A convenient synthesis of chiral 1,2,4-oxadiazoles from N-protected ( α -aminoacyl)benzotriazoles

1,2,4-Oxadiazoles ( 4a-k , 6a-c, 7a-d , and 11a-f ) derived from chiral α -amino acids were synthesized in 70–94% yields via a fast and easy procedure under mild conditions. They were shown to be at least 97% enantiomerically pure by HPLC and NMR


Results and Discussion
Preparation of 1,2,4-oxadiazoles (4a-k, 6a-c, 7a-d) using N-protected (α-aminoacyl) benzotriazoles (1a-k).Refluxing a symmetric Boc-amino acid anhydride and an amidoxime in pyridine provided one-pot preparations of chiral 1,2,4-oxadiazoles in 20-81% yield calculated on the amidoxime utilizing only 50% of the Boc-amino acid.Retention of chirality was proved by HPLC analysis.19c Although these reaction procedures give reasonable yields (50-80%), carbodiimides (DIC and DCC) and their intermediates with HOBt are frequently moisture sensitive, and isolation and purification processes often involve column chromatography due to the formation of ureas from the coupling reagents.
The O-acylation of 1 with p-tolyl amidoxime (2a) proceeded immediately after addition of 1 equivalent of Et 3 N in EtOH at room temperature.Subsequent cyclization occurred surprisingly quickly (3-5 min) when the mixture was refluxed in EtOH in the presence of Et 3 N (Scheme 2).These reactions were complete within 5 min, and the products 4a-k were precipitated in 70-94% yield by adding water to the reaction mixture (Table 1).To support the proposed mechanism of the reaction (Scheme 2), intermediates 3c and 3g were isolated in 96, 97% yield by filtration from water-EtOH solution, and subjected to cyclization by heating under reflux in EtOH for 5 minutes to afford 1,2,4,-oxadiazoles 4c and 4g in 83 and 75% yields, respectively.
a Isolated yield.b 4c in 83% yield was obtained by cyclization of 3c.c 4g in 75% yield was obtained by cyclization of 3g.
Utilizing conditions similar to those described for the preparation of 4a-k, the synthesis of 6c was first attempted by reaction of 1e with 4-pyridinyl amidoxime (2b).However, 6c was obtained along with N,O-disubstituted amidoxime as by-product formed by a reaction of 2b with two molecules of 1e.This result can be explained by the higher reactivity of amidoxime 2b compared to 2a.To overcome this problem, 2b was initially converted into the hydrochloric salt by adding 1 equivalent of HCl (10% aq.) and then coupled with 1a,c,e under refluxing EtOH to give the intermediates 5a-c, which were cyclized to give 6a-c by heating under reflux in EtOH in the presence of two equivalents of Et 3 N.The products 6a-c were isolated in 90-93% yield after column chromatography, and fully characterized by NMR and elemental analysis (Scheme 3, Table 2).We also investigated the preparation of 1,2,4-oxadiazoles derived from benzyl amidoxime (2c) (Scheme 4) to produce 7a-d in 83-89% yields following the procedure used for preparation of 4a-l, but with extended refluxing times (Table 3).When the conditions for the preparation of 4 were applied, yields of 7 did not exceed 10%, presumably due to the lower reactivity of 2c compared to 2a.

Stereochemistry
Dipeptides and tripeptides prepared from N-protected (α-aminoacyl)benzotriazoles were previously shown to be more than 97% enantiomerically pure by HPLC analysis and NMR spectra. 28We have now made N-protected diastereomers of peptidolylbenzotriazoles 10a-f from 1a,b,e,f and amino acid 8a-d.The extent of racemization during 1,2,4-oxadiazole ring-formation was then checked by NMR and HPLC of products 11a-f from reactions of 10a-f with 2a (Scheme 5).

