Preparation of 2-substituted oxazoles

Article abstract of DOI:10.1081/SCC-120006015

A simple and economical method for 2-substituted oxazole synthesis and its scope are described.

Full text of DOI:10.1081/SCC-120006015

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PREPARATION OF 2-SUBSTITUTED OXAZOLES
Chennagiri R. Pandit a , Richard P. Polniaszek b & John K. Thottathil a
a Department of Process Research and Development, Bristol Myers Squibb Pharmaceutical
Research Institute, New Brunswick, NJ, 08903, U.S.A.
b Department of Process Research and Development, Bristol Myers Squibb Pharmaceutical
Research Institute, New Brunswick, NJ, 08903, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Chennagiri R. Pandit , Richard P. Polniaszek & John K. Thottathil (2002): PREPARATION OF 2-SUBSTITUTED
OXAZOLES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
32:15, 2427-2432
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 15, pp. 2427–2432, 2002
PREPARATION OF
2-SUBSTITUTED OXAZOLES
*
Chennagiri R. Pandit, Richard P. Polniaszek,
and John K. Thottathil
Bristol Myers Squibb Pharmaceutical Research
Institute, Department of Process Research and
Development, New Brunswick, NJ 08903, USA
ABSTRACT
A simple and economical method for 2-substituted oxazole
synthesis and its scope are described.
As part of a development program of a cardiovascular drug candidate,
it was necessary to prepare large quantities of 2-(4-iodophenyl)oxazole, 3d.
Known methods for the synthesis of 2-substituted-4,5-unsubstituted oxa-
zoles are either indirect,[1] low yielding,[2,4] or require expensive reagents.[3]
The simplest way to prepare these heterocycles appeared to be cycloconden-
sation of the corresponding aroyl amidoacetals, 2. Cass reported two low
yielding examples of this reaction in 1942 (2j,k to 3a,b).[4] We describe herein
improved cyclization conditions as well as a survey of the scope of the
reaction.
A variety of aromatic acid chlorides 1 underwent Schotten-Baumann
reaction with aminoacetaldehyde dimethyl acetal[5] and the resultant amides 2
were isolated in 75–99% yield by simple extractive workup. The amides thus
*Corresponding author.
2427
DOI: 10.1081/SCC-120006015
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2428
PANDIT, POLNIASZEK, AND THOTTATHIL
obtained were used in the subsequent step without purification. Preliminary
cyclization studies were carried out with the 4-iodophenyl carboxamide 2d as
substrate. Initial screening experiments revealed that catalytic amounts of
carboxylic acids in toluene resulted in no reaction, catalytic MeSO3H in
toluene or neat MeSO3H produced many products, and cyclization in poly-
phosphoric acid afforded the oxazole 3d in moderate yield.
The high viscosity of PPA makes this reagent impractical for large
[5,6]
scale workand Eaton’s reagent,
a mixture of 1 : 10 P2O5 : MeSO3H, is
a less viscous, practical alternative with solvent properties similar to PPA. In
the event, cyclization of 2d in neat Eaton’s reagent at 130ꢀC for 7.5 h
afforded oxazole 3d which was isolated by precipitation upon dilution of
the reaction mixture with water. The oxazole was obtained in 93% unpu-
rified yield with an HPLC purity of 98%. Crystallization afforded analyti-
cally pure material in 83% yield from the acid chloride on 200 g scale.
The generality of the method was evaluated by cyclization of a series
of amides 2 derived from aromatic and aliphatic acid chlorides. Reactions
were run on a 2–4 mmol scale at a concentration of 10 mL/g. Isolation of the
oxazoles was effected by dilution onto 10 volumes of water containing 2 g/g
of celite, filtration and extractive workup. The methanol liberated during the
cyclization was trapped by the mixed anhydride of P2O5–MeSO3H (Eaton’s
reagent) and formed methyl methanesulfonate as a reaction byproduct.
Typically the MeSO3Me was removed by vacuum drying 48 h at RT and
ꢁ1 torr. Purification was achieved by silica gel chromatography.

