A new efficient synthesis of 5-aryloxazoles from arylidene diacetates and application to the preparation of BMS-337197, a novel IMPDH inhibitor

Article abstract of DOI:10.3987/COM-05-10569

A new method for the synthesis of 5-aryloxazoles is described. Treatment of arylidene diacetates with one equivalent of TosMIC reagent in the presence of excess of potassium carbonate in methanol afforded 5-aryloxazoles in "one-pot" in 90-94%. Heteroaryli

Full text of DOI:10.3987/COM-05-10569

HETEROCYCLES, Vol. 68, No. 1, 2006
167
HETEROCYCLES, Vol. 68, No. 1, 2006, pp. 167 – 173. © The Japan Institute of Heterocyclic Chemistry
Received, 20th September, 2005, Accepted, 28th October, 2005, Published online, 1st November, 2005. COM-05-10569
A NEW EFFICIENT SYNTHESIS OF 5-ARYLOXAZOLES FROM
ARYLIDENE DIACETATES AND APPLICATION TO THE
PREPARATION OF BMS-337197, A NOVEL IMPDH INHIBITOR
Bang-Chi Chen,* Mark S. Bednarz, Huiping Zhang, Rulin Zhao, T. G. Murali
Dhar, Balu Balasubramanian, and Joel C. Barrish
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, NJ 08543, USA
Email: bangchi.chen@bms.com
Abstract – A new method for the synthesis of 5-aryloxazoles is described.
Treatment of arylidene diacetates with one equivalent of TosMIC reagent in the
presence of excess of potassium carbonate in methanol afforded 5-aryloxazoles in
"one-pot" in 90-94%. Heteroarylidene diacetates reacted in a similar way.
Application of the new method to the synthesis of the novel IMPDH inhibitor
BMS-337197 is also presented.
1
p-Tosylmethyl isocyanide (TosMIC) is a versatile reagent in organic synthesis. It is particularly useful
1
,2
in the synthesis of azoles such as oxazoles, imidazoles, thiazoles, 1,2,4-triazoles, pyrroles and others.
Recently, we extended the application of TosMIC reagent to the synthesis of
2
a,2d
2b-d
1
-arylimidazole-5-carboxylates
and imidazo[1,5-a]quinoxalin-4-ones, both important intermediates
for the preparation of biologically important and medicinally useful agents.
In the course of our study towards the discovery of the novel inosine monophosphate dehydrogenase
3
,4
(
IMPDH) inhibitor BMS-337197 and others, we required an easy access to large amounts of
4
5
-(2-methoxy-4-nitrophenyl)oxazole (3a). This compound was previously prepared in astepwise fashion
from 2-methoxy-4-nitrobenzylidene diacetate (1a) in 61% overall yield with a key step being TosMIC
5
mediated oxazole formation through aldehyde (2a) (Scheme 1). Thus, acidic hydrolysis of 1a with
concentrated HCl in dioxane under reflux overnight afforded 2-methoxy-4-nitrobenzaldehyde (2a) in 89%
yield. Subsequent reaction of 2a with TosMIC reagent in methanol using potassium carbonate as base
5
,6
gave 3a in 68% yield. While this stepwise method can be used to prepare the desired compound (3a),

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HETEROCYCLES, Vol. 68, No. 1, 2006
we envisioned that this synthesis could be improved by direct treatment of the arylidene diacetate with
TosMIC reagent. Under the reaction conditions,thediacetates (1)are expected to undergo basic hydrolysis,
giving rise to aldehydes (2) in situ which in turn would react with TosMIC reagent to give oxazole
products (3). A similar strategy has been recently used in our synthesis of 1-arylimidazole-5-
2
a,2d
carboxylates.
Scheme 1
O
OAc
OAc
conc. HCl/dioxane
Ar
H
Ar
89%
2a
1
TosMIC
TosMIC
K CO /MeOH
K CO /MeOH
2
3
2
3
68%
a, Ar=2-MeO-4-NO C H
6 3
2
O
b, Ar=4-NO C H
2
6
4
4
N
c, Ar=2-NO C H
2
6
Ar
d, Ar=C H
6
5
e, Ar=2-Thienyl
3
Indeed, treatment of 1a with three equivalents of potassium carbonate in the presence of one equivalent of
4
TosMIC reagent in methanol at 55°C for 15 min afforded cleanly the desired product (3a). Compound
(
3a) was readily isolated in 91% yield by crystallization after quenching the reaction with water.
Compared to the original stepwise preparation of 3a, the new "one-pot" method not only shortened the
synthesis, but also improved the overall yield by 30% (91% vs 61%).
To determine if this new reaction of TosMIC reagent is general, several commercially available arylidene
7
,8
diacetates (1b-e) were subjected to the above reaction conditions and the results are summarized in
Table 1.
Table 1. Preparation of 5-Aryloxazoles (3) via Reaction of TosMIC Reagent with Arylidene Diacetates (1):
a,b
Entry
Ar
Time (h)
0.25
3 Yield (%)
4
1
2
3
4
5
2-MeO-4-NO
2
C
6
H
3
91[68]
9
4-NO
2
2
C
6
6
H
4
4
0.25
90[91]
1
0
2-NO
C
H
0.25
92[42]
9
C
6
H
5
1.75
90[91]
1
1
2-Thienyl
16.0
94[80]
a
b
Isolated yields for the new "one-pot" synthesis. Yields in [ ] are those reported in the literature.

