Utilization of hypervalent iodine in organic synthesis: A novel and facile two-step protocol for the synthesis of new derivatives of 1H-imidazo[1,2-b] pyrazole by the cyclocondensation involving α-tosyloxyacetophenones

Article abstract of DOI:10.1002/jhet.5570420205

A series of new 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2- e]pyrazoles (5) have been synthesized in moderate to good yields, via a two-step cyclocondensation procedure of 5-amino-4-cyano/ethoxycarbonyl-3-methylthio-1H- pyrazole (1) and α-b

Full text of DOI:10.1002/jhet.5570420205

March 2005
209
Utilization of Hypervalent Iodine in Organic Synthesis: A Novel and
Facile Two-Step Protocol for the Synthesis of New Derivatives
of 1H-Imidazo[1,2-b]Pyrazole by the Cyclocondensation involving
α-Tosyloxyacetophenones
†‡
†
†
†
Ming Li* , Guilong Zhao , Lirong Wen , Wei Cao ,
†
‡
Shusheng Zhang , Huazheng Yang
†
College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao,
266042, P. R. China
State Key Laboratory of Elemental Organic Chemistry, Nankai University, Tianjin, 300071, P. R. China
‡
Received July 21, 2004
A series of new 2-aryl-7-cyano/ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]pyrazoles (5) have been
synthesized in moderate to good yields, via a two-step cyclocondensation procedure of 5-amino-4-
cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole (1) and α-bromoacetophenones (3) or α-tosyloxyaceto-
phenones (2), which were prepared by the reactions of acetophenones with [hydroxy(tosyloxy)iodo]benzene
(HTIB). The intermediates, 5-amino-1-(aroylmethyl)-4- cyano/ethoxycarbonyl-3-methylthio-1H-pyrazoles
(4), have been isolated, serving as evidence for the regioselectivity. When utilizing α-tosyloxy-acetophe-
nones, the reactions were more eco-friendly, the reaction time was significantly reduced and the synthetic
procedure was more convenient and easier to manipulate. Surprisingly, using potassium carbonate to dis-
place sodium carbonate in the synthesis of 4, in the case of 1 (R= CN), two novel cyclocondensation prod-
ucts have been isolated and fully characterized, followed by the proposal of a plausible mechanism.
J. Heterocyclic Chem., 42, 209 (2005).
Imidazo[1,2-b]pyrazole derivatives have rarely been
reported; they, however, exhibit various bioactivities [1-7].
Inspired by these observations, we are interested in inves-
tigating the synthetic methods and bioactivities of these
fused heterocyclic compounds.
There have been a variety of methods for the synthesis
of imidazo[1,2-b]pyrazoles [1,5-13], among which, how-
ever, many involved tedious and time-consuming multi-
step procedures. Consequently, we would like to herein
report a novel and facile two-step protocol for this hetero-
cyclic nucleus.
The α-haloketones are useful and versatile reagents in
organic synthesis, which are, nevertheless, difficult to obtain
and highly lachrymatory, toxic, and not readily available. In
this work they have been replaced by eco-friendly reagents
such as α-tosyloxyketones (α-tosyloxyacetophenones in
these cases). The α-tosyloxyacetophenones were prepared
by the α-tosyloxylation of acetophenones with a exten-
sively employed and versatile hypervalent iodine reagent,
[hydroxy(tosyloxy)iodo]benzene (HTIB) in refluxing ace-
tonitrile [14-17]. Encouraged by all these observations, we
now would like to report an eco-friendly and easily manipu-
lated protocol for the synthesis of a series of new and poten-
tially bioactive derivatives of 1H-imidazo[1,2-b]pyrazole
(5) by a two-step cyclocondensation reaction of 5-amino-4-
cyano/ethoxycarbonyl-3-methylthio-1H-pyrazole (1) and
α-bromoacetophenones (3) or α-tosyloxyacetophenones
(2). The syntheses of all compounds involved 2, some ran-
domly selected compounds (4a, 4b and 4c) involved 3,
which was used in comparison with 2, to ensure that the
properties of leaving groups would not affect the regioselec-
tivity between the nucleophilic substitution of 1 to 3.
Results and Discussion.
