Indian Journal of Chemistry Vol. 55B, September 2016, pp. 1107-1111
Design and synthesis of polycyclic indoles under green conditions via Fischer indolization Sambasivarao Kotha*, Ajay Kumar Chinnam, Nampally Sreenivasachary & Rashid Ali Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India E-mail:
[email protected] Received 5 February 2016; accepted (revised) 10 August 2016 A simple and useful synthetic route to aza-polyquinane derivatives involving Fischer indolization under green conditions has been demonstrated. Selenium dioxide is found to be useful for oxidizing some of these indole derivatives. Keywords: Indole, polyquinanes, Fischer indolization, low melting mixtures, green chemistry
In continuation of our interest to design new polycycles via Fischer indolization1a-d, and olefin metathesis1e-l, here we report new indole derivatives under green reaction conditions involving L-(+)tartaric acid (TA) and dimethyl urea (DMU) mixture2. To expand the scope of Fischer indolization we have chosen quinane based carbonyl compounds (1 and 2, Figure 1) as viable substrates to test Fischer indolization process3. To expand the scope of Fischer indolization strategy with polyquinanes4, initially we prepared a known and intricate building block such as the tetracyclic dione 1. This tetraquinane preparation was started with Weiss‒Cook dione5 3. Later, Grignard addition, hydroboration-oxidation and rearrangment sequence followed by catalytic hydrogenation gave the dione 1 (Scheme I)6. The dione 1 was then subjected to a two fold Fischer indolization with 1-methyl-1-phenylhydrazine 6 in the presence of low melting mixture to generate the diindole 7 (73%, Scheme II) and it was characterized by 1H and 13C NMR and finally HRMS spectral data. It is interesting to note that the diindole 7 containing six stereo centres and eight rings was assembled in five steps. One can clearly see the power
Figure 1 — Building blocks used for Fischer indolization sequence
of two directional approach, when we consider the ease with which 7 has been assembled. To extend this methodology to intricate azapolyquinane derivatives, we next used triquinacenebased dione 2. The tricyclic dione 2 can be prepared from commercially available dicyclopentadiene 8. In this context, the dicyclopentadiene 8 was subjected to oxidation, protection and photochemical cleavage followed by aldol condensation reaction and oxidation to deliver the tricyclic dione 2 (Scheme III)7. Later, the tricyclic dione 2 was subjected to a two fold Fischer indolization with 1-methyl-1-phenylhydrazine 6 in the presence of low melting mixture (TA:DMU) to generate the diindole derivative 11 (72%, Scheme IV). Since we were interested in expanding the chemical space8 related to functionalized indoles1a in a diversity oriented manner, various diindole derivatives were subjected to SeO2 oxidation. In this regard diindole 12a, was treated with SeO2 in 1,4-dioxane, which under reflux conditions delivered the diindole dione 13 in 45% yield (Scheme V)9. The dione 13 can be further synthetically manipulated to deliver advanced intermediates. For example, Beckmann rearrangement of 13 can produce new heterocycles. Following similar lines, other diindole derivatives such as dimethyl substituted diindole 12b and propellane containing diindole derivatives (12c, 12d) were subjected to the oxidation sequence and the results are shown in Figure 2. When we treated the diindole1a 14 with SeO2 in 1,4-dioxane, we were unable to get the desired oxidation product 15 in reflux conditions as well as
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Reagents and conditions: (a) Allyl bromide, Mg-ether/THF; (b) NaBH4, BF3-Et2O, THF, Jones; (c) Methanesulphonic acid, P2O5; (d) 10% Pd/C, EtOAc, 3 atm. Scheme I — Synthesis of tetraquinane 1
Scheme II — Fischer indolization of 1
Reagents and conditions: (a) Hg(OAc)2, HgO/BF4, PCC; (b) 2,2-dimethylpropane-1,3-diol, benzene, p-toluenesulfonic acid; (c) ultraviolet irradiation; (d) 3N HCl, acetone; (e) C2H5ONa, C2H5OH. Scheme III — Preparation of tricyclic dione 2
L-(+)-TA:DMU
6 70 °C, 6 h, 72% O
O
2
N Me
N Me
11 Scheme IV — Two fold Fischer indolization of dione 2
Scheme V — Synthesis of diindole derivative 13
KOTHA et al.: POLYCYCLIC INDOLES VIA FISCHER INDOLIZATION
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Figure 2 — Synthesis of diindole dione derivatives
Scheme VI — Attempted synthesis of diindole derivative 15
RT. In this regard, various attempts were not fruitful (Scheme VI).
