Synthesis of Benzo[]fluorenone Nuclei of Stealthins

Abstract

Two routes, one based on a Michael-initiated aldol condensation and the other on an intramoleculer carbonyl-ene reaction, have been found to be feasible for an entry to benzo[]fluorenones. Reaction of 4,9-dimethoxybenz[]indenone with nitromethane in the presence of DBU gave the corresponding Michael adduct, which afforded 2-methyl-5,10-dimethoxybenzo[b]fluorenone on reaction with methacrolein under a variety of basic conditions. Similarly, 2-methallyl-4,9-dimethoxybenz[]indenone reacted with nitromethane to give the corresponding Michael adduct, Nef reaction of which furnished 3-formyl-2-methyl-4,9-dimethoxybenz[]indanone. This underwent ene-cyclization under the influence of SnCl4. 5H2O, and yielded 2-methyl-5,10-dimethoxybenzo[]fluorenone.

1. Introduction

Stealthins A (1a) and B (1b), isolated from Streptomyces viridochromogenes as potent radical scavengers, are the first known members of natural benzofluorenones [1]. Interest in this group of compounds grew considerably due to the identification of structurally allied natural products, stealthin C (1c) [2], kinafluorenone (2) [3], prekinamycin (3) [4], and kinamycin antibiotics (e.g., kinamycin D, 4) [5] (Figure 1). Their synthesis became an active area of research since 1996 [6–19]. In line with the Ishikawa approach [19], we intended to explore the chemistry of benzindenones (e.g., 5b) to establish new synthetic routes to functionalized benzofluorenones [20]. Herein, we report regiospecific construction of the D-ring of benzofluorenones (e.g., 6) from the corresponding benzindenones.

Figure 1 

Naturally occurring benzofluorenones.

2. Results and Discussion

Initial studies were focused on the utilization of the readily accessible benzindenones 5a and 5b [21]. DBU-promoted Michael addition of nitromethane to the indenones furnished indenones 7a and 7b, respectively. The intended annulation of 7b with methacrolein was then studied with different base-solvent systems (Scheme 1). But, none of the attempts gave desired product 8. Instead, most of the methods produced benzofluorenone 6 in low yields. The best yield was 25%, which was obtained with DBU in benzene. The presence of singlet at δ 2.23 for Ar-C in NMR spectrum was indicative of the structure 6. It is probable that the compound 6 was formed from tetracycle 8 through elimination of HN. Considering the fact that even a weak base such as -BP caused the elimination of N group, we examined the route (Scheme 2), involving an acid-catalyzed cyclization. The Synthon equivalent 9 was prepared in two steps from methacrolein by adaptation of Miyakoshi protocol [22] (Scheme 2). Conjugate addition of the reagent 9 to benzindenone 5b in the presence of DBU provided 10 in good yield. NMR spectrum of the product indicated the formation of a 1:1 mixture of diastereomers. When treated with 1 N HCl, the mixture afforded the expected product 8 in trace amount, the major product being 6 (25%). Repeated attempts to optimize the transformation of 10 into 8 were of no avail.

Scheme 1 

Michael-aldol sequence.

Scheme 2 

Michael-aldol sequence.

As an alternative avenue, the strategy (Scheme 3) based upon the intramolecular carbonyl-ene reaction [23] of 11 was undertaken. Preparation of the key precursor 11 is depicted in Scheme 3. LDA-promoted allylation of 12 [21] with allyl bromide 13a furnished 14a. Characteristic multiplets at δ 5.6 and two doublets at δ 5.1 and δ 4.87 in NMR spectrum were in complete agreement with the structure 14a. The cis-relationship between the angular allyl group and the methano bridge was inferred by comparing the NMR signals of C-4a H of an angularly methylated analog [24]. Flash vacuum pyrolysis (FVP) of the adduct 14a at C/0.01 mm gave enone 5c in sufficiently pure form for the next use. It was then subjected to conjugate addition with nitromethane in the presence of DBU to produce allylated nitro adduct 15a as a single isomer in 92% yield (Scheme 3). Similarly, precursor 15b was obtained in three steps from 12. Methallylation of 12 with methallyl iodide 13b in the presence of LDA gave 14b (91%), FVP of which furnished 5d. Addition of nitromethane to 5d in the presence of DBU-furnished intermediate 15b in 80% yield. Nef reaction [25] of 15b with NaOMe and TiC-buffer provided aldehyde 11 in moderate yield (50%). The singlet at δ 9.94 in NMR spectrum and the band at 1718 in IR spectrum confirmed the presence of CHO functionality in 11. When a solution of the aldehyde in dichloromethane was treated with SnC 5O [26], D-ring aromatized compound 6 was formed in 45% yield.

