xx
Yan Xiao, Xiaopeng Wu, Jiangang Teng, Song Sun*, Jin-Tao Yu, and Jiang Cheng
DOI: 10.1039/x0xx00000x
A copper-catalyzed direct acylation of alkenyl C-H bond in 1,2-dihydro-3H-pyrazol-3-ones has been
developed, affording a series of 4-acylpyrazolones in moderate to good yields. Notably, this protocol has
readily accessible substrates and reagents, good functional group tolerance leading to pyrazolone derivatives
under mild reaction conditions.
treatment of fever, and inflammation in clinical practice
(Figure 1).9 Hence, developing novel synthetic methods for the
construction of pyrazolones with diverse functional groups
Introduction
Unsaturated ketones occupy pivotal positions as
intermediates and are ubiquitous in natural products and
pharmaceutical compounds.1 Various synthetic methods have
been developed, including: the oxidation of secondary
alcohols,2 coupling reactions of carboxylic anhydrides,3 esters4
and thiol esters5 with organometallic compounds. In all the
aforementioned cases, the procedures suffered from either
the need of stoichiometric amounts of oxidant with
concomitant formation of undesired byproducts or pre-
functionalization, such as bromination. Undoubtedly, the
direct employment of alkene and aldehyde6,7 via oxidative C-H
functionalization is a facile, sustainable and economical
pathway to access such frameworks, because both of these
compounds are readily available and the pre-functionalization
is not required.
have attached great attention in recent years.10 For instance,
Xia and co-workers reported Au-Catalyzed C4-alkynylation of
N-alkyl pyrazolone with hypervalent iodine reagent.11 Kuang
developed a Pd catalyzed C–H alkenylation of 5-pyrazolones
with alkenes toward a series of 4-vinylpyrazolones.12 Recently,
Yotphan and coworkers provided a sufficient and sustainable
pathway toward 4-acylpyrazolones via oxidative C−H acylation
of N-substituted pyrazolones with α-oxocarboxylic acids as the
acyl sources.13 However, the preparation of α-oxocarboxylic
acids is rather difficult and time-consuming. Thus, the
development of more practical and efficient procedures using
simple starting materials to access 4-acylpyrazolones remains
an area of synthetic interest. Herein, we wish to report a
copper catalyzed acylation of alkenyl C-H bond in 1,2-dihydro-
3H-pyrazol-3-ones by using commercially available aromatic
aldehydes as the acyl source.
nBu
nPr
O
O
NaO3SH2C
O
N
CH3
N
O
H3C
N
O
N
N
CH3
N
N
N
N
Results and discussion
CH3
We initiated our work via the coupling of phenazone 1a
(0.25 mmol) with benzaldehyde 2a (0.37 mmol), and the
selected conditions are summarized in Table 1. Firstly,
Pd(OAc)2 and Pd(TFA)2 were found to be totally ineffective in
Phenybutazone
Analgin
Rheumox
Figure
1.
Representative
pyrazolone
NSAIDs
Among various unsaturated ketones, pyrazolones and their the presence of K2S2O8 (Table 1, entries 1-2). The first glimpse
came from the application of CuCl as catalyst, as the desired
product 3aa could be isolated in 28% yield (Table 1, entry 3).
CuBr (23%), CuI (26%) and CuCl2 (15%) showed similar
efficiencies (Table 1, entries 4-6). Gratifyingly, the yield
increased when the reaction was catalyzed by CuO (43%) or
Cu(OAc)2 (45%) in the presence of K2S2O8 after stirring for 12 h
at 80 °C (Table 1, entries 7 and 8). Encouraged by these
preliminary results, we continued to improve the reaction
efficiency. Replacing MeOH with EtOH (31%), H2O (30%),
derivatives have a range of biological activities such as
antibacterial, antiviral and antitumor activities.8 In particular,
pyrazolone and its derivatives are valuable non-steroidal anti-
inflammatory drugs (NSAIDs) which are commonly used in the
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, and Jiangsu Province Key Laboratory of Fine
Petrochemical Engineering, Changzhou University, Gehu Road 1, Changzhou,
213164, P. R. China E-mail: sunsong@cczu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any CH3CN (23%), and DMSO (25%), all decreased the reaction
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
efficiency (Table 1, entries 9-12). Worse more, no desired
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Journal Name
product was observed in the solvent of 1,4-dioxane and
toluene (Table 1, entries 13-14). Unbelievably, the yield
increased to 83% in a co-solvent system of MeOH/H2O (1/1)
(Table 1, entry 15). Moreover, the reaction efficiency
decreased under lower (25 °C, < 5%; 60 °C, 32%) or elevated
temperature (100 °C, 75%) (Table 1, entry 16). Additionally,
control experiment revealed that the reaction atmosphere
had no obvious effect on the reaction efficiency (Table 1,
entry 16).
