Isoxazole to oxazole: a mild and unexpected transformation

Abstract

3-Aryltetrahydrobenzisoxazoles prepared en route to the coleophomone natural products and analogues, were found to undergo a remarkable base-mediated rearrangement to 2-aryltetrahydrobenzoxazoles. The scope of this unprecedented, facile transformation was probed: a range of analogues was produced, a mechanism proposed, and an application demonstrated by synthesis of a known herbicidal compound.

---

As an extension of our interest in natural products containing the cyclic trione unit 1,^1,2 we were attracted to the coleophomone natural products, exemplified by coleophomones A (2) and B (3), reported as being in equilibrium via an aldol process.^3,4 This group of metabolites have enzyme inhibitory properties towards bacterial cell wall transglycosylase and human heart chymase.^4,5

Applying our previously reported isoxazole masking strategy for the cyclic trione unit^1,2 led us to propose the disconnection of Scheme 1, requiring 3-aryltetrahydrobenzisoxazole building blocks to access the natural products and (masked) analogues. Whilst manipulating one such arylbenzisoxazole, we observed a remarkable rearrangement to a 2-arylbenzoxazole. We report here our exploration of this unprecedented, facile transformation.

Scheme 1 Strategic disconnection of coleophomones.

A suitable set of 3-aryltetrahydrobenzisoxazoles 4 was prepared by 1,3-dipolar cycloaddition of aryl nitrile oxides [available from benzaldehyde oximes via C-chlorination (NCS, CHCl₃ reflux) and 1,3-elimination] with cyclohexane-1,3-diones under basic conditions (Scheme 2).⁶

Scheme 2 Synthesis and rearrangement of 3-aryltetrahydrobenzisoxazoles 4. Reagents: (i), NaOi-Pr, i-PrOH; (ii), Cs₂CO₃, THF reflux; (iii), H₂C=CHCH₂Br, Cs₂CO₃, THF reflux.

During attempts to complete O-allylation of 3-(2-hydroxyphenyl)benzisoxazole 4a (R = R¹ = H) under standard basic conditions (Cs₂CO₃, THF reflux), we did not observe the expected product but instead isolated 2-(2-allyloxy)tetrahydrobenzoxazole 5. This rearrangement also took place in the absence of alkylating agent (Scheme 2); the phenolic product 6a (R = R^1–4 = H) was stable to the basic conditions, and was successfully O-allylated to give ether 5 on addition of allyl bromide. We have verified the structures of both isoxazole 4a and dimethyl product oxazole 6b (R = Me, R^1–4 = H; vide infra) through X-ray crystal structure determinations, Fig. 1a and b.‡

Fig. 1 (a and b) X-Ray crystal structures of isoxazole 4a and oxazole 6b (O = red, N = blue, C = grey, H = light grey).

We further investigated the scope of the remarkable rearrangement of benzisoxazoles 4 to benzoxazoles 6. Using isoxazole 4a, rearrangement was found to occur in aprotic solvents with reaction time of 4 h under a range of basic conditions (Table 1) including carbonates, alkoxide and amidine, but failed with tertiary amines. In the presence of water or ethanethiol (entries 12, 13) the amide products 7a,b, respectively, of ring opening of the oxazole 6a were isolated; the constitutions of the amides were confirmed by X-ray crystal structures.⁷

Table 1 Rearrangement of isoxazole 4a to oxazole 6a under various reaction conditions^a

Entry	Base	Solvent	Yield^b (%)
a Isoxazole 1 (2.18 mmol), base (4.37 mmol), reaction time 4 h, solvent under reflux. b Isolated yields refer to 6a unless otherwise stated.
1	Cs2CO3	THF	87
2	K2CO3	THF	84
3	Na2CO3	THF	5
4	Et3N	THF	0
5	DMAP	THF	0
6	DBU	THF	83
7	LDA	THF	37
8	Cs2CO3	Toluene	97
9	NaOi-Pr	i-PrOH	85
10	Cs2CO3	EtOH–H2O	87 (for 7a)
11	None	H2O	8
12	Cs2CO3	H2O	91 (for 7a)
13	Cs2CO3 & EtSH	THF	6 (for 7b)

