Suzuki-Miyaura cross-coupling and ring-closing metathesis: A strategic combination for the synthesis of cyclophane derivatives

Article abstract of DOI:10.1002/ejoc.200600549

The synthesis of cyclophane derivatives through a sequence involving Suzuki-Miyaura cross-coupling between α,α′-dibromo-m-xylene and arylboronic acid derivatives, alkenylation and ring-closing metathesis has been achieved. One of the cyclophanes was obtai

Full text of DOI:10.1002/ejoc.200600549

FULL PAPER
DOI: 10.1002/ejoc.200600549
Suzuki–Miyaura Cross-Coupling and Ring-Closing Metathesis: A Strategic
Combination for the Synthesis of Cyclophane Derivatives
Sambasivarao Kotha*[a] and Kalyaneswar Mandal[a]
Keywords: Cyclophanes / Isomerization / Olefin metathesis / Palladium / Ruthenium / Suzuki–Miyaura cross-coupling
The synthesis of cyclophane derivatives through a sequence
involving Suzuki–Miyaura cross-coupling between α,αЈ-di-
bromo-m-xylene and arylboronic acid derivatives, alkenyl-
ation and ring-closing metathesis has been achieved. One of
the cyclophanes was obtained by tandem isomerization and
metathesis. Significant magnetic anisotropic effects on the
intra-annular hydrogen atoms were observed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Ruthenium-catalysed metathesis and palladium-catalysed
cross-coupling reactions have recently made a profound im-
pact on carbon–carbon bond formation in organic synthe-
sis. In particular, with the advent of the commercially avail-
able and well defined metal carbene complexes[1] (Figure 1)
of Grubbs (e.g., 1 and 2) and Schrock (e.g., 3), metathesis
has attracted renewed interest and has been quickly ac-
cepted into the mainstream of organic synthesis.[2] These
catalysts function under mild reaction conditions and exhi-
bit a wide range of functional group tolerance, and these
advances have opened up a completely new set of possibil-
ities in organic synthesis. Of the various modes of olefin
metathesis, the intramolecular version (i.e., ring-closing me-
tathesis, RCM) has become more popular than other me-
tathesis processes. RCM is a powerful tool for the construc-
tion of small (Ն5 members), medium and large carbocyclic
(or heterocyclic) ring systems starting from acyclic precur-
sors.[3]
Similarly, of the various Pd-catalysed cross-coupling re-
actions, the Suzuki–Miyaura (SM) cross-coupling reaction
is one of the most efficient methods for the construction of
C–C bonds.[4] The preferred status of the SM cross-coup-
ling reaction over other Pd-catalysed cross-coupling reac-
tions is not coincidental: its key advantages are its mild re-
action conditions and the commercial availability of diverse
boronic acids, which are also environmentally safer than
other organometallic reagents. In addition, the handling
and removal of boron-containing by-products are easier
than those associated with the use of other organometallic
reagents, especially in large-scale syntheses. The combina-
Figure 1. Commonly used olefin metathesis catalysts.
tion of these two powerful tools should therefore open up
new and short synthetic routes to various complex targets.
A cyclophane is defined as a molecule containing a
bridged aromatic ring and usually contains a molecular cav-
ity of varied size. Cyclophanes, subjects of investigations
since the 1950s, are useful model systems for studying
through-space interactions,[6] have also found many applica-
tions in supramolecular chemistry, metal ion transport and
catalysis, and represent intricate resources for a variety of
host–guest interactions,[7] as a result of which there is a con-
tinuous need to develop new and simple strategies for their
synthesis. Several such strategies have been developed over
the years, but methods for the synthesis of cyclophanes
based on the usage of metathesis, Suzuki–Miyaura (SM)
cross-coupling or combinations of these two reactions are
limited.
Very few groups have successfully employed metathesis
as a key step for the synthesis of cyclophane derivatives,[8]
application of SM cross-coupling for the synthesis of cy-
clophanes is less explored than that of metathesis,[9] whilst
reports involving a combination of metathesis and SM
coupling are rare in organic synthesis. Guan and co-workers
were the first to use the combination of palladium-catalysed
SM cross-coupling and RCM for the efficient synthesis of
[a] Department of Chemistry, Indian Institute of Technology,
Bombay
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: srk@chem.iitb.ac.in
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S. Kotha, K. Mandal
FULL PAPER
m-terphenyl-based cyclophane, with the aid of Grubbs’ 2nd
generation catalyst 2.[10]
Here we report a simple and straightforward synthetic
strategy for cyclophane derivatives using the SM cross-
coupling reaction and RCM as key steps. The strategy
adopted in our study is shown in Scheme 1. The prelimi-
nary results of this research were published elsewhere.[5]
Scheme 3. The reaction was conducted with boronic acid
(1.5 equiv. for each bromine atom in the substrate), Pd(PPh3)4 (10–
15 mol-%).
Table 2. Suzuki cross-coupling reactions between 7 and various
functionalized boronic acids.
Entry Boronic acids
R
Products
Yield[a] (%)
Scheme 1. Synthetic strategy for cyclophane synthesis.
i
ii
iii
5a
5b
5c
p-OMePh
p-CHOPh
p-CNPh
8a
8b
8c
61
70
82
[a] Isolated yields.
