A three-component synthesis of benzochromenodiazocines and chromenopyridines

Article abstract of DOI:10.1016/j.tetlet.2013.01.122

An efficient and straightforward method for the synthesis of benzochromenodiazocines and chromenopyridines via the catalyst-free, three-component condensation of 3-formylchromones, amines and isatoic anhydride or a dialkyl acetylenedicarboxylate is reported.

Full text of DOI:10.1016/j.tetlet.2013.01.122

Tetrahedron Letters 54 (2013) 1960–1962
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A three-component synthesis of benzochromenodiazocines and
chromenopyridines
⇑
Zahra Dolatkhah, Mahnaz Nasiri-Aghdam, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University G.C., Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward method for the synthesis of benzochromenodiazocines and chromeno-
pyridines via the catalyst-free, three-component condensation of 3-formylchromones, amines and isatoic
anhydride or a dialkyl acetylenedicarboxylate is reported.
Received 15 August 2012
Revised 8 January 2013
Accepted 30 January 2013
Available online 8 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chromene
Multi-component
Chromenodiazocines
Chromenopyridines
The reactions of binucleophiles with 3-formylchromone have
been used to prepare a variety of biologically active chromene-
fused heterocycles due to the presence of an unsaturated keto
function, a conjugated second carbonyl group at C-3 and an
electrophilic centre at C-2.1 However, there are no reports on the
synthesis of benzochromenodiazocine derivatives via reactions of
binucleophiles with 3-formylchromone. In this Letter, we report
or conjugates. These hybrids combine two active moieties in a
single molecule with the goal of creating a chemical entity that is
medically more effective than its individual components.14–18 As
a result, benzochromenodiazocines, which combine two heterocy-
clic cores, are expected to be of pharmacological interest.
The three-component, catalyst-free condensations of 3-form-
ylchromones 1, isatoic anhydrides 2 and amines 3 proceeded
rapidly in toluene at reflux, and were complete after 5 hours
a
new three-component method for the synthesis of
benzochromenodiazocines.
affording benzo[g]chromeno[2,3-b][1,5]diazocine-diones
4
in
Benzochromenodiazocines comprise two heterocyclic cores.
The chromene moiety often appears as an important structural
component in both biologically active and natural compounds.
Moreover, substituted chromenes have played increasing roles in
synthetic approaches to promising compounds in the field of
medicinal chemistry.2–5 The azocine and diazocine moieties are
structural elements of several pharmacologically active com-
pounds.6–8 For example, teleocidines activate protein kinase C
(PKC) isozymes,9 and buflavine is known to possess interesting
adrenolytic and anti-serotonin activities.10 Also, derivatives of
diazocine are used as amoebicidal agents.11 Despite their wide
spectrum of bioactivity, diazocines have not been investigated
extensively; one barrier to their access generally being the
unsatisfactory synthetic procedures due to their associated
torsional, transannular and large-angle strain, and the high
activation energy needed for their ring closure.12,13
moderate to good isolated yields (Table 1).19 This method was
applicable for the synthesis of several different types of
benzo[g]chromeno[2,3-b][1,5]diazocines. In addition, the work-up
of these clean reactions required only filtration and washing with
ethanol.
The elucidation of the product structures is detailed here for 4a
as a representative example. The IR spectrum of 4a exhibits a broad
absorption band at 1652 cmÀ1due to the carbonyl groups, and two
broad absorption bands for the NH groups at 3410 and 3304 cmÀ1
.
