Carbocations, from amines

The first-formed carbocation from the deamination of threo-1-amino-1-phenyl-2-p-tolyl-2-propanol (26) is stabilized by resonance and longer lived than the carbocation formed from the deamination of 25. In rotamers 26b and 26c the bulky phenyl and/>-tolyl groups are next to each other, and thus again the ground state amine will be almost entirely in the conformation represented by rotamer 26a. The carbocation formed from 26a presumably has time to rotate about the... 

Nitrogen-containing compounds form an important class of N-bases due to their role in life processes. This is one of the reasons for our interest in reactions of free carbenium ions with amines [1-3]. In the course of these studies we found that, in contrast to the other N-bases, the interaction of carbocations with amines occurs via two competing channels, i.e. the formation of the condensation complex as a result of the overlap of the vacant p-orbital of the cation with the lone pair orbital of nitrogen and the proton transfer from the carbenium cation to the amine. The latter channel is very effective, due to the high proton affinities of amines. 

Strong acids produce carbocations from a variety of functional molecules. Protonation of alcohols, epoxides, carbonyl compounds, and alkenes does so. Lewis acids such as anhydrous aluminum chloride can combine with these substrates and can also remove halide ions from carbon to give carbocations. Diazotization of primary amines in acid solution is another source. 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another well-estabhshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles like proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibility with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a SnI nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMUlan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

Carbocations stabilized by functional groups can also effect 3-alkylalion of indoles. From a synthetic point of view the most important are jV.jV-dialkyl-methyleneiminium ions which can be generated under Mannich conditions from formaldehyde and secondary amines[13]. The products, 3-(A/,A-dialkyl-aminornethyl)indoles, are useful synthetic intermediates (see Chapter 12). 

Treating 5.5 g of 2-amino-4,5-dimethylthiazole HCl with 0.66 g of solid sodium hydroxide 15 min at 220°C yields 53% of 4.4. 5.5 -tetramethyT 2,2 -dithiazolylamine, whose structure w as proved by identification with the produa obtained from the reaction between dithiobiuret and 3-bromo-2-butanone (467). This result is comparable to the reaction between 2-aminopyridine and its hydrochloride to yield bis(pyridyl-2)amine (468). Gronowitz applied this reaction to 2-aminothiazole, refluxing it with its hydrochloride 4 hr in benzene and obtained the dimeric 2-aminothiazole (236). He proposed a mechanism (Scheme 143) that involves the addition of a proton to the 5-position of the ring to give 234. The carbocation formed then reacts on the 5-position of a second... 

Elimination unimolecular (El) mechanism (Section 5 17) Mechanism for elimination characterized by the slow for mation of a carbocation intermediate followed by rapid loss of a proton from the carbocation to form the alkene Enamine (Section 17 11) Product of the reaction of a second ary amine and an aldehyde or a ketone Enamines are char actenzed by the general structure... 

When double bonds are reduced by lithium in ammonia or amines, the mechanism is similar to that of the Birch reduction (15-14). ° The reduction with trifluoro-acetic acid and EtsSiH has an ionic mechanism, with H coming in from the acid and H from the silane. In accord with this mechanism, the reaction can be applied only to those alkenes that when protonated can form a tertiary carbocation or one stabilized in some other way (e.g., by a OR substitution). It has been shown, by the detection of CIDNP, that reduction of a-methylstyrene by hydridopenta-carbonylmanganese(I) HMn(CO)5 involves free-radical addition. ... 

With simple aliphatic amines, the initial diazonium cations (56) will break down extremely readily to yield carbocations (cf. p. 107) which are, for reasons that are not wholly clear, markedly more reactive than those obtained from other fission processes, e.g. RBr- R Bre. Where the prime purpose is the formation of carbocations, the nitrosation is better carried out on a derivative of the amine (to avoid formation of H20) under anhydrous conditions ... 

Moss and coworkers provided an early example of the way in which micellization can control the stereochemical course of a reaction. Deamination of chiral primary aliphatic amines in water proceeds with net inversion and extensive racemization, and the extent of racemization depends upon the lifetime of the carbocation-like intermediate. The situation changes dramatically if the salts of the primary amine can self-micellize, because now the nucleophile, typically water, is directed in from the front-side so that there is extensive retention of configuration (Moss et al., 1973). 

N8 of the azide adds to the carbocation to give an amine with an N2+ leaving group attached. Concerted 1,2-migration of C6 from C2 to N8 and expulsion of N2 gives a N-stabilized carbocation, which is reduced by NaBH4 to give the product. 

A similar mechanism can be drawn if 08 is protonated first (not shown). Cleavage of the 08-C6 bond gives a C6 carbocation to which Oil adds. After cleavage of the N1-C6 bond, H+ transfer from C7 to C3 occurs to give an enol and an iminium ion. C7 then attacks C2, and elimination of the amine follows to give the products. 

The key reaction, based on a method for removing glutamate residues in peptides, involves the conversion of the sole primary amine in the molecule to a diazo function. The most expeditious method consists of reacting (18-1) with nitrosyl chloride. The resulting diazo function in the product (18-2) can be displaced formally by oxygen from the enol form of the amide at the 7 position to form the iminolactone (18-3) the reaction may involve a spontaneous loss of nitrogen followed by capture of the resulting carbocation. Hydrolysis of the imine function in the product the leads to one of the key intermediates in this series, 7-ACA (18-4) [22]. 

There is direct evidence, from ir and nmr spectra, that the f-butyl cation is quantitatively formed when f-butyl chloride reacts with A1CI3 in anhydrous liquid HCI.246 In the case of olefins, Markovnikov s rule (p. 750) is followed. Carbocation formation is particularly easy from some reagents, because of the stability of the cations. Triphenylmethyl chloride247 and 1-chloroadamantane248 alkylate activated aromatic rings (e.g., phenols, amines) with no catalyst or solvent. Ions as stable as this are less reactive than other carbocations and often attack only active substrates. The tropylium ion, for example, alkylates anisole but not benzene.249 It was noted on p. 337 that relatively stable vinylic cations can be generated from certain vinylic compounds. These have been used to introduce vinylic groups into aryl substrates.250... 

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