Synthesis of 6H-benzo[c]chromen-6-ones by cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin

Article abstract of DOI:10.1016/j.tetlet.2011.07.140

6H-benzo[c]chromen-6-ones were prepared by base mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin.

Full text of DOI:10.1016/j.tetlet.2011.07.140

Tetrahedron Letters 52 (2011) 5910–5912
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Tetrahedron Letters
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Synthesis of 6H-benzo[c]chromen-6-ones by cyclocondensation of
1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin
Viktor O. Iaroshenko a,b, , Muhammad S.A. Abbasi a, Alexander Villinger a, Peter Langer a,c,
⇑
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kyiv-33, Ukraine
c 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:
6H-benzo[c]chromen-6-ones were prepared by base mediated cyclocondensation of 1,3-dicarbonyl com-
pounds with 4-chloro-3-formylcoumarin.
Received 8 June 2011
Revised 27 July 2011
Accepted 29 July 2011
Available online 16 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclizations, Domino reaction
Coumarins
Benzo[c]chromen-6-ones
Heterocycles
Benzo[c]chromen-6-ones (biaryl lactones) are of considerable
pharmacological relevance and occur in various natural products,
such as autumnariol, autumnariniol, alternariol, altenuisol, ellagic
acid, or coruleoellagic acid ( Fig. 1).1,2 Benzo[d]naphthopyran-6-
ones, such as defucogilvocarcin V, gilvocarcins, chrysomycins,
and ravidomycins,3 also occur in nature and exhibit a wide range
of pharmacological activities, such as antimicrobial and antitumor
activity. Other pharmacological activities include inhibition of
endothelic cells4 and oestrogene receptor5 growth.
contrast to the reactions mentioned above, the reactions reported
herein follow a 2:1 instead of a 1:1 stoichiometry and proceed
by double nucleophilic attack of the dicarbonyl compound to the
coumarin and subsequent cyclization.12
The K2CO3 mediated reaction of b-ketoester 2a (1.0 equiv) with
4-chloro-3-formylcoumarin (1) afforded 6H-benzo[c]chromen-6-
one 3a, albeit, in only approx. 10% yield. The yield of 3a was
dramatically increased (75%) when 2.0 equiv of 2a was employed
H-Benzo[c]chromen-6-ones are available by intramolecular
Pd(II)-catalyzed coupling reactions of aryl benzoates.6 Snieckus
et al. developed an efficient approach to 6H-benzo[c]chromen-6-
ones by directed ortho-metalation (DoM) and subsequent Suzuki
reaction.3 In addition, 6H-benzo[c]chromen-6-ones have been
prepared by palladium-catalyzed reaction of CO with boroxarenes
derived from ortho-hydroxybiaryls.7 6H-Benzo[c]chromen-6-ones
were also prepared by cyclization reactions of 1,3-bis(silyloxy)-
1,3-butadienes.8,9 Recently, we have reported10 the synthesis of
functionalized 9-hydroxy-6H-benzo[c]chromen-6-ones by cycliza-
tion of 1,3-bis(silyloxy)-1,3-butadienes with readily available11 4-
chloro-3-formylcoumarin (4-chloro-2-oxo-2H-chromene-3-carbal-
OH
CH3
OH
HO
O
O
Alternariol
H3CO
CH3
OH
H3CO
HO
O
O
OH
O
O
dehyde). Herein, we report
a convenient synthesis of 6H-
O
benzo[c]chromen-6-ones by base mediated cyclocondensations of
1,3-dicarbonyl compounds with 4-chloro-3-formylcoumarin. In
HO
O
O
HO
H
OH
Ellagic acid
Figure 1. Natural products with benzo[c]chromen-6-one subunit.
OH
H3C
HO
⇑
Corresponding authors. Fax: +49 381 4986412.
E-mail addresses: viktor.iaroshenko@uni-rostock.de (V.O. Iaroshenko), peter.-
Gilvocarcin M
langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.140

V. O. Iaroshenko et al. / Tetrahedron Letters 52 (2011) 5910–5912
5911
O
O
R1 OR2
(2 equiv.)
2a-l
O
R1
O
R2O
OR2
i
Cl
O
O
O
O
+
3a-l
O
1
Scheme 1. Synthesis of 3a–l. Reagents and conditions: (i) K2CO3 (2.0 equiv), THF,
50 °C, 4–8 h.
