Amides nucleophilic

The first example in Table 20 2 mlroduces a new aspecl of nucleophilic acyl sub slilulion lhal applies nol only lo acid anhydrides bul also lo acyl chlorides Ihioeslers esters and amides Nucleophilic acyl subslilulions can be calalyzed by acids... 

The first example in Table 20.2 introduces a new aspect of nucleophilic acyl substitution that applies not only to acid anhydrides but also to acyl chlorides, thioesters, esters, and amides. Nucleophilic acyl substitutions can be catalyzed by acids. 

Among the different chemical reactions usable to synthesize polymeric materials by step polymerisation are esterification, amidation, nucleophilic aromatic substitution and urethane (carbamate) formation. Polymerisation... 

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. 

Cobalt-coordinated amide nucleophiles have also been observed to attack coordinated phosphate esters (equation 38),148 disulfides (Scheme 47)149 150 and nitriles (Scheme 48).151>152 Chelated amides can also be formed by intramolecular attack of cobalt hydroxides.153... 

Amide nucleophiles can add to ir-allylpalladium complexes by either ligand or metal addition. Only a limited number of examples have been examined, but these nucleophiles show a surprising tendency to add to the more substituted allyl terminus (equation 271).197 However, in common with amine nucleophiles, they do add to the more distant terminus from remotely substituted polar functionalities (equation 272).197... 

Figure 8-19. In the Chichibabin reaction a pyridine reacts with sodium amide in a solvent such as yV,yV-dimethylaminobenzene. The initial product is a dihydropyridine, which is oxidised to give a 2-aminopyridine. The attack of the amide nucleophile occurs predominantly at the 2-position of the pyridine.

The rather unusual precatalyst silver(i) isocyanate was found to efficiently catalyze the cyclization of propargyl carbamates 420 to 4-alkylideneoxazolidin-2-ones 421 in good to high yields (Scheme 123).348 The presence of a base such as potassium /-butoxide or triethylamine is required for formation of the amide nucleophile which undergoes a stereoselective intramolecular attack at the activated triple bond (/rstereo-isomer 421 exclusively. Likewise, homopropargyl carbamates are converted into six-membered (Z)-4-alkylidene-l,3-oxazinane-2-ones under the same conditions. 

Acid derivatives differ in the nature of the nucleophile bonded to the acyl carbon —OH in the acid, —Cl in the acid chloride, —OR in the ester, and —NH2 (or an amine) in the amide. Nucleophilic acyl substitution is the most common method for interconverting these derivatives. We will see many examples of nucleophilic acyl substitution in this chapter and in Chapter 21 ( Carboxylic Acid Derivatives ). The specific mechanisms depend on the reagents and conditions, but we can group them generally according to whether they take place under acidic or basic conditions. 

The direct synthesis of fully functionalized sugars possessing amino or hydroxyl functions at C-2 has also been studied. Thus, activation of glycals by thianthrene-5-oxide 287 and Tf20, followed by treatment with an amide nucleophile and a glycosyl acceptor, led directly to various 2-acylamido glycosides 288 [610,611] (Scheme 4.59). 

To begin with, it seems very likely that chymotrypsin acts in two stages. In the first stage, acting as an alcohol, it breaks the peptide chain. We recognize this as alcoholysis of a substituted amide nucleophilic acyl substitution. The products are an amine—the liberated portion of the substrate molecule—and, as we shall... 

Characterization. Spectroscopic techniques have made it possible to identify ff-adducts in liquid ammonia. They have been detected and assigned structures by H- and C-NMR spectroscopy. The addition of the amide nucleophile to the sp carbon in the aromatic heterocycle changes its hybridization to sp, which causes an upheld shift of the carbon and hydrogen atoms. 

The process by which bi-or poly-functional reactants are condensed to form polymer chains with the elimination of small molecules in each condensing step, is known as condensation polymerisation. As the polymer chains are grown incrementally, it may also be called step growth polymerisation. Esterification (direct or ester exchange), amidation, nucleophilic and electrophilic substitution are the general reactions for this polymerisation process. The formation of vegetable oil-based polyester is an example of this type of polymerisation (Fig. 1.1). 

Scheme 9 An N9-alkyl 2-fluoro-6-chloropurine reacts preferentially with amide nucleophiles at the 2-position...

Scheme 2 ROP of s-caprolactam by lithium amides (nucleophilic activated monomer). ...

This trend persists in solvents (e.g., toluene, dioxane, and dichloromethane) where macrocyclization can take place, albeit with lower yields of 18a and higher yields of 16a (entries 7-9). This AlMes-mediated cyclohexamerization reaction likely proceeds via an intermediate aluminum amide formed by reaction of AlMes with RNH2 with loss of methane, followed by coordination of the A1 center to the carbonyl to activate the ester and deliver the amide nucleophile to form amide bonds. In light of this mechanism, such reactions are expected to be prone to inhibition by Lewis basic solvents and additives. The use of Lewis basic solvents such as DMF, DMSO, CH3CN, acetone, and ethyl acetate indeed completely halts the macrocyclization reaction, resulting in no generation of 16a and 18a. Similarly, in the presence of Lewis basic additives such as HMPA, TMEDA, and PMDTA, circular products 16a and 18a remain undetectable either. 

Highly complex 3-pyrrolin-2-ones can be obtained from intermolecular cycUzations that combine aldol condensations (to form the c bond) and nucleophilic additions by amide nucleophiles (to form the e bond). This strategy was pioneered by Howard and coworkers for the synthesis of... 

Several studies have explored the influence of modified reaction conditions or special techniques to facilitate Pd-catalyzed iV-arylation reactions. For example, Buchwald has demonstrated that water can be used to preactivate Pd(OAc)2/ biarylphosphine catalyst systems, which leads to enhanced reactivity in N-arylations [118]. The addition of small amounts of water has been shown to accelerate Pd/Xantphos-catalyzed A -arylations of amide nucleophiles when CS2CO3 is used as base [119]. Particle size, shape, and molar excess also have a large influence on reaction rates for Cs2C03-mediated reactions [120]. The use of microwave irradiation to facilitate A -arylation has been explored [121-124], and transformations have been conducted in continuous flow microreactors [125], or with supercritical CO2 as solvent [126]. 

Scheme 34 Cul-catalyzed amidation/nucleophilic substitution for assembling polysubstituted indolines...

Subsequently, Buchwald et al. developed a more efficient one-pot procedure for the synthesis of indolines 95 and their homologues 96 based on a domino Cu-catalyzed amidation/nucleophilic substitutimi reaction of aryl iodides 94 and primary amines (Scheme 34) [68]. Polysubstituted indolines could be obtained in good yields. 

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