Results and Discussion
In an attempted synthesis of the target cyclophane 11,
compound 6a was allylated by treatment with allyl bromide
in the presence of indium (Scheme 4)[13] and the diol 9 was
then subjected to RCM in the presence of Grubbs’ 1st gen-
eration catalyst 1, giving a complex mixture of products.
However, use of the 2nd generation catalyst 2 under high-
dilution conditions (0.001 ) at room temp. delivered the
cyclophane derivative 10 as a mixture of diastereomers (1:2;
In general, the majority of SM cross-coupling reactions
described so far have been associated with the coupling of
aryl halides with arylboronic acids. The use of benzyl bro-
mides as SM coupling partners, however, is less well ex-
plored.[11]
To test the feasibility of the first step in our strategy,
various functionalized boronic acids were coupled with the
two-armed benzyl bromide 4 (Scheme 2). We found that 4
would react with various boronic acids in the presence of
the palladium catalyst [Pd(PPh3)4] to generate the required
cross-coupling products in good yields (Table 1).[12]
1
determined by H NMR integration) in 47% yield.[14] The
lower yield could be accounted for by the formation of vari-
ous oligomeric side products during the macrocyclization
reaction, as reported earlier.[2] The successful formation of
10 was indicated by its 1H NMR spectroscopic data, whilst
the molecular ion peak at m/z = 393 [M + Na] in the mass
spectrum further confirmed the structure of the desired cy-
clophane derivative. Subsequent PCC oxidation of the
above mixture gave cyclophane 11, the structure of which,
with the assigned trans geometry, was confirmed by X-ray
crystallographic data.[5] The crystal structure of 11 reveals
that in the solid state arrangement, the ethylene bridge is
disordered with an averaged population of 70:30, perhaps
due to the availability of void space. Further, this disorder
is dynamic in nature, as the crystals did not show any disor-
der when cooled to 133 K.
Scheme 2. The reaction was conducted with the boronic acid
(1.5 equiv. for each bromine atom in the substrate), Pd(PPh3)4 (6–
10 mol-%).
Table 1. Suzuki cross-coupling reactions between 4 and various
functionalized boronic acids.
To generalize the method, we turned our attention to the
preparation of the higher analogues of 11 as depicted in
Scheme 5. The RCM precursor 12 was prepared by Grig-
nard treatment of 6b with 4-bromobut-1-ene in 71% yield,
and exposure of the diolefinic compound 12 to Grubbs’ 2nd
generation catalyst 2 in dichloromethane under high-di-
lution conditions (0.001 ) at room temp. resulted in the
formation of the cyclophane derivative 13 (1:1.7; mixture of
Entry
Boronic acids
R
Products
Yield[a] (%)
i
5a
5b
5c
5d
p-OMePh
p-CHOPh
p-CNPh
p-AcPh
6a
6b
6c
6d
32
ii
iii
iv
80
84[b]
71[b]
[a] Isolated yields. [b] Purification was carried out by repeated
recrystallization after column chromatography.
1
two diastereomers as determined from the H NMR inte-
This methodology was also extended to the three-armed gration ratio) as the major product. The successful forma-
benzyl bromide derivative 7 (Scheme 3, Table 2). Since C3- tion of 13 was indicated by its 1H NMR spectroscopic data,
symmetric molecules are valuable core units for dendrimer and the structure of the desired cyclophane derivative 13
design and for the synthesis of useful ligands, this method- was further confirmed by the molecular ion peak at m/z =
ology is likely to find applications in these areas.
421 [M + Na] in the mass spectrum. To our surprise, a
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Suzuki–Miyaura Cross-Coupling and Ring-Closing Metathesis
FULL PAPER
Scheme 4. Synthesis of 11 with RCM as a key step.
Scheme 5. Synthesis of higher analogues of 11.
minor product was isolated along with the target product clophane derivatives 15 and 16, respectively, each as a single
as a mixture of two diastereomers (1:2.2; determined from isomer in modest yield. The formation of compounds 15
1
1H NMR integration ratio) in significant yield. The struc- and 16 was confirmed by their IR and H NMR spectro-
ture of this minor product was assigned as 14 and its un- scopic data, and the exclusive trans geometry of the cy-
1
symmetrical nature is supported by its H NMR spectrum. clophane derivative 16 was assigned through the observed
The molecular ion peak at m/z = 407 [M + Na] in the mass coupling constant (J = 15.0 Hz) of the olefinic proton in its
spectrum further confirmed the assigned structure of com- 1H NMR spectrum. Finally, the structures of 15 and 16
pound 14.
were further confirmed by high-resolution mass spectral
Interestingly, significant magnetic anisotropic effects on
The unusual formation of compound 14 could be ex- analysis.
plained in terms of a tandem isomerization induced by the
Grubbs’ catalyst, followed by a RCM sequence through the the intra-annular aromatic hydrogens (Hi) were observed in
intermediacy of 17 (Scheme 5).[15] Finally, oxidation of the all the cyclophane derivatives, as shown in Figure 2. The Hi
mixture of diastereomers gave the cyclophanedione as a sin- protons in the open-chain analogues 9 and 12 absorb in the
gle compound. Treatment of diols 13 and 14 with PCC in region of δ = 7.02 ppm, but in the cyclic forms (i.e., in the
dichloromethane at room temp. for 2 h thus gave the cy- cyclophane derivatives 10, 11 and 13–16) the intra-annular
Figure 2. Magnetic anisotropic effects in various cyclophane derivatives.
