Synthesis of 2-substituted 3-acylbenzo[b]furans via the palladium catalysed carbonylative cyclisation of ortho-hydroxytolans

Article abstract of DOI:10.1055/s-1999-2764

A palladium-catalysed cyclisation with concomitant carbonylation via insertion of carbon monoxide was used to prepare several potential adenosine antagonists possessing a benzo[b]furan skeleton with a formyl group in the 3-position.

Full text of DOI:10.1055/s-1999-2764

LETTER
1079
Synthesis of 2-Substituted 3-Acylbenzo[b]furans via the Palladium Catalysed
Carbonylative Cyclisation of ortho-Hydroxytolans
Henning Lütjens, Peter J. Scammells*
School of Biological and Chemical Sciences, Deakin University, Geelong, Victoria, Australia, 3217
Fax: +61 (3) 52271040; E-mail: scam@deakin.edu.au
Received 9 March 1999
1, entries 1 and 6), the crude coupling product was diffi-
Abstract: A palladium-catalysed cyclisation with concomitant car-
cult to purify and was therefore deprotected directly.
bonylation via insertion of carbon monoxide was used to prepare
several potential adenosine antagonists possessing a benzo[b]furan
skeleton with a formyl group in the 3-position.
Key words: benzofuran, carbonylative cyclisation, palladium, ade-
nosine antagonist
Recently, we reported two new syntheses of XH-14 (1)
(1,2) which was isolated from the plant, Salvia miltiorrhiza
and found to be a potent antagonist of the A1 adenosine re-
Scheme 1 (i) HC∫CR2, CuI, PdCl2(PPh3)2, NEt3; MeCN; (ii) HO2C-
CO2H, MeOH
ceptor(3-5)
.
Table 1
In our original synthesis, XH-14 was prepared in six steps
starting from eugenol(1). The synthesis featured improve-
ments associated with the construction of the hydroxypro-
pyl side chain, which was formed and protected in two
steps. The key steps developed by Yang and co-workers
for the formation of the benzofuran ring system (coupling
a cuprous acetylide with an ortho-bromophenol) and in-
troduction of the 3-formyl group (a regioselective Gatter-
mann-Adams reaction)(3-5) were retained. Unfortunately,
the scope of this approach is limited by the Gattermann-
Adams reaction, which proved to be unreliable in our syn-
thesis of 1(2) and unsatisfactory for the synthesis of other
2-substituted analogs. To facilitate a structure-activity
evaluation of the importance of the group in the 2-position
in A1 adenosine receptor binding, we developed a new and
more versatile pathway. In this case the benzo[b]furan
ring system with the desired substituent in the 2-position
and an acyl group in the 3-position was accessed in one
step via a palladium-mediated carbonylative cyclisation
reaction(2).
The ortho-hydroxytolans thus obtained showed a strong
tendency to cyclise. For example, after storage of the
deprotected ortho-hydroxytolan used for the synthesis of
XH-14 (Table 1, entry 2) at 4 °C overnight, only autocyc-
lised material was apparent by NMR. Spontaneous cycli-
sation also proved to be a problem when attempting the
ensuing carbonylative cyclisation reaction. Indeed, under
the conditions described in the first report of this type of
reaction(6), mostly non-carbonylated benzofurans were
obtained. It was discovered that replacement of the
potassium carbonate with weaker bases favoured car-
bonylative cyclisation over self-cyclisation. A number
of bases were evaluated (triethylamine, sodium acetate,
sodium carbonate, sodium hydrogen carbonate, potassium
carbonate and potassium hydrogen carbonate) and sodium
acetate was found to give the best results. Several
reoxidants (hydrogen peroxide, copper(II) chloride,
potassium ferricyanide, potassium permanganate, sodium
The starting materials for the cyclisations were prepared
by Sonogashira coupling of the appropriately substituted
aryl iodides and alkynes (Scheme 1, Table 1), followed by
deprotection of the phenol. In the case of R2 = Ph (Table
Synlett 1999, No. 07, 1079–1081 ISSN 0936-5214 © Thieme Stuttgart · New York

1080
H. Lütjens, P. J. Scammells
LETTER
bromate and sodium iodate) were evaluated, but only cop- disappointing results in the case of the 7-demethoxy com-
per(II) chloride allowed the use of a catalytic amount of pounds (Table 2, entries 6 and 7). This may be attributed
palladium. In some cases, it was still necessary to use one to the lack of the electron donating effect of this group in
equivalent of palladium.
the central aromatic ring.
Four compounds were then elaborated into the desired 3-
formyl-5-hydroxypropyl compounds (Scheme 3, Table
3). Hydrogenation, with simultaneous debenzylation in
the case of entry 3, followed by reduction with 5 equiva-
lents of DiBAL afforded the diols. As the benzylic alcohol
moiety of the intermediate diols proved to be extremely
acid labile, workup with sodium sulfate decahydrate was
employed. Selective oxidation of the diols with manga-
nese dioxide gave the final aldehydes.
Scheme 2 (i) PdCl2, CO, CuCl2, NaOAc, MeOH
Table 2
Scheme 3 (i) H2, Pd-C, EtOAc; (ii) DiBAL, CH2Cl2/toluene; (iii)
MnO2, CHCl3
Table 3
As can be seen from entry 2, the reduction-oxidation pro-
tocol can be conveniently carried out in one pot by addi-
tion of the manganese dioxide to the slurry of the
reduction reaction with good results.
In summary, a variety of different 2-substituted analogs of
the adenosine antagonist XH-14 (1) have been prepared.
Their biological activities will be reported elsewhere in
due course.
Acknowledgement
The authors thank the Australian Research Council for financial
support.
As can be observed from Table 2, yields of desired prod-
ucts were the higher when the terminal alkynes had a less
electron withdrawing substituent (entries 4 and 5). This is
mirrored by the greatly reduced tendency of the corre-
sponding ortho-hydroxytolans to self-cyclise on storage.
Unfortunately, the carbonylative cyclisation reaction gave
References and Notes
(1) Hutchinson S.A.; Lütjens H.; Scammells P.J. Bioorg. Med.
Chem. Lett. 1997, 7, 3081-3084.
(2) Luetjens, H.; Scammells, P.J. Tetrahedron Lett. 1998, 39,
6581.
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LETTER
Synthesis of 2-Substituted 3-Acylbenzo[b]furans
1081
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