[111-30-8] · C5H8O2 · Glutaraldehyde · (MW 100.13)
(useful annulating reagent for constructing heterocycles; most widely used in cross-coupling of proteins)
Alternate Name: pentanedial.
Physical Data: oil, bp 71 °C/10 mmHg; n
Solubility: very sol water, alcohol, ether.
Form Supplied in: 25 or 50% aqueous solution; commercially available.
Preparative Methods: in many cases, used as the commercial aqueous solution, but anhydrous glutaraldehyde can be obtained either by extraction of the aqueous solution by organic solvent followed by drying and distillation at reduced pressure,1 or by preparation from 2-ethoxy-3,4-dihydro-2H-pyran.2
Handling, Storage, and Precautions: whereas aqueous glutaraldehyde solutions are stable, anhydrous glutaraldehyde has to be used immediately after distillation due to rapid polymerization. In ether solution, glutaraldehyde rapidly polymerizes even at low temperature.3 Use in a fume hood.
The classical Robinson synthesis2 of pseudopelletierine was the first example of a double Mannich reaction of glutaraldehyde (eq 1). It involved reaction of glutaraldehyde with methylamine and acetonedicarboxylic acid in a slightly acidic aqueous solution (for similar reactions, see also Succindialdehyde).
Synthesis of cis-2,6-diacetonylpiperidine has been reported using this methodology (eq 2).4
In the absence of a nucleophile, 1,4-dihydropyridine is formed (eq 3).3
Stable equivalents of 1,4-dihydropyridine can also be obtained by the use of heteroatomic nucleophiles. The double condensation of glutaraldehyde with a chiral nonracemic amino alcohol in the presence of cyanide leads to the formation of a 2-cyano-6-oxazolopiperidine in an enantiomerically pure form and in 80% yield (eq 4).5 This compound has proved to be a very useful tool for the asymmetric synthesis of piperidine derivatives and has been used largely in the asymmetric synthesis of alkaloids.5b
N-Substituted piperidines are obtained when glutaraldehyde reacts with primary amines in the presence of a reducing agent (reductive alkylation). The most popular reagent is Sodium Cyanoborohydride (eq 5),6a but other reagents are also efficient in this transformation.6 This method is generally preferred to the condensation of a primary amine with 1,5-dihalogenopentane.
In the condensation of glutaraldehyde with tryptamine, one of the iminium salts can be trapped by the indole ring in a Pictet-Spengler reaction, and in the presence of Sodium Borohydride an indoloquinolizidine is obtained (eq 6).7
Pyran derivatives can be prepared from glutaraldehyde, generally by monoalkylation with a carbon nucleophile,1,8 as depicted in eq 7.
Active methylene compounds can add to glutaraldehyde to give cyclohexane derivatives (eq 8).9
Glutaraldehyde monoacetals have been reported. Their preparations include the partial acetalization of glutaraldehyde and the partial hydrolysis of 2-ethoxy-3,4-dihydro-2H-pyran. These monoacetals are widely used in many organic syntheses and have been reviewed.10
Université René Descartes, Paris, France
CNRS, Gif-sur-Yvette, France