Convenient Preparation of Novel Fused Tri-heterocyclic Compounds

Article abstract of DOI:10.1081/SCC-120027248

Novel pyrazolotriazolopyrimidine and dipyrazolopyrimidine fused triheterocyclic compounds were prepared in a convenient method and in good yields. The structures of the title compounds were confirmed by elemental analysis, ¹H NMR, ¹³C NMR, IR and MS. Preliminary bioassay study showed that some compounds displayed high inhibition to mosquito (10 ppm).

Full text of DOI:10.1081/SCC-120027248

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Convenient Preparation of Novel Fused
Tri‐heterocyclic Compounds
Ying Liu b , Xiao‐Hong Zhang a , Jun Ren a & Gui‐Yu Jin a
a Institute of Elemento‐organic Chemistry, State Key Laboratory of Elemento‐organic
Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, P.R. China
b State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute
of Physical Chemistry and College of Chemistry and Molecular Engineering, Peking
University, Beijing, P.R. China
Version of record first published: 16 Aug 2006
To cite this article: Ying Liu, Xiao‐Hong Zhang, Jun Ren & Gui‐Yu Jin (2004): Convenient Preparation of Novel Fused
Tri‐heterocyclic Compounds, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:1, 151-157
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 1, pp. 151–157, 2004
Convenient Preparation of Novel Fused
Tri-heterocyclic Compounds
Ying Liu,2 Xiao-Hong Zhang,1 Jun Ren,1 and Gui-Yu Jin1,
*
1Institute of Elemento-organic Chemistry, State Key Laboratory of
Elemento-organic Chemistry, Nankai University, Tianjin, P.R. China
2State Key Laboratory for Structural Chemistry of Unstable and Stable
Species, Institute of Physical Chemistry and College of Chemistry and
Molecular Engineering, Peking University, Beijing, P.R. China
ABSTRACT
Novel pyrazolotriazolopyrimidine and dipyrazolopyrimidine fused tri-
heterocyclic compounds were prepared in a convenient method and in
good yields. The structures of the title compounds were confirmed by
elemental analysis, 1H NMR, 13C NMR, IR and MS. Preliminary bioassay
study showed that some compounds displayed high inhibition to mosquito
(10 ppm).
Key Words: Pyrazole; Condensation; Pyrazolotriazoloyrimidine;
Dipyrazolopyrimidine; Biological activity.
*
Correspondence: Gui-Yu Jin, Institute of Elemento-organic Chemistry, State Key
Laboratory of Elemento-organic Chemistry, Nankai University, 94 Weijin Road,
Tianjin 300071, P.R. China; Fax: 0086-22-23503438; E-mail: lylucy@yahoo.com.
151
DOI: 10.1081/SCC-120027248
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

152
Liu et al.
INTRODUCTION
Study of fused heterocyclic compounds is an attractive field for both
academic interests and the diverse applications of these compounds. Many
pyrazole fused heterocyclic compounds have been found to exhibit biological
activity and were widely studied in pesticide and medicine,[1–4] for example,
pyrazinoxindoles are protein kinase inhibitors,[5] and pyrazolotriazolopyri-
midines are antagonists of the human A3 adenosine receptor.[6]
In this letter, we undertake the synthesis of novel fused tri-heterocyclic
compounds containing a pyrazole moiety in order to get the compounds which
possess novel structure and high biological activity. Our work started from
1-substituted-3-methyl-5-chloropyrazole-4-carboxylic acid 1[7] Acylation of
1 by thionyl chloride, 1-substituted-3-methyl-5-chloropyrazole-4-carbonyl
chloride 2 was got in high yields. Then 2 reacted with 3-substituted-5-
aminotriazole, two kinds of 1H-pyrazole-4-carboxamides 3 and 4 were
prepared in different condition. When heated at 808C in DMSO with K2CO3, 3
or 4 was condensed to give product 5 or 6 respectively, general route is shown
in Sch. 1.
DISCUSSION
The route allows facile introduction of aminotriazole or aminopyrazole
substituents in the 4-position (formyl) of the 5-chloropyrazoles and flexibility
for the construction of novel pyrazolotriazolopyrimidine or dipyrozolopy-
rimidine fused tri-heterocyclic systems. Many problems in the experiment
were resulted, discusses in following.
Get Fused Tri-heterocyclic Compound
The synthesis of pyrazolo [3, 4-d] [1, 2, 4] triazolo [1, 5-a] pyrimidine 5
gave a particular problem. Our initial efforts in the presence of various basic
catalysts such as DBN or NaH to obtain 5m did not succeed under many
conditions. When using sodium hydride catalyzed 3m to synthesize fused tri-
heterocyclic compound, a new compound was produced, but it was
transacylated product 4m rather than the expected product 5m, as shown in
Sch. 2. The detailed transacylation was reported in another article[8] and the
study of transacylative mechanism is in progress. When 3m with K2CO3 in
DMSO was heated at 808C for 6 h, to our surprised, only one product was
produced, which was characterized as 1,7-diphenyl-3-methyl-1H-pyra-
zolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine-4(9H)-one 5m by spectral data.

