Ring transformation of chromone-3-carboxamide

Article abstract of DOI:10.1016/j.tet.2009.06.107

4-Hydroxycoumarin-3-carboxaldehyde (5) was obtained from chromone-3-carboxaldehyde (1) via chromone-3-carboxamide (2) and 3-aminomethylene-2H-chroman-2,4-dione (3). 3-Alkylaminomethylenechroman-2,4-diones (7,8) were obtained from the reaction of primary a

Full text of DOI:10.1016/j.tet.2009.06.107

Tetrahedron 65 (2009) 7687–7690
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Tetrahedron
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Ring transformation of chromone-3-carboxamide
*
Magdy A. Ibrahim
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Hydroxycoumarin-3-carboxaldehyde (5) was obtained from chromone-3-carboxaldehyde (1) via
chromone-3-carboxamide (2) and 3-aminomethylene-2H-chroman-2,4-dione (3). 3-Alkylaminomethy-
lenechroman-2,4-diones (7,8) were obtained from the reaction of primary aliphatic amines with
chromone-3-carboxamide (2). Treatment of chromone-3-carboxamide with sodium methoxide gives
3-(2-hydroxybenzoyl)-2H-chromeno[2,3-b]pyridine-2,5(1H)-dione (9).
Received 2 March 2009
Received in revised form 3 June 2009
Accepted 25 June 2009
Available online 2 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chromone-3-carboxamide
Chroman-2,4-diones
4-Hydroxycoumarin-3-carboxaldehyde
Chromeno[2,3-b]pyridine
1. Introduction
2. Results and discussion
Chromone derivatives have received considerable attention due
to their medicinal activities1 and they can be converted to a broad
range of heterocyclic systems through reactions with nucleo-
philes.2 Several reports describe the action of different nucleophiles
on various 3-substituted chromones. The structures of the products
obtained depend on the substituents at the 3-position and the
reaction conditions. New derivatives of 3-(2-hydroxybenzoyl)-1H-
pyrroles were obtained from the reaction of chromone-3-carbox-
aldehyde with hetarylmethylamines and glycine derivatives.3
Piperidine undergoes 1,4-addition to chromone-3-carboxaldehyde
with subsequent deformylation giving rise to 1-(2-hydroxyphenyl)-
3-piperidin-1-yl propenone.4 Reaction of chromone-3-carbox-
aldehyde with active methylene compounds in the presence of
ammonia gives 5-(2-hydroxybenzoyl)pyridines.5 Chromone-3-car-
boxaldehyde-oxime and chromone-3-carbonitrile on treatment
with aqueous sodium hydroxide solution afforded 2-amino-
chromone-3-carboxaldehyde.6 Furthermore, heating chromone-3-
carboxylate with concentrated ammonium hydroxide leads to
3-formimidoyl-4-hydroxycoumarin.7 Primary and secondary
amines reacted with 3-bromochromone to yield ring contraction
products and 3-aminochromones.8 As an extension of work in the
area of 3-substituted chromones, the present investigation de-
scribes the action of bases (NH4OH, NaOH, RNH2 and sodium
methoxide) on chromone-3-carboxamide (2).
Chromone-3-carboxamide (2) was prepared previously from
chromone-3-carboxaldehyde (1) via conversion to the corre-
sponding carboxylic acid using Jones’ reagent (22% yield), followed
by transformation to the acid chloride and subsequently to the
amide by reaction with ammonia.9 In contrast to this difficult
method, chromone-3-carboxamide (2) was prepared easily using
an elegant method which relied upon the feasibility of oxidation of
chromone-3-carboxaldehyde (1) using N-bromosuccinamide (NBS)
followed by quenching with ammonia in a one step synthesis.
