Stille coupling reactions of 4-substituted-2,5-diphenyloxazoles

Full text of DOI:10.1021/jo0107150

J . Org. Chem. 2001, 66, 9033-9037
9033
Sch em e 1
Stille Cou p lin g Rea ction s of
4-Su bstitu ted -2,5-Dip h en yloxa zoles†
Bruce Clapham‡ and Andrew J . Sutherland*
Department of Chemical Engineering and
Applied Chemistry, Aston University, Aston Triangle,
Birmingham B4 7ET, U.K.
robust C-C bonds. Although Stille couplings of oxazole-
containing molecules are known, most employ couplings
remote from the oxazole center. In contrast, reactions
that involve coupling directly onto the oxazole ring are
comparatively rare, and therefore, little is known about
their efficiency.6,7 Because of our interest in the produc-
tion of polymerizable scintillants, we wished to develop
optimal conditions for Stille couplings at the 4-position
of the oxazole ring in the presence of bulky neighboring
groups. Using 2,5-diphenyloxazole as the electrophile in
a Stille coupling, we generated two of the required
scintillant monomers in excellent yield. Unfortunately,
other monomers proved inaccessible via this route.
However, by reversing the Stille strategy and using the
oxazole as the stannane, in conjunction with stoichio-
metric quantities of copper(II) oxide, these other mono-
mers were obtained in good yield. Moreover, the success
of a variety of further coupling reactions suggests that
this latter approach has general applicability. Herein, we
report the first examples of 4-stannyl-2,5-bifunctional
oxazoles and their efficiencies in Stille coupling reactions
with a variety of electrophiles.
a.j.sutherland@aston.ac.uk
Received J uly 16, 2001
In tr od u ction
Many naturally occurring biologically active com-
pounds contain one or more oxazole heterocyclic units,
and recently, there has been considerable interest in the
synthesis of such oxazole-containing natural products.1
In addition, certain oxazole derivatives, most notably, 2,5-
diphenyloxazole, scintillate or emit light in the presence
of ionizing radiation. Our interest in these heterocycles
derives from this latter activity. Previously, we have
synthesized a variety of 4-functionalized-2,5-diphenylox-
azoles and evaluated their scintillation efficiencies for use
as reporter tags in molecular recognition systems.2 More
recently, we have developed a series of scintillant-
containing chemically functionalized polystyrene resin
beads for application in combinatorial chemistry.3 These
“scintillating” polymers can serve as supports for both
solid-phase synthesis and subsequent on-bead scintilla-
tion proximity assay (SPA) of library compounds. Among
other reagents, the preparation of these resins requires
the “scintillant monomer” 2,5-diphenyl-4-vinyloxazole 3,
which was synthesized previously in six steps from ethyl
benzoyl acetate.3,4 To enable scale-up production and the
development of new resins, more efficient routes to 2,5-
diphenyl-4-vinyloxazole (3) and related oxazole-contain-
ing monomers were required.
Resu lts a n d Discu ssion
To establish optimal Stille coupling conditions for use
of 2,5-diphenyloxazole as the electrophile, model coupling
reactions of 4-bromo-2,5-diphenyloxazole (1) and 4-bro-
momethyl-2,5-diphenyloxazole (2) with a range of com-
mercially available tributyltin reagents were investi-
gated. Preliminary investigations determined that the
highly active catalytic systems described by Farina,
prepared conveniently in situ by mixing a palladium
source with an appropriate ligand, gave higher yields
than traditional triphenylphosphine-derived catalytic
systems (Scheme 1).
When triphenylarsine was used in conjunction with
tris(dibenzylidineacetone)dipalladium(0) (Pd2(dba)3) (pal-
ladium/ligand ) 1/4), the desired products were isolated
in modest yields. In each case, recovery of starting
materials led us to believe that the relatively weak
coordinating nature of the triphenylarsine ligand was
responsible for premature catalyst decomposition, which,
in turn, was responsible for reduced product yields.
Substitution of triphenylarsine with the tri-2-furylphos-
phine ligand (palladium/ligand ) 1/4) gave a good
compromise between reaction rate and catalytic stability
and resulted in higher yields of cross-coupled products
in each case (Table 1).
The mild conditions employed in the Stille reaction5
made it an ideal method for introducing polymerizable
groups directly onto the 2,5-diphenyloxazole skeleton via
* Author to whom correspondence should be addressed. Tel.: +44
(0)121 359 3611. Fax: +44 (0)121 359 4094.
