Microwave-assisted synthesis of 4-keto-4,5,6,7-tetrahydrobenzofurans

Article abstract of DOI:10.1016/j.tetlet.2008.10.139

The use of TMSCl in methanol under microwave irradiation allows the facile intramolecular condensation of a large panel of triketones, giving rise to 4-keto-4,5,6,7-tetrahydrobenzofurans in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.10.139

Tetrahedron Letters 50 (2009) 274–276
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Microwave-assisted synthesis of 4-keto-4,5,6,7-tetrahydrobenzofurans
z
*
*
Sylvie Goncalves, Alain Wagner , Charles Mioskowski , Rachid Baati
Faculté de Pharmacie, Université Louis Pasteur, Institut Gilbert Laustriat UMR7175 LC1, Laboratoire de Synthèse Bio-Organique, 74 Route du Rhin, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of TMSCl in methanol under microwave irradiation allows the facile intramolecular condensation
Received 26 September 2008
Revised 28 October 2008
Accepted 29 October 2008
Available online 3 November 2008
of a large panel of triketones, giving rise to 4-keto-4,5,6,7-tetrahydrobenzofurans in good to excellent
yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Charles
Mioskowski deceased on June 2nd 2007
Keywords:
Microwave
Cyclodehydration
Tetrahydrobenzofuran
Oxazol
The core structure of 6,7-dihydrobenzofuran-4(5H)-one 1, or
more commonly referred to as 4-keto-4,5,6,7-tetrahydrobenzo-
furan, is an important intermediate in the preparation of a wide
range of synthetic compounds with diverse biological applications
(Fig. 1).1 Indeed, Hayakawa demonstrated recently that tetra-
hydrobenzofuran derivatives (1) represent an interesting alterna-
tive scaffold to benzofuran, for the generation of new
heterocyclic libraries.2 Interestingly, higher oxidized analogues of
1, such as Stemofuran B 2, are isolated from natural plants.3 In
addition, such molecules 1 (R = alkyl) have also been used as useful
building blocks for the total synthesis of other natural products like
the angular furanocoumarin oroselone 3.4
Among them, the thermal [3+2]-cycloaddition of copper or rho-
dium stabilized carbenoids with acetylenes or alkenes has been
widely applied with more or less success.5,6 Pekel and Kim have
described the addition of a-carbon radicals of 1,3-cyclohexandione
on alkynes affording tetrahydrobenzofuran derivatives.7 A photo-
chemical approach that involves phenyliodonium dimedonide
with phenylacetylene has also been reported as another alternative
for the preparation of 1.8 Finally, the last methods reported so far
for the synthesis of scaffold 1 are based on the intramolecular
cyclization of triketones or the cycloisomerization of alkynyl-1,3-
cyclohexanediones using protic acid, the Lawesson’s reagent or
To date, several synthetic methods have been reported for the
synthesis of 4-keto-4,5,6,7-tetrahydrobenzofuran derivatives of 1.
Table 1
Optimization conditions for the cyclization of 4
O
O
MeOH
O
O
Conditions
O
O
OH
O
OH
O
5
4
R
Entry
Promoter
Time (h)
Temperature
Yielda (%)
O
O
O
b
OCH3
1
2
3
4
5
6
H2SO4
0.5
14
14
14
14
rt
rt
rt
rt
/
R = H, alkyl, aryl
1
2
3
HCl (4 equiv)
31
61
90
65
100
AcCl (4 equiv)
TMSCl (4 equiv)
TMSCl (1.6 equiv)
TMSCl (4 equiv)
Stemofuran B
Oroselone
rt
Figure 1. Structures of 1 and natural compounds 2 and 3.
0.13
90 °Cc
a
Isolated yields.
Reaction performed in pure 96% H2SO4.
Reaction performed under microwave irradiation.
* Corresponding authors. Tel.: +33 390 244 301; fax: +33 390 244 306 (R.B.).
E-mail address: baati@bioorga.u-strasbg.fr (R. Baati).
Deceased.
b
c
z
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.139

