Generation of substituted styrenes via Suzuki cross-coupling of aryl halides with 2,4,6-trivinylcyclotriboroxane

Article abstract of DOI:10.1021/jo020074o

The synthesis of functionalized styrene derivatives can be readily achieved utilizing a Suzuki cross-coupling protocol between aryl halides and 2,4,6-trivinylcyclotriboroxane-pyridine complex. The scope and limitations of the procedure were demonstrated by investigation of an array of ortho-substituted aryl halides.

Full text of DOI:10.1021/jo020074o

sion but had considerable difficulty in removing all of the
toxic organotin residues from the styrene products. As
this is a known drawback of organotin reagents, it is
perhaps surprising that an equivalent vinylboronic acid
derivative has not previously been described for the
generation of styrenes. A review of the literature shows
that only vinylboronate esters have been investigated and
reported to give mixtures of Heck- and Suzuki-type
products under various conditions.11 As a result, we
undertook an investigation to develop a synthetic equiva-
lent boronic acid for tributyl(vinyl)tin.
Gen er a tion of Su bstitu ted Styr en es via
Su zu k i Cr oss-Cou p lin g of Ar yl Ha lid es w ith
2,4,6-Tr ivin ylcyclotr ibor oxa n e
Fergal Kerins and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, Conway
Institute, Department of Chemistry, University College
Dublin, Belfield, Dublin 4, Ireland
donal.f.oshea@ucd.ie
The synthesis of vinylboronic acid 1 from vinylmag-
nesium bromide and trimethyl borate was first reported
by Matteson,12 who described the compound as undergo-
ing uncontrollable polymerization during the final stages
of isolation (Scheme 1). Following the described proce-
dures, we found that vinylboronic acid could be isolated
Received J anuary 30, 2002
Abstr a ct: The synthesis of functionalized styrene deriva-
tives can be readily achieved utilizing a Suzuki cross-
coupling protocol between aryl halides and 2,4,6-trivinylcy-
clotriboroxane-pyridine complex. The scope and limitations
of the procedure were demonstrated by investigation of an
array of ortho-substituted aryl halides.
SCHEME 1
Functionalized styrenes are of considerable synthetic
importance for the generation of new polymeric materials
and as key synthetic intermediates. Specifically, ortho-
substituted styrenes act as intermediates for the syn-
thesis of benzo-fused ring systems such as indenes,1
indoles,2 2,3-dihydroindoles,3 quinolines,4 and isocou-
marins.5 Traditional methods for the generation of sty-
renes require dehydration under acidic conditions or an
elimination under basic conditions to generate the double
bond. Several palladium-catalyzed methods have been
developed that utilize aryl halides as starting materials
in reaction with a variety of reagents to provide the
alkene functional group; the Heck6 methodology uses
ethene under high pressures, and the Stille7 procedure
exploits a tributyl(vinyl)tin reagent. Vinylmagnesium
bromide,8 vinyltrimethylsilane,9 and vinylpolysiloxanes10
have also been demonstrated as viable reagents utilizing
aryl iodides as starting reagents. To date, the Heck and
Stille methodologies have possibly been the most widely
exploited in general synthetic procedures. We required
an efficient method for the generation of ortho-substi-
tuted styrenes as a key step of an indole synthesis. We
found tributyl(vinyl)tin effective for the desired conver-
but the reaction had very poor reproducibility and did
indeed on several attempts spontaneously polymerize.
Even when successfully isolated, it always degraded over
a time period of several days. This was not acceptable
for use as a general synthetic reagent, and we sought to
convert the vinylboronic acid into a bench stable form,
which would still be capable of undergoing Suzuki-type
couplings.13 The conversion of the 1 into its anhydride
form by stirring in pyridine has been reported to yield a
bench stable solid.14 From this earlier report, we have
devised a modified direct synthetic procedure to the
anhydride form, 2,4,6-trivinylcyclotriboroxane-pyridine
complex 2 (Scheme 2). The synthesis of 2 was achieved
SCHEME 2
(1) Brase, S.; Rumper, J .; Voigt, K.; Albecq, S.; Thurau, G.; Villard,
R.; Waegell, B.; de Meijere, A. Eur. J . Org. Chem. 1998, 671.
(2) (a) Harrington, P. J .; Hegedus, L. S. J . Org. Chem. 1984, 49,
2657. (b) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J . K. J .
Org. Chem. 1988, 53, 1170. (c) Larock, R. C., Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J . Org. Chem. 1996, 61, 3584. (d) Soederberg, B.
C.; Shriver, J . A. J . Org. Chem. 1997, 62, 5838. (e) Ucciani, E.; Bonfand,
A. Chem. Commun. 1981, 82. (f) Yamaguchi, M.; Arisawa, M.; Hirama,
M. Chem. Commun.1998, 1399.
(3) Larock, R. C.; Pace, P.; Yang, H.; Russell, C. E.; Cacchi, S.;
Fabrizi, G.; Tetrahedron 1998, 54, 9961.
(4) Hibino, S.; Sugino, E. Heterocycles 1987, 26, 1883.
(5) Izumi, T.; Nishimoto, Y.; Kohei, K.; Kasahara, A. J . Heterocycl.
Chem. 1990, 27, 1419.
reproducibly by the reaction of vinylmagnesium bromide
and trimethyl borate at -78 °C in dry THF followed by
acid hydrolysis to the boronic acid and in situ conversion
to the cyclic anhydride 2 by stirring with pyridine,
resulting in a 79% isolated yield (Scheme 2). The isolated
(6) Plevyak, J . E.; Heck, R. F., J . Org. Chem. 1978, 43, 2454.
(7) McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J . K. J . Org.
Chem. 1987, 52, 422.
(8) Bumagin, N. A.; Luzikova, E. V. J . Organomet. Chem. 1997, 532,
271.
(9) J effery, T. Tetrahedron Lett. 1999, 40, 1673.
(10) (a) Denmark, S. E.; Wang, Z. Synthesis 2000, 999. (b) Denmark,
S. E.; Wang, Z. J . Organomet. Chem. 2001, 624, 372.
(11) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1993,
34, 3599.
(12) Matteson, D. S. J . Am Chem. Soc. 1960, 82, 4228.
(13) Suzuki A. Pure Appl. Chem. 1994, 66, 213.
(14) Matteson, D. S. J . Org. Chem. 1962, 27, 3712.
10.1021/jo020074o CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/23/2002
4968
J . Org. Chem. 2002, 67, 4968-4971

