Development of a Sulfur Extrusion Route to Carbazole Natural Products

 

Background: There has been a strong interest in molecules which contain the carbazole ring structure, by chemists and biologists, due to their intriguing structural features1 and wide variety of biological activities. In particular, murrayafoline A has been shown to have significant cytotoxic activity,2 carbazomycin has antibacterial and antiyeast activity,3 and ellipticine is a DNA intercalation agent that has potent antitumor activity.4 Also, carbazole containing polymers are interesting because they have been shown to have photoluminescent,5 electroluminescent,6 and hole conducting properties.7 The versatility of the carbazole ring structure has led to its use in many modern applications such as dendrimers8 and molecular computers.9 Because of this strong interest, new methods for synthesizing the carbazole ring structure are a current topic in publications.10

 

 

An efficient method for the ring contraction desulfurization of phenothiazine to make carbazole would prove useful because most regiochemically controlled synthesis routes to phenothiazine derivatives11 could then be directly applied to the corresponding carbazoles. Although many examples of the hydrodesulfurization of phenothiazine to make diphenylamine have been reported,12 much less effort has focused on this ring contraction.13-15 Due to a lack of efficient techniques for this conversion, my initial efforts focused on creating effective methods of the conversion of phenothiazine to carbazole (Figure 1).

 

 

Figure 1: The Conversion of Phenothiazine to Carbazole.

 

Recently, we have developed two methods for the high yield, low temperature conversion of phenothiazine to carbazole (Li/PPh3, Li/Na).16 As part of our ongoing investigation into new methods for this conversion, we investigated whether oxidation of the sulfur in phenothiazine could promote the ring contracting sulfur extrusion and/or allow for new methods to be used. In this study we applied our previous work using lithium and sodium, and Badgers work17 with degassed Raney nickel to provide the first reported ring contracting desulfurization of the phenothiazine-5-oxide or the phenothiazine-5,5-dioxide ring system to produce the corresponding carbazole.18 In addition, degassed Raney nickel was used to provide a novel method for the conversion of phenothiazine to carbazole. Currently, we are extending this work and investigating the ability of these reagents to remove sulfur from other heterocycles. We have had some success demonstrating that these reagents can produce efficient desulfurization from oxidized dibenzothiophene ring systems.19

Currently, I am interested in exploiting these new methods for the synthesis of interesting natural products containing the carbazole ring system. A proposed sulfur extrusion pathway to murrayafoline A, as seen in Figure 2, represents an improvement on the current literature method17 because it is a step shorter. Also, it forms the central pyrrole ring in a last regiochemically controlled step, thus substituents on the carbazole ring can be modified by simply changing the starting materials. This project intends to utilize the generalized nature of this new pathway to synthesize a library of derivatives based on Murrayafoline A and, via collaboration, examine their biological activity. Once this is accomplished the sulfur extrusion pathway will then be applied to more complex examples of natural products which contain the carbazole ring system, such as carbazomycin or ellipticine.

 

 

Figure 2: The Proposed Sulfur Extrusion Pathway to Murrayafoline A.

References:

1. (a) Ramsewak, R. S.; Muraleedharan, G. N.; DeWitt, D. L; Nitiss, J. L. Biologically Active Carbazole Alkaloids from Murrayakoenigii. J. Agric. Food Chem., 1999, 47, 444-447. (b) Knolker, H.; Reddy, K. R. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102 (11), 4303-4428 and references therein.

 

2. Itoigawa, M.; Kashiwada, Y.; Ito, C.; Furukawa, H.; Tachibana, Y.; Bastow, K. F.; Lee, K-H. Antitumor Agents. 203. Carbazole Alkaloid Murrayaquinone A and Related Synthetic Carbazolequinones as Cytotoxic Agents. J. Nat. Prod., 2000, 63 (7), 893-897.

 

3. Clive, D. L. J.; Etkin, N.; Joseph, T.; Lown J. W. Synthesis of Carbazomycin B. J. Org. Chem. 1993, 58 (9), 2442-2445.

