Facile synthesis of various 2-substituted-4-(2-pyridyl) benzopyran analogues as target potassium channel opener

A series of 2-substituted-4-(2-pyridyl)benzopyran analogues 6a-e have been prepared in 20-34% overall yields by the reductive condensation of 2-substituted-3,4-dihydro-2 H -1-benzopyran derivatives 5a-e with pyridine, as a key step.


Introduction
4-substituted benzopyran derivatives constitute a class of compounds with application as potassium channel openers, which regulate changes in the intracellular level of adenosine triphosphate (ATP).These channels are closed when intracellular ATP levels are elevated and opened when the level declines, thus linking membrane potential to the metabolic state of the cell. 1 Opening them allows the passage of potassium ions out of the cell, causing transmembrane hyperpolarization which in turn reduces intracellular calcium concentration by a blocking function of voltage-dependent calcium channels and inhibiting intracellular calcium release, resulting in smooth muscle relaxation and antispasmodic action. 2 The use of potassium channel openers [3][4][5][6][7][8][9][10][11][12][13] may therefore, be valuable in treating disorders caused by smooth muscle contraction, such as hypertension, angina pectoris, asthma, 14 urinary incontinence, 15 and baldness. 160][21][22][23][24] as potassium channel openers.
There are two broad approaches for the synthesis of 4-substituted benzopyrans.The first approach 18,25 deals with the opening of an epoxide at the 3,4-double bond of the benzopyran nucleus (Scheme 1a) by nucleophilic attack of electron rich heterocycles in the presence of base and dehydration to afford 4-substituted chromenes.
Another strategy 26 involves reaction of benzopyran-4-one with Tf 2 O followed by concominent attack of organozinc compounds to displace the resulting triflate affording 4pyridyl benzpyran analogues (Scheme 1b).
Both the approaches suffer from poor yields and multiple reaction steps.In particular, the second approach requires the presence of electron withdrawing groups such as trifluoromethyl group at the 2-position of the benzopyran ring.Thus, development of a more flexible and direct approach for the construction of a substituted cromakalim is highly desirable considering the potential medicinal value.In continuation of our recent work 27 towards the development of novel protocols for the synthesis of substituted benzopyrans for the exploration of potentially biologically active leades, we now report synthesis of various 2-substituted-4-(2-pyridyl) benzopyrans using aluminium amalgam as catalyst in reductive condensation of 2-substituted-2H-1-benzopyran derivatives with pyridine as a key step.

Results and Discussion
For the synthesis of 2-substituted-7-hydroxy-benzopyran, the Tripathi-Taneja 28 procedure, a modified general procedure for the preparation of benzopyrans, was chosen (Scheme 2).
The 2-substituted-7-hydroxy-chromanones were prepared by the base catalysed condensation of substituted acetophenones with carbonyl compounds to give 2,2-disubstituted-7-hydroxybenzopyran-4-ones 3a-d (93-98%).As anticipated, yields in the condensation reaction decreased with sterically more demanding ketones and the highest yield was observed with acetone as carbonyl partner (Table 1) Methylation of the phenolic group afforded 7-methoxy derivatives 4a-d.In order to investigate the effect of substituents in the reductive condensation reaction, 4d was subjected to nitration with silver nitrate and Tf 2 O in dichloromethane to afford 4e in 79% yield.To introduce a pyridyl group at C-4, we resorted to the heterogeneous reductive condensation method reported by Emmert and Asendorf, 29 with some modification.Thus the reaction was carried out by condensation of benzopyran with pyridine in the presence of aluminium amalgam [Al/HgCl 2 ] to afford the desired 4-(2-pyridyl)-substituted benzopyrans 5a-e (Scheme 3).
Reagents and conditions: (iii) CH 3 I, acetone, K 2 CO 3 , reflux; (iv) i. AgNO 3 , TFAA, DCM; ii, pyridine, HgCl 2 -Al, reflux; (vi) p-TSA, benzene, reflux.The structure corroborated by its mass spectrum which showed the M + peak at m/z 286 and characteristic fragment peaks at m/z 268 (M + -H 2 O) and m/z 189 (M + -pyridine).The structure was further confirmed by its 13 C-NMR spectrum showing the presence of a quaternary carbon signal at δ 75.5 for C-4.It was observed that electron withdrawing group at C-6 reduced the yield of the coupling reaction to some extent.Dehydration of compounds 5a-e with p-TSA afforded the desired 4-(2-pyridyl)chromans 6ae in good yields.The formation of dehydration products were confirmed by the disappearance of C-3 methylene resonances at δ 2.2-2.7 and the appearance of an H-3 olefinic proton signal at δ 5.80-6.30.
In summary: a series of 2-(7-methoxy-2H-cromen-4-yl)pyridines 6a-e have been prepared by reductive condensation of 2-substituted-3,4-dihydro-2H-1-benzopyrans 5 with pyridine.The structures of all new products have been confirmed by elemental analysis and spectral studies (IR, 1 H NMR and Mass Spectrometry).Further biological studies, e.g.cytoxicity, antihypertensive, potassium channel openers, etc of short listed compounds are in progress and will be reported in due course.

Experimental Section
General.Solvents and other chemicals were of reagent grade and were used without further purification.Laboratory grade solvents were purified and dried by reported methods.All melting points were determined in capillary tubes on a Buchi technical apparatus (BUCHI-510) and are uncorrected.NMR spectra were obtained on Bruker Supercon 200 MHz and 500 MHz instruments and are expressed in δ values downfield from tetramethylsilane (TMS) as the internal standard.Mass spectra were recorded with a JEOL MS-D 300 mass spectrometer.IR spectra (KBr pellet or neat sample) were recorded on Perkin Elmer-377 and Shimadzu IR-435 spectrophotometers.Column chromatography was performed on silica gel (100-200 mesh) and TLC on silica gel 60 F 254 (Merck).For the visualization of spots either UV or iodine vapour or 10% aqueous sulfuric acid containing 2% ceric ammonium sulfate or 5% ethanolic solution of 2,4-dinitrophenylhydrazine was used.Atomic Absorption spectroscopy of all final compounds were performed in Perkin Elmer A Analyst 800 and below detection level (BDL) of Hg 2+ ion observed in the range 0.001-0.0006% in all cases.

Synthesis of 2-substituted-4-hydroxy-3,4-dihydro-4-(2-pyridyl)-2H-1-benzopyran 5a-e General procedure
To a mixture of HgCl 2 (0.037 mole) and freshly prepared aluminium powder heated at 120 °C for 20 minutes was added a mixture of pyridine (1.20 ml) and 5 (0.0080 mol) with vigorous stirring and the contents were refluxed for 1 h.The reaction mixture was cooled and then poured into 6N NaOH solution (20 ml) with vigorous stirring.The aqueous layer was extracted with ethyl acetate.The organic layer was washed with water and finally distilled to give an oily residue.The crude product was chromatographed on silica gel column using petroleum ether:ethyl acetate (80:20) as eluent to give 5 as a semisolid.

Table 1 .
Condensation of acetophenones with carbonyl compounds