Solid-phase combinatorial synthesis of ester-type banana-shaped molecules by sequential palladium-catalyzed carbonylation

Article abstract of DOI:10.1039/b901788g

16 five-ring ester-type Br-substituted banana-shaped molecules were synthesized in a combinatorial manner using palladium-catalyzed carbonylative esterification on a polymer-support and their mesophase behavior was investigated. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b901788g

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COMMUNICATION
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Solid-phase combinatorial synthesis of ester-type banana-shaped
molecules by sequential palladium-catalyzed carbonylationw
Masahito Yoshida,ab Takayuki Doi,ab Sungmin Kang,c Junji Watanabec
and Takashi Takahashi*a
Received (in Cambridge, UK) 27th January 2009, Accepted 26th February 2009
First published as an Advance Article on the web 23rd March 2009
DOI: 10.1039/b901788g
16 five-ring ester-type Br-substituted banana-shaped molecules
were synthesized in a combinatorial manner using palladium-
catalyzed carbonylative esterification on a polymer-support and
their mesophase behavior was investigated.
by palladium-catalyzed carbonylative esterification of aryl
iodides B–E with polymer-supported phenols. Aryl iodides
can be used as masked activated esters in the presence of a
palladium catalyst under a carbon monoxide atmosphere as
we previously reported.3 We planned that the fragment A can
be added onto a polymer-support via a silyl linker that could
be displaced with a halogen atom in the final stage of the
synthesis of 1. After acylation of polymer-supported phenol 5
with alkoxyphenyl iodide B by palladium-catalyzed carbonyl-
ation, selective deprotection of phenol and carbonylation can
be sequentially performed using aryl iodides C, D and E to
afford 4. Displacement of the silyl linker in 4 with Br2 would
lead to the desired 1 by electrophilic substitution. According to
this strategy, four alkyl chains (C2, C4, C6 and C8) will be
independently introduced in the side wings toward the combi-
natorial synthesis of a 16-member library of 1.
Combinatorial chemistry has been exploited in broad area of
research fields. Since a split & pool method using a solid-support
enables a high speed synthesis of a variety of compounds, such
libraries of compounds have been applied to exploration for
drugs, catalysts, materials, and so on.1,2 We have reported that
palladium-catalyzed carbonylation is efficiently performed on
solid-phases3 and is utilized for combinatorial syntheses of liquid
crystals4 as well as natural products, such as macrosphelide.5 In
this study, Br-substituted banana-shaped molecules 1 that
possess four phenol ester linkages were synthesized by way of
palladium-catalyzed carbonylative esterification on a polymer-
support.
Attachment of resorcinol A onto a polymer-support using a
silyl linker was investigated (Scheme 2). Direct attachment of
A to the polymer-support was unsuccessful either by addition
of the corresponding lithiated derivative to the polymer-
supported chlorosilane15 or by palladium-catalyzed coupling
of aryl bromide with the polymer-supported trialkylsilane.16
Therefore, the rearrangement of trialkyl(2-bromophenoxy)-
silane 7 was carried out. Commercially available PS-DES resin
(6) was converted to the corresponding silyl triflate, which was
treated with phenol A to afford 7.17 The loading amount of 7
was determined to be 0.5 mmol/g-resin by gravimetric analysis
Banana-shaped molecules P-n-O-PIMB (2a) possessing two
phenol ester and two imine linkages exhibits ferroelectric and
antiferroelectric properties even though it is achiral (Fig. 1).6
We have already reported a combinatorial synthesis of
banana-shaped molecules 4Br-P-n-O-PIMB (2b), 4Cl-P-n-O-PIMB
(2c) and 5Cl-P-n-O-PIMB (2d) having halogen atoms on the
phenyl ring in the central core7 and unsymmetrical P-(m,n)-O-
PIMB (3) having flexible alkyl chains with different lengths on
both side wings.8 Interestingly, the mesomorphic behavior and
mesophase structures of the 4Br-P-n-O-PIMB (2b) homo-
logous series differ from those of the parent P-n-O-PIMB
(2a) homologues.7,9 Recently, it was found that the analogues
in which all five benzene rings are connected by ester linkages
also exhibit mesophase behavior similarly as 2.10–12 We
became interested in the development of a facile synthetic
method for a variety of banana-shaped molecules 1 that have a
halogen substituent at the central core, four phenol ester
linkages, and alkyl chains with the different lengths at the side
wings.13,14
We divided 1 into five fragments A–E as illustrated in
Scheme 1. All phenol ester linkages in 1 can be constructed
a Department of Applied Chemistry, Tokyo Institute of Technology,
2-12-1 Ookayama, Meguro, Tokyo, 152-8552, Japan.
