C-C Bond Formation between Isocyanide and β,β-Difluoroalkene Moieties via Electron Transfer: Fluorinated Quinoline and Biquinoline Syntheses

Abstract

o-Isocyano-substituted β,β-difluorostyrenes are reduced with tributylstannyllithium to the anionic species, which in turn undergo intramolecular substitution of the isocyano carbon for the vinylic fluorine, followed by reaction with electrophiles or self-coupling to afford 2,4-disubstituted 3-fluoroquinolines or 4,4′-di­substituted 3,3′-difluoro-2,2′-biquinolines, respectively, in good yield.

isocyanides - fluorinated alkenes - electron transfer - cyclizations - fluorinated quinolines

References

1 Yates FS. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon; New York: 1984.  Chap. 2.09.

For reviews, see:

2a Silvester MJ. Adv. Heterocycl. Chem.  1994,  1:  59 

2b Silvester MJ. Aldrichimica Acta  1991,  24:  31 

2c Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum; New York: 1994. 

3 Hirano Y. Uehara M. Saeki K. Kato T. Takahashi K. Mizutani T. J. Health Sci.  2002,  48:  118 ; and references therein

4 Kato T. Saeki K. Kawazoe Y. Hakura A. Mutat. Res.  1999,  439:  149 ; and references therein

5a Mongin F. Mojovic L. Guillamet B. Trécourt F. Quéguiner G. J. Org. Chem.  2002,  67:  8991 

5b Arzel E. Rocca P. Marsais F. Godard A. Quéguiner G. Tetrahedron  1999,  55:  12149 

For the synthesis of fluoroquinolines, see:

6a Wada Y. Mori T. Ichikawa J. Chem. Lett.  2003,  1000 

6b Ichikawa J. Wada Y. Miyazaki H. Mori T. Kuroki H. Org. Lett.  2003,  5:  1455 

6c Chambers RD. Parsons M. Sandford G. Skinner CJ. Atherton MJ. Moilliet JS. J. Chem. Soc., Perkin Trans. 1  1999,  803 ; and references therein

6d Strekowski L. Kiselyov AS. Hojjat M. J. Org. Chem.  1994,  59:  5886 

6e Shi G.-Q. Takagishi S. Schlosser M. Tetrahedron  1994,  50:  1129 

For the synthesis of 2,4-disubstituted quinolines, see:

7a Wolf C. Lerebours R. J. Org. Chem.  2003,  68:  7077 

7b Kobayashi K. Yoneda K. Mano M. Morikawa O. Konishi H. Chem. Lett.  2003,  76 

7c Huma HZS. Halder R. Kalra SS. Das J. Iqbal J. Tetrahedron Lett.  2002,  43:  6485 

See also for recent reports on the construction of quinoline framework:

7d Kim JN. Chung YM. Im YJ. Tetrahedron Lett.  2002,  43:  6209 

7e Cho CS. Oh BH. Kim JS. Kim T.-J. Shim SC. Chem. Commun.  2000,  1885 ; and references therein

For the synthesis of quinolines from aryl isocyanides, see the following and references cited therein:

7f Kobayashi K. Yoneda K. Mizumoto T. Umakoshi H. Morikawa O. Konishi H. Tetrahedron Lett.  2003,  44:  473 

7g Curran DP. Du W. Org. Lett.  2002,  4:  3215 

7h Suginome M. Fukuda T. Ito Y. Org. Lett.  1999,  1:  1977 

8a Smart BE. In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum; New York: 1994.  Chap. 3.

8b Lee VJ. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  Chap. 1.2.

9a Gros P. Fort Y. Eur. J. Org. Chem.  2002,  3375 ; and references therein

9b Gros P. Fort Y. Caubère P. J. Chem. Soc., Perkin Trans. 1  1997,  3597 

10 McCombie SW. In Comprehensive Organic Synthesis   Vol. 8:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  Chap. 4.2.

Under free radical conditions with n-Bu₃SnH or EtSH, this type of C-C bond formation is well known in the Fukuyama indole synthesis. See:

11a Fukuyama T. Chen X. Peng G. J. Am. Chem. Soc.  1994,  116:  3127 

11b Tokuyama H. Fukuyama T. Chem. Rec.  2002,  2:  37 

12

The redox potential of 1a was measured by cyclic voltam-metry. A reduction peak of 1a was observed at -2.79 V [1 mM in THF; supporting electrolyte: 0.1 M n-Bu₄NClO₄; working electrode: glassy carbon; counter electrode: platinum wire; reference electrode: Ag/AgCl (E_1/2 (ferrocene/ferricinium) = +0.26 V) at 25 °C; scan rate: 100 mVs^-1].

