Short communication One-pot, Three-component Synthesis of Dialkyl 4-(alkylamino)-7-alkoxy-5-oxo-1-pyridine-2-yl-1,5-dihydrofuro[3,4-b]pyridine-2,3-dicarboxylate Sakineh Asghari* and Fatemeh Iravani Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, 47416-95447, Iran * Corresponding author: E-mail: s.asghari@umz.ac.ir Fax: 00981125342350 Received: 21-01-2012 Abstract A one-pot isocyanide-based three-component reaction of 2-aminopyridine and acetylenic esters with alkyl isocyanides afforded tetraalkyl 4-(alkylamino)-2_ff-1,2'-bipyridine-2,3,5,6-tetracarboxylate and dialkyl 4-(alkylamino)-7-alkoxy-5-oxo-1-pyridin-2-yl-1,5-dihydrofuro[3,4-b]pyridine 2,3-dicarboxylate in good to high yields under mild reaction conditions. Keywords: 2-aminopyridine, alkyl isocyanide, acetylenic esters, 1,2'-bipyridine, three-component synthesis 1. Introduction 1,2-Dihydropyridines are useful intermediates for synthetic transformations. They undergo selective elec-trophilic substitutions1 like formylation2 and are also good dienes. Furthermore, Diels-Alder reactions of 1,2-dihy-dropyridines provided the starting point for the synthesis of several alkaloids and aminosugars.3 The majority of synthetic methods to prepare 1,2-dihydropyridines relies on nucleophilic addition to N-acyl or N-alkyl pyridinium salts.4,5 A good example of a synthetically useful application of this kind of reaction is provided by the reduction of pyridine in the presence of chloroformate esters.6 Recently, other strategies for the synthesis of 1,2-dihydropyridines have been reported.7 However, lack of general synthetic approaches for the regioselective synthesis of fully functionalized 1,2-dihydropyridines and their synthetic potential remains largely unexplored. In a recent study, Yavari et al. reported the syntheses of the functionalized 1,2-dihydropyridines from primary alkyl amines, alkyl isocyanides, and acetylenic esters.8 In line with our general interest in the syntheses of heterocyclic com-pounds,9-13 we report here on a simple and efficient method for the preparation of novel 1,2'-dihydropyridine derivatives. 2. Results and Discussion 2-Aminopyridine reacts with alkyl isocyanide 1 and dialkyl acetylenedicarboxylate 2 at room temperature in diethyl ether as solvent to produce compounds 3, 4 and 5 in good to high yields (Scheme 1). In particular, three-component reactions of 2-ami-nopyridine, alkyl isocyanides and double insertion of di-alkyl acetylenedicarboxylates lead to dialkyl 4-(alkylami-no)-7-alkoxy-5-oxo-1-(pyridin-2-yl)-1,5-dihydrofu-ro[3,4-fc]pyridine-2,3-dicarboxylates (3a-b and 3d-e) in good to high yields. When di-tert-butyl acetylenedicar-boxylate is used, the reaction produces tetra-tert-butyl 4-(tert-butylamino)-2H- [ 1,2'-bipyridine] - 2,3,5,6-tetracar-boxylate 4c in good yield and (1Z,3E)-tetra-tert-butyl 1-(pyridin-2-ylamino)buta-1,3-diene-1,2,3,4-tetracarboxy-late 5c in low yield without the formation of 3c. On the basis of the established chemistry of isocyanides,14-21 the initial Michael addition of alkyl isocyanide to acetylenic ester presumably leads to zwitterionic intermediate 6. The intermediate 6 is protonated by the enami-noester 7, generated in situ from 2-aminopyridine and acetylenic ester, to produce intermediates 8 and 9. Keteni-mine 10, generated from the addition of 8 to 9, undergoes a cyclization reaction to afford 11 which is converted to 4 Scheme 1. 3,4,5 R R' Yield(%) of 3 Yield(%) of 4 Yield (%) of 5 a tBu Me 90 b tBu Et 75 c tBu tBu 52 28 d e Cy-hexyl Cy-hexyl Me Et 72 60 by a proton transfer from carbon to nitrogen atom. Compound 4 was tautomerized to enol 12 that undergoes a cyclization reaction, lossing alcohol, to produce compound 3 (Scheme 2). As shown in Scheme 1, compounds 4a-b and 4d-e undergo cyclization reactions at room temperature to produce 3a-b and 3d-e, respectively, but this is not true for compound 4c to give compound 3. This is probably due to the existence of the hindered ieri-butyl groups in the isoc-yanide and acetylenic ester molecules. However, compound 5c was formed from the nucleophilic addition of 2-aminopyridine to two molecules of acetylenic esters followed by a proton transfer from nitrogen to carbon atom. The structures of compounds 3a-b, 3d-e, 4c and 5c were deduced from their 1H and 13C NMR, IR and mass spectra as well as from elemental analyses. 1H NMR spectrum of 3a in CDCl3 displayed a singlet at 1.64 ppm for the ieri-butyl group, three singlets at 3.64, 3.79 and 3.83 ppm for the three methoxy groups and a singlet at 9.76 ppm for amino proton. The protons of the pyri-dine ring exhibited characteristic multiplets in the appropriate regions of the 1H NMR spectrum. 13C NMR spec- trum of 3a exhibited nineteen signals in agreement with the proposed structure. The partial assignment of these resonances is given in the experimental section. The IR spectrum of 3a displayed characteristic carbonyl (1725 and 1705 cm1) and N-H (3430 cm1) stretching vibrations. 1H and 13C NMR spectra of 3b and 3d-e are similar to those of 3a except for the alkyl groups of ester moieties and alkyl amino groups. The mass spectra of 3a-b and 3d-e displayed the molecular ion peaks at the appropriate m/z values. The fragmentations involved the loss of side chains such as al-koxy, ester and amino groups. 1H NMR spectrum of 4c exhibited five singlets at 1.40, 1.46, 1.47, 1.48 and 1.53 ppm for four tert-butoxy groups and tert-butylamino group; a broad singlet at 4.04 ppm for the NH group, a singlet at 4.08 ppm for the met-hine group and four characteristic multiplets in the appropriate regions for the pyridine ring protons, consistent with the proposed structure for 4c. 13C NMR spectrum displayed twenty four sharp lines in agreement with the structure of 4c. IR spectrum of 4c showed two absorption bands at 3430 and 1725 cm-1 indicating the presence of R'0,0 -co,r' N NH, -CO,R' CO2R\ 1 \ Cyclization CO,R' r'0,c > n i H\ 7 co,r' r'0,c F 6 R CO R' Pro