Iminium ion complex

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

Trapping the carbonyl compound 1 in Scheme 3.3 with various nucleophiles provides various catalytic oxidative transformations of alcohols. When a primary or secondary amine is employed as a nucleophile, intermediate 13 undergoes nucleophilic reaction with amine to give iminium ion complex 14 along with water. Intramolecular hydride transfer of 14 gives the corresponding N-alkylated amine 15 with regen-... 

Nucleophilic attack of selenolate anions on the iminium ion complex, generated... 

Todd revealed that the three-component iminium ion complex 79 is a reactive intermediate in the oxidative C-C coupling reaction between isoquinolines and DDQ, and the yields of product 78 from the indirect reaction are much higher than those from the direct reaction (Scheme 8.34). ... 

Scheme 8.34 DDQ-Mediated oxidative addition reactions between isoquinolines, or the intermediate iminium ion complex (79), and a range of nucleophiles.

Radical vs. ionic mechanisms were described as possible routes to the formation of the iminium ion complex using similar mechanisms to those we have already encountered in this chapter. The radical processes were thought to involve HAT and SET in either order, and the ionic process was thought to involve elimination of water from a nitrogen-amine coordination complex (29). A copper-catalyzed CDC reaction between Al-phenyl tetrahydroisoquinoline (THIQ) and nitromethane was found to proceed in 70% yield when BHT was added, which was taken as evidence for the ionic mechanism. 

Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below. 

The catalytic Pd complex and the aryl bromide together suggest the first step is oxidative addition of Pd(0) to the C5-Br bond. (The reduction of Pd(II) to Pd(0) can occur by coordination to the amine, p-hydride elimination to give a Pd(II)-H complex and an iminium ion, and deprotonation of Pd(IE)-H to give Pd(0).) The C10-C11 k bond can then insert into the C5-Pd bond to give the C5-C10 bond. P-Hydride elimination then gives the Cl 1-C12 n bond and a Pd(II)-H, which is deprotonated by the base to regenerate Pd(0). The overall reaction is a Heck reaction. 

The combined reaction thus involves initial formation of the iminium ion from the carbonyl compound and amine at pH 6, and this intermediate is then reduced by the complex metal hydride to give the amine. This can also he a way of making methyl-suhstituted amines via intermediate imines with formaldehyde. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

In a collection of insightful pieces of work Enders has incorporated an iminium ion conjugate addition of nitroalkanes to a,P-unsaturated aldehydes into a triple cascade reaction generating up to four contiguous stereocentres in one pot, again indicative of the complexity attainable from superficially simple catalysts and techniques [175-177] (Scheme 46). 

It is clear that, as understanding of the underlying principles of both iminium ion and enamine catalysis improves, the trae power of these cascade sequences will be fully exploited. It can be expected that introduction of subsequent independent catalytic cycles will add to the complexity and applicabihty of these processes and provide highly regulated cascades that mimic the power of enzymatic pathways. 

Although the precise mechanisms for each of these examples have yet to be determined, a pathway involving iminium ion intermediates appears reasonable. Further optimisation of the complex dual catalyst systems may well lead to a general and robust procedure that will prove of considerable use in synthesis. 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

---