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Synlett 2011(16): 2311-2314  
DOI: 10.1055/s-0030-1260304
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Four-Component Synthesis of Functionalized 2,2′-Bipyridines Based on the Blaise Reaction

Paul Hommes, Phillip Jungk, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
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Publication History

Received 15 June 2011
Publication Date:
13 September 2011 (online)

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Abstract

In situ C-acylation of the Blaise intermediate - as reported by Lee and coworkers - provides α-acyl-β-enamino esters that are versatile building blocks for the preparation of N-heterocycles. The corresponding N-acylated β-ketoenamides can be employed in the synthesis of 4-hydroxypyridine derivatives. N-Acylation of the α-acyl-β-enamino esters with 2-picolyl chloride furnished β-keto­enamides, and the subsequent TMSOTf/base-promoted intramolecular condensation reaction led to 4-hydroxy-2,2′-bipyridine derivatives. Conversion into 2,2′-bipyrid-4-yl nonaflates allowed further functionalization such as palladium-catalyzed coupling reactions.

Key words

condensation - 2,2′-bipyridines - β-ketoenamides - multicomponent reaction - nonaflates - pyridines

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For a proposed mechanism, see ref. 5l.

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Representative Procedure for the N-Acylation of α-Acyl-β-enamino Esters with 2-Picolyl Chloride: Ethyl 3-oxo-2-[phenyl(picolinamido)methylene]butanoate (7a) SOCl2 (0.29 mL, 4.00 mmol) was added dropwise to a solution of 2-picolinic acid (492 mg, 4.00 mmol), and Et3N (0.55 mL, 4.00 mmol) in CH2Cl2 (13 mL) under an argon atmosphere. After addition of catalytic amounts of DMF the mixture was stirred for 4 h at r.t. A solution of α-acyl-β-enamino ester 3a (467 mg, 2.00 mmol) in CH2Cl2 (7 mL) was added at 0 ˚C. While stirring overnight the mixture was allowed to warm up to r.t. (in some cases conversion of the starting material was complete after a few hours) and sat. aq NaHCO3 solution (20 mL) was added. The layers were separated, and the aqueous layer was extracted three times with CH2Cl2 (20 mL). The combined organic layers were dried with Na2SO4, and after filtration the solvent was removed under reduced pressure. Purification of the crude product by flash chromatography (silica gel, hexane-
EtOAc = 4:1 → 2:1) afforded 590 mg (87%) of 7a (major/minor isomer ca. 3.5:1) as brownish oil. IR (ATR): 3170 (NH), 3060 (=CH), 2980, 2930 (CH), 1710 (C=O), 1650, 1550 (C=C, C=N) cm-¹. Chemical shifts are listed for the major isomer only. ¹H NMR (500 MHz, CDCl3): δ = 0.83 (t, J = 7.1 Hz, 3 H, CH3), 2.39 (s, 3 H, COCH3), 3.84 (q, J = 7.1 Hz, 2 H, OCH2), 7.33-7.44 (m, 5 H, Ph), 7.48 (ddd, J = 7.7, 4.5, 1.0 Hz, 1 H, 5′-H), 7.82 (td, J = 7.7, 1.7 Hz, 1 H, 4′-H), 8.04 (dbr, J = 7.7 Hz, 1 H, 3′-H), 8.78 (dbr, J = 4.5 Hz, 1 H, 6′-H) ppm; the NH signal could not be detected. ¹³C NMR (126 MHz, CDCl3): δ = 13.4 (q, CH3), 29.7 (q, COCH3), 61.2 (t, OCH2), 116.7 (s, CCOCH3), 123.2 (d, C-3′), 127.0 (d, C-5′), 127.5, 127.9, 129.3, 134.5 (3 d, s, Ph), 137.4 (d, C-4′), 148.8 (d, C-6′), 149.2 (s, C-2′), 153.4 (s, CNH), 163.3 (s, CONH), 168.0 (s, CO2Et), 197.3 (s, COCH3) ppm. HRMS (ESI-TOF): m/z calcd for C19H18N2O4Na [M + Na]+: 361.1164; found: 361.1166. Anal. calcd for C19H18N2O4 (338.4): C, 67.44; H, 5.36; N, 8.28; found: C, 66.80; H, 5.28; N, 8.16.

