Protonation, Alkylation, and Acylation

These compounds have proven to be the most versatile building blocks for construction of other ynamines mainly through protonation, alkylation and acylation. Such reactions are called aminoethynylation 131). More recent development involves the use of stable stannyl ynamines. Lithio ynamines 44 are prepared in situ and alkylation is achieved by adding the corresponding alkyl halide or tosylate. The D3-ynamine 45 was prepared via the latter method (80) 132). Two selected examples (81, 82) where the acetylene chain carries a latent functionality follow 133,134). 

In addition to protons, alkyl and acyl groups, silyl groups are sufficiently electropositive to initiate carbocationic polymerizations. Silicon is more electropositive than carbon, and therefore reacts with many nucleophiles, especially those based on oxygen. The resulting silicon-heteroatom bonds are relatively labile trimethylsilyl is thus often referred to as a bulky... 

The range of reactions which are possible at the ring nitrogens of imidazole and benzimidazole has been outlined (Section 4.02.1.3). As they are the most basic of the azoles, imidazoles are particularly prone to such reactions as protonation, alkylation and acylation, and they readily become involved in complex formation with transition metals. Benzimidazoles, too, are reactive, but less so than the non-condensed species. 

Protonation, alkylation, and acylation of 1,2,4-triazines were discussed in detail in CHEC-I <84CHEC-I(3)369>, and TV -oxidation was dealt with in Section 6.11.5.4. In this section some additional information is presented. 

The nucleophilic imino group reacts as expected in protonation, alkylation, and acylation for protonation processes see Section III,F. 

Consequently, pyridine has a reduced susceptibility to electrophilic substitution compared to benzene, while being more susceptible to nucleophilic attack. One unique aspect of pyridine is the protonation, alkylation, and acylation of its nitrogen atom. The resultant salts are still aromatic, however, and they are much more polarized. Details for reactivity of pyridine derivatives, in particular, reactions on the pyridine nitrogen and the Zincke reaction, as well as C-metallated pyridines, halogen pyridines, and their uses in the transition metal-catalyzed C-C and C-N cross-coupling reactions in drug synthesis, will be discussed in Section 10.2. 

Cocatalysts of two types occur (/) proton-donor substances, such as hydroxy compounds and proton acids, and (2) cation-forming substances (other than proton), including alkyl and acyl haUdes which form carbocations and other donor substances leading to oxonium, sulfonium, halonium, etc, complexes. 

The intermediacy of an anhydro base (57) was referred to in Scheme 46. Analogous anhydro bases (pyridone methides) can be formed by deprotonation of quaternary salts of 2- and 4-benzylpyridines and the like. The pyridone methides are usually highly reactive and not readily isolable some stable examples are shown in Scheme 49. Pyridine methides are intermediates in the base-catalyzed alkylation and acylation reactions of pyridinium salts at the exocyclic carbon. Compounds of type (60) have been estimated to have 25-30% dipolar character. Protonation of (60) occurs at the 2 - and 3 -positions in the ratio 4 1 respectively (70JCS(C)800). 

Organonitrogen-lithium compounds, and particularly lithium amides (R2NLi), are widely used both in organic and in organometallic syntheses. For the former, these strong bases are employed as proton abstractors (5-8), to generate new organolithiums. These can then be derivatized with so-called electrophiles, e.g., alkyl and acyl halides (E+ = R+ and R—C+=0) and trimethylsilylchloride (E+ = MeaSi+) [Eq. (1)]. 

Alkylation and acylation of 1,2,3-triazines have not yet been studied extensively. Protonation of monocyclic 1,2,3-triazines usually takes place at N-2. The tetrafluoroborate salt of 5-chloro-4,6-bis(dimethylamino)-l,2,3-triazine could be isolated. Similarly, reaction of... 

Aromatic compounds react mainly by electrophilic aromatic substitution, in which one or more ring hydrogens are replaced by various electrophiles. Typical reactions are chlorination, bromination, nitration, sulfonation, alkylation, and acylation (the last two are Friedel-Crafts reactions). The mechanism involves two steps addition of the electrophile to a ring carbon, to produce an intermediate benzenonium ion, followed by proton loss to again achieve the (now substituted) aromatic system. 

In particular, the alkylation and acylation of protonated heteroarenes under oxidative conditions, commonly known as Minisci reaction, has attracted increasing interest in recent decades because of its synthetic involvement in biochemistry and pharmacology [3]. Beyond the fact that this reaction can be applied to all heteroaromatic bases and almost all carbonyl and alkyl radicals (without electron-withdrawing groups directly bonded to the radical center), the main characteristics of this process are high chemoselectivity and regioselectivity, the substitution usually occurring only in a and y positions. 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

Carboxylic acids are the most general, versatile and useful source of carbon-centered radicals successfully used for selective alkylation and acylation of protonated heteroarenes. Alkyl, acyl, carbamoyl, and alkoxycarbonyl radicals have been obtained by oxidative decarboxylation of the corresponding acids with peroxydisulfate as an oxidant and Ag(I) as catalyst. 

As shown in Fig. (7), the relative configurations for the diastereo-meric adducts were determined by NOESY correlations and coupling constants for ring protons. All the IMDA reactions proceeded with high endo/exo selectivity (A+B/C+D), while the n-facial selectivity of the endo-adducts (A/B) depended on the protecting group at C-l. The C-l alkyl- and acyl-protected substrates (88, 95, or 96) and non-protected substrate 89 provided the undesired cycloadduct B preferentially... 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

In the first step, the carbon centered radical is generated. The second step involves the addition of this radical to the protonated ring. The third step consists of the rearomatization of the radical adduct by oxidation. The rates of addition of alkyl and acyl radicals to protonated heteroaromatic bases are much higher than those of possible competitive reactions, particularly those with solvents. Polar effects influence the rates of the radical additions to the heteroaromatic ring by decreasing the activation energy as the electron deficiency of the heterocyclic ring increases. 

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