Synthesis and reaction of the first oxazol-4-ylboronates: Useful reagents for the preparation of the oxazole-containing biaryl compounds

Article abstract of DOI:10.1055/s-2006-932471

The first oxazol-4-ylboronates were prepared from the corresponding 4-bromo- and 4-trifluoromethanesulfonyloxy-oxazoles. The Suzuki coupling using the resulting boron reagents with various aryl halides, including benzene, pyridine, oxazole and thiazole ri

Full text of DOI:10.1055/s-2006-932471

LETTER
555
Synthesis and Reaction of the First Oxazol-4-ylboronates: Useful Reagents for
the Preparation of the Oxazole-Containing Biaryl Compounds
S
ynthesis andRea
i
c
tionof
r
the Firs
o
t
O
xazol-4-y
s
lboronateshi Araki,a Tadashi Katoh,b Munenori Inoue*a,c
a
b
c
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Sagami Chemical Research Center, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
Fax +81(467)774113; E-mail: inoue@sagami.or.jp
Received 3 December 2005
Suzuki coupling8 is currently regarded as a powerful and
general transition-metal-catalyzed cross-coupling reac-
tion for the preparation of biaryl compounds including
heterocyclic rings9 due to their relatively low toxicity,
Abstract: The first oxazol-4-ylboronates were prepared from the
corresponding 4-bromo- and 4-trifluoromethanesulfonyloxy-ox-
azoles. The Suzuki coupling using the resulting boron reagents with
various aryl halides, including benzene, pyridine, oxazole and thia-
zole rings, in the presence of palladium catalyst proceeded to pro- easily availability, air stability, and wide functional-group
duce the oxazole-containing biaryl compounds in moderate to good
yields.
tolerance, to our knowledge, there have been no reports
with respect to the Suzuki coupling reaction using ox-
Key words: oxazoles, oxazol-4-ylboronates, Suzuki coupling, bi-
aryl compounds, palladium-catalyzed cross-coupling
azolylboron reagents to date. In the course of our synthetic
studies of the natural products containing oxazole rings,
we have demonstrated the first preparation and reaction of
oxazol-4-ylboronates for the biaryl synthesis in this paper
Oxazoles are an important class of heterocyclic com- (Scheme 1).
pounds due to their occurrence in natural product chemis-
try, medicinal chemistry and materials science. A great
X
O
B
number of literatures for their preparations and reactions
N
have been reported and reviewed.1 Among them, oxazole-
N
O
R
O
borylation
O
R'
R
containing biaryl structure is especially characteristic in
R'
X = Br, OTf
natural product chemistry, where recently unprecedented
natural products such as diazonamide A,2a the
hennoxazoles2b the mycalolides,2c the sulfomycins,2d
telomestatin,2e and YM-2163912f have been isolated and
reported to exhibit a wide variety of biological activities.
Ar-X
Pd(0)
Ar
R'
N
R
Suzuki
coupling
O
With increasing necessity for supplies of biaryl com- Scheme 1 Suzuki coupling of oxazol-4-ylboronate, leading to the
oxazole-containing biaryl compound.
