Amides enamide

With all other pieces of the synthesis in place our attention now focused on the final piece in the jigsaw-the asymmetric hydrogenation of the amide enamide 42. Screening of hydrogenation conditions rapidly led to identification of a number of conditions which allowed the desired hydrogenation to proceed at low catalyst loadings and in non-chlorinated solvents (Table 9.9). 

Allyl amides (enamides), for example, 225, 228, and 230 cyclize to oxazolines, for example, 226, 229, and 231 when the double bond is activated by an electrophile. The double bond can also be conjugated to a ketone, or present as an allylic epoxide. Reagents commonly used to promote the cyclization include acids,iodine,selenium reagents,and trimethylsilyl triflate (Scheme 8.63). ... 

The photochemical rearrangement of enamides to vinylogous amides was described (65],652). Rearrangement of cyclopropyl ketimines to enamines with acid was applied to syntheses of myosamine, apoferrosamine, mesembrine, and desmethoxymesembrine (653-656). 

Reactions of benzoylperoxide with morpholinocyclohexene and morpho-linocyclopentene furnished the corresponding a-benzoyloxyketones in modest yields (480,481). This oxidation has also been applied to some vinylogous amides (482), and the expected faster rate of reaction of the enamine system as compared with enamides has been noted in derivatives of 20-ketosteroids, in reactions with perbenzoic acid (59,483). 

Several enamines also participate in these cycloaddition reactions. For example, the addition of methyl lithium to benzaldehyde 5 and the sequential introduction of the vinylogous amide and magnesium bromide results in the cycloaddition elimination product chromene 63 (method G, Fig. 4.33).27 The introduction of methyl magnesium bromide to a solution of the benzaldehyde 5 and two equivalents of the morpholine enamine produces the cycloadduct 64 in 70% yield with better than 50 1 diastereoselectivity (method F). Less reactive enamides, such as that used by Ohwada in Fig. 4.4, however, fail to participate in these conditions. 

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

In recent years, cross-coupling methodology has emerged as a viable tool for enamide synthesis, and, indeed, there are a number of published protocols which employ palladium- or copper-catalyzed stereospecific amidations of vinyl halides [17]. For example, Buchwald and coworkers had recently shown that a copper-catalyzed cross-coupling of vinyl bromides or iodides proceeded with retention of stereochemistry (Scheme 9.16), though the only example using a tetrasubstituted vinyl halide, 23, lacked the need for any stereochemical control in the halide portion [18]. Based on this it seemed feasible that the desired enamide 22 could potentially be assembled via a comparable coupling between amide 24 and a stere-odefined vinyl halide such as 25. 

The reaction conditions were optimized to afford clean coupling of enol tosylate 32 using only a slight excess of amide 24 (1.05equiv) at 100 °C, 5mol% Pd2(dba)3/ dppb catalyst, and a toluene/tert-amyl alcohol solvent system. Even under the harsh reaction conditions required for complete conversion of the tosylate (100 °C, 20 h) no detectable E/Z isomerization was seen, providing further proof that the hindered nature of the enamide aids stability to isomerization. Treatment of the mixture with activated carbon (Darco KB-B) at the end of the reaction followed by isolation of the product by crystallization, afforded enamide 22 in 92% isolated yield. 

The pseudobenzylisoquinoline alkaloids are fairly widespread in nature, being found among members of Berberidaceae, Annonaceae, Fumariaceae, and Ranunculaceae. The biogenesis of the pseudobenzylisoquinoline alkaloids assumes their formation from protoberberinium salts by C-8—C-8a bond scission in a Baeyer-Villiger-type oxidative rearrangement to produce the enamides of type 73 and 74. These amides may be further biotransformed either to rugosinone (76) type alkaloids by hydrolytic N-deformylation followed by oxidation or to ledecorine (75) by enzymatic reduction. These transformations were corroborated by in vitro studies (80-82). It is suggested that enamide seco alkaloids may be precursors of aporphine alkaloids (80), on one hand, and of cularine alkaloids (77), on the other. 

A wide range of substrates have been reported to proceed successfully to conjugate addition products with the monobasic forms of phosphorous acids, including esters,371415416 amides,417-419 nitriles,415 420 acid chlorides,421 enamides,375 and nitro compounds.422-424... 

The low ee-values obtained with simple unsaturated acids as compared to the enamides of dehydroamino acid derivatives show that the oxygen atoms of the amide is a key to complex formation with the metal center. Knowles also proposed a quadrant model that has been adapted for many reactions [5, 22]. The mechanism of the reaction has been investigated, and it is known that the addition of the substrate to the metal is regioselective and that competing catalytic cycles can occur [5, 10, 22, 25, 27, 30-46]. 

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. 

Only few general methods allow for the introduction of a substituent at the C-7 position. However, treatment of cyano-enamide 335 with LiTMP followed by reaction with electrophiles has been successfully used to introduce an alkyl chain at G-7. It is worth noting that the amide obtained by acidic hydrolysis of the cyano-enamide group can be further alkylated to form tricyclic hexahydro-oxazolo[3,2- ]pyridin-5-ones 337 (Scheme 92) <1998JOC1619>. 

Although understanding the effect of the a-substituent on relative alkyl hydride stabilities is straightforward, understanding the effect on the catalyst-enamide diastereomers is not. To clarify this matter we performed a series of calculations on a variety of substituted enamides [78], To eliminate the effect of the amide oxygen, we examined frontier orbitals of the [Rh(PH3)2(formamide)]+ fragment (15) and those of model enamides (16). 

In addition, recent studies of amides include the 1,3-acyl migration of enamides to obtain the enamines through a photo-Fries like mechanism (equations 103160 and 104161). 

The reaction of but-l-en-3-yl diethyl phosphate with diethylamine produces N,N-diethylpent-3-enamide (86%), indicating that a Ji-allyl complex is involved in the carbonylation reaction. No isomerism to the a,p-unsaturated amides was observed. 

Firstly, the system will also hydrogenate enamides with high e.e., provided that the amide substituent and the one substituent at the other carbon are cis to one another. Secondly, the Ru(BINAP)(RC02)2 catalyst gives enantioselective hydrogenation of acrylic derivatives, see the examples below for Naproxen and the like. 

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