Substituted 2,2′-bipyridines by nickel catalysis: 4,4′-Di- tert -butyl-2,2′-bipyridine

Article abstract of DOI:10.1055/s-0033-1338520

A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyridine is presented. 5,5′-Bis(trifluoromethyl)-2,2′-bipyridine is also synthesized by the same protocol. The syntheses efficiently couple the parent 2-chloropyridines by a nickel-catalyzed dimerization with manganese powder as the terminal reductant. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338520

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Synthesis (Stuttg). Author manuscript; available in PMC 2014 November 01.
Published in final edited form as:
Synthesis (Stuttg). 2013 November 1; 45(22): 3099–3102. doi:10.1055/s-0033-1338520.
Substituted 2,2′-bipyridines by nickel-catalysis: 4,4′-di-tert-
butyl-2,2′-bipyridine
Joseph A. Buonomo, Daniel A. Everson, and Daniel J. Weix*
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216 USA
Abstract
A simple, ligand-free synthesis of the important bipyridyl ligand 4,4′-di-tert-butyl-2,2′-bipyridine
is presented. 5,5′-bis(trifluoromethyl)-2,2′-bipyridine is also synthesized by the same protocol.
The syntheses efficiently couple the parent 2-chlorpyridies by a nickel-catalyzed dimerization with
manganese powder as the terminal reductant.
Keywords
nickel; 4,4′-di-tert-butyl-2,2′-bipyridine; pyridine; catalysis; reductive
Bipyridine ligands have long been used with transition-metals in both catalysis and materials
applications, but their chemistry is less well studied than the more frequently employed
1
mono- and bisphosphines. Among many recent applications, 4,4′-di-tert-butyl-2,2′-
bipyridine (3a) has been found to be useful in the iridium-catalyzed C-H borylation
2
3
reaction, a variety of nickel-catalyzed cross-electrophile coupling reactions, the nickel-
4
catalyzed cross-coupling of tertiary alkyl bromides with organoboron reagents, the copper-
5
6
mediated trifluoromethylation of aryl iodides, the manganese-catalyzed reduction of CO ,
2
7
and in iridium dyes used in photocatalysis and OLED. At the same time that the utility of
4
,4′-di-tert-butyl-2,2′-bipyridine has become increasingly evident, the ligand has become
8
more difficult to obtain commercially. Aldrich, the sole supplier in the United States, was
continually backordered for a period of 6 months in 2012. The limited availability prompted
us to consider alternate synthetic routes and we present here our results with a nickel-
catalyzed reductive homocoupling.
Of the methods reported for the synthesis of 3a (Figure 1), the most convenient is reported
to be that of McGill, which heats a mixture of 4-tert-butylpyridine with sodamide at 145 °C
9
to form 3a in 8-15% yield. The other reported method is the dehydrogenative coupling of
4
-tert-butylpyridine catalyzed by either nickel10 or palladium11 at elevated temperature.
Reported yields range from <10% up to 64% yield, but vary considerably. In our hands, the
reported procedures were inconvenient because they often suffered from low conversions
©
Thieme Stuttgart · New York
*Fax: 1-585-276-0205., daniel.weix@rochester.edu.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
Primary Data for this article are available online at http://www.thieme-connect.com/ejournals/toc/synthesis and can be cited using
the following DOI: (number will be inserted prior to online publication).

Buonomo et al.
Page 2
that required distillation of the remaining, valuable 4-tert-butylpyridine, and because the
dehydrogenative conditions provided inconsistent yields. The limited availability of 3a may
be related to the difficulties associated with these procedures.
A number of substituted bipyridines have been synthesized by the nickel12 or palladium13
catalyzed reductive homocouplings of 2-halogenated pyridines. Most of the methods require
high catalyst loadings (up to 30 mol% nickel, up to 10 mol% palladium), ancillary ligands,
and/or additives, such as Cp ZrCl .
