Nucleophilic aromatic substitution adducts

The absence of nitro groups in these substrates is noteworthy. The observed adducts are exclusively stabilized by the electron-withdrawing capacity of the aza groups present in the fused ring system of purine. Accordingly, all ring protons in the adducts are more shielded than the corresponding protons in the substrates. Adducts 19 and 20 can be taken as models for intermediates in nucleophilic aromatic substitution at the C-6 position of purine. Moreover, their formation support the view that a tetrahedral carbon at C-6 is involved in the mechanism of the adenosine deaminase-catalyzed hydrolysis of 6-substituted purine ribonucleosides.43... 

Two of three nitrofluorobenzene isomers react with methoxide, but the third is unreactive. Obtain energies of methoxide anion (at left), ortho, meta and para-nitrofluorobenzene, and the corresponding ortho, meta and para-methoxide anion adducts (so-called Meisenheimer complexes). Calculate the energy of methoxide addition to each of the three substrates. Which substrate is probably unreactive What is the apparent directing effect of a nitro group Does a nitro group have the same effect on nucleophilic aromatic substitution that it has on electrophilic aromatic substitution (see Chapter 13, Problem 4) Examine the structures and electrostatic potential maps of the Meisenheimer complexes. Use resonance arguments to rationalize what you observe. 

The attack of the nucleophile that forms anionic adducts (or zwitterionic adducts, with neutral nucleophiles) parallels the other attacks of nucleophiles on derivatives bearing unsaturated (sp2) carbon atoms, such as alkenes or aromatic substrates, which are both activated by electron-withdrawing groups. The formation of a anionic (or zwitterionic) complexes between nitroaromatic derivatives and nucleophiles is a well-known step in nucleophilic aromatic substitution reactions155,210. 

In 1,2-type azole N-oxides, leaving groups at the 3- and 5-positions are activated toward nucleophilic aromatic substitution since nucleophilic attack at these positions renders intermediates 28 and 34 in which the positive N-oxide nitrogen atom adopts the negative charge brought to the adduct by the nucleophile. Nucleophilic attack at the 4-substituted isomer 30 would give rise to intermediates like 31 in which such stabilization is impossible (Scheme 6). 

Mechanistically, the one-pot transformation can be rationalized by a sequence of chemoselective coupling of ort/to-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, followed by nucleophilic addition of the sulfide ion to the a,p-unsaturated system 86 to furnish the anionic Michael adduct 87, and finally an intramolecular nucleophilic aromatic substitution in the sense of an addition-elimination process concludes the sequence (Scheme 46). 

The trichloromethyl group of 4-(trichloromethyl)quinazoline can be replaced by methoxy, hydroxy, aliphatic amino, and pyrrolidino groups to give quinazolines 1. From a preparative point of view, these nucleophilic aromatic substitution reactions are similar to the replacement of other more common leaving groups. In the reaction of 4-(trichloromethyl)quinazoline with a methoxide ion, in contrast to the usual aromatic substitution mechanism, a covalent solvation adduct was isolated as intermediate. Whereas 4-(trichloromethyl)quinazoline prefers to undergo aromatic substitution, 4-(tribromomethyl)quinazoline prefers aliphatic substitution. 2-Methyl-4-(tribromomcthyl)quinazoline affords 2-methylquinazolin-4(3/f)-one in 74% yield on treatment with sodium hypobromite in dioxane, probably via an aromatic substitution reaction of a tribromomethyl group. 

Buncel E, Dust JM, and Terrier F, Rationalizing the regioselectivity in polynitroarene anionic sigma-adduct formation. Relevance to nucleophilic aromatic substitution, Chem. Rev., 95, 2261, 1995. 

One of the features of the current state of heterocyclic chemistry is a growing interest in the so-called Sn methodology (nucleophilic aromatic substitution of hydrogen) and related processes initiated by a nucleophilic attack at unsubstituted carbon in 7t-deficient azaaromatics addition of nucleophiles (An), oxidative elimination of hydrogen from cr -adducts, or auto -aromatization of cr -adducts, the tandem addition (An-An) or substitution (Sn -Sn ) reactions, and other transformations . All aspects of this relatively new branch of the chemistry of 1,2,4-triazines are discussed in detail in this chapter. 

Alternative procedure involves N-protonation, addition of the amino compound, and oxidation of the o -adduct with silver carbonate. This scheme can be regarded as a typical example of oxidative nucleophilic aromatic substitution of hydrogen (Sn )- It is worth to mention that hydrogen of the C-H bond is eliminated due to the oxidation procedure (Scheme 9) [55]. 

