Reaction of 2-acyl-6-methylbenzo[b]furan-3-acetic acids derivatives with hydrazine

Article abstract of DOI:10.1002/jhet.5570420510

Reaction of 2-acyl-6-methylbenzo[e]furan-3-acetic acids and their derivatives such as amides and esters with hydrazine does not give expected 1-alkyl-5H-benzofuro[2,3-e]diazepin-4-ones ones but results in 2-amino-7-methyl-2H-benzo[4,5]furo[2,3-c]pyridin-3

Full text of DOI:10.1002/jhet.5570420510

Reaction of 2-Acyl-6-methylbenzo[b]furan-3-acetic
Acids Derivatives with Hydrazine
Jul-Aug 2005
811
Valery S. Tolkunov, Igor F. Perepichka* and Vladimir I. Dulenko
L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
R. Luxemburg Str. 70, Donetsk 83114, Ukraine;
E-mails: i.f.perepichka@durham.ac.uk; tolkunov@uvika.dn.ua
Received September 13, 2004
Reaction of 2-acyl-6-methylbenzo[b]furan-3-acetic acids and their derivatives such as amides and esters
with hydrazine does not give expected 1-alkyl-5H-benzofuro[2,3-e]diazepin-4-ones ones but results in
2-amino-7-methyl-2H-benzo[4,5]furo[2,3-c]pyridin-3-ones or (3-R-6-methylbenzo[b]furan-2-yl)alkyl
ketone azines.
J. Heterocyclic Chem., 42, 811 (2005).
Scheme 1
Introduction.
The 2,3-benzodiazepines derivatives are of great inter-
est because of their proven biological action upon the
nervous system [1-7]. Among the 2,3-benzodiazepine
derivatives tranquilizers and anticonvulsants have been
found [2-4,8]. Thus, 1-(4-aminophenyl)-4-methyl-7,8-
methylenedioxy-5H-2,3-diazepine (GYKI 52466) was
shown to be a highly selective, noncompetitive antago-
nist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxa-
zolepropionate) and kainate receptor responses [9,10].
Several 2,3-benzodiazepine derivatives are used in clini-
cal practice, e.g. tofizopam [1]. Much attention was paid
to the synthesis and investigations of the pharmacologi-
cal activity of diazepines fused with various heterocyclic
rings [3,4,6].
Figure 1
Known methods to obtain 2,3-benzodiazepin-4-ones are
based on the reaction of 2-aroyl(acetyl)-4,5-dimethoxy-
phenyl acetic acids with hydrazine [7,11-13]. Thus, 3H-
[1,2]diazepino[5,6-b]indole, 1H- and 3H-[1,2]diazepino-
[4,5-b]indole derivatives were obtained by cyclization of
derivatives of ethyl indole-2-acetate and indole-2-carboxy-
late with hydrazine hydrate (Scheme 1) [14-16]. Such
transformations for the benzo[b]furan series were not
described and therefore we were interested if this route to
diazepines can be extended onto derivatives with the
benzo[b]furan fragment.
This paper describes investigations of reactions of 2-
acyl-6-methylbenzo[b]furan-3-acetic acid and its deriva-
tives (esters and amides) with hydrazine hydrate, aiming to
determine whether the cyclization reactions into benzodi-
azepine derivatives (of type BFD, Schemes 2 and 3) take
place in this case.

812
V. S. Tolkunov, I. F. Perepichka and V. I. Dulenko
Vol. 42
1
Results and Discussion.
as confirmed by H nmr spectrum (Scheme 2). The tem-
perature of the reaction had no effect on the decarboxyla-
tion process in 1a, and the same azine 3 was formed inde-
pendently whether compound 1a reacted with hydrazine
hydrate at reflux (1 h) or at room temperature (5 h). In both
cases only azine 3 was isolated in high yields (> 90 %).
Thus, the reaction of benzo[b]furan derivative 1a with
hydrazine does not follow the common cyclization way
into 5H-benzofuro[2,3-e]diazepin-4-ones (BFD-a) but
results in azine 3.
The reaction of acid 1a with an excess of hydrazine
hydrate in 2-propanol at reflux resulted in low-soluble
hydrazinium salt of 2-acetyl-6-methylbenzo[b]furan-3-
acetic acid hydrazone (2a). When an aqueous solution of
salt 2a was heated, the decarboxylation was observed
resulting in azine 3 (Scheme 2). The same azine 3 was also
isolated by the acidification of aqueous solution of hydra-
zone 2a with acetic acid.
Similar behavior was observed for the sodium salt of
ketoacid 1a, which reacted with hydrazine in water to yield
hydrazone 2a’'. The later on attempt to isolate by acidifi-
cation (even at below the room temperature) gave azine 3,
Similar reaction of azine 4 (and not diazepinone BFD-b)
formation was observed in reaction of sodium salt of 6-
methyl-2-propionylbenzo[b]furan-3-acetic acid 1b with
Scheme 2
Scheme 3

Jul-Aug 2005
Reaction of 2-Acyl-6-methylbenzo[b]furan-3-acetic Acids Derivatives
813
hydrazine under the same conditions. However, in this
case no decarboxylation occurred and the reaction resulted
in azine 4, thus demonstrating the importance of alkyl sub-
stituents at 2-carbonyl centre on the stability of the acetic
acid fragment in position 3 towards decarboxylation
(Scheme 3).
to yield the corresponding 2,3-benzodiazepinones as a
major product with N-phenylaminoisoquinoline deriva-
tives as only minor by-products [.13]. In our case, cycliza-
tion of compound 5 in the presence of DCC resulted in 1,7-
dimethyl-2-phenylamino-2H-benzo[4,5]furo[2,3-c]-
pyridin-3-one (6) in 64 % yield (Scheme 4).
