3- Amino-4-nitrothiophenes

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). 

Raney nickel desulfurization has been applied especially to the synthesis of different kinds of amino acids. a-Amino acids have been prepared by the Strecker synthesis of substituted thiophenealdehydes, followed by desulfurization of the thiophene a-amino acids. a-Amino-n-enantic acid, a-amino-n-caprylic acid, and norleucin have been obtained in about 50% yield from the appropriate thiophene aldehydes. From the desulfurization of thiophene -amino acids, obtained from the reaction of thiophenealdehydes with malonic acid in ammonia, aliphatic j8-amino acids, isolated as acetates, have been obtained in high yields. The desulfurization of 3-nitrothiophenes, such as (232), in ammonia leads to y-substituted amino acids (233). ... 

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). 

Isolated examples of syntheses of thieno[2,3-,7 pyrimidines commencing with either amino- or nitrothiophene possessing no other functionality have been described <2004CHE370, 1996J(P1)417, 1996J(P1)1403>. 

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. 

Azides are formed by the reaction of lithio derivatives with />-toliicncsulfonyl azide, and these in turn can be converted into the corresponding amino compounds by a variety of reductive procedures. Nitro compounds are available by a novel reversal of the general pattern of reaction with electrophiles. This approach requires the initial conversion of the lithio compound into an iodonium salt followed by reaction with nitrite ion. This is illustrated by the preparation of 3-nitrothiophene (Scheme 145). Other nucleophiles, such as thiocyanate ion which yields the 3-thiocyanate, can be employed. The preparative significance of these reactions is again that products not accessible by electrophilic substitution can be obtained. 

Nucleophilic displacement of bromine in the readily available benzo[Z>]thiophene-l,l-dioxide 44 with phenols proceeds often in very good yields, as demonstrated by preparation of the molecule 45 <07TL2349>. It has also been found that 4-alkyl-2-nitrothiophenes participate in nucleophilic substitution reactions with secondary aliphatic amines in the presence of silver nitrate, rendering the corresponding 3-alkyl-2-amino-5-nitrothiophenes. In contrast, 2-nitrothiophene itself is ring-opened under such conditions <07JOC5771>. 

In the presence of strongly electropositive or electronegative substituents, values outside this range are observed a 73 4 of 6.0 Hz is observed for 2-amino-5-nitrothiophene <1981JHC851>. 

Scheme 3 Michael-type addition of secondary amines to nitrothienyl substituted alkynes and NLO data of selected P-amino vinyl nitrothiophenes...

Miiller TJJ, Robert JP, Schmalzlin E, Brauchle C, Meerholz K (2000) A straightforward modular approach to NLO-active P-amino vinyl nitrothiophenes. Org Lett 2 2419-2422... 

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. ... 

The S-alkylation of thio-nitroacetamides with 2-bromoketones produces 2-amino-3-nitrothiophenes. The scheme below shows how the 3,4-bond making involves the intramolecular interaction of the introduced ketone carbonyl with an enamine/ thioenol / -carbon. ... 

A very promising new route to substituted thiophens has recently been developed by Hartmann. The reaction of 2-aryl-1,3-oxathiolium salts such as (33) with malononitrile in the presence of base yields 3-amino-4-cyanothiophens (34), with ethyl malonate or ethyl cyanoacetate 3-hydroxy-thiophens (34a), and finally with nitromethane 3-nitrothiophens (34b). The... 

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