HETEROCYCLES, Vol. 68, No. 1, 2006
169
As can be seen from Table 1,the new reaction of TosMIC works with benzylidene diacetates (1a-d) as well
as heteroarylidene diacetate (1e). Compared to the reactions of TosMIC reagent with aldehydes reported
in the literature,the new reaction gave improved or comparable yields for all the desired oxazole products.
With compound (3a) readily accessible from the diacetate (1a),the next step was the nitro group reduction
4
to give the corresponding aniline (4)(Scheme 2). Thus,treatment of 3a in ethanol with 10% palladium on
charcoal under 35-45 psi hydrogen smoothly gave 4 in 95% isolated yield. Reaction of aniline (4) with
1
3
,1'-thiocarbonyldi-2(2H)-pyridone (5) in methylene chloride at room temperature for 3 h afforded
-methoxy-4-(5-oxazolyl)phenyl isothiocyanate (6) in 94% yield after silica gel chromatographic
3
separation, which was further elaborated to BMS-337197, our newly discovered IMPDH inhibitor.
Scheme 2
O
S
O
O
O
N
N
OAc
OAc
N
N
H , Pd/C
2
TosMIC
5
EtOH
CH Cl
K CO /MeOH O N
OMe
2
2
2
3
2
H N
2
OMe
O N
2
OMe
95%
4
94%
1a
91%
3a
O
N
O
O
N
ref. 3
O
N Me
N
N
SCN
OMe
O
N
OMe
6
H
BMS-337197
In summary, an improved method for the synthesis of 5-(2-methoxy-4-nitrophenyl)oxazole, an important
3
,4
intermediate in the synthesis of biologically active compounds, has been developed. The new method
involved a direct reaction of TosMIC reagent with arylidene diacetate in a "one-pot" fashion and could be
readily carried out in multigram scale. In addition, the new reaction of TosMIC is general for both
arylidene and hetreoarylidene diacetates, giving 5-substituted oxazoles in >90% yields. While
5
-aryloxazoles could be prepared from aldehydes and TosMIC reagent in many cases, the new method is
particularly advantageous for those occasions where the aldehydes need to be prepared from arylmethanes
through arylidene diacetate intermediates. Furthermore, the new method was successfully used in the
preparation of BMS-337197, our newly discovered IMPDH inhibitor.
EXPERIMENTAL
Preparation of 5-aryloxazoles 3, general procedure: In a 100 mL rounded bottom flask was added

