Substituted 3-aminofurans

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 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>. 

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. 

An iodine-catalysed ring-opening 5 2 reaction of 2-substituted epoxides by 2-phenyl-l,3-oxazolan-5-one in the ionic liquid [BmimjOH forms 3-(A-substituted)aminofuran-2-ones in yields ranging from 84 to 95% with a diasteroselectivity of 95-98%P [BmimjOH was the best of five ionic liquid solvents tested and increasing the size of the cation did not affect the yield. A tentative multistep mechanism is presented. 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

The authors applied the similar methodology for a three-component reaction of dimethyl acetylenedicarboxylate, cyclohexyl isocyanide and several substituted ben-zaldehydes to obtain a small library of aminofurans (Scheme 9). Batch conversions reported in previous work required refluxing in benzene for 2-9 h [26] to achieve similar yields as reactions in dimethylformamide (DMF) under capillary flow using... 

Both 2- and 3-nitrothiophenes are reduced by tin and hydrochloric acid to the corresponding aminothiophenes. Reduction of 2,5-dibromo-3,4-dinitrothiophene gives 3,4-diaminothiophene as a stable crystalline solid. 2-Acetamido-furans are prepared by the reduction of 2-nitrofurans in the presence of acetic anhydride. 2-Substituted 5-nitrofurans can be reduced to the S-aminofurans by an electrochemical method. Although catalytic reduction gives 2-aminofurans only in low yields, they can be trapped using ethyl ethoxymethylenecyanoacetate or ethoxymethylenemalononitrile. Benzofuranone 412 and not 2-aminobenzofuran is obtained from tin and hydrochloric acid treatment of 2-nitrobenzo[ ] furan 411. 

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. 

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 parent 2-aminofuran 103 is extremely unstable but when generated in situ, by catalytic reduction of 2-nitrofuran, and immediately reacted with the electrophiles ethoxymethylene malononitrile (EMMN) and ethyl ethoxymethylenecyanoacetate (EMCA) the 5-substitution products 104 were formed in low yield (Eq. (16)) (93JHC113). If the 5-position is blocked as in the case of the 5-methyl derivative 105, or 2-aminobenzo[Z>]furan, then substitution occurs at position 3, e.g. 106 (Eq. (17)) (93JHC113). 

Volume 92 of Advances in Heterocyclic Chemistry commences with a survey of 2- and 3-aminofurans authored by C. A. Ramsden (Keele University, UK), and V. Milata (Slovak University of Technology, Bratislava). The review concentrates on the synthesis and properties of furans with primary amino groups these highly reactive structures are unstable unless substituted with electron-withdrawing groups. 

So little has been described of the chemistry of amino-furans that general comment on their reactivity is difficult to make it seems likely that simple amino-furans are too unstable to be isolable, though 2-acylamino-furans have been described, for example Boc-masked 2-aminofuran is obtained via a Schmidt degradation of the carbonyl azide in i-butanol. Heavily substituted amino-furans, in particular those with electron-withdrawing substituents on the ring or on the nitrogen are known. For example methyl 2-aminofuran-5-carboxylate is relatively stable it undergoes Diels-Alder cycloadditions in the usual manner (cf. 18.7). ... 

Later, Tu and coworkers [57] reported domino synthesis of furo[3,4-h][l, Sjnaphthyridines 93 through three-component reactions of aldehydes 69, 2-aminoprop-l-ene-l,l,3-tricarbonitrile 29, and N-substituted 4-aminofuran-2(5H)-ones 57 in EtOH using EtONa as a base (Scheme 12.36). N-substituted 3-aminocyclohex-2-enones were also suitable for this domino reaction, affording 21 examples of benzo[h][l,8]naphthyridines in 69-84% chemical yield, with the concomitant formation of two new pyridine rings. 

Recently, Tu, Li, and coworkers [58] described the first domino [4-1-1]/ [3- -2- -l]/[5- -l] and double [4-1-3] cyclization reactions of o-phthalaldehyde 94 and 4-hydroxy-6-methyl-2H-pyran-2-one 95 with N-substituted enaminones 57 (Scheme 12.37). Using N-substituted 3-aminocyclohex-2-enones as enaminone led to pentacyclic pyrano[3, 2 2,3]indeno[2,l-c]pyridines 96 in 44-68% yield, whereas by employing N-substituted 4-aminofuran-2(5H)-ones the reaction occurred in another direction to form multifunctionalized pentacyclic pyrano[4,3- j]oxepines 97. This work provides an attractive strategy for the construction of structurally diverse pentacyclic oxa-azaspiro and oxa-azabridged skeletons. 

J.S. Yadav, B.V.S. Reddy, S. Shubashree, K. Sadashiv, J. Naidu, Ionic liquids-promoted multi-component reaction Green approach for highly substituted 2-aminofuran derivatives. Synthesis 14 (2004) 2376-2380. 

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