C-H bond activation: A versatile protocol for the direct arylation and alkenylation of oxazoles

Article abstract of DOI:10.1055/s-0029-1216987

The versatile palladium, complex Pd(PPh₃)₄ catalyses both direct arylation and alkenylation of oxazoles efficiently. The method is regioselective and stereospecific with respect to bromoalkenes and tolerates a wide range of functional groups.

Full text of DOI:10.1055/s-0029-1216987

SPECIAL TOPIC
3511
C–H Bond Activation: A Versatile Protocol for the Direct Arylation and
Alkenylation of Oxazoles
D
irec
t
A
rylatio
r
n and
A
a
lkenylation
n
of
O
xazole
s
çois Besselièvre,a Sabrina Lebrequier,b Florence Mahuteau-Betzer,b Sandrine Piguel*a
a
Univ Paris-Sud 11, 91405 Orsay, France
Fax +33(1)69075381; E-mail: sandrine.piguel@curie.u-psud.fr
b
Institut Curie/CNRS, UMR176, Bât. 110, Centre Universitaire, 91405 Orsay, France
Received 29 March 2009
polyfluorobenzene and benzotriazepine, respectively, but
a general method remains elusive.10
Abstract: The versatile palladium complex Pd(PPh3)4 catalyses
both direct arylation and alkenylation of oxazoles efficiently. The
method is regioselective and stereospecific with respect to bro-
moalkenes and tolerates a wide range of functional groups.
In pursuit of our efforts dedicated to C–H bond activation,
we now disclose a general, rapid, efficient and functional
Key words: oxazole, arylation, alkenylation, palladium, C–H acti- group tolerant protocol for both arylation and stereospe-
vation
cific alkenylation of oxazoles at position C-2.
Our group recently described the first direct alkenylation
of azoles with (E)-b-bromostyrenes using copper catalyst9
Metal-catalyzed direct functionalization of both electron-
rich and electron-poor heteroarenes has gained enormous
attention over the past decade as an effective and straight-
forward method for creating aryl/alkenyl–heteroaryl link-
ages since it presents many advantages over traditional
cross-coupling reactions. Clearly, major time and atom
economy can be achieved once the need to prepare a suit-
ably activated heteroarene has been eliminated. An im-
(CuI, trans-N,N¢-dimethylcyclohexane-1,2-diamine as
ligand, t-BuOLi as base, and dioxane as solvent). The
method is both regio- and stereoselective and tolerates a
variety of functional groups. A wide range of (E)-2-vinyl-
substituted oxazoles were obtained in high yields. Howev-
er, the reaction did not proceed with (Z)-b-bromostyrene
(2) and optimization work to find an efficient copper cat-
alyst-based protocol for the coupling of 5-phenyloxazole
(1) with 2 failed. The problem was overcome by using the
pressive array of reaction conditions has been developed
most often using aryl iodides or bromides as the coupling
classical and readily available palladium catalyst
partner in the presence of a metal catalyst (palladium,
Pd(PPh3)4 instead of the copper/diamine duet. Indeed, the
rhodium, ruthenium, or copper) with or without a ligand
coupling of 5-phenyloxazole (1) with (Z)-b-bromostyrene
(2, 2 equiv), employing Pd(PPh3)4 (5 mol%), t-BuOLi (2
equiv) as base, and dioxane as solvent at 120 °C for two
hours, afforded the desired (Z)-5-phenyl-2-styryloxazole
and with an inorganic base in polar solvents.1 In an inter-
esting recent development, Greaney proposed an alterna-
tive to these classical protocols using an ‘on water’ green
strategy2. Ackermann has shown that direct arylation can
(5a) in 73% yield, as a single diastereoisomer (Scheme 1).
also be performed with tosylate and mesylate derivatives,3
Interestingly, whilst this catalyst gave a stereospecific re-
whilst in a very recent work, Miura and Itami indepen-
action, various other metal/ligand combinations gave poor
dently reported the first examples of nickel-catalyzed di-
conversions and/or E/Z isomer mixtures. Furthermore, at-
rect arylation of azoles with aryl halides and triflates.4
tempts to change the base or the solvent gave disappoint-
ing results. Polar solvents such as DMF or DMSO were
ineffective while only trace amounts of 5a were isolated
when the reaction was performed in toluene. The choice
of t-BuOLi was found to be optimal since weaker bases
(Cs2CO3, K3PO4), organic base (Et3N), and other alkox-
ides (t-BuOK, t-BuONa) failed to give 5a.
