Carbonium ions cyclization

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

When dihydromyrcene is treated with formic acid at higher temperatures (50°C) than that required to produce dihydromyrcenol and its formate, an unexpected rearrangement occurs to produce a,3,3-trimethylcyclohexane methanol and its formate (106). The product is formed by cyclization of dihydromyrcene to the cycloheptyl carbonium ion, which rearranges to give the more stable cyclohexyl compound (107). The formate ester, a,3,3-trimethylcyclohexane methanol formate [25225-08-5] (57) is a commercially avaUable product known as Aphermate. 

In this reaction, three steps, ie, acylation, cyclization, and replacement of the chlorine atom by the hydroxyl group, take place simultaneously in concentrated sulfuric acid. In the course of cyclization 2,7-dichlorofluoran (31) may be formed as a by-product presumably through the carbonium ion (30) ihustrated as follows. The addition of boric acid suppresses this pathway and promotes the regular cyclization to form the anthraquinone stmcture. The stable boric acid ester formed also enables the complete replacement of chlorine atoms by the hydroxyl group. Hydrolysis of the boric acid ester of quinizarin is carried out by heating in dilute sulfuric acid. The purity of quinizarin thus obtained is around 90%. Highly pure product can be obtained by sublimation. 

This method is suitable only for the preparation of 4-substituted and/or 3,4-disubstituted derivatives, the substituents being only alkyl, aryl or heteroaryl groups. The presence of electron-withdrawing groups in the unsaturated side chain prevents the cyclization step. This is understandable if the influence of such groups on the stability of the intermediate carbonium ion is considered. Of more limited application is the analogous cyclization of diazotized o-aminophenylpropiolic acids, the reaction being referred to as the Richter synthesis (Scheme 70). A related synthesis (also referred to as the Neber-Bossel synthesis)... 

The acyl residue controls the formation and stability of the carbonium ion. If the carbonium ion is destabilized (by electron withdrawing groups), then cyclization to the phenanthridine nucleus will be sluggish. The slower the rate of cyclization, the greater the chance of side reactions with the cyclization reagent. Therefore, the yield of the phenanthridine will depend on the relative rates of cyclization and side reactions, which is controlled by the stability of the carbonium ion. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

The few exceptions to this general rule arise when the a-carbon carries a substituent that can stabilize carbonium-ion development well, such as oxygen or sulphur. For example, 1-trimethylsilyl trimethylsilyl enol ethers give products (72) derived from electrophilic attack at the /J-carbon, and the vinylsilane (1) reacts with a/3-unsaturated acid chlorides in a Nazarov cyclization (13) to give cyclopentenones such as (2) the isomeric vinylsilane (3), in which the directing effects are additive, gives the cyclopentenone (4) ... 

Base-catalyzed condensation between phenylacetic acid and phthalic acid produces enol lactone 78, which is reduced to benzoate 79 with HI and phosphorous. Friedel-Crafts cyclization by polyphosphoric acid followed by reduction produces alcohol 80. This alcohol forms ethers exceedingly easily, probably via the carbonium ion. Treatment with N-methyl-4— piperidinol in the presence 6f acid leads to the antidepressant hepzidine (81). 

As noted previously, a wide variety of aromatic systems serve as nuclei for arylacetic acid antiinflammatory agents. It is thus to be expected that fused heterocycles can also serve the same function. Synthesis of one such agent (64) begins with condensation of indole-3-ethanol (60) with ethyl 3-oxo-caproate (61) in the presence of tosic acid, leading directly to the pyranoindole 63. The reaction may be rationalized by assuming formation of hemiketal 62, as the first step. Cyclization of the carbonium ion... 

Sometimes acylium ions lose carbon monoxide to generate an ordinary carbonium ion. It will be recalled that free acyl radicals exhibit similar behavior at high temperatures. Whether or not the loss of carbon monoxide takes place seems to depend on the stability of the resulting carbonium ion and on the speed with which the acylium ion is removed by competing reactions. Thus no decarbonylation is observed in Friedel-Crafts reactions of benzoyl chloride, the phenyl cation being rather unstable. But attempts to make pivaloyl benzene by the Friedel-Crafts reaction produce tert-butyl benzene instead. With compound XLIV cyclization competes with decarbonylation, but this competition is not successful in the case of compound XLV in which the ring is deactivated.263... 

