An unexpected and green synthetic protocol for ethyl 1-aroyl/aroylmethyl-5- methyl-3-methylthiopyrazole-4-carboxylates: High regioselectivity in alkylation and acylation reactions between n-1 and n-2 of a pyrazole ring

Article abstract of DOI:10.1002/jccs.200500143

Two series, totaling twelve, of new compounds, ethyl 1-aroyl/(aroylmethyl)- 5-methyl-3-methylthiopyrazole-4-carboxylates (5/6), have been synthesized via highly regioselectively acylation and alkylation reactions of ethyl 3-methyl-5-methylthio-1H-pyrazole

Full text of DOI:10.1002/jccs.200500143

Journal of the Chinese Chemical Society, 2005, 52, 1021-1028
1021
An Unexpected and Green Synthetic Protocol for Ethyl
1-Aroyl/Aroylmethyl-5-methyl-3-methylthiopyrazole-4-carboxylates: High
Regioselectivity in Alkylation and Acylation Reactions between N-1 and
N-2 of a Pyrazole Ring
Li-Rong Wena (
Wen-Ying Qia (
), Shu-Wen Wanga (
), Xiu-Li Zhangb (
), Ming Lia* (
),
) and Hua-Zheng Yangc (
)
aCollege of Chemistry and Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China
bOcean Food and Drug Institute, Ocean University of China, Qingdao 266003, P. R. China
cState Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
Two series, totaling twelve, of new compounds, ethyl 1-aroyl/(aroylmethyl)-5-methyl-3-methylthiopyr-
azole-4-carboxylates (5/6), have been synthesized via highly regioselectively acylation and alkylation reac-
tions of ethyl 3-methyl-5-methylthio-1H-pyrazole-4-carboxylate (2a) with aroyl chloride (3) and eco-friendly
reagents alpha-tosyloxysubstituted acetophenones (4), respectively, and a green protocol has been developed.
The acylation reactions were carried out under ultrasound irradiation, and the alkylation reactions were under
microwave irradiation and ultrasound irradiation, respectively. Conventional reaction conditions, as well as
the use of alpha-bromosubstituted acetophenone (4¢) have also been applied in the synthesis of some ran-
domly selected compounds in both series and have generated identical compounds correspondingly. Unex-
pected structures of compounds were unambiguously determined by X-ray crystallographic analysis.
Keywords: Pyrazole; Regioselectivity; X-ray crystallographic analysis; 2D NMR.
INTRODUCTION
It is known that a pyrazole ring has two main tauto-
we all know the one-dimensional 1H NMR, even plus IR, MS
and elemental analysis is unable to distinguish between either
of the two isomers of starting material 2 and the two potential
products generated from the alkylation or acylation at N-1 or
N-2 in each case. An attempt to determine the structure of 2a
by two-dimensional nuclear magnetic resonance (2D NMR)
spectroscopy was unsuccessful. 2D NMR spectrum of 2a ex-
hibited a broad singlet at d 11.60, which has been safely as-
meric isomers1-3 (as shown in Scheme I; one carbon atom has
been labeled by an asterisk in order to make the tautomerism
easier to understand) due to the migration of the proton at the
unsubstituted N-position between the two nitrogen atoms of
the pyrazole ring. Both (a) and (b) are the main isomers; how-
ever, (c), and the others are not, since they are highly unstable
due to the absence of a conjugate system which exists in both
(a) and (b). It still holds true in the case of the intermediate 2a
as also shown in Scheme I. Consequently, the acylation or
alkylation of the N-position of intermediate 2a has the possi-
bility to take place at the nitrogen atom near the methylthio
group or the one near the methyl group, or both. Taylor and
Purdum4 are the first to report the synthesis of 2 as a form of
the other isomer 2a. And so far, only Zhao,5 Fan,6 and their
coworkers have used this pyrazole derivative in their works
as a form of 2a rather than 2, both consequently reporting
acylated or alkylated products at the N-1 of 2a. The regio-
chemistry of the reported products by the above authors,
nonetheless, has never been unambiguously proved, and as
Scheme I Tautomerism occurring in the case of pyra-
zole and 2a
H
H
etc
N
*
N
*
N
*
H
N
H
N
N
(b)
(c)
(a)
H3C
H
COOEt
SCH3
COOEt
SCH3
COOEt
SCH3
H3C
H3C 3
N
4
5
etc
N
N
2
N
H
N
N
1
H
(2)
(2a)
(2b)

1022 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Wen et al.