The azoles have been the focus of intensive work in the
field of metal-catalyzed direct arylation5 or alkenylation6
and in particular the oxazole ring, a commonly occurring
motif in natural molecules, pharmaceuticals, and many
other compounds bearing various interesting properties.7
Our previous contributions in this area were concerned
with the microwave-accelerated Pd/Cu-catalyzed and
Satisfyingly, these reaction conditions also appeared to be
ligandless direct arylation of oxazoles with aryl bromides8
efficient for the direct arylation of 5-phenyloxazole (1)
and the direct copper-catalyzed alkenylation of azoles
with bromobenzene (3) and the direct alkenylation with
(E)-b-bromostyrene (4) to give compounds 6a and 7a in
89% and 79% yield, respectively. With this promising
protocol in hand, we examined the direct arylation and
alkenylation processes of oxazole derivatives with aryl
and alkenyl bromides as coupling partners.
with bromoalkenes.9 Whilst a single protocol for both ary-
lation and alkenylation would present huge advantages to
access structurally diverse targets, few examples have
been described. Daugulis and later Ellman, have shown
that copper catalyzes both arylation and alkenylation of
First, the scope of the direct arylation was evaluated with
a wide range of aryl bromides (Table 1), as the analogous
chlorinated derivatives are not reactive in this case. Both
SYNTHESIS 2009, No. 20, pp 3511–3518
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1216987; Art ID: C03309SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3512
F. Besselièvre et al.
SPECIAL TOPIC
N
Br
O
+
73%
89%
2
3
4
5a
N
N
Br
O
+
O
1
6a
N
Br
+
O
79%
7a
Scheme 1 Reagents and conditions: b-Bromostyrene (2 equiv) or bromobenzene (1.5 equiv), Pd(PPh3)4 (5 mol%), t-BuOLi (2 equiv), dioxane
(0.35 M), 120 °C (2 h for 5a and 6a, 4 h for 7a). Yields are calculated on isolated pure products.
electron-withdrawing and electron-donating aryl bro- fully applied to oxazoles 6j–n bearing electronically
mides reacted regioselectively at the C-2 position of the different groups at position C-5. Both electron-rich and
oxazole in good to high yields. Substitutions at the ortho, electron-poor oxazoles can be efficiently arylated even in
meta, or para positions of the phenyl ring were well toler- the extreme case 6l where both the substrate and the aryl
ated. However, in the case of ortho-substituted bromoben- bromide are very electron-rich and sterically crowded.
zenes 6b, 6c, 6l, steric hindrance induced a decrease in the Noteworthy is the 2,5-diaryloxazole, uguenenazole (6m),
yield. Nevertheless, the conditions proved to be compati- recently isolated from the root of Vepris uguenensis,11
ble with a wide range of functional groups including nitro, which was synthesized using this methodology in excel-
chloro, and cyano, which may be used for further transfor- lent yield (94%).
mations. Furthermore, the conditions were also success-
Table 1 Scope of the Direct Arylation of 5-Phenyloxazole with Aryl Bromidesa
N
N
R
Pd(PPh3)4
t-BuOLi
dioxane
120 °C
Br
O
O
+
R
1
3
6
Product
Time (h)
4
Yield (%)
64
N
O
6b
6c
N
O
5
58
OMe
OMe
OMe
N
O
6d
6e
2
2
75
96
N
O
Cl
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct Arylation and Alkenylation of Oxazoles
3513
Table 1 Scope of the Direct Arylation of 5-Phenyloxazole with Aryl Bromidesa (continued)
N
N
R
Pd(PPh3)4
t-BuOLi
dioxane
120 °C
Br
O
O
+
R
1
3
6
Product
Time (h)
3
Yield (%)
94
N
O
6f
6g
6h
6i
N
N
O
4
2
2
4
93
96
72b
71
CF3
N
O
CN
N
O
NO2
N
BnO
BnO
6j
O
N
N
N
BnO
BnO
6k
6l
4
5
68
48
O
MeO
N
BnO
BnO
OMe
O
MeO
N
6m
6n
2
2
94
85
O
MeO
N
O
F3C
a Reaction conditions: aryl bromide (1.5 equiv), Pd(PPh3)4 (5 mol%), t-BuOLi (1.5 equiv), dioxane (0.35 M), 120 °C. Yields are calculated on
isolated products.
b In this particular example, yields fluctuated when using different sources of t-BuOLi (0 to 72%). At present, we have no explanation for these
irregular results.
Next, these new conditions were applied to the direct alk- alkenylated oxazoles, albeit in slightly lower yields than
enylation of 5-phenyloxazole (1) with various alkenyl those observed in the direct arylation process. Crucially,
bromides 2 and 4 (Table 2). Importantly, the reaction pro- the alkenylation with (Z)-b-bromostyrenes has to be care-
ceeds equally well with E- or Z-isomers and with tri- and fully monitored as isomerization of the Z-product to the
tetrasubstituted alkenes (8, 9). As expected, diverse func- corresponding E-form can occur when the reaction time is
tional groups survive the reaction conditions to give the prolonged. Therefore, a compromise between conversion
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

