2- aminofurans

The parent aminofurans 1 and 2 (R1 = R2 = R3 = H) appear to be the least stable of the simple heterocyclic amines and this is consistent with the view that they are the least aromatic. Although unstable, both 2- and 3-aminothiophene 3 and 4 have been isolated and characterised (13MI1155, 14AC403, 73JHC1067). The 2-aminopyrroles 5 have been characterised in solution (95TL9261). We have previously reviewed the chemistry of 4- and 5-aminoimidazoles (94AHC1). 

The instability of the parent 2-aminofuran ring may be due to facile tautomerism to an imine followed by ring-opening to 4-hydroxybutyronitrile. In spite of the apparent greater stability of the 3-aminofurans, much more is known about the chemistry of the 2-aminofurans and this probably reflects the greater availability of 2-substituted precursors. 

This review is principally concerned with the preparation and reactions of the furan primary amines 1 and 2. Where appropriate we have included related secondary and tertiary amines, and also amides and similar N-substituted amines but no attempt has been made to provide comprehensive coverage of non-primary amines or polycyclic derivatives. 

Properties of aminofurans have been investigated using semi-empirical 71-electron methods (70JA2929, 81AQ105), semi-empirical all valence electron AMI 

For 2-aminofurans the results of semi-empirical calculations have been found to be entirely consistent with the regioselectivity of substitution and cycloaddition reactions (93JHC113, 97JOC4088, 01JCS(P1)680). 

The substituted 3-aminofurans (91, R = H, Me) resinify in air, can be diazotized (structure 91), and are easily hydrolyzed (structure 92 ). ° The infrared spectra of both 2- and 3-acctamidofuran show a strong NH stretching band indicating that these compounds do, indeed, exist in the acetamido form.  

The a-aminobenzofuran 92a exists in the amino form shown, as evidenced by infrared and proton resonance spectra 

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The potential 2-hydroxy-3-aminofurans exist as enaminoketones 177 (89T6631). 

The present review covers the Thorpe-Ziegler syntheses of 3-aminofurans, 3-aminopyrroles, 3-aminothiophenes, 3-aminoselenophenes, and diverse aminoazoles as well as the corresponding annulated systems that appeared from 1983 to 1996 but excludes examples considered in the 3-cyanopyridine review (92MI1). Moreover, examples are included that do not report a separate Thorpe-Ziegler cyclization but are likely to involve this type of reaction (e.g., cases in which precursors 1 were not isolated and identified but directly formed in the reaction mixture). Special attention is paid to synthetic aspects, although some reaction mechanisms are discussed too. 

The highly substituted 3-aminofurans 240 can be conveniently prepared via a three-component reaction of thiazo-lium salts 239, aldehydes, and dimethyl acetylenedicarboxylate (Scheme 134) <2005JOC8919>, and 3,4-disubstituted thiophenes 242 are synthesized by an intermolecular cycloadditioncycloreversion procedure between substituted acetylenes and 4-substituted thiazoles 241 (Scheme 135) <1996CC339>. 

In dimethyl sulfoxide (DMSO) solution, both C-C and C-N rotational isomerism was observed in 3-aminofuran-2-carbaldehyde 35 (EjZ ratio 57 43), 3-aminofuran-2-thiocarbaldehyde 36 (EjZ ratio 78 22), 3-aminobenzo[ ]furan-2-thiocarbaldehyde 37 (EjZ ratio 72 28), and 2-aminobenzo[7]furan-3-thiocarbaldehyde 38 (EjZ ratio 55 45). Depending on the solvent the C-C rotational barriers of 35-38 were found at 16.2-22.2 kcalmoP and the corresponding C-N rotational barriers at 8.4-13.0 kcalmoP <1997JOC2263>. 

The lithiation of 3-(A -/i t7-butoxycarbonylamino)furan occurred regioselectively at the 2-position as a result of the apparent ort o-directing effect of the NHBOC group, providing 2-substituted-3-aminofurans after subsequent reactions with electrophiles, as represented in Scheme 25 <2006SL789>. In contrast, the lithiation of Z-(N-tert-butoxycarbonylamino)furan took place exclusively at the 5-position instead of the 3-position <2003T5831>. 

Substituted 3-aminofuran-2-carboxylate esters can be prepared following a simple two-step procedure (Scheme 10) <20000L2061>. n-Cyano ketones are coupled with ethyl glyoxylate under Mitsunobu conditions to provide a-cyanovinyl ethers in good yield. Subsequent treatment of the vinyl ether with sodium hydride affords the 3-aminofuran. It was found that carrying out the reaction sequence in a one-pot procedure afforded the 3-aminofuran in comparable yields. 

This review covers the literature on 2-aminofurans 1 and 3-aminofurans 2 up to the end of 2005. Most of the known derivatives of these amines are associated with electron-withdrawing substituents (typically CO.R or CN) either on the furan ring or on the amine nitrogen. In the case of 2-aminofurans this appears to be essential for the amine to be isolated and characterised. The parent amine 1 (R1 = R2 = R3 = H) is too unstable to be isolated or even trapped in useful yield. The 3-aminofurans seem to be relatively more stable although the parent system 2 (R1 = R2 = R3 = H) has not been reported, the 2-methyl and 2,5-dimethyl derivatives 2 (R1 = H, Me, R2 = H, R3 = Me) were reported in 1937, but have received no attention since. 

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