signed to the proton in NH group. The broad singlet is caused
by the rapid migration of the proton in NH between the two
nitrogen atoms and has no coupling with any carbon atom in
the molecule, revealing that compound 2a exists as a mixture
of rapid tautomeric equilibrium in deuteriochloroform which
is basically the same solvent as the one in the synthesis of 5
(see experimental section). A plausible reaction mechanism
was herein proposed (Scheme III; see Results and Discus-
sion). Recently, Ren7 and coworkers have reported two
regioselective reactions between ethyl 5-amino-3-methyl-
thio-1H-pyrazole-4-carboxylate and 5-amino-3-methylthio-
1H-pyrazole-4-carbonitrile with iodomethane in acetone in
the presence of potassium carbonate, respectively (Scheme
II), but the result was less representative (with only one alkyl-
ating reagent, no acylating reagents and only one reaction
condition), and the reaction generated large amounts of iso-
mer when using 5-amino-3-methylthio-1H-pyrazole-4-car-
bonitrile. Herein we would like to report our systematic re-
search result with excellent regioselectivity, more represen-
tative alkylating reagents and acylating reagents with sub-
stituents from electron-withdrawing groups to electron-
donating ones, various reaction conditions (microwave irra-
diation, ultrasound irradiation, and conventional stirring at
room temperature or refluxing), and unambiguous character-
ization of the structures.
RESULTS AND DISCUSSION
Various substituents have been attached to the pyrazole
ring at 3-, 4-, or 5-position, but the functional groups at N-1
position have been mainly focused on alkyl and substituted-
phenyl groups. Zhao5 and coworkers consequently reported
the substituted formylation at N-1 of 2a with an attempt to
search lead compounds with good bioactivities, yet unfortu-
nately the compounds produced by acylation at “N-1 of 2a”
exhibited not very satisfactory fungicidal activities. Inspired
by all these facts, we hoped to synthesize a series of N-aro-
ylated 2a with an attempt to improve the fungicidal activities
of these compounds and explore other biological activities
through the modification of the substituents attached to the
benzene ring (Scheme III and Table 1). Unexpectedly, X-ray
crystallographic analysis (Fig. 1 for 5c) showed that the N-
position aroylation had occurred at N-1 in 2 rather than N-1 in
2a, and more surprisingly, the aroylation occurred at this po-
sition in the manner of high regioselectivity, with a result that
the aroylation occurred almost regiospecifically at this posi-
tion by the assay of High-Performance Liquid Chromatogra-
phy (HPLC), and less than one percent of the other isomer
was detected in all cases, that is, with R being from electron-
withdrawing groups (such as R3 = o-NO2-p-CF3 for 5c) to
Table 1. The compounds which have been synthesized
Scheme II A previously reported regioselective ex-
R
Compound
R
Compound
ample
R1 = p-Cl
5a
5b
5c
5d
5e
5f
R1 = p-F
6a
6b
6c
6d
6e
R2 = p-CF3
R2 = p-CH3
R3 = 2,5-dichloro
R4 = H
NH
H
2
SCH
H C
NH
3
R3 = o-NO2-p-CF3
R4-Ph = 2-Furyl
R5 = p-CH3O
R6 = m-CH3
H C
3
2
K CO
2
3
3
N
N
N
+
CH I
3
N
N
N
R
R5 = p-Cl
R
2
R
SCH
3
NH
SCH
3
R7 = p-C2H5O
5g
R= CN, COOEt
The ultrasound-assisted8 and microwave-promoted9-11
reactions have long been the focus of research interests and
have showed such advantages as enhanced reaction rates,
higher yields, milder reaction conditions, and higher selec-
tivities.
