A Modified Approach to 2-(N-Aryl)-1,3-oxazoles: Application to the Synthesis of the IMPDH Inhibitor BMS-337197 and Analogues

Article abstract of DOI:10.1021/ol020073i

(Matrix Presented) A modified approach to the synthesis of 2-(N-aryl)-1,3-oxazoles, employing an optimized iminophosphorane/heterocumulene-mediated methodology, and its application to the synthesis of BMS-337197, a potent inhibitor of IMPDH, are described

Full text of DOI:10.1021/ol020073i

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2091-2093
A Modified Approach to
2-(N-Aryl)-1,3-oxazoles: Application to
the Synthesis of the IMPDH Inhibitor
BMS-337197 and Analogues
T. G. Murali Dhar,* Junqing Guo, Zhongqi Shen, William J. Pitts, Henry H. Gu,
Bang-Chi Chen, Rulin Zhao, Mark S. Bednarz, and Edwin J. Iwanowicz
Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, New Jersey 08543-4000
dharm@bms.com
Received April 8, 2002
ABSTRACT
A modified approach to the synthesis of 2-(N-aryl)-1,3-oxazoles, employing an optimized iminophosphorane/heterocumulene-mediated
methodology, and its application to the synthesis of BMS-337197, a potent inhibitor of IMPDH, are described.
The 2-amino-1,3-oxazole moiety is associated with a broad
spectrum of biological activity, e.g., antifungal, antibacterial,
and antiviral.1 We recently reported on the identification of
BMS-337197 as a potent inhibitor of inosine monophosphate
dehydrogenase (IMPDH).2 The central 2-amino-1,3-oxazole
moiety is the key structural element in BMS-337197.
However, there are only a few methods known for the
synthesis of 2-(N-aryl)-substituted 1,3-oxazoles.3a-d
For example, Froyen3b and Molina3c have reported the
synthesis of 2-(N-phenyl)-substituted 1,3-oxazoles via a
tandem iminophosphorane/heterocumulene-mediated annu-
lation.
Ibata and co-workers3d have employed a Rh2(OAc)4-
catalyzed reaction of R-diazoacetophenones with N,N-
disubstituted cyanamides to give the corresponding 2-(N,N-
disubstituted)-5-aryloxazoles. However, the reaction gave low
yields with monosubstituted cyanamides. For the purpose
of synthesizing BMS-337197 and analogues, the iminophos-
phorane/heterocumulene-mediated synthesis of 2-(N-phenyl)-
1,3-oxazoles3b,c appeared particularly appealing since the
reaction is carried out under mild conditions and leads to
high yields of the product (Scheme 1). This is particularly
true when R1 in the â-ketoazide (I, Scheme 1) is a phenyl
group that is unsubstituted or has an electron-donating
substituent like methoxy or methyl. However, very few 2-(N-
aryl)-substituted 1,3-oxazoles have been made employing this
method and therefore the scope and limitations of the reaction
have not been completely studied. For example, we found
that nitrophenyl-substituted â-ketoazides (I, Scheme 1, R1
) o-nitrophenyl) do not undergo the cyclization reaction
under the reported conditions (CH2Cl2/room temperature,
vide infra).
(1) Peshakova, L. S.; Kalcheva, V. B.; Simov, D. A. Chem. Heterocycl.
Compd. 1982, 741-752.
(2) Dhar, T. G. M.; Shen, Z.; Guo, J.; Liu, C.; Watterson, S. H.; Gu, H.
H.; Pitts, W. J.; Fleener, C. A.; Rouleau, K.; Sherbina, N. Z.; Mcintyre, K.
W.; Witmer, M.; Tredup, J. A.; Chen, B. C.; Zhao, R.; Bednarz, M. S.;
Cheney, D.L.; MacMaster, J. F.; Miller, L. F.; Berry, K. K.; Harper, T. W.;
Barrish, J. C.; Hollenbaugh, D. L.; Iwanowicz, E. J. J. Med. Chem. 2002,
45, 2127-2130.
(3) (a) Van Leusen, A. M.; Jeuring, H. J.; Wildeman, J.; Nispen van, P.
J. M.S. J. Org. Chem. 1981, 2069-2072. (b) Froyen, P. Phosphorous, Sulfur
Silcon Relat. Elem. 1991, 60, 81-84. (c) Molina, P.; Fresneda, P. M.;
Almendros, P. Synthesis 1993, 54-56. (d) Fukushima, K.; Ibata, T.
Heterocycles 1995, 149-154.
Retrosynthetically, compounds (1) and (2) would be the
ideal precursors to achieve the synthesis of BMS-337197
10.1021/ol020073i CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/22/2002