Thus, although the reaction conditions used in the above
described studies are not very different from those reported
for the preparations of 2,3-benzodiazepinones from 2-
aroylacetic acids (excess of hydrazine hydrate, ethanol,
reflux 2-3 h) [17], the reaction of 2-acylbenzo[b]furan-3-
acetic acids 1 does not afford the corresponding benzodi-
azepinones BFD but results in non-cyclized hydrazones 2
or azines 3,4.
In the next step of variation of hydrazones structure and
reaction conditions, we studied cyclization of phenylhy-
drazone 5 (prepared by reflux of ketoacid 1a with phenyl-
hydrazine in 2-propanol) in the presence of N,N-dicyclo-
hexylcarbodiimide (DCC). Similar cyclization of arylhy-
drazones of 2-acylhomoveratric acid by DCC was shown
Pyrolytic dehydration of 2-acetylphenylacetic acid
phenylhydrazone was shown to give the 2,3-benzodi-
azepinone derivative, while warming in a 1 M solution of
sulfuric acid in acetic acid results in cyclization into the
3-isoquinolone derivative [18]. In this context we studied
the thermal cyclization of hydrazone 8 (Scheme 5). Ethyl 2-
acetylbenzo[b]furan-3-acetate (7) reacted first with
hydrazine yielding compound 8. Compound 8 was formed
even when minimal excess of hydrazine was used. Reflux of
compound 8 in ethylene glycol resulted in thermal hetero-
cyclization to afford 1,7-dimethyl-2-amino-2H-benzo-
furo[2,3-c]pyridin-3-one (9) (Scheme 5).
The failed attempts to synthesize 5H-benzofuro[2,3-
e]diazepin-4-ones (BFD) from the ketoacids 1a,b lead us
to investigate the interaction of 1,7-dimethyl-3-R-benzo-
furo[2,3-c]pyrylium salts (11a-e) [19,20] with hydrazine.
However, reflux of perchlorates 11a-d with hydrazine in 2-
propanol resulted in hydrazones 10a-d only, whereas 1,7-
dimethyl-3-hydroxybenzofuro[2,3-c]pyrylium perchlorate
(11e) in these conditions gave azine 3 (see Method C in the
Experimental part) (Scheme 6).
Scheme 4
Further heterocyclizations of hydrazones 10a-d pro-
ceeded in acidic media only. Thus, the morpholide or
dimethylamide of 2-acetylbenzo[b]furan-3-acetic acid
hydrazones (10a,b) underwent a cyclization reaction into
2-amino-2H-benzofuro[2,3-c]pyridin-3-one (9) being
refluxed in acetic acid (Scheme 5). In contrast, 2-acetyl-
benzo[b]furan-3-(N-arylacetamide) hydrazones (10c,d) in
the same conditions gave azines 12a,b, whereas being
refluxed in trifluoroacetic acid they also gave pyridone 9.
Scheme 5

814
V. S. Tolkunov, I. F. Perepichka and V. I. Dulenko
Vol. 42
Scheme 6
impact) were determined with Finnigan MAT INCOS 50 and
VG7070E mass spectrometers, both operating at an ionizing
potential of 70 eV.
(2-Acetyl-6-methylbenzo[b]furan-3-yl)acetic Acid (1a).
To a suspension of 1,7-dimethyl-3-hydroxybenzofuro[2,3-c]-
pyrylium perchlorate (11e) [19] (3.13 g, 10 mmol) in ethanol (20 ml)
an aqueous sodium hydroxide (5 %, 50 ml) was added and the mix-
ture was heated under reflux for 1 hour. After cooling the solution
was neutralized with diluted hydrochloric acid. The precipitate was
collected by filtration, washed with water, dried and recrystallized
from 2-propanol to afford compound 1a (2.1 g, 90 %) as yellowish
1
needles, mp 160 °C. H nmr (DMSO-d , 500 MHz): δ 2.45 (s, 3H, 6-
6
CH ), 2.54 (s, 3H, COCH ), 4.06 (s, 2H, CH ), 7.18 (d, J = 8.2 Hz,
3
3
2
1H, C5-H), 7.49 (s, 1H, C7-H), 7.69 (d, J = 8.2 Hz, 1H, C4-H), 12.53
The acetylhydrazones 13a,b did not undergowent hetero-
cyclizations in acetic acid, but heating in trifluoroacetic
acid resulted in 2-acetylaminopyridone 14 (Scheme 7).
1
(s, 1H, COOH). H nmr (acetone-d ; 300 MHz): δ 2.49 (s, 3H, 6-
6
CH ), 2.56 (s, 3H, COCH ), 4.18 (s, 2H, CH ), 7.20 (d, J = 8.1 Hz,
3
3
2
13
1H, C5-H), 7.43 (s, 1H, C7-H), 7.69 (d, J = 8.1 Hz, 1H, C4-H).
