Enamines as synthons in the synthesis

Enamines and imines, cyclic, 6, 147 Enamines as synthons in the synthesis of heterocycles, 72, 283 /j-Enamino esters, heterocyclic, as heterocyclic synthons, 38, 299 -Excessive heteroannulenes, medium-large and large, 23, 55... 

Despite the numerous studies devoted to the synthesis of five-membered ring heterocycles using enamines as synthons, most publications on the use of enamines in the synthesis of heterocycles deal with six-membered heterocyclic ring systems, especially pyridine, pyrimidine, and pyran derivatives. 

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. ... 

An impressive number of alkaloids has been generated from the synthon (202), which is accessible by an acid catalyzed rearrangement of the appropriately substituted cyclopropyl-imine. The endocyclic enamine (202) should react with electrophiles on the /8-carbon in a process which simultaneously renders the a-carbon electrophilic and therefore susceptible to capture by nucleophilic reagents. The application of this methodology to the synthesis of ipalbidine (191a) and septicine (204) is shown in Scheme 30. Here, the unusual 3-phenylthio-2-pyrroline intermediate (203) serves as a relatively stable equivalent synthon of the unsubstituted 2-pyrroline analogue which is notoriously unstable (77ACR193). 

There is a rich synthetic potential for enamines in heterocyclic synthesis. Enamines can react as electrophiles or nucleophiles and as new partners in cycloaddition reactions. Various derivatives of nitrogen-, oxygen-, and sulfur-containing heterocycles have been prepared, and these, in turn, are of interest as starting materials for additional syntheses. They represent potential synthons for the development of various new directions in organic chemistry. 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

SMP enamines have a very broad range of applications as d synthons. Cyclohexanone SMP enamine can be used for efficient Michael additions to nitroalkenes, Knoevenagel acceptors, and to a nitroallylic ester in a [3 + 3] carbocyclization with excellent stereoselectivities (eq 1). The synthesis of y-oxo-a-amino acids using SMP enamines has been developed (eq 2). ... 

The ease with which cyclopent-2-enones are prepared by intramolecular aldol cyclizations of 1,4-diones has been much exploited in synthesis. A particularly attractive route to y-keto-aldehydes has been described by Martin etal, which has as a key stage the reaction between 2,3-dibromopropene (functioning as a 2-oxopropyl synthon) with an enamine (Scheme 11). In a similar type of approach to... 

Like enamines, dihalocarbenes add smoothly to enol ethers and in many cases it is possible to isolate the dihalocyclopropyl intermediates which are valuable synthons for chloroenones (cf. Section 4.7.3.7.1). The earliest example of the addition of a dihalocarbene to an enol ether was provided by Parham,6,79 who studied the addition of dichlorocaibene to dihydropyran (equation 22). An example which illustrates the synthetic potential of the process is the conversion of the cyclohexanone enol ether (6) to the dichlorocy-clopropane (7 equation 23).80 The latter served as a useful intermediate in a stereospecific synthesis of Prelog-Djerassi lactonic acid. 

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