Glutaraldehyde cyclized

In view of the ability of nitromethane to undergo a cyclizing bis-aminoalkylation when reacted with dialdehydes in the presence of amines 80,61) its application to other nitromethylene compounds seems an obvious extension. This reaction has already been verified when glutar-aldehyde is allowed to react with nitromethane and benzylamine in a 1 2 4 molar ratio in water, lr-methyl-l-nitro-2c,6c-bis-benzylamino-cyclohexane (110) is obtained in 56% yield 2) xhe same product is isolated in even higher yield (83%) on treatment of the nitroethane-glutaraldehyde cyclization product (6) with benzylamine However, further work is required to evaluate the preparative utility of this reaction principle for the synthesis of C-methyl branched triaminosugars. 

Vinyl ethers and a,P unsaturated carbonyl compounds cyclize in a hetero-Diels-Alder reaction when heated together in an autoclave with small amounts of hydroquinone added to inhibit polymerisation. Acrolein gives 3,4-dihydro-2-methoxy-2JT-pyran (234,235), which can easily be hydrolysed to glutaraldehyde (236) or hydrogenated to 1,5-pentanediol (237). With 2-meth5lene-l,3-dicarbonyl compounds the reaction is nearly quantitative (238). 

For the cyclization of dialdehydes, however, its utility seems limited. Being a nitromethane addition product, it can readily undergo retro-nitromethane addition with alkali to give formaldehyde and nitromethane. Thus, it is not surprising that reaction of glutaraldehyde with 2-nitroethanol under the usual conditions (i.e. 1 molar equivalent of sodium hydroxide in aqueous ethanol) should yield 2-nitrocyclohexane-1,3-diol 5), a nitromethane cyclization product With catal5dic amounts of sodium hydroxide (pH 8—9), however, 1-hydroxymethyl-l-nitro-cyclohexane-2-6-diol (80) can be isolated in yields of 24—29%... 

Several other nitromethylene compounds, such as 1-nitropropane 8) phenyl nitromethane. 52) and 3-nitropropionic acid derivatives "9, have been tested for their ability to form cyclization products, in each case with glutaraldehyde as the standard dialdehyde component. 

Compounds of m.p. 99-100 (20%)3), 123-123,5° (35%) and 133—135° (50%) have been described as resulting from the reaction of glutaraldehyde with phenylnitromethane. It is not yet clear whether they have to be formulated as cyclization products (i.e. (105) 8) or as monoaddition products to the hemialdal form of glutaraldehyde (104) 52) but the deviations in melting points may well be due to these structural differences. 

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

The cyclizing bis(aminoalkyl)ation of nitromethane,305 which provides a ready entry into pyranoid and cyclohexane nitrodiamines, and, hence, triamino sugars,308 may also be extended to nitroalkanes. Accordingly, glutaraldehyde reacts with nitroethane in the presence of benzylamine to afford the C-methyl-branched nitrodiamine 171 (56%) which may be obtained from the nitrodiol 172 in even better yield (83%) by exposure to the same conditions.305,307 This procedure carries considerable potential for the preparation of C-branched triamino sugars. 

Hydrolysis of 2-alkoxy-3,4-dihydro-l,2-pytans with dilute hydrochloric acid furnishes a convenient synthesis of glutaraldehyde (R = H) and other l,5 dicarbonyl compounds. The starting materials are obtained by the 1,4-addition of vinyl ethers to a,/3-unsaturated carbonyl compounds. The wide selection of diene systems includes acrolein, crotonaldehyde, meth-acrolein, cinnamaldehyde, /3-furylacrolein, methyl vinyl ketone, benzal-acetone, and benzalacetophenone. Ethyl vinyl ether is preferred as the dienophile. The yields in the cyclization step are in the range of 25 87% and in the subsequent hydrolysis Step, 55 85%. ... 

Cyclization of glutaraldehyde (129) with nitromethane, which, when first attempted, seemed unprofitable,121 has been so elaborated122,123 as to provide, in 66% yield, frans,frans-2-nitro-l,3-cyclo-hexanediol (130, R = H), the thermodynamically most stable of the three possible isomers (one dl and two meso forms). The reaction has been extended to include nitroethane,124,125 nitroethanol,128 ethyl nitroacetate125 [which gave, preponderantly, 130 (R = Me, CH2OH, and C02Et)], 1-nitropropane,124 and phenylnitromethane (a-nitro-toluene)124 [which yielded products 131 (R = Et and Ph) that had the Dlu-cis-trans configuration]. 

Optically active tetrahydropyran derivatives can be obtained by domino cross aldol/acetal cyclization reaction of aromatic aldehydes with glutaraldehyde generated from the inexpensive tetrahydro-2/f-pyran-2,6-diol under equilibrium conditions, in yields ranging from 42% to 78% and good diastereo- (60-75% de) and enantioselectivities (93-99% ee) [75],... 

A similar "oxime-driven" methodology was applied to the aldehyde moiety in 4,4-dimethyl-glutaraldehyde 1.100), which was converted to oxime I.IOI. In this example, catalytic hydrogenation of the oxime gave an amine, but the amino acid spontaneously cyclized to give 4,4-dimethyl valerolactam, 1.102 (see chapter two, section 2.3). An acid hydrolysis step was required to liberate 5-araino-4,4-dimethyl-pentanoic acid, 1.103. In some cases, reduction in this type of system leads to a mono-amide as an intermediate product rather than a lactam. Similar formation of... 

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