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S. Kotha, K. Mandal
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flux for 12 h and worked up as described in the General Procedure,
and the crude product was purified by column chromatography.
Elution of the column with petroleum ether gave compound 6a
(10 mg, 32%) as a white solid. Rf = 0.5 (silica gel, EtOAc/petroleum
ether 1:39); m.p. 73 °C (from hexane). 1H NMR (300 MHz,
CDCl3): δ = 3.78 (s, 6 H, 2×OCH3), 3.88 (s, 4 H, 2×CH2), 6.82
(d, J = 8.8 Hz, 4 H, ArH), 6.98 (d, J = 8.1 Hz, 2 H, ArH), 7.01 (s,
1 H, ArH), 7.08 (d, J = 8.8 Hz, 4 H, ArH), 7.18 (t, J = 7.3 Hz, 1
H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 41.0, 55.3, 113.9,
126.6, 128.6, 129.5, 129.9, 133.4, 141.7, 158.0 ppm. UV:
λmax(CHCl3)/nm 279 (ε/dm3 mol–1 cm–1 3908). HRMS (EI): calcd.
for C22H22O2: 318.1619; found: 318.1612.
hydrogen atoms (Hi) located between the planes of the two
para-substituted benzene rings are found to be shifted mod-
erately upfield. As the cavity size (or aliphatic chain length)
in such phane systems decreased, the upfield shifts of Hi
increased, due to the increase in shielding effects (Figure 2).
Conclusions
In summary, we have demonstrated a new approach for
the synthesis of cyclophane derivatives through the use of
a combination of SM cross-coupling and RCM as key steps.
One of the cyclophane derivatives was obtained through a
tandem isomerization and metathesis reaction. Significant
magnetic anisotropic effects on the intra-annular hydrogen
atoms were observed, so these macrocyclic compounds
could be potential targets for charge density studies in ad-
dition to host–guest complex experiments.
1,3-Bis(4-formylbenzyl)benzene (6b): 4-Formylphenylboronic acid
(170 mg, 1.14 mmol) and aqueous Na2CO3 (2  solution, 4 equiv.)
were added to a solution of 4 (100 mg, 0.38 mmol) in THF, and
the resulting reaction mixture was degassed with argon for 20 min.
Pd(PPh3)4 (36 mg, 0.03 mmol, 8 mol-%) was then added, the reac-
tion mixture was heated at reflux for 12 h and worked up as de-
scribed in the General Procedure, and the crude product was puri-
fied by silica gel column chromatography. Elution of the column
with EtOAc/petroleum ether (10%) gave compound 6b as a colour-
less oil (95 mg, 80%). Rf = 0.38 (silica gel, EtOAc/petroleum ether
1:4). 1H NMR (300 MHz, CDCl3): δ = 4.02 (s, 4 H, 2×CH2), 7.01
(s, 1 H, ArH), 7.04 (d, J = 7.5 Hz, 2 H, ArH), 7.25 (t, J = 7.5 Hz,
1 H, ArH) 7.33 (d, J = 8 Hz, 4 H, ArH), 7.8 (d, J = 8.2 Hz, 4 H,
ArH), 9.97 (s, 2 H, 2×CHO) ppm. 13C NMR (100.6 MHz, CDCl3):
δ = 42.1, 127.3, 129.2, 129.7, 129.8, 130.1, 134.9, 140.4, 148.3,
Experimental Section
General Remarks: All reactions were monitored by thin layer
chromatography (TLC) carried out on glass plates coated with Ac-
me’s silica gel GF 254 (containing 13% calcium sulfate as a binder).
Visualization of the spots on TLC plates was achieved by exposure
either to iodine vapour or to UV light. Flash chromatography was
performed with Acme’s silica gel (100–200 mesh). Petroleum ether
refers to the fraction of boiling point 60–80 °C. All the commercial
grade reagents were used without further purification. 1st and 2nd
generation Grubbs’ catalysts (1 and 2), α,αЈ-dibromo-m-xylene, 4-
bromobut-1-ene and all the boronic acids used here were purchased
from Aldrich Chemical Co., Inc. (Milwaukee, WI USA). Magne-
sium, indium and allyl bromide (s. d. fine-Chem Ltd.) were used
as received. Pd(PPh3)4 was prepared by the reported procedure.[16]
Infrared spectra were recorded on a Nicolet Impact 400 FT-IR
spectrometer in KBr/CHCl3/CCl4. 1H NMR (300, 400 MHz) and
13C NMR (75.4, 100.6 MHz) spectra were determined at room tem-
perature on a Varian VXR 300 or an AX 400 mercury plus in
CDCl3 solutions. Coupling constants (J values) are given in Hertz
(Hz). Chemical shifts are expressed in parts per million (ppm)
downfield from tetramethylsilane (TMS) as internal reference.