pounds, the transition-metal-catalyzed reaction of metal-
lated heteroaromatic compounds with aromatic halides
has been recognized as a powerful strategy for the biaryl
synthesis.3 In terms of the synthesis of the oxazole-con-
taining biaryl compounds by palladium-catalyzed cross-
coupling reaction using the metallated oxazoles, Dondoni
et al. reported the synthesis of 2-stannyloxazoles and the
Stille reaction of these stannanes to lead to the formation
of 2-(hetero)aryloxazoles.4 Since then, other groups have
proved the efficiency of the stannyloxazoles to synthesize
the (hetero)aryloxazole derivatives.5 On the other hand,
Anderson et al. disclosed the Negishi coupling of oxazol-
2-ylzinc reagents with several aryl halides to produce the
2-substituted oxazoles and applied this methodology to
the synthesis of the oxazole-containing partial ergot alka-
loids.6 In addition, to attain the purpose of establishing the
oxazole-containing biaryl systems, the reaction of ox-
azolyl halides (triflates) with metallated arene derivatives
was also utilized as an alternative method.7 Although
We first studied the synthesis of oxazol-4-ylboronates
from the corresponding 4-trifluoromethanesulfonyloxy-
oxazole and 4-bromooxazole as shown in Scheme 2. Ac-
cording to the normal reaction condition,10 we have suc-
ceeded in the synthesis of 2-phenyloxazol-4-ylboronate 2
from the known 2-phenyl-4-trifluoromethanesulfonyl-
oxyoxazole (1).11 Borylation was achieved by treatment
of 1 with 2.5 mol% of Pd2(dba)3 and 15 mol% of PCy3 in
the presence of 1.1 equivalents of bis(pinacolato)diboron
(pinB-Bpin) and 1.5 equivalents of KOAc in refluxing di-
oxane to furnish the desired 2-phenyloxazol-4-ylboronate
2 in 75% yield after recrystallization.12 On the other hand,
lithiation of the known 4-bromo-5-methyl-2-phenyl-
oxazole (3)13 with n-BuLi, followed by borylation with
triisopropyl borate at –78 °C and transesterification with
pinacol afforded the expected 5-methyl-2-phenyloxazol-
4-ylboronate 4 in 55% yield after recrystallization.14
These boron reagents are stable under Ar at room temper-
ature and can be stored for a long time.
SYNLETT 2006, No. 4, pp 0555–0558
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932471; Art ID: U30705ST
© Georg Thieme Verlag Stuttgart · New York
With the desired oxazol-4-ylboronates in hand, we turned
our attention to the Suzuki coupling reaction using these

556
H. Araki et al.
LETTER
Pd2(dba)3·CHCl3 (2.5 mol%)
Next, we explored the applicability of the Suzuki coupling
of oxazolylboron reagents (2 and 4) with other aromatic
halides, possessing benzene, pyridine, oxazole, and thi-
azole rings, to synthesize the oxazole-containing biaryl
compounds by applying our preliminary reaction condi-
tion [Ar-X (1 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (3
equiv), DMF, 100 °C]15,16 as shown in Table 2. All reac-
tions went to completion within three hours to give rise to
the desired coupling products in moderate to high yields.
When the aryl bromide having electron-withdrawing
group was used (entry 1), the reaction proceeded smooth-
ly to give a good yield of the 2,4-diaryloxazole, however,
the presence of electron-donating or stereocongested sub-
stitutes markedly decreased the yield of the coupling
products due to the slow reaction, which resulted in the
formation of homocoupling product (entries 2 and 3).17
Heteroaromatic (pyridine, oxazole, and thiazole rings) ha-
lides were also coupled with 2 and 4 without any difficulty
(entries 5–7, 9, 10). This single-step reaction to elaborate
the heteroaromatic–oxazole linkage would be especially
useful for the synthesis of natural products possessing the
oxazole-containing biaryl structure. Comparing the
reactivity of 2 with that of 4, the 5-methyl group effected
an increase of the yield (entries 8–10). In addition, the
coupling reaction of 2 with the vinyl bromide derivative
also proceeded to give the corresponding vinyloxazole
(entry 4).