product is bench stable for prolonged periods and can be
obtained analytically pure by vacuum distillation. The
1:1 ratio of pyridine to trivinylcyclotriboroxane was
confirmed by 1H NMR, and the single observed 11B NMR
signal was consistent with a rapid ligand exchange
process between the pyridine nitrogen and the three
borons of the boroxane ring.15 It is known that boronic
anhydrides are converted into their corresponding acids
in the presence of water. As a result, our expectation was
that with the commonly used coupling solvent conditions
of 1,2-dimethoxyethane (DME)/water, it would be possible
to generate the vinylboronic acid in situ. To test the
suitability of 2 as a viable reagent, a model set of
conditions were employed for all reactions with aryl
halides as follows: tetrakis(triphenylphosphine)palladium-
(0) as catalyst, potassium carbonate as base, and DME/
water (3:1) as solvent, under reflux for 20 h (Scheme 3).
Reaction conversions were determined by GC-MS and
1H NMR.
benzene under our model reaction conditions with 1 and
5 mol % catalyst (entries 14 and 15). Although the
conversions to styrene 3a were low (3%, 12%, respec-
tively) it does show the potential for use of 2 with
reported specialized catalyst ligands to achieve improved
conversions.16
In summary, we have described a facile method for the
generation of substituted styrene derivatives using 2,4,6-
trivinylcyclotriboroxane-pyridine complex in a Suzuki
cross-coupling protocol, which has the potential to become
a new versatile synthetic reagent for the vinylation of
aryl halides. A direct synthesis of the key vinylation
reagent is described.
Exp er im en ta l Section
Ma ter ia ls. All commercially available solvents and reagents
were used as supplied unless otherwise stated. Tetrakis(triph-
enylphosphine)palladium(0) was supplied by Aldrich Chemical
Co. and used without any modification. 1,2-Dimethoxyethane
was passed through a bed of aluminum oxide immediately before
use.
SCHEME 3
An a lysis. GC-MS was recorded using a ThermoQuest Trace
MS 2000. 1H and 13C NMR were recorded on a 300 MHz
instrument and were referenced to tetramethylsilane (TMS). 11
B
NMR spectrum was recorded on a 270 MHz instrument and
referenced to BF3‚OEt2. Melting points are uncorrected.
2,4,6-Tr ivin ylcyclotr ibor oxa n e-P yr id in e Com p lex (2).
A solution of trimethyl borate (10 mL, 89.2 mmol) in dry THF
(75 mL) was cooled to -78 °C under N2 in a dry ice-acetone
bath. Vinylmagnesium bromide (50 mL of a 1.0 M solution in
THF, 50.0 mmol) was added dropwise over 1 h and the reaction
stirred for a further 1 h. Hydrochloric acid (1 M, 25 mL) was
added over 5 min and the solution removed from the cooling bath
and allowed to warm to room temperature. Brine (20 mL) was
added, the solution was extracted with diethyl ether (4 × 50
mL), and the combined extracts were washed with water (50
mL) and brine (50 mL), dried over sodium sulfate, and concen-
trated under reduced pressure to 25 mL. The diethyl ether
solution was treated with pyridine (10 mL) and stirred at room
temperature for 4 h. The solvents were evaporated under
reduced pressure to give a pale yellow oil. Distillation under
reduced pressure (75-85 °C, 0.1 Torr) gave the product as a
white solid 3.2 g, 79%, mp 46-48 °C. Samples were routinely
stored in a sample bottle, under air, at 0 °C, which showed no
deterioration by 1H NMR over a 4 week period. 1H NMR (CDCl3)