Table 1
Synthesis of 3a–l
2,3
R1
R2
Time (h)
% (3)a
Figure 3. Ortep plot of 3g0.
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Et
CH2Cl
CH2Cl
Pr
Ph
CH2OMe
Me
iPr
Et
4
6
6
8
8
4
4
4
4
5
8
6
75
72
71
60
76
62
45
72
73
66
62
77
(CH2)2OMe
O
O
O
Allyl
CH2Ph
Me
Me
Et
Et
Et
Me
O
OH
O
RO
+
OR
4a,b
RO
OR
i
Cl
O
j
k
l
O
O
O
O
5a (R = Me): 79%
5b (R = Et): 81%
1
a
Isolated yields.
Scheme 2. Synthesis of 5a,b. Reagents and conditions: (i) THF, K2CO3, 50 °C, 2 h.
O
O
Me
O
Me
Me
(2.0 equiv.)
Me
6
i
Cl
O
O
O
O
+
O
1
7 (54%)
Scheme 3. Synthesis of 7. Reagents and conditions: (i) THF, K2CO3, 50 °C, 4 h.
cyclocondensation via the aldehyde group and carbon atom C-4
of 1 and subsequent elimination of water.
The K2CO3 mediated reaction of 1 with acetylacetone (6)
followed a 2:1 stoichiometry and afforded 6H-benzo[c]chromen-
6-ones 7 (Scheme 3).13,17 The structure of 7 was independently con-
firmed by X-ray crystal structure analysis (Fig. 4).15
Figure 2. Ortep plot of 3a.
(Scheme 1, Table 1).13,14 Following the optimized conditions,
products 3a–l were prepared in 45–77% yield by cyclization of 1
with b-ketoesters 2a–l. The reactions were carried out using
K2CO3 as the base and THF as the solvent. The yields decreased
when the reactions were carried out at 20 instead of 50 °C. The
reaction time had to be adjusted for each individual reaction
(TLC control). In the case of the synthesis of 3g (45%), 3g0 is formed
as a by-product by decarboxylation in 30% yield.
The formation of products 3a–l can be explained as follows
(Scheme 4): the Knoevenagel-type condensation of 1 equiv of the
b-ketoester with the b-chlorovinylaldehyde followed by nucleo-
philic substitution of the chlorine atom by a second equivalent of
the b-ketoester gave the intermediate A. A base mediated cycliza-
tion afforded intermediate
B which subsequently underwent
cleavage of the acetate (intermediate C) and aromatization. The
cyclization proceeds by regioselective attack onto the keto group
which is more electrophilic than the ester group.
The Suzuki reaction of b-halovinylaldehydes with alkenylbo-
ronic acids and subsequent Horner–Wadsworth–Emmons reaction
The structures of the products 3a and 3g0 were independently
confirmed by X-ray crystal structure analyses (Figs. 2 and 3).15
The K2CO3 mediated cyclization of dimethyl and diethyl
acetone-1,3-dicarboxylate, containing two rather than only one
CH acidic methylene groups, afforded the 6H-benzo[c]chromen-
6-ones 5a and 5b, respectively (Scheme 2).13,16 The formation of
the products follows a 1:1 stoichiometry and can be explained by
and 6p-electrocyclization has been reported to give annulated ring
systems.18 However, such electrocyclization reactions require high
temperatures and presumambly do not account for the formation
of products 3a–l.

5912
V. O. Iaroshenko et al. / Tetrahedron Letters 52 (2011) 5910–5912
References and notes
1. (a) Sidwell, H. W. T.; Fritz, L.; Tamm, C. Helv. Chim. Acta 1971, 54, 207; (b)
Tamm, C. Arzneim.-Forsch. 1972, 22, 1776; (c) Raistrick, H.; Stilkings, C. E.;
Thomas, R. Biochemistry 1953, 55, 421; (d) Pero, R.; Harvan, W. D.; Blois, M. C.
Tetrahedron Lett. 1973, 14, 945; (e)Römpp Lexikon Naturstoffe; Steglich, W.,
Fugmann, B., Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
2. (a) Sayer, J. M.; Haruhiko, Y.; Wood, A. W.; Conney, A. H.; Jerina, D. M. J. Am.
Chem. Soc. 1982, 104, 5562; (b) Gunawardana, Y. A. G. P.; Kumar, N. S.;
Sultanbawa, M. U. S. Phytochemistry 1979, 18, 1017.
3. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.; Snieckus, V. J. Org.
Chem. 1991, 56, 3763. and Refs. 6–10 cited therein.
4. Schmidt, J. M.; Tremblay, G. B.; Page, M.; Mercure, J.; Feher, M.; Dunn-Dufault,
R.; Peter, M. G.; Redden, P. R. J. Med. Chem. 2003, 46, 1289.
5. Pandey, J.; Jha, A. K.; Hajela, K. Bioorg. Med. Chem. 2004, 12, 2239.
6. Bringmann, G.; Reuscher, H. Tetrahedron Lett. 1989, 30, 5249.
7. Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69, 5147.
8. Hussain, I.; Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.;
Langer, P. J. Org. Chem. 2007, 72, 6255.
9. Appel, B.; Saleh, N. N. R.; Langer, P. Chem. Eur. J. 2006, 12, 1221.
10. Fatunsin, O.; Iaroshenko, V. O.; Dudkin, S.; Mkrtchyan, S.; Villinger, A.; Langer,
P. Tetrahedron Lett. 2010, 51, 4693.
11. El-Saghier, A. M. M.; Naili, M. B.; Rammash, B. Kh.; Saleh, N. A.; Kreddan, K. M.
Arkivoc 2007, 83.
Figure 4. Ortep plot of 7.
12. For related cyclizations of 1,3-dicarbonyl compounds with carbacyclic b-
bromovinylaldehydes, see: Ray, D.; Ray, J. K. Tetrahedron Lett. 2007, 48, 673.
13. General procedure for the cyclocondensation reactions: To a solution of 1 (0.100 g,
0.5 mmol) in THF (10 mL) was added K2CO3 (0.140 g, 2.0 equiv). To the stirred
solution was dropwise added the 1,3-dicarbonyl compound (2.0 equiv). The
reaction mixture was allowed to stir at 50 °C and was monitored by TLC. After
the complete consummation of the starting material 1, the reaction mixture
was acidified using hydrochloric acid (1 M) and the mixture was extracted
with ethyl acetate. The combined organic layers were dried (Na2SO4) and the
solvent was removed under reduced pressure. The residue was purified by
column chromatography (silica gel, heptanes/EtOAc).
O
O
O
Me
O
Me
OMe
(2.0 equiv.)
MeO
OMe
K2CO3
(2 equiv.)
2a
Cl
O
O
O
14. Dimethyl
Starting with 1 (0.100 g, 0.5 mmol) and 2a (0.120 g, 1.0 mmol), 3a (0.120 g,
75%) was isolated as
white crystalline solid, mp 173–175 °C. 1H NMR
9-methyl-6-oxo-6H-benzo[c]chromene-8,10-dicarboxylate
(3a):
+
3a
O
O
a
(300 MHz, CDCl3): d = 2.58 (s, 3H), 3.88 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 7.17–
7.23 (m, 1H, Ar), 7.31 (dd, J = 8.3 Hz, J = 1.29 Hz, 1H, Ar), 7.42–7.48 (m, 1H, Ar),
7.70 (dd, J = 8.3 Hz, J = 1.3 Hz, 1H, Ar), 8.89 (s, 1H, Ar). 13C NMR (62.5 MHz,
CDCl3): d = 18.1 (CH3), 52.6, 53.1 (OCH3), 116.2 (C), 118.4 (CH), 119.9 (C), 124.7,
124.8 (CH), 131.2 (C), 131.7 (CH), 131.8, 133.5 (C), 133.8 (CH), 144.1 (C), 151.8,
1
2 K2CO3
KOH
O
KOH, CO2
159.9, 166.1, 170.0 (CO). IR (ATR, cmꢀ1):
m = 2949 (w), 1716 (s), 1599 (m), 1429
_
O
K+
O
O
HO Me
_
K+
OMe
O
(m), 1115 (m), 1194 (s), 1292 (w) 1041 (m), 971 (m), 748 (s), 640 (m). GC–MS
(EI, 70 eV): m/z (%) = 326 ([M]+, 100), 295 (77), 266 (19), 237 (16), 208 (4).
HRMS (EI): calcd for C18H14O6 ([M]+): 326.0748; found: 326.0784. Anal. Calcd
for C18H14O6: C, 66.26; H, 4.32. Found: C, 66.48; H, 4.73.