High-resolution mass spectra were determined on a Micromass Q-
Tof spectrometer.
192.0 ppm. IR (neat): ν = 1699 (C=O) cm–1. UV: λmax(CHCl3)/nm
˜
265 (ε/dm3 mol–1 cm–1 17327). HRMS (Q-Tof): m/z calcd. for
C22H18O2Na [M + Na]: 337.1204; found: 337.1208.
1,3-Bis(4-cyanobenzyl)benzene (6c): 4-Cyanophenylboronic acid
(125 mg, 0.85 mmol) and aqueous Na2CO3 (2  solution, 4 equiv.)
were added to a solution of 4 (77 mg, 0.29 mmol) in THF, and
the resulting reaction mixture was degassed with argon for 20 min.
Pd(PPh3)4 (27 mg, 0.02 mmol, 8 mol-%) was then added, the reac-
tion mixture was heated at reflux for 12 h and worked up as de-
scribed in the General Procedure, and the crude product was puri-
fied by column chromatography. Elution of the column with
EtOAc/petroleum ether (15%) gave compound 6c as a white solid
(76 mg, 84%). Rf = 0.20 (silica gel, EtOAc/petroleum ether 1:4);
m.p. 114–115 °C (from DCM/hexane 1:9). 1H NMR (300 MHz,
CDCl3): δ = 4.0 (s, 4 H, 2×CH2), 6.97 (s, 1 H, ArH), 7.02 (d, J =
7.3 Hz, 2 H, ArH), 7.23–7.27 (m, 5 H, ArH), 7.57 (d, J = 8 Hz, 4
H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 41.9, 110.1,
119.0, 127.3, 129.2, 129.6, 132.4, 139.9, 146.5 ppm. UV:
λmax(CHCl3)/nm 284 (ε/dm3 mol–1 cm–1 5621). HRMS (Q-Tof): m/z
calcd. for C22H17N2 [M + H]: 309.1392; found: 309.1398.
General Procedure for Coupling between Arylboronic Acids and α,αЈ-
Dibromo-m-xylene (4): A mixture of α,αЈ-dibromo-m-xylene (4,
1 equiv.), the arylboronic acid (3 equiv.), Pd(PPh3)4 (6–10 mol-%)
and Na2CO3 (4 equiv.) in water and THF (1:1) was heated at 80 °C.
The reaction mixture was degassed with argon for 20 min prior to
the addition of the catalyst. At the conclusion of the reaction (TLC
monitoring), the reaction mixture was diluted with water and ex-
tracted with ethyl acetate, and the combined organic layer was
washed with water and brine and dried with anhydrous MgSO4.
The solvent was evaporated and the crude product was loaded onto
a silica gel column. Elution of the column with EtOAc/petroleum
ether gave the desired cross-coupling product.
1,3-Bis(4-acetylbenzyl)benzene (6d): 4-Acetylphenylboronic acid
(93 mg, 0.57 mmol) and aqueous Na2CO3 (2  solution, 4 equiv.)
were added to a solution of 4 (50 mg, 0.19 mmol) in THF, and
the resulting reaction mixture was degassed for 20 min. Pd(PPh3)4
(21.8 mg, 10 mol-%) was then added, the reaction mixture was
heated at reflux for 12 h and worked up as described in the General
Procedure, and the crude product was purified by column
chromatography. Elution of the column with EtOAc/petroleum
ether (25%) gave compound 6d (46 mg, 71%). Rf = 0.4 (silica gel,
EtOAc/petroleum ether 3:7); m.p. 81 °C (from DCM/hexane 1:9).
1H NMR (300 MHz, CDCl3): δ = 2.56 (s, 6 H, 2×CH3), 3.99 (s, 4
H, 2×CH2), 7.01 (s, 1 H, ArH), 7.02 (d, J = 7.9 Hz, 2 H, ArH),
7.20–7.26 (m, 5 H, ArH), 7.87 (d, J = 8.5 Hz, 4 H, ArH) ppm. 13C
NMR (75.4 MHz, CDCl3): δ = 26.6, 41.9, 127.1, 128.7, 129.0,
1,3-Bis(4-methoxybenzyl)benzene (6a): 4-Methoxyphenylboronic
acid (50 mg, 0.33 mmol) and aqueous Na2CO3 (2  solution,
4 equiv.) were added to a solution of 4 (26 mg, 0.1 mmol) in dime-
thoxyethane (3 mL), and the resulting reaction mixture was de-
gassed with argon for 20 min. Pd(PPh3)4 (12 mg, 0.01 mmol,
10 mol-%) was then added, the reaction mixture was heated at re-
129.1, 129.6, 135.3, 140.5, 146.7 ppm. IR (neat): ν = 1681 cm–1
˜
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Suzuki–Miyaura Cross-Coupling and Ring-Closing Metathesis
(C=O). UV: λmax(CHCl3)/nm 274 (ε/dm3 mol–1 cm–1 18273). HRMS bined organic layer was washed with water and brine and dried
FULL PAPER
(Q-Tof): m/z calcd. for C24H22O2Na [M + Na]: 365.1517; found:
365.1515.