aldehyde (2m) only could afford trace amount desired
products.
View Article Online
DOI: 10.1039/C9OB01486A
O
H
O
O
Cu(OAc)2 (32 mol %)
Ph
N
ArCHO
+
Ar
N
N
K2S2O8 (1.37 equiv),
MeOH/H2O (1/1, 2 mL), 80 o
N
Ph
C
2
1a
3aa-ai
O
O
O
O
O
Ph
Ph
Ph
O
N
N
N
N
N
N
Table 1. Screening of optimal reaction conditionsa
O
H
O
O
Ph
Cl
N
+
PhCHO
Ph
N
3aa
, 83%
N
3ab
3ac
, 68%
, 80%
O
N
Ph
O
O
O
1a
2a
3aa
O
O
Ph
Ph
Ph
N
N
N
N
N
N
Entry
1
Catalyst
Pd(OAc)2
Pd(TFA)2
CuCl
Oxidant
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
Yieldb (%)
trace
<5
Br
CF3
F
2
3ad
, 64%
O
3ae
3af
, 58%
, 61%
O
3
28
O
O
O
Ph
O
Ph
4
CuBr
23
Ph
N
N
N
N
N
5
CuI
26
N
Cl
6
CuCl2
15
S
CN
7
CuO
43
3ag
, 68%
3ah
, 73%
3ai
, 43%
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
45
O
O
O
R
9
31
O
Ph
Ph
N
3aj
R = Me,
R = Et,
R = n-Pr,
, trace
N
N
10
11
12
13
14
H2O
30
3ak
, trace
N
3al
, trace
CH3CN
toluene
1,4-dioxane
DMSO
23
3am
, trace
trace
trace
25
Scheme 1. The Substrate Scope of Aldehydes. Reaction conditions:
Conditions: 1a (0.25 mmol), 2 (0.37 mmol), K2S2O8 (0.37 mmol), Cu(OAc)2
(0.08 mmol, 32 mol %), MeOH/H2O (1/1, 2 mL), 80 °C, 12 h.
15c
16c
Cu(OAc)2
Cu(OAc)2
K2S2O8
K2S2O8
MeOH/H2O
MeOH/H2O
83
Next, the scope of phenazone derivatives was also
investigated (Scheme 2). Notably, phenazone derivatives
bearing methyl, fluoro and chloro at the para- positions of the
aryl moiety all worked well to afford 3ba (80%), 3ca (75%) and
3da (73%) in good yields, respectively. The analogues
possessing chloro on the ortho- or meta- position provided the
corresponding products in good yields (3ga, 3ha, 76-80%).
However, the strong electron-withdrawing groups such as
trifluoromethyl (3ea, 52%) and cyano (3fa, 49%) slightly
decreased the reaction efficiency. Meanwhile, pyrazolone
substrate 1i (R2 = Bu) ran smoothly to afford 3ia in 64% yield.
To our delight, the substrate bearing n-propyl (1j) in the β
position could give the desired product 3ja in 55% yield,
however, the substrates bearing phenyl (1k) groups in the β-
position or substrate without β-substituent 1l, almost did not
work under the standard conditions. Additionally, free NH
substrate 1m also resulted in no reaction.
< 5d, 32e, 75f,
83g, 82h
a
Reaction conditions: Conditions: 1a (0.25 mmol), 2a (0.37 mmol), K2S2O8
(0.37 mmol), catalyst (0.08 mmol, 32 mol %), solvent (2 mL), 80 °C, 12h,
under air in a sealed Schlenk tube, unless otherwise noted. b Isolated yield.
