Reactions of substituted furo[3,2-b]pyrrole-5-carbohydrazides under classical and microwave conditions

Article abstract of DOI:10.1135/cccc20052101

Substituted hydrazones 5 and 6 were synthesized by the reaction of the corresponding furo[3,2-b]pyrrole-5-carboxyhydrazides 1 with 6-substituted 4-oxochromene-3-carbaldehydes 2 and methyl 2-formylfuro[3,2-b]pyrrole-5- carboxylates 3 under microwave irradiation as well as by the classical method. The beneficial effect of the microwave irradiation on these reactions was a shortening of the reaction time and an increase in the yields. The reactions of 1 with 4-[(4-oxochromen-3-yl)methylidene]-2-phenyloxazol-5(4H)-one (4) were also studied. Compounds 7 or 8 were obtained, depending on the reaction temperature.

Full text of DOI:10.1135/cccc20052101

Furo[3,2-b]pyrrole-5-carbohydrazides
2101
REACTIONS OF SUBSTITUTED FURO[3,2-b]PYRROLE-
5
-CARBOHYDRAZIDES UNDER CLASSICAL AND
MICROWAVE CONDITIONS
Renata GAŠPAROVÁ , Margita LÁCOVÁ and Alžbeta KRUTOŠÍKOVÁa2,*
a1
b
a
Department of Chemistry, Faculty of Natural Sciences, University of St. Cyril and Methodius,
Námestie Jozefa Herdu 2, Sk-917 01 Trnava, Slovak Republic;
e-mail: renata.gasparova@ucm.sk, alzbeta.krutosikova@ucm.sk
Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University,
Mlynská dolina CH-2, Sk-842 15 Bratislava, Slovak Republic; e-mail: lacova@fns.uniba.sk
1
2
b
Received Septem ber 21, 2004
Accepted July 8, 2005
Substituted h ydrazon es 5 an d 6 were syn th esized by th e reaction of th e correspon din g
furo[3,2-b]pyrrole-5-carboxyh ydrazides 1 with 6-substituted 4-oxoch rom en e-3-carbaldeh ydes
2
an d m eth yl 2-form ylfuro[3,2-b]pyrrole-5-carboxylates 3 un der m icrowave irradiation as
well as by th e classical m eth od. Th e ben eficial effect of th e m icrowave irradiation on th ese
reaction s was a sh orten in g of th e reaction tim e an d an in crease in th e yields. Th e reaction s
of 1 with 4-[(4-oxoch rom en -3-yl)m eth yliden e]-2-ph en yloxazol-5(4H)-on e (4) were also stud-
ied. Com poun ds 7 or 8 were obtain ed, depen din g on th e reaction tem perature.
Keyw ord s: 4-Oxoch rom en e-3-carbaldeh ydes; Furo[3,2-b]pyrrole-5-carboh ydrazides; Meth yl
2
-form ylfuro[3,2-b]pyrrole-5-carboxylates; Hippuric acid; Fused h eterocycles; Hydrazon es;
Microwave irradiation .
N-Aroyl an d N-h eteroaroyl h ydrazon es h ave been described as useful build-
in g blocks for various h eterocyclic rin gs1 . A large n um ber of h ydrazon es
–3
4
h ave exh ibited a wide variety of biological activities, e.g. an tibacterial , an -
5
6
algesic an d an ti-in flam m atory , an tim ycobacterial an d th e reduction of
7
th e fatigue of skeletal m uscles . Syn th esis an d study of ph ysical an d ch em i-
cal properties of h eterocyclic com poun ds con tain in g furan rin g fused with
various h eterocycles, in cludin g furo[3,2-b]pyrrole derivatives, attracted a
8
great in terest durin g th e recen t decades . Th e ben zopyran e m oiety is
kn own as th e structural un it of m an y n atural products an d ph arm aceutic-
9
–11
, an d h as been widely used as a syn th etic in term ediate12–14
.
als
In con tin uation of our program aim ed at developin g efficien t syn th eses
of fused oxygen -n itrogen con tain in g h eterocycles, we h ave reported th e use
1
5–19
of substituted furo[3,2-b]pyrroles an d th eir derivatives in syn th esis
.
4
-Oxoch rom en e-3-carbaldeh yde an d its derivatives h ave also played an im -
2
0–23
portan t role in our research
as th eir syn th etic poten tial.
because of th eir biological activity as well
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20052101

2
102
Gašparová, Lácová, Krutošíková:
Th e use of m icrowave irradiation in organ ic syn th esis h as becom e h igh ly
valued for its rem arkable in fluen ce on th e rate en h an cem en t of a wide vari-
2
4–27
ety of reaction s as well as on th e purity an d yields of products
.
Th e aim of th is study was to syn th esize som e n ew h ydrazon es 5a–6b de-
rived from furo[3,2-b]pyrrole-5-carboh ydrazides 1 by th eir reaction s with
substituted 4-oxoch rom en e-3-carbaldeh ydes 2 an d m eth yl 2-form ylfuro-
[
3,2-b]pyrrole-5-carboxylates 3 (Sch em e 1). Our goal was to obtain n ew
com poun ds with poten tial biological activity an d to com pare th e classical
m eth od with th e effect of m icrowave irradiation , with a view to fin din g
con dition s un der wh ich th e yield or th e rate of reaction would in crease.
O
8
'
H
O
R3
R2
N
2'
7'
O
R1
2
O
O
3
N
6'
N
H
R3
7
5'
2
6
O
R
O
R2
N
O
3
R1
5a - 5k R = H, CH , Cl, NO
3
2
NH2
R3
N
H
TsOH
N
R
CO CH
R3
4'
O
2
3
1
H
N
CO2CH3
O
R2
3
'
3
O
O
R1
2'
6'
3
N
N
N
H
O
7
R1
H
H
H
H
CH3
H
R1
H
H
H
Bn
CH3
Bn
Bn
H
2
R
H
CH3
Ph
6
R
O
a
b
c
d
e
f
3
6a, 6b R = H,CH3
H
CH3
CH3
CH3
g
h
CH3
CH=CH-CH=CH
SCHEME 1
An oth er goal of th is study was to in vestigate th e reaction s of 1 with
-oxo-4,5-dih ydrooxazole derivatives 4 wh ich con stitute an efficien t
5
m eth od of th e syn th esis of N-h eterocycles (Sch em e 2).
