and regio-selective synthesis of hexacyclic indeno

Tetrahedron 72 (2016) 5903e5908

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Tetrahedron journal homepage: www.elsevier.com/locate/tet

Chemo- and regio-selective synthesis of hexacyclic indeno-fused coumarins via domino DielseAlder dimerization/BaeyereVilliger oxidation Tanmoy Chanda, Sushobhan Chowdhury, Suvajit Koley, Maya Shankar Singh * Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 24 June 2016 Received in revised form 8 August 2016 Accepted 9 August 2016 Available online 15 August 2016

2-Arylindenones have been employed into two parallel chemoselective synthetic transformations. In one path, molecular oxygen was incorporated into the reaction intermediate, leading to hexacyclic benzo indeno-fused coumarins via domino head-to-head DielseAlder dimerization/BaeyereVilliger oxidation. On the other hand, under catalyst-free and solvent-free thermal conditions, hexacyclic indeno-fused dihydronaphthalenes were achieved through head-to-head DielseAlder dimerization of 2/3arylindenones. Atmospheric oxygen serves as efficient oxidant during dehydrogenative aromatization and BaeyereVilliger rearrangement. Ó 2016 Elsevier Ltd. All rights reserved.

Keywords: DielseAlder dimerization BaeyereVilliger oxidation Domino transformation Benzo indeno fused coumarins Indeno fused dihydronaphthalenes

1. Introduction There has always been a periodic addition of new synthetic protocols such as chemo-, regio-, diastereo- and enantio-selective methods in the field of organic synthesis to achieve the desired molecular entities via cheaper, shorter, eco-compatible, and effortless route.1 In this regard, a milestone in organic methodology is the addition of domino protocol.2 During the recent past, our group disclosed some new sustainable strategies like organocatalytic, solvent-free, multicomponent, and domino reactions.3 DielseAlder cycloaddition reactions have been successfully applied towards the syntheses of various natural products and drug molecules.4e6 Besides DielseAlder reaction, BaeyereVilliger rearrangement is another widely studied reaction protocol where aldehydes and ketones are converted into their corresponding esters and lactones. In general, BaeyereVilliger oxidation involves peroxide as a source of external oxygen, which has several limitations.7 Furthermore, limited reports are available where peroxides are generated in situ by the reaction of externally added aldehyde with molecular oxygen.8 In this report, we reveal a highly atomeconomic domino protocol involving the above two strategies that incorporate atmospheric oxygen into the final molecule via

* Corresponding author. Fax: þ91 542 2368127; e-mail address: mayashankarbhu@ gmail.com (M.S. Singh). URL: http://drmssinghchembhu.com http://dx.doi.org/10.1016/j.tet.2016.08.025 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

domino DielseAlder dimerization/BaeyereVilliger oxidation reaction sequence. In our recent report, we devised a regioselective quadruple domino aldolization/aldol condensation/Michael/SNAr-cyclization strategy to construct hexacyclic indeno-fused naphthalene and quinoline derivatives.3a This reaction involves 3-arylindenone as one of the reaction intermediate. Relevant experiments were performed and optimized to discard the head-to-tail DielseAlder dimerization pathway of 3-arylindenones (see Scheme 1).

Scheme 1. Strategies utilizing indenone as a synthon toward DielseAlder reaction.

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T. Chanda et al. / Tetrahedron 72 (2016) 5903e5908

The use of indenone as a synthon toward DielseAlder reaction was accidentally discovered by Balci and co-workers, and has recently been extended by Shen et al.9 This time, we envisioned to check the outcomes of DielseAlder reaction involving 2/3-aryl substituted indenones10 as the initial substrate. Further investigation to prove the regioselectivity of the cycloaddition reaction (either head to head or head to tail dimerization) was done (Scheme 2). Moreover, the utility of this method was demonstrated by synthesizing polycyclic benzo indeno-fused coumarins (expected to exhibit promising bioactivity profile, Fig. 1) via domino DielseAlder dimerization/BaeyereVilliger oxidation aided by molecular oxygen.

Scheme 2. Possible mode of DielseAlder dimerization of 2-aryl indenones.

Fig. 1. Structurally related natural product molecules.

2. Results and discussion We started our study using 5-bromo-2-phenylindenone (1a) as an initial substrate, which was subjected to different thermal DielseAlder reaction conditions. Theoretical evidences by Dewar and co-workers suggest that DielseAlder reaction might possibly be non-concerted, and propagates via diradical intermediate states.11 Therefore, we selected such a solvent that could solvate the polar diketodiradical intermediate (expected to form in the case of head-to-head dimerization of 2-arylindenones). Dimethyl formamide (DMF) a high boiling polar aprotic solvent with high dielectric constant was found to be a suitable choice.5g,12 Consequently, the solution of 1a (0.2 mmol) in DMF (4 mL) was heated at 120 C in open atmosphere. Even after 72 h of heating, no trace of the desired DielseAlder cycloadduct 3a (head-to-head) or 30 a (head-to-tail) was found. Surprisingly, an entirely unexpected hexacyclic coumarin molecule 2a was obtained in 15% yield via the direct incorporation of atmospheric oxygen into the final molecule (Table 1, entry 1). The structure of compound 2a was fully established by its satisfactory spectral (NMR and mass) studies and unambiguously confirmed by single crystal X-ray diffraction analysis of one of the representative molecule 2b.13 The most interesting feature of this hexacyclic coumarin molecule is the fusion between dibenzo[c,h]chromen-6-one and C-norD-homo-steroid skeleton. Both the motifs are core structure of various bioactive natural products. For example, natural products such as arnottin, gilvocarcin and ravidomycin contain dibenzo[c,h] chromen-6-one skeleton, while jervine and nakiterpiosinone have C-nor-D-homo-steroid framework (Fig. 1).14

Table 1 Optimization of the domino protocola

Entry

Temp ( C)b

Solvent

Catalyst (mol %)

Time (h)

Yieldc (conv.)

