Additions to a,p-Unsaturated Amides

Inspired by their previous work dealing with enantioselective conjugate addition of t-butyl acetoacetate to crotonoylthiazolidinethione catalysed by a preformed nickel catalyst from/ -To 1-BINAP ligand 30, and by those of Kane-masa on enantioselective nickel-catalysed additions of thiols and 1,3-dike-tones to unsaturated acylpyrazoles and oxazolidinones with a chiral amine ligand, Evans et al. investigated the scope of enantioselective Michael 

---

Preliminary results for the addition to a,P-unsaturated amides are shown in Eq. 3. The %ee thus obtained were higher than the corresponding addition to a, 3-unsaturated esters. 

Michael addition to unsaturated amides. This system (1 equiv. of each) effects Michael addition of ketones, nitro compounds, ethyl cyanoacetate, and diethyl malonate to a,p-unsaturated amides. Addition to methacrylamides is interesting because the final products are glutarimides or dihydropyridinones. Examples ... 

Chamberlin and Reich investigated hydride additions to a,p-unsaturated ketones and the correlation of conformational preferences in enones with the ( )/(Z) stereoselectivity in formation of the corresponding enolates. They found that in acyclic systems s-trans enones gave enolates A and s-cis enones gave enolates B (Scheme 15).53 The reduction of a,p-unsaturated amides with L-selectride gave the same stereochemical results (Scheme 16).54... 

The asymmetric conjugate addition reaction has been applied to a,P-unsaturated amides,alkenylphosphonates, and ethenesulfonamides. Hayashi and co-workers have also applied the standard reaction conditions to nitroalkenes. The reaction was found to be applicable to a variety of arylboronic acids. The reaction was also extended to acyclic nitroalkenes without loss of selectivity, but not to nitrocycloheptene or nitrocyclopentene. Interestingly, the thermodynamically less stable cis isomers, e.g., 266, were formed in the reaction of nitrocyclohexene (265) with a wide range of arylboronic acids, e.g., 254. The initial products could be readily converted to the more stable trans isomers by treatment with base. 

Scheme 2.30 Conjugate addition of substituted malononitriles to a,P-unsaturated amides of 3,5-dimethylpyrazoles with an in situ generated bisoxazo-line nickel catalyst.

In a complementary study, the use of Ai-benzyl-2(/ )-methoxy-(-F)-10-bornylamide as chiral lithium amide in the addition to a,p-unsaturated esters, followed by an aldol reaction with aromatic and aliphatic aldehydes, gave products similar to 62 with diastereoselectivities up to 78% [66]. 

Wu H, Radomkit S, O Brien JM, Hoveyda AH. Metal-free catalytic enantioselective C—B bond formation (pinacolato)boron conjugate additions to a,p-unsaturated ketones, esters, Weinreb amides, and aldehydes promoted by chiral N-heterocychc carbenes. J Am Chem Soc. 2012 134 8277-8285. 

Soai K, Machida H, Ookawa A. Asymmetric conjugate addition of Grignard reagents in the presence of tertiary amines to a,p-unsaturated amides derived from (5)-2-(l-hydroxy-l-methylethyljpyrrolidine or (S)-prolinol. J. Chem. Soc., Chem. Commun. 1985 469-470. 

Table 11.5 Organocuprate reagents in conjugate additions to a,p-unsaturated esters and amides.

Takasu examined a series of five imidazolidinone catalysts in the intramolecular conjugate addition of amides to a,p-unsaturated aldehydes to prepare a series of tetrahydroisoquinolines [114]. Although yields were high for these organo-catalytic transformations (70-90%), enantiomeric excesses were low (18-53%) showing further optimisation with regards to the co-acid and solvent are necessary to bring this potentially useful transformation in line with other reactions of this class. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

Itoh reports that copper-catalyzed Grignard additions to N-tosyl-N-alkyl-a.p-unsaturated amides and N-tosyl-a,(3-unsaturated lactams proceed efficiently while deprotonation occurs exclusively with the corresponding A/-alkyl-a,(3-unsaturated lactams (Scheme 45).94... 

Corriu and coworkers have reported an alternative procedure for the conjugate addition of ketones to a.P-unsaturated acceptors which employs CsF-(RO)4Si (Scheme 56) 126 this procedure affords adducts with a,3-enones, oc.fj-unsaturated esters and a,3-unsaturated amides. Mechanistically, silyl enol ether formation occurs initially, followed by fluoride ion catalyzed enolate formation. 

Diastereoselective Conjugate Addition of Organometallic Reagents to Chiral a,P-Unsaturated Amides and Imidazolidi-nones Derived from Ephedrine. Grignard reagents (2 equiv) add to chiral a,P-unsaturated amides derived from ephedrine in a 1,4-addition manner with high diastereoselectivities. Subsequent acidic hydrolysis affords optically active p-substituted carboxylic acids with 85-99% ee (eq 3). ... 

A one-pot epoxidation/azide-opening sequence has been developed <05JA2147>. A samarium-BINOL-PhjAsO complex is used as a catalyst for enantioselective epoxidations of a,p-unsaturated amides. Upon addition of TMSN, a new samarium azide complex is generated which regioselectively opens the epoxide to form 120. This method has also been extended to thiols and cyanide. 

A highly enantioselective catalytic conjugate addition of iV-heterocycles including purines 76 to a,P-unsatured ketones and amides 77 has been developed to give 6,9-disubstituted purines 78 <05AG(E)2393>... 

Lithium enolates of propionamides of chiral amines undergo stereoselective 1,4-addition reactions to a,P-unsaturaled esters. The highest selectivities are obtained with C2-symmetric amides derived from 1.65 (R = CH OCH QMie) bearing a substituent that is capable of metal chelation (Figure 7.61). After hydrolysis, diacid 7.95 is obtained with a good selectivity [161]. Some nonracemic natural... 

Compare the way butyllithium adds to this a, p-unsaturated aldehyde and a,P unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives (for details see Chapter 12) from direct addition to the carbonyl group, while with the ester it undergoes conjugate addition to give an... 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,p-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepaied by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chi rally-controlled aldol addition and Mannich condensation on a starting acetamide. 

---