Imonium salts

The imonium salt (199), obtained from ynamines and phosgeneimonium chloVide, underwent ready reaction with monosubstituted hydrazines to give the 3,5-bis(dimethyl-amino)pyrazole (200) (68T4217, 69T3453). Similarly, the adduct (201), resulting from the addition of phosgene to ynamines, likewise reacted with sym-disubstituted hydrazines to give pyrazoles (202). With hydroxylamine derivatives the isoxazolinone (203) was obtained. 

The key step in syntheses of if/-quebrachamine (122-127) and if/-dihydro-cleavamine (12S) is the oxidation of tertiary amines with mercuric acetate to cyclic imonium salts, which give rise to an intramolecular electrophilic attack on an indole. 

The oxidation of unsymmetrical tertiary amines with mercuric acetate may also lead to isomeric enamines. In such cases, structures can often be established by NMR and IR spectra of the enamines and their corresponding imonium salts, through comparison with model systems (202-205). 

Extensions of the enamine alkylation to a-tetralones have also been used (245-248), but product yields were lower, presumably due to steric crowding in a transition state where generation of an imonium salt gives rise to a repulsion between a methylene group on nitrogen and a peri aromatic proton. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Fluorination of an enamine, enol ether, or enol acetate with CF3OF gave 60-70% yields of fluoroketone (708). Bromination of an endiamine gave the bis-imonium salt (647). 

Extension of the hydration reaction to hydrogen peroxide has shown that stable peroxides are formed from enamines and the imonium salts derived from secondary amines and ketones (506,507). 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

Similarly, a-trichloromethylamines (522) were obtained by decomposition of trichloroacetic acid in morpholine enamines, but an amide ester was formed from sodium trichloroacetate and the imonium salt of pyrrolidino-cyclohexene (523). The product is presumably derived from opening of an intermediate dichloroaziridinium salt. 

A more general aecess to the synthetie potential of aziridinium salts is found in the reactions of imonium salts with diazomethane 225,524,525, 536). 

Grignard reagents do not add directly to enamines, but their reactions with the corresponding imonium salts readily furnish tertiary amines (225,526). The reductive removal of halogen has been observed in the addition of Grignard reagents to a-bromoimonium salts (527). 

The addition of isocyanides and azide to aldehyde-derived enamines has led to tetrazoles (533,536). On the other hand the vinylogous amide of acetoacetic ester and related compounds reacted with aldehydes, isocyanides and acids to give a-acylaminoamides (534). Iminopyrrolidones and imino-thiopyrrolidones were obtained from the addition of cyclohexylisocyanide and isocyanates or isothiocyanates to enamines (535). An interesting method for the formation of organophosphorus compounds is found in the reactions of imonium salts with dialkylphosphites (536). 

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

An asymmetric synthesis has used the reduction of imonium salts to optically active tertiary amines with lithium aluminum alkoxy hydrides derived from optically active alcohols (538,539). 

Olefins are also the products of hydroboratlon of enamines, followed by treatment of the organoborane products with hot acid (543,544). The reduction of enamines with sodium borohydride and acetic acid (545) and the selective reduction of dienamines with sodium borohydride to give homo-allylic tertiary amines (138-140,225,546,547), has been applied to the synthesis of conessine (548) and other aminosteroid analogs (545,549-552). Further examples of the reduction of imonium salts by sodium borohydride can be found in the reduction of Bischler-Napieralski products, and other cyclic imonium salts (102). 

The stereochemical course of reduction of imonium salts by Grignard reagents was found to depend on the structure of the reagent 714). Hydro-boration of enamines and oxidation with hydrogen peroxide led to amino-alcohols (7/5). While aluminum hydrogen dichloride reacted with enamines to yield mostly saturated amines and some olefins on hydrolysis, aluminum hydride gave predominantly the unsaturated products 716). 

