Synthesis and properties of substituted 2-methylene-hydrazono-2,3-dihydro- 3-benzo[b]furanones

Article abstract of DOI:10.1007/s10593-007-0111-0

The reaction of 2,3-dihydro-2,3-benzo[b]furandione with the triphenylphosphazines of diazo compounds leads to substituted 2-methylenehydrazono-2,3-dihydro-3-benzo[b]furanones, which are hydrolyzed in an acidic medium to the substituted methylenehydrazides

Full text of DOI:10.1007/s10593-007-0111-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 6, 2007
SYNTHESIS AND PROPERTIES
OF SUBSTITUTED 2-METHYLENE-
HYDRAZONO-2,3-DIHYDRO-
3-BENZO[b]FURANONES
N. A. Pulina1 and V. V. Zalesov2
The reaction of 2,3-dihydro-2,3-benzo[b]furandione with the triphenylphosphazines of diazo compounds
leads to substituted 2-methylenehydrazono-2,3-dihydro-3-benzo[b]furanones, which are hydrolyzed in
an acidic medium to the substituted methylenehydrazides of o-hydroxyphenylglyoxalic acid and react
with amines to form the products of addition at the activated CH=N bond of the side chain or
2-hydrazono-2,3-dihydro-3-benzo[b]furanone respectively.
Keywords: substituted 2-methylenehydrazono-2,3-dihydro-3-benzo[b]furanones, aminolysis, hydrolysis.
Earlier we showed that 5-aryl-2,3-dihydrofuran-2,3-diones react with triphenylphosphor-
anylidenehydrazones (subsequently referred to as triphenylphosphazines), synthesized from various diazo
compounds, to form substituted 2-methylenehydrazono-2,3-dihydro-3-furanones [1]. The reaction takes place
regioselectively at the lactone carbonyl group [2], but this path is an example of an anomalous Staudinger
reaction in the presence of a ketone carbonyl in the heterocycle, which is not typical of triphenylphosphazines
[3]. The limits of this reaction can be extended through the benzo[b] analog of the studied heterocycles –
2,3-dihydro-2,3-benzo[b]furandione. We established that the triphenylphosphazines obtained from
diphenyldiazomethane, fluorenyldiazomethane, benzoyldiazomethane, and adamantanoyldiazomethane and
(1-methyl-2-oxo-3-indolinylidene)triphenylphosphazine react with 2,3-dihydro-2,3-benzo[b]furandione in an
inert solvent at room temperature with the formation of substituted 2-methylenehydrazono-2,3-dihydro-
3-benzo[b]furanones 1a-e (Table 1) and triphenylphosphine oxide.
O
O
R1
R2
Ph3P=N–N=CR1R2
– Ph3PO
O
N N
O
O
1a–e
1a R1 = R2 = Ph, b R1 + R2 = C13H8 (fluorenyl), c R1 = H, R2 = Bz, d R1 = H,
R2 = AdCO, e R1 + R2 = C10H7NO (1-1-methyl-2-oxo-3-indolinylidene)
__________________________________________________________________________________________
1Perm State Pharmaceutical Academy, Perm 614990, Russia; e-mail: perm@pfa.ru. 2Perm State
University, Perm, Russia; e-mail: obtkbiomed@permonline.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 6, pp. 817-822, June, 2007. Original article submitted July 1, 2005.
0009-3122/07/4306-0685©2007 Springer Science+Business Media, Inc.
685

It is known that 2,3-dihydro-2,3-benzo[b]furandione is very readily decyclized to form o-hydroxy-
phenylglyoxalic acid [6]. Substitution of the oxygen atom of the lactone carbonyl of the heterocycle by a less
electronegative nitrogen atom in compounds 1a-e changes the distribution of electron density in the molecule
and leads to greater stability for the benzofuran ring. Nevertheless, in a water–dioxane medium in the presence
of catalytic amounts of hydrochloric acid at room temperature compounds 1c-e are hydrolyzed to substituted
methylenehydrazides of o-hydroxyphenylglyoxalic acid 2a-c. Compounds 1a,b, in which there is no acyl
substituent at the C=N bond, are not hydrolyzed under mild conditions.
O
R1
R2
+
H3O
NHN
O
O
H
2a–c
O
R1
H2N
H2N
H2NC6H4R3-p
N
N
+
R2
O
1c–e
3
-p
O
NHC6H4R
Ph
B
N
N
H
O
O
O
N
N
3
A
+
Ph
N
NH2
– p-R3C6H4N
CHBz
O
4
2 a R1 = H, R2 = Bz, b R1 = H, R2 = AdCO, c R1 + R2=C10H7NO, 3 R3 = H
TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
1а
1b
1c
1d
1e
2a
2b
2c
3
С21H14N2O2
С21H12N2O2
С16H10N2O3
С20H20N2O3
С18H11N3O3
С16H12N2O4
С20H22N2O4
С17H13N3O4
С22H17N3O3
С8H6N2O2
77.20
77.29
77.52
77.77
73.16
73.28
71.55
71.41
66.75
66.88
64.92
64.86
67.89
67.78
63.01
63.15
4.36
4.32
3.65
3.73
3.67
3.84
5.81
5.99
3.69
3.62
4.12
4.08
6.14
6.25
4.25
4.05
8.49
8.50
8.66
8.63
10.51
10.68
8.28
8.32
13.70
13.76
9.36
9.45
7.79
7.90
12.83
12.99
138-139
197-198
146-147
133-134
245-246
160-161
196-197
194-195
149-150
196-197
72
89
87
68
76
83
77
89
92
70.89
71.15
60.12
59.26
4.42
4.61
3.59
3.73
11.38
11.37
17.18
17.25
4
58 (A),
81 (B)
686