Ratiod (2a:3a)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16h 17i 18j

120 120 120 120 120 120 120 120 120 120 120 120 120 100 160 160 120 rt

DMF DMF DMF DMF PhNO2 DMSO DME Toluene BS (1:1) BS (1:2) BS (1:1) BS (1:1) BS (1:1) S. F. S. F. S. F. BS (1:1) BS (1:1)

d InCl3(20) Y(OTf)3(20) Zn(OTf)2(20) InCl3(20) InCl3(20) InCl3(20) InCl3(20) InCl3(20) InCl3(20) InCl3(10) InCl3(20)g InBr3(20) d d d InCl3(20) InCl3(20)

72 72 72 72 72 72 72 72 72 72 120 48 72 48 6 24 72 60 day

15(100) 52(100) 39(100) Trace(100) nd(10) Trace(100)e Trace(80)f 74(100) 64(100) 62(100) 55(100) 66(100) 60(100) 62(100) 82(100) 42(100) 60(100) Trace(5)

1:0 1:0 1:0 d d d d 1:1 1:0 15:1 1:0 1:0 1:0 1:1 1:9 1:20 1:0 1:0

BS¼Binary solvent system consisting mixture of DMF and toluene in different proportions. S.F.¼Solvent-free. nr¼No reaction. nd¼No desired product. a All the optimization reactions were done in 0.2 mmol scale. b Preheated oil bath was used. c Isolated yield in %, ratio of 2a and 3a was determined from NMR, conversion was determined in terms of the amount of 1a recovered after the mentioned reaction time. d Ratio of 2a and 3a is determined by calculating the relative abundance of the peaks in crude reaction mixture for the aliphatic proton at d 4.8 ppm for 2a and d 4.5 ppm for 3a. e Only a trace of 2a and mixture of inseparable products were formed. No evidence of 3a was observed. f Only a trace of the mixture of 2a and 3a and unreacted 1a along with inseparable intermediates was obtained. g InCl3 was added in 2 portions at 24 h interval. h Reaction was performed under argon atmosphere. i Reaction was performed in dark and rest of the conditions was kept similar to entry 12. j 0.2 mmol of 1a was dissolved in 1:1 mixture of DMF:toluene (4 mL) in a sealed tube filled with oxygen and kept under 15 W white LED light.

Motivated by a strange observation that furnished a highly interesting polycyclic molecule 2a, we focused to improve the efficiency of this reaction. Hence, different Lewis acids were screened with the vision that they could further assist the reaction steps.11 Consequently, when the solution of 1a in DMF was heated at 120 C for 72 h in the presence of 20 mol % of InCl3, the desired product 2a was obtained in 52% yield (Table 1, entry 2). Other Lewis acids like Y(OTf)3 and Zn(OTf)2 could not improve the result (Table 1, entries 3 and 4). Further to improve the yield of 2a, some other polar solvents like nitrobenzene, DMSO having dielectric constant similar to DMF, and high boiling ethereal solvent like DME were also screened and found to be inefficient (Table 1, entries 5e7). Interestingly, when non-polar solvent toluene was used, head-to-head DielseAlder cycloadduct 3a was obtained along with 2a. However, no trace of head-to-tail DielseAlder cycloadduct 30 a was observed (Table 1, entry 8). The structure of 3a was confirmed by its satisfactory spectral (NMR, mass) studies, and explicitly established by the single crystal X-ray diffraction analysis of one of the representative molecule 3h.13 Upon use of binary solvent system like 1:1 mixture of toluene and DMF, the reaction became cleaner and the yield of 2a was improved to 64% (Table 1, entry 9). The reaction took 48 h to


complete when the catalyst InCl3 (20 mol %) was added in two portions (10 mol % each time) at 24 h interval, affording the desired product 2a in 66% yield (Table 1, entry 12). Thus, the entry 12 of Table 1 was found to be the optimum reaction conditions for the synthesis of 2 (Scheme 3).

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The fate of 3-arylindenones in the optimized thermal DielseAlder reaction conditions was also tested. For this purpose, 1.0 mmol of 3-phenyl-1H-inden-1-one 1j was heated at 160 C under solvent-free conditions in open atmosphere. After 6 h of heating, a trace amount of head-to-head (4þ2) cycloadduct 3j was obtained. No trace of head-to-tail (4þ2) cycloaddition product was formed (Scheme 5). The structure and regioselectivity of 3j was assigned as per the obtained analytical data, trend of the regioselective outcomes of the respective DDA reaction of some other 2arylindenone substrates (1aei), and comparing the spectroscopic data with our previously synthesized head-to-tail dimer.3a Under similar reaction conditions used to convert 1aeg to 2, 1j provided a complex reaction mixture. Despite having 100% conversion, we could not isolate any fruitful reaction outcome, and no desired coumarin molecule was obtained.

