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Cite this: Org. Biomol. Chem., 2014, 12, 8196
Received 24th June 2014, Accepted 19th August 2014 DOI: 10.1039/c4ob01309c www.rsc.org/obc
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Regiodivergent and short total synthesis of calothrixins† Dipakranjan Mal,* Joyeeta Roy and Kumar Biradha The anionic annulation of MOM-protected furoindolone with 4-bromoquinoline followed by deprotection of the N-MOM group provides calothrixin B, whereas that with 3-bromoquinoline yields isocalothrixin B. The outcomes are explained by the divergence of the reaction mechanism from commonly perceived quinolyne intermediate. A sequence of addition–cyclization–elimination is proposed to account for the formation of calothrixin from 4-bromoquinoline.
Introduction Calothrixins (1 & 2) have been attractive synthetic targets since their isolation in 1999 from cell extracts of Calothrix cyanobacterium.1 Owing to their extraordinary activity against P. falciparum, human HeLa cancer cells, inhibition of RNA polymerase activity and structural novelty as pentacyclic indolo [3,2-j]phenanthridine core, several total syntheses have been reported (Fig. 1).2–7 Seven different strategies have been successfully employed for the synthesis of calothrixin B (2). These include (i) 6π-pericyclic reaction,2 (ii) N-assisted nuclear lithiation,3 (iii) biomimetic oxidation,4 (iv) intramolecular acyl radical addition,5 (v) Pd-catalyzed intramolecular cross-coupling,6 (vi) Cadogan cyclization7 and (vii) intermolecular hetero-Diels–Alder reaction.8 Some of the approaches have also found application in the synthesis of related indoloquinones of medicinal value such as ellipticine (3), murrayaquinone A, koeniginequinone A, koeniginequinone B, and carbazoquinocin C.9 The challenging aspect of the synthesis of the heterocyclic quinonoid
Fig. 1
natural products is the regiochemical issue of installing the functionalities and the heteroatoms. Our enduring interest in the annulation chemistry of carbazole synthesis9 and phthalides10 prompted us to explore the chemistry of hetarynes11 as reactive intermediates for the heterocyclic quinones. The annulation of arynes with phthalides has been successful for the synthesis of anthraquinone natural products.12 In the initial report from our laboratory, annulation of a furoindolone with 3-bromopyridine was described as the route to ellipticine quinone.9 In the pursuit of an extension of the chemistry, we now report a similar but remarkably selective annulation culminating in the total synthesis of both calothrixin B (2) and its geometric isomer (4) in only five steps from commercially available starting materials or in two steps from the known compounds 5 and 6 in 41% and 35% overall yields respectively.
Results and discussion For the synthesis of polycyclic quinonoids, the Hauser annulation of phenylsulfonylphthalides 7 and cyanophthalides 8 with arynes is established (Fig. 2).12 Accordingly, analogous furoindolone sulfone 7 was first chosen as the Hauser donor for an entry to calothrixin B (2) to address the problem of regiochemistry. It was anticipated that the reaction of 9 with a fused hetaryne like 5a would be biased due to steric effects of the phenylsulfonyl group with the indicated peri-hydrogen of 5a and result in a pronounced regioselectivity of annulation (Scheme 1).
Naturally occurring indoloquinones.
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures, crystal data and characterization data. CCDC 997846. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01309c
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Fig. 2
Hauser donor phthalides.
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Scheme 1
Retrosynthesis of calothrixin (2) by annulation.
Furoindolone 9 was prepared from compound 10a, which in turn was prepared in three simple steps from commercially available α-acetobutyrolactone.9a Benzylic bromination of 10a with NBS afforded 11. Due to its instability to chromatography, it was directly subjected to the reaction with sodium benzenesulfinate in DMF. The resulting crude product was purified by column chromatography to give sulfone 9 in 60% yield over two steps. Sulfone 9 was subjected to annulation with 4-bromoquinoline (5) under the conditions for generation of 3-quinolyne, i.e. LDA, THF at −78 °C, resulting in the MOM protected calothrixin B 12 (Scheme 2). Although the yield of the reaction was abysmally low, the regiochemistry was very striking. Formation of the geometric isomer 13 was not observed. Alternatively, we turned to the cyano analog of the sulfone 9 in analogy with Biehl’s work.13 However, its preparation was not fruitful from 11 or from 3-formyl-indole-2carboxylate. Next, the reactivity of the simple MOM protected furoindolone 10a was examined as the donor in the annulation. To our surprise, the reaction of 10a with 4-bromoquinoline (5) in the presence of LDA in THF at −78 °C produced the desired product 12 with a small percentage of the diastereoisomer 13. Although the products 12 and 13 were inseparable, the corresponding hydrolysed products 2 and 4 were easily separated by chromatography. The ratio of calothrixin B (2) : isocalothrixin B (4) was 87 : 13.
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Scheme 2 Synthesis of calothrixin B from 3-phenylsulfonylfuroindolone. Reagents and conditions: (a) NBS, CCl4, 1.5 h, reflux; (b) PhSO2Na, DMF, overnight, 60% over two steps; (c) 4-bromoquinoline (5), LDA, THF, −78 °C to rt, overnight, 7%; (d) conc. HCl, CHCl3, reflux, 3 h, 97%.
Mechanism If the prevailing mechanism with quinolyne intermediate 5a were operative, the ratio of products 12 and 13 from the reaction of 5 and 10a would have been 1 : 1, as predicted by Garg et al.11d Since this is not the case, our results in explicit favour of compound 12 remained inexplicable. In order to delineate a plausible mechanism for the reaction in Scheme 3, several related experiments were performed. Firstly, 3-bromoquinoline (6) in the place of 5 was reacted with furoindolone 10a in the presence of LDA in THF. Work-up of the reaction mixture also furnished annulated products 12 and 13. But the ratio of the products 12 and 13 was 13 : 87, which is in sharp contrast to that with 4-bromoquinoline (5). Upon deprotection of the MOM group of the product 13, isocalothrixin B (4) was obtained in 41% yield. If the quinolyne 5a were the intermediate in the annulations, the ratio of the products 12 and 13 would have been the same for both the annulations described in Schemes 3 and 4. The contrasting annulation reactivity of bromoquinolines 5 and 6 prompted us to survey the literature on 3,4-dihydroquinolyne. Except for the original work11b,13 on the action of LDA on 3-chloroquinoline, there is only one report13 on the reactivity of quinolynes derivable from 3- or 4-bromoquinolines. This report described the
Scheme 3
Synthesis of calothrixin B (2). Reagents and conditions: (a) LDA, THF, −78 °C to rt, overnight, 48%; (b) conc. HCl, CHCl3, reflux, 3 h, 98%.
Scheme 4 3 h, 97%.
Synthesis of calothrixin B isomer (4). Reagents and conditions: (a) LDA, THF, −78 °C to rt, overnight, 42%; (b) CHCl3, conc. HCl, reflux,
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Scheme 5
Probable mechanism of the annulation with 4-bromoquinoline.