13 The cyclization similarly proceeded even in the dark. For electron transfer from triorganostannyl anions, see: Yammal CC. Podesta JC. Rossi RA. J. Org. Chem.  1992,  57:  5720 

For recent reports on biquinoline synthesis, see:

14a Uchida Y. Echikawa N. Oae S. Heteroat. Chem.  1994,  5:  409 

14b Fort Y. Becker S. Caubère P. Tetrahedron  1994,  50:  11893 

Biquinolines are widely used as bulky, chelating nitrogen ligands. See for example:

15a Bhattacharyya R. Drago RS. Abboud KA. Inorg. Chem.  1997,  36:  2913 

15b Gogoll A. Gomes J. Bergkvist M. Grennberg H. Organometallics  1995,  14:  1354 

15c Kubow SA. Marmion ME. Takeuchi KJ. Inorg. Chem.  1988,  27:  2761 

See also for a chiral 2,2′-biquinoline N,N′-dioxide as an asymmetric catalyst:

15d Nakajima M. Saito M. Shiro M. Hashimoto S. J. Am. Chem. Soc.  1998,  120:  6419 

16

4-Butyl-3-fluoroquinoline ( 4a): To a solution of (n-Bu₃Sn)₂ (0.51 mL, 1.0 mmol) in THF (3 mL) was added n-BuLi (0.64 mL, 1.59 M in hexane, 1.0 mmol) over 15 min at 0 °C. To the resulting solution was added 1a (75 mg, 0.34 mmol) in THF (3 mL) dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction was quenched with phosphate buffer (pH 7), and organic materials were extracted with Et₂O (10 mL × 3). The combined extracts were washed with brine and then dried over MgSO₄. After removal of the solvent under reduced pressure, the residue was purified by preparative TLC (hexane-EtOAc, 5:1) to give 4a (55 mg, 80%) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 0.97 (3 H, t, J = 7.4 Hz), 1.46 (2 H, tq, J = 7.4, 7.4 Hz), 1.64-1.72 (2 H, m), 3.08 (2 H, td, J = 7.8 Hz, J _HF = 1.8 Hz), 7.59 (1 H, dd, J = 8.0, 8.0 Hz), 7.66 (1 H, ddd, J = 8.0, 8.0, 0.8 Hz), 7.98 (1 H, dd, J = 8.0, 0.8 Hz), 8.11 (1 H, dd, J = 8.0, 0.8 Hz), 8.74 (1 H, d, J _HF = 1.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 22.8, 23.9 (d, J _CF = 3 Hz), 31.8, 123.5 (d, J _CF = 6 Hz), 127.2, 127.9 (d, J _CF = 3 Hz), 128.0 (d, J _CF = 4 Hz), 130.3, 131.6 (d, J _CF = 12 Hz), 141.0 (d, J _CF = 29 Hz), 145.5 (d, J _CF = 2 Hz), 154.3 (d, J _CF = 251 Hz). ¹⁹F NMR (471 MHz, CDCl₃/C₆F₆): δ_F = 28.6 (s). IR (neat): 2960, 2931, 1512, 1464, 1379, 1323, 1225, 1142, 760, 665 cm^-1. HRMS: calcd for C₁₃H₁₄NF: 203.1110 (M⁺); found: 203.1128.

17

4,4′-Dibutyl-3,3′-difluoro-2,2′-biquinoline (5a): To a solution of (n-Bu₃Sn)₂ (0.44 mL, 0.86 mmol) in THF (3 mL) was added n-BuLi (0.54 mL, 1.60 M in hexane, 0.86 mmol) over 15 min at 0 °C. The resulting solution (n-Bu₃SnLi in THF) was added to a solution of 1a (76 mg, 0.35 mmol) in THF (3 mL) over 1 h at 0 °C. The reaction mixture was stirred at r.t. for 1 h. The reaction was quenched with phosphate buffer (pH 7), and organic materials were extracted with Et₂O (10 mL × 3). The combined extracts were washed with brine and then dried over MgSO₄. After removal of the solvent under reduced pressure, the residue was purified by preparative TLC (hexane-EtOAc, 5:1) to give 5a (41 mg, 59%) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.00 (6 H, t, J = 7.5 Hz), 1.51 (4 H, tq, J = 7.5, 7.5 Hz), 1.72-1.80 (4 H, m), 3.20 (4 H, t, J = 7.8 Hz), 7.66 (2 H, ddd, J = 8.0, 8.0, 1.2 Hz), 7.72 (2 H, ddd, J = 8.0, 8.0, 1.5 Hz), 8.06 (2 H, dd, J = 8.0, 8.0 Hz), 8.31 (2 H, dd, J = 8.0, 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 13.8, 22.7, 24.1, 31.8, 123.3, 127.6, 128.2, 128.5, 130.9, 132.8 (dd, J _CF = 10, 3 Hz), 145.2 (dd, J _CF = 13, 4 Hz), 145.3, 152.9 (dd, J _CF = 256, 2 Hz). ¹⁹F NMR (471 MHz, CDCl₃/C₆F₆): δ_F = 31.0 (s). IR (neat): 2958, 2929, 2872, 1504, 1456, 1377, 1338, 1221, 1188, 1144, 762 cm^-1. HRMS: calcd for C₂₆H₂₆N₂F₂: 404.2064 (M⁺); found: 404.2057.

18

The corresponding 2-quinolyltin was not detected in the reaction mixture by ¹⁹F NMR. Over the course of the reaction, the corresponding ditin and tin hydride were produced probably via the tin radical.

19

The formation of biquinoline 5 via the reaction of 3 and 1 was confirmed as follows: When quinolyl anion 3a (R =
n-Bu), generated by the addition of 1a to n-Bu₃SnLi, was reacted with 0.8 equiv of 1b (R = Et), unsymmetrical 4-butyl-4′-ethyl-3,3′-difluoro-2,2′-biquinoline was obtained in 59% yield (based on the consumed 1b).

20 Shimano M. Meyers AI. Tetrahedron Lett.  1994,  35:  7727