---

A range of 3-(2-hydroxyphenyl)tetrahydrobenzisoxazoles 4a–i, differently substituted in the aryl and the cyclohexane ring were shown to undergo rearrangement (Table 2) using the convenient Cs₂CO₃ conditions (THF reflux) to afford oxazoles 6a–i.§

Table 2 Rearrangement of oxazole 4 to isoxazole 6^a

Isoxazole 4	Oxazole 6	Yield (%)
a Isoxazole 4 (2.18 mmol), Cs2CO3 (4.37 mmol), THF at reflux. b Reaction time 4 h. c Reaction time 12 h. d Reaction time 2 h.
		87^b
		59^b
		82^b
		70^c
		28^c
		55^c
		58^d
		75^d
		77^d

---

We propose the mechanism illustrated in Scheme 3 for the rearrangement. Until the oxazole structure was determined, we had supposed that a Boulton–Katritzky ring transposition⁸ (similar to that reported by Suzuki et al.⁹) was taking place, so we retain this as the initial step in this remarkable isoxazole-to-oxazole conversion.¹⁰ This can be followed by a Neber rearrangement¹¹ to give an azirine, thus overall replacing the N–O bond of the isoxazole by an N–C bond. The azirine may be envisaged to be in equilibrium with a nitrile ylide¹² stabilised at the formal negative end by the 1,3-dione system, and at the formal positive end by the electron-rich 2-hydroxyphenyl substituent. The 1,3-dipole finally collapses to the oxazole in a 6π electrocyclic ring closure.

Scheme 3 Proposed mechanism for isoxazole–oxazole rearrangement.

Previous reports indicate that it is possible to form oxazoles from azirines, and also that an azirine can be generated from an isoxazole either thermally or photolytically.^13,14 However, the energies required well exceed those of our reaction conditions and thus an alternative rationale was required. The Neber rearrangement is an alternative way of generating azirines given the appropriate leaving group.¹⁵ This mechanism implies that the base is catalytic, and this was supported by isolation of 6a (66%) from 4a using 0.1 mol equiv. of Cs₂CO₃ (THF reflux, 1.5 h). An intermediate with m/z identical to both the isoxazole and oxazole was observed by LC-MS during the rearrangements of 4a and 4c to 6a,c, respectively, and isolated by HPLC. We were not able to unambiguously identify the structure, but NMR studies indicate the cyclohexane portion to be symmetrical, supporting either the azirine or nitrile ylide formulation.¹⁶ An attempt to crystallise the dimethyl intermediate formed from 4c led merely to recovery of the oxazole 6c. The oxazole ring opening to form amides 7a,b is consistent with nucleophilic attack at C-5 of the oxazole.

To discount the possibility of the oxazoles being formed by retro-cycloaddition from the isoxazoles and recombination via a different connectivity, we have shown that treatment of a mixture of the two tetrahydrobenzisoxazoles 4c and 4i under the Cs₂CO₃–THF reflux conditions led only to the tetrahydrobenzoxazoles 6c and 6i predicted by the mechanism of Scheme 3, with no crossover products observed.

The tetrahydrobenzoxazoles prepared herein are closely related to a series of herbicides described in a patent by Ueda et al.¹⁷ Using benzoxazole 6a we have prepared an example 8 of this group by reaction with 2-chloropyrimidine (47%) (Scheme 4).

Scheme 4 Reagents: (i), 2-chloropyrimidine, Cs₂CO₃, Cu, dry DMF, 1 day.

In conclusion, we have discovered an unexpected, remarkably facile novel base-mediated rearrangement of tetrahydro-benzisoxazoles to tetrahydrobenzoxazoles, demonstrated the scope and probed the reaction mechanism of this surprising transformation. The synthetic utility of this rearrangement has been demonstrated by synthesis of a known bioactive compound.