(HRMS) was performed with a TOF mass spectrometer in positive ESI mode.
Experimental Section All reactions were performed under argon or nitrogen atmosphere using well-dried reaction flask. All commercially available products were used as received without further purification. All solvents used as reaction media were dried over pre-dried molecular sieves (4 Å) in a microwave oven. Column chromatography was performed with silica gel (100200 mesh) using a mixture of petroleum ether and EtOAc as eluent. 1H and 13C NMR spectral data were recorded on 400 MHz and 100 MHz or 500 MHz and 126 MHz spectrometers using tetramethylsilane (TMS) as an internal standard and CDCl3 as solvent. Chemical shifts are expressed in parts per million (δ, ppm) downfield from internal reference, TMS. The standard abbreviation s, d, t, q, m, dd and td, refer to singlet, doublet, triplet, quartet, multiplet, doublet of doublet, and triplet of the doublet respectively. Mass spectral data was recorded on a Q–TOF micromass spectrometer. High resolution mass spectroscopy
General procedure for the preparation of diindole derivatives In a typical experiment, 1.5 g of L-(+)-tartaric acid and N,N′−dimethylurea (30:70) mixture was heated at 70 °C to obtain a clear melt. To this melt, 2 mmol of 1-methyl 1-phenyl hydrazine 6 and 1 mmol of symmetrical diketone were added at 70°C. At the conclusion (TLC monitoring by mini work-up) of the reaction, the reaction mixture was quenched with water while hot. The reaction mixture was then cooled to RT and the solid product filtered and washed with water (2 × 5 mL). The crude product was dried under vacuum and then purified by silica gel column chromatography to deliver the diindole product. Diindole derivative, 7: White colour solid. Yield 48% [45 mg, obtained from tetracyclic dione 1 (100 mg, 0.23 mmol)]. m.p.210-12°C. Rf 0.34 (Silica gel, 10% EtOAc_petroleum ether); IR (KBr): 3058, 2986, 2941, 2908, 1465, 1246, 1047 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.02−1.12 (m, 2H), 1.80−1.83
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(m, 2H), 2.36 (t, J = 2.1 Hz, 1H), 2.40 (t, J = 2.2 Hz, 1H), 2.83−2.92 (m, 4H), 3.39−3.46 (m, 2H), 3.73 (s, 6H), 3.76 (m, 2H), 7.00−7.04 (m, 2H), 7.08−7.12 (m, 2H), 7.21−7.25 (m, 2H), 7.33 (d, J = 7.7 Hz, 2H); 13 C NMR (100.6 MHz, CDCl3): δ 31.04, 31.35, 36.38, 45.27, 49.86, 50.39, 109.22, 116.96, 118.58, 118.84, 119.88, 124.52, 141.60, 146.57; HRMS (ESI, Q-Tof): m/z Calcd for C28H29N2 [M + H]+: 393.2325. Found: 393.2321. 7,8-Dimethyl-2a,2a1,7,7b,8,12c-hexahydrocyclopenta [3,4]pentaleno[1,2-b:6,5-b']diindole, 11: White colour solid. Yield 72% [79 mg, obtained from triquinacene dione 2 (53 mg, 0.32 mmol)]. m.p.210-12°C. Rf 0.55 (Silica gel, 10% EtOAc-petroleum ether); IR (neat): 3054, 3014, 2931, 1603, 1527, 1463 cm−1; 1H NMR (500 MHz, CDCl3): δ 3.83 (s, 6H), 4.27 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 8.2 Hz, 1H), 5.14, 5.18 (ABq, J = 8.6 Hz, 1H), 6.00 (s, 2H), 