Diastereofacial-selective synthesis of the trindane-based molecular scaffold cis,cis,cis-2,5,8-tribenzyltrindane-2,5,8-tricarboxylate and an arylamine analogue for the construction of C3v-symmetric architectures

Article abstract of DOI:10.1055/s-2007-990828

Efficient syntheses of potentially valuable C_3v-symmetric trindane-based triester scaffolds are reported. In the synthesis of 2,5,8-tribenzyltrindane-2,5,8-tricarboxylate by the benzylation of the corresponding triester by treatment with lithium diisopropylamide in tetrahydrofuran, the diastereoselectivity and yield of the cis,cis,cis- and cis,trans,trans-isomers depended primarily on the reaction temperature and the amount of hexamethylphosphoramide used as additive. High diastereofacial selectivity was achieved at -90°C in tetrahydrofuran, and the cis,cis,cis-isomer was obtained as the major product in 45% yield and in a diastereomeric ratio of 1.12. Under the same reaction conditions the 2,5,8-tris(4-bromobenzyl)trindane-2,5,8-tricarboxylate analogue was synthesized in 46% yield; it was efficiently converted into the 2,5,8-tris(4-aminobenzyl) trindane-2,5,8-tricarboxylate by palladium-catalyzed aromatic C-N bond formation by reaction with hexamethyldisilazide as nitrogen source in the presence of bis(dibenzylideneacetone)palladium with tri-tert-butylphosphine as catalyst in toluene. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990828

3290
PAPER
Diastereofacial-Selective Synthesis of the Trindane-Based Molecular Scaffold
cis,cis,cis-2,5,8-Tribenzyltrindane-2,5,8-tricarboxylate and an Arylamine
Analogue for the Construction of C3v-Symmetric Architectures
Synthesisof
Trind
e
ane-BasedM
u
olecular Sc
n
a
ffold
s
g-Jin Choi,* Jie Song, Chan Young An, Quoc-Thiet Nguyen, Hong-Seok Kim
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Fax +82(53)9505582; E-mail: choihj@knu.ac.kr
Received 9 July 2007; revised 8 August 2007
yl)benzene and was inefficient, especially in the diastere-
Abstract: Efficient syntheses of potentially valuable C3v-symmet-
ric trindane-based triester scaffolds are reported. In the synthesis of
2,5,8-tribenzyltrindane-2,5,8-tricarboxylate by the benzylation of
the corresponding triester by treatment with lithium diisopropyl-
ofacial-selective benzylation of triethyl trindane-2,5,8-
tricarboxylate (1). Previously, the diastereofacial-selec-
tive benzylation was achieved by formation of p-complex
amide in tetrahydrofuran, the diastereoselectivity and yield of the 3 from a chromium complex and triester 1, followed by
cis,cis,cis- and cis,trans,trans-isomers depended primarily on the
reaction temperature and the amount of hexamethylphosphoramide
decomplexation of the carbonylchromium complex after
alkylation (Scheme 1). Blocking of the central aromatic
used as additive. High diastereofacial selectivity was achieved at
ring by complexation with hexacarbonylchromium differ-
–90 °C in tetrahydrofuran, and the cis,cis,cis-isomer was obtained
entiates two diastereofaces, and this results in an en-
as the major product in 45% yield and in a diastereomeric ratio of
hanced yield of the desired all-cis-triester 2 in 68%
(Scheme 1). However, direct benzylation of the enolate of
triester 1 formed by treatment with lithium diisopropyl-
amide in tetrahydrofuran gave all-cis triester 2 in a low
yield (21%) of at –30 °C (Scheme 1).
1.12. Under the same reaction conditions the 2,5,8-tris(4-bro-
mobenzyl)trindane-2,5,8-tricarboxylate analogue was synthesized
in 46% yield; it was efficiently converted into the 2,5,8-tris(4-ami-
nobenzyl)trindane-2,5,8-tricarboxylate by palladium-catalyzed aro-
matic C–N bond formation by reaction with hexamethyldisilazide
as nitrogen source in the presence of bis(dibenzylideneacetone)pal-
ladium with tri-tert-butylphosphine as catalyst in toluene.
