propellane derivatives via ring-closing metathesis

Indian Journal of Chemistry Vol. 56B, October 2017, pp. 1065-1069

Synthesis of indane-based [n.3.3] propellane derivatives via ring-closing metathesis Sambasivarao Kotha* & Ajay Kumar Chinnam Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India E-mail: [email protected] Received 27 March 2017; accepted (revised) 5 September 2017 Two examples of indene-based [n.3.3]propellane derivatives are described involving selective alkylation, olefin metathesis and catalytic hydrogenation as key steps. Final compounds were analyzed by NMR and HRMS spectral data. Keywords: Indane, metathesis, ring-closing, [n.3.3]propellane, alkylation, hydrogenation

The propellane core structure is present in many natural (e.g., modhephene 1) and non-natural products such as triquinacene derivative 2 (Figure 1)1,2. Some of the propellane derivatives are found to be highly congested and unstable entities3. Recently, several research groups reported propellanes containing heteroatoms such as nitrogen and oxygen4. In view of our interest to develop new synthetic strategies to propellanes5, here, we envisioned a simple approach to indene-based propellanes via ring-closing metathesis (RCM) as a key step and we describe our results in this endeavor. Results and Discussion Our journey to design new propellane derivatives starts with commercially available synthons. To this end, the known compound 4b,9b-dihydroindeno[2, 1a]indene-5,10-dione 3 was prepared using ethyl phenylacetate 4 under oxidative coupling followed by cyclization which furnished the indene dione 3 (Scheme I)6. To achieve our goal, the indene dione 3 was treated for selective allylation with 3-bromoprop-1-ene in the presence of NaH/THF under reflux conditions to give mono-allyl indene dione 6 in 58% yield. Subsequently, mono-allyl indene dione derivative 6 was treated with excess amount of 3-bromoprop-1-ene in the presence of NaH/THF under reflux conditions to deliver diallyl indene dione 7 in 76% yield. Similarly, the mono-allyl indene dione 6 was treated with 5-bromo1-pentene in the presence of NaH/THF under reflux conditions and catalytic amount of tetrabutylammonium iodide (TBAI) delivered the dione 8 in 63% yield (Scheme II).

Having the diolefin indene dione derivatives 7 and 8 in hand, our next task was to construct the propellane derivatives via RCM by using a ruthenium catalyst. In this regard, compound 7 was subjected to RCM under the influence of the Grubbs second generation catalyst (G-II) in anhydrous CH2Cl2 to furnish the RCM product 9 in 92% yield. The unsaturated propellane derivative 9 was subjected to catalytic hydrogenation in the presence of Pd/C (10 mol %) in anhydrous EtOAc, under H2 atmosphere to afford the saturated [4.3.3]propellane derivative 10 in 98% yield (Scheme III). Similarly, the unsymmetrical indene dione olefin 8 was treated with G-II catalyst in anhydrous CH2Cl2 to generate the desired RCM product 11 (82%). The unsaturated propellane derivative 11 was subjected to catalytic hydrogenation in the presence of Pd/C (10 mol %) in anhydrous EtOAc under H2 atmosphere to afford the saturated [6.3.3]propellane derivative 12 in 96% yield (Scheme IV). Experimental Section NMR spectra were recorded at room temperature on 400 MHz Bruker NMR spectrometer in CDCl3 solution. Coupling constants (J values) are given in

Figure 1 — Structures of modhephene 1 and derivative 2

triquinacene

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Scheme I — Preparation of dione 3

Reagents and conditions: (a) NaH, 3-bromoprop-1-ene, THF, reflux, 2 h,58%; (b) NaH, 3-bromoprop-1-ene, THF, reflux, 6 h, 76%; (c) NaH, 5-bromo-1-pentene, TBAI, THF, reflux, 8 h, 63%. Scheme II — Synthesis of diallyl 7 and allylpentenyldione 8 derivatives