Preparation of Novel Fused Tri-heterocyclic Compounds
153

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Liu et al.
Scheme 2.
The corresponding 3g, 4m and 4g were reacted smoothly under identical
conditions to afford the corresponding 5g, 6m and 6g (Sch. 1) in 88%, 81%
and 98% yields, respectively.
Distinguish 5 and 6
5 and 6 have similar structures. They have very similar orders of chemical
1
shifts in H NMR, and their mass spectra showed the similar fragmentation
pattern. But their infrared absorption displayed a slightly difference, amide-
carbonyl group of 6m absorbed at 1681 cm21, 6g absorbed at 1693 cm21, and
carbonyl group of 5m absorbed at 1670 cm21, 5g absorbed at 1683 cm21. The
latter 5 absorbed at a lower frequency about 10 cm21 than the former 6 due to
the lack of conjugation. 5 and 6 can be distinguished by these.
Confirm the New Structure
Which element of the pyrimidine ring will 6m or 6g bearing active
hydrogen adjoin, oxygen or nitrogen? The infrared spectra showed amide
rather than hydroxyl group absorptions. This indicated the preponderance of
the amide over the imidic acid tautomer of the compounds in their solidity, the
active hydrogen adjoins nitrogen of the pyrimidine ring, as shown in Sch. 3.
Bioactivities of some new compounds were evaluated in vivo. A
preliminary bioassay study showed that 6m displayed high inhibition to
mosquito (10 ppm) (no data).

Preparation of Novel Fused Tri-heterocyclic Compounds
155
Scheme 3.
In summary, we have demonstrated a base-mediated to synthesize novel
structural pyrazolotriazolopyrimidine and dipyrazolopyrimidine. These
protocols are especially attractive as they allow for the synthesis of fused
tri-heterocyclic systems in mild conditions. Expanding the scope of this
methodology will be useful to the synthesis of other interesting heterocyclic
compounds.
EXPERIMENTAL
Melting points were determined with a model Yanaco MP-500 apparatus
and uncorrected. IR spectra were recorded on a Nicolet Magna-IR 750
spectrometer in Nic-Plan IR microscope-54183. 1H NMR spectra were
recorded on a Bruker APX400 spectrometer with TMS as internal standard.
Elemental analyses were carried out on a Yanaco MT-3 instrument. Mass
spectra were obtained on an HP 5989 mass spectrometer (EI).
The solvents were available commercially and were purified according to
conventional methods. Substituted pyrazoleamides 3a-n and 4a-n were
prepared according to the literature.[8]
1,7-Diphenyl-3-methyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyr-
imidine-4(9H)-one (5m). A solution of 1.51 g (4mmol) 3m, 0.55 g
(4 mmol) K2CO3, 20 ml DMSO were stirred at 808C until compound 3m
was consumed (checked by TLC). The reaction mixture was cooled and mixed
with water (50 ml), then the mixture was acidified to pH ¼ 7 with 10% HCl,
white precipitate resulted. The precipitate was filtered off, washed with water
and finally recrystallized from DMF/ethanol(3/1). 1.11 g of the desired
product 5m, corresponding to 63%, was obtained. Mp . 2808C; IR
1
(microscopy) 3261, 1670 cm21; H NMR (400 MHz, DMSO): 2.52 (s, 3H,
3-CH3), 7.38–7.92 (m, 10 H, 2 Ph); MS m/z 342 (Mþ, 100), 225 (29.0), 77
(86.0). Anal. calcd. for C19H14N6O (342.36): C, 66.66; H, 4.12; N, 24.55.
Found: C, 66.35; H, 3.95; N, 24.49.

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Liu et al.
5g, 6g and 6m were prepared in the same method of 5m.
1-phenyl-3-methyl-7-(o-chloro)phenyl-8-cyano-1H-dipyrazolo[1,5-
a:30,40-d]pyrimidine-4(9H)-one (5g). White solid; mp . 2808C; yield 88%;
IR (microscopy) 2228, 1683 cm21; 1H NMR (400 MHz, DMSO): 2.50 (s, 3H,
3-CH3), 7.47–7.70 (m, 9H, 2Ph); MS m/e 400 (Mþ, 100), 365 (14.0), 225
(9.0), 77 (39.0). Anal. calcd. for C21H13N6OCl (400.83): C, 62.93; H, 3.27; N,
20.97. Found: C, 62.73; H, 3.15; N, 20.70.
1-Phenyl-3-methyl-6-cyano-7-(o-chloro)phenyl-1H-dipyrazolo[1,5-
a:40, 30-e]pyrimidine-4(5H)-one (6g). White solid; mp . 2808C; yield
1
98%; IR (microscopy) 2228, 1693 cm21; H NMR (400 MHz, DMSO): 2.54
(s, 3H, 3-CH3), 7.47-7.70 (m, 9H, 2Ph); MS m/e 400 (Mþ, 100). Anal. calcd.
for C21H13N6OCl (400.83): C, 62.93; H, 3.27; N, 20.97. Found: C, 62.96; H,
3.25; N, 20.95.
1,8-Diphenyl-3-methyl-1H-pyrazolo[4,3-e][1,2,4]triazolo[2,3-a]pyri-
midine-4(5H)-one (6m). White solid; mp . 2808C; yield 81%; IR
1
(microscopy) 1670cm21; H NMR (400 MHz, DMSO): 2.51 (s, 3H, 3-CH3),
7.38–7.91 (m, 10H, 2Ph); MS m/e 342 (Mþ, 100). Anal. calcd. for
C19H14N6O (342.36): C, 66.66; H, 4.12; N, 24.55. Found: C, 66.47; H, 4.40;
N, 24.50.
ACKNOWLEDGMENT
The project is generously supported by Natural Science Foundation of
China (Grant No.29832050).
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Received in Japan May 7, 2003