MeOH/H2O (1/1, 2 mL). 25 °C. 60 °C. 100 °C. O2 atmosphere. h N2
c
d
e
f
g
atmosphere.
With the optimized conditions in hand, the C–H acylation
reaction was explored with various aldehydes, as shown in
Scheme 1. This procedure was applicable for para- (3ab-ag, 58-
80%), and meta- substituted benzaldehydes (3ah, 73%).
Moreover, the reaction tolerated aldehydes bearing both
electron-donating (3ab) and electron-withdrawing (3ac-ag)
groups. Notably, some functional groups such as fluoro (3ae,
61%), chloro (3ac, 68%; 3ah, 73%), bromo (3ad, 64%), cyano
(3ag, 68%) and trifluoromethyl (3af, 58%) worked in good to
moderate yields, which provided handles for their further
functionalization. Typically, 1-(thiophen-3-yl)ethan-1-one gave
the acylation product 3ai in 43% yield. However, ortho-
substituted, aliphatic aldehydes (2j-2l) and unsaturated
2 | J. Name., 2012, 00, 1-3
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O
tetramethylpiperidinooxy (TEMPO) was added to the system
O
O
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Cu(OAc)2 (32 mol %)
R1
N
(Scheme 3, eq 1). The addition oDfOI:21,06.1-0d3i-9t/eCr9tO-bBu0t1y48l-64A-
methylphenol (BHT) also obviously suppressed the reaction
(Scheme 3, eq 2). Thus, these results indicated a radical
pathway should be involved in this reaction. Additionally, the
the competitive reaction of 2b and 2f under the standard
conditions of confirmed that the electron-donating group was
beneficial for this transformation, which could be attributed to
the stability of acyl radical intermediates (Scheme 3, eq 3).
Moreover, we conducted a reaction of methyl blocked
substrate 4a with benzaldehyde 2a under the standard
conditions, however, there is no product derived from C-H
acylation of the N-aryl moiety in 4a could be detected (Scheme
3, eq 4).
R1
PhCHO
Ph
N
+
K2S2O8 (1.37 equiv),
MeOH/H2O (1/1, 2 mL), 80 o
N
N
R2
R3
R3
C
F
R2
3ba-ia
1
2a
Cl
O
O
O
O
O
O
N
N
N
N
N
N
Ph
Ph
Ph
3ca
, 73%
O
3ba,
80%
O
3da
, 75%
Cl
NC
F3C
O
O
O
O
N
N
N
N
Ph
N
N
Ph
Ph
3ea
3fa
, 52%
, 49%
O
3ga
, 76%
O
ArCHO
O
Cl
O
O
S
O
K2S2O8
O
O
KO
O
N
N
O
N
N
N
N
Ar
Ph
Ph
Ph
O
Cu(II)
R3
O
Ar
3ha
, 80%
, R3 = n-Pr, 55%
Cu(III)
3ia
, 64%
O
3ja
O
N
, R3 = Ph, trace
N
3ka
Ph
A
B
O
O
N
O
Ph
N
Ph
H
N
N
N
O
N
O
Ph
Ph
HN
Ph
O
S
O
N
3la
, nr
N
3ma
Ph
, nr
KO
O
N
O
Ph
Scheme 2. Scope of Substituted Phenazones. Reaction conditions:
Conditions: 1 (0.25 mmol), 2a (0.37 mmol), K2S2O8 (0.37 mmol), Cu(OAc)2
(0.08 mmol, 32 mol %), MeOH/H2O (1/1, 2 mL), 80 °C, 12 h, under air in a
sealed Schlenk tube, unless otherwise noted.
Cu(II)
3aa
Cu(I)
Scheme 4. Possible Reaction Mechanism.