Reagents and conditions: (a) G-II (5 mol %), CH2Cl2, RT, 24 h, 92%; (b) Pd/C (10 mol %), H2, EtOAc, RT, 12 h, 98%. Scheme III — Synthesis of indene-based [4.3.3]propellane derivative 10 by RCM and hydrogenation

Reagents and conditions: (a) G-II (5 mol %), CH2Cl2, RT, 24 h, 82%; (b) Pd/C, H2, EtOAc, RT, 28 h, 96%. Scheme IV — Synthesis of indene-based [6.3.3]propellane derivative 12 by RCM and hydrogenation

KOTHA & CHINNAM: INDANE-BASED [n.3.3] PROPELLANE DERIVATIVES

Hertz (Hz). Melting points were recorded with Buchi melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded on Nicolet Impact-400 FT IR spectrometer in KBr. The high-resolution mass measurements were carried out using a Micromass Q-ToF spectrometer. Analytical thin layer chromatography (TLC) was performed on (10 × 5 cm) glass plates coated with Acme’s silica gel GF 254 (containing 13% calcium sulfate as a binder). Chromatography was performed using Acme’s silica gel (100-200 mesh) using double spray bellows for application of pressure and the column is eluted with ethyl acetate-petroleum ether mixture. The organic solvents used in this study were dried over appropriate drying agents and distilled prior to use. Synthesis of 4b-allyl-4b,9b-dihydroindeno[2,1-a] indene-5,10-dione, 6 To a suspension of NaH (68 mg, 2.82 mmol) in anhydrous THF (10 mL), the 4b,9b-dihydroindeno [2,1-a]indene-5,10-dione 3 (300 mg, 1.28 mmol) was added at RT under nitrogen. Then, the resulting reaction mixture was stirred at RT for 15 min. 3-Bromoprop-1-ene (0. 16 mL, 1.92 mmol) was added to the reaction mixture in a drop-wise manner and stirring was continued at RT for 2 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was diluted with EtOAc (10 mL), washed with water, brine and dried over anhyd. Na2SO4, and concentrated at reduced pressure. The crude product obtained was purified by silica gel column chromatography (5% EtOAc-petroleum ether) to deliver the compound 6 (203 mg, 58%) as yellow liquid. Rf 0.42 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 2945, 2836, 2523, 1671, 1420, 1115 cm−1; 1H NMR (400 MHz, CDCl3):  2.86-2.91 (m, 1H), 2.96-3.00 (m, 1H), 4.17 (s, 1H), 5.00-5.15 (m, 2H), 5.46-5.55 (m, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.64-7.70 (m, 4H), 7.85-7.88 (m, 2H); 13C NMR (125 MHz, CDCl3):  40.21, 57.38, 60.55, 119.86, 124.67, 124.95, 125.47, 126.58, 129.24, 129.42, 132.75, 134.75, 134.84, 136.07, 149.16, 153.21, 201.55, 203.72; HRMS (ESI, Q-ToF): m/z [M+H]+ Calcd for C19H15O2: 275.1072. Found: 275.1080. Synthesis of 4b,9b-diallyl-4b,9b-dihydroindeno[2,1a]indene-5,10-dione, 7 To a suspension of NaH (30 mg, 1.25 mmol) in anhydrous THF (10 mL), the monoallyldione 6 (150 mg, 0.54 mmol) was added at RT under nitrogen. Then,

