One-pot synthesis of pyrazolyl-containing α-aminophosphonates

Article abstract of DOI:10.1080/10426507.2011.625510

A series of novel pyrazolyl-containing -aminophosphonates were synthesized by one-pot reaction from 4-formylpyrazole, substituted aromatic amines, and dialkylphosphites. The synthesized compounds were characterized by elemental analysis, ¹H NMR, and IR spectroscopy. Single-crystal X-ray diffraction data of compounds 4a and 5b were obtained, and some of these compounds showed inhibitory effect on eggplant-infecting Botrytis cinerea. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: Tables S1-S4. Figures S1 and S2.cif files.

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One-Pot Synthesis of Pyrazolyl-
Containing α-Aminophosphonates
Si-Yao Lang a b , Fan Yue a & Ling-Hua Cao a
a College of Chemistry and Chemical Engineering, Xinjiang
University, Urumqi, China
b Fiber Inspection Bureau of Guizhou Province, Guiyang, China
Published online: 31 Jan 2012.
To cite this article: Si-Yao Lang , Fan Yue & Ling-Hua Cao (2012): One-Pot Synthesis of Pyrazolyl-
Containing α-Aminophosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:4,
461-467
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Phosphorus, Sulfur, and Silicon, 187:461–467, 2012
Copyright ꢀC Xinjiang University
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.625510
ONE-POT SYNTHESIS OF PYRAZOLYL-CONTAINING
α-AMINOPHOSPHONATES
Si-Yao Lang,1,2 Fan Yue,1 and Ling-Hua Cao1
1College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi,
China
2Fiber Inspection Bureau of Guizhou Province, Guiyang, China
GRAPHICAL ABSTRACT
2
R
3
R
3
R
NH
CHO
1
1
2
NH
OR
1
1
OR
P
+
+
HO
P
OR
N
OR
O
2
N
R
N
Ph
N
Ph
4a-d, 5a-d
6a-d, 7a-d
1a, 1b
2a-d
3a, 3b
Abstract A series of novel pyrazolyl-containing α-aminophosphonates were synthesized by
one-pot reaction from 4-formylpyrazole, substituted aromatic amines, and dialkylphosphites.
The synthesized compounds were characterized by elemental analysis, 1H NMR, and IR spec-
troscopy. Single-crystal X-ray diffraction data of compounds 4a and 5b were obtained, and
some of these compounds showed inhibitory effect on eggplant-infecting Botrytis cinerea.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Tables S1-S4. Figures S1 and S2 .cif files.
Keywords Pyrazole; α-aminophosphite; synthesis; crystal structure
INTRODUCTION
Organophosphorus compounds have found a wide range of applications in the areas
of industrial, agricultural, and medicinal chemistry owing to their biological and physical
properties as well as owing to their utility as synthetic intermediates. Due to the bioactivity
of α-aminophosphonate, an analogue of natural amino phosphoric acid, a growing amount
of research since 1959 has been focused on α-aminophosphonates, which possess anti-plant
virus, herbicidal, plant growth regulation, inhibitive enzyme, and fungicidal activity.1–4 As a
Received 10 May 2011; accepted 17 September 2011.
The authors are grateful for the support of Ms. Hua Yang and Ms. Yuan-Yu Cuion on the biological activity
texts of this work. This work was supported by the National Natural Science Foundation of China (grant no.
20462006) and the Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry.
Address correspondence to Ling-Hua Cao, College of Chemistry and Chemical Engineering, Xinjiang
University, Urumqi 830046, China. E-mail: clhxj@xju.edu.cn
461

462
S-Y. LANG ET AL.
facile way to synthesize α-aminophosphonates by dialkylphosphites, the Kabachnik–Fields
reaction needs a Lewis acid catalyst such as indium (III) chloride, rare earth elements
triflates, and scandium tris (dodecyl sulfate). LiClO4, SmI2, TaCl5–SiO2, and metal triflates
[M(OTf)n, M = Li, Mg, Al, Cu, Ce] have also been reported as the catalysts in this one-pot,
three-component reaction. A broad range of catalysts, although some are expensive, has
been employed for the Kabachnik–Fields reaction; however, the catalyst-free synthesis of
α-aminophosphonates, to some extent, is rather limited.5–8
Pyrazolyl-containing heterocycles are subunits found in numerous natural products
and in many biologically active pharmaceuticals. A great number of pyrazole derivatives
are reported to exhibit a wide range of bioactivities, including antiviral activity in vitro
against HIV-1, antipyretic, analgestic, and anti-inflammatory activities.9–13
In this paper, the catalyst-free synthesis and physical characterization of new α-
aminophosphonates containing the pyrazolyl group are presented. Based on previously
reported work,14,15 compounds 4a–5d, 5a–5d, 6a–6d, 7a–7d were synthesized and single-
crystal structures of compounds 4a and 5b were obtained. All the new compounds were
1
analyzed by elemental analysis, H NMR, and IR spectroscopy. Preliminary tests by a
greenhouse pot experiment showed that some of these compounds, to some extent, have
an inhibitory effect on eggplant-infecting Botrytis cinerea. The synthetic route of new
compounds is shown in Scheme 1.
R2
R3
R3
NH2
CHO
OR1
OR1
NH
OR1
OR1
P
+
+
HO
P
N
O
R2
N
N
Ph
N
Ph
4a-d, 5a-d
6a-d, 7a-d
1a, 1b
2a-d
3a, 3b
R1 4a
-
d, 6a
-
d: CH3; 5a
-
d, 7a
-
d: C2H5
R2 4a, 5a, 6a, 7a: H; 4b, 5b, 6b, 7b: 2-CH3; 4c, 5c, 6c, 7c: 4-CH3; 4d, 5d, 6d, 7d: 4-OCH3
R3 4a
d, 5a d: H; 6a d, 7a d: OCH3
Scheme 1 Synthetic route of new compounds.
-
-
-
-
RESULTS AND DISCUSSION
In the synthesis of all these new compounds, we found that the reaction could proceed
at a faster rate if the solvent used was toluene not chloroform. Furthermore, good yields
◦
of the target compounds were obtained if the temperature was about 110 C. The data of
physical properties and elemental analysis of all new compounds are presented in Table 1.

