Aryl-substituted enamides

Shortly thereafter, Zhou and coworkers independently reported the enantioselec tive F C reaction of indoles with a aryl substituted enamides catalyzed by chiral phosphoric acid catalyst lq (Scheme 3.22) [52], in which the quaternary stereogenic center bearing the nitrogen atom vas constructed in a highly enantioselective manner. 

Rh-catalyzed hydrogenation of simple enamides has attracted much attention recently. With the development of increasingly efficient chiral phosphorus ligands, extremely high ee-values can be obtained in the Rh-catalyzed hydrogenation of a-aryl enamides. E/Z-isomeric mixtures of -substituted enamides can also be hydrogenated, with excellent ee-values. Some efficient examples (>95% ee) of hydrogenation of a-phenylenamide and E/Z-isomeric mixtures of / -methyl-a-phenylenamide are listed in Table 26.3. 

Recently, high enantioselectivity was obtained in the rhodium-catalyzed hydrogenation of a-aryl enamides and E/Z-isomeric mixtures of y9-substituted enamides. Tab. 1.3 lists some examples for the hydrogenation of a-phenylenamide and the /Z-isomeric mixture of yS-methyl-a-phenylenamide. A P-chiral ligand, TangPhos, proved to be particularly efficient for the rhodium-catalyzed hydrogenation of enamides, given the excellent enantioselectivity and reactivity, with up to 10000 turnovers. 

Figure 1.15 Sections of the potential energy profiles for the double bond coordination and migratory insertion steps for the aryl (a) and f-butyl (b) substituted enamides. (Reprinted with permission from Gridnev, I. D. and Imamoto, T. Izv. Akad. Nauk, Ser. Khim., 1514-1534,2016. With permission.)...

The hydrogenation of enamides and enol acetates without acid function is often more demanding, and at present is not applied widely. Besides a bench-scale application by Roche with a Ru-biphep catalyst [55], two examples are of interest a pilot process for a cyclic enol acetate by Roche [55], and a feasibility study by Bristol-Myers Squibb [56], both using Rh-DuPhos catalysts (Fig. 37.11). In the latter case, despite very good ee-values, a chiral pool route was finally chosen. Chiral Quests Rh-f-KetalPhos (see Fig. 37.9) has been shown to hydrogenate a variety of substituted aryl enamide model substrates at r.t., 1 bar, with very promising catalyst performance (ee 98-99%, TON 10000) [47]. 

Iminopropadienones are highly reactive species that have been used as three-carbon fragments in the synthesis of 1,4-diazepines <2002JOC2619>. Aryl- and neopentyl-substituted iminopropadienone derivatives are stable at 25 °C and the latter, 99, reacted with iV,iV -dimethyl-l,2-diaminoethane to afford a 55% yield of the l,4-diazepin-5-one 100, a compound that partially tautomerized to the enamide 101 upon Kugelrohr distillation. 

Another important entry to the skeletal framework of the alkaloids related to lycorine has involved the formation of the B ring from an ACD precursor by different arylation protocols. Although the first examples of these processes typically involved photocyclizations of substituted A-benzoyl indolines such as 158-160 and enamides such as 165-167, cyclizations of benzyne intermediates and electrochemical oxidative cyclizations have recently proved to be useful. Early workers in this area noted that when 158 was irradiated, it suffered... 

Rhodium-BisP and -MiniPHOS catalysts are capable of high enantioselective reductions of dehydroamino acids in 96-99.9% ee.109 A variety of aryl enamides give optically active amides with 96-99% ee with the exception of ort/jo-substituted substrates.111 Despite the high enantio-selectivity, the rate of reaction in this transformation is slow. Rhodium-BisP and -MiniPHOS catalysts perform excellently in the asymmetric reduction of ( >P-(acylamino)acrylates to the corresponding protected-P-amino esters in 95-99% ee.112 Within the family of BisP and MiniPHOS, the ligands that contain t-Bu groups were found to be the most effective in a variety of asymmetric hydrogenations. 

A second example for a sulfur-directed cyclization, in which even two thio-phenyl groups were present as substituents on the target alkene 36, is shown in Scheme 14 [85]. This substitution pattern is capable of reversing the usual regios-electivity observed for aryl radical additions to enamides. In the presence of a fivefold excess of tributyltin hydride, one sulfur group is removed immediately after the cyclization step. The resulting tricyclic thioether 37 was further converted to mappicine ketone 38. 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

Another common use of carbopalladation is to effect a net annelation by side chain installation followed by cyclization. One example from the synthesis of a protected form of the 2-quinolone portion of streptonigrin 40 begins with iodide 37 (Scheme Heck reaction of this electron-rich fully substituted aryl iodide 37 with methyl acrylate provides the substimtion product 38. Extended reflux of 38 under acidic conditions promotes double deprotection, isomerization, and cyclization reaction yielding enamide 39. Another example from the synthesis of ( )-aurantioclavine 41 involves coupling of aryl bromide Standard Heck conditions provide the substitution product 43 in excellent yield at the appropriate oxidation state for cyclization to form the azepine ring en route to the natural product... 

Rigby s studies on the synthesis of alkenylisocyanates fostered the preparation of a suitable substituted aryl enamide, which on photocyclization yielded the polysubstituted pentacyclic system. Key to the success of this process is the hydrogen bond between the phenolic OH and the carbonyl group, which restricts the rotation around the aryl-amide bond and directs the cyclization. Further functionalization allowed the total synthesis of pancratistatin (272) and narciclasine (68) (275) (Scheme 11). The [4-1-1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates was the key process in a recent synthesis of (+)-mesembrine (92) 274). 

Heteroatom-substituted alkenes, such as vinyl ethers and enamides, constitute easily accessible and versatile building blocks. For example, these vinylic substrates can be - after regiocontrolled arylation/vinylation and optional hydrolysis and/or hydrogenation - easily... 

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