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Whether already the α-acyl-β-enamino esters 3 were isolated as mixtures of E and Z isomers (no isomerization could be detected by NMR spectroscopy), or isomerization occurred during N-acylation or chromatography of the β-keto-enamides 7 is currently unclear.

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Representative Procedure for the Cyclization of β-Ketoenamides Followed by Nonaflation of the Crude Product - 5-Ethoxycarbonyl-6-phenyl-2,2′-bipyrid-4-yl Nonaflate (9a) TMSOTf (0.94 mL, 5.17 mmol) was added dropwise to a solution of β-ketoenamide 7a (350 mg, 1.03 mmol) and DIPEA (0.68 mL, 4.14 mmol) in DCE (25 mL) under argon. The mixture was stirred for 5 d at 90 ˚C in a sealed tube. All volatile components were removed under reduced pressure, the crude product was dissolved in THF (15 mL) and treated with an excess of NaH (309 mg, 7.73 mmol, 60% in mineral oil, washed with hexane prior to use). After addition of Nf2O (778 mg, 1.34 mmol) the mixture was stirred overnight at r.t. and then quenched by slow addition of sat. aq NH4Cl solution (20 mL). The layers were separated, and the aqueous layer was extracted three times with CH2Cl2 (20 mL). The combined organic layers were dried with Na2SO4, and after filtration the solvent was removed under reduced pressure. Purification of the crude product by flash chromatography (silica gel, hexane-EtOAc = 40:1 → 20:1) afforded 434 mg (70%) of 9a as colorless oil. IR (ATR): 3070 (=CH), 2985, 2940-2930, 2905 (CH), 1735 (C=O), 1600, 1575, 1545 (C=C, C=N) cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.15 (t, J = 7.1 Hz, 3 H, CH3), 4.26 (q, J = 7.1 Hz, 2 H, OCH2), 7.40 (ddd, J = 7.8, 4.7, 0.8 Hz, 1 H, 5′-H), 7.47-7.50, 7.71-7.74 (2 m, 3 H, 2 H, Ph), 7.85 (td, J = 7.8, 1.3 Hz, 1 H, 4′-H), 8.49 (s, 1 H, 3-H), 8.54 (dbr, J = 7.8 Hz, 1 H, 3′-H), 8.74 (ddd, J = 4.7, 1.3, 0.8 Hz, 1 H, 6′-H) ppm. ¹³C NMR (126 MHz, CDCl3): δ = 13.5 (q, CH3), 62.6 (t, OCH2), 111.2 (d, C-3), 121.7 (d, C-5), 121.9 (s, C-3′), 125.1 (d, C-5′), 128.5, 128.6, 129.6 (3 d, Ph), 137.2 (d, C-4′), 138.5 (s, Ph), 149.4 (d, C-6′), 153.5, 155.0, 159.1, 159.4 (4 s, C-2, C-2′, C-4, C-6), 164.2 (s, CO2Et) ppm. ¹9F NMR (471 MHz, CDCl3): δ = -125.6 (td, J = 13.7, 4.4 Hz, 2 F, CF2), -120.5 (mc, 2 F, CF2), -108.7 (t, J = 13.7 Hz, 2 F, CF2), -80.5 (t, J = 9.7 Hz, 3 F, CF3) ppm. HRMS (ESI-TOF): m/z calcd for C23H16F9N2O5S [M + H]+: 603.0636; found: 603.0629. Anal. calcd for C23H15F9N2O5S (602.4): C, 45.86; H, 2.51; N, 4.65; S, 5.32. Found: C, 45.75; H, 2.51; N, 4.69; S, 5.47.

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Nf2O = nonafluorobutanesulfonic acid anhydride; nonaflation employing nonafluorobutanesulfonyl fluoride (NfF) was slow and incomplete.