Synthesis and heterocyclization of β-aroyl-α- diphenylphosphorylpropionic acids

Article abstract of DOI:10.1023/B:COHC.0000033535.93962.f5

It has been established that diphenylphosphine oxide reacts smoothly with β-aroylacrylic acids with the formation of β-aroyl-α- diphenylphosphorylpropionic acids, which were cyclized under the action of hydroxylamine, hydrazine hydrate, and phenylhydrazin

Full text of DOI:10.1023/B:COHC.0000033535.93962.f5

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
SYNTHESIS AND HETEROCYCLIZATION
OF β-AROYL-α-DIPHENYL-
PHOSPHORYLPROPIONIC ACIDS
R. A. Khachatryan, R. J. Khachikyan, N. V. Karamyan, G. A. Panosyan,
and M. G. Indzhikyan
It has been established that diphenylphosphine oxide reacts smoothly with β-aroylacrylic acids with the
formation of β-aroyl-α-diphenylphosphorylpropionic acids, which were cyclized under the action of
hydroxylamine, hydrazine hydrate, and phenylhydrazine hydrochloride into phospho derivatives of
dihydrooxazinone and tetrahydropyridazinone respectively. It was shown that imidazole may serve as
nucleophilic protection for the synthesis of dihydropyridazinone derivatives from β-aroylacrylic acids.
Keywords: β-aroylacrylic acids, dihydropyridazinones, diphenylphosphine oxide, diphenylphosphoryl-
dihydrooxazinones, diphenylphosphoryltetrahydropyridazinones, imidazole, pyrazolinecarboxylic acids.
Due their high electrophilicity aroylacrylic acids react readily with nucleophiles, including primary and
secondary amines, but, as was shown by one of us, do not interact with diethyl phosphite in the absence of
catalysts. The reaction was successfully effected in an alcoholic solution of sodium ethylate or under conditions
of interphase catalysis [1]. A conclusion on the order of addition has been made by analogy with amines and on
the basis of the results of quantum chemical calculations [2].
The present work is devoted to the study of the interaction of aroylacrylic acids 1a-c with
diphenylphosphine oxide. It was established that the reaction proceeded smoothly on heating the reactants and
the addition products 2a-c are formed in high yield (70-81%, Table 1). The structures of the latter were
established on the basis of the exclusive formation of β-(benzoylethyl)diphenylphosphine oxide (3), on
decarboxylation of acid 2a and not the isomeric α-(benzoylethyl)diphenylphosphine oxide.
ArCCH2–CH–COOH
ArCCH=CHCOOH
Ph2PH
O
+
O
O
O=PPh2
2a–c
1a–c
2a
ArCCH2CH2PPh2
∆
O
O
3
Here and subsequently: a Ar = Ph, b Ar = C6H4Me-4, c Ar = C6H4Br-4
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences (NAN) of Armenia, Erevan 375091;
e-mail: MVM@lx2.yerphi.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 541-546,
April, 2004. Original article submitted March 15, 2002; revision submitted March 4, 2003.