Scheme 3 

Intramolecular carbonyl-ene approach.

3. Conclusion

We have validated two synthetic routes to benzofluoren-11-ones from benzindenones 5. The intramolecular carbonyl-ene reaction of the intermediate 11 (Scheme 3) proved to be better pathway than the tandem Michael-aldol route (Scheme 2) to benzofluoren-11-one 6.

4. Experimental

The general experimental is described in [27].

Benzinden-1-One 5c
This compound was prepared from 14a. Mp: 80–85; yellow; yield 93%; IR (): 1684; NMR (200 MHz), 8.20 (d, 1H, J = 8.1), 7.97 (d, 1H, J = 8.1), (m, 3H), (m, 1H), (m, 2H), 4.28 (s, 3H), 4.02 (s, 3H), (m, 2H); NMR (50 MHz): 193.99, 152.2, 144.6, 141.5, 139.8, 134.5, 132.9, 131.1, 129.4, 127.1, 126.2, 125.7, 123.0, 117.1, 115.5, 62.8, 62.7, 29.5; MS (m/z): 280 (M+, 100%), 265, 250, 223, 178, 165.

Benzinden-1-One 5d
This compound was prepared as a yellow oil in 90% yield from 14b. IR (): 1689; NMR (300 MHz): 8.10 (d, 1H, J = 8.1), 7.97 (d, 1H, J = 8.1), (m, 3H), 4.85 (d, 2H, J = 10.8), 4.28 (s, 3H), 4.02 (s, 3H), 3.04 (s, 2H), 1.79 (s, 3H); NMR (75 MHz): 192.9, 152.0, 144.5, 142.6, 140.9, 140.4, 132.7, 131.0, 129.3, 127.0, 126.0, 125.6, 122.9, 115.3, 112.5, 62.9, 62.7, 33.3, 22.5; MS (m/z): 294 (M+, 100%), 279, 263, 236, 165, 152, 139.

Benzofluorenone 6: Method A
To a stirred solution of the nitro compound 7a (100 mg, 0.33 mmol), and methacrolein (60 mg, 0.86 mmol) in benzene (5 mL) at 0 was added DBU (10 mg, 0.066 mmol). Stirring was continued for 24 hours at rt. The reaction mixture was diluted with diethyl ether (50 mL), washed with saturated sodium bicarbonate solution (10 mL) and then with brine (10 mL). The organic phase was dried (NS) and concentrated. The resulting residue was purified by preparative TLC to give a yellow crystalline solid of 6 (26 mg, 25%).

Method B
To a stirred solution of aldehyde 11 (50 mg, 0.154 mmol) in dichloromethane (6 mL) was added SnC O (5 mg) under nitrogen atmosphere. The stirring was continued for 30 hours. After usual work up of the reaction mixture, the residue was purified by preparative TLC to provide 6 (21 mg, 45%). Mp: 150-151; IR (): 1695; NMR (200 MHz): 8.29 (d, 1H, J = 7.4), 8.04 (d, 1H, J = 7.4), 7.88 (d, 1H, J = 7.7), (m, 4H), 4.28 (s, 3H), 4.00 (s, 3H), 2.42 (s, 3H); NMR (50 MHz): 190.4, 153.7, 146.4, 140.0, 138.8, 136.4, 135.4, 133.6, 130.8, 129.4, 127.8, 126.7, 125.5, 124.4, 124.1, 122.4, 119.9, 63.1, 61.1, 21.3; MS (m/z): 304 (M+, 100%), 289, 218, 189, 149, 57.