Scheme 6
Probable mechanism of the annulation with 3-bromoquinoline.
annulation between 3,4-quinolyne and cyanophthalides (8) where regiochemical issues did not arise due to a lack of substitution in 8. In the present annulation (Scheme 3), an explicit preference for 12 can be explained by invoking 3,4-quinolyne and steric effects of peri-hydrogen. However, the same explanation does not apply to the annulation with 3-bromoquinoline because the selectivity of the reaction was in favor of 13 instead of 12. Consequently, we propose a non-hetaryne mechanism, i.e., the addition–cyclization–elimination route as shown in Scheme 5. The anion generated by deprotonation of C-3 of furoindolone 10a adds to C-3 of quinoline, forming carbanion 14. The driving force for the formation of 14 may be twofold: (i) electronegativity of bromine and (ii) stabilization of the anion by an adjacent benzene ring. Subsequently, cyclization of 14 occurs to form 15. Elimination of hydrogen bromide from 15 gives pentacycle 16, aerial oxidation of which furnishes the desired pentacyclic quinone 12. Such a mechanism also accounts for the formation of 13 from 3-bromoquinoline and 10b. The conjugate addition of 10b to 6 is driven by both bromine and nitrogen. Intermediate 17 cyclizes to 19 via elimination of hydrogen bromide from 18.
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Support for the mechanism To support the proposed mechanism by isolation of the intermediate in Schemes 5 and 6, we performed a few model reactions. The results are presented in Table 1. The reaction of parent phthalide (20) with 4-bromoquinoline gave 22 (42%) and 24 (15%). Although the formation of products is accounted for by the hetaryne mechanism, the formation of the substituted phthalide 22 indicates the mechanism proposed in Scheme 5. The competing cyclization step (cf. 14 to 15) accounts for the formation of 24. Similarly, the reaction (entry 2) of 5 and 21 gave 23 and 25 in 38% and 9% yield, respectively. The structure (Fig. 3) of compound 25 was confirmed by an X-ray analysis (Fig. 3). Their formation can only be explained by initial ipso-addition of the incipient anion of 21 to 5. The structures of 22 and 23 were confirmed on the basis of HMBC and HSQC, and coupling constants ( J) of C2-H and C3-H. For 3-bromoquinoline the characteristic protons have J = 2.1 Hz, and for 4-bromoquinoline, J = 4.4 Hz. In the case of 22, it is found that 3J = 4.4 Hz and for 23, 3J = 4.4 Hz. Both the phthalides 22 and 23 were separately treated with LDA at −40 °C to establish their intermediary. Both the
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Reactions of phthalides with quinolinesa
Serial no.
Donor
Acceptor
Product (% yield)
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1
2
3
4
5
6
7
a
All reactions were carried out using LDA as the base at −78 °C to −40 °C to rt. All yields refer to the yield of isolated pure compounds.
Fig. 3
Crystal structure of azabenz[a]anthracenone 25.
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phthalides were recovered unchanged, although there was a color change with 22 indicating formation of the conjugate anion. The results of the annulations with 3-bromoquinoline and 3-bromopyridine are presented in entries 3–5. With 10a, 20 and 21, the products 24, 25, 26, 27 and 28 were obtained. No formal substitution product was formed, strongly favoring the hetaryne mechanism. Perhaps the formation of quinolyne 5a is more facile in the case of 3-bromoquinoline due to the higher acidity of C4-H than that of C3-H of 4-bromoquinoline. When 3-bromopyridine is reacted with furoindolone 10a under the conditions
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described in Table 1, a 1 : 1 inseparable mixture of quinones 27 and 28 was obtained. This result clearly supports a 3,4-pyridine intermediate. Since 27 has been reported in the literature,5b NMR data of 28 were easily extracted from those of the mixture. The reactions of LDA, generated in situ, with bromoquinolines 5 and 6 afforded 29 as the sole product, the structure of which was ascertained on the basis of the 4J2,4 coupling constant. These results also clearly established the steric bias caused by the peri-hydrogen of quinolyne 5a.
Conclusion We have presented remarkably short and stereodivergent syntheses of calothrixins 2 and 4 from furoindolone 10a. These syntheses require essentially one step from the known compounds, i.e., furoindolone 10a and bromoquinolines 5 and 6. This strongly suggests an uncommon addition–cyclization–elimination for annulation with 4-bromoquinoline. An in-depth study on the mechanism and reaction conditions including the chemistry of isomeric furoindolones is in progress.
Experimental section General procedure All reactions with moisture-sensitive reagents were performed under an inert atmosphere. Solvents were dried prior to use according to standard protocols. Reactions were monitored by thin layer chromatography (TLC) with 0.25 mm silica gel plates (60-F254). The products were purified by column chromatography over silica gel (60–120 mesh) with distilled hexane and ethyl acetate as eluents. NMR spectra were recorded with a 400 (1H: 400 MHz, 13C: 100 MHz) MHz spectrometer and are referenced to the signals of CHCl3 at δ = 7.26 (1H) and 77.23 ppm (13C). Unless mentioned otherwise, the solvent is always CDCl3. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; m, multiplet. Infrared spectra were recorded with FTIR spectrophotometers and are reported in cm−1. High-resolution mass spectra were recorded with a mass spectrometer in the positive-ion mode. All known compounds were characterized by comparison of the 1H and 13C NMR spectroscopic data with those reported in the literature. Commercially available starting materials were used without further purification. Calothrixin B (2). Compound 12 (20 mg, 0.09 mmol) was dissolved in 5 mL chloroform, and 1 mL of conc. HCl was added to it. The mixture was refluxed for 3 h, until completion of the reaction as monitored by TLC analysis. The reaction mixture was concentrated under reduced pressure, quenched with a saturated solution of sodium bicarbonate and the residue was diluted with ethyl acetate (10 mL). The aqueous part was again extracted with ethyl acetate (10 mL), and the total organic phase was washed with water (2 × 10 mL) and