446
0009-3122/04/4004-0446©2004 Plenum Publishing Corporation

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
81
С
Н
N
Р
2а
C22H19O4P
69.79
69.84
4.98
5.03
—
8.16
8.20
154-155
2b
2с
C23H21O4P
70.36
71.41
57.72
57.76
75.38
75.45
67.21
67.17
67.79
67.81
55.89
55.93
70.43
70.40
70.91
70.95
57.98
58.15
70.54
70.59
71.17
71.13
58.26
58.28
74.62
74.66
74.96
75.00
63.49
63.52
70.93
70.97
5.28
5.36
3.89
3.94
5.71
5.69
5.11
5.09
5.39
5.41
3.98
4.03
4.69
4.80
5.09
5.14
3.79
3.74
5.11
5.08
5.39
5.41
3.94
3.97
5.09
5.11
5.35
5.39
4.09
4.16
5.29
5.37
—
—
—
7.93
7.91
6.81
6.78
9.32
9.28
7.88
7.89
7.67
7.62
6.54
6.57
8.30
8.27
7.89
7.97
6.85
6.83
8.26
8.29
7.94
7.99
6.82
6.84
6.84
6.88
6.68
6.68
5.89
5.86
190-192
204-205
131-133
211-212
214-216
210-211
172-173
179-180
176-177
240-241
231-232
245-246
201-203
195-197
204-205
242-243
235-237
203-204
173-175
205-206
70.5
76.5
48
C22H18BrO4P
С21Н19РО2
3
4а
4b
4с
C22H20 NO4P
C23H22NO4P
C22H19BrNO4P
C22H18NO3P
C23H20NO3P
C22H17BrNO3P
C22H19N2O2P
C23H21N2O2P
C22H18BrN2O2P
C28H23N2O2P
C29H25N2O2P
C28H22BrN2O2P
C11H10N2O
3.49
3.56
3.46
3.44
3.01
2.96
3.76
3.73
3.58
3.60
3.12
3.08
7.46
7.49
7.19
7.22
6.16
6.18
6.18
6.22
6.00
6.03
5.27
5.29
14.95
5.05
11.14
11.15
14.72
14.74
13.69
13.72
81.5
87.3
76
5а
5b
5с
54
52
71
6а
6b
6с
57.7
78.6
65.7
93.1
78
7а
7b
7с
74.4
64.5
51.6
53.1
56.2
46.3
9b
9с
—
—
—
—
—
C10H7BrN2O
C10H10N2O2
C11H12N2O2
C10H9BrN2O2
47.76
47.81
63.12
63.15
64.74
64.71
44.59
44.61
2.81
2.79
5.29
5.26
5.89
5.88
3.38
3.35
10а
10b
10с
10.42
10.41
It is known that heterocyclic compounds with a phosphorus atom in the side chain possess high
biological activity and belong to a new generation of pesticides.
With the aim of transferring to compounds of this type we have obtained oximes 4a-c of the synthesized
β-aroyl-α-diphenylphosphorylpropionic acids 2a-c and have heterocyclized them by heating with a catalytic
amount of sulfuric acid. As a result phospho derivatives of 3-aryl-4,5-dihydro-1,2-oxazin-6-one 5a-c were
obtained in 52-71% yield (Table 1).
O
Ar
PPh2
O
+
H
ArC–CH2–CH–COOH
N
O
N
O=PPh2
5a–c
HO
4a–c
447

The similarly constructed 6-aryl-2,3,4,5-tetrahydropyridazin-3-ones 6a-c and 7a-c were obtained by
heating the same α-phosphorylaroylpropionic acids 2a-c with hydrazine hydrate or phenylhydrazine
hydrochloride respectively.
O
Ar
PPh2
O
.
NH2NH2 H2O
2a–c
N
N
R
.
or PhNHNH2 HCl
6a–c, 7a–c
6 R = H; 7 R = Ph
Interesting results were obtained by us on boiling β-aroyl-α-(N-imidazolyl)propionic acids 8b,c,
synthesized by one of us previously [3], with an aqueous solution of hydrazine. In place of the expected
aminotetrahydropyridazinones the reaction products proved to be the 6-aryl-2,3-dihydropyridazin-3-ones 9b,c.
Ar
N
.
NH2NH2 H2O
N
N
N
H
O
ArCCH2CH–COOH
9b,c
O
8b,c
The latter might have been formed as a result either of preliminary fission of imidazole with subsequent
heterocyclization or by initial heterocyclization with subsequent fission of imidazole. Specially designed
experiments showed that the interaction of aroylacrylic acids 1a-c with hydrazine hydrate leads not to the
formation of pyridazinone derivatives but to pyrazolinecarboxylic acids 10a-c.
Ar
.