E-mail: ttak@apc.titech.ac.jp; Fax: (+81) 3 5734-2884;
Tel: (+81) 3 5734-2120
b Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
c Department of Organic and Polymeric Materials, Tokyo Institute of
Technology, 2-12-1 Ookayama, Meguro, Tokyo, 152-8552, Japan
w Electronic supplementary information (ESI) available: Experimental
1
details and H NMR spectra. See DOI: 10.1039/b901788g
Fig. 1 Five-ring banana-shaped liquid crystals.
ꢀc
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Scheme 1 Synthetic strategy for the solid-phase synthesis of a
16-member combinatorial library of banana-shaped molecules 1(m,n)
repeatedly utilizing palladium-catalyzed carbonylation of aryl iodides
B, C, D1–D4 and E1–E4.
Scheme 3 Reagents and conditions: (i) B (0.3 M), Pd(PPh3)4 (0.01 M),
NEt3 (0.4 M), DMAP (0.1 M), CO (30 atm), DMF, 80 1C, 48 h;
(ii) CSA (0.1 M), THF–MeOH (2 : 1), rt, 4 h; (iii) C (0.2 M), Pd(PPh3)4
(0.01 M), NEt3 (0.3 M), DMAP (0.1 M), DMF, 48 h; (iv) D1 (n = 8)
(0.2 M), Pd(PPh3)4 (0.01 M), NEt3 (0.3 M), DMAP (0.1 M), DMF,
80 1C, 48 h; (v) 20% TFA–CH2Cl2, rt, 3 h; (vi) (a) BzCl (0.2 M),
DMAP (0.3 M), CH2Cl2, rt, 4 h, (b) Br2–CH2Cl2, rt, 30 min.
Toward the completion of the solid-phase synthesis of 1,
acylation of the left wing in 14 by the carbonylative esterifica-
tion using fragment E1 (m = 2) was investigated (Scheme 4).
The reaction was initially attempted under the same reaction
conditions described above [Pd(PPh3)4/Et3N/DMAP/DMF,
80 1C, 48 h, CO (30 atm)]. Surprisingly, 1 (2,2) having C2
chains in the both side wings was obtained after cleavage from
the polymer-support (Br2–CH2Cl2). It is conceivable that
trans-esterification of the initial product 16 with the
Scheme 2 Reagents and conditions: (i) (a) TMSCl (0.3 M), CH2Cl2, rt,
1 h (b) TfOH (0.2 M), CH2Cl2, rt, 30 min, (c) A (0.2 M), 2,6-lutidine
(0.4 M), CH2Cl2, rt, 12 h; (ii) BuLi (0.3 M), THF, À78 1C, 1.5 h;
(iii) (a) CSA (0.1 M), THF–MeOH (2 : 1), rt, 4 h, (b) BzCl (0.2 M),
DMAP (0.3 M), CH2Cl2, rt, 4 h, (c) Br2–CH2Cl2, rt, 30 min.