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brine (10 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Rf 0.28 in 25% ethyl acetate in hexane) to give compound 2 (17 mg, 0.05 mmol) as a red solid in 98% yield; mp 296–299 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.14 (brs, 1H), 9.61 (s, 1H), 9.56 (d, J = 8.4 Hz, 1H), 8.17–8.14 (m, 2H), 7.94 (t, J = 8 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 180.7, 180.1, 151.0, 147.3 (CH), 138.1, 137.9, 132.5, 131.4 (CH), 130.1 (CH), 129.6 (CH), 127.04 (CH), 127.02 (CH), 124.7, 124.1, 123.2, 122.4 (CH), 122.1 (CH), 115.4, 113.8 (CH). 8H-5,8-Diazaindeno[2,1-b]phenanthrene-7,13-dione (4). Compound 13 (20 mg, 0.09 mmol) was treated with conc. HCl using the same procedure as that mentioned above for calothrixin B. The crude product was purified by column chromatography (Rf 0.35 in 30% ethyl acetate in hexane) to give compound 4 as a red solid (15 mg, 0.04 mmol) in 97% yield; mp >300 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.16 (brs, 1H), 9.68 (d, J = 8.8 Hz, 1H), 9.53 (s, 1H), 8.23 (d, J = 8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): 184.1, 177.8, 151.9, 147.0 (CH), 138.4, 135.5, 134.2, 131.9 (CH), 130.0, 129.9 (CH), 129.7 (CH), 128.0 (CH), 127.2 (CH), 124.4 (CH), 124.2, 124.1, 123.1, 122.4 (CH), 118.6, 114.0 (CH). 3-Benzenesulfonyl-8-methoxymethyl-3,8-dihydro-2-oxa-8-azacyclopenta[a]inden-1-one (9). A mixture of 10a (1.8 g, 8.29 mmol), NBS (1.6 g, 8.97 mmol) and benzoyl peroxide (70 mg) in CCl4 was heated at reflux under the exposure to a 100 watt bulb for 2 h. The mixture was cooled to 0 °C, filtered and then concentrated under reduced pressure. The crude product was dissolved in dry DMF (20 mL) and treated with sodium benzenesulfinate (0.91 g, 5.55 mmol) in portions. The mixture was stirred overnight at rt and then diluted with cold water (50 mL). The solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (3 × 10 mL) and brine (10 mL), and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was chromatographed (Rf 0.58 in 20% ethyl acetate in hexane) to give a white crystalline solid 9 (1.78 g, 4.98 mmol) in 60% overall yield; mp 201–205 °C; IR (KBr): νmax in cm−1 2364, 1740, 1560, 1447, 1358, 1212, 1150, 995, 750; 1H NMR (400 MHz): δ 8.02 (d, J = 8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.63–7.58 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.46–7.40 (m, 3H), 6.31 (s, 1H), 5.56 (q, J = 12.8 Hz, 2H), 3.05 (s, 3H); 13C NMR (50 MHz): δ 160.1, 144.2, 135.0 (CH), 134.1, 130.4, 129.9 (CH), 129.4 (CH), 129.3, 128.1 (CH), 123.6 (CH), 122.8 (CH), 121.2, 112.8 (CH), 88.9 (CH), 74.7 (CH2), 56.2 (CH3); HRMS (TOF MS ES+) m/z calcd for C18H16NO5S [M + H]+ 358.0748, found 358.0749. 12-Methoxymethyl-12H-5,12-diazaindeno[1,2-b]phenanthrene7,13-dione (12). In a flame dried flask flushed with nitrogen, LDA was prepared by adding N,N-diisopropylamine (0.34 mL, 2.6 mmol) to a solution of n-BuLi (2.5 M in hexane) (0.88 mL,
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2.2 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the phthalide donor 10a (150 mg, 0.69 mmol) in THF (10 mL) was then added dropwise. The reaction mixture was stirred at −78 °C for another 15 min and then slowly the temperature was raised to −40 °C, and stirring was continued for another 15 min. A solution of 4-bromoquinoline (160 mg, 0.76 mmol) in THF (10 mL) was added dropwise, and immediately a colour change was observed. The mixture was further stirred at −40 °C for another 30 min. The resulting mixture was allowed to warm slowly to room temperature and stirred overnight. The dark coloured solution was quenched with a saturated ammonium chloride solution (10 mL). The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (30 mL). The aqueous part was again extracted with ethyl acetate (20 mL), the total organic phase was washed with water (2 × 10 mL) and brine (10 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was passed through a column (Rf 0.5 in 15% ethyl acetate in hexane) to give a mixture of compounds 12 and 13 (12 : 13 being 6.39 : 1, i.e., 87% regioselective) as a red solid 12 (98 mg, 0.28 mmol) in 42% yield. The characterisation data of 12 being: mp 230–232 °C; 1H NMR (400 MHz) (NMR data extracted from the spectra of a mixture of 12 & 13): δ 9.76 (s, 1H), 9.60 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 6.10 (s, 2H), 3.42 (s, 3H); 13C NMR (100 MHz): δ 181.9, 181.0, 151.3, 147.3 (CH), 140.4, 135.6, 134.1, 132.2 (CH), 130.7 (CH), 129.8 (CH), 128.6 (CH), 127.9 (CH), 125.6 (CH), 124.6, 124.1 (CH), 123.5, 123.3, 118.8, 112.1 (CH), 75.7 (CH2), 56.9 (CH3). Compound 12 was synthesised from sulfone 9 using a similar procedure. 8-Methoxymethyl-8H-5,8-diazaindeno[2,1-b]phenanthrene7,13-dione (13). This compound was prepared by the same annulation procedure as that described for compound 12 using 3-bromoquinoline instead of 4-bromoquinoline. The compound was passed through a column (Rf 0.5 in 15% ethyl acetate in hexane) to give a mixture of compounds 12 and 13 (12 : 13 being 1 : 6.44, i.e., 87% regioselective) as a red solid (84 mg, 0.23 mmol) in 36% yield; mp: 250–255 °C; 1H NMR (400 MHz) (NMR data extracted from the spectra of mixture of 12 & 13): δ 9.75 (d, J = 8.8 Hz, 1H), 9.70 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz, 1H), 6.14 (s, 2H), 3.42 (s, 3H); 13C NMR (100 MHz): δ 184.6, 178.8, 152.5, 147.5 (CH), 139.9, 135.4, 133.2, 131.9 (CH), 130.2 (CH), 130.1 (CH), 128.4, 128.3 (CH), 128.2 (CH), 125.4 (CH), 124.1, 123.8 (CH), 123.2, 120.9, 112.1 (CH), 75.5 (CH2), 56.7 (CH3). 3-Quinolin-4-yl-3H-isobenzofuran-1-one (22). Using the same annulation procedure as that described for compound 12, here phthalide 20 (100 mg, 0.75 mmol) was used as a donor and 4-bromoquinoline as an acceptor (140 mg, 0.67 mmol), the two compounds obtained were purified by
