2- Amino-5- thiophene

Pharmaceuticals and Agrochemicals. ThioglycoHc acid and its esters are useful as a raw material to obtain biologically active molecules. In cephalosporine syntheses, (4-pyridyl)thioacetic acid [10351-19-8] (65) and trifluoromethane (ethyl) thioglycolate [75-92-9] (66) are used as intermediates. Methyl-3-amino-2-thiophene carboxylate can be used as intermediate for berbicidal sulfonylureas (67) and various thiophenic structures (68). 

The cyclic thioketone, 3-oxotctrahydrothiophene (11), gives a mixture of enamines (12,13) when caused to react with a secondary amine such as piperidine or pyrrolidine (31). The enamine mixture can be reduced to the 3-aminotetrahydrothiophene using formic acid or oxidized to the 3-amino-thiophene using diisopentylsulfide. 

Gewald K, Schinke E, Bottcher H. 2-Amino-thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Scwefel. Chem Ber 1966 99 94-100. 

Thieno[3,4- ]pyrrolizin-8-one 4 <2004JEZ585> has been synthesized from 4-amino-thiophene-3-carboxylate 268 (Scheme 48). This useful starting material was converted into ester 269 and the amide 270, to afford 4 (Scheme 48). 

Zum Ersatz des Jod-Atoms in Aryl-jodiden durch die unsubstituierte Amino-Gruppe eig-net sieh auch die Reaktion mit Kupfer(I)-bis-[trimethylsilyl]-amid in siedendem Pyridin das auf diese Weise zunachst erhaltene Aryl-bis-[trimethylsilyl]-amin ergibt bei der Methanolyse das primare aromatische Amin, z. B. Anilin (60%), 4-Methoxy- (45%), 4-Me-thyl-anilin (50%), 2-Amino-thiophen (45%). Das Kupfer(I)-bis-[trimethylsilyl]-amid wird in situ aus Hexamethyldisilazane, Butyllithium und Kupfer(I)-jodid erzeugt4. 

Chakrabarti and coworkers at Eli Lilly in the United Kingdom have reported the initial discovery and synthesis of olanzapine (Schemes 5 and,6). The thiophene 22 was synthesized by adding a DMF solution of malononitrile to a mixture of sulfur, propionaldehyde and triethylamine in DMF. The anion of amino thiophene 22 underwent a nucleophilic aromatic substitution with 2-fluoronitrobenzene to provide 23. The nitro group was reduced with stannous chloride and the resulting anihne cyclized with the cyano group to form amidine 24. Finally, a mixture of N-methylpiperazine and 24 were refluxed in DMSO/toluene to afford olanzapine (2). 

Hoener, A.P.F., Henkel, B. and Gauvin, J.C., Novel one-pot microwave-assisted Gewald synthesis of 2-acyl amino thiophenes on solid support, Synlett, 2003, 63-66. 

Furthermore, the Gewald reaction [66] opened a simple and economic route from aliphatic reactants to amino thiophenes that were formerly only accessible from multistep reactions [67] (see, e.g., the dye 31). For example, 2-amino-3-car-bethoxy-5-nitrothiophene, a precursor for the dye 32, can be prepared by reaction of 1,4-dithiane with ethyl cyanoacetate and subsequent nitration. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Neidlein and Sui (91HCA579) prepared methyl 3- [2-alkoxycarbonyl)-l-amino-2-cyanoethenyl]amino thiophene-2-carboxylates 225 by treating the potassium salt of alkyl dicyanoacetates 224 with o-aminoester 220 in refluxing hydrochloric acid. Carboxylates 225 were then cyclized to (4-oxothienopyrimidin-2-ylidene)acetates 226 in boiling DMF without catalyst. Prolonged heating of the ester 220 and the salts 224 in hydrochloric acid provided a direct route to the acetates 226, albeit in lower yield. 

Trioxopyrido[3,2, 4,5]thieno[3,2-<7]pyrimidin-4(3//)-ones were synthesized by the reactions of 3-amino-2-ethoxycarbonylthieno[2,3-Z>]pyridines with isothiocyanates (1997JHC937) or by the reactions of 3-amino-2-cyano(carbamoyl)thieno[2,3-Z>]pyridines with carbon disulfide (1998M523). An analogous reaction of 2-amino-thiophene-3-carboxamide with carbon disulfide yielded thioxopyrimidinone 10 (1990PS181, 1993MI1). 

Mit uberschiissigem Chlormethylen-dimethyl-iminium-dichlorphosphat kann 2-Acet-amino-thiophen zum 2-Acetamino-3,5-diformyl-thiophen (94%) diformyliert werden500. 2-Fo rmyl-se le nop hen (70-74%) erhalt man mit Chlormethylen-dimethyl-iminium-di-chlorphosphat bzw. N-Chlormethylen-N-methyl-N-phenyl-iminium-dichlorphosphat unter ahnlichen Bedingungen wie das Thiophen-Derivat503-505. 

Just as in benzene chemistry, Wolff-Kischner or Clemmensen reduction of ketones is a much-used route to alkyl-thiophenes, hypochlorite oxidation of acetyl-thiophenes a good route to thiophene acids, Beckmann rearrangement of thiophene oximes is a useful route to acylamino-thiophenes and hence amino-thiophenes, and esters and acids are interconvertible without complications. 

Here again, these thiophene derivatives are much less stable than their benzenoid counterparts, unless the ring is provided with other substitution. " The unsubstituted amino-thiophenes (thiophenamines) can be obtained by reduction of the nitro-thiophenes, "" 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. 3,4-Dinitration of 2,5-dibromothiophene, then reduction, produces 3,4-diaminothio-phene. " " 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 amino-thiophenes the amino form is the only detectable tautomer. " ... 

Microwave irradiation in the presence of triethylamine was used for the synthesis of 4,5-unsubstituted 2-amino-thiophenes using thioacetaldehyde dimer. ... 

Amino-3-cyano-thiophenes or 2-amino-thiophene-3-esters result from this route, generally conducted as a one-pot process, involving a ketone that has an a-methylene, ethyl cyanoacetate or malononitrile, sulfur, and morpholine. Various improvements to the original procedure include using microwave irradiation on solid snpport, or with potassium fluoride on alumina as the base, or solvent-free,and using morpho-lininm acetate in excess morpholine for aryl alkyl ketones. 

The Structures and Reactions of Hydroxy-, Mercapto-, and Amino-thiophens.-... 

Tiamenidine, N-(2-Chloro 4-methyl-3-thitnyl)-4,5-dihydro-1 H-imidazot-2-amine 2-1(2 -chloro -4 -methyl -3-thienyl)amino]-2-imidazoline 2-chloro-4-methyl-3-(2 -imidazolin-2 -y]amino)thiophene- C,HwCINjS mol wt 215.70. C 44.55%, H 4.67%, Cl 16.43%, N 19.48%, S 14.86%. A thiophene analog of clonidine, q.v. Prepn R. 

Thiourea has been used similarly to prepare, at 175°C (3 hr) up to 205°C (20 min), good yields of annelated 2-thioxopyrimidin-4-ones such as 8-methyl-2-thioxo-8-azapurin-6-one (156) from 4-amino-1,2,3-triazole-5-car-boxamides (see 20),254 as well as pyrazolo[4,3-d]- and pyrazolo[3,4-d]pyri-midinediones from the appropriate aminopyrazolecarboxamides (see 15) 24,221 and thieno[2,3-d]pyrimidine-2,4-diones (see 12) from 2-amino-thiophene-3-carboxamide.25 5... 

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