RESULTS AND DISCUSSION
3
1
2
N′-[(6-R -4-O xo ch ro m en -3-yl)m et h ylid en e]-2-R -3-R -4-R-fu ro [3,2-b]-
3
pyrrole-5-carboh ydrazides 5a–5k an d N′-{[(4-R -5-m eth oxycarbon yl)furo-
3,2-b]pyrrol-2-yl]m eth yliden e}-2-R -3-R -4-R-furo[3,2-b]pyrrole-5-carbo-
1
2
[
h ydrazides 6a, 6b were syn th esized in h igh yields (72–83%) by th e reaction
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Furo[3,2-b]pyrrole-5-carbohydrazides
2103
of 1 with 2 an d 3, respectively, in eth an ol in th e presen ce of 4-m eth yl-
ben zen e-1-sulfon ic acid by h eatin g at 50–60 °C over 1–4.5 h .
Microwave-assisted syn th esis of 5a–6b was perform ed usin g an output of
9
0 W. Th e reaction tim es were on ly 4–9 m in , wh ile th e yields were com pa-
rable or sligh tly h igh er (73–94%) th an th ose ach ieved un der th e classical
1
con dition s (Table I). Th e H NMR spectra of com poun ds 5a–6b displayed
th e sign als of H-6 pyrrole proton s in th e 6.47–7.23 ppm ran ge, an d th e sig-
n als of H-7 of th e double bon d in 8.10–8.70 ppm ran ge. Th e reson an ce sig-
n als an d th eir m ultiplicity con firm ed th e proposed structures.
H3C
H3C
CH3
O
H
N
N
O
O
N
O
O
N
Ph
9
8
'
O
O
7
7'
2'
O
H
N
9
O
R2
R2
N
6'
O
5'
N
R1
H
HN
N
8
6''
R1
NH2
6
N
H
5
''
O
R
O
O
1
2''
4
''
R
2
3''
1
1
e R,R ,R = CH3
f R = CH3, R = H, R2 = Bn
1
1
2
7a R,R ,R = CH
3
2
7
b R = CH3, R1 = H, R = Bn
110 °C
R2
O
R1
N
O
110 °C
or MWO)
2
O
O
HN
O
N
6
9
'
R
O10a'
N
O
O
(
Ph
8'
2
''
3''
AcOH
3'
7'
NHCO
4''
5''
6'
4'
4
AcOK
O
6''
1
2
O
8a R,R ,R = CH3
8
b R = CH3, R1 = H, R2 = Bn
NH2
N
H
1
0
NHCO
9
'
O10a'
N
O
8
'
1
10 °C
2''
3''
3'
7
'
NHCO
4''
6'
4'
O
6'' 5''
8c
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2
104
Gašparová, Lácová, Krutošíková:
It is kn own th at th e reaction s of aldeh ydes with h ippuric acid lead to
2
8,29
oxazol-5(4H)-on e derivatives
, wh ich can serve as precursors of am in o
3
0
31
acids or as con ven ien t reagen ts for th e syn th esis of n ew h eterocycles .
Th us, Nálepa an d co-workers32 described th e syn th esis of 1-(arylam in o)-
substituted im idazol-5(4H)-on es by th e treatm en t of substituted 4-aryliden -
2
-ph en yloxazol-5(4H)-on es with substituted ph en ylh ydrazin es. Th erefore,
we in vestigated th e reaction of 4-[(4-oxoch rom en -3-yl)m eth yliden e]-
2
5
-ph en yloxazol-5(4H)-on e (4) with 2,3,4-trim eth ylfuro[3,2-b]pyrrole-
-carboh ydrazide (1e) with th e in ten tion to obtain com poun d 9, as th is
process would offer a con ven ien t syn th etic route to furo[3,2-b]pyrrole de-
rivatives, bearin g th e ch rom on e as well as im idazolon e m oieties.
TABLE I
Yields an d reaction tim es of com poun ds 5a–8c in m icrowave m eth od (MW) an d classical
m eth od (C)
Rection tim e
Yield, %
m in
h
Com p.