If the aromatic moiety of a cinnamylamine derivative has an ort/io-halogen substituent, 1,2-dihydroquinoline would be obtained yia the subsequent S Ar reaction. In the presence of catalytic amounts of tosylamide, MBH adduct 603 was rearranged to the thermodynamically more stable tosylamide derivative, which then could be easily subjected to nucleophilic aromatic substitution reaction at the ortho position, giving 1,2-dihydroquinoline 605 in 81% yield. Furthermore, using DBU as a base, elimination of p-toluenesulfinic acid afforded quinoline 606 in 69% yield (Scheme 4.178). However, interestingly, Xn-substituted MBH adducts 607 were directly converted into quinolines 608 in a one-pot reaction in moderate yields. The discrepancy between 604 and 607... 

Straightforward approach to benzo[ r]selenophenes in which 4-(3-nitroaryl)-1,2,3-selenadiazoles undergo a base-promoted transformation to an intermediate eneselenoate followed by 5-exo-trig cyclization. The regiochemistry of the cyclization is dependent upon the conditions of the reaction. In the presence of an oxidant, the adduct is formed rapidly by the oxidative nucleophilic substitution of hydrogen (ONSH, SnAt ) followed by oxidative aromatization of the rapidly formed adduct. In the absence of an oxidant, the reaction proceeds via intermediate formation of the adduct, followed by nucleophilic aromatic substitution of the halogen (SnAt ). 

Conventional nucleophilic substitution of halogens and other nucleofugal groups X in electron-deficient arenes, particularly nitroarenes, proceeds via addition of nucleophiles at positions occupied by X to form o -adducts. The addition is coimected with dearomatization—thus, the adducts, which are in fact nitronate anions of nitro cyclohexadienes, undergo rapid rearomatization via spontaneous departure of X" to form products of nucleophilic aromatic substitution (Sj Ar) reaction. Detailed discussion of these processes is presented in Chapter 6. 

The above reaction resembles previously mentioned preparation of Meisenheimer adducts by reaction of benzofuroxan with potassium carbonate in aqueous solution. It is interesting that using 7-chlorofuroxan instead of furoxan as a starting material, under otherwise similar conditions, leads to a nucleophilic aromatic substitution and formation of fully aromatic phenol salts. The same is true for furazans (Read, Personal Communication). 

Tomioka documented the use of organolithium reagents in enantioselec-tive conjugate additions to conjugated imines (Equation 31) [136]. The readily available chiral diether 173 served to mediate such additions with high asymmetric induction for example, the addition of PhLi to 172 furnished aldehyde 174 in 94% ee after hydrolysis of the imine adduct. In subsequent developments, Tomioka reported the enantioselective preparation of biaryls in which a naphthyllithium participates in a nucleophilic aromatic substitution catalyzed by only 5mol% of 173 (see insert on the left) and delivers the product in 82% ee [137]. 

The extent to which 151 phosphorylates the aromatic amine in the phenyl ring is highly dependent upon the solvent. For instance, aromatic substitution of N-methylaniline is largely suppressed in the presence of dioxane or acetonitrile while pho.sphoramidate formation shows a pronounced concomitant increase. The presence of a fourfold excess (v/v) or pyridine, acetonitrile, dioxane, or 1,2-di-methoxyethane likewise suppresses aromatic substitution of N,N-diethylaniline below the detection limit. It appears reasonable to assume that 151 forms complexes of type 173 and 174 with these solvents — resembling the stable dioxane-S03 adduct 175 — which in turn represent phosphorylating reagents. They are, however, weaker than monomeric metaphosphate 151 and can only react with strong nucleophiles. 

The photochemical nucleophile-olefin combination aromatic substitution (photo-NOCAS) reaction received considerable attention from many groups not only because of its synthetic value because the yields of nucleophile-olefm-arene (1 1 1) adducts can be high but also because of interesting mechanistic details (Scheme 48). 

The free radicals generated by nucleophilic attack on phenylcyclopropane radical cations 43 react exclusively in the benzylic position. In contrast, the free radical 37 has two reactive sites.The major adduct 51 is formed by aromatic substitution at the less hindered allylic site, whereas adduct 52 requires attack on the more hindered site (C5). Interestingly, the diastereomer of 52 is not observed. 

---