3514
F. Besselièvre et al.
SPECIAL TOPIC
Table 2 Scope of the Direct Alkenylation of 5-Phenyloxazole with
and isomerization has to be made. For instance, for com-
pounds 5a and 5b, no E-isomer was detected at comple-
tion (2 h) whereas after prolonged heating (overnight), a
9:1 Z/E-diastereoisomer mixture was isolated. In the case
of (Z)-styryloxazoles 5c and 5e bearing ortho-substituents
isomerization appeared before total conversion. Extend-
ing the reaction time for 5c (15 h) led to a significant in-
crease in the Z/E isomer ratio, from 95:5 to 1:1. In
addition, (Z)-b-Bromostyrenes bearing strong electron-
withdrawing groups such as CF3 or NO2 did not react at
all. This is likely due to the increased acidity of the olefin-
ic protons, which in the presence of lithium tert-butoxide
afford the corresponding alkynes via the anti-elimination
of HBr. The direct alkenylation process is then totally
overrun.
Alkenyl Bromidesa (continued)
R3
R3
N
N
Pd(PPh3)4
t-BuOLi
dioxane
120 °C
R2
Br
O
O
+
R2
R1
2/4
R1
1
5/7
Product
Time Yield
(h)
(%)
N
NO2
7e
3
54
O
N
Clearly, using our protocol with C-5 substituted oxazoles,
direct arylation/alkenylation proceeds exclusively at C-2.
However, we were keen to investigate the regioselectivity
of C–H activation of the unsubstituted oxazole ring,
which has received only meager attention in the litera-
ture.4b,5b,c,g,i We were intrigued to discover that, under our
conditions, the reaction of oxazole (10) with two equiva-
lents of bromobenzene for four hours at 100 °C afforded
the 2-phenyloxazole (11) as a single regioisomer in good
yield (75%, Scheme 2). Furthermore, the 2,5-diphenylox-
azole only started to appear upon prolonged reaction time
at elevated temperature (>120 °C). In this way, (Z)-2-
styryloxazole (12) and (E)-2-styryloxazole (13) have been
synthesized from the corresponding bromostyrenes in
56% and 64% yield, respectively (Scheme 2).12
O
5b
5c
4
4
90
F
N
54b
O
Cl
N
O
5d
2
73
MeO
Table 2 Scope of the Direct Alkenylation of 5-Phenyloxazole with
N
Alkenyl Bromidesa
R3
O
R3
N
N
5e
5f
2
4
68b
Pd(PPh3)4
t-BuOLi
dioxane
120 °C
R2
Br
O
O
+
R2
R1
2/4
R1
1
5/7
N
Product
Time Yield
50c
O
(h)
(%)
N
OMe
7b
6
61
O
N
OMe
8
9
4
4
66
71
O
N
7c
4
2
57
77
O
N
Cl
O
N
7d
O
a Reaction conditions: alkenyl bromide (2 equiv), Pd(PPh3)4 (5
mol%), t-BuOLi (2 equiv), dioxane (0.35 M), 120 °C. Yields are cal-
culated on isolated geometrically pure products.
CF3
b (Z)-Bromostyrenes are contaminated with 5% of E-isomers, there-
fore 5c and 5e contain 5% and 11% of the E-isomer coupling product,
respectively. In the case of 5e, isomers are not separable.
c Less than 10% of the E-isomer was observed.
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct Arylation and Alkenylation of Oxazoles
3515
Pd(PPh3)4-Catalyzed Direct Arylation of 5-Phenyloxazole (1)
with Aryl Bromides 3; General Procedure
N
Br
+
75%
56%
64%
O
A flame-dried tube filled with argon was charged with 5-phenylox-
azole (1; 100.0 mg, 0.69 mmol, 1 equiv), the appropriate aryl bro-
mide 3 (1.04 mmol, 1.5 equiv), Pd(PPh3)4 (40.4 mg, 0.035 mmol,
0.05 equiv), t-BuOLi (82.8 mg, 1.04 mmol, 1.5 equiv), and dioxane
(2 mL). The tube was sealed and heated to 120 °C for the time indi-
cated in Table 1. The reaction mixture was taken into EtOAc (10
mL) and H2O (20 mL) was added. This mixture was extracted with
EtOAc (3 × 20 mL) and the combined organic layers were washed
with brine (20 mL), and dried (MgSO4). Solvents were removed un-
der reduced pressure and the crude was purified by flash chroma-
tography on silica gel using cyclohexane–EtOAc (starting from
95:5 ratio) as a solvent mixture (Table 1).
11
N
N
O
Br
+
O
10
12
N
Br
+
O
13
2,5-Diphenyloxazole (6a)
Yield: 136 mg (89%); white crystals; mp 72–74 °C.
1H NMR (300 MHz, CDCl3): d = 7.35 (t, J = 7.2 Hz, 1 H), 7.40–7.55
(m, 6 H), 7.73 (d, J = 7.7 Hz, 2 H), 8.10–8.15 (m, 2 H).