C
Scheme 7
Conclusion.
nmr (acetone-d , 75 MHz): δ 21.90, 27.56, 29.97, 112.75, 121.46,
6
122.41, 126.15, 127.13, 140.01, 149.29, 155.21, 171.05, 191.22.
In conclusion, hydrazones of 2-acylbenzo[b]furan-3-
acetic acids (and its derivatives), in contrast to similar
phenylacetic and indolylacetic acid derivatives, do not
undergo expected heterocyclization into 5H-benzo-
furo[2,3-e]diazepin-4-ones (BFD). Instead, depending on
their structure and the reaction conditions the reaction
results in 2-amino-7-methyl-2H-benzofuro[2,3-c]pyridin-
3-ones 6, 9, 14 or (3-R-6-methylbenzo[b]furan-2-yl)alkyl
ketone azines 3, 4, 12.
Anal. Calcd. for C
H O : C, 67.34; H, 5.16. Found: C,
13 12 4
67.23; H, 5.21.
(2-Propionyl-6-methylbenzo[b]furan-3-yl)acetic Acid (1b).
This compound was obtained by hydrolysis of the 1-ethyl-3-
hydroxy-7-methylbenzofuro[2,3-c]pyrylium perchlorate 15 [19]
in similar way as described above for 1a. Yield 97 %, mp 136-
1
137 °C (from toluene-heptane, 1:3). H nmr (DMSO-d , 500
6
MHz): δ 1.12 (t, J = 7.3 Hz, 3H, CH ), 2.49 (s, 3H, 6-CH ), 3.06
3
3
(q, J = 7.3 Hz, 2H, CH ), 4.11 (s, 2H, CH ), 7.22 (d, J = 8.1 Hz,
2
2
1H, C5-H), 7.52 (s, 1H, C7-H), 7.72 (d, J = 8.1 Hz, 1H, C4-H),
EXPERIMENTAL
1
12.56 (s, 1H, COOH). H nmr (acetone-d ; 300 MHz): δ 1.15 (t,
6
J = 7.3 Hz, 3H, CH ), 2.49 (s, 3H, 6-CH ), 3.02 (q, J = 7.2 Hz,
3
3
Melting points were determined on a Kofler-type hot-stage
microscope apparatus and are uncorrected. The nmr-spectra were
2H, CH ), 4.20 (s, 2H, CH ), 7.20 (d, J = 7.8 Hz, 1H, C5-H), 7.42
(s, 1H, C7-H), 7.68 (d, J = 7.8 Hz, 1H, C4-H). C nmr (acetone-
2
2
13
1
13
recorded on VARIAN VXR-300 ( H: 300 MHz; C: 75 MHz)
d , 75 MHz): δ 7.62, 21.89, 29.97, 33.34, 112.73, 121.30, 122.35,
6
1
13
and Bruker DRX500 ( H: 500 MHz; C: 125 MHz) spectrome-
ters in DMSO-d or acetone-d solutions. Chemical shifts are
126.09, 127.12, 139.87, 149.10, 155.15, 171.11, 194.23.
Anal. Calcd. for C
H O : C, 68.28; H, 5.73. Found: C,
6
6
14 14 4
given in δ (ppm) and J values in Hz. Mass spectra (ms) (electron
68.40; H, 5.66.

Jul-Aug 2005
Reaction of 2-Acyl-6-methylbenzo[b]furan-3-acetic Acids Derivatives
815
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
Hydrazinium Salt (2a).
{6-Methyl-2-[1-(phenylhydrazono)ethyl]-benzo[b]furan-3-
yl}acetic Acid (5).
To a solution of 1a (2.3 g, 10 mmoles) in 2-propanol (50ml) 80
% aqueous hydrazine (2.5 ml, 50 mmol) was added and the mix-
ture was refluxed for 1 hour. After cooling the solid was collected
by filtration and washed with 2-propanol to yield compound 2a
To a solution of 2-acetyl-6-methylbenzo[b]furan-3-acetic acid
(1a) (2.3 g, 10 mmol) in 2-propanol (20 ml), phenylhydrazine
(1.62 g, 15 mmol) was added and the mixture was refluxed for 1
hour. The mixture was cooled, and the solid was collected by fil-
tration, washed with cold 2-propanol and dried to afford com-
pound 5 (2.3 g, 83 %) as yellow needles, mp 173–174 °C (from
1
(2.3 g, 83 %) as yellowish needles, mp 140 °C (dec.). H-nmr
(DMSO-d 500 MHz): δ 2.11 (s, 3H, 6-CH ), 2.43 (s, 3H,
6
3
1
CH C=N), 3.75 (s, 2H, CH ), 5.25 (m, 5H, ONH NH ), 6.67 (s,
methanol). H nmr (DMSO-d , 500 MHz): δ 2.32 (s, 3H, 6-CH ),
3
2
3
2
6
3
2H, C=NNH ), 7.02 (d, 1H, J = 8.0 Hz, C5-H), 7.30 (s, 1H, C7-
2.43 (s, 3H, CH C=N), 4.03 (s, 2H, CH ), 6.78 (m, 1H, C4'-H),
2
3
2
13
H), 7.41 (d, 1H, J = 8.0 Hz, C4-H). C nmr (acetone-d , 75
7.07 (d, J = 8.0 Hz, 1H, C5-H), 7.21–7.23 (m, 4H, phenyl), 7.33
(s, 1H, C7-H), 7.47 (d, J = 8.1 Hz, 1H, C4-H), 9.48 (s, 1H, NH),
6
MHz): δ 11.70, 21.17, 31.83, 110.43, 110.90, 119.67, 123.48,
128.16, 133.23, 136.46, 149.95, 152.65, 173.53.