with MgSO4, the solvent was evaporated, and the crude product
was loaded onto a silica gel column. Elution of the column with
EtOAc/petroleum ether (20%) gave the desired product 9 (34 mg,
85%). Rf = 0.27 (silica gel, EtOAc/petroleum ether 1:4); m.p. 60–
1,3,5-Tris(4-methoxybenzyl)-2,4,6-trimethylbenzene (8a): 4-Meth-
oxyphenylboronic acid (89 mg, 0.59 mmol) and aqueous Na2CO3
(1.5 mL, 2  solution, 6 equiv.) were added to a solution of 7
(52 mg, 0.13 mmol) in THF, and the resulting reaction mixture was
degassed for 20 min. Pd(PPh3)4 (22 mg, 0.02 mmol, 15 mol-%) was
then added, the reaction mixture was heated at reflux for 24 h and
worked up as described in the General Procedure, and the crude
product was purified by column chromatography. Elution of the
column with EtOAc/petroleum ether (20%) gave compound 8a
(38 mg, 61%). Rf = 0.25 (silica gel, EtOAc/petroleum ether 1:3);
1
61 °C (from hexane). H NMR (300 MHz, CDCl3): δ = 2.04 (d, J
= 4.4 Hz, 2 H, 2×OH), 2.47–2.53 (m, 4 H, 2×CH2CH=CH2), 3.93
(s, 4 H, 2×ArCH2), 4.71 (t, J = 6.2 Hz, 2 H, 2×CHOH), 5.12–5.2
(m, 4 H, 2×CH2CH=CH2), 5.74–5.88 (m, 2 H, 2×CH2CH=CH2),
7.0–7.02 (m, 3 H, ArH), 7.13–7.22 (m, 5 H, ArH), 7.27 (d, J =
8.1 Hz, 4 H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 41.6,
43.9, 73.2, 118.5, 126.0, 126.8, 128.6, 129.0, 129.6, 134.6, 140.5,
141.3, 141.7 ppm. IR (neat):
ν =
3398 cm–1 (OH). UV:
˜
λmax(CHCl3)/nm 265 (ε/dm3 mol–1 cm–1 1956). HRMS (EI): m/z
1
m.p. 148 °C (from chloroform). H NMR (300 MHz, CDCl3): δ =
calcd. for C28H30O2Na [M + Na]: 421.2143; found: 421.2139.
2.15 (s, 9 H, 3×ArCH3), 3.77 (s, 9 H, 3×OCH3), 4.07 (s, 6 H,
3×ArCH2), 6.79 (d, J = 9.0 Hz, 6 H, ArH), 6.95 (d, J = 8.7 Hz, 6
H, ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 16.8, 35.4, 55.3,
113.9, 128.8, 132.4, 134.6, 135.2, 157.7 ppm. UV: λmax(CHCl3)/nm
279 (ε/dm3 mol–1 cm–1 6734). HRMS (Q-Tof): m/z calcd. for
C33H36O3K (M + K): 519.2302; found: 519.2318.
1,3-Bis[4-(1-hydroxypent-4-enyl)benzyl]benzene (12): A small crystal
of iodine was added to a suspension of magnesium (19 mg,
0.79 mmol) under argon in dry ether (3 mL). While the contents
were stirred, 4-bromobut-1-ene (0.09 mL, 0.89 mmol, dissolved in
5 mL of dry ether) was added slowly. The iodine colour disap-
peared completely and the reaction mixture was then stirred at
room temp. for 1 h. Compound 12 (80 mg, 0.25 mmol) in diethyl
ether (5 mL) was then added slowly, the ice-cold temperature being
maintained. The reaction mixture was then allowed to stir at room
temp. for 24 h, quenched with saturated ammonium chloride, di-
luted with water (10 mL) and extracted with ethyl acetate
(3×10 mL). The combined organic layer was washed with water
and brine and dried with MgSO4, the solvent was evaporated, and
the crude product was loaded onto a silica gel column. Elution of
the column with EtOAc/petroleum ether (20%) gave compound 12
as a colourless liquid (77 mg, 71%). Rf = 0.36 (silica gel, EtOAc/
1,3,5-Tris(4-formylbenzyl)-2,4,6-trimethylbenzene (8b): 4-Formyl-
phenylboronic acid (155 mg, 1.03 mmol) and aqueous Na2CO3 (2 
solution, 6 equiv.) were added to a solution of
7 (104 mg,
0.26 mmol) in THF, and the resulting reaction mixture was de-
gassed for 20 min. Pd(PPh3)4 (45 mg, 0.04 mmol, 15 mol-%) was
then added, the reaction mixture was heated at reflux for 24 h and
worked up as described in the General Procedure, and the crude
product was purified by column chromatography. Elution of the