Compound 7a
This was prepared from benzindenone 5a and nitromethane in 89% yield according to the procedure described earlier [25]. Mp: 124; IR (): 1711; NMR (200 MHz): 8.37 (s, 1H, ArH) 8.03 (d, 1H, J = 8.1), (m, 2H), (m, 2H), (ABq, 1H, J = 12.8, 5.8), (ABq, 1H, J = 12.8, 5.8), (m, 1H), (ABq, 1H, J = 19.2, 8.2), (ABq, 1H, J = 19.2, 3.9).

Compound 7b
This was prepared from 5b, following the procedure described for compound 7a. Mp: 179-180; white solid; yield: 89%; IR (): 1715; NMR (200 MHz): 8.40 (d, 1H, J = 8.2), 8.10 (d, 1H, J = 8.5), (m, 2H), (m, 1H), (m, 2H), 4.18 (s, 3H), 4.03 (s, 3H) (m, 1H), (m, 1H); NMR (50 MHz): 200.4, 152.9, 148.6, 134.1, 132.7, 129.7, 126.9, 125.3, 122.7, 121.8, 77.8, 77.2, 63.4, 61.8, 42.3, 34.4; MS (m/z): 301 (M+), 254, 239, 197, 141, 115.

Compound 8
To a mixture of enone 5b (0.178 g, 0.740 mmol) and 1,1-ethanediyldioxy-2-methyl-4-nitrobutane 9 (0.389 g, 2.22 mmol) in CC (4 mL) was added DBU (12 mg, 0.078 mmol) and the mixture was stirred at rt for 6 hours. It was then concentrated and purified by column chromatography to afford 10 as an oil (0.2 g, 65%). NMR spectrum revealed the presence of two isomers as indicated by three signals δ 4.15, 4.08, and 4.05, corresponding to the methoxy groups. The peak at δ 4.15 was not resolved. The methine hydrogens of CHN appeared at δ 5.19. To a stirred solution of above nitro acetal 10 (100 mg, 0.24 mmol) in THF (8 mL) was added 10% HCl (1 mL) solution. Stirring was continued for 20 hours. After usual work up of the reaction mixture, the residue was chromatographed to afford 6 (18 mg, 25%) and 8 (2.5 mg, 3%).

Compound 9
Yield: 50%; colorless oil; IR (): 1541; NMR (200 MHz): 4.66 (d, 1H, J = 4), 4.46 (t, 2H, J = 6), (m, 4H), (m, 3H), 1.00 (d, 3H, J = 6.7); NMR (50 MHz): 106.8, 74.1, 65.1, 65.0, 34.3, 29.0, 14.7.

Compound 11
This was prepared from compound 15b by Nef reaction [25]. Yield: 50%; purity > 80%; NMR (500 MHz): 9.94 (s, 1H), 8.40 (d, 1H, J = 8.4), 8.10 (d, 1H, J = 8.4), 7.69 (t, 1H, J = 8.2), 7.52 (t, 1H, J = 8.2), 4.87 (s, 1H), 4.78 (s, 2H), 4.21 (s, 3H), 4.16 (brs, 1H), 4.02 (s, 3H) (m, 1H); (ABq, 1H, J = 14.0, 4.3) 1.75 (s, 3H).

Compound 12
NMR (200 MHz): 8.37 (d, 1H, J = 8.0, 1H), 8.05 (d, 1H, J = 8.0, 1H), (m, 2H), 6.85 (brs, 1 H), (m, 1H), 4.32 (s, 3H), 3.70 (s, 3H), 2.85 (brs, 1H), (m, 1H), (m, 2H), (m, 3H).

Compound 14a
This was prepared as thick brownish oil in 88% yield from pentacycle 12, following an earlier method [24]. IR (): 1705; NMR (300 MHz): 8.33 (d, 1H, J = 8.7), 8.06 (d, 1H, J = 8.4), 7.61 (m, 1H), 7.49 (m, 1H), (m, 1H), (m, 2H), 5.07 (d, 1H, J = 16.8), 4.85 (d, 1H, J = 10.2), 4.08 (s, 3H), 4.03 (s, 3H), 3.78 (d, 1H, J = 4.2), 3.45 (brs, 1H), (m, 2H), (m, 1H), 2.0 (ABd, 1H, J = 8.7), 1.80 (ABd, 1H, J = 8.7); NMR (75 MHz): 207.1, 151.2, 147.6, 138.0, 135.2, 135.1, 134.3, 132.4, 128.9, 126.6, 125.8, 125.0, 121.8, 117.5, 63.0, 62.4, 62.1, 50.8, 50.9, 47.0, 46.6, 41.6.