Scheme 5. Fate of 3-phenylindenone (1j) in DielseAlder dimerization reaction.

Scheme 3. Synthesis of 2 via domino DielseAlder dimerization/BaeyereVilliger oxidation.

Next, we performed the reaction under solvent-free and catalyst-free conditions (Table 1, entries 14e16). Thus, when 1a was heated at 160 C without any solvent and catalyst, 3a was obtained in 82% yield along with 2a as the minor product (Table 1, entry 15). Thus, this optimized reaction conditions was used toward the chemoselective synthesis of 3 (Scheme 4).

Scheme 4. Synthesis of 3 via thermal DielseAlder dimerization.

Incorporation of one extra oxygen atom and the presence of a lactone ring along with a fluorene skeleton in molecule 2 suggested that in this domino transformation BaeyereVilliger type oxidation is also operative along with the DielseAlder dimerization reaction (Scheme 6). Probable first step of this transformation is the head-to-head dimerization of 2-arylindenones 1 to provide more stable diradical intermediate A instead of intermediate A0 . This could be the reason for the head-to-head regiospecificity.11 Intermediate A is transformed to intermediate B through radical cyclization, which is then converted to intermediate C by exclusion of one hydrogen radical (possibly as hydroperoxy radical).15 Removal of the second hydrogen radical (possibly as hydrogen peroxide) provided the head-to-head DielseAlder cycloadduct 3 (Scheme 6, Step iv). Successive elimination of two hydrogen radicals is facilitated by atmospheric oxygen, as the rate and yield of the reaction decreased drastically when performed under inert atmosphere (Table 1, entry 16). The conversion of the intermediate B to 3 under anaerobic conditions could also take place via concerted elimination of hydrogen gas as proposed by Matsubara et al.16 and experimentally evidenced by Brummond and co-workers.5g However, theoretical evidence suggests that aromatization by hydrogen atom abstraction by triplet oxygen is thermodynamically more favourable than the direct expulsion of H2. Hence, the former pathway is operating under aerobic conditions.5g Interestingly, while DMF is used as the reaction medium, polar diketointermediate C gets stabilized, may be due to the greater extent of solvation and hence persists in the reaction medium to some extent. The radical intermediate C then trapped by the hydroperoxy radical present in the reaction medium, and converted into intermediate D which further transformed to dioxetane type intermediate E. Further rearrangement by cleavage of one CeC bond and formation of a new CeO bond provided intermediate G (via intermediate F), which then converted to desired molecule 2 after dehydration. Although the reaction steps iev are radical processes, polar mechanism is more favourable for rest of the paths (steps vieix). In case of radical pathway, the carboxyl radical F would likely lose CO2 but no such decarboxylated product H was found, while mass analysis of the crude was performed. Polar mechanism also explains the involvement of the Lewis acid catalyst in the oxidative process. Since there is a possibility of involvement of light to initiate the radical process, the reaction was performed at 120 C in dark (Table

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Scheme 6. Mechanism of the domino DielseAlder dimerization/BaeyereVilliger oxidation.

1, entry 17). No deviation from the standard outcome was observed (Table 1, entry 12). To further check the effect of light on the reaction, 0.2 mmol of 1a was dissolved in 1:1 DMF:toluene mixture (4 mL) in a sealed tube filled with oxygen and kept under 15 W white LED light. Even after 5 days, we did not find any indication of the formation of 2a. Keeping the reaction mixture for longer duration of time (60 days) provided a trace of the desired product 2a (Table 1, entry 18). These results suggest that probably the reaction could be triggered either photochemically or thermally but the effect of light is too slow to record. When 3a was put to conditions similar to that mentioned in Scheme 3, only a trace of 2a was obtained after 48 h (evident from mass analysis). More than 95% of 3a was recovered as such unutilized. Thus, aerial oxidation route for the conversion of molecule 3a to 2a could be ruled out. Another regioselective factor, parallel to head-to-head regioselectivity of the product formation was also evidenced. The substrate 1g can provide two regioselective outcomes since both the two ortho-positions of the 2-aryl substituent of the indane ring in 1g is not equivalent (due to the presence of 3,4-dichloro substituents). In this particular case, DielseAlder dimerization is taking place via the sterically more favourable route (only 2g and 3g were formed respectively, in the two optimized chemoselective reaction conditions). 3. Conclusions We successfully devised two parallel chemoselective synthetic transformations using 2/3-aryl substituted indenones as a synthon in DielseAlder reaction. Under solvent-free and catalyst-free conditions, indenones were transformed to hexacyclic indeno-fused dihydronaphthalenes through DielseAlder dimerization. In the presence of catalytic amount of Lewis acid in DMF, the free-radical intermediate of DielseAlder reaction is trapped by dioxygen leading to indeno-fused hexacyclic coumarin molecules via further rearrangements. The experimental outcomes, literal evidences and the head to head regiospecificity supported a non-concerted biradical pathway of this DielseAlder dimerization reaction. This domino DielseAlder cycloaddition/BaeyereVilliger oxidation reaction involving 2/3-arylindenones is the first of its kind. 4. Experimental section 4.1. General 1

H and 13C NMR spectra were recorded at 300 and 75 MHz, respectively. Chemical shift (d) values are given in parts per million