Key words: trindane, diastereofacial selectivity, benzylation, su-
pramolecular chemistry, receptors
CO2Et
a
O
O
Preorganized molecular structures with groups of appro-
priate affinity in well-defined orientations are important
for high selectivity and association in supramolecular
chemistry, and are especially useful in the field of molec-
ular recognition.1 A number of target molecules for mo-
lecular sensors have C3 symmetry, especially in anions
which have diverse geometries compared to most spheri-
cal cations.2 Receptors with C3 symmetry will efficiently
interact with C3-symmetrical anions such as nitrate, car-
bonate, chlorate, sulfate, and phosphate in a shape-selec-
tive manner.3 Complementary scaffolds with threefold
symmetry are popular as building blocks in supramolecu-
lar assemblies.4
OEt
OEt
EtO2C
CO2Et
O
1
2
OEt
b
O
OEt
c
Cr(CO)3
EtO
O
O
OEt
3
A novel C3v-symmetric molecular scaffold based on a trin-
dane backbone, providing concave and convergent preor-
Scheme 1 Reagents and conditions: (a) LDA, BnBr, THF, –30 °C,
21%; (b) Cr(CO)6, Bu2O–THF, reflux, 95%; (c) LDA, BnBr, THF,
ganized functional groups for supramolecular interaction, –30 °C, then I2, air, 68%.
was recently developed by our group.5 We have demon-
strated its use as an anion receptor with three urea ligands
Here we report the diastereofacial-selective synthesis of
that could strongly interact with the phosphate anion. The
synthesis of the key scaffold compound, triethyl
cis,cis,cis-2,5,8-tribenzyltrindane-2,5,8-tricarboxylate (2)
(Scheme 1) required seven steps from hexakis(halometh-
all-cis triester 2 by the direct benzylation of triester 1.
These reaction conditions could also be applied to the syn-
thesis of a potentially valuable C3v-symmetric trisaryl-
amine scaffold. The efficient syntheses developed for
these novel trindane scaffolds can be utilized in a variety
of applications, especially in the construction of supramo-
lecular assemblies.
SYNTHESIS 2007, No. 21, pp 3290–3294
x
x.
x
x
.
2
0
0
7
Advanced online publication: 16.10.2007
DOI: 10.1055/s-2007-990828; Art ID: F12707SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Trindane-Based Molecular Scaffolds
3291
Table 1 Effects of Solvent Additive and Temperature on the Yields
and Diastereoselectivities of 2 Prepared by Benzylation of 1a,b
Direct benzylation of 1 will produce the cis,cis,cis-2 iso-
mer in a maximum yield of 25% if the reaction is consid-
ered from a statistical point of view (Scheme 2), because
the planar tris(enolate) intermediate of 1 formed by lithi-
um diisopropylamide may react with benzyl bromide at
random. However, the characteristics of the reaction inter-
mediates formed during consecutive benzylation
(Scheme 2), and formation of the subsequent enolates as
well as product 2 may influence the selective formation of
cis,cis,cis-2 over cis,trans,trans-2 under specific reaction
conditions, although these characteristics might not be
readily rationalized. Preliminary experiments showed that
the yield of cis,cis,cis-2 formed by direct benzylation of
the enolate of 1 formed by treatment with lithium diiso-
propylamide in tetrahydrofuran varied from 21% at
–30 °C to around 30% at –78 °C. We therefore envisaged
that an enhanced yield of cis,cis,cis-2 could be achieved
by variation of reaction temperature and amount of addi-
tives to the reaction medium, for example hexameth-
ylphosphoramide, which stabilizes the enolates formed by
lithium diisopropylamide in tetrahydrofuran.
OEt
1) LDA
THF
O
O
O
O
1
+
2) BnBr
OEt
OEt
OEt
O
O
OEt
cis,cis,cis-2
OEt
cis,trans,trans-2
Temp
Solvent
HMPA–THF HMPA–THF HMPA–THF
THF
(5:95)
(10:90)
(15:85)
–30 °C
–50 °C
–78 °C
–90 °Cc
c,c,c: 21%
c,t,t: 55%
dr: 0.38
c,c,c: 28%
c,t,t: 52%
dr: 0.54
c,c,c: 36%
c,t,t: 58%
dr: 0.62
To investigate the reaction conditions, the reaction tem-
perature was varied from –30 °C to –50 °C, –78 °C, and
–90 °C, and the relative amount of hexamethylphosphor-
amide in tetrahydrofuran was also varied to 5%, 10%,
15%, and 20% (by volume) (Table 1).
