Heterocyclic aromatic substrates

CYP1A2. CYP1A2 has been implicated in the activation of procarcinogenic species such as aflatoxin Bl, 2-acetylaminofluorene, and other arylamines. It tends to favor aromatic substrates, both heterocyclic aromatic substrates like caffeine and aromatic substrates like phenacetin (10). In the case of caffeine, 1A2 is the major isoform catalyzing the... 

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

An instance of an apparent electrophilic aromatic substitution (in this case 61 is an aromatic substrate, of Scheme 31), which actually is an electrophilic addition, is the halo-genation of 2-aminothiazole derivatives which was usually considered a simple attack of the electrophilic reagent on the heterocyclic aromatic substrate activated by the amino group see reaction 12. When the bromination of 2-aminothiazole derivatives is carried out in nucleophilic solvents (ROH) and at low temperatures, the partially saturated derivatives (64) of Scheme 33 were isolated in 80-95% yields133. By heating 64, the usual halogenated 2-aminothiazoles are obtained, as indicated by Scheme 33. An apparent electrophilic aromatic substitution is actually an addition reaction to the C=C double bond the elimination reaction is the following, separate step. 

Other well-known reactions are those offluorinated olefins with fluoride ion and negatively substituted aromatic compounds leading to the formation of per-fiuoroalkylated aromatic compounds The reaction may be considered an amonic version of a Fnedel Crafts process and can result in introduction of one or several perfluoroalkyl substituents [/ /] Aromatic substrates include substituted and unsuhstiluled perfiuorobenzenes [J3l, 212, 213, 214], fiuorinated heterocycles [131, 203, 215, 216, 217, 218, 219, 220, 221, 222, 223],perchlorinated heterocycles [224] (equation 44), and other activated aromatic compounds [225] (equation 45) The fluonnated olefins can be linear or cyclic [208] (equation 46)... 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Stockman has reported the preparation of alkyl-, aryl-, and vinyl-disubstituted aziridines with good diastereoselectivities and in good yields through treatment of tert-butylsulfmylimines with the ylide 119, derived from S-allyl tetrahydrothio-phenium bromide (Scheme 1.39) [64]. A range of substrates were tolerated, including heterocyclic, aromatic, and aliphatic substrates (Table 1.16). 

A quantitative scale of reactivity for aromatic substrates (fused, heterocyclic, and substituted rings) has been devised, based on the hard-soft concept (p. 338). From MO theory, a quantity, called activation hardness, can be calculated for each position of an aromatic ring. The smaller the activation hardness, the faster the attack at that position hence the treatment predicts the most likely orientations for incoming groups. 

In certain cases, the SrnI mechanism has been found (p. 856). When the substrate is a heterocyclic aromatic nitrogen compound, still a different mechanism [the Sn(ANRORC) mechanism], involving opening and reclosing of the aromatic ring, has been shown to take place. 

In principle, aliphatic amines may interact as n electron donor molecules towards electron acceptor centres such as aromatic substrates, both homocyclic and heterocyclic, containing electron-withdrawing groups, usually nitro groups. These interactions are mainly electron donor-acceptor (EDA) interactions, in which aromatic amines are considered n or/and tt electron donors. 

Olah" has conducted extensive studies into transfer nitration with A-nitro heterocycles. Studies were conducted into the effect of the heterocycle and its counterion on reactivity towards aromatic substrates. 

In addition to these classical aromatic ring hydroxylations, many nitrogen heterocycles are substrates for molybdenum-containing enzymes, such as xanthine oxidase and aldehyde oxidase, which are present in the hepatic cytosolic fractions from various animal species. The molybdenum hydroxylases (B-75MI10902) catalyze the oxidation of electron-deficient carbons in aromatic nitrogen heterocycles. The reactions catalyzed by these enzymes are generally represented by equations (2) and (3). 

A. Formation of the heterocyclic ring from an aromatic substrate... 

A. Formation of the Heterocyclic Ring from an Aromatic Substrate... 

GATTERMANN ALDEHYDE SYNTHESIS. Preparation of aldehydes of phenols, phenol ethers, or heterocyclic compounds hy treatment of the aromatic substrate with hydrogen cyanide and hydrochloric acid in the presence of Lewis acid catalysts. 

By using a different length of tether between the aldehyde and the dienophile moiety in the aromatic or hetero-aromatic substrates various different highly diversified heterocyclic compounds can be prepared. Thus, reaction of 19 and 15b led to 20 containing a new 5,6-ring system, whereas reaction of 21 and 15b gave 22 with a 7,6-ring system (Scheme 5.5) [11],... 

Prior to, and perhaps also after, the formation of the a complex, a 77 complex (with the aromatic ring behaving as electron donor) can form, although it has not been proved that its formation is a necessary step in the reaction path.44 It has recently been suggested that the formation of the n complex could in some cases become rate-determining, when the electrophile is a very powerful one.45 This hypothesis, although questioned both from the experimental and theoretical point of view,46-48 is a possibility and could be applicable also when the aromatic substrate is a powerful nucleophile (as is the case with many five-membered heterocyclic rings). 

Trifluoroacetylation142,143,143a by trifluoroacetic anhydride in an inert solvent has proved to be particularly suitable for such studies of comparative reactivity. Trifluoroacetic anhydride is, in fact, able to acylate reactive aromatic substrates in the absence of any added Friedel-Crafts catalyst,144 a circumstance which avoids the above-mentioned complications arising from the interactions of many heterocycles with such catalysts.139... 

Figure 13.10. NAT-mediated metabolic activation of heterocyclic aromatic amines. 2-AF is not a NAT substrate for A-aectylation (compare with 2-NA, 4-ABP A-acetylation in Figure 13.9). 2-AF is detoxified by P4502B1 ring hydroxylation. 2-AF is also metabolized via P4501A2-mediated A-hydroxylation. The resultant A-hydroxy 2-AF is a good substrate of conjugation reactions by NATs as well as by UGTs and SULTs and is converted to reactive metabolites for DNA adduct formation.

Alternatively, the aryl radical may add to an aromatic substrate yielding biaryls, as in the reactions of polyhalocyanobenzenes with anisole [107-108] and of halobenzenes with IV,IV-dimethylaniline [109-110], Related intramolecular reactions are useful for the synthesis of heterocycles [111-112],... 

This methodology was employed to prepare many heterocyclic cyanohydrin acetates in high yields and with excellent enantioselectivities, Candida antarctica lipase A (CAL-A) being the lipase of choice (Scheme 5.7) [23]. A recent detailed study of the reaction conditions revealed that the carrier on which the lipase is immobilised is important generally Celite should be used for aromatic substrates. With Celite R-633 as support for Candida antarctica lipase B (CAL-B)... 

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