The authors thank Loughborough University for a studentship (A. C.) and Lilly UK for financial support, and ENSIACET (Toulouse) for support for a work placement (R. M.).

Notes and references

1. 3-Acyltetramic acids. For leading references, see: R. C. F. Jones and T. A. Pillainayagam, Synlett, 2004, 2815–2817; R. C. F. Jones, C. C. M. Law and M. R. J. Elsegood, ARKIVOC, 2013, iii, 81–97.
2. 3-Acyl-4-hydroxypyridones. For leading references, see: R. C. F. Jones, A. K. Choudhury, J. N. Iley, M. E. Light, G. Loizou and T. A. Pillainayagam, Beilstein J. Org. Chem., 2012, 8, 308–312; R. C. F. Jones, A. K. Choudhury, C. E. Dawson, C. Lumley and V. McKee, ARKIVOC, 2012, vii, 12–24.
3. For a total synthesis, see: K. C. Nicolaou, T. Montagnon, G. Vassilikogiannakis and C. J. N. Mathison, J. Am. Chem. Soc., 2005, 127, 8872–8888.
4. K. E. Wilson, N. N. Tsou, Z. Guan, C. L. Ruby, F. Pelaez, J. Gorrochategui, F. Vicente and H. R. Onishi, Tetrahedron Lett., 2000, 41, 8705–8709.
5. T. Kamigakinai, M. Nakashima and H. Tani, Japanese Pat., JP 10101666 A2, 1998; T. Kamigaichi, M. Nakashima and H. Tani, Japanese Pat., JP 11158109 A2, 1999.
6. J. W. Bode, Y. Hachisu, T. Matsuura and K. Suzuki, Org. Lett., 2003, 5, 391–394.
7. Crystallographic data for amides 7a and 7b are deposited at the Cambridge Crystallographic Data Centre, CCDC 962974, 962975 respectively.
8. For leading references, see: A. Palumbo Piccionello, S. Buscemi, N. Vivona and A. Pace, Org. Lett., 2010, 12, 3491–3493; A. J. Boulton, A. R. Katritzky and A. M. Hamid, J. Chem. Soc. C, 1967, 2005–2007.
9. J. W. Bode, H. Uesuka and K. Suzuki, Org. Lett., 2003, 5, 395–398.
10. Studies with the 3-phenyltetrahydrobenzisoxazole confirm the requirement for the phenolic substituent: unpublished observations.
11. P. W. Neber and A. V. Friedolsheim, Justus Liebigs Ann. Chem., 1926, 449, 109–134 . For an application in synthesis, see: N. Garg, D. D. Caspi and B. M. Stoltz, J. Am. Chem. Soc., 2004, 126, 9552–9553.
12. Cf. S. Lopes, C. M. Nunes, A. Gomez-Zavaglia and T. M. V. D. Pinho de Melo, Tetrahedron, 2011, 67, 7794–7804.
13. See, for example: I. J. Turchi and M. J. S. Dewar, Chem. Rev., 1974, 75, 389–437; K. K. Zhigulev and M. A. Panina, Khim. Geterotsikl. Soedin., 1974, 4, 457–460; M. Maeda and M. Kojima, J. Chem. Soc., Perkin Trans. 1, 1977, 239–247; S. M. Fonseca, H. D. Burrows, C. M. Nunes and T. M. V. D. Pinho de Melo, Chem. Phys. Lett., 2009, 474, 84–87; C. M. Nunes, I. Reva, T. M. V. D. Pinho de Melo, R. Fausto, T. Solomek and T. Bally, J. Am. Chem. Soc., 2011, 133, 18911–18923.
14. For a base-catalysed isoxazole–oxazole transformation in which the oxazole ring atoms are not all derived from the isoxazole: G. Doleschall and P. Seres, J. Chem. Soc., Perkin Trans. 1, 1988, 1875–1879.
15. A. Padwa, in Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier, Oxford, 2008, vol. 1, pp. 94–95.
16. Selected spectral data for the intermediate in rearrangement of 4a to 6a: δ_H (500 MHz; CDCl₃) 2.05–2.15 (m, 2H, CH₂CH₂CH₂), 2.67 (4H, t, J = 6.4, 2 × CH₂CO), 7.30–7.33 (1H, m, Ar–H), 7.52–7.60 (2H, m, 2 × Ar–H), 8.21 (1H, d, J = 8.2, Ar–H), 11.18 (s, 1H, OH).
17. A. Ueda, Y. Miyazawa, Y. Hara, M. Koguchi, A. Takahashi and T. Kawana, US Pat., US 6268310 B1, 2001.