PCy3 (15 mol%)
pinB-Bpin (1.1 equiv)
TfO
O
B
N
O
Ph
N
O
O
KOAc (1.5 equiv)
dioxane, reflux for 2 h
(75% after
Ph
1
recrystallization)
2
n-BuLi, (i-PrO)3B
Br
Me
O
N
O
THF at –78 °C
Ph
B
N
O
O
pinacol, AcOH
Ph
(55% after
recrystallization)
Me
3
4
Scheme 2 Preparation of oxazol-4-ylboronates (2 and 4).
boron reagents. The reaction conditions were standard-
ized by optimization of the coupling reaction of 2-phenyl-
oxazolylboronate 2 with one equivalent of bromobenzene
in the presence of 5 mol% of Pd(PPh3)4 under various
reaction conditions as summarized in Table 1. In entries
1–6, we initially investigated the base (3 equiv) for the
coupling reaction in refluxing dioxane. Na2CO3 and Et3N
were not effective for the reaction, producing a low yield
of 2,4-diphenyloxazole (5, entries 1 and 2).13 t-BuOK was
strong enough to destroy the boronate to give a complex
mixture (entry 3). In the case of using KF, moderate yield
(41%) of 5 was afforded (entry 4). K2CO3 and K3PO4 were
found to be the most effective base to furnish a 71% yield
of 5 (entries 5 and 6). In testing four solvents (dioxane,
DMF, toluene, and MeCN), it was found that DMF was
the best solvent in this coupling reaction (entry 7), in
which 88% yield of 5 was obtained in a short reaction
time, while other solvents also worked well to produce 5
in 67–78% (entries 6, 8, 9).
In conclusion, we have successfully synthesized oxazol-
4-ylboronates (2 and 4) from the corresponding 4-bromo
and 4-trifluoromethanesulfonyloxyoxazoles. The palladi-
um-catalyzed Suzuki cross-coupling reaction of these
boronates with several aryl halides, involving benzene,
pyridine, oxazole, and thiazole rings, gave rise to the 4-
Table 1 Reaction of 2-Phenyloxazol-4-ylboronate 2 with Bromobenzene under Various Conditions
BrPh (1 equiv)
Pd(PPh3)4 (5 mol%)
O
B
Ph
N
O
Ph
N
O
O
base (3 equiv)
Ph
2
5
Entry
Solvent
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
Base
Temperature
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100 °C
100 °C
Reflux
Time (h)
24
Yield (%)a
1
2
3
4
5
6
7
8
9
Na2CO3
Et3N
16
16
8
t-BuOK
KF
16
Complex mixture
8
41
71
71
88
78
67
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
1
1.5
0.5
1.0
1.5
Toluene
MeCN
a Isolated yields after chromatography.
Synlett 2006, No. 4, 555–558 © Thieme Stuttgart · New York

LETTER
Synthesis and Reaction of the First Oxazol-4-ylboronates
557
Table 2 Suzuki Coupling of Oxazolylboronates with Various Aryl Halides
halide (1 equiv)
Pd(PPh3)4 (5 mol%)
Ar
O
B
N
O
Ph
N
O
O
K2CO3 (3 equiv), DMF
at 100 °C
R
Ph
R
Entry
R
H
Halide
Time (h)
Product
Yield (%)a 1H NMR (500 MHz, CDCl3), d
1
2
3
0.5
1
83
56
54
1.42 (t, J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1
