A simple and efficient method for the synthesis of 4-tosyloxazoles from tosylmethyl isocyanide with α-ketoimidoyl chlorides

An efficient one-pot method for the synthesis of potentially biologically active 4-tosyloxazole derivatives is described via reaction of imidoyl chloride adducts generated in situ from the reaction of isocyanide and acyl chlorides with p -toluenesulfonylmethyl isocyanide (TosMIC). This reaction was carried out in the presence of sodium hydride as a base and in THF to produce 4-tosyloxazoles in excellent yield


Results and Discussion
A literature search revealed that only 5-phenyl-4-tosyloxazole has been synthesized from reaction of benzoyl chloride and TosMIC in the presence of K 2 CO 3 as base in dimethoxyethane at 20 o C, but the yield of this reaction is low (50-55%) 39 (Scheme 1).Scheme 1. Methods for the synthesis of 4-tosyloxazoles.
Due to the importance of oxazoles in medicinal chemistry and drug discovery, and also, in continuation of our work to develop syntheses of heterocyclic compounds from imidoyl chlorides, 48 we were looking to synthesize 4-tosyloxazole derivatives by condensation of aromatic and aliphatic α-ketoimidoyl chlorides with cyclohexyl isocyanide.In this work, we report a simple method for the synthesis of 4-tosyloxazole derivatives by condensation of aromatic and aliphatic α-ketoimidoyl chlorides with TosMIC in THF as solvent in excellent yields without using any catalyst.The Nef isocyanide adducts 3 obtained from addition of isocyanide 1 with aromatic or aliphatic acyl chloride 2 was reacted at ambient temperature with TosMIC to afford 5-phenyl-4tosyloxazole (5a, Scheme 2).
In search for selective and efficient conditions, different solvent such as THF, CH 3 CN and CH 2 Cl 2 (at room temperature and reflux conditions) and also a variety of bases, including K 2 CO 3 , NaH, and Et 3 N were studied.As mentioned in Table 1, in the presence of Et 3 N or K 2 CO 3 (in THF solvent at room temperature and reflux conditions) and also in the presence of K 2 CO 3 (in CH 2 Cl 2 solvent at room temperature), we did not obtain any products (Table 1, entries 1-5).But when NaH was used as a base in THF or CH 3 CN at room temperature, the corresponding product was produced in excellent yields (entry 6-7).Therefore, all of the reactions were performed in THF in the presence of NaH at room temperature.To extend the scope of the reaction, the optimized protocol was applied for the synthesis of 4-tosyloxazoles by reaction with different imidoyl chlorides (Table 2).α-Ketoimidoyl chlorides 1a-i bearing various electron-donating functional groups at various positions reacted with TosMIC (2) smoothly and the corresponding compounds (5a-i) were obtained in excellent yield (Table 2).But α-ketoimidoyl chlorides with electron-withdrawing functional groups such as 4-NO 2 -C 6 H 4 , 3-NO 2 -C 6 H 4 , pyridin-4-yl, EtO 2 CCO and MeO 2 CCO in the same reaction conditions, did not produce any products.The results are summarized in Table 2.A possible mechanism is proposed in Scheme 2. The formation of 4-tosyloxazole 5 by reaction of cyclohexyl isocyanide, acyl chloride and TosMIC can be rationalized by initial formation of the ketoimidoyl chloride adducts 3 by the reaction of cyclohexyl isocyanide 1 with acyl chlorides 2.Then, the intermediate 3 is attacked by TosMIC 4 to form the intermediate A, which then undergoes an intramolecular cyclization reaction to afford product 5 (Scheme 2).

Scheme 2. Plausible mechanism for the synthesis of 4-tosyloxazole.
According to the reaction, the second step (intramolecular cyclization reaction of intermediate A to product 5) is suggested to be very important.So, the electron-donating groups on the α-ketoimidoyl chlorides increase the reaction rate and the electron-withdrawing groups on the α-ketoimidoyl chlorides decrease the reaction rate.The structures of compounds 5a-i were deduced by the IR, NMR spectral and elemental analytical data.For example the 1 H-NMR spectrum of 5a exhibited a singlet at δ= 8.90 due to the oxazole proton.Multiplet at δ= 7.89-7.91,doublet at δ= 7.84, 3 J HH = 8.0 Hz, multiplet at δ= 7.59-7.61and doublets at δ= 7.46, 3 J HH = 8.2 Hz correspond to nine aromatic protons present in the molecule.The signal a δ= 2.41 was assigned to the methyl protons.The 13 C-NMR spectrum of 5a displayed a downfield signal at δ= 152.22 for the carbon C2 of the oxazole ring and at δ= 21.60 for methyl carbon.

Conclusions
In summary, the reaction of ketoimidoyl chlorides with TosMIC in THF in the presence of sodium hydride (NaH) as base at room temperature provides a facile and efficient route for the synthesis of 4-tosyloxazole derivatives in excellent yields.The advantages of this method are high yield, readily starting materials, simple procedure and a straightforward purification of the products.

Experimental Section
General. 1 H-NMR spectra were recorded in DMSO-d 6 on a Bruker model DRX-400 AVANCE spectrometer (400 MHz) with TMS as internal standard 13 C-NMR spectra were taken a by a Bruker model DRX-400 AVANCE (100 MHz) spectrometer.Chemical shifts are given in ppm relative to TMS, the coupling constants J are given in Hz.Melting points were determined on a Melt-Tem II melting point apparatus and are uncorrected.IR spectra were obtained on a Thermo scientific, Nicolet is10 FT-IR spectrometer.Peaks are reported in wave numbers (cm -1 ).analyses (CHN) were performed with a EUROVECTOR EuroEA3000 CHNSO analyzer.Lenochka, d has to be italic (not 6).Could you please change in all Experimental Section.Thanks.General procedure for the synthesis of compounds 5a-i In a typical experimental procedure, a dry, two-necked, 50 mL round bottomed flask was charged with 1.0 mmol of acyl chloride derivatives and 1.0 mmol of cyclohexyl isocyanide and heated at 60 o C for 1 h.Then a mixture of TosMIC (1.0 mmol) and sodium hydride (60% w/w) (1.0 mmol) in THF (10 ml) was added.The mixture was stirred at room temperature for 45 min.After completion of the reaction, as indicated by TLC (ethyl acetate : n-hexane = 1 : 3) , the solvent was evaporated at reduced pressure; the precipitate was washed with diethyl ether (10 ml) and was recrystallized from 95% ethanol to afford pure products 5a-i.5-Phenyl-4-tosyloxazole (5a).Light yellow solid, mp 134-135°C (Yield: 98%).IR (KBr) (ῡ max , cm -1 ); 1595 (C=N), 1314, 1144 (S=O). 1

Table 1 .
Model reaction, conditions and yields