4-Functionally substituted 3-heterylpyrazoles: IV. Benzylamino[3-aryl(heteryl)-4-pyrazolyl]methylphosphonic acids

Article abstract of DOI:10.1023/A:1012494221885

Derivatives of N-benzyl[3-aryl(heteryl)-4-pyrazolyl]methanimines react with diethyl phosphite to afford diethyl benzylamino[3-aryl(heteryl)-4-pyrazolyl]-4-methylphosphonates that on hydrolysis with 18% hydrochloric acid yield the corresponding aminophosphonic acids.

Full text of DOI:10.1023/A:1012494221885

Russian Journal of Organic Chemistry, Vol. 37, No. 4, 2001, pp. 560 563. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 4, 2001,
pp. 594 597.
Original Russian Text Copyright
2001 by Bratenko, Chornous, Vovk.
4-Functionally Substituted 3-Heterylpyrazoles: IV.
Benzylamino[3-aryl(heteryl)-4-pyrazolyl]methylphosphonic
Acids
M. K. Bratenko1, V. A. Chornous1, and M. V. Vovk2
1Bukovinskaya State Medical Academy Chernovtsy, 58000 Ukraine
2Institute of Organic Chemistry, Ukrainian Academy of Sciences, Kiev, 02094 Ukraine
Received June 23, 1999
Abstract Derivatives of N-benzyl[3-aryl(heteryl)-4-pyrazolyl]methanimines react with diethyl phosphite to
afford diethyl benzylamino[3-aryl(heteryl)-4-pyrazolyl]-4-methylphosphonates that on hydrolysis with 18%
hydrochloric acid yield the corresponding aminophosphonic acids.
In extension of our studies on planned construction
of acyclic and heterocyclic systems with a pyrazole
moiety we set a target to synthesize previously
unknown benzylamino(4-pyrazolyl)methylphosphonic
acids. The recent high interest in heteryl(amino)-
methylphosphonic acids [2] is due mostly to applica-
tion thereof as sinthons for preparation of peptidyl-
phosphonates.
The synthesis of aldimines IIa f (Table 1) was
performed by heating aldehydes Ia f with benzyl-
amine in boiling benzene in the presence of catalytic
amounts of acetic acid. We selected as amine in this
reaction just benzylamine since it might be easily
transformed if required into an unsubstituted amino
group by reductive hydrogenation [3]. The reaction of
azomethines IIa f with diethyl phosphite is carried
out in toluene at boiling for 4 h and results in diethyl
benzylamino(4-pyrazolyl)methylphosphonates IIIa f
in high yield. The latter when subjected to acid
hydrolysis with18% hydrochloric acid afford the cor-
responding methylphosphonic acids IVa f (see the
Scheme).
Taking into account the published data [3, 4] on
the synthesis of heteryl(amino)methylphosphonic
acids with 2-furyl, 2-,3-thienyl, 3-pyrazolyl, and
4-imidazolyl moieties we started the preparation of
the target amino[3-aryl(heteryl)-4-pyrazolyl]methyl-
phosphonic acids from 3-aryl(heteryl)-4-formylpyr-
azoles (Ia f) that underwent a chain of successive
Diethyl aminomethylphosphonates IIIa f (Table 2)
and aminomethylphosphonic acids proper IVa f
(Table 3) are colorless crystalline substances whose
structure is consistent with the corresponding
transformations: formylpyrazoles Ia f
IIa f diethyl aminomethylphosphonates IIIa f
aminomethylphosphonic acids IVa f.
aldimines
Table 1. Yields, melting points, IR spectra and elemental analyses of N-benzyl[3-aryl(heteryl)-1-phenyl-1H-pyrazolyl]-
methanimines IIa f
Compd.
no.
Yield,
%
mp,
(ethanol)
C
IR spectrum,
(C=N),
Found, %
H
Calculated, %
H
Formula
1
cm
C
N
C
N
IIa
IIb
IIc
IId
IIe
IIf
87
84
83
76
81
90
67 68
105 107
90 92
132 136
75 76
1650
1655
1650
1645
1650
81.44 5.31
73.98 4.61
66.12 4.11
84.02 5.38
73.19 4.76
12.12
11.08
9.88 C23H18BrN3
9.92 C29H23N3
12.03
10.10
C23H19N3
C23H18ClN3
81.89 5.63
74.29 4.84
66.34 4.32
84.26 5.56
73.46 4.95
77.03 4.69
12.46
11.30
10.09
10.16
12.24
10.37
C21H17N3S
C26H19N3O2
179 181
1655, 1750a 76.86 4.42
a
(O C=O).
1070-4280/01/3704-0560$25.00 2001 MAIK Nauka/Interperiodica

