Metal-assisted Lossen Rearrangement

Abstract

A new reaction mechanism for the Lossen rearrangement of hydroxamic acids catalyzed by basic salts is presented. It is shown that the rearrangement proceeds in metal complexes of deprotonated hydroxamic acids. The deprotonation can occur either at the oxygen atom (observed for the zinc complexes) or at the nitrogen atom (observed for the potassium complexes). Both anionic forms are characterized by infrared multiphoton dissociation spectroscopy. The rearrangements proceed from the reactive N-deprotonated metal hydroxamates and lead to metal carbamates. The mechanism is elucidated by computational chemistry, mass-spectrometric studies, and preparative experiments.

Lossen Rearrangements under Heck Reaction Conditions

“…A recent combined experimental and theoretical study demonstrates that metals (zinc and potassium) efficiently catalyze Lossen rearrangements. [19] Following this mechanism, hydroxamic acid deprotonation followed by metal complexation gives a metal hydroxamate complex (11,Scheme 4). This activated hydroxamic acid complex rearranges from the N-deprotonated form to yield a metal carbamate that proceeds to products (Scheme 4).…”

“…This activated hydroxamic acid complex rearranges from the N-deprotonated form to yield a metal carbamate that proceeds to products (Scheme 4). [19] Presumably, addition of PdA C H T U N G T R E N N U N G (OAc) 2 would also form a metal hydroxamic acid complex (11, Scheme 4) that could progress in Table 2. Yields of Lossen products under Heck reaction conditions in the absence of PdA C H T U N G T R E N N U N G (OAc) 2 .…”

“…a similar fashion or the direct reaction of 11 with TEA may facilitate proton migration and Lossen rearrangement to give the isocyanate (13, Scheme 4). [19] A separate previously proposed mechanism provides an explanation for base-catalyzed Lossen rearrangement (Scheme 4). [11,20] The base-assisted dehydration of the hydroxamic acid upon heating may directly yield an isocyanate (13, Scheme 4) or two molecules of hydroxamic acid may condense to form an O-acylhydroxamate (12), which can rearrange with heat to 13 with release of the carboxylate salt.…”

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

“…The potassium-mediated Lossen rearrangement is initiated by hydrogen migration from the nitrogen atom to the oxygen atom to form an N-deprotonated hydroxamate–metal complex, which is of similar energy as the original complex. [28] Next, the metal hydroxamate undergoes Lossen rearrangement, followed by facile hydrogen migration from oxygen to nitrogen, to yield a metal carbamate (Scheme 1c). Although these metal-assisted Lossen rearrangements may provide another route for the transformation of hydroxamates in biological systems in addition to the acetylase-initiated pathway, further studies to assess their actual contribution in biological systems may be warranted.…”

A Combined Experimental and Computational Investigation on the Unusual Molecular Mechanism of the Lossen Rearrangement Reaction Activated by Carcinogenic Halogenated Quinones

“…The Lossen rearrangement, which was first reported by Lossen in 1872, is a thermal or alkaline conversion of hydroxamic acid into isocyanate via the intermediacy of its O-activated (such as O -acyl, -sulfonyl, or -phosphoryl) derivative. 1 − 8 It has been established that the O-activation of hydroxamic acids is essential for Lossen rearrangement to take place. 1 − 4 Recently, we found that benzohydroxamic acid (BHA) was able to dechlorinate tetrachloro-1,4-benzoquinone (TCBQ) via an unusually mild and facile Lossen rearrangement mechanism (Scheme 1 ).…”