Hemiaminal ethers

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

Scheme 3.31 Two carbon homologation of hemiaminal ethers by enecarbamate.

Antilla and coworkers further extended their methodology to the addition of an oxygen nucleophile, instead of a nitrogen nucleophile (see Scheme 3.54), to imines (Scheme 3.56) [115]. They successfully developed the catalytic enantioselective addition reaction of alcohols as oxygen nucleophiles with N benzoyl imines using chiral phosphoric acid Ig. The method provides straightforward access to chiral hemiaminal ethers with high enantioselectivities. 

Scheme 3.56 Preparation of hemiaminal ethers via addition of alcohols to imines.

For other examples of use of chiral phosphoric acid as catalyst in the synthesis of indole derivatives, see (a) Q. Kang, Z.-A. Zhao, S.-L. You, Tetrahedron 2009, 65, 1603-1607. Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines. (b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem. Int. Ed. 2009, 48, 2553-2556. Activation of hemiaminal ethers by chiral Brpnsted acids for facile access to enantioselective two-carbon homologation using enecarbamates. 

Synthetically important chiral 1-monosubstituted 1,3-diamines (145) are synthesized in Mannich-t)fpe reactions of enecarbamates (140) with aromatic and aliphatic hemiaminal ethers (141) in the presence of phosphoric acid 95a. This process involves the highly reactive Mannich-t)fpe product (144), which is entrapped by a methanol molecule generated during the formation of the imine (143) derived from the hemiaminal ether (141) (Scheme 28.15) [72]. Similarly, diastereo- and enantio-enriched anti-l,2-disubstituted 1,3-diamines are prepared by the Mannich-type reaction of aldehydes, anilines, and enecarbamates in the presence of chiral phosphoric acid [73]. 

Primary amines (RNH2) also add reversibly to ketones or aldehydes to give imines (Schiff bases) and related compounds via the intermediate hemiaminals. The position of the equilibrium depends on the structure of the amine and the carbonyl compound. With alkylamines, the equilibrium favors the carbonyl compound, but it can be driven to the imine by removal of H20. With hydrazines (R2NNH2) and hydroxyl-and alkoxylamines (RONH2), the equilibrium greatly favors the hydrazone, oxime, or oxime ether, and it is difficult to drive the reaction in the reverse direction. Secondary amines (R2NH) can form hemiaminals, but they cannot form imines. 

Hemiaminal (1.0 mmol) and CHjClj were placed in a flask under Nj. TiC (120 /rl, 1.1 mmol) was slowly added to the solution at — 78 °C and the resulting yellow slurry was stirred for another 30 min. The ketene silyl acetal was added dropwise and the mixture was kept at — 78 °C for 1 h. Then the mixture was poured into sat. aq NaHCOj (50 mL) and extracted with EtjO (3 x 25 mL). Pure products were obtained from the EtjO extracts by flash chromatography (petroleum ether/Et O). 

The a-C-glycoside derivative 27 was first synthesized in six steps from N-acetylglucosamine as described by Cipolla et al (Scheme 3) (54). The 6-hydroxyl group of compound 27 was then protected as the 6-TBDPS silyl ether followed by 3,4-isopropylidenation to afford compound 28. Based on our previous experience, we decided to double protect the acetamido group at C-2 position in order to avoid cyclic hemiaminal formation later in the scheme when the C-6 position will be oxidized to the corresponding aldehyde. Thus, 28 was treated... 

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. 

The one-pot diphenylproHnol silyl ether 1 catalyzed Michael reaction of cro-tonaldehyde and nitroalkene arrives at the intermediate 247, which is followed by the an aza-Henry reaction/hemiaminalization process to a proposed alcohol intermediate, followed by Lewis acid-mediated allylation or cyanation (Scheme 7.54). A later report of polysubstituted piperidine 251 preparation was carried out through a Michael addition of 249 and 250 and an aminahzation reaction process, remarkably in water [123]. This process was also carried out to form tetrahydropyrans... 

---