c,c,c: 33%
c,t,t: 54%
dr: 0.61
c,c,c: 34%
c,t,t: 54%
dr: 0.63
c,c,c: 37%
c,t,t: 57%
dr: 0.65
c,c,c: 36%
c,t,t: 54%
dr: 0.67
c,c,c: 45%
c,t,t: 40%
dr: 1.13
c,c,c: 44%
c,t,t: 41%
dr: 1.07
CO2Et
a Reagents and conditions: 1 (0.3 mmol), LDA (4.5 equiv), BnBr (3.9
equiv), solvent (10 mL), 6 h.
1
b c,c,c = cis,cis,cis-2; c,t,t = cis,trans,trans-2; yields (%) are of isolat-
ed products, and are the averages of at least two runs; dr = diastereo-
meric ratio cis,cis,cis-2/cis,trans,trans-2.
EtO2C
CO2Et
–O
OEt
c Modified conditions: BnBr (9 equiv), 8 h.
LDA
As the reaction temperature was lowered, the yield of the
desired product cis,cis,cis-2 in tetrahydrofuran gradually
increased from 21% at –30 °C to 45% at –90 °C, and the
total yield of the isomers of 2 also increased from 76% at
–30 °C to 87% at –78 °C (Table 1). The total yield at
–90 °C was only 85%, compared to 87% at –78 °C
(Table 1); this is probably because the reaction tempera-
ture was too low for the reaction to proceed efficiently. It
is noticeable that as the reaction temperature was lowered
from –30 °C to –78 °C, the yield of the desired cis,cis,cis-
2 isomer increased, but the yield of the other diastereo-
mer, cis,trans,trans-2, was almost unvaried or slightly
decreased, resulting in the diastereomeric ratio cis,cis,cis-
2/cis,trans,trans-2 increasing from 0.38 at –30 °C to 0.61
at –78 °C (Table 1). The reaction at –90 °C gave, among
the reactions performed, the highest yield of cis,cis,cis-2,
namely 45%, and the diastereoselectivity reached 1.13
(Table 1), which means that the desired cis,cis,cis-2 dia-
stereomer become the major product at this low tempera-
ture. At temperatures above –78 °C the major product was
cis,trans,trans-2, which is apparently a thermodynamical-
ly more stable product than cis,cis,cis-2. However, at very
low temperatures, such as –90 °C, the other diastereomer
≡
BnBr
Bn
EtO
O–
OEt
O–
Bn
Bn
Bn
+
Bn
(50%)
(50%)
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
+
+
Bn
Bn
Bn
(25%)
Bn
(25%)
(25%)
(25%)
cis,trans,trans-2
cis,cis,cis-2
(75%)
(25%)
Scheme 2 Statistical yields of cis,cis,cis-2 and cis,trans,trans-2 iso-
mers resulting from consecutive benzylation of 1
Synthesis 2007, No. 21, 3290–3294 © Thieme Stuttgart · New York

3292
H.-J. Choi et al.
PAPER
Br
Br
NH2
NH2
cis,cis,cis-2 formed much faster than cis,trans,trans-2. It
suggests that the cis,cis,cis-2 isomer is a kinetic product
under the given reaction conditions.
Br
NH2
Even though it is difficult to estimate the stability of two
diastereomers without considering the solvent stabiliza-
tion, it is reasonable to rationalize that repulsive interac-
tions between the polar ester groups and between the
nonpolar benzyl groups might play an important role in
the relative stability of the two isomers, as expected from
the structure of cis,trans,trans-2. Polar solvation stabiliza-
tion is energetically favored at lower temperature, rather
than at higher temperature. At low temperature, attractive
solvation interactions between the polar tetrahydrofuran
solvent and the ester groups are enhanced, directing the
ester groups onto the same diastereoface during formation
of cis,cis,cis-2 from the enol intermediate of 2-benzyltrin-
dane-2,5,8-tricarboxylate at both the second and third
benzylation steps.