R
R1
R2
R3
MW
C
MW
C
5
5
5
5
5
5
5
5
5
5
5
6
6
7
7
8
8
8
a
b
c
d
e
f
C H
H
H
H
86
83
80
86
85
79
77
81
79
77
83
94
79
–
80
80
72
83
74
73
76
72
75
73
81
81
77
76
78
70
75
71
8
4
6
5
5
C H
H
H
Cl
NO2
Cl
H
5
4
6
H
H
CH C H
4
2
2
6
5
CH3
CH3
CH3
H
H
H
5
4
H
CH C H
7
2.5
1
2
6
5
5
CH3
H
CH C H
NO2
H
4.5
7
2
6
g
h
i
H
H
H
1.5
1
H
H
NO2
CH3
Cl
H
5
H
H
6.5
9
1.5
3
j
CH3
CH3
CH3
H
k
a
b
a
b
a
b
c
CH=CH–CH=CH
CH3 CH3
CH=CH–CH=CH
6.5
8.5
6
3
H
H
3
H
CH3
–
1.5
2
CH3
CH3
CH3
CH3
–
CH3
H
CH3
–
CH C H
–
–
–
2
2
6
5
CH3
H
CH3
–
72
–
11
4
C H
–
–
8
5
6
5
–
–
–
68
6
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Furo[3,2-b]pyrrole-5-carbohydrazides
2105
Wh en 4-[(4-oxoch rom en -3-yl)m eth yliden e]-2-ph en yloxazol-5(4H)-on e
4) was treated with 2,3,4-trim eth ylfuro[3,2-b]pyrrol-5-carboh ydrazide (1e)
(
in acetic acid in th e presen ce of a catalytic am oun t of fused potassium ace-
tate eith er un der reflux for 4 h or with m icrowave irradiation for 11 m in ,
un expected pyran opyridon e 8a was obtain ed in 72% yield (Sch em e 2). On
th e oth er h an d, N′-{2-ben zam ido-[3-(oxoch rom en -3-yl)]propen oyl}-2,3,4-
trim eth ylfuro[3,2-b]pyrrole-5-carboh ydrazide (7a) was obtain ed in 76%
yield, wh en th e reaction m ixture was h eated at lower tem perature (60 °C)
for 2 h . Subsequen tly, 7a was cyclized eith er un der 2 h reflux in acetic
acid–potassium acetate m edium or upon irradiation in a m icrowave oven
for 9 m in to give 65% yield of 8a. Th e form ation of 7a in th e m icrowave
oven was n ot observed (Sch em e 2). Sim ilar results were obtain ed by th e
classical reaction of 4-ben zyl-2-m eth ylfuro[3,2-b]pyrrole-5-carboh ydrazide
(
1f) with oxazolon e 4 to give eith er 7b in 78% yield after h eatin g at 60 °C
for 2 h or 8b in 75% yield after h eatin g at 110 °C for 5 h . Com poun d 8c
was obtain ed by th e reaction of 4 with ben zoh ydrazide (10) in 71% yield
after irradiation in th e m icrowave oven for 8 m in , wh ile classical h eatin g
1
for 6 h led to 68% yield of 8c. Th e H NMR spectra of com poun ds 7a an d
7
b displayed th e sign als of th ree NH proton s at 9.90–10.16 ppm , pyrrole
H-6 at 6.88 or 6.30 ppm , an d th e sign als of H-9 on th e double bon d at
7
8
.02 or 7.09 ppm . Proton s H-2′ of th e ch rom en e rin g sh owed a sin glet at
.64 ppm . Th e H NMR spectra con firm ed structures of 8a–8c, based on
1
m issin g H-2′ sign als an d th e reson an ces of two NH proton s, wh ich can
serve as a good in dication of th e addition reaction . Th e sign als of th e two
NH proton s were at 9.82–9.88 an d 11.11–11.79 ppm . Th e sin glet sign als of
H-10a′ proton s appeared in th e 7.41–7.44 ppm ran ge, an d th e sign als of H-6
proton s in com poun ds 8a an d 8b were at 6.36 an d 6.95 ppm , respectively.
Th e form ation of pyran opyridon e rin g system of 8a–8c could be explain ed
by an acid catalyzed 1,6-addition , with a possible m ech an ism outlin ed in
Sch em e 3. To th e best of our kn owledge, ch rom on e derivatives are usually
readily rin g-open ed via n ucleoph ilic attack at C-2, but in th e presen ce of
3
3
suitable groups, e.g. 3-(arylim in om eth yl) , th e reactivity towards n ucleo-
ph iles is altered an d n ucleoph ilic 1,4-addition rath er th an th e rin g cleavage
can be preferred. However, th e reaction with h ydrazin e or its derivatives led
to th e pyran e rin g cleavage, an d a n um ber of pyrazole derivatives were ob-
3
4
tain ed . In our case, a h ith erto un described 1,6-addition took place.
In sum m ary, we h ave sh own th at th e con version of th e startin g h ydra-
zon es 1 in to substituted com poun ds 5 an d 6 can be substan tially im proved
upon usin g m icrowave irradiation , wh ich led to th e reduction of th e reac-
tion tim es from h ours to secon ds an d, in a n um ber of cases, to an in crease
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2
106
Gašparová, Lácová, Krutošíková:
of th e yields as well. We h ave also dem on strated th at th e reaction of h ydra-
zon es 1e an d 1f with oxazolon e 4 gave rise, depen din g on th e con dition s,
eith er to th e cleavage of th e oxazolon e m oiety an d th e form ation of substi-
tuted h ydrazon es 7a an d 7b or to a tan dem sequen ce, in wh ich th e above
oxazolon e rin g fragm en tation was followed by an un expected, form al 1,6-
addition to yield pyran opyridon es of type 8.
R1
HN
R1
NH
R1
H
O
O
O
R
O
O
R
O
O
N
O
R
H
-H
OH
H
R1
R1
N
O
O
N
O
R
O
O
R
R = PhCONH
HNOC
CH3
CH3
CH3
R1
N
=
H
O
O
SCHEME 3
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler h ot plate an d are un corrected. 1H NMR spectra
were recorded on a 300 MHz spectrom eter Varian Gem in i 200 in DMSO-d6 or CDCl3 with
TMS as in tern al stan dard. Ch em ical sh ifts are given in ppm , couplin g con stan ts (J) in Hz.
Th e course of th e reaction was m on itored by TLC in eth yl acetate–h exan e. All m icrowave
experim en ts were perform ed in a Wh irlpool M401 h om e m icrowave oven in an apparatus,
adapted for laboratory application s; h exan e was used as a coolin g m edium for th e con -
den ser. Elem en tal an alyses were determ in ed usin g a Carlo Erba CHNS-OEA 1108-Elem en tal
An alyser.
Furo[3,2-b]pyrrole-5-carboh ydrazides 1 were prepared accordin g to ref.37, 4-oxoch rom en e-
3
-carbaldeh ydes 2 accordin g to ref.36, m eth yl 2-form ylfuro[3,2-bpyrrole-5-carboxylates 3
3
5
accordin g to ref. an d 4-[(4-oxoch rom en -3-yl)m eth yliden e]-2-ph en yloxazol-5(4H)-on e (4)
2
9
was prepared accordin g to ref. Ben zoh ydrazide 10 was prepared by th e reaction of ben zoyl
ch loride with sodium m eth an olate an d subsequen t h eatin g of m eth yl ben zoate with h ydra-
zin e h ydrate un der reflux for 12 h .