Spectral data were in agreement with those previously reported.15
Scheme 2 Reagents and conditions: Alkenyl bromide (2 equiv at
120 °C) or aryl bromide (2 equiv at 100 °C), Pd(PPh3)4 (5 mol%), t-
BuOLi (2 equiv), dioxane (0.35 M), 120 °C, 4 h. Yields are calculated
on isolated pure products.
It is interesting to note that by combining our C-2 selec-
tive arylation methodology with Greaney’s on water
procedure2 to arylate selectively at position C-5 and the
Fagnou method13 to functionalize at position C-4, the ox-
azole ring can be now arylated at all three available posi-
tions (Scheme 3). Therefore, this direct arylation strategy
offers a quick and flexible route to triarylated oxazoles.
Moreover, this methodology should be suitable for paral-
lel synthesis of combinatorial libraries of oxazole deriva-
2-(Naphthalen-1-yl)-5-phenyloxazole (6b)
Yield: 120 mg (64%); off-white solid; mp 104–106 °C.
1H NMR (300 MHz, CDCl3): d = 7.37 (t, J = 7.3 Hz, 1 H), 7.48 (t,
7.7 Hz, 2 H), 7.55–7.65 (m, 3 H), 7.68 (t, J = 7.6 Hz, 1 H), 7.79 (d,
J = 7.4 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H),
8.31 (d, J = 7.2 Hz, 1 H), 9.34 (d, J = 8.5 Hz, 1 H).
Spectral data were in agreement with those previously reported.8
2-(2,6-Dimethylphenyl)-5-phenyloxazole (6c)
tives bearing different aryl groups in C-2, C-4, and C-5 Yield: 100 mg (58%); off-white solid; mp <40 °C.
1H NMR (300 MHz, CDCl3) d = 2.34 (s, 6 H, 2 CH3), 7.14 (d, J = 7.5
Hz, 2 H), 7.25–7.40 (m, 2 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.51 (s, 1 H),
7.69 (d, J = 7.4 Hz, 2 H).
positions.
In conclusion, we have developed new conditions for C–
H bond functionalization, which enable both direct aryla-
tion and stereospecific alkenylation of various oxazoles
with aryl and Z- or E-alkenyl bromides. The method toler-
ates a wide variety of functional groups and allows the
rapid preparation of 2,5-diphenyloxazoles and (Z)- or (E)-
2-vinyl-5-phenyloxazoles in good to high yields using the
simple and easily accessible tetrakis(triphenylphos-
phine)palladium(0) catalyst.
Spectral data were in agreement with those previously reported.8
5-Phenyl-2-(3,4,5-trimethoxyphenyl)oxazole (6d)
Yield: 161 mg (75%); off-white solid; mp 108–110 °C.
1H NMR (300 MHz, CDCl3): d = 3.91 (s, 3 H), 3.97 (s, 6 H), 7.30–
7.40 (m, 3 H), 7.40–7.50 (m, 3 H), 7.71 (d, J = 7.4 Hz, 2 H).
Spectral data were in agreement with those previously reported.8
2-(4-Chlorophenyl)-5-phenyloxazole (6e)
Yield: 169 mg (96%); off-white solid; mp 110–112 °C.
1H NMR (300 MHz, CDCl3): d = 7.35 (t, J = 7.3 Hz, 1 H), 7.40–7.50
(m, 5 H), 7.71 (d, J = 7.3 Hz, 2 H), 8.03 (d, J = 8.5 Hz, 2 H).
Spectral data were in agreement with those previously reported.8
Commercially available reagents and solvents were used without
further purification. Pd(PPh3)4 was prepared according to Coulson’s
protocol.14 Yields refer to isolated and purified products. Reactions
were monitored by TLC carried out on silica gel plates (60F-254)
visualized under UV light. Column chromatography was performed
1
on silica gel 60, 40–63 mm. Chemical shifts of H NMR and 13C
3-(5-Phenyloxazol-2-yl)pyridine (6f)
Yield: 144 mg (94%); white solid; mp 88–90 °C.
NMR were reported in ppm (d units) and residual non deuterated
solvent was used as internal reference.
R3
N
N
Greaney
Fagnou
N
O
O
R1
O
R1
R2
R1
R2
Scheme 3 Synthesis of polyarylated oxazoles
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

3516
F. Besselièvre et al.
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): d = 7.49–7.36 (m, 5 H), 7.73 (m, 2 H),
8.37 (dt, J = 8.1, 1.8 Hz, 1 H), 8.70 (dd, J = 4.9, 1.6 Hz, 1 H), 9.35
(d, J = 1.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.4, 56.0, 71.2, 71.4, 90.6, 99.9,
111.2, 115.2, 117.8, 121.6, 122.3, 127.1, 127.2, 127.4, 127.8, 127.9,
128.5, 137.0, 148.9, 149.1, 151.1, 156.2, 160.7, 163.1.
