Metalation Route to Ferroelectric Liquid Crystals
A R T I C L E S
polarization. To test this hypothesis, we designed the novel fluor-
enol mesogens 3a-e, which are derived from the fluorenones
2a-e.
cyclization reactions,22,23 intramolecular cycloadditions of con-
jugated aryl enynes24 and diynes,25 and oxidation of fluo-
renes.26,27 Recent advances in transition-metal-catalyzed C-H
bond insertion reactions have led to the development of
palladium-catalyzed cyclizations of o-iodobenzophenones28 and
cyclocarbonylation of o-iodobiaryls.29 However, difficulties in
the synthesis of appropriate 2,7-disubstituted fluorenes or
cyclization precursors to 2,7-disubstituted fluorenones prompted
us to develop a different approach based on the DreM30 of
o-biarylcarboxamides derived from a combined DoM/cross-
coupling strategy.
The fluorenols 3a-e were obtained as mixtures of (R,R) and
(S,R) diastereomers by sodium borohydride reduction of the
corresponding fluorenones 2a-e. The synthesis of the fluo-
renones began with N,N-diethyl-3-methoxybenzamide (4), which
was metalated preferentially between the two directed metalation
groups (DMGs) and quenched with trimethylsilyl chloride to
give the TMS-protected benzamide 5 in 81% yield (Scheme
1). The second DoM step occurred selectively ortho to the
stronger amide DMG, and the lithiated intermediate, upon
quenching with B(OMe)3 and hydrolysis, gave the boronic acid
6. Interestingly, reaction of the crude 6 with a variety of
protected 4-iodophenols under Suzuki-Miyaura cross-coupling
conditions gave homocoupling products. As an alternative,
4-bromoiodobenzene was used as coupling partner, with the
intention of subsequent replacement of the bromo function by
an alkoxy group. Suzuki-Miyaura cross-coupling was achieved
regioselectively to give the biphenyl 7 in 70% overall yield from
5. Removal of the TMS group with TBAF, and demethylation
with BBr3, gave the hydroxybiphenyl 9 in 75% yield. The chiral
(R)-2-octyloxy side chain was introduced via a Mitsunobu
inversion reaction to give 10 in 93% yield and >99% ee
according to chiral stationary phase HPLC analysis (Daicel
Chiralpak-AS, 2% IPA/hexanes). Subsequent conversion of the
Br group to OH was achieved via lithium-halogen exchange
followed by trapping with B(O-i-Pr)3 and peroxide oxidation
to give 11 in 88% yield. Protection of the OH group as a
methoxymethyl ether (94%) proved necessary for the subsequent
DreM to take place. Hence, cyclization of 12 was achieved by
treatment with 5 equiv of LDA at 0 °C, followed by warming
to room temperature to give the fluorenone 13 in 81% yield.
After demomylation in quantitative yield, esterification of 14
with 4-alkoxybenzoic acids with alkyl chain lengths ranging
from C8 to C12 using DCC gave a homologous series of five
chiral fluorenone esters (2a-e) in 95-99% yields. Chemose-
lective reduction of 2a-e with NaBH4 gave the corresponding
fluorenols 3a-e as mixtures of diastereomers in 89-92% yields.
The synthesis of the fluorenol 3d in diastereomerically pure
form was achieved by an indirect route. Recently, Velasco et
al. reported the asymmetric reduction of 1-substituted fluo-
renones with moderate enantioselectivities but in relatively poor
yields.31 Given the small amounts of fluorenones available for
There are two stereopolar units in 3 that can contribute to
the spontaneous polarization: the conventional (R)-2-octyloxy
side chain and the fluorenol core. In this design, the coupling
of the 2-octyloxy side chain to the fluorenol core is intended to
force these two stereopolar units to act cooperatively in produc-
ing a spontaneous polarization, and thus facilitate the assessment
of core contribution to the spontaneous polarization by compar-
ing PS values for the (R,R) and (S,R) diastereomers of 3. The
presence of the 2-octyloxy side chain ensures that a measurable
spontaneous polarization is indeed observed. In this paper, we
report the syntheses of the mesogenic fluorenones 2a-e and
fluorenols 3a-e as mixtures of (R,R) and (S,R) diastereomers,
and of the fluorenols (R,R)- and (S,R)-3d in diastereomerically
pure form, using a combined directed ortho metalation (DoM)
-directed remote metalation (DreM) strategy. The results
suggest that intermolecular hydrogen bonding stabilizes the
SmC* phase formed by 3a-e and that the chiral fluorenol core
contributes significantly to the spontaneous polarization.
Results and Discussion
Synthesis. Several methods have been reported for the
synthesis of substituted fluorenones, including Friedel-Crafts
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