Regioselective 1,6-Conjugate Addition of Boronic Acids and Grignard Reagents to Dienylpyridines

Abstract

Functionalization of the lateral chain of dienylpyridines was achieved by the regioselective 1,6-addition of boronic acids catalyzed by rhodium(I) or Grignard reagents under iron(II) catalysis.

addition - catalysis - pyridines - rhodium - iron

References and Notes

See, for example:

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1d Dryanska V. Ivanov C. Synthesis  1983,  143 

1e Houpis IN. Lee J. Dorziotis I. Molina A. Reamer B. Volante RP. Reider PJ. Tetrahedron  1998,  54:  1185 

1f Dondoni A. Fantin G. Fogagnolo M. Medici A. Pedrini P. Tetrahedron  1988,  44:  2021 

1g Clariana J. Gálvez N. Marchi C. Moreno-Mañas M. Vallribera A. Molins E. Tetrahedron  1999,  55:  7331 

1h Baschieri A. Bernardi L. Ricci A. Suresh S. Adamo MFA. Angew. Chem. Int. Ed.  2009,  48:  9342 

1i Mineyama K. Maekawa H. Kohsaka A. Yamamoto Y. Nishiguchi I. Tetrahedron  2009,  65:  7706 

1j Sun H.-W. Liao Y.-H. Wu Z.-J. Wang H.-Y. Zhang X.-M. Yuan W.-C. Tetrahedron  2011,  67:  3991 

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5 For the synthesis of starting materials (1) from 2-methyl-pyridine, see: Braun M. Mroß S. Schwarz I. Synthesis  1998,  83 

6

Recovery of starting material was observed when treating 1a with PhB(OH)₂ using [Rh(cod)]₂BF₄ or [Rh(cod)Cl]₂ as catalysts (5 mol%) in the presence of Ba(OH)₂, K₃PO₄, or KOH (1.0 equiv) at 50 ˚C in dioxane-H₂O (4:1) for 18 h.

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8

Recovery of starting material was observed when treating 1a with PhMgBr in THF in the presence of CuI (10 mol%) or in the absence of catalyst at r.t. for 18 h.

9

Typical Procedure for the Addition of Grignard Reagents to Dienylpyridines (1)
Synthesis of ( Z )-2-[4-( p -Methoxyphenyl)-3-methylhex-2-enyl]pyridine (2m)
To a stirred solution of 1e (86.6 mg, 0.5 mmol) and FeCl₂ (6.4 mg, 0.05 mmol) in anhyd THF (3.5 mL) under Ar was added p-methoxyphenylmagnesium bromide (1.0 M in THF, 0.9 mmol, 0.9 mL) at 0 ˚C. The solution was stirred at 0 ˚C for 15 min and at r.t. for 1 h. The reaction was terminated by the addition of a sat. NH₄Cl aq solution (5 mL). The organic products were extracted with Et₂O (3 × 5 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product was chromatographed on silica gel (hexane-EtOAc = 8:2). ^¹H NMR (300 MHz, CDCl₃): δ = 8.55 (d, J = 4.7 Hz, 1 H), 7.60 (td, J = 7.7, 1.8 Hz, 1 H), 7.07-7.22 (m, 4 H), 6.82 (dt, J = 8.7, 2.1 Hz, 2 H), 5.55 (t, J = 7.1 Hz, 1 H), 3.72-3.90 (m, 3 H), 3.78 (s, 3 H), 1.66-1.96 (m, 2 H), 1.54 (d, J = 1.0 Hz, 3 H), 0.90 (t, J = 7.3 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 12.4, 18.9, 24.2, 36.9, 46.2, 55.3, 113.7 (2 C), 121.2, 122.7, 123.0, 128.7 (2 C), 135.8, 136.6, 139.7, 149.4, 157.9, 161.5.

10

Determined by NOE measurement upon irradiation of the vinyl-H signal.