Syntheses of 4,5-disubstituted oxazoles via regioselective C-4 bromination

Article abstract of DOI:10.1021/op700176n

A scaleable and highly regioselective C-4 bromination of 5-substituted oxazoles is described. The use of DMF as solvent played a critical role in significantly improving the C-4/C-2 bromination ratio. The resulting 4-bromooxazoles were shown to be good Su

Full text of DOI:10.1021/op700176n

Organic Process Research & Development 2007, 11, 951–955
Full Papers
Syntheses of 4,5-Disubstituted Oxazoles via Regioselective C-4 Bromination
Bryan Li,* Richard A. Buzon, and Zhijun Zhang
Research API–Pharmaceutical Science, Pfizer Global Research and DeVelopment, Groton, Connecticut 06340, U.S.A.
Scheme 1
Abstract:
A scaleable and highly regioselective C-4 bromination of 5-sub-
stituted oxazoles is described. The use of DMF as solvent played
a critical role in significantly improving the C-4/C-2 bromination
ratio. The resulting 4-bromooxazoles were shown to be good
Suzuki–Miyaura coupling partners with arylboronic acids. Fur-
thermore, a simple and convenient method that employs triethy-
lamine efficiently purged residual levels of palladium and iron to
less than 10 ppm.
tion was required to obtain 1 in suitable quality. This chemistry
was not deemed scaleable due to the difficulty in the preparation
of isocyanide 2 and its thermal instability. The thermal lability
of isocyanide 2 is probably attributed to the additional fluorines7
on the phenyl group. Therefore, we sought a more robust,
efficient and scaleable synthesis.
Introduction
Oxazoles with substitution at both C-4 and C-5 have recently
attracted increased attention in the pharmaceutical community
for their therapeutic potential in treating inflammation, cancer,
and asthma1,2 The 4,5-disubstituted oxazole 1 is a potent and
selective inhibitor of the stress-activated kinase p38R.3 It
possesses good oral bioavailability in preclinical species and
was expected to capture attributes of currently marketed
rheumatoid arthritis therapies such as cyclooxygenase-II (COX-
II) inhibitors and the antitumor necrosis factor (TNF) biological
agents.4
Discussion
A number of syntheses of 4,5-disubstituted oxazoles8 have
been described in the literature, and the C-4 iodination method
via 2-lithiooxazole (Scheme 2), as reported by Vedejs,9 appeared
most attractive to us as it allows the introduction of highly
functionalized C-4 substituents. In this reaction (Scheme 2), the
The original synthesis of 1 (Scheme 1) condensed an aryl-
substituted tosylmethylisocyanide 25 with aldehyde 3.3 The
condensation and cyclization proceeded in low yield following
literature procedent.6 Also extensive chromatographic purifica-
(3) (a) McClure, K. F.; Abramov, Y. A.; Laird, E. R.; Barberia, J. T.;
Cai, W.; Carty, T. J.; Cortina, S. R.; Danley, D. E.; Alan J. Dipesa,
A. J.; Donahue, K. M.; Dombroski, M. A.; Elliott, N. C.; Gabel, C. A.;
Han, S.; Hynes, T. R.; LeMotte, P. K.; Mansour, M. N.; Marr, E. S.;
Letavic, M. A.; Pandit, J.; Ripin, D. B.; Sweeney, F. J.; Tan, D.; Tao,
Y. J. Med. Chem. 2005, 48, 5728–5737. (b) McClure, K. F.; Letavic,
M. A.; Kalgutkar, A. S.; Gabel, C. A.; Audoly, L.; Barberia, J. T.;
Braganza, J. F.; Carter, D.; Thomas, J.; Carty, T. J.; Cortina, S. R.;
Dombroski, M. A.; Donahue, K. M.; Elliott, N. C.; Gibbons, C. P.;
Jordan, C. K.; Kuperman, A. V.; Labasi, J. M.; LaLiberte, R. E.;
McCoy, J. M.; Naiman, B. M.; Nelson, K. L.; Nguyen, H. T.; Peese,
K. M.; Sweeney, F. J.; Taylor, T. J.; Trebino, C. E.; Abramov, Y. A.;
Laird, E. R.; Volberg, W. A.; Zhou, J.; Bach, J.; Lombardo, F. Bioorg.
