A New Focused Microwave Approach to the Synthesis of Amino-Substituted Pyrroloisoquinolines and Pyrroloquinolines via a Sequential Multi-Component Coupling Process

Abstract

A multi-component reaction has been developed allowing direct access to pyrroloisoquinolines and pyrroloquinolines with new, electron-rich substitution patterns. The synthesised amino-substituted heterocyclic compounds and intermediates involved in their formation represent novel compounds. Focused microwave irradiation was used extensively to allow simple access to a wide temperature range using low boiling point solvents.

Key words

focused microwave irradiation - fused-ring systems - heterocycles - multi-component reactions - pyrroloisoquinolines - solid-supported reagents

References

• 1 Gundersen L.-L. Negussie AH. Rise F. Ostby OB. Arch. Pharm. (Weinheim, Ger.)  2003,  336:  191 
• 2 Nasir AI. Gundersen L.-L. Rise F. Antonsen O. Kristensen T. Langhelle B. Bast A. Custers I. Haenen GRMM. Wikstrom H. Bioorg. Med. Chem. Lett.  1998,  8:  1829 
• 3 Gundersen L.-L. Malterud KE. Negussie AH. Rise F. Teklu S. Ostby OB. Bioorg. Med. Chem.  2003,  11:  5409 
• 4 Hagishita S. Yamada M. Shirahase K. Okada T. Murakami Y. Ito Y. Matsuura T. Wada M. Kato T. Ueno M. Chikazawa Y. Yamada K. Ono T. Teshirogi I. Ohtani M. J. Med. Chem.  1996,  39:  3636 
• 5 Okada S, Sawada K, Kuroda A, Watanabe S, and Tanaka H. inventors; Eur. Patent Appl. EP  519353.  ; Chem. Abstr. 1993, 118, 212886
• 7 Ono M, Przewloka T, James D, Chimmanamada D, Lu R, Nagai M, Koya K, and Sun L. inventors; US Patent Appl. US  2003204090.  ; Chem. Abstr. 2003, 139, 350631
• 8 Sabb AL, and Vogel RL. inventors; US Patent Appl. US  2006094752.  ; Chem. Abstr. 2006, 144, 450610
• 9 Harrell WB. Doerge RF. J. Pharm. Sci.  1967,  56:  225 
• 10a Rosseels G. Peiren M. Inion H. Deray E. Prost M. Descamps M. Bauthier J. Richard J. Tornay C. Colot M. Claviere M. Eur. J. Med. Chem.  1982,  17:  581 
• 10b Gubin J, Descamps M, Chatelain P, and Nisato D. inventors; Eur. Patent Appl. EP  235111.  ; Chem. Abstr. 1988, 109, 6405
• 11 Hynd G, Ray NC, Finch H, Middlemiss D, Cramp MC, Blaney PM, Williams K, Griffon Y, Harrison TK, and Crackett P. inventors; PCT Int. Appl. WO  2006136859.  ; Chem. Abstr. 2006, 146, 100556
• 12 Nayler JHC. inventors; Brit. Patent Appl. GB  1174124.  ; Chem. Abstr. 1970, 72, 55285
• 13a Gubin J. de Vogelaer H. Inion H. Houben C. Lucchetti J. Mahaux J. Rosseels G. Peiren M. Clinet M. Polster P. J. Med. Chem.  1993,  36:  1425 
• 13b Glasser SP. Singh SN. Humen DP. J. Clin. Pharm.  1997,  37:  53 
• 13c Gubin J. Lucchetti J. Mahaux J. Nisato D. Rosseels G. Clinet M. Polster P. Chatelain P. J. Med. Chem.  1992,  35:  981 
• 13d Gupta SP. Mathur AN. Nagappa AN. Kumar D. Kumaran S. Eur. J. Med. Chem.  2003,  38:  867 
• 14 King FD, Gaster LM, and Joiner GF. inventors; PCT Int. Patent Appl. WO  9308187.  ; Chem. Abstr. 1993, 119, 160281
• 15 Chai W. Breitenbucher JG. Kwok A. Li X. Wong V. Carruthers NI. Lovenberg TW. Mazur C. Wilson SJ. Axe FU. Jones TK. Bioorg. Med. Chem. Lett.  2003,  13:  1767 
• 16 Ostby OB. Dalhus B. Gundersen L.-L. Rise F. Bast A. Haenen GRMM. Eur. J. Org. Chem.  2000,  3763 
• 17a Inagaki Y, and Kubo T. inventors; Jpn. Patent Appl. JP  03074471.  ; Chem. Abstr. 1991, 115, 138212
• 17b Naef R. Dyes Pigm.  1983,  4:  101 
• 17c Weidner CH. Wadsworth DH. Bender SL. Beltman DJ. J. Org. Chem.  1989,  54:  3660 
• 17d Cuny GD. inventors; Eur. Patent Appl. EP  780443.  ; Chem. Abstr. 1997, 127, 110293
• 18 Wheeler JW. inventors; Eur. Patent Appl.  EP161789.  ; Chem. Abstr. 1986, 104, 170108
• For reviews, see:
• 19a Uchida T. Matsumoto K. Synthesis  1976,  209 
• 19b Swinbourne FJ. Hunt JH. Klinkert G. Adv. Heterocycl. Chem.  1978,  23:  103 
• 19c Flitsch W. In Comprehensive Heterocyclic Chemistry   Vol. 4:  Katritzky AK. Rees CW. Pergamon; Oxford: 1984.  p.443 
• 19d Flitsch W. In Comprehensive Heterocyclic Chemistry II   Vol. 8:  Katritzky AK. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.237 
• 19e Shipman M. In Science of Synthesis   Vol. 10:  Thomas EJ. Thieme; Stuttgart: 2001.  p.745 
• For examples:
• 20a Pauls H. Kroehnke F. Chem. Ber.  1977,  110:  1294 
• 20b Kobayashi M. Tanabe M. Kondo K. Aoyama T. Tetrahedron Lett.  2006,  47:  1469 
• 20c Ohsawa A. Abe Y. Igeta H. Chem. Lett.  1979,  241 
• 20d Smith CR. Bunnelle EM. Rhodes AJ. Sarpong R. Org. Lett.  2007,  9:  1169 
• 21a Baxendale IR. Lee A.-L. Ley SV. Synlett  2001,  1482 
• 21b Baxendale IR. Davidson TD. Ley SV. Perni RH. Heterocycles  2003,  60:  2707 
• 21c Siu J. Baxendale IR. Ley SV. Org. Biomol. Chem.  2004,  2:  160 
• 21d Baxendale IR. Ley SV. Martinelli M. Tetrahedron  2005,  61:  5323 
• 21e Baxendale IR. Ley SV. J. Comb. Chem.  2005,  7:  483 
• 21f Saaby S. Baxendale IR. Ley SV. Org. Biomol. Chem.  2005,  3:  3365 
• 21g Smith CJ. Iglesias-Sigüenza FJ. Baxendale IR. Ley SV. Org. Biomol. Chem.  2007,  5:  2758 
• 22 Alvarez-Builla J. Gandasegui MT. Novella JL. Otero S. Quintanilla MG. J. Chem. Res., Synop.  1987,  63 
• 23 For a review, see: Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 24a Ley SV. Taylor SJ. Bioorg. Med. Chem. Lett.  2002,  12:  1813 
• 24b Ley SV. Leach AG. Storer RI. J. Chem. Soc., Perkin Trans. 1  2001,  358 
• 25 Berthet J.-C. Nierlich M. Ephritikhine M. Eur. J. Org. Chem.  2002,  375 
• 26 Baldwin JE. J. Chem. Soc., Chem. Commun.  1976,  734 
• 28a Roth M. Dubs P. Goetschi E. Eschenmoser A. Helv. Chim. Acta  1971,  54:  710 
• 28b Michael JP. de Koning CB. van der Westhuyzen CW. Fernandes MA. J. Chem. Soc., Perkin Trans. 1  2001,  2055 
• 29 Boyer JH. Ramakrishnan VT. J. Org. Chem.  1972,  37:  1360 
• 32 Fraser M. McKenzie S. Reid DH. J. Chem. Soc. B  1966,  44 
• 34a Cohen BJ. Kraus MA. Patchornik A. J. Am. Chem. Soc.  1977,  99:  4165 
• 34b For a review see: Solinas A. Taddei M. Synthesis  2007,  2409 
• 35 Kappe CO. Dallinger D. Nat. Rev. Drug Discovery  2006,  5:  51 ; and references cited therein