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2-SUBSTITUTED OXAZOLES
2429
Table 1.
Yield 2
(%)
Cyclization
Conditions
Yield 3
(%)
Entry
R
1
2
3
4
5
6
7
8
9
2a: 2-NO2–C6H4
2b: 4-NO2–C6H4
2c: 4-Br–C6H4
85a
84
79
99
92
95
130ꢀC, 1 h
130ꢀC, 5 h
150ꢀC, 1.5 h
130ꢀC, 7.5 h
135ꢀC, 4 h
135ꢀC, 5 h
135ꢀC, 3 h
125ꢀC, 6 h
125ꢀC, 6 h
24
73
80
2d: 4-I–C6H4
83b
60
2e: 2-CH3–C6H4
2f: 3-CH3-4-BrC6H3
2g: 4-CH3OC6H4
2h: 4-HOC6H4
65
0c
71, 3i
72
90
75d
85e
2i: 4-CH3O3SOC6H4
b
aPrepared from 2-nitrobenzoic acid via the acyl imidazole; 200 g scale, crystallized
c
yield; Oxazole not detected, only degradation products; dPrepared from 4-acetox-
ybenzoyl chloride,[7] Isolated as the phenol after hydrolysis of the acetate; ePrepared
by mesylation of 2j.
Table 1 lists the results of the cyclocondensation of substituted benza-
mides classified in descending order into strongly electron deficient (2a–b),
mildly electron deficient (2c–d), mildly electron rich (2e–f), and electron rich
(2g–i) cases. Eaton’s reagent effected cyclization of the ortho and para nitro
benzamides 2a–b (Entries 1,2). A significant amount of decomposition
occurred during cyclization of 2a. The cyclization is presumably inhibited
for steric reasons, and in this case the rate of degradation was competitive
with the rate of cyclization. Although the yield of the ortho derivative was
modest, the para derivative 2b cyclized efficiently. The cyclization worked
well for substrates possessing mildly electron deficient aromatic rings
(Entries 3–4). Although the 2-toluic derivative 2e cyclized in 60% yield
(Entry 5), more electron rich substrates like the 4-methoxy derivative 2g
(Entry 7) of 1-naphthyl (not in Table) suffered extensive degradation
under the strongly acidic conditions. The phenol derivative 2h underwent
cyclization to a mesylate ester 3i.

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2430
PANDIT, POLNIASZEK, AND THOTTATHIL
Presumably in this case, the phenol was converted to the mesylate 2i
in situ, which was then deactivated enough to survive the harshly acidic reac-
tion medium. Cyclization of authentic 2i afforded 3i in 72% yield (Entry 9),
consistent with the intermediacy of 2i in the cyclization of phenol 2h.
The method therefore appears to be limited to those substrates which
are tolerant of the highly acidic reaction conditions.
In summary, a simple and economical method for the preparation of
certain 2-substituted oxazoles amenable to large scale has been achieved
which complements existing methods[1–3,8] of oxazole synthesis. The
procedure employs inexpensive, commercially available starting materials
and reagents.
EXPERIMENTAL
KHCO3 (80.0 g, 0.80 mol) was added to a solution of aminoacetalde-
hyde dimethyl acetal[5] (82.9 g, 86.0 mL, 0.79 mol) in water (900 mL) and
acetone (400 mL) and the resulting solution was cooled in an ice bath to
0ꢀC. A solution of 4-iodobenzoyl chloride (200.0 g, 0.75 mol) in acetone
(600 mL) was added dropwise over 1.5 h with stirring. The ice bath was
removed and the reaction mixture was stirred at RT for 3 h. One liter of
solvent was removed in vacuo and the mixture extracted with EtOAc
(4 ꢂ 350 mL). The organic layers were pooled, washed sequentially with
saturated NaHCO3 (1 ꢂ 250 mL), H2O (1 ꢂ 250 mL), dried over anhydrous
MgSO4 (50.0 g), filtered and concentrated to afford the amide 2d as a white
solid (246.5 g, 98%, HPLC area percent 99.7, mp 89–90ꢀC). 1H NMR:
(CDCl3 300 MHz, ppm): 7.77 (d, 2H); 7.49 (d, 2H); 6.27 (s, 1H); 4.46
(t, 1H); 3.58 (t, 2H); 3.42 (s, 6H), MS 334 (MHþ).
A solution of the unpurified amide (200.0 g, 0.60 mol) and Eaton’s
reagent[5,6] (2 L) was stirred and heated under argon, maintaining the
internal temperature between 130–134ꢀC. After 7.5 h the reaction mixture

