Enals amines

Acetylene is also protected as propargyl alcohol (300)[2H], which is depro-tected by hydrolysis with a base, or oxidation with MnOi and alkaline hydrolysis. Sometimes, propargyl alcohols are isomerized to enals. Propargyl alcohol (300) reacts with 3-chloropyridazine (301) and EtiNH to give 3-diethylami-noindolizine (303) in one step via the enal 302[2I2]. Similarly, propargyl alcohol reacts with 2-halopyridines and secondary amines. 2-Methyl-3-butyn-2-ol (304) is another masked acetylene, and is unmasked by treatment with KOH or NaOH in butanol[205,206,213-2l5] or in situ with a phase-transfer cata-lyst[2l6]. 

Scheldt and co-workers have also accessed enolate equivalents from enals to furnish cyclopentanes 236 asymmetrically. Formation of the enolate equivalent from enals 235 with the NHC, followed by an intramolecular Michael reaction and 0-acylation, gives the lactone products 236, which are readily opened by either alcohols or amines to generate functionalised cyclopentane derivatives 237 in excellent ee. 

Another Ti-catalyzed domino reaction has been developed by Riick-Braun and coworkers [313] using 3-cyclopentadienyl (dicarbonyl)iron-substituted enals 6/4-129 and primary amines 6/4-130 to give dihydropyrrolones 6/4-131 (Scheme 6/4.32). 

Intramolecular [4 + 2]cycloaddition of an enaminelenal(enone). Generation in situ of an aldehyde enamine of a substrate also containing an enal or enone group can result in a facile intramolecular [4 + 2]cycloaddition resulting in bicyclic dihydropyrans. Although several sec-amines can be used, N-methylaniline is particularly suitable because of the stability of the adducts. 

Fig. 15 Amines used in conjunction with TRIP for the epoxidation of enones and enals...

Fp-substituted enones and enals undergo cyclocarbonylations on treatment with metal hydrides or metal alkyls to provide y-lactones (Scheme 1.15) [45], Similarly, electron-rich primary amines afford dihydropyrrolones with iron-substituted (Z)-enals in the presence of titanium tetrachloride and triethylamine [46],... 

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

The MacMillan catalysts (42, 45), the Jorgensen catalyst (51), and proline itself can promote Michael additions by iminium ion formation with the acceptor enal or enone (A, Scheme 4.22). Secondary amines can also activate a carbonyl donor by enamine formation (Scheme 4.22, B) [36, 37]. 

Gaunt et al. recently reported that tertiary amines such as DABCO catalyze the reaction of enoates, enones, enals, a,/funsaturated amides, nitriles, and sulfones... 

Selective reductions.1 Zinc bo and a,P-enals at -15° without effc Reduction of azomethines.s Z ary amines or the amine-BH3 compfc alkylation-reduction of nitriles to j... 

A primary alcohol and amines can be used as an aldehyde precursor, because it can be oxidized by transfer hydrogenation. For example, the reaction of benzyl alcohol with excess olefin afforded the corresponding ketone in good yield in the presence of Rh complex and 2-amino-4-picoline [18]. Similarly, primary amines, which were transformed into imines by dehydrogenation, were also employed as a substrate instead of aldehydes [19]. Although various terminal olefins, alkynes [20], and even dienes [21] have been commonly used as a reaction partner in hydroiminoacylation reactions, internal olefins were ineffective. Recently, methyl sulfide-substituted aldehydes were successfully applied to the intermolecu-lar hydroacylation reaction [22], Also in the intramolecular hydroacylation, extension of substrates such as cyclopropane-substituted 4-enal [23], 4-alkynal [24], and 4,6-dienal [25] has been developed (Table 1). 

General Procedure for Chiral Amine-Catalyzed Epoxidations of Enals with H202 [50] (p. 104)... 

Another important example of the Michael addition in biochemistry and molecnlar biology is the reaction of 4-hydroxynon-2-enal with amines and snlfydryl gronps (Winter, C.K., Segall, H.J., and Haddon, W.F., Formation of cyclic addncts of deoxygnanosine with the aldehyde trans-4-hydroxy-2-hexenal and fran.y-4-hydroxy-2-nonenal in vitro. Cancer Res. 46, 5682-5686, 1986 Sayre, L.M., Arora, P.K., Iyer, R.S., and Salomon, R.G., Pyrrole formation from 4-hydroxynonenal and primary amines, Chem. Res. Toxicol. 6, 19-22, 1993 Hartley, D.P, Ruth, J.A., and Petersen,... 