Compounds 4, 5, 6 and 7 were synthesized through the
procedure involving 2. The randomly selected compounds
4a, 4b and 4c have been through the procedure involving
3. Both procedures gave identical compounds as proven
1
through melting points, IR, and H NMR. However,
employing 2 rather than 3 showed such advantages as
reduced reaction time, enhanced isolated yields and a more
eco-friendly procedure.
Theoretically, the reaction of 1 with 2 or 3 may not gen-
erate the compounds 5 under a single reaction condition.
The reason is that the first step, a nucleophilic substitution
(Scheme 1), usually requires alkaline conditions to remove
the proton of 1 in order to improve the nucleophilicity of
the endocyclic nitrogen, while the second step often
requires an acidic one to improve the electrophilicity of the
carbonyl group. The acidic conditions in the second step
may be required because the electron-withdrawing effect
of the pyrazole ring significantly reduces the nucleophilic-
ity of the exocyclic amino group, and electron-withdraw-
ing conjugate effect of benzene ring also reduces elec-
trophilicity of the carbonyl group. We have substantiated
the aforementioned acidic reaction conditions by provid-
ing an acidic atmosphere through the addition of several
drops of concentrated hydrochloric acid in absolute
ethanol. This improved the electrophilicity of the carbonyl
group of 4, allowing the cyclocondensation reaction of 4 to
furnish 5 after several hours at reflux.
In theory, the reaction of 1 with 2 or 3 may produce 4 or
its regioisomer 4-1 because of the possibility that both the
endocyclic and exocyclic nitrogen atoms can attack the

210
M. Li, G. L. Zhao, L. R. Wen, W. Cao, S. S. Zhang, H. Z. Yang
Vol. 42
carbon atom at the α-position of 2 or 3 under alkaline con-
ditions. The cyclocondensation of 4 or 4-1 would produce
5 or its tautomer 5-1, and 5-2 or its tautomer 5-3, respec-
tively. This is based on the principle that equilibrium usu-
ally exists between the imine and enamine structures
(Scheme 2). The isolation of intermediates 4, as pure com-
pounds whose structures have been unambiguously char-
acterized, provide strong evidence for the proposed mech-
anism that 1 with 2 or 3 react highly regioselectively. The
reason for this observation is that the endocyclic nitrogen
atom is more nucleophilic than that of the exocyclic nitro-
gen atom due to the electron-withdrawing effect of the
pyrazole ring. Under acidic conditions the cyclocondensa-
tion reaction of intermediates 4 yields products 5. The
overall thermodynamic stability of 5 is greater than that of
5-1, because structure 5 is fully conjugated while that of 5-
1 is not. In structure 5-1 the CH group disrupts the conju-
2
gation system compared with that of 5, which cannot be
compensated for by the more stable imine sub-structure.
An interesting phenomenon was observed when 1
(R'=CN) reacted with 2 or 3. When 1 (R'=CN) reacted with
2 or 3 in the presence of sodium carbonate, the reaction
generated 4 followed by the cyclocondensation under an
acidic condition to give 5, as described above. However,
when the reaction was carried out in the presence of potas-
sium carbonate, two novel compounds, 6 and 7, were iso-
lated and identified unexpectedly (Scheme 1). When 1
(R'=COOEt) was used, the above phenomenon was not
observed. That is, the reaction of 1 (R'=COOEt) with 2 or
3 generated 4, with neither 6 nor 7 being detectable.
Scheme 1
Synthetic route for the synthesis of compounds 4, 5, 6 and 7.

March 2005
Utilization of Hypervalent Iodine in Organic Synthesis
211
A plausible mechanism for the formations of 6 and 7 is
proposed in Scheme 3. X. L. Ren et al [18] recently
reported a regioselective reaction occurring in the case of
methylation of 1 (R'= COOEt or CN) in presence of potas-
sium carbonate in acetone (Scheme 3 section one), where
the regioselectivity methylated products are formed
through anion intermediates. When R'=COOEt, the methy-
lation occurred almost exclusively at the N-position near
the amino group to afford the product BIII, which agrees
with our result (the highly regioselective formation of 4a-
b). However when R'=CN, the reported methylated ratio of
AII to AIII is 83:100. This also also agrees well with our
results, where the amounts of 6 and 7 were comparable
(Scheme 3, section two). A detailed mechanism is shown
for the formation of 6 and 7 is shown in Scheme 4. The for-
mation of 6 seems to be inconsistent with formation of 5
rather than its tautomer 5-1. Perhaps, the role played by
potassium ion can be reasonably stated as follows: the
potassium ion stabilizes the generated anion thus diminish-
ing the nucleophilic character of the endocyclic nitrogen
atom. On the other hand, concerning the function of R', we
believe that an intramolecular hydrogen bond can be
formed between COOEt and the amino group at C-4 posi-
tion in the case of R'= COOEt, but it can not in the case of
R'= CN. However, further investigation into the reason is
under way in our laboratory.
