2-Diphenylphosphinoyloxybenzaldehyde 4-nitrophenyl-, 4-phenyl-1-phthalazinyl-, and aroylhydrazones and thiosemicarbazone

Article abstract of DOI:10.1023/A:1021603829630

Condensation of aryl- and aroylhydrazines and thiosemicarbazide with 2-diphenylphosphinoyloxybenzaldehyde results in formation of the corresponding hydrazones and thiosemicarbazone. The products give rise to conformational equilibrium between rotational and Z,E isomers, which is strongly displaced toward the E,E′,Z″ isomer and is determined by the nature of substituent in the hydrazine fragment.

Full text of DOI:10.1023/A:1021603829630

Russian Journal of Organic Chemistry, Vol. 38, No. 9, 2002, pp. 1309 1313. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 9, 2002,
pp. 1364 1368.
Original Russian Text Copyright
2002 by Bagrov, Vasil’eva.
2-Diphenylphosphinoyloxybenzaldehyde 4-Nitrophenyl-,
4-Phenyl-1-phthalazinyl-, and Aroylhydrazones
and Thiosemicarbazone
F. V. Bagrov and T. V. Vasil’eva
Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
Received April 24, 2002
Abstract Condensation of aryl- and aroylhydrazines and thiosemicarbazide with 2-diphenylphosphinoyloxy-
benzaldehyde results in formation of the corresponding hydrazones and thiosemicarbazone. The products give
rise to conformational equilibrium between rotational and Z,E isomers, which is strongly displaced toward
the E,E ,Z isomer and is determined by the nature of substituent in the hydrazine fragment.
Hydrazones are physiologically active compounds,
some of which are successfully used in chemotherapy
of tuberculosis [1, 2]. The therapeutic action of
organophosphorus compounds is based on their ability
to inactivate choline esterase. Phosphorus compounds
are known as myotic drugs which are successfully
used in the treatment of glaucoma, paralyses, and
disturbances of central nervous system, as well as in
obstetrics and oncology [3]. It is known that intro-
duction of pharmacophoric fragments into molecules
of biologically active compounds could lead to more
efficient analogs or substances possessing quite a dif-
ferent kind of biological activity. From this viewpoint,
hydrazones having a phosphorus-containing group in
the carbonyl fragment attract considerable interest in
both chemical and pharmacological aspects.
Acylhydrazones derived from aldehydes [4 6] exist
in solution as two rotational isomers (about the amide
N C or hydrazine N N bond) of a single E isomer
(about the C N bond). The isomeric composition of
benzaldehyde aroylhydrazones strongly depends on
the nature of substituents in both acyl and benzylidene
fragments. The effect of phosphorus-containing
groups in the carbonyl moiety on the state of equilib-
rium between different hydrazone isomers has not
been studied. Taking into account the above stated
and the results reported in [4 11], in the present work
we studied the structure of products formed by reac-
tions of 2-diphenylphosphinoyloxybenzaldehyde with
nucleophilic reagents (monosubstituted hydrazine
derivatives as -nucleophiles). The goal of the study
was to elucidate the effect of diphenylphosphinoyloxy
group on the above equilibrium.
We have found that chlorodiphenylphosphine oxide
readily reacts with salicylaldehyde in dry benzene in
the presence of triethylamine as hydrogen chloride
acceptor. The reaction involves exclusively the phenol
hydroxy group and gives 2-diphenylphosphinoyloxy-
benzaldehyde (I) in a good yield; here, triethylamine
hydrochloride is formed in a quantitative yield.
Phosphorylated salicylaldehyde I reacted in boiling
ethanol with various -nucleophiles, namely 4-nitro-
phenylhydrazine, 4-phenyl-1-phthalazinylhydrazine,
substituted benzohydrazides, and thiosemicarbazide
(Scheme 1). The presence of diphenylphosphinoyloxy
group in the ortho position of the aromatic ring in
the aldehyde molecule did not affect appreciably the
reactivity of the carbonyl group. The condensation
readily occurs, following the usual scheme of nucleo-
philic addition at the aldehyde carbonyl group with
subsequent elimination of water. Regardless of the
-nucleophile nature, the final products were the
corresponding hydrazones II IX and thiosemicarba-
zone X. Products II X (Table 1) are colored finely
crystalline substances which are stable on exposure to
air. Compounds II X are insoluble in water, diethyl
ether, and hexane, but soluble in DMF and DMSO;
Their purity was checked by TLC, and the composi-
tion was determined by elemental analysis.
2-Diphenylphosphinoyloxybenzaldehyde hydra-
zones II X can exist as different stereoisomers (or
their equilibrium mixture) originating from E,Z
isomerism with respect to the double C N bond and
rotation about the single C N and N N bonds.
Among a large number of possible structures,
1070-4280/02/3809-1309$27.00 2002 MAIK Nauka/Interperiodica