column with EtOAc/petroleum ether (20%) gave compound 8b
(87 mg, 70%). Rf = 0.25 (silica gel, EtOAc/petroleum ether 3:7);
1
m.p. 198 °C (from chloroform). H NMR (300 MHz, CDCl3): δ =
1
petroleum ether 3:7). H NMR (300 MHz, CDCl3): δ = 1.73–1.93
2.13 (s, 9 H, 3×CH3), 4.24 (s, 6 H, 3×CH2), 7.20 (d, J = 8.1 Hz,
6 H, ArH), 7.79 (d, J = 8.1 Hz, 6 H, ArH), 9.97 (s, 3 H,
3×CHO) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.1, 36.8,
(m, 6 H, 2×OH, 2×CH2CH2CH=CH2), 2.05–2.20 (m, 4 H,
2×CH2CH=CH2), 3.93 (s, 4 H, 2×ArCH2), 4.67 (dd, J = 7.8,
5.6 Hz, 2 H, 2×CHOH), 4.98 (d, J = 10.4 Hz, 2 H, 2×CH=CHH),
5.04 (d, J = 16.8 Hz, 2 H, 2×CH=CHH), 5.79–5.89 (m, 2 H,
2×CH=CH2), 7.01 (d, J = 6.4 Hz, 2 H, 2×ArH), 7.02 (s, 1 H,
ArH), 7.17 (d, J = 8.4 Hz, 4 H, 4×ArH), 7.20 (t, J = 8.4 Hz, 1 H,
ArH), 7.25 (d, J = 7.2 Hz, 4 H, 4×ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 30.3, 38.2, 41.7, 74.0, 115.1, 126.2, 126.9,
128.6, 130.3, 134.5, 134.8, 135.3, 147.9, 192.1 ppm. IR (neat): ν
˜
= 1690 cm–1 (C=O). UV: λmax(CHCl3)/nm 293 (ε/dm3 mol–1 cm–1
13354). HRMS (Q-Tof): m/z calcd. for C33H31O3 [M + H]:
475.2273; found: 475.2296.
1,3,5-Tris(4-cyanobenzyl)-2,4,6-trimethylbenzene (8c): 4-Cyano-
phenylboronic acid (75 mg, 0.51 mmol) and aqueous Na2CO3
(2 mL, 2  solution) were added to a solution of 7 (51 mg,
0.13 mmol) in THF (15 mL), and the resulting reaction mixture
was degassed for 20 min. Pd(PPh3)4 (22 mg, 0.02 mmol, 15 mol-%)
was then added, the reaction mixture was heated at reflux for 24 h
and worked up as described in the General Procedure, and the
crude product was purified by column chromatography. Elution of
the column with EtOAc/petroleum ether (20%) gave compound 8c
(49 mg, 82%) Rf = 0.19 (silica gel, EtOAc/petroleum ether 3:7);
128.8, 129.2, 129.8, 138.4, 140.7, 141.4, 142.5 ppm. IR (neat): ν =
˜
3402 cm–1 (OH). UV: λmax(CHCl3)/nm 265 (ε/dm3 mol–1 cm–1 1975).
HRMS (Q-Tof): m/z calcd. for C30H34O2Na [M + Na]: 449.2457;
found: 449.2471.
RCM of 1,3-Bis[4-(1-hydroxybut-3-enyl)benzyl]benzene (9) in the
Presence of 2nd Generation Grubbs’ Catalyst 2: Grubbs’ catalyst 2
(7 mg, 10 mol-%) was added to a solution of compound 9 (32 mg,
0.08 mmol) in dry degassed DCM (80 mL, 1 mmolar) and the solu-
tion was stirred for 18 h at room temp. The reaction mixture was
then concentrated, and the crude product was purified on a silica
gel column. Elution of the column with EtOAc/petroleum ether
(20%) gave compound 10 as a white solid (14 mg, 47%) and as
a mixture of diastereomers (1:2; determined from the 1H NMR
integration ratio of the protons attached to the chiral carbon
atom). The spectroscopic data are for the major isomer: Rf = 0.23
(silica gel, EtOAc/petroleum ether 3:7); m.p. 222–223 °C (from
1
m.p. 232 °C (from chloroform). H NMR (300 MHz, CDCl3): δ =
2.09 (s, 9 H, 3×CH3), 4.2 (s, 6 H, 3×CH2), 7.12 (d, J = 8.1 Hz, 6
H, ArH), 7.56 (d, J = 8.1 Hz, 6 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 17.0, 36.6, 110.2, 119.0, 128.6, 132.5,
134.2, 135.4, 145.9 ppm. IR (neat): ν = 2227 cm–1 (CϵN). UV:
˜
λmax(CHCl3)/nm 252 (ε/dm3 mol–1 cm–1 13345). HRMS (Q-Tof):
m/z calcd. for C33H28N3 [M + H]: 466.2283; found: 466.2262.
1
1,3-Bis[4-(1-hydroxybut-3-enyl)benzyl]benzene (9): Allyl bromide
(32 mg, 0.26 mmol) and indium metal (26 mg, 0.23 mmol) were
added to a solution of 6b (32 mg, 0.1 mmol) in DMF (2 mL), and
the resulting reaction mixture was allowed to stir at room temp.
