Synthesis of novel 2-pyridyl-substituted 2,5-dihydro-2-imino-and 2-amino-furan derivatives via a three component condensation of alkyl isocyanides and acetylenic esters with di-(2-pyridyl) ketone or 2-pyridinecarboxaldehyde

The reactive 1:1 intermediate is trapped from reaction between alkyl isocyanides and activated acetylenic esters by di-(2-pyridyl) ketone or 2-pyridinecarboxaldehyde. An effective and one-pot route is presented to synthesize novel iminolactones and 2-aminofurans.


Results and Discussion
The reaction of alkyl isocyanides 1 or 5 with dialkyl acetylenedicarboxylates 2 in the presence of pyridine-containing carbonyl compounds 3 or 6 leads to the stable products 4a-c or 7a,b in excellent yields.A mechanistic rationale could be proposed for the formation of iminolactones or 2-aminofurans is shown (Scheme 2).The 1:1 zwitterionic intermediate which adds to the di-(2pyridyl) ketone leading to a dipolar species, cyclization of the latter leads to the iminolactone derivatives 4a-c, in the presence of 2-pyridinecarboxaldehyde, furan forms.This reaction, undergoes a [1,5]-hydrogen shift to yield the aminofuran derivatives 7a, b.
It is conceivable that these multicomponent reactions will be applicable to the synthesis of heterocyclic rings with high hindrance.Products 4a-c and 7a, b are stable solids which structures were deduced from their IR, 1 H-, and 13 C-NMR, Mass spectral data and elemental analysis.The 1 H-NMR spectrum of compound 4a exhibited two singlet sharp lines, readily recognizable as arising from carbomethoxy groups (at δ 3.82 and 3.93) ppm.The 13 C-NMR spectrum of 4a showed seventeen distinct resonances in a good agreement with iminolactone structure.The characteristic signals resulting from the quaternary carbon and C=N group of iminolactone were discernible at (δ 94.73 and 155.84) ppm respectively in the 13 C-NMR spectrum.Partial assignments of these resonances are given in the experimental data.
The 1 H-NMR spectrum of compound 7a exhibited three single sharp lines, readily recognizable as arising from tert-butyl (δ 1.52) and two carbomethoxy groups (δ 3.79 and 3.98) ppm and NH proton resonated at (δ 6.92) ppm supporting the IR absorption at 3335 cm -1 .The 13 C-NMR spectrum of 7a showed fifteen distinct resonances in an agreement with proposed structure.Signals resulting from two ester carbonyl were discernible at (δ 164.26 and 164.91) ppm in the 13 C NMR spectrum.The mass spectra of these compounds 7a, b displayed molecular ion peaks at appropriate m/z values.The 1 H-and 13 C-NMR spectra of 7b are similar to 7a with the exception of the carboalkoxy groups.

Scheme 2
In conclusion, we describe here, the reaction of alkyl isocyanides with activated acetylenes in the presence of pyridine-containing carbonyl compounds that leads to the one-pot and important synthesis of highly hindered and functionalized iminolactone or 2-aminofuran derivatives.The

Experimental Section
General Procedures.tert-Butyl-and cyclohexyl isocyanides, dialkyl acetylenedicarboxylates, di-(2-pyridyl) ketone and 2-pyridinecarboxaldehyde were purchased from Fluka and Aldrich, respectively, and used without further purification.Melting points and IR spectra were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-470 spectrometer, respectively.Elemental analysis for C, H and N were performed using a Heraeus CHN-O-Rapid analyzer.The 1 H-and 13 C NMR spectra were measured with a Bruker DRX-300 AVANCE instrument with CDCl 3 as solvent at 300.1 and 75.5 MHz, respectively.Mass spectra were recorded on a Shimadzu GC/MS QP 1100 EX mass spectrometer operating at an ionization potential of 70 eV.

General experimental procedure (exemplified by 4a)
The process for the preparation of 4a is described as an example.The solution of cyclohexyl isocyanide (0.131 g or 1.2 mmol) in 3 mL of CH 2 Cl 2 solvent was slowly added dropwise, to the mixture of di-(2-pyridyl) ketone (0.184 g or 1 mmol) and DMAD (0.171 g or 1.2 mmol) in 20 mL of CH 2 Cl 2 solvent at room temperature for 3 minutes.After the complete addition, the solution was refluxed at 38˚C for 16 hours.Then, the solvent was removed under reduced pressure, and the solid residual washed with cold diethyl ether (2×5 mL) and the product (4a) was obtained as a brown powder.

General procedure (exemplified by 7a)
The preparation of 7a is described as an example.To the solution of 2-pyridinecarboxaldehyde (0.107 g or 1 mmol) and DMAD (0.171 g or 1.2 mmol) in 20 mL of benzene solvent, was slowly added, dropwise, a mixture of tert-butyl isocyanide (0.100 g or 1.2 mmol) in 3 mL of benzene.To this mixture was allowed to stand for at room temperature for 3 min, then the reaction mixture was refluxed at 75˚C for 48 h.The solvent was removed under reduced pressure, and the solid product washed with cold diethyl ether and n-hexane with 1:3 ratios (2×3 mL) and the product (7a) was obtained as a brown powder.