From Immonium Salts

Rapoport and co-workers have established that brief heating of an a-tertiary amino acid, e.g., 24, in phosphorus oxychloride leads regiospecifically to a high yield of the corresponding immonium salt (25). This salt can be 

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Under ordinary conditions, reduction of these imines in dimethylformamide is a two-electron process involving saturation of the carbon-nitrogen double bond [181] because the radical from protonation of the radical-anion is more easily reduced than the starting imine. Immonium salts with two or more phenyl substituents are reduced reversibly in acetonitrile to the radical-zwitterion such as 42. Other immo-niura salts, e.g. 43, are reduced irreversibly to the dimer [182]. Radical-zwitterion intermediates generated from immonium salts exhibit nucleophilic character on carbon. Intramolecular interaction between the reduced immonium function and a... 

Dieckmann reaction, 4, 471 Indolizidine alkaloids mass spectra, 4, 444 Indolizidine immonium salts reactions, 4, 462 Indolizi dines basicity, 4, 461 circular dichroism, 4, 450 dipole moments, 4, 450 IR spectra, 4, 449 reactivity, 4, 461 reviews, 4, 444 stereochemistry, 4, 444 synthesis, 4, 471-476 Indolizine, 1-acetoxy-synthesis, 4, 466 Indolizine, 8-acetoxy-hydrolysis, 4, 452 synthesis, 4, 466 Indolizine, I-acetyl-2-methyI-iodination, 4, 457 Indolizine, 3-acyloxy-cyclazine synthesis from, 4, 460 Indolizine, alkyl-UV spectra, 4, 449 Indolizine, amino-instability, 4, 455 synthesis, 4, 121 tautomerism, 4, 200, 452 Indolizine, 1-amino-tautomerism, 4, 38 Indolizine, 3-amino-synthesis, 4, 461, 470... 

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

Enamines derived from 1-azabicycloalkanes, readily accessible by mercuric acetate oxidation of saturated bases (112), have been extensively studied recently (113-115). Since an immonium salt is formed during dehydrogenation, the composition of the liberated enamine mixture shows the relative stability of the various possible isomers. The study of infrared and NMR spectra has shown that the position of the enamine double bond is determined by factors similar to those determining the relative stability of simple olefins. 

The immonium salts derived from 1-azabicycloalkanes have very characteristic NMR spectra (115,116), as illustrated by the spectrum of -indolizinium perchlorate. Assignments of the peaks at t = 5.85 and +... 

Fig. 9.10. Positive-ion FAB spectrum of an immonium salt. [97] The perchlorate counterion can well be identified from the first and second cluster ion. By courtesy of H. Im-gartinger. University of Heidelberg.

Azomethine ylides can be generated in situ from various readily accessible starting materials. One of the easiest approaches to produce 1,3-dipoles involves the decarboxylation of immonium salts derived from condensation of a-amino acids with aldehydes or ketones [3, 204—206]. For example, the azomethine ylide 203, obtained by decarboxylating the condensation product of N-methylglycine and paraformaldehyde in refluxing toluene, reacts with Cjq to give the N-methyl-pyrrolidine derivative 204 in 41% yield (Scheme 4.32) [204]. 

The immonium salt (98) on reaction with numerous nucleophiles yields 9-substituted indolizidines. From the reaction with benzylmagnesium chloride, (100 R = Ph) is obtained (100 R = C02Et) results from a Reformatsky reaction. Reaction of the bridgehead substituted indolizidines (100) with methyl iodide and base results in /3-elimination with ring opening, a nine-membered heterocycle (101) being formed. This type of reaction has been varied widely. 

Protonation of 3H-pyrrolizine (1) takes place at positions 2 and 5, yielding the immonium salts 193 and 194, respectively, in approximately equal amounts (see Section III,B,4). From HMO calculations, however, 193 is more stable than the cross-conjugated isomer 194.116... 

