Michael intramolecular aza

Scheme 37.7 Synthesis of 5-hydroxyisoxazolidines through a domino aza-Michael-intramolecular acetalization reaction (Cbz = benzyloxycarbonyl).

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

In 2008 Yang and coworkers have reported an efficient synthesis of substituted a-alkilidene-fi-lactams via aNaOH- promoted intramolecular aza-Michael addition of a-carbamoyl, a-(l-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution reaction in alcoholic media (Scheme 90), [198]. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

Michael additions to conjugated carbonyls can be catalyzed by gold species. Among them, arene additions are the most studied area but other nucleophiles can attack the gold-coordinated enones as well. In fact, the intermolecular aza-Michael additions of carbamates to enones was reported in 2002 with both Au(I) and Au(III) salts, and in 2007 an intramolecular aUcoxide and amide conjugate addition has been developed and applied to the synthesis of (+)-andrachcinidine (equation 132). In the latter case, the enones are formed as intermediates in a previous gold-catalyzed step that is the hydration of an alkyne and methanol loss. Then the cyclization takes place to give piperidines. 

Fustero, S., Jimenez, D., Sanchez-Rosello, M. and del Pozo, C. (2007) Microwave-assisted tandem cross metathesis intramolecular aza-Michael reaction an easy entry to cyclic P-amino carbonyl derivatives. J. Am. Chem. Soc., 129, 6700-6701. 

One-pot metal-catalyzed reaction sequences were also studied for the synthesis of isoquinolines. Tetrahydroisoquinolines were formed in moderate yields using a Pd(OAc)/tri-2-furylphosphine catalyzed one pot 3-bond formation consisting of metal mediated o-alkylation/alkenylation and an intramolecular aza-Michael reaction <04TL6903> shown in... 

Lithium enolate 329 and a nitrile-furnished enamino ester 330, which on condensation with isocyanates/isothiocyanates gave N-3 substituted 331 (X = O, S) through a tandem nucleophilic addition-intramolecular aza-Michael reaction (Scheme 126) (09JFC1145). 

Oxa- and aza-Michael additions followed by intramolecular cyclizations occur when propargyl alcohols are treated with a, -unsaturated nitroalkenes in the presence of t-BuOK in THF. Although exo-3-methylene tetrahydrofurans are usually the major products of these reactions, 3,4-dihydropyrans are also obtained in some cases, depending upon the substituents present within the donor and acceptor. Equation 59 shows the results of the reactions of propargyl alcohol with four nitroalkenes. Similar reactions of methyl propargylamine with these same acceptors give exclusively 3-methylenepyrrolidines."... 

In fact, the only example of a simple hetero-Michael reaction under PTC conditions which does not involve a cascade process consists of an intramolecular aza-Michael reaction of conveniently 2-substituted indole compounds incorporating an a,p-unsaturated ester moiety at the side chain (Scheme 5.35)." This methodology shows up as a very straightforward and efficient method for building up the l,2,3,4-tetrahydropyrazino[l,2-u]indole... 

Scheme 5.35 Enantioselective intramolecular aza-Michael reaction under PTC conditions.

Indazoles were prepared by many different methods. Indazoles 41 were synthesized from nitroaromatics 39 and N-tosylhydrazones 40 with bases (14CC5061). A rhodium(III)-catalyzed oxidative olefination of 1,2-di-substi-tuted arylhydrazines with alkenes via sp C-H bond aaivation followed by an intramolecular aza-Michael reaction yielded indazoles (140L2494). Copper-catalyzed C-H amidation with aromatic imines 42 with tosyl azide provided a route to 3-substituted indazoles 43 (14OL4702). 4,5,6,7-Tetrahydro-lH-inda-zol-3-(2fJ)-one derivatives were prepared in two-step one-pot process (14SC1076). A regioselective synthesis of 2H-indazoles 45 was achieved using... 

An elegant one-pot sequential protocol to prepare stereochemically diverse acyl sultanas was reported (140L82), where vinyl sulfonamides and amino acids undergo aza-Michael addition followed by an intramolecular amidation. An array of acyclic and cyclic amino acids can be used to prepare mono- and bicyclic sultams, respectively, one example, using hydroxy-proline, results in the seven-membered acylsulfonamides 208. 

Huang [80] and Liu [81] independently described a copper-catalyzed indole synthesis involving 2-iodoaniline and allenes (e.g., ethyl buta-2,3-dienoate) in a process that involved in situ formation of an aza-Michael addition adduct (vinylogous carbamate) and intramolecular Hecklike cyclization. Both groups used similar reaction... 

Scheme 1.36 Enantioselective phase-transfer-catalyzed intramolecular aza-Michael Reaction...

C2 halogenated tryptamine precursor 261, followed by intramolecular aza-Michael addition. In this example, by Stewart and Pfeifer, the order of these reaction was controlled by the type of protecting group on the nitrogen, while a range of acrylate systems were reported in good to excellent yields. Others have also reported similar Heck/Michael processes [129-131]. 

Scheme 7.62 Enantioselective domino aza-MBH/intramolecular aza-Michael reaction.

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