3- Aminothiophene derivatives

In this chapter, four different essential MCRs have been compiled, in particular Radziszewski, (aza-)Sakurai, Gewald, and Kabachnik-Fields reactions (Scheme 12.31). These reactions give access to five types of products substituted imidazoles, homoallylic ethers(amines), 2-aminothiophene derivatives, and a-aminophosphonates. The interest in these moieties is broadly recognized in the scientific community, since, among other properties, they are found in the structure of numerous biologically active natural or synthesized molecules. 

An elegant method for the utility of unstable 3-unsubsti-tuted 2-aminothiophene derivatives 385 in the Yonemitsu-type reaction has been elaborated by Krayushkin et al. (Scheme 13.81) [153]. Starting from stable 4,5-disubstituted ethyl 2-aminothiophene-3-carboxylates 383, the ester functionality is hydrolyzed to yield the corresponding alkali metal carboxylates 384. These are directly subjected to the three-component Yonemitsu-type reaction in acetic acid as the reaction medium. Protonation of the carboxylate followed by decarboxylation generates the 2-aminothiophene derivatives 385 that directly undergo Yonemitsu reaction without the need of isolation of those intermediates. This method has been applied to methyl 2,4-diaminothiazole-5-carboxylates 388 [154], ethyl 5-aminopyrazole -carboxylates 389 [155], dimethyl 3-aminopyrrol-2,4-dicarboxylates 390 [156], 4,5-disubstituted methyl 3-aminothiophene-2-carboxylates 391 [157], dimethyl 3-amino-4-phenylthiophene-2,5-dicarboxylate 392 [156], and ethyl 5-amin(Mmidazol-4-carboxylates 393 [158]. 

The aminothiophene derivative 2, which is produced by reduction of the corresponding nitro compound 1, cyclizes spontaneously to the thienodiazepinedione 3. An analogous reaction of 4 yields compound 5.307... 

A greatly improved experimental procedure for the synthesis of thieno[2,3-d]-1,2,3-thiadiazole caiboxylates 68 was reported by Stanetty et al. and involved diazotisation of aminothiophene derivatives 67 <99JHC761>. In these systems, substituents could be introduced into the 5-position by nucleophilic displacement of a chlorine atom or by metallation of the unsubstituted compound (68 R = H) and subsequent electrophilic quenching <99JPR391>. 

The transformation is not limited to anilines. Other or//w-disubstitutcd aromatic compounds work also well as substrates. The TV-Boc protected 2-iodo-3-aminothiophene derivative was transformed into the corresponding pyrrolothiophene in good yield (3.86.). The use of a silyl group was also... 

Poly(3-aminothiophene) derivatives have also been prepared showing absorptions in solutions at 482-535 nm and in film at 510-545 nm (05SM (152)137). The electropolymerization of 3,4-dimethoxythiophene gave the corresponding polymer showing absorptions in the 300 100 nm region. It emits at 534 and 537 nm (01SM(123)365). 

A number of densely substituted 3-aminothiophene derivatives, including several fused systems, have been obtained by cyclization reactions of suitable acrylonitriles or similar precursors with ethyl mercaptopyruvate in the presence of a base, as illustrated by the conversion of the pyridine-1-oxide 4 into the pyridothiophene 5 <05JHC661>. Similar annulations involving 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde and methyl mercaptoacetate leading to thieno[2,3-t/]pyrimidine derivatives have also been reported <05JHC1305>. 

Thus, treatment of the resin bound (cyanoacetyl)piperazine 160 with aliphatic or aromatic isothiocyanates in the presence of DBU, followed by S-alkylation with a-haloketones under slightly acidic or neutral conditions resulted in the formation of the intermediates 161 and 162 (which one being the predominant form was determined by the electronic properties of the substituents R -R ). The treatment of these intermediates 161/162 with DBU in DMF following acidolytic cleavage of the resin with TFA yielded 3-aminothiophene derivatives 163 as trifluoroacetates. This synthetic sequence towards 163 encountered however some limitations. For instance, complex mixtures of products were obtained in those cases, where strongly electron-donating isothiocyanates or a-haloketones were used, and in general, no thiophenes resulted from aliphatic haloketones, except for 3-bromo-l,l,l-trifluoro-2-propanone. 

The key intermediate for the synthesis of penthiopyrad, l-methyl-3-trifluoro-methylpyrazole-4-carboxylate 29, is prepared as shown in Scheme 11.8 by treatment of ethyl trifluoroacetate with ethyl cyanoacetate in the presence of a base such as sodium methoxide to give butenoate 27 followed by treatment of methyUiydrazine sulfate in the presence of trifluoroacetic acid. The deamination of 28 by diazotization-deazotization gives the key intermediate 29. The final steps to penthiopyrad involve amination of ester 29 with the appropriate 2-alkenyl-3-aminothiophene derivative followed by hydrogenation using a noble metal catalyst. ... 

Aminothiophene derivatives possessing an ortho-c thoay or nitrile substituent are good precursors for several heterocondensed thiophene systems. It is impossible to list all the different structures that have been synthesized by this procedure. Only a few examples are given below. Thieno[2,3-t/]pyrimidines have been made from 2-aminothiophene-3-carbonitrile and guanidine... 