13
12.31 (s, 1H, COOH). C nmr ( DMSO-d , 75 MHz): δ 12.75,
6
Anal. Calcd. for C H N O : C, 56.10; H, 6.52; N, 20.13.
21.20, 30.05, 109.09, 110.77, 112.83 (2C), 119.28 (2C), 124.14,
127.74, 128.81 (2C), 134.04, 135.16, 145.24, 150.22, 152.83,
171.82.
13 18
4 3
Found: C, 56.23; H, 6.66; N, 20.30.
(3,6-Dimethylbenzo[b]furan-2-yl)methyl Ketone Azine (3).
Method A.
Anal. Calcd. for C H N O : C, 70.79; H, 5.63; N, 8.69.
19 18
2 3
Found: C, 70.91; H, 5.74; N, 8.60.
A solution of compound 2a (2.0 g, 7.2 mmoles) in water (50
ml) was stirred at 70 °C for 0.5 hour (precipitation was observed
after 5 minutes). The mixture was cooled and the yellow solid
was collected by filtration and dried. The crude product was
recrystallized from DMF to yield azine 3 (1.3 g, 93 %), mp
1,7-Dimethyl-2-phenylamino-2H-benzofuro[2,3-c]pyridin-3-one
(6).
To a solution of compound 5 (1.0 g. 3.1 mmol) in
dichloromethane (20 ml) N,N'-dicyclohexylcarbodiimide (DCC)
(0.72 g, 3.5 mmol) was added and the mixture was stirred at room
temperature for 5 hours. N,N'-Dicyclohexylurea formed in the
reaction was removed by filtration, the dichloromethane solution
was washed with dilute sodium bicarbonate solution and water.
The dichloromethane layer was dried with sodium sulfate and the
solvent was evaporated to yield compound 6 as yellow needles.
The yield after recrystallization from 2-propanol was 0.6 g (64
1
218–219 °C. H nmr (DMSO-d , 500 Mhz): δ 2.35 (s, 3H, 3-
6
CH ), 2.42 (s, 6H, CH C=N and 6-CH ), 7.06 (d, J = 8.0 Hz, 1H,
3
3
3
C5-H), 7.27 (s, 1H, C7-H), 7.49 (d, J = 8.0 Hz, 1H, C4-H). ms:
+
m/z 372 (M , 80 %), 185 (100 %).
Anal. Calcd. for C H N O : C, 77.39; H, 6.49; N, 7.52.
24 24
2 2
Found: C, 77.28; H, 6.37; N, 7.61.
Method B.
1
%), mp 227-228 °C. H nmr (DMSO-d , 500 MHz): δ 2.48 (s,
6
3H, 1-CH ), 2.50 (s, 3H, 7-CH ), 6.57 (d, J = 7.7 Hz, 2H, C2'-H
3
3
A solution of compound 1a (2.3 g, 10 mmoles) in 0.2 M aque-
and C6'-H), 6.81 (t, J = 7.4 Hz, 1H, C4'-H), 6.88 (s, 1H, C4-H),
ous NaHCO (50 ml) and 80 % hydrazine (2.5 ml, 50 mmoles)
3
7.11-7.19 (m, 3H, C3'-H, C5'-H, C6-H , 7.36 (s, 1H, 8-H), 7.91
was refluxed for 1 h. After cooling the solution was acidified by
acetic acid to pH < 7. The precipitate was collected by filtration,
washed with water and recrystallized from DMF to give com-
pound 3 (1.8 g, 97 %).
)
13
(d, J = 7.9 Hz, 1H, 5-H), 9.04 (s, 1H, NH). C nmr (DMSO-d ;
6
75 MHz): δ 12.55, 21.64, 102.92, 111.96, 112.73, 119.02, 120.18,
123.32, 124.52, 128.95, 132.51, 138.12, 138.33, 142.67, 147.60,
+
159.25, 160.03. ms: m/z 304 (M , 100%).
Method C.
Anal. Calcd. for C H N O : C, 74.98; H, 5.30; N, 9.20.
19 16
2 2
Found: C, 75.09; H, 5.22; N, 9.29.
The mixture of 1,7-dimethyl-3-hydroxybenzofuro[2,3-c]-
pyrylium perchlorate (10e) (3.13 g, 10 mmoles) and 80 %
hydrazine (5 ml, 0.1 mol) in ethanol (30 ml) was refluxed for 2
hours. The solid was collected by filtration, washed with ethanol
and recrystallized from DMF to give compound 3 (1.43 g, 77 %).
A mixture of the samples of compound 3 prepared by Methods
Ethyl 2-Acetyl-6-methyl-3-benzo[b]furylacetate (7).
2-Acetyl-6-methylbenzo[b]furan-3-acetic acid 1a (2.3 g 10
mmol) was dissolved in triethyl orthoformate (10 ml) and the
mixture was refluxed for 3 hours. Evaporation of triethyl
orthoformate in vacuo gave a white solid, which was recrystal-
lized from cyclohexane to yield compound 7 (1.0 g, 40 %), mp
1
A–C did not gave a depression of the melting point and their H
nmr spectra were identical.
