Enamides heterocyclic—

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

Kametani, X, Takagi, N., Kanaya, N., Honda, X, and Fukumoto, K., Studies on the syntheses of heterocyclic and natural products. Part 979 (1). Attempted asymmetric synthesis of yohimbol by photocyclization of the enamide, /. Heterocyclic Chem., 19, 1217-1219, 1982. 

The double-Heck-approach can also be employed for the preparation of novel heterocyclic compounds as 6/1-25 and 6/1-26 (Scheme 6/1.4) [24]. Thus, the palladium-catalyzed reaction of 6/1-21 and the cyclic enamide 6/1-22 gave a Oil-mixture of 6/1-23 and 6/1-24, which in a second Heck reaction using the palladacene 6/1-15 led to 6/1-25 and 6/1-26 in an overall yield of 44—49%. The synthesis can also be performed as a domino process using a mixture of Pd(OAc)2 and the palladacene 6/1-15. 

Dominguez and coworkers [41] used a twofold Heck reaction for the construction of annulated N-heterocycles such as 6/l-64a-c, starting from the enamides 6/1-63 which can be easily obtained from the corresponding amines 6/l-62a-c and o-iodo-benzoic acid chloride (Scheme 6/1.15). 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

A similar reaction of vincinal aromatic or heterocyclic diamines 104 with 2-benzoylamino-3-chloropropenoic acid 102 resulted in sprro-2-oxazolines fused to a pyrazinone nucleus 108. It is believed that the enamide 102 first isomerizes to the A-acyl imine 103 followed by Michael addition of the diamine 104. The resulting Michael adduct 105 cyclizes to 106 or 107 either of which leads to the same oxazoline 108. Single-crystal X-ray confirmed the structure of 108. Unsymmetrical diamines gave two isomeric products with the predominant product... 

Photochemistry of Carboxylic Acid Derivatives J. D. Coyle, Chem. Rev., 1978,78,97-123. Application of Enamide Photocyclization to the Synthesis of Natural Products I. Ninomiya, Heterocycles, 1974, 2, 105-123. 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

Tandem radical additions have been used in the preparation of piperidines. Substituted nitrogen containing heterocycles with ring sizes ranging from 5-8 have been synthesized by radical methods [95JCS(P1)19]. Addition of sulfur radicals to 225 occurs selectively at the enamide portion followed by an intramolecular 6-exo cyclization to produce a diastereomeric mixture of 226 in good yield. 

A three component coupling reaction of A-acetyl-2-azetine, aromatic imines and aromatic amines allows a rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines, via fused tricyclic azetidines 1 <02CC444>. Fused heterocycles 1 were formed through an aza Diels-Alder reaction between aromatic imines and A-acetyl-2-azetine, which acts as an enamide substrate. This strategy has been used for the formal synthesis of luotonin A <02TL5469>. 

Acylation of heterocyclic compounds carrying an imine grouping has been studied630-632. Although E Z isomerism is possible, the Z-isomer is usually formed exclusively633,634. A variety of other methods has been used to synthesize enamides. 

An analogous reaction carried out on a heterocyclic enamide showed a more complex feature42. In addition to the usual fragmentation a ring enlargement product was obtained (Scheme 29). 

Treatment of heterocyclic enamides with peracids resulted in the oxidative fission of the double bond, followed by Baeyer-Villiger reaction of the methoxylated benzaldehyde intermediate45 (Scheme 30). 

Some particular thia-substituted heterocyclic enamides underwent both reduction and ring fission when treated with NaBH4133 (Scheme 98). 

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 assumption that the azomethine 34 is formed by an intermolecular hydride transfer from aldehyde 30 to the nitrilium salt 31 is not confirmed because the different Schiff bases 34 obtained carry the group R which are originated from the aldehyde 30. In this way, the process described in equation 14 can be reversed and applied as an enamide synthesis by acylation of imines2,3. However, the 7V-ethylbenzonitrilium salt 35 reacts with benzaldehyde to give the more stable Af-benzoyl-7V-ethyliminium ions 3647,49 which add to trimethylethylene to form 5,6-dihydro-4i/-l,3-oxazinium salt 37. On the other hand, the reaction of ions 36 with phenylacetylene leads to another type of 1,3-oxazinium heterocycle, namely to 4i/-l,3-oxazinium hexachloroantimonate 38 (equation 15). 

Cyclic enamides 79 are formed by treatment of the 2-arylaminonicotinonitriles 75 with either anhydrous hydrogen chloride in benzene, ethanol or dioxane, or perchloric acid in glacial acetic acid, followed by the acylation of heterocycles 76 by acetic, succinic, trifluoroacetic anhydrides as well as benzoyl chloride67 (equation 28). 

Consequently, the acid-catalyzed reaction between ketones and nitriles via intermediate formation of Af-acyliminium ions and enamides provides various modes to connect the reactants as well as different ways of assembling end products, depending on the conditions and the structure of the substrate. The reaction is therefore very promising as a synthetic tool for making polyfunctional and heterocyclic compounds. 

