Synthesis of Tetrahydrofuro[2,3-d]oxazoles and Oxazoles by Hypervalent Iodine (III)-Promoted [2 + 2 + 1] Annulation

Abstract

Reaction of a hypervalent iodine reagent with bistriflimide efficiently promotes three-component regioselective cyclization of tetrahydrofuro[2,3-d]oxazoles and oxazoles from homopropargyl alcohols bearing a phenyl group, with different substituents on the aryl alkyne compounds affecting the selectivity of the resulting product. Utilizing the hydroxyethyl oxazole derivatives obtained in this research could aid in the development of various peroxisome proliferator-activated receptor agonist derivatives.

Introduction

Oxazoles, which are 5-membered heterocycles, form the basic skeleton of many natural compounds^1–3) and bioactive compounds^4–6) such as medicines.^7,8) Oxazole is used in organic synthesis, including as a ligand in reactions using transition metal catalysts.^9–11) Many methodologies such as oxidative [2 + 2 + 1] annulations have been developed for constructing oxazole-based compounds over the past several decades.^12–20)

We previously developed a regioselective synthetic method for constructing the tetrahydrofuro[2,3-d]oxazole skeleton by [2 + 2 + 1] annulation of homopropargyl alcohols, benzonitrile, and O atoms from hypervalent iodine reagents.²¹⁾ Furthermore, we succeeded in converting tetrahydrofuro[2,3-d]oxazole to 2,4,5-trisubstituted oxazole containing the hydroxyethyl group (Chart 1).

Chart 1. Schematic of Our Previous Method for Synthesis of Tetrahydrofuro[2,3-d]oxazole and Corresponding Oxazole

In contrast, our efforts using alkyne 1a bearing the phenyl group gave only oxazole 3a (Chart 2). Few applications of substrates have been reported, making it difficult to identify the selectivity of tetrahydrofuro[2,3-d]oxazole and oxazole. Herein, we report the oxidative [2 + 2 + 1] annulation of homopropargyl alcohols having various aryl groups terminating the alkyne moiety, with the aim of elucidating the reaction mechanism and the selectivity of the product.

Chart 2. Reaction of Homopropargyl Alcohols Bearing a Phenyl Group

Results and Discussion

We began with the synthesis of aryl alkyne derivatives, which are substrates for oxidative [2 + 2 + 1] annulation. The thirteen alkynes 1b–n were prepared by reacting various aryl halides with 3-butyn-1-ol under the Sonogashira reaction condition^22–25) (Chart 3).

Chart 3. Preparation of Aryl Alkyne Derivatives

Next, we investigated homopropargyl alcohols bearing various substituents using the optimized conditions determined in our previous study²¹⁾ (Table 1). The reaction of alkynes 1b–g containing a mono-substituted aryl group proceeded smoothly and gave only the corresponding tetrahydrofuro[2,3-d]oxazole 2b–g in 33–75% yield (Table 1, entries 1–6). In contrast, the reaction of alkyne 1h bearing the 4-MeO-phenyl group gave only the oxazole 3h (entry 7). Interestingly, 1i and 1j, which bear a methoxy group as a substituent on the phenyl group at the 2- or 3-position, did not result in the desired cyclization reaction and only provided a complex mixture (entry 8, 9), likely due to the preferential formation of diaryliodonium salt.^26,27) On the other hand, conducting this annulation reaction using 1k–m bearing an electron-donating methyl group exclusively provided the corresponding oxazole 3k–m but in low yield (entries 10–12), with oxazole 3n being obtained selectively from alkyne 1n bearing a 2-naphthyl group (entry 13). Furthermore, in this study, the yield of products were low in many cases when there was a substituent at the 2- or 3-position on the phenyl group. It is presumed that this was because the steric hindrance of the substituent on the phenyl group inhibited the activation of alkyne by the hypervalent iodine reagent, or the nucleophilic addition of benzonitrile.²¹⁾

