Cinnamyl amides

A rigorous examination of this scheme has not been carried out. However, preliminary tracer experiments with the labeled cinnamyl amides 156 and 157 and the related amine 158 did not result in observable incorporation into... 

Lithiated secondary cinnamyl amides (258) undergo a preferred contra-MichaeF addition of Bu"Li complexed with (—)-sparteine, in a non-polar solvent, to produce (260). Tertiary amides, which cannot be deprotonated, follow the usual Michael pathway, giving (259) (Scheme 34 and Table 5). ... 

Nucleophilic addition of (-)-sparteine-organolithium reagent complexes to secondary cinnamyl amides (261), derived from (R)- and (5)-a-methylbenzylamine, occurs in matched or mis-matched pairs, with the contra-Michael addition being the major pathway [(262) (263) < 20 80]. " ... 

A few other hydroxylamine derivatives were tested with cinnamyl diethyl phosphate as substrate (Scheme 9.30, Ar= Ph) and Cs(OH)-H20 as base [39]. The addition of a base was necessary in the case of N,0-dibenzoylhydroxylainine, whereas the reaction with N, O-dibenzylhydroxylamine proceeded without base. The corresponding amide N-benzoylbenzylamine did not undergo the reaction. 

Scheme 22 (a, b) Amination of the enantiopure alcohols 26a and 24a yields racemic cinnamyl and propargyl amides 27a and 25g. (c) Bismuth-catalyzed C-N bond cleavage makes this process reversible... 

In good agreement with previous results, both the enantio-enriched cinnamyl alcohol 26a and propargyl alcohol 24a resulted in racemic amides 27a and 25g (Scheme 22a, b). These results can be either explained by a carbocationic... 

The electron-rich oxygen atom of a secondary amide derivative of cinnamic acid can be as effective as that of a cinnamyl ether or alcohol in directing anr/-Michael additions to some amide Michael acceptors. For example, BuLi adds to the amide 51 to give a 90 10 ratio of anti-Michael Michael addition products 52 53.31 With the alkyne54 the effect is even more pronounced MeLi gives solely the anti-Michael product 55. These reactions are however very sensitive to starting material and reagent structure. 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

The cinnamyl-substituted amide 63 (R = Ph) was selected to enhance the difficult step, because resonance stabilisation in the cychsed radical 66 (R = Ph) should favour this. However, initiation with di-ferf-butyl peroxide (DTBP) or benzoyl peroxide gave low yields, probably because of slow H-atom abstraction by the delocalised radical 66. Use of lauroyl peroxide as initia-... 

Bis(4-methylphenyl)bismuth A -(4-methylphenyl)sulfonylamide 4 is obtained in moderate yield by the reaction of tris(4-methylphenyl)bismuth [A -(4-methylphenyl)sulfonyl]imide with anise alcohol or cinnamyl alcohol [96JCR(S)24]. This amide is insoluble in benzene, but soluble in chloroform, and not so sensitive to oxygen md moisture in the solid state. However, it slowly decomposes to tris(4-methylphenyl)bismuthine and a white powdery deposit when the amide is stood in CDCI3. 

Allyl and cinnamyl a-phenylthioacetates rearrange on deprotonation with lithium diisopropyl-amide at room temperature or slightly above, e.g., formation of 250. ... 

As previously described (see section 2) the solvent dependence of ESIPT in flavonols has been found to play a key role in the reactivity of the photogenerated intermediates. Porco and co-workers reported that protic solvents such as 2,2,2-trifluoroethanol (TFE) are able to promote ESIPT pathway, leading to an increase of the population of the excited phototautomers (It) 119 7hus, the irradiation of 3-hydroxyflavone derivatives in chloroform/ TFE (TFE) 70 30 mixture and in the presence of methylcynnamate resulted in an improved cycloaddition yield (up to 55%) and diasteroselectivity (up to 5 1 d.r.). Furthermore, the use of protic TFE increased the photo-tautomerization yield, allowing the use of less reactive dipolarophiles including cinnamyl thioesters, amides or nitriles.The enanthioselective synthesis of potent cytotoxic (-)-Silvestrol (37) via TADDOL derivatives-mediated [3-1-2] cycloaddition has been reported. (Scheme 10). ... 

Finally, the Eschenmoser-Claisen rearrangement has found appUcations in drug synthesis. Mulzer s synthesis of the antidepressant (J )-rolipram serves as an example (Scheme 7.36) [84]. Rearrangement of chiral cinnamyl alcohol 104 gave unsaturated amide 105 with Uttle erosion of optical purity. Ozonolysis and reduction afforded alcohol 106 and set the stage for a subsequent Mitsunobu reaction with hydrazoic acid. Reduction of the azide function followed by intramolecular transamidation gave y-lactam 107, which was converted into (R)-rolipram in two straightforward steps. 

Methyl migrates less readily than benzyl or even homologous alkyl groups do. This rule applies also to A -ylides and a-lithiated amines 346. Outpacing methyl completely, benzyl, cinnamyl, and 2-(dimethylamino)ethyl migrate exclusively to afford the rearranged lithium amides at +25 °C in 70-90% yield (Scheme 1-271). ... 

Similarly, this laboratory has recently described the synthesis of constrained peptidomimetics (118, Scheme 11.14) via intramolecular palladium-catalysed cinnamylation of a variety of amino acid side chains containing heteroatom nucleophiles (117, XH = amine, imidazole, phenol, carbo y). This procedure is remarkable for its scope and efficiency, proceeding rapidly and in high yield independent of the nature of the residues and chain length of the peptide. Further, protection of guanidine, alcohol and amide side chains was not required. These and similar templates would appear to be quite suitable for library investigations. 

---