2
2
We provide here a simple route to 3a that is reliable and scalable (Scheme 1). Reaction of 4-
tert-butylpyridine with peracetic acid forms the N-oxide. This then reacts with POCl to
3
form 4-tert-butyl-2-chloropyridine (2a).14 Dimerization of 2a is achieved by nickel catalysis
(
0.5 mol %) with manganese as the terminal reducing agent. No added ligand is required and
purification is achieved by simple aqueous work-up and sublimation (Table 1). Additionally,
-chloro-5-trifluoromethylpyrdine (2b) dimerized to form 3b in 70% yield. This bipyridine
2
has been reported as a ligand in ruthenium dyes15 and for catalysis,16 but has not been
extensively explored in either arena. Previous syntheses were lower yielding or required
expensive palladium catalysts.17 Lastly, simple 2-chloropyridine (2c) dimerized in 86%
yield with only 0.2 mol% nickel catalyst.
Vital to the success of these new, ligand-free dimerization conditions is the use of
manganese powder as the reducing agent. Replacing manganese with zinc dust results in
quantitative hydrodehalogenation of the chloropyridine. If NiBr •3H O is not available,
2
2
NiCl •6H O also formed product in similarly high yield. Reactions in toluene, butanol,
2
2
acetone, or ethanol did not form product at all, but a reaction in 1:3 DMF:THF worked as
well as a reaction in pure DMF. Finally, although nickel hydrate salts were effective pre-
catalysts, reactions run in DMF from an open-bottle off the shelf (measured to be ~10000
ppm H O) were half as fast as our standard reaction in dry DMF (85 ppm H O).
2
2
Although no ligand is added to these reactions, the first turnover of the catalyst generates a
suitable ligand for the coupling reaction. Reactions of halopyridines that do not form
bidentate ligands, such as 3-bromopyridine, do not consume starting material unless an
external ligand is added.
Mechanistically, we have not conducted any investigations, but we currently favor the
disproportion mechanism proposed by Osakada and Yamamoto.18
We expect that this method will provide improved and reliable access to 3a. The low
catalyst loading, ligand- and additive-free reaction conditions combined with high substrate
concentrations makes this route particularly useful for large-scale laboratory experiments.
4
,4′-di-tert-butyl-2,2′-bipyridine [72914-19-3] (3a)19
On the benchtop, a 50 mL round bottom flask equipped with a 1/2 inch Teflon coated
magnetic stir bar was charged with NiBr ·3H O (401 mg, 1.47 mmol) and DMF (20.0 mL).
2
2
The vessel was stoppered with a rubber septum and heated to 60 °C until a green
homogenous solution resulted (approx. 20 min). Once homogeneity was achieved, the vessel
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Buonomo et al.
Page 3
was removed from the heat and allowed to cool to room temperature. Once at room
temperature 4-tert-butyl-2-chloropyridine (2a) (4.99 g, 29.4 mmol) and manganese powder
−325 mesh, 3.30 g, 60.0 mmol) were added, and the vessel was resealed with the septum,
(
purged with argon, and heated again to 60 °C for the duration of the reaction. Reaction
progress was monitored by GC analysis of aliquots of crude reaction mixture. In general the
reaction turns very dark brown or black in color when complete, and the color change is a
reliable indicator for the reaction endpoint. Upon completion, the reaction was cooled to
room temperature, diluted with ether (80 mL) and filtered through a short pad of celite
(approx. 2 in × 2 in × 2 in) that had been wetted with ether to remove metal salts. The
reaction vessel was washed with ether (2 × 40 mL) and the washes were then passed through
the filter. The filtrate was transferred to a separatory funnel and washed with 1M sodium
hydroxide (200 mL). A brown emulsion formed in the separatory funnel during the work-up
that slowly separated. Care was taken to keep the brown emulsion with the organics. Once
separated, the aqueous layer was extracted with additional ether (3 × 150 mL). The
combined organic extracts and brown emulsion were washed with brine (500 mL). Again
care was taken to keep the brown emulsion with the organics. The organics were dried with
copious amounts of MgSO . The solid drying agent was removed by filtration, ground into a
4
fine powder and washed with additional ether (3 × 150 mL). The filtrate was evaporated to
dryness to give 3a (3.57 g) as faintly yellow crystals in 90% yield. This material was judged
analytically pure by NMR and combustion analysis. If necessary the product can be further
purified by sublimation (140 °C, 300 mtorr). Analytical data reported below is for material
that was not sublimed.
1
H-NMR (400 MHz; CDCl ): δ 8.60 (d, J = 5.2 Hz, 2H), 8.41 (d, J = 1.0 Hz, 2H), 7.30 (dd,
3
J = 5.2, 1.7 Hz, 2H), 1.39 (s, 18H).