Azomethine ylides are organic 1,3-dipoles possessing a carbanion next to an im-monium ion [ 12]. Cycloadditions to dipolarophiles provide access to pyrrolidine derivatives, useful intermediates in organic synthesis with stereo- and regiochem-ical control. Azomethine ylides can be readily produced upon decarboxylation of immonium salts derived from the condensation of a-amino acids with aldehydes or ketones. When they are added to C60, a fulleropyrrolidine monoadduct is formed in which a pyrrolidine ring is fused to the junction between two six-memberedrings of afullerene [13-15].Very importantly,functionalized aldehydes lead to the formation of 2-substituted fulleropyrrolidines, whereas reaction with AT-substituted glycines leads to AT-substituted fulleropyrrolidines (Scheme 1). 

Other imino derivatives arise, as by-products or in side reactions, on heterocyclization. Thus, the treatment of cinnamoyltropolones 75 with hy-droxylamine (Scheme 19) yields, in the case of the 5-nitro derivative, the corresponding isoxazolotroponeoxime (89JHC371). The formation of oximes and several hydrazones from 3-acetyltropolone or its derivatives has also been mentioned (Section II,A,3,c). Moreover, an azine was obtained in addition to quinoxalotropone 213 (Section II,B,2,c) a tropone immonium salt was isolated after an extremely complex diene reaction of an 6-amino-2-azaazuIene (93CB441). 

In the formation of salts, addition of a proton occurs at the free electron pair of one of the mesomerie forms of the enamine. The salts are usually derived from the immonium structure. With tertiary enamines, there is a substantial difference between the free bases which possess a fixed vinylamine structure and their immonium salts. 

Though l-methyl-2-alkyl-d2-piperideines react with acids to yield only the immonium salts, a mixture of the ammonium and immonium perchlorates is obtained from piperideines unsubstituted in position 21 (Eq. 4). 

Dienamines derived from A 4-3-oxosteroids give as the final products immonium salts with a system of conjugated double bonds (40), as shown by ultraviolet spectroscopy.32... 

Similar a,a -annulations were achieved from reaction of oc,/ -unsaturated acid chlorides with cyclic ketone enamines which afforded bicyclo[3.3.1]nonane-2,9-diones41,60 65 or bicyclo[4.3.1]decanones66. In this reaction, 7V-acylation of the enamine 109 occurs as the first step giving 110, followed by a [3,3] sigmatropic rearrangement to a ketene intermediate (111). Ketene 111 subsequently cyclized via 112 to a bicyclic immonium salt (113) which after hydrolysis gave the corresponding dione 11463. If there is an axially oriented electrophilic substituent at C-4 of the enamine (for example, R = COPh) the enolate anion 115 may cyclize to an adamantane derivative 116 (equation 20). 

Cyclic immonium salts such as 205 are reduced in a nonaqueous solvent such as acetonitrile through a radical to a dimer (206).207 The reaction is analogous to pinacol formation from carbonyl compounds. 

An important advance in immonium Diels-Alder methodology has been reported by Grieco and co-workers (c/. Sections 4.2.2.3 and 4.2.2.8). The procedure consists of treating a 1,3-diene with an amine hydrochloride and an aldehyde under aqueous conditions to produce a Diels-Alder adduct, presumably via an in situ produced immonium salt. Conversion of ( , )-hexadiene to adduct (61) (Scheme 8) exemplifies the method. Waldman has recently applied the Grieco approach to various a-amino acid meAyl ester derivatives. It was found that condensation of the immonium intermediates with various cyclic and acyclic 1,3-dienes gave mixtures of diastereomers (cf. 62 and 63) ranging from 93 7 to 63 37 depending upon the particular substrates utilized. 

Radicals from reduction of derivatives of benzophenone immonium salts are rather stable under aprotic conditions, whereas less conjugated radicals dimerize at the central carbon with rates depending on the conjugation [41]. 

From an electrochemical reduction of some cyclic immonium salts of the type N-cyclohexylidenepyrrolidinium fluoborate in aprotic media, the enamine and the saturated tertiary amine were the major products [42]. It was suggested that the reaction was a one-electron transfer followed by a rate-determining radical-radical disporportionation involving hydrogen atom transfer. 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

Jasor, Y., Luche, M. J., Gaudry, M., Marquet, A. Regioselective synthesis of Mannich bases from unsymmetrical ketones and immonium salts. J. Chem. Soc., Chem. Common. 1974, 253-254. 

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