a
b
1
O
O
O
O
OEt
OEt
OEt
OEt
O
O
OEt
OEt
cis,cis,cis-5
cis,cis,cis-4
Scheme 3 Reagents and conditions: (a) LDA, PBBBr, THF,
–90 °C, 46%; (b) LHMDS, Pd(dba)2, t-Bu3P, THF, 50 °C, 67%.
isomer was obtained in 27% yield at –30 °C, 34% yield at
–50 °C, 37% yield at –78 °C, and 46% yield at –90 °C,
and the diastereoselectivity ratio cis,cis,cis-4/
cis,trans,trans-5 was 0.71 at –30 °C, 0.65 at –50 °C, 0.77
at –78 °C, and 1.05 at –90 °C. The additive hexameth-
ylphosphoramide similarly enhanced the total yield of 4 as
in the benzylation to prepare 2, but it also had no notice-
able effect on the diastereoselectivity. In 10% hexameth-
ylphosphoramide in tetrahydrofuran at –90 °C, the
desired cis,cis,cis-4 was obtained in up to 46% yield, just
comparable with the yield at –90 °C in tetrahydrofuran.
To increase the yield of the desired cis,cis,cis-2 diastereo-
mer, hexamethylphosphoramide, which has been used ex-
tensively in organolithium chemistry, was chosen as an
additive to the reaction medium. It enhances the rates of a
wide variety of organolithium reactions, and also has a
significant influence on regio- or stereochemistry.6 In the
5–15% hexamethylphosphoramide in tetrahydrofuran sol-
vent mixture at –78 °C, benzylation reactions of the eno-
late of 1 generated by lithium diisopropylamide were
generally enhanced to give the isomers of 2 in 88–94% to-
tal yield, but the diastereoselectivities were almost un-
affected at around 0.63–0.67 (Table 1). The 10%
hexamethylphosphoramide in tetrahydrofuran mixture
was the most effective mixed reaction medium, and lower
reaction temperatures led to increased diastereoselectivi-
ties, as in pure tetrahydrofuran, from 0.62 at –50 °C to
0.65 at –78 °C and 1.07 at –90 °C (Table 1). Although the
hexamethylphosphoramide additive increased the total
yield of 2, the diastereoselectivity was not affected signif-
icantly. The highest yield of the desired cis,cis,cis-2 iso-
mer amongst the reactions performed was 45%, and that
was in tetrahydrofuran alone at –90 °C (Table 1).
A number of useful and practical synthetic methods for
arylamines have been well developed recently, because of
their importance in a variety of fields, especially in phar-
maceuticals and electronic materials.7 To synthesize aryl-
amine scaffold 5 with its three primary aniline moieties
from tribromide 4 with its electrophilic ester groups re-
quires a highly efficient synthetic method for triple C–N
bond formation. One of the mildest and most convenient
synthetic methods to primary anilines from aryl halides is
palladium-catalyzed aromatic C–N bond formation, in
which hexamethyldisilazide is used in the presence of the
bis(dibenzylideneacetone)palladium [Pd(dba)2]/tri-tert-
butylphosphine catalytic system.8 Reaction of tribromide
4 with a slight excess of lithium hexamethyldisilazide in
the presence of 5 mol% of the catalyst bis(dibenzylidene-
acetone)palladium and tri-tert-butylphosphine (1:1) in
toluene gave, after 48 hours at 50 °C, tris(aniline) 5 clean-
ly in up to 67% yield after hydrolysis of the corresponding
silylamine; here the yield of 67% corresponds to 88%
yield for each C–N bond formation. The clean conversion
of tribromide 4 into tris(aniline) 5 demonstrates that this
method is very efficient for aryl bromide reactants with
multiple reaction sites, which require very high reaction
yields.
This highly diastereoselective synthesis allowed us to sep-
arate the desired product cis,cis,cis-2 from the minor dia-
stereomer cis,trans,trans-2 by means of fractional
crystallization. The practical and efficient reaction condi-
tions, easy workup procedure, and simple operation make
this method applicable to reaction on large scale, and the
product was synthesized in gram quantities, and isolated
in 30% yield as crystals from hexane–dichloromethane.
These reaction conditions were applied in the preparation
of C3v-symmetric tris(arylamine) scaffold 5 via 4-bro-
mobenzyl analogue 4 (Scheme 3). Derivative 5 is a poten-
tially valuable amine for a variety of applications,
especially for construction of supramolecular assemblies.