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the resulting reaction mixture was stirred at RT for 15 min. 3-Bromoprop-1-ene (0. 07 mL, 0.82 mmol) was added to the reaction mixture in a drop-wise manner, and the reaction mixture was stirred at reflux temperature for 6 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was diluted with EtOAc (10 mL), washed with water, brine and dried over anhyd. Na2SO4, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (5% EtOAc-petroleum ether) to deliver the compound 7 (130 mg, 76%) as yellow solid. m.p.205-207°C. Rf 0.42 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 2945, 2836, 2523, 1671, 1420, 1115 cm−1; 1 H NMR (400 MHz, CDCl3):  2.98-3.03 (m, 2H), 3.28-3.33 (m, 2H), 4.95-5.13 (m, 4H), 5.31-5.41 (m, 2H), 7.37-7.41 (m, 2H), 7.58-7.62 (m, 2H), 7.66-7.72 (m, 4H); 13C NMR (100 MHz, CDCl3):  36.27, 64.03, 118.75, 124.81, 125.41, 129.34, 133.56, 133.60, 135.68, 153.33, 203.60; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C22H18NaO2: 337.1204. Found: 337.1199. (4bS,9bS)-5H,10H-4b,9b-but[2]enoindeno[2,1-a] indene-5,10-dione, 9 A solution of di-allyldione7 (100 mg, 0.32 mmol) in anhydrous CH2Cl2 (50 mL) was degassed with N2 for 10 min, then was added G-II (7.5mol%) at RT and the resulting mixture was stirred at RT for 24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed at reduced pressure and the crude product was purified by silica gel column chromatography (5% EtOAc-petroleum ether) to deliver (4bS,9bS)-5H,10H-4b,9b-but[2]enoindeno [2, 1-a]indene-5,10-dione 9 (84 mg, 92%) as colourless solid. m.p. 232-35°C. Rf 0.40 (Silica gel, 5% EtOAcpetroleum ether); IR (KBr): 3053, 2956, 1713, 1422, 1266, 1050 cm−1; 1H NMR (400 MHz, CDCl3):  2.63-2.68 (m, 2H), 2.94-2.99 (m, 2H), 5.87 (t, J = 3.1 Hz, 2H), 7.39-7.43 (m, 2H), 7.64-7.68 (m, 4H), 7.85-7.87 (m, 2H); 13C NMR (100 MHz, CDCl3):  32.07, 61.79, 124.52, 125.33, 128.14, 129.32, 135.05, 136.17, 153.72, 204.48; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C20H14NaO2: 309.0891. Found: 309.0886. (4bS,9bS)-5H,10H-4b,9b-butanoindeno[2,1-a]indene5,10-dione, 10 To a solution of propellane 9 (50 mg, 0.17 mmol) in anhydrous EtOAc (10 mL), Pd/C (10 mol %) was

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added and the reaction mixture was stirred at RT under H2 (1 atm) for 12 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was filtered through celite-pad and washed with EtOAc (20 mL). Evaporation of the solvent at reduced pressure gave the crude product. Further purification by silica gel column chromatography (5% EtOAcpetroleum ether) to deliver (4bS,9bS)-5H,10H-4b,9bbutanoindeno[2,1-a]indene-5,10-dione 10 (49 mg, 98%) as colourless solid. m.p. 245-47°C. Rf 0.42 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 2945, 2867, 1711, 1653, 1462, 1265, 1095 cm−1; 1 H NMR (500 MHz, CDCl3):  1.38-1.48 (m, 4H), 2.00-2.05 (m, 2H), 2.39-2.45 (m, 2H), 7.39-7.42 (m, 2H), 7.63-7.69 (m, 4H), 7.81 (d, J = 7.8 Hz, 2H); 13 C NMR (125 MHz, CDCl3):  17.94, 29.25, 60.47, 124.69, 125.39, 129.20, 134.37, 135.96, 154.19, 205.02; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C20H16O2Na: 311.1043. Found: 311.1042. Synthesis of 4b-allyl-9b-(pent-4-en-1-yl)-4b,9bdihydroindeno[2,1-a]indene-5,10-dione, 8 To a suspension of NaH (50 mg, 0.18 mmol) in THF (10 mL), the monoallyldione 6 (150 mg, 0.54 mmol) was added at RT under N2. Then, the resulting reaction mixture was stirred at RT for 15 min. 5-Bromo-1-pentene (0. 03 mL, 0.22 mmol) was added to the reaction mixture in a drop-wise manner, and the resulting mixture was stirred at reflux temperature for 8 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was diluted with EtOAc (10 mL), washed with water, brine and dried over anhyd. Na2SO4, concentrated at reduced pressure. The crude product obtained was purified by silica gel column chromatography (5% EtOAcpetroleum ether) to deliver the compound 8 (40 mg, 63%) as yellow liquid. Rf 0.43 (Silica gel, 5% EtOAcpetroleum ether); IR (KBr): 2965, 2851, 2543, 1641, 1424, 1015 cm−1; 1H NMR (400 MHz, CDCl3):  0.92-1.01 (m, 1H), 1.13-1.22 (m, 1H), 1.99-2.08 (m, 2H), 2.12-2.19 (m, 1H), 2.45-2.54 (m, 1H), 2.83-2.90 (m, 1H), 3.28-3.35 (m, 1H), 4.95-5.12 (m, 4H), 5.29-5.40 (m, 1H), 5.63-5.75 (m, 1H), 7.36-7.40 (m, 2H), 7.57-7.61 (m, 2H), 7.64-7.69 (m, 4H); 13C NMR (100 MHz, CDCl3):  25.18, 31.06, 34.28, 36.95, 63.94, 64.89, 115.45, 118.78, 124.82, 125.36, 125.38, 129.23, 129.33, 133.57, 133.63, 133.81, 135.57, 138.02, 153.34, 153.83, 203.82, 204.15; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C24H22NaO2: 365.1512. Found: 365.1510.