SYNTHESIS OF PYRAZOLYL-CONTAINING α-AMINOPHOSPHONATES
463
Table 1 Physical data and elemental analysis of compounds
Analysis found (calcd.) (%)
Compound
m.p. (◦C)
Yield (%)
Formula
C
H
N
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
163–164
166–167
172–173
183–184
196–198
166–168
177–178
185–187
192–194
195–197
198–200
194–195
159–160
155–156
160–162
164–166
75.9
61.2
69.8
68.7
58.7
43.6
74.1
85.4
68.5
69.1
64.4
68.0
50.7
85.0
73.7
74.5
C24H24N3O3P
66.38 (66.51)
67.16 (67.10)
66.85 (67.10)
64.69 (64.79)
67.55 (67.67)
68.08 (68.20)
68.33 (68.20)
66.12 (65.98)
64.68 (64.79)
65.53 (65.40)
65.29 (65.40)
63.40 (63.28)
65.87 (65.98)
66.63 (66.52)
66.40 (66.52)
64.33 (64.48)
5.57 (5.58)
5.88 (5.86)
5.84 (5.86)
5.63 (5.65)
6.14 (6.12)
6.34 (6.36)
6.38 (6.36)
6.13 (6.15)
5.63 (5.65)
5.93 (5.91)
5.89 (5.91)
5.70 (5.72)
6.13 (6.15)
6.40 (6.38)
6.36 (6.38)
6.16 (6.18)
9.66 (9.69)
9.41 (9.39)
9.37 (9.39)
9.09 (9.07)
9.13 (9.11)
8.86 (8.84)
8.82 (8.84)
8.57 (8.55)
9.05 (9.07)
8.82 (8.80)
8.78 (8.80)
8.53 (8.51)
8.57 (8.55)
8.33 (8.31)
8.29 (8.31)
8.08 (8.06)
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
25H26N3O3P
25H26N3O3P
25H26N3O4P
26H28N3O3P
27H30N3O3P
27H30N3O3P
27H30N3O4P
25H26N3O4P
26H28N3O4P
26H28N3O4P
26H28N3O5P
27H30N3O4P
28H32N3O4P
28H32N3O4P
28H32N3O5P
In the IR spectra, all new compounds exhibited medium-to-strong bands at 3470–
3200 cm−1, assigned to their NH stretches. The strong band appeared at about 1250 cm−1
and the band at 1020 cm−1 was assigned to the P = O and P–O–C groups in the compounds.
1
In the H NMR spectra, the proton in pyrazole at C5 position appeared at about
δ = 8.2. Because of coupling with the phosphorus atom, the proton of P(O)CH exhibited
doublet at about δ = 5.0 and their coupling constants (2JHP) were around 20.0–24.0 Hz.
The data of the 1H NMR and IR spectra of the new compounds are presented in Table 2.
Single crystals of compounds 4a and 5b were gained by slow evaporation of solvent
in its diluted anhydrous alcohol solution. The structures of compounds 4a and 5b were
solved by direct methods using the SHELXS–9716 and refined by full-matrix least-square
techniques. The structure of the phosphorus atom in both compounds 4a and 5b is distorted
tetrahedron. Intermolecular H-bond exists in this structure, and the structure is stabilized by
the hydrogen bond between the hydrogen attached to the amine nitrogen and the phosphonic
oxygen of neighboring molecule, the N3–H . . . O1 distance is 2.839(4) Å for 4a and the
N3−H3A . . . O1 distance is 3.120(4) Å for 5b. The data of crystals of compounds 4a and
5b are presented in Table 3. The molecular structures of the title compounds 4a and 5b are
shown in Figures 1 and 2. The packing diagram of the unit cell of compounds 4a and 5b
are presented in the Supplemental Materials (Figures S1 and S2).
In summary, a novel series of pyrazolyl-containing α-aminophosphonates were syn-
thesized by the catalyst-free Kabachnik–Fields reaction. This method is an easy, rapid,
one-pot, economic reaction for the synthesis of α-aminophosphonates.
EXPERIMENTAL
General Methods
Melting points were determined through a Yanaco MP–S3 micro melting point appa-
ratus. The IR spectra were recorded as KBr pellets on a Bruker FT-IR Equinox 55 apparatus.
The 1H NMR spectra were recorded on an Inova 400 (using TMS as the internal standard,