In summary, we have developed a synthetic method for
the useful C3v-symmetric scaffold 2 by temperature-con-
trolled diastereofacial-selective benzylation of triethyl
trindane-2,5,8-tricarboxylate (1). These efficient reaction
conditions could be extended to the synthesis of the
tris(bromobenzyl) analogue 4, which could be converted
into the C3v-symmetric tris(aniline) 5, potentially valuable
for a variety of applications.
The diastereofacial selectivity of the 4-bromobenzylation
of 1 to give cis,cis,cis-4 (Scheme 3) in tetrahydrofuran
was similar to that of the benzylation of 1 to give
cis,cis,cis-2 in tetrahydrofuran. The desired cis,cis,cis-4
Synthesis 2007, No. 21, 3290–3294 © Thieme Stuttgart · New York

PAPER
Synthesis of Trindane-Based Molecular Scaffolds
3293
All reagents were purchased from Sigma-Aldrich and used as re-
ceived. THF was freshly distilled from sodium–benzophenone un-
der N2. Compound 1 was prepared as described previously.5 TLC
analysis was performed on silica gel 60 F254 coated glass slides
(Merck). Chromatographic purifications were performed by flash
chromatography on 70–230 mesh silica gel (Merck). Reaction tem-
peratures at –30, –50 and –90 °C were regulated in an acetone bath
cooled by a Flexi-Cool immersion cooler from FTS systems, and
–78 °C was achieved in a dry ice–acetone bath. NMR data were ob-
tained at 400 (1H) and 100 MHz (13C) on a Bruker Avance Digital
400 spectrometer. Chemical shifts d are relative to TMS or residual
undeuterated solvent. Infrared spectra were recorded on a Shimadzu
IR Prestige-21 spectrometer. HRMS spectra were obtained in ESI
positive scan mode on a Q-TOF Premier mass spectrometer from
Waters. Elemental analyses were performed by Kyungpook Center
for Scientific Instruments.
Anal. Calcd for C45H48O6: C, 78.92; H, 7.06. Found: C, 78.88; H,
7.12.
Triethyl cis,trans,trans-2,5,8-Tribenzyltrindane-2,5,8-tricar-
boxylate (cis,trans,trans-2)
Mp 79.0–80.8 °C; Rf = 0.37 (silica gel, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.17–7.29 (m, 10 H), 7.03–7.10
(m, 5 H), 4.17 (q, J = 7.2 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 4 H), 3.20–
3.30 (m, 6 H), 3.06 (d, J = 13.6 Hz, 2 H), 3.00 (s, 2 H), 3.00 (d,
J = 13.6 Hz, 2 H), 2.93–2.83 (m, 6 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.23
(t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 176.4, 176.3, 137.88, 137.86,
135.48, 135.43, 135.37, 129.7, 128.2, 126.6, 60.8, 56.0, 55.8, 43.81,
43.76, 40.1, 40.0, 39.7, 14.22, 14.18.
Triethyl cis,cis,cis-2,5,8-Tris(4-bromobenzyl)trindane-2,5,8-tri-
carboxylate (cis,cis,cis-4)
Mp 141.0–142.8 °C; Rf = 0.43 (silica gel, CH2Cl2).
IR (KBr): 3008, 2947, 1750, 1252 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39 (d, J = 8.4 Hz, 6 H), 6.98 (d,
J = 8.4 Hz, 6 H), 4.12 (q, J = 7.2 Hz, 6 H), 3.22 (d, J = 15.6 Hz, 6
H), 2.99 (s, 6 H), 2.82 (d, J = 15.6 Hz, 6 H), 1.22 (t, J = 7.2, 9 H).
13C NMR (100 MHz, CDCl3): d = 176.0, 136.8, 135.2, 131.32,
131.27, 120.7, 60.9, 55.5, 43.2, 39.9, 14.2.
HRMS (ESI): m/z (%) [M + Na]+ calcd for C45H45Br3O6: 941.0664
(30.8), 942.0698 (15.7), 943.0648 (94.1), 944.0679 (46.6),
945.0634 (100), 946.0661 (46.9), 947.0630 (40.9), 948.0648 (16.8);
found: 941.0609 (35), 942.0858 (18), 943.0662 (99), 944.0695 (51),
945.0735 (100), 946.0553 (57), 947.0603 (46), 948.0546 (41).
