Nucleophilic dealkylation

A-Alkoxypyridinium salts can be nucleophilically dealkylated to give back the A-oxide. Hydroxide attack at the ring a-position can lead to ring opening of the carbinolamine derivative formed. Nucleophilic removal of a proton from the A-alkoxy side chain a-carbon results in elimination of the parent heterocycle and formation of an aldehyde, e.g. Scheme 112. 

Racemic hydroxy ester 225 was converted, via a Sharpless kinetic resolution, to the enantiomerically pure epoxide 226. This epoxide was then converted to the diol "/-lactone by intramolecular attack of the ester, assisted by nucleophilic dealkylation with iodide ion. Deprotonation and methylation anti to the alkoxide followed by acetonide formation afforded 227 in 56% yield. Dibal reduction, protection of the resulting aldehyde as the terminal olefin, silylation of the tertiary alcohol, and liberation of the aldehyde via ozonolysis provided a 45% yield of the C-9 to C-15 fragment 228. 

On the other hand, when the Arbuzov reactions of aroyl (/ -nitrobenzoyl, benzoyl, p-chlorobenzoyl or / -toluoyl) chlorides were carried out in the presence of proton sources (i.e. excess of a carboxylic acid), phosphate phosphonates were obtained as shown in equation 19 The formation of these resulted from protonation of the initially formed carbanion, to form a phosphonate trialkoxyphosphonium ion, followed by nucleophilic dealkylation of the trialkoxyphosphonium moiety. Indeed, the formation of carboxylate esters as additional products was noted in these reactions. The type of products shown in this reaction show characteristic resonances in the NMR spectrum in the ranges 0.8-1.25 and 16-17 ppm with /pp = 29 Hz. Analogous results were observed in the reaction of 2-pyridoyl chloride with triethyl phosphite. ... 

The acidic character of the hydrogen atoms of C-methyl groups linked to the pyrazolium ring (Figure 22 Section 4.04.2.1.1(11)) facilitates a number of reactions difficult to carry out with neutral pyrazoles. Since efficient methods of dealkylation have been described (Section 4.04.2.3.lO(ii)), the synthesis via the pyrazolium salt is a useful alternative. The same behaviour is observed for indazolium salts, for example, nucleophilic addition to aromatic aldehydes (78JOC1233). 

S-Alkylthiiranium salts, e.g. (46), may be desulfurized by fluoride, chloride, bromide or iodide ions (Scheme 62) (78CC630). With chloride and bromide ion considerable dealkylation of (46) occurs. In salts less hindered than (46) nucleophilic attack on a ring carbon atom is common. When (46) is treated with bromide ion, only an 18% yield of alkene is obtained (compared to 100% with iodide ion), but the yield is quantitative if the methanesulfenyl bromide is removed by reaction with cyclohexene. Iodide ion has been used most generally. Sulfuranes may be intermediates, although in only one case was NMR evidence observed. Theoretical calculations favor a sulfurane structure (e.g. 17) in the gas phase, but polar solvents are likely to favor the thiiranium salt structure. 

Pyrimidine, I-alkyl-2-methyltetrahydro-C-thioacylation, 4, 807 Pyrimidine, 4-alkylsulfinyl-nucleophilie displaeement reaetions, 3, 97 Pyrimidine, 6-alkylsulfinyl-nucleophilic displacement reactions, 3, 97 Pyrimidine, 2-alkylsulfonyl-nueleophilie displaeement reactions, 3, 97 Pyrimidine, 4-alkylsulfonyl-nucleophilic displacement reactions, 3, 97 Pyrimidine, 6-alkylsulfonyl-nucleophilie displaeement reactions, 3, 97 Pyrimidine, alkylthio-dealkylation, 3, 95 desulfurization, 3, 95 oxidation, 3, 96 synthesis, 3, 135, 136 Pyrimidine, 2-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Prineipal Synthesis, 3, 136 Pyrimidine, 4-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Pyrimidine, 6-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Pyrimidine, 4-allenyloxy-rearrangement, 3, 93 Pyrimidine, 4-allyloxy-2-phenyl-rearrangement, 3, 93 Pyrimidine, 4-allynyloxy-rearrangement, 3, 93 Pyrimidine, 4-anilino-2,5,6-trifluoro-NMR, 3, 63 Pyrimidine, 2-aryl-pyrroleaeetic aeid from, 4, 152 Pyrimidine, arylazo-synthesis, 3, 131 Pyrimidine, 4-arylazo-reduetion, 3, 88... 

