RSS-Feed abonnieren
DOI: 10.1055/s-2007-968011
New Indolizine Template from the Ugi Reaction
Publikationsverlauf
Publikationsdatum:
24. Januar 2007 (online)
![](https://www.thieme-connect.de/media/synlett/200702/lookinside/thumbnails/10.1055-s-2007-968011-1.jpg)
Abstract
Ugi reactions and [3+2] cycloaddition of pyridinium salts have been associated to provide an efficient multicomponent access to indolizines. The pyridinium salts are formed by an Ugi reaction using chloroacetic acid and propargylamine followed by pyridine addition on the Ugi adduct. The coupling of these salts with aryl iodides gives directly indolizine derivatives in a Sonogashira-cycloaddition-oxidation reaction cascade.
Key words
indolizine - isocyanide - multicomponent reaction - Ugi reaction - Sonogashira coupling
- For recent reviews, see:
-
1a
Banfi L.Riva R. Org. React. 2005, 65: 1 -
1b
Zhu J. Eur. J. Org. Chem. 2003, 1133 -
1c
Ugi I.Werner B.Dömling A. Molecules 2003, 8: 53 -
1d
Hulme C.Gore V. Curr. Med. Chem. 2003, 10: 51 -
1e
Bienaymé H.Hulme C.Oddon G.Schmitt P. Chem. Eur. J. 2000, 6: 3321 -
1f
Dömling A.Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168 -
1g
Dömling A. Chem. Rev. 2006, 106: 17 -
2a
Lu K.Luo T.Xiang Z.You Z.Fathi R.Chen J.Yang Z. J. Comb. Chem. 2005, 7: 958 -
2b
Paulvannan K. J. Org. Chem. 2004, 69: 1207 -
2c
Zhang J.Jacobson A.Rusche JR.Herlihy W. J. Org. Chem. 1999, 64: 1074 -
2d
Akritopoulou-Zanze I.Gracias V.Moore JD.Djuric SW. Tetrahedron Lett. 2004, 45: 3421 -
2e
Janvier P.Bienaymé H.Zhu J. Angew. Chem. Int. Ed. 2002, 41: 4291 -
2f
Wright DL.Robotham CV.Aboud K. Tetrahedron Lett. 2002, 43: 943 -
3a
Gracias V.Moore JD.Djuric SW. Tetrahedron Lett. 2004, 45: 417 -
3b
Xiang Z.Luo T.Lu K.Cui J.Shi X.Fathi R.Chen J.Yang Z. Org. Lett. 2004, 6: 3155 -
4a
Krelaus R.Westermann B. Tetrahedron Lett. 2004, 45: 5987 -
4b
Kazmaeir U.Hebach C.Watzke A.Maier S.Mues H.Huch V. Org. Biomol. Chem. 2005, 3: 136 -
4c
Sello JK.Andreana PR.Lee D.Schreiber SL. Org. Lett. 2003, 5: 4125 -
4d
Banfi L.Basso A.Guanti G.Riva R. Tetrahedron Lett. 2003, 44: 7655 -
4e
Beck B.Larbig G.Mejat B.Magnin-Lachaux M.Picard A.Herdtweck E.Dömling A. Org. Lett. 2003, 5: 1047 -
5a
Faggi C.Marcaccini S.Pepino R.Pozo MC. Synthesis 2002, 2756 -
5b
Marcaccini S.Miliciani M.Pepino R. Tetrahedron Lett. 2005, 46: 711 -
5c
Nixey T.Tempest P.Hulme C. Tetrahedron Lett. 2002, 43: 1637 -
6a
Pourashraf M.Delair P.Rasmussen MO.Greene AE. J. Org. Chem. 2000, 65: 6966 -
6b
Cossy J.Willis C.Bellosta V.Jalmes LS. Synthesis 2002, 951 -
6c
Diederich M.Nubbemeyer U. Synthesis 1999, 286 -
6d
Chalard P.Remuson R.Mialhe YG.Gramain JC.Canet I. Tetrahedron Lett. 1999, 40: 1661 -
6e
Park SH.Kang HJ.Ko S.Park S.Chang S. Tetrahedron: Asymmetry 2001, 12: 2621 -
6f
Carroll AR.Arumugan G.Quinn RJ.Redburn J.Guymer G.Grimshaw P. J. Org. Chem. 2005, 70: 1889 -
7a
Gubin J.Lucchetti J.Mahaux J.Nisato D.Rosseels G.Clinet M.Polster P.Chatelain P. J. Med. Chem. 1992, 35: 981 -
7b
Gubin J.Vogelaer H.Inion H.Houben C.Lucchetti J.Mahaux J.Rosseels G.Peiren M.Clinet M.Polster P.Chatelain P. J. Med. Chem. 1993, 36: 1425 -
7c
Gupta SP.Mathur AN.Nagappa AN.Kumar D.Kumaran S. Eur. J. Med. Chem. 2003, 38: 867 -
7d
Olden K.Breton P.Grzegorzewski K.Yasuda Y.Gause BL. Pharmacol. Ther. 1991, 50: 285 -
7e
Ahrens PB.Ankel H. J. Biol. Chem. 1987, 262: 7575 -
7f
Sasak VW.Ordovas JM.Elbein AD.Berninger RW. Biochem. J. 1985, 232: 759 -
7g