The alpha-haloketones are a class of versatile reagents
in organic synthesis; they are, however, difficult to obtain and
highly lachrymatory, toxic, and not readily available and
which have been replaced in this work by eco-friendly al-
pha-tosyloxyketones prepared from [hydroxy(tosyloxy)-
iodo]benzene (HTIB)12-14 and corresponding ketones in the
refluxing acetonitrile.

An Unexpected and Green Synthetic Protocol
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1023
electron-donating groups (such as R5 = p-CH3O for 5e), and
the reactions proceeding either under ultrasound irradiation
or under the conventional stirring at room temperature. En-
couraged by all these observations, we subsequently investi-
gated the application of this procedure to alkylation of N-1 of
2, with the alkylating reagents being alpha-tosyloxysubsti-
tuted acetophenones (4) or alpha-bromosustituted acetophen-
ones (4¢). And, to our surprise, the alkylation also occurred at
the N-1 in 2, rather than the previously reported N-1 in 2a,
which has also been unambiguously determined by X-ray

1024 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Wen et al.
1
crystallographic analysis (Fig. 2 for 6b). And the alkylation
reactions were more regioselective with the other isomer in
each case undetectable even by HPLC, regardless of the re-
action condition, and the substituent. A plausible reaction
mechanism was proposed (Scheme III) based on the facts that
2a exists as a mixture of rapid equilibrium in solution but its
N-alkylation of or N-acylation showed high regioselectivity.
The anion generated by the removal of the proton at N-1 in 2a
might well exist as a form of 2-1 rather than 2a-1, which is
presumably caused by (i) the repelling effect between the
negative charge of the anion 2a-1 and the more bulky methyl-
thio group than the methyl group; (ii) by the repelling effect
between the negative charge of the anion 2a-1 and the more
negative charge of the sulfur atom in methylthio group than
the methyl group (Scheme III); and (iii) the repelling effect
between the bulky acylating or alkylating reagents and the
more bulky methylthio group occurring when the remarkably
bulky acylating or alkylating reagents approach the negative
charge of the substrate (Fig. 3). Great care has been taken to
determine the proposed regiochemistry of the reported com-
pounds (5a-g and 6a-e). Up to now, all attempts to obtain sin-
gle crystals of the other compounds (in addition to the afore-
mentioned 5c and 6b) have been unsuccessful, and unfortu-
nately, our attempt to employ the 2D NMR technique to dis-
tinguish between the two possible regioisomers in each case
has also failed. The long-range H-13C couplings useful for
this purpose in 2D NMR technique (1H-1H NMR, HMQC and
HMBC) have not been detected (Fig. 4; exemplified by 5a
and 6d). Therefore, the structures of the other reported com-
pounds are based on the plausible reaction mechanism as de-
scribed above, and the involved steric and electronic repel-
ling effects have been strongly supported by similar earlier
reports.15-18
In addition to the synthesis of all the 5 under ultrasound
irradiation at room temperature and 6 under ultrasound mi-
crowave irradiation, some randomly selected compounds, 5a
and 5b, were also obtained by conventional reaction condi-
tions (stirring at room temperature), and 6a and 6c by con-
ventional refluxing in acetonitrile from 2 and corresponding
4 or under ultrasound irradiation at reflux temperature of
acetonitrile. In the case of the synthesis of 5, as summarized
in Table 2, utilizing ultrasound irradiation to replace the con-
ventional stirring significantly enhanced the reaction rates
and slightly improved the yields, while generating identical
compounds correspondingly, which have been substantiated
by m.p., mixed m.p., IR, and 1H NMR. In the case of the syn-
thesis of 6 by microwave irradiation and ultrasound irradia-
tion, respectively; the qualitative relationship of the reaction
time and reaction temperature was preliminarily studied. As
summarized in Table 3, under the ultrasound irradiation, the
reaction seemed to proceed more rapidly than it did under mi-
crowave irradiation, and the reason might well be that the re-
action temperature could go up to the reflux temperature of
acetonitrile (b.p. 81.6 °C; hot-water-bath temperature was
kept at 85-90 °C) in the case of ultrasound irradiation, while it
could only reach 60-70 °C in the case of microwave irradia-
tion. The above explanation was supported by a further study
(as shown in Table 3): when irradiated by microwave at
1200W (instead of 500W), the reaction could come to an end
in 10 minutes with basically unchanged isolated yield, in
which situation the reaction temperature also went up to the
H CS
3
COOEt
N
CH
H
N
C
2
ul long-range
e not been
O
Cl
(5a)

An Unexpected and Green Synthetic Protocol
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1025
reflux temperature of acetonitrile. It is worth noting that in
the case of microwave irradiation, the reacting system was
poorly mixed, that is, the solution and the solid proton-accep-
tor were not fully stirred; rather, the solid proton-acceptor
precipitated in the bottom of the solution. In reality, the mi-
crowave-assisted reactions were carried out discontinuously
(5 minutes each) with vigorous shaking at each end of a pe-
riod.
