Intramolecular nucleophilic aliphatic

Tandem cyclization from [5+1,6+0] atom fragments took place when 3-isothiocyanatobutyraldehyde was reacted with 2-aminobenzylamine 228 (X = NH) to give 229. Based on literature analogies the first step involves the attack of the most nucleophilic aliphatic amino group onto the isothiocyanate and then onto the aldehyde carbon to form 1-(n-aminobenzyl)-6-hydroxytetrahydropyrimidine-2-thione, which undergoes intramolecular cyclocondensation to 229 (Scheme 38) <2005BMC3185>. 

Also alkynylcarbene complexes can react as Michael acceptors with nucleophiles, forming 1,3-dien-l-ylcarbene complexes (Figure 2.17). Both carbon nucleophiles, such as, e.g., enamines [246-249], and non-carbon nucleophiles, such as imidates [250], amines [64,131,251], aliphatic alcohols [48,79,252], phenols [252], and thiols [252] can add to the C-C triple bond of alkynylcarbene complexes. Further reactions of the C-C triple bond of alkynylcarbene complexes include 1,3-dipolar [253,254], Diels-Alder [64,234,238,255-258] and [2 -i- 2] cycloadditions [259 -261], intramolecular Pauson-Khand reactions [43,262], and C-metallation of ethynylcarbene complexes [263]. 

Inter- and Intramolecular Reactions with Aliphatic Amines and Ammonia as Nucleophiles... 

Catalyst activation became a necessity when reactions with bulky aliphatic amines and arylamines (cf Section 9.4.2) as nucleophiles were probed. It was also required for intramolecular aminations [8,18]. Thus, with Ph2CHNH2, an ammonia equivalent, conversion was only 11% upon application of procedure (a) (Table 9.2, entry 11), while the reaction promoted by the activated catalyst proceeded with high selectivity and yield. Catalyst activation is faster with ligand L2 than LI, and accordingly in situ activation occurs more readily for the former (cf entries 10 and 12). Examples presented in entries 16-20 further demonstrate the advantages of catalyst activation [53] (note that excellent results can be achieved with the simpH-fied ligand L5a). 

Diamines of varying structure show rate enhancements of 20-200 fold, compared to monofunctional aliphatic amines, in nucleophilic reactions with N-acetylimidazole (Page and Jencks, 1972). These were attributed to intramolecular general base catalysis of proton removal from the attacking nitrogen, viz.. 

Various aldehydes 184 and alcohols have been shown to be competent in the redox esterification of unsaturated aldehydes in the presence of the achiral mesityl triazo-lium pre-catalyst 186. Both aromatic and aliphatic enals participate in yields up to 99% (Table 13). Tri-substituted enals work well (entry 3), as do enals with additional olefins present in the substrate (entries 4 and 7). The nucleophile scope includes primary and secondary alcohols as well as phenols and allylic alcohols. Intramolecular esterification may also occur with the formation of a bicyclic lactone (entry 8). 

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

There have been several reports of the use of intramolecular displacements of nitro groups in the synthesis of heterocyclic compounds. Thus, reaction16 of the intermediate (2) with a strong base in DMF results in the substitution of a nitro group by the amide function to yield a dibenzothiazepinone derivative (3). Nucleophilic addition across the double bond of 2,4,6-trinitrostyrene may occur with thiophenol, aniline, and aliphatic amines. The adducts so formed with primary amines may undergo intramolecular substitution of an o-nitro group to give IV-substituted 4,6-dinitroindoles.17... 

Conditions were found under which 2,4,6-trinitrostyrene adds nucleophiles (thio-phenol, aniline, and aliphatic amines) at the vinyl moiety to form the corresponding / -X-ethyl-2,4,6-trinitrobenzenes (X = PhS, PhNH, or R2N). In the reactions with primary aromatic amines, the initially formed adducts undergo an intramolecular replacement of the nitro group followed by aromatization of the indolines, giving rise to the corresponding A-substi Luted 4,6-dinitroindoles.219... 

Oxidative addition of the silane to the metal is fast and reversible 30 therefore unless the pentacoordinated silane drastically slows down the oxidative addition process, pentacoordination will not alter the rate of the reaction at this stage of the cycle. The increased reactivity of le may be explained by the attack of the alcohol on the pentacoordinated silane that would form after oxidative addition (Figure 9A). The rate of the alcohol addition is increased by the higher reactivity of the pentacoordinated silicon center. This may explain the slower reactivity for those alkoxysilanes that cannot form this intramolecular coordination complex due to the absence of a nearby Lewis basic atom. We had observed during the comparison of aliphatic alcohol to benzyl alcohol that the nucleophilicity of the alcohols has an effect on the rate of the reaction. This is evidence that the alcohol and the silane are involved in the rate-determining step with 10 % Pd/C catalytic system. 

Apart from these two examples, in the rest of the olefin activations, gold coordinates to the olefin, turning it susceptible to nucleophilic attack. The early examples of alkene functionalization by gold catalysis (equation 144) focused on the intermolecular addition of 1,3-diketones to styrenes. " An intramolecular version with ketoamides to yield pyrrolidinones was later developed and followed by the intermolecular addition of phenols (equation 145) and carboxylic acids to double bonds,a work that included an example of intramolecular addition of an aliphatic alcohol to an olefin. 

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