Med. Chem. Lett. 2006, 16, 4339–4344. (c) Buzon, R. A.; Castaldi,
M. J.; Li, Z. B.; Ripin, D. H. B.; Tao, Y. PCT Int. Appl. WO
2004020438, 2004; Chem. Abstr. 140:235721.
* To whom correspondence should be addressed. Fax: 1-860-715-7305.
E-mail: bryan.li@pfizer.com.
(1) (a) Laszo, R.; Schlapbach, A. PCT Int. Appl. WO 0063204, 2000;
Chem. Abst. 133:321897. (b) Lipton, S. A. PCT Int. Appl. WO
0101986, 2001. (c) Andersson, M.; Hansen Peter; L.; Nikitidis, A.;
Sjoelin, P. PCT Int. Appl. WO 2005026123, 2005; Chem. Abstr. 142:
316705. (d) Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel,
R.; Gram, H.; Hiestand, P.; Manning, U.; Rucklin, G. Bioorg. Med.
Chem. Lett. 2004, 14, 3595–3599. (e) Blumberg, L. C.; Munchhof,
M. J. PCT Int. Appl. WO 2004026863, 2004; Chem. Abstr. 140:
287371. (f) Svenstrup, N.; Kuhl, A.; Flubacher, D.; Brands, M.; Ehlert,
K.; Ladel, C.; Otteneder, M.; Keldenich, J. PCT Int. Appl. WO
2003072574, 2003; Chem. Abstr. 139:230786. (g) Alcaraz, L.; Furber,
M.; Purdie, M.; Springthorpe, B. PCT Int. Appl. WO 2003068743,
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Guo, J.; Pitts, W. J.; Murali, D. T. G.; Shen, Z.; Chen, P.; Gu, H. H.;
Fleener, C. A.; Rouleau, K. A.; Cheney, D. L.; Townsend, R. M.;
Hollenbaugh, D. L. Bioorg. Med. Chem. Lett. 2003, 13, 2059–2063.
(i) Varghese, J.; Maillard, M.; Jagodzinska, B.; Beck, J. P.; Gailunas,
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L.; Hom, R. PCT Int. Appl. WO 2003040096, 2003; Chem. Abstr.
138:385173. (j) Revesz, L.; Schlapbach, A. PCT Int. Appl. WO
2000063204, 2000; Chem. Abstr. 133:321897. (k) Kline, T.; Bowman,
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(7) Preparation and handling of 4-fluorophenyl and 3,4-difluorophenyl
tosylmethylisocyanides were considerably less problematic. See ref
3b.
10.1021/op700176n CCC: $37.00
Published on Web 10/19/2007
2007 American Chemical Society
Vol. 11, No. 6, 2007 / Organic Process Research & Development
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951

Scheme 2
Scheme 4
aldehye 3. Iodination of C-4 following the literature procedure
gave modest yields (21–37%) of 5 and selectivity of ca. 4:1 in
favor of 5 over 6. Several other issues were noted during
optimization of this reaction. First, the iodination reaction could
not be driven to completion, despite the addition of excess
reagents. The crude reaction mixture was typically contaminated
with the starting material (20–26%) and di-iodooxazole 7
(5–10%). Silica gel chromatography was required to isolate the
desired product. Second, a cost-effective alternative to DMPU
as solvent (6 mL/g) would need to be identified prior to kilo
campaigns. Finally, 4-iodooxazole 5 proved to be thermally
unstable and therefore unsuitable going forward.
Scheme 3a
We envisioned some of the aforementioned issues could be
addressed by preparing the 4-bromooxazole. Indeed, when NBS
(1.0 equiv) was used as the electrophile under otherwise
identical reaction conditions, the halogenation proceeded to
completion, affording a 5:1 ratio of regioisomers 8 and 9
(Scheme 3), favoring the desired 4-bromooxazole 8. The crude
reaction mixture also contained 5% of dibromide 10. After two
crystallizations from methyl tert-butyl ether, 8 was isolated in
56% yield in >97% purity.11 4-Bromooxazole 8 showed good
thermal stability; the compound decomposes at the DSC onset
temperature of 198 °C.