The 1H NMR spectrum of 4a consists of a singlet for the methine
hydrogen (dH 6.85), and one broad resonance for the NH of the
amine group (dH 8.13) which was determined by almost instanta-
neous exchange with D2O. A doublet (dH 13.01, J = 12.9 Hz) was
observed for the NH of the amide group. As a result of coupling
with the NH of the amide group, the CH vinylic group is observed
as a doublet (dH 8.01, J = 12.9 Hz). It is notable that when the NH of
the amide group is exchanged with D2O (takes place over 3 h), the
vinylic proton is observed as a singlet. On the other hand, in
products 4b–o (without an amide hydrogen, R = alkyl or aryl),
the vinylic proton is observed as a singlet confirming the proposed
structure of the regioisomer (Fig. 1). The aromatic hydrogen atoms
There has been significant interest in the combination of two
pharmacophores in the same scaffold leading to hybrid molecules
⇑
Corresponding author. Fax: +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.122

Z. Dolatkhah et al. / Tetrahedron Letters 54 (2013) 1960–1962
1961
Table 1
Synthesis of benzo[g]chromeno[2,3-b][1,5]diazocines 4
R4
N
O
O
R3
O
R1
O
R1
R2
CHO
N
O
toluene, reflux
5 h
R4NH2
O
N
O
R3
O
R2
1
2
3
4
Product
R1
R2
R3
R4NH2
Yield (%)
a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
H
H
H
H
H
H
H
H
Cl
H
Cl
Cl
Cl
H
H
H
H
H
H
H
Cl
H
Cl
H
Cl
Cl
H
Cl
H
H
H
H
H
H
H
H
H
H
Me
H
H
NH3
87
95
94
60
67
72
95
75
70
65
71
73
78
69
88
MeNH2
EtNH2
4-HOC6H4NH2
PhCH2NH2
HC„CCH2NH2
4-MeOC6H4NH2
MeNH2
EtNH2
PhCH2NH2
MeNH2
4-MeOC6H4NH2
PhNH2
EtNH2
Me
Me
Me
H
4-MeOC6H4NH2
a
NH4OAc was used as the source of NH3.
J = 12.9 Hz
H
H
O
O
H
N
O
O
N
O
N
N
H
O
H
Produced
Not produced
Figure 1. Possible regioisomers of product 4.
give rise to characteristic signals in the aromatic region of the 1H
NMR spectrum. The 1H decoupled 13C NMR spectrum of 4a showed
17 distinct signals, in agreement with the proposed structure.
The formation of products 4 can be rationalized by the initial
formation of 2-aminobenzamide 5 via the condensation reaction
of anhydride 2 and amine 3 (RNH2). Subsequent Michael-type
addition of the aminobenzamide 5 to the 3-formylchromone 1, fol-
chromeno[2,3-b]pyridine framework, which is
a
commonly
prescribed antiallergic and topical antiulcer agent.21 Therefore, to
further explore the potential of this protocol for the synthesis of
chromene-fused heterocycles, we investigated the reaction of
3-formylchromones 1, dialkyl acetylenedicarboxylates
6 and
amines 3, and obtained chromeno[2,3-b]pyridines 7 in good
isolated yields (Table 2).22
lowed by cyclization afforded the corresponding product
(Scheme 1).
4
Compounds 4 and 7 are all stable solids the structures of which
were established by IR, 1H and 13C NMR spectroscopy, mass
spectrometry and elemental analysis.
Chromeno[2,3-b]pyridine has been reported to inhibit
mitogen-activated protein kinase activated protein kinase 2 and
In conclusion, an efficient, catalyst-free and convenient three-
component method for the preparation of benzochromenodiazo-
cines and chromenopyridines is reported. The present synthesis
attenuate the production of pro-inflammatory cytokine TNF-a 20
.
Amlexanox is an example of an approved drug containing a
H
O
O
O
R
O
O
N
O
NH2
NHR
RHN
RNH2
CO2
CHO
N
O
1
O
2
O
HN
4
O
N
H
5
Scheme 1. Proposed mechanism.

1962
Z. Dolatkhah et al. / Tetrahedron Letters 54 (2013) 1960–1962
Table 2
Synthesis of chromenopyridines 7
O
NH2
O
O
COOR1
R
COOR1
COOR1
R
CHO
EtOH, reflux
7 h
O
N
R3
COOR1
6
R2
1
3
7
R3
R2
Product
R
R1
R2
R3
Yield (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
H
Cl
Cl
Me
Me
Cl
Me
Me
Me
Et
t-Bu
Et
t-Bu
Me
t-Bu
OH
OMe
Cl
OMe
Me
Me
OMe
OH
OMe
H
H
H
H
Me
Me
H
H
H
78
70
85
70
74
82
78
86
80
added and the mixture was stirred at reflux for 4 h. After completion of the
reaction, the mixture was filtered and the precipitate washed with EtOH to
afford the pure product 4. 13a,14-dihydro-5H-benzo[g]chromeno[2,3-
b][1,5]diazocine-5,8(6H)-dione (4a): Light yellow powder (0.25 g, 87%). Mp
shows attractive characteristics such as one-pot conditions, short
reaction times, easy work-up/purification and reduced waste pro-
duction without using any catalyst or additive.