pyrazole derivatives regioselectively. Microwave and ultra-
sound irradiations were also applied in both reactions.
Also, some randomly selected compounds (6a and 6b)
were obtained from alpha-bromoacetophenones (4¢), in com-
parison with the alpha-tosyloxyacetophenones (4), in reflux-
ing acetonitrile with a result that the refluxing procedures
also generated the same compounds correspondingly in slight-
ly lower isolated yields but were overwhelmingly time-con-
suming (a period of around 10 hours was often necessary in
both cases).
EXPERIMENTAL
Melting points were measured with a RY-1 apparatus in
capillaries and were uncorrected. IR spectra were obtained on
a Nicolet 501P FT-IR instrument as KBr pellets. NMR (1H
NMR 13C NMR and 2D NMR, including HMQC and HMBC)
spectra were recorded on a Jeol JNM-ECP 600M spectrome-
ter (600 MHz) in DMSO-d6 (unless otherwise stated), and the
chemical shifts were expressed in ppm with reference to TMS
as internal standard. Coupling constants are reported in Hertz
(Hz). Elemental analyses were performed with a Perkin-
Elmer 2400 instrument. High-Performance Liquid Chro-
matographic assays were carried out employing a Waters
1525 instrument under conventional conditions. Thin layer
chromatography was used to monitor the course of reactions
and ascertain the purity of compounds, and detection of the
components was made by exposure to ultraviolet light. Ultra-
sound irradiations were carried out in a hot-water-bath (85-
90 °C) at 25 W using a CX-250 apparatus with the frequency
being 33 KHz. Microwave irradiations were performed using
a Galanz WP750L23-6 instrument at 2450 MHz, which has
been modified with a hole in the top of the oven equipped
with a refluxing condenser.
Pyrazole derivatives have been reported to possess var-
ious and potent bioactivities.19-22 And, we have determined
the fungicidal activity of the two series, totaling twelve, of
new compounds bearing pyrazole rings, and preliminary
studies showed that some of the title compounds exihibited
satisfactory antifungal activities (at 50 ppm) against Phoma
asparagi (5c, 5e and 6a) and Alternaria solani (5c, 5d, 6c and
6d), and further studies in herbicidal and other bioactivities
are underway.
CONCLUSION
In summary, we have developed an efficient and facile
protocol for the synthesis of ethyl 1-aroyl/(aroylmethyl)-5-
methyl-3-methylthiopyrazole-4-carboxylates (5/6) via a
highly regioselective nucleophilic substitution reaction of
ethyl 3-methyl-5-methylthio-1H-pyrazole-4-carboxylate (2a)
with aroyl chloride (3) and eco-friendly reagents alpha-tosyl-
oxysubstituted acetophenones (4), respectively. This protocol
might well have the potential to be extensively applied to the
acylation and alkylation at the N-position of N-unsubstituted
The intermediate 1 and synthon 2 were prepared ac-
cording to the literature procedures.4,23 4¢ was also prepared
by reported procedures.12-14
All the physical properties of 5 reported in this paper
were from the reactions under ultrasound irradiation. And all
physical properties of 6 were from the reactions under micro-
wave irradiation using alpha-tosyloxysubstituted acetophen-

1026 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
ones (4) as starting materials.
