Hydrazinolytic recyclization of (Z)-3-acetyl-2-methyl-2,3-dihydro-1,4-benzodioxin-2-ol

Article abstract of DOI:10.1023/A:1017647803950

A convenient preparative method has been developed for obtaining previously unknown 4-(o-hydroxyphenoxy) substituted pyrazoles by the reaction of (Z)-3-acetyl-2-methyl-2,3-dihydro-1,4-benzodioxin-2-ol with hydrazine.

Full text of DOI:10.1023/A:1017647803950

Chemistry of Heterocyclic Compounds, Vol. 37, No. 4, 2001
HYDRAZINOLYTIC RECYCLIZATION
Z)
OF ( -3-ACETYL-2-METHYL-
2,3-DIHYDRO-1,4-BENZODIOXIN-2-OL
I. V. Dzvinchuk and M. O. Lozinskii
A convenient preparative method has been developed for obtaining previously unknown
4-(o-hydroxyphenoxy) substituted pyrazoles by the reaction of (Z)-3-acetyl-2-methyl-2,3-dihydro-1,4-
benzodioxin-2-ol with hydrazine.
Keywords: 1,4-benzodioxins, hydrazines, pyrazoles, recyclization.
One of the general methods of constructing the pyrazole ring is based on linking hydrazines at both
nucleophilic centers (nitrogen atoms) with a three carbon 1,3-dielectrophilic chain [1]. 3-Acyl substituted
heterocycles are also 1,3-dielectrophiles (one of the reaction centers is position 2 of the ring and the second is
the carbonyl group), which may form a pyrazole ring as a result of hydrazinolytic recyclization of the starting
material [2]. For example, pyrazoles substituted at position 4 with o-hydroxy, o-mercapto, or o-aminophenyl
groups are obtained from 3-acyl substituted benzofurans [3-5], benzothiophenes [6], or indoles [7] respectively.
As is evident from these examples the nature of the substituent in the pyrazole ring is determined by the nature
of the initial heterocycle. With the aim of extending the range of functionalized substituents being introduced
into the pyrazole ring, we have studied for the first time the hydrazinolytic recyclization of (Z)-3-acetyl-2-
methyl-2,3-dihydro-1,4-benzodioxin-2-ol (1). This compound is also a 1,3-dielectrophile in which one of the
reaction centers, the hemiketal carbon atom, is found in a heterocycle.
We found that compound 1 reacted with hydrazines 2a-j with the formation of pyrazoles 3a-j
substituted in position 4 with an o-hydroxyphenoxy group.
Me
Me
H
O
N
N
80-100°C, 0.2-2 h
–2H2O
O
H
O
NH2NHR
2a–j
+
R
O
O
Me
OH
Me
3a–j
1
2, 3 a R = H, b R = Et, c R = Ph, d R = 2-HO2CC6H4, e R = 4-HO2CC6H4, f R = 4- O2NC6H4,
g R = 2,4,6-Cl3C6H2, h R = 2-naphthyl, i R = 2-pyridyl, j R = 2-benzothiazolyl
The reconstruction of the initial heterocycle into a pyrazole occurs under relatively mild conditions with
a high degree of selectivity. The process is effected on boiling in aqueous acetic acid (1:1) with hydrazine bases
or in acetonitrile with their hydrochlorides. The recyclization has satisfactorily wide preparative limits since in
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 253660; e-mail:
iochkiev@sovam.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 507-510, April, 2001.
Original article submitted October 25, 1999.
0009-3122/01/3704-0459$25.00©2001 Plenum Publishing Corporation
459

addition to pyrazole 3a unsubstituted at the nitrogen atom the N-ethyl, aryl, and heteryl derivatives were
obtained. The reaction time depends on the reactivity of the hydrazine used and is 0.2-2 h. The yields of
products were 60-93%. Preparatively acceptable yields were obtained even with the 2- and 4-carboxy-, 4-nitro-,
and 2,4,6-trichlorophenyl-substituted hydrazines 2d-g, in which the nucleophilicity of one of the nitrogen atoms
is significantly reduced.
The synthesized pyrazoles are stable crystalline substances soluble in aqueous alkaline solution.
Compounds 3a-e,g-j were colorless, their nitrophenyl analog 3f had an orange color. Pyrazoles 3h,i are inclined
to form fairly stable crystallosolvates. To obtain them in the pure state it is necessary to dry them at increased
temperature and reduced pressure after crystallization. Certain physicochemical characteristics of compounds
3a-j and data of elemental analysis are given in Table 1.
The structure of pyrazoles 3a-j was confirmed by data of 1H NMR spectra, which are given in Table 2.
The chemical shifts of the singlet signal of the phenolic hydroxyl proton (disappearing on addition of D2O), and
also of the multiplet signals of the aromatic protons of the o-hydroxyphenoxy group were practically identical
for the whole series. They depended little on the nature of the substituent R, since the o-hydroxyphenyl
fragment is separated from it and is not linked to it by a conjugation chain. The methyl groups of pyrazole 3a
unsubstituted at the nitrogen atom were chemically equivalent, which is in agreement with the tautomerism
known for pyrazoles [8], caused by the rapid migration of proton between the two ring nitrogen atoms. The
isomeric structure of hydrazones of type 4a-j for the compounds synthesized may therefore be excluded.
Me
O
NNHR
O
Me
4a–j
TABLE 1. Physicochemical Characteristics of the Synthesized Pyrazoles 3a-j
Found, %
——————
Com-
Empirical
Reaction
time, h
Yield,
%
mp, °C*
Calculated, %
pound formula
C
H
N
С11H12N2O2
64.52
64.69
5.85
5.92
13.85
13.72
0.2
0.4
1.5
2
188.5-190.5
153-154
93
81
85
60
65
69
85
83
80
85
3а
3b
3c
3d
3e
3f
C13H16N2O2
C17H16N2O2
C18H16N2O4
C18H16N2O4
C17H15N3O4
C17H13Cl3N2O2
C21H18N2O2
C16H15N3O2
C18H15N3O2S
67.45
6.89
12.20
67.22
6.94
12.06
72.89
72.84
5.87
5.75
10.11
9.99
162-163
66.51
5.19
8.67
178-180
66.66
4.97
8.64
66.48
66.66
4.91
4.97
8.49
8.64
2
220-221.5
153.5-155
149-150.5
139-143
62.63
4.58
12.85
2
62.76
4.65
12.92
53.37
53.22
3.61
3.42
7.22
7.30
2
3g
3h
3i
76.20
5.61
8.63
2
76.34
5.49
8.48
68.42
68.31
5.50
5.37
15.07
14.94
2
123.5-125
172-173.5
64.15
4.59
12.63
2
3j
64.08
4.48
12.46
_______
* Crystallized from acetic acid–water, 1:1 (a,b,f), 2-propanol (c), and
acetonitrile (d,e,g-j).
460