Treatment of 462 with iodine and pyridine leads to a-iodination [208]. Successive reduction under Luche conditions, alcohol silylation, carbonylation of the iodoalkene, reduction of the obtained enal and alcohol silylation leads to 463. Ozonolysis of 463 gives the corresponding keto-aldehyde, which is then transformed into 464 via reductive amination with high diastereoselectivity syn anti> Deprotection delivers (-f)-465 (Scheme 13.107). 

Nucleophilic reactions of unmodified aldehydes are usually diiScult to control, affording complex mixture of products, often due to the high reactivity of the formyl group under either basic or acidic reaction conditions. The activity order of the supported amines was secondary > primary > tertiary, which may suggest the intervention of an enamine pathway the enals were exclusively obtained as ( ) isomers. Notably, FSM-16-(CH2)3-NHMe exhibited higher activity than conventional solid bases such as MgO and Mg-Al-hydrotalcite [hexanal self-aldol condensation FSM-16-(CH2)3-NHMe 97% conversion and 85% yield in 2h, MgO 56% conversion and 26% yield in 20 h, Mg-Al-hydrotalcite 22% conversion and 11% yield in 24 h]. 

Azadienes 24 are easily made from amines and enals such as 23. The Diels-Alder reaction of 24 with maleic anhydride looks very attractive 25 and you might expect 26 to be the product. 

In order to broaden the scope of the amine-catalyzed Michael addition, Yamaguchi examined the system of amine and alkali metal salt [2]. Although amine did not promote the addition of malonate to enones, the LiCl04-Et3N catalyst turned out to be effective. Optically active amines, however, gave racemic adducts. As an extension, the (S)-proline rubidium salt, (S)-21, was developed, which possessed a cation and an amine moiety in the same molecule [2, 22]. The catalyst (S)-21 in chloroform promoted the asymmetric addition of malonate to a wide range of enones and enals as exemplified by the reaction of... 

The imino-amine (51.6) reacts at room temperature with aldehydes or ketones with the formation of purines. The products obtained from aldehydes are slowly oxidized (by loss of two hydrogen atoms from the pyrimidine ring) at room temperature, but the ketone-derived purines are stable and are accompanied by smaller amounts of an imidazo[l,S-c]imidazoIe. During cyclization, the nitrile group is converted into a carboxamide. Pentane-2,4-dione, 2-furfuraldehyde and but-2-enal give the fully aromatized purine as the main or only product isolated (in 38-49% yield). Stirring an imino-nitrile for several hours or heating it for a few minutes with an anhydride converts it into a fused pyrimidine. 

But-2-enal condenses with 5-aminouracil and its 1,3-dimethyl derivative,443 or with 2,5-di-aminopyrimidin-4(3//)-one (8)444 in the presence of hydrochloric acid to give the corresponding 6-methy lpyrido[3,2-rf]pyrirnidine-2,4(1/7,3/7)-diones 7 and 9, respectively. Because of the hydrolysis of the methoxy groups, the same procedure with 2,4-dimethoxypyrimidin-5-amine also yields 6-methylpyrido[3,2-c/]pyrimidine-2,4(1/7,3//)-dione, whereas with acetic acid as catalyst the methoxy groups are retained.443... 

The 3-component condensation for synthesis of 3-acy 1-4-ary 1-1,4-dihydropyridines from amines, (3-dicarbonyl compounds and enals proceeds from enamine formation, Michael reaction and cyclodehydration is amenable to asymmetric induction, such as using ent-octahydro-lB. ... 

For a closely related method for the synthesis of a-substituted a-amino acids via rearrangement of allyloxy-substituted oxazoles (derived from At-benzoyl-protected a-amino acids) see p 3448. For the synthesis of substituted 2-aminopent-4-enals by Claisen rearrangement of substituted (l-methyl-3-oxahexa-l,5-dienyl)amines see ref 85. 

Asymmetric Diels-Alder reaction and its applications based on catalysis by bis(oxa-zoline)copper(II) complexes have been published in full details. This method has been further extended to the synthesis of 2,3-dihydropyran-6-ylphosphonates, 4-aminodihy-dropyrans, and piperidones. Note that both epimeric amines are accessible by merely changing the diene substrate, that is, ( )- versus (Z)-configuration. Diazolidi-none 75 serves as a chiral catalyst that also activates enals (actual dienophiles being the iminium ions)." ... 

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