Substituent-Dependent Chemoselective Synthesis of Highly Functionalized Benzo[h]quinolines and 4-Benzylpyrans from 2-Methyl-5-nitro-benzonitrile

Abstract A facile, efficient and atom-economic synthesis of highly substituted benzo[h]qninolines was established by reaction of 2-methyl-5-nitrobenzonitrile with suitably functionalized 2H-pyran-2-ones under basic conditions. We observed that the presence of a thiomethyl group at the C-4 position of pyran provides 6-aryl-4-(2-cyano-4-nitrobenzyl)-2-oxo-2H-pyran-3-carbonitrile exclusively without any trace of benzo[h]quinolines. Depending on the nature of the functional group at C-4 of the pyran ring, different products were achieved. To probe the mechanism, we performed control experiments and isolated 3-(1-amino-7-nitro-3-thiophen-2-yl-naphthalen-2-yl)-3-piperidin-1-yl-acrylonitrile, which, on further treatment with base, provided the benzo[h]quinolines. The structure of one the products was characterized by single-crystal X-ray diffraction.

Polycyclic Nand O-heterocycles such as amsacrine, benzo [c]phenanthridines, ellipticines, intoplicine and coralyne exhibit excellent biological properties such as DNA topoisomerase inhibition and anticancer activity. [1][2][3][4][5] Among the N-heterocycles, fused and isolated quinolines are very important and exhibit a wide range of biological properties including anaesthetic, 6a antiestrogenic, 6b-c antimalarial, 7 anti-HIV, 8 anticancer, 9 antitubercular, 10 and antimicrobial activities. 11 They have also been widely used in agrochemical areas 12 and in material chemistry. 13 Recently, our research group has reported the synthesis and anticancer activity of functionalized benzo [h]quinolines. 14 This class of compounds has also been used in the construction of nano and meso structures that exhibit novel electronic and photonic properties. 15 Various synthetic methodologies have been reported for the synthesis of fused and isolated quinolines, from Skraup, Doebner and von Miller syntheses, [16][17][18][19] through Diels-Alder reactions 20 and Friedlander condensations reactions. 21 Quinolines have also been synthesized by palladium, 22 copper, 23 nickel, 24 and zinc 25 catalyzed inter-and intramolecular cyclization reactions. The reaction of aryl isothiocyanates, alkynes, and alkyl triflates also provides quinolines and fused quinolines. 26 In another approach, partially reduced benzo[h]quinolines were obtained by reaction of arylidenes and 1-tetralone in the presence of ammonium acetate and sodium methoxide. 27 Benzo[h]quinolines have also been afforded by reaction of 6-methoxy-1-tetralone and methyl propiolate in saturated ammonical methanol. 28 Ram and co-workers reported the synthesis of partially reduced benzo[h]quinolines by reaction of 5,6-dihydro-2oxobenzo[h]chromenes with formamidine or benzamidine and S-methylisothiourea under basic conditions. 29 Recently, our group established a one-pot chemoselective synthesis of benzo[h]quinolines by reaction of 2-pyranones and 2-cyanomethylbenzonitrile in DMF in the presence of sodamide. This reaction requires extended reaction times (up to 36-50 h) with conventional heating but 55 minutes under microwave irradiation. [30][31][32] In this connection, we wanted to use 2-methyl-5-nitrobenzonitrile as the carbanion source instead of 2-cyanomethylbenzonitrile to study its effect on reactivity with 2-pyranone and to achieve the benzo[h]quinolines without a nitrile group, because regioselective removal of a nitrile group is difficult and requires additional steps.

