Deprotonation at carbon

The first proton to be removed from /V-methylpyrrole by n-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. In both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(Pl)887). N-Methylindole, benzo[/j]furan, benzo[b thiophene, selenophene, benzo[b]selenophene, tellurophene and benzof/jjtellurophene similarly yield 2-lithio derivatives (77AHC(21)119). 

Competitive metallation experiments with (V-methylpyrrole and thiophene and with /V-methylindole and benzof/j]thiophene indicate that the sulfur-containing heterocycles react more rapidly with n-butyllithium in ether. The comparative reactivity of thiophene and furan with butyllithium depends on the metallation conditions. In hexane, furan reacts more rapidly than thiophene but in ether, in the presence of tetramethylethylenediamine (TMEDA), the order of reactivity is reversed (77JCS(Pl)887). 

Directive effects on lithiation have also been studied. The regiospecific (3-metallation of N-methylpyrrole derivatives and 2-substituted furans has been effected by employing the directive effect 

The oxazolinyl group directs metallation to the adjacent position. Thus, whereas a 2-furyloxazoline undergoes Friedel-Crafts reactions at the 4-position, metallation allows the introduction of the same functional groups at the 3-position (92T149). 

S-Arylbenzo[fi]thiophenium ions (143) undergo ring opening by cleavage of the S - C2 bond when treated with NaOMe in MeOH (92CL1357). With 3-unsubstituted compounds, the primary process is abstraction of the proton attached to C-3 subsequent cleavage of the S-C2 bond results in the formation of acetylenes (144) in quantitative yield. 

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The study of the chemistry of carbonyl compounds has shown that they can act as carbon nucleophiles in the presence of acid catalysts as well as bases. The nucleophilic reactivity of carbonyl compounds in acidic solution is due to the presence of the enol tautomer. Enolization in acidic solution is catalyzed by O-protonation. Subsequent deprotonation at carbon gives the enol ... 

Deprotonation at carbon adjacent to a carbonyl group leads to an enolate anion, e.g., deprotonation of acetone. 

In the dihapto mode the pyridine ring can be protonated intermolecularly at nitrogen, or even intramolecularly deprotonated at carbon. The first evidence for metal C—N insertion is the reaction of the metallaaziridine complex (111) with homogeneity LiHBEt3 in THF at low temperature that yields (112) (Scheme 49).251-254 Experiments with carbon nucleophiles (RMgCl, MeLi) in place of LiHBEt3 have provided valuable information to allow discrimination between... 

When the binding energy of a hydrogen to a heteroatom is weak, heteroatom-centered radicals are readily produced by H-abstraction or one-electron oxidation followed by H+ loss. Typical examples are phenols (e.g vitamin E in non-aqueous media), tryptophan and related compounds and thiols. Deprotonation of radical cations is indeed often a source of heteroatom-centered radicals even if a deprotonation at carbon or OH addition upon reaction with water would be thermodynamically favored. The reason for this is the ready deprotonation at a heteroatom (Chap. 6.2). 

Whereas base-induced deprotonation at a heteroatom is very fast (practically diffusion-controlled), deprotonation at carbon is generally much slower (Eigen et al. 1964, 1965). Thus, this type of 02 -elimination is observed at higher pH values compared to the reactions discussed before. The elimination of HO2 is subject to steric restrictions, but the OH -induced 02 -elimination is not, and at high pH all hydroxycyclohexadienylperoxyl radicals eliminate 02 bringing the phenolate yield close to 100% [reactions (9) and (14)/(15)] competing reactions (see below) are thereby suppressed. 

Radical cations are strongly oxidizing intermediates, but also after deprotonation at a heteroatom (in the present systems at nitrogen) some of this oxidizing property remains. Thus a common feature of these intermediates is that they are readily reduced by good electron donors. Since the heteroatom-centered radicals and the radical cations are always in equilibrium, it is, at least in principle, possible that such intermediates react with water at another site (canonical mesomelic form), that is at carbon. This reaction leads to OH-adduct radicals. Although deprotonation at a heteroatom is usually faster (but also reversible) than deprotonation at carbon, the latter reaction is typically "irreversible". This also holds for a deprotonation at methyl (in Thy). 

