Carbonyl compounds amide chlorides

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

Carboxylic acids, RC02H, occupy a central place among carbonyl compounds. Not only are they valuable in themselves, they also serve as starting materials for preparing numerous acyl derivatives such as acid chlorides, esters, amides, and thioesters. In addition, carboxylic acids are present in the majority of biological pathways. We ll look both at acids and at their close relatives, nitriles (RC=N), in this chapter and at acyl derivatives in the next chapter. 

Now, the van der Waals radii are hydrogen 1.2, oxygen 1.4, nitrogen 1.5, chlorine 1.8 and methyl 2 A.20 If the above theory is correct, ketones would be the least reactive of all carbonyl compounds and acid chlorides would be less reactive than esters or even amides Another hypothesis suggests that the resonance hybrid... 

CARBONYL ADDITIONS, CERIUM(III) CHLORIDE-PROMOTED, 76, 237 Carbonyl compounds, reactions with organolithiums or Grignard reagents, 76, 228 Carboxylic acid amides, 77, 27 Cells, storage of, 76, 80 Centrifugation, 76, 78... 

In the initial studies about the reaction of /V.zV-disubstituted formamides with alkaline metals to give glyoxylic amides, the participation of carbamoyl metal derivatives as intermediates was postulated83. The first preparation of the carbamoyllithium 77 was described two years later by a mercury-lithium transmetallation from compound 76 at —75 °C (Scheme 20)84. The authors proposed also an aminocarbene structure 78 and studied its reactivity with methanol, methyl iodide, carbonyl compounds, esters, acyl chlorides, mercury(II) chloride and tri-n-butyltin chloride providing compounds 79. 

All types of electrophiles have been used with 2-lithio-l,3-dithiane derivatives, including alkyl halides, sulfonates, sulfates, allylic alcohols, arene-metal complexes, epoxides, aziridines, carbonyl compounds, imines, Michael-acceptors, carbon dioxide, acyl chlorides, esters and lactones, amides, nitriles, isocyanates, disulfides and chlorotrialkylsilanes or stannanes. The final deprotection of the dithioacetal moiety can be carried out by means of different types of reagents in order to regenerate the carbonyl group by heavy metal coordination, alkylation and oxidation184 or it can be reduced to a methylene group with Raney-nickel, sodium or LiAIII4. 

Chapter 22 focuses on carbonyl compounds that contain an acyl group bonded to an electronegative atom. These include the carboxylic acids, as well as carboxylic acid derivatives that can be prepared from them acid chlorides, anhydrides, esters, and amides. 

The carbocation that is formed upon protonation of a carbonyl compound can lose H+ from the a-carbon to give an enol. Enols are good nucleophiles. Thus, under acidic conditions, carbonyl compounds are electrophilic at the carbonyl C and nucleophilic at the a-carbon and on oxygen, just like they are under basic conditions. Resonance-stabilized carbonyl compounds such as amides and esters are much less prone to enolize under acidic conditions than less stable carbonyl compounds such as ketones, aldehydes, and acyl chlorides in fact, esters and amides rarely undergo reactions at the a-carbon under acidic conditions. 

Carbonylation of chloropyrazines in methanol or amines gave the corresponding esters or amides in excellent yields [80a]. The alkoxycarbonylation of various A -heteroaryl chlorides was examined with dppb and dppf as hgands [80b]. Several heterocyclic compounds have been prepared with appropriate catalyst and hgand with excehent yields. A catalyst turnover number up to 13,000 was obtained for the carbonylation of heteroaryl chloride [80b]. 

Acyloxaziridines are easily obtained from compounds unsubstituted at nitrogen by reaction with acid chlorides or isocyanates. Acylation proceeds so smoothly that, in the amination of carbonyl compounds, oxaziridine compounds are obtained in better yields on addition of acid chlorides than in the absence of the acylating agent. With aliphatic aldehydes, amination does not succeed at all except in the presence of benzoyl chloride. Proof of structure comes from reduction by iodide to give the acid amide and carbonyl compound. 

Since conjugate (Michael) addition and Diels-Alder reactions use a,p-unsat united carbonyl compounds, asymmetric versions of these reactions could use the auxiliaries that we have seen in aldol reactions in the form of 118 and 119. Diels-Alder reactions work very well with these unsaturated amides and also with amides 121 derived from Oppolzer s chiral sultam14 120, prepared simply from camphorsulfonyl chloride. 

Another important part of Organic II is carbonyl chemistry. We look at the basics of the carbonyls in Chapter 9. It s like a family reunion where I (John, one of your authors) grew up in North Carolina — everybody is related. You meet aldehydes, ketones, carboxylic acids, acyl chlorides, esters, amides, and on and on. It s a quick peek, because later we go back and examine many of these in detail. For example, in Chapter 10 you study aldehydes and ketones, along with some of the amines, while in Chapter 11 we introduce you to other carbonyl compounds, enols and enolates, along with nitroalkanes and nitriles. 

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