A Facile and Inexpensive Synthesis of 6-Ethynylbipyridine

doi:10.4236/ijoc.2011.12006

Paper Menu >>

Journal Menu >>

International Journal of Organic Chemistry, 2011, 1, 33-36

doi:10.4236/ijoc.2011.12006 Published Online June 2011 (http://www.SciRP.org/journal/ijoc)

A Facile and Inexpensive Synthesis of 6-Ethynylbipyridine

Jianqiang Huo, John O. Hoberg

Department of C hemi st ry , University of Wyoming, Laramie, USA

E-mail: [email protected]

Received April 6, 2011; revised May 16, 2011; accepted May 21, 2011

Abstract

An inexpensive synthesis of 6-ethynylbipyridine has been accomplished using Sonogashira coupling of

2-bromo-6-iodopyridine with 2-methyl-3-butyn-2-ol. Subsequent Stille coupling with 2-(trimethylstannanyl)

pyridine and hydrolysis provided the target compound in an overall high yield.

Keywords: 6-Ethynylbipyridine, 2-Bromo-6-Iodopyridine, 2-Methyl-3-Butyne-2-ol, Palladium Coupling

1. Introduction

Bipyridines are widely used structures that are found in a

large range of functions. These include ligands in coor-

dination chemistry, photocatalysts, functionalized poly-

mers, sensors, supramolecular assemblies and met-

allo-DNA conjugates. Thus, their importance in inor-

ganic, organic and medicinal chemistry cannot be over-

stated. The syntheses of functionalized 2,2’-bipyridines

for the above areas are therefore needed and although

numerous methods exist in the literature inexpensive and

facile procedures are desirable. One such bipyridine is

6-ethynylbipyridine (1), which has the ability to undergo

Sonogashira coupling to a host of other materials and has

therefore been used in the synthesis of metallo-DNA

conjugates [1], nucleosides bearing metal complexes for

antiviral activity [2-4] and photoactive materials [5-8].

The reported synthesis [1] (Scheme 1) relies on a Stille

reaction in the first step for the formation of 6-bromo-

2,2’-bipyridine (a Suzuki coupling has also been reported

in 54% yield [9]), which, in a second step, undergoes

further coupling of the resulting bromobipyridine prod-

uct with the expensive trimethylacetylene (TMSA). We

recently required large amounts of this material and en-

visioned that both these issues could easily be resolved

by the use of alternative reagents.

2. Results

Our strategy for an alternative synthesis involved the use

of 2-bromo-6-iodopyridine and 2-methyl-3-butyn-2-ol as

replacement reagents (Scheme 2). The synthesis of

2-bromo-6-iodopyridine has been reported in which a

bromine-magnesium exchange using iPrMgCl in THF is

employed [10], however we found this procedure diffi-

cult to reproduce. Therefore, we adapted Peterson’s [11]

procedure, in which the formation of 2-bromo-6-lithio-

pyridine is accomplished using n-butyllithium in di-

chloromethane. Treatment of this with iodine provided 2

in high yield. Sonogashira coupling of 2 with 2-methyl-

3-butyn-2-ol proceeded in excellent yield as expected,

and overcomes the use of expensive TMSA as the cost of

2-methyl-3-butyn-2-ol is inconsequential. We did at-

tempt to couple 2-methyl-3-butyn-2-ol with 2,6-dibro-

mopyridine, however unacceptable yields and complex

mixtures resulted.

Stille coupling of 3 with 2-(trimethylstannyl)pyridine

[12] gave 4 in excellent yield, which was easily hydrolized

to give target bipyridine 1 in an overall very good yield.

In conclusion, we have developed an inexpensive and

facile synthesis of 6-ethynylbipyridine. In particular, a ro-

bust synthesis of 2-bromo-6-iodopyridine (2) has been ac-

complished, which is critical to this chemistry and is a

compound used in a variety of other reported couplings

NBr Br

Me3Sn

PdL4

toluene

reflux

67%

NBr

TMSA

PdL2Cl2

CuI

Et3N, THF

89%

NTMS

THF, MeOH

98%

Scheme 1

J. Q. HUO ET AL.

NBr BrNBr I NBr

3OH

iii

86% 93%

83%

92%

Scheme 2. Reagents and conditions: (i) n-BuLi then I2,

CH2Cl2, 78˚C, 3 h; (ii) 2-methyl-3-butyn-2-ol, Pd(PPh3)4,

CuI, Et2NH, r.t., 20 h; (iii) 2-(trimethylstannyl)pyridine,

Pd(PPh3)4, toluene, 110˚C, 12 h; (iv) NaOH, toluene, 90˚C -

100˚C, then H+40 min.

