Enamides N-acyl

Hydrogenation of N-Acyl Enamides, Enol Esters and Enol Carbamates... 

Rhodium-catalyzed enantioselective hydrogenation of N-acyl enamides provides access to enantioenriched amides which can be hydrolyzed to the free amines. The synthesis of the substtates is considerably less sttaightforward than that of N-acyl dehydroamino acids, which explains the smaller number of reports devoted to N-acyl enamides. 

Table 28.4 Enantioselective hydrogenation of acyclic terminal N-acyl enamides.

Table 28.5 Enantioselective hydrogenation of cyclic and substituted N-acyl enamides.

O Shea PD, Gauvreau D, Gosselin F, Hughes G, Nadeau C, Roy A, Shultz CS (2009) Practical synthesis of a potent bradykinin B1 antagonist via enantioselective hydrogenation of a pyridyl N-acyl enamide. J Org Chem 74 4547-4553... 

Other Rearrangement Reactions.—In addition to the above-mentioned ring expansion and contraction reactions, miscellaneous rearrangements such as the photochemical [1,3] sigmatropic shift have been used in synthesis. An early example was in the synthesis of model corrins the formation of the vinylogous amide (141) occurred in 50% yield by irradiation of the N-acyl-enamide (140) in cyclohexane.3-Acetylcyclohexanone (143) was similarly obtained by irradiating the vinyl alcohol (142) in benzene. ... 

Halogen-free A/-acyl aldimines and N-acyl ketiimnes tautomenze readily to give enamides [J6] In contrast, perfluonnatedyV-acylimines are stable compounds These electron-deficient itnmes not only exhibit high thermal stability but also show umque properties both as electrophiles and as strongly polanzed hetero-1,3-dienes... 

N-acyl enaminc (104, R = CHjCHj) gave an unstable enamine (106) which decomposed readily to 3-cholestanone. The steroidal N-acetyl enamines (107 and 108, R = C HjCHj) can be reduced by lithium aluminum hydride in tctrahydrofuran to the corresponding enamines (109, R = CJH5CH2) in 90 and 68% yield, respectively 100). Attempts to reduce the enamide (107, R = CH3) led to the formation of the impure enamine (109, R = CHj), which decomposed to the hydroxy ketone (110). 

Enantioselective catalytic hydrogenation. The ruthenium(II) complexes of (R)- and (S)-l, bearing a chiral BINAP ligand, catalyze asymmetric hydrogenation of N-acyl-l-alkylidenetetrahydroisoquinolines to give (1R)- or (lS)-tetrahydroiso-quinolines in 95-100% ee.1 Thus the (Z)-enamide (2), prepared by acylation of 3,4-dihydropapaverine, is hydrogenated in the presence of (R)-l to (1R)-tetrahydroisoquinolines (3). The enantiomeric (lS)-3 is obtained on use of (S)-l as catalyst. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Intramolecular Diels-Alder reactions have been used to considerable advantage in the development of concise synthetic approaches to lycorine (1). One such entry commenced with the enamides 126 [Ar = Ph, 4-(MeO)CeH4] (Scheme 12), which were prepared by the N-acylation of imines derived from homopiperonal with the acid chloride 125 117). Thermal unmasking of the latent diene moiety of 126 [Ar = Ph, 4-(MeO)C6H4] in refluxing xylene contain-... 

Enamides R2C=CHNRCOR (N-acylated enamines) are thermally stable compounds under neutral or basic conditions. However, they show sensitivity to aqueous acid, hydrolysing to form aldehydes or ketones and amides. The photocyclization of enamides has been used to form a wide variety of natural products because it gave higher yields than the conventional thermal syntheses620-623. 

Besides N-acylated enamines, enamides containing a functional group in the carbon skeleton are obtained in the acid-catalyzed reactions of carbonyl compounds with nitriles. Some of them were shown in equations 18, 28, 31, 33, 38, 58, 59, 63, 65, 75 and 87 and they are mainly the polyacylated enamines (e.g. /Lacylaminovinyl ketones 79, 87, 93, 200, 207 and 278). Most of them are intermediates in the synthesis of oxygen and nitrogen containing heterocycles or products of further conversions of the latter. 

The pyrylium salts can be easily ring-opened by hydrolysis to yield 1,5-pentene-diones158. Consequently, 4-acylaminopyrylium salts 396 and 397 can be precursors to enamides 395. It should be expected that / -acylaminovinyl ketones (e.g. 207 and 278) obtained by other methods (e.g. by N-acylation of enaminones159,160) can be converted into 3-azapyrylium salts116 and, by the reaction described above, they can undergo the functionalization together with lengthening of the linear carbon chain. 

The accessibility of prochiral precursors is a key factor to a successful hydrogenation process from a practical point. There are several common and efficient methods for the formation of various enamides. An example is the preparation of N acyl a arylenamides as illustrated in Scheme 9.2. 

In 1986, Noyori reported a hexa coordinate BINAP Ru(II) complex that can efficiently catalyze the asymmetric hydrogenation of (Z) N acyl 1 alkylidenete tra hydroisoquinolines (70) in the presence of 0.5 1 mol% of the catalyst loadings in a 5 1 mixture of ethanol and dichloromethane under 1 4 atm of hydrogen at 23 °C (Scheme 9.18) [63]. However, the corresponding E enamide substrates were inert to this catalytic system under the same hydrogenation conditions. 

Systematic studies on the isomerization of W-allylamides 24 and -imides to aliphatic enamides 25 were carried out with iron, rhodium, and ruthenium complexes as catalysts, Eq. (8). Regrettably, no prochiral substrate was applied for the rhodium catalyst bearing polymer-anchored DIOP [33]. In the framework of a study on the conjugative interaction in the isomerization of 1-azabicyc-lo[3.2.2]non-2-ene 26 to orthogonal enamine 27, catalyzed by either f-BuOK or RuH(NO)(PPh3)3, the enamine formation was calculated to be favored by 4 kcal mob, Eq. (9) [34]. Recently, the palladium-catalyzed isomerization of the N-acyl-2,5-dihydropyrroles 28 to N-formyl-2,3-dihydropyrroles 29 was reported, Eq. (10) [35]. 

Zhang Catalytic Enantioselective N-acyl-a-Aryl-Enamide Reductions... 

N-acyl imines [144]. A slightly modified chiral Br0nsted acid 185 was found to catalytically induce addition of indoles to N-Boc-protected enecarbamates ISK) in high yields and enantioselectivities (Scheme 8.51) [145]. In a related study, Zhou demonstrated the use of a-aryl enamides to obtain optically enriched tertiary amine products [146]. 

Metal-catalyzed reductive acylation reactions of ketoximes into N-acetyl enamides are known for long time [144, and references cited therein]. Recently, an example promoted by the ruthenium dimer [ RuCl(p-Cl)(t -p-cymene) 2] has been described (Scheme 37) [145]. Remarkably, the process was successfully applied to the synthesis of 49, a key intermediate in the preparation of leukocyte elastase inhibitor DMP 777. 

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