Amidation reactions, tandem

Tandem conjugate addition ofenolates and aldol reactions Tandem conjugate addition of chiral amines and aldol reactions Part III - Intermediate is an Unstable Imine or Enamine Intermediate Would Be Formed by Amide Condensation... 

Scheme 14.7 Tandem catalytic cycle of for NHC-promoted amidation reactions.

Similar reactions have also been observed with tertiary amides and the adducts can be alkylated by tandem SN2 reactions. 

An intramolecular palladium-catalyzed tandem cyclization of dienamides 67 in which the amide nucleophile adds twice has been developed (equation 29)60. This reaction constitutes a formal [4+1] cycloaddition and provides a new route to pyrrolizidine and indolizidine alkaloids. Reaction of dienamides 67 in the presence of catalytic amounts of Pd(OAc)2 and CUCI2/O2 as the oxidant afforded bicyclic compounds 68 in good yields. The pyrrolizidine derivative 68 (R = Me, n = 1) was transformed to the alkaloid ( )-heliotridane. 

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of W-aryl enaminones 97, this reaction could be applied in a tandem... 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

The fourth method also involves a tandem bond-forming strategy of N1-C2 and N4—C5, in which simultaneous formation of both amide bonds of a 2,5-DKP occurs in a one-pot reaction from an a-amino ester derivative. ... 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

The structural diversity (and complexity) of the products obtained by the MCR between tertiary isocyano amides, aldehydes, and amines could be increased to various heterocyclic scaffolds by combining the initial 2,4,5-tiisubstituted oxazole MCR with in situ intramolecular tandem processes (Fig. 17). Most tandem processes reported are based on the reactivity of the oxazole ring toward C=C or C=C bonds in hetero Diels-Alder reactions followed by ring opening reactions generating the rather complex heterocyclic products with high degrees of variation. 

Dihydroquinoline-3-carbonitriles can also be prepared by the tandem reaction between 2-(mediylamino)-benzophenone and a,/3-unsaturated carbonitriles in the presence of magnesium amide under the same conditions as for the reaction with a,-unsaturated carboxylates (equation 39). 

Similarly, cyclizative tandem double-carbonylation reactions of 4-pentenyl iodide under irradiation conditions, is boosted by the addition of a catalytic amount of palladium complexes [72]. When performed in the presence of diethylamine, the carbonylation provided a triply carbonylated a,<5-diketo amide as the major product along with the doubly carbonylated y-keto amide (Scheme 6.48). Experimental evidence supports the interplay of two reactive species, radicals and organopalladium... 

Feldman and co-workers developed a nicely designed intramolecular version of the MCI reaction [Eq. (108)] [190]. Treatment of the tosylamide-bearing alkynylstannane 118 with PhI(CN)OTf 19 gave via ligand exchange a labile alkynyliodane 119, which on exposure to a base undergoes an intramolecular tandem MCI reaction to afford the amide 120. Hydroxyalkynyl-A3-iodanes similarly undergo the intramolecular MCI reaction [191]. 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

A 63-membered library of pyrazoloquinazolinones was prepared from nine hydrazinobenzoic acids and seven cyanoketones [71] in a microwave-assisted tandem a-aminopyrazole formation—an amide bond-forming ring closure reaction. In many cases, the products precipitated out of the reaction mixture and simple washing with diethyl ether furnished the products with purities greater than 95%. Alternatively, heterocycles were isolated in a high-throughput fashion via preparative HPLC (Scheme 24). 

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