It is known from the literature that the regioselectivity of
this reaction is determined by the equilibrium between the
2-lithooxazole 11 and acyclic tautomer 12 (Scheme 4).12,13 In
polar aprotic solvents, the acyclic form is expected to predomi-
nate because of improved solvation. We envisioned that DMF,
as a strongly polar aprotic solvent, would be an ideal choice to
substitute for DMPU in this reaction. It is cheap and com-
mercially available in anhydrous form, and most importantly,
it has a low freezing point of -61 °C. Other common polar
aprotic solvents were ruled out because of their high freezing
points (DMAC, NMP, DMSO, DMI, acetonitrile), ability to
react with anions (acetone, acetonitrile, DMSO), cost (DMI,
DMPU), and worker safety and environmental concerns (HMPT,
HMPA).14
a (a) TosMIC, K2CO3, MeOH; (b) (1) LHMDS, DMPU/THF, -78 °C, (2) I2
or NBS; (c) (1) LHMDS, DMF, –15 °C, then –70 °C, (2) NBS; (d)
2,4,5-trifluorophenylboronic acid, Pd(dppf)Cl2 · CH2Cl2, CsF, K2CO3, water/
2-MeTHF.
initially formed 2-lithiooxazole tautomerized to the acyclic eno-
late with 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU)
as reaction solvent. Trapping the acyclic lithio species with
iodine gave the 4-iodooxazole as the major product. Both
2-iodooxazoles and 2,4-diiodooxazoles were formed as byprod-
ucts in the reaction. The latter could be treated with 1 equiv of
nBuLi to generate the corresponding 4-iodooxazole. Thus,
oxazole 4 (Scheme 3) was prepared by condensation10 of
commercially available tosylmethyl isocyanide (TosMIC) and
(8) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer,
G. K. Org. Lett. 2006, 8, 5231–5234. (b) Davies, J. R.; Kane, P. D.;
Moody, C. J. Tetrahedron 2004, 60, 3967–3977. (c) Xia, Q.; Ganem,
B. Synthesis 2002, 14, 1969–1972. (d) Ohba, M.; Kubo, H.; Seto, S.;
Fujii, T.; Ishibashi, H. Chem. Pharm. Bull. 1998, 46, 860–862. (e)
Matsumoto, K.; Suzuki, M.; Yoneda, N.; Miyoshi, M. Synthesis 1976,
12, 805–7. (f) Theilig, G. Chem. Ber. 1953, 86, 96–109.
(11) Contaminated with <2% of the 2-bromoxazole 9 and <0.2% of the
2,4-dibromo 10.
(12) Schroeder, R.; Schollkopf, U.; Blume, E.; Hoppe, I. Justus Liebigs
Ann. Chem. 1975, 533.
(9) Vedejs, E.; Luchetta, L. M. J. Org. Chem. 1999, 64, 1011.
(10) (a) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.;
Olsen, M. A. J. Org. Chem. 2000, 65, 1516–1524. (b) Sisko, Joseph;
Mellinger, Mark; Sheldrake, Peter W.; Baine, Neil, H. Tetrahedron
Lett. 1996, 37, 8113–8116.
(13) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J.
Org. Chem. 1987, 52, 3413–3420.
(14) (a) Sarrif, A. M.; Krahn, D. F.; Donovan, S. M.; O’Neil, R. M. Mutat.
Res. 1997, 380, 167–177. (b) Ashby, J.; Styles, J. A.; Paton, D. Br. J.
Cancer 1978, 38, 418–427.
952
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Scheme 5a
Our initial attempts to selectively brominate 4 employing
DMF as solvent at -70 °C15 gave poor to modest C-4/C-2
regioselectivity. We reasoned that the initially formed 2-lithioox-
azole did not have ample opportunity to fully equilibrate to the
acyclic form at low temperatures within the time scale of the
reaction. We therefore decided to perform the lithiation at -15
°C and equilibrate the anion for 30 min before cooling to -70
°C and quenching with NBS. Employing these conditions, a
regioselectivity of 98:2 favoring the desired C-4 bromide was
obtained. Due to both the adiabatic temperature rise during the
addition of the NBS and the highly exothermic bromination, it
was necessary to lower the reaction temperature before the
quench.16 The product was isolated by crystallization (MTBE/
hexanes) in 87% yield and contained less than 0.2% of
2-bromooxazole 9 as an impurity.17 As expected, the lithium
anions 11 and 12 behave similarly to stabilized enolates in that
we were unable to detect any formylated products (from
nucleophilic addition to DMF) in the reaction mixtures.
