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Summer Research Fellowship Programme of India's Science Academies

One pot sequential synthesis of fused isoquinolines by C-H/N-H annulation

Surya Pravo Mookerjee

Department of Chemistry, Presidency University, Kolkata

Prof. Bhisma Kumar Patel

Department of Chemistry, IIT, Guwahati

Abstract

A simple and practical procedure for the synthesis of 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a] isoquinoline-3-carbonitrile is described. This protocol is accomplished by a copper mediated cyclization of 2-(3-oxo-1,3-diphenylpropyl) malononitrile in glacial acetic acid followed by ruthenium catalysed C-H/N-H annulation with diphenylacetylene. The whole process is going on in one pot sequential two step addition via ta intermediate 2-oxo-4,6-diphenyl-1,2-dihydropyridine-3-carbonitrile with formation of C=O, C-N, C-C and C=C bond.

Keywords: one-pot sequential reaction, , oxidative annulation, C-C, C-N, C=C and C=O bonds, isoquinoline

INTRODUCTION

Various heterocyclic compounds possessing biological activities have been synthesized via Michael type addition reactiont with carbon nucleophiles.1 Malanonitrile is one of the useful and convenient reagent for synthesis of wide range of heterocyclic skeletons.2 In the past few centuries huge number of publications dedicated to nitrogen containing six membered heterocyclic systems highlighting their biological importance. In the midst of fused-ring nitrogen heterocycles, isoquinolines and isoquinolones are special class possessing comprehensive biological activities (Figure 1) and exists in many synthetic drugs and natural products.3-5 Moreover, numerous organic transformations use isoquinolones as one of the key intermediate.6 Therefore it was very interesting for the chemists to synthesise these potentially active heterocycles as target structures for biological studies. Recently, Jeganmohan group have reported a cobalt catalyzed annulation of benzamides with alkynes to synthesize isoquinolines [Scheme 1, (i)].7 Van der Eycken, et al. described a microwave-assisted Ru(II)-catalyzed highly efficient intermolecular C-H functionalization sequence to access substituted isoquinolones using a-amino esters as the directing group [Scheme 1, (ii)].8

image 2.png
    Representative biologically active isoquinolines/isoquinolones.

     Nowadays, transition-metal-catalyzed C-H bond activation9,10 has a wide impact for the synthesis of bioactive complex polycyclic N-containing heterocyclic compounds, specially isoquinolines and isoquinolones. In this context Rh(III), Pd(II), Ni(II) and Ru(II) catalysts are most commonly used to prepare the corresponding isoquinolones by oxidative coupling between internal alkynes and amides.11

    Inspired by transition-metal-catalyzed direct annulation of CH bonds12 we carried out synthesis of 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a) from a Michael-adduct,13 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1). The selective hydrolysis of one of the cyano groups in g--keto dicyano compound (1) would lead to an amide similar to hydrolysis of methylene malononitriles [Scheme 1, (iii)].14 The in situ generated monoamide may undergo an intermolecular dehydrative cyclization followed by aromatization/oxidation to form a cyclic amide, 1,2-dihydropyridone which has potential C-H/N-H sites for annulation with an alkyne to afford 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a). This reaction involves an intramolecular dehydrative cyclization followed by an intermolecular annulation with an alkyne to obtained a fused isoquinolone framework [Scheme 1, (iv)].