Table 1. Formation of Tetrahydrofuro[2,3-d]oxazoles from Corresponding Alkynes

Entry	Substrate	Ar1	Products (%)a)
			Tetrahydrofuro[2,3-d]oxazole	Oxazole
1	1b	4-NO2-Ph	2b (59)	N. Db)
2	1c	3-NO2-Ph	2c (66)	N. Db)
3	1d	2-NO2-Ph	2d (30)	N. Db)
4	1e	4-CN-Ph	2e (75)	N. Db)
5	1f	3-CN-Ph	2f (35)	N. Db)
6	1g	2-CN-Ph	2g (34)	N. Db)
7	1h	4-MeO-Ph	N. Db)	3h (25)
8	1i	3-MeO-Ph	N. Db)	N. Db)
9	1j	2-MeO-Ph	N. Db)	N. Db)
10	1k	4-Me-Ph	N. Db)	3k (29)
11	1l	3-Me-Ph	N. Db)	3l (22)
12	1m	2-Me-Ph	N. Db)	3m (28)
13	1n	2-Naphthyl	N. Db)	3n (43)

a) isolated yield. b) Not detected (decomposed or complex mixture).

Based on the above and previous results, having an electron-withdrawing group on the phenyl group of alkyne 1 improves both the activation of alkynes by the hypervalent iodine reagent and the stability of the bicyclic structure, suggesting that tetrahydrofuro[2,3-d]oxazole 2 is obtained selectively (Table 1, entries 1–6). In contrast, the electron-donating group on the phenyl group of 1 promotes selective formation of the oxazole skeleton under acidic conditions because the bicyclic structure is destabilized by electron donation from the phenyl group and the activation energy for ring opening is decreased. It is assumed that the substituent effect on homopropargyl alcohols contribute to the cation stability of the reaction intermediates, and the results of this study support the proposed mechanism in our previous study.²¹⁾ Further, when the substituent on the phenyl group is located at the o-position, the yield of the product tends to decrease regardless of the electronic properties of the substituent. Thus, steric hindrance of the aryl moiety also affects the yield in the cyclization reaction.

Finally, we converted the bicyclic skeleton to the oxazole skeleton. Heating neat 2b–g at 180 °C for two to three hours gave the corresponding oxazoles 3b–g in good yield (Table 2). Thus, we succeeded in obtaining the desired trisubstituted oxazole bearing a hydroxyethyl group.

Table 2. Results for Conversion of Tetrahydrofuro[2,3-d]oxazole Compounds to Their Corresponding Oxazoles

Entry	Substrate	Ar1	Reaction time (h)	Oxazole (%)a)
1	2b	4-NO2-Ph	2	3b (91)
2	2c	3-NO2-Ph	2	3c (86)
3	2d	2-NO2-Ph	2	3d (78)
4	2e	4-CN-Ph	3	3e (81)
5	2f	3-CN-Ph	2	3f (77)
6	2g	2-CN-Ph	2	3g (79)

a) Isolated yield.

Conclusion

In summary, we have developed a regioselective synthetic method for generating the tetrahydrofuro[2,3-d]oxazole skeleton and oxazole by [2 + 2 + 1] annulation from homopropargyl alcohols bearing a mono-substituted aryl group. Furthermore, we have shown that the electronic properties of the substituents on the phenyl group change the selectivity of the product in this reaction. This result supports the reaction mechanism we have proposed.²¹⁾ We believe that this reaction is suitable for structure–activity relationship studies of trisubstituted oxazole units, as demonstrated by Farglitazar^28–30) (Fig. 1) with a peroxisome proliferator-activated receptor agonist that is currently a target molecule for treating metabolic syndrome.

Fig. 1. Farglitazar Possessing a Phenyl Oxazole Moiety

Acknowledgments

This work was supported by a Grant-in-Aid for Young Scientists of Showa Pharmaceutical University.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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