Besides N-acylated enamines, enamides containing a functional group in the carbon skeleton are obtained in the acid-catalyzed reactions of carbonyl compounds with nitriles. Some of them were shown in equations 18, 28, 31, 33, 38, 58, 59, 63, 65, 75 and 87 and they are mainly the polyacylated enamines (e.g. /Lacylaminovinyl ketones 79, 87, 93, 200, 207 and 278). Most of them are intermediates in the synthesis of oxygen and nitrogen containing heterocycles or products of further conversions of the latter. 

Started in the late 1960s, studies on enamide photocyclization and its application to the synthesis of alkaloids have been successfully accumulated and have achieved a number of total syntheses of various types of isoquinoline and indole alkaloids and related heterocyclic compounds (11). 

In addition to the works on enamide photocyclization described in this chapter, there are some interesting reports on the mechanistic study (46,47) and also on the application of nonoxidative cyclization to the synthesis of pharmacologically active heterocyclic compounds (39,48-52). 

One of the major areas of research in enamide chemistry has been the application of enamide cyclization to the synthesis of natural alkaloids and related heterocyclic compounds. Ever since Ninomiya and co-workers discovered nonoxidative photocyclization of the A-benzoylenamine-type ena-mides in 1969 (9), several types of alkaloids have been synthesized, starting from enamides of rather simple structures, by applying enamide cyclization under both photochemical and thermal conditions. 

Successful berbine synthesis summarized in Section IV,C prompted Nin-omiya s group (25,26,117,118) to extend enamide photocyclization to har-malane, therefore giving rise to a novel and facile synthesis of polycyclic heterocycles such as the yohimbine group of compounds. Before reductive photocyclization was introduced, the use of nonoxidative photocyclization with indole alkaloids was limited to simple systems and those possessing a large degree of aromaticity. 

A solid-phase Ugi-Reissert reaction on chloroformate resin, has been reported. The product, the ot-carbamoylated isoquinoline 230, is released by oxidative cleavage (Scheme 33a). Interestingly, the enamide moiety in the adduct can be exploited to perform this process in tandem with a Povarov MCR [189, 190]. In this way, by interaction of dihydroisoquinoline 231 with aldehydes, anilines and a suitable Lewis acid catalyst, the polyheterocyclic system 232 was prepared (Scheme 33b). The Zhu group devised an innovative approach for the synthesis of this class of compounds. They employed the heterocyclic amine 233, which was oxidized in situ to the dihydroisoquinoline 234 with IBX, to undergo the classic Ugi reaction. Remarkably, all the components are chemically compatible, allowing the sequence to proceed as a true MCR (Scheme 33c) [191]. 

Stannyl ketyl radicals were generated from an amide carbonyl group and when incorporated in cinnamic enamides, indolizidinone rings can be assembled [37]. Du and Curran have shown that a-thioaminoalkyl radicals such as 24 resulting from the addition of a tris(trimethylsilyl)radical onto N-aryl thiocarbamates, thioamides or thioureas 22, can be exploited in the context of the synthesis of carbocyclic and heterocyclic fused quinolines 23 (Scheme 8) [38]. 

The hydroamination reactions which are assisted or catalyzed by transition metal species can be utilized in the cyclization of unsaturated amines. Palladium(II) is not recommended for such transformations, since low yields were obtained even using stoichiometric amounts of palladium chloride47. Since an enamide is formed by /J-hydride elimination, a reduction step must be performed to obtain the saturated nitrogen heterocycle. A catalytic cyclization reaction, analogous to the Wacker process, was performed from /V-alkenyl tosylamides, such as 1, using... 

On the other hand, unsaturated aldehydes and ketones were obtained using allylic alcohols as alkene components [68]. Similarly, allyl f-butyldimethylsilyl ether and N-allylamides gave silyl enol ethers [69] and enamides [70], respectively. The ruthenium-catalyzed alkene-alkyne coupling was successfully combined with the palladium-catalyzed intramolecular asymmetric allylic alkylation [71] to provide a novel one-pot heterocyclization method [72]. 

An efficient two-step procedure for the introduction of an acetic acid substituent into the 4-posltion of 2-methyl-l(2H)-isoquinollnone Involves reaction with ethyl diazoacetate in the presence of a copper catalyst to give a mixture of exo and endo adducts, which are then isomerlzed t g4-carboethoxymethyl-N-methyl-2(lH)-isoqulnollnog0 with ethanolic HCl. Uracil 5-acetlc acids could be prepared analogously. The cyclopropane adduct from 2-methyl-l(2H)-lsoquinolinone and dichlorocarbene can be ring-contracted to an isolndole, or ring-expanded to a benzazeplnone P The reaction of carbenes with other heterocyclic enamides has been reviewed. 

---