Compound 14b
This was prepared from pentacycle 12, following the procedure adopted for compound 14a. Yield: 89%; thick oil; IR (): 1705; NMR (400 MHz): 8.32 (d, 1H, J = 8.1), 8.07 (d, 1H, J = 8.1), 7.62 (br t, 1H), 7.49 (br t, 1H), 6.00 (dd, 1H, J = 2.8, 5.6), 5.49 (dd, 1H, J = 2.8, 5.6), 4.70 (brs, 1H), 4.66 (brs, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 3.93 (d, 1H, J = 4), 3.44 (brs, 1H), 3.05 (ABd, 1H, J = 13.8), 2.94 (brs, 1H), 2.41 (ABd, 1H, J = 13.8), 1.98 (ABd, 1H, J = 8.8), 1.79 (ABd, 1H, J = 8.8), 1.46 (s, 3H); NMR (50 MHz): 207.4, 151.0, 147.6, 143.1, 138.3, 135.5, 135.3, 134.6, 132.3, 128.8, 126.7, 125.8, 125.0, 121.8, 114.3, 62.8, 61.8, 61.6, 52.5, 50.8, 46.8, 46.1, 45.7, 23.8.

Compound 15a
This was prepared from 5c, following the procedure described for compound 7a. Mp: 98-99; white solid; yield: 92%; IR (): 1712; NMR (300 MHz): 8.40 (d, 1H, J = 8.7), 8.10 (d, 1H, J = 8.4), (m, 1H), 7.58 (m, 1H), (m, 1H), (m, 3H), (m, 1H), 4.20 (s, 3H), 4.10 4.05 (m, 1H), 4.01 (s, 3H), (m, 1H); (m, 2H); NMR (75 MHz): 202.7, 153.1, 148.7, 133.8, 133.3, 133.0, 129.8, 127.0, 125.4, 122.3, 121.9, 118.8, 77.7, 77.3, 63.4, 61.8, 52.2, 39.4, 36.1; MS (m/z): 341 (M+), 307, 290, 280 (100%), 265, 165.

Compound 15b
This was prepared from 5d, following the procedure adopted for compound 7a. Mp: 122-123; white solid; yield: 90%; IR (): 1707; NMR (300 MHz): 8.41 (d, 1H, J = 8.4), 8.10 (d, 1H, J = 8.4), (m, 1H), (m, 1H), 5.07 (dd, 1H, J = 12.8, 4.2), 4.88 (s, 1H), 4.76 (s, 1H), 4.59 (dd, 1H, J = 12.8, 8.7), 4.20 (s, 3H), (m, 1H), 4.00 (s, 3H), (m, 1H); 2.63 (dd, 1H, J = 13.8, 5.1), 2.34 (dd, 1H, J = 13.8, 9.0), 1.73 (s, 3H); NMR (75 MHz): 202.8, 153.3, 148.8, 142.5, 133.3, 132.9, 129.9, 129.8, 126.9, 125.3, 122.0, 114.2, 77.8, 63.3, 61.9, 50.8, 40.5, 39.9, 21.9. MS (m/z): 355 (M+), 319, 304, 294 (100%), 279, 265, 253, 236, 223, 165, 152, 139; anal. calcd for N: C, 67.59; H, 5.96; N, 3.94, found C, 67.51; H, 5.93; N, 3.93.

Acknowledgments

This work was supported by the Council of Scientific and Industrial Research (CSIR) and the Department of Science and Technology, New Delhi. The second and the third authors are grateful to the CSIR, for their research fellowships.

