Iminium species

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

The electrophile 4 adds to the aromatic ring to give a cationic intermediate 5. Loss of a proton from 5 and concomitant rearomatization completes the substitution step. Subsequent hydrolysis of the iminium species 2 yields the formylated aromatic product 3. Instead of the highly toxic hydrogen cyanide, zinc cyanide can be used. The hydrogen cyanide is then generated in situ upon reaction with the hydrogen chloride. The zinc chloride, which is thereby formed, then acts as Lewis acid catalyst. 

Another mechanism has been formulated, which is based on results obtained by Knoevenagel, and which is supported by more recent investigations. It involves the formation of an intermediate iminium species 7 ... 

The carbonyl compound 1 is assumed to react first with amine 2 to give the unstable a-aminoalcohol 5 as intermediate, from which an iminium species 6 is... 

Alternatively a Mannich-like pathway may be followed (see Mannich reaction), where ammonia reacts with the aldehyde 1 to give an intermediate iminium species, that adds hydrogen cyanide to give the a-amino nitrile 2. The actual mechanistic pathway followed depends on substrate structure and reaction conditions. 

This strategy normally involves the generation of an iminium species from a tetrahydroisoquinoline and formaldehyde, followed by its Pictet-Spengler cyclization. It can be exemplified by the preparation of the berberine derivative 330 from tetrahydroisoquinoline 329 (Scheme 72) <2001JOC3495>. 

Another method of activation we considered was the use of a secondary amine to generate a more electrophilic iminium species, examples of which have been used in vinylsilane-terminated cyclization reactions, particularly by Overman and co-workers [Eq. (4.8)] [51]. In our case, the unsaturated iminium ion would be activated for... 

Kassahun K, Skordos K, McIntosh I, et al. Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic alpha,beta-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme. Chem Res Toxicol 2005 18(9) 1427-1437. 

For the biosynthetic conversion of cathenamine (76) to the 19- and 20-epi derivatives, an equilibrium should exist between the enamine and imi-nium forms of cathenamine (i.e., 76 and 97) (767). This was examined (209) with deuterium labeling studies of incorporation into tetrahydro-alstonine (75), whereupon C-21 was labeled from both the enamine and iminium forms. When the enamine form was present, a second deuterium was incorporated (presumably at C-20) on reduction with NaBD DjO. Sulfate was effective in pushing the equilibrium toward the iminium species (209). 

For determination of its configuration via a conformationally restricted cyclic derivative, A -allylamino alcohol derivative 475 was treated with tris(triphenylphosphine)rhodium(l) chloride to afford a 19 1 mixture of the C-2-epimeric tetrahydro-l,3-oxazines 476 and 477 by intramolecular trapping of the intermediate iminium species, in equilibrium with the enamine generated in the isomerization of the allyl double bond (Equation 52) <1997CC565>. 

N-Demethylation of Nicotine. Trapping of a Reactive Iminium Species with Cyanide Ion", J. Med. Chem. 1976, 1168-1169. 

Both a,p-unsaturated iminium species and enals react with 4-hydroxypyran-2-ones to give pyrano[43-h]pyranones in a formal [3+3] cycloaddition (Scheme 24) <99JOC690>. In the presence of butadienes, the malononitrile derivative 42 obtained from a 3-hydroxypyran-4-one undergoes a one-pot sequential intramolecular [S+2] pyranone - alkene cycloaddition and a Diels-Alder reaction to give the O-bridged tricyclic system 43 (Scheme 25) <99JOC966>. 

Addition to iminium species This constitutes a mild, general method for the introduction of a sulfur substituent [74JCS(P1)698]. The underlying principle is as shown in (Scheme 33). For the N-acyldehydro-amino acid system (104), /8-addition prevails under weakly acidic, neutral, or basic... 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

Another interpretation involves the formation of an intermediate iminium species as the electrophile T. Laue, A. Plagens, Named Organic Reactions, John Wiley and Sons, Inc., New York, 1998, 164-... 

Cycloadditions where the 2ir component is an inline or iminium species have been much used for the synthesis of reduced pyridines and pyridones (B-87MI505-01), see also a general review of imine cycloadditions (87H(26)777). 

Oxidation of the salt (125) with active manganese dioxide gives a high yield of thiophene-2-carbaldehyde (67G397). Amines, both primary and secondary, readily cleave the ring with expulsion of hydrogen sulfide and generation of the iminium species (128) in up to 90%... 

Dihydro-1,3-benzoxazines (196) are formed by the reaction of phenols with a mixture of formaldehyde and primary aromatic amines in the molar ratio 2 1. Presumably the phenol first reacts with the appropriate iminium species to form an intermediate amine (195), which is then cyclized in a Pictet-Spengler type reaction (Scheme 81) (44JA1875). If 2-hydroxybenzylamines are employed then methylene derivatives are obtained, and if the formaldehyde is replaced by a-dicarbonyl compounds dehydro dimers (197) are produced (Scheme 82) <70BCJ226>. 

Mechanism 2, Scheme (3), involves initial protonation at C-2 and the formation of an intermediate enabling cleavage of the C-2 - C-3 bond to give an iminium ion. Acid-induced recyclization of the iminium species gives rise to the epimerized product. 

In 1989, Cook and co-workers [29] reinvestigated the epimerization reaction in connection with reserpine (1). One of their key observations, based on the results of Martin et al. [30] and of Sakai and Ogawa [31], is that Mechanism 2 cannot be primarily responsible for the epimerization reaction of reserpine (1). Both Martin and co-workers and Sakai and Ogawa report that the iminium species 32, Fig. (7), cyclizes under acidic conditions mainly to reserpine (1) and not to isoreserpine (2). If Mechanism 2 alone were responsible for epimerization, then isoreseipine (2), not 1 should be the main product. Mechanism 2 was accordingly discredited. 

Electrochemical reduction of imines (25 Schiff bases) in acidic media proceeds via the iminium species, i.e. the protonated imine (26) (Scheme 5)29. Since 26 bears a positive charge, it is very easily reduced, so much so that the resulting neutral radical (27) is formed at a potential positive of its reduction potential. The products are therefore derived from 27 rather than the corresponding carbanion (28). This stands in contrast with the electrochemical behavior of imines in neutral media, where 27 is immediately reduced to 2830. Thus, cathodic reduction of /u. s-irnincs of 1,2-diamines (29) in DMF containing methanesulfonic acid affords tetrahydropyrazines (equation 13)31. A similar reaction can... 

Shono and others have shown that electrochemical oxidation of amides in nucleophilic media results in incorporation of the nucleophile into the alpha-position of the N-alkyl group via an intermediate iminium species (equation 36). This so-called anodic alpha-functionalization reaction has been shown to be of considerable synthetic value. The reaction has been extensively reviewed98. 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

Imidazolidinone (94.pTSA) has been developed as an enantioselective organocata-lyst for the addition of various silyloxycarbamate nucleophiles (e.g. BnOCONHOTBS, having a raised HOMO) to a range of a,/3-unsaturated aldehydes RCH=CHCH=0, affording /i-aminoaldehydes (96) (<96% ee), which can be converted into /3-amino acids (97) in two steps. The reaction proceeds via the corresponding iminium species (95) with a lowered LUMO.144... 

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