Facile synthesis of 4-acetyl-coumarins, -thiocoumarin and -quinolin-2(1H)-one via very high α-regioselective Heck coupling on tosylates

Article abstract of DOI:10.1016/j.tetlet.2011.04.033

An efficient synthesis of a series of methyl ketones at the C4 position of coumarins, coumarin-containing heterocycles and analogous scaffolds is reported via very high α-regioselective Heck coupling using tosylates and in very high yields. Although α-reg

Full text of DOI:10.1016/j.tetlet.2011.04.033

Tetrahedron Letters 52 (2011) 3429–3432
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Tetrahedron Letters
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Facile synthesis of 4-acetyl-coumarins, -thiocoumarin and -quinolin-2(1H)-
one via very high
a-regioselective Heck coupling on tosylates
⇑
Sergio Valente, Gilbert Kirsch
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol, Université Paul Verlaine, FR CNRS 2843, 1 Boulevard Arago, 57070 Metz, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 February 2011
Revised 6 April 2011
Accepted 8 April 2011
Available online 22 April 2011
An efficient synthesis of a series of methyl ketones at the C4 position of coumarins, coumarin-containing
heterocycles and analogous scaffolds is reported via very high
lates and in very high yields. Although -regioselectivity in Heck coupling can be obtained with triflates
as substrates, tosylates are less toxic, less expensive and, importantly, more stable.
Ó 2011 Elsevier Ltd. All rights reserved.
a-regioselective Heck coupling using tosy-
a
Keywords:
2H-1-Benzopyran-2-one
Quinolin-2(1H)-one
Heck coupling
a-Regioselectivity
So far a large number of natural products bear a 2H-1-benzopy-
described four methods to obtain 4-acetylcoumarin in moderate
yields. Nothing is reported for 4-acetyl-1-thiocoumarin whereas
the synthesis of 4-acetyl-quinolin-2(1H)-one is restricted to old
methods19 or to Grignard reaction.20 The preparation of non-
ran-2-one (coumarin) as part of their structure.1 2H-1-benzopy-
ran-2-ones show wide biological activity, for example, as
antioxidants,2 anticoagulants,3 antifungal agents,4 MAO-B selective
inhibitors,5 hAChE and BACE1 inhibitors,6 NFkB inhibitors,7 Hsp90
inhibitors,8 HIV-1 integrase inhibitors,9 Cdc25 phosphatase inhibi-
tors,10 17-b-HSD1 inhibitors.11 1-Thiocoumarin and quinolin-
2(1H)-one, during the past years have been of prominent biological
interest, too. Thiocoumarin has been very recently described for
carbonic anhydrase inhibition12 whereas quinolone was reported
as a scaffold for type I fatty acid synthase inhibitors13 and for
NMDA/glycine site antagonists.14
protected acetophenones by Heck21–25
a-arylation of alkyl vinyl
ether followed by hydrolysis23 has been known for almost two
decades.26–30 Aryl/alkenyl electrophiles carrying halogens prefer-
entially follow a neutral Heck mechanism leading to a higher
degree of the b-substituted product and this limits the use of these
compounds regarding couplings with electron-rich alkenes, which
often leads to a mixture of regioisomeric products. A high regiose-
lective vinyl group insertion can be obtained using the bidentate
ligands introduced by Cabri et al.30 which promote internal aryla-
tion of electron-rich olefins and ensure that the reaction follows a
cationic route.31 Cationic intermediates are created by spontane-
ous dissociation of the weakly coordinating triflate anion.32 Never-
Although there are classical methods, such as the Perkin and
Pechman reactions,15 Knoevenagel15c and Wittig16 condensation,
for the synthesis of a wide variety of substituted coumarins, these
methods often require the use of strong acids and high tempera-
tures, so the scope of these transformations is, therefore, some-
what limited. So, with the aim of improving the coumarin
scaffold’s functionality, and describing a few methods for prepar-
ing it, we decided to study a different way to synthesize methyl ke-
tone at the C4 of the coumarin nucleus, which represents a very
relevant functional group.
theless
a-regioselective Heck coupling with electron-rich olefins
can be performed on
a
,b-unsaturated tosylates and mesylates, as
reported by Hansen and Skrydstrup33 using Pd2dba3 as the palla-
dium(0) source, DPPF as the bidentate ligand, and DIPEA as the
Indeed little is described in the literature about the synthesis of
4-acetylcoumarin, by oxidation17 or via Stille coupling.18 According
to the method reported by Ito and Nakajima.17a 4-Acetylcoumarin
was obtained in a very low yield (16%), whereas Yee et al.18
⇑
Corresponding author. Tel.: +33 3 87315295; fax: +33 3 87325801.
E-mail address: kirsch@univ-metz.fr (G. Kirsch).
Scheme 1. Synthesis of methyl ketones at C4 position of coumarins and its
analogous scaffolds.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.033