1310
BAGROV, VASIL’EVA
Scheme 1.
II, R = 4-O2NC6H4; III, R = 4-phenyl-1-phthalazinyl; IV, R = H; V, R = 4-I; VI, R = 4-O2N; VII, R = 4-Me;
VIII, R = 2-OH; IX, R = 2-H2N.
1
Scheme 1 shows E,E ,E and E,E ,Z rotamers of one
E isomer with respect to the C N bond.
give rise to strong absorption at 1585 1602 cm ,
which is overlapped by absorption of the aromatic
ring. Amide I bands in the spectra of IV VIII appear
The IR spectra of all crystalline compounds II X
1
at 1610 1675 cm , and amide II bands are observed
(Table 2) contain absorption bands in the regions
1
1
at 1510 1550 cm . Broad medium-intensity bands in
1175 1203 and 1435 1445 cm , which belong,
1
the high-frequency region (3167 3225 cm ) belong
respectively, to vibrations of the P O Ar and P Ph
groups. Strong absorption bands in the region 1195
to stretching vibrations of the N H bonds. It should
be noted that some authors [12, 13] assign the amide
1
1275 cm correspond to vibrations of the phos-
1
absorption at 3150 3200 cm to N H vibrations
phinoyl group. Stretching vibrations of the C N bond
1
in dimers like A, and bands at 3250 3350 cm , to
polyassociates like B and C (Scheme 2).
Scheme 2.
The presence in the IR spectra of benzoylhydra-
1
zones IV VIII of amide II band at 1530 cm , which
is typical of trans-configuration [13] and also of N H
1
absorption below 3200 cm led us to conclude that
the isolated products in the crystalline state exist as
equilibrium mixtures of the E,E ,E and E,E ,Z
rotamers as associates A and B. Hydrazone VIII is
additionally stabilized by intramolecular hydrogen
bond in the 2-hydroxybenzoyl radical; the IR spec-
trum of VIII lacks absorption bands typical of
stretching vibrations of free phenolic hydroxy group.
The IR spectra of hydrazones IX and X are analogous
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