The synthetic versatility of the Fiesselman and Gewald reaction is further highlighted in the synthesis of both 2-amino- and 3-aminothiophene derivatives by Romagnoli and co-workers. " ... 

Given the plethora of new and "improved" methods, it is perhaps surprising that the original Hofinann conditions still find utility. Thus, the action of bromine and sodium hydroxide solution effects the conversion of 3-acetamidothiophene to 3-aminothiophene derivatives (70-82%), 6-fluoropicolinamide to 2-amino-6-fluoropyridine (87%)," 2-azidobenzamide to 2-azidoaniline (49%), A-a-tosylasparagine to 2-(5)-tosylamino-p-alanine multi-kilogram scale (70%), 3-(4 -methoxyphenyl)-2-methyl-... 

Agrochemical Products. The principal thiophene derivative in herbicidal protection, one of a range of sulfonylurea herbicides, is Harmony [79277-27-3] (Du Pont) (60), based on the intermediate methyl 3-aminothiophene-2-carboxylate (9). The product is characterized by a rapid biodegradabHity in the soil. Many other thiophene derivatives have been shown to have agrochemical activity, but few of these have been developed to the commercial level. 

Both 2- and 3-nitrothiophenes are reduced by tin and hydrochloric acid to the corresponding aminothiophenes. In contrast to anilines, the free bases are very unstable their salts and acyl derivatives, however, are stable. 2-Aminothiophene can be diazotized and the resulting diazonium salt coupled with /3- naphthol. The chemical instability of aminothiophenes compared with aniline is illustrated by the ring opening of 2-amino-3-ethoxycar-bonylthiophenes (157) with ethanolic sodium ethoxide to give cyanothiolenones (158) <75JPR861). 

Most aminothiophenes are prepared by the reduction of nitrothio-phenes. Aminothiophenes or their derivatives have also been obtained through the Hofmann rearrangement of the acid amides, which, however, fails with 2-thenamide, in contrast to the 3-isomer. The Beckmann rearrangement of the oxime of 2-acetylthiophene has been applied successfully to the preparation of 2-acetamidothiophene. The free aminothiophenes are very unstable compounds and it has not been possible to distil 3-aminothiophene. They are best stored as the stannic-chloride double salts and give stable acetyl derivatives. 

The reactivity of the 5-position of 2-aminothiophene in diazo coupling, which is present also in the acylated derivatives, complicates the formation of a diazonium salt from 2-aminothiophene. Thus Steinkopf and Miiller obtained only an azo dyestuff, although they proved, through the isolation of small amounts of 2-thienyl diazonium chloride, the diazotizability of 2-aminothiophene which had earlier been denied. However, recent Russian work claims the preparation of 2-thienyldiazonium chloride by treating the double salt in 10% hydrochloric acid with sodium nitrite. Amazingly high yields (over 90%) of azo compounds were then achieved by coupling the diazonium salt solution with y9-naphtol, w-toluidine or with the 2-aminothiophene double salt. These authors have also studied the... 

Synthesis of the central ring. Several syntheses of thienopyridopyrimidines start from 2-aminothiophene-3-carboxylic esters and substituted derivatives (Equations 173-175) <1996CHE689, 2000J(P1)3686, 2000PS(167)133, 2003MOL322>. 

The most common method for the preparation of 1,2,3-benzothiadiazoles is the diazotization of 2-aminobenzenethiol. This method was discussed and exemplified in CHEC-II(1996). The method has been extended in recent years to include heterocyclic derivatives. The 2-aminothiophene 79 can be converted into the thienothiadiazole 82 on treatment with sodium nitrite in HC1 but in poor yield (16%). The bis(BOC)-protected derivative 80 or the mono(BOC)-protected derivative 81 when reacted under similar conditions afford product 82 in much higher yields (BOC = /-butoxycarbonyl Scheme 9). The increase in yield is explained in terms of hard and soft electrophilic character. The intermediate in the BOC-protected examples has a soft character allowing attack by sulfur to proceed more easily <1999JHC761>. 

The reaction of 2-aminothiophene-3-carboxylic acids (55) or 2-aminotet-rahydrobenzo(b)thiophene-3-carboxylic acid [55, R = R1 = —(CH2)4—] and EMME by heating at 110-120°C for 1-2 hr gave a mixture of 3-carboxylic acids (56) and decarboxylated derivatives (57) (75GEP2435025). 

Sodium 3-aminothiophene-2-carboxylates were reacted with EMME in boiling toluene in the presence of acetic acid for 4-6 hr to give 3-thienylaminomethylenemalonates (58) in moderate yields (87T3295 88EUP269295). The 5-bromo derivative of compound 58 (R = Br) was prepared in the reaction of 3-amino-5-bromothiophene and EMME, but 2-amino-5-nitrothiophene failed to react (87T3295). 

Aminothiophene, readily available from methyl 3-aminothiophene-2-carboxylate, undergoes a condensation reaction with compound 92, followed by heating at elevated temperatures in Dowtherm , to produce pyridone product (Equation 28). The pyridone can be converted into a thieno[3,2- ]pyridine derivative in a few straightforward steps <2004BML21>. 

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