Preparation of Enamides

The reduction of Z-protected enamide methyl esters of 2- and 3-furyl, and thienyl with Rh-DIPAMP has been reported to give enantioselectivities of from 85 to 91% at an S/C ratio of 4000 [16]. 

The properties of the N-acyl amino acid derivative and the amino acid itself can be important if crystallization is employed to ensure high optical purity. However, in the experience of the authors, it is seldom a problem. Only 3-pyridylalanine could not be purified to high optical purity by recrystallization. Use of enzymes to enhance enantiomeric excess as well as allowing the use of mild hydrolysis conditions has been advocated by others [12]. Amino acids are surprisingly stable to acid-induced racemization. 

As noted above, a stereoselective synthesis of the enamide is important. The azlac-tone method (Fig. 3) results in the preferential formation of the Z-enamide when an aromatic aldehyde is employed. In addition, this isomer usually precipitates from the reaction mixture and this simplifies purification. When an alkyl aldehyde is used, the ratio of enamide isomers is often 1 1 or close to this. In addition, many of these alkyl examples are not crystalline and physical separations such as chromatography have to be employed. This is obviously a limitation of the methodology when compared with catalysts that employ the DuPHOS ligands, and related ligand families where both isomers can be reduced down to the same enantiomer of the desired amino acid [12]. 

An alternative approach to the enamides is to use a Wadsworth-Emmons variation of the Wittig reaction (Fig. 4) [13, 16, 19]. As the parameters that control this reaction are well understood, it is possible to control the stereochemical outcome of the reaction in favor of the desired enamide isomer. 

The mechanism for the asymmetric hydrogenation of enamides by Knowles catalyst is well understood due to the work of Halpern (Fig. 5) [20], The intermediates were identified by spectroscopy. The surprising finding was that two catalytic cycles were possible. The one that contains the lower concentrations of intermediates gives rise to the major product isomer as the reaction rates are faster compared with the cycle that has more detectable intermediates. 

---

The general method used for the preparation of enamides is the acylation of the imine624-627. The imine may be prepared by usual methods and also by chlorination of the amino group of an amine with N-chlorosuccinimide, and subsequent dehydrochlorination of the N-chloroamine62 8,629 (equation 43). 

Two methods for the preparation of enamides from nitriles are generally used. Reaction of ethylmagnesium bromide with a variety of aromatic nitriles in refluxing ether and subsequent treatment of the suspension of the iminomagnesium bromide with acetyl or benzoyl chloride or with a variety of esters638-640 yielded the enamides in 25-60% yield (equation 44). 

From such a viewpoint, further possibilities for the preparation of enamides seem obvious. Among them the most interesting is the application of acid derivatives such as... 

Two other syntheses that involve enamides as radical acceptors are shown in Eqs. (25) and (26). Clive has reported syntheses of the ACE inhibitors A-58365 [57] and A-58365B [58]. The latter synthesis involved preparation of enamide 89 via a short reaction sequence, followed by a triphenyltin hydride-initiated addition-... 

The transition metal catalyzed addition of amides to alkynes provides a useful approach to the preparation of enamides. In this context, Gooden and coworkers have developed efficient ruthenium catalysts, which allow the anti-Markovnikov addition of amide to terminal alkynes (Scheme 4.46) [187]. 

SCHEME 3.117 Preparation of enamides using copper salts and DMEDA [123],... 

Example 3.18 Preparation of Enamides through Cross-Coupling in Air [51]. 

An interesting approach to the preparation of enamides entailed a formal vinyl transfer from vinyl ethers (Scheme 3.122) [130]. The reaction was catalyzed by palladium complexes bearing a phenanthroline derivative as the solubilizing/stabilizing ligand. Several secondary amides including cyclic and acyclic substrates were screened, and... 

An interesting gold-catalyzed approach to the preparation of enamides has been devised starting from propargyl alcohols (Scheme 3.130) [141]. The overall process was... 

Need a reliable method for the synthesis of an enamine Need a method for the preparation of enamides from vinyl halides Can vinylboronates be converted into enamines The palladium-catalyzed cross-coupling between vinyl bromides and secondary amines would be a reasonable approach [120] An assortment of copper-catalyzed reactions are known to promote this reaction [121, 123] Using copper compounds to promote the coupling of nitrogen nucleophiles with vinylboronates would be a good starting point [51, 125]... 

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael additions, e.g. of tetralone 130 to methacrylamide, followed hy cyclization of the addition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition of the lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas < -valerolactam 134, with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69]. Whereas 10mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59 seem to be necessary for preparation of 135 [69] (Scheme 3.11). 

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]. 

The double-Heck-approach can also be employed for the preparation of novel heterocyclic compounds as 6/1-25 and 6/1-26 (Scheme 6/1.4) [24]. Thus, the palladium-catalyzed reaction of 6/1-21 and the cyclic enamide 6/1-22 gave a Oil-mixture of 6/1-23 and 6/1-24, which in a second Heck reaction using the palladacene 6/1-15 led to 6/1-25 and 6/1-26 in an overall yield of 44—49%. The synthesis can also be performed as a domino process using a mixture of Pd(OAc)2 and the palladacene 6/1-15. 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

The photocyclization of enamides to quinolines or isoquinolines has become an important reaction in the synthesis of alkaloids 219,358). It has recently been applied in the preparation of the isoquinoline alkaloid polycarpine 359). The principle of the reaction is demonstrated in the preparation of dihydroquinolines 360> (3.39) and of spirocyclohexaneisoquinoline derivatives (3.40) 361K In each case the electrocyclic ring closure product undergoes a subsequent 1,5-hydrogen shift. 

The total synthesis of ( )-yohimbine via regioselective functionalization of 18,19-dehydroyohimbinone (434) has been reported by Ninomiya et al. (231). Key intermediate 434 was prepared by enamide photocyclization of 432, fol-... 

The 1,3-dipolar cycloaddition of equimolar amounts of enamide and aryl azide at room temperature, over a period of time (3 days to 10 months), affords the A -1,2,3-triazolines (733) as stable crystalline products (Equation (63)). In refluxing ethanol, however, the reaction yields the corresponding triazoles as the major product with loss of the amides <92JOC3075>. 5-Amino-1-aryl-1,2,3-triazolines (e.g., (734)-(735)) are readily prepared from the [3 -I- 2] cycloaddition of azides to... 

Heating 4-alkyl-2-substituted-5(477)-oxazolones 287 (Rj = Me, Ph) effects elimination of CO to generate A -acylimines 288 that rearrange to the more stable enamides 289 if an acidic a-hydrogen is present (Scheme 7.94). Representative examples of enamides prepared in this manner are shown in Table 7.25 (Fig. 7.27). 

---