[13-17]. Furthermore, the use 2-methyl-3-butyn-2-ol in

replacement of TMSA has been shown to be successful

in bipyridine chemistry.

3. Experimental

1H and 13C NMR spectra were recorded at 400 and 100

MHz, respectively in the indicated solvent. Chemical

shifts are reported in δ units, J in Hz relative to CDCl3

(7.24 ppm for 1H NMR and 77.0 ppm for 13C NMR).

Infrared spectra were determined on a Perkin Elmer

Paragon 500 FT-IR spectrophotometer. Et2O was distilled

from NaK; toluene and CH2Cl2 were distilled from cal-

cium hydride. Flash chromatography was performed us-

ing Silicycle ultra pure silica gel 60 Å (230 - 400 Mesh).

Standard syringe techniques were employed for handling

air-sensitive reagents and all reactions were carried out

under argon.

3.1. 2-Bromo-6-iodopyridine (2)

To a flame-dried flask containing 2,6-dibromopyridine

(1.00 g, 4.22 mmol), dry CH2Cl2 (100 mL) and cooled to

–78˚C was slowly added n-BuLi (3.3 mL, 4.6 mmol of a

1.4 M hexanes solution). The reaction was stirred for 20

minutes at –78˚C then a solution of I2 (1.06 g, 4.2 mmol,

dissolved in 20 mL of CH2Cl2) was added via cannula.

The resulting mixture was stirred at –78˚C for 3 h, the

cold bath removed, and the mixture stirred for 30 minutes

at room temperature. The mixture was quenched with

saturated NaHCO3 solution, the layers were separated and

the aqueous layer extracted twice with CH2Cl2. The

combined organic layers were dried over MgSO4, filtered

and concentrated in vacuo. Gradient flash chromatogra-

phy on silica gel (cyclohexane then 15:1 cyclohex-

ane/EtOAc) afforded 1.13 g (3.63 mmol, 86%) 2 as a light

yellow solid. 1H NMR and 13C NMR spectra were con-

sistent with published data [10].

3.2. 4-(6-Bromopyridin-2-yl)-2-methyl-3-butyn-

2-ol (3)

In an oven-dried flask, 2-bromo-6-iodopyridine (2) (470

mg, 1.65 mmol), 2-methyl-3-butyn-2-ol (152 μL, 1.57

mmol), Pd(PPh3)4 (10 mg, 0.008 mmol) and copper(I)

iodide (10 mg, 0.069 mmol) were dissolved in Et2NH (50

mL) and stirred for 20 h at room temperature. The mixture

was concentrated in vacuo, and quenched with water (20

mL), extracted with Et2O (2 × 20 mL). The combined

organic layers were dried (MgSO4), filtered and concen-

trated in vacuo. Flash chromatography on silica gel, (1:1

cyclohexane/EtOAc) afforded 370 mg (93%) of 3 as a

yellow oil. 1H NMR (CDCl3): δ1.62 (s, 6H, (CH3)2C),

2.70 (s, 1H, OH), 7.34 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.8

Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3): δ

30.9, 65.2, 80.2, 95.5, 125.9, 127.4, 138.3, 141.4, 143.3.

IR (neat): 3450, 2910, 2231, 1550, 1420, 1300 cm–1.

3.3. 2-(Trimethylstannyl)pyridine [12]

2-Bromopyridine (4.25 g, 27.0 mmol) was dissolved in

dry Et2O (100 mL) cooled to –78˚C and then n-BuLi (38.0

mL, 1.4M hexanes solution) was added dropwise fol-

lowed by stirring at –78˚C for 2 h. Me3SnCl (5.75 g, 28.8

mmol) dissolved in Et2O (20 mL) was added dropwise

from a syringe, and the reaction mixture stirred 3 h at

–78˚C followed by slowly warming to room temperature

over 12 h. The reaction flask was concentrated in vacuo

and dry hexanes (30 mL) were added from a syringe and

the slurry was stirred for 10 minutes. Filtration under

argon, concentration in vacuo gave the crude product that

can be stored in a freezer and is used in the next step

without further purification.

