A,P-unsaturated 1,4-addition reactions

Addition of hydrazines to 1,3-difunctional compounds is one of the most common methods employed for the preparation of pyrazoles. For example, several synthesis of pyrazoles have been reported where azide reagents are added to a,P-unsaturated systems. Reactions of trifluoroacetyl enol ether (thiophene) 1 with hydrazines afforded 3-(2-furyl) or 3-(2-thienyl)pyrazoles 2 <05S2744>. A regiospecific one-pot synthesis of trifluoromethyl-substituted heteroaryl pyrazolyl ketones has also been disclosed <05JHC631, 05JHC1055>. 1,3,5-... 

Thioamide enolates may be prepared by conjugate addition of organometallics to a.p-unsaturated thioamides. Reaction of these enolates with aldehydes affords anti aldols, often in excellent dia-stereomeric excess (equation 103 Table 15).133 It is believed that the conjugate addition reactions provide (Z)-enolates, via a cyclic, six-centered transition state.135 The anti stereochemistry observed in the aldol reactions of these (Z)-enolates would result from a boat-like, chelated transition state. The transition state has boat-like character to avoid a serious gauche interaction between R3 and the bulky secondary alkyl group in the thioamide enolate. Several of the intermediate enolates in this study (e.g. Table 15,... 

Reviews Synthesis 1972, 63 Tetrahedron 1984, 40,641 Organic Reactions 1972, 19, 1. - selective 1,4-addition to a,p-unsaturated carbonyls... 

Conjugation of the newly formed double bond with the carbonyl group stabilizes the a p unsaturated aldehyde provides the driving force for the dehydration and controls Its regioselectivity Dehydration can be effected by heating the aldol with acid or base Normally if the a p unsaturated aldehyde is the desired product all that is done is to carry out the base catalyzed aldol addition reaction at elevated temperature Under these conditions once the aldol addition product is formed it rapidly loses water to form the a p unsaturated aldehyde... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

A reaction of great synthetic val ue for carbon-carbon bond for mation Nucleophilic addition of an enolate ion to a carbonyl group followed by dehydration of the 3 hydroxy aldehyde yields an a p unsaturated aldehyde... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Other reactions similar to the aldol addition include the Claisen and Perkin reactions. The Claisen reaction, carried out by combining an aromatic aldehyde and an ester in the presence of metallic sodium, is useful for obtaining a,P-unsaturated esters. 

The formation of pyridine derivatives from a, P-unsaturated aldehydes and ammonia involves formation of three bonds during the ring synthesis. For example, with an a, P-unsaturated aldehyde, both 2,5-substituted as well as 3,4-substituted pyridines can be obtained, depending on whether a 1,2- (eq. 17) or 1,4-addition (eq. 18) occurs with ammonia. Reactions are performed in the vapor phase with catalysts. 

Physical and Chemical Properties. The (F)- and (Z)-isomers of cinnamaldehyde are both known. (F)-Cinnamaldehyde [14371-10-9] is generally produced commercially and its properties are given in Table 2. Cinnamaldehyde undergoes reactions that are typical of an a,P-unsaturated aromatic aldehyde. Slow oxidation to cinnamic acid is observed upon exposure to air. This process can be accelerated in the presence of transition-metal catalysts such as cobalt acetate (28). Under more vigorous conditions with either nitric or chromic acid, cleavage at the double bond occurs to afford benzoic acid. Epoxidation of cinnamaldehyde via a conjugate addition mechanism is observed upon treatment with a salt of /-butyl hydroperoxide (29). 

Addition of Carbanions to a,p-Unsaturated Ketones The Michael Reaction... 

ADDITION OF CARBANIONS TO a.p-UNSATURATED KETONES THE MICHAEL REACTION... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

In particular, a,P-unsaturated aldehydes seldom give 1,4 addition. The Michael reaction has traditionally been performed in protic solvents, with catalytic amounts of base, but more recently better yields with fewer side reactions have... 

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