And cine substitution

Nucleophilic reactions take place in the homocyclic ring, SwAr or AEc when it is activated by electron-withdrawing substituents. It has been described that halides can be displaced by a great number of nucleophiles via a normal and cine substitution [54,55]. Nitro containing Bfx has represented a class of neutral lO-TT-electron-defident system which exhibit an extremely high electrophilic character in many covalent nucleophihc addition and substitution processes. 4,6-Dinitrobenzofuroxan and others 4-nitro-6-substitutedbenzofuroxans (Scheme 2) have been defined as superelectrophiles and used as convenient probes to assess to the C-basicity of... 

All the bridged [1 ljannulenones condense with malondinitrile in acetic anhydride and yield the corresponding dicyanomethanohendecafulvenes (e.g. 11 - 38) and these on treatment with strong acid furnish the substituted l,6-methano[ll]an-nulenium ions. 11 -Chloro-3,8-methano[ 11 Jannulenone 31, in parallel with the behaviour of the similarly 2-substituted tropone, undergoes reaction with sodium meth-oxide at room temperature to afford chiefly the products of normal 39 and cine substitution 40. 

Nucleophilic attack is faster at unsubstituted ring positions than at similarly activated but substituted ring positions.8-15-43 5 Since the addition is in most cases reversible, the opportunity exists for competing reactions. Indeed an extremely varied spectrum of reactivities is found in these systems, depending on reactants and reaction conditions. Examples are known of competing SNAr and cine substitution,46 NAr and tele substitution,47 SnAt and cine and tele substitution (equation l),5 SsAr and VNS,16 and SnAt and Sn(ANRORC).48... 

This chapter has provided a summary of the reactions that naphthyridines can undergo with KNH2/NH3. The complex behavior of these naphthyridines toward this reagent (ipso, tele, and cine substitutions, as well as ring transformations) is shown in the Table VIII. 

Dinitroquinoxaline gives normal and cine substitution reaction with piperidine the ratio of products depends on reaction conditions, and it appears that the amine concentration plays a major role in determining the ratio of normal to cine substitution. The normal/cinc ratios have been determined by integration of the relevant NMR peaks. 

Under the same conditions, o -[fluoro(dimethyl)silyl]styrene gave a 75 25 mixture of ipso and cine substitution products. Formation of the ipso substitution product was favored with the substrate having an electron-withdrawing group, whereas an electron-donating group gave preferential cine substitution [Eq.(l3)] [10]. 

Scheme 7.10 Ipso and cine substitution through an ortho-benzyne intermediate.

Halo-substituted 3-hydroxypyridazin-6(lFf)-ones react in some instances by cine substitution. For example, 4-chloro-l-methyl-2-phenylpyridazin-6(lFf)-one, when treated with piperidine, yields a mixture of the corresponding 4- and 5-piperidino isomers in nearly equal amounts. 

The question of the occurrence of cine or aryne substitution in some of these reactions has been raised but not answered adequately. The normal product, 2-methoxynaphthalene was shown to be formed from 2-chloronaphthalene and methoxide ion, and the normal 6- and 8-piperidinoquinolines were proved to be products of piperidino-debromination of 6- and 8-bromoquinolines, all in unspecified yield. More highly activated compounds were then assumed not to react via the aryne mechanism. Even if the major product had been characterized, the occurrence of a substantial or predominant amount of aryne reaction may escape notice when strong orientation or steric effects lead to formation of the normal displacement product from the aryne. A substantial amoimt of concurrent aryne reaction may also escape detection if it yields an amount of cine-substituted material easily removed in purification or if the entire reaction mixture is not chromatographed Kauffman and Boettcher have demonstrated that activated compounds such as 4-chloropyridine do indeed react partially via the aryne mechanism (Section I,C,1). 

It had been known many years earlier that aromatic nucleophilic substitution occasionally results in substitution at a different position. This is called cine substitution and can be illustrated by the conversion of o-bromoanisole to m-aminoanisole. In this particular case, only the meta isomer is formed. The... 

This is called the SrnI mechanism," and many other examples are known (see 13-3, 13-4,13-6,13-12). The lUPAC designation is T+Dn+An." Note that the last step of the mechanism produces ArT radical ions, so the process is a chain mechanism (see p. 895)." An electron donor is required to initiate the reaction. In the case above it was solvated electrons from KNH2 in NH3. Evidence was that the addition of potassium metal (a good producer of solvated electrons in ammonia) completely suppressed the cine substitution. Further evidence for the SrnI mechanism was that addition of radical scavengers (which would suppress a free-radical mechanism) led to 8 9 ratios much closer to 1.46 1. Numerous other observations of SrnI mechanisms that were stimulated by solvated electrons and inhibited by radical scavengers have also been recorded." Further evidence for the SrnI mechanism in the case above was that some 1,2,4-trimethylbenzene was found among the products. This could easily be formed by abstraction by Ar- of Ft from the solvent NH3. Besides initiation by solvated electrons," " SrnI reactions have been initiated photochemically," electrochemically," and even thermally." ... 

When aromatic nitro compounds are treated with cyanide ion, the nitro group is displaced and a carboxyl group enters with cine substitution (p. 854), always ortho to the displaced group, never meta or para. The scope of this reaction, called the von Richter rearrangement, is variable. As with other nucleophilic aromatic substitutions, the reaction gives best results when electron-withdrawing groups are in ortho and para positions, but yields are low, usually < 20% and never > 50%. 

The reaction of l,2-dimethyl-5-nitroimidazole with 2-nitropropane anion gives the new highly branched imidazole derivative, which is formed via cine-substitution and SRN I substitution (Eq. 5.67).slb... 

As a synthetic route to the grossularine natural products, Hibino and Potier independently studied the Stille coupling of ethyl 3-iodo-2-indolylcarboxylate, and / -protected analogs, with imidazolylstannanes [188-192], An example is illustrated for 180 to 182 [191]. During the course of their studies in this area, Hibino and co-workers discovered an interesting case of cine-substitution, which seems to be the first such example in heterostannane reactions [190]. 

In a similar way, Kim and Bunnett (1970) demonstrated that the substitution of amino group for iodine in iodotrimethylbenzene proceeds via the ion-radical mechanism, in contrast to the bromo and chloro analogs. The reaction of 5- and 6-halo-l,2,4-trimethylbenzenes with potassium amide in liquid ammonia gives rise to 5- and 6-aminoderivatives. This is the cine-substitution reaction (see Scheme 4.12). 

The nitrophenyl radical can react with the iodide ion and solvent, methanol, as well. Transference of hydrogen radical from methyl alcohol to nitrophenyl radical gives rise to nitrobenzene and formaldehyde (CHjOH —> CH2O). Though carefully sought among the products of the reaction, 3-iodonitro-benzene and 4-nitroanisole were lacking. This completely rejects another possible mechanism of the reaction, cine-substitution, which involves the formation of dehydrobenzene as described earlier. 

When 4-bromo- or 4-iododibenzofuran is treated with sodamide or a lithium dialkylamide, cine substitution occurs and the 3-amino derivative results. The 4,6-diiodo derivative similarly gives the 3,7-diamino compound. ... 

---