3
1
2
N′-[(6-R -Oxoch rom en -3-yl)m eth yliden e]-2-R-3-R -4-R -furo[3,2-b]pyrrole-
3
5
-carboh ydrazides (5a–5k) an d N′-[(4-R -5-carboxym eth ylfuro[3,2-b]pyrrole-2-yl)-
m eth yliden e]-2-R -3-R -4-R-furo[3,2-b]pyrrole-5-carboh ydrazides (6a, 6b)
1
2
Classical Method
A
m ixture of furo[3,2-b]pyrrole-5-carboh ydrazide 1 (1 m m ol) an d 4-oxoch rom en e-
3
-carbaldeh yde 2 or m eth yl 2-form ylfuro[3,2-b]pyrrole-5-carboxylate 3 (1 m m ol) was h eated
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Furo[3,2-b]pyrrole-5-carbohydrazides
2107
for 1–4 h at 50–60 °C in eth an ol (3 m l) in th e presen ce of 4-m eth ylben zen e-1-sulfon ic acid.
Th e solid products were filtered off, dried an d crystallized from eth an ol.
Microwave Method
Th e m ixture of th e sam e com position as above was irradiated in th e m icrowave oven at 90 W
output over th e period, given in Table I. Th e products were isolated an d purified in th e
sam e m an n er as above.
N′-[(Oxochromen-3-yl)methylidene]-2-phenylfuro[3,2-b]pyrrole-5-carbohydrazide (5a). Yield 86%
1
(
MW), 80% (C), tim e 8 m in (MW), 4 h (C), m .p. 260–263 °C (eth an ol). H NMR (DMSO-d ):
6
6
.92 s, 1 H (H-3); 7.17 s, 1 H (H-6); 7.28–7.59 m , 5 H (C H ); 7.74–7.91 m , 4 H (H-5′, H-6′,
6 5
H-7′, H-8′); 8.18 s, 1 H (H-7); 8.87 s, 1 H (H-2′); 11.65 bs, 1 H (NH); 11.76 br, 1 H (NH). For
C23H15N O (397.4) calculated: 69.52% C, 3.80% H, 10.57% N; foun d: 69.73% C, 3.80% H,
3
4
1
0.52% N.
N′-[(6-Chloroxochromen-3-yl)methylidene]-2-phenylfuro[3,2-b]pyrrole-5-carbohydrazide (5b ).
1
Yield 83% (MW), 80% (C), tim e 5 m in (MW), 4 h (C), m .p. 239–242 °C (eth an ol). H NMR
(
DMSO-d ): 6.93 s, 1 H (H-3); 7.10 s, 1 H (H-6); 7.18–7.50 m , 5 H (C H ); 7.80–7.92 m , 3 H
6 6 5
(
H-5′, H-7′, H-8′); 8.11 s, 1 H (H-7); 8.89 s, 1 H (H-2′); 11.66 br, 1 H (NH); 11.85 br, 1 H
(
NH). For C23H14ClN O (431.8) calculated: 63.97% C, 3.27% H, 8.21% Cl, 9.73% N; foun d:
3
4
6
3.91% C, 3.23% H, 8.17% Cl, 9.55% N.
N′-[(6-Nitrooxochromen-3-yl)methylidene]-4-benzylfuro[3,2-b]pyrrole-5-carbohydrazide (5c).
1
Yield 80% (MW), 72% (C), tim e 4 m in (MW), 2 h (C), m .p. 181–185 °C (eth an ol). H NMR
(
CDCl ): 5.73 s, 2 H (CH ); 6.18 s, 1 H (H-3); 6.73 s, 1 H (H-6); 7.15–7.31 m , 6 H (H-2,
3 2
C H ); 7.59–7.84 m , 3 H (H-5′, H-7′, H-8′); 8.25 s, 1 H (H-7); 8.96 s, 1 H (H-2′); 11.32 br, 1 H
6
5
(
NH). For C24H16N O (456.4) calculated: 63.16% C, 3.53% H, 12.28% N; foun d: 63.71% C,
4
6
3
.65% H, 12.10% N.
N′-[(6-Chlorooxochromen-3-yl)methylidene]-2-methylfuro[3,2-b]pyrrole-5-carbohydrazide (5d ).
1
Yield 86% (MW), 83% (C), tim e 5 m in (MW), 4 h (C), m .p. 232–235 °C (eth an ol). H NMR
DMSO-d ): 2.39 s, 3 H (CH ); 6.20 s, 1 H (H-3); 7.00 s, 1 H (H-6); 7.79–7.93 m , 3 H (H-5′,
(
6
3
H-7′, H-8′); 8.10 s, 1 H (H-7); 8.86 s, 1 H (H-2′); 11.48 bs, 1 H (NH); 11.56 bs, 1 H (NH). For
C28H12ClN O (369.9) calculated: 58.47% C, 3.27% H, 9.59% Cl, 11.36% N; foun d: 58.36% C,
3
4
3
.28% H, 9.57% Cl, 11.29% N.
N′-[(Oxochromen-3-yl)methylidene]-4-benzyl-2-methylfuro[3,2-b]pyrrole-5-carbohydrazide (5e).
