Cinnam amide

Cinnamate salts and cinnamic amides react with low regioselectivity to yield mixtures of the 2- and 3-alkylated products . orflzo-Substituted aryllithium-(-)-sparteine complexes 468 add with good enantiofacial discrimination to orf/zo-substituted ferf-butyl cinnamates 467 to give 469 (equation 128) ". The ehiral additive (i ,i )-l,2-dimethoxy-1,2-diphenylethane in some cases gave improved ee values. 

Most remarkably, catalytic aminohydroxylation of cinnamate amides with sulfonamides in the absence of cinchona alkaloid ligands showed a remarkable chemoselectivity in favor of amino alcohol formation [75]. 

Lamottke was the first to execute this variant. He found that a solution of 23, saturated with acetylene gas and exposed to an excess of CpCo(C2H4)2, formed the desired target 40 in 43% yield (Scheme 16). This promising result was the starting point for the experimental efforts of one of the authors. While the process was reproducible, attempts to scale it up beyond sub-millimolar quantities, necessary for a fairly early and critically important synthetic step, led to significant decreases in yield (17-24%). The difficulty appeared to be formation of cinnamic amide 41, isolated in 50-60% yields as a mixture of cis and trans isomers.39 Minimization of this unwanted product required consideration of the [2 + 2 +2]cycloaddition mechanism. 

Thus, in tetrahydrofuran solution, indole 1093 (R =(CH2)2NHAc) was converted to tetracyclic lactam 1094 (in 46% yield as a single diastereomer) in the presence of CpCo(C2H4)2 and acetylene gas (the experiment was performed on a submillimolar scale). The primary by-products of this reaction, isolated in 20-30% yield, are the cis- and trans- (3 1) cinnamic amides 1095. Presumably, these arise from the cyclization of the terminal acetylene moiety of indole 1093 with two acetylene molecules and subsequent equilibration. Attempts to scale-up the procedure to 0.5 mmol or more of indole 1093 led to a significant decrease in yield (17-24%) of tetracycle 1094. The main product of the reaction was amide 1095, isolated in 50-60% yield as a mixture of cis- and /ra j-isomers. Utilizing the reactivity of CpCo(C2H4)2 at low temperatures to minimize cyclobutadiene formation, reaction of unsubstituted enynoylindole 1093 (R = H) with bis(trimethylsilyl)acetylene (R = TMS), which is resistant to... 

Reaction of chlorocarbonyl ketenes 126 with N-substituted cinnamic amides, resulted in mesoionic 1,3-oxazinium 4-olates 341 which can be subjected to ring-opening to afford ketenes 342 which in turn is submitted to an intramolecular criss-cross [2 - - 2] cycloaddition reaction via TS to give 3-aza-bicyclo[3.1.1]heptanetriones 343 in reasonable yields (Scheme 106) (2005JOC5859). 

Ethylenic Amides. a,/3-Unsaturated amides give satisfactory yields of urethans when treated with methanolic sodium hypochlorite." Thus, cinnamic amide gives a 70% yield of methylstyrylcarbmnate... 

Phenylacetaldehyde. An alkaline solution of sodium hypochlorite is prepared by passing 55 g. of chlorine into a mixture of 600 g. of cracked ice and a cold solution of 100 g. of sodium hydroxide (95%) in 150 cc. of water. Water is then added until the total volume of the solution is 11. (The solution is best kept in the dark until used.) To a solution of 14.7 g. (0.1 mole) of cinnamic amide (m.p. 147°) in 125 cc. of methanol is added 130 cc. of the stock solution of sodium hypochlorite. The mixture is warmed on the water bath. A thick sludge of crystals soon forms. The mixture is cooled rapidly and filtered, and the crystals are washed with dilute ethanol and with water. The yield of methyl styrylcarbamate so obtained is 13 g. (70%), m.p. 117-118°. 

C9H9ON Cinnamic amide NaOCl(CH OH) (a) Methyl styrylcarbamate (a) 70% 4la... 

The catalyst is inactive for the hydrogenation of the (isolated) benzene nucleus and so may bo used for the hydrogenation of aromatic compounds containing aldehyde, keto, carbalkoxy or amide groups to the corresponding alcohols, amines, etc., e.g., ethyl benzoate to benzyl alcohol methyl p-toluate to p-methylbenzyl alcohol ethyl cinnamate to 3 phenyl 1-propanol. 

Condensation of m-fluorobenzaldehyde with malonic acid leads to the trans cinnamic acid 96 acylation of the acid chloride with cyclopropylaminc leads to amide 97 (cinflumide), a muscle relaxant [24]. 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

In 1989, Isayama and Mukaiyama reported a related Co-catalyzed coupling reaction that employs a,b-unsaturated nitriles, amides, and esters with PhSiLb as a hydrogen source [9]. Cobalt-bis(diketonato) complex, Co(II)(dpm)2 [dpm = bis(dipivaloylmethanato)] (5mol%), exhibited high catalytic activity at 20 °C in the coupling of excess acrylonitrile and ben-zaldehyde to provide b-hydroxy nitrile 4 in 93% yield (syn anti = 50 50) (Scheme 5). N,N-Dimethylacrylamide and methyl cinnamate both reacted... 

The use of chiral amide ligands has been restricted to rhodium, where the catalyst precursor is [Rh(BH4)(amide)py2Cl2]. The work has been reviewed (10, 35) cinnamate derivatives were reduced to up to 57% ee, and hydrogenation of a carbon- nitrogen double bond in folic acid leads to tetrahydrofolic acid with high biological activity (308). 

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). 

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). 

An enormous variety of olefinic types have been found to undergo such solid-state (2 + 2) photocyclodimerizations. These include cinnamic acids (128,132) derivatives of cinnamic acids such as esters (133) and amides (134) styrene derivatives (135) stilbenes (136) aliphatic mono- (137), di- (138), and triene (139) dicarboxylic acids and derivatives 1,4-diarylbutadienes (140) and their vinylogs (141), benzylidene acetones (142) and benzylidene acetophenones (143) ... 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

A somewhat different route is used to prepare an analogue that bears additional oxygen. The sequence, in this case, starts by base-catalyzed formylation of the hydro-cinnamic acid derivative (40-1) with ethyl formate. Condensation of the product (40-2) with guanidine in this case leads to a pyrimidone (40-3), with the cyclization involving an ester-amide interchange between guanidine and the ester. Reaction of... 

EXTENSIONS AND COMMENTARY There are about twenty different synthetic routes in the literature for the preparation of MDA. Many start with piperonal, and employ it to make methylenedioxyphenylacetone or a mcthylcnedioxydihydro-cinnamic acid amide instead of the nitrostyrene. The phenylacetone can be reduced in several ways other than the cyanoborohydride method mentioned here, and the amide can be rearranged directly to MDA. And there are additional methods for the reduction of the nitrostyrene that use no lithium aluminum hydride. Also there are procedures that have safrole or isosafrole as starting points. There is even one in the underground literature that starts with sassafras root bark. In fact, it is because safrole is one of the ten essential oils that MDA can humorously be referred to as one of the Ten Essential Amphetamines. See the comments under TMA. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

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