Hz, 2 H), 7.46–7.52 (m, 3 H), 7.89–7.92
(m, 2 H), 8.06 (s, 1 H), 8.09–8.15 (m, 4
H)
EtO2C
EtO2C
Br
N
O
Ph
H
H
3.86 (s, 3 H), 6.95–6.99 (m, 2 H), 7.45–
7.50 (m, 3 H), 7.74–7.77 (m, 2 H), 7.88
(s, 1 H), 8.09–8.13 (m, 2 H)
MeO
MeO
Br
N
Ph
O
3
2.51 (s, 3 H), 7.25–7.33 (m, 5 H), 7.45–
7.51 (m, 3 H), 7.82 (s, 1 H), 7.91–7.94
(m, 1 H), 8.11–8.15 (m, 2 H)
N
O
Br
Ph
Me
Me
Me
Me
4
5
H
H
1.5
3
65
73
1.94 (s, 3 H), 2.01 (s, 3 H), 6.13 (s, 1 H),
7.42–7.48 (m, 3 H), 7.56 (s, 1 H), 8.02–
8.07 (m, 2 H)
N
O
Br
Ph
Me
Me
7.23 (ddd, J = 1.0, 4.9, 7.5 Hz, 1 H),
7.46–7.52 (m, 3 H), 7.79 (dt, J = 1.7, 7.7
Hz, 1 H), 8.02 (d, J = 7.9 Hz, 1 H), 8.12–
8.16 (m, 2 H), 8.32 (s, 1 H), 8.61 (br d,
J = 4.3 Hz, 1 H)
N
O
N
Br
N
Ph
N
6
7
H
H
0.5
3
71
80
1.41 (t, J = 7.1 Hz, 3 H), 4.43 (q, J = 7.1
Hz, 2 H), 7.48–7.53 (m, 3 H), 8.12–8.16
(m, 2 H), 8.32 (s, 1 H), 8.43 (s, 1 H)
EtO2C
EtO2C
N
N
Ph
Cl
O
O
O
7.40 (d, J = 3.2 Hz, 1 H), 7.48–7.52 (m,
3 H), 7.88 (d, J = 3.2 Hz, 1 H), 8.11–8.15
(m, 2 H), 8.28 (s, 1 H)
N
S
N
S
N
O
Br
Ph
8
9
Me
Me
1
1
98
84
2.62 (s, 3 H), 7.31–7.35 (m, 1 H), 7.42–
7.48 (m, 5 H), 7.72–7.75 (m, 2 H), 8.07–
8.10 (m, 2 H)
Ph
N
Br
Ph
O
Me
1.41 (t, J = 7.1 Hz, 3 H), 4.42 (q, J = 7.1
Hz, 2 H), 2.82 (s, 3 H), 7.46–7.50 (m, 3
H), 8.08–8.13 (m, 2 H), 8.30 (s, 1 H)
EtO2C
EtO2C
N
N
N
Ph
Cl
O
O
O
Me
10
Me
2
88
2.81 (s, 3 H), 7.34 (d, J = 3.3 Hz, 1 H),
7.45–7.49 (m, 3 H), 7.88 (d, J = 3.3 Hz,
1 H), 8.06–8.10 (m, 2 H)
N
S
N
S
N
Br
Ph
O
Me
a Isolated yields after chromatography.
aryl- and 4-heteroaryloxazole derivatives. Applying this References and Notes
method to the synthesis of natural products is currently in
progress, and will be discussed in due course.
(1) For a recent review, see: Palmer, D. C.; Venkatraman, S.
Oxazoles: Synthesis, Reactions and Spectroscopy, In The
Chemistry of Heterocyclic Compounds, Part A, Vol 60;
Palmer, D. C., Ed.; John Wiley and Sons: New York, 2003,
1–390; and references therein.
Acknowledgment
(2) (a) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J.
J. Am. Chem. Soc. 1991, 113, 2303. (b) Ichiba, T.; Yoshida,
W. Y.; Scheuer, P. J.; Higa, T.; Gravalos, D. G. J. Am. Chem.
Soc. 1991, 113, 3173. (c) Fusetani, N.; Yasumuro, K.;
We are grateful to professor emeritus J. Tsuji (Tokyo Institute of
Technology) for helpful discussions. We also thank Dr. T. Mori
(Tokyo Institute of Technology) for his assistance in MS spectra
measurements.
Synlett 2006, No. 4, 555–558 © Thieme Stuttgart · New York

558
H. Araki et al.
LETTER
Matsunaga, S.; Hashimoto, K. Tetrahedron Lett. 1989, 30,
2809. (d) Egawa, Y.; Umino, K.; Tamura, Y.; Shimizu, M.;
Kaneko, K.; Sakurazawa, M.; Awataguchi, S.; Okuda, T. J.