Based on the photo-induced NBS oxidation of some aldehydes by
Cheung,10 herein we disclose our present successful results. Treat-
ment of a suspension of carboxaldehyde 1 in CCl4 with 1.2 mol
equiv of NBS under irradiation using a 200 W Tungsten lamp for
40 min afforded, after quenching with ammonia at 0 ꢀC, chromone-
3-carboxamide (2) in one pot (Scheme 1). The structure of com-
pound 2 was deduced from its elemental analysis and spectral data.
The IR spectrum of 2 displayed characteristic absorption bands at
3364, 3284 (NH2), 1682 (C]Oamide) and 1615 (C]Opyrone) cmꢁ1. Its
1H NMR spectrum showed two characteristic singlet signals at
d
8.53 (NH2 exchangeable with D2O) and 9.03 (H-2).
In another experiment, quenching the reaction product of chro-
mone-3-carboxaldehyde (1) and NBS with an excess of ammonia at
room temperature (40 ꢀC) afforded 3-aminomethylene-2H-chro-
man-2,4-dione (3) (Scheme 1) which was erroneously reported by
Klutchko7 as 3-formamidoyl-4-hydroxycoumarin.1H NMR spectrum
of compound 3 displayed a characteristic triplet at d 8.39 for the vinyl
proton. In addition, compound 3 was also obtained when carbox-
amide 2 was allowed to react with concentrated ammonium hy-
droxide at room temperature (40 ꢀC). This result supports the
* Tel.: þ2 0107887204.
E-mail address: magdy_ahmed1977@yahoo.com
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.107

7688
M.A. Ibrahim / Tetrahedron 65 (2009) 7687–7690
O
CHO
O
1
1) NBS, CCl4, h ν
1) NBS, CCl4, h ν
2) excess NH4OH, 40 °C
2) NH4OH, 0 °C
53%
45%
+
+
3) H
3) H
O
O
O
O
1) excess NH4OH, 40 °C
2) H+
NH2
-NH3
NH2
NH2
NH2
90%
O
O
O
2
OH O
3
4
1) NaOH
1) NaOH
75%
65%
+
+
2) H
2) H
O
O
-NH3
OH
NH2
OH
OH O
O
O
6
OH
CHO
O
O
5
Scheme 1. Conversion of chromone-3-carboxaldehyde (1) to 4-hydroxycoumarin-3-carboxaldehyde (5).
postulated mechanism for the formation of enaminone 3 from car-
boxaldehyde 1 which may proceed through the formation of the
corresponding amide which undergoes direct ring opening under
the influence of ammonia followed by ring closing (RORC) through
lactonization of intermediate 4 with loss of one molecule of
ammonia (Scheme 1).
single geometrical isomeric products. These are expected to be E
isomers and showed low values for the NH protons and higher
d
stretching absorption values for the OC]O groups compared to the
Z isomers.13 The structures of compounds 7 and 8 were established
from their IR and 1H NMR spectra. The formation of 7 and 8 may
proceed through a mechanism similar to that depicted in Scheme 1.
According to our knowledge this is the only method for the prep-
aration of 3-(alkylaminomethylene)chroman-2,4-diones (7,8) as
pure isomers. These compounds were obtained previously as
mixtures of Z and E isomers together with 2-alkylamino-3-for-
mylchromone via rearrangement of C-(chromon-3-yl)-N-alkylni-
trones in refluxing xylene.14
A new derivative of heteroannulated chromone, namely 3-(2-
hydroxybenzoyl)-2H-chromeno[2,3-b]pyridine-2,5(1H)-dione (9)
was obtained from the reaction of chromone-3-carboxamide (2)
with sodium methoxide solution (Scheme 3). The suggested
mechanism for the formation of compound 9, as depicted in
Scheme 4, proceeds through methoxide catalysed ring-ring addi-
tion in which two consecutive Michael additions gave the in-
termediate A. The intermediate A underwent ring opening via
nucleophilic attack of hydroxide ion at the acetal carbon giving rise
to the aldehyde intermediate B which in turn be heterocyclized via
loss of ammonia to give the imide intermediate C. Intramolecular
Treatment of carboxamide 2 with aqueous 1 M NaOH solution
resulted in the facile rearrangement to the known 4-hydroxy-
coumarin-3-carboxaldehyde (5).11 The reaction may proceed through
RORC through lactonization of the postulated intermediate 6. The
same conversion was also observed when enaminone 3 was treated
with 1 M NaOH solution under the same conditions (Scheme 1).