The novel structures of 6 and 7, as well as the reaction
procedure have great potential for applications in the syn-
thesis of bioactive analogues. Great care has been taken in
the determination of the novel structure of compound 7,
1
which was based on IR, H NMR, MS, and elemental
analysis. As summarized in the experimental section, the
1
IR, H NMR, and elemental analysis are all in good accor-
dance with the proposed structure; nevertheless, the MS
spectrum showed no molecular ion peak even employing
electrospray ionization technique (ESI), but only several
reasonable fragment ion peaks which were in good agree-
ment with the above structure (Scheme 5).
The imidazo[1,2-b]pyrazole derivatives, have been
mainly reported to be anti-cancer reagents[3-6]. We herein
would like to report their fungicidal activity, with the result
that both the intermediates and the title compounds exhib-
ited certain inhibitory activities (at 50 ppm) against
Gibberella zeae (4a), Alternaria solani (4d and 5e) and
Phoma asparagi (5e) [19]. Further studies on other bioac-
tivities are also under investigation.
Scheme 2
The proposed reaction pathway for cyclocondensation.

212
M. Li, G. L. Zhao, L. R. Wen, W. Cao, S. S. Zhang, H. Z. Yang
Vol. 42
Scheme 3
The proposed reaction mechanism for the formation of 6 and 7.
Scheme 4
Detailed mechanism for the formation of 6 and 7.

March 2005
Utilization of Hypervalent Iodine in Organic Synthesis
213
Scheme 5
Proposed structures for fragment ions observed in the ESI-MS spectrum of compound 7.
EXPERIMENTAL
In a typical procedure, 1.961 g (5 mmol) of [hydroxy(tosy-
loxy)iodo]benzene (HTIB) and 5 mmol of p-methylacetophenone
were dissolved in 30 mL of acetonitrile, and the solution was
refluxed for about 45 minutes until the starting materials disap-
peared, as indicated by tlc, to obtain a solution of 2a in
acetonotrile [14-17]. After cooling, 5 mmol of 1 and 0.5 g of
sodium carbonate were added to the above solution, and the sus-
pended solution was then refluxed for another 3 hours until com-
pletion of the reaction, as indicated by tlc. A similar workup to
the procedure through α-bromoacetophenones 3a gave the pure
intermediate 4a.
Melting points were determined with RY-1 apparatus in capil-
laries and are uncorrected. IR spectra were obtained on a Nicolet
501P FT-IR spectrophotometer as KBr plates. H NMR spectra
1
were recorded on a Jeol JNM-ECP 600M or on a Bruker AC-300
spectrometer in DMSO-d , and the chemical shifts were
6
expressed in ppm with reference to TMS as internal standard.
The elemental analyses were performed with a Yanaco MT-3
CHN analyzer or Vario EL III analyzer. Mass specta was
obtained on a Thermo Finnigan LCQ Advantage instrument
employing the technique of electrospray ionization (ESI).
Column chromatography was carried out using Silica Gel H-60
(Qingdao Haiyang Co. Ltd., 60-100 mesh). Thin layer chro-
matography (Whatman K6F) was used to control the course of
reactions and ascertain the purity of the reported compounds, and
detection of the components was made by exposure to ultraviolet
light. Compound 1 was prepared according to the literature
procedure [20].
5-Amino-1-(p-methylbenzoylmethyl)-4-ethoxycarbonyl-3-
methylthio-1H-pyrazole (4a).
