Michael/Pictet-Spengler reaction

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

The second procedure worth presenting involves the Michael addition of tryptophan ester (22) to pro-pynoate ester (33 R = H) to give (34 R = H), and subsequent acid-induced cyclization via the iminium salt (35 R = H Scheme 19), to afford tetrahydro-P-carboline (36 R = H), which could not be prepared by the simple Pictet-Spengler reaction with malonic hemialdehyde. Again, asymmetric induction can be achieved through the amino acid derived ester function. Extension of this procedure to... 

The Pictet-Spengler reaction has been utilised in a three-component reaction between iV-(2-aminoethyl)pyrroles, enals and keto esters (Scheme 8.29). This reaction afforded chiral pyrrolopiperazines. Vinylogous reactivity of 2-vinyl pyrrole has been utilised in the formal [2 + 2] cycloaddi-tion, which proceeds via Michael addition followed by cyclisation. ... 

Zhao and coworkers have reported an enantioselective three-component Michael addition/Pictet-Spengler reaction... 

In a transition-metal-free approach to indolo[2,3-d]quinolizines, our group has shown that the four-component reaction between tryptamines, a,p-unsaturated aldehydes, p-dicarbonyl compounds, and ethanol in the presence of cerium(IV) ammonium nitrate as a Lewis acid catalyst gives direct access to indolo[2,3-a]quinolizines 93 (Scheme 3.29) [72], On the basis of previous work on related multicomponent reactions [73], this domino transformation was proposed to comprise the initial formation of a p-enaminone by reaction between the primary amine and dicarbonyl components, its Michael addition to the unsaturated aldehyde, a hemiaminalization reaction, and a final Pictet-Spengler reaction initiated by the formation of a vinylo-gous acyliminium species. This method could also be extended to the preparation of benzo[fl]quinolizines. 

Plants of the Nitraria genus have yielded a large number of structurally unusual alkaloids [77]. Poupon has reported a very straightforward biomimetic synthesis of one of these compounds, tangutorine, that starts from compound 98, readily available from a double aldol reaction between two molecules of glutaraldehyde. Treatment of 98 with tryptamine under mildly acidic conditions directly afforded compound 100 via a Michael/Pictet-Spengler domino process, and a final reduction step afforded tangutorine 101 (Scheme 3.31) [78]. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

As initially stated, the definition of multicomponent reaction could be extended also to those reactions that implicate the addition of further reagents only after a suitable time from the very beginning of the procedure. Among others, few Chinese groups reported two notable examples of one-pot Michael addition/Pictet-Spengler cyclization sequence. In particular, in 2011, Zhao et al. developed a high enantioselective organocatalytic synthesis of several... 

In 2012, Zhao and coworkers developed an enantioselective strategy for the synthesis of spiroindolenines 94 by a Michael-hemiaminal formation/Pictet-Spengler cascade reaction [54]. The indoles 93 bearing a ketoamido group in 3-position reacted with the enals 16 in the presence of the Jprgensen-Hayashi catalyst (XXIV) to afford the corresponding spiroindolines in excellent yields and enantioselectivities but moderate diastereoselectivities (Scheme 10.33). 

Scheme 14.8 (a) Synthesis of (+)-conicol from three components, (b) Double Michael reaction/Pictet Spengler cychzation for the synthesis of inside yohimbanes. (c) Michael/Michael/Aldol-Henry polycycbzation that furnishes steroids. 

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