1
Yield 85% (MW), 74% (C), tim e 7 m in (MW), 2.5 h (C), m .p. 238–240 °C (eth an ol). H NMR
(
DMSO-d ): 2.35 s, 3 H (CH ); 5.66 s, 2 H (CH ); 6.23 s, 1 H (H-3); 7.02 s, 1 H (H-6);
6 3 2
7
7
.17–7.29 m , 5 H (C H ); 7.51–7.56 m , 1 H (H-6′); 7.66, 7.69 d, 1 H, J(7′,8′) = 8.1 (H-8′);
6 5
.81–7.83 m , 1 H (H-7′); 8.12, 8.15 d, 1 H, J(5′, 6′) = 8.1 (H-5′); 8.49 s, 1 H (H-7); 8.71 s, 1 H
(
H-2′); 11.34 bs, 1 H (NH). For C25H19N O (425.5) calculated: 70.58% C, 4.50% H, 9.88% N;
3 4
foun d: 70.74% C, 4.73% H, 10.14% N.
N′-[(6-Nitrooxochromen-3-yl)methylidene]-4-benzyl-2,3-dimethylfuro[3,2-b]pyrrole-5-carbo-
hydrazide (5f). Yield 79% (MW), 73% (C), tim e 4.5 m in (MW), 1 h (C), m .p. 240–243 °C
1
(
eth an ol). H NMR (DMSO-d ): 2.08 s, 3 H (CH ); 2.27 s, 3 H (CH ); 5.79 s, 2 H (CH ); 7.02 s,
6
3
3
2
1
8
1
H (H-6); 7.26–7.28 m , 5 H (C H ); 7.93–8.26 m , 3 H (H-5′, H-7′, H-8′); 8.46 s, 1 H (H-7);
6 5
.81 s, 1 H (H-2′); 11.43 bs, 1 H (NH). For C26H20N O (484.5) calculated: 64.40% C, 4.13% H,
4
6
1.56% N; foun d: 64.27% C, 4.25% H, 11.59% N.
N′-[(Oxochromen-3-yl)methylidene]furo[3,2-b]pyrrole-5-carbohydrazide (5g). Yield 77% (MW),
7
6% (C), tim e 7 m in (MW), 1.5 h (C), m .p. 249–252 °C (eth an ol). 1H NMR (DMSO-d ): 6.58,
6
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2
108
Gašparová, Lácová, Krutošíková:
6
2
.59 d, 1 H, J(3,2) = 2 (H-3); 7.03 s, 1 H (H-6); 7.55, 7.57 d, 1 H, J(2,3) = 2.1 (H-2); 7.68–7.71 m ,
H (H-6′, H-8′); 7.81–7.85 m , 1 H (H-7′); 8.16, 8.19 d, 1 H, J(5′, 6′) = 9.3 (H-5′); 8.38 s, 1 H
(
H-7); 8.78 s, 1 H (H-2′); 11.37 bs, 1 H (NH); 11.46 bs, 1 H (NH). For C17H11N O (321.3)
3 4
calculated: 63.55% C, 3.45% H, 13.08% N; foun d: 63.52% C, 3.59% H, 13.06% N.
N′-[(6-Nitrooxochromen-3-yl)methylidene]furo[3,2-b]pyrrole-5-carbohydrazide (5h ). Yield 81%
1
(
MW), 72% (C), tim e 5 m in (MW), 1 h (C), m .p. 261–263 °C (eth an ol). H NMR (DMSO-d ):
6
6
7
2
5
.59, 6.60 d, 1 H, J(3,2) = 2.2 (H-3); 7.05 s, 1 H (H-6); 7.70, 7.71 d, 1 H, J(2,3) = 2.2 (H-2);
.95, 7.98 d, 1 H, J(8′,7′) = 9 (H-8′); 8.38 s, 1 H (H-7); 8.56–8.60 m , 1 H (H-7′); 8.84–8.87 m ,
H (H-2′, H-5′); 11.33 bs, 1 H (NH); 11.44 bs, 1 H (NH). For C17H10N O (366.3) calculated:
4
6
5.74% C, 2.75% H, 15.30% N; foun d: 55.54% C, 3.01% H, 15.16% N.
N′-[(6-Methyloxochromen-3-yl)methylidene]furo[3,2-b]pyrrole-5-carbohydrazide (5i). Yield 79%
1
(
MW), 75% (C), tim e 6.5 m in (MW), 1.5 h (C), m .p. 232–235 °C (eth an ol). H NMR (CDCl ):
3
2
.35 s, 3 H (CH ); 6.57, 6.59 d, 1 H, J(3,2) = 2.2 (H-3); 7.04 s, 1 H (H-6); 7.71–7.72 d, 1 H,
3
J(2,3) = 2.2 (H-2); 7.76–7.87 m , 2 H (H-7′, H-8′); 8.32 s, 1 H (H-7); 8.59–8.61 m , 1 H (H-5′);
.77 s, 1 H (H-2′); 11.35 bs, 1 H (NH); 11.42 bs, 1 H (NH). For C18H13N O (335.3) calcu-
8
3
4
lated: 60.48% C, 3.91% H, 12.53% N; foun d: 60.55% C, 4.16% H, 12.22% N.
N′-[(6-Chloroxochromen-3-yl)methylidene]-2,3,4-trimethylfuro[3,2-b]pyrrole-5-carbohydrazide
(
1
5j). Yield 77% (MW), 73% (C), tim e 9 m in (MW), 3 h (C), m .p. 215–219 °C (eth an ol).
H NMR (CDCl ): 2.19 s, 3 H (CH ); 2.32 s, 3 H (CH ); 4.08 s, 3 H (CH ); 6.55 s, 1 H (H-6);
3
3
3
3
7
.45, 7.48 d, 1 H, J(8′,7′) = 9 (H-8′); 7.63, 7.66 d, 1 H, J(7′,8′) = 9 (H-7′); 8.21, 8.22 d, 1 H,
J(5′,7′) = 2.4 (H-5′); 8.70 s, 1 H (H-7); 8.91 s, 1 H (H-2′); 10.97 bs, 1 H (NH). For
C20H16ClN O (397.8) calculated: 60.38% C, 4.05% H, 8.91% Cl, 10.56% N; foun d: 60.41% C,
3
4
4
.08% H, 8.88% Cl, 10.51% N.