The use of N-trifluoroacetyl in place of the piotonated N-methyl function in these oxidative cyclization reactions has been explored. Generally these substrates lead to products of the O-methylflavinanthine type. In one instance, the delocalised carbonium ion intermediate 34 was found to undergo a competitive rearrangement when lack of a nucleophile in solution led to a slow demethylation step [137],... 

Reaction of the ierf-butyl carbonium ion with octene (ethylene tetramer), for example, will produce isobutane and an unsaturated carbonium ion which may form a diene by loss of a proton or which may cyclize to yield an ethylcyclohexyl carbonium ion ... 

Formation of aromatic compounds involves either the dehydrogenation (by way of reaction with carbonium ions) of the cyclohexane compounds or, less likely, the cyclization of a triolefinic carbonium ion. 

The alkylating agents have in common that, through intramolecular cyclization to form an ethylenei-minium ion, they become strong electrophiles which may directly or via formation of a carbonium ion intermediate transfer of an alkyl group to cellular target molecules. These reactions result in the... 

The carbonium ion 97 would lead to the N-acylglycosylamine (102), usually produced in low yield, by cyclization through attack (101) by a lone electron-pair of a hydroxyl group conveniently located in the chain (see Scheme 2). N-Acylglycosylamines (102) are not precursors... 

When the chromene has a side chain with a double bond in a suitable position, acids induce an intramolecular cyclization. Thus for gainbogic acid74 and cannabichromene211,263 the simplest product (68) comes from attack of the olefin on the benzylic carbonium ion [Eq. (21)]. 

Neither C5- nor C6-cyclization involve carbonium-ion intermediates over platinum metal. The rates of the -propylbenzene - indan reaction (where the new bond is formed between a primary carbon atom and the aromatic ring) and the n-butylbenzene- 1-methylindan reaction (which involves a secondary carbon atom) are quite similar (13). Furthermore, comparison of the C6-cyclization rates of -butylbenzene and n-pentylbenzene (forming naphthalene and methylnaphthalene, respectively) over platinum-on-silica catalyst shows that in this reaction a primary carbon has higher reactivity than a secondary carbon (Table IV) (29). Lester postulated that platinum acts as a weak Lewis acid for adsorbed cyclopentenes, creating electron-deficient species that can rearrange like carbonium ions (55). The relative cyclization rates discussed above strongly contradict Lester s cyclization mechanism for platinum metal. 

The stability of the intermediate carbonium ion determines whether cyclization forms five- or six-membered rings. In the case of n-butylbenzene and 2-phenylpentane, acid-catalyzed six-ring cyclization would involve very unstable primary carbonium ions C6H5-CH2-CH2-CH2-CH2+ or C6H5-CH(CH3)-CH2-CH2-CH2 +. Therefore, only five-membered rings could be formed in acid-catalyzed cyclization from these two hydrocarbons. 

On the other hand, the n-pentylbenzene - methylnaphthalene reaction proceeds through C6H5-CH2-CH2-CH2-C+H-CH3, a secondary carbonium ion. As a consequence, acid-catalyzed cyclization produces both five- and six-membered rings. The possible carbonium ion intermediates leading to five- or six-membered ring closure may have similar structures (e.g., both are secondary carbonium ions, as in the case of n-pentylbenzene). If so, acid-catalyzed cyclization favors six-membered ring products, as shown by the k5/k6 ratios (Table IV). 

Treatment of polyolefinic ketal 230 with stannic chloride in pentane gave a mixture (30% yield) of about equal amounts of the two racemic D-homoster-oidal tetracyclic isomers 231 (88). In this cyclization, the first cationic intermediate is not chiral and the two faces of the 5,6-double-bond can react with equal facility with the carbonium ion as a consequence, the product obtained (231) is necessarily racemic. The conversion of the open-chain tetraenic acetal 230 having no chiral centers into a tetracyclic system having seven such centers and producing only two (231) out of a possible 64 racemates is a striking tribute to the power of stereoelectronic effects. 

Once the carbonium ions are formed, the modes of interaction constitute an important means by which product formation occurs during catalytic cracking. For example, isomerization either by hydride ion shift or by methyl group shift, both of which occur readily. The trend is for stabilization of the carbonium ion by movement of the charged carbon atom toward the center of the molecule, which accounts for the isomerization of a-olefins to internal olefins when carbonium ions are produced. Cyclization can occur by internal addition of a carbonium ion to a double bond which, by continuation of the sequence, can result in aromatization of the cyclic carbonium ion. 

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