Hypervalent iodine in synthesis: A novel two-step procedure for the synthesis of new derivatives of 1H-imidazo[1,2-b]-pyrazole by the cyclocondensation between 5-amino-4-cyano-3-phenyl-1H-pyrazole and α-tosyloxyacetophenones or α-haloacetophenones

Article abstract of DOI:10.1081/SCC-200049761

A series of new 7-cyano-6-phenyl-2-aryl-1H-imidazo[1,2-b]pyrazoles (5) by the cyclocondensation reactions between 5-amino-4-cyano-3-phenyl-1H-pyrazole (1) and α-bromoacetophenones (3) or α-tosyloxyacetophenones (2) obtained by the reactions of acetophenon

Full text of DOI:10.1081/SCC-200049761

This article was downloaded by: [Duke University Libraries]
On: 24 December 2012, At: 15:22
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Hypervalent Iodine in Synthesis: A Novel
Two‐Step Procedure for the Synthesis of New
Derivatives of 1H‐Imidazo[1,2‐b]‐pyrazole
by the Cyclocondensation Between
5‐Amino‐4‐cyano‐3‐phenyl‐1H‐pyrazole
and α‐Tosyloxyacetophenones or
α‐Haloacetophenones
Li Ming a b , Zhao Guilong a , Wen Lirong a & Yang Huazheng b
a College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao, P.R. China
b Institute of Elemento‐Organic Chemistry, Nankai University, Tianjin, P.R.
China
Version of record first published: 12 Apr 2011.
To cite this article: Li Ming , Zhao Guilong , Wen Lirong & Yang Huazheng (2005): Hypervalent Iodine in
Synthesis: A Novel Two‐Step Procedure for the Synthesis of New Derivatives of 1H‐Imidazo[1,2‐b]‐pyrazole
by the Cyclocondensation Between 5‐Amino‐4‐cyano‐3‐phenyl‐1H‐pyrazole and α‐Tosyloxyacetophenones
or α‐Haloacetophenones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:4, 493-501
To link to this article: http://dx.doi.org/10.1081/SCC-200049761
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 35: 493–501, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200049761
Hypervalent Iodine in Synthesis: A Novel
Two-Step Procedure for the Synthesis of
New Derivatives of 1H-Imidazo[1,2-b]-
pyrazole by the Cyclocondensation Between
5-Amino-4-cyano-3-phenyl-1H-pyrazole
and a-Tosyloxyacetophenones or
a-Haloacetophenones
Li Ming
College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao, P.R. China and Institute of Elemento-
Organic Chemistry, Nankai University, Tianjin, P.R. China
Zhao Guilong and Wen Lirong
College of Chemistry and Molecular Engineering, Qingdao University of
Science and Technology, Qingdao, P.R. China
Yang Huazheng
Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin, P.R. China
Abstract: A series of new 7-cyano-6-phenyl-2-aryl-1H-imidazo[1,2-b]pyrazoles (5)
by the cyclocondensation reactions between 5-amino-4-cyano-3-phenyl-1H-pyrazole
(1) and a-bromoacetophenones (3) or a-tosyloxyacetophenones (2) obtained by the
reactions of acetophenones with [hydroxy(tosyloxy)iodo]benzene (HTIB) have been
synthesized in good yields, and the intermediates 5-amino-4-cyano-6-phenyl-1-
Received in Japan 20 August 2004
Address correspondence to Li Ming, College of Chemistry and Molecular
Engineering, Qingdao University of Science and Technology, Qingdao 266042,
P.R. China and Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin, P.R. China. Fax: þ86-532-4023927. E-mail: liming928@263.net

