Regioselective synthesis of benzo[c]chromen-6-ones by one-pot cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde

Article abstract of DOI:10.1016/j.tetlet.2010.06.138

The cyclocondensation of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with 1,3-bis(silyloxy)-1,3-butadienes provides a convenient synthesis of benzo[c]chromen-6-ones.

Full text of DOI:10.1016/j.tetlet.2010.06.138

Tetrahedron Letters 51 (2010) 4693–4695
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of benzo[c]chromen-6-ones by one-pot
cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
with 4-chloro-2-oxo-2H-chromene-3-carbaldehyde
a
a
a
Olumide Fatunsin a, Viktor O. Iaroshenko a, , Sergii Dudkin , Satenik Mkrtchyan , Alexander Villinger ,
*
Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b 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 cyclocondensation of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with 1,3-bis(silyloxy)-1,3-but-
adienes provides a convenient synthesis of benzo[c]chromen-6-ones.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 20 March 2010
Revised 29 June 2010
Accepted 30 June 2010
Available online 23 July 2010
Keywords:
Cyclization
Coumarine
Heterocycles
Silyl enol ethers
Pyrroles
Benzo[c]chromen-6-one
The benzo[c]chromen-6-one core structure represents a highly
privileged and biologically relevant molecular scaffold which occurs
in many natural products. For example, autumnariol has been iso-
OH
H3CO
CH3
O
O
OH
H3CO
HO
lated from onions of Eucomis autumnalis Greab. (Liliaceae).1
A
number of related natural products, such as autumnariniol,2 alterna-
riol,3 and altenuisol,4 have been isolated (Fig. 1).5 6H-Benzo[c]chro-
men-6-ones are inhibitors of endothelic cell6 and oestrogene
receptor7 growth. Ellagic and coruleoellagic acid are isolated from
plants, they occur both as glycosides and aglycons.8 Moreover many
benzo[d]naphthopyran-6-ones are known as antibiotics and
antitumor compounds isolated from Streptomyces. This includes,
for example, defucogilvocarcin V, gilvocarcins, chrysomycins, and
ravidomycins.9
O
O
HO
O
O
O
HO
OH
H
Gilvocarcin M
Ellagic acid
OH
H3C
HO
OH
CH3
OH
O
The first synthetic approach to benzo[c]chromen-6-one was
developed in 1929 by Hurtley, based on the cyclization of o-bromo-
benzoic acids with phenols. This method is limited to the activated
substrates and the yields are often low.10 Harris and Hay prepared
9-O-methylalternariol by condensation of dilithiated 2,4-pentane-
dione with a protected salicylate and subsequent domino cycliza-
tion.11 In the last 3 decades, a number of syntheses using
transition-metal-catalyzed reactions have been reported. For exam-
HO
O
Alternariol
Figure 1. Natural occurring products with benzo[c]chromen-6-one core.
ple, 6H-benzo[c]chromen-6-ones can be obtained by intramolecular
Pd(II)-catalyzed coupling reactions of aryl benzoates.12 An efficient
and versatile synthesis of 6H-benzo[c]chromen-6-ones, developed
by Snieckus and co-workers, relies on a sequence of directed
* Corresponding authors. Tel.: +49 381 4986410; fax: +49 381 4986412 (P.L.).
E-mail addresses: viktor.iaroshenko@uni-rostock.de, iva108@googlemail.com
(V.O. Iaroshenko), peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.138