7.05 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.1 Hz, 2H), 7.18 (t, J = 7.6 Hz, 2H); 7.47 (d, J = 7.7 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 32.65, 42.45, 48.38, 65.62, 109.88, 118.82, 119.57, 121.12, 123.24, 123.55, 132.33, 142.25, 144.72; HRMS (ESI, Q-Tof): m/z Calcd for C24H20N2Na [M+Na]+: 359.1519. Found: 359.1530. General procedure for the oxidation of diindole derivatives To diindole (1 eq.) in anhydrous 1,4-dioxane (10 mL) was added SeO2 (4 eq.), and the reaction mixture was stirred at 80-90°C for 3-4 h. At the conclusion of the reaction (TLC monitoring), the reaction mixture was cooled to RT and filtered through a Celite-pad and washed with 10 mL of 1:1 (CHCl3:CCl4) and concentrated under vacuum. The crude product was purified by silica gel column chromatography with appropriate mixture of EtOAcpetroleum ether to deliver the product. (6aR,12aR)-5,6a,11,12a-Tetramethyl-11,12a-dihydropentaleno[2,1-b:5,4-b']diindole-6,12(5H,6aH)-dione, 13a: White colour solid. Yield 76% [41 mg, obtained from diindole 12a (54 mg, 0.16 mmol)]. m.p.267-69°C. Rf 0.31 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 3009, 2892, 2851, 1676, 1264, 1043 cm−1; 1 H NMR (400 MHz, CDCl3): δ 1.83 (s, 6H), 3.81 (s, 6H), 7.21−7.25 (m, 2H), 7.29−7.31 (m, 2H), 7.36−7.41 (m, 2H), 8.09 (d, J = 8.1 Hz, 2H); 13 C NMR (100.6 MHz, CDCl3): δ 18.32, 30.33, 63.01, 111.18, 121.20, 122.44, 123.41, 127.34, 133.18, 143.72, 144.96, 193.18; HRMS (ESI, Q-Tof): m/z Calcd for C24H20N2NaO2 [M + Na]+: 391.1417. Found: 391.1416.
(6aR,12aR)-5,11-Dimethyl-6a,12a-propanopentaleno [2,1-b:5,4-b']diindole-6,12(5H,11H)-dione, 13b: White colour solid. Yield 80% [28 mg, obtained from diindole 12b (33 mg, 0.09 mmol)]. m.p.265-67°C. Rf 0.39 (Silica gel, 10% EtOAc_petroleum ether); IR (KBr): 3012, 2952, 2865, 1668, 1271, 1048 cm−1; 1 H NMR (400 MHz, CDCl3): δ 1.94−2.01 (m, 2H), 2.10−2.19 (m, 2H), 2.37−2.45 (m, 2H), 3.84 (s, 6H), 7.22−7.26 (m, 2H), 7.31−7.34 (m, 2H), 7.38−7.43 (m, 2H), 8.04 (d, J = 8.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 29.24, 30.27, 31.45, 71.35, 111.14, 121.26, 122.33, 123.20, 127.37, 135.05, 141.81, 145.02, 192.86; HRMS (ESI, Q-Tof): m/z Calcd for C25H20N2NaO2 [M + Na]+: 403.1417. Found: 403.1422. 5,11-Dimethyl-6a,12a-butanopentaleno[2,1-b:5,4b']diindole-6,12(5H,11H)-dione, 13c: White colour solid. Yield 76% [27 mg, obtained from diindole 12c (33 mg, 0.09 mmol)]. m.p.305-307°C. Rf 0.42 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 2929, 2851, 1686, 1267, 1047 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.49−1.54 (m, 2H), 1.58−1.63 (m, 2H), 2.26−2.34 (m, 2H), 2.50−2.57 (m, 2H), 3.84 (s, 6H), 7.21−7.27 (m, 2H), 7.31−7.34 (m, 2H), 7.38−7.42 (m, 2H), 8.06 (d, J = 8.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 17.33, 28.24, 30.42, 63.28, 111.21, 121.17, 122.73, 123.46, 127.36, 134.93, 142.90, 144.97, 193.46; HRMS (ESI, Q-Tof): m/z Calcd for C26H23N2O2 [M + H]+: 395.1760. Found: 395.1750. 