Thiophene-2-carboxylic acid, lithiation

Lithiation at a thiophene P-position, in the presence of a free a-position, can be achieved with the assistance of an ort/to-directing substituent at C-2. Thiophene-2-carboxylic acid lithiates at C-3, via ortho assistance, using n-butylhthium, but at C-5 using lithium diispropylamide. 3-(Hydroxyalkyl)thiophenes, again with orthx) assistance, are lithiated at C-2. The lithiation of 2-chloro-5-methoxythiophene at C-4 and C-3, in a ratio of 2 1, is instructive, as is the deprotonation of 2- and 3-bromothiophenes at 5- and 2-positions, respectively, with lithium diisopropylamide. The conversion of 3-isopropylthiophene into the 2-aldehyde by Vilsmeier formylation, but into the 5-aldehyde via lithiation, presents a nice contrast. Lithiation of 3-hexyloxythiophene can be carried out with thermodynamic control at C-2 using n-butyllithium and with kinetic control using lithium diisopropylamide at C-5. ... 

Thiophene-2-carboxylic acid lithiates at C-3, via ortho assistance, using butyllithium, but at C-5 using lithium diisopropylamide. The lithiation of 2-chloro-5-methoxythiophene at C-4 and C-3, in a ratio of 2 1, is instructive. 2-and 3-Bromothiophenes undergo lithium-halogen exchange with w-butyllithium, but a-deprotonation with LDA. ... 

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

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... 

H2O, 5 h, 20°C). Use of 3.3 equiv. of jec-butyllithium has been shown to give the dilithiated compound (112), thus making it possible to synthesize 3,5-disubstituted thiophene-2-carboxylic acids <85TL5335>. Surprisingly, the acyclic imidates (113) do not show any C-3 directing effect on lithiation <94T4149>. A wide variety of conditions has been tried, (n-BuLi, jec-BuLi. LDA, THF, DME, hexane, Et20, TMEDA), but in all cases, virtually exclusive C-5 lithiation has been shown to occur. This is in contrast to the behavior of the cyclic imidate (109). 

The carboxylate anion itself can function as a )S-directing group towards metalation if it is attached to position 2 of the thiophene ring <85TL1777>. However, this effect is dependent on the reagent employed for lithiation. Treatment of thiophene-2-carboxylic acid with 2.2 equiv. of n-BuLi... 

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. 

The synthesis of thieno[3,2- >]thiophene [17, 18] is shown in Scheme 3.3. The commercially available 3-bromothiophene undergoes formylation via lithiation at the 2-position and the addition of Al-formy[piperidine. Subsequent treatment of 3 with ethyl 2-sulfanylacetate affords the ester 4, which is converted to thieno[3,2- >]thiophene by hydrolysis and decarboxylation steps. The product is thus obtained in a very satisfactory overall yield of 60%. A similar method can be used to prepare thieno[2,3- >]thiophene from thiophene-3-carboxaldehyde via the carboxylic acid [19], but an attractive alternative route was published in full by Otsubo et al. [20] following a brief communication from de Jong and Brandsma [21], In this strategy, trimethylsilyl-l,3-pentadiyne is treated with potassium rerr-butoxide, butyllithium and carbon disulfide and then with ferr-butanol in HMPA, to obtain thieno[2,3-fi]thiophene in 46 % yield. The reaction sequence can be used to obtain the product in multigram quantities and the diacetylene derivative can be easily prepared from (Z)-l-methoxybuten-3-yne in 65 % yield. 

The preparation of thieno[3,2-fc]thiophene was reported by Iddon and co-workers [76, 77] and it is readily prepared in four steps from commercially available 3-bromothiophene (Scheme 17.1). Thus 3-bromo-thiophene can be lithiated in the 2-position with a bulky non-nucleophilic base such as lithium diisopropylamine. Quenching of the resulting thiophene anion with dimethylfonnamide or tV-formylpiperidine afforded the thiophene aldehyde. Treatment of this o-bromoaldehyde with ethyl 2-sulfanylacetate in the presence of base afforded thieno[3,2-fc]thiophene carboxylate ester in good yield. Hydrolysis of the ester group, followed by thermal decarboxylation of the resulting acid with quinoline in the presence of copper, afforded the unsubstituted thieno[3,2-f>]thiophene in overall yields of approximately 60 % over the four steps. 

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