1
3
C-NMR (126 MHz; CDCl ): δ 161.1, 156.7, 149.2, 120.8, 118.4, 35.1, 30.8.
3
Anal. Calc. for C H N requires: C, 80.55; H, 9.01; N, 10.44; found: C, 80.29; H, 9.12;
1
8 24 2
N, 10.44%.
MP = 157 -158 °C (lit.19 = 159 -160 °C).
5
,5′-Bis(trifluoromethyl)-2,2′-bipyridine [142946-80-3] (3b)15, 17
The procedure for 3a was followed on 15.0 mmol scale and with 1M ammonium hydroxide
in place of 1M sodium hydroxide. The product was purified by sublimation (110 °C, 200
mtorr) to give 3b (1.54 g) as white solid in 70% yield.
1
H-NMR (500 MHz; CDCl ): δ 8.96 (s, 2H), 8.62 (d, J = 8.3 Hz, 2H), 8.08 (dd, J = 8.3, 1.8
3
Hz, 2H).
1
3
C-NMR (126 MHz; CDCl ): δ 157.9, 146.47 (q, J = 4.3 Hz), 134.47 (q, J = 3.2 Hz),
3
1
27.31 (q, J = 33.3 Hz), 123.67 (q, J = 272.8 Hz), 121.4.
1
9
F-NMR (376 MHz; CDCl ): δ −0.1.
3
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Buonomo et al.
Page 4
Anal. Calc. for C H F N requires: C, 49.39; H, 2.07; N, 9.59; found: C, 49.60; H, 2.15;
1
2 6 6 2
N, 9.59%.
MP = 128-130 °C (lit.17 = 124-126 °C (hexanes)).
2
,2′-bipyridine [366-18-7] (3c)20
The procedure for 3a was followed on 15.0 mmol scale with 0.2 mol% nickel, and with 1M
ammonium hydroxide in place of 1M sodium hydroxide. The product was purified by
sublimation (95 °C, 100 mtorr) to give 3c (1.00 g) as white solid in 86% yield.
1
H-NMR (500 MHz; CDCl ): δ 8.69 (d, J = 4.6 Hz, 2H), 8.40 (d, J = 8.0 Hz, 2H), 7.82 (td,
3
J = 7.7, 1.6 Hz, 2H), 7.31 (ddd, J = 7.4, 4.8, 1.0 Hz, 2H).
1
3
C-NMR (126 MHz; CDCl ): δ 156.2, 149.2, 137.0, 123.8, 121.1.
3
Anal. Calc. for C H N requires: C, 76.90; H, 5.16; N, 17.94; found: C, 76.72; H, 5.08; N,
1
0 8 2
1
7.93%.
MP = 70-72 °C (lit.21 = 71-72 °C).
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
This work was supported by the University of Rochester, the NIH (R01 GM097243), an NSF Graduate Research
Fellowship to DAE, and the NSF Research Experience for Undergraduates Program (CHE-1156340 for JAB).
Analytical data were obtained from the CENTC Elemental Analysis Facility at the University of Rochester, funded
by NSF CHE-0650456.
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Figure 1.
Literature methods for the synthesis of 4,4′-di-tert-butyl-2,2′-bipyridine (3a).
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Buonomo et al.
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Scheme 1.
Improved and convenient synthesis of 4,4′-di-tert-butyl-2,2′-bipyridine (3a).
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Buonomo et al.
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Table 1
a
Nickel-catalyzed reductive dimerization of 2-chloropyridines.
Entry
3
Yield
b
(%)
1
90
c
70
86
2
d
3
aReaction conditions: 2a (4.99g, 29.4 mmol), NiBr2·3H2O (401 mg, 1.47 mmol), DMF (20 mL), and manganese powder (−325 mesh, 3.30 g, 60.0
mmol) were heated under argon for 20 h.
b
Yield of isolated and purified product.
c
Reaction run on 15.0 mmol scale with 2b.
dReaction run on 15.0 mmol scale with 2c with 0.2 mol% NiBr2·3H2O for 18 h.
Synthesis (Stuttg). Author manuscript; available in PMC 2014 November 01.