Design and Synthesis of Pyrano[2,3-a]carbazoles by Multicomponent Reaction

Abstract A facile, efficient, three-component reaction of 2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and aromatic/heteroaromatic aldehydes in dimethylformamide (DMF) gave pyrano[2,3-a]carbazoles in good yields, at reflux condition, using a catalytic amount of piperidine. GRAPHICAL ABSTRACT


INTRODUCTION
Multicomponent reactions (MCRs) are processes in which three or more reactants are combined in a single chemical step to produce products that incorporate substantial portions of all the reactants. MCRs have emerged as an attractive and powerful strategy for organic synthesis compared to multistep reactions because of the creation of several new bonds in a single-step reaction, low number of reaction and purification steps, selectivity, synthetic convergence, high atom economy, simplicity, and synthetic efficiency. [1] Therefore, academic and industrial research groups have focused on the use of MCRs to synthesize a broad range of products. [2] These reactions are also effective in building highly functionalized small organic molecules from readily available starting molecules in a single step with inherent flexibility for creating molecular complexity. [3] Hence, MCRs are considered as a pivotal theme in the synthesis of many important heterocyclic compounds.
Pyranocarbazole alkaloids are very attractive because of their fascinating structural features and potential biological activity, [23] and they have prompted several research groups to develop synthetic strategies such as Fischer indolization, oxidative cyclization of diarylamines, and transition-metal-mediated and catalyzed processes for the total synthesis of naturally occurring pyranocarbazole compounds. [24] These classes of compounds led to the discovery of many pyranocarbazole alkaloids. As specific examples, pyrano-carbazole alkaloids such as girinimbine, mupamine, mahanimbine, murrayanol, and mahanine have been isolated from plants of the Rutaceae family. [4] Girinimbine was the first isolated pyrano[2,3-a] carbazole alkaloid. [25,26] Carbazoles having α -pyrano as part of their structures with [2,3-a] fusion are biogenetically possible, as evident from the naturally available mupamine. [27] Some of the naturally occurring pyrano carbazoles are represented in Fig. 1.
As part of our ongoing program directed toward the development of new methodologies for the synthesis and biological evaluation of diverse heterocyclic compounds, [28][29][30][31] herein we disclose the synthesis of amino pyrano[2,3-a]carbazole in the presence of piperidine.

RESULTS AND DISCUSSION
To find the optimized conditions, a systematic study considering different variables affecting the reaction yield was carried out for the reaction of substituted 2,3,4,9-tetrahydro-1H-carbazol-1-ones [32] (1) with malononitrile (2) and aromatic/  Table 1. We found that the base and solvent have profound effects on the reaction yield. The reaction condition was optimized using various base catalysts and DMF as solvent. The reaction conditions optimized using various bases are shown in Table 1. When K 2 CO 3 and KOH were used as bases, the reaction time was longer and yield was less than 40%. Using triethylamine as base, the reaction time was 8 h and the product was obtained in poor yield. With morpoline and pyridine as bases, the reaction time was reduced to 6 h but moderate yield of 60% was obtained. The best yield for the reaction was obtained by switching to piperidine as the base in refluxing DMF as the solvent at 120°C. Further increase in temperature beyond 120°C does not influence the yield of the reaction.
The infrared (IR) spectrum of 4a shows an absorption band at 3272 cm À1 due to the presence of the NH group and asymmetric and symmetric stretchings at 3414 and 3365 cm À1 corresponding to the amino group. A sharp band at 2207 cm À1 confirmed the presence of the cyano group (CN). Its 1 H NMR spectrum shows a broad singlet at δ 9.24 due the indole NH proton. The eight aromatic protons appeared as a multiplet between δ 7.13-7.54. A singlet at δ 5.13 implied the presence of amino protons (NH 2 ). The four aliphatic protons of C 5 and C 6 appeared as a multiplet between δ 2.64 and 2.84. Methyl protons appeared as a singlet at δ 2.44. The total number of protons matched perfectly with its structure. Its 13 C NMR spectrum shows the presence of 23 carbons. The molecular ion peak appears at m/z 353. The elemental Scheme 2. Mechanism for the formation of compounds 4-8. analysis agreed well with the proposed molecular formula C 23 H 19 N 3 O. All the spectral and analytical data revealed the product as 2-amino-8-methyl-4-phenyl-5,6-dihydro-11H-pyrano[2,3-a]carbazol-3-carbonitrile (4a). The generality of the reaction was tested with various aromatic/heteroaromatic aldehydes to form the corresponding products, which are represented in Table 2.
The structures of the products were deduced from their elemental analysis data and from their IR, mass, 1 H NMR, and 13 C NMR spectra.
The possible mechanism for the formation of the products 4-8 is shown in Scheme 2. The initial step is the formation of arylidene malononitrile intermediate I

CONCLUSION
In conclusion, we have established a fast and efficient route for the synthesis of pyrano[2,3-a]carbazoles by multicomponent reaction of 2,3,4,9-tetrahydro-1Hcarbazol-1-one with malononitrile and aromatic/heteroaromatic aldehydes in DMF, and the reaction condition was optimized using various bases. The best yield of product was obtained using piperidine as base under refluxing condition. All the synthesized compounds were characterized by IR, 1 H NMR, 13 C NMR, and mass spectroscopic techniques.

EXPERIMENTAL
Melting points (mp) were determined on a Mettler FP 51 apparatus (Mettler Instruments, Switzerland) and are uncorrected. They are expressed in degrees centigrade (°C). A Nicolet Avatar model FT-IR spectrophotometer was used to record the IR spectra (4000-400 cm À1 ). 1 H NMR and 13 C NMR spectra were recorded on Bruker AV 400 (400 MHz, 1 H, and 100 MHz, 13 C) spectrometer using tetramethylsilane (TMS) as an internal reference. The chemical shifts are expressed in parts per million (ppm). Mass spectra (MS) were recorded on an Auto Spec EIþ Shimadzu QP 2010 Plus gas chromatography-mass spectrometry (GC-MS) instrument. Microanalyses were performed on a Vario EL III model CHNS analyzer (Vario, Germany) at the Department of Chemistry, Bharathiar University. X-ray diffraction measurements were performed on a Bruker Kappa Apex-II diffractometer equipped with an Oxford Cryostream chiller and graphite monochromatized CuK alpha radiation. The purity of the products was tested by thin-layer chromatography (TLC) with plates coated with silica gel G; petroleum ether and ethyl acetate were used as developing solvents.