Synthesis of [6.3.3]propellans derivative, 11 A solution of allylpentenyldione 8 (35 mg, 0.10 mmol) in dry CH2Cl2 (20 mL) was degassed with N2 for 10 min, then was added G-II (7.5 mol%) at RT and the resulting mixture was stirred at RT for 24 h. At the conclusion of the reaction (TLC monitoring), the solvent was removed at reduced pressure and the crude product was purified by silica gel column chromatography (5% EtOAc-petroleum ether) to deliver the RCM compound 11 (26 mg, 82%) as colourless solid. m.p. 195-97°C. Rf 0.43 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 3043, 2986, 1723, 1463, 1242, 1046 cm−1; 1H NMR (400 MHz, CDCl3):  1.73-1.74 (m, 2H), 2.04-2.08 (m, 2H), 2.29-2.32 (m, 1H), 2.62-2.63 (m, 1H), 2.91-2.97 (m, 1H), 3.03-3.09 (m, 1H), 5.21-5.27 (m, 1H), 5.58-5.64 (m, 1H), 7.34-7.43 (m, 2H), 7.56-7.75 (m, 6H); 13C NMR (100 MHz, CDCl3):  26.42, 27.62, 29.87, 66.14, 68.61, 124.57, 124.74, 125.48, 125.55, 127.37, 129.18, 133.47, 135.51, 135.61, 153.30, 204.09, 204.16; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C22H18NaO2: 337.1199. Found: 337.1194. Synthesis of [6.3.3]propellans derivative, 12 To a solution of propellane 11 (23 mg, 0.07 mmol) in dry EtOAc (10 mL), Pd/C (10 mol%) was added and the reaction mixture was stirred at RT under H2 (1 atm) for 28 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was filtered through Celite-pad and washed with EtOAc (10 mL). Evaporation of the solvent at reduced pressure gave the crude product. Further purification by silica gel column chromatography (5% EtOAc-petroleum ether) to deliver the hydrogenated product 12 (22 mg, 96%) as colourless solid. m.p. 204-206°C.Rf 0.42 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 2956, 2862, 1721, 1642, 1424, 1266, 1056 cm−1; 1H NMR (400 MHz, CDCl3):  1.07-1.10 (m, 2H), 1.17-1.21 (m, 2H), 1.49-1.51 (m, 2H), 1.72-1.74 (m, 2H), 2.32-2.39 (m, 2H), 2.45-2.51 (m, 2H), 7.34-7.38 (m, 2H), 7.58-7.76 (m, 4H), 7.78 (d, J = 1.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3):  25.72, 26.17, 31.40, 64.92, 124.56, 126.16, 129.11, 133.35, 135.54, 154.55, 205.01; HRMS (ESI, Q-ToF): m/z [M+Na]+ Calcd for C22H20NaO2: 339.1361. Found: 339.1367. Conclusions We have developed a simple synthetic strategy to dibenzo[a,e]pentane-based[n.3.3]propellanes using simple starting materials involving olefin metathesis

