Iminium compounds

The addition of cyanide was first examined by Kaufmann(//5-7/9), who found that aromatic iminium compounds such as quinolinium methiodide (77) added potassium cyanide to give 1,4-addition product 78. 

The use of iminium ion activation in cycloaddition reactions has some precedent with synthetic and biogenetic examples. Baum showed that acetylinic iminium compounds underwent facile [4+2] and [3+2] cycloaddition reactions and describes them to be among the best partners within these reactions" [25]. Baldwin has also proposed an iminium ion accelerated [4+2] cycloaddition in the biosynthesis of the Galbulimina type I alkaloids, highlighting the facile nature of these stoichiometric reactions [26-28],... 

Iminium compounds are reactive electrophiles toward both alkenyl and allylic silanes. Useful techniques for closing nitrogen-containing rings are based on in situ generation of iminium ions from amines and formaldehyde.77... 

In the three different approaches envisaged for the total syntheses of rhazinilam, the construction of the pyrrole ring was operated in two different manners a Knorr-type reaction in the Smith synthesis and a 1,5-electrocyclization of an allyl-iminium compound in the Sames and Magnus syntheses. 

The hydroamination of terminal alkynes with NaAuCLi was developed in 1987. In 1991, Utimoto described the preparation of tetrahydropyridines from 5-alkynylamines with Au(III) catalysts. This idea was further extended by Muller to give the corresponding iminium compounds. ... 

Coverage in this chapter is restricted to the use of alkenes or alkynes as enophiles (equation 1 X = Y = C) and to the use of ene components in which a hydrogen is transferred. Coverage in Sections 1.2 and 1.3 is restricted to ene components in which all three heavy atoms are carbon (equation 1 Z = C). Thermal intramolecular ene reactions of enols (equation 1 Z = O) with unactivated alkenes are presented in Section 1.4. Metallo-ene reactions are covered in the following chapter. Use of carbonyl compounds as enophiles, which can be considered as a subset of the Prins reaction, is covered in depth in Volume 2, Chtqiter 2.1. Addition of enophiles to vinylsilanes and allylsilanes is covered in Volume 2, Chapter 2.2, while addition of enophiles to enol ethers is covered in Volume 2, Chapters 2.3-2.S. Addition of imines and iminium compounds to alkenes is presented in Volume 2, Part 4. Use of alkenes, aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.9. Coverage of singlet oxygen, azo, nitroso, S=N, S=0, Se=N or Se=0 enophiles are excluded since these reactions do not result in the formation of a carbon-carbon bond. 

In the alkylation of lactams the equilibrium position also lies at the side of the iminium compounds (80 equation SO), so it is not surprising that 4- to 12-membered ring lactams have been methylated by dimethyl sulfate to produce the corresponding cyclic iminium salts. "... 

The alkylation of amides by alkyl halides or simple sulfonic acid esters is usually of little importance because the alkylation equilibrium is placed on the side of the starting compounds. This is not the case, however, in either the alkylation of vinylogous amides (which has been achieved even with alkyl iodides ) or if intramolecular alkylation is possible, e.g. in -(2-haloethyl)amides. In the latter case cyclic iminium compounds (81 equation 51) are readily available by replacing the more nucleophilic halide by less nucleophilic complex anions, which can be achieved by addition of Lewis acids or AgBF4. °-2 ... 

Strong Lewis acids abstract alkoxide groups from amide acetals or lactam acetals to give the corresponding iminium salts, e.g. (96 Scheme 10). Alkoxide transfer from amide acetals to less stable carb-enium ions is also a route from amide acetals to iminium compounds (97). 

Protonation of ketene 0,N-acetals with strong acids gives rise to the formation of iminium compounds, e.g. (98 equation 57). Ketene OA -acetals are transformed by alkyl halides or acyl halides to a-sub-stituted amides via unstable iminium salts (99 equation 58).Iminium compounds of this type are isol-able if they are immediately precipitated, e.g. as perchlorate salts (100 equation 59), Heterocumulenes such as isocyanates, isothiocyanates or S02 form 1,4-dipoles with ketene OA -acetals, which can be stabilized by protonation with perchloric acid to give salts, e.g. (101 equation 60). 

In alkoxymethyleneiminium salts the anions are exchangeable (Cl versus C104" or SbCU etc.). This procedure can be used to purify the iminium compounds for analytical purposes. Tetraphenylborates (105), which are easy to obtain from the iminium salt and sodium tetraphenylborate in d acetonitrile (equation 64), and which crystallize easily, are suitable reagents. The carbon skeleton of a,p-unsaturated alkoxymethyleneiminium compounds can be altered by cycloadditions, e.g. Diels-Alder reactions, to give compounds of type (106 equation 65). - °... 

A simple and efficient route to alkylmercaptomethyleneiminium salts (110 equation 67) is the action of alkyl thiochloroformates on thioamides. - - 3-Chlorovinyl ketones react with thioamides to form iminium compounds (111 equation 68), - - which can serve as precursors for 1,3-thiazinium salts. Bromine forms labile S-bromoiminium salts (112) with thioamides, - which react with en-amines to give S-vinyl-substituted salts (113 equation 69). ... 