δ: 5.78-5.86 (m, 3H), 5.93-6.07 (m, 6H), 7.54-7.59 (m, 2H),
7.94-8.01 (m, 1H), 8.79-8.81 (m, 2H). 13C NMR (CDCl3) δ:
125.3, 131.5, 138.0 (broad) 140.1, 145.1. 11B NMR (CDCl3) δ:
Our first model aryl bromide, 2-bromo-6-methoxynaph-
thalene, gave an excellent result of a 100% conversion of
starting aryl bromide and an isolated purified product
yield of 76%, utilizing 1.0 mol % catalyst (Table 1, entry
1). As sterically hindered couplings are reported to be
the most challenging to achieve,13 we tested the scope of
the reaction with a range of ortho-substituted aryl halides
with varying electronic and steric properties. We discov-
ered that as with other boronic acid couplings the
reaction was tolerant of a wide range of sensitive
functional groups, which enabled the generation of a
diverse array of ortho-substituted styrenes 3a -i (Scheme
3, Table 1). The reactivity followed was as expected for a
Suzuki coupling with electron-withdrawing substituents
on the aryl halide achieving better conversions than
electron donating substituents. The steric factors of the
ortho substituents did not appear to significantly impede
the reactions. Entries 2-8 were all fully converted in the
reaction time with 1 mol % catalyst and gave good
isolated yields. The tolerance of nitro 3a , amide 3b, nitrile
3c, aldehyde 3d , and carbamic ester 3e functional groups
to the reaction conditions being demonstrated. The
coupling reaction proved successful for aryl bromides and
iodides, entries 2 and 3. The carbamic acid tert-butyl ester
derivative 3g (entries 9 and 10) gave only 25% conversion
with 1 mol % catalyst, but the reaction could be driven
to completion by increasing the catalyst ratio to 5 mol
%. The aryl halides with ortho-electron-donating methyl
(entries 11 and 12) and methoxy (entry 13) groups also
gave improved conversions at increased catalyst levels.
Currently, there is an increasing demand for achieving
palladium-catalyzed coupling reactions using aryl chlo-
rides as starting reagents. We examined 1-chloro-2-nitro-
17.68. EI-MS: m/z 242 (3) 161 (30), 79 (100). IR (KBr) cm-1
:
1620, 1442. Anal. Calcd for C11H14B3NO3: C, 54.90; H, 5.86; N,
5.82. Found: C, 54.76; H, 5.83; N, 5.75.
Gen er a l Su zu k i Cou p lin g P r oced u r e. Aryl halide (1.25
mmol) was dissolved in DME (10 mL), treated with tetrakis-
(triphenylphosphine)palladium(0) (0.0125 or 0.0625 mmol), and
stirred at room temperature under N2 for 20 min. Potassium
carbonate (1.25 mmol), water (3 mL), and 2 (1.25 mmol) were
added, and the reaction was heated under reflux under N2 for
20 h. The reaction mixture was cooled to ambient temperature,
extracted with ether (25 mL), dried over sodium sulfate, and
diluted with hexane (25 mL). The solution was passed through
a
short aluminum oxide column, solvent evaporated, and
analyzed by GC, GC-MS, and 1H NMR. If required, further
purification by column chromatography on silica, eluting with
hexanes/diethyl ether, was performed.
Analytical data for new compounds is shown in Table 1.
(16) (a) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387. (c) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.;
Petersen, J . L. J . Org. Chem. 1999, 64, 6797.
(15) Comparison to 11B NMR data of (CH3)3B3O3‚L. Beckett, M. A.;
Brassington, D. S.; Owen, P.; Hursthouse, M. B.; Light, M. E.; Abdul
Malik, K. M.; Sukumar Varma, K. J . Organomet. Chem. 1999, 585, 7.
J . Org. Chem, Vol. 67, No. 14, 2002 4969