† Dedicated to Professor Ian O. Sutherland on the occasion of his
70th birthday.
‡ Current address: Department of Chemistry, BCC582, The Scripps
Research Institute, 10550 N. Torrey Pines Road, La J olla, CA 92037.
(1) For illustrative examples, see: (a) Evans, D. A.; Cee, V. J .; Smith,
T. E.; Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533.
(b) Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536.
(c) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J . J . Am.
Chem. Soc. 2000, 122, 3301. (d) Chattopadhyay, S. K.; Kempson, J .;
McNeil, A.; Pattenden, G.; Reader, M.; Rippon, D. E.; Waite, D. J .
Chem. Soc., Perkin Trans. 1 2000, 15, 2415. (e) Chattopadhyay, S. K.;
Pattenden, G. J . Chem. Soc., Perkin Trans. 1 2000, 15, 2429. (f) Smith,
A. B., III; Friestad, G. K.; Barbosa, J .; Bertounesque, E.; Duan, J . J .-
W.; Hull, K. G.; Iwashima, M. Qiu, Y.; Spoors, P. G.; Salvatore, B. A.
J . Am. Chem. Soc. 1999, 121, 10478. (g) Mulder, R. J .; Shafer, C. M.;
Molinski, T. F J . Org. Chem. 1999, 64, 4995. (h) Williams, D. R.;
Brooks, D..A.; Berliner, M. A. J . Am. Chem. Soc. 1999, 121, 4924.
(2) Clapham, B.; Richards, A.; Wood, M.; Sutherland, A. J . Tetra-
hedron Lett. 1997, 38, 9061.
These findings consolidate existing literature pre-
(3) (a) Clapham, B.; Sutherland, A. J . Tetrahedron Lett. 2000, 41,
2253. (b) Clapham, B.; Sutherland, A. J . Tetrahedron Lett. 2000, 41,
2257. (c) Clapham, B.; Sutherland, A. J . International Patent WO 00/
20475, 2000.
cedent6,7a and demonstrate that Stille coupling proce-
(6) Schaus, J . V.; Panek, J . S. Org. Lett. 2000, 2, 469.
(7) (a) Liu, C.-M.; Chen, B.-H.; Liu, W.-Y.; Wu, X.-L.; Ma, Y.-X. J .
Organomet. Chem. 2000, 598, 348. (b) For the synthesis of 4-bromo-
2,5-diphenyloxazole (1), see: Gilchrist, T. L.; Pearson, D. P. J . J . Chem.
Soc., Perkin Trans. 1 1976, 989.
(4) Tanaka C.; Saito, N. Chem. Abstr. 1963, 58, 3407f.
(5) For reviews of the Stille reaction, see: Farina, V.; Krishnamur-
thy, V.; Scott, W. J . Org. React. 1997, 50, 1-652. Stille, J . K. Angew.
Chem., Int Ed. Engl. 1986, 25, 508.
10.1021/jo0107150 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/29/2001

9034 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
Ta ble 1. Tr i-2-fu r ylp h osp h in e/P d 2(d ba )3-Ca ta lyzed Stille
Cou p lin g Rea ction s of 4-Br om o-2,5-d ip h en yloxa zole (1)
a n d 4-Br om om eth yl-2,5-d ip h en yloxa zole (2) w ith Va r iou s
Sta n n a n es
Sch em e 2
in preparing a 2-oxazolylstannane via direct metal
exchange,8 we were delighted to find that treatment of
4-lithio-2,5-diphenyloxazole9 with the appropriate tri-
alkylstannyl chloride gave good yields of both 2,5-
diphenyl-4-trialkylstannanyloxazoles (5) (Scheme 2).
It has been reported that tributyl tin compounds give
greater aryl/alkyl selectivity than the corresponding
trimethyl tin compounds.10 Consequently, Stille coupling
reactions involving 2,5-diphenyl-4-tributylstannanylox-
azole (5b) were selected primarily for study. Unfortu-
nately, attempts to couple stannane 5b with a variety of
electrophiles under standard reaction conditions gave
disappointing results. Although it was possible to syn-
thesize 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), the
reaction proved capricious, and the best yield obtained
for oxazole 6 was 57% after a reaction time of 20 h.
The use of cocatalytic copper(I) salts in conjunction
with palladium catalysts in Stille reactions has been
widely reported.11 In particular, these systems have given
superior results for cross-couplings of sterically hindered
reaction partners.11a,d Unfortunately, when cocatalytic
copper(I) iodide was added to Stille coupling reactions
employing stannane 5b, no enhancement of either reac-
tion rate or yield was observed.