Antibiot. 1969, 22, 12. (e) Shinya, K.; Wierzba, K.; Matsuo,
K.; Ohtani, T.; Yamada, Y.; Furihata, K.; Hayakawa, Y.;
Seto, H. J. Am. Chem. Soc. 2001, 123, 1262. (f) Sohda, K.;
Nagai, K.; Yamori, T.; Suzuki, K.; Tanaka, A. J. Antibiot.
2005, 58, 27. (g) Sohda, K.; Hiramoto, M.; Suzumura, K.;
Takebayashi, Y.; Suzuki, K.; Tanaka, A. J. Antibiot. 2005,
58, 32.
(13) (a) Prager, R. H.; Smith, J. A.; Weber, B.; Williams, C. M.
J. Chem. Soc., Perkin Trans. 1 1997, 2665. (b) The method
reported in ref. 13a is inconvenient to synthesize 3. We
developed the alternative method to prepare bromide 3 from
benzoyl chloride and propargylamine as follows
(Scheme 3).
Et3N
O
O
CH2Cl2
+
H2N
Ph
Cl
Ph
N
H
at 0 °C
30 min
(63%)
(3) Undheim, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis, Vol 1; Negishi, E., Ed.; John Wiley
and Sons: New York, 2002, 409–492; and references therein.
(4) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. Synthesis 1987, 693.
NBS
DMF
NaH
dioxane
Br
Me
N
O
N
Ph
Ph
r.t., 6 h
(32%)
reflux, 4 h
(77%)
O
Me
(5) (a) Barrett, A. G. M.; Kohrt, J. T. Synlett 1995, 415.
(b) Collins, I.; Castro, J. L.; Street, L. J. Tetrahedron Lett.
2000, 41, 781. (c) Clapham, B.; Sutherland, A. J. J. Org.
Chem. 2001, 66, 9033.
3
Scheme 3
(6) (a) Anderson, B. A.; Harn, N. K. Synthesis 1996, 583.
(b) Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh,
M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P.
J. Org. Chem. 1997, 62, 8634. (c) Vedejs, E.; Luchetta, L.
M. J. Org. Chem. 1999, 64, 1011.
(7) (a) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623.
(b) Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron
Lett. 1998, 39, 8167. (c) Liu, C.-M.; Chen, B.-H.; Liu, W.-
Y.; Wu, X.-L.; Ma, Y.-X. J. Organomet. Chem. 2000, 598,
348. (d) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4,
2905. (e) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5,
2911. (f) Maekawa, T.; Sakai, N.; Tawada, H.; Murase, K.;
Hazama, M.; Sugiyama, Y.; Momose, Y. Chem. Pharm.
Bull. 2003, 51, 565. (g) Young, G. L.; Smith, S. A.; Taylor,
R. J. K. Tetrahedron Lett. 2004, 45, 3797.
(8) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(9) Tyrrell, E.; Brookes, P. Synthesis 2004, 469; and references
therein.
(10) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.;
Miyaura, N. Tetrahedron Lett. 1997, 38, 3447.
(14) Preparation of 5-Methyl-2-phenyl-4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)oxazole (4).
n-BuLi in n-hexane (1.58 M, 0.42 mL, 0.67 mmol) was
added to a stirred solution of 4-bromo-5-methyl-2-phenyl-
oxazole (3, 144 mg, 0.65 mmol) in THF (3 mL) at –78 °C
under Ar. After 30 min, triisopropylborate (0.17 mL, 0.73
mmol) was added to the resulting solution and stirred for 1 h
at the same temperature. The reaction mixture was allowed
to warm to r.t. and stirred for 1 h. Pinacol (86 mg, 0.73
mmol) and glacial AcOH (42 mL, 0.73 mmol) were added to
the resulting solution and the resulting mixture was stirred
for 1 h. The reaction mixture was diluted with Et2O (30 mL)
and washed with H2O (10 mL) and then dried over Na2SO4.