KOTHA & CHINNAM: INDANE-BASED [n.3.3] PROPELLANE DERIVATIVES

as a key step. We have successfully synthesized dibenzo[a,e]pentane based [4.3.3]propellane 10 and [6.3.3]propellane derivative 12 using RCM and catalytic hydrogenation sequence. Acknowledgment The authors thank CSIR and Department of Science and Technology (DST), New Delhi for the financial support. SK thanks DST for the award of a J. C. Bose fellowship. AKC thanks University Grant Commission (UGC), New Delhi for the award of a research fellowship.

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References 1

2 3

(a) Altman J, Babad E, Itzchaki J & Ginsburg D, Tetrahedron, 22 (1966) 279; (b) Ginsburg D, Acc Chem Res, 5 (1972) 249; (c) Ginsburg D, Acc Chem Res, 2 (1969) 121; (c) Kuck D, Chem Rev, 106 (2006) 4885. (a) Ginsburg D, Top Curr Chem, 137 (1987) 1; (b) Gupta A K, Lannoye G S, Kubiak G, Schkeryantz J, Wehrli S & Cook J M, J Am Chem Soc, 111 (1989) 2169. Pihko A J & Koskinen A M P, Tetrahedron, 61 (2005) 8769.

6

1069

(a) Alizadeh A, Bayat F, Moaf L & Zhu L-G, Tetrahedron, 71 (2015) 8150; (b) Hassan A A, Mohamed N K, Makhlouf M M, Bräse S & Nieger M, Synthesis, 47 (2015) 3036; (c) Hassan A A, El-Shaieb K M A, Abd El-Aal A S A, Bräse S & Nieger M, Arkivoc, (v) (2016) 406; (d) Kotha S & Gunta R, Beilstein J Org Chem, 12 (2016) 1877; (e) Hassan A A, Mohamed N K, Abd El-Haleem L E, Bräse S & Nieger M, Curren Org Synth, 13 (2016) 426. (a) Kotha S & Dipak M K, Chem Eur J, 12 (2006) 4446; (b) Kotha S, Chavan A S & Dipak M K, Tetrahedron, 67 (2011) 501; (c) Kotha S, Chinnam A K & Tiwari A, Beilstein J Org Chem, 9 (2013) 2709; (d) Kotha S & Dipak M K, Beilstein J Org Chem, 10 (2014) 2664; (e) Kotha S, Ali R & Chinnam A K, Tetrahedron Lett, 55 (2014) 4492; (f) Kotha S, Saifuddin M, Ali R & Sreevani G, Beilstein J Org Chem, 10 (2014) 2664; (g) Kotha S & Gunta R, Beilstein J Org Chem, 11 (2015) 1727; (h) Kotha S & Aswar V R, Org Lett, 18 (2016) 1808. (a) Wawzonek S, J Am Chem Soc, 62 (1940) 745; (b) Chuen C C & Fenton S W, J Org Chem, 23 (1958) 1538; (c) Kuck D, Eckrich R & Tellenbriiker J, J Org Chem, 59 (1994) 2511; (d) Rao V D & Periasamy M, Synthesis (2000) 703; (e) Yang J, Lakshmikantham M V & Cava M P, J Org Chem, 65 (2000) 6739; (f) Song S, Jin Y, Kim S H, Moon J, Kim K, Kim J Y, Park S H, Lee K & Suh H, Macromolecules, 41 (2008) 7296.