MeO
OMe
K+
Me
Me
15. CCDC-xxx contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ. Fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
OMe
O
O
O
O
O
C
A
16. Dimethyl
9-hydroxy-6-oxo-6H-benzo[c]chromene-8,10-dicarboxylate
(5a):
O
KOH
Starting with 1 (0.100 g, 0.5 mmol) and 4a (0.170 g, 1.0 mmol), 5a (0.130 g,
79%) was isolated as a slight yellow crystalline solid, mp 219–221 °C. 1H NMR
(300 MHz, CDCl3): d = 3.97 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 7.17–7.23 (m, 1H,
Ar), 7.30 (dd, J = 8.3 Hz, J = 1.2 Hz, 1H, Ar), 7.44–7.50 (m, 1H, Ar), 7.70 (dd,
J = 8.2 Hz, J = 1.3 Hz, 1H, Ar), 8.96 (s, 1H, Ar), 11.69 (s, 1H, OH). 13C NMR
(75 MHz, CDCl3): d = 53.2, 53.3 (OCH3), 113.5, 113.8, 116.0 (C), 118.5 (CH),
118.6 (C), 124.7, 125.3, 132.4, 135.4 (CH), 137.2 (C), 152.2, 159.8, 162.9, 167.6,
_
K+
O
Me
O
O
_
MeO
Me
OMe
Me
_
O
OH
O
2 K+
169.2 (CO). IR (ATR, cmꢀ1):
m = 3138 (w), 2954 (w), 1723 (s), 1687 (s), 1593 (m),
1430 (m), 1275 (m), 1197 (s), 1109 (m), 739 (s), 636 (m). GC–MS (EI, 70 eV): m/
O
B
O
z (%) = 265 ([M]+, 100), 328 (94), 296 (62), 125 (22). HRMS (EI): calcd for
C
17H12O7 ([M]+): 328.0577; found: 328.0581. Anal. Calcd for C17H12O7: C,
62.20; H, 3.68. Found: C, 62.21; H, 3.96.
17. 8-Acetyl-9-methyl-6H-benzo[c]chromen-6-one (7): Starting with
1 (0.100 g,
Scheme 4. Possible mechanism of the formation of 3a.
0.5 mmol) and 6 (0.100 g, 1.0 mmol), 7 (0.065 g, 54%) was isolated as a slight
yellow crystalline solid, mp 210–212 °C. 1H NMR (300 MHz, CDCl3): d = 2.63 (s,
3H,), 2.67 (s, 3H), 7.27–7.32 (m, 2H, Ar), 7.44–7.50 (m, 1H, Ar), 7.89 (s, 1H, Ar),
8.01 (d, J = 8.2 Hz, 1H, Ar), 8.67 (s, 1H, Ar). 13C NMR (300 MHz, CDCl3): d = 21.6,
28.4 (CH3), 116.2, 117.0 (C), 117.8, 122.2, 123.8, 124.1, 130.5, 131.1 (CH), 135.9,
The formation of product 7 can be explained by a mechanism
similar to the one discussed for the formation of 3g0.
In conclusion, we have reported the synthesis of highly
functionalized 6H-benzo[c]chromen-6-ones by base mediated
cyclocondensations of 1,3-dicarbonyl compounds with 4-chloro-
3-formylcoumarin. These reactions follow a 2:1 stoichiometry.
The scope, limitations and applications of the methodology are
currently being studied.
136.5, 145.4 (C), 151.0, 159.6, 198.7 (CO). IR (ATR, cmꢀ1):
m = 2964 (w), 2922
(w), 1719 (s), 1681 (s), 1607 (s), 1354 (m), 1305 (m), 1175 (m), 754 (s), 657
(m). GC–MS (EI, 70 eV): m/z (%) = 237 ([M]+, 100), 252 (41), 181 (23), 152 (21).
HRMS (EI): calcd for C16H13O3 (M+H)+: 253.0859; found: 253.0855; calcd for
C
16H12NaO3 (M+Na)+: 275.0678; found: 275.0675. Anal. Calcd for C16H12O3: C,
76.18; H, 4.79. Found: C, 76.01; H, 4.96.
18. Kálai, T.; Jek, J.; Hideg, K. Synthesis 2009, 2591. and references cited therein.
Acknowledgements
Financial support by the BMBF (Grant No. 03IS2081A) and by
the DAAD (scholarship for M.S.A.A.) is gratefully acknowledged.