The addition of copper(II) oxide has also been reported
to enhance Stille coupling reactions. For example, reac-
tions involving 2-pyridyltin compounds have been im-
proved by the addition of CuO under both traditional12
and microwave-promoted fluorous phase13 conditions.
However, only one instance of a CuO-enhanced Stille
coupling reaction involving an oxazole heterocycle has
been reported.7a Moreover, in this case, which involved
the Pd(PPh3)4-mediated coupling of tributylstannylfer-
rocene to 4-bromo-2,5-diphenyloxazole (1), the oxazole
was the electrophile, rather than the stannane.
We were delighted, therefore, to find that, when a
stoichiometric quantity of CuO was added to Stille
coupling reactions involving 2,5-diphenyl-4-tributylstan-
nanyloxazole (5b), a dramatic increase in both reaction
rates and product yields was observed (Scheme 3). For
example, in the case of monomer 2,5-diphenyl-4-(4′-
vinylbenzyl)oxazole (6), the rate of reaction was short-
ened dramatically from 20 to 4 h, and the yield of product
increased from 57 to 95%.
a
All reactions were carried out on a 1 mmol scale in dry
1-methyl-2-pyrrolidinone in the presence of 2.5 mol % Pd2(dba)3,
20 mol % tri-2-furylphosphine, and 1.2 mmol of stannane. Based
on pure material after purification by flash chromatography on
SiO2.
b
dures involving 4-bromo-2,5-diphenyloxazole (1) and
4-bromomethyl-2,5-diphenyloxazole (2) are viable meth-
ods for introducing substituents at the 4-position of a 2,5-
di-functionalized oxazole system either directly or via a
methylene linker. This Stille coupling strategy also
provided an efficient two-step route to 2,5-diphenyl-4-
vinyloxazole (3) from commercially available 2,5-diphe-
nyloxazole in overall 82% yield. In addition, a route to
4-allyl-2,5-diphenyloxazole (4), required for comparative
polymerization studies, has been established. Notably,
the optimum route to this compound utilized 4-bromo-
methyl-2,5-diphenyloxazole (2) rather than 4-bromo-2,5-
diphenyloxazole (1) as the electrophile. Unfortunately,
it did not prove possible to construct styrene-containing
2,5-diphenyloxazoles in this manner. Because these
monomers were needed for comparative polymerization
studies, an alternative coupling strategy was required.
A reversal of the Stille coupling approach, i.e., coupling
a 2,5-diphenyl-4-trialkylstannanyloxazole with an elec-
trophile, was viewed as an attractive alternative. If
successful, this approach would constitute a new and
synthetically flexible method for constructing trisubsti-
tuted oxazole ring systems from 2,5-disubstituted oxazole
precursors. We wished to evaluate whether steric factors
would preclude this alternative route. Accordingly, 2,5-
diphenyl-4-trimethylstannanyloxazole (5a ) and 2,5-
diphenyl-4-tributylstannanyloxazole (5b) were synthe-
sized. Although Barrett had previously reported difficulties
To determine whether this novel coupling strategy
might have generic applicability, we examined the cou-
(8) Barrett, A. G. M.; Kohrt, J . T. Synlett 1995, 415.
(9) Whitney, S. E.; Rickborn, B. J . Org. Chem. 1991, 56, 3058.
(10) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J . Org.
Chem. 1993, 58, 5434.
(11) (a) Han, X.; Stoltz, B. M.; Corey, E. J . J . Am. Chem. Soc. 1999,
121, 7600. (b) Nicoloau, K. C.; Sato, M.; Miller, N. D.; Gunzer, J . L.;
Renaud, J .; Untersteller, E. Angew. Chem., Int. Ed. Engl. 1996, 35,
889. (c) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J . Org. Chem. 1994, 59, 5905. (d) Saa, J . M.; Martorell, G. J .
Org. Chem. 1993, 58, 1963. (e) Liebeskind, L. S.; Riesinger, S. W. J .
Org. Chem. 1993, 58, 408. (f) Liebeskind, L. S.; Fengl, R. W. J . Org.
Chem. 1990, 55, 5359.
(12) Gronowitz, S.; Bjo¨rk, P.; Malm, J .; Ho¨rnfeldt, A. B. J . Orga-
nomet. Chem. 1993, 460, 127.