Wen et al.
Ethyl 1-(p-methoxybenzoyl)-5-methyl-3-methylthiopyra-
zole-4-carboxylate (5e)
General procedure for the synthesis of ethyl 1-aroyl-5-
methyl-3-methylthiopyrazole-4-carboxylates (5)
Substituted benzoic acid or furoic acid (5 mmol) was
dissolved in 10 mL of freshly distilled SOCl2. The resulting
solution was refluxed for around 4 hours, and the excessive
SOCl2 was evaporated in vacuo to afford crude compounds 3.
To the crude 3 were added 10 mL of CHCl3, 2 (1.000 g, 5
mmol) and NaOH (0.2 g, 5 mmol), and the suspended solu-
tion was stirred at room temperature or irradiated with ultra-
sound until the starting materials were completely consumed.
After the removal of solids in the reacting system by filtration
through a Hirsch funnel, the solvent was evaporated in vacuo
to give a residue, which was purified by recrystallization
from absolute ethanol.
Yield 72%. White needle-like crystals, m.p. 123-124
°C. IR (KBr) n: 1701, 1696; 1H NMR (CDCl3) d: 1.31 (t, 3H,
J = 7.8 Hz), 4.28 (q, 2H, J = 7.8 Hz), 2.38 (s, 3H), 2.81 (s,
3H), 7.10, 7.99 (dd, 4H, J = 7.8 Hz), 3.87 (s, 3H); Anal. Calcd
for C16H18N2O4S: C, 57.47%, H, 5.43%, N, 8.38%. Found: C,
57.49%, H, 5.45%, N, 8.39%.
Ethyl 1-(m-methylbenzoyl)-5-methyl-3-methylthiopyra-
zole-4-carboxylate (5f)
Yield 68%. White prism-like crystals, m.p. 115-116 °C.
IR (KBr) n: 1716, 1696; 1H NMR (CDCl3) d: 1.32 (t, 3H, J =
7.8 Hz), 4.30 (q, 2H, J = 7.8 Hz), 2.38 (s, 3H), 2.84 (s, 3H),
7.40-7.74 (m, 3H), 2.34 (s, 3H); Anal. Calcd for C16H18N2O3S:
C, 60.36%, H, 5.70%, N, 8.80%. Found: C, 60.34%, H,
5.72%, N, 8.82%.
Ethyl 1-(p-chlorobenzoyl)-5-methyl-3-methylthiopyra-
zole-4-carboxylate (5a)
Ethyl 1-(p-ethoxybenzoyl)-5-methyl-3-methylthiopyra-
zole-4-carboxylate (5g)
Yield 89%. White needle-like crystals, m.p. 101.5-
102.5 °C. IR (KBr) n: 1723, 1689; 1H NMR (CDCl3) d: 1.31
(t, 3H, J = 7.5 Hz), 4.27 (q, 2H, J = 7.5 Hz), 2.34 (s, 3H), 2.85
(s, 3H), 7.62, 7.95 (dd, 4H, J = 8.1 Hz); Anal. Calcd for
C15H15ClN2O3S: C, 53.25%, H, 4.47%, N, 8.28%. Found: C,
53.19%, H, 4.49%, N, 8.23%.
Yield 74%. White needle-like crystals, m.p. 147-148
°C. IR (KBr) n: 1703, 1687; 1H NMR (CDCl3) d: 1.31 (t, 3H,
J = 7.8 Hz), 4.28 (q, 2H, J = 7.8 Hz), 1.40 (t, 3H, J = 8 Hz),
4.28 (q, 2H, J = 8 Hz), 2.38 (s, 3H), 2.82 (s, 3H), 7.32, 8.36
(dd, 4H, J = 7.8 Hz); Anal. Calcd for C17H20N2O4S: C,
58.60%, H, 5.79%, N, 8.05%. Found: C, 58.56%, H, 5.76%,
N, 8.01%.