2-DIPHENYLPHOSPHINOYLOXYBENZALDEHYDE 4-NITROPHENYL-. . .
1311
Table 1. Yields, melting points, and elemental analyses of 2-diphenylphosphinoyloxybenzaldehyde hydrazones II X
Found, %
Calculated, %
Comp
no.
Yield,
%
mp,
C
Formula
C
H
N
P
C
H
N
P
II
65
86
60
61
76
74
60
70
78
222 224 65.69
185 187 73.35
117 119a 70.96
201 203 55.12
4.51
4.65
4.87
3.60
4.13
5.14
4.62
4.89
4.64
9.14
10.33
6.40
5.01
8.67
6.19
6.11
9.28
10.66
6.81
5.67
7.06
5.52
6.35
6.88
6.73
6.84
7.79
C25H20N3O4P
C33H25N4O2P
C26H21N2O3P
C26H20IN2O3P
C26H20N3O5P
C27H23N2O3P
C26H21N2O4P
C26H22N3O3P
C20H18N3O2PS
65.64
73.32
70.90
55.14
64.33
71.36
68.42
68.57
60.75
4.47
4.66
4.81
3.56
4.15
5.10
4.64
4.87
4.59
9.19
10.36
6.36
4.95
8.66
6.16
6.14
9.23
10.63
6.77
5.73
7.03
5.47
6.38
6.82
6.79
6.80
7.83
III
IV
V
VI
VII
VIII
IX
X
220
64.37
194 196 71.33
228a
110
244
68.48
68.54
60.80
a
With decomposition.
1
Table 2. Data of TLC (Rf) and IR spectra ( , cm ) of 2-diphenylphosphinoyloxybenzaldehyde hydrazones II X
Comp.
no.
Rf (system)a
N H
Amide I
Amide II
C N
P O
P O Ar
P Carom
II
0.47 (A)
0.40 (A)
0.47 (A)
0.43 (B)
0.47 (A)
0.51 (B)
0.48 (A)
0.48 (A)
3167
3186
3190
3200
3200
3180
3225
1589
1602
1590
1597
1590
1595
1595
1590
1275
1203
1240
1195
1210
1275
1210
1220
1191
1167
1185
1175
1185
1202
1185
1190
1440
1435
1440
1435
1445
1435
1435
1445
III
IV
V
VI
VII
VIII
IX
1625, 1660
1648, 1675
1640, 1670
1635
1535
1535
1510
1535
1550
1540
1630
3200, 3335, 1610, 1625
3370
X
0.41 (A)
3110, 3170, 1475 (C S)
3260, 3290
1535
1585
1220
1190
1435
a
Eluent benzene 2-propanol, 10:1 (A) or 7:1 (B).
to those considered above, but in the high-frequency
region, apart from the secondary amide N H band,
two bands corresponding to symmetric and antisym-
metric vibrations of the primary amino group are
observed.
NH and CH protons indicates that arylhydrazones II
and III in solution exist exclusively as E,E stereo-
isomers with E configuration of the C N bond.
Benzoylhydrazones IV IX and thiosemicarbazone X
in DMSO solution exist as mixtures of two stereo-
isomers due to isomerism in the hydrazone fragment.
This follows from the presence of a double set of
signals from the secondary amide NH and benzylidene
CH protons. According to published data [14, 15], the
NH signal of the E,E ,Z conformer of hydrazones
IV IX is located in a stronger field, and the aldehyde
CH signal, in a weaker field relative to the corre-
Final conclusions on the structure of compounds
II X were drawn on the basis of their 1H NMR
1
spectra (Table 3). The downfield region of the H
NMR spectrum of 4-nitrophenylhydrazone II contains
a set of aromatic proton signals at 7.17 8.11 ppm
(with an overall intensity corresponding to 18 protons)
and two one-proton singlets with
8.39 and
1
11.29 ppm. The latter corresponds to proton of the
secondary amino group, and the former belongs to
the benzylidene CH proton. The spectrum of III is
analogous to that of hydrazone II. The presence in
sponding signals of the E,E ,E isomer. In the H
NMR spectrum of X, the amide proton signal of the
E,E ,Z isomer is displaced downfield relative to the
analogous signal from the E,E ,E isomer due to effect
of the thiocarbamoyl group. The fractions of stereo-
1
the H NMR spectra of one-proton singlets from the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1312
BAGROV, VASIL’EVA
1
Table 3. Stereoisomeric composition ( ) and parameters of the H NMR spectra ( , ppm) of 2-diphenylphosphinoyloxy-
benzaldehyde hydrazones II X
Comp.
no.
(E,E ,Z ),
N H
CH
Aromatic (other) protons
%
II
100 (E,E )
100 (E,E )
11.29 s
12.28 s
8.38 s
8.74 s
7.17 d, 7.22 t, 7.27 d, 7.56 m, 7.64 t, 7.88 d, 7.90 d,
7.97 d, 8.11 d
7.16 t, 7.23 t, 7.25 q, 7.45 m, 7.55 m, 7.59 m, 7.66 t,
7.72 t, 7.75 m, 7.90 d, 7.92 d
III
IV
V
96
70
11.87 s, 11.99 s 8.63 s, 8.82 s 7.19 t, 7.30 t, 7.40 d, 7.56 m, 7.62 q, 7.91 d, 7.94 d
11.90 s, 12.00 s 8.63 s, 8.80 s 6.91 t, 7.18 t, 7.30 t, 7.38 d, 7.49 d, 7.55 m, 7.62 t,
7.72 t, 7.90 d, 7.93 d
VI
65
96
96
80
80
12.15 s, 12.25 s 8.68 s, 8.83 s 6.93 d, 7.21 t, 7.31 q, 7.38 d, 7.57 m, 7.64 t, 7.91 d,
7.94 d, 8.18 t, 8.38 d
11.79 s, 11.90 s 8.61 s, 8.80 s 7.18 t, 7.29 t, 7.34 d, 7.40 d, 7.54 m, 7.63 t, 7.83 d,
7.94 d, (CH3, 2.43 s)
VII
VIII
IX
11.90 s, 11.99 s 8.67 s, 8.81 s 6.96 t, 6.98 d, 7.20 t, 7.32 t, 7.39 d, 7.44 t, 7.56 m,
7.63 t, 7.89 d, 7.92 d, 7.95 d, (HO, 11.78 s)
11.66 s, 11.80 s 8.57 s, 8.75 s 6.50 t, 6.60 t, 6.77 d, 7.17 t, 7.20 t, 7.28 t, 7.42 d,
7.55 m, 7.61 q, 7.92 d, 7.95 d, (NH2, 6.25 br.s)
X
11.26 s, 11.60 s 8.37 s, 8.52 s 6.81 t, 6.86 d, 7.12 t, 7.19 t, 7.27 t, 7.45 d, 7.56 m,
7.62 t, 7.81 d, 7.90 d, 7.92 d, 8.13 d, (NH2, 7.86 s,
8.07 s)
isomers ( ) were estimated from the intensities of
the corresponding proton signals.
HMDS as internal reference. Silufol UV-254 plates
were used for thin-layer chromatography; eluent
2-propanol benzene; development with iodine vapor.
The data in Table 3 show that the conformational
equilibrium of 2-diphenylphosphinoyloxybenzalde-
hyde benzoylhydrazones and thiosemicarbazone in
polar DMSO is strongly displaced toward the E,E ,Z
isomer and that its position depends on the substituent
in the hydrazine fragment. This is explained by the
presence of a bulky diphenylphosphinoyloxy group
in the ortho-position relative to the aldehyde moiety.
Introduction of an electron-acceptor substituent into
the para-position of the benzoyl group (compounds
IV and V) leads to displacement of the equilibrium
toward less polar E,E ,E conformer. The fraction of
the latter increases with rise in electron-acceptor
power of the substituent (compound VI). Methyl and
hydroxy groups in the aromatic ring of hydrazones
VII and VIII do not affect the conformational equilib-
rium, while the presence of primary amino group in
molecule IX slightly increases the fraction of the
E,E ,E rotamer.
2-Diphenylphosphinoyloxybenzaldehyde (I). Tri-
ethylamine, 32 mmol, was added over a period of
30 min to a solution of 32 mmol of chlorodiphenyl-
phosphine oxide and 32 mmol of salicylaldehyde in
70 ml of dry benzene, maintaining the temperature
at 0 5 C. The mixture was heated to 70 C and was
kept for 1.5 h at that temperature, triethylamine
hydrochloride was filtered off, the filtrate was
evaporated, and the residue was recrystallized from
benzene. Yield 83%, mp 60 C, Rf 0.73 (2-propanol
benzene, 1:10). Found, %: P 9.66, 9.60. C19H15O3P.
Calculated, %: P 9.61.
2-Diphenylphosphinoyloxybenzaldehyde 4-nitro-
phenylhydrazone (II). 2-Diphenylphosphinoyloxy-
benzaldehyde, 11 mmol, was added to a warm solu-
tion of 10 mmol of 4-nitrophenylhydrazine in 15 ml
of anhydrous ethanol. The mixture was refluxed for
15 min, the solvent was distilled off under reduced
pressure (water-jet pump), and the residue was recrys-
tallized from ethanol and washed with diethyl ether.
EXPERIMENTAL
2-Diphenylphosphinoyloxybenzaldehyde
4-phenyl-1-phthalazinylhydrazone (III) was syn-
thesized in a similar way from 10 mmol of 4-phenyl-
1-phthalazinylhydrazine in 15 ml of ethanol and
11 mmol of aldehyde I.
The IR spectra of compounds I X were recorded
on a Specord 75IR instrument from samples dispersed
in mineral oil. The 1H NMR spectra were measured on
a Bruker DRX-500 spectrometer in DMSO-d6 using
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