accompanied by a number of byproducts, which were not
characterized. Use of the more reactive and less bulky
tributylphosphine3c did not improve the yield or the spectrum
of byproducts obtained. Hypothesizing that the low yield in
the cyclization step might be due to incomplete iminophos-
phorane formation (I to II, Scheme 1), we decided to run
the reaction at a higher temperature.
Scheme 1
We were gratified to find that heating a mixture of the
isothiocyanate (1), â-keto azide (2), and triphenylphosphine
in dioxane to 90 °C resulted in the formation of the desired
2-(N-aryl)-1,3-oxazole (5) in 95% isolated yield.5-7 It is
possible that heating the reaction mixture also aids in the
cyclization of the carbonyl group (or the enol form) across
the carbodiimide (III to IV, Scheme 1). After achieving this
key transformation in high yield, the synthesis of BMS-
337197 was completed in a two-step sequence as outlined
in Scheme 3. We employed this sequence for the synthesis
of gram quantities of BMS-337197 to support its further
development.
via the iminophosphorane/heterocumulene-mediated annu-
lation (Scheme 2). The isothiocyanate (1) was synthesized
To further explore the structure activity relationships in
this series, we had to incorporate electron-withdrawing
groups (e.g., nitro and ester) on the 5-phenyl moiety of BMS-
337197 (Table 1, entries 1 and 2). However, when the
o-nitro-â-keto azide (6) and isothiocyanate (1) were subjected
to the iminophosphorane/heterocumulene-mediated annula-
tion in the presence of triphenylphosphine under the reported
conditions,3b there was no trace of the desired 2-(N-phenyl)-
1,3-oxazole (10). One plausible explanation could be that
the electron-withdrawing nitro group on the aromatic ring
decreases the electron density across the carbonyl group of
intermediate III (Scheme 1) thus preventing the cyclization
to the desired product. However, when the reaction was
carried out using the optimized conditions (dioxane, 90 °C),
it proceeded in the desired fashion to yield 2-(N-aryl)-1,3-
oxazole (10) in 70% isolated yield. In a similar manner,
reaction of the â-keto azide 7, bearing an electron-withdraw-
ing ester group at the ortho position, gave the desired 2-(N-
aryl)-1,3-oxazole (11) in 50% isolated yield. As Table 1
reveals, these optimized reaction conditions can also be
applied to the synthesis of 2-(N-aryl)-1,3-oxazoles bearing
a nonaromatic heterocycle at the C-5 position of the oxazole
(Table 1, entry 3) and to isothiocyanates having electron-
withdrawing substituents (Table 1, entries 4-6). Although
Scheme 2
employing a known literature procedure.4 The â-keto azide
(2) was synthesized employing the protocol outlined in
Scheme 3. Treatment of o-bromoaniline with acetoxyacetyl
chloride followed by methylation gave the N-methyl amide
(3) in quantitative yield. Stille coupling of (3) with tributyl-
(1-ethoxyvinyl)tin gave the enolether (4). Reaction of the
enolether with N-bromosuccinamide in water gave the â-keto
bromide, which when treated with sodium azide afforded
the key intermediate (2), which was set for the iminophos-
phorane/heterocumulene-mediated annulation.
(5) General experimental procedure for the modified iminophospho-
rane/hetrocumulene-mediated cyclization (e.g., prepartion of compound (3),
Scheme 3): To a solution of (2) (1.7 g, 5.68 mmol) and 3-methoxy-4-(5-
oxazolyl)phenyl isothiocyanate (1) (1.1 g, 4.74 mmol) in anhydrous dioxane
(10 mL) was added triphenylphosphine (1.5 g, 5.68 mmol). The contents
were immersed into a preheated oil bath maintained between 90 and 100
°C and heated at that temperature for 15 min. The reaction mixture was
concentrated under reduced pressure and partitioned between 6 N HCl (30
mL) and ethyl acetate (30 mL). The aqueous layer was cooled to 0 °C,
made basic using 20% KOH, and extracted into ethyl acetate (2 × 50 mL).
The ethyl acetate layer was dried over sodium sulfate and purified using
silica gel column chromatography (hexane/ethyl acetate) to yield the title
compound (2.1 g, 95%). 1H NMR (DMSO-d6): δ 10.7 (s, 1H), 8.35 (s,
1H), 7.00-7.8 (m, 9H), 4.4 (d, J ) 15 Hz, 1H), 4.1 (d, J ) 15 Hz, 1H),
3.9 (s, 3H), 3.1 (s, 3H), 2.0 (s, 3H). HRMS (ESI) calcd for C26H27N5O5
(M + H)+ 490.2091, found 490.2087.
Reaction of the â-keto azide (2) with the isothiocyanate
(1) under the reported conditions3b (CH2Cl2/rt) gave the
desired 2-(N-aryl)-1,3-oxazole (5) in 20% isolated yield
(6) Although we did not experience any explosions while doing this
reaction at 90 °C in dioxane, extreme care should be exercised while heating
an azide solution because of the possibility of explosions.
(7) All compounds were of g98% purity by LC/MS and analytical HPLC
systems.
(4) Armistead, D. M.; Badia, M. C.; Bemis, G. W.; Bethiel, R. S.; Frank,
C. A.; Novak, P. M.; Ronkin, S. M.; Saunders: J. O. Patent WO9740028,
1997.
2092
Org. Lett., Vol. 4, No. 12, 2002

Scheme 3a
a (a) ClCOCH2OAc, pyridine, CH2Cl2, 2 h; (b) NaH, MeI, DMF, 1 h; (c) Pd(PPh3)2Cl2, CH2C(OEt)(Bu3Sn), dioxane, 100 °C, 18 h; (d)
NBS, H2O, 50 °C, 10 min; (e) NaN3, acetone, H2O, rt, 30 min.; (f) PPh3, dioxane, 90 °C, 15 min.; (g) LiOH, MeOH, H2O, rt, 30 min; (h)
MsCl, Et3N, THF, 1 h, then morpholine, Et3N, DMF, rt.
Table 1. Modified Approach to the Synthesis of 2-(N-Aryl)-1,3-oxazoles
has been used to prepare a variety of 2-(N-phenyl)-1,3-
oxazoles for the IMPDH program. Notably, this reaction can
now be carried out in the presence of an electron-withdrawing
group on the aromatic ring bearing a phenacyl azide moiety,
using the optimized conditions.
the yields are moderate, this optimized procedure represents
a significant advance in the synthesis of 2-(N-aryl)-1,3-
oxazoles that are not accessible by earlier reported methods.
In conclusion, a high yielding synthesis of BMS-337197
has been achieved that employs an optimized iminophos-
phorane/heterocumulene-mediated methodology. This method
OL020073I
Org. Lett., Vol. 4, No. 12, 2002
2093