A convenient synthesis of novel 7-phosphonylbenzyl-2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]-pyrimidine derivatives

Article abstract of DOI:10.1002/hc.20478

A series of pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine derivatives, bearing phosphonylbenzyl chain in position 7, were conveniently synthesized in an attempt to obtain potent and selective antagonists for the A_2A adenosine receptor or potent pesticide lead compounds. Diethyl[(5-amino-4-cyano- 3-methylsulfanyl-pyrazol-1-yl)-benzyl]phosphonate (3), which was prepared by the cyclization of diethyl 1-hydrazinobenzylphosphonate (1) with 2-[bis(methylthio)methylene]malononitrile (2), reacted with triethyl orthoformate to afford diethyl[(4-cyano-5-ethoxymethyleneamino-3-methykulfanyl- pyrazol-l-yl)-benzyl]phosphonate (4), which reacted with various acyl hydrazines in refluxing 2-methoxyethanol to give the target compounds 5a-h in good yields. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The crystal structure of 5e was determined by single crystal X-ray diffraction

Full text of DOI:10.1002/hc.20478

Heteroatom Chemistry
Volume 19, Number 6, 2008
A Convenient Synthesis of Novel
7-Phosphonylbenzyl-2-Substituted
Pyrazolo[4,3-e]-1,2,4-Triazolo[1,5-c]-
Pyrimidine Derivatives
Lin-Xia Xiao, Ke Li, Liu Meng, and De-Qing Shi
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, People’s Republic of China
Received 22 October 2007; revised 28 February 2008
INTRODUCTION
ABSTRACT:
A
series of pyrazolo[4,3-e]-1,2,4-
triazolo-[1,5-c]pyrimidine derivatives, bearing phos-
phonylbenzyl chain in position 7, were conveniently
synthesized in an attempt to obtain potent and
selective antagonists for the A2A adenosine receptor or
potent pesticide lead compounds. Diethyl[(5-amino-4-
cyano-3-methylsulfanyl-pyrazol-1-yl)-benzyl]phospho-
nate (3), which was prepared by the cyclization of
diethyl 1-hydrazinobenzylphosphonate (1) with 2-
[bis(methylthio)methylene]malononitrile (2), reacted
with triethyl orthoformate to afford diethyl[(4-cyano-
5-ethoxymethyleneamino-3-methylsulfanyl-pyrazol-1-yl)-
benzyl]phosphonate (4), which reacted with various
acyl hydrazines in refluxing 2-methoxyethanol to
give the target compounds 5a–h in good yields. Their
Adenosine modulates a wide range of physiological
functions by interacting with specific cell surface re-
ceptors that have been classified as A1, A2A, A2B, and
A3 adenosine receptor subtypes [1,2]. Efforts made
in medicinal chemistry over the last two decades
have led to the discovery of a series of adenosine
analogs that possess specific agonist properties at
A1, A2A, A2B, or A3 receptors [3,4]. As for adenosine
receptor antagonists, a large number of xanthine
derivatives have been synthesized in an attempt to
improve both receptor subtype affinity and selec-
tivity of the natural compounds caffeine and theo-
phylline [3]. Recently, pyrazolo[4,3-e]-1,2,4-triazolo-
[1,5-c]pyrimidine derivatives, such as SCH 58261,
SCH 63390, and 8FB-PTP, have been found to be po-
tent adenosine A2A antagonists [5,6]. However, they
are unselective, while being potent at A1 receptor
as well. In recent years, it is found that 1-amino
phosphonates act as the phosphorus analogues of
natural amino acids and have received an increas-
ing attention in medicinal chemistry and pesticide
science [7,8] due to their wide biological activ-
ities such as enzyme inhibition [9], antibiotics
[10], and haptens of catalytic antibodies [11], an-
tifungal agents, herbicides, plant regulators, and
plant virucides [12]. To find potent and selec-
tive antagonists for the A2A adenosine receptor or
potent pesticide lead compounds, herein we re-
port a convenient synthesis of pyrazolo[4,3-e]-1,2,
1
structures were confirmed by IR, H NMR, 13C NMR,
MS, and elemental analysis. The crystal structure of
5e was determined by single crystal X-ray diffrac-
ꢀ
C
tion
2008 Wiley Periodicals, Inc. Heteroatom Chem
19:634–638, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20478
Correspondence to: De-Qing Shi; e-mail: chshidq@mail.ccnu.
edu.cn.
Contract grant sponsor: Natural Science Foundation of China.
Contract grant number: 20302002.
Contract grant sponsor: Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry.
