A new method for the formation of 2,4-disubstituted oxazoles: Internal transfer of oxidation state through a molecular framework

Article abstract of DOI:10.1016/S0040-4039(00)00573-6

A new method for the synthesis of 2,4-disubstituted oxazoles is described from readily available starting materials. The synthesis avoids the necessity for the oxidation of an oxazoline to an oxazole by utilising an internal transfer of oxidation state across a molecular framework and has been performed on multigram scale. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00573-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4239–4242
A new method for the formation of 2,4-disubstituted oxazoles:
internal transfer of oxidation state through a molecular
framework
Kevin S. Cardwell, Stephen A. Hermitage ∗ and Asa Sjolin
GlaxoWellcome Research and Development, Chemical Development Division, Medicines Research Centre, Stevenage,
Hertfordshire, SG1 2NY, UK
Received 21 March 2000; accepted 4 April 2000
Abstract
A new method for the synthesis of 2,4-disubstituted oxazoles is described from readily available starting
materials. The synthesis avoids the necessity for the oxidation of an oxazoline to an oxazole by utilising an internal
transfer of oxidation state across a molecular framework and has been performed on multigram scale. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: oxazoline; oxazole; oxidation.
Oxazoles are found in many naturally occurring and biologically active materials as sub-structures
within more complicated molecular arrays.1–9 In particular oxazoles functionalised at both the 2- and
4-position with differing oxidation state of the appending carbon atom have found important application
in the synthesis of the more complex natural products.1,5,8,9 We have been interested in the pyrrolidine
5,5-trans-fused lactam10 1, containing a 2,4-disubstituted oxazole, as a potential therapy for respiratory
diseases such as acute respiratory distress syndrome, cystic fibrosis, emphysema and chronic bronchitis.
In conjunction with our wider programme aimed at developing a manufacturing route for 1, (Fig. 1) we
sought an efficient, scalable, and inexpensive route into the potassium salt of carboxylic acid 2 (R=K,
X=pyrrolidino). This route should also be suitable for scale up to pilot plant, be safe, environmentally
acceptable and avoid the need of chromatography for purification.
In this paper we wish to present a new method for the preparation for 2,4-disubstituted oxazoles
that fulfils the above requirements. In particular the facile preparation of ‘chloro oxazole’ 7 may find
application in the synthesis of more elaborate oxazole containing molecules. Imidate 4 was prepared
on multigram scale by a modification of the literature procedure11 whereby dichloroacetonitrile 3 was
added to a cold (−10°C) solution of a catalytic quantity of sodium methoxide in methanol. Serine methyl
∗
Corresponding author. E-mail: sah45573@glaxowellcome.co.uk (S. A. Hermitage)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00573-6
tetl 16852

4240
Fig. 1.
ester hydrochloride was added to the imidate 4 to give the dichlorooxazoline 512 in a crude yield of 88%
(Scheme 2).
Central to our strategy for the synthesis of oxazoles from oxazolines was the avoidance of oxidising
agents. The oxidation of an oxazoline heterocycle to the corresponding oxazole analogue (Scheme 1)
is a well known reaction in organic synthesis, and there are a number of synthetic methods to achieve
this transformation. Generally these methods13 require the use of environmentally unacceptable metals,
solvents and reagents.
Scheme 1.
Treatment of the dichlorooxazoline 5 with one molar equivalent of sodium methoxide in methanol led
to the elimination of chloride and formation of the methoxy-oxazoline 6. The proton NMR of 6 contains
a characteristic pair of doublets at δH 4.39 and 4.59 (J=10.5) for the ring CH2 protons. This synthetic
transformation has effectively transferred oxidation state of the gem-dichloro carbon to that adjacent
to the methyl ester and offers an ‘internal transfer of oxidation state through a molecular framework’. A
similar elimination reaction has been observed in the synthesis of oxazolones in a tryptophan derivative.14
Elimination of methanol from 6 by treatment with a catalytic amount of CSA in toluene at 70°C gave the
chlorooxazole 79 in 48% yield from dichloroacetonitrile 3. (Scheme 2).
Scheme 2.
In summary, we have demonstrated a new method for the synthesis of 2,4-disubstituted oxazoles
from readily available inexpensive starting materials on a multigram scale. This novel chemistry has
safely been applied on scale in our pilot plant to provide multi-kilogram quantities of 7. Our approach