1
73–74 °C. H nmr (DMSO-d , 500 MHz): δ 1.21 (t, J = 7.0 Hz,
6
(3-Carboxymethyl-6-methylbenzo[b]furan-2-yl)ethyl Ketone
Aazine (4).
3H, CH ), 2.50 (s, 3H, 6-CH ), 2.56 (s, 3H, CH ), 4.10 (q, 2H,
3
3
3
J = 7.0 Hz, CH CH ), 4.13 (s, 2H, CH ), 7.20 (d, J = 8.1 Hz,
2
3
2
1H, C5-H), 7.48 (s, 1H, C7-H), 7.67 (d, 1H, J = 8.1 Hz, C4-H).
This compound was obtained by reaction of 2-propionyl-6-
methylbenzo[b]furan-3-acetic acid (1b) (2.46 g, 10 mmol) with
80 % hydrazine (2.5 ml, 50 mmol) similarly to the procedure
described for compound 3 (Method B). Yield 2.27 g (93 %), mp
1
H nmr (CDCl , 300 MHz): δ 1.25 (t, J = 7.1 Hz, 3H, CH ),
3
3
2.50 (s, 3H, 6-CH ), 2.61 (s, 3H, CH ), 4.16 (s, 2H, CH ), 4.18
3
3
2
(q, 2H, J = 7.1 Hz, CH CH ), 7.14 (d, J = 8.1 Hz, 1H, C5-H),
2
3
13
1
7.32 (s, 1H, C7-H), 7.51 (d, 1H, J = 8.1 Hz, C4-H). C nmr
204–205 °C. H nmr (DMSO-d , 500 MHz): δ 1.17 (t, J = 7.4 Hz,
6
(CDCl , 75 MHz): δ 14.19, 22.03, 27.59, 30.10, 61.10, 112.22,
3H, CH ), 2.48 (s, 3H, 6-CH ), 3.02 (q, J = 7.4 Hz, 2H, CH ),
3
3
3
2
120.26, 121.13, 125.40, 126.02, 139.16, 148.40, 154.52,
169.98, 191.30.
4.14 (s, 2H, CH ), 7.14 (d, J = 8.0 Hz, 1H, C5-H), 7.42 (s, 1H,
2
C7-H), 7.57 (d, J = 8.0 Hz, 1H, C4-H), 12.32 (s, 1H, COOH).
Anal. Calcd. for C H N O : C, 68.84; H, 5.78; N, 5.73.
Anal. Calcd. for C H O : C, 69.22; H, 6.20. Found: C,
28 28
2
6
15 16 4
Found: C, 68.72; H, 5.88; N, 5.82.
69.13; H, 6.31.

816
V. S. Tolkunov, I. F. Perepichka and V. I. Dulenko
Vol. 42
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
Hydrazide (8).
δ 2.17 (s, 3H, 7-CH ), 2.43 (s, 3H, CH C=N), 3.89 (s, 2H,
3
3
CH ), 6.97 (s, 2H, NH ), 7.07 (d, J = 8.0 Hz, 1H, C5-H), 7.30
2
2
(d, J = 8.6 Hz, 2H, C2'-H and C6'-H), 7.32 (s, 1H, C7-H), 7.46
(d, J = 8.0 Hz, 1H, C4-H), 7.60 (d, J = 8.6 Hz, 2H, C3'-H and
To a solution of 7 (1.0 g, 3.8 mmol) in 2-propanol (30 ml) was
added 0.2 ml 80 % hydrazine and the mixture was refluxed for 1
hour. After cooling, water was added (100 ml) and the precipitate
was collected by filtration, washed with water and recrystallized
from 2-propanol to yield compound 8 (0.51 g, 47 %), mp 174–176
13
C5'-H), 10.44 (s, 1H, NH). C nmr (DMSO-d , 75 MHz): δ
6
11.71, 21.17, 32.83, 108.78, 110.86, 119.16, 120.38, 124.13,
126.46, 127.17, 128.50, 134.07, 136.40, 137.98, 150.69,
152.76, 169.56.
1
°C. H nmr (DMSO-d , 500 MHz): δ 2.08 (s, 3H, 6-CH ), 2.39 (s,
6
3
Anal. Calcd. for C H ClN O : C, 64.14; H, 5.10; Cl, 9.96;
19 18
3 2
3H, CH ), 3.68 (s, 2H, CH ), 4.14 (s, 2H, C=NNH ), 6.75 (s, 2H,
3
2
2
N, 11.81. Found: C, 64.26; H, 5.03; Cl, 9.87; N, 11.73.
1,7-Dimethyl-2-amino-2H-benzo[4,5]furo[2,3-c]pyridin-3-one (9).
Method A.
NH ), 7.04 (d, J = 7.9 Hz, 1H, C5-H), 7.30 (s, 1H, C7-H), 7.40 (d,
2
13
J = 7.9 Hz, 1H, C4-H), 8.91 (s, 1H, NH). C nmr (DMSO-d , 75
6
MHz): δ 11.65, 21.17, 29.81, 30.97, 108.98, 110.71, 119.37,
123.86, 127.30, 133.77, 136.31, 150.56, 152.71, 169.20.
Anal. Calcd. for C H N O : C, 59.99; H, 6.20; N, 21.52.
A solution of 10a or 10b (5 mmol) in acetic acid (30 ml) was
refluxed for 1 hour. After cooling, water was added (50 ml) and
the mixture was neutralized with solution of 10 % aq. ammonia.