NH2NH2 H2O
1a–c
+
N
N
H
COOH
10a–c
Analogous results have been obtained by several authors studying the reaction of aroylacrylic acids and
their esters with phenylhydrazine [4-6].
It can therefore be assumed that dihydropyridazinones 9 owe their origin to the fission of imidazole from
the initially formed imidazolo derivatives of tetrahydropyridazinone. The results obtained permit the conclusion
that imidazole may serve as nucleophilic protection for the synthesis of pyridazinone derivatives from β-
aroylacrylic acids.
The composition and structure of all the compounds obtained were confirmed by the results of elemental
analysis (Table 1) and data of NMR spectra (Table 2, the spectra of compounds 8b,c missing from [3] are also
given in this Table).
448

TABLE 2. 1H, 13C* , and 31P*2 NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (coupling constants, J, Hz)*3
1
2
2а
12.35 (1Н, br. s, СО2Н); 7.91 (6Н, m, C6H5); 7.40-7.58 (9Н, m, C6H5); 4.26 (1Н, ddd,
J1 = 13.5, J2 = 11.0, J3 = 2.7, CH); 3.81 (1Н, ddd, J1 = 18.3, J2 = 11.0, J = 5.4, CH2);
3.03 (1Н, ddd, J1 = 18.3, J2 = 9.0, J3 = 2.8, CH2)
2b
12.37 (1Н, br. s, СООН); 7.90 (4Н, m, C6H5); 7.80 (2Н, d, J = 8.1, Ar);
7.51 (6H, m, C6H5); 7.23 (2Н, d, J = 8.1, Ar); 4.23 (1Н, ddd, J1 = 13.2, J2 = 11.1,
J3 = 2.8, PCH); 3.76 (1Н, ddd, J1 = 18.0, J2 = 11.1, J3 = 5.4, CH2);
2.98 (1Н, ddd, J1 = 18.0, J2 = 9.0, J3 = 2.8, CH2); 2.40 (3Н, s, CH3)
2с
12.3 (1Н, br. s, СО2Н); 7.91 (4Н, m, C6H5); 7.84 (2Н, d, J = 8.5, Ar);
7.60 (2Н, d, J = 8.5, Ar); 7.45-7.55 (6Н, m, C6H5); 4.26 (1Н, ddd, J1 = 13.2,
J2 = 10.5, J3 = 2.9, CH); 3.78 (1Н, ddd, J1 = 18.3, J2 = 10.5, J3 = 5.7, CH2);
3.01 (1Н, ddd, J1 = 18.3, J2 = 8.7, J3 = 2.9, CH2)
3
7.91 (2H, d, J = 8.1, C6H5); 7.80 (4H, m, C6H5); 7.40-7.57 (9H, m, C6H5);
3.20 (2H, m, CH2); 2.66 (2H, m, CH2)
4а
12.19 (1Н, br. s, СО2Н); 11.27 (1Н, s, NОН); 7.79-7.94 (4Н, m, C6H5);
7.43-7.59 (8Н, m, C6H5); 7.22-7.35 (3Н, m, C6H5); 4.09 (1Н, td, J1 = 10.8,
J2 = 3.3, CH); 3.32 (1Н, ddd, J1 = 13.8, J2 = 11.1, J3 = 6.3, CH2); 2.90 (1Н, ddd,
J1 = 13.8, J2 = 10.2, J3 = 3.3, CH2)
4b