4694
O. Fatunsin et al. / Tetrahedron Letters 51 (2010) 4693–4695
R2
Me3SiO
R2
OSiMe3
OR1
OH
O
OH
R1
R2
OR1
R2
CO2R1
Cl
O
O
O
2a-r
H
OH
i, ii
O
O
O
O
O
O
3a-r
1
Ref. 14 and 15
This work
Scheme 2. Synthesis of 3a–r. Reagents and conditions: (i) TiCl4, CH2Cl2, À78?
20 °C, 16 h; (ii) HCl (10%).
Figure 2. Retrosynthetic analysis.
ortho-metalation (DoM) and Suzuki reactions.13 Zhou et al. reported
the palladium-catalyzed insertion of carbon oxide into boroxarenes,
which are readily synthesized from ortho-hydroxybiaryls.9
Table 1
Synthesis of 9-hydroxy-6H-benzo[c]chromen-6-ones 3a–l
a
3
R1
R2
%
(3)
During the last 5 years, we have been involved in a program
dedicated to the exploration of new synthetic methods for the
assembly of 6H-benzo[c]chromen-6-ones. We have reported the
synthesis of 6H-benzo[c]chromen-6-ones by TiCl4-mediated [3+3]
cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 3-(2-methoxy-
phenyl)-3-silyloxy-2-en-1-ones and subsequent BBr3-mediated
lactonization.14 An alternative approach relies on the Me3SiOTf-
mediated reaction of 1,3-bis(silyloxy)-1,3-butadienes with chro-
mones and subsequent NEt3-mediateddomino retro-Michael-al-
dol-lactonization reaction.15 Both methods provide an access to
functionalized 7-hydroxy-6H-benzo[c]chromen-6-ones which
may contain a substituent located at carbon atoms C-8 or C-9.
The new bonds are formed between carbon atoms C8 and C9 and
between C6a and C10a (Fig. 2).
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
r
Me
Me
Et
Me
Me
Me
Et
H
Me
Et
nPr
nPent
nHex
nHex
nDec
Cl
MeO
H
H
H
CH2Ph
CH2CH2Ph
CH2CH2CH2Ph
CH2CH2CH2Cl
40
41
52
44
47
50
45
47
41
44
53
46
49
47
44
48
43
Et
Et
Me
(CH2)2OMe
iPr
tBu
Me
Me
Me
Me
Herein, we report a new synthesis of functionalized 9-hydroxy-
6H-benzo[c]chromen-6-ones based on the cyclocondensation of
1,3-bis(silyloxy)-1,3-butadienes with 4-chloro-2-oxo-2H-chro-
mene-3-carbaldehyde. The new bonds of the benzo[c]chromen-6-
a
Yields of isolated products.
onesystemareformedbetweencarbonatomsC7andC8andbetween
C10 and C10a (Fig. 2). Previously this type of strategy was reported
only once. The cyclization of 3-acetyl-2H-chromen-2-one with ethyl
2-cyanoacetate has been reported to lead to the formation of a
benzo[c]chromene system.16
The reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde 1
with enolate synthons has, to the best of our knowledge, not been
previously reported. In contrast to previously reported syntheses of
benzo[c]chromen-6-ones, the approach reported herein allows the
assembly of the products in a single step and with a different sub-
stitution pattern.
OH
O
Me3SiO
OSiMe3
OMe
Cl
O
O
O
OMe
2a
i, ii
H
3a
O
O
O
1
TiCl4
ii
-[TiCl3OH]
4-Chloro-2-oxo-2H-chromene-3-carbaldehyde (1) is readily
available in one step from commercially available 4-hydroxycoum-
Me3Si
SiMe3
OMe
O
O
O
H
OMe
TiCl3
Cl
O
O
O
H
O
O
O
TiCl4
C
A
Me3SiCl
Me3Si
O
O
Me3SiCl
OMe
H
O
TiCl4
O
O
B
Scheme 1. Proposed mechanistic pathway for the [3+3] cyclization of 1 with 2a.
Reagents and conditions: (i) TiCl4, CH2Cl2, À78?20 °C, 16 h; (ii) HCl (10%).
Figure 3. Crystal structure of 3c.

