2-acyl-3-aminothiophenes

Another valuable multicomponent reaction is the Gewald synthesis leading to 2-acyl-3-aminothiophenes these are of current interest because they are commercially used as dyes or conducting polymers and have much pharmaceutical potential. 

Microwave irradiation has been used to accelerate the Gewald reaction for the one-pot synthesis of N-acyl aminothiophenes on solid support [67]. A suspension of cyanoacetic acid Wang resin 35, elemental sulfur, DBU and an aldehyde or ketone 36 in toluene was irradiated for 20 min at 120 °C in a single-mode microwave synthesizer (Scheme 13). Acyl chloride 37 was added, followed by DIPEA, and the mixture was irradiated for 10 min at 100 °C. After cooling to room temperature, the washed resin was treated with a TEA solution to give M-acylated thiophenes 38 in 81-99% yield and purities ranging from 46-99%. 

Thiocyanation of 2-(acyl)aminothiophenes gives 3-thiocyano derivatives which cyclize to 2-(acyl)aminothieno[2,3-d]thiazoles (73JPR539). 5-Amino-3-phenyl-4-thiocyanatopyrazole, under a variety of conditions, afforded 2-amino-6-phenylthiazolo[4,5-cJpyrazole (equation 48) (79JHC61). 

Microwave assisted Gewald synthesis of 2-acyl aminothiophenes 13 on solid support has been carried out by Gauvin and co-workers <03SL63>, wherein the solid support was a cyanoacetic acid Wang resin 12 (Scheme 3),... 

Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis <0314851>. While alkyl or aromatic substitutions on the P position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3- disubstituted thiophene. 

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). 

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... 

The free bases are much less stable than aniline, particularly 2-amino-pyrroles and -furans which are very easily oxidized or hydrolyzed. 2-Aminofurans substituted with electron-withdrawing groups (e.g. N02) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Aminothiophene can be diazotized and the resulting diazonium salt coupled with (3-naphthol. 2,3-Diaminothiophene has been prepared and isolated as the hydrobromide. The free base is not stable (85JCR(S)296). 

Aminothiophenes (isolated as acyl derivatives) result from reduction of nitrothiophenes (63AHC(l)l). Catalytic reduction of 2- or 3-nitrobenzo[7>]thiophene followed by immediate acylation gives acylaminobenzo[6]thiophene (70AHC(11)177). Reduction of 2-nitrobenzo[6]-thiophene with ethanolic ammonium sulfide gives thiooxindole. 

Owing to their high reactivity, acylated 2-aminothiophenes react readily with oxalyl chloride in the absence of catalysts to give thieno[2,3-Z>]pyrroles (equation 11). Thieno[3,2- >]pyrroles were prepared in a similar fashion from 3-acylaminothiophenes (75CHE666). 

MO calculations on simple aminothiophenes show them to exist in the aromatic amino form rather than in the nonaromatic imino tautomeric form <1981AQ105>. The 2- and 3-aminothiophenes are generally unstable in air. They are much more stable as salts or as their A -acyl derivatives and are also more stable in solution than in the neat liquid state. 

The Gewald synthesis can be performed on a solid support. Treatment of resin-bound nitrile 559 with carbonyl compounds and sulfur gives resin-bound aminothiophenes 560. Acylation and removal of the resin provide thiophenes 561 (Scheme 88) <2001TL7181>. The same resin-bound nitrile 559 reacts under MW irradiation to give 560 <2004S3055>. MW-assisted synthesis of 2-A -acylthiophenes 563 from 562 on a solid support has also been reported <2003SL63>. 

Here again, these thiophene derivatives are much less stable than their benzenoid counterparts, unless the ring is provided with other substitution. The unsubstituted aminothiophenes (thiophenamines) can be obtained by reduction of the nitrothiophenes, but in such a way as to isolate them as salts - usually hexachlorostannates - or via Beckmann rearrangements or Hofmann degradation, as acyl derivatives which are stable. Many substituted amines have been prepared by nucleophilic displacement of halogen in nitro-halo-thiophenes. In so far as it can be studied, in simple cases, and certainly in substituted thiophenamines, the amino form is the only detectable tautomer. ... 

In this context, microwave-assisted Gewald synthesis on commercially available cyanoacetic acid Wang resin as solid support has been investigated [55]. By application of microwave irradiation the overall two-step reaction procedure, including the acylation of the initially formed 2-aminothiophenes, could be performed in less than 1 h (Scheme 16.32). This solid-phase one-pot two-step microwave-... 

---