Synthesis of 4-Halofuro[3,4- c ]pyridin-3(1 H )-ones from 2-Halopyridine-3,4-dicarbonitriles
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hesis of 4-Halofuro[3,4-c]pyridin-3(1H)-ones from 2-Halopyridine-3,4-dicarbonitriles S. V. Fedoseeva,*, M. Yu. Belikova, O. V. Ershova, and V. A. Tafeenkob a b
I.N. Ul’yanov Chuvash State University, Cheboksary, 428015 Russia
Faculty of Chemistry, Moscow State University, Moscow, 119992 Russia *e-mail: [email protected] Received April 6, 2020; revised April 14, 2020; accepted April 28, 2020
Abstract—Heating of 2-halopyridine-3,4-dicarboxylic acids in propionic anhydride led to the formation of 4-halofuro[3,4-c]pyridine-1,3-diones as a result of intramolecular dehydration of the vicinal carboxy groups. The subsequent reduction of 4-halofuro[3,4-c]pyridine-1,3-diones with sodium tetrahydridoborate in THF at room temperature afforded 4-halofuro[3,4-c]pyridin-3(1H)-ones as the major products. Keywords: pyridine-3,4-dicarbonitrile, cinchomeronic acid, dehydration, reduction, furan-2(5H)-ones, furopyridines
DOI: 10.1134/S1070428020090067 Current interest in compounds containing a 2-oxo2,5-dihydrofuran fragment is related to the fact that it constitutes a structural unit of a number of natural compounds exhibiting various biological activities such as antifungal, antibacterial, antiprotozoal, anticancer, cytotoxic, antiviral, anti-inflammatory, cardiotonic, and anti-Alzheimer [1–13]. Fusion of a 2-oxo-2,5-dihydrofuran fragment to a pyridine ring opens the possibility of obtaining new derivatives of biologically active molecules, in particular NAMPT (nicotinamide phosphoribosyltransferase) inhibitors [14], selective P2X3 receptor antagonists [15], GlyT1 inhibitors [16], topoisomerase IB (Top1) inhibitors [17], and pyridoxine (vitamin B6) inhibitors [18]. We previously reported that 2-halopyridine-3,4-dicarbonitriles 1 [19–23] are converted to 2-halopyridine3,4-dicarboxylic acids 2 on heating in 95% sulfuric acid for 2–3 h [24] (Scheme 1). Further study of the
transformations of dicarboxylic acids 2 showed that they underwent dehydration of the vicinal carboxy groups to give 4-chlorofuro[3,4-c]pyridine-1,3-diones 3a–3d in 87–93% yield on heating in propionic anhydride. The subsequent reduction of 3a–3d with sodium tetrahydridoborate in THF at room temperature afforded 4-halofuro[3,4-c]pyridin-3(1H)-ones 4a–4d (Scheme 1). The reduction of 3 could produce regioisomeric lactones 4 and 4* (Scheme 2). However, due to higher reactivity of the carbonyl group in the para position of the pyridine ring (C1 in 4-halofuro[3,4-c]pyridine-1,3dione 3), isomer 4 is formed as the major product [17, 25]. The crude product obtained after neutralization of the reaction mixture may contain up to 12% of isomer 4*. By column chromatography, followed by recrystallization from propan-2-ol, we isolated 4-halofuro[3,4-c]pyridin-3(1H)-ones 4a–4d in 64–74% yield, whereas no isomers 4* were isolated.
Scheme 1. O CN R
2
R1
CN
N
O
COOH H2O, H2SO4
R
2
R1
Hlg
1a–1d
COOH
N
(EtCO)2O
R1
Hlg
2a–2d
Hlg = Cl,
R1
=
R2
= Me (a);
R1
R
O
2
O N
NaBH4, THF
R1
Hlg
3a–3d
=
R2
= Ph (b);
R1R2
1540
= (CH2)4 (c); Hlg = Br,
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