This compound was obtained as white needle, yield 77%; mp
162.5-163.5°; ir: 1695 (C=O, of ester), 1687 (C=O, of ketone),
-1 1
3242, 3324(N-H) cm . H nmr: δ 1.26 (t, 3H, J = 7Hz, CH CH ),
2
3
4.18 (q, 2H, J = 7Hz; CH CH ), 2.30 (s, 3H, SCH ), 5.55 (s, 2H,
2
3
3
NCH ), 6.35 (s, 2H, NH ), 7.39, 7.93 (dd, 4H, J= 8.7 Hz Ph-H),
2
2
2.41 (s, 3H, Ph-CH ).
3
General Procedure for the Synthesis of 4 via α-Bromoaceto-
phenones (3).
Anal. Calcd. for C
H N O S: C, 57.64; H, 5.75; N, 12.61.
16 19 3 3
Found: C, 57.66; H, 5.74; N, 12.63.
In a typical procedure, a suspended solution of 5 mmol of 1, 5
mmol of p-methyl-α-bromoacetophenone (3a), which was pre-
pared from p-methylacetophenone and bromine according to the
literature [21], and 0.5 g of sodium carbonate in 30 mL of ace-
tonitrile was refluxed for around 10 hours until the starting mate-
rial was consumed completely, as indicated by tlc. On cooling,
the solid was removed through filtration, and the filtrate was
evaporated to give crude 4a, which was purified by column chro-
matography using ethyl acetate/petroleum ether (1:4) as eluent.
5-Amino-1-(p-chlorobenzoylmethyl)-4-ethoxycarbonyl-3-
methylthio-1H-pyrazole (4b).
This compound was obtained as white needle, yield 69%; mp
174-175°; ir: 1698 (C=O, of ester), 1670 (C=O, of ketone),
-1
1
3240, 3325(N-H) cm
. H nmr: δ 1.27 (t, 3H, J = 7Hz,
CH CH ), 4.17 (q, 2H, J = 7Hz, CH CH ), 2.30 (s, 3H, SCH ),
2
3
2
3
3
5.58 (s, 2H, NCH ), 6.37 (s, 2H, NH ), 7.67, 8.04 (dd, 4H, J=
2
2
8.7 Hz, Ph-H).
Anal. Calcd. for C
H
ClN O S: C, 50.98; H, 4.57; N, 11.90.
General Procedure for the Intermediate (4) via α -
Tosyloxyacetophenones (2).
15 16
3 3
Found: C, 50.96; H, 4.56; N, 11.88.

214
M. Li, G. L. Zhao, L. R. Wen, W. Cao, S. S. Zhang, H. Z. Yang
Vol. 42
5-Amino-1-(p-fluorobenzoylmethyl)-4-cyano-3-methylthio-1H-
pyrazole (4c).
2-(p-Fluorophenyl)-7-ethoxycarbonyl-6-methylthio-1H-imi-
dazo[1,2-b]pyrazole (5d).
This compound was obtained as white needle, yield 58%; mp
168-169°; ir: 1658 (C=O, of ester), 3159 (=C-H), 3269 (N-H)
This compound was obtained as white prism, yield 79%; mp
148-149°; ir: 2207 (CN), 1701 (C=O, of ketone), 3251, 3363 (N-
-1 1
-1
1
cm . H nmr: δ 1.31 (t, 3H, J = 7 Hz; CH CH ), 4.24 (q, 2H, J =
H) cm . H nmr: δ 2.42 (s, 3H, SCH ), 5.58 (s, 2H, CH ), 6.77
2
3
3
2
3
3
7 Hz; CH CH ), 2.48 (s, 3H, SCH ), 8.22 (s, 1H, =CH), 12.24 (s,
(s, 2H, NH ), 7.40~7.46, 8.08~8.13 (t+q, 2H+2H, J
= J
2
3
3
2
H-H
H-F
4
1H, NH), 7.33, 7.89 (mm, 4H, J= 8.8 Hz, Ph-H) [22].
Anal. Calcd. for C FN O S: C, 56.41; H, 4.42; N, 13.17.
= 8.7 Hz, J
= 5.7Hz, Ph-H).
H-F
H
Anal. Calcd. for C H FN OS: C, 53.78; H, 3.82; N, 19.31.
15 14
3 2
13 11
4
Found: C, 56.43; H, 4.41; N, 13.15.
Found: C, 53.79; H, 3.81; N, 19.33.
2-Phenyl-7-ethoxycarbonyl-6-methylthio-1H-imidazo[1,2-b]-
pyrazole (5e).