3.4. 2-Methyl-4-(6-(2,2-bipyridin)3-butyn-2-ol (4)

The 2-(trimethylstannyl)pyridine obtained above (1.20 g,

4.96 mmol) was dissolved in dry toluene (30 mL), can-

nulated into a flask equiped with condensor and side-arm

containing 3 (770 mg, 3.21 mmol) and the mixture de-

gassed with argon for 1 h. Pd(PPh3)4 (10 mg, 0.008 mmol)

was added and the reaction mixture was heated under

reflux while stirring for 12 h. The mixture was cooled and

poured into 2M NaOH (20 mL) and extracted with toluene

(2 × 30 mL). The combined organic phases were dried

(Na2SO4), filtered and concentrated. Flash chromatogra-

phy on silica gel (10:1 cyclohexane/ EtOAc) afforded 710

mg (92%) of 4 as a yellow oil. 1H NMR (400 MHz,

CDCl3): δ 1.67 (s, 6H, (CH3)2C), 2.97 (s, 1H, OH), 7.31

J. Q. HUO ET AL.35

(dq, J = 7.5,1.2 Hz, 1H), 7.41 (dd, J = 7.6,1.0 Hz, 1H),

7.77 (t, J = 7.7 Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H),

8.34 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.68 (d,

J = 5.1 Hz, 1H); 13C NMR (CDCl3): δ 31.2, 65.4, 81.8,

93.5, 120.4, 121.6, 124.0, 127.2, 137.0, 142.3, 149.0,

155.4, 156.3. IR (neat) 3455, 2228, 1685, 1265, 1250,

1150, 1125 cm–1.

3.5. 2-Ethynyl-6-2,2-bipyridine (1)

NaOH (1.61 g, 40.18 mmol) and 4 (450 mg, 2.0 mmol),

were dissolved in toluene (50 mL) and then brought to a

boil for 40 minutes. The resulting golden-brown solution

was concentrated and the residues were quenched with

H2O (20 mL), with CH2Cl2 (30 mL) being added at the

same time. The pH of the mixture was adjusted to 7 by

adding 2M HCl dropwise then the layers were separated,

and the aqueous layer was extracted with CH2Cl2 (2 × 20

mL). The combined organic extractions were dried

MgSO4, filtered and concentrated. Flash chromatography

on silica gel (5:1 cyclohexane/EtOAc) afforded 301 mg

(83%) of 1 as a white solid. 1H NMR and 13C NMR

spectra were consistent with published data [11].

4. Acknowledgements

This work was supported by a grant from the School of

Energy Research, University of Wyoming, which is

gratefully acknowledged.

5. References

[1] S. T. Gaballah, C. E. Kerr, B. E. Eaton and T. L. Netzel,

“Synthesis of 5-(2,2’-Bipyridinyl and 2,2’-Bipyridin-

ediiumyl)-2’-deoxyuridine Nucleosides: Precursors to

Metallo-DNA Conjugates,” Nucleosides, Nucleotides Nu-

cleic Aci ds , Vol. 21, No. 8-9, 2002, pp. 547-560.

doi:10.1081/NCN-120015068

[2] M. Vrabel, M. Hocek, L. Havran, M. Fojta, I. Votruba, B.

Klepetarova, R. Pohl, L. Rulisek, L. Zendlova, P. Hobza, I.

Shih, E. Mabery and R. Mackman, “Purines Bearing

Phenanthroline or Bipyridine Ligands and Their RuII

Complexes in Position 8 as Model Compounds for Elec-

trochemical DNA Labeling—Synthesis, Crystal Structure,

Electrochemistry, Quantum Chemical Calculations, Cy-

tostatic and Antiviral Activity,” European Journal of In-

organic Chemistry, Vol. 2007, No. 12, 2007, pp.

1752-1769. doi:10.1002/ejic.200700030

[3] M. Vrabel, R. Pohl, B. Klepetarova, I. Votruba, M. Hocek,

“Synthesis of 2’-Deoxyadenosine Nucleosides Bearing

Bipyridine-Type Ligands and their Ru-Complexes in Po-

sition 8 through Cross-Coupling Reactions,” Organic and

Biomolecular Chemistry, Vol. 5, No. 17, 2007, pp.

2849-2857. doi:10.1039/b709245h

[4] M. Vrábel, I. Rosenberg and M. Hocek, “Synthesis of

Modified Nucleosides and Oligonucleotides Bearing

Bipyridine or Phenanthroline Ligands,” Collection Sym-

posium Series, Vol. 7, 2005, pp. 485-486.

[5] T. Pautzsch, E. Klemm, “Ruthenium-Chelating

Poly(heteroaryleneethynylene)s: Synthesis and Proper-

ties,” Macromolecules, Vol. 35, No. 5, 2002

1569-1575.