    image3.png
      Strategies for the Synthesis of Fused Isoquinolones

      RESULTS AND DISCUSSIONS

      Our initial investigation started with choosing one-pot one step protocol using 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1). (0.2 mmol), diphenyl acetylene (a) (1.2 equiv.), Cu(OAc)2 H2O (1 equiv.) ,1,10-phenanthroline (10 mol%) and [Ru(p-cymene)Cl2]2 (2 mol%) in glacial AcOH at 110 o C. Interestingly, the reaction resulted in the formation of a new yellow fluorescent product as shown by TLC. Unfortunately the yield (1a, 7%), was so meagre that even after changing the reaction conditions it could not be separated for characterization. Then we changed our strategy to two step protocol using 2-(3-oxo-1,3-diphenylpropyl)malanonitrile (1). (0.2 mmol), and Cu(OAc)2 H2O(10 mol %.) in glacial AcOH at 110 C in one step. After 5-6 h in another step we added diphenyl acetylene (a) (1.2 equiv.), Cu(OAc)2 H2O (1 equiv.) and [Ru(p-cymene)Cl2]2 (5 mol%) to the same reaction pot. Fortunately we succeed to produce a decent yield (1a, 30%), and the product was separated and characterized. Spectroscopic analysis confirmed its structure to be 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a). This one-pot transformation of 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) to a 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a) is accompanied by the formation of new C-C, C-N, C=C and C=O bonds.

      Encouraged by the above one-pot two fold sequential reaction, further optimizations were carried out by varying various reaction parameters using 2-(1-(4-chlorophenyl)-3-oxo-3-(p-tolyl)propyl)malononitrile (4) and diphenyl acetylene (a) as the coupling partners in the presence of Cu(OAc)2.H2O and [Ru(p-cymene)Cl2]2 . Initially, keeping the conditions for the second step fixed, [i.e. diphenyl acetylene (a) (1 equiv), Cu(OAc)2·H2O (1 equiv) and [Ru(p-cymene)Cl2]2 (5 mol %)] reaction parameters for the first steps (i.e. cyclization) were varied. Among various solvents such as p-xylene (00%), toluene (00%), DMF (00%) and DMSO (00%) were tested (Table 1, entries 2-5) all were found to be ineffective compared to AcOH (45%) (Table 1, entry 1). When the reaction was carried out in the absence of Cu(II)-catalyst very poor yield (<10%) of (4a) was detected (Table 1, entry 6), suggesting an important role of copper salt in facilitating the reaction, possibly via the coordination with the cyano (-CN) group. The selective hydrolysis of one of the cyano group in the presence of Cu(II) catalyst is in agreement with earlier report.14 An improvement in the yield (55%) was observed when the ligand 1,10-phenanthroline (10 mol %) was used (Table 1, entry 7). Keeping the catalyst loading constant (10 mol%), an increase in the ligand loading to 15 and 20 mol % improved the yield to 60 and 65% respectively (Table 1, entry 8-9). After screening of various reaction parameters, the optimized condition for this transformation in the first step is the use of 2-(1-(4-chlorophenyl)-3-oxo-3-(p-tolyl)propyl)malononitrile (4) (0.2 mmol), Cu(OAc)2·H2O (10 mol %), and 1,10-phenanthroline (20 mol %), at 110 C in AcOH (2 mL) (Table 1.1, entry 9).

      image4.png
        Optimisation of reaction conditions for first step

        Keeping fixed the optimized condition for the cyclization of the first step, further optimizations were carried out for the rapid and effective synthesis of isoquinolones using [Ru(p-cymene)Cl2]2 as the catalyst in AcOH at 110 oC. Increasing the amount of catalyst loading (from 2 to 5 mol %) marginally enhanced the yield of the desired product (27 to 38%, Table 2, entries 1-2). No significant improvement in the product yield (40%) was observed even when the catalyst loading was increased to 10 mol % (Table 2, entry 3). Among the additives such as, AgSbF6 (31%), AgOTf (33%), Cu(OAc)2 (36%) and Cu(OAc)2·H2O (38%) (Table 2, entries 4-7), the latter proved to be the best choice (Table 2, entry 7). The yield progressively improved from 38 to 52% as the additive Cu(OAc)2·H2O loading increased from 10 to 50 mol % (Table 2, entries 7-10). No significant improvement in the product yield (53%) was observed even when the additive loading was increased up to 1 equiv (Table 2, entry 11). Since the intermediate dihydropyridone () formed in the first step precipitated in AcOH medium, thus, it was felt necessary to have additional co-solvent in the second step to make the medium homogeneous. Among few representative solvents tested such as tAmOH (18%), MeOH (12%), iso-propanol (16%) (Table 2, entries 12-15), PEG-400 proved to be the best choice, affording the annulated product (4a) in 72% yield (Table 2, entry 15). No major improvement in the yield was observed even when the quantity of diphenylacetylene (a) was increased to 1.5 equiv (74%) and 2 equiv (75%) (Table 2, entry 16 and 17)