References

1. K. Shin-ya, K. Furihata, Y. Teshima, Y. Hayakawa, and H. Seto, “Structures of stealthins A and B, new free radical scavengers of microbial origin,” Tetrahedron Letters, vol. 33, no. 46, pp. 7025–7028, 1992. View at: Publisher Site | Google Scholar
2. S. J. Gould, N. Tamayo, C. R. Melville, and M. C. Cone, “Revised structures for the kinamycin antibiotics: 5-diazobenzo[$b$]fluorenes rather than benzo[$b$]carbazole cyanamidines,” Journal of the American Chemical Society, vol. 116, no. 5, pp. 2207–2208, 1994. View at: Publisher Site | Google Scholar
3. M. C. Cone, C. R. Melville, M. P. Gore, and S. J. Gould, “Kinafluorenone, a benzo[$b$]fluorenone isolated from the kinamycin producer Streptomyces murayamaensis,” The Journal of Organic Chemistry, vol. 58, no. 5, pp. 1058–1061, 1993. View at: Publisher Site | Google Scholar
4. S. J. Gould, J. Chen, M. C. Cone, M. P. Gore, C. R. Melville, and N. Tamayo, “Identification of prekinamycin in extracts of Streptomyces murayamaensis,” The Journal of Organic Chemistry, vol. 61, no. 17, pp. 5720–5721, 1996. View at: Publisher Site | Google Scholar
5. J. Marco-Contelles and M. T. Molina, “Naturally occurring diazo compounds: the kinamycins,” Current Organic Chemistry, vol. 7, no. 14, pp. 1433–1442, 2003. View at: Publisher Site | Google Scholar
6. D. Mal and N. K. Hazra, “The first approach to kinamycin antibiotics: synthesis of kinafluorenone scaffold,” Tetrahedron Letters, vol. 37, no. 15, pp. 2641–2642, 1996. View at: Publisher Site | Google Scholar
7. F. M. Hauser and M. Zhou, “Total synthesis of the structure proposed for prekinamycin,” The Journal of Organic Chemistry, vol. 61, no. 17, p. 5722, 1996. View at: Publisher Site | Google Scholar
8. S.-I. Mohri, M. Stefinovic, and V. Snieckus, “Combined directed Ortho-, remote-metalation and cross-coupling strategies. Concise syntheses of the kinamycin biosynthetic grid antibiotics phenanthroviridin aglycon and kinobscurinone,” The Journal of Organic Chemistry, vol. 62, no. 21, pp. 7072–7073, 1997. View at: Publisher Site | Google Scholar
9. G. Qabaja and G. B. Jones, “Annnulattion strategies for benzo[$b$]fluorene synthesis: efficient routes to the kinafluorenone and WS-5995 antibiotics,” The Journal of Organic Chemistry, vol. 65, no. 21, pp. 7187–7194, 2000. View at: Publisher Site | Google Scholar
10. E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, and A. M. Echavarren, “Synthesis of the benzo[$b$]fluorene core of the kinamycins by arylalkyne-allene and arylalkyne-alkyne cycloadditions,” European Journal of Organic Chemistry, vol. 2006, no. 6, pp. 1430–1443, 2006. View at: Publisher Site | Google Scholar
11. V. B. Birman, Z. Zhao, and L. Guo, “Benzo[$b$]fluorenes via indanone dianion annulation. A short synthesis of prekinamycin,” Organic Letters, vol. 9, no. 7, pp. 1223–1225, 2007. View at: Publisher Site | Google Scholar
12. A. Martínez, J. C. Barcia, A. M. Estévez et al., “A novel approach to the synthesis of benzo[$b$]fluoren-11-ones,” Tetrahedron Letters, vol. 48, no. 12, pp. 2147–2149, 2007. View at: Publisher Site | Google Scholar
13. X. Lei and J. A. Porco Jr., “Total synthesis of the diazobenzofluorene antibiotic (–)-kinamycin C 1,” Journal of the American Chemical Society, vol. 128, no. 46, pp. 14790–14791, 2006. View at: Publisher Site | Google Scholar
14. K. C. Nicolaou, H. Li, A. L. Nold, D. Pappo, and A. Lenzen, “Total synthesis of kinamycins C, F, and J,” Journal of the American Chemical Society, vol. 129, no. 34, pp. 10356–10357, 2007. View at: Publisher Site | Google Scholar