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2-SUBSTITUTED OXAZOLES
2431
was cooled to RT, poured onto a slurry of ice/water (12.0 L) with vigorous
stirring and external cooling (ice water). The resulting suspension was stir-
red for 2 h, the solid collected, washed with ice cold water (2 L), the filter
cake broken and the solid suction dried for 5 days affording a gray powder
(151.7 g, 93%, HPLC area percent 98.0). The crude material (151.7 g) was
dissolved in acetonitrile (2 L), activated charcoal (15.2 g) was added, stirred
at RT for 1 h, filtered through a pad of celite (100 g), the celite pad washed
with acetonitrile (2 ꢂ 100 mL), and the filtrate concentrated to approxi-
mately 1180 mL. The mixture was warmed until the solid dissolved, boiling
water (295 mL) was slowly added, the mixture reheated to effect dissolution,
ꢀ
the flaskcooled to RT, allowed to stand for 48 h, and then at 4 C. The
oxazole was collected, washed with an ice cold acetonitrile/water (4 : 1,
150 mL), and air dried for 16 h, affording 3d as pale yellow needles
(54.8 g, 66%, HPLC area percent 99.7, m.p. 107–109ꢀC). 1H NMR:
(CDCl3, 300 MHz, ppm): 7.74–7.82 (m, 4H); 7.70 (s, 1H), 7.22 (s, 1H).
Elemental Analysis Calcd for C9H6NOl: C, 39.88; H, 2.23; N, 5.17.
Found: C, 40.00; H, 2.09; N, 5.14. MS: 272 (MHþ). A second crop from
the mother liquor gave an additional 17%, HPLC area percent 98.4.
1
The H NMR spectra of 2a–i and 3a–f and 3h–i were consistent with
the assigned structures. The oxazoles 3 displayed the following high resolu-
tion mass spectra: 3a: C9H7N2Oþ3 , Calcd: 191.0457; Found: 191.0460, m.p.
35–37ꢀC, lit.[4a] 38–39ꢀC; 3b: C9H7N2Oþ3 , Calcd: 191.0457; Found:
191.0461, m.p. 159–161ꢀC, lit.[4b] 163.5–164.5ꢀC; 3c: C9H7NOBrþ, Calcd:
223.9711; Found: 223.9710, m.p. 84–85.5ꢀC; 3e: C10H10N2O3þ Calcd:
160.0762; Found: 160.0765; oil; 3i: C10H10NO4Sþ, Calcd: 240.0331;
Found: 240.0334, m.p. 92–93.5ꢀC. Elemental analysis was obtained for 3f:
Calcd for C10H8BrNO: C, 50.45; H, 3.39; N, 5.88; Br, 33.56. Found:
C, 50.10; H, 3.36; N, 5.75; Br, 33.52; m.p. 56ꢀC.
ACKNOWLEDGMENTS
We thankDr. Kumar Gadamasetti for technical assistance with the
preparation of substrates 3f and 3i.
REFERENCES
1. Kashima, C.; Arao, H. Synthesis 1989, 873; Eisenstat, M.A.; Weaver
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Lett. 1994, 35, 2481.

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2432
PANDIT, POLNIASZEK, AND THOTTATHIL
2. Ferrini, P.G.; Marxer, A. Angew. Chemie Int. Ed. Engl. 1963, 2, 99;
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Received in the USA August 8, 2001