Ghosh12 has reported that 3-(alkyl-/arylaminomethylene)chro-
man-2,4-diones are considered as very good precursors for the
synthesis of various heterocycles fused at the 3,4-position of
a 1-benzopyran and may be a synthetic equivalent of the versatile
substrate 4-hydroxycoumarin-3-carboxaldehyde (5). Therefore,
3-(methyl-/ethylaminomethylene) chroman-2,4-diones (7 and 8)
were prepared by refluxing an ethanolic solution of 2 with methyl-
or ethyl amine for 15 min, respectively (Scheme 2). This new
preparation of 7 and 8 involved a short reaction time, easy work-up
and was devoid of any chromatographic separation producing
O
O
R
CONH2
O
O
O
O
O
O
OH
RNH2
N
H
CONH2
EtOH
O
O
CH3ONa
54%
O
R = CH3
(95%)
2
N
7: R = CH3
8: R = CH2CH3
H
R = CH2CH
3 (87%)
2
9
Scheme 2. Synthesis of enaminones 7 and 8.
Scheme 3. Formation of annulated chromone 9.

M.A. Ibrahim / Tetrahedron 65 (2009) 7687–7690
7689
O
O
O
O
O
NH2
O
O
O
-MeO-
NH2
..
CONH2
OMe
O
H2N
O
O
A
O
OH
2
CH3
CONH2
CHO
O
O
O
O
O
O
-NH3
X
X
O
O
CONH2
O
H
B
X = CONH2
CH3
O
CHO
O
O
O
O
O
O
O
O
CHO
N
O
N
O
O
H
H
OH
C
D
O
O
O
O
O
O
O
O
OH
HCl
54 %
N
O
N
H
H
9
Scheme 4. The proposed mechanism for the formation of compound 9.
ring closure of the imide C was conducted by attack of the phe-
251–252 ꢀC (lit.9 250–252 ꢀC), yield (1 g, 53%). Anal. Calcd for
C10H7NO3 (189.17): C, 63.49; H, 3.73; N, 7.40%. Found: C, 63.16; H,
3.71; N, 7.54%. IR (KBr, cmꢁ1): 3364, 3284 (NH2), 3061 (CHarom.),
nolate oxygen at the
a-carbon giving chromenopyridine D and
deformylation led to formation of the product 9.15
1682 (C]Oamide), 1615 (C]Opyrone). 1H NMR (DMSO-d6,
d): 7.56 (t,
J¼7 Hz, 1H, H6), 7.63 (d, J¼6.8 Hz, 1H, H8), 7.93 (t, J¼6.8 Hz, 1H, H7),
8.21 (d, J¼7 Hz,1H, H5), 8.53 (br s, 2H, NH2 exchangeable with D2O),
9.03 (s, 1H, H-2).
3. Experimental
3.1. General
All melting points are uncorrected and were recorded in open
capillary tubes on Stuart SMP3 melting point apparatus. Infrared
spectra were recorded on FT-IR Bruker Vector 22 spectrophotom-
3.3. 3-Aminomethylene-2H-chroman-2,4-dione (3)
3.3.1. From chromone-3-carboxaldehyde (1)
eter using KBr wafer technique. 1H NMR spectra (chemical shift in
d)
A mixture of 1 (1.74 g, 10 mmol) and NBS (2.14 g, 12 mmol) in
CCl4 (100 mL) was stirred under irradiation from a 200 W Tungsten
lamp for 40 min. The solvent was evaporated under vacuum and
the residue was cooled to room temperature followed by addition
of concentrated ammonium hydroxide (8 mL) with continuous
stirring. The reaction mixture was neutralized with 5% acetic acid.