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column chromatography. The top spot is the same as (24) which was obtained in 15% yield. (22): Rf 0.25 in 50% ethyl acetate in hexane; liquid (81 mg, 0.31 mmol) in 42% yield; 1H NMR (400 MHz): δ 8.83 (d, J = 4.4 Hz, 1H), 8.24–8.18 (m, 2H), 8.00 (dd, J = 4.4, 6.8 Hz, 1H), 7.80 (t, J = 6.8 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.64–7.56 (m, 2H), 7.40 (d, J = 6 Hz, 1H), 7.21 (s, 1H); 13C NMR (100 MHz): 170.2, 150.4 (CH), 148.7, 148.4, 141.9, 134.7 (CH), 130.7 (CH), 130.1 (CH), 130.0 (CH), 127.9 (CH), 126.4 (CH), 125.9, 125.3, 123.0 (CH), 122.9 (CH), 117.8 (CH), 78.0 (CH); IR (KBr) νmax in cm−1: 3429, 2360, 1771, 1634, 1219, 1059, 771; HRMS (TOF ESI+) m/z calcd for C17H12NO2 [M + H]+ 262.0868, found 262.0837. 3-Methyl-3-quinolin-3-yl-3H-isobenzofuran-1-one (23). Using the same annulation procedure as that described for compound 12, here 3-methyl phthalide 21 (150 mg, 1.01 mmol) was used as a donor and 4-bromoquinoline as an acceptor (200 mg, 0.97 mmol), and the two compounds obtained were purified by column chromatography. The top spot is the same as (25) which was obtained in 9% yield (39 mg, 0.14 mmol). (23): Rf 0.25 in 50% ethyl acetate in hexane; white solid (106 mg, 0.38 mmol) in 38% yield; 1H NMR (400 MHz): δ 8.82 (s, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.37 (s, 1H), 2.24 (s, 3H); 13C NMR (100 MHz): δ 168.9, 151.9, 149.4 (CH), 144.1, 134.2 (CH), 130.4 (CH), 129.8 (CH), 129.2 (CH), 126.9 (CH), 126.4 (CH), 126.3 (CH), 125.6, 125.5, 123.7 (CH), 118.4 (CH), 88.1, 28.7 (CH3); mp: 138–142 °C; IR (KBr) νmax in cm−1: 1767, 1276, 1119, 1033, 921; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1020. Benzo[ j]phenanthridine-7,12-dione (24).14 Using the same annulation procedure as that described for compound 12, here phthalide 20 (150 mg, 1.12 mmol) was used as a donor and 3-bromoquinoline as an acceptor (208 mg, 1.00 mmol). A yellow crystalline solid was obtained after purification by column chromatography in 43% yield (125 mg, 0.48 mmol); Rf = 0.6 in 30% ethyl acetate in hexane; mp: 200–205 °C; 1H NMR (400 MHz): δ 9.85 (s, 1H), 9.60 (dd, J = 1.2, 8.4 Hz, 1H), 8.33–8.29 (m, 2H), 8.24 (d, J = 8.4 Hz, 1H), 7.93–7.80 (m, 2H); 13 C NMR (100 MHz): δ 187.7, 184.7, 151.9, 149.5 (CH), 137.0 (CH), 136.9 (CH), 136.4, 135.1 (CH), 133.9, 133.2 (CH), 131.1, 130.6 (CH), 129.7 (CH), 128.9 (CH), 127.2, 125.4. 12-Hydroxy-12-methyl-12H-benzo[ j]phenanthridin-7-one (25) & 7-hydroxy-7-methyl-7H-benzo[ j]phenanthridin-12-one (26). Using the same annulation procedure as that described for compound 12, here 3-methyl phthalide 21 (400 mg, 2.7 mmol) was used as a donor and 3-bromoquinoline as an acceptor (613 mg, 2.9 mmol), and the two compounds obtained were purified by column chromatography. 12-Hydroxy-12-methyl-12H-benzo[ j]phenanthridin-7-one (25). Rf 0.5 in 25% ethyl acetate in hexane; white solid (208 mg, 0.75 mmol) in 28% yield; mp: 115–120 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.36 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8 Hz, 2H), 8.07 (d, J = 8 Hz, 1H), 7.92 (t, J = 8 Hz, 1H), 7.85 (t, J = 8 Hz, 1H), 7.77 (t, J = 8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 6.77
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(s, 1H), 1.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 182.8, 154.7, 152.0, 150.6, 148.4 (CH), 134.9 (CH), 132.0 (CH), 130.7 (CH), 129.7 (CH), 128.4 (CH), 127.5 (CH), 127.4 (CH), 126.0 (CH), 124.7, 121.9, 70.3, 35.0 (CH3); IR (KBr) νmax in cm−1: 2121, 1646, 1275, 770; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1018. 7-Hydroxy-7-methyl-7H-benzo[ j]phenanthridin-12-one (26). Rf 0.3 in 25% ethyl acetate in hexane; yellow liquid (230 mg, 0.83 mmol) in 31% yield; 1H NMR (400 MHz): δ 9.30 (s, 1H), 9.11 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.52–7.42 (m, 3H), 4.67 (brs, 1H), 1.71 (s, 3H); 13C NMR (100 MHz): δ 185.5, 149.8 (CH), 147.6, 147.3, 141.5, 134.2 (CH), 130.7, 129.6 (CH), 129.4 (CH), 129.3, 128.9 (CH), 128.5 (CH), 127.2 (CH), 126.8 (CH), 125.7 (CH), 123.0, 69.0, 36.2 (CH3); IR (KBr) νmax in cm−1: 1665, 1360, 1267, 1032, 758; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1020. 6-Methoxymethyl-6H-pyrido[4,3-b]carbazole-5,11-dione & 10-methoxymethyl-10H-pyrido[3,4-b]carbazole-5,11-dione (27 & 28). Using the annulation procedure described for compound 12, phthalide 10 (250 mg, 1.15 mmol) was reacted with 3-bromopyridine (162 mg, 1.03 mmol). Compounds 27 & 28 were obtained as a yellow solid in 54% yield. Since the compounds are inseparable, the NMR data are reported for the mixture. Rf = 0.6 in 30% ethyl acetate in hexane. The NMR data are reported as a mixture of 27 and 28. 1 H NMR (400 MHz): δ 9.42 (s, 1H), 9.39 (s, 1H), 9.04 (s, 1H), 8.45–8.41 (m, 2H), 8.01 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.66–7.62 (m, 2H), 7.54–7.50 (m, 2H), 7.46–7.42 (m, 2H), 6.14 (s, 2H), 6.12 (s, 2H), 3.39 (s, 3H), 3.38 (s, 2H); 13C NMR (100 MHz): 181.0, 180.2, 180.1, 178.44, 178.41, 177.9, 177.8, 155.6, 155.5, 155.0 (CH), 154.9 (CH), 148.4, 148.37 (CH), 148.32 (CH), 140.4, 140.1, 139.6, 139.3, 134.8, 134.6, 128.9 (CH), 128.7 (CH), 125.75 (CH), 125.71 (CH), 124.3 (CH), 124.07 (CH), 124.01 (CH), 123.9, 120.5, 119.0 (CH), 112.4 (CH), 112.2 (CH), 75.73 (CH2), 75.71 (CH2), 56.9 (CH3), 56.8 (CH3). 3-N,N-Diisopropylquinoline (29). In a flame dried flask flushed with nitrogen, LDA was prepared by adding N,N-diisopropylamine (0.13 mL, 1.05 mmol) to a solution of n-BuLi (2.5 M in hexane) (0.38 mL, 0.96 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the 4-bromoquinoline (100 mg, 0.48 mmol) in THF (5 mL) was then added dropwise and stirred for another 30 min at the same temperature, and then slowly allowed to stir at rt overnight. The dark coloured solution was quenched with a saturated ammonium chloride solution (5 mL). The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (15 mL). The aqueous part was again extracted with ethyl acetate (10 mL), and the total organic phase was washed with water (2 × 7 mL) and brine (7 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was passed through a column (Rf 0.7 in 15% ethyl acetate in hexane) to give compound 29 as a liquid in 40% yield (44 mg, 0.19 mmol); IR (KBr) νmax in cm−1: 2969, 2360, 1590, 1474,
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1369, 1336, 1290, 1147, 772; 1H NMR (400 MHz): δ 8.77 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.40 (m, 2H), 7.44–7.34 (d, J = 2.8 Hz, 1H), 3.90–3.83 (m, 2H), 1.28 (d, J = 6.8 Hz, 12H); 13C NMR (100 MHz): δ 146.2 (CH), 142.1, 129.3, 128.6 (CH), 126.6 (CH), 126.3 (CH), 125.5 (CH), 118.9 (CH), 48.0 (CH), 21.5 (CH3).
Acknowledgements The authors are grateful to the Department of Science and Technology for financial support. J. R. is thankful to CSIR for her research fellowship. We also acknowledge the support of FIST, DST, New Delhi.
