A novel domino approach has been described for an easy access of the privileged nucleus of 5-carbomethoxy substituted 1,4-benzodiazepin-2-ones 4(a–i) from an in situ methanolic hydrolysis of an incipient species formed from the interaction of 1-chloroacetylisatin 2(a–i), hexamethyldisilazane, and n-butyl lithium. The reaction is believed to take place through a consecutive series of intramolecular reactions in a cascade to first generate a highly reactive carbene intermediate 3(a–i) from 1-chloroacetylisatin and n-butyl lithium which is simultaneously trapped by hexamethyldisilazane before undergoing its in situ hydrolysis with methanol to initiate its concomitant cyclocondensation to produce 4(a–i) in high yield and purity. 1. Introduction Exploration of synthetic processes that lead to the development of small molecules of medicinal interest by telescoping the multicomponent operations into a single step or resorting to a process such as domino reactions is a rapidly emerging subject in medicinal chemistry. Ever since Koch et al. [1] carried out a quantitative analysis of physiologically active natural product scaffolds and showed that ones with two or three rings were most often found in bioactive natural products, the interest on various facets of the chemistry of small molecules has expanded exponentially thereafter. Benzodiazepines and their analogues have been recognized recently to belong to the class of privileged heterocyclic structures, [2–5] by virtue of their ability to form ligands to a number of functionally and structurally discrete biological receptors [6–13]. This property stimulated chemists to utilize their potential in the design and development of molecular probes for biological evaluations. Ubiquitous presence of this nucleus in the psychopharmacologically active agents and in molecules active against HIV infection, for example, TIBO (1) [14–17] and FDA approved dipyrido diazepine analogue nevirapine (2) [18–24] in Figure 1 provided an impetus for an enormous research effort to be directed towards the development of their structural analogues of medicinal importance [25, 26]. Figure 1 2. Results and Discussion This communication reports the application of a novel domino process for an easy access of the privileged nucleus of 5-carbomethoxy substituted 1,4-benzodiazepin-2-ones 4(a–i) from the ring expansion of 1-chloroacetylisatins 2(a–i), initiated by hexamethyldisilazane under the influence of n-butyl lithium. N-Butyl lithium formed an obvious choice since it has been used as a catalyst in amination of active alkyl halides with
References
[1]
M. A. Koch, A. Schuffenhauer, M. Scheck et al., “Charting biologically relevant chemical space: a structural classification of natural products (SCONP),” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 48, pp. 17272–17277, 2005.
[2]
W. Nawroca, B. Sztuba, A. Opolski, J. Wietrzk, M. W. Kowalska, and T. Glowiak, “Synthesis and antiproliferative activity in vitro of novel 1,5-benzodiazepines. Part II,” Archive der Pharmazie-Pharmaceutical and Medicinal Chemistry, vol. 334, no. 1, pp. 3–10, 2000.
[3]
B. E. Evans, K. E. Rittle, M. G. Bock et al., “Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists,” Journal of Medicinal Chemistry, vol. 31, no. 12, pp. 2235–2246, 1988.
[4]
R. Yarchoan, H. Mitsuya, R. V. Thomas, et al., “In vivo activity against HIV and favorable toxicity profile of 2′,3′-dideoxyinosine,” Science, vol. 245, no. 4916, pp. 412–415, 1989.
[5]
J. R. Lokensgard, C. C. Chao, G. Gekker, S. Hu, and P. K. Peterson, “Benzodiazepines, glia, and HIV-1 neuropathogenesis,” Molecular Neurobiology, vol. 18, no. 1, pp. 23–33, 1998.
[6]
J. Poupaert, P. Carato, E. Colacino, and S. Yous, “2(3H)-benzoxazolone and bioisosters as “privileged scaffold” in the design of pharmacological probes,” Current Medicinal Chemistry, vol. 12, no. 7, pp. 877–885, 2005.
[7]
D. J. Triggle, “1,4-dihydropyridines as calcium channel ligands and privileged structures,” Cellular and Molecular Neurobiology, vol. 23, no. 3, pp. 293–303, 2003.
[8]
R. W. DeSimone, K. S. Currie, S. A. Mitchell, J. W. Darrow, and D. A. Pippin, “Privileged structures: applications in drug discovery,” Combinatorial Chemistry and High Throughput Screening, vol. 7, no. 5, pp. 473–493, 2004.
[9]
A. A. Patchett and R. P. Nargund, “Chapter 26. Privileged structures: an update,” Annual Reports in Medicinal Chemistry, vol. 35, pp. 289–298, 2000.
[10]
J. Yang, Q. Dang, J. Liu, Z. Wei, J. Wu, and X. Bai, “Preparation of a fully substituted purine library,” Journal of Combinatorial Chemistry, vol. 7, no. 3, pp. 474–482, 2005.
[11]
J. Liu, Q. Dang, Z. Wei, H. Zhang, and X. Bai, “Parallel solution-phase synthesis of a 2,6,8,9-tetrasubstituted purine library via a sulfur intermediate,” Journal of Combinatorial Chemistry, vol. 7, no. 4, pp. 627–636, 2005.
