Iminium ions synthesis

Step 2 of Figure 29.11 Decarboxylation The TPP addition product, which contains an iminium ion j8 to a carboxylate anion, undergoes decarboxylation in much the same way that a jB-keto acid decarboxylates in the acetoacetic ester synthesis (Section 22.7). The C=N+ bond of the pyruvate addition product acts... 

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

Other methods for the synthesis of a-oxygenated A-alkylamides (or carbamates) include addition of oxygen nucleophiles to A-acyl (or A-alkoxycarbonyl) iminium ions, generated via either... 

Scheme 19 Asymmetric synthesis of 2-(l-aminoalkyl)pyrrolidines and 2,2 -dipyrrolidines from chiral imines and iminium ions...

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

Entries 11 to 13 are examples of iminium ion and acyliminium ion reactions. Note that in Entries 11 and 12, vinyl, rather than allylic, silane moieties are involved. Entries 14 and 15 illustrate the synthesis of (3,-y-unsaturated ketones by acylation of allylic silanes. 

Each of the unsaturated cyclic amines shown below has been synthesized by reaction of an amino-substituted allylic silane under iminium ion cyclization conditions (CH2=0, TFA). By retrosynthetic analysis, identify the appropriate precursor for each cyclization. Suggest a method of synthesis of each of the required amines. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Tropinone is a structural component of several alkaloids, including atropine. The synthesis is based on a double Mannich process with iminium ions as intermediates. The Mannich reaction in itself is a three-component domino process, which is one of the first domino reactions developed by humankind. 

Very recently, a highly efficient synthesis of the erythrina and B-homoerythrina skeleton by an AlMe3-mediated three-step domino condensation-type/iminium ion formation/iminium ion cyclization sequence has been reported by Tietze and co-... 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

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]. 

Cooke and coworkers reported on the synthesis of the amino acid N-benzyl-4-acetylproline (2-889) (Scheme 2.198) [453], as this might represent an interesting synthon for the preparation of bioactive compounds. These authors also used a domino iminium ion formation/aza-Cope/Mannich protocol. Thus, treatment of the secondary amine 2-885 with glyoxylic acid (2-888) primarily provided the corresponding iminium ion, which led to 2-889 in 64% yield as a mixture of diastereom-ers. 

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 stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

The formation of iminium ions of 20-epipandoline occurred only under Polo-novski-Potier conditions. Thus on treatment of the TV-oxide of 165 with tri-fluoroacetic anhydride followed by an aqueous solution of KCN, the iminium ion 329 was obtained, readily isolated as the corresponding a-amino nitrile 331 (Scheme 17). The reaction was completely regioselective and no traces of the enamine 332 could be obtained. This made the synthesis of spiroketone 333... 

An alternative total synthesis of ( )-deplancheine, applying stereocontrolled formation of the exocyclic double bond, has also been reported (118). The final ring closure was reached in this case by an acid-catalyzed iminium ion-vinylsi-lane cyclization (170—>7). 

An intramolecular Heck cyclization of substrate 178 was the central feature in Overman s synthesis of pyridinomorphinans [139]. Octahydroisoquinoline 178, derived from an allylsilane-iminium ion cyclization as a single stereoisomer, was cyclized under forcing conditions to afford enantiomerically pure 179, an intermediate for a (-)-morphine (180) analog. 

---