Synthesis of Highly Substituted Oxazoles through Iodine(III)-Mediated Reactions of Ketones with Nitriles

In the presence of trifluoromethanesulfonic acid (TfOH) or bis(trifluoromethane-sulfonyl)imide (Tf2NH), iodosobenzene (PhI=O) efficiently promoted the reactions of dicarbonyl compounds as well as monocarbonyl compounds with nitriles to give 2,4-disubstituted and 2,4,5-trisubstituted oxazole in a single step under the mild conditions.


Introduction
The synthesis of oxazole compounds has attracted a great deal of attention due to the widespread application of oxazole derivatives in biologically active compounds as well as versatile building blocks in organic synthesis [1][2][3]. For the purpose of synthesizing highly substituted oxazole compounds, an intramolecular reaction, the so-called Robinson-Gabriel cyclocondensation of -acylamino ketones in the presence of dehydrating reagents [H 2 SO 4 , POCl 3 , (CF 3 SO 2 ) 2 O, and so on] has been commonly employed [4][5][6]. As for the intermolecular approaches to highly substituted oxazoles, -diazo ketones [7][8][9], -halo ketones [10,11], -sulfonyloxy ketones [12], and iodonium ylides of ketones [13] have been used as a reactive synthetic intermediate. The preparation of -acylamino ketones or these intermediates, however, requires a multi-step synthesis and/or the harsh reaction conditions. Although

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the direct synthesis of oxazoles from simple ketones and nitriles with oxidants based on Tl(III) [14], Hg(II) [15], Fe(III) [16], or Cu(II) [17] have been developed as a convenient procedure, these procedures have met with the drawbacks including the limitation of the substrates and/or the use of toxic oxidants.
Hypervalent iodine(III) reagents have gained increasing popularity in organic syntheses due to their low toxicity, mild reactivity, high stability, easy handling, and so on [18]. Among them, [hydroxyl-(tosyloxy)iodo]benzene (Koser's reagent) and related reagents have been reported to work well for the -sulfoxylations of ketones [19,20]. [Hydroxy (2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) has been used in the stepwise and one-pot synthesis of oxazoles via the formation of -sulfonyloxy ketones as intermediate from simple ketones [21]. In addition, phenyliodine(III) diacetate (PIDA) with trifluoromethanesulfonic acid (TfOH) [22] or the iodoarene-oxone-TfOH system [23] efficiently promoted the direct synthesis of oxazoles from monocarbonyl compounds, such as alkyl aryl ketones with nitriles. To the best of our knowledge, however, there is no report about the direct synthesis of oxazoles from simple dicarbonyl compounds and nitriles [21,24,25]. As a part of our study on the iodine(III)-mediated synthesis of heterocycles [26,27], we carried out research on iodine(III) reagents for the direct synthesis of oxazoles from monocarbonyl or dicarbonyl compounds. In this article, we describe a single-step synthesis of highly substituted oxazoles by the reaction of ketones with nitriles in the presence of iodosobenzene (PhI=O) and a Brønsted acid.
For the formation of oxazole 5a from -keto ester 4a in MeCN, PhI=O/Tf 2 NH system turned out to display superior activity to iodine(III) reagents/TfOH (Table 2). Thus, PhI=O (1.5 equiv.) with Tf 2 NH (3.0 equiv.) improved the yield of 5a to 51% at 80 °C for 16 h (entry 4), compared to the use of 1.5 equiv. PIDA or 1.5 equiv. PhI=O in the presence of TfOH (3.0-4.5 equiv.), in which 4a were converted to 5a in only 4-7% yields even at 80 °C for 24-25 h (entries 1 and 2). In the case of the extension of the reaction time (72 h) or the increase in the amount of Tf 2 NH (6.0 equiv.), 5a was obtained in 79-81% yields (entries 5 and 6).