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PAPER
Cite this: Org. Biomol. Chem., 2014, 12, 8196
Received 24th June 2014, Accepted 19th August 2014 DOI: 10.1039/c4ob01309c www.rsc.org/obc
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Regiodivergent and short total synthesis of calothrixins† Dipakranjan Mal,* Joyeeta Roy and Kumar Biradha The anionic annulation of MOM-protected furoindolone with 4-bromoquinoline followed by deprotection of the N-MOM group provides calothrixin B, whereas that with 3-bromoquinoline yields isocalothrixin B. The outcomes are explained by the divergence of the reaction mechanism from commonly perceived quinolyne intermediate. A sequence of addition–cyclization–elimination is proposed to account for the formation of calothrixin from 4-bromoquinoline.
Introduction Calothrixins (1 & 2) have been attractive synthetic targets since their isolation in 1999 from cell extracts of Calothrix cyanobacterium.1 Owing to their extraordinary activity against P. falciparum, human HeLa cancer cells, inhibition of RNA polymerase activity and structural novelty as pentacyclic indolo [3,2-j]phenanthridine core, several total syntheses have been reported (Fig. 1).2–7 Seven different strategies have been successfully employed for the synthesis of calothrixin B (2). These include (i) 6π-pericyclic reaction,2 (ii) N-assisted nuclear lithiation,3 (iii) biomimetic oxidation,4 (iv) intramolecular acyl radical addition,5 (v) Pd-catalyzed intramolecular cross-coupling,6 (vi) Cadogan cyclization7 and (vii) intermolecular hetero-Diels–Alder reaction.8 Some of the approaches have also found application in the synthesis of related indoloquinones of medicinal value such as ellipticine (3), murrayaquinone A, koeniginequinone A, koeniginequinone B, and carbazoquinocin C.9 The challenging aspect of the synthesis of the heterocyclic quinonoid
Fig. 1
natural products is the regiochemical issue of installing the functionalities and the heteroatoms. Our enduring interest in the annulation chemistry of carbazole synthesis9 and phthalides10 prompted us to explore the chemistry of hetarynes11 as reactive intermediates for the heterocyclic quinones. The annulation of arynes with phthalides has been successful for the synthesis of anthraquinone natural products.12 In the initial report from our laboratory, annulation of a furoindolone with 3-bromopyridine was described as the route to ellipticine quinone.9 In the pursuit of an extension of the chemistry, we now report a similar but remarkably selective annulation culminating in the total synthesis of both calothrixin B (2) and its geometric isomer (4) in only five steps from commercially available starting materials or in two steps from the known compounds 5 and 6 in 41% and 35% overall yields respectively.
Results and discussion For the synthesis of polycyclic quinonoids, the Hauser annulation of phenylsulfonylphthalides 7 and cyanophthalides 8 with arynes is established (Fig. 2).12 Accordingly, analogous furoindolone sulfone 7 was first chosen as the Hauser donor for an entry to calothrixin B (2) to address the problem of regiochemistry. It was anticipated that the reaction of 9 with a fused hetaryne like 5a would be biased due to steric effects of the phenylsulfonyl group with the indicated peri-hydrogen of 5a and result in a pronounced regioselectivity of annulation (Scheme 1).
Naturally occurring indoloquinones.
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures, crystal data and characterization data. CCDC 997846. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01309c
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Fig. 2
Hauser donor phthalides.
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Scheme 1
Retrosynthesis of calothrixin (2) by annulation.
Furoindolone 9 was prepared from compound 10a, which in turn was prepared in three simple steps from commercially available α-acetobutyrolactone.9a Benzylic bromination of 10a with NBS afforded 11. Due to its instability to chromatography, it was directly subjected to the reaction with sodium benzenesulfinate in DMF. The resulting crude product was purified by column chromatography to give sulfone 9 in 60% yield over two steps. Sulfone 9 was subjected to annulation with 4-bromoquinoline (5) under the conditions for generation of 3-quinolyne, i.e. LDA, THF at −78 °C, resulting in the MOM protected calothrixin B 12 (Scheme 2). Although the yield of the reaction was abysmally low, the regiochemistry was very striking. Formation of the geometric isomer 13 was not observed. Alternatively, we turned to the cyano analog of the sulfone 9 in analogy with Biehl’s work.13 However, its preparation was not fruitful from 11 or from 3-formyl-indole-2carboxylate. Next, the reactivity of the simple MOM protected furoindolone 10a was examined as the donor in the annulation. To our surprise, the reaction of 10a with 4-bromoquinoline (5) in the presence of LDA in THF at −78 °C produced the desired product 12 with a small percentage of the diastereoisomer 13. Although the products 12 and 13 were inseparable, the corresponding hydrolysed products 2 and 4 were easily separated by chromatography. The ratio of calothrixin B (2) : isocalothrixin B (4) was 87 : 13.
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Scheme 2 Synthesis of calothrixin B from 3-phenylsulfonylfuroindolone. Reagents and conditions: (a) NBS, CCl4, 1.5 h, reflux; (b) PhSO2Na, DMF, overnight, 60% over two steps; (c) 4-bromoquinoline (5), LDA, THF, −78 °C to rt, overnight, 7%; (d) conc. HCl, CHCl3, reflux, 3 h, 97%.
Mechanism If the prevailing mechanism with quinolyne intermediate 5a were operative, the ratio of products 12 and 13 from the reaction of 5 and 10a would have been 1 : 1, as predicted by Garg et al.11d Since this is not the case, our results in explicit favour of compound 12 remained inexplicable. In order to delineate a plausible mechanism for the reaction in Scheme 3, several related experiments were performed. Firstly, 3-bromoquinoline (6) in the place of 5 was reacted with furoindolone 10a in the presence of LDA in THF. Work-up of the reaction mixture also furnished annulated products 12 and 13. But the ratio of the products 12 and 13 was 13 : 87, which is in sharp contrast to that with 4-bromoquinoline (5). Upon deprotection of the MOM group of the product 13, isocalothrixin B (4) was obtained in 41% yield. If the quinolyne 5a were the intermediate in the annulations, the ratio of the products 12 and 13 would have been the same for both the annulations described in Schemes 3 and 4. The contrasting annulation reactivity of bromoquinolines 5 and 6 prompted us to survey the literature on 3,4-dihydroquinolyne. Except for the original work11b,13 on the action of LDA on 3-chloroquinoline, there is only one report13 on the reactivity of quinolynes derivable from 3- or 4-bromoquinolines. This report described the
Scheme 3
Synthesis of calothrixin B (2). Reagents and conditions: (a) LDA, THF, −78 °C to rt, overnight, 48%; (b) conc. HCl, CHCl3, reflux, 3 h, 98%.
Scheme 4 3 h, 97%.
Synthesis of calothrixin B isomer (4). Reagents and conditions: (a) LDA, THF, −78 °C to rt, overnight, 42%; (b) CHCl3, conc. HCl, reflux,
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Scheme 5
Probable mechanism of the annulation with 4-bromoquinoline.