Spectral data were in agreement with those previously reported.16
MS (ESI): m/z (%) = 524.1 (100, [M + H]+), 546 (50, [M + Na]+).
HRMS (ESI): m/z calcd for C29H33NO6 [(M + H)+]: 524.2073;
found: 524.2070.
5-Phenyl-2-(3-trifluoromethylphenyl)oxazole (6g)
Yield: 189 mg (93%); white solid; mp 126–128 °C.
1H NMR (300 MHz, CDCl3): d = 7.37 (t, J = 7.2 Hz, 1 H) 7.40–7.55
(m, 3 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.65–7.80 (m, 3 H), 8.28 (d,
J = 7.6 Hz, 1 H), 8.36 (s, 1 H).
Uguenenazole (6m)
Yield: 134 mg (94%); white solid; mp 133–135 °C.
1H NMR (300 MHz, CDCl3): d = 3.86 (s, 3 H), 6.97 (d, J = 9.0 Hz,
2 H), 7.32 (s, 1 H), 7.45 (m, 3 H), 7.65 (d, J = 9.0 Hz, 2 H), 8.09 (dd,
J = 8.1, 1.7 Hz, 2 H).
Spectral data were in agreement with those previously reported.8
4-(5-Phenyloxazol-2-yl)benzonitrile (6h)
Yield: 161 mg (96%); white solid; mp 174–176 °C.
Data are in agreement with those previously published.11
1H NMR (300 MHz, CDCl3): d = 7.30–7.55 (m, 4 H), 7.60–7.85 (m,
4 H), 8.18 (d, J = 8.2 Hz, 2 H).
2-Phenyl-5-(4-trifluoromethylphenyl)oxazole (6n)
Yield: 173 mg (85%); white solid; mp 97–99 °C.
Spectral data were in agreement with those previously reported.8
1H NMR (300 MHz, CDCl3): d = 7.45–7.52 (m, 3 H), 7.56 (s, 1 H),
7.69 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 8.2 Hz, 2 H), 8.10–8.15 (m, 2
2-(3-Nitrophenyl)-5-phenyloxazole (6i)
H).
Yield: 132 mg (72%); pale yellow solid; mp 148–150 °C.
Data are in agreement with those previously published.2
1H NMR (300 MHz, CDCl3): d = 7.38 (t, J = 7.2 Hz, 1 H), 7.45–7.55
(m, 3 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.74 (d, J = 7.3 Hz, 2 H), 8.30 (d,
J = 7.9 Hz, 1 H), 8.42 (d, J = 7.7 Hz, 1 H), 8.91 (s, 1 H).
Pd(PPh3)4-Catalyzed Direct Alkenylation of 5-Phenyloxazole
(1) with Alkenyl Bromides 2, 4; General Procedure
A flame-dried tube filled with argon was charged with 5-phenylox-
azole (1; 100.0 mg, 0.69 mmol, 1 equiv), the appropriate alkenyl
bromide 2, 4 (1.38 mmol, 2 equiv), Pd(PPh3)4 (40.4 mg, 0.035
mmol, 0.05 equiv), t-BuOLi (110.4 mg, 1.38 mmol, 2 equiv), and
dioxane (2 mL). The tube was sealed and heated to 120 °C for the
time indicated in Table 2. The reaction mixture was taken into
EtOAc (10 mL) and H2O (20 mL) was added. This mixture was ex-
tracted with EtOAc (3 × 20 mL) and the combined organic layers
were washed with brine (20 mL), and dried (MgSO4). Solvents were
removed under reduced pressure and the crude was purified by flash
chromatography on silica gel using cyclohexane–EtOAc (starting
from 97:3 ratio) as a solvent mixture (Table 2).
Spectral data were in agreement with those previously reported.8
3-{5-[3,4-Bis(benzyloxy)phenyl]oxazol-2-yl}pyridine (6j)
Reaction run on 500 mg; yield: 432 mg (71%); white crystals from
heptane; mp 126–128 °C.
1H NMR (300 MHz, CDCl3): d = 5.21 (s, 2 H), 5.24 (s, 2 H), 6.98
(d, J = 8.2 Hz, 1 H), 7.20–7.50 (m, 14 H), 8.30 (ddd, J = 8.0,
1.9, 1.9 Hz, 1 H), 8.68 (dd, J = 4.8, 1.5 Hz, 1 H), 9.29 (d, J = 1.5 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 71.1, 71.6, 111.4, 115.0, 118.1,
121.1, 122.5, 123.6, 123.7, 127.2, 127.4, 127.9, 128.0, 128.5, 128.6,
133.2, 136.8, 136.9, 147.4, 149.2, 149.6, 150.8, 151.8, 158.2.
(E)-5-Phenyl-2-styryloxazole (7a)
Yield: 136 mg (79%); white solid; mp 102–104 °C.