12.18 (1Н, br. s, СО2Н); 11.14 (1Н, s, NОН); 7.86 (4Н, m, C6H5);
7.45-7.57 (6Н, m, C6H5); 7.42 (2Н, d, J = 8.2, Ar); 7.06 (2Н, d, J = 8.2, Ar);
4.06 (1Н, td, J1 = 10.8, J2 = 3.2, PCH); 3.31 (1Н, ddd, J1 = 13.8, J2 = 11.1,
J3 = 6.0, CH2); 2.87 (1Н, ddd, J1 = 13.8, J2 = 10.2, J3 = 3.2, CH2); 2.33 (3Н, s, CH3)
4с
12.17 (1Н, br. s, СО2Н); 11.23 (1Н, s, NОН); 7.91 (4Н, m, C6H5); 7.83 (2Н, d,
J = 8.5, Ar); 7.62 (2Н, d, J = 8.5, Ar); 7.45-7.56 (6Н, m, C6H5); 4.05 (1Н, td,
J1 = 10.8, J2 = 3.2, PCH); 3.32 (1Н, ddd, J1 = 13.8, J2 = 11.1, J3 = 6.2, CH2);
2.89 (1Н, ddd, J1 = 13.8, J2 = 10.2, J3 = 3.2, CH2)
5а
7.91 (2Н, d, J = 8.1, C6H5); 7.80 (4Н, m, C6H5); 7.40-7.57 (9Н, m, C6H5);
4.29 (1Н, ddd, J1 = 15.0, J2 = 8.3, J3 = 4.2, PCH); 3.68 (1Н, ddd, J1 = 17.3,
J2 = 12.5, J3 = 4.2, CH2); 3.19 (1Н, ddd, J1 = 26.4, J2 = 17.3, J3 = 8.3, CH2)
5b
5с
6а
8.00-7.78 (6H, m, C6H5); 7.60-7.40 (6H, m, C6H5); 7.20 (2H, m, Ar); 4.25 (1H, ddd,
J1 = 15.0, J2 = 8.4, J3 = 3.6, PCH); 3.80 (1H, ddd, J1 = 17.3, J2 = 12.8, J3 = 4.2, CH2);
3.05 (1H, ddd, J1 = 27.3, J2 = 17.3, J3 = 8.3, CH2)
7.60-7.85 (6H, m, C6H5); 7.40-7.62 (9H, m, C6H5); 4.39 (1H, ddd, J1 = 15.0, J2 = 8.4,
J3 = 3.6, PCH); 3.85 (1H, ddd, J1 = 17.3, J2 = 12.9, J3 = 3.6, CH2); 3.15 (1H, ddd,
J1 = 27.3, J2 = 17.3, J3 = 8.4, CH2)
10.87 and 10.73 (1H, s, NH); 7.00-8.00 (15Н, m, C6H5); 4.70 (0.5H, dd, J1 = 11.7,
J2 = 8.4, PCH); 4.02 (0.5H, ddd, J1 = 13.8, J2 = 8.1, J3 = 5.4, CH2); 3.35 (0.5Н, ddd,
J1 = 17.1, J2 = 12.9, J3 = 5.4, CH2); 3.78-3.16 (1H, m, CH2); 2.53 (0.5H, dd,
J1 = 17.1, J2 = 13.2, PCH)
6b
11.01 (1H, s, NH);7.89 (2H, m, C6H5);7.73 (2Н, m, C6H5); 7.37-7.65 (6Н, m, C6H5);
7.40 (2H, d, J = 8.4, Ar); 7.19 (2H, d, J = 8.4, Ar); 4.26 (1Н, m, РСН);
2.95-3.25 (2Н, m, СН2); 2.32 (3Н, s, CH3)
6с
7а
10.93 and 10.81 (1Н, s, NH); 7.97 (2Н, m, Ar); 7.10-7.70 (12Н, m, Ar and C6H5);
4.71 and 4.02 (1Н, m, СН); 2.43-3.41 (2Н, m, СН2)
8.05 (2Н, m, C6H5); 7.12-7.76 (18Н, m, C6H5); 4.29 (1Н, ddd, J1 = 15.0, J2 = 8.3,
J3 = 4.2, PCH); 3.69 (1Н, ddd, J1 = 17.3, J2 = 12.5, J3 = 4.2, CH2); 3.29 (1Н, ddd,
J1 = 26.4, J2 = 17.3, J3 = 8.3, CH2)
7b
