Synthesis of a 4,6-disubstituted dibenzofuran β-sheet initiator by reductive radical arylation of benzene

Article abstract of DOI:10.1021/jo0478914

(Chemical Equation Presented) Tributyltin hydride mediated addition of 3-iodosalicylaldehyde to benzene in the presence of catalytic benzeneselenol affords (1,4-cyclohexadien-3-yl)salicylaldehyde. Homologation of the aldehyde group is followed by cycloeth

Full text of DOI:10.1021/jo0478914

SCHEME 1. Synthesis of Carbazomycin B
Synthesis of a 4,6-Disubstituted
Dibenzofuran â-Sheet Initiator by
Reductive Radical Arylation of Benzene
David Crich* and Daniel Grant
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
Received November 26, 2004
The phenylselenyl group introduced as electrophile in
the carbazomycin synthesis provided a convenient handle
for rearomatization, in view of the known oxidation of
indolines to indoles by benzeneseleninic acid.5 However,
the simple elimination of the electrophile in this manner
may be viewed as a lost opportunity for the introduction
of further functionality in the broader context of complex
molecule total synthesis. As a first step in the direction
of exploiting this functionality more completely we
describe here a synthesis of the â-sheet initiator (13),6
from two simple precursors, 2-hydroxy-3-iodosalicyl al-
dehyde and benzene.
Although 3-iodosalicyl aldehyde has been prepared
previously by mercuration of salicyl aldehyde followed
by iodination,7 and by formylation of 2-iodophenol,8 we
developed an alternative protocol from benzofuran which
reproducibly gave good yields of clean product. Thus,
metalation of benzofuran and quenching with trimeth-
ylsilyl chloride gave 2-trimethylsilylbenzofuran (1)9 in
high yield. A second metalation10,11 with an iodine quench
afforded crude 7-iodo-2-trimethylsilylbenzofuran (2) which,
on ozonolysis, gave the desired iodoaldehyde 3 (Scheme
2).
Tributyltin hydride mediated addition of 3-iodosalicylalde-
hyde to benzene in the presence of catalytic benzeneselenol
affords (1,4-cyclohexadien-3-yl)salicylaldehyde. Homologa-
tion of the aldehyde group is followed by cycloetherification
with dimethyl dioxirane to give a 4,6-disubstituted tetrahy-
drodibenzofuran. Adjustment of oxidation states and intro-
duction of a second chain by Wittig olefination affords the
â-sheet initiator, ethyl 4-(2-tert-butoxycarbonylaminoethyl)-
6-dibenzofuranpropanoate.
We have recently described a process whereby cyclo-
hexadienyl radicals, produced on rapid addition of aryl
radicals to benzene in a stannane-mediated radical chain
reaction, may be trapped by benzeneselenol to give a
series of 3-aryl-1,4-cyclohexadienes.1
Dropwise addition of a benzene solution of tributytin
hydride and AIBN (10 mol %) to a solution of 3 and 20
mol % diphenyl diselenide in benzene at reflux under Ar
gave, after evaporation of the volatiles and chromatog-
raphy over silica gel, 61% of the desired adduct 4 as 5:1
mixture of 1,4- and 1,3-dienes, as is typical for this kind
of addition reaction.1,3,4 A Wittig reaction afforded the R,â-
The complete propagation sequence, described by eqs
1-4, is facilitated by the generation of benzeneselenol
in situ from diphenyl diselenide and tributyltin hydride
(eq 5),2 thereby eliminating the need to handle the
noxious selenol itself.
(4) Crich, D.; Rumthao, S. Tetrahedron 2004, 60, 1513-1516.
(5) (a) Barton, D. H. R.; Luscinchi, W.; Milliet, P. Tetrahedron 1985,
41, 4727-4738. (b) Ninomia, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.;
Barton, D. H. R.; Luscinchi, X.; Milliet, P. J. Chem. Soc., Perkin Trans.
1 1990, 529-532.
(6) Tsang, K. Y.; Diaz, H.; Graciani, N.; Kelly, J. W. J. Am. Chem.
Soc. 1994, 116, 3988-4005.
(7) Whitmore, F. C.; Middleton, E. B. J. Am. Chem. Soc. 1923, 45,
1330-1334.
When the aryl iodide bears a nucleophile in the
o-position, subsequent activation of the cyclohexadienyl
moiety leads to cyclization and provides a rapid entry
into functionalized tetrahydrocarbazoles, dibenzofurans,
etc.,3 as illustrated by our synthesis of carbazomycin B
(Scheme 1).4
(8) Feldman, K. S.; Eastman, K. J.; Lessene, G. Org. Lett. 2002, 4,
3525-3528.
(9) Gill, M. Tetrahedron 1984, 40, 621-626.
(10) Metalation of 2-substituted benzofurans is known to take place
at the 7-position: Coture, A.; Grandclaudon, P.; Cires, L.; Ofenberg,
H. Synth. Commun. 1997, 27, 3669-3676. Likewise metalation of
dibenzofuran was known to take place adjacent to the oxygen. Indeed,
such a metalation is a key step in Kelly’s original synthesis6 of the
present target molecule.
(1) Crich, D.; Hwang, J.-T. J. Org. Chem. 1998, 63, 2765-2770.
(2) Crich, D.; Jiao, X.-Y.; Yao, Q.; Harwood, J. S. J. Org. Chem.
1996, 61, 2368-2373.
(11) In principle, direct dimetalation of benzofuran at the 2- and
7-positions is possible, but we have found the two step protocol to be
more suitable for our purposes: Chadwick, D. J.; Willbe, C. J. Chem.
Soc., Perkin Trans. 1 1977, 887-893.
(3) Crich, D.; Sannigrahi, M. Tetrahedron 2002, 58, 3319-3322.
10.1021/jo0478914 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/09/2005
2384
J. Org. Chem. 2005, 70, 2384-2386