, pp.

doi:10.1021/ma011712s

[6] A. Ambroise, R. W. Wagner, P. D. Rao, J. A. Riggs, P.

Hascoat, J. R. Diers, J. Seth, R. K. Lammi, D. F. Bocian, D.

Holten and J. S. Lindsey, “Design and Synthesis of Por-

phyrin-Based Optoelectronic Gates,” Chemi

rials, Vol. 13, No. 3, 2001, pp

stry of Mate-

. 1023-1034.

doi:10.1021/cm000773m

[7] M. Hissler and R. Ziessel, “Versatile Ruthenium(II) Met-

allo-Synthons for the Stepwise Construction of Ordered

Networks,” New Journal of Chemistry, Vol. 21, No. 6-7,

ganic

, 1997, pp. 1491-1500.

1997, pp. 843-846.

[8] V. Grosshenny, F. M. Romero and R. Ziessel, “Construc-

tion of Preorganized Polytopic Ligands via Palladium-

Promoted Cross-Coupling Reactions,” Journal of Or

Chemistry, Vol. 62, No. 5

doi:10.1021/jo962068w

[9] N. A. Jones, J. W. Antoon, A. L. Bowie, J. B. Borak and E.

P. Stevens, “Synthesis of 2,2’-Bipyridyl-Type Compounds

via the Suzuki-Miyaura Cross-Coupling Reaction,”

Journal of Heterocyclic Chemistry, Vol. 44, No. 2, 2007,

pp. 363-367. doi:10.1002/jhet.5570440213

[10] F. Trecourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais, G.

Queguiner, “New Syntheses of Substituted Pyridines via

Bromine-Magnesium Exchange

No. 10, 2000, pp. 1349-1360.

,” Tetrahedron, Vol. 56,

doi:10.1016/S0040-4020(00)00027-2

[11] M. A. Peterson and J. R. Mitchell, “Efficient Preparation

of 2-Bromo-6-lithiopyridine via Lithium-Bromine Ex-

change in Dichloromethane,” The Journal of Organic

Chemistry, Vol. 62, No. 23, 1997, pp. 8237-8239.

doi:10.1021/jo971532+

[12] P. F. H. Schwab, F. Fleischer and J. Michl, “Preparation of

5-Brominated and 5,5’-Dibrominated 2,2’-Bipyridines

and 2,2’-Bipyrimidines,” The Journal of

istry, Vol. 67, No. 2, 200

Organic Chem-

2, pp. 443-449.

doi:10.1021/jo010707j

[13] Y. Takayama, T. Hanazawa, T. Andou, K. Muraoka, H.

Ohtani, M. Takahashi and F. Sato, “Site-Selective Mono-

titanation of Dialkynylpyridines and Its Application for

Preparation of Highly Fluorescent π-Conjugated Oli-

gomers,” Organic Letters, Vol. 6, No. 23, 2004, pp.

4253-4256. doi:10.1021/ol048316p

[14] N. Pagano, J. Maksimoska, H. Bregman, D. S. Williams, R.

D. Webster, F. Xue and E. Meggers, “Ruthenium

Half-Sandwich Complexes as Protein Kinase Inhibitors:

Derivatization of the Pyridocarbazole Pharmacophore

Ligand,” Or ganic and Biomolecular Chemistry, Vol. 5, No.

8, 2007, pp. 1218-1227. doi:10.1039/b700433h

[15] B. T. Holmes, W. T. Pennington and T. W. Hanks,

“Synthesis of ‘Acetylene-Expanded’ Tridentate

Molecules, Vol. 7, No. 5

Ligands,”

, 2002, pp. 447-455.

J. Q. HUO ET AL.

doi:10.3390/70500447

[16] F. Cottet and M. Schlosser, “Trifluoromethyl-Substituted

Pyridines through Displacement of Iodine by in situ

Generated (Trifluoromethyl)copper,” European Journal

of Organic Chemistry, Vol. 2002, No. 2, 2002, pp.

327-330.

doi:10.1002/1099-0690(20021)2002:2<327::AID-EJOC3

27>3.0.CO;2-V

[17] M. Benaglia, F. Ponzini, C. R. Woods and J. S. Siegel,

“Synthesis of Oligopyridines and Their Metal Complexes

as Precursors to Topologically Interesting Molecules,”

Organic Letters, Vol. 3, No. 7, 2001, pp. 967-969.