Determination of Yield and Diastereofacial Selectivity; General
Procedure
Reactions were conducted in septum-capped, 25-mL, oven-dried
flasks under N2. All additions were performed with vacuum-dried
gas-tight syringes and oven-dried disposable plastic syringes. The
yields reported for the final products in Table 1 are isolated yields
and are the averages of at least two runs. The cis,cis,cis-2/
cis,trans,trans-2 diastereoselectivity ratios of the reaction mixtures
were also examined and confirmed from the 1H NMR spectra, be-
1
side those of the isolated products. The d = 2.95–3.10 H NMR
spectral region showing the methylene groups of the benzyl moi-
eties of the two diastereomers were analyzed by deconvolution of
the peaks: cis,cis,cis-2 shows a singlet at d = 3.04 and
cis,trans,trans-2 shows five peaks at d = 2.98, 3.00, 3.01, 3.04, and
3.09.
Anal. Calcd for C45H45Br3O6: C, 58.65; H, 4.92. Found: C, 58.41;
H, 4.95.
Synthesis of 2,5,8-Tribenzyltrindane-2,5,8-tricarboxylates 2;
Typical Procedure
Triethyl cis,trans,trans-2,5,8-Tris(4-bromobenzyl)trindane-
2,5,8-tricarboxylate (cis,trans,trans-4)
Mp 45.5–49.8 °C; Rf = 0.67 (silica gel, CH2Cl2).
LDA (2.0 M in heptane–THF–ethylbenzene; 0.68 mL, 1.35 mmol)
was added by syringe to a soln of 1 (125 mg, 0.3 mmol) in HMPA–
THF (10 mL) cooled at the appropriate temperature. After the mix-
ture had stirred for 60 min, BnBr (140 mL, 1.17 mmol) was added
dropwise by syringe. [For the addition of solid PBBBr, PBBBr (292
mg, 1.17 mmol) was dissolved in THF (2 mL) and the soln was add-
ed.] After the soln had stirred for 6 h, it was quenched by the addi-
tion of sat. aq NH4Cl (2 mL). The mixture was allowed to warm to
r.t., and additional aq NH4Cl (10 mL) was added. The organic layer
was separated and the aqueous layer was extracted with Et2O (2 ×
10 mL). The combined organic fraction was then washed with sat.
aq NaCl (15 mL), dried (MgSO4, 10 min), filtered under reduced
pressure, and concentrated on a rotary evaporator. The diastere-
omers were then separated and purified by flash column chromatog-
raphy (silica gel, CH2Cl2–MeOH, 95:5). (CH2Cl2 was used as eluent
for product 4.) For the reactions at –90 °C, excess BnBr or PBBBr
(2.7 mmol) was added, and longer reaction times were used (up to
8 h).
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 8.0 Hz, 4 H), 7.37 (d,
J = 8.4 Hz, 2 H), 6.95 (d, J = 8.0 Hz, 4 H), 6.92 (d, J = 8.4 Hz, 4 H),
4.17 (q, J = 7.0 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 4 H), 3.29–3.19 (m, 6
H), 3.02 (d, J = 13.6 Hz, 2 H), 2.96 (s, 2 H), 2.93 (d, J = 13.6 Hz, 2
H), 2.87–2.78 (m, 6 H), 1.27 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.2 Hz,
6 H).
13C NMR (100 MHz, CDCl3,): d = 176.00, 175.98, 136.79, 136.76,
135.39, 135.32, 135.21, 131.31, 131.30, 131.26, 131.25, 120.64,
60.90, 55.85, 55.66, 43.10, 43.02, 40.34, 39.96, 39.59, 14.25, 14.19.
Large Preparative-Scale Syntheses of cis,cis,cis-2 and cis,cis,cis-
4
The reactions were carried out on tenfold scale for 4 and on 20-fold
scale for 2, and were allowed to run for longer time periods.
cis,cis,cis-2
Triethylcis,cis,cis-2,5,8-Tribenzyltrindane-2,5,8-tricarboxylate
(cis,cis,cis-2)
LDA (2 M in heptane–THF–ethylbenzene; 13.5 mL, 27 mmol) was
added dropwise by syringe to a soln of 1 (2.49 g, 6 mmol) in THF
(180 mL) cooled at –90 °C under N2. After the mixture had stirred
for 60 min, BnBr (4.4 mL, 36 mmol) was added dropwise by sy-
ringe. The soln was allowed to stir for 15 h and was then quenched
by the addition of sat. aq NH4Cl (10 mL). After the mixture had
warmed to r.t., additional aq NH4Cl (90 mL) was added. The organ-
ic layer was separated, dried (MgSO4, 10 min), filtered under re-
Mp 120.5–122.0 °C; Rf = 0.20 (silica gel, CH2Cl2).
