Enamine cycloadducts, formation

One of the most widely applied cycloaddition techniques for the preparation of thietanes is the reaction of sulfenes with enamines. The stereochemistry of these reactions has been extensively investigated by Truce and Rach. Whether the mechanism is a two-step or a concerted process, both in accordance with the stereoselective formation of the cis form in Scheme 1, is still unresolved. The special orientation of the 1,4-dipolar intermediate 64, in which the charged phenyl and dimethylamino moieties are in proximity, enforces the cis geometry of the resulting thietane dioxide. In the concerted mode of reaction, formation of the orthogonal oriented unsaturated system, 65 should also yield the cis cycloadduct. 

The stereoselective or stereospecific formation of these compounds and their interaction with butyllithium was studied with the help of NMR. Paquette and Freeman first applied asymmetric induction to the synthesis of four-membered rings, especially with the sulfene-enamine 2 -F 2 cycloaddition. The in situ generation of sulfene 68 by dehydrochlorination with butyllithium of the sulfonyl chloride allowed the formation of cycloadduct 69 in 88 % yield. In a variation, the sulfene may be generated by base-induced... 

There are numerous studies on the synthesis of pyrrolizines from enam-ines. In these reactions, one of the step is the closure to a new hydrogenated pyrrole ring. In polar solvents, the reaction of enamines with dimethyl acetylenedicarboxylate follows two different pathways, the formation of cycloadducts (18) and Michael adducts (19) (81T3525). Subsequent studies of this reaction have demonstrated (by low-temperature NMR) that compounds of the type 20 are intermediates in this cyclization (83JA4775). On the basis of this information (83JA4775), the authors then studied this type of cyclization using dienamines (21). The reaction follows the scheme shown, with a [1,6] antarafacial hydrogen shift and the formation of a dipo-... 

Cycloadducts with more than six carbon atoms have been obtained by reaction of enamines of cyclic ketones (e.g. 14) with acetylenic esters such as 189 in apolar solvents. The reaction involves formation of the [2 + 2] cycloadduct 190 followed by thermal electrocyclic reaction of the cw-fused cyclobutene (see Section It has been... 

Thermolysis of 1,2,4-triazines with a side-chain terminal nitrile group leads to the formation of condensed pyrazines <89JOCl245>. This reaction involves cycloaddition of the nitrile dienophile across C-3 and C-6 of the 1,2,4-triazine followed by aromatization of the intermediate cycloadduct by extrusion of the N—N bridge. As a typical example, the 5,6-diphenyl-1,2,4-triazine (167) is fused under nitrogen at 225-235°C to form the condensed pyrazine (168) in 71% yield (Equation (21)). Intermolecular cyclization of oxadiazinones with enamines also yields condensed pyrazines. The bicyclic intermediates lose carbon dioxide to generate 1,4-diazadienes, which aromatize to the... 

Reaction of methanedisulfonyl chloride (103) with enamines in the presence of triethylamine gave an acyclic product 104 (equation 78)76. The formation of 104 is to be contrasted with the double four-membered ring cycloadduct obtained in the reaction of 103 with ketene diethyl acetal (see Section V.B.2). 

The primary cycloadduct 2 eliminates N2 in a retro-DiELS-AiDER reaction and thus affords the 3,4-dihydropyridine 3, which aromatizes to the pyridine derivative 4 by elimination of amine or alcohol. Remarkably, if in the enamine component an N-allyl group is present, the cycloreversion 2 -> 3 is followed - instead of amine elimination - by an intramolecular (4 + 2)-cycloaddition of the N-allyl-C=C-bond to the 2-azadiene unit in 3, which gives rise to formation of N-containing polycycles in high yields [322]. 

The enamine derived from styrene and morpholine reacts with CS2 to form a 1,4-dipole, which is intercepted with a second equivalent of the enamine to give the [4-f2] cycloadduct 96. Heating of 96 results in elimination of morpholine and formation of 4,6-diphenylthiopyran-2-thione 97 . 

The reactivity of isocyanates in [2+2] cycloaddition reactions is as follows alkyl < aryl < nitroaryl << arenesulfonyl < halosulfonyl. Also, the reactivity of the substrate is determined by the substituents. For example, vinyl ethers and enamines are more reactive than olefins. Often the formation of the [2+2] cycloadducts involves polar linear intermediates, which can be intercepted by the isocyanate or the substrate to form six-membered ring [2+2+2] cycloadducts (see Section 3.3.1.4). Also, diynes react with isocyanates to give six-membered ring [2+2+2] cycloadducts. In the latter reactions catalysts play an important role. From Q, ty-diynes macrocyclic adducts are obtained. 

The formation of four-membered ring cycloadducts 87 from enamines occurs better when the y3-carbon atom is fully alkylated. The rearrangement of the initial cycloadducts 87 to linear 1 1 adducts most likely involves the enol form of the jS-lactam. In Table 3.8. some of the /9-lactams obtained from enamines and isocyanates are listed. The yields are not optimized, but they are generally high. 

The cycloadduct 113 was then transformed into y,3-unsaturated cyclohexenone 114, which was subjected to intramolecular [4 + 2] cycloaddition. Upon exposure to pyrrolidine in MeOH at 60°C, enone 114 afforded intramolecular Diels-Alder adduct 116 in 78% yield after chromatography. This seemed to be the result of initial reversible iminium formation via dehydrative condensation of pyrrolidine and enone 114. Under the reaction condition, isomerization of the transient iminium species to several distinct dienamine constitutional and stereoisomeric forms would occur. Among all possible isomers in dynamic equilibration, only dienamine 115 is conducive to a favorable intramolecular Diels-Alder transition state, resulting in ketone 116 after enamine hydrolysis. The final steps of the synthesis involved Wittig methylenation followed by... 

---