[12]
Q. Dang and J. E. Gomez-Galeno, “An efficient synthesis of pyrrolo[2,3-d]pyrimidines via inverse electron demand Diels-Alder reactions of 2-amino-4-cyanopyrroles with 1,3,5-triazines,” Journal of Organic Chemistry, vol. 67, no. 24, pp. 8703–8705, 2002.
[13]
P. Bhuyan, R. C. Boruah, and J. S. Sandhu, “Studies on uracils. 10. A facile one-pot synthesis of pyrido[2,3-d]- and pyrazolo[3,4-d]pyrimidines,” Journal of Organic Chemistry, vol. 55, no. 2, pp. 568–571, 1990.
[14]
R. H. Smith Jr., W. L. Jorgen, J. Tirado-Rives, et al., “Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method,” Journal of Medicinal Chemistry, vol. 41, no. 26, pp. 5272–5286, 1998.
[15]
B. A. Roberte, K. Andries, J. Desayter et al., “Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives,” Nature, vol. 343, no. 6257, pp. 470–474, 1990.
[16]
H. J. Breslin, M. J. Kukla, T. Kromis et al., “Synthesis and anti-HIV activity of 1,3,4,5-tetrahydro-2H-1,4- benzodiazepin-2-one (TBO) derivatives. Truncated 4,5,6,7-tetrahydro-5- methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-ones (TIBO) analogues,” Bioorganic and Medicinal Chemistry, vol. 7, no. 11, pp. 2427–2436, 1999.
[17]
W. Ho, M. J. Kukla, H. J. Breslin et al., “Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 4,” Journal of Medicinal Chemistry, vol. 38, no. 5, pp. 794–802, 1995.
[18]
B. D. Puodziunaite, R. Janciene, L. Kosychova, and Z. Stumbreviciute, “On the synthetic way to novel peri-annelated imidazo[1,5]benzodiazepinones as the potent non-nucleoside reverse transcriptase inhibitors,” Arkivoc, vol. 2000, no. 4, pp. 512–522, 2000.
[19]
M. D. Braccio, G. Grossi, G. Roma, L. Vargiu, M. Mura, and M. E. Marongiu, “1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues,” European Journal of Medicinal Chemistry, vol. 36, no. 11-12, pp. 935–949, 2001.
[20]
A. Kamal, M. V. Rao, N. Laxman, G. Ramesh, and G. S. Reddy, “Recent developments in the design, synthesis and structure-activity relationship studies of pyrrolo[2,1-c][1,4]benzodiazepines as DNA-interactive antitumour antibiotics,” Current Medicinal Chemistry—Anti-Cancer Agents, vol. 2, no. 2, pp. 215–254, 2002.
[21]
P. Sharma, B. Vashistha, R. Tygai et al., “Application of microwave induced Delepine reaction to the facile one pot synthesis of 7-substituted 1,3-dihydro-2H-[1,4]-benzodiazepin-2-one-5-methyl carboxylates from the corresponding 1-chloroacetylisatins,” International Journal of Chemical Sciences, vol. 8, no. 1, 2010.
[22]
A. Singh, R. Sirohi, S. Shastri, and D. Kishore, “A facile one-pot synthesis of 7-substituted-5-methoxycarbonyl-1H-2, 3-dihydro-1, 4-benzodiazepin-2-ones from 5-substituted- -chloroacetyl isatins,” Indian Journal of Chemistry B, vol. 42B, no. 12, pp. 3124–3127, 2003.
[23]
P. D. Popp, “The chemistry of isatin,” in Advances in Heterocyclic Chemistry, vol. 18, pp. 1–58, 1975.
[24]
M. Pal, N. K. Sharma, Priyanka, and K. K. Jha, “Synthetic and biological multiplicity of isatin: a review,” Journal of Advanced Scientific Research, vol. 2, no. 2, pp. 35–44, 2011.
[25]
N. Blazevic, D. Kolbah, B. Belin, V. Sunjic, and F. Kajfez, “Hexamethylenetetramine, “A versatile reagent in organic synthesis”,” Synthesis, pp. 167–176, 1979.
[26]
B. Rigoa, P. Caulieza, D. Fasseurb, and D. Couturierb, “Reaction of hexamethyldisilazane with diacylhydrazines: an easy 1,3,4-oxadiazole synthesis,” Synthetic Communications, vol. 16, no. 13, pp. 1665–1669, 1986.
[27]
M. Ogata and H. Matsumoto, “A convenient synthesis of 5-substituted 1,3-dihydro-2H-1,4-benzodiazepine-2-ones,” Chemistry and Industry, p. 1067, 1976.
[28]
H. Fujishima, H. Takeshita, S. Suzuki, M. Toyota, and M. Ihara, “Hexamethyldisilazanes mediated one-pot intramolecular Michael addition-olefination reactions leading to ejvo-olefinated bicyclo[6.4.0]dodecanes,” Journal of the Chemical Society, Perkin Transactions 1, no. 18, pp. 2609–2616, 1999.