The solid obtained was filtered, washed with water and crystallized
from ethanol to give 3 as white crystals, mp 240–241 ꢀC, yield
(0.85 g, 45%).
were measured on Gemini spectrometer 200 MHz using DMSO-d6
as solvent and TMS as an internal standard. Elemental microanal-
yses were performed at the Cairo University Microanalytical Center.
Chromone-3-carboxaldehyde (1) was prepared by Vilsemier–Haack
double formylation according to the published method by
Nohara.16
3.2. Chromone-3-carboxamide (2)
A mixture of chromone-3-carboxaldehyde (1) (1.74 g, 10 mmol)
and NBS (2.14 g, 12 mmol) in CCl4 (100 mL) was stirred under ir-
radiation from a 200 W Tungsten lamp for 40 min. The solvent was
evaporated under vacuum and the residue was cooled in an ice bath
followed by addition of concentrated ammonium hydroxide (3 mL)
with continuous stirring. The reaction mixture was neutralized
with 5% acetic acid. The solid obtained was filtered, washed with
water and crystallized from ethanol to give 2 as white crystals, mp
3.3.2. From chromone-3-carboxamide (2)
A mixture of 2 (0.189 g, 1 mmol) and concentrated ammonium
hydroxide (2 mL) was stirred at 40 ꢀC for 30 min, after cooling to
room temperature the reaction mixture was diluted with water
(5 mL) and neutralized with 5% acetic acid. The solid obtained was
filtered, washed with water and crystallized from ethanol to give 3
as white crystals, mp 240–241 ꢀC, yield (0.17 g, 90%). Anal. Calcd for
C10H7NO3 (189.17): C, 63.49; H, 3.73; N, 7.40%. Found: C, 62.96; H,

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M.A. Ibrahim / Tetrahedron 65 (2009) 7687–7690
3.70; N, 7.37%. IR (KBr, cmꢁ1): 3277, 3128 (NH2), 1694 (C]Olactone),
1630 (C]Oenaminone). 1H NMR (DMSO-d6,
): 7.26–7.35 (m, 2H, H6
134.8 (C-5), 145.0 (C vinyl), 149.8 (C-8a), 162.7 (C-2 as OC]O), 181.8
(C-4 as C]O).
d
and H8), 7.65 (t, J¼7.2 Hz, 1H, H7), 7.93 (d, J¼7.4 Hz, 1H, H5), 8.39 (t,
1H, ]CH), 9.85 (br s, 1H, 1H of NH2 exchangeable with D2O), 10.85
(br s, 1H, 1H of NH2 exchangeable with D2O).
3.7. 3-(2-Hydroxybenzoyl)-2H-chromeno[2,3-b]pyridine-
2,5(1H)-dione (9)
A mixture of 2 (0.189 g, 1 mmol) and sodium methoxide (pre-
pared by dissolving 0.1 g sodium in 20 mL methanol) was refluxed
for 2 h. The reaction mixture was neutralized with dilute HCl. The
solid obtained was filtered and crystallized from dioxane to give 9
as yellow crystals, yield (0.09 g, 54%), mp 275 ꢀC. Anal. Calcd for
C19H11NO5 (333.30): C, 68.47; H, 3.33; N, 4.20%. Found: C, 68.35; H,
3.54; N, 3.91%. IR (KBr, cmꢁ1): 3448 (OH), 3365 (NH), 3085
3.4. 4-Hydroxycoumarin-3-carboxaldehyde (5)
A mixture of 2 and/or 3 (0.189 g, 1 mmol) and 1 M aqueous
sodium hydroxide solution (10 mL) was stirred overnight at room
temperature followed by neutralization with 5% acetic acid. The
solid obtained was filtered and crystallized from petroleum ether
60–80 to give 5 as white crystals, mp 135–137 ꢀC (lit.11 136–137).