Ethyl 1-(p-trifluromethylbenzoyl)-5-methyl-3-methylthio-
pyrazole-4-carboxylate (5b)
Yield 85%. White needle-like crystals, m.p. 96.5-97
°C. IR (KBr) n: 1715, 1699; 1H NMR (CDCl3) d: 1.43 (t, 3H,
J = 7.8 Hz), 4.39 (q, 2H, J = 7.8 Hz), 2.41 (s, 3H), 2.99 (s,
3H), 7.75, 8.12 (dd, 4H, J = 8.6 Hz); Anal. Calcd for
C16H15F3N2O3S: C, 51.60%, H, 4.60%, N, 7.53%. Found: C,
51.55%, H, 4.63%, N, 7.55%.
General procedure for the synthesis of ethyl 1-aroyl-
methyl-5-methyl-3-methylthiopyrazole-4-carboxylates (6)
Into a 25 mL three-necked round-bottomed flask con-
taining 15 mL of acetonitrile, were introduced compound 2
(1.000 g, 5 mmol), 4 or 4¢ (5 mmol) and potassium carbonate
(1 g), followed by:
Ethyl 1-(o-nitro-p-trifluromethylbenzoyl)-5-methyl-3-
methylthiopyrazole-4-carboxylate (5c)
(i) the microwave irradiation at 500W or 1200W for a
specified period discontinuously (5 minutes each; vigorous
shaking at the end of each period) until the reaction was com-
pleted as indicated by TLC.
Yield 87%. White prism-like crystals, m.p. 147.5-148.5
°C. IR (KBr) n: 1736, 1709; 1H NMR (CDCl3) d: 1.31 (t, 3H,
J = 7.8 Hz), 4.28 (q, 2H, J = 7.8 Hz), 2.06 (s, 3H), 2.51 (s,
3H), 8.10, 8.60 (m, 3H); Anal. Calcd for C16H14F3N3O5S: C,
46.04%, H, 3.38%, N, 10.07%. Found: C, 46.11%, H, 3.35%,
N, 10.04%.
(ii) irradiation by ultrasound at 25W using a CX-250
apparatus for a specified period in a hot-water-bath (85-90
°C) until the reaction was completed.
(iii) the conventional refluxing in acetonitrile until the
reaction was completed.
Ethyl 1-(2-furoyl)-5-methyl-3-methylthiopyrazole-4-car-
boxylate (5d)
The resulting solution was filtered through a Hirsch
funnel to remove the solids existing in solution, and the sol-
vent was evaporated in vacuo to give a residue, which was pu-
rified by recrstallization from absolute ethanol.
Ethyl 1-[(p-fluorobenzoyl)methyl]-5-methyl-3-methylthio-
pyrazole-4-carboxylate (6a)
Yield 85%. White needle-like crystals, m.p. 130-131
°C. IR (KBr) n: 1718, 1693; 1H NMR (CDCl3) d: 1.31 (t, 3H,
J = 7.8 Hz), 4.28 (q, 2H, J = 7.8 Hz), 2.50 (s, 3H), 2.85 (s,
3H), 6.80-8.20 (m, 3H); Anal. Calcd for C13H14N2O4S: C,
53.05%, H, 4.80%, N, 9.52%. Found: C, 53.09%, H, 4.78%,
N, 9.55%.
Yield 87%. White needle-like crystals, m.p. 157-158

An Unexpected and Green Synthetic Protocol
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1027
°C. IR (KBr) n: 3066, 1702, 1688, 1507, 1544, 1596, 1495,
1270, 1230; 1H NMR (CDCl3) d: 1.29 (t, 3H, J = 7.1 Hz), 4.21
(q, 2H, J = 7.1 Hz), 2.37 (s, 3H), 2.37 (s, 3H), 5.92 (s, 2H),
7.45, 8.17 (t+q, 2H+2H, 3JH-H = 3JH-F = 8.7 Hz, 4JH-F = 5.7 Hz);
Anal. Calcd for C16H17FN2O3S: C, 57.13%, H, 5.10%, N,
8.33%. Found: C, 57.36%, H, 5.11%, N, 8.37%.