2-DIPHENYLPHOSPHINOYLOXYBENZALDEHYDE 4-NITROPHENYL-. . .
1313
2-Diphenylphosphinoyloxybenzaldehyde ben-
zoylhydrazones IV IX were synthesized as described
above for hydrazone II using 10 mmol of the corre-
sponding substituted benzohydrazide in 20 ml of
ethanol and 11 mmol of aldehyde I.
2-Diphenylphosphinoyloxybenzaldehyde thio-
semicarbazone (X) was synthesized in a similar way
by reaction of 10 mmol of thiosemicarbazide with
11 mmol of aldehyde I in 15 ml of ethanol.
Izv. Akad. Nauk SSSR, Ser. Khim., 1991, no. 1,
pp. 75 81.
6. Aldoshin, S.M., Chuev, I.I., Atovmyan, L.O., Ned-
zvetskii, V.S., and Kulikov, A.S., Izv. Akad. Nauk
SSSR, Ser. Khim., 1991, no. 1, pp. 87 90.
7. Bagrov, F.V., Zh. Obshch. Khim., 1989, vol. 59,
no. 6, pp. 1320 1325.
8. Bagrov, F.V., Vasil’eva, T.V., and Kormachev, V.V.,
Russ. J. Gen. Chem., 1993, vol. 63, no. 7, pp. 1109
1111.
The yields, melting points, and elemental analyses
of compounds II X are given in Table 1.
9. Bagrov, F.V., Zh. Org. Khim., 1994, vol. 30, no. 5,
pp. 741 743.
10. Bagrov, F.V., Russ. J. Org. Chem., 2000, vol. 36,
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