TABLE 1. Cr oss-Cou p lin g Exp er im en ts of Ar yl Ha lid es w ith 2,4,6-Tr ivin ylcyclotr ibor oxa n e P yr id in ea
a
b
c
Reaction times are not minimized. Average of two or more runs. Isolated yield.
4970 J . Org. Chem., Vol. 67, No. 14, 2002

4-F lu or o-2-vin ylp h en ylca r ba m ic Acid ter t-Bu tyl Ester
129.1, 132.5, 135.3, 153.3. IR (KBr disk) cm-1: 3327, 2990, 1689.
EI-MS: m/z 219.1. HRMS: calcd for C13H17NO2 219.1259, found
219.1259. Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.95; H, 7.80; N, 6.25.
1
3f. Mp: 70-71 °C. H NMR (CDCl3) δ: 1.50 (s 9H), 5.42 (dd, J
) 1.0, 11.0 Hz, 1H), 5.65 (dd, J ) 1.0, 17.4 Hz), 6.27 (bs, 1H),
6.76 (1H, m), 6.94 (1H, m), 7.1 (1H, m), 7.63 (m, 1H). 13C NMR
(CDCl3) δ: 28.5, 80.9, 111.8 (d, J CF ) 22.9 Hz), 114.1 (d, J CF
)
22.1 Hz), 114.6, 117.4, 123.7, 129.9 (d, J CF ) 2.3 Hz), 130.4 (d,
J CF ) 1.5 Hz), 152.3, 158.6 (d, J CF ) 242.6 Hz). IR (KBr disk)
cm-1: 3268, 2948, 1768. EI-MS: m/z 237.3. HRMS: calcd for
Ack n ow led gm en t. We gratefully acknowledge En-
terprise Ireland for financial support.
C
13H16FNO2 237.1165, found 237.1160. Anal. Calcd for C13H16-
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 11B
NMR spectral characterization of 2,4,6-trivinylcyclotriboroxane
pyridine complex 2. 1H and 13C NMR spectra for the new
compounds 3f and 3g. This material is available free of charge
via the Internet at http://pubs.acs.org
FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.6; H, 6.78; N,
5.90.
(2-Vin ylp h en yl)ca r ba m ic Acid ter t-Bu tyl Ester 3g. Mp:
47-48 °C. 1H NMR (CDCl3) δ: 1.51 (s, 9H), 5.36 (dd, J ) 1.3,
11.0 Hz, 1H), 5.61 (dd, J ) 1.3, 17.3 Hz, 1H), 6.44 (bs, 1H), 6.80
(dd, 1H), 7.05 (m, 1H), 7.25 (m, 1H), 7.24 (m, 1H), 7.77 (m, 1H).
13C NMR (CDCl3) δ: 28.5, 80.7, 118.0, 122.0, 124.2, 127.1, 128.7,
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