Carbonyl compounds enamines, synthesis

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). 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Stork Enamine Synthesis A reaction leading to the formation of an a-alkyl or a-carbonyl compound from an alkyl or aryl halide reacting with an enamine. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As described in Chapter 3, Section 3,7r-allylpalladium complexes react with soft carbon nucleophiles such as malonates, /3-keto esters, and enamines in DMSO to form carbon-carbon bonds[2, 3], The characteristic feature of this reaction is that whereas organometallic reagents are considered to be nucleophilic and react with electrophiles, typically carbonyl compounds, 7r-allylpalladium complexes are electrophilic and react with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

Enamines are the stable products of a similar reaction between secondary amines (such as pyrrolidine or morpholine) and aldehydes and ketones.218 These vinylamines are reactive reagents of value in synthesis they function as specific enol equivalents of carbonyl compounds, readily undergoing alkylation and acylation processes (e.g. Section 5.9.2, p. 632). 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

Enamines are highly valued intermediates in organic synthesis. Almost invariably they are prepared by reaction of a carbonyl compound with a secondary amine. In principle, another attractive route to enamines could be based on construction of the double bond by a Wittig- or Horner-Wittig reaction. The enamines J thus obtained could be easily converted into the corresponding homologous aldehydes, if desired fitted with an extra electrophilic substituent at the original carbonyl carbon atom. 

The synthesis 10 is straightforward the condensation is indeed regioselective and it doesn t matter which way round hydrazine reacts or indeed which carbonyl compound reacts first. The enamine will form so as to be in conjugation with the remaining carbonyl group. 

Reactions proceeding more than once in the transformation of a substrate can be more effective than a single process If the reaction in question is a condensation of an N nucleophile with a carbonyl compound, the combination of the of two such reactions—allows for the synthesis of heterocycles like, the two depicted in Figure 9.27. The synthesis of quinoxaline (B) from glyoxal dihydrate (A) and orfho-phenylene diamine consists of two imine formations. Somewhat more complicated is the synthesis of dimethylpyrrole D from acetonyl acetone (C) and ammonia. After the formation of the first imine, an imine enamine isomerization occurs. A condensation followed by another imine — enamine isomerization leads to the product. 

Oxazolones are attacked by a variety of electrophiles at C(4) these reactions, which require the presence of bases, proceed through the enolate anions (197). This type of anion adds to carbonyl compounds, a key step in the Erlenmeyer synthesis of unsaturated azlactones (equation 35) (see Section 4.18.4.3.4). The anions are intermediates in the formation of the amides (198) when oxazolones are treated with enamines (Scheme 15) (71JCS(C)598>. 

In the last two sections, it was emphasised that the intermediate formation of enol ethers and enamines in alcohols and in the presence of amines, respectively, provides favourable routes for halogenation and isotope exchange in carbonyl compounds. Since this conclusion is probably also valid for other reactions which usually involve the enol or enolate, studies under these experimental conditions are probably of great interest, especially for the purposes of synthesis. 

We can use an enolatc for one reagent but the other will have to have umpolung. This is not a very serious kind of umpolung as an a-bromo carbonyl compound will do the job nicely if we select our enol(ate) equivalent carefully. In Chapter 26 we suggested enamines for this job. The synthesis becomes ... 

The simplest synthesis for a heterocycle emerges when we remove the heteroatom and see what electrophile we need. We shall use pyrroles as examples. The nitrogen forms an enamine on each side of the ring and we know that enamines are made from carbonyl compounds and amines. 

Besides N-acylated enamines, enamides containing a functional group in the carbon skeleton are obtained in the acid-catalyzed reactions of carbonyl compounds with nitriles. Some of them were shown in equations 18, 28, 31, 33, 38, 58, 59, 63, 65, 75 and 87 and they are mainly the polyacylated enamines (e.g. /Lacylaminovinyl ketones 79, 87, 93, 200, 207 and 278). Most of them are intermediates in the synthesis of oxygen and nitrogen containing heterocycles or products of further conversions of the latter. 

A standard method for enamine synthesis from aldehydes or ketones is to heat the carbonyl compound and the secondary amine in benzene or toluene and remove the water formed by azeotropic distillation. This method cannot, however, be used the preparation of enamines from methyl ketones which undergo self-condensation under these conditions. A procedure which overcomes these difficulties has been given by White and Weingarten [31]. The method employs anhydrous titanium tetrachloride as water scavenger. In the original procedure by White and Weingarten, titanium tetrachloride is added dropwise to a cooled... 

Stork enamine reaction. Synthesis of a-al-kyl or a-acyl carbonyl compounds from enamines and alkyl or acyl halides. 

A standard method for enamines synthesis from carbonyl compounds is to heat the parent aldehyde or ketone and a secondary amine in benzene or toluene and to remove the eliminated water by azeotropic distillation. However, this method fails with methyl ketone substrates which are prone to self-condensation imder these conditions. These difficulties could be overcome by a procedure using anhydrous titanium tetrachloride as water scavenger.[6] In the original procedure, titanium tetrachloride was added dropwise to a cold solution of the ketone and the amine, followed by prolonged stirring at room temperature. It was later found that the reaction time could be considerably shortened by a modified procedure, in which the... 

---