Having worked out a reliable preparation of 4-bromooxazole
8, the last step proceeded without incident. Suzuki–Miyaura
coupling of 8 with the commercially available 2,4,5-trifluo-
rophenylboronic acid using Pd(dppf)Cl2 as catalyst, CsF and
K2CO3 in aqueous 2-MeTHF proceeded to completion in 1 h
at 70 °C. The isolation of 1 from the reaction mixture proved
to be difficult initially, due to the presence of the ferrocene
ligand on the catalyst. Fortunately, the weak basicity of 1
rendered a unique solubility behavior of the compound. We
discovered that 1 partitioned predominantly in the aqueous phase
when distributed between aqueous HCl solution and toluene,
yet it partitioned favorably in the organic phase when distributed
between aqueous HCl and CH2Cl2. This provided an opportunity
to clean up the reaction mixture with extractive manipulations
that are detailed in the Experimental Section.
Another issue was removal of palladium from the final API.
This is a topic that has received significant attention, and several
common methods for Pd removal have been described in the
literature.18 For 1, we rationalized that Pd was chelating through
the weakly basic triazole moiety, and envisioned that treatment
of 1 with a more basic amine (e.g., triethylamine) should
displace palladium from 1 by competitive binding. This strategy
was realized in practice; in the event, crude 1 (2100 ppm Pd,
3200 ppm Fe) was heated with a mixture of 3 mL/g of
triethylamine and 2 mL/g of 2-propanol at reflux for 2–3 h.
After cooling to 35 °C, addition of water (20–25 mL/g)
crystallized the product out of solution. After a single repetition,
1 was isolated in 99.74% purity by HPLC with a Pd level of
9.0 ppm and Fe at 8.85 ppm.
a (a) (1) LHMDS, –15 °C f –70 °C, DMF, (2) NBS; (b) PhB(OH)2,
Pd(dppf)Cl2, CsF, K2CO3, water/2-MeTHF.
oxazoles (Scheme 5). We note that both the thiophene and nitrile
moieties (15 and 16, respectively) remained intact under the
reaction conditions. Subsequent Suzuki–Miyaura coupling reac-
tions with phenylboronic acid proceeded uneventfully.
In summary, we have described a highly regioselective
bromination at C-4 of 5-substituted oxazoles. The use of DMF
as solvent and aging of the lithiated oxazole is critical to drive
the equilibrium in favor of the acyclic isonitrile enolate, resulting
in significantly improved C4/C2 regioselectivity. These 4-bro-
mooxazoles were shown to be good Suzuki–Miyaura coupling
partners with arylboronic acids. The bromination protocol was
demonstrated on multikilogram scale supporting the develop-
ment of 1. Finally, we have demonstrated that the use of
triethylamine is effective in purging residual palladium and iron
from the Suzuki–Miyaura coupled product.
Experimental Section
General. NMR chemical shifts are reported in part per
million (ppm) with TMS as an internal standard. LCMS was
recorded using API-ES ionization mode. Reagents and solvents
were obtained from commercial sources and used without
further purifications. Achiral HPLC analyses were carried out
using Agilent SB-CN columns (4.6 mm × 250 mm) with
acetonitrile/0.2% perchloric acid aqueous buffer (20/80 or 40/
60) as mobile phase (2 mL/min) and detection at 210 nm
wavelength. HPLC purity is reported by area %.
