16 in a 63% overall yield after 90 min. The indene skeleton
13 favors the regioisomer 18 over 17 with a 4.4:1.0 ratio
and 70% overall yield after 75 min. Of some interest is the
oxidation of the tetralin 14, which favors the regioisomer
19 over 20 in a 3.5:1.0 ratio with a combined yield of 59%
after 90 min. However, this reversal of selectivity was
expected given the examples of electrophilic aromatic
substitution shown in Scheme 2. It should be noted that when
reactions were left unattended for lengthier periods of time
without in situ reduction to the corresponding catechol, the
o-quinone products began to decompose at different rates.
As the yield decreases, the regiomeric ratio can appear to
improve or worsen.
Scheme 4. Synthesis of Indenones and Unusual Proximity
Effects of Phenols; Comparison of H+- and Rh2+-Promoted
Cyclizations
With our worries concerning the oxidation of phenol 8
laid to rest, we began our synthesis of brazilin 1 in earnest.
Sequential treatment of the 2-(3-hydroxyphenyl)acetic acid
11 (0.07 M in CH2Cl2/THF (10:1)) with oxalyl chloride (1.05
equiv), dimethylformamide (0.03 equiv), and diazomethane
(2.2 equiv in ether) smoothly affords the phenolic diazo-
ketone 21 in 68% yield. However, acid-promoted cyclization
of the diazoketone 21 proved unsatifactory; trifluoroacetic
acid affords the 2,2,2-trifluoroacetate adduct 22 (90% yield)
from 21 and a small amount of the 4-hydroxy-1H-inden-
2(3H)-one 9.18 On the other hand, addition of boron
trifluoride etherate led to unidentified products and a 1:1
mixture of compounds 23 and 9 in a 40% overall yield. We
were surprised to find that addition of rhodium acetate (0.02
equiv) to the diazoketone 21 (0.045 M in CH2Cl2) exclusively
furnishes the more congested 4-hydroxy-1H-inden-2(3H)-
one 23 in a 53% yield.19 Formation of product 23 suggests
to us that the site of cyclization is governed by the
unprotected phenol residue. This suspicion was confirmed
by subjecting the 3-(methoxymethoxy)phenyl derivative 24,
prepared from 21, to rhodium acetate for cyclization. The
ensuing regioselective cyclization affords the 5-(meth-
oxymethoxy)-1H-inden-2(3H)-one 25 in 74% yield. The
desired indanone skeleton 9 was also prepared by treatment
of the diazoketone 26, derived from 4-hydroxyphenylacetic
acid in 71% yield, with rhodium acetate. However, the
resulting 28% yield implies that the cyclization suffers
without the appropriately positioned and protected oxygen
substituent.
9 (0.42 equiv) or solid 25 (0.83 equiv) directly to a solution
of the lithium species (0.6 M in THF, precooled to -100
°C) derived from addition of n-butyllithium to the stannane
27. Although the former sequence precludes protection and
deprotection, we chose the latter. Compound 28 undergoes
quantitative deprotection to phenol 8 (MeOH, concentrated
HCl). Oxidation of the phenol 8 (0.03 M in DMF, room
temperature) with IBX (1.05 equiv) affords the o-quinone 7
Next, we examined nucleophiles in 1,2-addition reactions
with the ketones 9 and 25. The acidity of the methylene
residues in the inden-2(3H)-ones 9 and 25 was an anticipated
problem. Alkylation of the commerically available 3-(ben-
zyloxy)phenol with (bromomethyl)-tributyl-stannane affords
the stannane 27.20 After considerable experimentation, we
found that adducts 8 (Scheme 4) and 28 are accessible in
yields of 26% and 61%, respectively, by the addition of solid
1
in 67% yield as determined by H NMR. Inspection of the
crude 1H NMR spectrum reveals an 84% yield of a 4:1 ratio
of 7 and what we tentativelly assign as the regiomeric
o-quinone. However, over 1-2 h the undesired material
succumbs to selective destruction most likely through po-
lymerization. After 2 h, in situ reduction of the crude reaction
mixture with sodium hydrosulfite (3 equiv) affords the
benzylated catechol 29 in 58% isolated yield without
contamination by the corresponding regiomeric catechol.
After chromotography, the o-quinone 7 can be reformulated
by oxidation (0.03 M in THF) with bis-trifluoroacetate-
phenyliodine (PIFA, 1.00 equiv)21 or by oxidation (0.03 M
in DMSO) with silver oxide (5 equiv). Without further
purification, the o-quinone 7 (0.03 M in THF) is readily
trapped through a 1,6-conjugate addition with phenyl thiol
(16) Nilsson, J. L. G.; Selander, H.; Sievertsson, H.; Skanberg, I.;
Svensson, K.-G. Acta Chem. Scand. 1971, 25, 94-100.
(17) Lange, J.; Hoogeveen, S.; Veerman, W.; Wals, H. Heterocycles
2000, 53, 197-204.
(18) Rosnati, V.; Di Vonna, M. L.; Pusino, A.; Saba, A. Tetrahedron
Lett. 1988, 29, 4193-4196.
(19) Watanabe, N.; Ogawa, T.; Ohtaka, Y.; Ikegami, Y.; Hashimoto, S.
Synlett 1996, 85-86.
(20) Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195-
7203.
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