Thioamides with bulky substituents bound to the nitrogen can be rearranged to iminium compounds (119 equation 75) by treatment with HCl, provided the bulky groups can form stable carbenium ions. - ... 

Ketene S/v -acetals are usually attacked by electrophilic reagents at the -carbon, yielding iminium salts, thus ketene 5,lV-acetals have been alkylated and acylated. Similar reactions are described with chlo-roformic acid esters, cyanuric chloride, m-nitrophenylsulfenyl chloride, 2,4-dinitrochlorobenzene, 3-chloro-2-cyanoacrylonitriles and 2-chlorovinyl phenyl ketone. Usually it is not the initially formed iminium compounds but the substituted ketene Sfl-acetals which are isolated, e.g. (120) and (121 Scheme 12). ... 

In diazophosphoryl compounds (191) electrophilic substitution occurs on treatment with bis(form-amidinium) ether salts (192) to afford the diazoarnidinium salts (193 equation 105). In the alkylation of l,3-dialkyl-S,5-dimethylhexahydropyrimidines with alkyl iodides mixtures of ammonium salts and iminium compounds (194 equation 106) result, which can be the sole products if R, and R are bulky groups. ... 

This transformation, leading to C, was plausibly interpreted as involving oxidation with iodine to an iminium compound XCVII corresponding to XCVIII. lodination of the acetyl side chain in XCVIII is followed by cyclization to C. The structure of this six-membered ketone was largely established from its NMR-spectrum. 

Morphinan derivative 58a, which was synthesized from naltrexone (1) [25, 66, 67], was dehydrated with SOCl2 in pyridine to afford the dehydrated product 60 and an abnormal rearrangement product 59 (iminium salt) (Scheme 25). The reaction mixture was separated by silica gel column chromatography with a CHCl /MeOH eluent to isolate pure iminium ion 59 in 28% yield, together with the dehydrated product 60 in 71% yield. In H NMR analysis, a vinyl proton of iminium chloride 59 was observed at 10.13 ppm this suggested that 59 was an iminium compound, not an ot-chloroamine. In contrast, when 4,5-epoxymorphinan 35 was subjected to the same reaction conditions, only the dehydrated product 61 was obtained (Scheme 25) [22]. We became interested in the abnormal stability of the iminium salt and attempted to improve its yield. A plausible mechanism for the rearrangement reaction that produced the iminium chloride 59 is shown in Scheme 26. 

Using phenobarbital-induced rabbit liver microsomes and an NADPH regenerating system, data was obtained on metabolic rates and products, cytochrome P-450 inactivation, and the effect of CN trapping on these parameters (Engelhart 1994). The methods have been described in an initial report (Sayre et al. 1991), and are not duplicated here. Synthetic procedures for the amines and iminium compounds (figure 4) are described separately. 

Osawa, Y., and Coon, M.J. Selective mechanism-based inactivation of the major phenobarbital-inducible P-450 cMochrome from rabbit liver by phencyclidine and its oxidation product, the iminium compound. DrugMetab Dispos 17(1) 7-13, 1989. 

Due to the n,n-conjugation of the amino group with the C=C double bond, the electron density is increased at the y -carbon atom as shown below by the mcsomeric formula lb. As a consequence enamines may be attacked by electrophiles (E X ) under neutral and mild conditions either at the electronegative nitrogen (as shown by the mesomeric formula la) leading often reversibly to ammonium salts (6) or at the electron-rich -carbon (as indicated by the mesomeric formula lb) leading to iminium compounds (7). The second reaction sequence shows the important course of electrophilic substitution of enamines derived from ketones (5) by selective mono-alkylation or -acylation. This leads to ketones (9) into which they are converted by hydrolysis of the intermediate iminium salt (7) or of the isolable substituted enamine (8) if is hydrogen. These electrophilic substitutions of enamines are called the Stork reaction in honour of their inventor. ... 

The ene and Prins reactions are not mechanistically distinct. Coverage will therefore be organized by the nature of the carbonyl compound, with intermolecular reactions presented first, followed by intramolecular reactions. The emphasis will be on material published since the field has been reviewed " and on examples demonstrating the stereo-, regio- and chemo-selectivity of these reactions. Coverage is restricted to the addition of carbonyl and thiocarbonyl compounds to simple alkenes. Addition of carbonyl compounds to vinylsilanes, allylsilanes and enol ethers is covered in the following chapters. Addition of imines and iminium compounds to alkenes is presented in Part 4 of this volume. Ene reactions with alkenes and alkynes as enophiles are covered in Volume 5, Chapter 1.1. Use of aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.6. 

Cycloadditions of iminium compounds with 1,3-dienes to afford Diels-Alder adducts seems to be a reaction of general applicability.46 On the other hand, simple electron-rich imino species are less reliable dienophiles. Some electron-rich imines will undergo Diels-Alder reactions under acid catalysis and thus are probably actually reacting as iminium salts. However, inverse electron demand [4 + 2] cycloadditions of neutral imines with electron-deficient dienes have been reported, as have additions to exceptionally reactive dienes (vide infra). 

Cyclic ketones with a fused aromatic ring usually form chloroenals without side reaction, as in the case of compounds 112 and heteroatom-substituted analogs such as compounds 113 (Eq. 101) 2-indanone gives the iminium compound 114 (Eq. 102). ... 

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