Immonium salts

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

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... 

Important for the hydrolysis is the observation (10) that protonation of enamines with hydrogen chloride does not immediately lead to immonium salts, but in most, if not all, cases first to the formation of the corresponding enammonium ions, which afterward rearrange more or less rapidly to the more stable immonium ions [Eq. (1)] ... 

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 +... 

The ultraviolet absorption at 222-232 nm is comparable only with immonium structure (186a). No active hydrogen (Zerewitinov) was present in the immonium salts (1,186b) and no deformation vibrations of nitrogen-hydrogen linkage were detected (186a). 

Since there are two available sites for electrophilic attack in an enamine, the electrophile can add to the nitrogen atom to form an ammonium salt, or it can add to the position to form an immonium salt. 

It is noteworthy that only in the case of dehydroquinolizidine derivatives does monomethylation produce the N-alkylated product. The formation of dialkylated products can be explained by a disproportionation reaction of the monoalkylated immonium salt caused by either the basicity of the starting enamine or some base added to the reaction mixture (most often potassium carbonate) and subsequent alkylation of the monoalkylated enamine. Reinecke and Kray 113) try to explain the different behavior of zJ -dehydroquinolizidine and zJ -dehydroquinolizidine derivatives by the difference in energies of N- and C-alkylation transition states because of the presence of I strain. 

Dibenzoylperoxide oxidation of zl - -dehydroquinolizidine affords an immonium salt, which can be reduced with sodium borohydride to 1-benzoyloxyquinolizidine. Treatment of the salt with base liberates l-benzoyloxy-/l -dehydroquinolizidine (221). 

J -Dehydroquinolizidine reacts with the enantiomeric (—)- and (-l-)-menthyl chloroformates forming (—)- and (-l-)-menthoxycarbonyl- -dehydroquinolizidines. These can be reduced as such or in the form of their immonium salts with sodium borohydride to (—)- and (+)-l-menthoxy-carbonylquinolizidines, which give (+)- and (-)-lupinin, respectively, on reduction with lithium aluminum hydride (243). The optical yield of the asymmetric reduction is about 10%. 

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

Reduction of the quaternary immonium salt 161, obtained by treatment of l-methyl-2-ethylidenepyrrolidine with ethyl bromoacetate, by means of either sodium borohydride or formic acid, leads to (—)-erythro-2-(2-N-methylpyrrolidyl)butyric acid (162), in agreement with Cram s rule (196). 

Reaction of organometallic compounds with enamine salts have been successfully used for the synthesis of some natural products (256). Thus reaction of the immonium salt of 0-alkylated enamino ketone 122 with isobutyllithium affords the compound 169. 

The cyclization reaction of some substituted 1,2-dihydroisoquinolines is of interest (255). The reduction of papaverine with tin and hydrochloric acid affords the 1,2-dihydro compound in the form of immonium salt 172, which then undergoes a cyclization reaction in the acidic medium to give compound 173, called pavine (257). 

The mercuric acetate dehydrogenation of carbomethoxydihydro-cleavacine (177) yields immonium salt 178, which undergoes transannular cyclization to give a mixture of coronaridine (180, R = Et, R, = H) and dihydrocantharanthine (180, R = H, Ri = Et). The reaction is accompanied... 

Curiously, neither J -piperideine nor tetrahydroanabasine undergo aldolization in strongly acidic or strongly alkaline media the reaction occurs only at pH 2-13, when both the free base and its salt are present (295). This relation between the rate of aldolization and pH indicates that aldolization occurs by condensation of the methylene group of the immonium salt with the free base. 

The only stable monomeric form of l-methyl-.d -piperideine is as the immonium salt. 

The alkaloid sedamine has been prepared under physiological conditions too (318). Aldolization of the immonium salt 200, obtained by mercuric acetate dehydrogenation of (2S,8R)-(—)-sedamine (199), with benzoylacetic acid produces (2S,6R,8S)-(—)-8,10-diphenyllobelinol (i.e., (—)-lobeline) (201). This determines its absolute configuration (319, 320). 

Unstable chlorides were converted to stable SnCU complexes. In their IR spectra there is an intense absorption band in the 1900 cm region, which is consistent with the band of allenic system (structure C). Unlike unstable chlorides A and B, the SnCl4 complexes are stable and, when kept in an inert atmosphere, remain intact for several days. The allenic structure of the immonium salt was confirmed by studying the mercuration of the same aminobutenynes (74DIS). 

Immonium salts are sufficiently reactive to add organozinc halides in the absence of a catalyst.161 Diallylamines were used because of the ease of subsequent deallylation (see Section 3.5.2). 

Diaryl imines 109 > and immonium salts no) have been found to undergo bimolecular reduction to v/c-diamines under the appropriate experimental... 

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.

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... 

Although they are much less common, the fragmentations can also be assisted by nitrogen or sulfur substiments at the a-carbon atom. An immonium salt has to be an intermediate in the fragmentation of a-amino oximes, which on hydrolysis produce a carbonyl group (ketone or aldehyde). 

It was observed that a-amino oximes 511, when treated with sodium borohydride in boiling acetonitrile, produced the expected fragmentation products 513 in moderate to good yields (31-87%) (equation 225). The use of the hydride-induced fragmentation in cyclic oximes leads to amino nitrile compounds, as a result of the reduction of the immonium salt intermediates 512. Careful selected oxime structures showed that the reaction time increases when the stabihty of the immonium intermediate decreases, showing the importance of the mesomeric assistance. 

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]. 

Further methods [205] successfully employed to synthesize fuUeropyrroUdines include acid-catalyzed [213] or thermal [214] desilylation of trimethylsilyl amino derivatives, tautomerization of a-aminoesters of immonium salts [215] and imines [216, 217], reaction with aldehydes in the presence of aqueous ammonia [218], reaction with oxazolidinone [204] or photochemical reaction with some amino derivatives [219-223], The reaction with amino acids and aldehydes was also carried... 

Other experimental conditions can be important.84 Thus the electroreduc-tive coupling between 4-chlorobutyryl chloride and nitrosobenzene to 2-phenyltetrahydro-2H-1,2-oxazine-3-one gives low yields in DMF at room temperature. An acceptable yield is obtained in acetonitrile at room temperature, still more at - 18°C. The lower yield obtained using DMF is due mainly to a higher reactivity of the electrophile, which forms an immonium salt with DMF. 

Analogous to the electrochemical reductive alkylation of ketones,127 immonium salts may be reductively benzylated.128 This has been used in a... 

Much work has been done on the reactions of indolizidine immonium salts, which has been reviewed to some extent <78AHC(23)103). A general view may be obtained using Scheme 14, the chemistry of indolizidine itself being taken as an example. 

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