169–171 °C; IR (KBr) (m
max/cmÀ1): 3410, 3304, 1652, 1608. 1H NMR (300 MHz,
DMSO-d6): dH 6.85 (1H, s, CH), 7.07–7.16 (3H, m, Ar-H), 7.49–7.84 (5H, m, Ar-
H), 8.01 (1H, d, J = 12.9 Hz, @CH), 8.13 (1H, br s, NH), 13.01 (1H, d, J = 12.9 Hz,
NHCO). 13C NMR (75 MHz, DMSO-d6): dC 54.8, 101.8, 104.6, 114.8, 117.5, 121.4,
122.2, 122.7, 125.9, 128.9, 132.0, 133.7, 140.1, 141.8, 155.4, 169.3, 179.5. MS
(EI, 70 eV) m/z: 291 (M+À1). Anal. Calcd for C17H12N2O3: C, 69.86; H, 4.14; N,
9.58. Found: C, 69.74; H, 4.07; N, 9.50. 6-Methyl-13a,14-dihydro-5H-
benzo[g]chromeno[2,3-b][1,5]diazocine-5,8(6H)-dione (4b): White powder
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
(0.29 g, 95%). Mp 214–216 °C; IR (KBr) (m
max/cmÀ1): 3315, 1633, 1606. 1H
References and notes
NMR (300 MHz, DMSO-d6): dH 2.96 (3H, s, CH3), 6.49 (1H, s, CH), 6.65–6.74 (2H,
m, Ar-H), 6.97 (1H, br s, NH), 7.16-7.84 (5H, m, Ar-H), 8.03 (1H, s, @CH), 8.09
(1H, d, J = 7.9 Hz, Ar-H). 13C NMR (75 MHz, DMSO-d6): dC 32.6, 66.3, 114.7,
115.0, 118.1, 119.0, 121.0, 123.5, 125.4, 126.4, 127.8, 133.9, 135.2, 146.3, 153.9,
156.2, 164.5, 176.7. Anal. Calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15.
Found: C, 70.69; H, 4.56; N, 9.08.
1. Plaskon, A. S.; Grygorenko, O. O.; Ryabukhin, S. V. Tetrahedron 2012, 68, 2743.
2. Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Gorbunov, S. V.; Nasybullin, R.
F.; Stepanov, N. O.; Nikishin, G. I. Tetrahedron Lett. 2006, 47, 7629.
3. Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.; Hammond, M.
L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468.
4. Stachulski, A. V.; Berry, N. G.; Lilian Low, A. C.; Moores, S. L.; Row, E.; Warhurst,
D. C.; Adagu, I. S.; Rossignol, J.-F. J. Med. Chem. 2006, 49, 1450.
5. Asal, F. T.; Rakesh, T.; Amir, N. S.; Tahmineh, A.; Deendayal, M.; Abbas, S.;
Keykavous, P.; Alireza, F. Med. Chem. 2011, 7, 466.
6. Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Org. Lett. 2005, 7, 2723.
7. Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2002, 41,
3247.
8. Vedejs, E.; Galante, R. J.; Goekjian, P. G. J. Am. Chem. Soc. 1998, 120, 3613.
9. Kazanietz, M. G.; Caloca, M. J.; Fujii, T.; Eroles, P.; Garcia-Bermejo, M. L.; Reilly,
M.; Wang, H. Biochem. Pharmacol. 2000, 60, 1417.
10. Viladomat, F.; Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee, S.
Phytochemistry 1995, 40, 307.
11. Paudler, W. W.; Zeiler, A. G. J. Org. Chem. 1969, 34, 2138.
12. Yet, L. Chem. Rev. 2000, 100, 2963.
13. Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Chem. Eur. J. 2007, 13, 6452.
14. Kogen, H.; Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.;
Koyama, K.; Naruto, S.; Abe, K.; Yamazaki, R.; Hara, T.; Aoyagi, A.; Abe, Y.;
Kaneko, T. Org. Lett. 2002, 4, 3359.
15. Harnett, J. J.; Auguet, M.; Viossat, I.; Dolo, C.; Bigg, D.; Chabrier, P.-E. Bioorg.
Med. Chem. Lett. 2002, 12, 1439.
20. Anderson, D. R.; Hegde, S.; Reinhard, E.; Gomez, L.; Vernier, W. F.; Lee, L.; Liu,
S.; Sambandam, A.; Snider, P. A.; Masih, L. Bioorg. Med. Chem. Lett. 2005, 15,
1587.
21. Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8,
899.
22. Typical procedure for the preparation of chromenopyridines 7: A mixture of
dialkyl acetylenedicarboxylate 6 (1 mmol) and amine 3 (1 mmol) was stirred in
refluxing EtOH (5 mL) for 2 h. 3-Formylchromone 1 (1 mmol) was added and
the mixture was stirred at reflux for 5 h. After completion of the reaction, the
mixture was filtered and the precipitate washed with EtOH to afford the pure
product 7. Dimethyl 1-(4-chlorophenyl)-5-oxo-5,10a-dihydro-1H-chromeno[2,3-
b]pyridine-2,3-dicarboxylate (7c): Yellow powder (0.36 g, 85%). Mp 150–152 °C;
IR (KBr) (m
max, cmÀ1): 2959, 1746, 1706; 1H NMR (300 MHz, CDCl3) dH 3.34 (3H,
s, OMe), 3.71 (3H, s, OMe), 6.93 (1H, d, J = 8.8 Hz, H-Ar), 7.03 (1H, s, CH), 7.12–
7.61 (6H, m, H-Ar), 7.70 (1H, s, @CH), 7.79 (1H, d, J = 6.9 Hz, H-Ar). 13C NMR
(75 MHz, CDCl3): dC 49.8, 49.9, 94.7, 106.9, 108.4, 112.8, 118.5, 121.6, 122.1,
123.7, 124.6, 125.6, 127.6, 128.7, 149.2, 151.2, 154.2, 160.3, 165.6, 177.1. MS
(EI, 70 eV) m/z: 425 (M+). Anal. Calcd for C22H16ClNO6: C, 62.05; H, 3.79; N,
3.29. Found: C, 61.92; H, 3.70; N, 3.35. Diethyl 1-(4-methoxyphenyl)-5-oxo-
5,10a-dihydro-1H-chromeno[2,3-b]pyridine-2,3-dicarboxylate
(7d):
Yellow
powder (0.31 g, 70%). Mp 125–127 °C; IR (KBr) (
m
max, cmÀ1): 2979, 1739,
16. Pillai, A. D.; Rathod, P. D.; Franklin, P. X.; Patel, M.; Nivsarkar, M.; Vasu, K. K.;
Padh, H.; Sudarsanam, V. Biochem. Biophys. Res. Commun. 2003, 301, 183.
17. Antonello, A.; Hrelia, P.; Leonardi, A.; Marucci, G.; Rosini, M.; Tarozzi, A.;
Tumiatti, V.; Melchiorre, C. J. Med. Chem. 2005, 48, 28.
18. Detsi, A.; Bouloumbasi, D.; Prousis, K. C.; Koufaki, M.; Athanasellis, G.;
Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Kontogiorgis, C.;
Hadjipavlou-Litina, D. J. J. Med. Chem. 2007, 50, 2450.
19. Typical procedure for the preparation of benzochromenodiazocines 4: A mixture of
isatoic anhydride (1 mmol) and NH4OAc (1.5 mmol) or an amine (1 mmol) was
stirred in refluxing toluene (5 mL) for 1 h. 3-Formylchromone 1 (1 mmol) was
1699, 1626; 1H NMR (300 MHz, CDCl3) dH 1.05–1.07 (3H, m, Me), 1.31–1.33
(3H, m, Me), 3.84 (3H, s, OMe), 4.04–4.07 (2H, m, OCH2), 4.25–4.29 (2H, m,
OCH2), 6.64 (1H, s, CH), 6.85–7.09 (3H, m, Ar-H), 7.22–7.24 (1H, m, Ar-H), 7.44–
7.55 (3H, m, Ar-H), 7.75 (1H, s, @CH), 7.91–7.94 (1H, m, Ar-H). 13C NMR
(75 MHz, CDCl3): dC 9.8, 10.1, 56.6, 57.9, 58.9, 94.0, 107.0, 110.4, 112.8, 118.3,
121.2, 122.0, 124.0, 127.0, 128.2, 128.4, 128.5, 149.1, 155.1, 156.0, 160.6, 165.2,
168.7. MS (EI, 70 eV) m/z: 449 (M+). Anal. Calcd for C25H23NO7: C, 66.81; H,
5.16; N, 3.12. Found: C, 66.73; H, 5.12; N, 3.17.