after acid cleavage. Lithiation of 7 with BuLi at À78 1C
induced 1,3-silyl rearrangement to provide the desired
polymer-supported trialkylsilylphenol 5.18 Removal of the
THP group, dibenzoylation of the resulting resorcinol with
BzCl, and displacement of the silyl group using Br2 afforded 8
in 96% yield from 7.19,20
The first acylation of polymer-supported phenol 5 by the
palladium-catalyzed carbonylation of the fragment B was
performed using Et3N/DMAP in the presence of Pd(PPh3)4
at 80 1C for 48 h under 30 atm of CO (Scheme 3).3 The THP
group in the central core of 9 was selectively removed under
mild acidic conditions (PPTS/MeOH/THF, 24 h). The second
acylation of 10 by the carbonylation of the fragment C was
carried out under the same reaction conditions described
above. After selective removal of the THP group in 11, the
third acylation of 12 was performed using the fragment D4
(n = 8) in the same manner to provide four-ring bent core
compound 13. The MEM group in 13 was removed by
treatment with 20% TFA–CH2Cl2. Benzoylation of 14 with
BzCl–DMAP, followed by treatment with Br2 provided 15 in
84% overall yield.
Scheme 4 The final step for the solid-phase synthesis of banana-
shaped molecule 1(2,8) by way of palladium-catalyzed carbonylation.
Reagents and conditions: (i) E1 (m = 2) (0.2 M), Pd(PPh3)4 (0.01 M),
NEt3 (0.3 M), DMAP (0.1 M), CO (30 atm), DMF, 48 h;
(ii) Br2–CH2Cl2, rt, 30 min.
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acylpalladium intermediate formed from E1 (m = 2) would
occur in the presence of base under heating conditions leading
to 17. After optimization of the reaction conditions, it was
found that the trans-esterification was suppressed when the
reaction was carried out at room temperature. Ultimately, the
desired five-ring bent molecule 1(2,8) was provided in 65%
overall yield with 94% selectivity.
significant when compared with symmetric 1(m = n). More
interestingly, it has been found that for the compounds with a
big difference between m and n, for example (8,2), (2,8) and
(6,2), an additional nematic phase (N) could be derived over the
smectic range. In addition to the report that a nematic phase
could be obtained by an increase of bending angle,22 this
clearly indicates that the appearance of a nematic phase for
bent-shaped molecules can also be achieved by a significant
unsymmetrical effect in the length of the terminal alkyl moieties.
In summary, we have demonstrated the rapid synthesis of a
16-member combinatorial library of ester-type Br-substituted
On the basis of the above solid-phase synthesis, we
constructed a 16-member combinatorial library of ester-type
banana-shaped molecules 1 by a split & pool method utilizing
radiofrequency tags.21 Sixteen MicroKanst each containing
30 mg of PS-DES resin (6) were pooled and used together in a
single flask in the synthesis of 12. Then, the MicroKans were
decoded and split into four parts. The carbonylation of fragment
D1–D4 with 12 was performed in four individual autoclaves and
the MicroKans were pooled together for washing and drying.
After removal of the MEM group in a single flask, the
MicroKans were decoded and split into four parts. The
carbonylation of E1–E4 was accomplished in four individual
autoclaves and the MicroKans were pooled for washing and
drying. Finally, the sixteen MicroKans were decoded and were
treated with Br2 in parallel. After purification of the crude
products by gel permeation chromatography (GPC), a 16-member
library of banana-shaped molecules 1(m,n) (m = 2, 4, 6, 8 and
n = 2, 4, 6, 8) were isolated in 41–90% overall yields. The
phase transition behaviors of all synthetic compounds 1(m,n)
measured on cooling by using a polarized optical microscopy
(POM) are summarized in Table 1.
banana-shaped molecules
1 utilizing palladium-catalyzed
carbonylation on a polymer-support and preliminary results
on their mesophase behavior. This synthetic method can apply
to the introduction of a halogen atom in the central core and
modification of the side wings including alkyl chain lengths in
both sides, individually. We are currently investigating the
properties of the library 1.
This work was supported by Special Coordination Funds
for Promoting Science and Technology from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Notes and references
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(2,4)
(4,2)
(4,4)
(2,6)
(6,2)
(2,8)
(8,2)
(4,6)
(6,4)
(6,6)b
(4,8)
(8,4)
(6,8)
(8,6)
(8,8)b
82
53
49
90
61
67
65
73
50
49
85
61
63
53
41
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ꢀc
This journal is The Royal Society of Chemistry 2009
2758 | Chem. Commun., 2009, 2756–2758