IR (KBr): 3026, 2925, 1720, 1202 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.10 (m, 15 H), 4.13 (q,
J = 7.1 Hz, 6 H), 3.22 (d, J = 15.9 Hz, 6 H), 3.04 (s, 6 H), 2.88 (d,
J = 15.9 Hz, 6 H), 1.21 (t, J = 7.1 Hz, 9 H).
13C NMR (100 MHz, CDCl3): d = 176.3, 137.9, 135.3, 129.7, 128.2,
126.6, 60.8, 55.7, 43.8, 39.9, 14.2.
HRMS (ESI): m/z (%) [M + H]+ calcd for C45H48O6: 685.3529
(100), 686.3563 (51.0), 687.3595 (13.9), 688.3625 (2.7); found:
685.3516 (100), 686.3594 (54), 687.3594 (15).
duced pressure, and concentrated on
a rotary evaporator.
Purification of the residue by short-column chromatography (silica
gel, hexane–CH2Cl2, 6:4) removed most of the cis,trans,trans-2 dia-
stereomer. The major diastereomer cis,cis,cis-2 eluted with the
Synthesis 2007, No. 21, 3290–3294 © Thieme Stuttgart · New York

3294
H.-J. Choi et al.
PAPER
CH2Cl2. Concentration and recrystallization (hexane–CH2Cl2) of
this fraction gave the product as needle-shaped crystals.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD, Basic Research
Promotion Fund) (KRF-2006-521-C00101 and KRF-2005-211-
C00082).
Yield: 1.2 g (30%).
cis,cis,cis-4
LDA (2 M in heptane–THF–ethylbenzene; 6.8 mL, 13.6 mmol) was
added dropwise by syringe to a soln of 1 (1.25 g, 3 mmol) in THF
(90 mL) cooled at –90 °C under N2. After the mixture had stirred for
60 min, a soln of PBBBr (4.50 g, 18 mmol) in THF (30 mL) was
added dropwise by syringe. The soln was allowed to stir for 15 h and
was then quenched by the addition of sat. aq NH4Cl (10 mL). After
the mixture had warmed to r.t., additional aq NH4Cl (90 mL) was
added. The organic layer was separated, dried (MgSO4, 10 min), fil-
tered under reduced pressure, and concentrated on a rotary evapora-
tor. Purification of the residue by column chromatography (silica
gel, CH2Cl2) gave the product cis,cis,cis-4 as a slightly yellowish
solid.
References
(1) (a) Lehn, J.-M. Supramolecular Chemistry: Concepts and
Perspectives; VCH: New York, 1995. (b) Beer, P. D.; Gale,
P. A.; Smith, D. K. Supramolecular Chemistry; Oxford
University Press: New York, 1999. (c) Steed, J. W.;
Atwood, J. L. Supramolecular Chemistry; Wiley: New
York, 2000.
(2) For a recent review, see: Kuswandi, B.; Nuriman; Verboom,
W.; Reinhoudt, D. N. Sensors 2006, 6, 978.
(3) For some recent examples, see: (a) Kim, S.-G.; Kim, K.-H.;
Jung, J.; Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2002,
124, 591. (b) Kim, Y.-K.; Ha, J.; Cha, G. S.; Ahn, K. H. Bull.
Korean Chem. Soc. 2002, 23, 1420. (c) Sasaki, S.; Ozawa,
S.; Citterio, D.; Iwasawa, N.; Suzuki, K. Anal. Sci. 2001, 17,
i1659. (d) Sasaki, S.; Citterio, D.; Ozawa, S.; Suzuki, K. J.