15. I. Hussain, M. A. Yawer, M. Lau et al., “Regioselective synthesis of fluorinated phenols, biaryls, 6$H$-benzo[c]chromen-6-ones and fluorenones based on formal [3+3] cyclizations of 1,3-bis(silyl enol ethers),” European Journal of Organic Chemistry, vol. 2008, no. 3, pp. 503–518, 2008. View at: Publisher Site | Google Scholar
16. S. Reim, M. Lau, and P. Langer, “Synthesis of fluorenones based on a ‘[3+3] cyclization/Suzuki cross-coupling/Friedel-Crafts acylation’ strategy,” Tetrahedron Letters, vol. 47, no. 38, pp. 6903–6905, 2006. View at: Publisher Site | Google Scholar
17. W. Williams, X. Sun, and D. Jebaratnam, “Synthetic studies on the kinamycin family of antibiotics: synthesis of 2-(Diazobenzyl)-$p$-naphthoquinone, 1,7-Dideoxy-3-demethylprekinamycin, and 1-deoxy-3-demethylprekinamycin,” The Journal of Organic Chemistry, vol. 62, no. 13, pp. 4364–4369, 1997. View at: Publisher Site | Google Scholar
18. N. Chen, M. B. Carrière, R. S. Laufer, N. J. Taylor, and G. I. Dmitrienko, “A biogenetically-lnspired synthesis of a ring-D model of kinamycin F: insights into the conformation of ring D,” Organic Letters, vol. 10, no. 3, pp. 381–384, 2008. View at: Publisher Site | Google Scholar
19. N. Etomi, T. Kumamoto, W. Nakanishi, and T. Ishikawa, “Diels-Alder reactions using 4,7-dioxygenated indanones as dienophiles for regioselective construction of oxygenated 2,3-dihydrobenz[$f$]indenone skeleton,” Beilstein Journal of Organic Chemistry, vol. 4, no. 15, pp. 1–8, 2008. View at: Publisher Site | Google Scholar
20. D. Mal, S. K. Ghorai, and N. K. Hazra, “A convenient synthesis of 4,8,9-trimethoxybenz[$f$]indenone, a potential BCD ring intermediate for stealthins and kinamycins,” Indian Journal of Chemistry, Section B, vol. 40, no. 10, pp. 994–996, 2001. View at: Google Scholar
21. D. Mal, N. K. Hazra, K. V. S. N. Murty, and G. Majumdar, “Benz[$f$]indenones: a novel synthesis by an anionic [4+2] cycloaddition/retro Diels-Alder pathway,” Synlett, vol. 1995, no. 12, pp. 1239–1240, 1995. View at: Publisher Site | Google Scholar
22. T. Miyakoshi, “A convenient synthesis of 4-oxoalkanals,” Synthesis, vol. 1986, no. 9, pp. 766–768, 1986. View at: Publisher Site | Google Scholar
23. M. L. Clarke and M. B. France, “The carbonyl ene reaction,” Tetrahedron, vol. 64, no. 38, pp. 9003–9031, 2008. View at: Publisher Site | Google Scholar
24. A. Usman, I. A. Razak, S. Chantrapromma et al., “1,4-methano-11a-methyl-4,4a,11,11a-tetrahydro-1$H$-benzo[$b$]fluoren-11-one,” Acta Crystallographica, Section C, vol. 57, part 9, pp. 1118–1119, 2001. View at: Publisher Site | Google Scholar
25. S. K. Ghorai, N. K. Hazra, and D. Mal, “Facile synthesis of 4-functionalized cyclopentenones,” Synthetic Communications, vol. 37, no. 12, pp. 1949–1956, 2007. View at: Publisher Site | Google Scholar
26. F. M. Hauser and D. Mal, “A novel route for stereospecific construction of the A ring of anthracyclinones: total synthesis of ($\pm$)-$\gamma$-citromycinone,” Journal of the American Chemical Society, vol. 106, no. 6, pp. 1862–1863, 1984. View at: Publisher Site | Google Scholar
27. A. Patra, S. K. Ghorai, S. R. De, and D. Mal, “Regiospecific synthesis of benzo[$b$]fluorenones via ring contraction by benzil-benzilic acid rearrangement of benz[$a$]anthracene-5,6-diones,” Synthesis, vol. 2006, no. 15, pp. 2556–2562, 2006. View at: Publisher Site | Google Scholar

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Copyright © 2009 Sujit Kumar Ghorai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.