Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin

Article abstract of DOI:10.1016/j.tetlet.2010.05.084

The base-mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin provides a convenient approach to various chromeno[3,4-b]pyrrol-4(3H)-ones.

Full text of DOI:10.1016/j.tetlet.2010.05.084

Tetrahedron Letters 51 (2010) 3897–3898
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Tetrahedron Letters
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Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by cyclocondensation of
1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin
a
Muhammad Zeeshan a, Viktor O. Iaroshenko a, , Sergii Dudkin , Dmitriy M. Volochnyuk b,c, Peter Langer a,d,
*
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
c ‘Enamine Ltd’ 23 A. Matrosova st., 01103 Kyiv, Ukraine
d Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The base-mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin pro-
vides a convenient approach to various chromeno[3,4-b]pyrrol-4(3H)-ones.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 April 2010
Revised 13 May 2010
Accepted 19 May 2010
Available online 25 May 2010
Keywords:
Cyclization
Coumarin
Heterocycles
1,3-Diketones
Pyrrole
Chromeno[3,4-b]pyrrol-4(3H)-ones
Pyrrolocoumarins are of considerable pharmacological rele-
vance and occur in variety of natural products. chro-
meno[3,4-b]pyrrol-4(3H)-one core structure occurs, for example,
in the marine alkaloids ningalin B and lamellarin D which exhibit
HIV-1 integrase inhibition, immunomodulatory activity and cyto-
toxicity (Scheme 1).1
Previous syntheses of chromeno[3,4-b]pyrrol-4(3H)-ones rely
on the formation of the pyrrole moiety by Claisen reaction2 or by
Fischer indole synthesis3 using 3-aminocoumarins as starting
materials. Recently, the Sonogashira reaction of 4-chloro-3-nitro-
coumarin (3) to give a 4-alkynyl-3-nitrocoumarin and subsequent
reductive cyclization has been reported.4 Herein, we report what
are, to the best of our knowledge, the first cyclocondensation reac-
tions of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocouma-
rin. These reactions provide a convenient approach to various
chromeno[3,4-b]-pyrrol-4(3H)-ones. These products are not read-
ily available by other methods.
The employment of other bases (e.g., NaOMe, MeOH) resulted in
a decrease of the yield. The formation of 3a can be explained by
conjugate addition and subsequent cleavage of the chloride group.
The hydrogenation of 3a, in the presence of Pd/C (10 mol %),7 affor-
ded the chromeno[3,4-b]pyrrol-4(3H)-one 4a8 in 67% yield.
The preparative scope was studied. The reaction of 1 with 3-
oxoalkanoates 2b–e and subsequent hydrogenation afforded the
chromeno[3,4-b]pyrrol-4(3H)-ones 4b–e. The reaction of 1 with
1,3-diketones 2f–i and subsequent hydrogenation afforded the
chromeno[3,4-b]pyrrol-4(3H)-ones 4f–i. The cyclization of 3g,h–
4g,h proceeded with excellent regioselectivity via the more elec-
trophilic keto group (i.e., the keto group attached to the alkyl
rather than the phenyl group). The tetracyclic products 4j,k were
a
A
OH
OMe
OH
HO
OMe
HO
4-Chloro-3-nitrocoumarin (1) is readily available in two steps
from 4-hydroxycoumarin (by nitration and subsequent exchange
of the OH-group to chlorine). The reaction of 1 with methyl aceto-
acetate (2a), in the presence of K2CO3 (DMF, 20 °C, 3 h),5 afforded
the condensation product 3a6 in 85% yield (Scheme 2, Table 1).
N
O
HO
HO
N
O
MeO
OH
O
HO
O
OH
Ningalin B
Lamellarin D
* Corresponding authors. Fax: +49 381 4986412.
E-mail addresses: viktor.iaroshenko@uni-rostock.de, iva108@googlemail.com
(V.O. Iaroshenko), peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Structure of ningalin B and lamellarin D.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.084