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HETEROCYCLES, Vol. 68, No. 1, 2006
2 3
arylidene diacetate (1, 10 mmol), TosMIC reagent (2.0 g, 10.4 mmol), K CO (4.4 g, 31.6 mmol) and
MeOH (30 mL). The reaction mixture was heated to 55°C and stirred under argon for 15 min to 16 h
when HPLC showed the reaction was complete (Table 1). Water (30 mL) was added and the resulting
slurry was cooled to rt. The solids were filtered, washed with water (3x5 mL) and dried in a vaccum
oven at 50°C to give 3. Analytical samples (3a-d) were obtained by recrystallization from
dichloromethane and hexane.
1
5
-(2-Methoxy-4-nitrophenyl)oxazole (3a): 91%; mp 151-152 °C (from CH Cl /hexane). H NMR
2
2
13
(CDCl
3
) δ 8.01 (s, 1H), 7.92 (m, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 4.10 (s, 3H). C NMR (CDCl
3
) δ 155.5,
1
3
5
50.8, 147.8, 146.2, 128.6, 126.0, 122.9, 116.3, 106.1, 56.2. Anal. Calcd for C10
.66; N, 12.72. Found: C, 54.28; H, 3.42; N, 12.35.
H N O : C, 54.55; H,
8 2 4
9
-(4-Nitrophenyl)oxazole (3b): 90%; mp 136-138 °C (from CH
2
Cl
2
/hexane), lit., mp 136-138.5 °C.
The spectroscopic data were consistent with the structure of the product.
-(2-Nitrophenyl)oxazole (3c): 92%; mp 77.5-79.5 °C (from CH Cl
1
5
2
2
/hexane). H NMR (CDCl
3
) δ 7.34
1
3
(
s, 1H), 7.45-7.50 (m, 1H), 7.58-7.62 (m, 1H), 7.65-7.67 (m, 1H), 7.78-7.81 (m, 1H), 7.91 (s, 1H). C
NMR (CDCl
3
9 6 2 3
) δ 152.0, 148.2, 132.9, 130.1, 130.0, 126.2, 124.8, 122.0. Anal. Calcd for C H N O : C,
5
6.85; H, 3.18; N, 14.73. Found: C, 56.65; H, 2.99; N, 14.89.
9
5
2 2
-Phenyloxazole (3d): 90%; mp 38-40 °C (from CH Cl /hexane), lit., mp 36-38 °C. The spectroscopic
data were consistent with the structure of the product.
1
5
-(2-Thienyl)oxazole (3e): 94%; oil. H NMR (CDCl
3
) δ 7.68 (s, 1H), 7.16 (d, J=1.2 Hz, 1H), 7.14 (d,
1
3
J=3.5 Hz, 1H), 7.05 (s, 1H), 6.90 (dd, J=1.2 Hz, J=3.5 Hz, 1H). C NMR (CDCl ) δ 149.8, 146.9, 129.5,
3
+
1
5
0
27.8, 125.8, 124.6, 121.1. HRMS Calcd for C
7
H
5
NOS (M +H): 152.0170. Found: 152.0172.
-(2-Methoxy-4-aminophenyl)oxazole (4): In a 2 L hydrogenation flask was placed 3a (130.0 g,
.6131 mol), Pd/C (10%, 26.2 g) and dry EtOH (1280 mL). The mixture was hydrogenated at 35-45 psi
H
2
until the reaction was complete. The mixture was filtered over a pad of celite (20 g) and the cake
was washed with EtOH (3x100 mL). The filtrate was concentrated to a volume of 350 mL. Heptane
500 mL) was added to the resulting slurry. After stirring for 2 h at rt, the slurry was filtered. The cake
(
was washed with heptane (3x100 mL) and dried to give 4 (80.0 g). A second portion of product (30.2 g)
was recovered from the mother liquor affording a total yield of 95%. mp 114.5-116.5 °C (from
1
CH Cl /hexane). H NMR (CDCl ) δ 7.88 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4,
2
2
3
1
3
2
1
1
5
.1 Hz, 1H), 6.34 (d, J=2.1 Hz, 1H), 3.98 (br s, 2H), 3.94 (s, 3H).
C NMR (CDCl
3
) δ 55.7, 98.4, 107.7,
08.3, 123.0, 126.6, 148.4, 148.9, 149.0, 157.5. Anal. Calcd for C10
10 2 2
H N O
: C, 63.15; H, 5.30; N,
4.73. Found: C, 63.03; H, 5.44; N, 14.85.
-(4-Isothiocyanato-2-methoxyphenyl)oxazole (6): In a 250 mL rounded bottom flask was placed 4

HETEROCYCLES, Vol. 68, No. 1, 2006
171
(3.50 g, 18.4 mmol), 1,1'-thiocarbonyldi-2(2H)-pyridone (5) (4.41 g, 18.4 mmol) and methylene chloride
(
100 mL). The reaction mixture was stirred under argon at rt for 3 h. The solvent was evaporated
under vacuum and the residue was subjected to column chromatography (30% AcOEt/hexane) to afford 6
1
(
4.02 g, 94%) as white crystals. mp 116-117.5 °C. H NMR (CDCl
3
) δ 7.92 (s, 1H), 7.74 (d, J=8.4 Hz,
1
3
1
H), 7.57 (s, 1H), 6.93 (dd, J=8.4, 1.8 Hz, 1H), 6.81 (dd, J=1.8 Hz, 1H), 3.98 (s, 3H).
CDCl ) δ 55.9, 108.5, 116.4, 118.4, 126.1, 126.7, 131.6, 136.2, 147.0, 149.8, 156.1. Anal. Calcd for
S: C, 56.88; H, 3.47; N, 12.06; S, 13.80. Found: C, 56.61; H, 3.20; N, 12.10; S, 13.56.
C NMR
(
3
C
11 8 2 2
H N O
ACKNOWLEDGEMENTS
The authors thank Ms Stacey Gove, Amanda P. Skoumbourdis for some of their assistances related to this
project as summer interns and Drs. Edwin J. Iwanowicz and Joseph E. Sundeen for some helpful
discussions.
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