Anal. Calcd for C10H6O4 (190.16): C, 63.16; H, 3.18%. Found: C, 63.88;
H, 3.20%. IR (KBr, cmꢁ1): 3436 (OH), 3078 (CHarom.), 1733 (C]Olac-
(CHarom.),1648 and 1630 (3C]O). 1H NMR (DMSO-d6,
d): 6.95 (t, 2H,
Ar–H), 7.45–7.79 (m, 5H, Ar–H), 8.17 (s, 1H, H-4pyridine), 8.62 (d,
tone), 1675 (C]Oald.). 1H NMR (DMSO-d6,
d): 7.39–7.47 (m, 2H, H6
J¼7.2 Hz, 1H, H-6), 10.88 (br s, 1H, NH exchangeable with D2O),
13.03 (br s, 1H, OH exchangeable with D2O). 13C NMR (DMSO-d6,
d):
and H8), 7.82 (t, J¼7.6 Hz, 1H, H7), 8.02 (d, J¼8.2 Hz, 1H, H5), 9.87 (s,
108.2 (C-4a),114.3 (C-9),118.9 (C-30),119.4 (C-5a),120.9 (C-50),124.6
(C-10), 125.9 (C-6), 126.7 (C-7), 132.6 (C-3), 133.4 (C-40), 135.9 (C-8),
137.3 (C-60), 140.4 (C-4), 149.2 (C-9a), 154.8 (C-20), 160.8 (C-10a),
161.2 (C-2 as C]O), 163.1 (C-5 as C]O), 196.5 (C]Oketone). MS (m/z,
%): 333 (Mþ,100), 316 (35), 313 (59), 240 (45), 213 (59),121 (63) and
93 (25).
1H, CHO).
3.5. 3-Methylaminomethylenechroman-2,4-dione (7)
A mixture of chromone-3-carboxamide (2) (0.189 g, 1 mmol)
and aqueous methyl amine (0.26 mL, 3 mmol, 36% w/v) in ethanol
(5 mL) was heated on a water bath with continuous stirring for
15 min. After cooling, the yellow crystals obtained were filtered and
recrystallized from methanol to give 7 as white crystals, mp 204–
205 ꢀC, yield (0.18 g, 95%). Anal. Calcd for C11H9NO3 (203.20): C,
65.02; H, 4.46; N, 6.89%. Found: C, 64.95; H, 4.40; N, 6.91%. IR (KBr,
cmꢁ1): 3177 (NH), 3040 (CHarom.), 2987, 2950 (CH3), 1721
References and notes
1. (a) Walenzyk, T.; Carola, C.; Buchholz, H.; Ko¨nig, B. Tetrahedron 2005, 61, 7366;
(b) Siddiqui, Z. N.; Khuwaja, G.; Asad, M. Heterocycl. Commun. 2006, 12, 443; (c)
Boumendjel, A.; Nicolle, E.; Moraux, T.; Gerby, B.; Blanc, M.; Ronot, X.;
Boutonnat, J. J. Med. Chem. 2005, 48, 7275; (d) Lee, K. S.; Seo, S. H.; Lee, Y. H.;
Kim, H. D.; Son, M. H.; Chung, B. Y.; Lee, J. Y.; Jin, C.; Lee, Y. S. Bioorg. Med. Chem.
Lett. 2005, 15, 2857.
(C]Olactone), 1629 (C]Oenaminone). 1H NMR (DMSO-d6,
d): 3.30 (s,
2. (a) Panja, S. K.; Maiti, S.; Drew, M. G. B.; Bandyopadhyay, C. Tetrahedron 2009,
65, 1276; (b) Terzidis, M. A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.;
Terzis, A.; Raptopoulou, C. P.; Psycharis, V. Tetrahedron 2008, 64, 11611; (c)
Sosnovskikh, V. Ya.; Moshkin, V. S.; Kodess, M. I. Tetrahedron Lett. 2008, 49, 6856.
3. Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.; Shivanyuk, A. N.; Tolmachev,
A. A. Tetrahedron 2008, 64, 5933.
3H, CH3), 7.26–7.35 (m, 2H, H6 and H8), 7.62 (t, J¼7 Hz, 1H, H7), 7.93
(d, J¼7.8 Hz, 1H, H5), 8.50 (d, 1H, ]CH), 11.45 (br s, 1H, NH).
3.6. 3-Ethylaminomethylenechroman-2,4-dione (8)
4. Ghosh, C. K.; Khan, S. Synthesis 1981, 719.
5. (a) Ghosh, C. K.; Ray, A.; Patra, A. J. Heterocycl. Chem. 2001, 38, 1459; (b)
Sosnovskikh, V. Y.; Irgashev, R. A.; Kodess, M. I. Tetrahedron 2008, 64, 2997.
6. Petersen, U.; Heitzer, H. Liebigs Ann. Chem. 1976, 1659.
7. Klutchko, S.; Shavel, J.; von Strandtmann, M. V. J. Org. Chem. 1974, 39, 2436.
8. (a) Gammill, R. B.; Nash, S. A.; Mizsak, S. A. Tetrahedron Lett. 1983, 24, 3435; (b)
Huang, W.; Liu, M.-Z.; Li, Y.; Tan, Y.; Yang, G.-I. Bioorg. Med. Chem. 2007, 15, 5191.
9. Klutchko, S.; Cohen, M. P.; Shavel, J.; Strandtmann, M. V. J. Heterocycl. Chem.
1974, 11, 183.
A mixture of chromone-3-carboxamide (2) (0.189 g, 1 mmol)
and aqueous ethyl amine (0.19 mL, 3 mmol, 70% w/v) in ethanol
(5 mL) was heated on a water bath with continuous stirring for
15 min. After cooling, the white crystals obtained were filtered and
recrystallized from methanol to give 8 as white crystals, mp 184 ꢀC,
yield (0.18 g, 87%). Anal. Calcd for C12H11NO3 (217.23):C, 66.35; H,
5.10; N, 6.45%. Found: C, 66.44; H, 5.42; N, 6.25%. IR (KBr, cmꢁ1):
3181 (NH), 3080 (CHarom.), 2969, 2932, 2872 (CH2 and CH3), 1705
10. Cheung, Y. F. Tetrahedron Lett. 1979, 20, 3809.
11. Ziegler, E.; Maier, H. Monatsh. Chem. 1958, 89, 787.
12. Ghosh, T.; Bandyopadhyay, C. Tetrahedron Lett. 2004, 45, 6169.
13. (a) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Sen, A. Tetrahedron 2000, 56, 3583;
(b) Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett. 1998, 39, 6547.
14. Singh, G.; Singh, R.; Girghar, N. K.; Ishar, M. P. S. Tetrahedron 2002, 58, 2471.
15. (a) Ghosh, C. K.; Sahana, S. Tetrahedron 1993, 49, 4127; (b) Ghosh, C. K.; Sahana,
S. Indian J. Chem. 1992, 31B, 346.
(C]Olactone), 1640 (C]Oenaminone). 1H NMR (DMSO-d6,
d): 1.27 (t,
J¼7 Hz, 3H, CH3), 3.64 (q, J¼7 Hz, 2H, CH2), 7.32 (m, 2H, H6 and H8),
7.66 (t, J¼7.3 Hz, 1H, H7), 7.94 (d, J¼7.2 Hz, 1H, H5), 8.47 (d, 1H,
]CH), 11.66 (br s, 1H, NH). 13C NMR (DMSO-d6,
d): 15.2 (CH3), 43.6
(CH2), 98.2 (C-3), 120.4 (C-8), 123.1 (C-6), 124.3 (C-4a), 126.4 (C-7),
16. Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron Lett. 1973, 22, 1995.