Nucleophilic Attack at Ring Carbon

Appel salt 20 is sensitive to attack of nitrogen, oxygen, and sulfur nucleophiles, especially at the 5-carbon, to form corresponding 5-imines 56, ketone, thione 41, and 5-ylidenes (i.e., 42) which can participate in further reactions with nucleophiles at the same carbon atom with extrusion of diatomic sulfur (S2) and chloride anion. This chemistry started in 1985 when Appel salt was discovered, and is extensively studied at the present time. 

Previously unknown azomethylene derivatives of 1,2,3-dithiazoles 84 were synthesized by the reaction of Appel salt 20 with N-monosubstituted hydrazones 85 (Equation 16) 2004JHC37 . Their formation probably includes the generation of the carbon anion, under the action of a base, which then adds to salt 20. 

Chloride ion in benzyl(triethyl)ammonium chloride can activate a nitrile group in dicyanomethylenedithiazole 42 which then cyclizes onto S-l to form the aromatic isothiazole ring and a new cyano group (Equation 17) 1997J(P1)3345 . The yield of isothiazole 86 is quantitative. 

Thienopyrimidinones 92 were also synthesized by this reaction 2002H(57)1471 . Ethylene diamine produces in this conversion the novel and rare tricyclic pyrazinoquinazolinone 93 2004TL3097 . 

An interesting synthesis of T-vinyl-l,2,3-dithiazolylimines 94 from Appel salt 20 and aziridines has been described 2005H(65)1601 . This procedure involves elimination of hydrogens from different nitrogen and carbon atoms. The reaction with aziridinecarboxylic acid ester or its amide 95 having the frarcr-configuration produces one of the possible 

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Nucleophilic attack at C-5 has been proposed as a reaction mechanism for a number of ring transformations and the instability of the parent compound toward alkalis probably involves initial attack at this carbon. Since the publication of CHEC-II(1996), there have been no definitive reports of nucleophilic attack at ring carbon atoms. 

Nucleophilic Attack at Ring Carbon with Concomitant Ring Opening 235... 

For conjugated structures thermolytic reactions with loss of sulfur have been studied since 1980 and afford various types of cyclic and acyclic products (Section 4.11.5.1). Nucleophilic attack at ring carbon is very characteristic of 1,2,3-dithiazoles (Section 4.11.5.4). This type of reaction was especially prolific with Appel s salt, studied mostly by Appel, Rees and their co-workers. The preferential site of attack is C(5) but nucleophilic substitution may occur at C(4) when the C(5) site is blocked by poorly leaving substituents, see the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) for examples of 1,2,3-dithiazoles <84CHEC-I(6)924> and 1,2,3-oxathiazoles <84CHEC-l(6)930>. Nucleophilic attack at ring sulfur in 1,2,3-dithiazoles occurs on S(2) (Section 4.11.5.5), see... 

As mentioned earlier, nucleophilic attack at ring carbon atoms a and y to a heteroatom is a reaction characteristic of the ir-deficient six-membered heterocycles. Within this context we do not regard hydrogen atoms attached to ring carbon atoms as substituent groups, and hence proton removal to generate a carbanionic centre is classified as a reaction at a ring carbon atom. There are thus six major reaction types, summarized in equations (21)—(26) in terms of the initial mechanistic steps. 

Pyridones are normally resistant to nucleophilic attack at ring carbon atoms, but the pyrones react rather readily. There is a useful correlation between the position of attack and the hardness or softness of the nucleophile, and the situation for the pyrones is summarized in Schemes 12 and 13. Representative transformations illustrating these concepts are shown in equations (45)-(51). ANRORC reactions are also very common and examples are given in equations (52)—(55). 

Nucleophilic attack at ring carbon occurs in benzenes only when electron-withdrawing substituents are present. Even with pyridine, only the strongest nucleophiles react. This is because the formation of the initial adduct (2) involves de-aromatization of the pyridine ring and, once formed, many such adducts tend to re-aromatize by dissociation (1 2). Benzo fusion decreases the loss in aromaticity for the formation of the adduct and thus quinoline (3) and especially acridine (4) react more readily with nucleophiles. 

Reactions in which the ring is cleaved or completely fragmented are fairly common in these systems. Ring contraction to form five-membered rings is also common especially where sulfur is extruded, and these reactions are considered separately, as are reactions which involve desulfurization or reduction. Reactions which lead to ring opening but are initiated by nucleophilic attack at ring carbons have already been discussed in Section 2.28.3.3.3. 

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