464

SYNTHESIS OF PYRAZOLYL-CONTAINING α-AMINOPHOSPHONATES
Table 3 Crystal data and structure refinement for 4a and 5b
465
Compound
4a
5b
Empirical formula
Formula weight
Temperature
C
24H24N3O3P
C27H32N3O3P
477.53
293(2) K
433.43
293(2) K
Wavelength
0.71073 Å
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P2(1)/c
a = 11.840(2) Å,
b = 11.947(2) Å,
c = 15.886(3) Å,
β = 98.81(3)◦
Monoclinic, P2(1)/c
a = 10.893(2) Å,
b = 23.616(5) Å,
c = 9.4799(19) Å,
β = 90.44(3)◦,
2438.6(8) Å3
Volume
2220.4(8) Å3
Z, calculated density
Absorption coefficient
F(000)
4, 1.297 mg/m3
0.154 mm−1
912
4, 1.301 mg/m3
0.147 mm−1
1016
Crystal size
0.383 mm × 0.311 mm ×
0.752 mm × 0.684 mm ×
0.243 mm
0.219 mm
Theta range for data collection
Limiting indices
3.19◦–27.48◦
3.11◦–27.48◦
−15 ≤ h ≤ 15, 15 ≤ k ≤ 15,
−14 ≤ h ≤ 14, −30 ≤ k ≤ 28,
−19 ≤ l ≤20
−12 ≤ l ≤ 12
Reflections collected/unique
Completeness to theta = 27.48
Refinement method
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Extinction coefficient
Largest differential peak
and hole
20108/5075 [R(int) = 0.0219]
99.5%
23714/5583 [R(int) = 0.0189]
99.8%
Full-matrix least-square on F2
5075/0/287
Full-matrix least-square on F2
5583/0/345
1.097
1.037
R1 = 0.0379, ωR2 = 0.0996
R1 = 0.0530, ωR2 = 0.1062
0.0061(8)
0.293 and −0.286 e. Å−3
R1 = 0.0478, ωR2 = 0.1180
R1 = 0.0530, ωR2 = 0.1219
0.0083(9)
0.392 and −0.391 e. Å−3
CDCl3–d6 as solvent). Elemental analyses were performed on a Thermo Flash EA–1112
elemental analyzer. Analytical thin-layer chromatography (TLC) was performed on silica
gel GF254 (Tsingtao, China) with petroleum ether (fraction boiling in the range of 60–
90 ◦C) and ethyl acetate (1:2) and detection was done by UV light. All reagents were com-
mercial products of analytical grade and were used directly without additional purification.
Single-crystal X-ray diffraction was recorded on an R-AXIS SPIDER X-ray diffractometer.
The procedure followed was:
1. First, compounds 1 and 3 were prepared according to reported methods17,18
2. Next, N-substituted aryl-α-amino-α-(pyrazol-4-yl)-O,Oꢁ-dialkylphosphonates (4a–4d,
5a–5d, 6a–6d, 7a–7d) were prepared.
To a stirred solution of compound 3a or 3b (1 mmol), substituted aniline (1 mmol)
in anhydrous toluene (40 mL) was added equimolar of dialkylphosphonate (1a or 1b).
The mixture was refluxed for 2–5 h. The end of the reaction was detected by TLC. The
reaction mixture was concentrated. The precipitate was filtered off and recrystallized from
ethanol–water.

466
S-Y. LANG ET AL.
Figure 1 Molecular structure of compound 4a (displacement ellipsoid view with 30% ellipsoids) (the colored
figure is available online).
Figure 2 Molecular structure of compound 5b (displacement ellipsoid view with 30% ellipsoids) (the colored
figure is available online).

SYNTHESIS OF PYRAZOLYL-CONTAINING α-AMINOPHOSPHONATES
467
SUPPLEMENTARY DATA
Complete crystallographic data for the structural analysis of compounds 4a and
5b have been deposited with the Cambridge Crystallographic Data Centre, CCDC num-
bers 712245 and 713614, respectively. Copies of this information may be obtained free
of charge from the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK (Tel.: +44-01223-762910, Fax: +44-01223-336033, E-mail:
deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk). Supplementary data (tables con-
taining selected bond lengths and bond angles for the compounds 4a and 5b [Tables S1–
S4] and Figures S1 and S2) are available online in Supplemental Materials. To view sup-
plementary data, go to the publisher’s online edition of Phosphorus, Sulfur, and Silicon and
the Related Elements.
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