After completion of the reaction (15 min, TLC monitoring) the re-
action mixture was quenched with HCl (50%), diluted with water
(10 mL) and extracted with ethyl acetate (3×10 mL). The com-
methanol). H NMR (300 MHz, CDCl3): δ = 1.74 (d, J = 4 Hz, 2
H, 2×OH), 2.50–2.55 (m, 4 H, 2×CH2CH=CH), 3.89 (s, 4 H,
2×ArCH2), 4.67–4.71 (m, 2 H, 2×ArCHOH), 5.10 (t, J = 3.7 Hz,
2 H, 2×CH2CH=), 6.33 (s, 1 H, ArH), 6.97 (d, J = 8.4 Hz, 4 H,
ArH), 7.07 (d, J = 8.1 Hz, 4 H, ArH), 7.14 (d, J = 8.4 Hz, 2 H,
ArH), 7.26 (t, J = 7.5 Hz, 1 H, ArH) ppm. IR (neat): ν = 3392 cm–1
˜
(OH). UV: λmax(CHCl3)/nm 262 (ε/dm3 mol–1 cm–1 1700). HRMS
Eur. J. Org. Chem. 2006, 5387–5393
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5391

S. Kotha, K. Mandal
FULL PAPER
(Q-Tof): m/z calcd. for C26H26O2Na [M + Na]: 393.1831; found:
393.1823.
added and decanted off, and the black residue was washed with
further diethyl ether (3×5 mL). The combined ether extracts were
concentrated, and the crude product was purified by silica gel col-
umn chromatography. Elution of the column with EtOAc/petro-
leum ether (10%) gave compound 15 (7 mg, 79%) as white, needle-
like crystals. Rf = 0.35 (silica gel, EtOAc/petroleum ether 1:4); m.p.
159–160 °C (from DCM/hexane 1:4). 1H NMR (300 MHz, CDCl3):
δ = 2.33–2.40 (m, 4 H, 2×COCH2CH2), 2.85 (dd, J = 8.1, 7.1 Hz,
4 H, 2×COCH2), 3.97 (s, 4 H, 2×ArCH2), 5.55 (t, J = 4.8 Hz, 2
H, 2×CH2CH=), 6.52 (s, 1 H, ArH), 7.08 (d, J = 8.4 Hz, 4 H,
ArH), 7.17 (d, J = 6.9 Hz, 2 H, ArH), 7.29 (t, J = 7.5 Hz, 1 H,
RCM of 1,3-Bis[4-(1-hydroxypent-4-enyl)benzyl]benzene (12) in the
Presence of 2nd Generation Grubbs’ Catalyst 2: Grubbs’ catalyst 2
(11 mg, 10 mol-%) was added to a solution of compound 12
(50 mg, 0.12 mmol) in dry degassed DCM (100 mL, 1.26 mmolar)
and the solution was stirred for 24 h at room temp. The reaction
mixture was then concentrated, and the crude product was purified
on a silica gel column. Elution of the column with EtOAc/petro-
leum ether (40%) gave compound 13 as a white solid (22 mg, 47%)
1
and as a mixture of diastereomers (1:1.7; determined from the H
ArH), 7.73 (d, J = 8.4 Hz, 4 H, ArH) ppm. IR (neat): ν = 1679 cm–1
˜
NMR integration ratio of the protons attached to the chiral carbon
atom). The spectroscopic data are for the major diastereomer of
13: Rf = 0.4 (silica gel, EtOAc/petroleum ether 1:1); m.p. 213–
(C=O). UV: λmax(CHCl3)/nm 255 (ε/dm3 mol–1 cm–1 5549). HRMS
(Q-Tof): m/z calcd. for C28H27O2 [M + H]: 395.2011; found:
395.2019.
1
214 °C (from methanol). H NMR (300 MHz, CDCl3): δ = 1.48–
2.0 [m, 10 H, 2×CH(OH)CH2CH2C=], 3.90 (s, 4 H, 2×ArCH2), 1,5(1,4),3(1,3)-Tribenzenacyclododecaphan-8-ene-6,12-dione
(16):
4.53–4.59 (m, 2 H, 2×CHOH), 5.34–5.38 (m, 2 H, 2×HC=), 6.69 Compound 14 (8 mg, 0.02 mmol) in anhydrous DCM (3 mL) was
(s, 1 H, ArH), 6.99–7.32 (m, 11 H, ArH) ppm. IR (neat): ν =
added in one portion to a vigorously stirred suspension of PCC
(13 mg, 0.06 mmol) in anhydrous DCM (2 mL). Stirring was con-
tinued at room temp. for 2 h, anhydrous diethyl ether (25 mL) was
added and decanted off, and the black residue was washed with
further diethyl ether (3×5 mL). The combined ether extracts were
concentrated, and the crude product was purified by silica gel col-
umn chromatography. Elution of the column with EtOAc/petro-
leum ether (10%) gave compound 16 (6 mg, 76%) as white, needle-
like crystals. Rf = 0.34 (silica gel, EtOAc/petroleum ether 1:4); m.p.