494
L. Ming et al.
(aroylmethyl)pyrazoles (4) were isolated as a potent evidence for the regioselectivity.
The syntheses of 4 and 5 have been achieved successfully through the procedure
involving a-tosyloxyacetophenones and some through the procedure involving a-bro-
moacetophenones. When utilizing a-tosyloxyacetophenones, the reactions were more
eco-friendly, the reaction time was significantly reduced, and the synthetic procedure
was more convenient and easier to manipulate.
Keywords: 1H-imidazo[1,2-b]pyrazole, cyclocondensation, [hydroxy(tosyloxy)iodo]
benzene (HTIB), synthesis
Imidazo[1,2-b]pyrazoles have been reported to be bioactive
compounds,[1–4,9,12,13] which encouraged us to investigate the synthesis and
bioactivities of these compounds.
There have been many methods to synthesize imidazo[1,2-
b]pyrazoles;[1,5–13] we herein would like to report a novel two-step
procedure for the synthesis of this fused heterocyclic framework.
The a-haloketones are a kind of useful and versatile reagent in organic
synthesis; they are, however, difficult to obtain and highly lachrymatory,
toxic, and not readily available. Encouraged by all these observations, we
now would like to report an eco-friendly and easily operated procedure for
the synthesis of a series of new derivatives of 1H-imidazo[1,2-b]pyrazole
(5) by the cyclocondensation between 5-amino-4-cyano-3-phenyl-1H-
pyrazole (1) and a-tosyloxyacetophenones (2) a-tosyloxylated from
acetophenones with [hydroxy(tosyloxy)iodo]benzene (HTIB) in excellent
yields. The intermediates (4) were isolated as pure compounds and determined
1
by IR, H NMR and elemental analysis to substantiate the regioselectivity.
Two couples of 4 and 5 have also been synthesized through the procedure
involving a-bromoacetophenones (3).
RESULTS AND DISCUSSION
The synthetic route to compound 5 is outlined in Scheme 1. The physical
properties, yields, and elemental analysis data for both 4 and 5 are showed
1
in Table 1, IR data is given in Table 2, and H NMR data in Table 3.
Using a-tosyloxyacetophenones (2) to replace a-bromoacetophenones
(3) in the reactions has such advantages that the reactions gave the final
products in higher yields, became more eco-friendly as well as less time-
consuming, and avoided highly lachrymatory and toxic a-haloketones
which are now not available commercially.
Both 4 and 5 have been synthesized through the procedures involving 2,
and two couples of 4 and 5 (when R ¼ p-F and p-Cl) through the procedure
involving 3: Both procedures gave the same 4 and 5 accordingly, which has
1
been proved through melting points, IR, and H NMR.

Hypervalent Iodine in Synthesis
495
Scheme 1. The procedure for the synthesis of 5.
As we all know that, it is impossible that 1 reacts with 2 or 3 to produce
the target molecules 5 under one simple reaction condition, since the first step
(see Scheme 2) usually requires an alkaline condition to improve the nucleo-
philicity of the endocyclic nitrogen atom, while the second step must be an
acidic one to improve the electrophilicity of the carbonyl group. In the case
of the second step, the electron-withdrawing effect of pyrazole ring reduces
the nucleophilicity of the amine group and electron-withdrawing conjugate
effect of benzene ring also reduces electrophilicity of the carbonyl group,
and under such circumstances, the reaction between the amino group
and the carbonyl group is hard to occur even in the presence of sodium
carbonate as a base to improve the nucleophilicity of the amino group.