It has been mentioned above that the pyrimidine radical cations are reasonably strong acids and rapidly deprotonate at a heteroatom. As all protonation/ deprotonation reactions at heteroatoms are reversible [e.g., equilibrium (22)], the radical cations are regenerated upon reprotonation. Deprotonation at carbon or reaction with water yield the final free-radical products. For the l,3Me2Thy system, where the deprotonation/reprotonation equilibria such as reaction (22) fall away, reactions (25)-(28) have been postulated to account for the fact that in the presence of 02 l,3Me25HOMeUra and l,3Me25(CHO)Ura [reaction (29)] are formed in a combined yield of 80% of primary S04 radicals (Rashid et al. 1991). The formation of these products has been taken as evidence that a free radical cation must be an intermediate. It is, however, also possible that the allylic radical is formed in a concerted reaction HS04 elimination. For such a process, a six-membered transition state can be written. 

The optimal base for closure to epoxide 2 is sodium ethoxide in ethanol, as potassium hydroxide in ethanol, sodium or potassium carbonate in ethanol, or benzyllrimethylammonium hydroxide in ethanol resulted in the formation of a complex mixture of decomposition products arising mainly from deprotonation at carbon. 

Scheme 1.4 Substrates to assay enolization and deprotonation at carbon.

By contrast, kcat/f m for enzymatic catalysis of deprotonation at carbon is not strongly dependent on intrinsic carbon acidity. For example, kcat/ m is close to the diffusion-controlled limit for both the ketosteroid-isomerase-catalyzed deprotonation of the ketone 1 (pK 13) [39] and the triosephosphate-isomerase-catalyzed deprotonation of the ketone 3 (pK 18) [40]. An extreme example is the small difference in the values of kcat/Km = 3 x 10 and 1.4 x 10 s for enzyme-... 

Pulse radiolysis shows that the pyrimidine radical cations are fairly strong acids and rapidly deprotonate at a heteroatom [reaction (98)]. As protonation/deprotonation reactions at heteroatoms are easily reversible, the radical cations are regenerated upon reprotonation. Deprotonation at carbon or reaction with water yields the final free-radical products [reactions (99) - (101)]. It is noted that in thymidine [23] and 5 -thymidylic acid [104] the allylic thymine radical is observed by EPR and there is very little question that its precursor is the thymine radical cation. The identification of the C(6)-OH-5-yl radical by EPR supports the view [100] that reaction with water competes with the deprotonation at methyl. Due to the ready oxidation of the (reducing) C(5)-OH-6-yl by peroxodisulfate, this type of radical is only observed at low peroxodisulfate concentrations in these systems, i.e. the (oxidizing) C(6)-OH-5-yl radicals are correspondingly enriched under conditions favourable to a chain reaction [22]. In the case of 1,3-dimethyluracil the interesting characteristics of... 

Enolization in acidic solution is catalyzed by O-protonation. Subsequent deprotonation at carbon gives the enol ... 

The condensations of amines described so far are possible only for primary derivatives, because the nitrogen of the amine has to supply both of the hydrogens necessary to form water. Reaction with a secondary amine, such as azacyclopentane (pyrrolidine), therefore takes a different course. After the initial addition, water is eliminated by deprotonation at carbon to produce an enamine. This functional group incorporates both the ene function of an alkene and the amino group of an amine. 

Another classic in asymmetric synthesis is Oppolzer s sultam 91 [48], and various JV-acyl derivatives 92 were used - inter alia - for diastereoselective alkylations. Early attempts for enolate generation from amides 92 were plagued by competing deprotonation at carbon 10, adjacent to the sulfonyl group, but regioselective metallation at the a-carbonyl position was achieved by treatment with -butyllithium, LICA, or NaHMDS. The method is applicable not only to the sultam derived from propionic acid 92 (R = Me) but also to substituted and... 

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