3-tert-Butyl-6-(oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyri-
dine(4). 3-tert-Butyl-[1,2,4]triazolo[4,3-a]pyridine-6-carbalde-
hyde 33 (5.08 kg, 25.0 mol), K2CO3 (6.05 kg, 43.8 mol) and
tosylmethylisocyanide (4.88 kg, 25.0 mol) in methanol (106
L) was heated to 64–66 °C for 4 h. Water (54 L) was added,
and methanol was removed under vacuum. The reaction was
cooled to 20 °C and allowed to granulate overnight. The mixture
was filtered, washed with water, and dried under full vacuum
at 45 °C for 20 h to afford the product 4 (4.25 kg, 17.5 mol,
1
70% yield) as a yellow solid: HPLC purity 99.8%. H NMR
(400 MHz, CDCl3) δ 1.61 (s, 9H), 7.41 (s, 1H), 7.43 (d, J )
9.6 Hz, 1H), 7.81 (d, J ) 9.6 Hz, 1H), 7.97 (s, 1H), 8.46 (s,
1H).
The regioselective C-4 bromination, outline above, was
applied to a series of C-5 substituted aryl and heteroaryl
6-(4-Bromooxazol-5-yl)-3-tert-butyl-[1,2,4]triazolo[4,3-
a]pyridine (8). To a reactor were charged 4 (3.5 kg, 14.4 mol)
and anhydrous DMF (14 L). The resulting solution was cooled
to -15 °C, and 1 N LHMDS in THF (1.05 equiv, 13.1 Kg)
was then added. The reaction was stirred at -15 °C for 30 min
and then cooled to -70 °C. A solution of NBS (2.57 kg, 14.4
mol) in DMF (7 L) was added while maintaining the temper-
ature below -60 °C. The reaction was stirred for 30 min at the
(15) Although the freezing point of DMF is -61 °C, the reaction mixture
had a freezing point of < -70 °C.
(16) Quenching the reaction at -15 °C with NBS led to a ca. 2/1 ratio of
regioisomers, favoring the C-4 product. NBS was added as a solution
in DMF (2.7 mL/g of NBS) at room temperature. Pre-cooling of the
NBS solution would be desirable, but it reduced the solubility
significantly. More studies are needed to determine if the anion quench
can be adapted in a flow reactor under non-cryogenic conditions.
(17) A trace amount (<1%) of the dibromide 10 was observed in the
reaction but was purged during the isolation of 8.
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same temperature and quenched by addition of 2 N aqueous
NaOH solution (62 L). The reaction was extracted with CH2Cl2
(3 × 30 L). The combined organic extract was washed with
0.5 N NaOH solution and brine solution. The solution was
concentrated, and solvent-exchanged with MTBE (18 L).
Hexanes (18 L) was added, and the resulting slurry was
granulated for 2 h at room temperature. The product was
collected by filtration and dried at 40 to 50 °C under full vacuum
to give 4.04 kg (12.6 mol, 87%) of 8 as an off-white solid: 1H
NMR (400 MHz, CDCl3) δ 1.65 (s, 9H), 7.78 (d, J ) 9.6 Hz,
1H), 7.93 (d, J ) 9.6 Hz, 1H), 7.97 (s, 1H), 8.93 (s, 1H). LCMS:
321 (M + 1), 322 (M + 2).
7.09–7.45 (m, 1H), 7.48 (d, J ) 9.6 Hz, 1H), 7.53–7.62 (m,
1H), 8.04 (d, J ) 9.6 Hz, 1H), 8.11 (s, 1H), 8.42 (s, 1H). LCMS
374 (M + 2), 373 (M + 1).
4-Bromo-5-(3-chlorophenyl)oxazole (13). Following the
same procedure as described for the synthesis of 8, 5.31 g was
prepared in 82% yield. 1H NMR (400 MHz, CDCl3) δ7.74 (t,
J ) 1.7 Hz, 1H), 7.70 (s, 1H), 7.66 (dt, J ) 7.1, 1.7 Hz, 1H),
7.24–7.17 (m, 2H). MS m/z 257.9 (M + H). HRMS
C9H6BrClNO (M + H+) calcd 257.9326; found 257.9321.
4-Bromo-5-(2-nitrophenyl)oxazole (14). Following the
same procedure as described for 4-bromooxazole 8, 4.44 g was
prepared in 78% yield. 1H NMR (400 MHz, CDCl3) δ 7.88 (d,
J ) 7.5 Hz, 1H), 7.74 (s, 1H), 7.61–7.54 (m, 2H), 7.47 (t, J )
7.9 Hz, 1H). MS m/z 269.0 (M + H). HRMS C9H6BrN2O3 (M
+ H+) calcd 268.9562; found 268.9560.
