7,5-Unsaturated imines, formation

Scheme 52 MCRs proceeding via unsaturated imines formation...

Skraup proposed a simple mechanism involving imine formation followed by an acid-mediated cyclization. Unfortunately the observed regioselectivity is not consistent with the proposed mechanism when, for example, electron-rich aniline 4 reacts with a, 3-unsaturated aldehyde 5 to give quinoline 6. ... 

After reduction of the nitro function of the porphyrin, the porphyrinamine intermediate can be reacted with z./l-unsaturated carbonyl compounds to yield porphyrins with a fused pyridine ring, which is formed by Michael addition, imine formation and dehydrogenation. 

The reaction is assumed to occur via the formation and cyclization of a ketyl, 141, followed by the addition of a second electron and two protons, leading to an unstable a-hydroxyimine 142. Hydrolysis affords the ketol 139, while elimination of water, followed by a second reduction of the resulting a,)S-unsaturated imine and hydrolysis, leads to the ketone 140. 

Scheme 53 Mechanism of the MCRs via formation of unsaturated imines...

A few pyrolytic methods of synthesis are known, leading directly to the formation of pyridine rings by formation of the /3, y-bond. Alkylpyridines are obtained when unsaturated imines (116) or (117) are passed over heated zeolites (80IZV655) or alumina (72IZV2263). More dehydrogenation is achieved by the use of nickel or alumina, as in the synthesis of tetrahydroquinolines (118) or octahydrophenanthridine (119) (78IZV1446). 

Secondary amine reacts with aldehyde and ketone to produce enamine. An enamine is an a,P-unsaturated tertiary amine. Enamine formation is a reversihle reaction, and the mechanism is exactly the same as the mechanism for imine formation, except the last step of the reaction. 

Thus, nucleophilic attack of the nitrogen of the a, 3-unsaturated imine (21) (Scheme 6) on the electrophilic carbon atom of ketenes (2) leads to the formation of zwitterionic intermediates (22) in the (3 and 8 conformations. The thermally allowed [n4c] reaction (22(3) leads to the formation of (3-lactams (23), whereas the [n6d] electrocyclization of (228) leads to the formation of the corresponding 8-lactams (24) (Scheme 6). 

In two steps, Wang and Ganesan convert 4 first into the a,/l-unsaturated imine 6 and then, by an acyliminium Pictet-Spengler condensation, into the /i-carboline 8 (Scheme 1) [5]. The trans diastereomer was formed as a side product, and had to be separated. Treatment of 8 with NBS in aqueous acetic acid by a procedure described in 1969 by van Tamelen [6] results in the formation of the oxindoline 9 through a spiro ring-contraction. The intermediate bromonium ion is generated on the less hindered a-face, in the position opposite to the... 

The cyclocarbonylation of a,/ -unsaturated imines 54 also gave five-membered lactams 55 or 56 with or without 57 depending on the substitution patterns of the starting materials (Eq. 26) [40]. Such a useful [4+1] cycloaddition was applied to a cyclic imine 58 conjugated with a cyclohexenyl group to afford an interesting aza-tricycle 59 in 65% yield (Eq. 27). In the presence of an alkene such as ethylene, norbornene, and vinyltrimethylsilane, a similar cyclocarbonylation of a,/l-unsaturated imines 60 gave rise to a-alkylated /5,y-unsaturated lactam 61 in various yields (Eq. 28) [41,42]. Several plausible mechanisms are proposed for the formation of 61, but the elucidation of the entire mechanism calls for further work. 

Thus tryptophan synthetase, which catalyzes the addition of serine to indole via an QE.P-unsaturated imine derivative, is inactivated by QE-cyanoglycine (33). In this case, QE-cyanoglycine, an analogue of the substrate serine, undergoes Schiff base formation. Proton abstraction then occurs and the resultant QE-cyano carbanlon is apparently reprotonated to generate a reactive keteneimlne which can alkylate a nucleophilic active site residue. 

A small library of isoxazole fused azepines 39 was synthesised by the acid catalysed conjugate addition of 3,5-dimethyl-4-nitroisoxoazole 36 to a,p-unsaturated ketones 37 yielding the adduct 38 followed by tin(II) chloride reduction of the nitro group and imine formation <07ARK266>. 

Dithiol-2-imines, formation in 1,3-anionic cycloaddition reactions of a,/3-unsaturated thiolates 87UK267. 

Three-component reactions of aldehydes, amines, and allyltributyltin also proceeded smoothly in micellar systems with Sc(OTf)3 as Lewis acid catalyst, to afford the corresponding homoallylic amines in high yields (Eq. 19) [68]. Not only aromatic aldehydes but also aliphatic, unsaturated, and heterocyclic aldehydes worked well. The procedure is very simple—merely mixing an aldehyde, an amine, and allyltributyltin in the presence of Sc(OTf)3 and SDS in water no homoallylic alcohol (an adduct between an aldehyde and allyltributyltin) was produced. It was suggested that imine formation from aldehydes and amines was very fast under these conditions, and that the selective activation of imines rather than aldehydes was achieved. 

Muller and coworkers have recently developed a coupling-isomerization reaction, initially identified as a side reaction which occurred under standard Sonogashira conditions [79]. As demonstrated below, the coupling reaction is followed by a shuffling of oxidation states via an alkyne-allene isomerization [80]. The product, a,P-unsaturated ketone 146, is reminiscent of a product which would be obtained from a Heck reaction. The utility of this reaction was further demonstrated when diamine 147 was added to the reaction pot. Following a conjugate addition reaction and imine formation, compound 148 resulted from the three-component, one-pot reaction sequence enabled by the coupling-isomerization reaction. 

Jia et al. [396] have recently disclosed an example of a solid-phase application of their ytterbium] 111) triflate-mediated cyclization of glyoxylate-derived unsaturated imines. Instead of the expected imino-ene products, the authors observed the sole formation of y-lactones, in good to high yields and with good trans stereoselectivity. An explanation of both the mechanism and the observed preferred trans selectivity was presented. The importance of using the lanthanide triflate in its hydrated form in order to fadhtate a catalytic process is also in accordance with the proposed mechanism, in which water plays a role in attacking the oxonium ion intermediate. 

The observed enantiofacial selection has been interpreted in terms of lithium-coordinated complex formation between the organolithium, the imine and the chiral diether 1 (Fig. 1). The R group of the organolithium is then transferred from the favored complex to the less hindered face of the double bond of the unsaturated imine. 

Improvements to the regime for Doebner-Miller ring closures include the use of a two-phase orgaific/ aqueous acid system" to minimize alkene polymerization and the nse of indinm(ni) chloride on silica with microwave irradiation." It is sigifificant that the accepted and proved regiochemistry for these cyclisations is reversed when the reaction is carried out in trifluoroacetic acid, imine formation being the first step, at least for unsaturated 2-keto esters. "... 

The inactivation of Ala-R by trihaiogenated alanine analogues is shown in Figure 38. According to the mechanism proposed by Faraci and Walsh,the addition of the halogenated analogue leads to an initial transaldimination, followed by the elimination of the first fluoride ion and formation of the /3-difluoro-a,/3-unsaturated imine complex. The subsequent nucleophilic attack of the enzyme on the olefinic terminus induces the loss of the second fluoride ion and the formation of a stable inactive complex." ... 

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