Based on the above mentioned experimental results and
14
former reported works,13,
a proposed mechanism was
O
H
outlined in Scheme 4. First, the homo-cleavage of K2S2O8
produces an O-centered radical, which abstracts the H
attached in the carbonyl leading to acyl radical. Meanwhile,
the reaction of phenazone 1a with Cu(OAc)2 provides the Cu(II)
species A. Then, the reaction of Cu(II) species A and acyl
radical affords the Cu(III) species B. Afterward, the reductive
elimination of Cu(III) species B delivers the acylation product,
along with the formation of Cu(I). Finally, Cu(I) is oxidized to
Cu(II) to fulfill the catalytic cycle.
Ph
O
O
standard conditions
TEMPO (3 eqiuv)
+
eq 1
N
PhCHO
N
N
1a
Ph
N
Ph
2a
3aa,
no detected
O
H
Ph
O
O
standard conditions
BHT (3 eqiuv)
+
N
PhCHO
2a
N
N
eq 2
N
1a
Ph
Ph
3aa,
21%
CH3
standard conditions
CF3
Conclusions
H
OHC
O
2b
2f
In conclusion, we have described a copper catalyzed direct
acylation of alkenyl C-H bond in 1,2-dihydro-3H-pyrazol-3-ones
with aldehydes as the acyl source, affording a series of 4-
acylpyrazolones in moderate to good yields. Notably, this
protocol has readily accessible substrates and reagents, good
functional group tolerance leading to pyrazolone derivatives
under mild reaction conditions.
3ab
3af
23%
eq 3
75%
N
N
Ph
1a
OHC
O
O
standard procedure
N
+
eq 4
PhCHO
N
N
N
Ph
O
Ph
5aa
4a
2a
, not detected
Experimental
Scheme 3. Inhibition and Competition Experiments.
General procedure for the synthesis of 3
A 20 mL of Schlenk tube equipped with a stir bar was
charged with substituted phenazone 1 (0.25 mmol, 1.0 equiv),
To gain more insight into the reaction mechanism, some
control experiments were conducted. The transformation was
completely inhibited when the radical scavenger 2,2,6,6-
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J. Name., 2013, 00, 1-3 | 3
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aldehyde 2 (0.37 mmol, 1.5 equiv), Cu(OAc)2 (14.5 mg, 32 mol 128.0 (d, JC-F = 4.5 Hz), 114.8 (d, JC-F = 21.8 Hz),Vi1ew06Ar.t5ic,le3O4nl.in0e,
+
DOI: 10.1039/C9OB01486A
%), K2S2O8 (0.37 mmol, 1.5 equiv) and MeOH/H2O (1/1, 2.0 12.5. MS (m/z): 310.1 [M] . HRMS (ESI) m/z calcd for
mL). The tube was sealed with a PTFE cap. The reaction C18H16FN2O2+ (M+H)+311.1190, found 311.1189.
mixture was stirred at 80 °C under air atmosphere for 12 h in
an oil bath. After the completion of the reaction, the mixture
was then allowed to cool to room temperature. The residue dihydro-3H-pyrazol-3-one
1,5-dimethyl-2-phenyl-4-(4-(trifluoromethyl)benzoyl)-1,2-
(3af). Flash column
was purified by flash column chromatography on silica gel with chromatography on a silica gel (petroleum ether : ethyl acetate,
petroleum ether-EtOAc (V1/V2, 1:1) as the eluent to give the 1: 1) give 3af (52.2 mg, 58% yield) as a orange solid. mp =
o
1
desired products 3.
165.3-166.2 C. H NMR (CDCl3, 400 MHz) δ 7.94-7.92 (d, J =
8.0 Hz, 2H), 7.65-7.63 (d, J = 8.0 Hz, 2H), 7.50-7.37 (m, 3H),
7.31-7.28 (m, 2H), 3.37 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz,
Characterization Data for the Products
4-benzoyl-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3- CDCl3) δ 189.5, 163.0, 156.8, 141.8, 133.6, 132.9 (d, JC-F = 32.3
one (3aa).13 Flash column chromatography on a silica gel Hz), 129.6, 129.5, 128.8, 126.7,123.9 (d, JC-F = 270.8 Hz),124.7
(petroleum ether : ethyl acetate, 1: 1) give 3aa (60.6 mg, 83% (d, JC-F = 3.8 Hz), 105.7, 33.8, 12.6. MS (m/z): 360.1 [M]+. HRMS
yield) as a white solid. H NMR (CDCl3, 400 MHz) δ 7.90-7.88 (ESI) m/z calcd for C19H16F3N2O2 (M+H)+ 361.1158, found
(m, 2H), 7.50-7.44 (m, 3H), 7.42-7.36 (m, 3H), 7.35-7.29 (m, 361.1155.
