Imines condensation with active

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

Taylor and Blackburn proved64 that the in situ condensation of an aldehyde with an amine can be made to occur in an intermolecular fashion. Thus, treatment of primary allylic, propargylic and benzylic alcohols with active Mn02 in the presence of diverse primary amines and molecular sieves in boiling CH2C12 leads to the selective oxidation of the alcohols in the presence of the primary amines and to the formation of the corresponding imines by reaction of the alcohols with the intermediate aldehydes. 

A propargylic alcohol is selectively oxidized with active M11O2 in the presence of a primary aliphatic amine. The resulting alcohol condenses with the amine, thanks to the action of the added molecular sieves as dehydrating agent, leading to the formation of an imine in a very... 

A benzylic alcohol is transformed with active MnC>2 in a benzaldehyde that condenses in situ with ammonia, in the presence of MgS04 as dehydrating agent, delivering an imine that is oxidized to a nitrile with active Mn02. 

Panek et al. employed the optically active amines 252 and 254 [57]. Their condensation with various aldehydes in the presence of MgS04 probably afforded the corresponding imines, which were treated with TiCl4. The resulting substituted 1,2,5,6-tetrahydro pyridines were finally protected, affording the corresponding tri-fluoroacetamides 253 and 255. In all cases, the desired tetrahydropyridines 253 and 255 could be isolated in excellent yields. The IMSC condensation also displays a high diastereoselectivity (Scheme 13.93). 

This limitation was overcome, when Dy(OTf)3 was used in place of In(OTf)3. This catalyst exhibited similar activity in both [C4Ciim][BF4] and [C4Ciim][PF6], and afforded better yields and reaction rates in these solvents relative to aqueous media.[63] With either hexanal or acetone as substrates, only a slight deterioration in activity occurred after six catalytic runs. The dysprosium salt also catalysed the reaction between the indole and various imines, but with relatively low selectivity towards the condensation product. 

Trichlorotitanium enolates are directly prepared from a ketone, TiCU, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-129], ketones [129], and imines [130,131], Intramolecular condensation with esters is also known [132-137], Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SNl-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123], Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138], Aminoalkylation of trichlorotitanium enolates with (a-chloroalkyl)amine has been performed analogously [139,140],... 

If other active groups are y or 8 to the nitro group, hydrogenation can result in the formation of cyclic products. Esters condense with the product amine to give lactams. Ketones or aldehydes produce imines that can be hydrogenated further to an amine. The hydrogenation of y- or 5-nitro carboxylic acids under mild conditions, however, gives the amino acids in excellent yields.58.59 The... 

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