        image5.png
          Optimisation for the second step

          This one-pot two step synthesis of 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a] isoquinoline-3-carbonitrile was then explored with various 2-(3-oxo-1,3-diarylpropyl) malononitrile and diphenyl acetylene (a) under the optimized reaction condition. (Scheme 2) A substrate (1), having both unsubstituted phenyl rings coupled with diphenylacetylene (a), yielded its fused isoquinoline (1a, 45%) in moderate yield (Scheme 2). Reactant having electron-donating substituents such as p-Me (2) in the aroyl phenyl ring and electron-neutral substituent (-H) in the other phenyl ring reacted successfully with diphenylacetylene (a), yielding their fused isoquinoline (2a) in 51% yields (Scheme 2). When the phenyl ring a to the malononitrile is substituted with electron-withdrawing substituents such as p-Cl (3) provided respective product (3a) in 49% yield (Scheme 2). The substrate (4) having both electron-donating p-Me and electron-withdrawing p-Cl gave good yield (72%) of the product (4a).

          image6.png
            Substrate Scope for the Synthesis of 4-Oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrilesa,b,c

            In order to expand the scope of this methodology, 2-(3-oxo-1,3-diphenylpropyl) malononitrile (1) was tested with two different symmetrical alkynes (b and c) (Scheme 3). The reaction proceeded smoothly providing their expected fused isoquinolines (1b, 46%), and (1c, 41%) respectively. (Scheme 3).

            image7.png
              Substrate scope for alkynes

              MECHANISM

              Based on the previous reports,14,15,16 a plausible mechanism is depicted in Scheme 4. In the first step, one of the nitrile (-CN) group of the substrate (1) is hydrolyzed selectively to a mono amidic intermediate (I). The NH2 of the amide then attacks at the carbonyl group and undergoes a dehydrative-cyclization to produce a six-membered cyclic intermediate (II). The intermediate (II) is oxidized/aromatized under the reaction conditions to an aromatic pyridone intermediate (III). In the second step the catalyst [RuCl2(p-cymene)]2 undergoes exchange of ligand with Cu(OAc)2·H2O to generate the active catalytic species, which coordinates with the nitrogen atom of the intermediate (III) via N-H deprotonation. This is then followed by ortho C-H bond activation through the elimination of AcOH, forming a five-membered ruthenacycle (V). Further coordination of the alkyne (a), followed by an alkyne insertion and reductive elimination afforded the final product (1a) via the intermediate (VI). The active catalyst species is then regenerated by the oxidant Cu(OAc)2·H2O and air for the next catalytic cycle (Scheme 4).

              image8.png
                Proposed Mechanistic Pathway

                CONCLUSION

                In conclusion, we have utilized a Michael-adduct g-keto malononitrile, obtained from the reaction between a,b-unsaturated aromatic ketone and malononitrile as the substrate for the C-H/N-H annulation with an alkyne. In this one-pot sequential two component synthesis of π-conjugated fused ring N-containing heterocycle 4-oxo-2,6,7-triaryl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile is accomplished via the formation of six new bonds namely a C-C, two C-N, two C=C and a C=O bonds. The success of the strategies lies in the selective hydrolysis of one of the cyano group of g-keto malononitrile to an aromatic cyclic amide and finally C-H/N-H annulation with disubstituted alkynes in the presence of Ru(II) catalyst.