3-tert-Butyl-6-(4-(2,4,5-trifluorophenyl)oxazol-5-yl)-
[1,2,4]triazolo[4,3-a]pyridine (1). A mixture of 8 (3.0 kg, 9.34
mol), CsF (141 g, 0.93 mol), K2CO3 (1.55 kg, 11.2 mol), 2,4,5-
trifluorophenylboronic acid (1.80 kg, 10.2 mol) and
Pd(dppf)Cl2 ·CH2Cl2 complex (374 g) in water (4.5 L) and
2-MeTHF (45 L) was heated to 70 °C for 1 h. 2-MeTHF was
removed by distillation under reduced pressure. The resulting
mixture was partitioned between 2 N aqueous HCl (30 L) and
CH2Cl2 (48 L). The product-rich CH2Cl2 layer was concentrated
atmospherically and displaced with toluene (45 L). This was
followed by addition of 4 N HCl (30 L), which took the product
to the aqueous phase. The product-rich aqueous layer was
separated, and the pH was adjusted to 10 with 50 wt % NaOH.
The crude product that crystallized out was collected by
filtration. The palladium purging and polymorph conversion
were carried out as follows. The crude product was treated with
isopropanol (6 L) and TEA (9 L) at reflux for 3 h. After cooling
to 35 °C, water (75 L) was charged. The batch was then cooled
to 15 °C and filtered. The wet filter cake was charged back to
the reactor, and the treatment was repeated. After cooling to
35 °C, water (75 L) was added. The batch was then cooled
to 15 °C and filtered. After drying under vacuum, 3.08 kg (8.28
mol, 88.7% yield) of the desired product was isolated. Isopro-
panol (76 L) was added, and the resulting slurry was distilled
to remove approximately 5 L of solvent to ensure no water
was present. The solution was then cooled to 50 °C and filtered
via a 0.2 µm filter for a particle-free operation. The filtrate was
concentrated under partial vacuum to a final volume of 24 L.
The concentration was then continued atmospherically to a final
volume of approximately 6 L. The batch was cooled to 22 °C,
stirred for 48 h, filtered and dried to afford 2.83 kg of 1 as a
white solid (7.60 mol, 91.9% recovery). The material was of
99.74% purity with Pd and Fe at 7.86 and 11.95 ppm,
4-Bromo-5-(thiophen-2-yl)oxazole (15). Following the
same procedure as described for 4-bromooxazole 8, 12.13 g
1
was prepared in 87% yield. H NMR (400 MHz, CDCl3) δ
7.82 (s, 1H), 7.63 (dd, J ) 3.7, 0.9 Hz, 1H), 7.45 (dd, J ) 5.0,
0.9 Hz, 1H), 7.63 (dd, J ) 5.0, 3.7 Hz, 1H). MS m/z 229.8 (M
+ H+). HRMS C7H5BrNO (M + H+) calcd 229.9275; found
229.9284.
4-Bromo-5-(4-cyanophenyl)oxazole (16). Following the
same procedure as described for 4-bromooxazole 8, 4.44 g was
prepared in 78% yield. 1H NMR (400 MHz, CDCl3) δ
7.85–7.77 (m, 4H), 7.67 (S, 1H). MS m/z 248.95 (M – H). 13C
NMR (400 MHz, CDCl3) δ 153.02, 136.60, 133.06, 129.46,
125.97, 125.53, 117.81, 113.84, 108.42.
5-(2-nitrophenyl)-4-phenyloxazole (17). To a 100-mL
round-bottomed flask were charged 4-bromo-5-(2-nitrophenyl)-
oxazole (2.0 g, 7.43 mmol), cesium fluoride (0.113 g, 0.743
mmol), potassium carbonate (1.23 g, 8.92 mmol), phenyl-
boronic acid (2.0 g, 15.6 mmol), Pd(dppf)Cl2 · CH2Cl2
complex (0.341 g, 0.409 mmol), water (3 mL), and 2-methyl
THF (30 mL). The mixture was heated to 75 °C under
nitrogen atmosphere and held for 18 h. The reaction mixture
was diluted with CH2Cl2 (40 mL) and water (20 mL). The
organic layer was separated and washed with HCl aqueous
(0.5%, 20 mL) and brine (20 mL). The organic solution was
concentrated, and the crude was purified with flash chroma-
1
tography to give 1.21 g (61%) of 17 as a white solid. H
NMR (400 MHz, CDCl3) δ 8.11 (m, 1H), 8.01 (s, 1H),
7.66–7.63 (m, 2H), 7.61–7.55 (m, 5H), 7.36–7.31 (m, 3H).