5-Amino-1-(p-methylbenzoylmethyl)-4-cyano-3-methylthio-1H-
pyrazole (4d).
This compound was obtained as white needle, yield 60%; mp
166-167°; ir: 3346, 3251, (N-H), 3127 (=C-H), 1680 (C=O, of
This compound was obtained as white prism, yield 72%; mp
148-149°; ir: 2215 (CN), 1694 (C=O, of ketone), 3220, 3327 (N-
-1
1
ester) cm . H nmr: δ 1.33 (t, 3H, J = 7Hz, CH CH ), 4.26 (q,
-1
1
2
3
H) cm . H nmr: δ 2.41 (s, 3H, SCH ), 2.43 (s, 3H, Ph-CH ),
3
3
2H, J = 7Hz, CH CH ), 2.48 (s, 3H, SCH ), 8.25 (s, 1H, =CH),
2
3
3
5.68 (s, 2H, CH ), 6.71 (s, 2H, NH ), 7.39~7.41, 7.93~7.96 (dd,
2
2
12.24 (s, 1H, NH) 7.47-7.85 (m, 5H, Ph-H).
Anal. Calcd. for C N O S: C, 59.78; H, 5.02; N, 13.95.
2H+2H, J 8.2 Hz, Ph-H).
H
15 15
3 2
Anal. Calcd. for C
H N OS: C, 58.72; H, 4.93; N, 19.58.
14 14 4
Found: C, 59.76; H, 5.02; N, 13.97.
Found: C, 58.74; H, 4.94; N, 19.56.
2-(p-Fluorophenyl)-7-cyano-6-methylthio-1H-imidazo[1,2-b]-
pyrazole (5f).
General Procedure for the Cyclocondensation of 4.
In a typical procedure, crude 4a, which was obtained from
either α-bromoacetophenone 3a or α-tosyloxyacetophenone 2a,
was dissolved in 30 mL of absolute ethanol, followed by the
addition of several drops of concentrated hydrochloric acid. The
resulting solution was then refluxed for around 3 hours, and
cooled to room temperature. The solution was then evaporated in
vacuo to afford crude 5a, which was crystallized from absolute
ethanol to afford pure final product 5a.
This compound was obtained as white needle, yield 88%; mp
-1
1
278° (dec); ir: 2218 (CN), 3012 (=C-H), 3183 (N-H) cm . H
nmr: δ 2.59 (s, 3H, SCH ), 8.35 (s, 1H, =CH), 7.33~7.39,
3
3
3
4
7.77~7.82 (t+q, 2H+2H, J
= J
= 8.7 Hz, J
= 5.7 Hz,
H-H
H-F
H-F
Ph-H), 12.93 (s, 1H, NH).
Anal. Calcd. for C H FN S: C, 57.34; H, 3.33; N, 20.59.
13
9
4
Found: C, 57.36; H, 3.34; N, 20.57.
2-(p-Methylphenyl)-7-cyano-6-methylthio-1H-imidazo[1,2-b]-
pyrazole (5g).
2-(p-Methylphenyl)-7-ethoxycarbonyl-6-methylthio-1H-imi-
dazo[1,2-b]pyrazole (5a).
This compound was obtained as white needle, yield 83%; mp 260°
(dec); ir: 2222 (CN), 3096 (=C-H), 3236 (N-H) cm . H nmr: δ 2.58
This compound was obtained as white needle, yield 65%; mp
-1 1
175-176°; ir: 1670 (C=O, of ester), 3133 (=C-H), 3236, 3338 (N-
(s, 3H, SCH ), 2.34 (s, 3H, Ph-CH ), 8.30 (s, 1H, =CH), 7.28~7.31,
3
3
-1 1
H) cm . H nmr: δ 1.31 (t, 3H, J = 7 Hz, CH CH ), 4.24 (q, 2H,
2
3
7.63~7.65 (dd, 2H+2H, J =8.2 Hz, Ph-H), 12.94 (s, 1H, NH).
Anal. Calcd. for C N S: C, 62.67; H, 4.51; N, 20.89.
J = 7 Hz, CH CH ), 2.47 (s, 3H, SCH ), 8.30 (s, 1H, =CH),
2
3
3
H
14 12
4
12.26, (s, 1H, NH), 7.50, 7.85 (dd, 4H, J = 8.8 Hz, Ph-H), 2.21 (s,
Found: C, 62.69; H, 4.52; N, 20.87.
