Cinnamide

Anhalonium alkaloids, pharmacology, 160 Anhalonium spp., 154 Anhydroberberilic acid, 332 Anhydroecgonine, 97 Anhydrolupinine, 120 Anhydroxatine, 770 Anisomeles malabaTica, 779 Af-(2-p-Anisylethyl)-AT-methyl-cinnamide, 330, 631 Annona anibotay, 371 Annotinine, 752, 753, 755 Anodmine, 47 Anolobine, 317... 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

Compounds structurally distinct from NSAIDs can act as modulators of y-secretase. A patent application has disclosed a series of diarylaminothiazoles (e.g. 64) that inhibit the cellular production of A (542 with IC50 values <200nM [138]. Cinnamide compounds capable of reducing A(542 production, while simultaneously enhancing the production of A(537, have been claimed in a recent application [139]. The preferred piperidone 65, for which a process patent has been published [140], has a reported cellular A(542 IC50 = 80 nM. 

C. Topochemical Reactions in Enantiopolar Crystals Cinnamide-Cinnamic... 

N-Methyl-E-cinnamide and p-chloro- -cinnamide were consequently tested as suitable additives. Both cause cinnamide crystals to grow as thin 100 plates (Figure 4c). In the presence of the former, the TV-methyl group of the additive molecule, which invariably adopts the synplanar conformation 3a (SO), prevents formation of the dimer, thus inhibiting the attachment of additional cinnamide molecules along a. The additive p-chloro-E-cinnamide inhibits the deposition of oncoming 100 layers, due to steric hindrance induced by the bulky chlorine atom. 

Figure 3. Packing arrangement of E-cinnamide (a) view along the a axis (b) view along the b axis.

The driving force for growth of the crystal in the b direction is the energy released by formation of the NH O bonds of the ribbon motif. E-Cinnamic acid in the stable synplanar conformation 2a can replace a E-cinnamide molecule at the end of the ribbon however, at the site of the additive, the attractive NH O bond (- 6 kcal/mol) is replaced by repulsion between the adjacent oxygen lone-pair electrons of the bound additive molecule and of the oncoming cinnamide molecule (1-2 kcal/mol), which leads to an overall loss in energy of 7-8 kcal/mol at the site of the additive (Scheme 6 on page 16). 

Figure 4. Measured habits of crystals of -cinnamide (a) pure (b)- d) grown in the presence of (b) cinnamic acid, (c) p-chloro- or A-methyl-E-cinnamide, (d) a- or P-chloro-Z-cinnamide.

As predicted, the presence of cinnamic acid in solution caused cinnamide to crystallize as flat prisms with prominent 011 faces (Figure 4b). The crystal morphology was modified along c by the use of amide additives that contain a bulky Cl substituent at the a- or P-carbons of cinnamide. When replacing a substrate molecule, these additive molecules interfere with the deposition of the next Oil layers (Figure 3), yielding 011 platelike crystals (Figure 4d). 

Benzamide (43,51) crystallizes from ethanol in space group Pljc. The main features of the crystal structure (52) (Figure 5) are similar to those found in cinnamide. Hydrogen-bonded cyclic dimers are interlinked along the 5.0-A b axis to form ribbons. The ribbons are stacked along the 5.6-A a axis, in an... 

This reduction in crystal symmetry is conveniently illustrated in the systems cinnamide, benzamide, or, in general, any amide RCONH2 packing in a ribbon motif comprising centrosymmetric hydrogen-bonded dimers interlinked by translation (Scheme 16). 

An asymmetric photosynthesis may be performed inside a crystal of -cinnamide grown in the presence of E-cinnamic acid and considered in terms of the analysis presented before on the reduction of crystal symmetry (Section IV-J). We envisage the reaction as follows The amide molecules are interlinked by NH O hydrogen bonds along the b axis to form a ribbon motif. Ribbons that are related to one another across a center of inversion are enantiomeric and are labeled / and d (or / and d ) (Figure 39). Molecules of -cinnamic acid will be occluded into the d ribbon preferentially from the +b side of the crystal and into the / ribbon from the — b side. It is well documented that E-cinnamide photodimerizes in the solid state to yield the centrosymmetric dimer tnixillamide. Such a reaction takes place between close-packed amide molecules of two enantiomeric ribbons, d and lord and / (95). It has also been established that solid solutions yield the mixed dimers (Ila) and (lib) (Figure 39) (96). Therefore, we expect preferential formation of the chiral dimer 11a at the + b end of the crystal and of the enantiomeric dimer lib at the —b end of the crystal. Preliminary experimental results are in accordance with this model (97). 

Figure 39. Four ribbons of cinnamide (phenyl = ) molecules. Ribbons / and l, d and d are related by translation. Ribbons d and /, d and l make plane-to-plane contacts of 4 A across centers of symmetry. Ribbon / is above d, and ribbon d is below l. Cinnamic acid molecules (filled circles) have been introduced into the structure in the allowed sites, assuming the crystal grows from the center in the two opposite directions +b and —b. The dimers obtained at the two opposite sides are enantiomeric.

The 1,3-dipolar cycloadditions of benzonitrile oxides with tertiary cinnamides yield the 5-phenyl and 4-phenyl regioisomers in a reversal of the expected regioselectiv-ities shown with methyl cinnamate. Calculations have shown that steric factors are responsible for this reversal of regioselectivity." The 1,3-dipolar cycloadditions of benzonitrile oxide with electron-rich and electron-poor dipolarophiles are accelerated by sodium dodecyl sulfate micelles. Phenyl nitrile ylides react with electron-deficient alkenes to produce five-membered -heterocycles where measured rate constants are between 4 x 10 and 7 x 10 lmoP ... 

Only few reports deal with a para photocycloaddition as the major reaction path. Recently, however, several cinnamide derivatives like 21 were efficiently transformed into the corresponding para adducts 22 (Sch. 6) [37]. Yields higher than 90% could be achieved. The para photocycloaddition is also observed with naphthalene derivatives like 1-acetylnaphthalene 23 and captodative enamino nitriles as 24 [38]. Other captodative substituted alkenes [39] as well as the fluorinated uracil derivative 26 [40] are transformed in the same way. Especially in the cases of 21 and 23, the... 

Liu G, Huth JR, Olejniczak ET, Herdoza R, DeVries P, Lietza S, Reilly EB, Okosinski GF, Fesik SW, vonGeldern TW, Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-l/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties, J. Med. Chem., 44 1202-1210, 2001. 

Aminocycloalkyl cinnamide derivatives, (III), prepared by Beatch (3) were effective in the treatment and termination of atrial fibrillation/flutter arrhythmia events. 

In an earlier investigation by the author, cinnamide-substituted diaryl sulfides (1) were prepared as illustrated in Eq. 1 ... 

The reaction is usually carried out be heating equimolar quantities of the aldehyde and salt with excess of the anhydride for 8 hours at 170-180°. Lower temperatures are often employed when potassium acetate or trialkylamines are used as condensing agents. Continuous removal of acetic acid during the reaction was found to have no effect on the yield of cinnamic acid. Substitution of diacetimide for acetic anhydride gives cinnamide (77%). ... 

---