Chem. Soc., Perkin Trans. 2 2001, 2309. (e) Beer, P. D.;
Gale, P. A. Angew. Chem. Int. Ed. 2001, 40, 486. (f) Seong,
H. R.; Kim, D.-S.; Kim, S.-G.; Choi, H.-J.; Ahn, K. H.
Tetrahedron Lett. 2004, 45, 723. (g) Hettche, F.; Hoffmann,
R. W. New J. Chem. 2003, 27, 172. (h) Berrocal, M. J.;
Cruz, A.; Badr, I. H. A.; Bachas, L. G. Anal. Chem. 2000, 72,
5295.
(4) (a) Schopohl, M. C.; Faust, A.; Mirk, D.; Fröhlich, R.;
Kataeva, O.; Waldvogel, S. R. Eur. J. Org. Chem. 2005,
2987. (b) Haberhauer, G.; Oeser, T.; Rominger, F. Chem.
Eur. J. 2005, 11, 6718. (c) Haberhauer, G.; Oeser, T.;
Rominger, F. Chem. Commun. 2004, 2044. (d) Hennrich,
G.; Lynch, V. M.; Anslyn, E. V. Chem. Eur. J. 2002, 8,
2274. (e) Sonntag, L.-S.; Ivan, S.; Langer, M.; Conza, M.
M.; Wennemers, H. Synlett 2004, 1270.
(5) Choi, H.-J.; Park, Y. S.; Yun, S. H.; Kim, H.-S.; Cho, C. S.;
Ko, K.; Ahn, K. H. Org. Lett. 2002, 4, 795.
(6) For reviews, see: (a) Reichardt, C. Solvent and Solvent
Effects in Organic Chemistry; VCH: Weinheim, 1988, 17.
(b) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27,
1624. (c) Normant, H. Angew. Chem., Int. Ed. Engl. 1967, 6,
1046.
(7) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
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2797.
Yield: 1.27 g (46%).
Triethyl cis,cis,cis-2,5,8-Tris(4-aminobenzyl)trindane-2,5,8-tri-
carboxylate (cis,cis,cis-5)
A 25-mL round-bottom flask containing 4 (185 mg, 0.2 mmol) was
loaded with Pd(dba)2 (17.3 mg, 0.03 mmol), t-Bu3P (9 mL, 0.03
mmol), and LHMDS (0.8 mL, 0.8 mmol), followed by toluene (12
mL) under N2. The soln was heated at 50 °C for 48 h. The solvent
was removed on a rotary evaporator, and the residue was dissolved
in CH2Cl2 (20 mL). The mixture was washed with 1 M aq HCl (10
mL) followed by sat. aq NaHCO3 (2 × 5 mL). The organic layer was
separated, dried (MgSO4, 10 min), filtered under reduced pressure,
and concentrated on a rotary evaporator. Purification of the residue
by flash column chromatography (silica gel, CH2Cl2–MeOH, 96:4)
gave the product as a slightly yellowish solid.
Yield: 97 mg (67%); Rf = 0.37 (CH2Cl2–MeOH, 95:5).
IR (KBr): 3405, 3372, 2978, 2924, 1716, 1624, 1516, 1184, 733
cm–1.
1H NMR (400 MHz, CDCl3): d = 6.89 (d, J = 8.4 Hz, 6 H), 6.59 (d,
J = 8.4 Hz, 6 H), 4.13 (q, J = 7.2 Hz, 6 H), 3.65 (br s, 6 H), 3.18 (d,
J = 15.5 Hz, 6 H), 2.92 (s, 6 H), 2.85 (d, J = 15.5 Hz, 6 H), 1.23 (t,
J = 7.2, 9 H).
13C NMR (100 MHz, CDCl3): d = 176.9, 145.3, 135.7, 130.9, 128.2,
115.3, 61.0, 56.2, 43.5, 40.1, 14.6.
HRMS (ESI): m/z (%) [M + H]+ calcd for C45H51N3O6: 730.3856
(100), 731.3889 (52.2), 732.3920 (14.5), 733.3949 (2.8); found:
730.3873 (100), 731.3919 (62), 732.3971 (20). 733.3831 (6).
Anal. Calcd for C45H51N3O6: C, 74.05; H, 7.04; N, 5.76. Found: C,
73.87; H, 7.10; N, 5.85.
Synthesis 2007, No. 21, 3290–3294 © Thieme Stuttgart · New York