The solid was collected by filtration, washed with water and
13 16
4 2
Found: C, 59.86; H, 6.31; N, 21.39.
General Procedure for the Reaction of Pyrylium Perchlorates
11a-d with Hydrazine.
recrystallized from 2-propanol to yield compound 9 in 92 and 91
To a suspension of pyrylium perchlorate 11a-d [19,20] (10
mmol) in 2-propanol (50 ml) was added 5 ml 80 % hydrazine and
the mixture was refluxed for 0.5 hour. After cooling, water was
added (50 ml) and the precipitate was collected by filtration,
washed with water and recrystallized from 2-propanol to afford
compounds 10a-d, respectively.
1
% yields, respectively; mp 255–256 °C. H nmr (DMSO-d , 500
6
MHz): δ 2.45 (s, 3H, 1-CH ), 2.61 (s, 3H, 7-CH ), 6.26 (s, 2H,
3
3
NH ), 6.82 (s, 1H, C4-H), 7.15 (d, J = 8.0 Hz, 1H, C6-H), 7.38 (s,
2
1H, C8-H), 7.89 (d, J = 8.0 Hz, 1H, C5-H).
1
H nmr (acetone-d , 300 MHz): δ 2.47 (s, 3H, 1-CH ), 2.62 (s,
6
3
3H, 7-CH ), 6.31 (s, 2H, NH ), 6.86 (s, 1H, C4-H), 7.19 (d, J = 7.8
3
2
Hz, 1H, C6-H), 7.43 (s, 1H, C8-H), 7.94 (d, J = 7.8 Hz, 1H, C5-H).
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
N,N-Dimethylamide (10a).
13
C nmr (acetone-d , 75 MHz): 12.74, 21.55, 99.24, 111.70, 119.28,
6
122.81, 124.34, 129.58, 134.43, 138.10, 141.55, 158.10, 158.36.
This compound was obtained as yellow needles, yield 81 %, mp
Anal. Calcd. for C H N O : C, 68.41; H, 5.30; N, 12.27.
13 12
2 2
1
127-128 °C (from 2-propanol). H nmr (DMSO-d , 500 MHz): δ
6
Found: C, 68.32; H, 5.19; N, 12.39.
2.06 (s, 3H, 6-CH ), 2.40 (s, 3H, CH C=N), 2.90 [s, 6H, N(CH ) ],
3
3
3 2
4.05 (s, 2H, CH ), 6.74 (s, 2H, C=NNH ), 7.07 (d, J = 8.0 Hz, 1H,
Method B.
2
2
C5-H), 7.30 (s, 1H, 7-H), 7.40 (d, J = 8.0 Hz, 1H, C4-H).
Anal. Calcd. for C H N O : C, 65.91; H, 7.01; N, 15.37.
Found: C, 65.83; H, 6.87; N, 15.24.
The same product 9 was obtained by reflux of compound 8 in
ethylene glycol for 2 hours; yield 90 %.
15 19
3 2
Method C.
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
Morpholide (10b).
A solution of 10c or 10d (5 mmol) in trifluoroacetic acid (30
ml) was heated at reflux for 1 hour and then evaporated in
vacuo. After cooling, water was added (50 ml) and the mixture
was neutralized with of 10 % aqueous ammonia. The solid was
collected by filtrationered, off, washed with water and recrystal-
lized from 2-propanol to afford compound 9 in 86 or 89 %
yields, respectively.
This compound was obtained as yellow needles, yield 89 %,
1
mp 124–125 °C (from 2-propanol). H nmr (DMSO-d , 500
6
MHz): δ 2.06 (s, 3H, 6-CH ), 2.40 (s, 3H, CH C=N), 3.36-3.52
3
3
(m, 8H, morpholine), 4.01 (s, 2H, CH ), 6.77 (s, 2H, C=NNH ),
2
2
7.02 (d, J = 8.0 Hz, 1H, C5-H), 7.31 (s, 1H, C7-H), 7.41 (d, J =
8.0 Hz, 1H, C4-H).
Anal. Calcd. for C H N O : C, 64.74; H, 6.71; N, 13.32.
Found: C 64.83; H 6.81; N 13.24.
17 21
3 3
(6-Methyl-3-(p-tolylcarbamoyl-methyl)benzo[b]furan-2-yl)-
methyl Kketone Aazine (12a).
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
N-(4-Methylphenyl)amide (10c).
Compound 12a was prepared from compound 10c similarly to
method A described above method A for compound 9, as yellow
crystals; yield 98 %, mp 306-307 °C (from N,N-dimethylfor-
This compound was obtained as yellow needles, yield 97 %,
1
mamide). H nmr (DMSO-d , 500 MHz): δ 2.23 (s, 3H, 4'-CH ),
1
6
3
mp 191 °C (from 2-propanol). H nmr (DMSO-d , 500 MHz): δ
6
2.42 (s, 3H, 6-CH ), 2.46 (s, 3H, CH C=N), 4.24 (s, 2H,
2.14 (s, 3H, 6-CH ), 2.22 (s, 3H, 4'-CH ), 2.40 (s, 3H, CH C=N),
3
3
3
3
3
CH CO), 7.00 (d, J = 8.2 Hz, 2H, C3' and C5'-H), 7.14 (d, J= 8.0
3.87 (s, 2H, CH ), 6.99 (s, 2H, NH ), 7.07 (d, J = 7.8 Hz, 3H,
2
2
2
Hz, 1H, C5-H), 7.31 (s, 1H, C7-H), 7.39 (d, 2H, C2'-H, C6'-H),
7.60 (d, J = 8.0 Hz, 1H, C4-H), 9.75 (s, 1H, NH).