Scheme 6
Probable mechanism of the annulation with 3-bromoquinoline.
annulation between 3,4-quinolyne and cyanophthalides (8) where regiochemical issues did not arise due to a lack of substitution in 8. In the present annulation (Scheme 3), an explicit preference for 12 can be explained by invoking 3,4-quinolyne and steric effects of peri-hydrogen. However, the same explanation does not apply to the annulation with 3-bromoquinoline because the selectivity of the reaction was in favor of 13 instead of 12. Consequently, we propose a non-hetaryne mechanism, i.e., the addition–cyclization–elimination route as shown in Scheme 5. The anion generated by deprotonation of C-3 of furoindolone 10a adds to C-3 of quinoline, forming carbanion 14. The driving force for the formation of 14 may be twofold: (i) electronegativity of bromine and (ii) stabilization of the anion by an adjacent benzene ring. Subsequently, cyclization of 14 occurs to form 15. Elimination of hydrogen bromide from 15 gives pentacycle 16, aerial oxidation of which furnishes the desired pentacyclic quinone 12. Such a mechanism also accounts for the formation of 13 from 3-bromoquinoline and 10b. The conjugate addition of 10b to 6 is driven by both bromine and nitrogen. Intermediate 17 cyclizes to 19 via elimination of hydrogen bromide from 18.
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Support for the mechanism To support the proposed mechanism by isolation of the intermediate in Schemes 5 and 6, we performed a few model reactions. The results are presented in Table 1. The reaction of parent phthalide (20) with 4-bromoquinoline gave 22 (42%) and 24 (15%). Although the formation of products is accounted for by the hetaryne mechanism, the formation of the substituted phthalide 22 indicates the mechanism proposed in Scheme 5. The competing cyclization step (cf. 14 to 15) accounts for the formation of 24. Similarly, the reaction (entry 2) of 5 and 21 gave 23 and 25 in 38% and 9% yield, respectively. The structure (Fig. 3) of compound 25 was confirmed by an X-ray analysis (Fig. 3). Their formation can only be explained by initial ipso-addition of the incipient anion of 21 to 5. The structures of 22 and 23 were confirmed on the basis of HMBC and HSQC, and coupling constants ( J) of C2-H and C3-H. For 3-bromoquinoline the characteristic protons have J = 2.1 Hz, and for 4-bromoquinoline, J = 4.4 Hz. In the case of 22, it is found that 3J = 4.4 Hz and for 23, 3J = 4.4 Hz. Both the phthalides 22 and 23 were separately treated with LDA at −40 °C to establish their intermediary. Both the
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Reactions of phthalides with quinolinesa
Serial no.
Donor
Acceptor
Product (% yield)
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1
2
3
4
5
6
7
a
All reactions were carried out using LDA as the base at −78 °C to −40 °C to rt. All yields refer to the yield of isolated pure compounds.
Fig. 3
Crystal structure of azabenz[a]anthracenone 25.
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phthalides were recovered unchanged, although there was a color change with 22 indicating formation of the conjugate anion. The results of the annulations with 3-bromoquinoline and 3-bromopyridine are presented in entries 3–5. With 10a, 20 and 21, the products 24, 25, 26, 27 and 28 were obtained. No formal substitution product was formed, strongly favoring the hetaryne mechanism. Perhaps the formation of quinolyne 5a is more facile in the case of 3-bromoquinoline due to the higher acidity of C4-H than that of C3-H of 4-bromoquinoline. When 3-bromopyridine is reacted with furoindolone 10a under the conditions
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described in Table 1, a 1 : 1 inseparable mixture of quinones 27 and 28 was obtained. This result clearly supports a 3,4-pyridine intermediate. Since 27 has been reported in the literature,5b NMR data of 28 were easily extracted from those of the mixture. The reactions of LDA, generated in situ, with bromoquinolines 5 and 6 afforded 29 as the sole product, the structure of which was ascertained on the basis of the 4J2,4 coupling constant. These results also clearly established the steric bias caused by the peri-hydrogen of quinolyne 5a.
Conclusion We have presented remarkably short and stereodivergent syntheses of calothrixins 2 and 4 from furoindolone 10a. These syntheses require essentially one step from the known compounds, i.e., furoindolone 10a and bromoquinolines 5 and 6. This strongly suggests an uncommon addition–cyclization–elimination for annulation with 4-bromoquinoline. An in-depth study on the mechanism and reaction conditions including the chemistry of isomeric furoindolones is in progress.
Experimental section General procedure All reactions with moisture-sensitive reagents were performed under an inert atmosphere. Solvents were dried prior to use according to standard protocols. Reactions were monitored by thin layer chromatography (TLC) with 0.25 mm silica gel plates (60-F254). The products were purified by column chromatography over silica gel (60–120 mesh) with distilled hexane and ethyl acetate as eluents. NMR spectra were recorded with a 400 (1H: 400 MHz, 13C: 100 MHz) MHz spectrometer and are referenced to the signals of CHCl3 at δ = 7.26 (1H) and 77.23 ppm (13C). Unless mentioned otherwise, the solvent is always CDCl3. Splitting patterns are indicated as follows: br, broad; s, singlet; d, doublet; t, triplet; m, multiplet. Infrared spectra were recorded with FTIR spectrophotometers and are reported in cm−1. High-resolution mass spectra were recorded with a mass spectrometer in the positive-ion mode. All known compounds were characterized by comparison of the 1H and 13C NMR spectroscopic data with those reported in the literature. Commercially available starting materials were used without further purification. Calothrixin B (2). Compound 12 (20 mg, 0.09 mmol) was dissolved in 5 mL chloroform, and 1 mL of conc. HCl was added to it. The mixture was refluxed for 3 h, until completion of the reaction as monitored by TLC analysis. The reaction mixture was concentrated under reduced pressure, quenched with a saturated solution of sodium bicarbonate and the residue was diluted with ethyl acetate (10 mL). The aqueous part was again extracted with ethyl acetate (10 mL), and the total organic phase was washed with water (2 × 10 mL) and
