Synthetic analogs of natural flavolignans. XII. Synthesis of 3,5-diarylsubstituted pyrazolines based on 1,3-benzodioxane and 1,4-benzodioxane chalcone analogs

Article abstract of DOI:10.1007/s10600-005-0031-0

3,5-Diarylsubstituted pyrazolines were synthesized by reaction of 1,3-benzodioxane and 1,4-benzodioxane chalcone analogs with hydrazine hydrate. The structures of the products were confirmed by PMR spectroscopy. 2004 Springer Science + Business Media, Inc

Full text of DOI:10.1007/s10600-005-0031-0

Chemistry of Natural Compounds, Vol. 40, No. 6, 2004
SYNTHETIC ANALOGS OF NATURAL FLAVOLIGNANS.
*
XII. SYNTHESIS OF 3,5-DIARYLSUBSTITUTED PYRAZOLINES BASED
ON 1,3-BENZODIOXANE AND 1,4-BENZODIOXANE CHALCONE ANALOGS
1
2
2
A. Aitmambetov, Z. Yu. Ibragimova, and A. Tokhtybaeva
UDC 547.814.5
3
,5-Diarylsubstituted pyrazolines were synthesized by reaction of 1,3-benzodioxane and 1,4-benzodioxane
chalcone analogs with hydrazine hydrate. The structures of the products were confirmed by PMR
spectroscopy.
Key words: chalcones, properties, hydrazine, pyrazoline.
2
′-Hydroxychalcones, which have structures similar to many natural pigments containing polyhydroxy-
and polymethoxychalcones and related flavones and flavonols, are some of the most interesting derivatives of
β-phenylacrylophenones. Chalcones are known to be convenient synthons for various heterocyclic compounds.
Pyrazoline derivatives possess various biological activity. Compounds characterized by antispasmodic, bactericidal,
fungicidal, antiestrogen, and therapeutic activity and monoamineoxidase inhibitors have been found among them [1].
In order to prepare new bioactive compounds, we studied the reaction of 1,3-benzodioxane and 1,4-benzodioxane
analogs of chalcone with hydrazine hydrate. Reaction of hydrazine hydrate with 1-4 [2-4] in alcohol at the boiling point of the
reaction mixture produced a pyrazoline ring to form 3-(2-hydroxyphenyl)-5-hetarylpyrazolines 5-8 [5].
R
1
R
1
R
R
OH
O
R
OH
N
2
2
NH NH
2
2
Het
Het
NH
R
3
3
1
- 4
5 - 8
5
c, d, f, g, Het = A; 6d, g, Het = B; 7g, Het = C; 8a, e, f, g, h, Het = D
a: R1 = R2 = R3 = H; c: R1 = R3 =H, R2 = CH3
d: R1 = R3 = H, R2 = OMe; e: R1 = R3 = H, R2 = Cl
f: R1 = R2 = H, R3 = Cl; g: R1 = R2 = H, R3 = F
h: R1 = R2 = Cl, R3 = H
Het:
A =
Cl
O
O
O
O
O
B =
Br
C =
O
O
O
HOOC
_
*
_____
For part XI, see [6].
1
) Nukus Filial, Tashkent SAU, Nukus, 742009, ul. Kh. Abdambetova; 2) Complex Institute of Natural Sciences,
Karakalpak Division, Academy of Sciences of the Republic of Uzbekistan, Nukus, 742006, pr. Berdakha, 41. Translated from
Khimiya Prirodnykh Soedinenii, No. 6, pp. 446-447, November-December, 2004. Original article submitted May 26, 2003.
©
0
009-3130/04/4006-0541 2004 Springer Science + Business Media, Inc.
541