(13) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg,
A. J . Org. Chem. 1997, 62, 5583.

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9035
Sch em e 3
Con clu sion
In summary, we have developed a mild and syntheti-
cally flexible Stille coupling procedure that exploits 2,5-
diphenyl-4-trialkylstannanyloxazoles (5) to provide an
attractive synthetic route for introducing the oxazole
heterocycle into target molecules. This straightforward,
clean, and high-yielding procedure should be of use in
natural product synthesis, combinatorial library genera-
tion, and the construction of scintillant-containing ma-
terials.
Ta ble 2. Cop p er (II) Oxid e-En h a n ced
P a lla d iu m -Ca ta lyzed Stille Cou p lin g Rea ction s of
2,5-Dip h en yl-4-tr ibu tylsta n n a n yloxa zole (5b) w ith
Va r iou s Electr op h iles
Exp er im en ta l Section
Gen er a l. Reactions were carried out in oven-dried glassware
under nitrogen atmosphere. All commercial reagents were used
without purification, and all solvents were reaction grade. THF
was freshly distilled from sodium/benzophenone under nitrogen.
All reaction mixtures were stirred magnetically and were
monitored by thin-layer chromatography using Merck silica gel
60 F254 precoated glass plates, which were visualized with UV
light and then developed using either iodine, a solution of 10%
phosphomolybdic acid in ethanol, or an aqueous solution of
potassium permanganate. Flash column chromatography was
carried out using Fluka silica gel 60 (0.035-0.070 µm, 220-
440 mesh). 1H NMR and 13C NMR spectra were recorded on a
Brucker AC300 spectrometer. Deuterated chloroform was used
as the solvent, and chemical shift values (δ) are reported in parts
per million relative to the residual signals of this solvent (δ 7.24
for 1H and δ 77.0 for 13C). 13C NMR spectra were recorded using
the PENDANT program.14 Low-resolution mass spectra were
recorded using a Finnigan LCQ ion-trap spectrometer using
atmospheric pressure chemical ionization (APCI). High-resolu-
tion mass spectra were recorded by Mr. Peter Ashton (School of
Chemistry, Birmingham University) using a Micromass LCT
mass spectrometer in the electrospray mode using a mobile
phase of methanol (200 µL min-1) and lock mass to correct the
mass scale. Elemental analyses were performed by Medac Ltd.,
Brunel Science Center, Cooper’s Hill Lane, Engelfield Green,
Egham, Surrey, U.K. Infrared spectra were recorded on a
Perkin-Elmer Paragon 1000 FT-IR spectrometer as either a thin
film pressed between two sodium chloride plates or as a solid
suspended in a potassium bromide disk.
2,5-Dip h en yl-4-vin yloxa zole (3). 4-Bromo-2,5-diphenylox-
azole (1) (300 mg, 1.00 mmol), tris(dibenzylidineacetone)di-
palladium(0) [23 mg, 25 µmol (5 mol % Pd)], and tri-2-
furylphosphine [46 mg, 200 µmol (20 mol % ligand)] were stirred
in 1-methyl-2-pyrrolidinone (20 mL) for 15 min. Tributyl(vinyl)
tin (351 µL; 381 mg, 1.20 mmol) was added, and the resultant
mixture was heated to 65 °C and stirred for 16 h, after which
time blackening of the mixture had occurred. The reaction
mixture was then stirred with a 10% aqueous solution of
potassium fluoride (75 mL) and diethyl ether (25 mL) for 1 h
before being filtered through a pad of Celite. The pad of Celite
was rinsed with a further portion of diethyl ether (25 mL). The
aqueous phase was separated and extracted with a further
portion of diethyl ether (25 mL). The combined organic extracts
were washed with a saturated aqueous solution of ammonium
chloride (4 × 25 mL), dried over magnesium sulfate, and
concentrated under reduced pressure to give a yellow solid. Flash
chromatography (4% diethyl ether in hexanes) gave 2,5-diphenyl-
4-vinyloxazole (3) as a white solid (244 mg, 98%), mp 70-71 °C.
IR (KBr) νmax/cm-1 3053, 2925, and 1637; 1H NMR (300 MHz,
CDCl3) δH 5.47 (1H, dd, J ) 10.9, 2.0 Hz), 6.28 (1H, dd, J )
17.0, 2.0 Hz), 6.79 (1H, dd, J ) 17.0, 10.9 Hz), 7.30-7.48 (6H,
m), 7.64-7.69 (2H, m), and 8.09-8.14 (2H, m); 13C NMR (75
MHz, PENDANT, CDCl3) δC 117.65, 125.8, 126.4, 126.6, 127.2,
128.4, 128.6, 128.7, 128.8, 130.4, 135.2, 146.1, and 160.2; LRMS
a
All reactions were carried out on a 1 mmol scale in dry
1-methyl-2-pyrrolidinone in the presence of 2.5 mol % Pd2(dba)3,
20 mol % ligand, 1 mmol of CuO, and 1.2 mmol of stannane.