1
+
2H), 3,31 (s, 3H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.6,
163.1, 157.1, 138.6, 134.0, 132.1, 129. 5, 129.1, 128.3, 127.8,
126.4, 106.7, 34.0, 12.5. MS (m/z): 292.1 [M]+.
4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-
carbonyl)benzonitrile (3ag). Flash column chromatography
13
on a silica gel (petroleum ether: ethyl acetate, 1: 1) give 3ag
1,5-dimethyl-4-(4-methylbenzoyl)-2-phenyl-1,2-dihydro-
(53.9 mg, 68% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz)
3H-pyrazol-3-one (3ab).13 Flash column chromatography on a δ 7.80-7.75 (m, 2H), 7.56-7.52 (m, 2H), 7.51-7.46 (m, 2H), 7.42-
silica gel (petroleum ether : ethyl acetate, 1: 1) give 3ab (61.2 7.37 (m, 1H), 7.32-7.30 (m, 2H), 3.36 (s, 3H), 2.64 (s, 3H); 13C
1
mg, 80% yield) as a white solid. H NMR (CDCl3, 400 MHz) δ NMR (75 MHz, CDCl3) δ 189.0, 162.9, 156.7, 142.5, 133.5,
7.81-7.79 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.28 (m, 3H), 7.20- 131.5, 129.7, 129.6, 129.0, 126.8, 118.7, 114.6, 105.3, 33.8,
7.18 (d, J = 7.92 Hz, 2H), 3,28 (s, 3H), 2.55 (s, 3H); 13C NMR (75 12.6. MS (m/z): 317.1 [M]+.
MHz, CDCl3) δ 190.2, 163.1, 157.2, 142.7, 135.9, 134.2, 129.7,
129.4, 128.5, 128.2, 126.2, 107.2, 34.1, 21.7, 12.4. MS (m/z):
306.1 [M]+.
4-(3-chlorobenzoyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3ah). Flash column chromatography on a silica
gel (petroleum ether : ethyl acetate, 1: 1) give 3ah (59.5mg, 73%
o
1
4-(4-chlorobenzoyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H- yield) as a yellow solid. mp = 183.6-184.1 C. H NMR (CDCl3,
pyrazol-3-one (3ac).13 Flash column chromatography on a 400 MHz) δ 7.87-7.75 (m, 2H), 7.49-7.45 (m, 2H), 7.42-7.36 (m,
silica gel (petroleum ether : ethyl acetate, 1: 1) give 3ac (55.4 2H), 7.34-7.29 (m, 3H), 3.35 (s, 3H), 2.63 (s, 3H); 13C NMR (101
1
mg, 68% yield) as a white solid. H NMR (CDCl3, 400 MHz) δ MHz, CDCl3) δ 189.2, 163.1, 157.0, 140.4, 134.0, 133.9, 131.9,
7.84-7.82 (m, 2H), 7.49-7.45 (m, 2H), 7.40-7.34 (m, 3H), 7.31- 129.7, 129.2, 129.1, 128.8, 127.9, 126.8, 106.3, 34.0, 12.6. MS
+
7.28 (m, 2H), 3.35 (s, 3H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) (m/z): 326.1 [M]+. HRMS (ESI) m/z calcd for C18H16ClN2O2
δ 189.2, 163.0, 157.0, 138.2, 136.9, 133.8, 131.0, 129.5, 128.6, (M+H)+ 327.0895, found 327.0892.
128.0, 126.5, 106.3, 33.9, 12.5. MS (m/z): 326.1 [M]+.