Scope of the Direct Synthesis of Oxazoles Using PhI=O with TfOH or Tf 2 NH
The scope of monocarbonyl compounds 1 and dicarbonyl compounds 4 by means of the PhI=O (1.5 equiv.)-mediated procedure A (acid: 3.0 equiv. TfOH), B (acid: 3.0 equiv. Tf 2 NH), or C (acid: 6.0 equiv. Tf 2 NH) was shown in Tables 3 and 4 and Scheme 1. Procedure A could be applied to the reactions of monocarbonyl compounds 1a-g in MeCN, and the corresponding oxazoles 2a-g were obtained in 53-94% yields at 80 °C (Table 3, entries 1, 3-6, 8, and 9). Furthermore, procedure B brought about the formation of 2a or 2e at ambient temperature (entries 2 and 7). In the case of benzoylacetonitrile (1g), an increase in the amount of Tf 2 NH (procedure C) improved the yield of 5f up to 69% at ambient temperature for 24 h (entry 11). Although the dicarbonyl compounds 4a,b required the long time (72-139 h) to give good yields of products through procedure B (entries 12 and 14), procedure C reduced the reaction times (3 h) giving rise to 5a-c in 67-83% yields (entries 13, 15 and 17). Bicyclic oxazole 5d could be formed by procedure C, albeit in only 40% yield after 167 h (entry 18). Unfortunately, p-methoxyacetophenone and 4-phenyl-2-butanone did not give the desired products with any of the procedures. By procedure A, the reaction of acetophenone (1a) in propionitrile (EtCN) or benzonitrile (PhCN) instead of MeCN smoothly proceeded at 80 °C for 4 h to yield the corresponding oxazole 6 or 7 in good yields (Scheme 1). The procedure C could be applied to the reaction of dicarbonyl compounds 4a-c in EtCN or PhCN (Table 4).

Mechanistic Considerations
Since it has been known that PhI=O reacts with two equiv. of TfOH in CH 2 Cl 2 to produce to the oxidant 10 [30], to better understand the present oxazole formation, we examined the reaction of acetophenone (1a) with 10 (Scheme 2). Thus, under conditions similar to those of entry 7 in Table 1, 1a was treated with 10 (0.75 equiv.) instead of PhI=O (1.5 equiv.) and TfOH (3 equiv.) in MeCN to give 2a in only 11% yield at 80 °C for 3 h. Therefore, 10 would not be considered to take part in the present oxazole formation. On the basis of abovementioned observations and the previous reports about the iodine(III)-mediated synthesis of oxazoles [21][22][23], the mechanism for the present oxazole formation from ketones 1 or 4 with nitriles as shown in Scheme 3 is proposed. That is, -iodanyl ketone Int-A, which is generated from 1 or 4 with PhI=O and H-X (TfOH or Tf 2 NH), would be converted to Int-B by the Ritter-type reaction with R 3 CN. Int-C generated by the reductive elimination of ArI might also be a possible intermediate for the formation of Int-B, and the subsequent cyclization of Int-B gives oxazoles 2 or 5. The formation of Int-A and/or Int-C is supported by the formation of -tosyloxy ketone 3 (69%) in the case of TsOH as an acid (Table 1, entry 3) [19,23].

Scheme 3.
Proposed reaction mechanism of direct synthesis of oxazoles.

General
All starting materials and reagents were commercially available. Dried organic solvents were purchased and used without further drying. Unless otherwise stated, all reactions were conducted under an argon atmosphere. Melting points were measured on a Yanaco SP-M1 melting point apparatus (Yanagimoto Co.) and were uncorrected. IR spectra were recorded on a HORIBA FT-710 FT-IR spectrometer. 1 H and 13 C-NMR spectra were measured in CDCl 3 with a Bruker AV300M FT NMR spectrometer at 300 and 75 MHz, and the chemical shifts are given in ppm using CHCl 3 (7.26 ppm) for 1 H-NMR and CDCl 3 (77.0 ppm) for 13 C-NMR as an internal standard, respectively. Mass spectra and HRMS were recorded by FAB method on a JMS-HX110 Mass spectrometer. Elemental analysis was measured on a Perkin-Elmer 240B or Elemental Vavio EL. For the TLC analysis, Merck precoated TLC plates (silica gel 60 F 254 ) were used. Column chromatography was performed on Silica gel 60N (63-200 m, Kanto Kagaku Co., Ltd.).

Formation of -Tosyloxy Ketone 3 under the Iodine(III)-Mediated Conditions
Ketone 1a (47 L, 0.4 mmol) was added to a solution of iodosobenzene (132 mg, 0.6 mmol) and p-toluenesulfonic acid monohydrate (114 mg, 0.6 mmol), which were premixed in MeCN (2 mL) at 0 °C for 5min, and the reaction mixture was stirred at 80 °C for 18 h. The mixture was diluted with ether and filtered through a short alumina column. After concentration of the filtrate to dryness, the subsequent purification gave 3 (73.2 mg, 0.25 mmol, 63%). Compound 3 was identified by the comparison with the 1 H-NMR spectrum reported in the literature [20].

Conclusions
We have demonstrated the single-step synthesis of highly substituted oxazoles from ketones and nitriles by the use of iodosobenzene with trifluoromethanesulfonic acid or bis(trifluoromethanesulfonyl)imide. The present procedure could be applied not only to monocarbonyl compounds, but also to dicarbonyl ones. In particular, we believe that the reactivity of iodosobenzene with bis(trifluoromethanesulfonyl)imide sheds light on a new possibility for the use of hypervalent iodine compounds in organic synthesis.