3H, Ph-CH ).
3
The Synthesis of Compounds 6 and 7.
Anal. Calcd. for C
H N O S: C, 60.93; H, 5.44; N, 13.33.
16 17 3 2
Found: C, 60.95; H, 5.44; N, 13.35.
In the synthetic procedure of compound 4c as described above,
the sodium carbonate was replace by potassium carbonate. A
similar workup gave 6 and 7 from one pot.
2-(p-Chlorophenyl)-7-ethoxycarbonyl-6-methylthio-1H-imi-
dazo[1,2-b]pyrazole (5b).
7-Cyano-3-(p-fluorophenyl)-6-methylthioimidazo[1,2-b]-3H-
pyrazole (6).
This compound was obtained as white needle, yield 40%; mp
214-215°; ir: 1674 (C=O, of ester), 3116 (=C-H), 3221(N-H)
-1 1
cm . H nmr: δ 1.31 (t, 3H, J = 7 Hz, CH CH ), 4.25 (q, 2H, J =
2
3
This compound was obtained as white needle, yield 39%; mp
7 Hz, CH CH ), 2.48 (s, 3H, SCH ), 8.30 (s, 1H, =CH), 12.29, (s,
-1 1
2
3
3
206-207°; ir: 2229 (CN), 1619 (C=N), 3111(=C-H) cm . H
1H, NH), 7.54, 7.88 (dd, 4H, J = 8.8 Hz, Ph-H).
Anal. Calcd. for C ClN O S: C, 53.72; H, 4.21; N, 12.54.
nmr: δ 2.71 (s, 3H, SCH ), 9.34 (d, 1H, J = 7 Hz, N=CH), 7.91 (d,
3
H
1H, J = 7Hz, N-CH), 7.43, 8.36 (mm, 2H+2H, Ph-H) [22].
15 14
3 2
Found: C, 53.74; H, 4.22; N, 12.56.
Anal. Calcd. for C H FN S: C, 57.34; H, 3.33; N, 20.59.
13
9
4
Found: C, 57.34; H, 3.35; N, 20.62.
2-(2,5-Dichlorophenyl)-7-ethoxycarbonyl-6-methylthio-1H-imi-
dazo[1,2-b]pyrazole (5c).
6-Cyano-2,9-di(p-fluorophenyl)-5-methylthio-(4,5,7-triazo-1-
oxa-2,5,7-cyclononatrieno)[4,5,6-a,b]pyrazole (7).
This compound was obtained as white prism, yield 65%; mp
189-190.5°; ir: 1674 (C=O, of ester), 3125 (=C-H), 3237, 3345
This compound was obtained as white prism, yield 50%; mp
252-253°; ir: 2221 (CN), 1234 (C-O),1622 (C=N), 3084 (=C-H)
-1 1
(N-H) cm . H nmr: δ 1.31 (t, 3H, J = 7 Hz, CH CH ), 4.25 (q,
2
3
-1 1
2H, J = 7 Hz, CH CH ), 2.48 (s, 3H, SCH ), 8.32 (s, 1H, =CH),
cm . H nmr: 2.72 (s, 3H, SCH ), 7.91 (s, 1H, =CH), 4.52 (s, 2H,
2
3
3
3
12.80, (s, 1H, NH), 7.74-7.98 (m, 3H, Ph-H).
Anal. Calcd. for C Cl N O S: C, 48.78; H, 3.55; N,
11.38. Found: C, 48.76; H, 3.56; N, 11.36.
CH ), 7.18, 7.44 (mm,2H+2H, Ph-H), 7.55, 8.29
2
+
H
(mm,2H+2H,Ph-H)[22]; ESI-ms: m/z 393 ([M-CH ] ), 285 ([M-
15 13
2 3 2
3
+
·+
A] , A = p- fluorobenzoyl free radical), 238 ([M-A-SCH ] ).
3

March 2005
Utilization of Hypervalent Iodine in Organic Synthesis
215
[8] H. Koga, M. Hirobe, T. Okamoto, Chem. Pharm. Bull., 22,
482 (1974).
