Amines heteroaromatic, alkylation

The vast majority of ILs are usually prepared by simple N- or T-alkylation of amines, heteroaromatics, and phosphines, often employing alkyl halides or alkyl sulfonates as alkylating agents, followed by association with metal halides or anion metathesis (Scheme 1). 

The greater acidities of the heteroaromatic azoles (pKa ca. 15), compared with simple acyclic and non-aromatic cyclic amines, is reflected in the ease with which the systems are /V-alkylated and /V-acylated. 

The mechanism of the photochemical alkylation shows particular characteristics as regards the formation of alkyl radicals, the reaction of these radicals with the heteroaromatic substrates, and the rearomatization of the intermediate products. A variety of alkylating agents (hydrocarbons, alcohols, amines, carboxylic acids, amino acids) have been used for photochemical and y-ray-induced alkylation. " ... 

The alkylation with alcohols and amines can lead to alkyl derivatives or a-hydroxy and a-aminoalkyl derivatives according to the nature of the heteroaromatic base and the reaction conditions. The intermediate products in both cases are, however, the a-hydroxy and a-aminoalkyl dihydro derivatives, which can be aromatized by disproportionation or oxidation, while the loss of water or ammonia leads to the alkyl derivatives (Scheme 7). 

The first class of amine-based nucleophilic catalysts to give acceptable levels of selectivity in the KR of aryl alkyl. yec-alcohols was a series of planar chiral pyrrole derivatives 13 and 14, initially disclosed by Fu in 1996 [25, 26]. Fu and co-workers had set out to develop a class of robust and tuneable catalysts that could be used for the acylative KR of various classes of. yec-alcohols. Planar-chiral azaferrocenes 13 and 14 seemed to meet their criteria. These catalysts feature of a reasonably nucleophilic nitrogen and constitute 18-electron metal complexes which are highly stable [54-58]. Moreover, by modifying the substitution pattern on the heteroaromatic ring, the steric demand and hence potentially the selectivity of these catalysts could be modulated. 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Also, the PET between polynuclear aromatic hydrocarbons (naphthalene, anthracene, phenanthrene, perylene) or heteroaromatics (phenazine, acridine) as acceptors and amines as donors can be used for polymerization initiation of AN and alkyl methacrylates [111-113]. In general, a reaction course as outlined in Scheme 3 also acts with these combinations. 

Torok et al. reported that the reaction of artemisinin and methanolic ammonia or primary alkyl-and heteroaromatic amines yielded azaartemisinin or A-substituted azaartemisinin (137) and A-substimted azadesoxyartemisinin (138) as byproducts (Scheme 5-22). Some A-substimted azaartemisinin had good antimalarial activity, such as compound 137 (R = CH2CHO), which was 26 times more active in vitro and 4 times more active in vivo than artemisinin. ... 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alkyl nitrite (isoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and ni-36. 

Katritzky AR, Rachwal S, Rachwal B (1987) The chemistry of //-substituted benzotriazoles. Part 4. A novel and versatile method for the mono-/V-alkylation of aromatic and heteroaromatic amines. J Chem Soc Perkin Trans 1 805-809... 

Vinyl Azides. Vinyl azides such as 37 or 38 react with alkyl-, aryl-, and heteroaryllithium reagents like other azides to give the corresponding triazenes. Hydrolysis of the latter leads to nitrogen-free carbonyl compounds when aliphatic lithium reagents are used (path A, Eq. 28),277 but when benzyl, aromatic, and heteroaromatic lithium reagents are used, amines are formed in fair to good yields (path B).278... 

Apparently, no alkylation, arylation, acylation or /V-amination of a heteroaromatic 1,2,4,5-tetrazine ring has been reported so far, but alkylation or acylation of substituents bound to the 1,2,4,5-tetrazine ring are known (see Section 5.1.4.6.). Treatment of 1,2,4,5-tetrazines with acids affords ring-opened products in the presence of water or alcohols a protonated 1,2,4,5-tetrazinium salt may be an intermediate in this reaction. 

The synthetically important methods can be classified into the following three categories (i) direct iV-amination of the heteroaromatic bases, (ii) cyclization of monohydrazone derivatives, and (Hi) iV-alkylation of N-aminoazoles. In addition, there are several special methods that have been used for the preparation of some particular heteroaromatic iV-imines and iV-aminoazonium salts. 

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