Enamines hindered aldehyde

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Only allyl and benzyl halides give good yields of C-alkylated aldehydes unless hindered enamines are used64. Otherwise N-alkylation or aldocondensation are often the only reactions observed54a,54ft 6 5. Hindered aldehyde enamines may also be prepared... 

They may eliminate so readily that the intermediate imidazoline cannot be isolated, but if the enamine is disubstituted, the 5,5-disubstituted imidazolines which are formed are so stable that it is necessary to heat them with 50% aqueous sulfuric acid, or in anhydrous medium with an equimolar amount of either triethylammonium or pyridinium chlorides, to effect arom-atization. Enamines derived from ketones or hindered aldehydes do not lead to imidazoles, and there are other difficulties (some enamines are difficult to prepare, only aryleneamines give good yields). Nevertheless, the reported results demonstrate the potential of the method [22-24]. 

C-Alkylations of hindered aldehyde enamines can be effected with a variety of alkylating agents, but only allylic and benzylic reagents are useful for alkylations of unhindered systems.Acyclic, homoan-nular and heteroannular dienamines undergo alkylation primarily at the a-positions. ° As discussed above, reactions of enamines with electrophiles containing sp -hybridized carbon atoms have numerous limitations. On the other hand, enamine reactions with electrophilic alkenes are highly useful and have received wide coverage in the literature. 

BUchi and coworkers have applied the Woodward conditions for the completely regioselective cycliza-tion of dialdehyde (37) to (38) (equation 101). 20 As in the earlier examples, the cyclization appears to occur by the enamine of the more hindered aldehyde reacting with the less hindered aldehyde. 

An exception to the generalization that the enamine of the more hindered aldehyde acts as the nucleophilic arm in intramolecular aldol reactions of unsymmetrical dialdehydes is seen in equation (103). -2 The regioselectivity of this cyclization is apparently very high none of the other isomer was detectable by HPLC or NMR the 57% yield quoted is the overall yield of the alcohol obtained by sodium borohy-... 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

The cross-aldol reaction between two enolizable aldehydes is not an easy task. Proper selection of reaction partners is of great importance. The most frequently studied reactions involved sterically hindered aldehydes since they form enamines... 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

The following compounds are unaffected by bis(p-methoxyphenyl) telluroxide dithi-olanes, enamines, aldehydes, ketones, alcohols, pyrroles, indoles, amino acids, aromatic amines, monohydroxyarenes, esters, hindered thiocarbonates, isonitriles, oximes, arylhy-drazones, sulphides, and selenides. ... 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

Zhong rationalized the enantioselectivity by proposing an enamine mechanism which proceeds via the chair transition state shown in Figure 7.1 [11]. In this transition state, the Si face of an E enamine formed from the aldehyde and the catalyst L-proline approaches the less-hindered oxygen atom of nitrosobenzene leading to the chiral product with (R) configuration. This mechanism is in accordance with the proposed reaction mechanism for the aldol reaction (see chapter 6.2). 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

A study on the scope of the reaction applied to different types of carbonyl compounds (aldehydes, cyclic ketones and some substituted alkyl aryl ketones75) has been published. Two different secondary amines (pyrrolidine, morpholine) were used. Titanium tetrachloride on various supports (e.g. A1203) acted as effective dehydrating agents for the preparation of enamines from hindered ketones and secondary amines76. 

A significant improvement in the alkylation of ketone and aldehyde enamines involves the use of sterically hindered amines63. N-Alkylation is prevented with consequent increase in C-alkylation. For example, reaction of the w-butylisobutylamine enamine of cyclohexanone (29) with methyl iodide in boiling acetonitrile (Scheme 16), or trimethy-loxonium tetrafluoroborate at room temperature gave 2-methylcyclohexanone in increased yields of 56% and 74%, respectively63 (compare Scheme 10). 

The observed absolute configuration of the products is in compliance with a simple transition state model where the phenyl group of the diox-ane moiety shields the Re face of the intermediate formed by addition of the nucleophilic carbene to the aldehyde, therefore, directing the attack of the enoate Michael acceptor to occur with the less hindered face, that is the Si face of the enamine (Fig. 16). The electrophilic part of the intermediate bearing the activated C=C double bond is approached by... 

Hindered rotation occurs on the NMR time scale for numerous other systems with partial double bonds, including carbamates, thioamides, enamines, nitrosamines, alkyl nitrites, diazoketones, aminoboranes, and aromatic aldehydes. Formal double bonds can exhibit free rotation when alternative resonance structures suggest partial single bonding. The calicene 5-5, for example, has a barrier to rotation about the central bond of only 20 kcal mol . ... 

As in the previous sections, secondary enamines in which either the nitrogen or the double bond is further conjugated with an electron-withdrawing or electron-donating substituent are not reviewed. Metal derivatives of imines (metalloenamines) are discussed in Chapter 25. We are only concerned with secondary enamines, in equilibrium with their imine tautomer, form by condensation of a primary amine with an aldehyde or ketone. Such condensations can readily be carried out using potassium hydroxide as catalyst or by azeotropic distillation in the presence or absence of add catalysts or, for more hindered or acid-sensitive ketones, titanium tetrachloride or dibutyltin dichloride, respectively, may be used. 

With unsymmetrical dialdehydes, a regiochemical issue exists. The first study of such a situation came as a part of Woodward s steroid synthesis." Dialdehyde (32) is cyclized by piperidinium acetate, via an intermediate enamine, to give predominantly the cyclopentenecarbaldehyde (33 equation 98). It was proposed that the P-aldehyde (that is, CHO of the C-14 formylmethyl group) is less hindered and therefore more susceptible to intramolecular attack by an enamine derived from the more encumbered aldehyde. 

---