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

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.

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

References and Notes

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4a Chun YS. Lee KK. Ko YO. Shin H. Lee S. Chem. Commun.  2008,  5098 

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5b Flögel O. Dash J. Brüdgam I. Hartl H. Reissig H.-U. Chem. Eur. J.  2004,  10:  4283 

5c Dash J. Lechel T. Reissig H.-U. Org. Lett.  2007,  9:  5541 

5d Lechel T. Dash J. Brüdgam I. Reissig H.-U. Eur. J. Org. Chem.  2008,  3647 

5e Eidamshaus C. Reissig H.-U. Adv. Synth. Catal.  2009,  351:  1162 

5f Dash J. Reissig H.-U. Chem. Eur. J.  2009,  15:  6811 

5g Lechel T. Brüdgam I. Reissig H.-U. Beilstein J. Org. Chem.  2010,  6:  No. 42 

5h Lechel T. Dash J. Eidamshaus C. Brüdgam I. Lentz D. Reissig H.-U. Org. Biomol. Chem.  2010,  8:  3007 

5i Lechel T. Dash J. Hommes P. Lentz D. Reissig H.-U. J. Org. Chem.  2010,  75:  726 

5j Bera MK. Reissig H.-U. Synthesis  2010,  2129 

5k Eidamshaus C. Kumar R. Bera MK. Reissig H.-U. Beilstein J. Org. Chem.  2011,  7:  962 

5l

Eidamshaus, C.; Reissig, H.-U. Eur. J. Org. Chem. 2011, DOI: 10.1002/ejoc.201100681.

6

For a proposed mechanism, see ref. 5l.

7a Lehn J.-M. Supramolecular Chemistry - Concepts and Perspectives   VCH; Weinheim: 1995. 

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7e Ye B.-H. Tong M.-L. Chen X.-M. Coord. Chem. Rev.  2005,  249:  545 

For reviews, see:

8a Kröhnke F. Synthesis  1976,  1 

8b Summers LA. The Bipyridines, In Advances in Heterocyclic Chemistry   Vol. 35:  Katritzky AR. Academic Press; Orlando, FL: 1984.  p.281 

8c Chelucci G. Thummel RP. Chem. Rev.  2002,  102:  3129 

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8f Hapke M. Brandt L. Lützen A. Chem. Soc. Rev.  2008,  37:  2782 

Selected recent examples:

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9b Gutz C. Lützen A. Synthesis  2010,  85 

9c Kremer C. Lützen A. Synthesis  2011,  210 

9d Duric S. Tzschucke CC. Org. Lett.  2011,  13:  2310 

10

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 (d_br, J = 7.7 Hz, 1 H, 3′-H), 8.78 (d_br, 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.

11

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.

2-PyCOBt = 1H-1,2,3-benzotriazol-1-yl(pyrid-2-yl)-methanone; for its preparation, see:

12a Katritzky AR. He H.-Y. Suzuki K. J. Org. Chem.  2000,  65:  8210 

For a review on N-acylbenzotriazoles, see:

12b Katritzky AR. Suzuki K. Wang Z. Synlett  2005,  1656 

13 Takaya H. Naota T. Murahashi S.-I. J. Am. Chem. Soc.  1998,  120:  4244 

14 For a review on aryl and alkenyl nonaflates, see: Högermeier J. Reissig H.-U. Adv. Synth. Catal.  2009,  351:  2747 

15

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 (d_br, 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 (m_c, 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.

16

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

17 Cacchi S. Ciattini PG. Morera E. Otar G. Tetrahedron Lett.  1986,  27:  5541