---

Footnotes

† Electronic supplementary information (ESI) available. CCDC 962972–962975. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc07999j

‡ Crystal data for 4a: C₁₃H₁₁NO₃, M = 229.23, orthorhombic, Pca2₁, a = 15.024(3) Å, b = 21.464(4) Å, c = 13.309(3) Å, V = 4291.8(15) ų, Z = 16, μ(Mo-Kα) = 0.102 mm⁻¹, 36 812 reflections measured, 8811 unique, R_int = 0.064, R₁[for 5081 data with F² > 2σ(F²)] = 0.056, wR₂ (all data) = 0.168, absolute structure x = −0.4(19). Four molecules in asymmetric unit. For 6b: C₁₅H₁₅NO₃, M = 257.28, orthorhombic, Pna2₁, a = 12.930(2) Å, b = 9.3159(15) Å, c = 21.663(4) Å, V = 2609.4(8) ų, Z = 8, μ(Mo-Kα) = 0.09 mm⁻¹, 25 390 reflections measured, 6484 unique, R_int = 0.034, R₁[for 5459 data with F² > 2σ(F²)] = 0.035, wR₂ (all data) = 0.088, absolute structure x = 0.2(4). Two molecules in asymmetric unit. CCDC 962972 and 962973.

§ Typical procedure for oxazole formation: 3-(2-hydroxyphenyl)-6,7-dihydrobenzo[d]isoxazol-4(5H)-one 4a (0.500 g, 2.18 mMol) and Cs₂CO₃ (1.42 g, 4.37 mMol) in dry THF (30.0 mL) was heated under reflux for 4 h. Hydrochloric acid (2 M; 5 mL) and CH₂Cl₂ (25 mL) were added after the reaction mixture had cooled to 20 °C. The mixture was separated and the combined organic layer washed with water (2 × 25 mL) and brine (25 mL). The organic layer was dried (MgSO₄), filtered and evaporated to dryness under reduced pressure to yield 2-(2-hydroxyphenyl)-6,7-dihydrobenzo[d]oxazol-4(5H)-one 6a (0.435 g, 87%) as a beige solid, mp 202–204 °C (decomp.); ν_max(CH₂Cl₂)/cm⁻¹ 3804, 1694; δ_H (400 MHz; CDCl₃) 2.20–2.27 (2H, m, CH₂), 2.57 (2H, t, J = 5.6, OxCH₂), 3.00 (2H, t, J = 6.0, CH₂C=O), 6.86–6.90 (1H, m, Ar–CH), 7.10 (1H, dd, J = 0.8, 8.4, Ar–CH), 7.30–7.34 (1H, m, Ar–CH), 7.74 (1H, dd, J = 1.6, 8.0, Ar–CH) 10.58 (1H, br s, OH); δ_C (100 MHz; CDCl₃) 22.2, 37.9 (CH₂), 110.0 (C), 117.6, 119.5, 126.3, 133.2 (Ar–CH), 133.7, 157.7, 161.2, 163.0 (C), 190.7 (C=O). HRMS: MH⁺ 230.0809; C₁₃H₁₁NO₃ requires MH⁺ 229.0812.

---