Table 1. The physical properties, yields, and elemental analysis data for 4 and 5
Yield/%
EA (Calcd./Found), %
R
Compd.
Appear.
m.p./8C
(A/B)a
C
H
N
p-F
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
white solid
white solid
white solid
white solid
white solid
white solid
white solid
white solid
white solid
white solid
177–178
340 (dec.)
163–164
330 (dec.)
240 (dec.)
324 (dec.)
185–186
332 (dec.)
162–163
335 (dec.)
88/75
85/69
90/73
87/70
86
67.42 (67.48)
71.57 (71.50)
64.35 (64.27)
67.85 (67.91)
71.61 (71.50)
75.92 (76.03)
72.18 (72.12)
76.47 (76.48)
58.45 (58.37)
61.28 (61.36)
4.06 (4.09)
3.62 (3.67)
3.93 (3.90)
3.45 (3.49)
4.62 (4.67)
4.31 (4.26)
5.08 (5.10)
4.74 (4.73)
3.24 (3.27)
2.82 (2.86)
17.58 (17.50)
18.48 (18.54)
16.76 (16.67)
17.67 (17.61)
18.45 (18.54)
19.64 (19.72)
17.65 (17.72)
18.69 (18.79)
15.23 (15.14)
16.02 (15.91)
p-Cl
H
80
80
p-CH3
2,5-dichloro
75
88
85
aA and B represent the yields obtained from the procedures using a-tosyloxyacetophenones (2) and a-bromoacetophenones (3), respectively.

Hypervalent Iodine in Synthesis
Table 2. The IR data for 4 and 5
497
Compd.
y/cm21 (KBr plate)
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
3344, 3248 (N22H) 2211 (CN) 1702 (C55O)
3151 (N22H) 2222 (CN) 1638 (C55C) 3103 (55C22H)
3345, 3249 (N22H) 2207 (CN) 1707 (C55O)
3153 (N22H) 2223 (CN) 1637 (C55C) 3099 (55C22H)
3388, 3235 (N22H) 2225 (CN) 1687 (C55O)
3157 (N22H) 2223 (CN) 1636 (C55C) 3102 (55C22H)
3333, 3243 (N22H) 2214 (CN) 1685 (C55O)
3152 (N22H) 2221 (CN) 1636 (C55C) 3108 (55C22H)
3236 (N22H) 2214 (CN) 1701 (C55O)
3172 (N22H) 2221 (CN) 1631 (C55C) 3097 (55C22H)
The above assumption was supported by the experimental result that the
reactions between 1 and 2 or 3 only gave 4 not the cyclized products 5
under alkaline conditions. In theory, the reaction of 1 and 2 may produce
(4) or (4–1) based on such a regioselectivity that both endocyclic and
exocyclic nitrogen atom can attack the carbon atom at the a position of 2 or
3 under alkaline conditions, and the cyclocondensation of (4) or (4–1) can
give (5), (5–1), (5–2), or (5–3) which is based on the principle that an equili-
brium usually occurs between the structure of imine and structure of enamine.
The isolation of intermediates as pure compounds whose structures have been
fully characterized offers a potent evidence for the proposed mechanism that 1
and 2 or 3 react regioselectively, as showed in Scheme 2. The 1H NMR spectra
of 4 showed a singlet (2H; deuterium oxide exchangeable) at d 6.70–6.90
1
Table 3. The H NMR data for 4 and 5
Compd.
d (DMSO-d6)
4a
5a
4b
5b
4c
5c
4d
5.70 (s,2H; CH2) 6.79 (s,1H; NH2) 7.40 ꢀ 8.20 (m,9H; Ph22H)
13.04 (s,1H; N22H) 8.42 (s,1H; 55C22H) 7.80 ꢀ 7.95 (m,9H; Ph22H)
6.78 (s,2H; NH2) 5.69 (s,2H; CH2) 7.38 ꢀ 8.10 (m,9H; Ph22H)
13.08 (s,1H; N22H) 8.48 (s,1H; 55C22H) 7.40 ꢀ 8.00 (m,9H; Ph22H)
6.79 (s,2H; NH2) 5.70 (s,2H; CH2) 7.70 ꢀ 8.10 (m,10H; Ph22H)
12.97 (s,1H; N22H) 8.38 (s,1H;55C22H) 7.56 ꢀ 7.88 (m,10H; Ar22H)
6.77 (s,2H; NH2) 5.66 (s,2H; CH2) 7.38 ꢀ 8.10 (m,9H; Ph22H)
2.42 (s,3H; 22CH3)
5d
12.96 (s,1H; N22H) 8.18 (s,1H; 55C22H) 7.30 ꢀ 7.95 (m,9H; Ph22H)
2.35 (s,3H; 22CH3)
6.87 (s,2H; NH2) 5.57 (s,2H; CH2) 7.3 ꢀ 8.10 (m,8H; Ph22H)
13.11 (s,1H; N22H) 8.41 (s,1H; 55C22H) 7.40 ꢀ 8.00 (m,8H; Ph22H)
4e
5e

