Efficient preparation of 4-Cyanooxazoles from aldehydes
In medicinal chemistry, efficient methodologies to construct heterocycles on small scale from common functional groups are essential to generate molecular diversity. Very recently, B. Xu and Coll. published an efficient TMSOTf-promoted one-pot selective triple consecutive insertions of tert-butyl isocyanide into aldehydes to prepare 4-cyanooxazoles derivatives as outlined in the Scheme below. [1]
This methodology presents a wide substrates scope with around 50 examples. A mechanism is proposed for this reaction which involves three consecutive insertions of tert-butyl isocyanide.
[1] S. Lu, C.-H. Ding, B. Xu, Org. Lett. 2023, 25, 849-854.
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1yAmazing!!!
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1yI couldn't see the whole article, but I can't stop wondering how many chemists feel an urge to use more dangerous chemicals / conditions instead of safer ones. In this particular case the reaction itself is interesting, but NOT practical. What to like here: 1) 3-5 eqs of toxic & volatile (b.p. 87C), available only in China tert-butylazomethine 2) 1 eq of TMS triflate - oh my... 3) carcinogenic dioxane or 4) sealed tube (+ "three consecutive insertions of tert-butyl isocyanide" means 3 eqs of isobutylene released and under pressure?). And target molecules (what was the goal of the article, I suppose) can be prepared much easier! Quick search (without access to SciFinder / Reaxys) shows Schollkopf reaction for oxazoles (attached). As I believe, easier to handle and available cyanomethyl-N=C (Methyleneglycinonitrile CAS 109-82-0, m.p. 130C, b.p.150C) NC-CH2-N=C can be also used in this reaction, giving 4-CN oxazole. Usually (aromatic) acid chlorides and aldehydes have similar availability and easily interchangeable.