Amidation reactivity

Although there is no shortage of applications for the lithiation of diethylamides, their potential would clearly be widened if the limitations of the amides reactivity could be... 

This new disilver system was found to be more active in intramolecular amidation reactivity compared to the original [Ag2(t-Bu3tpy)2] catalyst, showing both increased yields and decreased temperature (from 82 to 50°C). More importantly, this system was able to catalyze the intermolecular amination reaction of both benzylic and inert aliphatic C—Hbonds.Asimilar copper system reported similar activity however, it was only able to aminate benzylic C—H bonds (Table I). In the silver case, it was found that substitutions on the 2 and 9 positions of the phenanthroline shut down the reactivity of the catalyst, suggesting the importance of keeping a disilver core structure. 

Although comparison studies were carried out with a variety of other amide bases including diethylamide (which had proved superior to LDA in the non-asymmetric epoxide rearrangement) and the more sterically hindered dicyclohexylamide, LDA proved to give the highest yield and ee by combining the proper amounts of steric hindrance and amide reactivity. ... 

Sin Sinh, L. H., Son, B. T., Tmng, N. N., Lim, D.-G., Shin, S. H., Bae, J.-Y. Improvements in thermal, mechanical, and dielectric properties of epoxy resin by chemical modification with a novel amino-terminated liquid-crystalline copoly (ester amide). Reactive Ftmctional Polym. 72 (2012) 542-548. 

The choice of type of derivative should be based on whether the chloride or anhydride is aliphatic or aromatic, because this factoi largely determines the reactivity. Aliphatic acid chlorides are best converted into their anilides, as in 4 above aromatic acid chloride may be similarly converted into their anilides, or they may be converted into their amides by shaking with an excess of ammonia (p, 120). (M.ps., pp. 544-545.) Aliphatic acid anhydrides should be converted into their crystalline anilides, but aromatic acid anhydrides arc best hydrolysed to the acid, which can then be converted into one of the standard derivatives (p. 349). 

Acid derivatives are made directly from acids or by conversion from other acid derivatives depending on their stabihty. The most important are esters (RCOiEt), amides (RCO2NR2), anhydrides (RCOO COR) and add clilorides (RCOCI). Arrange these in an order of stabilily, the most reactive at the top of the list, the most stable at the bottom. 

Alkynyl anions are more stable = 22) than the more saturated alkyl or alkenyl anions (p/Tj = 40-45). They may be obtained directly from terminal acetylenes by treatment with strong base, e.g. sodium amide (pA, of NH 35). Frequently magnesium acetylides are made in proton-metal exchange reactions with more reactive Grignard reagents. Copper and mercury acetylides are formed directly from the corresponding metal acetates and acetylenes under neutral conditions (G.E. Coates, 1977 R.P. Houghton, 1979). 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

An intramolecular version offers useful synthetic methods for heterocycles. The total syntheses of a- and 7-lycoranes (373 and 374) have been carried out by applying the intramolecular aminochlorination of the carbamate of 5-(2-aminoethyl)-l,3-cyclohexadiene (372) as a key reaction[312,313]. Interestingly, the 4,6- and 5,7-diene amides 375 and 377 undergo the intramolecular amina-tion twice via x-allylpalladium to form alkaloid skeletons ofpyrrolizidine (376) and indolizidine (378), showing that amide group is reactive[314]. 

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

As an application of this nucleophilic reactivity, 2-aminothiazole was used to partially convert into amide the polymer obtained from acrylic acid, benzene, and acetic anhydride (271). An aqueous medium is reported to favor the reaction between acetic anhydride and 2-aminothiazole (272). 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

Two moles of /3-alkoxyaicene can condense on each other by means of their a- and /3-carbon atoms. The resulting intermediate reacts on the anhydrobase by elimination of a molecule of ethanol resulting in a neocyanine formation (Schemes 59 and 60). Both monoanilino and bis-anilino derivatives resulting from the condensation of dimethylform-amide have been isolated. They are capable of furnishing various condensations on either ketomethylene or another reactive nucleus (Scheme 61). 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

IS general for nucleophilic acyl substitution and well worth remembering The range of reactivities is quite large a factor of about 10 m relative rate separates acyl chlorides from amides... 

This difference m reactivity especially toward hydrolysis has an important result We 11 see m Chapter 27 that the structure and function of proteins are critical to life Itself The bonds mainly responsible for the structure of proteins are amide bonds which are about 100 times more stable to hydrolysis than ester bonds These amide bonds are stable enough to maintain the structural integrity of proteins m an aqueous environment but susceptible enough to hydrolysis to be broken when the occasion demands... 

Reaction with ammonia and amines (Sec tion 20 12) Esters react with ammonia and amines to form amides Methyl and ethyl esters are the most reactive... 

Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

Nitrogen is a better electron parr donor than oxygen and amides have a more stabilized carbonyl group than esters and anhydrides Chlorine is the poorest electron pair donor and acyl chlorides have the least stabi lized carbonyl group and are the most reactive... 

Section 20 6 Acid anhydrides are less reactive toward nucleophilic acyl substitution than acyl chlorides but are useful reagents for preparing esters and amides... 

Amines are convert ed to amides on reaction with acyl chlorides Other acylating agents such as carboxylic acid anhydrides and esters may also be used but are less reactive... 

Bromo 1 3 dimethylbenzene is inert to nucleophilic aromatic substitution on treatment with sodium amide in liquid ammonia It is recovered unchanged even after extended contact with the reagent Suggest an explanation for this lack of reactivity... 

Several chemical methods have been devised for identifying the N terminal ammo acid They all take advantage of the fact that the N terminal ammo group is free and can act as a nucleophile The a ammo groups of all the other ammo acids are part of amide linkages are not free and are much less nucleophilic Sanger s method for N terminal residue analysis involves treating a peptide with 1 fluoro 2 4 dimtrobenzene which is very reactive toward nucleophilic aromatic substitution (Chapter 23)... 

The reactivity of an ammo group is suppressed by converting it to an amide and ammo groups are most often protected by acylation The benzyloxycarbonyl group O... 

Benzyne is formed as a reactive intermediate in the reaction of aryl halides with very strong bases such as potassium amide... 

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