Thiophene acid-catalyzed rearrangement

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

In examining data on selectivity of electrophilic substitution, especially halogenations, one is well advised to examine the conditions under which the data were collected, owing to the fact that thiophenes bearing halogen substituents at the a-positions are often extremely subject to acid catalyzed rearrangements to the thermodynamically more stable isomers (68JOC2902). 

The acetyl derivative of 3-hydroxybenzo[ ]thiophene-2-carbaldehyde 222 undergoes acylotropic acid-catalyzed rearrangement to the 2-acetoxymethylenebenzo[ ]thiophen-3(2//)-one 223, which is stable in hydrocarbon solvents up to 100°C (Scheme 15) <1985JOU862>. 

The only simple example of the formation of 3-substituted thiophene derivatives is the indirect acid-catalyzed rearrangement of 24 (R = C02Et) to give ethyl 2-(3 -thienyl)acetate (25) (22LA154). More complex examples of this reaction are discussed in Section III,D. 

Efficient preparation of 2,3-diarylbenzo[ft]thiophenes (475) is accomplished in two ways starting from thioisatins (474) (Scheme 98) <83TL3381>, A series of reactions, that is, Grignard reaction, pinacol rearrangement, hydride reduction, and acid-catalyzed rearrangement, converts (474) to thiophenes (475). Another series of reactions, Friedel-Crafts reaction, hydride reduction, and acid-catalyzed rearrangement, also convert (474) to (475). 

Cyclization of benzophenones having an o -thioacetic acid, ester or amide group has been used in structure studies and to synthesize 3-phenylbenzo[6 ]thiophenes with specific substituents. Thus (57) was readily converted to (58 X = OH, OEt or NH2) as precursors to a variety of benzo[6 ]thiophenes (57AC(R)705>, and as precursor to the unequivocal synthesis of 3-phenylbenzo[6 jthiophene, to demonstrate a remarkable sulfur-catalyzed rearrangement (59AJC218). 

Ring-closure techniques are more commonly used to obtain 3-alkylbenzo[6]thiophenes. Thus, acid-catalyzed cyclization of arylthio methyl ketones gives the 3-alkylbenzo[6]thio-phenes in good yield, with little rearrangement (equation 3). Formation of the 3-aryl-benzo[6]thiophenes by this approach is complicated, however, by rearrangement to the 2-isomer (Section 3.15.2.3.2). 3-Methylbenzo[f> Jthiophene is also obtained by decarboxylation of the corresponding 2-carboxylic acid (equation 4), readily available from ar-mer-captocinnamic acids (Section 3.15.2.1.1). 

It appears, therefore, that such a rearrangement may occur also during the polyphosphoric acid-catalyzed ring closure of 2-thienyl dimethoxyethyl sulfide (23). Thus, the method of Tilak et a/.30-33,36 cannot be considered as an unambiguous route to a model thieno[2,3-61-thiophene (1). 

The base-catalyzed rearrangement of thenils leads to thiophene analogs of benzilic acids. These compounds are rather unstable, but their esters are not, and Schuetz and Nilles88 obtained good yields of the latter (38, R = R1 = H, F, Cl, Me R = H, R1 = Me) from a range of thenils (37, Eq. 15). 

Several other cyclizations have been achieved by intramolecular electrophilic attack on thiophene. Thus, acid-catalyzed cyclization of suitable substrates has been used to synthesize several thi-enomorphans <91H(32)107>. Interestingly, the product of cyclization of (69) depends on the acid catalyst employed. While polyphosphoric acid gives the expected (70), refluxing TFA leads to the rearranged product (71) (Scheme 15) <82CC793>. 

The pronounced acidity of the bridgehead hydrogen atoms in 4 (R = H) facilitates the regio-selective introduction of electrophiles. Rearrangements of 4 (R = H, Me, CHO, C02Me) catalyzed by dicarbonyldichlororhodium(I) lead to 4-substituted 1-benzothiepins 5,10 except in the case of R = Me where a mixture (1 1.3) of 3- and 4-methyl-l-benzothiepin is obtained (total yield 98 %). In the case of the dimethyl-substituted derivative 8 (R1 = R2 = Me), however, the rhodium(I)-catalyzed isomerization reaction leads to the thiophene isomer. 

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