Contract grant number: [2007] 1108.
2008 Wiley Periodicals, Inc.
c
ꢀ
634

Synthesis of Novel 7-Phosphonylbenzyl-2-Substituted Pyrazolo[4,3-e]-1,2,4-Triazolo[1,5-c]Pyrimidine Derivatives 635
4-triazolo-[1,5-c]pyrimidine derivatives, bearing a
in one step (Scheme 1), without the isolation
phosphonylbenzyl chain in position 7.
of
5-acylamino-4-imino-4,5-dihydropyrazolo[3,4-
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
O
N
O
N
O
N
N
N
N
N
N
N
F
SCH 58261
SCH 63390
8FB PTP
RESULTS AND DISCUSSION
d]pyrimidine intermediates, contrary to the report
by Baraldi et al. [14]. In Baraldi’s report, analogous
imidates reacted with acyl hydrazine in refluxing
2-methoxyethanol to provide 5-acylamino-4-
imino-4,5-dihydropyrazolo[3,4-d]pyrimidines.
Whereas the ring closure of these imidates to the
corresponding pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]
pyrimidines thermally needed a higher boiling point
solvent (260◦C) like diphenyl ether.
To confirm the structure of the regioisomer of
the cyclization and investigate its regioselectivity,
a single crystal of the compound 5e was obtained
as colorless crystals from the mixture of petroleum
ether and acetone (6:1 v/v) and its molecular struc-
ture was determined by X-ray diffraction (Fig. 1)
[15].
The synthesis of diethyl 1-hydrazinobenzyl-
phosphonate (1) has been reported by several
methods [13]. It was synthesized by a modified
procedure of Yuan’s report [13a]. For converting
benzaldehyde to diethyl 1-hydroxybenzyl phos-
phonate, an excess of catalyst (KF, four times)
was used, which caused difficulty in stirring and
incomplete reactivity. Instead, we used 1 equiv of
catalyst (Et3N) in CH2Cl2 to avoid these shortcom-
ings and obtained it in a better yield (85%). 1 can
be obtained in a better yield by the reaction of
diethyl 1-hydroxybenzyl phosphonate with mesyl
chloride, followed by the nucleophilic substitution
with hydrazine in a one-pot reaction.
Cyclization of
1
with 2-[bis(methylthio)-
In conclusion, we have developed an efficient
and selective synthesis of pyrazolo[4,3-e]-1,2,4-
methylene]malononitrile (2) in mild conditions gave
diethyl[(5-amino-4-cyano-3-methylsulfanyl-pyrazol-
1-yl)-benzyl]phosphonate (3), which can be easily
triazolo-[1,5-c]pyrimidine
derivatives,
bearing
phosphonylbenzyl chain in position 7, via the
directed ring closure of functionalized imidates
with various acyl hydrazines. Owing to the eas-
ily accessible and versatile starting materials
and straightforward product isolation, we think
that this method has potential in the synthesis
converted
to
diethyl[(4-cyano-5-ethoxymethyl-
eneamino-3-methylsulfanyl-pyrazol-1-yl)-benzyl]-
phosphonate (4) by refluxing triethyl orthoformate.
4 reacted with various acyl hydrazines to yield
the corresponding tricyclic target compounds
5a–h conveniently in refluxing 2-methoxyethanol
MeS
CN
N
MeS
CN
O
CH(OEt)3
SMe
SMe
EtOH
NC
NC
H
+
P(OEt)2
N
C
N
CHOEt
NH2
N O
N O
P(OEt)2
NHNH2
C
H
P(OEt)2
C
H
1
2
3
4
O
SMe
SMe
N
EtO
EtO
EtO
EtO
O
O
R
CNHNH2
N
N
N
N
P
P
NH
MeOCH2CH2OH
R
N
N
N
N
N
NHCOR
5
R= methyl; n-propyl; phenyl; phenoxymethyl; 4-chlorophenoxymethyl; 2,4-dichlorophenoxymethyl;
4-tert-butylphenoxymethyl; 3-trifluoromethylphenoxymethyl
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

636 Xiao, Li, Meng, and Shi
FIGURE 1 X-ray crystal structure of compound 5e.
of phosphonyl-substituted pyrazolo[4,3-e]-1,2,4-
triazolo-[1,5-c]pyrimidine derivatives with biologi-
cal and pharmaceutical activities.
were recrystallized from ethyl acetate and petroleum
(1:1, v/v) to give white crystals (5.58 g, 64% yield).