O. Fatunsin et al. / Tetrahedron Letters 51 (2010) 4693–4695
4695
arin by Vilsmeier–Haack formylation.17 Our starting point was the
reaction of 1 with the dianion of methyl acetoacetate which failed
under a variety of conditions. We were pleased to find that the
TiCl4-mediated reaction of 1 with 1-methoxy-1,3-bis(trimethylsi-
lyloxy)-1,3-butadiene (2a, Chan’s diene), which can be regarded
as a masked dianion,18 regioselectively afforded 9-hydroxy-6H-
benzo[c]chromen-6-one 3a (Scheme 1).
During the optimization of the reaction conditions, we have
found that the best yields were obtained when a stoichiometric ra-
tio of 1/2a/TiCl4 = 1.0:1.1:1.1 was used and when the reaction was
carried out in a fairly concentrated solution (c(1) = 0.5 M).19 The
relatively low yield (40%) can be explained by practical problems
during the chromatographic purification and by partial hydrolysis
of the starting materials.
The formation of the product 3a can be explained by TiCl4-med-
iated conjugate addition of 2a to 1 (intermediates A and B), intra-
molecular Mukaiyama aldol reaction (intermediate C), and
aromatization (before or during the aqueous work-up).
Encouraged by these findings we have studied the reaction of 1
with a set of substituted 1,3-bis(trimethylsilyloxy)-1,3-butadienes
3b–r. These reactions result in the formation of the desired
benzo[c]chromen-6-ones 3b–r in 40–53% yields (Scheme 2, Table
1).20 The structures of all the products 3a–r, were established by
spectroscopic methods. The structure of 3c was independently
confirmed by X-ray crystal structure analysis (Fig. 3).21
5. Römpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-Fugmann, S., Eds.;
Thieme: Stuttgart, 1997.
6. 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.
7. Pandey, J.; Jha, A. K.; Hajela, K. Bioorg. Med. Chem. 2004, 12, 2239.
8. (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.
9. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Snieckus, M. A.; Siddiqui, V. J. Org.
Chem. 1991, 56, 3763. and Refs. 6–10 cited therein.
10. Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
11. Harris, T. M.; Hay, J. V. J. Am. Chem. Soc. 1977, 99, 1631.
12. Bringmann, G.; Reuscher, H. Tetrahedron Lett. 1989, 30, 5249.
13. Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69, 5147.
14. Hussain, I.; Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.;
Langer, P. J. Org. Chem. 2007, 72, 6255.
15. Appel, B.; Saleh, N. N. R.; Langer, P. Chem. Eur. J. 2006, 12, 1221.
16. El-Saghier, A. M. M.; Naili, M. B.; Rammash, B. K.; Saleh, N. A.; Kreddan, K. M.
ARKIVOC 2007, 83.
17. (a) Strakova, I.; Petrova, M.; Belyakov, S.; Strakovs, A. Chem. Heterocycl. Compd.
2003, 39, 1608; (b) Weissenfels, M.; Hantschmann, A.; Steinfuehrer, T.; Birkner,
E. Z. Chem. 1989, 29, 166.
18. For a review, see: Langer, P. Synthesis 2002, 441.
19. General procedure for synthesis of 3a–r: To a stirred dichloromethane solution
(2 mL/1 mmol of starting materials) of 4-chloro-2-oxo-2H-chromene-3-
carbaldehyde 1 (1.0 equiv) and 1,3-bis(silyl enol ethers) 2 (1.1 equiv) was
added TiCl4 (1.1 equiv) at À78 °C under an argon atmosphere. The temperature
of the reaction mixture was allowed to rise to 20 °C in the period of 16 h. To the
solution was added hydrochloric acid (10%, 20 mL) and the mixture was
extracted with dichloromethane (3 Â 20 mL). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography (silica gel,
heptanes/EtOAc) to give 3a–r.
In summary, we have reported a facile and direct access to func-
tionalized 9-hydroxy-6-oxo-6H-benzo[c]chromenes by cyclization
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 4-chloro-2-oxo-
2H-chromene-3-carbaldehyde.
20. Ethyl
starting with
isolated by chromatography (silica gel, heptanes/EtOAc) as
10-ethyl-9-hydroxy-6-oxo-6H-benzo[c]-chromene-8-carboxylate
(0.313 g, 1.5 mmol) and 2c (0.499 g, 1.65 mmol), 3c was
pink solid
(3c):
1
a
(0.244 g, 52%); mp. 197–198 °C. 1H NMR (250 MHz, CDCl3): d 1.37–1.42 (m,
6H, 2 Â CH3), 3.12 (q, 3J = 7.4 Hz, 2H, CH2CH3), 4.40 (q, 3J = 7.1 Hz, 2H,
OCH2CH3), 7.23–7.46 (m, 3H, CHAr), 8.12–8.15 (m, 1H, CHAr), 8.83 (s, 1H,
CHAr), 11.89 (s, 1H, OH). 13C NMR (CDCl3, 75 MHz): d 11.6, 13.2 (CH3), 19.9
(CH2), 61.3 (OCH2), 111.5 (CCOOC2H5), 112.9 (CAr), 117.2 (CHAr), 117.6 (CAr),
123.2, 126.6 (CHAr), 127.7 (CAr), 129.9, 131.3 (CHAr), 137.5, 150.9 (CAr), 160.1
~
Acknowledgment
(COH), 163.8, 168.8 (CO). IR (neat, cmÀ1):
m = 3089 (w), 2983 (w), 2967 (w),
The financial support from the State of Mecklenburg-Vorpomm-
ern (scholarships for O.F., S.M., and S.D.) is gratefully
acknowledged.
2937 (w), 2875 (w), 1864 (w), 1727 (m), 1663 (m), 1604 (m), 1555 (m), 1455
(m), 1403 (m), 1341 (m), 1264 (s), 1205 (s), 1155 (m), 1115 (m), 1054 (m), 990
(m), 890 (m), 804 (s), 750 (s), 652(m), 591 (m), 562 (m), 536 (m). GC–MS (EI,
70 eV): m/z (%) = 312 ([M]+, 48), 265 (12), 251 (13), 238 (100), 223 (8), 152 (10),
139 (12). HRMS (EI): calcd for C18H16O5([M]+): 312.09923; found: 312.09959.
21. CCDC 778934 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.
References and notes
1. Sidwell, H. W. T.; Fritz, L.; Tamm, C. Helv. Chim. Acta 1971, 54, 207.
2. Tamm, C. Arzneim.-Forsch. 1972, 22, 1776.
3. Raistrick, H.; Stilkings, C. E.; Thomas, R. Biochemistry 1953, 55, 421.
4. Pero, R. W.; Harvan, D.; Blois, M. C. Tetrahedron Lett. 1973, 14, 945.