N′-[(Oxochromen-3-yl)methylidene]benzo[4,5]furo[3,2-b]pyrrole-5-carbohydrazide (5k). Yield 83%
1
(
(
(
MW ), 81% (C), tim e 6.5 m in (MW ), 3 h (C), m .p. 251–255 °C (eth an ol). H NMR
DMSO-d ): 7.13 s, 1 H (H-6); 7.32–7.35 m , 4 H (H-5′, H-6′, H-7′, H-8′); 7.71–8.16 m , 4 H
6
Hben zo); 8.54 s, 1 H (H-7); 8.81 s, 1 H (H-2′); 11.71 bs, 2 H (NH). For C21H13N O (371.4)
3
4
calculated: 67.92% C, 3.53% H, 11.32% N; foun d: 67.89% C, 3.51% H, 11.27% N.
N′-{[5-(Methoxycarbonyl)furo[3,2-b]pyrrol-2-yl]methylidene}-2,3-dimethylfuro[3,2-b]pyrrole-
5
-carbohydrazide (6a). Yield 94% (MW), 81% (C), tim e 8.5 m in (MW), 3 h (C), m .p. 302–305 °C
1
(
eth an ol). H NMR (DMSO-d ): 2.06 s, 3 H (CH ); 2.30 s, 3 H (CH ); 3.82 s, 3 H (CH ); 6.81 s,
6
3
3
3
1
H (H-3); 7.00 s, 2 H (H-6, H-6′); 11.48 bs, 2 H (NH); 11.91 s, 1 H (NH). For C18H16N O5
4
(
368.3) calculated: 58.69% C, 4.38% H, 15.21% N; foun d: 58.64% C, 4.33% H, 15.19% N.
N′-{[5-(Methoxycarbonyl)-4-methylfuro[3,2-b]pyrrol-2-yl]methylidene}benzo[4,5]furo[3,2-b]pyrrole-
5
-carbohydrazide (6b). Yield 79% (MW), 77% (C), tim e 6 m in (MW), 1.5 h (C), m .p. 282–286 °C
1
(
eth an ol). H NMR (DMSO-d ): 3.95 s, 3 H (CH ); 4.24 s, 3 H (CH ); 6.85 s, 1 H (H-3′); 7.07 s,
6 3 3
1
H (H-6′); 7.23 s, 1 H (H-6); 7.33–7.96 m , 4 H (Hben zo); 8.26 s, 1 H (H-7); 11.67 bs, 2 H
(
NH). For C21H16N O (404.4) calculated: 62.37% C, 3.99% H, 13.86% N; foun d: 62.31% C,
4
5
3
.94% H, 13.82% N.
1
2
N′-{2-Ben zam ido-[3-(oxoch rom en -3-yl)]propen oyl}-2-R-3-R -4-R -furo[3,2-b]pyrrole-
-carboh ydrazides (7a, 7b)
5
A m ixture of furo[3,2-b]pyrrole-5-carboh ydrazide 1e or 1f (1 m m ol) an d 4-[(4-oxoch rom en -
-yl)m eth yliden e]-2-ph en yloxazol-5(4H)-on e (4; 1 m m ol) was h eated in acetic acid (5 m l) in
3
th e presen ce of fresh ly fused potassium acetate at 60 °C for 2 h . Th e solid product was fil-
tered off, dried an d crystallized from eth an ol.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Furo[3,2-b]pyrrole-5-carbohydrazides
2109
N′-{2-Benzamido-[3-(oxochromen-3-yl)]propenoyl}-2,3,4-trimethylfuro[3,2-b]pyrrole-5-carbohydrazide
1
(
7a). Yield 76%, m .p. 237–241 °C (eth an ol). H NMR (DMSO-d ): 2.17 s, 3 H (CH ); 2.29 s,
6
3
3
7
2
H (CH ); 3.97 s, 3 H (CH ); 6.88 s, 1 H (H-6); 7.09 s, 1 H (H-9); 7.49–7.62 m , 5 H (C H );
3 3 6 5
.82–8.17 m , 4 H (H-5′, H-6′, H-7′, H-8′); 8.64 s, 1 H (H-2′); 9.90 s, 1 H (NH); 10.12, 10.15 d,
H, J(7,8) = 9 (NH). For C29H24N O (524.5) calculated: 66.40% C, 4.61% H, 10.68% N;
4
6
foun d: 66.28% C, 4.58% H, 10.71% N.
N′-{2-Benzamido-[3-(oxochromen-3-yl)]propenoyl}-4-benzyl-2-methylfuro[3,2-b]pyrrole-5-carbohydrazide
1
(
7b). Yield 78%, m .p. 220–221 °C (eth an ol). H NMR (DMSO-d ): 2.34 s, 3 H (CH ); 5.65 s,
6
3
2
7
7
8
H (CH ); 6.30 s, 1 H (H-6); 7.02 s, 1 H (H-3); 7.09 s, 1 H (H-9); 7.16–7.33 m , 5 H (C H );
2 6 5
.48–7.62 m , 4 H (H-6′, H-3′′, H-4′′, H-5′′); 7.64, 7.65 d, 1 H, J(8′,7′) = 7.9 (H-8′); 7.81,
.84 tt, 1 H, J(7′,8′) = 8.5, J(7′,5′) = 1.6 (H-7′); 7.77, 8.09 dd, 2 H, J(2′′,6′′) = 7.1, (H-2′′, H-6′′);
.14, 8.19 d, 1 H, J(5′,6′) = 7.9 (H-5′); 8.64 s, 1 H (H-2′); 10.01 s, 1 H (NH); 10.13, 10.16 d, 2 H,
J(7,8) = 9 (NH). For C34H26N O (586.6) calculated: 69.62% C, 4.47% H, 9.55% N; foun d:
4
6
6
9.89% C, 4.54% H, 9.68% N.