 

4. (a) Pommier, Y.; Schwartz, R. E.; Zwelling, L. A.; Kohn, K. W. Effects of DNA Intercalating Agents on Topoisomerase I1 Induced DNA Strand Cleavage in Isolated Mammalian Cell Nuclei. Biochemistry 1985, 24, 6406-6410. (b) Werbel, L. M.; Angelo, M.; Fry, D. W.; Worth, D. F. Basically Substituted Ellipticine Analogues as Potential Antitumor Agents. J. Med. Chem. 1986, 29, 1321-1322. (c) Honda, T.; Kato, M.; Inoue, M.; Shimamoto, T.; Shima, K.; Nakanishi, T.; Yoshida, T.; Noguchi T. Synthesis and Antitumor Activity of Quaternary Ellipticine Glycosides, a Series of Novel and Highly Active Antitumor Agents. J. Med. Chem. 1988, 31, 1295-1305.

 

5. (a) Li, Y.; Ding, J.; Day, M.; Tao, Y.; Lu, J.; D iorio, M. Synthesis and Properties of Random and Alternating Fluorene/Carbazole Copolymers for Use in Blue Light-Emitting Devices. Chem. Mater. 2004, 16, 2165-2173. (b) Wong, W-Y.; Liu, L.; Cui, D.; Leung, L. M.; Kwong, C-F.; Lee, T-H.; Ng, H-F. Synthesis and Characterization of Blue-Light-Emitting Alternation Copolymers of 9,9-Dihexylfluorene and 9-Arylcarbazole. Macromolecules 2005, 38 (12), 4970-4976.

 

6. (a) He, J.; Liu, H.; Dai, Y.; Ou, X.; Wang, J.; Tao, S.; Zhang, X.; Wang, P.; Ma, D. Nonconjugated Carbazoles: A Series of Novel Host Materials for Highly Efficient Blue Electrophosphorescent OLEDs. J. Phys. Chem. C 2009, 113, 6761-6767. (b) Tsai, M-H.; Ke, T-H.; Lin, H-W.; Wu, C-C.; Chiu, S-F.; Fang, F-C.; Liao, Y-L.; Wong, K-T.; Chen, Y-H.; Wu, C-I. Triphenylsilyl- and Trityl-Substituted Carbazole-Based Host Materials for Blue Electrophosphorescence. ACS Appl. Mater. Interfaces 2009, 1 (3), 567-574.

 

7. (a) Fulghum, T. M.; Taranekar, P.; Advincula, R. C. Grafting Hole-Transport Precursor Polymer Brushes on ITO Electrodes: Surface-Initiated Polymerization and Conjugated Polymer Network Formation of PVK. Macromolecules 2008, 41, 5681-5687. (b) Barik, S.; Valiyaveettil, S. Synthesis and Self-Assembly of Copolymers with Pendant Electroactive Units. Macromolecules 2008, 41, 6376-6386.

 

8. Albrecht, K.; Yamamoto, K. Dendritic Structure Having a Potential Gradient: New Synthesis and Properties of Carbazole Dendrimers. J. Am. Chem. Soc. 2009, 131, 2244-2251.

 


9. Ogasawara, S.; Ami, T.; Fujimoto, K. Autonomous DNA Computing Machine Based on Photochemical Gate Transition. J. Am. Chem. Soc. 2008, 130, 10050-10051.

 

10. (a) Lie gault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou. K. Intramolecular Pd(II)-Catalyzed Oxidative Biaryl Synthesis Under Air: Reaction Development and Scope. J. Org. Chem. 2008, 73, 5022-5028. (b) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. Palladium-Catalyzed Method for the Synthesis of Carbazoles via Tandem C-H Functionalization and C-N Bond Formation. J. Org. Chem. 2008, 73, 7603-7610. (c) Bude n, M. E.; Vaillard, V. A.; Martin, S. E.; Rossi, R. A. Synthesis of Carbazoles by Intramolecular Arylation of Diarylamide Anions. J. Org. Chem. 2009, 74, 4490-4498.

