Nucleophilic addition amides

All these reactions proceed by nucleophilic addition of the amine to the carbonyl group Dissociation of the tetrahedral intermediate proceeds m the direction that leads to an amide... 

Step 2 Nucleophilic addition of water to the protonated form of the amide... 

Many other reactions of ethylene oxide are only of laboratory significance. These iaclude nucleophilic additions of amides, alkaU metal organic compounds, and pyridinyl alcohols (93), and electrophilic reactions with orthoformates, acetals, titanium tetrachloride, sulfenyl chlorides, halo-silanes, and dinitrogen tetroxide (94). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

Nevertheless, the adjacent position of the amide and acetylenic groups was used in another type of heterocyclization. The nitrogen atom in the amide group is a weak nucleophile. Therefore, the N anion should be generated by potassium ethoxide. There are two possible variants of nucleophilic addition to the triple bond. Only one takes place, i.e., the formation of y-lactam. After 7 h of heating in EtOH in the presence of KOH, amide 72 isomerized into the known isoindoline 73 in 80% yield (Scheme 128). 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

Following formation of the amide intermediate, a second nucleophilic addition of hydroxide ion to the amide carbonyl group then yields a tetrahedral alkoxide ion, which expels amide ion, NHZ-, as leaving group and gives the car-boxylate ion, thereby driving the reaction toward products. Subsequent acidification in a separate step yields the carboxylic acid. We ll look at this process in more detail in Section 21.7. 

Nitriles are similar in some respects to carboxylic acids and are prepared either by SN2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C=N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with organometallic reagents to yield ketones. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Not only N-H bonds from amines can participate in the aminolysis reaction, but also less nucleophilic urea, thiourea and biuret NH units can react with halophosphanes in an effective manner, forming the corresponding phosphinous amides with additional functionalities at the nitrogen atom [39-44]. 

Oxazolines can be readily synthesized by means of a noncatalyzed solvent-free procedure by two successive nucleophilic additions on a carbonyl group with the formation of an amide as an intermediate [68] (Eq. 16). 

Bunting and Kanter have developed a modified form of the Marcus equation to treat the changes in intrinsic barrier A observed for deprotonation of /J-keto esters and amides.81 It would be useful to consider similar modifications of the Marcus equation to model the variable intrinsic barriers observed for carboca-tion-nucleophile addition reactions. 

Substituent effects on ks. The replacement of an a-methyl group at the 4-methoxycumyl carbocation CH3-[14+] by an a-ester or a-amide group destabilizes the parent carbocation by 7 kcalmol-1 relative to the neutral azide ion adduct (Scheme 11 and Table 3) and results in 5-fold and 80-fold decreases, respectively, in ks for nucleophilic addition of a solvent 50/50 (v/v) methanol/water.33 These results follow the trend that strongly electron-withdrawing substituents, which destabilize a-substituted 4-methoxybenzyl carbocations relative to neutral adducts to nucleophiles, do not lead to the expected large increases in the rate constants for addition of solvent.28,33,92-95... 

Several trivial but highly useful reactions are known to convert one acceptor-substituted allene into another. For example, the transformation of allenic carboxylic acids is possible both via the corresponding 2,3-allenoyl chlorides or directly to 2,3-allen-amides [182,185], Allenylimines were prepared by condensation of allenyl aldehydes with primary amines [199]. However, the analogous reaction of allenyl ketones fails because in this case the nucleophilic addition to the central carbon atom of the allenic unit predominates (cf. Section 7.3.1). Allenyl sulfoxides can be oxidized by m-CPBA to give nearly quantitatively the corresponding allenyl sulfones [200]. The reaction of the ketone 144 with bromine yields first a 2 1 mixture of the addition product 145 and the allene 146, respectively (Scheme 7.24). By use of triethylamine, the unitary product 146 is obtained [59]. The allenylphosphane oxides and allene-... 

The sensitivity of position 2 in 4-chloroquinazoline for nucleophilic addition was also demonstrated in the reaction with lithium piperidide (73RTC460). Whereas in the amination with potassium amide/liquid ammonia no open-chain intermediate could be isolated, with lithium piperi-dide/piperidine the open-chain compound ort/z6>-(piperidinomethy-leneamino)benzonitrile (78,60%) was obtained, in addition to 4-piperidino-quinazoline (80,19%) (Scheme 11.35). The formation of 80 from 78 involves... 

A new semipinacol rearrangement mediated by Sn(IV) was proposed by Bates and to explain the formation of 579 from 578 (equation 256). As stated by the authors, the mechanism of formation of 579 most likely involves an intermediate hydroxylamine 580 (equation 257). Nucleophilic addition of the hydroxylamine to the ketonic carbonyl leads to 581, which may undergo a tin-mediated pinacol-type rearrangement with preferred migration of the phenyl substituent to produce amide 582. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

Marvel, 1975 Ueda et al., 1985]. The reaction probably proceeds by a sequence of two nucleophilic reactions a nucleophilic substitution to form an amine-amide (Eq. 2-217) followed by cyclization via nucleophilic addition (Eq. 2-218). 

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