C3'-H, C5'-H and C5-H), 7.34 (s, 1H, C7-H), 7.43 (d, 3H, J = 7.8
Hz, C2'-H, C6'-H and C4-H), 10.20 (1H, c, NH).
Anal. Calcd. for C H N O : C, 75.21; H, 6.00; N, 8.77.
Anal. Calcd. for C H N O : C, 71.62; H, 6.31; N, 12.53.
40 38
4 4
20 21
3 2
Found: C, 75.11; H, 5.89; N, 8.91.
Found: C, 71.75; H, 6.22; N, 12.61.
(6-Methyl-3-(p-chlorophenylcarbamoyl-methyl)benzo[b]furan-
2-yl)methyl Ketone Azine (12b).
[2-(1-Hydrazono-ethyl)-6-methylbenzo[b]furan-3-yl]acetic Acid
N-(4-Chlorophenyl)amide (10d).
Compound 12b was prepared from compound 10d similarly to
method A described above for compound 9, as yellow crystals;
This compound was obtained as yellow needles, yield 96 %,
1
mp 201 °C (from 2-propanol). H nmr (DMSO-d , 500 MHz):
6

Jul-Aug 2005
Reaction of 2-Acyl-6-methylbenzo[b]furan-3-acetic Acids Derivatives
817
1
nmr (DMSO-d , 75 MHz): δ 12.33, 20.51, 21.63, 102.59, 11.93,
yield 97 %, mp 326–327 °C (N,N-dimethylformamide). H nmr
(DMSO-d , 500 MHz): δ 2.37 (s, 3H, 6-CH ), 2.45 (s, 3H,
6
118.81, 123.33, 124.54, 131.45, 138.10, 138.54, 142.88, 159.11,
159.26, 169.65.
6
3
CH C=N), 4.26 (s, 2H, CH ), 7.14 (d, J = 8.0 Hz, 1H, C5-H),
7.33 (d, J = 8.0 Hz, 2H, C2'-H, C6'-H), 7.45 (s, 1H, C7-H), 7.58-
7.64 (m, 3H, C3'-H, C5'-H, C4-H), 10.29 (s, 1H, NH). C nmr (
3
2
Anal. Calcd. for C H N O : C, 66.66; H, 5.22; N, 10.36.
15 14
2 3
13
Found: C, 66.78; H, 10.47
DMSO-d , 100 °C, 75 MHz): δ 12.43, 21.83, 33.58, 111.96,
6
116.01, 121.02, 121.84, 125.39, 127.75, 127.96, 129.12, 136.94,
138.79, 150.01, 154.73, 156.24, 168.54.
REFERENCES AND NOTES
Anal. Calcd. for C H Cl N O : C, 67.16, H, 4.75, Cl, 10.43,
N, 8.24. Found: C, 67.04, H, 4.88, Cl, 10.32, N, 8.33.
38 32
2 4 4
[1] T. Seppala, E. Palva, M. Mattila, K. Korttila and R.
Shrotriya,. Psychopharmacology, 69, 209 (1980).
[2] R. Gitto, M. L. Barreca, L. De Luca, G. De Sarro, G.
Ferreri, S. Quartarone, E. Russo, A. Constanti and A. Chimirri, J.
Med. Chem., 46, 197 (2003).
2-{2-[1-(Acetylhydrazono)-ethyl]-6-methylbenzo[b]furan-3-yl}-
N-p-tolylacetamide (13a).
To a solution of 10c (1.0 g, 3 mmol) in dioxane (25 ml) acetic
anhydride (0.2 g, 4 mmol) was added and the mixture was heated
at reflux for 1 h. After cooling, the solid was collected by filtra-
[3] G. De Sarro, R. Gitto, M. Zappala and A. Chimirri,. Il
Farmaco, 57, 129 (2002).
[4] A. Chimirri, R. Gitto, S. Quartarone, V. Orlando, A. De
Sarro and G. De Sarro, Il Farmaco, 57, 759 (2002).
[5] A. Chimirri, G. De Sarro, A. De Sarro, R. Gitto, S.
Quartarone, M. Zappala, A. Constanti and V. Libri, J. Med. Chem., 41,
3409 (1998).
[6] M. Zappala, R. Gitto, F. Bevacqua, S. Quartarone, A.
Chimirri, M. Rizzo, G. De Sarro and A. De Sarro, J. Med. Chem., 43,
4834 (2000).
[7] A. De Sarro, G. De Sarro, R. Gitto, S. Grasso, N. Micale
and M. Zappala, Il Farmaco, 54, 178 (1999).
[8]G. De Sarro, A. Chimirri, A. De Sarro, R. Gitto, S. Grasso, P..
Giusti, A. G. Chapman, Eur. J. Pharmacol., 294, 411 (1995).