1,5-dimethyl-2-phenyl-4-(thiophene-3-carbonyl)-1,2-
4-(4-bromobenzoyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H- dihydro-3H-pyrazol-3-one
(3ai).13
Flash
column
13
pyrazol-3-one (3ad).
Flash column chromatography on a chromatography on a silica gel (petroleum ether : ethyl acetate,
1
silica gel (petroleum ether: ethyl acetate, 1: 1) give 3ad (59.2 1: 1) give 3ah (32.0 mg, 43% yield) as a yellow solid. H NMR
1
mg, 64% yield) as a orange solid. H NMR (CDCl3, 400 MHz) δ (CDCl3, 400 MHz) δ 8.61-8.60 (m, 1H), 7.67-7.66 (m, 1H), 7.52-
7.91-7.88 (m, 2H), 7.68-7.66 (m, 2H), 7.51-7.46 (m, 2H), 7.42- 7.48 (m, 2H), 7.42-7.38 (m, 1H), 7.35-7.31 (m, 2H), 7.22-7.20
7.38 (m, 1H), 7.30-7.27 (m, 2H), 3.40 (s, 3H), 2.69 (s, 3H); 13C (m, 1H), 3.35 (s, 3H), 2.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
NMR (75 MHz, CDCl3) δ 189.4, 163.0, 156.9, 137.4, 133.8, 183.1, 163.1, 157.3, 142.1, 134.5, 134.2, 129.7, 128.6, 128.6,
131.1, 131.0, 129.5, 128.6, 126.9, 126.5, 106.2, 33.9, 12.5. MS 126.6, 124.4, 107.8, 34.1, 12.8. MS (m/z): 298.1 [M]+.
(m/z): 370.0 [M]+.
4-benzoyl-1,5-dimethyl-2-(p-tolyl)-1,2-dihydro-3H-pyrazol-
4-(4-fluorobenzoyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-
3-one (3ba). Flash column chromatography on a silica gel
pyrazol-3-one (3ae). Flash column chromatography on a silica (petroleum ether : ethyl acetate, 1: 1) give 3ba (61.2 mg, 80%
o
gel (petroleum ether : ethyl acetate, 1: 1) give 3ae (47.3 mg, 61% yield) as a yellow solid. mp = 139.5-140.3 C. 1H NMR (CDCl3,
o
yield) as a orange solid. mp = 153.8-154.6 C. 1H NMR (CDCl3, 400 MHz) δ 7.91-7.89 (m, 2H), 7.49-7.45 (m, 1H), 7.42-7.38 (m,
400 MHz) δ 7.97-7.94 (m, 2H), 7.52-7.48 (m, 2H), 7.42-7.38 (m, 2H), 7.28-7.26 (m, 2H), 7.20-7.18 (m, 2H), 3.34 (s, 3H), 2.62 (s,
1H), 7.34-7.31 (m, 2H), 7.12-7.06 (m, 2H), 3.38 (s, 3H), 2.65 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.8, 163.2,
3H); 13C NMR (75 MHz, CDCl3) δ 188.9, 165.2 (d, JC-F = 251.3 Hz), 156.4, 138.7, 132.2, 131.5, 130.2, 129.8, 129.6, 127.8, 126.8,
163.0, 157.1, 134.7, 134.7, 133.9, 132.2 (d, JC-F = 9.0 Hz), 128.5,
4 | J. Name., 2012, 00, 1-3
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106.8, 33.8, 21.3, 12.6. MS (m/z): 306.1 [M] +. HRMS (ESI) m/z 107.4, 34.6, 12.7. MS (m/z): 326.1 [M]+. HRMS (ESI) m/z calcd
View Article Online
+
calcd for C19H19N2O2+ (M+H)+ 307.1441, found 307.1438.