165 °C (from DCM/hexane 1:4). 1H NMR (300 MHz, CDCl3): δ =
2.53–2.59 (m, 2 H, COCH2CH2), 2.91–2.95 (m, 2 H, COCH2CH2),
3.48 (dd, J = 7.1, 1.2 Hz, 2 H, COCH2C=), 3.92 (s, 2 H, ArCH2),
3.96 (s, 2 H, ArCH2), 5.37 (dtt, J = 15.3, 6.6, 1.5 Hz, 1 H,
CH2CH2CH=), 5.67 (dtt, J = 15.6, 6.0, 1.5 Hz, 1 H, COCH2CH=),
6.27 (s, 1 H, ArH), 6.96 (d, J = 8.7 Hz, 2 H, ArH), 7.08 (d, J =
8.4 Hz, 2 H, ArH), 7.12–7.20 (m, 2 H, ArH), 7.25–7.30 (m, 1 H,
ArH), 7.63 (d, J = 8.4 Hz, 2 H, ArH), 7.72 (d, J = 8.1 Hz, 2 H,
˜
3401 cm–1 (OH). UV: λmax(CHCl3)/nm 263 (ε/dm3 mol–1 cm–1 2588).
HRMS (Q-Tof): m/z calcd. for C28H30O2Na [M + Na]: 421.2144;
found: 421.2157.
Continued elution of the column with the same solvent system gave
14 as a white solid (10 mg, 21%) and as a mixture of diastereomers
1
(1:2.2; determined from the H NMR integration ratio of the pro-
tons attached to the chiral carbon atom). The spectroscopic data
are for the major isomer of 14: Rf = 0.35 (silica gel, EtOAc/petro-
leum ether 1:1); m.p. 218–220 °C (from methanol). 1H NMR
(400 MHz, CDCl3): δ = 1.57–1.68 [m, 4 H, CH(OH)CH2CH2C=
and 2×OH], 2.31–2.38 [m, 2 H, CH(OH)CH2CH2C=], 2.50–2.57
[m, 2 H, CH(OH)CH2C=], 3.91 (s, 2 H, ArCH2), 3.92 (s, 2 H,
ArCH2), 4.52–4.58 (m, 2 H, 2×CHOH), 5.27–5.30 (m, 2 H,
CH=CH), 6.77 (s, 1 H, ArH), 6.99 (d, J = 8 Hz, 4 H, ArH), 7.04–
7.07 (m, 4 H, ArH), 7.17 (d, J = 8 Hz, 2 H, ArH), 7.29 (t, J =
7.6 Hz, 1 H, ArH) ppm. IR (neat): ν = 3402 cm–1 (OH). UV:
˜
ArH) ppm. IR (neat): ν = 1676 cm–1 (C=O). UV: λmax(CHCl3)/nm
˜
λmax(CHCl3)/nm 263 (ε/dm3 mol–1 cm–1 2678). HRMS (Q-Tof): m/z
255 (ε/dm3 mol–1 cm–1 13982). HRMS (Q-Tof): m/z calcd. for
calcd. for C27H28O2Na [M + Na]: 407.1987; found: 407.1979.
C27H24O2Na [M + Na]: 403.1674; found: 403.1676.
1,5(1,4),3(1,3)-Tribenzenacycloundecaphan-8-ene-6,11-dione
(11):
Compound 10 (12 mg, 0.03 mmol) in anhydrous DCM (3 mL) was
added in one portion to a vigorously stirred suspension of PCC
(15 mg, 0.07 mmol) in anhydrous DCM (10 mL). Stirring was con-
tinued at room temp. for 2 h. Anhydrous ether (50 mL) was added
and decanted off, and the black residue was washed with further
diethyl ether (3×10 mL). The combined ether extracts were con-
centrated, and the crude product was purified by silica gel column
chromatography. Elution of the column with EtOAc/petroleum
ether (10%) gave compound 11 (9 mg, 75%) as white, needle-like
crystals. Rf = 0.77 (silica gel, EtOAc/petroleum ether 3:7); m.p.
174 °C (from DCM/hexane 1:4). 1H NMR (300 MHz, CDCl3): δ =
3.61 (dd, J = 3.6, 1.5 Hz, 4 H, 2×COCH2), 3.91 (s, 4 H,
2×ArCH2), 5.75 (tt, J = 3.6, 1.5 Hz, 2 H, 2×CH=), 6.01 (s, 1 H,
Ar-Hi), 6.99 (d, J = 8.4 Hz, 4 H, ArH), 7.14 (d, J = 7.7 Hz, 2 H,
ArH), 7.26 (t, J = 7.5 Hz, 1 H, ArH); 7.7 (d, J = 8.4 Hz, 4 H,
ArH) ppm. 13C NMR (75.4 MHz, CDCl3): δ = 41.2, 43.9, 126.4,
128.1, 128.3, 129.0, 129.6, 133.5, 140.8, 146.2, 197.1 ppm. IR
Acknowledgments
We thank the DST for the financial support and the SAIF, Mum-
bai, for spectroscopic data. KM thanks the CSIR, New Delhi for
the award of a research fellowship.
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1,5(1,4),3(1,3)-Tribenzenacyclotridecaphan-9-ene-6,13-dione
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Compound 13 (9 mg, 0.02 mmol) in anhydrous DCM (3 mL) was
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www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5387–5393

Suzuki–Miyaura Cross-Coupling and Ring-Closing Metathesis
FULL PAPER
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Received: June 26, 2006
Published Online: September 28, 2006
Eur. J. Org. Chem. 2006, 5387–5393
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5393