Ethyl 1-[(p-methylbenzoyl)methyl]-5-methyl-3-methyl-
thiopyrazole-4-carboxylate (6b)
equipped with a graphite monochromated MoKalpha radia-
tion (l = 0.71073 Å) with an w scan mode in the range of 2.50
£ q £ 26.40° at 293(2) K. A total of 5352 reflections were col-
lected with 3739 unique ones (Rint = 0.021), of which 2273 re-
flections with I > 2s(I) were considered to be observed and
used in the succeeding refinements. Intensity data were cor-
rected for Lp factors and empirical absorption. The structure
was solved by direct methods and expanded by using Fourier
differential techniques with SHELXL-97. All non-hydrogen
atoms were located with successive difference Fourier syn-
theses. The structure was refined by full-matrix least-squares
method on F2 with anisotropic thermal parameters for all
non-hydrogen atoms. Hydrogen atoms were added according
to the theoretical models. Full matrix least-squares refine-
ment gave the final wR2 = 0.1273 and wR = 0.0467, W =
Yield 85%. White prism-like crystals, m.p. 136-137 °C.
IR (KBr) n: 3064, 1696, 1680, 1606, 1539, 1493, 1268, 1233;
1H NMR (CDCl3) d: 1.29 (t, 3H, J = 7.1 Hz), 4.21(q, 2H, J =
7.1 Hz), 2.36 (s, 3H), 2.37 (s, 3H), 5.88 (s, 2H), 2.51 (s, 3H),
7.41, 7.98 (dd, 2H+2H, J = 8.1 Hz); Anal. Calcd for
C17H20N2O3S: C, 61.42%, H, 6.07%, N, 8.43%. Found: C,
61.39%, H, 6.04%, N, 8.46%.
1/[s2(F0 ) + (0.1014P)2 + 0.29P], where P = (Fo2+2Fc2)/3, S
2
Ethyl 1-[(2,5-dichlorobenzoyl)methyl]-5-methyl-3-methyl-
thiopyrazole-4-carboxylate (6c)
= 1.000, (D/s)max = 0.000 e/Å3 (Dr)max = 0.180 e/Å3, (Dr)min
=
Yield 90%. White needle-like crystals, m.p. 130-132
°C. IR (KBr) n: 3072, 1733, 1691, 1462, 1492, 1535, 1269,
1202; 1H NMR (CDCl3) d: 1.29 (t, 3H, J = 7.1 Hz), 4.22 (q,
2H, J = 7.1 Hz), 2.38 (s, 3H), 2.41 (s, 3H), 5.79 (s, 2H), 7.67,
8.11 (d+m, H+2H); Anal. Calcd for C16H16Cl2N2O3S: C,
49.74%, H, 4.81%, N, 7.25%. Found: C, 49.88%, H, 4.79%,
N, 7.31%.
-0.230 e/Å3. The crystal belongs to a Triclinic, space group
P-1 with a = 8.450(3), b = 8.798(3), c = 13.604(4) Å, a =
98.903(6), b = 98.903(6)°, g = 109.126(5), V = 922.4(5) Å3, Z
= 2, Dc = 1.503 g/cm3, m = 0.239 mm-1, F(000) = 428.
