Enamides Diels-Alder reactions

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). 

Diels-Alder reaction of N-allylic enamides and lactam derivatives through iodine-mediated activation [98]... 

Asymmetric Diels-Alder reactions have been carried out to investigate the efficacy of anilide 44 and imide 45 as dienophiles. In the presence of iodine, the asymmetric Diels-Alder reaction of anilide (+)-44 shows a remarkable improvement in both reactivity and stereoselectivity (Table 5-1). Therefore, it is believed that, in the presence of I2, Diels-Alder reactions of A -al I yl ic enamides take place through an activating process involving the formation of a cationic iodocyclization intermediate. 

Ene-ynamide 14a gives cyclic enamide 15a, which gives indole derivative 16a by Diels-Alder reaction. In a similar manner, metathesis of ene-ynamide I4b, a one carbon-elongated homolog, followed by Diels-Alder reaction, affords... 

Base-induced isomerization of propargyl amide 29a gives chiral ynamide 30a, which is subjected to ring-closure metathesis to afford cyclic enamide 31a. Diels-Alder reaction of 31a with dimethyl acetylene dicarboxylate (DMAD) gives quinoline derivative 32. In a similar manner, propargyl amide 29b is converted into ynamide 30b, RCM of which gives bicyclic compounds 31b and 31b in a ratio of 1 to 1 (Scheme 10). 

Intramolecular Diels-Alder reactions have been used to considerable advantage in the development of concise synthetic approaches to lycorine (1). One such entry commenced with the enamides 126 [Ar = Ph, 4-(MeO)CeH4] (Scheme 12), which were prepared by the N-acylation of imines derived from homopiperonal with the acid chloride 125 117). Thermal unmasking of the latent diene moiety of 126 [Ar = Ph, 4-(MeO)C6H4] in refluxing xylene contain-... 

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). 

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>. 

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. 

Lycorane and Galanthane. Stork and Morgans (150,151) investigated the intramolecular Diels-Alder reaction of two types of enamides 312 and 319, in which an enamide group is positioned at the dienophile in the former (312) (150) and at the diene part in the latter (319) (151), respectively. 

Aspidospermine and Aspidospermidine. The substituted hydroindole and hydroquinoline rings, common to a diverse array of alkaloids found in nature, were synthesized by applying intramolecular Diels-Alder reaction of the endocyclic enamide as dienophile (152). 

The enamides 323 were prepared from tetrahydropyridine with 3,5-hexa-dienoyl chloride. Heating of a 1% solution of 322 in toluene resulted in the subsequential cheletropic expulsion of sulfur dioxide, followed by an intramolecular Diels-Alder reaction to give the hydroindoles 324 in 45-67% yields. Then 324a was converted to hydrolulolidine (325) and 324c to the ketolactam 326, thereby furnishing a new formal total synthesis of aspidospermine (327) (152) (Scheme 117). 

Magnus et al. (153,154) reported total synthesis of ( )-aspidospermidine (330) by applying the intramolecular Diels-Alder reaction to the enamide 329 prepared from the 2-methylindole derivative 328 (Scheme 118). 

Although they are often considered as poorer ligands than diphosphines, they lead also to very efficient and attractive enantioselective catalytic systems as exemplified here. As recent examples, diphosphinites 19 and 20 have been involved successfully in hydrogenation of olefins (mostly itaconate derivatives and enamides, up to > 99.9 % ee) ([84-89] and functionalized ketones (21) (up to 86 % ee) [90], hydrocyanation (19) [91], standard Pd-mediated allylic alkylation (20) [92] (up to 86% ee) [93], and Diels-Alder reaction between a,/l-enals and dienes (eq. (4) 99 % ee) [94]. 