MS (ESI): m/z (%) = 435.0 (100, [M + H]+), 457.0 (70, [M + Na]+).
Anal. Calcd for C28H22N2O3·0.25H2O: C, 76.61; H, 5.17; N, 6.38.
Found: C, 76.65; H, 4.81; N, 6.29.
1H NMR (300 MHz, CDCl3): d = 7.00 (d, J = 16.4 Hz, 1 H), 7.30–
7.50 (m, 7 H), 7.55–7.60 (m, 3 H), 7.70 (d, J = 7.3 Hz, 2 H).
Data are in agreement with those previously published.17
4-{5-[3,4-Bis(benzyloxy)phenyl]oxazol-2-yl}pyridine (6k)
Reaction run on 500 mg; yield: 413 mg (68%); white crystals from
heptane; mp 138–140 °C.
1H NMR (300 MHz, CDCl3): d = 5.21 (s, 2 H), 5.24 (s, 2 H), 6.99
(d, J = 8.1 Hz, 1 H), 7.20–7.50 (m, 13 H), 7.89 (d, J = 6.0 Hz, 2 H),
8.75 (d, J = 6.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 71.1, 71.6, 111.6, 114.9, 118.3,
119.7, 120.8, 122.9, 127.2, 127.4, 127.9, 128.0, 128.5, 128.6, 134.2,
136.7, 136.9, 149.2, 149.9, 150.5, 152.4, 158.2.
(E)-2-[2-(3,4-Dimethoxyphenyl)vinyl]-5-phenyloxazole (7b)
Yield: 133 mg (61%); pale yellow solid; mp 114–116 °C.
1H NMR (300 MHz, CDCl3): d = 3.92 (s, 3 H), 3.95 (s, 3 H), 6.85
(d, J = 16.3 Hz, 1 H), 6.89 (d, J = 8.1 Hz, 1 H), 7.05–7.15 (m, 2 H),
7.33 (t, J = 7.4 Hz, 1 H), 7.40 (s, 1 H), 7.46 (t, J = 7.7 Hz, 2 H), 7.51
(d, J = 16.3 Hz, 1 H), 7.69 (d, J = 7.4 Hz, 2 H).
Data are in agreement with those previously published.9
MS (ESI): m/z (%) = 435.0 (100, [M + H]+), 457.0 (35, [M + Na]+).
(E)-2-[2-(4-Chlorophenyl)vinyl]-5-phenyloxazole (7c)
Anal. Calcd for C28H22N2O3: C, 77.40; H, 5.10; N, 6.45. Found:
C, 77.14; H, 5.01, N, 6.37.
Yield: 111 mg (57%); pale yellow solid; mp 148–150 °C.
1H NMR (300 MHz, CDCl3): d = 6.95 (d, J = 16.6 Hz, 1H), 7.32–
7.55 (m, 9H), 7.67–7.72 (m, 2H).
5-[3,4-Bis(benzyloxy)phenyl]-2-(2,4,6-trimethoxyphenyl)ox-
azole (6l)
Data are in agreement with those previously published.18
Reaction run on 500 mg; 384 mg (48%); pale yellow solid; mp 126–
128 °C.
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 6 H), 3.86 (s, 3 H), 5.18
(s, 2 H), 5.19 (s, 2 H), 6.17 (s, 2 H), 6.95 (d, J = 8.4 Hz, 1 H), 7.20–
7.50 (m, 13 H).
(E)-5-Phenyl-2-[2-(4-trifluoromethylphenyl)vinyl]oxazole (7d)
Yield: 167 mg (77%); off-white solid; mp 154–156 °C.
1H NMR (300 MHz, CDCl3): d = 7.07 (d, J = 16.4 Hz, 1 H), 7.36 (t,
J = 7.3 Hz, 1 H), 7.40–7.50 (m, 3 H), 7.57 (d, J = 16.4 Hz, 1 H),
7.65 (br s, 4 H), 7.71 (d, J = 7.4 Hz, 2 H).
Data are in agreement with those previously published.9
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

SPECIAL TOPIC
Direct Arylation and Alkenylation of Oxazoles
3517
(E)-2-[2-(3-Nitrophenyl)vinyl]-5-phenyloxazole (7e)
Yield: 109 mg (54%); white solid; mp 168–170 °C.
(s, 1 H), 7.40–7.55 (m, 5 H), 7.64 (d, J = 7.0 Hz, 1 H), 7.90–7.95
(m, 2 H), 7.99–8.03 (m, 1 H).
