Amino-alcohols from enamines

Table 6.23 Synthesis of amino alcohols from p,p-disubstituted enamines [3]...

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Some chiral 1,3,2-dioxastannolanes were used as catalysts in asymmetric Diels-Alder reactions of cyclopentadiene with methyl acrylate <90JCR(S)278>. A-Alkenyl- and -cycloalkenyl 1,3,2-oxaza-stannolanes, generated in situ from chiral amino alcohols, gave optically active 2-substituted aldehydes and ketones in modest to high chemical and optical yields after alkylation with methyl acrylate or acrylonitrile (which is usual for enamines) and subsequent hydrolysis <85CC504,85JOC3863>. 

A route to pyrroles illustrated by the preparation of 292 involves initial treatment of the nitroketene-5, 5 -acetal 293 with an organometallic reagent, followed by conversion of the resulting alkene 294 to the enamine 295, and final annulation to the target heterocycle (Scheme 34) <1998T12973>. A related approach featuring constmction of /3-hydroxyenamines from 1,3-dicarbonyl compounds and /3-amino alcohols, and subsequent palladium-catalyzed cyclization to pyrroles, has been reported <1996TL9203>. 

The ketone 629 has been isolated from peony flowers. It had already been synthesized several times for example, by hydroboration of the enamine 630 of the isomeric ketone 627, then Cope elimination of the iV-oxide 631 of the amino alcohol. Chromyl acetate oxidation of 1,8-cineole (553) led first to 629 further oxidation gave diketones. Aspergillus niger also gave some 629, although the main products were the corresponding alcohols. ... 

Among the ethers of prolinol, (5)-2-methoxymethylpyrrolidinc [SMP, (S)-10] has found most applications. It is readily prepared from prolinol by the normal sodium hydride/iodo-methane technique9,13 (sec also Section 2.3. for O-alkylations of other amino alcohols) and is also commercially available. An improved synthesis from proline avoids the isolation of intermediates and gives the product (which is highly soluble in water) by continuous extraction14. SMP has been used as the lithium salt in deprotonation and elimination reactions (Section C.) and as an auxiliary for the formation of chiral amides with carboxylic acids, which in turn can undergo carbanionic reactions (Sections D.l.3.1.4., D.l. 1.1.2.. D.l. 1.1.3.1., in the latter experimental procedures for the formation of amides can be found). Other important derivatives are the enamines of SMP which are frequently used for further alkylation reactions via enolates (Sections D.l.1.2.2.. where experimental procedures for the formation of enamines are... 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

Chiral 3-amino carbonyl compounds and 1,2-amino alcohols are among the most valuable building blocks for asymmetric synthesis and catalysis. Efficient enanti-oselective syntheses of these compounds were reported from 2000 to 2006 using enamine-based organocatalysts. For example, Mannich reactions employing aliphatic aldehyde as a donor with a-imino glyoxylate as an acceptor provide syn-adducts (74) as the major product with excellent enantiomeric excess in the presence of (S)-proline (13) as a catalyst (Table 28.5, entry 1) [41]. When the ketone is employed as a donor, the sy -isomer is obtained with excellent diastereo-and enantioselectivities (entry 2) [42]. 

The formation of unsubstituted quinoxaline 1,4-dioxide in the Beirut reaction has been observed using a number of substrates benzoylacetalde-hyde and its enamines,395 vinyl acetate (Et2NH),396 acetylene (NEt3)397,398 propargyl alcohol, propiolic acid, and phenylacetylene (various amines).398 Some of these are unexceptional, but the apparent dephenylation in the case of the phenylacetylene is surprising. However, recently the reaction of benzofuroxan with diethylamine was reinvestigated399 (see Section V,E), and quinoxaline dioxide was found to be one of the major products from a complex sequence of oxidation and reduction reactions. It seems probable with phenylacetylene, and possible in other cases too, that the amines play more than a catalytic role in quinoxaline dioxide production. The amino-quinoxalinone 175 was reported, using vinyl acetate and morpholine.396... 

The initial product 2 loses N2 in a retro-DiELS-Alder reaction forming the 3,4-dihydropyridine 3, which aromatizes giving the pyridine derivative 4 by elimination of amine or alcohol. The geometry of the transition state of this [4+2] cycloaddition with inverse electron demand follows from the reaction of 3- or 6-phenyl-1,2,4-triazine 5 or 8 with enamines of cyclopentanone. It is apparently influenced by the secondary orbital interaction between the amino and phenyl groups. 3-Phenyl-1,2,4-triazine 5 favours the transition state 11. It leads first to the 3,4-dihydropyridine 6 which, on oxidation followed by a Cope elimination, affords the 2-phenyldihydrocyclopenta[c]pyridine 7. However, 6-phenyl-1,2,4-triazine 8 favours the transition state 12 leading to 3,4-dihydropyridine 9. Elimination of amine yields 5 -phenyldihydrocyclopenta[c]pyridine 10 ... 

Chiral y-amino-acids (e.g. 180) have been prepared from the corresponding optically active /8-amino-acids by the addition of one carbon atom using the Arndt-Eistert reaction.w-Amino-acids are available from cyclic anhydrides by treatment with stannyl azide (to give an w-isocyanatocarboxylic acid) followed by addition of an alcohol. In contrast to simple enamines, oxidation of N-acyl-a-aminocrotonates with thallium nitrate leads to the corresponding a/8-dimethoxy derivatives. 

Formation.—Preparation of thietan oxides by oxidation of thietans is covered in the previous section. Cycloaddition of sulphenes to electron-rich alkenes, the other important method of preparation of episulphones, has been further used for the preparation of a-chloro- and /S-amino-, cf-sila- and -amino-, and cf-alkoxycarbonyl- and -amino-thietan dioxides. The sulphonyl enamine (96) can be converted into the thietan dioxide (97) by treatment with acid, a procedure that usually hydrolyses enamines to ketones. Regeneration of (96) from (97) occurs on heating in alcoholic base. Thiet sulphone cyclo-adds to cyclopentadiene to give the Diels-Alder adducts with an exo/endo ratio of 0.25. ... 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chirality enhancer in the stereoselective synthesis of (i-lactams from amino acid derivatives [76, 77]. 

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