for C18H16ClN2O2 (M+H)+ 327.0895, founDdO3I2: 170..01083993/.C9OB01486A
4-benzoyl-2-(4-chlorophenyl)-1,5-dimethyl-1,2-dihydro-3H-
4-benzoyl-2-(2-chlorophenyl)-1,5-dimethyl-1,2-dihydro-3H-
pyrazol-3-one (3ca). Flash column chromatography on a silica pyrazol-3-one (3ha). Flash column chromatography on a silica
gel (petroleum ether : ethyl acetate, 1: 1) give 3ca (59.5 mg, 73% gel (petroleum ether : ethyl acetate, 1: 1) give 3ha (65.2 mg,
o
1
yield) as a yellow solid. mp = 161.5-162.3 C. 1H NMR (CDCl3, 80% yield) as a yellow solid. mp = 161.5-162.3 oC. H NMR
400 MHz) δ 7.89-7.86 (m, 2H), 7.51-7.47 (m, 1H), 7.45-7.38 (m, (CDCl3, 400 MHz) δ 7.90-7.88 (m, 2H), 7.55-7.52 (m, 1H), 7.45-
4H), 7.27-7.26 (m, 1H), 7.25-7.23 (m, 1H), 3.32 (s, 3H), 2.60 (s, 7.43 (m, 2H), 7.42-7.40 (m, 3H), 7.38-7.36 (m, 1H), 3.28 (s, 3H),
3H); 13C NMR (101 MHz, CDCl3) δ 190.5, 163.3, 158.4, 138.5, 2.63 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.7, 163.0, 154.8,
134.1, 132.8, 132.4, 129.8, 129.6, 128.0, 127.3, 107.3, 34.4, 138.7, 134.7, 132.5, 132.1, 131.8 131.6, 131.0, 129.6, 128.2,
12.7. MS (m/z): 326.1 [M]+. HRMS (ESI) m/z calcd for 127.8, 105.5, 32.8, 12.5. MS (m/z): 326.1 [M]+. HRMS (ESI) m/z
C18H16ClN2O2+ (M+H)+ 327.0895, found 327.0893.
calcd for C18H16ClN2O2+ (M+H)+ 327.0895, found 327.0893.
4-benzoyl-2-(4-fluorophenyl)-1,5-dimethyl-1,2-dihydro-3H-
4-benzoyl-1-butyl-5-methyl-2-phenyl-1,2-dihydro-3H-
pyrazol-3-one (3da). Flash column chromatography on a silica pyrazol-3-one (3ia). Flash column chromatography on a silica
gel (petroleum ether : ethyl acetate, 1: 1) give 3da (58.1 mg, gel (petroleum ether : ethyl acetate, 1: 1) give 3ia (53.4 mg, 64%
1
o
75% yield) as a yellow solid. mp = 153.8-154.6 oC. H NMR yield) as a yellow solid. mp = 105.5-106.3 C. 1H NMR (CDCl3,
(CDCl3, 400 MHz) δ 7.88-7.86 (m, 2H), 7.50-7.46 (m, 1H), 7.42- 400 MHz) δ 7. 89-7.87 (m, 2H), 7.50-7.45 (m, 3H), 7.42-7.35 (m,
7.37 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.11 (m, 2H), 3.32 (s, 3H), 3H), 7.33-7.30 (m, 2H), 3.76-3.74 (t, 2H), 2.65 (s, 3H), 1.52-1.44
2.60 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.6, 163.4, 162.3 (d, (m, 2H), 1.22-1.15 (m, 2H), 0.85-0.81 (t, 3H); 13C NMR (75 MHz,
JC-F = 247 Hz), 157.3, 138.6, 132.3, 130.2, 129.6, 128.6 (d, JC-F
=
CDCl3) δ 190.7, 163.8, 157.4, 138.6, 134.4, 132.0, 129.4, 128.2,
9 Hz), 127.9, 116.7 (d, JC-F = 23 Hz), 106.9, 34.0, 12.6. MS (m/z): 127.7, 126.3, 107.1, 46.3, 30.0, 19.6, 13.6, 12.6. MS (m/z):
310.1 [M]+. HRMS (ESI) m/z calcd for C18H16FN2O2 (M+H)+ 334.2 [M]+. HRMS (ESI) m/z calcd for C21H23N2O2 (M+H)+
+
+
311.1190, found 311.1189.
335.1754, found 335.1758.
4-benzoyl-1,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-1,2-
4-benzoyl-1-methyl-2-phenyl-5-propyl-1,2-dihydro-3H-
dihydro-3H-pyrazol-3-one
(3ea).
