Benzo thiophenes 2-lithiation

The most widely used routes to benzo[ >]thiophene-2-carboxylic acids are (a) successive lithiation and carbonation of the parent benzo[ >]thiophene,42,76 90 98,183,477, 481>487,521,685-687 (ft) oxidation of the corresponding aldehyde,90,91,106,189 424, 477,640 (c) hypohalite oxidation of the corresponding methyl ketone,82 °8,189,424 and (d) cyclization reactions (Section IV,D, and E). Acids prepared by these routes are listed in Table XV. Oxidation of aldehydes usually proceeds almost quantitatively with moist silver oxide,90,91,105, 189,424 hut potassium permanganate is satisfactory.477, 640... 

Competitive metallation experiments with IV-methylpyrrole and thiophene and with IV-methylindole and benzo[6]thiophene indicate that the sulfur-containing heterocycles react more rapidly with H-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(P1)887). Competitive metallation experiments have established that dibenzofuran is more easily lithiated than dibenzothiophene, which in turn is more easily lithiated than A-ethylcarbazole. These compounds lose the proton bound to carbon 4 in dibenzofuran and dibenzothiophene and the equivalent proton (bound to carbon 1) in the carbazole (64JOM(2)304). 

Benzo[b]thiophene, 3-mercapto-2-methyl-synthesis, 4, 931 Benzo[6]thiophene, 2-methoxy-lithiation, 4, 773 synthesis, 4, 929 Benzo[6]thiophene, 3-methoxy-alkylation, 4, 765 synthesis, 4, 929 Benzo[6]thiophene, 4-methoxy-anodic oxidation, 4, 798 Benzo[6]thiophene, 5-methoxy-synthesis, 4, 929 Benzo[6]thiophene, 6-methoxy-synthesis, 4, 929 Benzo[6]thiophene, 7-methoxy-synthesis, 4, 929-930... 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

Lithiation of benzo[6]thiophene occurs exclusively at position 2, leading to good yields of 2-substituted products. 2-Methoxybenzo[6]thiophene is reported to be lithiated at position 3 this is the only known direct lithiation at the /3-position (70AHC(11)177). Competitive metallation of benzo[6]thiophene and N-methylindole affords only 2-benzo[6]thienyl-lithium. 

The reaction of 2-lithiated benzo[7]thiophene with 8equiv of elemental sulfur gave pentathiepino[6,7-3]-benzoMthiophene 116 (Scheme 22) <2002JOC6220>. 

Lithiation of the tj -chromiurntricarbonyl complex of benzo[.J]thiophene occurs at C-2 with excess butyllithium the 2,7-dilithiated derivative results <2001AHC(78)1>. 

Benzo[fe]thiophenes, benzo[fc]furans and A -blocked indoles lithiate on the heterocyclic ring, a to the heteroatom. Lithiation at the other hetero-ring position can be achieved via halogen exchange, but low temperatures must be maintained to prevent equilibration to the more stable 2-lithiated heterocycle. 

Benzo[fe]furans and benzo[h]thiophenes undergo lithiation at their 2-positions, consistent with the behaviour of furans, thiophenes, and of iV-blocked pyrroles and indoles. 

Hexachlorobenzo[h]thiophene undergoes metal-halogen exchange first in the 2-position, then in the 6-position.342 When benzo[b]thiophene is lithiated in the presence of Al,N,M, M -tetramethylethylenediamine, under conditions which lead to 2,5-dilithiation in thiophene, some 2,7-dimetallated derivative (12%) is formed.580... 

Unusual polycyclic systems are available via lithiated benzo[f>]thiophenes. 3,3 -Di(benzo[h]thienyl) (136 X = H) is converted into the 2,2 -dialdehyde (136 X = CHO), which reacts with PhCH2NH2-Na2S204, to give the pentacyclic compound 137.583 The dilithio compound 136 (X = Li) dimerizes in the presence of CuCl2, to give 138 (X = BT).584 3-Benzo[f>]thienyllithium (1 mol) reacts with quinoxaline (1 mol), to give 2-(3-benzo[f>]thienyl)-... 

As shown in Exp. 14, methyl phenyl sulfide can be successfully converted into LiCH2SPh with one mol equivalent of the BuLiTMEDA reagent. Very recently Cabiddu et al. [1] reported that the mono-lithium compound can be specifically lithiated at the ortho-carbon atom in the ring by prolonged treatment with a second equivalent or butyllithium. A useful synthetic application is the preparation of benzo[b]thiophenes by reaction of the dilithio compounds with acyl chlorides [2]. 

Benzo[Z ]thiophene is somewhat less reactive in electrophilic substitutions than thiophene, and also less reactive than benzo[Z ]furan. Moreover, regioselectivity is poor, giving rise to mixtures. Frequently, the 3-position is attacked preferentially over the 2-position, e.g. in halogenation, nitration and acylation. Only the reaction with n-butyllithium is regioselective, giving 2-lithiated benzo[6]-thiophene. 

Diaminothiophene has been prepared and isolated as the hydrobromide. The free base is not stable <85JCR(S)296>. The t-butoxycarbonyl derivative of 3-aminothiophene was carboxylated at position 2 by lithiation (Bu"Li) followed by reaction with CO2. Reaction of this carboxylic acid (504) with diphenyl phosphorazidate in t-butanol gave the bis-carbamate (505). Removal of the protecting groups by HBr gave the hydrobromide salt of 2,3-diaminothiophene. 2,3-Diamino-benzo[Z>]thiophene was made by a similar procedure. 

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