(ppm) with reference to tetramethylsilane (TMS) as the internal standard. ‘J’ values are given in hertz (Hz). High resolution mass spectra were recorded by ESI method. Organic solvents used were dried by standard methods when necessary. Commercially obtained reagents were used as such without further purification. All these reactions were monitored by TLC with silica gel coated plates. Column chromatography was carried out using silica gel of 60e120 mesh. Mixture of hexane/ethyl acetate in appropriate proportion (determined by TLC analysis) was used as eluent solvent system. Melting points were measured and are uncorrected. Initial substrates (indenones) were synthesized via the reported methodology developed by our group.3a,b,10 4.2. General procedure for the synthesis of compounds 2aeg 1.0 mmol of 1 was dissolved in 1:1 (v/v) mixture of DMF and toluene (20 mL), 10 mol % of InCl3 was added and heated to 120 C for 24 h (reflux condenser to be attached) in open atmosphere. 10 mol % of InCl3 was added again and heating was continued for another 24 h. After complete conversion of the initial substrate (monitored by TLC), 50 mL of water was added to the reaction mixture and extracted with EtOAc (20 mL3). The combined organic layer was evaporated and the desired product 2 was purified by column chromatography using mixture of hexane/EtOAc in appropriate proportion over 60e120 mesh silica gel. 4.2.1. 2,14-Dibromo-10b-phenyldibenzo[c,h]indeno [1,2-f]chromene5,11(10bH,15bH)-dione (2a). Mp, >300 C. IR (n¼cm1) 3423, 2922, 2851, 1718, 1644, 1472. 1H NMR (300 MHz, CDCl3) d 8.29 (d, J¼8.4 Hz, 1H), 8.08 (d, J¼7.5 Hz, 1H), 7.82 (s, 1H), 7.75e7.70 (m, 2H), 7.66e7.58 (m, 3H), 7.48e7.36 (m, 2H), 7.27 (d, J¼7.5 Hz, 3H), 6.94 (d, J¼6.3 Hz, 2H), 4.86 (s, 1H); 13C NMR (75 MHz, CDCl3) d 202.7, 160.2, 151.9, 141.4, 138.4, 134.1, 132.7, 132.3, 132.0, 131.6, 131.2, 131.0, 130.7, 129.1, 128.6, 128.5, 127.8, 127.7, 127.3, 126.8, 126.4, 125.6, 125.2, 124.8, 123.7, 105.9, 62.7, 47.2; HRMS (ESI-TOF) of C30H16Br2O3¼606.9319 [MþNa]þ (Calculated 606.9338). 4 . 2 . 2 . 10 b - P h e n y l d i b e n z o [ c , h ] i n d e n o [ 1, 2 - f ] c h r o m e n e 5,11(10bH,15bH)-dione (2b). Mp, 285 C. IR (n¼cm1) 3436, 2920, 2850, 1713, 1646, 1486. 1H NMR (300 MHz, CDCl3) d 8.45 (d, J¼7.5 Hz, 1H), 8.08 (d, J¼6.3 Hz, 1H), 7.89e7.70 (m, 4H), 7.60e7.50 (m, 2H), 7.44e7.37 (m, 3H), 7.25e7.16 (m, 4H), 6.98 (d, J¼6.6 Hz, 2H), 4.93 (s, 1H); 13C NMR (75 MHz, CDCl3) d 204.5, 161.3, 151.0, 142.6, 137.4, 135.7, 135.2, 133.1, 130.5, 130.4, 129.4, 129.2, 128.7, 128.7, 128.6, 128.6, 128.3, 128.1, 128.0, 127.4, 127.3, 124.9, 124.3, 123.5,