5,8-Dimethyl-6a,12c-propanopentaleno[2,1-b:5,6b']diindole-6,7(5H,8H)-dione, 13d: White colour solid. Yield 78% [27 mg, obtained from diindole (38 mg, 0.11 mmol)]. m.p.295-97°C. Rf 0.39 (Silica gel, 10% EtOAc_petroleum ether). IR (KBr): 2992, 2868, 1659, 1276, 1049 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.95−2.04 (m, 2H), 2.25−2.28 (t, J = 6.5 Hz, 2H), 2.35−2.39 (t, J = 6.5 Hz, 2H), 3.87 (s, 6H), 7.25−7.41 (m, 6H), 8.08 (d, J = 8.1 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 29.49, 30.33, 31.66, 33.08, 53.36, 88.93, 111.57, 121.02, 121.67, 121.85, 127.29, 135.47, 144.69, 144.99, 188.83; HRMS (ESI, Q-Tof): m/z Calcd for C25H20N2NaO2 [M + Na]+: 403.1417. Found: 403.1416. 5,8-Dimethyl-6a,12c-butanopentaleno[2,1-b:5,6b']diindole-6,7(5H,8H)-dione, 13e: White colour solid. Yield 79% [25 mg, obtained from diindole (30 mg, 0.08 mmol)]. m.p.310-13°C. Rf 0.32 (Silica gel, 5% EtOAc-petroleum ether); IR (KBr): 3021, 2923, 2864, 1676, 1261, 1044 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.54−1.57 (m, 6H), 2.33 (t, J = 2.2 Hz, 2H), 2.59 (t, J = 2.2 Hz, 2H), 3.86 (s, 4H), 7.22−7.26 (m,
KOTHA et al.: POLYCYCLIC INDOLES VIA FISCHER INDOLIZATION
2H), 7.29−7.31 (m, 2H), 7.33−7.46 (m, 2H), 8.06 (d, J = 8.0 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 17.52, 17.97, 28.61, 30.34, 30.41, 46.53, 80.08, 111.58, 120.90, 121.97, 122.10, 127.22, 137.24, 144.93, 145.77, 189.24; HRMS (ESI, Q-Tof): m/z Calcd for C26H23N2O2 [M + H]+: 395.1760. Found: 395.1753. Conclusion In summary, a new and simple synthetic route to aza-polyquinane derivatives containing upto eight rings has been developed in a five step sequence starting with known quinane derivatives via Fischer indolization as a key step. Since polycyclic indole derivatives are implicated in medicinal chemistry, the present diversity oriented synthesis10 is likely to draw the attention of medicinal chemists. 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, New Delhi for the award of a research fellowship. References 1 (a) Kotha S & Chinnam A K, Synthesis, (2014) 301; (b) Kotha S & Ravikumar O, Eur J Org Chem, (2014) 5582; (c) Kotha S & Chinnam A K, Heterocycles, 90 (2015) 690; (d) Kotha S, Chinnam A K & Ali R, Beilstein J Org Chem, 11 (2015) 1123; (e) Kotha S, Shah V R & Mandal K, Adv Synth Cat, 349 (2007) 1159; (f) Kotha S & Dipak M K, Chem Eur J, 12 (2006) 4446; (g) Kotha S, Deb A C & Vinodkumar R, Bioorg Med Chem Lett, 15 (2005) 1039; (h) Kotha S, Mandal K, Arora K K & Pedireddi V R, Adv Synth Cat, 347 (2005) 1215; (i) Kotha S, Behera M & Shah V R, Synlett, (2005) 1877; (j) Kotha S, Mandal K, Deb A C & Banerjee S, Tetrahedron Lett, 45 (2004) 9603; (k) Kotha S & Mandal K, Tetrahedron Lett, 45 (2004) 1391; (l) Kotha S, Manivannan E, Ganesh T, Sreenivasachary N & Deb A C, Synlett, (1999) 1618. 2 (a) Gore S, Baskaran S & König B, Org Lett, 14 (2012) 4568; (b) Jella R R & Nagarajan R, Tetrahedron, 69 (2013) 10249.
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