13C NMR (400 MHz, CDCl3) δ 150.998, 141.428, 133.544,
132.543, 131.009, 130.957, 128.972, 128.680, 127.335,
125.458. MS m/z 267.1 (M + H). HRMS C15H11N2O3 (M
+ H+) calcd 267.0770; found 267.0768.
4-Phenyl-5-(thiophen-2-yl)oxazole (18). Following the
same procedures described above, a mixture of 4-bromo-5-
(thiophen-2-yl)oxazole (10.0 g, 0.0435 mol), cesium fluoride
(0.660 g, 0.00435 mol), potassium carbonate (14.4 g,
0.104 mol), phenylboronic acid (11.7 g, 0.0913 mol),
Pd(dppf)Cl2 ·CH2Cl2 complex (1.99 g, 0.00239 mol) in water
(15 mL) and 2-methyl THF (150 mL) was heated to 75 °C
under nitrogen atmosphere for 16 h. The reaction mixture was
1
respectively. H NMR (400 MHz, CDCl3) δ 1.59 (s, 9H),
(18) (a) Some examples of palladium purging methods: Welch, C. J.;
Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; DaSilva, J.; Hend-
erson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang, T.
Org. Process Res. DeV. 2005, 9, 198–205. (b) Koenigsberger, K.; Chen,
G.-P.; Wu, R. R.; Girgis, M. J.; Prasad, K.; Repic, O.; Blacklock,
T. J. Org. Process Res. DeV. 2003, 7, 733–742. (c) Chen, C.-Y.;
Dagneau, P.; Grabowski, E. J. J.; Oballa, R.; O’Shea, P.; Prasit, P.;
Robichaud, J.; Tillyer, R.; Wang, X. J. Org. Chem. 2003, 68, 2633–
2638. (d) Urawa, Y.; Miyazawa, M.; Ozeki, N.; Ogura, K. Org.
Process Res. DeV. 2003, 7, 191–195. (e) Ishihara, K.; Nakayama, M.;
Kurihara, H.; Itoh, A.; Haraguchi, H. Chem. Lett. 2000, 10, 1218–
1219. (f) Rosso, V. W.; Lust, D. A.; Bernot, P. J.; Grosso, J. A.; Modi,
S. P.; Rusowicz, A.; Sedergran, T. C.; Simpson, J. H.; Srivastava,
S. K.; Humora, M. J.; Anderson, N. G. Org. Process Res. DeV. 1997,
1, 311–314.
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cooled to room temperature and diluted with ethyl acetate (200
mL) and water (100 mL). The ethyl acetate layer was separated
and washed with HCl (0.5%, 100 mL) and brine. The organic
solution was concentrated and purified with flash chromatog-
Acknowledgment
We thank Drs. Martin Berliner and Peter Wuts for their
valuable comments on the manuscript and Mr. Silke Wunder-
wald for providing NMR characterization.
1
raphy to yield 5.33 g (54%) of 18 as an pale yellow oil. H
Supporting Information Available
Characterization spectra. This information is available free
of charge via the Internet at http://pubs.acs.org.
NMR (400 MHz, CDCl3) δ (ppm) 7.95 (s, 1H), 7.82–7.79 (m,
2H), 7.40–7.36 (m, 5H), 7.09–7.06 (m, 1H). 13C NMR (400
MHz, CDCl3) δ 149.903, 141.589, 134.979, 129.806, 128.923,
128.830, 128.243, 127.884, 127.017, 126.748120.206, 115.858.
MS m/z 228.0 (M + H). HRMS C13H10NOS (M + H+) calcd
268.0483; found 228.0479.
Received for review August 7, 2007.
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