SCHEME 2. Preparation of 3-Iodosalicylaldehyde
FIGURE 1. Key nuclear Overhauser interactions establishing
the stereochemistry of 11E.
SCHEME 4. Completion of the Synthesis
SCHEME 3. Reductive Radical Dearomatization
and Cycloetherification
9 which was achieved cleanly over palladium on charcoal
(Scheme 4). Dess-Martin oxidation of 9 afforded the
ketone 10 which, on heating with cyanomethylene triphen-
ylphosphorane afforded the alkene 11 as a 5:1 E/Z
mixture. The E-configuration of the major isomer in 11
was revealed by nOe interactions of the olefinic hydrogen
with the methylene groups of the second side chain;
together with the 8.5 Hz coupling of the two bridgehead
hydrogens this points to a boat conformation for the
exomethylidene substituted ring (Figure 1). Migration of
the exo-cyclic double bond into the ring and final aro-
matization was achieved by heating over palladium
characoal in the presence of nitrobenzene as hydrogen
acceptor, as described by Cossy.13 Finally, reduction of
the cyano group with nickel boride in the presence of
Boc2O14 afforded the target 13 (Scheme 4). This synthesis
of 13 requires eight steps from the iodide 3 making it
two steps longer than the existing synthesis from diben-
zofuran.6 However, the widespread availability of iodo-
phenols and the several stages at which diversity might
be introduced render this a more flexible synthesis with
the potential for the ready formation of analogues.
In conclusion, the reductive radical dearomatization of
benzene followed by a cyclo-etherification reaction pro-
vides a powerful means of entry into tetrahydrodiben-
zofuran derivatives. With suitable manipulation of the
functionality resulting from the cyclization step the
unsaturated ester 5 uneventfully. This was exposed to
dimethyl dioxirane in acetone at -78 °C12 followed by
concentration under vacuum and chromatography over
silica gel when the desired tricyclic system 8 was
obtained in 56% yield along with 13% of the epoxide 7
with the incorrect stereochemistry for cyclization. In this
last step the dimethyl dioxirane reaction affords a
mixture of the two diastereomeric alcohols 6 and 7,
favoring the former with a ratio of approximately 4:1,
with cyclization of 6 taking place on passage over silica
gel (Scheme 3). With m-CPBA as oxidant in place of
DMDO, a lower selectivity of ∼2:1 favoring 8 over 7 was
observed. The relative stereochemistry of 8 was antici-
pated on grounds of preferential epoxidation of 4 on the
less substituted face followed by ring opening of the
epoxide with inversion of configuration; it was confirmed
by nOe measurements which revealed the proximity of
the two bridgehead hydrogens. Interestingly, the same
two hydrogens exhibited a 3J coupling constant of 8.5 Hz
which suggests a near coplanarity and, possibly, a boat
conformation for this cyclohexene ring.
As befits a series of reactions beginning from a mixture
of skipped and conjugated dienes(4), each of 5-8 was
contaminated with a small amount of a regioisomer
which was difficult to separate and ultimately of no
consequence as the next step involved hydrogenation to
(13) Cossy, J.; Belotti, D. Org. Lett. 2002, 4, 2557-2559.
(14) Caddick, S.; Judd, D. B.; Lewis, A. K. K.; Reich, M. T.; Williams,
M. R. V. Tetrahedron 2003, 59, 5417-5423.
(12) Eaton, P. E.; Wicks, G. E. J. Org. Chem. 1988, 53, 5353-5355.
J. Org. Chem, Vol. 70, No. 6, 2005 2385

Supporting Information Available: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
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chemistry affords a straightforward synthesis of 4,6-
disubstituted dibenzofurans, illustrated here by the
synthesis of Kelly’s â-sheet initiator 13, which nicely
complements existing approaches to dibenzofurans15 and
Wacker-type ring closures of 6-(2-hydroxyphenyl)cyclo-
hexene to tetrahydrodibenzofuran.16
JO0478914
(15) Sargent, M. V.; Stransky, P. O. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: Orlando, 1984; Vol.
35, pp 1-81.
(16) (a) Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am.
Chem. Soc. 2004, 126, 3036-3037. (b) Hosokawa, T.; Miyagi, S.;
Murahashi, S.-I.; Sonoda, A. J. Org. Chem. 1978, 43, 2752-2757.
2386 J. Org. Chem., Vol. 70, No. 6, 2005