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to oxazoles has the potential to provide small heterocyclic building blocks that may be applied to the
synthesis of more complex oxazole containing molecules.
1. Experimental
A solution of NaOMe in MeOH (25% w/w, 5.75 ml, 24.9 mmol) was diluted with MeOH (50 ml) and
cooled to −10°C. Dichloroacetonitrile 3 (20 ml, 249 mmol) was added dropwise over 25 minutes whilst
the temperature was maintained below 0°C. The mixture was stirred for a further 20 minutes at −5°C,
then DL-serine methyl ester hydrochloride (38.7 g, 249 mmol) was added followed by methanol (40
ml). The mixture was stirred overnight, gradually warming to room temperature. CH2Cl2 (140 ml) and
water (80ml) were added and the layers separated. The aqueous layer was extracted with CH2Cl2 (80 ml)
and the combined organic extracts concentrated in vacuo to give dichlorooxazoline 5 (46.7 g, 88%, crude
from dichloroacetonitrile) as an orange oil. To a solution of crude dichlorooxazoline 5 (46.2 g, 218 mmol)
in methanol (40 ml) was added a solution of NaOMe in MeOH (25% w/w, 49.9 ml, 218 mmol) over 50
minutes, keeping the temperature below 10°C. The mixture was stirred overnight, gradually warming
to room temperature. CH2Cl2 (140 ml) and water (80 ml) were added and the layers separated. The
aqueous layer was extracted with CH2Cl2 (80 ml) and the combined organic extracts were concentrated
in vacuo to give the methoxy oxazoline 6 (43.3 g, 84%, crude from dichloroacetonitrile 3 in the previous
step) as an oil. To the methoxy oxazoline 6 (42.9 g, 207mmol) was added toluene (100 ml) and (±)-
camphorsulphonic acid (7.21 g, 31.0 mmol) at room temperature. The solution was heated to 70°C for 50
minutes. The solution was cooled to room temperature and washed with aqueous K2CO3 solution (10%
w/v, 60 ml) followed by water (80 ml). The combined aqueous extracts were back-extracted with toluene
(120 ml) and the combined organic layers concentrated in vacuo to give the chlorooxazole 7 (30.1 g) as
a brown solid.
An analytical sample of crude chlorooxazole (2.5 g) was purified by flash column chromatography
for analytical purposes (25:75 EtOAc:iso-octane) to give the pure chlorooxazole product9 (1.73 g, 48%
isolated pure from dichloroacetonitrile 3 in this sequence) as a white solid. (Found: MH+, 176.0127.
C6H6NO3Cl requires MH+, 176.0114); νmax (Nujol mull)/cm−1 1578 (C_C), 1715 (C_O); δH (400
MHz, CDCl3) 3.93 (3H, s, CO2CH3), 4.63 (2H, s, CH2Cl), 8.27 (1H, s, O-CH_C); δC (100 MHz, CDCl3)
35.31 (CO2CH3), 52.35 (CH2Cl), 133.85 (C_C-CO2CH3), 145.07 (O-CH_C), 159.91 (C_N), 161.08
(CO2CH3).
References
1. (a) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett., 1999, 40, 2287; (b) Williams, D. R.; Clark, M. P.
Tetrahedron Lett. 1999, 40, 2291.
2. Lewis, J. R. Nat. Prod. Rep. 1999, 16, 389.
3. Muir, J. C.; Pattenden, G.; Thomas, R. M. Synthesis 1998, 613.
4. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.
5. Lui, P.; Panek, J. S. Tetrahedron Lett. 1998, 39, 6143.
6. Vaccaro, H. A.; Levy, D. E.; Sawabe, A.; Jaetsch, T.; Masamune, S. Tetrahedron Lett. 1992, 33, 1937.
7. Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1998, 591.
8. Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J. Org. Chem. 1986, 51, 5111.
9. Breuilles, P.; Uguen, D. Tetrahedron Lett. 1998, 39, 3149.
10. Clarke, G. D. E.; Dowle, M. D.; Finch, H.; Harrison, L. A.; Inglis, G. G. A.; Johnson, M. R.; Macdonald, S. J. F.; Shah, P.;
Smith, R. A. WO9912933
11. Galeazzi, E.; Guzman, A.; Nava, J. L.; Lui, Y.; Maddox, M. L.; Muchowski, J. M. J. Org. Chem. 1995, 60, 1090.

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12. The ethyl ester analogue has been reported by: Bretschneider, H.; Piekarski, G. Mh. Chem. 1954, 85, 1110.
13. For leading references, see: Williams, D. R.; Lowder, P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331.
14. Bergman, J.; Lidgren, G.; Gogoll, A. Bull. Soc. Chim. Belg. 1992, 101, 643