Iminium ions rearrangement

The key feature of RawaTs synthetic strategy is the use of an intramolecular Diels-Alder reaction for the construction of the ABCE ring system (Scheme 7), which was previously developed for the synthesis of 19,20-dehydrotubifoline (86). First, pyrroline 66 was synthesized from 2-nitrophenylacetonitrile (62) using the Stevens strategy (87,88), which involves cyclopropanation and cyclopropyl iminium ion rearrangement [A AC]. Then, the diene moiety was assembled by... 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

The 2-azonia analog of the Cope rearrangement is estimated to be accelerated by 106, relative to the unsubstituted system.270 The product of the rearrangement is an isomeric iminium ion, which is a mild electrophile. In synthetic applications, the reaction is often designed to generate this electrophilic site in a position that can lead to a cyclization by reaction with a nucleophilic site. For example, the presence of a 4-hydroxy substituent generates an enol that can react with the iminiun ion intermediate to form a five-membered ring.271... 

Scheme 1.8. Domino cyclization/rearrangements via iminium ions.

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

A beautiful example of a domino [3+3]-sigmatropic rearrangement is the synthesis of the enantiopure antifungal antibiotic (-)-preussin (4-14) by Overman [5], which starts from the amine 4-10 and decanal to give the iminium ion 4-11 (Scheme 4.3). This undergoes a [3+3]-sigmatropic rearrangement to provide 4-12, followed by a Mannich reaction with the formation of 4-13. 

A combination of 2,3 sigmatropic rearrangement (Pummerer-type reaction) followed by an electrophilic aromatic substitution of the intermediate sulfenium ion, the formation of an iminium ion and, finally, a second electrophilic aromatic substitution, was used by Daich and coworkers for the synthesis of iso-indolo-isoquinolinones as 4-314 (Scheme 4.68) [106]. Thus, reaction of the two diastereo-meric sulfoxides 4-313, easily obtainable from 4-312 by a Grignard reaction and oxidation, led to 4-314 as a single product after crystallization in 42% yield. 

The diversity of the Ugi-MCR mainly arises from the large number of available acids and amines, which can be used in this transformation. A special case is the reaction of an aldehyde 9-26 and an isocyanide 9-28 with an a-amino acid 9-25 in a nucleophilic solvent HX 9-30 (Scheme 9.5). Again, initially an iminium ion 9-27 is formed, which leads to the a-adduct 9-29. This does not undergo a rearrangement as usual, but the solvent HX 9-30 attacks the lactone moiety. Such a process can be used for the synthesis of aminodicarboxylic acid derivatives such as 9-31 [3, 30],... 

The one-step Polonovski rearrangement by Kobayashi, which contains the reduction of a similar iminium ion, also supports this prediction. See [16]. 

The Nl-Cl 1 bond is easily made first. Cleavage of the Cl 1-012 bond gives an iminium ion that is also a l,5-(hetero)diene. The Cope rearrangement occurs to give a new iminium ion and an enol. Attack of the enol on the iminium ion (the Mannich reaction) affords the product. 

Now the stereochemistry. Assume the thermodynamically more stable iminium ion forms (Me groups cis). The Cope rearrangement occurs from a chair conformation. This puts the Ph, H2, and HI 1 all pointing up both before and after the rearrangement. Assuming the Mannich reaction occurs without a change in conformation (a reasonable assumption, considering the proximity of the nucleophilic and electrophilic centers), the Ph, H2, and HI 1 should all be cis in the product. 

However, a better known version of the 2-aza-Cope rearrangement is that carried out by using 2-aza-l,5-hexadienes 619 (equation 269) and particularly their iminium ion counterparts, usually N-acyliminium cations 620 (equation 270)365,366 (for reviews, see also Reference 367). Aza-Cope rearrangement of the norbomene ester 621 leads to tetrahydropyridine ester 622 when allowed to stand in solution at room temperature for... 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

The bromination of Az-piperideine (131) has been reported to give iminium ion (132). Treatment of this ion with triethylamine gave the bromoenamine (133), while treatment with hydroxide ion resulted in a rearrangement to give the pyrrolidine (134 Scheme 15) (76TL2437). The presence of the 2-aryl substituent undoubtedly stabilized the iminium ion facilitating these reactions. 

Overman15 discusses two conceivable mechanisms for the cyclization. One possibility assumes a direct cyclization of iminium ion 9 via p-silyl cation intermediate 24 to the indolizidinone 10. Cation 24 is stabilized by a p-effect of the silicon atom. Alternatively, iminium ion 9 might first undergo a charge-accelerated cationic aza-Co/fe rearrangement to allylsilaniminium ion 25, which would then cyclize to 10 with loss of a silyl cation. 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

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