Novel applications of ethyl glyoxalate with the Ugi MCR

Tetrahedron Letters

Volumn 40, Issue 29, 1999, Pages 5295-5299

  Hulme, Christopher ^a   Cherrier, M P ^a  

^a SANOFI   (France)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BENZODIAZEPINE 2,5 DIONE; BENZODIAZEPINE DERIVATIVE; DIHYDROQUINOXALINONE; GLYOXAL DERIVATIVE; GLYOXYLIC ACID ETHYL ESTER; KETOPIPERAZINE; PIPERAZINE DERIVATIVE; PIPERAZINEDIONE; QUINOXALINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL REACTION; CYCLIZATION; REACTION ANALYSIS;

EID: 0033575465     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(99)00960-0     Document Type: Article

References (31)

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2. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. (b) Ugi, I.; Steinbruckner, C. Chem Ber. 1961, 94, 734. (c) Ugi, I.; Domling, A.; Horl, W. Endeavor 1994, 18, 115.
3. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. (b) Ugi, I.; Steinbruckner, C. Chem Ber. 1961, 94, 734. (c) Ugi, I.; Domling, A.; Horl, W. Endeavor 1994, 18, 115.
4. Passerini, M. Gazz. Chim. Ital. 1921, 57, 126.
5. Gokel, G.; Ludke, G.; Ugi, I. Isonitrile Chemistry; Ugi, I., Ed.; Academic Press: New York, 1971; 145.
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7. (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635. (b) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. Engl. 1998, 37, 2234. (c) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis 1994, 672. (d) Park, S.-J.; Keum, G.; Kang, S.-B.; Koh, H.-Y.; Kim, Y. Tetrahedron Lett. 1998, 39, 7109.
8. (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635. (b) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. Engl. 1998, 37, 2234. (c) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis 1994, 672. (d) Park, S.-J.; Keum, G.; Kang, S.-B.; Koh, H.-Y.; Kim, Y. Tetrahedron Lett. 1998, 39, 7109.
9. (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39, 3635. (b) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. Engl. 1998, 37, 2234. (c) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis 1994, 672. (d) Park, S.-J.; Keum, G.; Kang, S.-B.; Koh, H.-Y.; Kim, Y. Tetrahedron Lett. 1998, 39, 7109.
10. Domling, A. Combinatorial Chemistry and High Throughput Screening 1998, 1, 1.
11. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
12. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
13. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
14. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
15. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
16. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
17. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
18. (a) Hulme, C.; Tang, S.-Y; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem. 1998, 63, 8021. (b) Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047. (c) Hulme, C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227. (d) Hulme, C.; Morrissette, M.; Volz, F.; Burns, C. Tetrahedron Lett. 1998, 39, 1113. (e) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935. (f) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842. g) Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65. (g) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
19. (a) Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146. (b) Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390. (c) Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res. 1986, 385, 74. (d) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. (e) Cho, N. S.; Song, K. Y; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807.
20. (a) Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146. (b) Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390. (c) Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res. 1986, 385, 74. (d) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. (e) Cho, N. S.; Song, K. Y; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807.
21. (a) Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146. (b) Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390. (c) Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res. 1986, 385, 74. (d) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. (e) Cho, N. S.; Song, K. Y; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807.
22. (a) Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146. (b) Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390. (c) Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res. 1986, 385, 74. (d) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. (e) Cho, N. S.; Song, K. Y; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807.
23. (a) Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa, S.; Ogawa, Y. Pharm. Res. 1997, 14, 1146. (b) Wright, H. B.; Martin, D. L. J. Med. Chem. 1968, 11, 390. (c) Piercey, M. F.; Moon, M. W.; Blinn, J. R. Brain Res. 1986, 385, 74. (d) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077. (e) Cho, N. S.; Song, K. Y; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807.
24. N-Boc anthranilic acids are readily accessible in multi-gram quantities via the synthetic route shown below from the corresponding anthranilic acid or isatin. N-Boc diamines are readily available as described in: Krapcho, A. P.; Maresh, M. J.; Lunn, J. Synth. Commun. 1993, 23, 2443.
25. (formula presented) MP-carbonate (Argonaut™ Technologies) was used to facilitate cyclization in the ketopiperazine series.
26. 3CN to 100% over 5 min. HPLC was interfaced with APCI techniques.
27. Note: during the preparation of this manuscript a similar one-pot procedure to this class of molecule was reported: Ugi, I.; Zychlinski, A. V. Heterocycles 1998, 49, 29.
28. Stoichiometric amounts (6.2 ml) of 0.1 M methanolic solutions of the three supporting Ugi components and ethyl glyoxalate (7.75 ml) were combined and stirred at reflux overnight. The solvent was evaporated in vacuo and crude Ugi product dried under high vacuum. A 10% solution of AcCl in MeOH (25 ml) or a 10% solution of TFA (trifluoroacetic acid) in dichloroethane (25 ml) was added to the crude material and stirred at room temperature overnight. The solvent was evaporated in vacuo. The crude material was pre-adsorbed onto flash silica and purified by flash column chromatography (EtOAc:hexane, 1:4) to yield the desired product, 11, (192 mg, 71%) as a white solid.
29. In a typical procedure, equal amounts (0.1 ml) of 0.1 M solutions in methanol of the 4 components are employed generating a theoretical 10 μmol of final product. Reagents were dispensed into a 96-well plate using either a Tom-tech™ or Rapid Plate™ 96-well dispenser. The deprotection/cyclization steps were performed using either a 10% solution of acetyl chloride in methanol or a 10% solution of TFA in dichloroethane. Evaporations were performed at 65°C in a SAVANT™ evaporator.
30. (a) Boojamara, C. G.; Burow, K. M.; Ellman, J. A. J. Org. Chem. 1995, 60, 5742. (b) Goff, D. A.; Zuckermann, R. N. J Org. Chem. 1995, 60, 5744.
31. (a) Boojamara, C. G.; Burow, K. M.; Ellman, J. A. J. Org. Chem. 1995, 60, 5742. (b) Goff, D. A.; Zuckermann, R. N. J Org. Chem. 1995, 60, 5744.