Heterocyclic glyoxylic acid

On the way to the 2-unsubstituted 3-aminoimidazo[l,2-a]heterocycles, Lyon and Kercher [141] suggested interesting approach involving glyoxylic acid as formaldehyde equivalent in the three-component reaction. According to the standard protocol, glyoxylic acid was introduced either in solution or captured on the macroporous... 

The use of diamine derivatives in the three-component process leads to peptidomimetic heterocycles, such as 2-oxopiperazines (piperazinones) [58], benzopiperazi-nones [58] and benzodiazepines. In fact, the 2-oxopiperazines 89 can be obtained directly in one step via the reaction of a diamine 85 with glyoxylic acid 86 and a boronic acid 87 (Scheme 7.12) [58]. Presumably, the intermediate amino acids 88 can undergo a subsequent boronic acid-catalyzed lactamization [29] to afford 89. A two-step approach was used for the synthesis of benzopiperazinones (e.g. 96) [58]. 

A simple reaction that creates both chiral centres in one step was already in the literature.3 It is a cross between a Mannich and a Prins reaction involving the condensation of an unsaturated amine 24 with glyoxylic acid (25 available as an aqueous solution - fortunately the reaction works in water) to give a heterocyclic bridged lactone 26 with the right relative stereochemistry (but of course racemic). 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

Rings containing One Heteroatom.—Oxygen Heterocycles. Base-catalysed addition of 17j8-hydroxy-5a-androstan-3-one to glyoxylic acid, to afford either the hydroxy-keto-acid (197) when the reaction is performed at room temperature, or the rra 5-ayS-unsaturated acid (199) in high yield when done under reflux, provides an entry to both cis-lactone (198) and trans-lactone (201). 

N-Acy derivatives of aromatic a-amino acids are available by amidoalkylation of aromatics and heterocycles with glyoxylic acidamide adducts (Scheme 53). ... 

---