8.20 (2Н, m, C6H5); 7.72 (2Н, d, J = 8.1, Ar); 7.44-7.64 (6Н, m, C6H5);
7.15-7.35 (7Н, m, C6H5); 7.06 (2Н, m, Ar); 3.96-4.11 (2Н, m, СН2);
3.24 (1Н, m, РСН); 2.43 (3Н, s, CH3)
7с
8.03 (2Н, dd, J1 = 11.7, J2 = 7.8, Ar); 7.46-7.66 (10Н, m, C6H5);
7.08-7.39 (7Н, m, C6H5 and Ar); 4.31 (1Н, ddd, J1 = 15.0, J2 = 8.4, J3 = 3.6, PCH);
3.65 (1Н, ddd, J1 = 17.3, J2 = 12.9, J3 = 3.6, CH2); 3.30 (1Н, ddd, J1 = 27.3,
J2 = 17.3, J3 = 8.4, CH2)
8b
8с
7.35-7.78 (7Н, m, Ar, Нet); 5.75 (1Н, dd, J1 = 8.4, J2 = 4.2, CH); 4.05 (1Н, dd,
J1 = 18.9, J2 = 8.4, CH2); 3.89 (1Н, dd, J1 = 18.9, J2 = 4.2, CH2); 2.35 (3Н, s, CH3)
7.38-7.71 (7Н, m, Ar, Нet); 5.78 (1Н, dd, J1 = 8.4, J2 = 4.2, CH); 4.07 (1Н, dd,
J1 = 18.9, J2 = 8.4, CH2); 3.91 (1Н, dd, J1 = 18.9, J2 = 4.2, CH2)
449

TABLE 2 (continued)
1
2
9b
12.97 (1Н, br. s, NH); 7.80 (1Н, d, J = 9.9, Het) 7.68 (2Н, d, J = 8.1, Ar);
7.20 (2Н, d, J = 8.1, Ar); 6.86 (1Н, d, J = 9.9, Het); 2.38 (3Н, s, CH3)
9с
13.09 (1Н, br. s, NH); 7.87 (1Н, d, J = 9.9, Het); 7.77 (2Н, d, J = 8.4, Ar);
7.56 (2Н, d, J = 8.4, Ar); 6.89 (1Н, d, J = 9.9, Het)
10а
9.00 (1H, br. s, NH); 7.59 (2Н, d, J = 7.5, C6H5); 7.32 (2Н, t, J = 7.5, C6H5);
7.25 (1Н, t, J = 7.2, C6H5); 4.23 (1Н, dd, J1 = 10.5, J2 = 9.5, CH);
3.21 (1Н, m, J1 = 16.5, J2 = 10.5, CH2); 3.19 (1Н, m, J1 = 16.5, J2 = 9.5, CH2)
10b
8.95 (1Н, br. s, NH); 7.47 (2Н, d, J = 8.1, Ar); 7.11 (2Н, d, J = 8.1, Ar);
4.20 (1Н, dd, J1 = 11.1, J2 = 9.3, CH); 3.18 (1Н, m, J1 = 16.5, J2 = 11.1, CH2);
3.16 (1Н, m, J1 = 16.5, J2 = 9.3, CH2)
10с
9.03 (1Н, br. s, NH); 7.51 (2Н, d, J = 8.7, Ar); 7.46 (2Н, d, J = 8.7, Ar);
4.24 (1Н, t, J = 10.2, CH); 3.18 (2Н, d, J = 10.2, СН2)
_______
* 13C NMR spectrum of 6b (DMSO–CCl4, 1:3), δ, ppm (J, Hz): 163.07 (CO,
d, J = 3.0); 147.94 (d, J = 5.0); 138.92 (4-CAr); 132.95 (2C, 4-CPh); 132.19
(d, J = 99.5); 131.89 (d, J = 99.1); 131.92 (d, J = 2.7); 131.65 (d, J = 2.7);
130.99 (2C, d, J = 9.4); 130.90 (2C, d, J = 9.4); 128.95 (2C, 3-, 5-CAr);
128.66 (2C, d, J = 11.7); 128.04 (2C, d, J = 12.0); 125.45 (2C, 2-, 6-CAr);
37.41 (CH, d, J = 62.8); 22.53 (CH2, d, J = 2.4); 20.76 (CH3).