122.6, 107.8, 62.6, 48.1; HRMS (ESI-TOF) of C30H18O3¼449.1147 [MþNa]þ (Calculated 449.1149). 4.2.3. 9-Chloro-10b-(4-chlorophenyl)dibenzo[c,h] indeno[1,2-f]chromene-5,11(10bH,15bH)-dione (2c). Mp, 283 C. IR (n¼cm1) 3433, 2924, 2853, 1716, 1643, 1464. 1H NMR (300 MHz, CDCl3) d 8.47e8.43 (m, 2H), 8.01e7.79 (m, 3H), 7.72e7.38 (m, 6H), 7.23e7.12 (m 2H), 6.93 (d, J¼8.4 Hz, 2H), 4.87 (s, 1H); 13C NMR (75 MHz, CDCl3) d 203.5, 160.9, 150.7, 146.9, 140.5, 137.0, 136.6, 136.1, 135.4, 135.2, 134.6, 133.6, 133.1, 130.7, 129.3, 129.0, 128.7, 128.3, 127.5, 125.8, 125.0, 124.6, 124.2, 122.6, 121.4, 107.8, 61.7, 47.9; HRMS (ESI-TOF) of C30H16Cl2O3¼495.0517 [MþH]þ (Calculated 495.0549). 4.2.4. 2,14-Dibromo-9-chloro-10b-(4-chlorophenyl)dibenzo[c,h]indeno[1,2-f]chromene-5,11(10bH,15bH)-dione (2d). Mp, >300 C. IR (n¼cm1) 3434, 2924, 1718, 1644, 1482. 1H NMR (300 MHz, CDCl3) d 8.30 (d, J¼8.4 Hz, 1H), 8.01 (d, J¼8.4 Hz, 1H), 7.77e7.63 (m, 2H), 7.63 (d, J¼8.7 Hz, 2H), 7.43 (d, J¼8.4 Hz, 1H), 7.26e7.23 (m, 4H), 6.89 (d, J¼8.7 Hz, 2H), 4.76 (s, 1H); 13C NMR (75 MHz, CDCl3) d 201.9, 160.1, 151.8, 148.4, 139.6, 138.3, 137.3, 134.5, 134.0, 133.9, 132.9, 132.4, 132.2, 131.8, 131.6, 129.4, 129.3, 129.3, 129.1, 128.0, 125.8, 125.5, 125.4, 125.0, 119.9, 106.1, 62.0, 47.5; HRMS (ESI-TOF) of C30H14Br2Cl2O3¼676.8669 [MþNa]þ (Calculated 676.8529). 4.2.5. 9-Methyl-10b-(p-tolyl)dibenzo[c,h]indeno [1,2-f]chromene5,11(10bH,15bH)-dione (2e). Mp, 265 C. IR (n¼cm1) 3435, 2924, 2852, 1715, 1642, 1490. 1H NMR (300 MHz, CDCl3) d 8.42 (d, J¼7.2 Hz, 1H), 7.96 (d, J¼7.8 Hz, 1H), 7.89 (d, J¼7.5 Hz, 1H), 7.78 (d, J¼6.6 Hz, 1H), 7.69 (d, J¼7.5 Hz, 1H), 7.53e7.50 (m, 3H), 7.43 (d, J¼7.5 Hz, 1H), 7.23e7.14 (m, 2H), 7.06 (d, J¼7.8 Hz, 2H), 6.87 (d, J¼7.8 Hz, 2H), 4.87 (s, 1H), 2.31 (s, 3H), 2.25 (s, 3H) 13C NMR (75 MHz, CDCl3) d 204.7, 161.4, 151.1, 148.1, 140.9, 139.7, 137.6, 137.0, 135.7, 135.5, 135.1, 133.6, 133.2, 130.5, 129.9, 129.3, 128.6, 127.9, 124.9, 124.8, 124.2, 123.5, 122.5, 121.2, 106.9, 62.5, 48.2, 21.6, 20.9. HRMS (ESI-TOF) of C32H22O3¼455.1636 [MþH]þ (Calculated 455.1642). 4.2.6. 2,14-Dibromo-9-methyl-10b-(p-tolyl)dibenzo [c,h]indeno[1,2f]chromene-5,11(10bH,15bH)-dione (2f). Mp, >300 C. IR (n¼cm1) 3434, 2922, 2853, 1720, 1641, 1485. 1H NMR (300 MHz, CDCl3) d 8.27 (d, J¼8.1 Hz, 1H), 7.96 (d, J¼7.8 Hz, 1H), 7.75 (d, J¼8.7 Hz, 2H), 7.68 (d, J¼8.4 Hz, 1H), 7.58 (d, J¼7.8 Hz, 1H), 7.44 (s, 1H), 7.25e7.22 (m, 2H), 7.08 (d, J¼7.5 Hz, 2H), 6.82 (d, J¼7.8 Hz, 2H), 4.76 (s, 1H), 2.32 (s, 3H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) d 203.2, 160.7, 152.3, 149.6, 141.7, 139.0, 138.8, 137.4, 134.5, 133.1, 132.5, 132.3, 132.2, 131.5, 131.3, 131.1, 129.8, 129.6, 129.4, 127.9, 125.5, 124.8, 124.5, 123.9, 119.7, 105.2, 62.8, 47.7, 21.6, 20.9; HRMS (ESI-TOF) of C32H20Br2O2¼634.9652 [MþNa]þ (Calculated 634.9651). 4.2.7. 8,9-Dichloro-10b-(3,4-dichlorophenyl) dibenzo[c,h]indeno[1,2f]chromene-5,11 (10bH,15bH)-dione (2g). Mp, >300 C. IR (n¼cm1) 3435, 2923, 2853, 1729, 1640, 1474. 1H NMR (300 MHz, CDCl3) d 8.48 (d, J¼7.5 Hz, 1H), 8.15 (s, 1H), 7.92e7.85 (m, 2H), 7.76 (s, 1H), 7.74e7.72 (m, 1H), 7.68 (t, J¼7.5 Hz, 1H), 7.59 (t, J¼7.2 Hz, 1H), 7.50 (t, J¼7.5 Hz, 1H), 7.37e7.30 (m, 1H), 7.17 (d, J¼7.5 Hz, 1H), 7.0 (s, 1H), 6.79 (d, J¼8.4 Hz, 1H), 4.86 (s, 1H); 13C NMR (75 MHz, CDCl3) d 202.7, 160.6, 150.5, 145.8, 141.8, 136.5, 136.4, 135.6, 134.8, 134.0, 133.1, 132.2, 131.9, 131.1, 130.9, 130.8, 129.9, 129.8, 129.3, 129.2, 127.5, 127.1, 126.7, 125.4, 124.9, 124.8, 122.8, 121.5, 108.7, 60.9, 47.9; HRMS (ESI-TOF) of C30H14Cl4O3¼564.9775 [MþH]þ (Calculated 564.9770). 4.3. General procedure for the synthesis of compounds 3aej 1.0 mmol of 1 was heated at 160 C (Pre-heated oil bath was used) for 6e8 h. After completion of the reaction (monitored by

