Deprotonation of benzylic ethers using a hindered phosphazene base. A synthesis of benzofurans from Ortho-substituted benzaldehydes

Article abstract of DOI:10.1021/ol0000758

(equation presented) The hindered nonionic phosphazene base P₄-t-Bu efficiently deprotonates o-arylmethoxy benzaldehydes, leading to a direct synthesis of benzofurans. Strong ionic bases such as LDA, LiTMP, and KH failed.

Full text of DOI:10.1021/ol0000758

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2409-2410
Deprotonation of Benzylic Ethers Using
a Hindered Phosphazene Base. A
Synthesis of Benzofurans from
Ortho-Substituted Benzaldehydes
George A. Kraus,* Ning Zhang, John G. Verkade,* Muthukaman Nagarajan, and
Philip B. Kisanga
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
jVerkade@iastate.edu
Received April 3, 2000
ABSTRACT
The hindered nonionic phosphazene base P4-t-Bu efficiently deprotonates o-arylmethoxy benzaldehydes, leading to a direct synthesis of
benzofurans. Strong ionic bases such as LDA, LiTMP, and KH failed.
Many natural products and biologically significant synthetic
compounds contain either a benzofuran or a dihydrobenzo-
furan subunit.1 As a consequence, a number of preparations
of benzofurans have been reported.2 Recently there has been
growing interest in developing general and versatile synthetic
methods for the synthesis of benzofuran derivatives because
of their activity as modulators of androgen biosynthesis
(furano steroids),3 as inhibitors of 5-lipoxygenase, as an-
tagonists of angiotensin II receptors,4 as blood coagulation
factor Xa inhibitors,5 and as ligands for the adenosine A1
receptor.6 Some 2-aryl benzofuran derivatives are potent
calcium blockers,7 and some of them show very good
fungicidal activity in vitro and in vivo.8 As part of a program
to develop direct syntheses of natural antiviral agents,9 we
report a novel strategy for the synthesis of benzofurans.
One route to benzofurans from substituted benzaldehydes
is illustrated below. This reaction is effective provided that
at least one of the substituents R or R′ on the benzyl subunit
is an electron-withdrawing group such as a nitro or cyano
group. Potassium tert-butoxide and sodium ethoxide are
typically used to effect this reaction.10 Another route to
benzofurans from substituted benzaldehydes involves a
photochemical hydrogen atom abstraction reaction to give a
dihydrobenzofuranol which can be converted into a benzo-
furan by dehydration.11 This strategy has rarely been
employed for the synthesis of highly functionalized benzo-
furans.
(1) Dean, F. M. The Total Synthesis of Natural Products; ApSimon, J.,
Ed.; Wiley: New York, 1973; Vol. 1, p 513.
(2) Rohrkasten, R.; Konrad, M. Houben-Weil Methoden der Org. Chemie;
Verlag: New York, 1944; p 33.
(3) Kumar, V.; Ackerman, J. H.; Alexander, M. D.; Bell, M. R.;
Christiansen, R. G.; Dung, J. S.; Jaeger, E.P.; Herrmann, J.L. Jr.; Krolski,
M.E.; McKloskey, P.; Batzold, F. H.; Juniewicz, P.E.; Reel, J.; Snyder, B.
W.; Winneker, R. C. J. Med. Chem. 1994, 37, 4227.
(4) Ohemeng, K.A.; Appollina, M. A.; Nguyen, V. N.; Schwender, C.
F.; Singer, M.; Steber, M.; Ansell, J.; Argentieri, D.; Hageman, W. J. Med.
Chem. 1994, 37, 3663.
(5) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya,
S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. J. Med. Chem. 1994, 37, 1200.
(6) (a) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C.
J. Org. Chem. 1992, 57, 7248. (b). Cagniant, P.; Cagniant, D. AdV.
Heterocycl. Chem. 1975, 18, 337.
We had originally planned to prepare 2 from benzaldehyde
1 (R ) OMe, R′ ) H) by the two-step sequence involving
10.1021/ol0000758 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/13/2000