Crystal structure determination of 6b
A colorless crystal of the compound 6b with a dimen-
sion of 0.22 mm ´ 0.18 mm ´ 0.12 mm was mounted on a
glass fiber in a random orientation. X-ray diffraction was per-
formed on a BRUKER SMART 1000 CCD diffractometer
equipped with a graphite monochromated MoKalpha radia-
tion (l = 0.71073 Å) with an w scan mode in the range of 3.03
£ q £ 22.60° at 293(2) K. A total of 8715 reflections were col-
lected with 3064 unique ones (Rint = 0.0351), of which 1982
reflections with I > 2s(I) were considered to be observed and
used in the succeeding refinements. Intensity data were cor-
rected for Lp factors and empirical absorption. The structure
was solved by direct methods and expanded by using Fourier
differential techniques with SHELXL-97. All non-hydrogen
atoms were located with successive difference Fourier syn-
theses. The structure was refined by full-matrix least-squares
method on F2 with anisotropic thermal parameters for all
non-hydrogen atoms. Hydrogen atoms were added according
to the theoretical models. Full matrix least-squares refine-
ment gave the final wR2 = 0.1399 and wR = 0.0351, W =
Ethyl 1-(benzoylmethyl)-5-methyl-3-methylthiopyrazole-
4-carboxylate (6d)
Yield 69%. White needle-like crystals, m.p. 138-139
°C. IR (KBr) n: 3060, 1702, 1700, 1598, 1546, 1491, 1449,
1272, 1227; 1H NMR (CDCl3) d: 1.29 (t, 3H, J = 7.1 Hz), 4.22
(q, 2H, J = 7.1 Hz), 2.37 (s, 3H), 2.41 (s, 3H), 5.77 (s, 2H),
7.29, 7.83 (t+m, H+4H); Anal. Calcd for C16H18N2O3S: C,
60.36%, H, 5.71%, N, 8.80%. Found: C, 60.30%, H, 5.73%,
N, 8.83%.
Ethyl 1-[(p-chlorobenzoyl)methyl]-5-methyl-3-methylthio-
pyrazole-4-carboxylate (6e)
Yield 87%. White needle-like crystals, m.p. 145-146
°C. IR (KBr) n: 3087, 1679, 1699, 1590, 1535, 1491, 1268,
1227; 1H NMR (CDCl3) d: 1.29 (t, 3H, J = 7.1 Hz), 4.22 (q,
2H, J = 7.1 Hz), 2.37 (s, 3H), 2.37 (s, 3H), 5.93 (s, 2H), 7.69,
8.09 (dd, 2H+2H, J = 8.1 Hz); Anal. Calcd for C16H17ClN2O3S:
C, 54.54%, H, 4.87%, N, 7.95%. Found: C, 54.59%, H,
4.89%, N, 7.99%.
1/[s2(F0 ) + (0.1014P)2 + 0.29P], where P = (Fo2+2Fc2)/3, S
2
Crystal structure determination of 5c
= 1.004, (D/s)max = 0.000 e/Å3 (Dr)max = 0.213 e/Å3, (Dr)min
=
A colorless crystal of the compound 5c with a dimen-
sion of 0.28 mm ´ 0.36 mm ´ 0.38 mm was mounted on a
glass fiber in a random orientation. X-ray diffraction was per-
formed on a BRUKER SMART 1000 CCD diffractometer
-0.159 e/Å3. The crystal belongs to a monoclinic, space group
P21/c with a = 16.690(6), b = 7.771(3), c = 13.720(4) Å, a =
90.00, b = 101.969(6), g = 90.00, V = 1740.8(10) Å3, Z = 4, Dc
= 1.268 g/cm3, m = 0.201 mm-1, F(000) = 704.

1028 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Wen et al.
Huaxue 2003, 20, 365.
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8. Peng, Y. Q.; Song, G. H. Green Chem. 2001, 302.
9. Chen, S. T.; Chiou, S. H.; Wang, K. T. J. Chinese Chem. Soc.
1991, 38, 85.
Crystallographic data (excluding structure factor) for
the structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publi-
cation numbers CCDC 240135 for 5c and CCDC 240136 for
6b.
10. Lu, T. J.; Tzeng, G. M. J. Chinese Chem. Soc. 2000, 47, 189.
11. Anshu, D.; Ruby, S.; Harshita, S.; Rajive, G.; Satya, P. J.
Chinese Chem. Soc. 2003, 50, 273.
ACKNOWLEDGMENTS
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The authors are very grateful to the Natural Science
Foundation of Shandong Province (No. Y2003B01) and the
National Science Foundation of China (No. 20172031) for fi-
nancial support.
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