3430
S. Valente, G. Kirsch / Tetrahedron Letters 52 (2011) 3429–3432
this system has been also applied by Hallberg and co-workers to
provide protected ketones, but only on vinyl triflates.31
Furthermore, we have extended the methodology to 1-
thiocoumarin and quinolin-2(1H)-one (Table 2) in order to validate
the reaction for coumarin analogues, too.
At first we have studied the effects of several solvents on the
coupling performed on the 4-coumarin tosylate (Scheme 2), as re-
ported in Table 1.
Scheme 2.
Table 1
All the solvents we used did not influence the grade of regiose-
lectivity (>99:1). When we carried out the reaction in polar and
non polar solvents, longer time of reaction was required and lower
yield was provided using solvents unable to reach 80 °C (THF).
However, the best yields were achieved with DMF and 1,4-dioxane,
although the latter allowed the coupling reaction to be completed
in shorter time (12 h) and provided the best yield (92%).
Therefore, we chose 1,4-dioxane to perform all of subsequent
Heck couplings. The coupling results are summarized in Table 2.
All tosylates 1a–j were synthesized using known literature pro-
cedures from starting substrates that were also prepared using the
methods reported in the literature.34 The Heck reactions35 were
carried out by reacting tosylates with butyl vinyl ether (4 equiv),
palladium acetate (0.025 equiv), 1,3-bis(diphenylphosphino)pro-
pane (DPPP) (0.0275 equiv) as the bidentate ligand and diisopropyl-
ethylamine (DIPEA) (3 equiv) as the base (Scheme 3).
Cross-coupling generally went to completion within 12 h when
performed on coumarin without substituents (Table 2, entry 1).
Nevertheless longer times (16 h) were necessary when a halogen
Effects of the solvent on the Heck couplinga
Solvent
Time (h)
Temp (°C)
a
/bb
Isolated yieldc (%)
Dioxane
DMF
DME
CH3CN
THF
PhCH3
12
18
18
18
24
18
80
80
80
80
67
80
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
92
84
74
66
40
72
a
Reaction conditions: 1.0 equiv of tosylate, 3 equiv of DIPEA, 4 equiv of butyl
vinyl ether, 2.5 mol % Pd(OAc)2, 2.75 mol % DPPP under argon atmosphere. Reaction
was performed in a screwcap-sealed tube.
b
Determined by NMR of the crude before the acidic treatment.
c
Greater than 95% purity by MS.
base. So, we herein describe the synthesis of several acetylcouma-
rins and coumarin-containing heterocycles via
Heck coupling on tosylates (Scheme 1).
a-regioselective
We performed the coupling with Pd(OAc)2 and DPPP, the biden-
tate ligand introduced by Cabri et al.,30 considering that until now
Table 2
4-Acetyl-coumarins, -thiocoumarin and -quinolin-2(1H)-one synthesis via
a
-regioselective Heck couplinga
Entry
Tosylate
OTs
Product
Time (h)
a
/bb
Isolated yieldc (%)
O
CH3
1
12
>99/1
>99/1
92
O
O
1a
O
O
O
2a
CH3
OTs
H3C
H3C
2
16
82
O
O
1b
O
O
2b
OTs
O
CH3
F
F
3
4
16
—
>99/1
77
—
O
O
1c
O
O
2c
OTs
O2N
No reaction
—
O
O
1d
OTs
O
CH3
5
10
>99/1
85
H3CO
O
O
H3CO
O
O
O
1e
1f
2e
OTs
O
CH3
O
6
7
16
16
>99/1
>99/1
76
81
O
O
O
2f
OTs
CH3
O
O
O
1g
O
O
O
2g

S. Valente, G. Kirsch / Tetrahedron Letters 52 (2011) 3429–3432
3431
Table 2 (continued)
Entry
Tosylate
Product
Time (h)
16
a
/bb
Isolated yieldc (%)
OTs
O
O
CH3
O
8
9
>99/1
79
O
O
O
O
1h
2h
OTs
O
O
CH3
5
8
>99/1
>99/1
86
93
S
O
1i
S
O
2i
OTs
CH3
10
N
H
O
N
H
O
1j
2j
a
Reaction conditions: 1.0 equiv of 1a–j, 3 equiv of DIPEA, 4 equiv of butyl vinyl ether, 2.5 mol % Pd(OAc)2, 2.75 mol % DPPP in dioxane under argon atmosphere. Reaction
was performed in a screwcap-sealed tube.
b
Determined by NMR of the crude before the acidic treatment.
Greater than 95% purity by MS.
c
Scheme 3.
(such as fluorine, entry 3) or a weak electron-donating group
(methyl, entry 2) was present in the C6 position. The same times
of reaction were used when a third aromatic cycle (benzene or fur-
an) did exist (entries 6–8). The coupling worked a little bit quicker
(10 h) when at the C7 position an electron-donating group (meth-
oxy, entry 5) was inserted, but, surprisingly no reaction occurred
with a strong electron-withdrawing group (nitro, entry 4) in the
C6 position of the coumarin nucleus.
Acknowledgement
The research leading to these results has received funding from
the [European Community’s] Seventh Framework Programme
([FP7/2007-2013] under grant agreement no. 215009.
Supplementary data
In this case we observed the consumption of the starting tosyl-
ate but only a mixture of by-products was observed.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.033.
Next we tested the possibility of applying this cross-coupling in
order to obtain 4-acetyl-thiocoumarin and -quinolin-2(1H)-one
(entries 9 and 10), respectively. Both reactions proceeded in very
high yields (93%, entry 10) and in a time as short as 5 h for thio-
coumarin (entry 9).
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3432
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35. General procedure for the synthesis of 4-acetyl-coumarin, -thiocoumarin and -
quinolin-2(1H)-one synthesis via a-regioselective Heck coupling (2a–j).
A mixture of the tosylate (0.56 mmol), butyl vinyl ether (2.24 mmol), DIPEA
(1.68 mmol), Pd(OAc)2 (0.014 mmol), DPPP (0.0154 mmol), in 10 mL dry
dioxane was stirred under argon in a screwcap-sealed tube (for the reaction
time and temperature see Table 1). When starting material was consumed the
reaction was cooled until 0 °C and after a 2 N HCl solution (20 mL) was added
during stirring which was continued for 2 h. After this time the acidic solution
was extracted with ethyl acetate (3 Â 20 mL), organic layers collected were
washed with brine (20 mL) and dried with MgSO4 and concentrated to be
purified by column chromatography eluting with ethyl acetate/cyclohexane to
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