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amination of 6-aryl-4-methylthio-2-oxo-2H-pyran-3-carbonitriles with secondary amines in ethanol provided 6aryl-4-amino-2-oxo-2H-pyran-3-carbonitriles 1. 34a-e To study the optimization, 6-(4-chlorophenyl)-2-oxo-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (1) and 2-methyl-5-nitrobenzonitrile (2) were selected as a model substrates. Initially, we performed the reaction using triethylamine as base in dimethyl sulfoxide (DMSO) and DMF at 100 °C, but no reaction was observed ( Table 1, entries 1 and 2). Similarly, the use of sodamide in DMF or DMSO at either room temperature or higher temperatures led mainly to starting material being recovered (entries 3-6); while use of sodium hydride afforded complex mixtures (entries 7-9) containing starting materials and desired product, along with unidentified decomposition products. When the reaction was performed in DMF using KOH as base at room temperature for 12 h, 45% yield of the desired product was isolated (entry 10) and when the same reaction mixture was heated at 100 °C for 6 h, 93% of the desired benzo[h]quinoline was isolated (entry 11). Use of DMSO instead of DMF, lowered the yield of product (entry 12). Use of potassium tert-butoxide as a base in DMF at 100 °C provided the desired product in 65% yield (entry 13); whereas using cesium carbonate as base was did not afford the desired product (entry 14). By using lithium hydroxide and sodium hydroxide under the same conditions noted in entry 11, a lower yield and complex reaction mixture were observed, respectively (entries 15 and 16). Use of KOH in water gave no reaction and starting materials were recovered (entry 17) and using KOH in DMSO for 6 hours provided only 40% yield of the desired product (entry 18). Thus, we chose the reaction of 2pyranone and 2-methyl-5-nitrobenzonitrile with potassium hydroxide in DMF at 100 °C as the optimal reaction conditions.
The generality of the optimized protocol was then tested by the synthesis of a range of functionalized benzo[h]quinolines (Scheme 1). We have used pyrans functionalized with different secondary amine and aryl groups and the yield was generally not affected significantly by their nature, although the presence of a 2-thienyl group lowered the yield of product.
The structure of one of the products (3g) was confirmed by single-crystal X-ray analysis ( Figure 1). 35 It was found that benzo[h]quinoline ring is completely planar and one unit cell contains eight molecules. It is interesting to note that the C8-C7-C4 angle is 115.29° and not 120°, probably due to steric repulsion by the piperidine ring at C17. Bond angles for C12-C7-C4, C18-C17-N4 are 124.81° and 120.76°, respectively. This repulsion also leads to a higher torsion angle of 59° between the benzo[h]quinoline ring and the pfluorophenyl ring.
Mechanistically, the reaction is probably initiated by the generation of the carbanion of 2-methyl-5-nitrobenzonitrile (Scheme 3), which reacts at C-4 or C-6 of the 2-pyranone, depending on the substrate selected. If 6-aryl-4-secamino-2-oxo-2H-pyran-3-carbonitriles are the substrate, the carbanion attacks at C-6 through Michael addition to af- Alternatively, if intermediate D were to be formed, then benzylic carbanion generated by the excess base could cyclize by involvement of vinylic nitrile to provide intermediate E. Subsequently, the imine group of intermediate E can cyclize onto the aromatic nitrile followed by decarboxylation to afford F, which, on tautomerization, provides functionalized phenanthridines. However, the reaction provides benzo[h]quinolines chemoselectively without any trace of phenanthridine.
It is interesting to note that, if 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles were used as precursors, the carbanion generated from 2-methyl-5-nitrotoluene attacks at C-4 rather than C-6, possibly due to the greater electrophilicity at C-4 caused by the vacant d-orbitals of sulfur and the better leaving group ability of the SMe group compared with the secondary amine.
Commercially available reagents were used directly. NMR spectra were recorded at 400 MHz for 1 H and 100 MHz for 13 C and chemical shifts () are given as parts per million. Spectra were referenced to the residual 1 H signal of CDCl 3 at  = 7.24 ppm, 13 C of CDCl 3 at  = 77.00 ppm, the residual 1 H of DMSO-d 6 at  = 2.49 ppm and the 13 C of of DMSO-d 6 at  = 39.50 ppm as the internal standards. Splitting patterns in 1 H NMR data are described as s, singlet; d, doublet; dd, double doublet; t, triplet; bs, broad singlet; m, multiplet and coupling constants given in hertz (Hz). HRMS was recorded using an Agilent LCMS with Quadropole time of flight using the ESI mode of ionization. All the required starting materials were synthesized by following reported procedures. 33a-c