Based on pure material after purification by flash chromatog-
b
raphy on SiO2.
pling of a diverse selection of electrophiles with 2,5-
diphenyl-4-tributylstannanyloxazole (5b). Table 2 dem-
onstrates that this variety of electrophiles, which includes
benzyl halide, aryl halides, and acid chlorides, undergoes
successful Stille couplings in generally good yield. It
should be noted that the more stubborn couplings,
involving the introduction of an aryl group directly
adjacent to another aryl group on the oxazole ring,
required the use of the more robust tri-2-furylphosphine-
based catalytic system. Using this new protocol, it also
proved possible to construct monomer 2,5-diphenyl-4-(4′-
vinylphenyl)oxazole (Table 2, entry 2), which had previ-
ously been inaccessible. The copper-mediated reaction is
also readily amenable to scale-up and has enabled the
routine production of multigram quantities of 2,5-diphe-
nyl-4-(4′-vinylbenzyl)oxazole (6) in our laboratories. Fi-
nally, 4-trimethylstannyl-2,5-diphenyloxazole (5a ) also
proved to be an excellent coupling partner in this
reaction, giving a similarly high yield of 2,5-diphenyl-4-
(4′-vinylbenzyl)oxazole (6). We are unaware of any previ-
ous reports involving either the synthesis or the use of
such 2,5-di-substituted-4-stannanyloxazoles.
(APCI) m/z 248 (M + H+); Found C, 82.8; H, 5.3; N, 5.7; C17H13
-
NO requires C, 82.6; H, 5.3; N, 5.7.
4-Allyl-2,5-d ip h en yloxa zole (4). Using the same procedure
as described for the preparation of 2,5-diphenyl-4-vinyloxazole
(14) Homer, J .; Perry, M. C. J . Chem. Soc., Chem. Commun. 1994,
373.

9036 J . Org. Chem., Vol. 66, No. 26, 2001
Notes
(3), 4-bromomethyl-2,5-diphenyloxazole (1) (314 mg, 1.00 mmol)
and tributyl(vinyl)tin (351 µL; 381 mg, 1.20 mmol) were coupled
together to form 4-allyl-2,5-diphenyloxazole (4), after flash
column chromatography (10% diethyl ether in hexanes), as a
white solid (257 mg, 98%), mp 60-62 °C. IR (KBr) νmax/cm-1
organic extracts were washed with a saturated aqueous solution
of ammonium chloride (4 × 25 mL), dried over magnesium
sulfate, and concentrated under reduced pressure to give a
yellow solid. Flash chromatography (10% diethyl ether in
hexanes) gave 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6) as a
white solid (321 mg, 95%), mp 106-108 °C. IR (KBr) νmax/cm-1
1
3058, 2956, 2922, 2853, and 1638; H NMR (300 MHz, CDCl3)
1
δH 3.64 (2H, dt, J ) 6, 2 Hz), 5.29-5.21 (2H, m), 6.10-6.23 (1H,
m), 7.32-7.51 (6H, m), 7.68-7.72 (2H, m), and 8.12-8.17 (2H,
m); 13C NMR (75 MHz, PENDANT, CDCl3) δC 31.5, 116.3, 125.4,
126.2, 127.3, 127.7, 128.5, 128.6, 130.0, 134.4, 135.0, 144.9, 145.9,
and 159.6; LRMS (APCI) m/z 262 (M + H+).
3057, 2925, and 1654; H NMR (300 MHz, CDCl3) δH 4.28 (2H,
s), 5.27 (1H, d, J ) 10.9 Hz), 5.78 (1H, d, J ) 17.6 Hz), 6.77
(1H, dd, J ) 17.6, 10.9 Hz), 7.35-7.54 (10H, m), 7.74-7.77 (2H,
m), and 8.21 (2H, dd, J ) 7.9, 1.8 Hz); 13C NMR (75 MHz,
PENDANT, CDCl3) δC 32.8, 113.1, 125.4, 125.8, 126.2, 126.3,
127.3, 127.8, 128.4, 128.5, 128.7, 130.0, 135.5, 135.7, 136.4, 138.1,
146.3, and 159.7; LRMS (APCI) m/z 338 (M + H+). Found C,
85.2; H, 5.6; N, 4.1; C24H19NO requires C, 85.4; H, 5.6; N, 4.1.