Flash
column pyrazol-3-one (3ja).13 Flash column chromatography on a silica
chromatography on a silica gel (petroleum ether : ethyl acetate, gel (petroleum ether : ethyl acetate, 1: 1) give 3ja (44 mg, 55%
o
1: 1) give 3ea (46.8 mg, 52% yield) as a yellow solid. mp = yield) as a yellow solid. mp = 118.7-119.5 C. 1H NMR (CDCl3,
o
165.5-166.3 C. 1H NMR (CDCl3, 400 MHz) δ 8.11-8.06 (m, 1H), 400 MHz) δ 7. 89-7.87 (m, 2H), 7.49-7.45 (m, 3H), 7.42-7.37 (m,
7.89-7.86 (m, 2H), 7.74-7.72 (m, 2H), 7.50-7.48 (m, 1H), 7.46- 3H), 7.33-7.30 (m, 2H), 3.36 (s, 3H), 3.01-2.97 (m, 2H), 1.83-
7.40 (m, 3H), 3.38 (s, 3H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) 1.75 (m, 2H), 1.12-1.08 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
δ 190.3, 163.2, 160.2, 138.2, 137.4, 133.3, 132.5, 129.4 (d, JC-F CDCl3) δ 190.5, 163.4, 161.0, 138.7, 134.1, 132.0, 129.4, 129.4,
= 33.0 Hz), 129.4, 128.4, 126.5 (d, JC-F = 3.8 Hz), 126.4 (d, JC-F
=
128.4, 127.8, 126.4, 106.3, 34.0, 27.7, 22.0, 14.1. MS (m/z):
222.0 Hz), 107.8, 34.9, 12.6. MS (m/z): 360.1 [M]+. HRMS (ESI) 320.2 [M]+.
m/z calcd for C19H16F3N2O2+ (M+H)+ 361.1158, found 361.1155.
Conflicts of interest
There are no conflicts to declare.
4-(4-benzoyl-2,3-dimethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl)benzonitrile (3fa). Flash column chromatography on a silica
gel (petroleum ether : ethyl acetate, 1: 1) give 3fa (38.8 mg, 49%
o
yield) as a yellow solid. mp = 180.6-181.0 C. 1H NMR (CDCl3,
400 MHz) δ 7.87-7.84 (m, 2H), 7.76-7.74 (d, J = 8.6 Hz, 2H),
7.54-7.41 (m, 5H), 3.38 (s, 3H), 2.63 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 190.2, 163.25, 161.9, 138.5, 138.2, 133.4, 132.7, 129.5,
128.1, 124.5, 118.3, 110.7, 108.5, 35.5, 12.9. MS (m/z): 317.1
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21602019, 21572025, and 21672028), “Innovation &
Entrepreneurship Talents” Introduction Plan of Jiangsu
Province, Natural Science Foundation of Jiangsu Province
(BK20171193), the Key University Science Research Project of
Jiangsu Province (15KJA150001), Jiangsu Key Laboratory of
Advanced Catalytic Materials & Technology (BM2012110), and
Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center for financial support.
+
[M]+. HRMS (ESI) m/z calcd for C19H16N3O2 (M+H)+ 318.1237,
found 318.1238.
4-benzoyl-2-(3-chlorophenyl)-1,5-dimethyl-1,2-dihydro-3H-
pyrazol-3-one (3ga). Flash column chromatography on a silica
gel (petroleum ether : ethyl acetate, 1: 1) give 3ga (61.9 mg, 76%
o
yield) as a yellow solid. mp = 162.5-163.3 C. 1H NMR (CDCl3,
400 MHz) δ 7.89-7.86 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.38 (m,
3H), 7.36-7.32 (m, 2H), 7.24-7.22 (m, 1H), 3.37 (s, 3H), 2.63 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 190.5, 163.4, 159.2, 138.5,
135.5, 135.2, 132.4, 130.5, 129.5, 128.3, 128.0, 125.9, 123.9,
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ARTICLE
Journal Name
Gradillas, A. G. Ovalles, B. Lopez, N. Acero, F. Llinares and D.
Notes and references
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