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brine (10 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Rf 0.28 in 25% ethyl acetate in hexane) to give compound 2 (17 mg, 0.05 mmol) as a red solid in 98% yield; mp 296–299 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.14 (brs, 1H), 9.61 (s, 1H), 9.56 (d, J = 8.4 Hz, 1H), 8.17–8.14 (m, 2H), 7.94 (t, J = 8 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 180.7, 180.1, 151.0, 147.3 (CH), 138.1, 137.9, 132.5, 131.4 (CH), 130.1 (CH), 129.6 (CH), 127.04 (CH), 127.02 (CH), 124.7, 124.1, 123.2, 122.4 (CH), 122.1 (CH), 115.4, 113.8 (CH). 8H-5,8-Diazaindeno[2,1-b]phenanthrene-7,13-dione (4). Compound 13 (20 mg, 0.09 mmol) was treated with conc. HCl using the same procedure as that mentioned above for calothrixin B. The crude product was purified by column chromatography (Rf 0.35 in 30% ethyl acetate in hexane) to give compound 4 as a red solid (15 mg, 0.04 mmol) in 97% yield; mp >300 °C; 1H NMR (400 MHz, DMSO-d6): δ 13.16 (brs, 1H), 9.68 (d, J = 8.8 Hz, 1H), 9.53 (s, 1H), 8.23 (d, J = 8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.83 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): 184.1, 177.8, 151.9, 147.0 (CH), 138.4, 135.5, 134.2, 131.9 (CH), 130.0, 129.9 (CH), 129.7 (CH), 128.0 (CH), 127.2 (CH), 124.4 (CH), 124.2, 124.1, 123.1, 122.4 (CH), 118.6, 114.0 (CH). 3-Benzenesulfonyl-8-methoxymethyl-3,8-dihydro-2-oxa-8-azacyclopenta[a]inden-1-one (9). A mixture of 10a (1.8 g, 8.29 mmol), NBS (1.6 g, 8.97 mmol) and benzoyl peroxide (70 mg) in CCl4 was heated at reflux under the exposure to a 100 watt bulb for 2 h. The mixture was cooled to 0 °C, filtered and then concentrated under reduced pressure. The crude product was dissolved in dry DMF (20 mL) and treated with sodium benzenesulfinate (0.91 g, 5.55 mmol) in portions. The mixture was stirred overnight at rt and then diluted with cold water (50 mL). The solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with water (3 × 10 mL) and brine (10 mL), and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was chromatographed (Rf 0.58 in 20% ethyl acetate in hexane) to give a white crystalline solid 9 (1.78 g, 4.98 mmol) in 60% overall yield; mp 201–205 °C; IR (KBr): νmax in cm−1 2364, 1740, 1560, 1447, 1358, 1212, 1150, 995, 750; 1H NMR (400 MHz): δ 8.02 (d, J = 8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.63–7.58 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.46–7.40 (m, 3H), 6.31 (s, 1H), 5.56 (q, J = 12.8 Hz, 2H), 3.05 (s, 3H); 13C NMR (50 MHz): δ 160.1, 144.2, 135.0 (CH), 134.1, 130.4, 129.9 (CH), 129.4 (CH), 129.3, 128.1 (CH), 123.6 (CH), 122.8 (CH), 121.2, 112.8 (CH), 88.9 (CH), 74.7 (CH2), 56.2 (CH3); HRMS (TOF MS ES+) m/z calcd for C18H16NO5S [M + H]+ 358.0748, found 358.0749. 12-Methoxymethyl-12H-5,12-diazaindeno[1,2-b]phenanthrene7,13-dione (12). In a flame dried flask flushed with nitrogen, LDA was prepared by adding N,N-diisopropylamine (0.34 mL, 2.6 mmol) to a solution of n-BuLi (2.5 M in hexane) (0.88 mL,
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2.2 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the phthalide donor 10a (150 mg, 0.69 mmol) in THF (10 mL) was then added dropwise. The reaction mixture was stirred at −78 °C for another 15 min and then slowly the temperature was raised to −40 °C, and stirring was continued for another 15 min. A solution of 4-bromoquinoline (160 mg, 0.76 mmol) in THF (10 mL) was added dropwise, and immediately a colour change was observed. The mixture was further stirred at −40 °C for another 30 min. The resulting mixture was allowed to warm slowly to room temperature and stirred overnight. The dark coloured solution was quenched with a saturated ammonium chloride solution (10 mL). The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (30 mL). The aqueous part was again extracted with ethyl acetate (20 mL), the total organic phase was washed with water (2 × 10 mL) and brine (10 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was passed through a column (Rf 0.5 in 15% ethyl acetate in hexane) to give a mixture of compounds 12 and 13 (12 : 13 being 6.39 : 1, i.e., 87% regioselective) as a red solid 12 (98 mg, 0.28 mmol) in 42% yield. The characterisation data of 12 being: mp 230–232 °C; 1H NMR (400 MHz) (NMR data extracted from the spectra of a mixture of 12 & 13): δ 9.76 (s, 1H), 9.60 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 6.10 (s, 2H), 3.42 (s, 3H); 13C NMR (100 MHz): δ 181.9, 181.0, 151.3, 147.3 (CH), 140.4, 135.6, 134.1, 132.2 (CH), 130.7 (CH), 129.8 (CH), 128.6 (CH), 127.9 (CH), 125.6 (CH), 124.6, 124.1 (CH), 123.5, 123.3, 118.8, 112.1 (CH), 75.7 (CH2), 56.9 (CH3). Compound 12 was synthesised from sulfone 9 using a similar procedure. 8-Methoxymethyl-8H-5,8-diazaindeno[2,1-b]phenanthrene7,13-dione (13). This compound was prepared by the same annulation procedure as that described for compound 12 using 3-bromoquinoline instead of 4-bromoquinoline. The compound was passed through a column (Rf 0.5 in 15% ethyl acetate in hexane) to give a mixture of compounds 12 and 13 (12 : 13 being 1 : 6.44, i.e., 87% regioselective) as a red solid (84 mg, 0.23 mmol) in 36% yield; mp: 250–255 °C; 1H NMR (400 MHz) (NMR data extracted from the spectra of mixture of 12 & 13): δ 9.75 (d, J = 8.8 Hz, 1H), 9.70 (s, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 8 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.65 (d, J = 8 Hz, 1H), 7.51 (t, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz, 1H), 6.14 (s, 2H), 3.42 (s, 3H); 13C NMR (100 MHz): δ 184.6, 178.8, 152.5, 147.5 (CH), 139.9, 135.4, 133.2, 131.9 (CH), 130.2 (CH), 130.1 (CH), 128.4, 128.3 (CH), 128.2 (CH), 125.4 (CH), 124.1, 123.8 (CH), 123.2, 120.9, 112.1 (CH), 75.5 (CH2), 56.7 (CH3). 3-Quinolin-4-yl-3H-isobenzofuran-1-one (22). Using the same annulation procedure as that described for compound 12, here phthalide 20 (100 mg, 0.75 mmol) was used as a donor and 4-bromoquinoline as an acceptor (140 mg, 0.67 mmol), the two compounds obtained were purified by