1
mp 161–163◦C. H NMR (CDCl3, 400 MHz): δ 1.19–
1.27 (m, 6H, 2CH3), 2.53 (s, 3H, SCH3), 4.01–4.16
(m, 4H, 2CH2), 5.54 (s, 2H, NH2), 5.75 (d, J = 24 Hz,
1H, PCH), 7.27–7.52 (m, 5H, Ar-H). Anal. Calcd for
C16H21N4O3PS: C 50.52, H 5.56, N 14.73; Found: C
50.69, H 5.48, N 14.89.
EXPERIMENTAL
Melting points were determined with a WRS-1B
digital melting point apparatus and were uncor-
rected. 1H and 13C NMR spectra were recorded
with a Varian mercury-plus 400 spectrometer with
TMS as the internal reference and CDCl3 as the
solvent, whereas mass spectra were obtained with
a Finnigan TRACEMS 2000 spectrometer using
the EI method. IR spectra were measured by a
Nicolet NEXUS470 spectrometer. Elemental anal-
yses were performed with an Elementar Vario
ELIIICHNSO elementary analyzer. X-ray diffraction
analysis was performed on a Bruker Smart 1000
CCD diffractometer. All of the solvents and mate-
rials were of high-reagent grade and were purified
as required. Diethyl 1-hydrazinobenzylphosphonate
(1), 2-[bis(methylthio)methylene]malononitrile (2),
and acyl hydrazines were prepared according to
the methods described in [13a], [16], and [17],
respectively.
Preparation of Diethyl[(4-cyano-5-
ethoxymethyleneamino-3-methylsulfanyl-
pyrazol-1-yl)-benzyl]phosphonate (4)
Compound 3 (2.28 g, 6 mmol) was dissolved in tri-
ethyl orthoformate (4 mL), and the mixture was re-
fluxed for 2 h; after cooling, the solvent was removed
under a reduced pressure, and the residues were pu-
rified on silica gel (EtOAc-light petroleum, 1:5, v/v)
to afford 4 as a white solid (2.48 g, 95%). mp 64–
1
66◦C. H NMR (CDCl3, 400 MHz) δ: 1.18–1.27 (m,
6H, 2CH3), 1.40 (t, J = 7 Hz, 3H, CH3), 2.62 (s, 3H,
SCH3), 4.01–4.20 (m, 4H, 2CH2), 4.39 (t, J = 6.6 Hz,
2H, CH2), 5.90 (d, J = 22.8 Hz, 1H, PCH), 7.33–7.55
(m, 5H, Ar-H), 8.39 (s, 1H, CH). Anal. Calcd for
C19H25N4O4PS: C 52.28, H 5.77, N 12.84; Found: C
52.41, H 5.54, N 12.72.
Preparation of Diethyl[(5-amino-4-cyano-3-
methylsulfanyl-pyrazol-1-yl)-
benzyl]phosphonate (3) [18]
Preparation of Diethyl{[9-(methylsulfanyl)-2-
substituted-7H-pyrazolo-[4,3-e]-1,2,4-triazolo-
[1,5-c]-pyrimidin-7-yl]-benzyl}phosphonate
(5a–h): General Procedure
A mixture of 1 (6.27 g, 24.3 mmol), 2 (3.89 g,
22.9 mmol), and ethanol (30 mL) was refluxed for
5 h. The reaction mixture was cooled to room tem-
perature, concentrated in vacuo, and the residues
A solution of 4 (0.65 g, 1.5 mmol) and acyl hydrazine
(such as acetyl hydrazine, benzoyl hydrazine, and
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Novel 7-Phosphonylbenzyl-2-Substituted Pyrazolo[4,3-e]-1,2,4-Triazolo[1,5-c]Pyrimidine Derivatives 637
565; 1H NMR (CDCl3, 400 MHz): δ 1.17–1.27 (m, 6H,
2CH3), 2.83 (s, 3H, SCH3), 4.04–4.22 (m, 4H, 2CH2),
5.41 (s, 2H, OCH2), 6.44 (d, J = 23 Hz, 1H, PCH),
7.05–7.73 (m, 10H, Ar-H), 9.07 (s, 1H, N CH); 13C
NMR (CDCl3, 100 MHz) δ: 164.6, 158.0, 148.3, 147.7,
142.2, 139.0, 132.9, 129.3, 128.9, 128.6, 128.4, 121.3,
114.6, 101.5, 63.6, 63.4, 63.2, 59.3, 57.8, 16.2, 14.6.
