A rapid access to coumarin derivatives (using Vilsmeier-Haack and Suzuki cross-coupling reactions)

Article abstract of DOI:10.1016/S0040-4039(01)02373-5

A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of δ-lactone.

Full text of DOI:10.1016/S0040-4039(01)02373-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1213–1215
A rapid access to coumarin derivatives (using Vilsmeier–Haack
and Suzuki cross-coupling reactions)
Ste´phanie Hesse and Gilbert Kirsch*
Laboratoire d’Inge´nierie Mole´culaire et de Biochimie Pharmacologique, Faculte´ des Sciences, Ile du Saulcy, 57045 Metz Cedex,
France
Received 4 December 2001; accepted 14 December 2001
Abstract—A four-step preparation of compounds containing a coumarinic moiety is presented. This synthesis involves notably a
Suzuki cross-coupling reaction (performed in aqueous media) and a ring closure by formation of d-lactone. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
offers new synthetic possibilities. For example, the syn-
thesis of defucogilvocarcins was reported the same year
by two different approaches5 (Scheme 1). The cross-cou-
pling methodology can be used in the ring-closure step
or in the formation of the biaryl system.6 We present here
a rapid access to polycyclic compounds containing a
coumarinic moiety. (Scheme 2). A key connection to the
target molecules is the closure of ring C by formation of
the d-lactone. Another important step of this retrosyn-
thetic pathway is the cross-coupling reaction between
b-chloroacroleins and boronic acids.
Several polycyclic natural products with a coumarinic
moiety display a large number of biological properties
(anti-bacterial,1 anti-tumoral,2 anti-HIV3…). Due to
those varied biological activities, a considerable amount
of synthetic work in the field of coumarins with [3,4]-car-
bocyclic or [3,4]-heterocyclic fused ring systems has been
done4. Classical reactions (such as Pechmann condensa-
tion, Michae¨l addition…) are still used but the develop-
ment of palladium-catalyzed cross-coupling reactions
OH
OMe
OH
OMe
O
H2SO4
EtO
O
O
OH
O
O
O
OBu OMe
OBu OMe
OMe
OMe
I
PdCl2 (PPh3) 2
O
O
O
O
OMe
Scheme 1.
Keywords: coumarin; palladium catalysis; b-chloroacroleins; Vilsmeier–Haack reaction.
* Corresponding author: Tel.: +(33) 3 87 31 52 95; e-mail: kirsch@sciences.univ-metz.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02373-5

1214
S. Hesse, G. Kirsch / Tetrahedron Letters 43 (2002) 1213–1215
Cl
X
D
B(OH)2
OMe
R
CHO
Cross-coupling
Cyclisation
Oxidation
O
MeO
C
R
R
CHO
n
O
A
B
R
n
n
X
X
R
R = H or Me; X = O or CH2; n = 1 or 2
R
Scheme 2.
2. Results and discussion
aluminum chloride in dichloromethane at room temper-
ature led to the desired tetracyclic systems 4 (a–d)10
(Scheme 3 and Table 1).
b-Chloroacroleins 1 (a–d) are easily synthesized from
the corresponding ketones by a Vilsmeier–Haack–
Arnold reaction.7 Those vinyl chlorides activated by the
presence of an electron-withdrawing group allow good
yields in coupling with boronic acids under mild condi-
tions:8 reactions were performed in aqueous media in
presence of 2 mol% of palladium(II) acetate, tetra-
butylammonium bromide and potassium carbonate;
they were almost complete after three hours at 45°C
(Scheme 3).
3. Conclusion
An easy access to b-chloroacroleins and boronic acids
associated to mild procedures in this four-step synthesis
allowed us the preparation of new coumarin derivatives
with moderate to good yields: compounds 4a and 4b
are obtained, respectively from a-tetralone and 5,7-
dimethyl-1-tetralone with only 25 and 29% yield
whereas products 4c and 4d are, respectively synthe-
sized from 4H-chromanone and 3,4-dihydro-2H-ben-
zo[b]oxepin-5-one with 62 and 53% of global yield.
Oxidation of aldehydes 2 (a–d) with sodium chlorite9 in
the presence of 30% H2O2 in acetonitrile at room
temperature allowed the formation of acids 3 (a–d).
Treatment of the corresponding acyl chlorides with
O
X
Cl
MeO
o-anisylboronic acid
Bu4NBr, K2CO3
R
R
CHO
R
CHO
POCl3
DMF
Pd(OAc)2, H2O, 45°C
n
n
X
n
X
R
R
R
2(a-d)
1(a-d)
NaClO2,
H2O2 30%,
CH3CN, RT
MeO
O
1) SOCl2, Et3N, Et2O, reflux
2) AlCl3, CH2Cl2, RT
R
CO2H
R
O
n
X
n
X
R
R
4(a-d)
3(a-d)
Scheme 3.
Table 1.
R
X
n
1 (Yield)
2 (Yield)
3 (Yield)
4 (Yield)
H
Me
H
CH2
CH2
O
1
1
1
2
1a (95)
1b (96)
1c (96)
1d (85)
2a (75)
2b (89)
2c (98)
2d (86)
3a (86)
3b (96)
3c (69)
3d (90)
4a (40)
4b (35)
4c (96)
4d (80)
H
O

S. Hesse, G. Kirsch / Tetrahedron Letters 43 (2002) 1213–1215
1215
7,8-Dihydro-naphtalen[1,2-c]chromen-6-one 4a: yellow oil;
lH (CDCl3): 2.74–2.85 (m, 4H), 7.29 (ddd, 1H, J=7.6 7.5
and 1.2 Hz), 7.34–7.42 (m, 4H), 7.51 (ddd, 1H, J=7.8 7.5
and 1.1 Hz), 7.82 (dd, 1H, J=8.0 and 1.9 Hz), 8.03 (dd,
1H, J=8.0 and 0.8 Hz); lC (CDCl3): 22.54 (CH2), 28.45
(CH2), 117.89 (CH), 118.03 (C), 124.19 (CH), 124.60 (C),
126.71 (CH), 126.74 (CH), 128.32 (CH), 128.87 (CH),
130.42 (CH), 130.72 (C), 130.81 (CH), 140.49 (C), 144.74
(C), 153.76 (C), 162.00 (CO2); m/z (%): 248 (100), 203
(27)
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