                EXPERIMENTAL SECTION

                General information

                All the reagents and solvents used were purchased from commercial available sources and used without further purification. Organic extracts were dried over anhydrous sodium sulphate. Solvents were removed in a rotary evaporator under reduced pressure. Silica gel (60-120 mesh size) was used for the column chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25mm). All NMR spectra were recorded in CDCl3 with tetramethylsilane (TMS) as the internal standard in 600 and 400 MHz NMR. The 1H spectra were referenced to the residual CDCl3 (7.26 ppm). The 13C spectra were referenced to the residual CDCl3 (77.230 ppm) 19F NMR spectra was recorded in 400 MHz, and hexafluorobenzene (C6F6) was taken as reference. Mass spectra were recorded using ESI mode (Q-TOF MS analyzer). IR spectra were recorded in KBr or neat in FT-IR spectrometer.

                General Procedure for the Synthesis of 2-(3-Oxo-1,3-diphenylpropyl) Malononitrile (1)19

                image9.png
                  Reaction scheme

                  To an oven-dried 25 mL round bottom flask was added chalcone (416 mg, 2 mmol), malononitrile (264 mg, 4 mmol), K2CO3 (552 mg, 4 mmol), and DCE (4 mL). The reaction mixture was stirred in room temperature for 12 h. Completion of the reaction was monitored by TLC. Then the reaction mixture was cooled to room temperature, admixed with ethyl acetate (50 mL) and the organic layer was washed with water (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate (Na2SO4), and solvent was evaporated under reduced pressure. The crude product so obtained was purified over a column of silica gel (hexane / ethyl acetate, 9:1) to give pure 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1)

                  General Procedure for the Synthesis Internal Alkynes (b-c)

                  image10.png
                    Reaction scheme

                    A 25 ml oven-dried round bottom flask was equipped with magnetic stirrer, [Pd(PPh3)2Cl2] (0.03 mmol), CuI (0.04 mmol), Iodobenzene derivative (1 mmol). To this reaction mixture trimethylamine (10 ml) was added as a solvent as well as a base. This reaction was carried out under nitrogen atmosphere at room temperature. After 5 minutes of stirring Phenyl acetylene derivative (1.2 mmol) was added dropwise and allow this reaction mixture for stirring overnight. After the completion the reaction mixture was filtered and extracted in ethyl acetate and dried over anhydrous sodium sulfate. The reaction mixture was concentrated in vacuum and subjected to purification in column chromatography by Ethylacetate : Hexane ( 1:99 ) mixed solvent.

                    General Procedure for the Synthesis of 4-Oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a) from 2-(3-Oxo-1,3-diphenylpropyl)malononitrile (1) and Diphenylacetylene (a)

                    image11.png
                      Reaction scheme

                      To an oven-dried 10 mL round bottom flask was added 2-(3-oxo-1,3-diphenylpropyl)malononitrile (1) (55 mg, 0.2 mmol), Cu(OAc)2·H2O (4 mg, 0.02 mmol), 1,10-phenanthroline (7 mg, 0.04 mmol), and glacial AcOH (2 mL). The reaction mixture was heated in an oil bath at 110 °C for 5 h. Then to this reaction mixture was added diphenylacetylene (a) (36 mg, 0.2 mmol), [Ru(p-cymene)Cl2]2 (6 mg, 0.01 mmol), Cu(OAc)2·H2O (20 mg, 0.1 mmol) and PEG-400 (2 mL). The reaction mixture was further heated for 24 h. Then the reaction mixture was cooled to room temperature, admixed with ethyl acetate (25 mL) and the organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL). The organic layer was dried over anhydrous sodium sulfate (Na2SO4), and solvent was evaporated under reduced pressure. The crude product so obtained was purified over a column of silica gel (hexane / ethyl acetate, 9:1) to give pure 4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a) (40 mg, yield 45%). The identity and purity of the product was confirmed by spectroscopic analysis.

                      SPECTRAL DATA

                      image12.png
                        4-Oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a).