Scheme 5
According to HPLC analysis, compounds 11a,b,e,f are single isomers (Table 4), and no peaks corresponding to another diastereomer were detected.The 1 H NMR spectra of compounds 11a-f contain signals of -NH protons as doublets, which resonate in different positions for each pair of diastereomers (Table 5).On Chirobiotic T column, retention times for diastereomers 11a and 11b were 24.2 and 27.0 minutes, respectively.Signals of the NH protons β to the oxadiazole ring for 11a and 11b appeared as doublets at 6.93 ppm (J = 6.5 Hz) and 6.76 ppm (J = 6.6 Hz), respectively.Using similar conditions, diastereomers 11c and 11d could not be separated on Chirobiotic T column.However, the 1 H NMR spectra of 11c and 11d showed significant difference in their N 3 H proton shifts as described in Table 5. Diastereomers 11e and 11f were observed in HPLC at 24.4 and 20.3 minutes, and demonstrated different values for N 3 H proton shifts at 6.89 ppm and 7.08 ppm, respectively.The 1 H NMR and 13 C NMR spectra of 11a-f indicated the absence of the peaks expected from racemization.Thus, HPLC and NMR analyses indicated less than 3% of racemization for 1,2,4-oxadiazoles 11a,b,e,f, and the racemization of the orginal chirality in 11c and 11d was illustrated by NMR to be less than 5%.

Preparation of 1,2,4-oxadiazoles (13a-d) utilizing aromatic N-acylbenzotriazoles (12a-c).
To extend the synthetic possibilities, we introduced the reaction of amidoximes 2a,b with aromatic N-acylbenzotriazoles 12a-c (Scheme 6).Compounds 12a-c were prepared directly from carboxylic acids according to the procedures developed in our group. 291,2,4-Oxadiazoles 13a-d were synthesized in 73-82% yields following the procedure illustrated for the preparation of compounds 4a-l.The starting materials 12a-c were less reactive in the cyclization reactions than their aliphatic analogues 1a-l and hence required longer refluxing times (Table 6).Since many previously reported methods for the synthesis of 1,2,4-oxadiazole require acyl halides, our method offers advantages, especially where acyl halides are not readily available or stable.

Conclusions
In summary, a convenient method for the preparation of 1,2,4-oxadiazoles utilizing N-protected (α-aminoacyl)benzotriazoles and aromatic N-acylbenzotriazoles has been developed.The reactions were demonstrated to give 1,2,4-oxadiazoles in high yields under mild conditions together with a simple process for isolation and purification.During the whole process, the original chirality has been preserved in >97% enantiomerically pure products, as demonstrated by HPLC and NMR analysis.

Experimental Section
General Procedures.Melting points were determined on a capillary point apparatus equipped with a digital thermometer.NMR spectra were recorded in CDCl

General procedure for amidoximes 2a-c
A mixture of a nitrile (0.1 mol), hydroxylamine hydrochloride (0.13 mol), and sodium carbonate (0.13 mol) were heated under reflux in ethanol (300 mL).After 6 hours, the reaction mixture was added another portion of hydroxylamine hydrochloride (0.13 mol) and sodium carbonate (0.13 mol), and then refluxed for another 14 hours.After cooling to room temperature, inorganic salts were filtered off, and the filtrate was concentrated in vacuum.Resulting white precipitate was filtered and washed on filter with water and small amount of ethanol to give amidoximes 2ac in 88-95% yield.Amidoximes 2a-c were used without further purification.

Stepwise procedure for 4c and 4g
A mixture of N-hydroxy-4-methylbenzenecarboximidamide (2a) (1 mmol) and Nacylbenzotriazole 1c (1 mmol) was stirred at room temperature in ethanol (30 mL) for 15 min in the presence of Et 3 N (1 mmol).The reaction mixture was quenched with water and a white precipitate was filtered and subsequently washed on the filter with aq 5% Na 2 CO 3 (10 mL), water (10 mL), EtOH/H 2 O 50% mixture (2×10 mL), and hexanes (10 mL) to give compound 3c in 96% yield.Following the above method, 3g was obtained in 97% yield.Without further purification intermediate 3a,g were converted to 4c and 4g, respectively, by refluxing in ethanol for 5 minutes in the presence of catalytic amount of Et 3 N and following workup procedure described for preparation of 4a-k.