Though these alkaloids are not truly composed of two identical monomeric units, they are popularly named dimers or dimeric alkaloids. We prefer to avoid this incorrect nomenclature and would like to encourage the use of the more adequate binary terminology. In another consideration of nomenclature, we describe quaternary salts derived from an imine functionality as imonium salts, in accord with the descriptor for other onium salts (ammonium, oxonium, etc.), rather than by the frequently used iminium terminology. This nomenclature was suggested earlier (/). 

For a synthesis of leurosidine (56), 15,20-dihydrocatharanthine iV-oxide (57) was subjected to coupling with vindoline (3) under the modified Polo-novski conditions. The initial adduct, imonium salt 58, was converted to the enamine 59 in base. Oxidation of this product with osmium tetrox-ide proceeded chemo- and stereoselectively, without reaction of the... 

Table 4.45. 13C Chemical Shifts of Representative Aldimines, Ketimes [344, 345], Guanidines [349] and Comparable Imonium Salts [350, 351] (V)c in ppm).

Intramolecular addition of lithiodithiane to an acetal leads to the fnination of cyclic derivatives (equation 35). Carbonyl additions have been extended to the analogous imonium salts (R2C NR2), which furnish a-amino ketones. ... 

The relative proportions of VI and VII obtained from the intermediate salt VIII (R = H) apparently vary with the nature of the reducing agent zinc-acid systems aiford corydaline predominantly 79) while boro-hydride reduction 80) is claimed to give corydaline exclusively. Products of types VI and VII may not originate exclusively from reduction of the imonium salt since a recent investigation (5i) of the reaction of methyl iodide with dihydroberine has indicated the imonium salt corresponding to VIII (R = H) readily disproportionates to berberine and tetrahydroberberine (IX). 

The reduction of d. S-imonium salts (XXXII) of substituted quinolizidines with sodium borohydride is influenced by substituents at position 3 44). The stereochemical course of the reaction is dependent upon the more stable conformation of the imonium salt. Quasiaxial hydrogen in position 3 hinders the approach of the reducing agent on that side and there result the energetically less stable quinolizidines XXXIII. 

Dehydroalbine (XLIV), C14H18ON2 (mp 50° [a] —103° perchlorate, mp 252°), was isolated from the seeds of L. albus (53). Its imonium salt has structure XLV. Vigorous hydrogenation converts it into XLVI which is epimeric at C-11 with dihydrodesoxyangustifoline. 

The product has a low thermal stability due to the formation of the cyclic imonium salt. After standing for two days at room temperature the product has become very viscous. 

The methoxybetaine (83), on treatment with aqueous acid followed by aerial oxidation in pyridine solution, is converted into the dioxoberberine (100). This can be converted by ammonium hydroxide in chloroform into aporhoeadane (101), which can be reduced with sodium borohydride and then converted into the enol acetate (102). When the imonium salt from (100) is allowed to stand in concentrated hydrochloric acid it is converted into the ether (103). ... 

This imine is rather unstable and removal of the solvent causes immediate polymerisation. Acid reconverts it into the imonium salt. 

These results indicate that the barrier to rotation about the imine bond is lower than in simple imonium salts, and this can be attributed to the positive charge being partially located on the ring, to produce an aminotropylium ion (XXXIII), as well as on the nitrogen atom. 

Cyclopropeneimonium salts have been made by reaction of cyclo-propenones with substituted ammonium salts [156] or of ethoxycyclo-propenium salts with amines [157]. Evidence that the positive charge is not located solely on the nitrogen atom as in [VA) but is shared with the cyclopropene ring as in (VB] comes from variable temperaturen.m.r. studies, which show that rotation about the carbon-nitrogen double bond is easier than in acyclic imonium salts [156]. 

Whereas the chemistry of formaldehyde, the unstable formyl chloride, phosgene, and their imines is well developed, the corresponding imonium salts, i.e. the di-chloromethyleneammonium salts ( phosgeneiminium salts ) 1767, were almost... 

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