[9] J. Elguero, L. Knutsson, S. Mignonac-Mondon, Bull. Soc.
Chim. Fr., (1-2, Pt. 2), 255 (1975).
Anal. Calcd. for C
S, 7.83. Found: C, 61.79; H, 3.48; N, 13.76; S, 7.84.
H F N OS: C, 61.75; H, 3.46; N, 13.73;
21 14 2 4
Acknowledgements.
[10] T. Sato, M. Matsuoka, Japanese Patent 07,278,455 (1994);
Chem. Abstr., 124, 90281y (1996).
[11] L. Knutsson, J. Elguero, An. Quim., 74, 795 (1978).
[12] H. A. Hammouda, A. A. El-Barbary, M. A. F. Sharaf, J.
Heterocyclic Chem., 21, 945 (1984).
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 finan-
cial support.
[13] G. E. H. Elgemeie, H. A. Elfahham, S. A. S. Ghozlan, M. H.
Elnagldi, Bull. Chem. Soc. Jpn., 57, 1650 (1984).
[14] M. Jag, S. Virender, K. Vineet, K. Sangeeta, J. Chem.
Research(s), 38 (1994).
[15] M. Jag, V. Pratima, S. Virender, Synth. Commun., 22, 1293
(1992).
[16] Y. Y. Xie, Z. C. Chen, Synth. Commun., 31, 3145 (2001).
[17] O. Prakash and R. M. Moriarty, Adv. Heterocycl. Chem., 69, 1
(1998).
[18] X. L. Ren, C. Wu, F. Z. Hu, X. M. Zou, H. Z. Yang, Chinese J.
Chem., 22, 194 (2004).
[19] Y. F. Chen, N. Y. Huang, M. W. Ding, Chinese J. Org. Chem.,
24, 1413 (2004).
[20] R. J. Lu, H. Z. Yang, L. X. Wang, Chem. J. Chinese
Universities, 17, 236 (1996).
[21] T. Ganesh, H. K. Chowdhoury and G. L. D. Krupadanam,
Synth. Commun., 29, 2069 (1999).
REFERENCES AND NOTES
*
Correspondence: Li Ming, College of Chemistry and
Molecular Engineering, Qingdao University of Science and
Technology, Qingdao, 266042, P. R. China; Fax: +86-532-4023927;
E-mail: liming928@263.net.
[1] E. Vanotti, F. Fiorentini, M. Villa, J. Heterocyclic Chem., 31,
737 (1994).
[2] K. E. Kinnamon, B. T. Poon, W. L. Hanson, V. B. Wait, Am. J.
Trop. Med. Hyg., 56, 804 (1998).
[3] K. E. Kinnamon, R. R. Engle, B. T. Poon, W. Y. Ellis, J. W.
McCall, M. T. Pzimianski, Proc. Soc. Exp. Biol. Med., 224, 45 (2000).
[4] O. Keshi, I. Bahar, R. L. Jernigan, J. A, Beutler, R. H.
Shoemaker, E. A. Sausville, D. G. Covell, Anti-Cancer Drug Des., 15, 79
(2000).
[5] K-L. L. Fong, D. H. Ho, B. S. Yap, D. Stewart, N. S. Brown,
R. S. Benjamin, E. J. Freireich, G. P. Bodey, Cancer Treat. Rep., 64, 1253
(1980).
[6] A. Terada, K. Wachi, H. Miyazawa, Y. Iizuka, K. Tabata, K.
Hasegawa, European Patent 353,047 (1988); Chem. Abstr., 114, 55777m
(1991).
[7] A. Terada, K. Wachi, H. Myazawa, Y. Iizuka, K. Hasegawa,
K. Tabata, Japanese Patent 07,278,148 (1994); Chem. Abstr., 124,
87009k (1996).
[22] p-Fluorophenyl group exists in compounds 6 and 7, result-
ing in complication of the spectra due to the coupling between the flu-
orine and hydrogen atoms in the proton nuclear magnetic resonance
spectra (300 MHz). As a result, the signals corresponding to the pro-
tons of benzene ring are not observed as dd-shaped peaks, but rather
as mm-shaped peaks. When the spectra were obtained on a Jeol JNM-
ECP 600M instrument (600 MHz), the aforementioned couplings
were observed clearly and the coupling constants (4c and 5f) were
also reported.