2,5-Dip h en yl-4-(4′-vin ylp h en yl)oxa zole (Ta ble 2, En tr y
2). Using the same procedure as described for the preparation
of 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), 2,5-diphenyl-4-
tributylstannanyloxazole (5b) (612 mg, 1.20 mmol) was coupled
to 4-bromostyrene (131 µL, 183 mg, 1.0 mmol). Tri-2-furylphos-
phine (46 mg, 200 µmol) was used as the ligand, and a reaction
time of 16 h at 65 °C and purification by flash column chroma-
tography (4% diethyl ether in hexanes) gave 2,5-diphenyl-4-(4′-
vinylphenyl)oxazole as a white solid (187 mg, 58%), mp 76-78
°C. IR (KBr) νmax/cm-1 3054, 2925, and 1654; 1H NMR (300 MHz,
CDCl3) δH 5.33 (1H, d, J ) 10.9 Hz), 5.84 (1H, d, J ) 17.6 Hz),
6.78 (1H, dd, J ) 17.6, 10.9 Hz), 7.38-7.53 (8H, m), 7.71-7.78
(4H, m), and 8.18-8.22 (2H, m); 13C NMR (75 MHz, PENDANT,
CDCl3) δC 114.1, 126.4, 126.5, 126.6, 127.3, 128.1, 128.5, 128.6,
128.64, 128.9, 129.1, 130.2, 131.9, 136.4, 137.3, 145.5, and 160.1;
LRMS (APCI) m/z 324 (M + H+).
4-Ben zyl-2,5-d ip h en yloxa zole (Ta ble 1, En tr y 5). Using
the same procedure as described for the preparation of 2,5-
diphenyl-4-vinyloxazole (3), 4-bromomethyl-2,5-diphenyloxazole
(1) (314 mg, 1.00 mmol) and tributylphenyltin (392 µL; 441 mg,
1.20 mmol) were coupled together at 100 °C for 3 h to form
4-benzyl-2,5-diphenyloxazole, after flash column chromatogra-
phy (7.5% diethyl ether in hexanes), as a white solid (262 mg,
84%), mp 90-92 °C. IR (KBr) νmax/cm-1 3059, 3023, and 2921;
1H NMR (300 MHz, CDCl3) δH 4.32 (2H, s), 7.31-7.56 (11H, m),
7.75-7.78 (2H, m), and 8.20-8.24 (2H, m); 13C NMR (75 MHz,
PENDANT, CDCl3) δC 33.2, 125.6, 126.4, 127.5, 128.0, 128.5,
128.6, 128.7, 128.9, 130.2, 135.8, 138.6, 146.5, and 159.9; LRMS
(APCI) m/z 312 (M + H+).
2,5-Dip h en yl-4-tr im eth ylsta n n a n yloxa zole (5a ). To a so-
lution of 2,5-diphenyloxazole (8.21 g, 37.1 mmol) and 2,2,6,6-
tetramethylpiperidine (0.63 mL; 0.53 g, 3.73 mmol) in tetrahy-
drofuran (150 mL) cooled to -78 °C was added sec-butyllithium
(1.3 M solution in cyclohexane, 31.5 mL, 40.1 mmol) over 30 min.
The mixture was allowed to warm to 0 °C over 30 min, and the
resultant solution, containing 2,5-diphenyl-4-lithio-oxazole, was
added via cannula to a solution, cooled to -78 °C, of trimethyltin
chloride (7.40 g, 37.1 mmol) in tetrahydrofuran (50 mL). After
the mixture was warmed to room temperature, the reaction was
quenched cautiously by the addition of a saturated aqueous
solution of ammonium chloride (100 mL). The organic layer was
separated, dried over magnesium sulfate, and concentrated
under reduced pressure to give a dark red solid. Recrystallization
from methanol gave 2,5-diphenyl-4-trimethylstannanyloxazole
4-Bip h en yl-4-yl-2,5-d ip h en yloxa zole (Ta ble 2, En tr y 3).