5907

TLC), the desired product 3 was purified by column chromatography over 60e120 mesh silica gel using mixture of hexane/EtOAc in appropriate proportion. 4.3.1. 2,13-Dibromo-5a-phenylbenzo[a]indeno[2,1-c]fluorene5,10(5aH,14cH)-dione (3a). Mp: 270 C. IR (n¼cm1) 3433, 2922, 2850, 1717, 1575, 1411. 1H NMR (300 MHz, CDCl3) d 8.40 (d, J¼7.7 Hz, 1H), 7.77e7.56 (m, 4H), 7.46e7.22 (m, 8H), 6.90e6.87 (m, 2H), 4.57 (s, 1H); 13C NMR (75 MHz, CDCl3) d 203.3, 193.5, 151.2, 150.8, 145.3, 142.9, 134.7, 132.7, 132.3, 131.7, 131.4, 130.6, 129.5, 129.4, 129.3, 128.8, 128.4, 127.9, 127.7, 127.4, 126.3, 125.9, 125.3, 125.2, 124.3, 123.1, 63.3, 48.4; HRMS (ESI-TOF) of C30H16Br2O2 [MþNa]þ¼590.9378 (Calculated 590.9389). 4.3.2. 5a-Phenylbenzo[a]indeno[2,1-c]fluorene-5,10(5aH,14cH)-dione (3b). Mp: 212 C. IR (n¼cm1) 3393, 2922, 2851, 1712, 1600, 1455 1H NMR (300 MHz, CDCl3) d 8.41 (d, J¼7.5 Hz, 1H), 7.91 (d, J¼7.5 Hz, 1H), 7.73 (d, J¼7.5 Hz, 1H), 7.59e7.22 (m, 12H), 6.95 (d, J¼7.2 Hz, 2H), 4.65 (s, 1H); 13C NMR (75 MHz, CDCl3) d 204.7, 195.0, 153.3, 150.1, 143.8, 143.5, 135.9, 133.7, 132.1, 131.9, 129.5, 128.8, 128.7, 128.7, 128.6, 128.5, 128.1, 128.0, 127.9, 127.1, 124.8, 124.7, 124.7, 122.9, 122.9, 120.0, 62.8, 48.9; HRMS (ESI-TOF) of C30H18O2¼433.1194 [MþNa]þ (Calculated 433.1199). 4.3.3. 7-Methyl-5a-(p-tolyl)benzo[a]indeno[2,1-c]fluorene5,10(5aH,14cH)-dione (3e). Mp: 209 C. IR (n¼cm1) 3411, 2920, 2856, 1708, 1596, 1432. 1H NMR (300 MHz, CDCl3) d 8.29 (d, J¼7.8 Hz, 1H), 7.90 (t, J¼7.8 Hz, 1H), 7.57e7.38 (m, 6H), 7.28e7.20 (m, 3H), 7.13 (d, J¼7.8 Hz, 1H), 7.06e6.99 (m, 1H), 6.83 (d, J¼8.1 Hz, 2H), 4.59 (s, 1H), 2.27 (s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) d 205.1, 195.3, 152.3, 150.2, 143.9, 140.9, 138.9, 136.8, 136.0, 135.8, 133.7, 132.2, 132.0, 130.0, 129.3, 128.9, 128.7, 127.9, 127.3, 125.5, 124.8, 124.7, 124.3, 123.5, 122.8, 119.8, 62.8, 49.0, 21.6, 20.9; HRMS (ESI-TOF) of C32H22O2¼439.1677 [MþH]þ (Calculated 439.1693). 4.3.4. 7,8-Dichloro-5a-(3,4-dichlorophenyl)benzo [a]indeno[2,1-c] fluorene-5,10(5aH,14cH)-dione (3g). Mp, 248 C. IR (n¼cm1) 2922, 2857, 2371, 1707, 1594, 1473. 1H NMR (300 MHz, CDCl3) d 8.51 (s, 1H), 7.94 (d, J¼7.5 Hz, 1H), 7.62 (s, 1H), 7.67 (t, J¼7.2 Hz, 1H), 7.58e7.46 (m, 5H), 7.35e7.30 (m, 2H), 7.05 (s, 1H), 6.76 (d, J¼9.3 Hz, 1H), 4.59 (s, 1H) 13C NMR (75 MHz, CDCl3) d 203.0, 194.0, 154.0, 149.6, 143.0, 142.8, 136.7, 135.2, 134.2, 133.3, 133.1, 132.8, 132.3, 131.9, 131.0, 130.8, 130.4, 129.7, 129.4, 129.0, 127.6, 126.4, 126.3, 125.2, 124.9, 123.5, 120.5, 61.2, 48.5; HRMS (ESI-TOF) of C30H14Cl4O2¼570.9601 [MþNa]þ (Calculated 570.9611). 4.3.5. 7-Fluoro-5a-(4-fluorophenyl)benzo[a] indeno[2,1-c]fluorene5,10(5aH,14cH)-dione (3h). Mp, 252 C. IR (n¼cm1) 3424, 2926, 2846, 1712, 1596, 1472. 1H NMR (300 MHz, CDCl3) d 8.35 (t, J¼7.5 Hz, 1H), 7.84 (d, J¼7.5 Hz, 1H), 7.57e7.52 (m, 1H), 7.45e7.34 (m, 5H), 7.22e7.16 (m, 2H), 6.96e6.86 (m, 1H), 6.85e6.83 (m, 4H), 4.52 (s, 1H); 13C NMR (75 MHz, CDCl3) d 203.7, 194.3, 163.7, 162.9, 160.4, 159.6, 151.8, 149.5, 142.9, 138.6, 135.8, 135.0, 134.3, 133.5, 131.5, 129.2, 128.6, 126.2, 124.4, 123.9, 122.6, 119.5, 116.3, 116.0, 115.3, 114.9, 61.6, 48.2; HRMS (ESI-TOF) of C30H16F2O2¼469.1006 [MþNa]þ (Calculated 469.1011). 4.3.6. 2,13-Dibromo-7-fluoro-5a-(4-fluorophenyl) benzo[a]indeno [2,1-c]fluorene-5,10(5aH,14cH)-dione (3i). Mp, 258 C. IR (n¼cm1) 3435, 2923, 2852, 1700, 1593, 1505. 1H NMR (300 MHz, CDCl3) d 8.33e8.28 (m, 1H), 7.69 (d, J¼8.1 Hz, 1H), 7.55 (d, J¼8.1 Hz, 1H), 7.47 (s, 1H), 7.42e7.39 (m, 1H), 7.33e7.27 (m, 2H), 7.16 (s, 1H), 6.99e6.74 (m, 5H), 4.43 (s, 1H); 13C NMR (75 MHz, CDCl3) d 202.7, 193.3, 163.6, 160.3, 151.0, 149.8, 145.2, 138.2, 134.7, 134.3, 132.9, 132.5, 131.8, 130.4, 129.6, 129.0, 128.0, 127.2, 126.1, 124.5, 123.9,

