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

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

<A NAME="RU06804ST-7A">7a</A> Wolf C. Lerebours R. J. Org. Chem.  2003,  68:  7077 

<A NAME="RU06804ST-7B">7b</A> Kobayashi K. Yoneda K. Mano M. Morikawa O. Konishi H. Chem. Lett.  2003,  76 

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<A NAME="RU06804ST-7E">7e</A> 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:

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<A NAME="RU06804ST-7G">7g</A> Curran DP. Du W. Org. Lett.  2002,  4:  3215 

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<A NAME="RU06804ST-8A">8a</A> Smart BE. In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum; New York: 1994.  Chap. 3.

<A NAME="RU06804ST-8B">8b</A> Lee VJ. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  Chap. 1.2.

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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:

<A NAME="RU06804ST-11A">11a</A> Fukuyama T. Chen X. Peng G. J. Am. Chem. Soc.  1994,  116:  3127 

<A NAME="RU06804ST-11B">11b</A> Tokuyama H. Fukuyama T. Chem. Rec.  2002,  2:  37 

<A NAME="RU06804ST-12">12</A>

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].

<A NAME="RU06804ST-13">13</A> 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 

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<A NAME="RU06804ST-14B">14b</A> Fort Y. Becker S. Caubère P. Tetrahedron  1994,  50:  11893 

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

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

<A NAME="RU06804ST-15D">15d</A> Nakajima M. Saito M. Shiro M. Hashimoto S. J. Am. Chem. Soc.  1998,  120:  6419 

<A NAME="RU06804ST-16">16</A>

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.

<A NAME="RU06804ST-17">17</A>

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.

<A NAME="RU06804ST-18">18</A>

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.

<A NAME="RU06804ST-19">19</A>

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).

<A NAME="RU06804ST-20">20</A> Shimano M. Meyers AI. Tetrahedron Lett.  1994,  35:  7727