a photochemical hydrogen atom abstraction reaction followed
by dehydration using POCl3 and pyridine. Although this
reaction sequence worked well on a millimole scale, the
photochemical step proved difficult to scale-up.
afforded 2-(2-methoxyphenyl)benzofuran in 49% isolated
yield. When benzene was used as the solvent, the yield was
47%. Results with a series of aldehydes are given in Table
1.
We next tried the base-mediated reaction. In view of the
absence of an electron-withdrawing group on the benzyl
moiety, we examined the deprotonation of the benzylic ether
of 1 using strong bases in anhydrous media. Treatment of 1
(R ) OMe, R′ ) H) with lithium diisopropylamide (LDA)
in THF from -78 to 25 °C returned recovered starting
material. The reaction of 1 with lithium tetramethypiperidide
(LiTMP) in THF from 0 to 25 °C afforded mostly recovered
starting material with byproducts that were not derived from
proton abstraction at the benzylic ether position. Benzalde-
hyde 1 did not react with sodium hydride or potassium
hydride in THF or DMF.
Recently, Verkade reported the use of nonionic phosphorus
“superbases” such as 3 to effect selective organic reactions.12
Schwesinger13 [who originally synthesized 414 (“P4-t-Bu”)]
and others15 have described carbanion chemistry employing
this base. In view of the demonstrated utility of these strong
nonionic bases for carbanion chemistry, phosphazane 3 and
phosphazene 4 were next examined.16
Table 1. Cyclizations Using P4-t-Bu
time
%
entry R1
R2
R3
solvent
(h) T (°C) yield
1
2
3
4
5
6
7
H
H
OMe
OMe
H
benzene
pivalonitrile
benzene
pivalonitrile 12 90
benzene
benzene
12 reflux 47
H
H
H
H
H
8
90
14 reflux 48
51
49
OMe OMe
OMe OMe
H
H
H
H
14 reflux 69
12 reflux 50
1
OCH2OCH3
H
NO2 benzene
reflux 78
Additionally, we examined the cyclizations of propenyloxy
benzaldehydes. The reaction of o-propenyloxybenzaldehyde
with 4 afforded a complex mixture of products. However,
the reaction of 3-phenylpropenyloxybenzaldehyde (shown
below) with 4 produced an 82% yield of the corresponding
benzofuran.
Although 3 did not deprotonate 1, 4 efficiently converted
a series of benzaldehydes directly into benzofurans in good
isolated yields.16 The reaction of 1 with 1.1 equiv of
commercially available 4 in pivalonitrile at 90-100 °C
The reaction of benzaldehydes with 4 offers a new strategy
for the synthesis of benzofurans. Reaction conditions are mild
and convenient. Functional groups such as ethers, acetals,
and alkenes are compatible with the reaction conditions.
(7) Gubin, J.; Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux,
J.; Rosseels, G.; Peiren, M.; Client, M.; Polster, P.; Chatelain, P. J. Med.
Chem. 1993, 36, 1425.
(8) Carter, G. A.; Chamberlain, K.; Wain, R. L. Ann. Appl. Biol. 1978,
88, 57.
(9) Kraus, G. A.; Wang, X. Bioorg. Med. Chem. Lett. In press.
(10) Dann, O.; Char, H.; Griessmeier, H. Liebigs Ann. Chem. 1982, 1836.
(11) (a) Pappas, S. P.; Pappas, B. C.; Blackwell, J. E. J. Org. Chem.
1967, 32, 3066. (b) Hu, S.; Neckers, D. C. J. Chem. Soc., Perkin Trans. 2
1999, 1771.
Acknowledgment. G.K. thanks the Center for Advanced
Technology Development for partial support of this research,
and J.V. is grateful to the NSF for a grant.
OL0000758
(12) See, for example: Yu, Z.; Verkade, J. G. J. Org. Chem. 1999, 64,
4298 and references therein.
(13) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987,
26, 1167 and references therein.
(14) Schwesinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.; Peters,
E.-M.; Peters, K.; Von Schnering, H. G. Angew. Chem., Int. Ed. Engl. 1993,
32, 1361.
(15) (a) Solladie-CaVallo, A.; Roche, D.; Fischer, J.; De Cian, A. J. Org.
Chem. 1996, 61, 2690. (b) Palomo, C.; Oiarbide, M.; Lopez, R.; Gomez-
Bengoa, E. Tetrahedron Lett. 2000, 41, 1283.
(16) General Procedure for making benzofurans: To a stirred solution
of the benzaldehyde (0.42 mmol) in dry benzene under N2 was added P4-
t-Bu (0.46 mmol as a 1 M solution in hexane available from Fluka) at room
temperature. The reaction was then carried out at the temperature given in
Table 1. When the reaction was complete, as indicated by TLC, the reaction
mixture was loaded directly onto a 40-140 mesh silica gel column and
eluted with 2% ethyl acetate in hexanes to give pure 2-arylated benzofurans
in good to moderate yields. Entry 1 of Table 1: Oishi, K.; Kurosawa, K.
Bull. Chem. Soc. Jpn. 1980, 53, 179. Entry 7 of Table 1: mp 177-179 °C
(177-178 °C, Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1999, 1357).
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Org. Lett., Vol. 2, No. 16, 2000