Alkylations ambident reactivity

El Shafei et al.162 have studied the ambident reactivity of quinoxalino-[2,3b]-l,4-benzothiazine(103) and observed that under phase transfer conditions the ratio of benzothiazine N-alkylation versus quinoxaline N-alkylation was nearly 2 1. 

The reaction of alkyl isothiocyanates, RNCS, with diphenylphosphinic hydrazide (338) in benzene has been reported.308 The bis(diethylamino)[(methylthio)thiocarbon-yl]carbenium salts (339 X = I or BF4) display ambident reactivity and can react either at carbenium carbon (hard nucleophiles) or at the thiocarbonyl sulfur atom (soft nucleophiles).309 Electrochemically generated superoxide reacts with dithioic S,S -diesters (dicarbothiolates) (340 Ar = C5H3N or C6H4) to give the monocarboxylate anions in 100% yield before giving the dicarboxylate anions.310... 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

DMF, in alkylation of aminothiazoles, 35 in ambident reactivity, 36 in cyclizations, 50 DMSO, reaction with CS2,61 Dopamine content in brain, 146 Dopamine hydroxylase inhibitor, 152 Double bond, addition to, 40 ozonolysis of, 71... 

S-alkylation in A-4-thiazoline-2-thione, 384,391,392 of ambident reactivities, 63 of Claisen rearrangement in 2-allyloxy-thiazole, 410... 

Retro-Hantzsch, mechanism of, 84, 85, 102 Rhodanine, alkylation of, 419 ambident reactivity of. 419 reaction with aryldiazonium salts, 419 reaction with halogenothiazoles, 79 Rice cultures, 135, 136, 137 Ring-chain tautomerism, 113 Ring opening, of A-2-thiazoline-5-one, 433 Ring transformation, 5 amino-A-4-thiazo-line-2-thione to 4-mercapto-imidazoline-2-thione, 399 5,5-diphenyl-2,4-thiazolidinedithione, to 4,5-diphenyl-A-4-thiazoline-2-thione, 37 3... 

Cyanide ion. One of the most useful aspects of the principle of hard and soft acids and bases is the way in which it sorts out our ideas on ambident reactivity. A cyanide ion, for example, can react with an alkyl halide, depending on the conditions, to give either a nitrile (30)27 or an isonitrile (31) 28... 

The phosphorothioic triamide (79) (R = H) exhibits ambident reactivity and when alkylated yields the pentacoordinated 5-derivatives (80), but when acylated affords (79) (R = PhCO or EtCO). The N io O rearrangement of the N-phosphorylated amino acid esters (81) to (82) proceeds 10-40 times faster in the presence of imidazole than in its absence. In a warm alcohol solution ester... 

Due to the ambident reactivity of pyrroles and indoles, alkylations of such jt-excessive heterocycles can provide a mixture of N- and C-alkylated products. It is therefore of note that Bogdal has been able to achieve the regioselective N-alkylation of a number of azaheterocycles (i.e., pyrrole, imidazole, pyrazole, indole and carbazole) in "dry" media under microwave irradiation <97H(45)715>. The reactions were carried out by simply adsorbing a mixture of the heterocyclic compound, an alkyl halide and a catalytic amount of tetrabutylammonium bromide on a solid support (e.g., KOH, K2CO3), followed by irradiation in an open vessel for 1-10 min. Alternatively, the direct benzylation of pyrrole by the thermal decomposition of N-benzyl-N-nitrosobenzamide, which is believed to proceed by an essentially free carbocation, afforded only the C-2 and C-3 substituted pyrroles <97JOC8091>. 

There has been much interest in the reactivity of nitronium salts, for example, toward amides in acetonitrile,the oxidation of alkanes in acetonitrile (via a carbenium ion intermediate),and toward organic sulfides, phosphines, arsines, and stibines. Reaction with diaryl, aryl alkyl, and dialkyl sulfides give sulfoxides, but a few percent of the ring C-nitro products were found for diphenyl sulfide. This is a result of the equilibrium between nitrito onium ions ] X-ONO and nitronium ions This is the first demonstration of the ambident reactivity... 

Alkylations in dry media of the ambident 2-naphthoxide anion were performed under the action of focused microwave activation. Whereas the yields were identical to those obtained under the action of A for benzylation, they were significantly improved under microwave irradiation conditions for the more difficult n-octylation (a less reactive electrophilic reagent). No change in selectivity was observed, however, indicating the lack of influence of ionic polarization [94],... 

The relationships between the components of the Hantzsch triangle were considered in-depth in the monograph 2 and references therein. Although the problem of reactivity of ambident substrates has been studied over many years and from different points of view, the complexity of the starting system and its numerous reaction pathways do not allow one to reliably predict the results of O-alkylation in each particular case, because it is necessary to take into account the rates of numerous reversible and irreversible processes as well as the thermodynamic factors responsible for the position of the equilibrium it is necessary to take solvent effects into consideration when estimating the thermodynamic factors. All accumulated observations are approximated by several empirical mles included in monographs 2 and 3. 

Smith and Hanson, 1971). Upon addition of NaBPh4, the free anion was converted into the ion pair, and upon addition of dibenzo-18-crown-6 [11] the ion pair was converted into the free anion. The results (Table 26) show the free anion to be much more reactive than the ion pair towards both methyl iodide and methyl tosylate. The increase in rate is again mainly due to the enhanced reactivity of the hard oxygen centre. The ratio of the rates of alkylation at the two sites of the ambident anion (kN/k0) decreased from about 1.2 for the ion pair to 0.55 and almost zero for the free anion. Increased alkylation of the hard... 

Hydroxylamines and alkylhydroxylamines possess high nucleophilicity and can react with a variety of primary and secondary alkylating agents. The reactivity of hydroxylamines in the majority of these reactions resembles that of primary and secondary amines. While hydroxylamine and Af-alkylhydroxylamines 1 are ambident nucleophiles, under neutral or weakly basic reaction conditions alkylation proceeds exclusively on nitrogen atom to give products of type 2 (equation 1). Deprotonation of the OH group of hydroxylamines results in O-alkylation products. 

However, since enolate anions are ambident nucleophiles with the distribution of charge between the a-carbon and oxygen conferring reactivity to both sites, alkylation may result at either site. 

Enamines are ambident nucleophiles giving C- and N-alkylated products. Acceptable yields of C-alkylated products are obtained by using reactive alkyl halides such as CH3I, ally lie and benzylic halides, and a-halocarbonyl compounds. The resultant iminium ion intermediates no longer behave as a enolates, thus dialkylation is avoided. The stereochemical course of alkylation of the enamine derived from 2-methylcy-clohexanone is depicted below. The reason for the preferred parallel alkylation via a boat-like transition state over antiparallel alkylation via a chair-like transition state is the synaxial RX // CH3 interaction in the latter case. ... 

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