Anal. Calcd for C25H27N6O4PS: C 55.75, H 5.05, N
15.60; Found: C 55.93, H 5.11, N 15.74.
substituted phenoxy acetyl hydrazine) (1 mmol) in
methoxyethanol (20 mL) was refluxed for 3–5 h. Af-
ter cooling, the solvent was removed under reduced
pressure, and the residues were purified on silica gel
(acetone and light petroleum, 1:6–7, v/v) to afford
the corresponding target compounds 5a–h.
Diethyl[(2-methyl-9-methylsulfanyl-pyrazolo
[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl)-
benzyl]phosphonate (5a)
Diethyl{[2-(4-chlorophenoxy)methyl-9-
methylsulfanyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,
5-c]pyrimidin-7-yl]-benzyl}phosphonate (5e)
Colorless crystals, yield, 75%, mp 95–96◦C. 1H NMR
(CDCl3, 400 MHz) δ: 1.17–1.27 (m, 6H, 2CH3), 2.64
(s, 3H, CH3), 2.83 (s, 3H, SCH3), 4.04–4.22 (m, 4H,
2CH2), 6.43 (d, J = 23 Hz, 1H, PCH), 7.27–7.72 (m,
5H, Ar-H), 8.97 (s, 1H, N CH); 13C NMR (CDCl3,
100 MHz) δ 166.1, 148.2, 147.9, 142.1, 138.7, 133.2,
129.0, 128.7, 128.5, 101.4, 63.8, 63.4, 63.3, 59.4, 57.8,
16.3, 14.7. Anal. Calcd for C19H23N6O3PS: C 51.11, H
5.19, N 18.82; Found: C 50.99, H 5.27, N 18.97.
White crystals, yield, 91%, mp 159.1–160.0◦C. IR
(KBr, cm−1) ν: 2983, 1493, 1248, 1050, 826, 563 H
1
NMR (CDCl3, 400 MHz): δ: 1.18–1.27 (m, 6H, 2CH3),
2.82 (s, 3H, SCH3), 4.00–4.24 (m, 4H, 2CH2), 5.38
(s, 2H, OCH2), 6.44 (d, J = 23 Hz, 1H, PCH), 6.96–
7.73 (m, 9H, Ar-H), 9.06 (s, 1H, N CH); MS (70
eV) m/z (%): 575 (6.5), 573.5 (10.5), 572 (M+, 24.6),
438 (14.3), 437.5 (25.7), 436.5 (74.0), 435 (100), 434
(69.9), 433 (36.5), 432.5 (16.9), 309 (9.2), 307 (12.1),
262 (12.7), 129 (5.0), 128 (5.9), 91 (5.4). Anal. Calcd
for C25H26ClN6O4PS: C 52.40, H 4.57, N 14.67; Found:
C 52.57, H 4.41, N 14.42.
Diethyl[(9-methylsulfanyl-2-propyl-pyrazolo[4,3-
e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl)-benzyl]-
phosphonate (5b)
Colorless oil, yield, 69%. 1H NMR (CDCl3, 400 MHz)
δ: 1.02 (t, J = 6.8 Hz, 3H, CH3), 1.17–1.27 (m, 6H,
2CH3), 1.90 (q, J = 7.5 Hz, 2H, CH2), 2.82 (s, 3H,
SCH3), 2.93 (t, J = 7.6 Hz, 2H, CH2), 4.02–4.22 (m,
4H, 2CH2), 6.43 (d, J = 23 Hz, 1H, PCH), 7.27–7.71
(m, 5H, Ar-H), 8.99 (s, 1H, N CH); MS (70 eV) m/z
(%): 476 (5.14), 474 (M+, 12.4), 337 (100), 291 (5.9),
262 (19.3), 109 (16.4), 91 (8.9), 81 (12.5). Anal. Calcd
for C21H27N6O3PS: C 53.15, H 5.74, N 17.71; Found
C: 53.23, H 5.81, N 17.50.
Diethyl{[2-(2,4-dichlorophenoxy)methyl-9-
methylsulfanyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,
5-c]pyrimidin-7-yl]-benzyl}phosphonate (5f)
White crystals, yield, 92%, mp 109.6–111.3◦C. IR
(KBr, cm−1) ν: 2968, 1511, 1250, 1019, 830, 805,
565; 1H NMR (CDCl3, 400 MHz) δ: 1.18–1.27 (m, 6H,
2CH3), 2.83 (s, 3H, SCH3), 4.05–4.22 (m, 4H, 2CH2),
5.46 (s, 2H, OCH2), 6.48 (d, J = 23 Hz, 1H, PCH),
7.01–7.71 (m, 8H, Ar-H), 9.06 (s, 1H, N CH); MS
(70 eV) m/z (%): 609 (10.3), 608 (31.2), 607 (14.6),
606 (M+, 42), 571 (11.4), 473 (16.1), 472 (20.3), 471
(74.5), 470 (29.2), 469 (100), 308 (17.4), 261 (8.8), 163
(23.0), 161 (37.3), 135 (20.0), 133 (32.7), 116 (14.3),
109 (36.2), 105 (14.0), 91 (40.6), 81 (41.2), 77 (35.1).