4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: IV.
561
Scheme.
R = Ph (a), C6H4Cl-4 (b), C6H4Br-4 (c), C6H4Ph-4 (d), 2-thienyl (e), 2-oxo-2H-chromen-3-yl (f).
1
Table 2. Yields, melting points, H and 31P NMR spectral data, and elemental analyses of diethyl benzylamino[3-aryl-
(heteryl)-1-phenyl-4-pyrazolyl]methylphosphonates IIIa f
Compd.
no.
Yield,
%
mp,
Ca
Found, %
H
Calculated, %
H
Formula
C
N
C
N
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
67
72
78
61
67
67
131 132
126 127
134 135
127 128
107 108
172 173
67.91
63.21
58.23
71.61
62.12
66.03
6.17
5.48
5.02
5.97
5.68
5.21
8.59
8.01
7.35
7.41
8.50
7.48
C27H30N3O3P
C27H29ClN3O3P 63.59
C27H29BrN3O3P 58.48
C33H34N3O3P
C25H28N3O3PS
C30H30N3O5P
68.21
6.31
5.69
5.23
6.17
5.82
5.49
8.84
8.24
7.58
7.62
8.73
7.73
71.86
62.37
66.29
Compd.
no.
1H NMR spectrum(CD3)2SO, , ppm
31P NMR spectrum,
(CD3)2SO, P, ppm
IIIa
8.67 s (1H, = CH), 7.98 d (2H, H arom), 7.18 7.56 m (13H, H arom), 4.06 d
(1H, CHP, JHP 21.1 Hz), 3.82 4.03 m (4H, OCH2), 3.67 d.d (2H, CH2N,
JHH 7.0 Hz), 2.84 m (1H, NH), 1.19 t (3H, CH3, JHH 7.0 Hz), 1.04 t (3H, CH3,
JHH 7.0 Hz)
25.08
IIIb
8.69 s (1H,=CH), 7.87 d (2H, H arom), 7.15 7.54 m (12H, H arom), 4.13 d
(1H, CHP, JHP 25.0 Hz), 3.80 3.99 m (4H, OCH2), 3.73 d.d (2H, CH2N, JHH
11.4 Hz), 2.89 m (1H, NH), 1.21 t (3H, CH3, JHH 7.1 Hz), 1.06 t (3H, JHH
7.1 Hz)
24.69
IIIc
IIId
IIIe
IIIf
8.74 s (1H, = CH), 7.21 7.75 m (14H, H arom), 3.85 4.07 m (4H, OCH2),
4.01 d.d (1H, CHP, JHP 23.7 Hz), 3.71 d.d (2H, CH2N, JHH 11.4 Hz),
2.89 m (1H, NH), 1.14 t (3H, CH3, JHH 7.1 Hz), 1.06 t (3H, JHH 7.2 Hz)
8.80 s (1H, = CH), 7.25 7.94 m (19H, H arom), 3.80 4.01 m (4H, OCH2),
3.96 d.d (1H, CHP, JHP 23.3 Hz), 3.69 d.d (2H, CH2N, JHH 11.5 Hz),
2.81 m (1H, NH), 1.21 t (3H, CH3, JHH 7.1 Hz), 1.07 t (3H, JHH 7.1 Hz)
8.74 s (1H, = CH), 7.03 7.94 m (13H, H arom), 4.12 d (1H, CHP, JHP 22.6 Hz),
3.80 4.01 m (4H, OCH2), 3.90 d.d (2H, CH2N, JHH 11.2 Hz), 2.80 m
(1H, NH), 1.11 t (3H, CH3, JHH 7.1 Hz), 1.03 t (3H, JHH 7.1 Hz)
8.73 s (1H, = CH), 7.11 7.91 m (15H, H arom), 4.09 d (1H, CHP, JHP 22.2
Hz), 3.85 4.04 m (4H, OCH2), 3.75 d.d (2H, CH2N, JHH 11.3 Hz), 2.90 m
(1H, NH), 1.11 t (3H, CH3, JHH 7.2 Hz), 1.03 t (3H, CH3, JHH 7.1 Hz)
24.73
25.12
24.30
24.94
a
Crystallization from benzene hexane mixture, 1: 1 (compound IIIe), 2: 1 (compounds IIIa, b, d), 3: 1 (compound IIIc), and
4: 1 (compound IIIf).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

