Hemiaminals, synthesis

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

The carbamate derivatives of amino alcohols also proved applicable for the synthesis of cyclic hemiaminal derivatives. Through the ring closures of W-BOC-substituted 1,3-amino alcohols with aldehydes or acetals, 3-BOC-1,3-oxazine derivatives were obtained <1998TL6561, 1999J(P1)1933, 2006JOC8481, 2006T8687, 2006TL7923>. 

The condensation of primary amines with aldehydes and ketones gives products known as imines which contain a C=N double bond. These compounds rapidly decompose or polymerize unless there is at least an aryl group bonded to the nitrogen or to the carbon atom. The latter imines are called Schiff bases, since their synthesis was first reported by Schiff.1 The most common method of obtaining a Schiff base (4) is straightforward, as indicated in the condensation reaction (1) between (1) and (2) with the formation of an intermediate hemiaminal (3). 

Scheme 4 Synthesis of an A -Nitroargininal Hemiaminal Ether Hydrochloride 361...

Recently, Kraus and Maeda have reported an elegant synthesis of the important C-4 o-anisyl derivative 26 in racemic form.85 This route involves pyrrolidine ring synthesis with key steps being Michael addition of the enolate of dimethyl a-ketoglutarate 174 to nitrostyrene derivative 175 followed by cyclization of the adduct 176 under reductive conditions to hemiaminal 177 (Scheme 63). 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

Aliphatic hydrazines react with cyclopropanone or cyclopropanone hemiacetals, providing good access to carbinol-type adducts which are versatile sources for the synthesis of cyclo-propylidenehydrazines. Upon reacting hemiacetal 10 with A,A-dimethylhydrazine, without solvent, the distillable but sensitive hemiaminal 39 was formed in 64% yield. ... 

Aldehydes, acetals, aminoacetals, and hemiaminals bearing a phenylsilyl or vinyl-silyl group undergo intramolecular phenylation or vinylation on treatment with a Lewis acid [527-530]. The reaction of a-vinylsiloxy- and a-phenylsiloxy-substituted aminoacetals is suitable for highly diastereoselective synthesis of / -aminoalcohols (Scheme 10.201) [529],... 

Scheme 2.125 Synthesis of trifluoroacetaldehyde hemiaminal derivatives and their use as nucleophilic trifluoromethylation reagents (TMS = trimethylsilyl) [59].

We have shown that heterogeneous catalysis can be applied to reductive alkylation with success in reactions such as ether synthesis or N-alkylation of amides and anilines. Concerning the mechanism, several pathways are in competition depending on the structure of the substrate and of the alkylating agent. The important point is that both the product of addition (the hemiacetal or hemiaminal) and the product of elimination (imine, enamine or enolether)... 

Synthesis of 7 -amino acid-oxazole fragment 68 of calyculins A and B from D-erythronol-actone 58 has been reported by conversion to 59," which was subjected to oxidation reaction to afford the hemiaminal 60 (Scheme 9) Acetylation of 60 furnished 61, which was converted to ketone 62 in 88% yield. Conversion of 62 to a silyl enol ether, ozonolysis with reductive workup and O-methylation of the resultant alcohol 63 furnished 7 -lactam 64. Treatment of 64 with CAN led to 65 (60%), which was reacted with (CHj)2 A1 derivative of 66 to provide 67 (62%), which upon removal of the silyl group provided 68. 

In 2006, Fukuyama and coworkers reported their independent synthesis of yatakemycin (150) [64]. The preparation of the left-hand fragment 165 started with dimethoxybenzene derivative 161. Dibromination of 161 in the presence of FeCls, removal of the TFA group, and oxidation provided a dihydroisoquinoline. Treatment with NsCl to form the hemiaminal, and reductive opening using NaBIl, gave cycUzatiOTi precursor 162. Amination using Cul to give the desired indoline. 

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