Dennis JW. Cancer Res. 1986, 46: 5131 -
8a
Tschitschibabin AE. Ber. Dtsch. Chem. Ges. 1927, 60: 1607 -
8b
Katritzky AR.Qui G.Yang B.He HY. J. Org. Chem. 1999, 64: 7618 -
9a
Scholtz M. Ber. Dtsch. Chem. Ges. 1912, 45: 734 -
9b
Boekelheide V.Windgassen RJ. J. Am. Chem. Soc. 1959, 81: 1456 -
10a
Padwa A.Austin DJ.Precedo L.Zhi L. J. Org. Chem. 1993, 58: 1144 -
10b
Wei X.Hu Y.Li T.Hu H. J. Chem. Soc., Perkin Trans. 1 1993, 2487 -
10c
Siriwardana AI.Nakamura I.Yamamoto Y. J. Org. Chem. 2004, 69: 3202 -
10d
Acheson RM.Robinson DA. J. Chem. Soc. 1968, 1633 -
10e
Dinculescu A.Balaban TS.Balaban AT. Tetrahedron Lett. 1987, 28: 3145 -
10f
Zhang L.Liang F.Sun L.Hu Y.Hu H. Synthesis 2000, 1733 -
10g
Fang X.Wu YM.Deng J.Wang SW. Tetrahedron 2004, 60: 5487 - 11
Bora U.Saikia A.Boruah RC. Org. Lett. 2003, 5: 435 -
12a
Bedjeguelal K.Bienaymé H.Poigny S.Schmitt Ph.Tam E. QSAR Comb. Sci. 2006, 25: 504 -
12b
Tielmann P.Hoenke C. Tetrahedron Lett. 2006, 47: 261 -
12c
Goff DA. Tetrahedron Lett. 1999, 40: 8741 - For recent uses of chloroacetic acid in Ugi reactions, see:
-
13a
Marcaccini S.Pepino R.Cruz Pozo M. Tetrahedron Lett. 2001, 42: 2727 -
13b
El Kaim L.Grimaud L.Miranda LD.Vieu E. Tetrahedron Lett. 2006, 47: 8259 -
16a
Dubowchik GM.Michne JA.Zuev D. Bioorg. Med. Chem. Lett. 2004, 14: 3147 -
16b
Kang KH.Pae AN.Choi K.Cho YS.Chung BY.Lee JE.Jung SH.Koh HY.Lee H. Tetrahedron Lett. 2001, 42: 1057
References and Notes
For similar oxidations, see: ref. 10a,c and ref. 11.
15
Typical Procedure (Given for 7c, Table 1): Anisaldehyde 1a (5 mmol, 608 µL), propargylamine (1 equiv, 343 µL), chloroacetic acid (1 equiv, 472 mg) and cyclohexyl iso-cyanide 2b (1 equiv, 622 µL) were added to MeOH (5 mL) and the mixture stirred overnight at r.t. The crude product was purified by flash chromatography using CH2Cl2 to give 1.41 g of 3b (70%). To the chloro derivative 3b (3.2 mmol) in EtOH (3 mL) was added 4-picoline (2 equiv, 0.52 mL) and the mixture stirred at 50 °C for 24 h. EtOH was evaporated, the crude product (1.6 mmol) was then added to 1-iodo-4-nitrobenzene (6b, 1.1 equiv, 876 mg) in a mixture THF-i-Pr2NH (1:1, 6 mL). Then, Pd(OAc)2 (0.04 equiv, 28 mg), CuI (0.08 equiv, 48 mg) and PPh3 (0.08 equiv, 66 mg) were added and the mixture was stirred for 2 d. Extraction, evaporation and flash chromatography using Et2O-PE (50: 50) afford 590 mg of 7c (33%).
1H NMR (400 MHz, CDCl3): δ = 8.56 (d, 1 H, J = 7.1 Hz), 8.26 (d, 2 H, J = 9.1 Hz), 7.63 (br s, 1 H), 7.59 (d, 2 H, J = 9.1 Hz), 7.39 (d, 2 H, J = 8.8 Hz), 6.93 (d, 2 H, J = 8.8 Hz), 6.71 (dd, 1 H, J = 7.1, 1.5 Hz), 6.00 (s, 1 H), 5.84 (br s, 1 H), 5.06 (d, 1 H, J = 17.2 Hz), 4.13 (d, 1 H, J = 17.2 Hz), 3.90-3.84 (m, 1 H), 3.82 (s, 3 H), 2.45 (s, 3 H), 1.99-1.93 (m, 2 H), 1.74-1.69 (m, 2 H), 1.39-1.10 (m, 6 H). 13C NMR (100.6 MHz, CDCl3): δ = 169.3, 162.0, 160.1, 145.1, 142.3, 138.1, 137.7, 135.0, 130.5, 128.0, 126.9, 125.9, 124.9, 120.7, 116.8, 115.7, 114.8, 106.3, 58.5, 55.7, 49.2, 45.3, 33.3, 25.9, 25.2, 22.3. MS (DI, CI NH3): m/z = 553. HRMS: m/z calcd for C32H32N4O5: 552.2373; found: 552.2385.
Modified Procedure (Table 2): Aldehyde 1a (5 mmol), propargylamine (1 equiv), chloroacetic acid (1 equiv) and the isocyanide (1 equiv) were added to MeOH (5 mL) and the mixture stirred overnight at r.t., pyridine was then added (2 equiv) followed by stirring at 50 °C for 24 h. Addition of Et2O and filtration gave pyridinium 5 which was further treated as shown for 7c.