562
BRATENKO et al.
1
Table 3. Yields, melting points, H and 31P NMR spectral data, and elemental analyses of benzylamino[3-aryl(heteryl)-
1-phenyl-4-pyrazolyl]methylphosphonic acids IVa f
Compd.
no.
Yield,
%
mp,
C
Found, %
Calculated, %
Formula
N
P
N
P
IVa
IVb
IVc
IVd
IVe
IVf
81
84
81
75
71
89
243 244
264 265
271 272
247 249
260 261
250 252
9.78
9.03
8.17
8.20
9.59
8.35
7.08
6.57
5.98
6.04
7.05
6.12
C23H22O3P
10.02
9.26
8.43
8.48
9.88
8.62
7.39
6.83
6.22
6.26
7.29
6.36
C23H21ClN3O3P
C23H21BrN3O3P
C29H26N3O3P
C21H20N3O3PS
C26H22N3O5P
Compd.
no.
1H NMR spectrum (CD3)2SO, , ppm
31P NMR spectrum,
(CD3)2SO, P, ppm
VIa
VIb
VIc
VId
VIe
VIf
9.10 s (1H, = CH), 7.91 d (2H, H arom), 7.03 7.87 m (13H, H arom), 4.37 d
(1H, CHP, JHP 24.3 Hz), 3.97 d.d (2H, CH2N, JHH 11.5 Hz), 3.54 m (1H,NH)
8.50
8.62
8.42
8.57
8.61
8.52
9.12 s (1H, = CH), 7.10 7.89 m (14H, H arom), 4.44 d (1H, CHP, JHP 25.7 Hz),
3.99 d.d (2H, CH2N, JHH 11.7 Hz), 3.59 m (1H, NH)
9.07 s (1H, = CH), 7.03 7.93 m (14H, H arom), 4.30 d (1H, CHP, JHP 26.1 Hz),
4.11 d.d (2H, CH2N, JHH 11.7 Hz), 3.60 m (1H, NH)
9.10 s (1H, = CH), 8.01 d (2H, H arom), 7.01 7.71 m (17H, H arom), 4.30 d
(1H, CHP, JHP 24.6 Hz), 4.05 d.d (2H, CH2N, JHH 11.5 Hz), 3.52 m (1H,NH)
9.12 s (1H, = CH), 7.86 d (2H, H arom), 7.00 7.54 m (11H, H arom), 4.31 d
(1H, CHP, JHP 25.1 Hz), 4.00 d.d (2H, CH2N, JHH 11.5 Hz), 3.59 m (1H, NH)
9.08 s (1H, = CH), 7.11 7.89 m (15H, H arom), 4.34 d (1H, CHP, JHP 24.9 Hz),
4.01 d.d (2H, CH2N, JHH 11.5 Hz), 3.55 m (1H, NH)
1H NMR spectra. In the downfield part of the spectra
of esters IIIa f appear the signals of protons C5H of
the pyrazole ring (8.6 8.8 ppm) and also multiplets
of the protons from the aromatic and heterocyclic
substituents. The presence of a chiral center results
in magnetic nonequivalence in the benzyl and diethyl-
phosphoryl moieties that give double sets of signals:
the protons of NH2Ph appear as two doublets at 3.6
3.8 ppm with the coupling constants 11.2 11.5 Hz,
protons of CH2O group appear as multiplet at 3.8
4.1 ppm, those of CH3 group as triplets at 1.1 1.3
and 0.8 1.1 ppm with coupling constants 7.1 7.3 Hz.
Methine proton signal in the range 4.0 4.2 ppm is
split into doublet with the coupling constants 21.0
25.2 Hz due to coupling with phosphorus. The
spectral pattern of the aminomethyl fragment of acids
IVa f consist of a doublet from CH proton (4.3
4.5 ppm) with the coupling constants 24.3 26.1 Hz
and two doublets of protons NCH2Ph (3.9 4.2 ppm)
with the coupling constants 11.4 11.7 Hz. The proton
of the amino group appears as unresolved broad
signal in the region 2.8 2.9 ppm for esters IIIa f and
3.5 3.6 ppm for acids IVa e.
EXPERIMENTAL
IR spectra were recorded on spectrometer UR-20
1
from KBr pellets. H NMR spectra were registered
on spectrometer Varian-Gemini (300 MHz), internal
reference TMS. 31P NMR spectra were measured on
spectrometer Varian-Gemini (121 MHz), external
reference H3PO4.
N-benzyl[3-aryl(heteryl)-1-phenyl-1H-pyrazol-
yl]methanimines IIa f. To a solution of 0.01 mol of
aldehyde Ia f in 20 ml of benzene was added 1.1 g
(0.01 mol) of benzylamine and 3 drops of glacial
acetic acid, and the mixture was heated for 2 h in a
flask equipped with a Dean Stark trap. On cooling
the separated precipitate was filtered off and crystal-
lized from ethanol.
Diethyl benzylamino[3-aryl(heteryl)-1-phenyl-4-
pyrazolyl]methylphosphonates IIIa f. A mixture
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001

4-FUNCTIONALLY SUBSTITUTED 3-HETERYLPYRAZOLES: IV.
of 0.005 mol of aldimine IIa f and 0.69g (0.005 mol) REFERENCES
563
of diethyl phosphite in 10 ml of toluene was heated
to boiling for 4 h. The solvent was removed at
reduced pressure, and the residue was crystallized
from a mixture benzene hexane.
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Benzylamino[3-aryl(heteryl)-1-phenyl-4-pyr-
azolyl]methylphosphonic acids IVa f. A mixture of
0.001 mol of phosphonate IIIa f and 20 ml of 18%
hydrochloric acid was heated to boiling for 6 h. On
cooling the separated precipitate was filtered off,
washed with ice water, dried, and crystallized from
ethanol.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 4 2001