The IR spectra of compounds 1a-e (Table 2) contain a band for the stretching vibrations of the ketone
carbonyl of the benzofuran ring in the region of 1710-1715 cm-1. The absence of the absorption band of the
lactone carbonyl in the region of 1800-1840 cm-1 [4, 5] indicates the formation of products from reaction at the
carbonyl group at position 2 of the heterocycle.
The low-frequency position of the absorption bands for the carbonyl groups of the acyl fragment of the
hydrazides 2a,b, the carbonyl at position 2 of the heterocycle in the hydrazide 2c, and the ketone carbonyl group
(in the region of 1595-1605 cm-1) in the IR spectra of these compounds and the downfield position of the signals
1
for the protons of the N–H and O–H groups in the H NMR spectra indicate that they exist in the form with an
intramolecular hydrogen bond, which is possible with the Z-configuration along the C=N bond.
O
N
N
O
O
O
H
.
.
.
N
O
O
H
N
H
O
H...O
N
Ph(Ad)
Me
2c
2a,b
TABLE 2. The Spectral Characteristics of the Synthesized Compounds
IR
1Н NMR spectrum, δ, ppm
(J, Hz)
UV spectrum,
Com-
pound
spectrum,
λ
max, nm (log ε)
ν, cm-1
1а
1b
1c
1715 (C(3)=O);
1595 (C=S, C=N)
6.79-7.83 (14H, m, HAr)
1710 (C(3)=O);
1590 (C=S, C=N)
310 (4.03);
385 (4.18)
6.96-8.03 (12H, m, HAr)
1720 (C(3)=O);
1660 (PhC=O);
1600 (C=S, C=N)
274 (4.36);
357 (3.72)
7.13-7.76 (9H, m, HAr);
8.05 (1H, s, CH=N)
1d
1e
1710 (C(3)=O);
1650 (AdC=O);
1580 (C=S, C=N)
2.06-1.26 (15H, m, Ad);
7.56-7.10 (4H, m, HAr);
7.70 (1H, s, CH=N)
1710 (C(3)=O);
312 (4.08);
361 (3.93)
3.11 (3H, s, CH3);
6.68-7.70 (8H, m, HAr)
1715 (C(2)=O
substituents R1 + R2);
1600 (C=S, C=N)
2a
2b
2c
3
3400 (OH); 3230 (NH);
1702 (NHC=O);
1625 (PhC=O);
6.78-7.80 (10H, m, 9HAr, CH=N);
10.95 (1H, s, OH); 12.55 (1H, s, NH)
1540 (amide II)
3420 (OH); 3240 (NH);
1698 (NHC=O);
1630 (AdC=O);
1.56-2.18 (15H, m, Ad);
6.99-7.56 (5H, m, 4HAr,
CH=N); 10.92 (1H, s, OH);
12.58 (1H, s, NH)
1545 (amide II)
3400 (OH); 3225 (NH);
1698 br. (NHC=O,
3.10 (3H, s, CH3);
6.65-7.76 (8H, m, HAr);
10.86 (1H, s, OH);
12.65 (1H, s, NH)
C(2)=O substituents
R1R2); 1550 (amide II)
3373 (NH-Ar); 3245
(NH-CH);
6.33-8.16 (16H, m, HAr,
CH-NH, NH-Ar);
1690 (С(3)=О);
1655 (PhC=O)
9.08 (1H, d, J = 6.0, NH-CH)
4
3400, 3280,
3215 (NH2);
1685 (C(3)=O)
263 (3.98);
302 (3.97);
382 (3.69)
7.03-7.75 (4H, m, HAr);
7.90-8.36 (2H, br. s, NH2)
687