5908


123.1, 116.9, 116.5, 116.0, 115.7, 62.5, 48.2; HRMS (ESI-TOF) of C30H14Br2F2O2¼622.0084 [MþNH4]þ (Calculated 621.9647). 4.3.7. 4b-Phenylbenzo[c]indeno[2,1-a]fluorene-13,14(4bH,13bH)-dione (3j). 1H NMR (300 MHz, CDCl3) d 8.27e8.24 (m, 1H), 7.87e7.79 (m, 2H), 7.63e7.42 (m, 4H), 7.33e7.30 (m, 1H), 7.23e7.19 (m, 7H), 6.68 (d, J¼7.5 Hz, 2H), 3.83 (s, 1H); 13C NMR (75 MHz, CDCl3) d 206.5, 201.6, 152.2, 143.2, 141.3, 140.6, 135.3, 133.0, 132.6, 131.1, 130.8, 130.7, 130.6, 129.5, 129.0, 128.8, 127.7, 127.5, 127.5, 126.8, 126.5, 126.5, 124.0, 123.0, 122.9, 61.3, 57.0; HRMS (ESI-TOF) of C30H18O2¼433.1225 [MþNa]þ (Calculated 433.1199). Acknowledgements We gratefully acknowledge the financial support from the Science and Engineering Research Board (Grant No. SB/S1/OC-30/ 2013) New Delhi, India and the Council of Scientific and Industrial Research (Grant No. 02(0072)/12/EMR-II) New Delhi, India. Supplementary data Supplementary data (Copies of 1H, 13C NMR and HRMS spectra; CCDC 945269 (2b) and 1053367 (3h)) related to this article can be found at http://dx.doi.org/10.1016/j.tet.2016.08.025. References and notes 1. Nicolaou, K. C.; Montagnon, T. Molecules that Changed the World: a Brief History of the Art and Science of Synthesis and its Impact on Society; WILEY-VCH, 2008. 2. (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; WILEY-VCH, 2006; and references therein; (b) Ho, T.-L. Tandem Organic Reactions; WILEY-VCH, 1992; (c) Tietze, L. F. Chem. Rev. 1996, 96, 115; (d) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223; (e) Pellissier, H. Chem. Rev. 2013, 113, 442; (f) Domino Reactions: Concepts for Efficient Organic Synthesis; Tietze, L. F., Ed.; WILEY-VCH: 2014. 3. (a) Chanda, T.; Chowdhury, S.; Ramulu, B. J.; Koley, S.; Jones, R. C. F.; Singh, M. S. Tetrahedron 2014, 70, 2190 and references therein; (b) Chanda, T.; Chowdhury, S.; Anand, N.; Koley, S.; Gupta, A.; Singh, M. S. Tetrahedron Lett. 2015, 56, 981; (c) Chanda, T.; Chowdhury, S.; Koley, S.; Anand, N.; Singh, M. S. Org. Biomol. Chem. 2014, 12, 9216; (d) Chanda, T.; Verma, R. K.; Singh, M. S. Chem.dAsian J. 2012, 7, 778; (e) Koley, S.; Chowdhury, S.; Chanda, T.; Ramulu, B. J.; Singh, M. S. Tetrahedron 2013, 69, 8013; (f) Singh, M. S.; Chowdhury, S. RSC Adv. 2012, 2, 4547. 4. For general idea of Diels-Alder reaction; (a) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98; (b) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779; (c) Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515; (d) Mackay, E. G.; Sherburn, M. S. Synthesis 2015, 47, 1; (e) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668; (f) Funel, J.-A.; Abele, S. Angew. Chem., Int. Ed. 2013, 52, 3822; (g) Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63; (h) Winkler, J. D. Chem. Rev. 1996, 96, 167; (i) Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359; (j) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007.