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column chromatography. The top spot is the same as (24) which was obtained in 15% yield. (22): Rf 0.25 in 50% ethyl acetate in hexane; liquid (81 mg, 0.31 mmol) in 42% yield; 1H NMR (400 MHz): δ 8.83 (d, J = 4.4 Hz, 1H), 8.24–8.18 (m, 2H), 8.00 (dd, J = 4.4, 6.8 Hz, 1H), 7.80 (t, J = 6.8 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.64–7.56 (m, 2H), 7.40 (d, J = 6 Hz, 1H), 7.21 (s, 1H); 13C NMR (100 MHz): 170.2, 150.4 (CH), 148.7, 148.4, 141.9, 134.7 (CH), 130.7 (CH), 130.1 (CH), 130.0 (CH), 127.9 (CH), 126.4 (CH), 125.9, 125.3, 123.0 (CH), 122.9 (CH), 117.8 (CH), 78.0 (CH); IR (KBr) νmax in cm−1: 3429, 2360, 1771, 1634, 1219, 1059, 771; HRMS (TOF ESI+) m/z calcd for C17H12NO2 [M + H]+ 262.0868, found 262.0837. 3-Methyl-3-quinolin-3-yl-3H-isobenzofuran-1-one (23). Using the same annulation procedure as that described for compound 12, here 3-methyl phthalide 21 (150 mg, 1.01 mmol) was used as a donor and 4-bromoquinoline as an acceptor (200 mg, 0.97 mmol), and the two compounds obtained were purified by column chromatography. The top spot is the same as (25) which was obtained in 9% yield (39 mg, 0.14 mmol). (23): Rf 0.25 in 50% ethyl acetate in hexane; white solid (106 mg, 0.38 mmol) in 38% yield; 1H NMR (400 MHz): δ 8.82 (s, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.37 (s, 1H), 2.24 (s, 3H); 13C NMR (100 MHz): δ 168.9, 151.9, 149.4 (CH), 144.1, 134.2 (CH), 130.4 (CH), 129.8 (CH), 129.2 (CH), 126.9 (CH), 126.4 (CH), 126.3 (CH), 125.6, 125.5, 123.7 (CH), 118.4 (CH), 88.1, 28.7 (CH3); mp: 138–142 °C; IR (KBr) νmax in cm−1: 1767, 1276, 1119, 1033, 921; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1020. Benzo[ j]phenanthridine-7,12-dione (24).14 Using the same annulation procedure as that described for compound 12, here phthalide 20 (150 mg, 1.12 mmol) was used as a donor and 3-bromoquinoline as an acceptor (208 mg, 1.00 mmol). A yellow crystalline solid was obtained after purification by column chromatography in 43% yield (125 mg, 0.48 mmol); Rf = 0.6 in 30% ethyl acetate in hexane; mp: 200–205 °C; 1H NMR (400 MHz): δ 9.85 (s, 1H), 9.60 (dd, J = 1.2, 8.4 Hz, 1H), 8.33–8.29 (m, 2H), 8.24 (d, J = 8.4 Hz, 1H), 7.93–7.80 (m, 2H); 13 C NMR (100 MHz): δ 187.7, 184.7, 151.9, 149.5 (CH), 137.0 (CH), 136.9 (CH), 136.4, 135.1 (CH), 133.9, 133.2 (CH), 131.1, 130.6 (CH), 129.7 (CH), 128.9 (CH), 127.2, 125.4. 12-Hydroxy-12-methyl-12H-benzo[ j]phenanthridin-7-one (25) & 7-hydroxy-7-methyl-7H-benzo[ j]phenanthridin-12-one (26). Using the same annulation procedure as that described for compound 12, here 3-methyl phthalide 21 (400 mg, 2.7 mmol) was used as a donor and 3-bromoquinoline as an acceptor (613 mg, 2.9 mmol), and the two compounds obtained were purified by column chromatography. 12-Hydroxy-12-methyl-12H-benzo[ j]phenanthridin-7-one (25). Rf 0.5 in 25% ethyl acetate in hexane; white solid (208 mg, 0.75 mmol) in 28% yield; mp: 115–120 °C; 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.36 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8 Hz, 2H), 8.07 (d, J = 8 Hz, 1H), 7.92 (t, J = 8 Hz, 1H), 7.85 (t, J = 8 Hz, 1H), 7.77 (t, J = 8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 6.77
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(s, 1H), 1.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 182.8, 154.7, 152.0, 150.6, 148.4 (CH), 134.9 (CH), 132.0 (CH), 130.7 (CH), 129.7 (CH), 128.4 (CH), 127.5 (CH), 127.4 (CH), 126.0 (CH), 124.7, 121.9, 70.3, 35.0 (CH3); IR (KBr) νmax in cm−1: 2121, 1646, 1275, 770; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1018. 7-Hydroxy-7-methyl-7H-benzo[ j]phenanthridin-12-one (26). Rf 0.3 in 25% ethyl acetate in hexane; yellow liquid (230 mg, 0.83 mmol) in 31% yield; 1H NMR (400 MHz): δ 9.30 (s, 1H), 9.11 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.52–7.42 (m, 3H), 4.67 (brs, 1H), 1.71 (s, 3H); 13C NMR (100 MHz): δ 185.5, 149.8 (CH), 147.6, 147.3, 141.5, 134.2 (CH), 130.7, 129.6 (CH), 129.4 (CH), 129.3, 128.9 (CH), 128.5 (CH), 127.2 (CH), 126.8 (CH), 125.7 (CH), 123.0, 69.0, 36.2 (CH3); IR (KBr) νmax in cm−1: 1665, 1360, 1267, 1032, 758; HRMS (TOF ESI+) m/z calcd for C18H14NO2 [M + H]+ 276.1025, found 276.1020. 6-Methoxymethyl-6H-pyrido[4,3-b]carbazole-5,11-dione & 10-methoxymethyl-10H-pyrido[3,4-b]carbazole-5,11-dione (27 & 28). Using the annulation procedure described for compound 12, phthalide 10 (250 mg, 1.15 mmol) was reacted with 3-bromopyridine (162 mg, 1.03 mmol). Compounds 27 & 28 were obtained as a yellow solid in 54% yield. Since the compounds are inseparable, the NMR data are reported for the mixture. Rf = 0.6 in 30% ethyl acetate in hexane. The NMR data are reported as a mixture of 27 and 28. 1 H NMR (400 MHz): δ 9.42 (s, 1H), 9.39 (s, 1H), 9.04 (s, 1H), 8.45–8.41 (m, 2H), 8.01 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.66–7.62 (m, 2H), 7.54–7.50 (m, 2H), 7.46–7.42 (m, 2H), 6.14 (s, 2H), 6.12 (s, 2H), 3.39 (s, 3H), 3.38 (s, 2H); 13C NMR (100 MHz): 181.0, 180.2, 180.1, 178.44, 178.41, 177.9, 177.8, 155.6, 155.5, 155.0 (CH), 154.9 (CH), 148.4, 148.37 (CH), 148.32 (CH), 140.4, 140.1, 139.6, 139.3, 134.8, 134.6, 128.9 (CH), 128.7 (CH), 125.75 (CH), 125.71 (CH), 124.3 (CH), 124.07 (CH), 124.01 (CH), 123.9, 120.5, 119.0 (CH), 112.4 (CH), 112.2 (CH), 75.73 (CH2), 75.71 (CH2), 56.9 (CH3), 56.8 (CH3). 3-N,N-Diisopropylquinoline (29). In a flame dried flask flushed with nitrogen, LDA was prepared by adding N,N-diisopropylamine (0.13 mL, 1.05 mmol) to a solution of n-BuLi (2.5 M in hexane) (0.38 mL, 0.96 mmol) in THF at −40 °C under a nitrogen atmosphere and stirred for 30 min at the same temperature. A solution of the 4-bromoquinoline (100 mg, 0.48 mmol) in THF (5 mL) was then added dropwise and stirred for another 30 min at the same temperature, and then slowly allowed to stir at rt overnight. The dark coloured solution was quenched with a saturated ammonium chloride solution (5 mL). The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (15 mL). The aqueous part was again extracted with ethyl acetate (10 mL), and the total organic phase was washed with water (2 × 7 mL) and brine (7 mL) and dried over anhydrous (Na2SO4). The organic phase was then filtered and concentrated under reduced pressure. The residue was passed through a column (Rf 0.7 in 15% ethyl acetate in hexane) to give compound 29 as a liquid in 40% yield (44 mg, 0.19 mmol); IR (KBr) νmax in cm−1: 2969, 2360, 1590, 1474,
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1369, 1336, 1290, 1147, 772; 1H NMR (400 MHz): δ 8.77 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.40 (m, 2H), 7.44–7.34 (d, J = 2.8 Hz, 1H), 3.90–3.83 (m, 2H), 1.28 (d, J = 6.8 Hz, 12H); 13C NMR (100 MHz): δ 146.2 (CH), 142.1, 129.3, 128.6 (CH), 126.6 (CH), 126.3 (CH), 125.5 (CH), 118.9 (CH), 48.0 (CH), 21.5 (CH3).
Acknowledgements The authors are grateful to the Department of Science and Technology for financial support. J. R. is thankful to CSIR for her research fellowship. We also acknowledge the support of FIST, DST, New Delhi.
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