S. Goncalves et al. / Tetrahedron Letters 50 (2009) 274–276
275
mercuric triflate as promoter, respectively.9–11 In the course of our
study toward the synthesis of natural products, we were interested
in the intramolecular cyclization of triketones substrates such as
Table 2
MW-assisted cyclization for the synthesis of 4,5,6,7-tetrahydrobenzofuran and other
heterocyclesa
Entry Substrate
Product
Yieldb (%)
100
compound
4 for the preparation of the 4-keto-4,5,6,7-tetra-
hydrobenzofuran derivative 5 (Table 1). However, reported methods
starting from triketones which use conventional chemical tech-
niques are plagued with some limitations such as drastic reaction
conditions, limited scope of application, or the use of highly toxic
Lewis acid.9d,11 As a consequence, the need of an efficient general
synthesis of this important class of compounds 1, starting from
triketone substrates, is still of great interest. Herein, we report a
new and expedient procedure for the intramolecular condensation
of triketones, promoted by TMSCl in MeOH under microwave irradi-
ation, leading to 4-keto-4,5,6,7 tetrahydrofurans in high yields.
We initially tested sulfuric acid, which is known to promote the
cyclization efficiently.9d However, the reaction performed in the
reported conditions with substrate 4 failed in providing the desired
cyclized product 5 (Table 1, entry 1). Complete degradation of the
starting material was observed instead, without traces of 5. In con-
trast, when 4 is treated with an excess (4 equiv) of aqueous HCl in
methanol at rt, product 5 is obtained with an isolated yield of 31%
(Table 1, entry 2). Interestingly, the use of in situ generated dry
HCl, by adding 4 equiv of AcCl in methanol, yielded 61% of the cy-
clized condensation compound (Table 1, entry 3). The reaction per-
formed in the presence of 4 equiv of TMSCl in MeOH, as another
source of anhydrous HCl, afforded the desired substrate with a
gratifiying yield of 90% (Table 1, entry 4). Attempts to decrease
the amount of TMSCl were not satisfactory, and 5 was always ob-
tained with lower isolated yields (Table 1, entry 5). With the aim to
get a quantitative yield while shortening the reaction time, we
decided to exploit the benefit of microwave irradiation. The treat-
ment of 4 with 4 equiv of TMSCl in MeOH and under microwave
irradiations in a sealed tube for 8 min at 90 °C, gave 5 in a quanti-
tative yield (Table 1, entry 6).
In this optimized conditions, we next investigated the scope of
the reaction with a panel of different triketone substrates. Several
triketone derivatives were prepared from commercially available
1,3-cyclohexandiones, according to known procedures.12 In gen-
eral, most of the microwave-assisted reactions13 proceeded
smoothly and without complications. The expected cyclized prod-
ucts were obtained in excellent to good yields (Table 2). Indeed,
triketones 6a and 6b, having 5-dimethyl- or 5-phenyl-substituted
1,3-cyclohexandiones moiety, behaved similarly to 4 and gave
the condensation products 7a9d and 7b6b in 100% and 99% yields,
respectively (Table 2, entries 1 and 2). In the case of aromatic
triketones 6c and 6d, bearing a p-electronwithdrawing substituent
(–Br and –NO2) on the exocyclic ketone counterpart, the cyclized
compounds 7c14 and 7d were obtained in 99% and 71% yields
(Table 2, entries 3 and 4).
O
O
1
O
O
O
O
6a
7a
7b
O
2
99
99
O
O
O
6b
Br
O
O
3
Br
O
O
6c
O
7c
NO2
O
O
O
O
O
4
71
86
NO2
O
O
O
O
O
6d
O
O
7d
5
O
7e
6e
O
O
OMe
OMe
6
81
O
O
O
O
6f
7f
O
7
100
O
O
O
6g
7g
7h
7i
O
O
8
100
90
O
O
O
6h
O
O
9
10
11
O
6i
O
O
O
c
Alkyl triketones 6e, 6f, and 6g were also well tolerated and the
corresponding 4-keto-4,5,6,7-tetrahydrobenzofurans 7e,15 7f, and
7g were isolated with high yields, ranging from 81% to 100% (Table
2, entries 5–7).
/
O
O
6j
OH
7j
O
O
O
It is noteworthy to mention that the cyclized product 7g is
accompanied with the complete isomerization of the olefinic dou-
ble bond. We next extended our methodology to acyclic triketone
6h, and triketone 6i bearing a 1,3-seven-membered diketone moi-
ety. In both cases, the cyclized products, 2,3,5-trisubstituted furan
7h6a and 5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-4-one 7i, were
obtained in excellent isolated yields, 100% and 90%, respectively
(Table 2, entries 8 and 9). In sharp contrast, C5-membered trike-
tones 6j and 6k were completely unreactive in the same condi-
tions, the starting material was recovered unchanged (Table 2,
entries 10 and 11). This intriguing lack of reactivity might be as-
cribed to the cyclic strain, precluding 1,4-addition of MeOH
(Scheme 1, step 1). Further experiments by using 1,3-dicarbonyl
c
/
O
O
6k
7k
O
O
H
N
O
N
12
56
O
O
6l
7l
a
All reactions were carried out in the following conditions: 0.5 mmol of sub-
strate, TMSCl (2 mmol), MeOH (2.3 mL), MW, 8 min at 90 °C.
b
Isolated yields of pure compounds.
Starting material recovered.
c

276
S. Goncalves et al. / Tetrahedron Letters 50 (2009) 274–276
References and notes
Cl
H
H
O
O
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O
O
MeO
5
OMe
Scheme 1. Proposed mechanism for the formation of 5.
substrate having an amide function allowed the preparation of
other heterocycles such as oxazoles 7l16 in an acceptable yield of
56% (Table 2, entry 12).
In a mechanistical point of view, it is envisioned that the reac-
tion proceeds through the intermediate 8 (Scheme 1). Evidences
supporting the proposed mechanism came from the isolation of 8
when the reaction was stopped after 12 h at rt without MW irradi-
ations. Furthermore, the treatment of 8 with TMSCl in MeOH under
MW furnished quantitatively the expected cyclized product 5.
In summary, we report herein the first synthesis of 4-keto-
4,5,6,7-benzofuran derivatives under microwave-assisted cyclo-
condensation. Under these optimal conditions (TMSCl/MeOH/
In a 5 mL reaction vial, trimethylsilylchloride (2 mmol) was added to a solution
of triketones (0.5 mmol) in methanol (2.3 mL). The vial was capped and the
mixture was irradiated for 8 min at a maximum power of 250 W and 90 °C. The
reaction mixture was then allowed to cool to room temperature and methanol
was removed under reduced pressure. The residue was taken up into water
(5 mL) and diethyl ether (5 mL). The aqueous phase was extracted with diethyl
ether (3 Â 10 mL). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated in vacuo to give the product. Compounds were then
purified by column chromatography on silica and characterized by 1H, 13C, IR,
and MS analysis.
MW/8 min/90 °C),
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to excellent yields.
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Acknowledgments
We acknowledge the Laboratoire Pierre Fabre (Plantes et Indus-
tries) and the CNRS for financial support of S.G.