1
2
3
2
1
-Ben zam ido-1-(2-R-3-R -4-R -furo[3,2-b]pyrrole-5-carboxam ido)-
,5-dioxo-3,10a-dih ydro-2H-ch rom en o[2,3-b]pyridin es (8a, 8b) an d
,3-Diben zam ido-2,5-dioxo-3,10a-dih ydro-2H-ch rom en o[2,3-b]pyridin e (8c)
Classical Method
Method A: A m ixture of a furo[3,2-b]pyrrole-5-carboh ydrazide (1e, 1f) or ben zoh ydrazide
(
10;
1
m m ol) an d 4-[(4-oxoch rom en -3-yl)m eth yliden e]-2-ph en yloxazol-5(4H)-on e (4;
1
m m ol) was h eated at reflux in acetic acid (5 m l) in th e presen ce of fresh ly fused potassium
acetate for 4–6 h . Th e yellow solid products 8a–8c were filtered off, dried an d crystallized
from eth an ol.
Method B: Carboh ydrazide 7a (1 m m ol) was h eated at reflux in acetic acid (5 m l) in th e
presen ce of fresh ly fused potassium acetate for 2 h . Th e isolation an d purification of th e
product 8a was th e sam e as described above.
Microwave Method
Method A: A m ixture of 2,3,4-trim eth ylfuro[3,2-b]pyrrole-5-carboh ydrazide (1e) or ben zo-
h ydrazide (10; 1 m m ol) an d 4-[(4-oxoch rom en -3-yl)m eth yl]-2-ph en yloxazol-5(4H)-on e (4;
1
m m ol) in acetic acid (5 m l) was irradiated in m icrowave oven at 90 W output in th e pres-
en ce of fresh ly fused potassium acetate for 8–11 m in (see Table I). Com poun ds 8a or 8c
were isolated an d purified in th e sam e m an n er as in th e classical m eth od.
Method B: Carboh ydrazide 7a (1m m ol), acetic acid (5 m l) an d a catalytic am oun t of
fresh ly fused potassium acetate were irradiated in th e m icrowave oven for 9 m in . Work-up
was th e sam e as in th e classical m eth od.
3
-Benzamido-1-(2,3,4-trimethylfuro[3,2-b]pyrrole-5-carboxamido)-2,5-dioxo-3,10a-dihydro-2H-
chromeno[2,3-b]pyridine (8a). Meth od A: Yield 72% (MW), 70% (C), tim e 11 m in (MW), 4 h
(
1
C). Meth od B: Yield 65% (MW), 65% (C), tim e 9 m in (MW), 2 h (C), m .p. 293–295 °C.
H NMR (DMSO-d ): 2.15 s, 3 H (CH ); 2.30 s, 3 H (CH ); 3.85 s, 3 H (CH ); 6.95 s, 1 H
6
3
3
3
(
H-6); 7.41 s, 1 H (H-10a′); 7.53–7.65 m , 5 H (H-3′, H-4′, H-7′, H-3′′, H-5′′); 7.75, 7.77 d, 1 H,
J(9′,8′) = 7.9 (H-9′); 7.87–7.93 m , 1 H (H-8′); 8.12, 8.15 dd, 3 H, J(2′′,3′′) = 8.5 (H-2′′, H-4′′,
H-6′′); 8.18, 8.22 d, 1 H, J(6′,7′) = 7.9 (H-6′); 9.82 s, 1 H (NH); 11.11 s, 1 H (NH). For
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2
110
Gašparová, Lácová, Krutošíková:
C29H24N O (524.5) calculated: 66.40% C, 4.61% H, 10.68% N; foun d: 66.68% C, 4.60% H,
4
6
1
0.41% N.
3
-Benzamido-1-(4-benzyl-2-methylfuro[3,2-b]pyrrole-5-carboxamido)-2,5-dioxo-3,10a-dihydro-
2
H-chromeno[2,3-b]pyridine (8b). Meth od A: Yield 71% (C), tim e 5 h (C), m .p. 279–280 °C.
1
H NMR (DMSO-d ): 2.36 s, 3 H (CH ); 5.49–5.60 q, 2 H, J = 15 (CH ); 6.36 s, 1 H (H-6);
6
3
2
6
7
1
2
1
6
.99–7.10 m , 3 H (H-3, H-3′, H-4′); 7.18–7.23 m , 3 H (H-8, H-9, H-10); 7.44 s, 1 H (H-10a′);
.50–7.60 m , 5 H (H-3′′, H-4′′, H-5′′, H-7, H-11); 7.64–7.66 dd, 1 H, J(7′,6′) = 7.9 (H-7′); 7.78 d,
H, J(9′,8′) = 8.2 (H-9′); 7.90, 7.92 tt, 1 H, J(8′,9′) = 8.5, J(8′,6′) = 1.4 (H-8′); 8.07, 8.14 dd,
H, J(2′′,6′′) = 7.5, (H-2′′, H-6′′); 8.18, 8.20 d, 1 H, J(6′,7′) = 7.9 (H-6′); 9.88 s, 1 H (NH);
1.31 s, 1 H (NH). For C34H26N O (586.6) calculated: 69.62% C, 4.47% H, 9.55% N; foun d:
4
6
9.91% C, 4.24% H, 9.61% N.