Indium trichloride and indium triflate are good catalysts also for the imino Diels-Alder reactions. With 20 mol% InClj, N-benzylideneaniline reacts with cyclopentadiene to give the corresponding tetrahydroquinoline derivative (Scheme 8.104) [134]. Similar InCls-catalyzed imino Diels-Alder reachons proceed with 3,4-dihy-dro-2H-pyrane, indene [135], and cychc enamides [136]. In contrast, cyclohexen-2-one gives no phenanthridinone, but azabicyclo [2.2.2]octanone is isolated (Scheme 8.105) [137]. The reachon seems to proceed through the formahon of die-nolate ion by strong coordinahon of InCb with the enone. 

AT-Alkoxy- or iV-aryloxycarbonyl-pyridiniums can be reductively trapped as dihydro derivatives by borohydride no further reduction occurs because the immediate product is an enamide and not an enamine and therefore does notprotonate under the conditions of the reduction. The 1,2-dihydro-isomers, which can be produced essentially exclusively by reduction at -70 °C in methanol, can serve as dienes in Diels-Alder reactions. Irradiation causes conversion into 2-azabicyclo[2.2.0]hexenes removal of the carbamate and iV-alkylation gives derivatives that are synthons for unstable iV-alkyl-dihydropyridines, and convertible into the latter thermally. °... 

Cycloaddition reactions. Asymmetric induction in cycloaddition of enals is based on the formation of conjugated iminium salts with bulky prolinol derivatives. Reaction partners include enamides and cyclopentadiene. The Diels-Alder reaction (catalyst 3B) is exo-... 

Inverse electron demand Diels-Alder reactions of 3,6-bismethylthio-l,2,4,5-tetrazine with a wide range of dienophiles have been shown to give substituted 3,6-bismethylthiopyridazines (148), generally in yields of 60% to 90% (Scheme 111). The reactivity of electron-rich alkynes and alkenes shows the expected order of ynamines > enamines > ketene acetals > enamides > trimethylsilyl or alkyl enol ethers > enol acetates reaction with ynamines is complete at room temperature in one... 

Hughes et al. achieved a synthesis of amythiamicin D (121) using a biosynthesis inspired hetero Diels-Alder reaction as a key step [36]. Synthesis of the key 1-alkoxy-2-azadiene 118 was conducted by coupling of the imidate 116 and amine hydrochloride 117 and subsequent elimination of the acetate with DBU [37]. The hetero Diels-Alder reaction of the azadiene 118 and enamide 119 proceeded under microwave conditions to give the pyridine 120, which was effectively converted into the natural product 121 (Scheme 7.26). 

Aza-Diels-Alder reactions, where the nitrogen is part of the diene component, have also featured prominently this year. Fowler and co-workers, in a continuation of their studies of the formation and trapping of 1-aza-dienes generated by thermal elimination of acetic acid from hydroxamic acid derivatives, have now described an application of the reaction to the total synthesis of the quino-lizidine alkaloid (-)-deoxynupharidine (288) (Scheme 25). Reaction to give (286) and (28 ) probably proceeds via exo, chair transition states where the major product (286) is derived from the transition state which has the methyl group on the connecting chain in an equatorial position. Kametani and co-workers have reported a useful extension to their earlier work on the Intramolecular aza-Diels-Alder reaction. Cycloaddition can now be carried out under much milder conditions than those previously described by using a trialkylsilyl trifluoromethanesulphonate as catalyst. BenzoCa ]-quinolizidine (290), for example, is obtained in excellent yield from the enamide (289). ... 

As illustrated above, simple olefins and acetylenes, unactivated by electron withdrawing groups, serve well as dienophiles in the intramolecular Diels-Alder reaction. This is in contrast to the intermolecular case. Heterosub-stituted olefins can also serve as dienophiles. In addition to the two examples cited above [58, 70] the preparation and cyclization of enamides should be noted [82]. 

In 2000, Pu et al. demonstrated asymmetric hetero-Diels-Alder reaction of enamide 40 and Danishefsky s diene 39 to give compound 41 as a precursor to natural compound fumonisins (Scheme 32) [56]. The most effective ligands for this reaction were 3,3 -disilyl substituted binaphthol ligand 42, and enantioselectivity of 41 reached 78% ee. 

---