Exocyclic enamines

The dehydrobromination and dequaternization of l,l,3-trimethyl-2-bromomethylpyrrolidinium bromide (158) has been accomplished by dry distillation from potassium acetate (123). Since the product was isolated as the perchlorate salt, no conclusion can be drawn as to whether the original reaction mixture contained the exocyclic enamine (159) or the endocyclic enamine (160) ora mixture of both. 

Fig. 8 Diphosphine ligands 5-8 applied in the Ir-catalyzed asymmetric hydrogenation of exocyclic enamines...

Direct /3-metalation of a tetrahydropyridine has not been achieved, but as with exocyclic enamine systems (Section V,A,2), halogen-metal exchange has been performed successfully. Thus, 2-aryl-3-bromo-l-methyltetrahydropyridines have been metalated with either n-BuLi or t-BuLi, in a procedure that starts with bromination of the parent system to give an a-bromoiminium salt, which can then be deprotonated to give the desired /3-bromoenamine (Scheme 147) [77JA8356 82BSF(2)297]. If the... 

NMR data have been recorded for numerous compounds with exocyclic enamine double bonds (79JHC1335). Examples of exocyclic imine double bonds are found in furan-2,3-dione 3-oxime and a related 5-oxime the vie proton coupling constant in the former is 5 Hz and so larger than expected, perhaps because of electron release from the hydroxy oxygen atom (72JCS(P1)2527). 

Exocyclic enamines react with azides to give heterocycles (see examples in Scheme 178).234,506-509... 

The isoindolinotriazolines (Scheme 86) are exceptions when X and/or Y = CN, a mixture of an exocyclic enamine and an isoindolenium methylide is formed via a zwitterionic intermediate, which is proposed to involve a C—N rather than an N—N bond cleavage of the triazoline ring (Scheme 189).324... 

For pyrrolidine N-oxides, one might a priori anticipate iminium ion formation to occur by a syn elimination process, since the N—O and adjacent Co—bonds cannot become antiperiplanar to each other. However, the N-oxide (29a) of the steroid alkaloid conanine reacts with acetic and trifluoroacetic anhydride exclusively by the anti pathway to give the exocyclic enamine (30 Scheme 6). Release of steric strain between the C-16 methylene and the ring methyl substituent is undoubtedly a major driving force in this reaction. More revealing is the reaction of N-oxide (29b), which would give the same enamine product if a syn pathway is favored. The observed formation of compounds (31) and (32) argues in favor of the anti elimination. 

The proposed mechanism for the formation of Compound Q is not without difficulties. The tautomer 31 with the position 6 exomethylene structure (an exocyclic enamine) would be expected to have a higher free energy than its hypothetical precursor, which has a more extended conjugated 7t electron system. Moreover, if we assume that the spontaneous reaction proceeds via the same mechanism as the enzyme-catalyzed reaction, the fact that the spontaneous reaction can proceed under acidic conditions is hardly in favor of the proposed anion intermediate 31. However, a mechanism has been proposed by Beach and Plant that starts with a protonated substrate molecule. 

N-Phenyl-l,2-phenylenediamine dissolved at 50° in 1 3 70%-HC104-acetic acid, and the resulting coned, soln. treated with diacetyl l-phenyl-2,3-dimethyl-quinoxalinium perdilorate. Y 93%. - Exocyclic enamines are formed in neutral soln. F. e. s. D. Schelz and M. Priester, Helv. 58, 317 (1975). 

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Ultraviolet spectra of A-4-thiazoline-2-thione in 10 A HCl show that protonation occurs on the exocyclic sulfur rather than on the cyclic nitrogen or on the enamine-like Co-position (56). 

The pyrrolidine enamine of cyclopentanone, in which the double bond is exocyclic to two five-membered rings, shows the vinylic proton at 237 Hz (7S). 

Enamines prepared from the more basic amines are alkylated more easily and in higher yield, but yields are also affected by the ease of formation of an exocyclic double bond in the transition state (32). Thus the enamines derived... 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

More complex compounds containing enamine grouping, e.g., holarrhena alkaloids such as conkurchine and conessidine, possess an endocyclic rather than exocyclic double bond (159). On the other hand, 1 -methyl-2-alky Ipiperi-... 

An enamine provides synthon (21) and the cleavage of (20) to (17) occurs in aqueous base. Attack on the slightly strained five-ring ketone isfaster than on the exocyclic ketone. 

The initial reaction has been extended to the IH of secondary aminoalkynes to give cyclic enamines with an exocyclic C=C bond [304]. 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

An example of an N/C conjugated system involving an exocyclic carbon is the enamine conjugation in cyanine dyes, in which, the j3-carbon atom constitutes the methine bridge ([164], n = 0), or part of the bridge ([164], n = 1). Protonation of these cations occurs in... 

Heterocyclic secondary 183-type enamines (exocyclic vinylogous urethanes) show ambident bisnucleophilicity their nucleophilic reaction... 

The acetic anhydride-induced cyclodehydration of the symmetrical diamide 411, derived from the tetrahydro-benzothiophene / -amino ester 410 and diethyl malonate, afforded the thieno[2,3-r7 [h3]oxazine derivative 413 rather than the expected bis-oxazine 412 (Scheme 78). The reaction probably takes place through sequential cyclizations, in which the pyridine ring of 413 is produced by condensation of the exocyclic double bond of the enamine tautomeric form of the 1,3-oxazine moiety and the mixed anhydride formed by the carboxylic group and acetic anhydride <2003PS245>. 

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