Condensation reactions, carbonyl compounds Michael reaction

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

In the Weiss reaction (Scheme 4), an a-di carbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c / s -b icy clo [ 3.3.0 ] o ct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if desired. While the reaction involves aldol and Michael sequences, the intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence that they are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

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. 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

Azole approach. 2-Amino-l,3,4-thiadiazoles react with appropriately substituted a,/3-unsaturated carbonyl compounds to form fused pyrimidines (729). The orientation of the substituents in the fusion products suggests that the reaction is initiated by Michael addition of the amino group. 1,3-Dicarbonyl compounds will condense in the same manner to yield the salt (729) from a /3-keto ester the 5-oxo derivative (730) is formed (73ABC1197). 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

Important laboratory applications involve the addition of hydrogen cyanide to an olefinic linkage which is activated by another group such as carbonyl, carbalkoxyl, cyano, or nitro on the adjacent carbon /3-cyano compounds are formed. The reaction is related to the Michael condensation (method 301). For the most part, the additions are base-catalyzed and are carried out by treating the unsaturated compound with an alkali cyanide in aqueous or aqueous-alcoholic solution. 

The Michael addition represents an extremely efficient synthetic method for achieving chain elongation by adding a three (or more) carbon fragment electrophile to a nucleophilic moiety. Notice that the typical Michael electrophiles (e.g. 90) are products of condensation of carbonyl compounds and can be easily formed via the aldol-like condensation, the Wittig reaction (with ylides like 81), the Perkin reaction, or the Mannich reaction (see below). 

When an a,P-unsaturated carbonyl compound is treated with a carbanion, particularly one that is stabilised by a carbonyl group as well, the resultant 1,4-addition with the formation of a new carbon/carbon bond is called the Michael reaction. Like the Claisen condensation, it is possible for this reaction to occur in an intramolecular manner with a suitably substituted compound. This reaction leads to the formation of a new ring and is called the Robinson annulation reaction. Write down the complete reaction sequence for the reaction between cyclohexanone and but-l-en-3-one. 

Lithium salts of t-butylhydrazones of aldehydes have been shown to be useful acyl anion equiv-alents. Treatment of an aldehyde r-butylhydrazone with an alkyllithium reagent or LDA gives the am-bident nucleophile (95), which reacts with both aldehydes and ketones to give carbon-substituted products as shown in equation (35). The condensation works best with nonenolizable carbonyl derivatives. Extension of this chemistry to the reaction of (95) with a,3-unsaturated carbonyl compounds met with mixed success. While good yields of Michael products were seen in the addition of (95) to methyl crotonate, other a,p-unsaturated electrophiles such as methyl acrylate, acrylonitrile and methyl P,p-di-methylacrylate gave negligible yields of carbon-substituted products. 

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