C. M. Frech and R. Gerber
The following experimental observations indicate that the
aminophosphine-based nickel system operates by a molecu-
lar (NiI/NiIII) reaction mechanism in which radicals are in-
volved. 1) Nitro-substituted aromatic halides are not tolerat-
ed, so no product formation was obtained when 1-bromo-4-
nitrobenzene, for example, was used as substrate. Indeed,
the catalysis was efficiently inhibited when, for example, ni-
trobenzene (0.5 equiv relative to aryl halide) was added to
reaction mixtures of aryl halide, diarylzinc reagent, and cata-
lyst. 2) The addition of (chloromethyl)benzene to reaction
mixtures of phenyl bromide, bis(4-methoxyphenyl)zinc, and
catalyst instantly induces a single-electron transfer (SET)
from the metal center to the organic halide (c.f. Scheme 8),
as indicated by the formation of dibenzyl. Indeed, no diben-
zyl was noticed in the absence of catalyst. 3) The presence
of radical scavengers (ꢀ5 equiv relative to catalyst) such as
galvinoxyl, 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO),
or dibenzyl viologen in reaction mixtures of aryl halide, dia-
rylzinc reagent, and catalyst lowers the levels of conversion
significantly and hence indicates that radicals are involve-
ment in the catalytic cycle. 4) Dramatic drops in activity are
observed when the cross-coupling reactions are performed
under dioxygen.
satile nickel-based Negishi catalysts for cross-couplings be-
tween aryl halides and arylzinc reagents. All the experimen-
tal observations indicate that the aminophosphine-based
nickel system operates by the generally accepted molecular
(NiI/NiIII) mechanism, whereas the involvement of nickel-
based nanoparticles in the catalytic cycle could be ruled out.
Experimental Section
General procedure for Negishi cross-coupling reactions: All catalytic re-
actions were carried out under air. A round-bottomed flask was charged
in air with NiCl2, PACHTNUGTRNE(UGN NC5H10)3 (2.05 equiv), and N-methylpyrrolidone
(4 mL) and the mixture was stirred for 15 min. Freshly prepared diary-
lzinc reagent (ꢀ1.0m; 1.5 equiv, THF/NMP 1:2) was then added, fol-
lowed by the aryl halide (2.0 mmol). The reaction vessel was closed and
the mixture was vigorously stirred and heated to 608C. Samples were
taken from the reaction mixture, quenched with aqueous HCl (ꢀ1m), ex-
tracted with ethyl acetate, and analyzed by GC/MS (for reactions per-
formed with substrates containing basic groups, samples were quenched
with NaOH (ꢀ1m) and extracted with ethyl acetate). At the end of cat-
alysis, the reaction mixtures were allowed to cool to room temperature,
quenched with sat. NH4Cl solution, and extracted with ethyl acetate (3ꢂ
20 mL). The combined extracts were dried (MgSO4) and concentrated to
dryness. The crude material was purified by flash chromatography on
silica gel where necessary.[29]
General procedure for the selective synthesis of 6-chloropyridin-2-amines
with aliphatic amines: A Young Schlenk tube was charged (in air) with
2,6-dichloropyridine (10.0 mmol), the amine (11.0 mmol), K3PO4
(40.0 mmol), and dioxane (30 mL) and closed with a Teflon screw cap.
The reaction mixture was then placed in a preheated 1008C oil bath and
stirred vigorously. Samples taken from the reaction mixture were
quenched with water. The products were extracted with ethyl acetate and
analyzed by GC/MS. At the end of the reaction the mixture was allowed
to cool to room temperature, quenched with water, and extracted with
ethyl acetate (30–50 mL). The combined extracts were washed with
NaOH (1m, 3ꢂ50 mL), dried over MgSO4, filtered, and concentrated to
dryness. Where necessary, the product was purified by flash chromatogra-
phy on silica gel or on alumina.
Conclusion
In conclusion, the newly introduced aminophosphine-based
nickel system is a rare example of a nickel-based system
that has been applied in cross-couplings between aryl hal-
ides and arylzinc reagents and hence in the synthesis of biar-
yls. Moreover, the aminophosphine-based nickel catalyst is a
simple and cheap—but also highly efficient, versatile, and
reliable—Negishi catalyst with high functional group toler-
ance, which allows cross-couplings of a large variety of elec-
tronically activated, non-activated, deactivated, and/or steri-
cally hindered and functionalized aryl halides, as well as of
6-chloropyridine-2-amines, with various diarylzinc reagents
in NMP/THF mixtures within 2 h at 608C in the presence of
only 0.1 mol% of catalyst. In addition, neither a large
excess of ligand nor any additive was required for reliable,
efficient, and clean product formation. The reaction proto-
col presented is thus very simple and, most importantly, the
same for all the reactions examined and can hence be direct-
ly applied to other substrates without the need to modify
the reaction conditions. With the exception of nitro-contain-
ing substrates, which are not tolerated, various aryl hal-
ides—which may contain trifluoromethyl groups, fluorides,
or other functional groups such as acetals, ketones, ethers,
esters, lactones, amides, imines, anilines, or alkenes—and
also their pyridine-, quinoline-, and pyrimidine-based coun-
terparts, were successfully converted into the corresponding
General procedure for the selective synthesis of 6-chloropyridin-2-amines
with aniline-derived amines: Inside a glovebox, a vial was successively
charged with the amine (11.0 mmol), KN
ACHTUGNRTEN(NUGN SiMe3)2 (11.0 mmol, secondary
aniline derivatives) or KN(SiMe3)2 (15.0 mmol, primary aniline deriva-
AHCTUNGTRENNUNG
tives), dioxane (30 mL), and 2,6-dichloropyridine (10.0 mmol). The reac-
tion mixture was then stirred at room temperature unless otherwise
stated. Samples taken from the reaction mixture were quenched with
NaOH (1m). The products were extracted with ethyl acetate and ana-
lyzed by GC/MS. At the end of the reaction the mixture was quenched
with NaOH (1m) and extracted with ethyl acetate (30–50 mL). The com-
bined extracts were washed with NaOH (1m, 3ꢂ50 mL), dried over
MgSO4, filtered, and concentrated to dryness. Where necessary, the prod-
uct was purified by flash chromatography on silica gel or on alumina.
Acknowledgements
Financial support by the University of Zurich and the Swiss National Sci-
ence Foundation (SNSF) is gratefully acknowledged.
biACHTUNGTRENNUNG(hetero)aryls. Electronic and steric variations are tolerated
[1] See for example: a) Metal-Catalyzed Cross-Coupling Reactions
(Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998; b)
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: A. de
Meijere, F. Diederich), Wiley-VCH, Weinheim, 2004; c) Transition
Metal Reagents and Catalysts: Innovations in Organic Synthesis
in both reaction partners. Demonstration of such a broad
applicability of a single catalyst under uniform reaction con-
ditions is unprecedented for nickel-based Negishi catalysts,
so 1 now certainly represents one of the most active and ver-
11902
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 11893 – 11904
Gerber, Roman