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

Dealkylation of labile disulfonium dications 75 derived from 2,2 -bis(alkylthio)-biphenyls gives rise to thiosulfonium salt 76. This reaction can also be classified as nucleophilic substitution at the a-carbon atom. The intermediate dication 75 is highly reactive, but can be detected spectroscopically (Scheme 29).93... 

Aryl and alkyl hydroxylations, epoxide formation, oxidative dealkylation of heteroatoms, reduction, dehalogenation, desulfuration, deamination, aryl N-oxygenation, oxidation of sulfur Oxidation of nucleophilic nitrogen and sulfur, oxidative desulfurization Oxidation of aromatic hydrocarbons, phenols, amines, and sulfides oxidative dealkylation, reduction of N-oxides Alcohol oxidation reduction of ketones Oxidative deamination... 

Pyrazolo[l,5-A benzisothiazoles 252 were prepared from 3(5)-[2 -methyl-thiophenyl]pyrazoles 251 and AT-chlorosuc-cinimide. The ring closure may involve a sequential nucleophilic heteroaromatic nitrogen displacement of a sulfonium chlorine atom followed by dealkylation of the resulting sulfonium salt to form the sulfenylimine moiety (Equation 110) <1996H(43)221>. 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

As in carboxylic esters it is possible to substitute alkoxy groups of Fischer-type carbene complexes by non-carbon nucleophiles, such as other alcohols [73,214,218], enols [219], aliphatic amines [43,64,66,220-224], aniline [79], imines [225], or pyrroles [226]. Strong nucleophiles can also lead to a dealkylation of methoxy-substituted carbene complexes (5 2 at the methyl group, [227]), in the same way as methyl esters can be cleaved by nucleophiles such as iodide. Carbon... 

Common esters such as alkyl and benzyl carboxylates are easily dealkylated by sodium hydrogen telluride, sodium telluride and sodium ditelluride in DMF. In accordance with a typical S 2 displacement at the aUcoxy group carbon, methyl, ethyl and benzyl esters react smoothly. The nucleophilicity of the reagents is enhanced by the polar aprotic solvent, and the reactivity decreases with higher alkoxy chains due to steric hindrance (e.g. 

As was already shown in Scheme 11, benzothiazine ylides have a nucleophilic nitrogen that was protonated with loss of the A-alkyl group even when heated in dimethyl sulfoxide (DMSO). Reacting the ylides 84, 183, and 184 with acid results in the same transformation (Equation 4) <1982J(P1)831>. Compound 114 and the 4-chlorophenyl derivative 185 could also be protonated with perchloric acid but in this case S-dealkylation did not occur and a salt was obtained (Equation 5) <1986LA1648>. 

A number of examples of the use of molten pyridinium chloride (mp 144 °C) in chemical synthesis are known, dating back to the 1940 s. Pyridinium chloride can act both as an acid and as a nucleophilic source of chloride. These properties are exploited in the dealkylation reactions of aromatic ethers [4]. An example involving the reaction of 2-methoxynaphthalene is given in Scheme 5.1-2 [16,18], and a mechanistic explanation in Scheme 5.1-3 [18]. 

Where the nucleophile is the conjugate base of a primary amine, NH2 can be a leaving group. The method has been used to prepare secondary amines.827 In another process, primary amines are converted to secondary amines in which both R groups are the same (2RNH2 — R2NH + NH3)828 by refluxing in xylene in the presence of Raney nickel.829 Quaternary salts can be dealkylated with ethanolamine.830... 

Hydrazines may be nucleophiles such as when they interact with aldehyde and keto groups to form hydrazones. This is the basis for the inhibition of enzymes such as transaminases, which rely on pyridoxal phosphate as a coenzyme. Mono-substituted hydrazines can be formed as metabolites when azo groups are reduced, dialkylated hydrazines are dealkylated or hydrazides are hydrolysed. 

When methanol is added to the DMSO solution of the adduct, dealkylation occurs irreversibly to lead to the conjugate base of 2-hydroxy-3,5-dini-tropyridine. The latter is characterized by an AB system centered at 8 8.9 and presumably results from a nucleophilic substitution at the methoxyl saturated carbon by MeO rather than through attack by traces of OH on the heteroaryl carbon 2.39,47... 

Step 3 Second nucleophilic reaction, release of remainder of substrate (dealkylation or deacylation step) ... 

Assume second nucleophilic reaction (dealkylation or deacylation)is slowest step... 

A number of methods are available to dequaternize heterocyclic and related compounds. Dealkylation methods may be desired for various reasons which include (a) removing a protecting group in a multistep synthesis and (b) activating a molecule for nucleophilic substitution by quaternization and then removing the group after substitution. 

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