3898
M. Zeeshan et al. / Tetrahedron Letters 51 (2010) 3897–3898
O
O
Acknowledgements
O
O
R1
R2
NO2
Cl
O
R1
O
R2
We are grateful to Mr. Muhammad Sharif and Mr. Imran Malik
for their help. Financial support from the State of Mecklenburg-
Vorpommern (scholarships for V.O.I. and S.D.) and from the DAAD
(scholarship for M.Z.) is gratefully acknowledged.
NO2
O
2a-m
i
O
O
1
3a-m
R2
ii
R1
References and notes
NH
1. (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. H. Chem. Rev. 2008, 108, 264; (b)
Ridley, C. P.; Reddy, M. V. R.; Rocha, G.; Bushman, F. D.; Faulknera, D. J. Bioorg.
Med. Chem. 2002, 10, 3285; (c) Reddy, S. M.; Srinivasulu, M.; Satyanarayana, N.;
Kondapi, A. K.; Venkateswarlu, Y. Tetrahedron 2005, 61, 9242.
O
O
4a-m
2. Raghu, R. S.; Krupadanam, G. L. D.; Srimannarayana, G. Synth. Commun. 1998, 28,
2421.
3. Khan, M. A.; de Brito, M. L. J. Heterocycl. Chem. 1978, 15, 1399.
4. Lei, Ch.; Ming-Hua, Xu. Adv. Synth. Catal. 2009, 351, 2005.
Scheme 2. Synthesis of 3a–m and 4–m. Reagents and conditions: (i) DMF, K2CO3,
20 °C, 3 h; (ii) MeOH, H2, Pd/C (10 mol %), 20 °C, 2 days.
5. General procedure for synthesis of 3a–m: To a solution of 1 (0.451 g, 2.0 mmol)
and 2a–m (4.0 mmol) in DMF (8 mL) was added anhydrous K2CO3 (0.453 g,
4.0 mmol) at 20 °C. The mixture was stirred at room temperature for 3 h and
then poured into ice/water (100 mL). The solution was acidified by addition of
concd hydrochloric acid to pH 1. The solution was allowed to stand for 12 h at
room temperature. The precipitate formed was filtered, washed with water until
the washing solution was neutral and subsequently dried.
Table 1
Synthesis of 3a–m and 4a–m
a
a
3, 4
R1
R2
%
(3)
% (4)
6. 2(3-Nitro-2-oxo-2H-chromen-4-yl)-3-oxo-butyric acid methyl ester (3a): starting
with 1 (0.451 g, 2.0 mmol) and 2a (0.465 g, 4.0 mmol), 3a (0.519 g, 85%) isolated
by filtration as a colourless solid, mp 183–185 °C. 1H NMR (300 MHz, CDCl3):
d = 3.64 (s, 3H), 3.78 (s, 3H, OCH3), 4.23 (s, 1H), 7.37–7.42 (m, 2H), 7.65–7.71 (m,
2H). 13C NMR (75 MHz, CDCl3): 20.4, 48.4 (CH2), 52.8 (OCH3), 117.1 (C), 117.6,
120.3, 125.9, 127.0, 134.6 (CH), 141.9, 152.6, 167.4, 168.1, 194.7 (C). GC–MS (EI,
70 eV): m/z (%) = 305 ([M]+, 100), 260 (15), 160 (9), 144 (8), 116 (14), 115 (17),
101 (46). HRMS (EI): calcd for C14H11NO7 ([M]+): 305.0536; found: 305.0537
7. General procedure for the synthesis of 4a–m: In a 50 mL one-necked round
Schlenk flask under a flow of dry argon were placed 1.0 mmol of compound 3
and Pd/C (50 mg, 10 mol %). Subsequently, 25 mL of dry degassed methanol was
added. The system was washed three times with hydrogen. The hydrogenation
was conducted with the help of a glass burette under atmospheric pressure.
After 3 equiv of hydrogen were consumed, the mixture was stirred for 2 days at
20 °C (TLC control). The reaction mixture was filtered through a Celite pad (2–
3 cm). The Celite was washed three times with methanol. The solvent of the
filtrate was removed under reduced pressure. The residue was purified by
preparative chromatography (silica gel, heptanes/EtOAc).
a
b
c
d
e
f
g
h
i
OMe
OMe
OMe
OEt
OEt
Me
Ph
Ph
Me
nPr
iPr
nBu
85
63
62
72
73
80
78
56
67
65
61
70
60
67
50
44
52
53
66
60
41
47
42
46
51
45
4-(MeO)C6H4
Me
Me
Et
Ph
Ph
j
k
l
–(CH2)3–
–CH2CMe2CH2–
OMe
CH2CO2Me
CO2Me
m
4-MeC6H4
a
Yields of isolated products.
8. 2-Methyl-4-oxo-1,4-dihydro-chromeno(3,4-b)pyrrol-1-carboxylic acid methyl ester
(4a): starting with 3a (0.305 g, 1.0 mmol), Pd/C (50 mg, 10 mol %) and 25 mL of
dry degassed methanol, 4a (0.172 g, 67%) was isolated by chromatography
(silica gel, heptanes/EtOAc) as a colourless solid, mp 300–302 °C. 1H NMR
(300 MHz, DMSO-d6): d = 2.56 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 7.31–7.50 (m, 3H),
8.92 (d, J = 8.0 Hz, 1H), 13.12 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): d = 14.3
(CH3), 51.3 (OCH3), 108.61, 115.9 (C), 116.8 (CH), 123.9 (C), 124.0, 126.3 (CH),
~
prepared from cyclohexane-1,3-dione (2j) and dimedone (2k),
respectively. The reaction of 1 with dimethyl acetone-1,3-dicar-
boxylate (2l) gave 3l which was transformed into 4l. The reaction
of 1 with pyruvate derivative 2m afforded 3m. The hydrogenation
of the latter resulted in regioselective formation of product 4m.
The moderate yields can be explained by practical problems during
the chromatographic purification (especially for second step).
In conclusion, we have reported the first cyclocondensation
reactions of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocou-
marin. These reactions provide a convenient approach to various
chromeno[3,4-b]-pyrrol-4(3H)-ones.
127.8 (C), 128.4 (CH), 145.9, 151.0, 153.6, 164.6 (CO). IR (neat, cmÀ1):
m = 3304
(w), 3216 (m), 3096 (w), 2950 (w), 2831 (w), 2568 (w), 1722 (m), 1682 (s), 1609
(w), 1548 (m), 1499 (m), 1442 (m), 1379 (m), 1318 (m), 1267 (s), 1177 (s), 1139
(m), 1081 (s), 1042 (m), 986 (m), 906 (w), 751 (s), 710 (m), 710 (m), 636 (m), 564
(w). GC–MS (EI, 70 eV): m/z (%) = 257 ([M]+, 100), 227 (11), 226 (81), 225 (34),
224 (10), 197 (12), 115 (8). HRMS (EI): calcd for C14H11NO4([M]+): 257.0428;
found: 257.0427.