TABLE 3. Reduction of 2a-l with LAHa-d
and orthogonally protected phenols toward the LAH reduction
protocol. Accordingly, treatment of 2a with excess LAH (4
equiv) at -78 °C for 2 h readily allowed for the formation of
the corresponding diol 4a17 with a 68% yield. By utilizing a
large excess of LAH, the free hydroxyl moiety of 2a did not
hinder the reaction progress as observed during the DIBAL-H
reduction procedure.
Gratifyingly, protection of the free hydroxyl group of 2a as
a variety of orthogonal protecting groups such as the benzyl
(2c), methoxymethyl (2d), tert-butyldimethylsilyl (2e), or allyl
(2f) ether allowed for the reduction of the 2,2-dimethyl-1,3-
benzodioxan-4-one functional group to provide the resultant
substituted 2-hydroxybenzylic alcohols 4c, 4d, 4e, and 4f in
good yields ranging from 53 to 93%. Correspondingly, the
fluoro, bromo, and chloro-substituted 2,2-dimethyl-1,3-benzo-
dioxan-4-ones (2h-2j)18-20 readily underwent reduction with
LAH to afford the corresponding 2-hydroxybenzylic alcohols
(4h-4j) (65-88% yield) with no over-reduction of the halide
susbtituents. Likewise, the conjugated vinyl (2g) functional
group was tolerant of the standard LAH conditions employed
at -78 °C, and the matching diol (4g) was isolated with a good
yield of 71%.21 The sterically hindered 2,2-dimethyl-1,3-
benzodioxan-4-one 2f also readily underwent reduction with
LAH to provide the corresponding diol 4f in good yield.
Unfortunately, carbonyl and halide reduction of the iodo-
substituted 2,2-dimethyl-1,3-benzodioxan-4-one (2l) was ob-
served, and diol 1c was isolated in 83% yield. Attempted
reduction of the triflate-substituted 2,2-dimethyl-1,3-benzo-
dioxan-4-one 2b under a variety of conditions with LAH led to
complete decomposition of the starting material and provided
none of the desired compound 4b. However, reduction of both
2b and 2l could be successfully carried out when utilizing LiBH4
to provide the corresponding diols 4b and 4l22 with yields of
67 and 71%, respectively.
a For specific reaction conditions, see the Experimental Section. b Yields
are of the isolated and purified compound. c NPO ) no product observed.
d Reduction of 2b and 2l with LiBH4 provided the matching diols 4b and
4l in 67 and 71% yields.
desired product aldehyde 3e, but unfortunately provided mostly
compound 2a and aldehyde 3a with isolated yields of 62 and
35%, respectively. In accordance with Corey’s previous report,16
we observed that DIBAL-H readily desilylated the TBS-
protected phenol of 2e at -78 °C. Additionally, the correspond-
ing diisobutyl aluminum alkoxide most likely impeded the
reduction of the 2,2-dimethyl-1,3-benzodioxan-4-one subunit to
3a as previous described for 2a.
With the successful partial reduction of the 2,2-dimethyl-
1,3-benzodioxan-4-one subunit containing a variety of substi-
tuted functional groups to the resultant substituted salicylalde-
hyde products with DIBAL, our focus was then shifted to
examining the reduction of such compounds to the correspond-
ing benzyl alcohol derivatives with LAH. As illustrated in Table
3, we investigated the stability of a variety of functional groups
In conclusion, we have developed two complementary
procedures that provide either substituted salicylaldehydes or
the corresponding 2-hydroxylbenzyl alcohols upon treatment of
the 2,2-dimethyl-1,3-benzodioxan-4-one functional group with
DIBAL-H or LAH (and in some cases LiBH4), respectively.
These two methodologies should readily allow for the production
of indispensable aromatic subunits that could be utilized during
the total synthesis of biologically active natural products. Efforts
in that direction are currently underway and will be reported in
due course.
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