1H NMR (300 MHz, CDCl3): d = 7.09 (d, J = 16.4 Hz, 1 H), 7.35 (t,
J = 7.4 Hz, 1 H), 7.40–7.50 (m, 3 H), 7.55–7.65 (m, 2 H), 7.70 (d,
J = 7.2 Hz, 2 H), 7.84 (d, J = 7.8 Hz, 1 H), 8.17 (dd, J = 8.1, 1.5 Hz,
1 H), 8.38 (s, 1 H).
13C NMR (75 MHz, CDCl3): d (mixture of isomers) = 116.3, 117.8,
122.8, 123.5, 123.7, 123.9, 124.1, 124.4, 124.8, 125.2, 125.7, 126.0,
126.2, 126.3, 126.5, 126.7, 127.5, 128.3, 128.4, 128.5, 128.7, 128.8,
128.9, 129.6, 130.0, 131.5, 133.6, 133.8, 134.2, 134.6, 150.9, 151.1,
160.0, 161.3
Data are in agreement with those previously published.9
MS (ESI): m/z (%) = 298.1 (100, [M + H]+), 320.1 (60, [M + Na]+).
(Z)-5-Phenyl-2-styryloxazole (5a)
Yield: 124 mg (73%); white solid; mp 98–100 °C.
1H NMR (300 MHz, CDCl3): d = 6.48 (d, J = 12.8 Hz, 1 H), 6.93 (d,
J = 12.8 Hz, 1 H), 7.25–7.50 (m, 9 H), 7.68 (m, 2 H).
HRMS (ESI): m/z calcd for C21H16NO [(M + H)+]: 298.1232; found:
298.1230.
2-(2-Cyclohexylvinyl)-5-phenyloxazole (5f)
Yield: 87 mg (50%); pale yellow oil.
13C NMR (75 MHz, CDCl3): d = 115.0, 123.2, 124.1, 127.7, 128.0,
128.4, 128.8, 129.2, 136.1, 136.2, 150.6, 159.9.
1H NMR (300 MHz, CDCl3): d = 1.14–1.87 (m, 10 H), 3.27 (m, 1
H), 5.89 (dd, J = 12, 9 Hz, 1 H), 6.20 (d, J = 12 Hz, 1 H), 7.29–7.43
(m, 4 H), 7.63 (d, J = 9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 25.8, 26.0, 32.6, 38.2, 113.1, 123.0,
124.0, 128.1, 128.3, 129.0, 146.3, 150.3, 160.8.
MS (ESI): m/z (%) = 248.1 (100, [M + H]+), 270.1 (30, [M + Na]+).
HRMS (ESI): m/z calcd for C17H14NO [(M + H)+]: 248.1075; found:
248.1065.
(Z)-2-[2-(3-Fluorophenyl)vinyl]-5-phenyloxazole (5b)
MS (ESI): m/z = 254.1 (100%, [M + H]+).
Yield: 165 mg (90%); pale yellow solid; mp 78–80 °C.
HRMS (ESI): m/z calcd for C17H20NO [(M + H)+]: 254.1545; found:
254.1541.
1H NMR (300 MHz, CDCl3): d = 6.52 (d, J = 12.8 Hz, 1 H), 6.84 (d,
J = 12.8 Hz, 1 H), 7.08 (m, 1 H), 7.25–7.50 (m, 8 H), 7.59 (d,
J = 10.0 Hz, 1 H).
2-(1,2-Dimethylpropenyl)-5-phenyloxazole (8)
Yield: 97 mg (66%); pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.96 (s, 3 H), 2.16 (s, 3 H), 2.24
(s, 3 H), 7.30–7.45 (m, 4 H), 7.65 (d, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 16.6, 22.9, 23.1, 117.4, 122.4,
123.9, 128.0, 128.3, 128.8, 139.2, 149.7, 163.6.
13C NMR (75 MHz, CDCl3): d = 115.3 (d, J = 21 Hz), 115.8, 115.9
(d, J = 22 Hz), 123.3, 124.1, 125.3 (d, J = 21 Hz), 127.6, 128.6,
128.9, 129.5 (d, J = 8 Hz), 134.5 (d, J = 2 Hz), 138.1 (d, J = 8 Hz),
150.9, 159.4, 162.0 (d, J = 243 Hz).
MS (ESI): m/z (%) = 266.1 (100, [M + H]+), 288.0 (20, [M + Na]+).
HRMS (ESI): m/z calcd for C17H13FNO [(M + H)+]: 266.0981;
MS (ESI): m/z (%) = 214.2 (100, [M + H]+), 230.2 (60, [M + Na]+).
found: 266.0984.
HRMS (ESI): m/z calcd for C14H16NO [(M + H)+]: 214.1232; found:
214.1229.
(Z)-2-[2-(2-Chlorophenyl)vinyl]-5-phenyloxazole (5c)
Yield: 105 mg, 54%; yellow solid.
2-(2,2-Dimethylethenyl)-5-phenyloxazole (9)
Yield: 97 mg (71%); colorless oil that slowly crystallized at r.t.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H), 2.28 (s, 3 H), 6.19
(br s, 1 H), 7.20–7.50 (m, 4 H), 7.6–7.8 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 6.62 (d, J = 12.4 Hz, 1 H), 7.02 (d,
J = 12.4 Hz, 1 H), 7.25–7.35 (m, 8 H), 7.47 (d, J = 7.7 Hz, 1 H),
7.63 (d, J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 117.1, 123.1, 124.0, 126.1, 127.6,
128.5, 129.3, 129.4, 130.7, 132.9, 133.3, 135.1, 150.9, 159.5.