TABLE 2. 1H NMR Spectra of Pyrazoles 3a-j
Com-
Chemical shifts (DMSO-d6), δ, ppm, J (Hz)
pound
1.99 (6H, s, 2CH3); 6.51-6.85 (4H, m, С6H4); 9.29 (1H, s, OH); 12.18 (1H, br. s, NH)
3a
3b
1.28 (3H, t, СH3CH2, J = 7); 1.91 (3H, s, CH3); 2.05 (3H, s, CH3);
3.98 (2H, q, CH2CH3, J = 7); 6.49-6.85 (4H, m, С6H4); 9.28 (1H, s, OH)
2.04 (3H, s, CH3); 2.19 (3H, s, CH3); 6.66-6.89 (4H, m, С6H4); 7.39-7.56 (5H, m, С6H5);
3c
3d
3e
9.42 (1H, s, OH)
1.94 (3H, s, CH3); 1.98 (3H, s, CH3); 6.69-6.91 (4H, m, С6H4O);
7.53-7.90 (4H, m, С6H4C=O); 9.38 (1H, s, OH); 13.06 (1H, br. s, СОOH)
2.05 (3H, s, CH3); 2.29 (3H, s, CH3); 6.67-6.90 (4H, m, С6H4O);
7.74 (2H, d, m-protons С6H4C=O, J = 8.4); 8.06 (2H, d, о-protons С6H4C=O, J = 7);
9.43 (1H, s, OH); 13.11 (1H, br. s, СОOH)
2.06 (3H, s, CH3); 2.33 (3H, s, CH3); 6.68-6.90 (4H, m, С6H4O);
7.91 (2H, d, m-protons С6H4NO2, J = 8.4); 8.34 (2H, d, о-protons С6H4NO2, J = 8.4);
9.43 (1H, s, OH)
3f
1.87 (3H, s, CH3); 2.03 (3H, s, CH3); 6.60-6.89 (4H, m, С6H4O); 7.99 (2H, s, С6H2Cl3);
3g
3h
3i
9.40 (1H, s, OH)
2.08 (3H, s, CH3); 2.29 (3H, s, CH3); 6.70-6.91 (4H, m, С6H4); 7.59-8.10 (7H, m, С10H7);
9.42 (1H, s, OH)
2.06 (3H, s, CH3); 2.48 (3H, s, CH3); 6.60-6.92 (4H, m, С6H4); 7.30-8.46 (4H, m, С5H4N);
9.42 (1H, s, OH)
2.08 (3H, s, CH3); 2.61 (3H, s, CH3); 6.72-6.92 (4H, m, С6H4O);
3j
7.37-8.06 (4H, m, NС6H4S); 9.46 (1H, s, OH)
As is known [2], many recyclization reactions allow the preparation of functionalized heterocycles the
synthesis of which by other methods is extremely complex or generally impossible. The approach developed by
us leads to previously unknown pyrazoles capable of further structural modification by simple reactions and
simplifies the search for new substances useful in practice.
EXPERIMENTAL
A monitoring on the progress of reactions and the homogeneity of compounds was carried out by TLC
(Silufol UV 254, benzene–ethanol, 9:1, visualization in UV light). After crystallization the synthesized
compounds were dried for 3 h in a Fischer pistol with a water-jet pump vacuum at 115°C. The 1H NMR spectra
were recorded on a Varian VXR 300 spectrometer with an operating frequency of 300 MHz (DMSO-d6, internal
standard was TMS). Compound 1 was obtained by the method of [9].
o
4-( -Hydroxyphenoxy)-3,5-dimethylpyrazoles (3a-j).
1
Compound (3.12 g, 15 mmol) was boiled
either with hydrazine 2a,b (30 mmol), with hydrazine 2c-j (15 mmol) in aqueous acetic acid (1:1) (15 ml), or
with hydrazine hydrochloride 2d,e (15 mmole) in acetonitrile (10 ml). Reaction times are shown in Table 1. To
isolate products 3b-j the hot reaction mixture was slowly diluted with water (10 ml) with stirring. After cooling,
the solid was filtered off, washed with 2-propanol (products 2a,b,h,i with water), and dried at 110-120°C.
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