Anal. Calcd for C25H25Cl2N6O4PS: C 49.43, H 4.15, N
13.83; Found: C 49.29, H 4.07, N 13.60.
Diethyl[(9-methylsulfanyl-2-phenyl-pyrazolo[4,
3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-yl)-benzyl
phosphonate (5c)
White crystals, yield, 88%, mp 111–113◦C.1H NMR
(CDCl3, 400 MHz) δ: 1.15–1.27 (m, 6H, 2CH3), 2.87 (s,
3H, SCH3), 4.03–4.25 (m, 4H, 2CH2), 6.46 (d, J = 23
Hz, 1H, PCH), 7.27–7.75 (m, 10H, Ar-H), 9.07 (s, 1H,
N CH); MS (70 eV) m/z (%): 508 (M+, 6), 371 (42),
261 (2), 109 (100). Anal. Calcd for C24H25N6O3PS: C
56.68, H 4.96, N 16.53; Found: C 56.40, H 5.03, N
16.75.
Diethyl{[2-(4-t-butylphenoxy)methyl-9-
methylsulfanyl-pyrazolo[4,3-e]-1,2,4-triazolo[1,
5-c]pyrimidin-7-yl]-benzyl}phosphonate (5g)
White crystals, yield, 84%, mp 121–122◦C. IR (KBr,
Diethyl[(9-methylsulfanyl-2-phenoxymethyl-
pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-7-
yl)-benzyl]phosphonate (5d)
1
cm−1) ν: 2960, 1514, 1251, 1017, 829, 697, 569; H
NMR (CDCl3, 400 MHz) δ: 1.17–1.31 (m, 15H, CH3),
2.83 (s, 3H, SCH3), 4.06–4.22 (m, 4H, 2CH2), 5.40
(s, 2H, OCH2), 6.44 (d, J = 23 Hz, 1H, PCH), 6.98–
7.73 (m, 9H, Ar-H), 9.08 (s, 1H, N CH); 13C NMR
White crystals, yield, 86%, mp 130.3–131.8◦C. IR
(KBr, cm−1) ν: 2982, 1497, 1245, 1027, 761, 694,
Heteroatom Chemistry DOI 10.1002/hc

638 Xiao, Li, Meng, and Shi
[6] Dionisotti, S.; Conti, A.; Sandoli, D.; Zocchi, C.; Gatta,
F.; Ongini, E. Br J Pharmacol 1994, 112, 659.
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(CDCl3, 100 MHz) δ: 165.0, 155.8, 148.4, 147.9, 144.1,
142.3, 139.0, 133.0, 129.0, 128.7, 128.5, 126.2, 114.2,
101.6, 63.9, 63.7, 63.3, 59.4, 57.9, 34.0, 31.4, 16.3,
14.7. Anal. Calcd for C29H35N6O4PS: C 58.57, H 5.93,
N 14.13; Found: C 58.69, H 6.08, N 14.00.
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Diethyl{[9-methylsulfanyl-2-(3-
trifluoromethylphenoxy)methyl-pyrazolo[4,3-e]-
1,2,4-triazolo[1,5-c]pyrimidin-7-yl]-benzyl}
phosphonate (5h)
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Hirchmann, R. Tetrahedron Lett 1994, 37, 6854.
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Colorless oil, yield, 85%. 1H NMR (CDCl3, 400 MHz)
δ: 1.18–1.27 (m, 6H, 2CH3), 2.83 (s, 3H, SCH3), 4.05–
4.22 (m, 4H, 2CH2), 5.44 (s, 2H, OCH2), 6.44 (d,
J = 23 Hz, 1H, PCH), 7.21–7.72 (m, 9H, Ar-H), 9.07
(s, 1H, N CH); MS (70 eV) m/z (%): 608 (10.6), 606
(M+, 23.0), 469 (100), 449 (4.6), 308 (6.0), 261 (6.1),
161 (9.7), 133 (11.9), 109 (21.3), 91 (17.5). Anal.
Calcd for C26H26F3N6O4PS: C 51.48, H 4.32, N 13.86;
Found: C 51.51, H 4.17, N 13.63.
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