Concentration of the solvent in vacuo gave a residue, which
was purified by silica gel column chromatography (hexane–
EtOAc, 1:1) to give 5-methyl-2-phenyl-4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-oxazole (4). After recryst-
allization from hot hexane, pure 4 (95 mg, 55%) was
obtained as colorless needles; mp 108–109 °C. 1H NMR
(500 MHz, CDCl3): d = 1.36 (12 H, s), 2.56 (3 H, s), 7.41 (3
H, m), 8.10 (2 H, m). 13C NMR (125 MHz, CDCl3): d = 11.8,
24.9, 83.9, 126.5, 127.6, 128.5, 129.9, 160.1, 161.0. IR
(neat): 2979, 1593, 1407, 1382, 1317, 1141, 1085, 1050, 696
cm–1. HRMS (EI): m/z calcd for C16H20BNO3 [M+]:
285.1536; found: 285.1532.
(11) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469.
(12) Preparation of 2-Phenyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)oxazole (2).
A suspension of Pd2(dba)3·CHCl3 (120 mg, 0.13 mmol) and
tricyclohexylphosphine (220 mg, 0.78 mmol) in 1,4-dioxane
(60 mL) was stirred for 30 min at r.t. under Ar.
(15) Although both K2CO3 and K3PO4 worked well in the
coupling reaction of 2 with bromobenzene, we chose K2CO3
as a base for further applications due to its milder basicity.
(16) General Procedure of the Suzuki Coupling [Synthesis of
2,4-Diphenyloxazole (5)].
Bis(pinacolato)diboron (1.46 g, 5.7 mmol), 2-phenyl-4-tri-
fluoromethanesulfonyloxyoxazole (1, 1.53g, 5.2 mmol) and
KOAc (769 mg, 7.8 mmol) were successively added to the
resulting solution. After being at reflux for 2 h, the reaction
mixture was diluted with Et2O (300 mL). The resulting
mixture was washed with H2O (100 mL) and then dried over
Na2SO4. Concentration of the solvent in vacuo gave a
residue, which was purified by silica gel column chromato-
graphy (hexane–EtOAc, 20:1 to 1:1) to give 2-phenyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (2).
After recrystallization from hot hexane, pure 2 (1.06 g, 75%)
was obtained as colorless needles; mp 124–125 °C. 1H NMR
(500 MHz, CDCl3): d = 1.38 (12 H, s), 7.44 (3 H, m), 8.07 (1
H, s), 8.14 (2 H, m). 13C NMR (125 MHz, CDCl3): d = 24.8,
84.3, 126.9, 127.3, 128.6, 130.4, 148.0, 162.8; IR (neat)
2996, 2973, 1567, 1363, 1319, 1081, 692 cm–1. HRMS (EI):
m/z calcd for C15H18BNO3 [M+]: 271.1380; found: 271.1374.
A solution of 2 (60 mg, 0.22 mmol), bromobenzene (23 mL,
0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (13
mg, 11 mmol) and K2CO3 (92 mg, 0.66 mmol) in DMF (1
mL) was heated at 100 °C for 30 min under Ar. The reaction
mixture was diluted with Et2O (30 mL) and washed with
H2O (10 mL) and then dried over Na2SO4. Concentration of
the solvent in vacuo gave a residue, which was purified by
silica gel column chromatography (hexane–EtOAc, 20:1) to
give 2,4-diphenyloxazole (5, 43 mg, 88%) as a white solid.
All characterization data of 5 were compatible with the
literature.13
(17) Self-coupling reaction of the borane reagent 2 occurred to
give 2,2¢-diphenyl-4,4¢-bioxazole in ca. 20% yield. This
undesired event sometimes happened in slow Suzuki
reaction, see: Moreno-Mañas, M.; Pérez, M.; Pleixats, R. J.
Org. Chem. 1996, 61, 2346.
Synlett 2006, No. 4, 555–558 © Thieme Stuttgart · New York