Enamides cycloaddition

The intramolecular cycloaddition reaction of enamides has been exploited in alkaloid synthesis (81JOC3763). One successful application is provided by the total synthesis of the fused indolizidine 5 from 4 as a 1 1 mixture of epimers in 43% total yield 5 is a key intermediate in aspidosperma alkaloid synthesis (79JA3294). 

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Diels-Alder reaction of dienophiles, N-allylic enamides and a,/l-unsaturated lactam derivatives with open chain and inner ring dienes is promoted by iodine [98]. Thus the cycloaddition of N-benzyl-N-methallyl acrylamide 147 with cyclo-pentadiene (1) proceeds smoothly in DMF at —78 °C in the presence of I2 (2 eq.) to give a prevalence of endo adduct l Vd) in 88% yield (Equation 4.17). 

Oxetanes are present in several biologically active natural compounds as, for example, the taxol ring skeleton. An interesting method used to obtain this particular ring is the thermal [2 -i- 2] cycloaddition reaction. Longchar and co-workers reported a novel [2-1-2] cycloaddition of /1-formil enamides 5, often used in other cycloaddition and condensation processes, with acetylenic dienophiles 6 under microwave irradiation (in a domestic oven) to afford ox-etenes 7 in 80% yields [29]. This reaction was directed towards the synthesis of D-ring annelated heterosteroids (Scheme 2). 

Several enamines also participate in these cycloaddition reactions. For example, the addition of methyl lithium to benzaldehyde 5 and the sequential introduction of the vinylogous amide and magnesium bromide results in the cycloaddition elimination product chromene 63 (method G, Fig. 4.33).27 The introduction of methyl magnesium bromide to a solution of the benzaldehyde 5 and two equivalents of the morpholine enamine produces the cycloadduct 64 in 70% yield with better than 50 1 diastereoselectivity (method F). Less reactive enamides, such as that used by Ohwada in Fig. 4.4, however, fail to participate in these conditions. 

A formal synthesis of y-lycorane was accomplished by Vollhardt and colleagues by employing a [2 + 2 + 2] cycloaddition between enyne 589 and 568h (equation 169)344. The reaction afforded a mixture of syn and anti adducts 590 and 591 in a 80 20 ratio when the reaction was conducted at room temperature. When the reaction was conducted in refluxing 568h/THF (1 1, v/v), a syn anti ratio of 60 40 was obtained. A small amount of [2 + 2] adduct 592 was also isolated. This product became the dominant product when the enamide double bond was substituted. The additional steric hindrance probably prevented the enamide double bond from participating in the cycloaddition reaction. 

Cycloaddition of nitrones (e.g. 166, equation 107) to alkoxyaUtenes proceeds in high yield with complete diastereoselectivity, giving 1,2-isoxazolidines of type 167. Similar reactions have been reported for vinyl ethers , vinyl acetate , enamines , vinyl imidazoles , enamides, vinyl sulfones and vinyl sulfides . Since the resultant 1,2-oxazolidines of type 167 and its analogs can be hydrolyzed under acidic conditions, this reaction may also be considered as an approach to O-unsubstituted N-alkylhydroxylamines . 

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... 

Kadaba (18) reported that the intermolecular 1,3-dipolar cycloaddition of the aryl azides 79 with the enamides 78 in refluxing ethanol gave the triazoles 80 (Scheme 9.18). 

The intramolecular cycloaddition reaction of enamides has recently been exploited in alkaloid synthesis (81JOC3763). Application of A2-piperideine derivatives resulted in the... 

The use of chiral catalysts can result in asymmetric induction in [2 + 2] cycloadditions. The cycloaddition of ketene dimethyl thioacetal (44) with various enamides (43) in the presence of a chiral titanium(IV) catalyst, generated in situ, gives good yields of cyclobutanes 45 with high enantioselectivity.18... 

Methyl-3-oxidopyrazinium salt (421) undergoes 1,3-dipolar cycloaddition with a variety of dipolarophiles to give the bicyclic compounds (422) existing in enamide tautomeric form (87TL2187). 

