For enamine formation

S Conditions for enamine formation and various acids used in the... 

In addition, acid cocatalysts can assist the formation of the enamine. With very basic, nucleophilic amines, such as pyrrolidine and its derivatives, acid catalysis is not necessarily required for enamine formation. However, with less basic amines, Brpnsted or Lewis acids are often used to assist in enamine formation (Scheme 7). 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

The same authors have also reported the synthesis of 2-amino quinolines46, Scheme 5.28. Secondary amines were reacted with aldehydes to form enamines subsequent addition of 2-azidobenzophenones initially forms triazoline intermediates, which undergo a thermal rearrangement and intermolecular base-catalysed cyclocondensation to produce 2-amino quinolines. The reactions were run at 180°C for 10 min (the time includes 3 min required for enamine formation) to give the products in 57-100% yields. 

In the worst case, there is no such simple distinction between the two sites for enamine formation and we must rely on other methods of control. The nonsteroidal anti-inflammatory drug indomethacin is a good example. Removing the N-acyl group reveals an indole with substituents in both halves of the molecule. 

The mechanism for enamine formation (Mechanism 21.6) is identical to the mechanism for imine formation except for the last step, involving formation of the n bond. The mechanism can be divided into two distinct parts nucleophilic addition of the 2° amine, followed by elimination of H2O. Each step involves a reversible equilibrium once again, so that the reaction is driven to completion by removing HpO. 

Two unusual and useful methods for enamine formation involving carbon-carbon bond formation have been developed from the pioneering work of Martin - o and are illustrated in equations (6) and (7). The moderate overall yields in both processes are offset by the complexity of alternative pathways for accomplishing the same transformation. 

By far the most common dehydrating agents used today are molecular sieves, which have demonstrated catalytic activity for enamine formation " . A less common method... 

The mechanism for enamine formation is exactly the same as that for imine formation, until the last step of the reaction. When a primary amine reacts with an aldehyde or a ketone, the protonated imine loses a proton from nitrogen in the last step of the reaction, forming a neutral imine. However, when the amine is secondary, the positively charged nitrogen is not bonded to a hydrogen. A stable neutral molecule is obtained by removing a proton from the a-carbon of the compound derived from the carbonyl compound. An enamine is the result. 

Enamines are the nitrogen analogues of enols but their formation from imines is thermodynamically more favourable than enol formation from ketones (Table 1). The equilibrium constant for enol formation is ca. 10 compared with a value of 10 for enamine formation. However, at pH 7 half of the imine exists as the iminium ion and the proportion of enamine present is 10 -fold greater than the proportion of enolate anion. In general, this implies that loss of an electrophile from... 

The first step of the mechanism for enamine formation is not acid-catalysed—amines need no help in attacking carbonyl compounds. But the dehydration step is acid-catalysed as HO is not a good leaving group. The selectivity for elimination into the unbranched chain is because the enamine is planar and there would be a bad steric clash between the methyl group and the nitrogen substituents (all of which are in the same plane) if elimination occurred the other way. 

A mechanism for the reaction is given in the following box. Note the difference between the previously described mechanism for imine formation and this mechanism for enamine formation. In enamine formation, which involves a secondary amine, there is no proton for removal from the nitrogen in the iminium cation intermediate. Hence, a neutral imine cannot be formed. A proton is removed from a carbon adjacent to the former carbonyl group instead, resulting in an enamine. We shall see in Chapter 18 that enamines are very useful for carbon—carbon bond formation (Section 18.9). 

Scheme 12.46). The secondary allylamines required for enamine formation were in situ-prepared from allylamines 88, which at the same time served as allyl donors. Stereoinduction is thought to proceed via H-bond-directed coordination of the enamine to the allylpalladium-bound chiral Bronsted acid [109c]. 

Enamines are compounds in which the nitrogen lone pair is delocalized by the presence of an adjacent C=C double bond. A mechanism for enamine formation is shown in Mechanism 20.7... 

Notice that the mechanism for enamine formation is exactly the same as that for imine formation, except for the last step. 

Nature s strategy of transient attachment of a stereodirecting enzyme via an enamine has been exploited by chemists using much simpler molecules, such as the natural amino acid proline (see also Section 26-1). Proline features the secondary amine function necessary for enamine formation, in addition to a carboxy substituent that renders the molecule chiral, the stereocenter exhibiting the S configuration. In the example shown below, proline catalyzes the enantioselective aldol addition of acetone to the — CHO group of 2-methylpropanal. As in the enzyme-catalyzed process, the sequence begins with enamine formation, now... 

Mechanism B (below) is yet another alternate acceptable mechanism for enamine formation. 

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