6

Sun L., Koya K., Li H., Przewloka T., James D., Chen S., Xia Z., Liang G., Tatsuta N., Wu Y., Zhou D., Korbut T., Du Z., Ono M.; Abstracts of Papers, 228th ACS National Meeting; Philadelphia PA, August 22-26, 2004 ; American Chemical Society: Washington DC, 2004.

27

The reactions showed excellent conversions, but isolation of the final compounds proved problematic.

30

Diethylaminomethyl polystyrene (3.2 mmol g^-1) is commercially available from Fluka (website:
http://www.fluka.com).

31

Crystallised from CH₂Cl₂-hexane.

33

PS-SO₃H is a macroporous polymer-supported sulfonic acid (4.45 mmol g^-1) available from Biotage (website:
http://www.biotage.com).

36

Biotage (website: http://www.biotage.com).

37

Varian, Inc. (website: http://www.varianinc.com).

38

Crystallographic data for 6d have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 678909 (Authors: J. E. Davies, M. D. Hopkin, S. V. Ley). Copies of the data may be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: [phone] or
e-mail: [e-mail]).

39

Crystallographic data for 10da have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 678908 (Authors: J. E. Davies, M. D. Hopkin, S. V. Ley). Copies of the data may be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: [phone] or
e-mail: [e-mail]).