*
2 31P NMR spectrum (DMSO–CCl4, 1:3), δ, ppm: 6a 33.84 and 33.03 (1:1
mixture of two tautomers); 6c 34.03 and 32.91 (1:1 mixture of two
tautomers).
3
*
Solvents: DMSO–CCl4, 1:3 (2-7a, 9, 10); CDCl3 (7b); DMSO–
CF3COOD, 1:3 (8b,c).
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra of the synthesized compounds were taken on a Varian Mercury-300
instrument (300, 75, and 121 MHz respectively).
β-Aroyl-α-(diphenylphosphoryl)propionic Acids (2a-c). A solution of diphenylphosphine oxide
(10 mmol) and β-aroylacrylic acid (10 mmol) in dry benzene (10 ml) was boiled for 6 h. After cooling, the
resulting precipitate of product 2 was filtered off, washed with benzene, and dried in vacuum.
Decarboxylation of β-Benzoyl-α-(diphenylphosphoryl)propionic Acid 2a. Compound 2a (1 g) was
kept at 140°C (5 mm Hg) for 5-10 min. After cooling, the resulting product was recrystallized from acetone.
(β-Benzoylethyl)diphenylphosphine oxide (3) (0.4 g) was obtained.
Oximes of β-Aroyl-α-(diphenylphosphoryl)propionic Acids (4a-c). A solution of hydroxylamine
hydrochloride (36 mmol) in the minimum amount of water was added to a saturated solution of compound 2a-c
(3 mmol) in methanol and the mixture obtained was boiled for 30 h. The resulting precipitate of oxime 4a-c was
filtered off, washed sequentially with methanol, and with water, and dried in vacuum.
3-Aryl-5-diphenylphosphoryl-4,5-dihydro-1,2-oxazin-6-one (5a-c). A solution of compound 4a-c
(15 mmol) in acetone (8 ml) containing a catalytic amount of conc. H2SO4 was boiled for 3 h. After cooling, the
reaction mixture was poured into water, the precipitate of product 5a-c formed was filtered off, washed with
water, and recrystallized from acetone.
6-Aryl-4-diphenylphosphoryl-2,3,4,5-tetrahydropyridazin-3-ones (6a-c). A solution of compound
2a-c (2.9 mmol) and 60% aqueous hydrazine hydrate solution (4 ml) in alcohol (5 ml) was boiled for 8 h. After
cooling, the resulting solid was filtered off, washed with alcohol, and dried in vacuum.
450

6-Aryl-4-diphenylphosphoryl-N-phenyl-2,3,4,5-tetrahydropyridazin-3-ones (7a-c). A solution of
compound 2a-c (1.5 mmol) and phenylhydrazine hydrochloride (1.5 mmol) in alcohol (10 ml) was boiled for
6 h. The reaction mixture was treated similarly to that described above for compounds 6a-c.
6-Aryl-2,3-dihydropyridazin-3-ones (9b,c). A mixture of acid 8b,c (2.5 mmol) and 60% aqueous
hydrazine hydrate solution (4 ml) was boiled for 4 h. After cooling, the precipitate of product 9b,c formed was
filtered off, washed with alcohol, and dried in vacuum.
3-Aryl-2-pyrazoline-5-carboxylic Acids (10a-c). A mixture of acid 1a-c (5 mmol), 60% aqueous
hydrazine hydrate solution (3 ml), and alcohol (3 ml) was boiled for 6 h. After cooling, the precipitate of product
10a-c was filtered off, washed with alcohol, and dried in vacuum.
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451