5. For dehydro-Diels-Alder reaction; (a) Wessig, P.; Muller, G. Chem. Rev. 2008, 108, 2051 and references therein; (b) Wessig, P.; Pick, C.; Schilde, U. Tetrahedron Lett. 2011, 52, 4221; (c) Wessig, P.; Matthes, A.; Pick, C. Org. Biomol. Chem. 2011, 9, 7599; (d) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208; (e) Klemm, L. H.; Lee, D. H.; Gopinath, K. W.; Klopfenstein, C. E. J. Org. Chem. 1966, 31, 2376; (f) Klemm, L. H.; Gopinath, K. W. Tetrahedron Lett. 1963, 4, 1243; (g) Kocsis, L. S.; Kagalwala, H. N.; Mutto, S.; Godugu, B.; Bernhard, S.; Tantillo, D. J.; Brummond, K. M. J. Org. Chem. 2015, 80, 11686; (h) Kocsis, L. S.; Brummond, K. M. Org. Lett. 2014, 16, 4158. 6. For dehydrogenative-Diels-Alder reaction; (a) Feng, H.-X.; Wang, Y.-Y.; Chen, J.; Zhou, L. Adv. Synth. Catal. 2015, 357, 940; (b) Qi, C.; Cong, H.; Cahill, K. J.; Mìller, P.; Johnson, R. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2013, 52, 8345; (c) Dong, S.; Hamel, E.; Bai, R.; Covell, D. G.; Beutler, J. A.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2009, 48, 1494; (d) Dong, S.; Qin, T.; Hamel, E.; Beutler, J. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2012, 134, 19782; (e) Zhou, L.; Xiu, B.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 9092; (f) Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133, 14892; (g) Zhou, L.; Zhang, M.; Li, W.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 6542. 7. (a) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625; (b) ten Brink, G.J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104, 4105; (c) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737; (d) Robertson, J. C.; Swelim, A. Tetrahedron Lett. 1967, 8, 2871. 8. (a) Sinhamahapatra, A.; Sinha, A.; Pahari, S. K.; Sutradhar, N.; Bajaj, H. C.; Panda, A. B. Catal. Sci. Technol. 2012, 2, 2375; (b) Hashemi, M. M.; Beni, Y. A. J. Chem. Res. 2000, 196. 9. (a) Tutar, A.; Cakmak, O.; Balci, M. Tetrahedron 2001, 57, 9759; (b) Tutar, A.; Berkil, K.; Hark, R. R.; Balci, M. Synth. Commun. 2008, 38, 1333; (c) Zheng, S.; Tan, H.; Zhang, X.; Yu, C.; Shen, Z. Tetrahedron Lett. 2014, 55, 975. 10. Chanda, T.; Chowdhury, S.; Koley, S.; Anand, N.; Singh, M. S. Tetrahedron Lett. 2015, 56, 4303. 11. (a) Dewar, M. J. S.; Olivella, S.; Stewart, J. J. P. J. Am. Chem. Soc. 1986, 108, 5771; (b) Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P. J. Org. Chem. 2011, 76, 9320; (c) Rodríguez, D.; , C. J. Org. Chem. 2003, 68, Navarro-V azquez, A.; Castedo, L.; Domínguez, D.; Saa , C. Org. Lett. 1938; (d) Rodríguez, D.; Navarro, A.; Castedo, L.; Domínguez, D.; Saa 2000, 2, 1497. 12. (a) Blokzijl, W.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1992, 114, 5440; (b) Breslow, R.; Rizzo, C. J. J. Am. Chem. Soc. 1991, 113, 4340; (c) Parker, A. J. Chem. Rev. 1969, 69, 1; (d) Muzart, J. Tetrahedron 2009, 65, 8313. 13. For detailed experimental procedure and characterization data of substrate 1 or the final products 2 and 3; see the Supplementary data. 2b (CCDC 945269) and 3h (CCDC 1053367) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 14. (a) Takemura, I.; Imura, K.; Matsumoto, T.; Suzuki, K. Org. Lett. 2004, 6, 2305; (b) Konno, F.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. J. Org. Chem. 2006, 71, 9818; (c) Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004; (d) Hou, J.; Liu, P.; Qu, H.; Fu, P.; Wang, Y.; Wang, Z.; Li, Y.; Teng, X.; Zhu, W. J. Antibiot. 2012, 65, 523; (e) Pahari, P.; Kharel, M. K.; Shepherd, M. D.; van Lanen, S. G.; Rohr, J. Angew. Chem., Int. Ed. 2012, 51, 1216; (f) Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori, K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41, 1063; (g) Ben, A.; Hsu, D.; Matsumoto, T.; Suzuki, K. Tetrahedron 2011, 67, 6460; (h) Kupchan, S. M.; Suffness, M. I. J. Am. Chem. Soc. 1968, 90, 2730; (i) Gao, S.; Wang, Q.; Huang, L. J.-S.; Lum, L.; Chen, C. J. Am. Chem. Soc. 2010, 132, 371. 15. (a) Hendry, D. G.; Schuetzle, D. J. Am. Chem. Soc. 1975, 97, 7123; (b) Bobrowski, M.; Liwo, A.; Oldziej, S.; Jeziorek, D.; Ossowski, T. J. Am. Chem. Soc. 2000, 122, 8112. 16. Ozawa, T.; Kurahashi, T.; Matsubara, S. Org. Lett. 2011, 13, 5390.