Aminofurans, synthesis

Synthesis ol 2-aminofurans (thiophenes, pyrroles) by cortdensation of malononitnles with ketones. 

Nair V, Vinod AU, Abhilash N et al (2003) Multicomponent reactions involving zwitterionic intermediates for the construction of heterocyclic systems one pot synthesis of aminofurans and iminolactones. Tetrahedron 59(51) 10279-10286... 

The reaction of a bis-alkynic alcohol (103) with aqueous dimethylamine gives dimethyl-aminofuran (104) (74IZV206). trans-Enynols cyclize presumably through a cis intermediate with base (75RTC70) or mercury(II) sulfate, a method used for the synthesis of the terpenoid bilabone (105) (69JOC857). 

Apart from reactions where Michael addition terminated the process, Gabriele and co-workers have developed a useful and expedient palladium-catalyzed synthesis of 4-aminofuran-2-one 113 starting from three simple starting components, a propargyl alcohol, a dialkyl amine and carbon monoxide [98] (Scheme 44). 

A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the 7-carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to constmct polyclic frameworks of natural products in a subsequent Diels-Alder reaction. 

An elegant application of the oxidation of 2-aminofurans has been described by Nicolaou and co-workers (02JA2190, 02JA2202) in model studies directed towards the total synthesis of CP molecules. In this study, the isolable iminobutenolide 80 is formed by cyclisation of the alkoxide 79 (Method B, Section II.B.l.b). Without a stabilising substituent on the ring the equilibrium favours the imine 80 rather than the amine 81 (Scheme 16). However, it is postulated that there is sufficient 2-ami -nofuran in equilibrium for this to be rapidly oxidised to the hydroperoxide 83. At this stage, the final product is determined by the reaction conditions. In strongly acidic conditions, tautomerism to the amine 85 and hydrolysis rationalises the formation of the isolated anhydride 88. Under weakly acidic conditions, formation of... 

Styryl derivatives of 2-aminofurans, as well as alkenyl compounds, also undergo intramolecular cycloaddition and the alkene function can be introduced by Stille coupling of a suitably functionalised aryl iodide. This approach is illustrated by the tetrahydroquinoline synthesis summarised in Scheme 26 (99JOC3595). The iodo derivative 143 is readily prepared from the carbamate ester 142 (67% yield) and Stille coupling with vinyltributyltin gives the styrene 144 (72% yield). Intramolecular cycloaddition and dehydration is then achieved simply by heating compound 144 in toluene under reflux (24 h) to give the tetrahydroquinoline 145 in 79% yield. 

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. 

On the contrary, with aromatic aldehydes carrying electron-releasing groups (such as 4-CH3, or 4-OCH3), products were obtained in poor yields. Several significant advantages, such as operational simplicity, mild reaction conditions, enhanced rates, improved yields, ease of isolation of products, recyclability, and the eco-friendly nature of the solvent, make this method a useful and attractive strategy for the synthesis of 2-aminofuran derivatives. 

Scheme 17.1 Synthesis of 2-aminofuran derivatives using [bmim]BF ...

The [4-1-3] cycloaddition between 2-aminofuran and oxyallyl cations, followed by base-induced elimination of the resulting adducts, was used in the synthesis of 3-aminotropones <05TL8475>. A chiral Lewis acid-catalyzed [4t-3] cycloaddition between furans and nitrogen-stabilized oxyallyl cations derived from allenamides was developed. As depicted below, the Cj-symmetric salen-based ligand is the most effective in promoting this asymmetric cycloaddition reaction <05JA50>. 

The thiazolium-mediated three-component reaction of thiazolium salts 201, aryl aldehydes and dimethyl acetylenedicarboxylate provides a facile synthesis of 2-amino-2-arylfurans 202 <05OL1343>. The reaction pathway may involve the sequential nucleophilic addition of thiazol-2-ylidene 203 with the aldehyde and DMAD to form the spirocyclic intermediate 204 through the simultaneous formation of two C-C bonds and a C-O bond Selective ring opening of the spirocyclic intermediate 204 followed by hydrolysis leads to 3-aminofuran 202 via 205. 

Scheme 5.33 Three-component synthesis of 2-aminofurans and 2-aminopyrroles.

Iron and cobalt carbene complexes are capable of much more selective furan synthesis. Reactions of cobalt methoxycarbenes with internal alkynes give good to excellent yields of 2-methoxyfurans and have been applied to a synthesis of a natural product, bovolide [75 b]. Both terminal and internal alkynes are viable substrates in the preparation of 2-aminofurans from iron (dimethylamino)carbenes [78], although the nature of the rearrangement of the heteroatom-containing substituent is also as yet unclear [Eq. (33)]. The inclusion of elevated carbon monoxide pressure can divert this reaction to the production of pyrones [75c, 79]. 

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