Four-Component Synthesis of Indazole through Ugi-Azide Coupling

Abstract

ortho-Nitrobenzaldehyde and trimethylsilyl azide were used in a Ugi-Cadogan cascade towards tetrazolyl indazoles. After the Ugi step, the intermediate tetrazoles were not purified but directly heated with triethyl phosphite to form the final indazoles.

Key words

Ugi - tetrazole - phosphite - cadogan - indazole

References and Notes

• For reviews concerning Ugi couplings, see:
• 1a Zhu J. Eur. J. Org. Chem.  2003,  1133 
• 1b Ugi I. Werner B. Dömling A. Molecules  2003,  8:  53 
• 1c Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
• 1d Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J.  2000,  6:  3321 
• 1e Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 1f Dömling A. Chem. Rev.  2006,  106:  17 
• 1g El Kaïm L. Grimaud L. Tetrahedron  2009,  65:  2153 
• For a selection of studies involving Ugi-Smiles couplings, see:
• 2a El Kaïm L. Grimaud L. Oble J. Angew. Chem. Int. Ed.  2005,  44:  7961 
• 2b El Kaïm L. Gizolme M. Grimaud L. Oble J. J. Org. Chem.  2007,  72:  4169 
• 2c El Kaïm L. Grimaud L. Gizzi M. Org. Lett.  2008,  10:  3417 
• 2d Coffinier D. El Kaïm L. Grimaud L. Org. Lett.  2009,  11:  995 
• 2e El Kaïm L. Grimaud L. Wagschal S.
  J. Org. Chem.  2010,  75:  5343 
• 2f El Kaïm L. Grimaud L. Wagschal S. Chem. Commun.  2011,  47:  1887 
• 3 El Kaim L. Grimaud L. Purumandla SR. Eur. J. Org. Chem.  2011,  6177 
• For reviews on the reaction of phosphites with nitroarenes, see:
• 4a Cadogan JIG. Acc. Chem. Res.  1972,  5:  303 
• 4b Söderberg BCG. Curr. Org. Chem.  2000,  4:  727 
• For a selection involving N-N bond formation, see:
• 4c Cadogan JIG. Cameron-Wood M. Mackie RK. Searle RJG. J. Chem. Soc.  1965,  4831 
• 4d Nyffenegger C. Pasquinet E. Suzenet F. Poullain D. Jarry C. Leger J.-M. Guillaumet G. Tetrahedron  2008,  64:  9567 
• 5a Ugi I. Angew. Chem.  1960,  72:  639 
• 5b Ugi I. Steinbrückner C. Chem. Ber.  1961,  94:  734 
• 5c

  See also reviews in ref. 1.

• 6a Paal C. Fritzweiler E. Ber.  1892,  25:  3590 
• 6b Kumar R. Maulik PR. Kundu B. Org. Lett.  2006,  8:  1525 
• 6c Frontana-Uribe BA. Moinet C. Acta Chem. Scand.  1999,  53:  814 
• 6d Reddy VRK. Reddy SN. Ratnam CV. Synth. Commun.  1991,  21:  49 
• 6e Stanley AL. Stanford SP. J. Heteroatom. Chem.  1994,  31:  1399 
• 7a Johnston D. Smith DM. Shepherd T. Thompson D. J. Chem. Soc., Perkin Trans. 1  1987,  495 
• 7b Avila B. Solano DM. Haddadin MJ. Kurth MJ. Org Lett.  2011,  13:  1060 
• For a selection of recent reports on bioactive indazoles, see:
• 9a Clutterbuck LA. Posada CG. Visintin C. Riddall DR. Lancaster B. Gane PJ. Garthwaite J. Selwood DL. J. Med. Chem.  2009,  52:  2694 
• 9b Jones P. Altamura S. Boueres J. Ferrigno F. Fonsi M. Giomini C. Lamartina S. Monteagudo E. Ontoria JM. Orsale MV. Palumbi MC. Pesci S. Roscilli G. Scarpelli R. Schultz-Fademrecht C. Toniatti C. Rowley M. J. Med. Chem.  2009,  52:  7170 
• 9c Qian S. Cao J. Yan Y. Sun M. Zhu H. Hu Y. He Q. Yang B. Mol. Cell. Biochem.  2010,  345:  13 
• 9d Akritopoulou-Zanze I. Wakefield BD. Gasiecki A. Kalvin D. Johnson EF. Kovar P. Djuric SW. Bioorg. Med. Chem. Lett.  2011,  21:  1480 
• 10a Schmidt A. Beutler A. Snovydovych B. Eur. J. Org. Chem.  2008,  4063 
• 10b Kumar MR. Park A. Park N. Lee S. Org. Lett.  2011,  13:  3542 
• 10c Barluenga J. Aznar F. Palomero MA. Chem. Eur. J.  2001,  7:  5318 
• 10d

  See ref. 8d.

8

General Procedure for the Synthesis of Indazoles: To a 3 M solution of o-nitrobenzaldehyde (1 mmol) in MeOH were added successively amine (1.0 equiv), isocyanide (1.0 equiv) and trimethylsilyl azide (1.0 equiv). The resulting mixture was stirred at r.t. overnight. After removal of the excess MeOH, the crude tetrazole product was used as such for the next step. A 2 M solution of tetrazole (1 mmol) and triethyl phosphite (5.0 equiv) in DMF was heated at 140 ˚C for 10 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel.
3-(1-Cyclohexyl-1 H -tetrazol-5-yl)-2-propyl-2 H -indazole (2a): Prepared on a 1-mmol scale according to the general procedure, 2a was isolated as a yellow solid in 62% yield; mp 110-111 ˚C; R _f 0.3 (petroleum ether-Et₂O, 20:80). ^¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.6 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 4.48 (t, J = 7.3 Hz, 2 H), 4.19-4.29 (m, 1 H), 2.05-2.18 (m, 2 H), 1.82-2.03 (m, 6 H), 1.63-1.72 (m, 1 H), 1.15-1.33 (m, 3 H), 0.88 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 148.1, 145.5, 126.5, 124.4, 122.1, 118.7, 117.5, 117.4, 58.7, 53.7, 33.4, 25.1, 24.5, 24.1, 11.0. IR (thin film): 2937, 2857, 1574, 1500, 1454, 1411, 1354, 1095, 1005 cm^-¹. HRMS: m/z calcd for C₁₇H₂₂N₆: 310.1906; found: 310.1901.