[9] S. D. Donevan and M. A. Rogawski, Neuron, 10, 51
(1993).
tion, washed with cold dioxane to afford compound 13a (1.0 g,
1
89 %) as yellow needles, mp 288–289 °C. H nmr (DMSO-d ,
6
500 MHz): δ 2.20 (s, 6H, 4'-and 6-CH ,), 2.38 (s, 3H, CH C=N),
3
3
2.43 (s, 3H, CH CO), 3.91 (s, 2H, CH CO), 7.02 (d, 2H, J = 8.0
3
2
Hz, C3'-H, C5'-H), 7.17 (d, 1H, J = 8.0 Hz, 5-H), 7.43 (s, 1H, C7-
H), 7.45 (d, 2H, J = 8.0 Hz, C2'-H, C6'-H), 7.70 (d, 1H, J = 8.0
Hz, C4-H), 10.21 (s, 1H, CONHAr), 11.07 (s, 1H, CONHN=).
Anal. Calcd. for C H N O : C, 70.01, H, 6.14, N, 11.13.
22 23
3 3
Found: C, 70.14, H, 6.25, N, 11.02.
2-{2-[1-(Acetylhydrazono)-ethyl]-6-methylbenzo[b]furan-3-yl}-
N-p-chlorophenylacetamide (13b).
Compound 13b was prepared from compound 10d in a similar
way to that described above for compound 13a, in 89 % yield as
colorless needles, mp 289-290 °C (from N,N-dimethylfor-
[10] S. D. Donevan, S. Yamaguchi and, M. A. Rogawski, J.
Pharmacol. Exp. Ther., 271, 25 (1994).
[11] F. Gatta, D. Piazza, M. R. Del Giudice and M. Massotti, Il
Farmaco Ed. Sc., 40, 942 (1985).
[12] F. Bevacqua, A. Basso, R. Gitto, M. Bradley and A.
Chimirri, Tetrahedron Lett., 42, 7683 (2001).
[13] A. Sotiriadis, P. Catsoulacos and D. Theodoropoulos, J.
Heterocyclic Chem., 11, 401 (1974).
[14] A. Monge, M. T. Martinez, J. A. Palop, J. M. Mateo and E.
Fernandez-Alvarez, J. Heterocyclic Chem., 18, 889 (1981).
[15] A. Monge, J. A. Palop, T. Goni, A. Martinez and E.
Fernandez-Alvarez, J. Heterocyclic Chem., 21, 381 (1984).
[16] A. Monge, J. A. Palop, T. Goni, A. Martinez and E.
Fernandez-Alvarez, J. Heterocyclic Chem., 22, 1445 (1985).
[17] A. Chimirri, G. De Sarro, A. De Sarro, R. Gitto, S. Grasso,
S. Quartarone, M. Zappala, P. Giusti, V. Libri, A. Constanti and A. G.
Chapman, J. Med. Chem. 40, 1258 (1997).
1
mamide). H nmr (DMSO-d , 500 MHz): δ 2.19 (s, 3H, 6-CH ,),
6
3
2.38 (s, 3H, CH C=N), 2.45 (s, 3H, CH CO), 3.90 (s, 2H,
3
3
CH CO), 7.13 (d, 1H, J = 7.6 Hz, C5-H), 7.19 (d, 2H, J = 8.0 Hz,
2
C2'-H and C6'-H), 7.32 (s, 1H, C7-H), 7.60 (d, 2H, J = 8.0 Hz,
C3'-H and C5'-H), 7.69 (d, 1H, J = 7.6 Hz, C4-H), 10.32 (s, 1H,
CONHAr), 11.03 c (s, 1H, CONHN=).
Anal. Calcd. for C H ClN O : C, 63.40, H, 5.07, Cl, 8.91,
21 20
3 3
N, 10.56. Found: C, 63.29, H, 4.91, Cl, 9.02, N, 10.67.
1,7-Dimethyl-2-acetylamino-2H-benzo[4,5]furo[2,3-c]pyridin-
3-one (14).
A solution of 13a or 13b (1 mmol) in trifluoroacetic acid (30
ml) was heated at reflux for 1 h and then evaporated in vacuo.
After cooling, water was added (50 ml) and the mixture was neu-
tralized with solution of 10 % aqueous ammonia. The precipitate
was collected by filtration, washed with water and recrystallized
from 2-propanol to yield compound 14 in 93 and 91 % yields,
[18] J. O. Halford, R. W. Raiford, Jr., and B. Weissmann, J. Org.
Chem., 26, 1898 (1961).
[19] S. V. Tolkunov, M. N. Kal''nitskii and E. A. Zemskaya,
Khim. Geterotsikl. Soed, 1552 (1991) (in Russian); Chem. Heterocycl.
Compd. (Engl. Transl.), 27, 1253 (1991).
[20] S. V. Tolkunov, V. S. Tolkunov, V. I. Dulenko, Khim.
Geterotsikl. Soed, 557 (2004) (in Russian); Chem. Heterocycl.
Compd. (Engl. Transl.), 40, 481 (2004).
1
respectively, mp. 253–254 °C. H nmr (DMSO-d , 500 MHz): δ
6
2.09 (s, 3H, 1-CH ), 2.37 (s, 3H, 7-CH ), 2.45 (s, 3H, COCH ),
3
3
3
6.88 (s, 1H, C4-H), 7.17 (d, 1H, J = 8.0 Hz, C6-H), 7.39 (s, 1H,
13
C8-H), 7.94 (d, 1H, J = 8.0 Hz, C5-H), 10.90 (s, 1H, NH).
C