,3-Dibenzamido-2,5-dioxo-3,10a-dihydro-2H-chromeno[2,3-b]pyridine (8c). Meth od A: Yield
1
1
7
7
8
7
1% (MW), 68% (C), tim e 8 m in (MW), 6 h (C), m .p. 276–279 °C. H NMR (DMSO-d ):
6
.43 s, 1 H (H-10a′); 7.55–7.69 m , 8 H (H-3′, H-4′, H-7′, C H ); 7.74, 7.77 d, 1 H, J(9′,8′) =
6
5
.4 (H-9′); 7.83–7.98 m , 4 H (H-8′, H-3′′, H-4′′, H-5′′); 8.12, 8.14 d, 2 H, J(2′′,3′′) = J(6′′,5′′) =
.25 (H-2′′, H-6′′); 8.15, 8.20 d, 1 H (H-6′); 9.83 s, 1 H (NH); 11.79 s, 1 H (NH). For
C26H19N O (453.5) calculated: 68.87% C, 4.22% H, 9.27% N; foun d: 69.17% C, 4.23% H,
3
5
9
.46% N.
The authors R. Gašparová and A. Krutošíková are grateful to the VEGA Grant Agency of the Slovak
Ministry of Education for financial support of project No. 1/0069/03.
REFERENCES
1
2
3
4
5
. Jedlovská E., Gavláková E.: Collect. Czech. Chem. Commun. 1994, 59, 1892.
. Jedlovská E., Leško J.: Synth. Commun. 1994, 24, 1879.
. Cao H. L., Cui J. P. Y.: J. Chin. Chem. Soc. 2003, 50, 903.
. Foltínová P., Lácová M., Loos D.: Farmaco 2000, 55, 21.
. Santos M. R. L., Barreiro E. J., Braz-Filho R., Miranda A. L. P.: J. Braz. Chem. Soc. 1997, 8,
4
71.
6
7
. El-Shaaer H. M., Lácová M., Odlerová Ž., Furdík M.: Chem. Pap. 1994, 48, 344.
. Gonzales-Serratos H., Chang R., Pereira E. F. R., Castro N. G., Aracava Y., Melo P. A.,
Lima P. C., Fraga C. A. M., Barreiro E. G., Albuquerque E. X.: J. Pharmacol. Exp. Ther.
2
001, 299, 588.
8
. Krutošíková A. in: Comprehensive Heterocyclic Chemistry II (C. A. Ramsden, Ed.), Vol. 7,
p. 1. Pergamon, Oxford 1996.
9
. Huttrer C. P., Dale E.: Chem. Rev. 1951, 48, 543.
1
1
0. Dann O., Illing G.: Arch. Pharm. 1956, 289, 718.
1. Groundwater P. W., Hibbs D. E., Hursthouse M. B., Nyerges M.: J. Chem. Soc., Perkin
Trans. 1 1997, 163.
1
1
1
2. Ghosh C. K.: J. Heterocycl. Chem. 1983, 20, 1437.
3. Abass M., Hassan A.: Chem. Pap. 2003, 57, 267.
4. Pinto D. C. G. A., Silva A. M. S., Almeida L. M. P. M., Carrillo J. R., Diaz-Ortiz A.,
de la Hoz A., Cavaleiro J. A. S.: Synlett 2003, 10, 1415.
1
1
5. Krutošíková A., Kováč J., Kráꢀovičová E.: Collect. Czech. Chem. Commun. 1983, 48, 1878.
6. Krutošíková A., Kováč J., Dandárová M.: Collect. Czech. Chem. Commun. 1984, 49, 65.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Furo[3,2-b]pyrrole-5-carbohydrazides
2111
1
7. Koreňová A., Krutošíková A., Dandárová M., Kováč J.: Collect. Czech. Chem. Commun.
984, 49, 1529.
8. Krutošíková A., Kováč J., Banák P.: Chem. Zvesti 1984, 38, 707.
9. Krutošíková A., Mastik S., Dandárová M., Lyčka A.: Collect. Czech. Chem. Commun. 1997,
2, 1612.
0. Lácová M., El-Shaaer H. M., Loos D., Matulová M., Chovancová J., Furdík M.: Molecules
998, 3, 120.
1
1
1
6
2
1
2
2
1. Gašparová R., Lácová M.: Collect. Czech. Chem. Commun. 1995, 60, 1178.
2. Stankovičová H., Gašparová R., Lácová M., Chovancová J.: Collect. Czech. Chem.
Commun. 1997, 62, 781.
2
2
3. Lácová M., Gašparová R., Loos D., Liptay T., Pronayová N.: Molecules 2000, 5, 167.
4. Loupy A., Petit A., Hamelin J., Texier-Boullet F., Jacquault P., Mathé D.: Synthesis 1998,
1
213.
2
2
2
2
2
3
3
5. Toma Š.: Chem. Listy 1993, 87, 627.
6. Galema S. A.: Chem. Soc. Rev. 1997, 26, 233.
7. Varma R. S.: Pure Appl. Chem. 2001, 73, 193.
8. Puterová Z., Sterk H., Krutošíková A.: Molecules 2004, 9, 11.
9. Fitton A. O., Frost J. R., Sushitzky H., Houghton P. G.: Synthesis 1977, 133.
0. Kidwai M. M., Khan N. H., Ali M.: Synth. Commun. 1979, 9, 363.
1. Cativiela C., de Villegas M. D., Mayoral J., Avenoza A., Roy M. A.: J. Heterocycl. Chem.
1
988, 25, 851.
2. Nálepa K., Zedníková G.: Acta Univ. Palacki. Olomuc., Fac. Rerum Nat., Chem. 1999, 38,
3; and references therein.
3. Fitton A. O., Frost J. R., Houghton P. G., Suschitzky H.: J. Chem. Soc., Perkin Trans. 1
978, 1691.
3
3
5
1
3
3
3
3
4. Ghosh C. K., Mhukopadhyay K. K.: J. Indian Chem. Soc. 1978, 55, 386.
5. Krutošíková A., Dandárová M., Alföldi J.: Chem. Pap. 1994, 48, 268.
6. Nohara A., Umetani T., Sanno Y.: Tetrahedron 1974, 30, 3553.
7. Krutošíková A., Dandárová M., Bobošík V.: Collect. Czech. Chem. Commun. 1994, 59, 473.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)