 

11. (a) Cadogan, J. I. G.; Done, J. N.; Lunn, G. Nitrene-induced Cyclisations Accompanied by Rearrangement in Thermolyses of Aryl 2-Azidophenyl Sulphones. J. Chem. Soc., Perkin Trans.1 1976, 16, 1749-1757. (b) Cadogan, J. I. G.; Kulik, S.; Thomson, C.; Todd, M. J. A New Synthesis of Phenothiazines involving a New Molecular Rearrangement. J. Chem. Soc. (C ) 1970, 2437-2444. ( c) Codogan, J. I. G.; Kulik, S. The Blocked ortho Effect in Reactions of 2,6-Di-substituted Aryl 2-Nitrophenyl and 2,6-Di-substituted Aryl 2-Azidophenyl Sulfides. J. Chem. Soc. (C ) 1971, 2621-2632.

 

12. (a) Becker, S.; Fort, Y.; Vanderesse, R.; Caubere, P. Activation of Reducing Agents. Sodium Hydride Containing Complex Reducing Agents. J. Org. Chem. 1989, 54, 4848-4853. (b) Gilman, H.; Honeycutt, J. B.; Ingham, R. K. Cleavage Studies in the Carbazole and Phenothiazine Systems. J. Am. Chem. Soc. 1957, 22, 338-339. (c) Back, T. G.; Yang, K. Desulphurization of Benzothiophene Derivatives with Nickel Boride. J. Chem. Soc., Chem. Commun. 1990, 11, 819-820.

 

13. (a) Eisch, J. J.; Kyoung, R. Hydrodesulfurization and Ring Contraction of Sulfur Heterocycles by Nickel (0) Complexes. J. Organomet. Chem. 1977, 139, C51-C55. (b) Eisch, J. J.; Hallenbeck, L. E.; Han, K. I. Hydrodesulfurization of Organosulfur Heterocycles by Metal Hydride-Nickel (0) Complexes. J. Am. Chem. Soc. 1986, 108, 7763-7767. (c) Klingstedt, T.; Hallberg, A.; Dunbar, P.; Martin, A. Preparation of Pyrrolo[3,2,1-jk]carbazole by Nickel(0) Mediated Ring Contraction of Pyrrolo[3,2,1-kl]phenothiazine. Proton NMR and Mass Spectral Studies. J. Heterocycl. Chem. 1985, 22, 1547-1550.

 

14. (a) Ris, C. Ueber das Thio-b-dinaphtylamin and einige Derivate desselben. Ber. Dtsch. Chem. Ges. 1886, 19, 2240-2246. (b) Goske, A. Carbazol aus Thiodiphenylamin. Ber. Dtsch. Chem. Ges. 1887, 20, 232-234. (c) Lin, D. C. K.; Thomson, M. L.; DeJongh, D. C. Effect of the N-Phenyl Substituent on the Pyrolyses of 1-Phenyl-2-benzothiazolinone and 1-Phenyl-2-benzothiazolinethione. Can. J. Chem. 1975, 53, 2293-2299.

 

15. Gilman, H.; Dietrich, J. J. Lithium Cleavages of Some Heterocycles in Tetrahydrofuran. J. Am. Chem. Soc. 1958, 80, 380-383.

 


16. Miller, R. B.; Farmer, S. C. Modified Methods for the Synthesis of Carbazole from Phenothiazine. Molecules 2001, 6, 668-672.

 

17. Badger, G. M.; Cheuychit, P.; Sasse, W. H. F. Synthetic applications of activated metal catalysts. XXIII. The desulfurization of thianthrene. Aust. J. Chem. 1964, 17, 366-370.

 

18. Farmer, S. C.; Berg, S. H. Ring Contracting Sulfur Extrusion from Oxidized Phenothiazine Ring Systems. Molecules 2008, 13, 1345-1352.

 

19. Manuscript in preparation.

 

20. Martin, T.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1988, 235-242.