498
L. Ming et al.
Scheme 2. The proposed reaction mechanism of cyclocondensation.
which can be assignable to the protons of the amino group in 4. However, the
1H NMR spectra of assumed 4–1 would show two singlet (1H each), which
has not been observed yet. The formation of intermediates (4) not (4–1)
indicates that the endocyclic nitrogen atom is more nucleophilic than the
exocyclic one due to the electron-withdrawing effect of pyrazole ring. The
cyclocondensation reaction of the intermediates (4) in acidic condition
generated products (5) instead of (5–1) based on such a fact and principle
that the stability of the molecule (5) is more preferable than that of the
molecule (5–1) thermodynamically, since formation of (5) produces a new
conjugated system while the formation of (5–1) will not: its newly formed
CH2 group blocks the formation of new conjugate system as in (5), even
though its local structure of imine is more stable than the structure of
enamine on most occasions.
The imidazo[1,2-b]pyrazoles in the respect of bioactivity have been mainly
reported to be anti-cancer reagents,[3,4,9,12] and we herein would like to report

Hypervalent Iodine in Synthesis
499
their fungicidal activity with the result that both the intermediates and the
title compounds had certain inhibitory activities (at 50ppm) against Gibberella
zeae (4a and 5e), Alternaria solani (4b, 5b, 4d, 4e, and 5e) and Phoma asparagi
(5d, 4e, and 5e). Further studies on other bioactivities are also under way.
EXPERIMENTAL
General
Melting points were determined with a RY-1 apparatus in capillaries and are
uncorrected. IR spectra were obtained on a Nicolet 501P FT-IR instrument as
KBr plates. 1H NMR spectra were recorded on a Jeol JNM-ECP 600M or on a
Bruker AC-200 spectrometer in DMSO-d6, and the chemical shifts were
expressed in ppm with reference to TMS as internal standard. Column chrom-
atography was carried out using Silica Gel H-60 (Qingdao Haiyang Co. Ltd.,
60–100 mesh). Thin Layer Chromatography (TLC; Whatman K6F) was used
to control the course of reactions and ascertain the purity of products, and
detection of the components was made by exposure to ultraviolet light.
1 was prepared according to the literature procedure.[14]
General Procedure for the Synthesis of Intermediate (4) through
a-Bromoacetophenones (3)
A suspended solution of 0.921 g of 1 (5 mmol), 5 mmol of a-bromoaceto-
phenones (3) prepared from acetophenones and bromine according to the
literature,[15] and 0.5 g of sodium carbonate in 30 mL of acetonitrile was
refluxed for around 10 h until the starting materials disappeared on TLC
plate. On cooling, the solid was filtered off, and the filtrate was evaporated
to give crude 4, which was purified by column chromatography using ethyl
acetate/petroleum ether (1:4) as eluent.
General Procedure for the Synthesis of Intermediate (4) through
a-Tosyloxyacetophenones (2)
1.961 g (5 mmol) of [hydroxy(tosyloxy)iodo]benzene (HTIB) and 5 mmol of
acetophenones were dissolved in 30 mL of acetonitrile, and the solution was
refluxed for about 45 min until the starting materials disappeared as
monitored by TLC to obtain a solution of 2 in acetonotrile.[16–19] On
cooling, 0.921 g of 1 (5 mmol) and 0.5 g of sodium carbonate were added to
the above solution, and the suspended solution was then refluxed for another
3 h until the completion of the reaction as monitored by TLC. A similar