                        As a yellow solid (40 mg, 45% yield, mp 262-246 °C); 1H NMR (CDCl3, 600 MHz): δ 8.42 (d, 1H, J = 8.4 Hz), 7.78 (d, 2H, J = 6.0 Hz), 7.66-7.64 (m, 1H), 7.62-7.56 (m, 5H), 7.50 (s, 1H), 7.31-7.27 (m, 3H), 7.125-7.115 (m, 3H), 7.06-7.04 (m, 4H); 13C NMR (CDCl3, 150 MHz): δ 160.9, 156.0, 145.1, 136.7, 136.51, 136.48, 135.1, 133.2, 132.4, 131.1, 130.9, 130.6, 129.24, 129.20,

                        128.6, 128.4, 128.3, 127.8, 127.5, 127.4, 127.3, 125.6, 124.7, 116.7, 100.9, 96.3; IR (KBr, cm-1): 2961, 2925, 2854, 2214, 1643, 1608, 1573, 1495, 1472, 1384, 1262, 1224, 1178, 1156, 1077, 1022, 839, 801, 762, 701; HRMS (ESI/Q-TOF) (m/z) calcd for C32H21N2O [M + H]+ 449.1648; found 449.1655.

                        image13.png
                          9-Methyl-4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (2a).

                          As a yellow solid (42 mg, 45% yield, mp 275-277 °C); 1H NMR (CDCl3, 400 MHz): δ 8.24 (d, 1H, J = 8.8 Hz), 7.72-7.69 (m, 2H), 7.49-7.47 (m, 2H), 7.39 (d, 2H, J = 8.0 Hz), 7.37 (s, 1H), 7.21-7.19 (m, 4H), 7.04-7.02 (m,2H), 6.99-6.94 (m, 5H), 13C NMR (CDCl3, 100 MHz): δ 161.0, 155.9, 145.3, 143.4, 136.9, 136.7, 135.3, 133.3, 131.1,

                          130.9, 130.8, 130.5, 129.2, 128.5, 128.4, 128.3, 127.7, 127.4, 127.24, 127.21, 124.8, 123.4, 116.9, 100.5, 95.5, 22.1; IR (KBr, cm-1): 2955, 2924, 2854, 2214, 1671, 1563, 1493, 1464, 1378, 1264, 1073, 800, 701; HRMS (ESI/Q-TOF) (m/z) calcd for C33H23N2O [M + H]+ 463.1805; found 463.1806.

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                          (16) (a) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Thirunavukkarasu, V. S.; Donati, M.; Ackermann, L. Org. Lett. 2012, 14, 3416. (d) Prakash, R.; Shekarrao, K.; Gogoi, S. Org.Lett. 2015, 17, 5264

                          SPECTRA

                          image14.png
                            4-Oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a): 1H NMR (CDCl3, 600 MHz)
                            image15.png
                              4-Oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (1a): 13C NMR (CDCl3, 150 MHz)
                              image16.png
                                9-Methyl-4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (2a): 1H NMR (CDCl3, 400 MHz)
                                image17.png
                                  9-Methyl-4-oxo-2,6,7-triphenyl-4H-pyrido[2,1-a]isoquinoline-3-carbonitrile (2a): 13C NMR (CDCl3, 100 MHz)

                                  ACKNOWLEDGEMENT

                                  I would like to express my sincere gratitude to my guide Prof. Bhisma Kumar Patel for his constant guidance, inspiration, priceless suggestions and support, which helped me to carry out my project with outmost success.

                                  I extend my sincere thanks to Nikita Chakraborty for her prolonged motivation, guidance and encouragement throughout the project. She has taught me a lot about laboratory life, about patience, about working hard and giving my best shot to achieve all the goals.

                                  I convey my special thanks to my lab seniors Amitava Rakshit, Anjali Dahiya, Tipu Alam, Ashish Kumar Sahoo, Shubhendu Ghosh, Bilal Ahmed Mir, Anju Modi, Suresh Rajamanickam and Tamanna Khandelia for their help and co-operation which has guided me up to this end.

                                  I am honestly grateful to my family members for their affection, mental, financial support, without which I couldn’t have achieved this. Finally, I would like to acknowledge INSA-NASI-IAS for giving me this opportunity to carry out research work and the Department Of Chemistry, Indian Institute of Technology Guwahati for providing me the facilities that were necessary to pursue my project.

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