Data are in agreement with those previously published.19
MS (ESI): m/z (%) = 282.1 (100, [M + H]+), 284.1 (60, [M + H]+).
2-Phenyloxazole (11)
Reaction run on 0.75 mmol at 100 °C; yield: 83 mg (75%); colorless
oil.
1H NMR (300 MHz, CDCl3): d = 7.24 (s, 1 H), 7.45 (m, 3 H), 7.70
(s, 1 H), 8.04 (m, 2 H).
HRMS (ESI): m/z calcd for C17H13CINO [(M + H)+]: 282.0686;
found: 282.0681.
(Z)-2-[2-(4-Methoxyphenyl)vinyl]-5-phenyloxazole (5d)
Yield: 139 mg (73%); yellow solid; mp 62–64 °C. Slight isomeriza-
tion was observed in CDCl3.
Data are in agreement with those previously published.20
1H NMR (300 MHz, DMSO-d6): d = 3.81 (s, 3 H), 6.39 (d, J = 13.0
Hz, 1 H), 6.88 (d, J = 13.0 Hz, 1 H), 7.00 (d, J = 8.6 Hz, 2 H), 7.36
(t, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.64 (d, J = 7.5 Hz, 2
H), 7.80 (s, 1 H), 7.93 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 55.3, 111.8, 113.6, 124.0,
124.1, 127.4, 128.1, 128.7, 129.2, 131.6, 135.9, 149.9, 159.7, 159.9.
(Z)-2-Styryloxazole (12)
Reaction run on 1 mmol; yield: 96 mg (56%); pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 6.43 (d, J = 12.9 Hz, 1 H), 6.86 (d,
J = 12.9 Hz, 1 H), 7.18 (s, 1 H), 7.30–7.40 (m, 3 H), 7.53 (s, 1 H),
7.64 (d, J = 6.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 114.5, 127.9, 128.1, 128.4, 129.3,
135.5, 136.3, 137.8, 160.4.
MS (ESI): m/z (%) = 278.1 (100, [M + H]+), 300.1 (45, [M + Na]+).
HRMS (ESI): m/z calcd for C18H16NO2 [(M + H)+]: 278.1181;
MS (ESI): m/z (%) = 172.2 (40, [M + H]+), 194.1 (100, [M + Na]+).
found: 278.1183.
HRMS (ESI): m/z calcd for C11H10NO [(M + H)+]: 172.0762; found:
172.0762.
(Z)-2-[2-(Naphthalen-1-yl)vinyl]-5-phenyloxazole (5e)
Yield: 140 mg (68%); yellow oil. Obtained as an inseparable mix-
ture of Z/E isomers (89:11, ratio determined by HPLC).
1H NMR (300 MHz, CDCl3): d (major isomer) = 6.79 (d, J = 12.3
Hz, 1 H), 6.95–7.00 (m, 2 H), 7.19 (dd, J = 5.0, 1.7 Hz, 2 H), 7.27
(E)-2-Styryloxazole (13)
Reaction run on 1 mmol; Yield: 109 mg (64%); pale yellow oil that
slowly crystallized.
Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York

3518
F. Besselièvre et al.
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): d = 6.97 (d, J = 16.4 Hz, 1 H), 7.19 (s,
(6) For examples of direct alkenylation of heteroarenes with
alkenyl bromides, see: (a) Oi, S.; Aizawa, E.; Ogino, Y.;
Inoue, Y. J. Org. Chem. 2005, 70, 3113; and references cited
therein. (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 4156. (c) Gottumukkala, A. L.; Derridj, F.;
Djebbar, S.; Doucet, H. Tetrahedron Lett. 2008, 49, 2926.
(d) Verrier, C.; Hoarau, C.; Marsais, F. Org. Biomol. Chem.
2009, 647. (e) Koubachi, J.; El Kazzouli, S.;
1 H), 7.30–7.45 (m, 3 H), 7.45–7.55 (m, 3 H), 7.64 (s, 1 H).
Data are in agreement with those previously published.9
Acknowledgment
The Région Ile-de-France (doctoral grant for F.B.) and the Agence
Nationale de la Recherche are thanked for financial support. Jason
Martin is acknowledged for proofreading the manuscript.
Berteina Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synthesis 2008, 2537.
(7) Palmer, D. C.; Venkatraman, S. In Oxazoles: Synthesis,
Reactions and Spectroscopy, Part A; Wiley: Hoboken / NJ,
2004.
References
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Synthesis 2009, No. 20, 3511–3518 © Thieme Stuttgart · New York