P,y-Unsaturated amides

Carbonylotion of allylamines,1 This is the most effective catalyst for carbon-ylation of allylamines to give p,y-unsaturated amides, which are reducible to homo-allylic amines. 

A reaction which transforms allylic alcohols to homologous P.y-unsaturated amides by means of a 2,3-sigmatropic process was first described by BUchi. When an allyl alcohol is heated with A -di-methylformamide aceuil, a rearrangement occurs apparently involving a nucleophilic carbene as an intermediate, leading to a product with 95-100% ( )-geometry of the double bond (Scheme 47). 

Janecki, T., Bodalski, R., Wieczorek, M., and Bujacz, G., Horner-Wadsworth-Emmons olefination of nonstabilized phosphonates. A new synthetic approach to P.y-unsaturated amides, Tetrahedron, 51, 1721, 1995. 

Y-Unsaturated amides can be prepared from allylamino [1], allylphosphate [2], or allylalcohol [3] with a one-carbon atom increase. Some of these are not stereodefined, and others require the use of valuable noble metal catalysts and carbon monoxide. However, it is possible to synthesize in a stereodefined manner ( )-p,-y-unsaturated amides from -9-alkenyl-9-BBN with N,N-dialkyl(di-methylsulfuranylidene)acetamide [4] with a two-carbon increase. N,N,-Di-alkyl-a-sulfonium substituted amides are easily prepared by the reaction of dimethylsulfide and N,N-dialkyl-a-bromoacetamide [5]. The terminal -9-al-kenyl-9-BBN generated [6] in situ reacts (Scheme 11.1) with N,N-dialkyl(dimet hylsulfuranylidene)acetamide, prepared from JV,JV-dialkyl-a-sulfonium-substi-tuted amide and sodium hydroxide at 0 °C in THE The reaction mixture after oxidation with HjOj/OAc affords ( )-p,y-unsaturated amides in 60-70% yields (Table 11.1) [4], The mechanism of the reaction is depicted in Scheme 11.2. 

Transition metal complexes are used as catalysts and as reagents in the synthesis of imides. Molybdenum hexacaibonyl activates strained aziridines and allows the nucleophilic attack of carbanions. Intramolecular rearrangement and a final oxidatimi yields imides completely stereospecifically (equation 59).38> Dicobalt octacarbonyl catalyzes the conversion of P.y-unsaturated amides to imides in the presence of carbon monoxide (equation 60). ... 

P,Y-Unsaturated amides also react in accordance with the above scheme and give glutarimides. Unsaturated aUcyclic amides yield five-membered glutarimides. 

The Sasai research group found an intramolecular Heck-type approach to simple 3-pyrrolin-2-ones (Scheme 50 2010CC9064). For example, treatment of P,y-unsaturated amide 218 with palladium acetate in the presence of the isoxazoline ligand 219 and p-benzoquinone gives 3-pyrroUn-2-one 220 via a S-endo-trig cyclization. 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

Under thermal activation conditions, ester 161 reacts with benzylamine to give a mixture of a-amino-p,y-unsaturated ester 164 and amide 165, but under 1.1 GPa pressure ester 161 gives the spiro-aziridines 162 and 163 in high yield and good diastereoselectivity. These are part of an attractive class of compounds that are formed by hetero-Michael addition of amine onto the unsaturated ester 161, followed by intramolecular nucleophilic substitution of the bromine atom (Scheme 7.41). ... 

Alternatively, we surmised that the lactone 14 could be converted to Weinreb amide 40, which provided additional options for generation of the homoallylic alcohol 42. For example, through the influence of an a-alkoxy group, homoallylic alcohol 42 could be obtained by either a chelation-controlled reduction of p,y-unsaturated ketone 41 or a non-chelation-controlled allylation of 13 (Scheme 14). Thus, elaboration of lactone 35 into amide 40 began by treatment of 35 with N,0-hydroxylamine hydrochloride in the presence of trimethylaluminum to give the amide 39 in 93% yield. Further, protection of the revealed... 

Recently, Smith and coworkers developed NHC-catalysed asymmetric formal [4-1-2] cycloadditions of all larylketenes with p,y-unsaturated a-ketocarbo)ylic esters and amides. With y-aiyl substituted p,y-unsaturated... 

The reaction of a,P- or P,y-unsaturated carboxylic acids or amides with nickel(O) or palladium(O) complexes also leads to metallacycles. Thus, reactions of acrylic or methacrylic acid with Ni(COD)2 and PCyj lead to the formation of the corresponding five-membered ring derivatives 26 (Eq. 12). Similarly, reaction of a,P-unsaturated carboxylic acids with a nickel(O) complex with bidentate ligand 22 leads to complexes 27 (Eq. 13). ... 

Arylalkylketenes react with P,y-unsaturated a-ketophosphonates with chiral catalysis by N-heterocyclic carbenes giving enantioselective formation of products of formal [4 + 2] cycloaddition (Eqn (4.103)). ° These ketenes react similarly with acylcarboxylates forming the corresponding esters and amides with high enantioselectivity (Eqn (4.104)). ° A similar lactone synthesis by [4 + 2] cycloaddition is shown in Eqn (4.99), and such ketene reactions catalyzed by N-heterocycHc carbenes have been recently reviewed. 

Loh, T.P., Cao, G.Q., and Yin, Z. (1999) A new method for the synthesis of 3,Y-unsaturated amides from allylic carbonate catalyzed by palladium in the presence of carbon monoxide and amine Studies towards the total synthesis of antillatoxin. Tetrahedron Lett., 40, 2649-2652. 

In 1993, Tiecco et al. reported a similar reaction for p,y-unsaturated esters, amides or nitriles with 10 mol% of diphenyl diselenide (449) and an excess of ammonium persulfate in alcohols or water to afford the y-alkoxy or y-hydroxy a,ji-unsaturated derivatives in good yields (Table 7.32) [311],... 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

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