During study of the chemical behavior of the methylenehydrazones 1 with aromatic amines it was
established that the direction of attack by the nucleophile depends on the nature of the substituents R1 and R2 in
the side chain of the substrate and on the nucleophilicity of the active amine. Thus, the methylenehydrazone 1c
reacts with aniline with the formation of 2-[(2-oxo-2-phenyl-1-phenylamino)ethyl]hydrazono-2,3-dihydro-
3-benzo[b]furanone (3). However, when the reaction of 1c was carried out with p-anisidine (R3 = OMe) under
analogous conditions 2-hydrazono-2,3-dihydro-3-benzo[b]furanone (4) was isolated instead of the expected
product of addition at the activated CH═N bond (method A). Obviously, during the reaction of compound 1c
and an amine with higher nucleophilicity than the formed hydrazone 4 the reaction does not stop at the stage of
addition of the amine at the activated CH═N bond in the initial compound, but the hydrazone 4 is displaced by
the more nucleophilic reagent with the formation of the products from transimination.
The hydrazone 4 was also obtained in the reaction of compound 1c with o-phenylenediamine (method
B). 2-Phenylquinoxaline was isolated from the reaction mixture together with the hydrazone 4. Here, as in the
case with aromatic amines, one amino group of the o-phenylenediamine probably adds initially at the CH═N
bond of the side chain. However, the addition product formed here is not stable and undergoes intramolecular
cyclization through the carbonyl group of the benzoyl fragment and the second amino group of the
o-phenylenediamine with cleavage of the NH–CH bond. It should be noted that the instability of the benzofuran
ring prevents the production of its 2-hydrazono derivative by direct reaction with the hydrazines [7]. Thus, the
reaction of methylenehydrazones (1) with o-phenylenediamine and p-anisidine is a convenient method in
preparative respects for the synthesis of the unsubstituted hydrazone 4.
EXPERIMENTAL
The IR spectra were recorded for suspensions in vaseline oil on an FSM-1201 instrument (Russian). The
1H NMR spectra were recorded on a Bruker DRX-500 spectrometer (500 MHz) in DMSO-d6 with TMS as
internal standard. The mass spectra were obtained on a Varian MAT-311 instrument with 70 eV ionizing
electrons with direct injection of the sample into the ion source. The UV spectra were recorded on an SF-46
spectrometer for solutions in ethanol. The reactions and the purity of the products were monitored by TLC on
Silufol UV-254 in the 10:9:1 ether–benzene–acetone system.
Substituted 2-Methylenehydrazono-2,3-dihydro-3-benzo[b]furanones 1a-e (General Method). To a
solution of 2,3-dihydro-2,3-benzo[b]furandione (1.48 g, 0.01 mol) in anhydrous toluene (10 ml) was added a
suspension of triphenylphosphazine (0.01 mol) in the same solvent (15 ml). The mixture was stirred at ~20°C
until the reagent had completely dissolved. The obtained solution was cooled to 0°C. The precipitate was filtered
off and recrystallized from toluene.
Substituted Methylenehydrazides of o-Hydroxyphenylglyoxalic Acid 2a-c (General Method). A
suspension of the compound 1c-e (0.01 mol) was stirred in a 3:1 mixture of dioxane and water (35 ml) in the
presence 10% HCl (5 ml) until the reagent had completely dissolved. The solution was kept at ~20°C for 24 h.
After removal of the solvent the residue was recrystallized from carbon tetrachloride. Mass spectrum of
o-hydroxyphenylglyoxalic benzoylmethylenehydrazide (2a), m/z (Irel, %): 296 [М]+ (55), 191 [М−С6Н5СО]+
(96), 164 [M−C6H5COCH═N]+ (17), 147 [М−ОНС6Н4СОСО]+ (26), 121 [ОНС6Н4СО]+ (100), 105 [С6Н5СО]+
(21).
2-[(2-Oxo-2-phenyl-1-phenylamino)ethyl]hydrazono-2,3-dihydro-3-benzo[b]furanone (3). To
a
solution of compound 1c (2.62 g, 0.01 mol) in anhydrous carbon tetrachloride (30 ml) was added dropwise a
solution of aniline (0.93 g, 0.01 mol) in the same solvent (10 ml) with stirring. The reaction mixture was kept at
~20°C for 24 h. The precipitate was filtered off and recrystallized from carbon tetrachloride. Mass spectrum of
compound (3), m/z (Irel, %): 278 [M−C6H5NH2]+ (46), 250 [M−C6H5NH2−CO]+ (100), 173
[M−C6H5NH2−C6H5CO]+ (28), 162 [M-C6H5COCH═NC6H5]+ (44), 105 [C6H5CO]+ (25), 93 [C6H5NH2] (38).
688

2-Hydrazono-2,3-dihydro-3-benzo[b]furanone (4). A. To a solution of compound 1c (2.62 g,
0.01 mol) in anhydrous carbon tetrachloride (30 ml) was added dropwise a solution of of p-anisidine (1.22 g,
0.01 mol) in the same solvent (15 ml) with stirring. The reaction mixture was cooled to 0°C, and the precipitate
was filtered off and recrystallized from toluene.
B. A solution of compound 1c (2.62 g, 0.01 mol) and o-phenylenediamine (1.08 g, 0.01 mol) in
anhydrous toluene (50 ml) was kept at ~20°C for 6 h. After the mixture had been cooled to 0°C the precipitate
was filtered off and recrystallized from toluene.
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