TABLE 1. Physicochemical Constants of 3-(2-Hydroxyphenyl)-5-hetarylpyrazolines 5-8
Compound
Empirical formula
C H CIN O
Yield, %
mp, °C
5c
97
79
88
73
92
89
58
64
67
88
75
96
114-115
124-125
164-165
168-169
141-142
167-168
208-209
104-105
131-132
138-139
124-125
134-136
1
8
17
2
3
4
5d
C H CIN O
18 17 2
5f
C H CI N O
17 14 2 2 3
5g
C H CIFN O
17 14 2 3
6d
6g
7g
8a
C H BrN O
18 17 2 4
C H BrFN O
2 3
1
7
14
C H FN O
2 5
1
8
15
C H N O
7 16 2 3
1
8e
C H CIN O
17 15 2 3
8f
C H CIN O
17 15 2 3
8g
C H FN O
17 15 2 3
8h
C H CI N O
17 14 2 2 3
TABLE 2. PMR Spectra of 3-(2-Hydroxyphenyl)-5-hetarylpyrazolines (δ, ppm, DMSO-d , J/Hz)
6
Protons
Compound
OH-2,
2H-2′′,
2H-4′′,*
H-3
6.73
6.50
6.92
R -4
R -5
H-6
7.15
Ha-4′, dd
Hb-4′, dd
Hc-5′, dd
N-H
2
3
br.s
5c
11.03
2.26
3.75
6.69
3.59
J = 10.3; 17.1)
3.57
2.90
(J = 10.3; 17.1)
2.89
4.85
(J = 10.3)
4.89
7.67 5.3; 4.9
7.55 5.3; 4.9
7.89 5.4; 4.9
7.89 5.4; 4.9
7.56 5.3; 4.9
7.04 5.4; 4.9
7.93 5.4; 4.97
7.77 4.21;
(
5
d
11.29
11.14
6.45
7.21
(
J = 10.3; 17.1)
3.62
(J = 10.3; 17.1)
2.98
(J = 10.3; 3.4)
4.98
5
f
7.22
-
7.34
(
J = 10.7; 17.6)
3.60
(J = 10.7; 17.6)
2.96
(J = 10.7; 2.9)
4.98
5
g
10.89 7.06 m
11.28 6.50
10.88 7.04 m
7.06 m
3.75
-
7.06 m
7.20
(
(
(
(
(
(
(
J = 11.2; 17.1)
3.58
(J = 11.2; 17.1)
2.87
(J = 11.2)
4.90
6d
6g
7g
8a
6.45
J = 10.5; 17.3)
3.61
(J = 10.5; 17.3)
2.94
(J = 10.5; 3.7)
4.94
7.04 m
-
7.04
J = 10.3; 17.1)
3.62
(J = 10.3; 17.1)
2.95
(J = 10.3)
4.20
10.94
11.19
11.44
11.24
10.98
11.97
6.8-7.22 m
-
6.8-7.2 m
7.28
J = 11.2; 17.1)
3.54
(J = 10.3; 17.1)
2.96
(J = 10.3; 3.4)
4.75
6.92
6.91
6.93
6.93
-
7.20
-
6.94
J = 10.8; 17.2)
3.53
(J = 10.8; 17.2)
2.95
(J = 4.8; 10.8) 7.80
4.22
4.22
8
c
6.91
7.29
4.76
(J = 10.8)
4.78
7.80
7.90
7.89
7.49
J = 10.8; 17.2)
3.54
(J = 10.8; 17.2)
2.99
8
f
7.23
7.03
8.10
-
-
-
7.32
4.22
4.22
4.21
J = 10.3; 17.2)
3.53
(J = 10.3; 17.2)
2.97
(J = 10.3)
4.78
8g
7.13
(
J = 10.8; 17.2)
3.50
(J = 10.8; 17.2)
2.95
(J = 10.8)
4.79
8h
7.32
(
J = 10.2; 16.6)
(J = 10.2; 17.3)
(J = 10.7)
_
_____
Protons of 1,3-benzodioxane and 1,4-benzodioxane:
1
1
,3-benzodioxane: 6.9-7.3 (1H, d, 2.5 Hz, H-5), 7.1 (1H, J = 2.5 Hz, H-7), 3g: 7.78 (H-5), 7.63 (H-7), 12.73 (1H, br.s, COOH-6);
,4-benzodioxane: 8a: 6.86 m (3H, m, H-5, H-7, H-8); 8e: 6.92 m (3H, m, H-5, H-7, H-8); 8f: 6.84 (1H, d, H-5), 6.86 m (2H,
m, H-7, H-8); 8g: 6.84 (1H, d, H-5), 6.86 m (2H, m, H-7, H-8).
*
–O(CH ) O–.
2 2
5
42

The structures of 5-8 were confirmed by elemental analysis and PMR spectroscopy in DMSO (Tables 1 and 2). These
compoundsdissolvereadilyin NaOHsolution (5%) and form bluish-green complexes with alcoholic iron chloride (3). ThePMR
spectra of 5-8 contain signals for the OH-2 protons at weak field at 10.3-11.4 ppm because they participate in intramolecular
H-bonds with the N atom of the pyrazoline ring. The N–H proton appears near 7.0-7.9 ppm and disappears first if heavy water
is added. The H-6 proton of the phenol group is shifted to strong field by 0.8-1.0 ppm compared with the analogous protons
in the starting chalcones. The CH -4 protons of the pyrazoline ring appear as two doublets with spin—spin coupling constants
2
(SSCC) 10.2-11.2 Hz and 17.0-17.7 Hz. Proton H-5 resonates as doublets at 4.8-5.0 ppm with SSCC 10.2-11.2 Hz.
Thus, reaction of substituted 1,3-benzodioxane and 1,4-benzodioxane analogs of chalcones with hydrazine hydrate
produce in good yields 3,5-diarylsubstituted pyrazolines.
The study of the biological activity of the substituted pyrazolines prepared by us showed that several of them possess
neuroleptic activity.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates using benzene as
eluent. PMR spectra were recorded on a Bruker WP-100 SY spectrometer at working frequency 100 MHz in DMSO-d with
6
TMC as an internal standard. Elemental analyses of 5-8 agreed with those calculated.
3
-(2-Hydroxyphenyl)-5-hetarylpyrazolines (5-8). A hot solution of the appropriate 2-hydroxychalcone (1-4, 10
mmol) in ethanol (100 mL) was treated with hydrazine hydrate (1 mL, 80%) and boiled for 20 min. The reaction mixture was
poured into water (100-150 mL). The resulting precipitate was filtered off and crystallized from ethanol.
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