Using the same procedure as described for the preparation of
2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), 2,5-diphenyl-4-tribu-
tylstannanyloxazole (5b) (612 mg, 1.20 mmol) was coupled to
4-bromobiphenyl (233 mg, 1.0 mmol). Tri-2-furylphosphine (46
mg, 200 µmol) was used as the ligand, and a reaction time of 24
h at 65 °C and purification by flash column chromatography (5%
diethyl ether in hexanes) gave 4-biphenyl-4-yl-2,5-diphenylox-
azole as a white solid (190 mg, 51%), mp 79-81 °C. IR (KBr)
(5a ) (9.50 g, 67%) as a white solid; mp 80-82 °C. IR (KBr) νmax
/
ν
max/cm-1 3056 and 1697; 1H NMR (300 MHz, CDCl3) δH 7.37-
cm-1 3057, 2981, and 2906; 1H NMR (300 MHz, CDCl3) δH 0.50
(9H, s), 7.37-7.54 (6H, m), 7.71-7.75 (2H, m), and 8.18-8.22
(2H, m); 13C NMR (75 MHz, PENDANT, CDCl3) δC -8.7, 125.7,
126.3, 127.8, 128.1, 128.5, 128.6, 129.7, 129.8, 136.0, 157.5, and
161.7; LRMS (APCI) m/z 386 (M + H+).
7.56 (9H, m), 7.67-7.71 (4H, m), 7.76-7.79 (2H, m), 7.85-7.89
(2H, m), and 8.19-8.22 (2H, m); 13C NMR (75 MHz, PENDANT,
CDCl3) δC 126.4, 126.6, 127.0, 127.2, 127.4, 128.4, 128.6, 128.65,
128.7, 128.75, 129.0, 130.3, 131.5, 136.4, 140.6, 140.8, 145.6, and
160.1; LRMS (APCI) m/z 374 (M + H+).
2,5-Dip h en yl-4-tr ibu tylsta n n a n yloxa zole (5b). Using the
same procedure as described for the preparation of 2,5-diphenyl-
4-trimethylstannanyloxazole (5a ), the lithiated anion of 2,5-
diphenyloxazole (8.84 g, 40.0 mmol) and tributyltin chloride (10.9
mL, 13.1 g, 40.2 mmol) were reacted together to give 2,5-
diphenyl-4-tributylstannanyloxazole (5b), after flash column
chromatography (gradient elution with 0-3% diethyl ether in
hexanes), as a colorless oil (15.4 g, 75%). IR (film) νmax/cm-1 3032,
2955, 2924, and 2851; 1H NMR (300 MHz, CDCl3) δH 0.85-1.60
(27H, m), 7.34-7.48 (6H, m), 7.66-7.69 (2H, m), and 8.14 (2H,
dd, J ) 8.3, 1.8 Hz); 13C NMR (75 MHz, PENDANT, CDCl3) δC
10.4, 13.7, 27.2, 29.0, 125.8, 126.4, 128.1, 128.6, 128.65, 129.7,
130.2, 132.0, 136.4, 157.8, 161.7; LRMS (APCI) m/z 512 (M +
2,5-Dip h en yl-4-th iop h en -2-yloxa zole (Ta ble 2, En tr y 4).
Using the same procedure as described for the preparation of
2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), 2,5-diphenyl-4-tribu-
tylstannanyloxazole (5b) (612 mg, 1.20 mmol) was coupled to
2-iodothiophene (110 µL, 209 mg, 1.0 mmol). Tri-2-furylphos-
phine (46 mg, 200 µmol) was used as the ligand, and a reaction
time of 24 h at 80 °C and purification by flash column chroma-
tography (3% diethyl ether in hexanes) gave 2,5-diphenyl-4-
thiophen-2-yloxazole as a white solid (127 mg, 42%), mp 66-68
°C. IR (KBr) νmax/cm-1 3053, 2923, 2853, and 1560; 1H NMR (300
MHz, CDCl3) δH 7.09 (1H, dd, J ) 5.3, 4.6 Hz), 7.37-7.54 (8H,
m), 7.79-7.82 (2H, m), and 8.15-8.20 (2H, m); 13C NMR (75
MHz, PENDANT, CDCl3) δC 125.8, 126.0, 126.5, 126.8, 127.0,
127.4, 127.7, 128.5, 128.66, 128.8, 130.4, 131.3, 134.6, 145.1, and
160.0; LRMS (APCI) m/z 304 (M + H+).
(2,5-Dip h en yloxa zol-4-yl)-p -t olylm et h a n on e (Ta ble 2,
En tr y 5). Using the same procedure as described for the
preparation of 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), 2,5-
diphenyl-4-tributylstannanyloxazole (5b) (612 mg, 1.20 mmol)
was coupled to p-toluoyl chloride (132 µL, 154 mg, 1.0 mmol).