Intramolecular [4 + 2] cycloaddition reactions of enamides have provided a route to hydroindole and hydroquinoline ring systems (80JA3294,5274). In this work, the diene portion was initially masked as a 2-substituted 2,5-dihydrothiophene 1,1-dioxide. Thus, reaction of the acid chloride (312) with 3,4,5,6-tetrahydropyridine (311) afforded the masked enamido diene (313), which was converted to the enamido diene (314) upon brief refluxing in xylene. Thermolysis of (314) afforded the hydrolulolidine (315) in 45-55% yield. Additionally, (313) could be transformed to (315) directly by passage of a 1% solution in toluene through a vertical tube (600 °C oven temperature) (Scheme 67). The method was used to prepare a known precursor to aspidospermine. 

Scheme 25 [2 + 2] Cycloaddition of steroidal formyl enamides with various alkynes...

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

This reactivity of N-acylenamines 1 has opened up new possibilities for the use of enamides. in photochemical rearrangements2 as well as in acid-catalyzed cyclizations3,4, which lead to a variety of complex nitrogen-containing heterocycles from readily available simple precursors. These reactions have also been used to form a wide variety of natural products and polyfunctional compounds. Enamides can be also used as electrophilic reagents for amidoalkylation5,6, which can occur under certain conditions as a [4 + 2] cycloaddition to form 1,3-oxazinium heterocycles7. 

The intramolecular Diels-Alder reaction promises to become widely used in the synthesis of natural products from reports of recent research (142-144). In natural alkaloid synthesis by a Diels-Alder reaction, an enamide was utilized as either a suitable dienophile or diene group. There exist numerous examples of bimolecular and intramolecular Diels-Alder reactions of enamides with various dienophiles as well as bimolecular (4 + 2) cycloadditions of enamines with electron-deficient dienes. On the other hand, there appear to be only few reports of the (4 + 2) cycloaddition reactions of enamides with unactivated dienes. 

Attempted Synthesis of Erythrina Alkaloids. During the course of investigating the intramolecular (4 + 2) cycloaddition reaction of enamides with unactivated butadiene moieties, efforts were directed toward the construction of the spirocyclic compounds (332) that possess the molecular framework characteristic to the Erythrina alkaloids (155,156). 

This is the first example of a cycloaddition reaction of enamide with unactivated butadiene (155,156) (Scheme 119). 

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

Cyclopropyl-containing carbocycles can be prepared from the initial [4 + 2] cycloadducts by an Af-acyliminium ion-enamide rearrangement. The unsaturated bicyclic lactam also undergoes 1,3-dipolar cycloadditions with azomethine ylides. Reduction of the bicyclic lactam with alane followed by hydrogenation affords enantiomerically pure 2-substituted pyrrolidines (eq 11). ... 

The incorporation of nitrogen into the enone system does not radically affect the cycloaddition reactions as seen in the (2+2)-addition reactions encountered with the enamides (48). In this study the influence of chain length on the intramolecular cyclization of the enones (48) has been evaluated. Thus with a four atom chain (48a) the product is the crossed addition compound (49a). With a six atom side chain (48b) the head-to-head adduct (50a) is formed exclusively while with a five atom chain (48c) a mixture of (49b) and (50b) is produced.The (2-f 2)-cycloadducts (51) are obtained in good yield on irradiation of the enone (52). The reaction is dependent on the nature of the substituent on C-3 and when this is H or Cl no cycloaddition reaction takes place on irradiation... 

Kametani s group (84TL4541) discovered that the intramolecular cycloaddition of 1-azadienes prepared in situ from an enamide such as 435 provided a useful tool for the construction of quinolizidines and indolizidines. Heating enamides 435 and 437 in the presence of trimethylchlorosilane, triethylamine, and zinc chloride in toluene at 170-180°C in a sealed tube gave quinolizidines... 

Later, this cycloaddition reaction was improved by the pretreatment of the enamide ester with an equimoler amount of trialkylsilyl trifluoromethanesul-fonate and triethylamine at ambient temperature. The synthesis of tyro-phorine (119) was achieved by the above improved method (Scheme 55). The enamide ester 441 was subjected to annulation using t-butyldimethylsilyl triflate and triethylamine at 15°C to produce the bicyclic lactam 442 in 68% yield. Oxidation of 442 with thallium(III) trifluoroacetate and boron triflu-oroetherate in a mixture of dichloromethane and trifluoroacetic acid at 4°C produced (83%) the pentacyclic compound 443. Hydrolysis of 443, followed by decarboxylation of the resultant acid, gave the pentacyclic lactam 444. Reduction of 444 with sodium bis(2-methoxyethoxy)aluminum hydride in refluxing dioxane afforded tyrophorine (119) (85CC1159). 

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