500
L. Ming et al.
workup with the procedure through a-bromoacetophenones (3) yielded the
pure intermediate (4).
General Procedure for the Cyclocondensation
Crude (4), which were obtained from either a-bromoacetophenones (3) or
a-tosyloxyacetophenones (2), were 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 h and cooled to room
temperature, from which white solid crystallized out. The white solid was
collected on Hirsch funnel, crystallized from absolute ethanol to afford pure
final products (5).
ACKNOWLEDGMENT
The authors are grateful to Natural Science Foundation of Shandong Province
(No. Y2003B01) and the NSFC of China (No. 20172031) for financial
assistance.
REFERENCES
1. Vanotti, E.; Fiorentini, F.; Villa, M. J. Heterocyclic Chem. 1994, 31, 737.
2. Kinnamon, K. E.; Poon, B. T.; Hanson, W. L.; Wait, V. B. Am. J. Trop. Med. Hyg.
1998, 56, 804.
3. Kinnamon, K. E.; Engle, R. R.; Poon, B. T.; Ellis, W. Y.; McCall, J. W.;
Pzimianski, M. T. Proc. Soc. Exp. Biol. Med. 2000, 224, 45.
4. Keshi, O.; Bahar, I.; Jernigan, R. L.; Beutler, J. A.; Shoemaker, R. H.;
Sausville, E. A.; Covell, D. G. Anti-Cancer Drug Des. 2000, 15 (2), 79.
5. Koga, H.; Hirobe, M.; Okamoto, T. Chem. Pharm. Bull. 1974, 22 (2), 482.
6. Elguero, J.; Knutsson, L.; Mignonac-Mondon, S. Bull. Soc. Chim. Fr. 1975 (1–2,
Pt. 2), 255.
7. Sato, T.; Matsuoka, M. JP 07,278,455, April 6, 1994.
8. Knutsson, L.; Elguero, J. An. Quim. 1978, 74 (5), 795.
9. Fong, K.-L. L.; Ho, D. H.; Yap, B. S.; Stewart, D.; Brown, Nita S.;
Benjamin, Robort, S.; Freireich, E. J.; Bodery, G. P. Cancer Treat. Rep. 1980,
64 (12), 1253.
10. Hammouda, H. A.; El-Barbary, A. A.; Sharaf, M. A. F. J. Heterocyclic Chem.
1984, 21 (4), 945.
11. Elgemeie, G. E. H.; Elfahham, H. A.; Ghozlan, S. A. S.; Elnagldi, M. H. Bull.
Chem. Soc. Jpn. 1984, 57 (6), 1650.
12. Terada, A.; Wachi, K.; Miyazawa, H.; Iizuka, Y.; Tabata, K.; Hasegawa, K. EP
353,047, July 26, 1988.
13. Terada, A.; Wachi, K.; Myazawa, H.; Iizuka, Y.; Hasegawa, K.; Tabata, K. JP
07,278,148, November 18, 1994.

Hypervalent Iodine in Synthesis
501
14. Hanefeld, U.; Rees, C. W.; White, A. J. P. J. Chem. Soc., Perkin Trans. 1 1996,
1545.
15. Ganesh, T.; Chowdhoury, H. K.; Krupadanam, G. L. D. Synth. Commun. 1999,
29 (12), 2069.
16. Jag, M.; Virender, S.; Vineet, K.; Sangeeta, K. J. Chem. Research(s). 1994, 38.
17. Jag, M.; Pratima, V.; Virender, S. Synth. Commun. 1992, 22 (9), 1293.
18. Xie, Y. Y.; Chen, Z. C. Synth. Commun. 2001, 31 (9), 3145.
19. Prakash, O.; Moriarty, R. M. Adv. Het. Chem. 1998, 69, 000.