Triphenylarsine (61 mg, 200 µmol) was used as the ligand, and
a reaction time of 4 h at 65 °C and purification by flash column
chromatography (10% diethyl ether in hexanes) gave (2,5-
diphenyloxazol-4-yl)-p-tolylmethanone as a white solid (234 mg,
69%), mp 110-112 °C. IR (KBr) νmax/cm-1 3058, 2921, and 1652;
1H NMR (300 MHz, CDCl3) δH 2.44 (3H, s), 7.30 (2H, d J 7.9),
7.43-7.51 (6H, m), and 8.07-8.19 (6H, m); 13C NMR (75 MHz,
PENDANT, CDCl3) δC 21.6, 126.6, 127.4, 127.6, 128.4, 128.7,
128.8, 130.0, 130.6, 130.8, 132.1, 134.8, 135.1, 143.8, 154.0, 158.8,
and 188.3; LRMS (APCI) m/z 340 (M + H+).
H+); HRMS (EI) m/z 512.1967 (M + H+) (calcd for C27H38NO120
-
Sn, 512.1975).
2,5-Dip h en yl-4-(4′-vin ylben zyl)oxa zole (6). Tris(dibenzy-
lidineacetone)dipalladium(0) [23 mg, 25 µmol (5 mol % Pd)],
triphenylarsine [61 mg, 200 µmol (20 mol % ligand)], and copper-
(II) oxide [79 mg, 1.00 mmol (1 equiv)] were stirred at room
temperature in 1-methyl-2-pyrrolidinone (10 mL) for 15 min.
4-Vinylbenzyl chloride (157 µL; 170 mg, 1.00 mmol as 90%) was
added, and the resultant mixture stirred for a further 15 min
before a solution of 2,5-diphenyl-4-tributylstannanyloxazole (5b)
(612 mg, 1.20 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was
added. The resultant mixture was heated to 65 °C and stirred
for 4 h, after which time blackening of the mixture had occurred.
The reaction mixture was then stirred with a 10% aqueous
solution of potassium fluoride (75 mL) and diethyl ether (25 mL)
for 1 h before being filtered through a pad of Celite. The pad of
Celite was subsequently rinsed with a further portion of diethyl
ether (25 mL). The aqueous phase was separated and extracted
with a further portion of diethyl ether (25 mL). The combined
(2,5-Dip h en yloxa zol-4-yl)ben za ld eh yd e (Ta ble 2, En tr y
6). Using the same procedure as described for the preparation

Notes
J . Org. Chem., Vol. 66, No. 26, 2001 9037
of 2,5-diphenyl-4-(4′-vinylbenzyl)oxazole (6), 2,5-diphenyl-4-
tributylstannanyloxazole (5b) (612 mg, 1.20 mmol) was coupled
to 4-bromobenzaldehyde (185 mg, 1.0 mmol). Tri-2-furylphos-
phine (46 mg, 200 µmol) was used as the ligand, and a reaction
time of 16 h at 65 °C and purification by flash column chroma-
tography (15% diethyl ether in hexanes) gave (2,5-diphenylox-
azol-4-yl)benzaldehyde as a white solid (267 mg, 82%), mp 126-
128 °C. IR (KBr) νmax/cm-1 3056, 2923, 2818, 2732, 1697; 1H
NMR (300 MHz, CDCl3) δH 7.38-7.49 (6H, m), 7.62-7.67 (2H,
this work. B.C. thanks the Research Enhancement Fund
of The Nottingham Trent University for the provision
of a Research Studentship. We thank Dr. Mike Perry
and Mrs. Karen Farrow (both of Aston University) for
NMR and LRMS measurements and Mr. Peter Ashton
(School of Chemistry, Birmingham University) for HRMS
measurements. We thank Dr. Anna V. Hine (Aston
University) for assistance with the preparation of this
manuscript.
m), 7.86-7.93 (4H, m), 8.12-8.15 (2H, m), and 10.0 (1H, s); 13
C
NMR (75 MHz, PENDANT, CDCl3) δC 126.3, 126.9, 126.95,128.1,
128.4, 128.7, 128.75, 129.1, 129.8, 130.5, 135.2, 135.6, 138.4,
146.9, 160.4, and 191.5; LRMS (APCI) m/z 326 (M + H+).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank both Aston University
and The Nottingham Trent University for supporting
J O0107150