Efficient cross-coupling of functionalized arylzinc halides catalyzed by a nickel chloride-diethyl phosphite system

Article abstract of DOI:10.1021/ol051615+

(Chemical Equation Presented) The combination of diethyl phosphite and DMAP as ligands for nickel in an 8:1 THF-N-ethylpyrrolidinone (NEP) mixture allows a very efficient cross-coupling reaction to be performed between various functionalized arylzinc halides and aryl bromides, triflates and activated chlorides. The reaction proceeds at 25°C within 1-48 h and requires only 0.05 mol % of the nickel catalyst.

Full text of DOI:10.1021/ol051615+

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4871-4874
Efficient Cross-Coupling of
Functionalized Arylzinc Halides
Catalyzed by a Nickel Chloride−Diethyl
Phosphite System
Andrei Gavryushin, Christiane Kofink, Georg Manolikakes, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received July 10, 2005 (Revised Manuscript Received September 27, 2005)
ABSTRACT
The combination of diethyl phosphite and DMAP as ligands for nickel in an 8:1 THF
cross-coupling reaction to be performed between various functionalized arylzinc halides and aryl bromides, triflates and activated chlorides.
The reaction proceeds at 25 C within 1 48 h and requires only 0.05 mol % of the nickel catalyst.
−N-ethylpyrrolidinone (NEP) mixture allows a very efficient
°
−
Transition-metal-catalyzed cross-couplings between aryl or-
ganometallics and aryl or heteroaryl halides are quite
important in modern organic chemistry, and a number of
the resulting biaryl products are of great industrial use.1
Although arylboronic acids and derivatives2 are favorite
nucleophiles for performing such cross-couplings due to their
good availability and excellent stability, in many cases
polyfunctional aryl or heteroaryl zinc reagents are an
attractive alternative.3 The required arylzinc compounds can
be prepared by transmetalation from the corresponding
magnesium or lithium organometallics,4 by direct zinc
insertion1 or by an I/Zn-exchange reaction.2 Palladium-
catalyzed cross-couplings require typically 1-3 mol % of a
palladium phosphine complex. Both catalyst components
(palladium and the phosphine) are expensive and complicate
large-scale applications. In light of this, we have turned our
attention to the use of nickel, an intrinsically more active
metal. Various Ni-catalyzed Suzuki cross-coupling reactions
have been described,3 whereas only a few nickel-catalyzed
cross-couplings of organozinc derivatives are known.4,9
Herein, we wish to report a new highly efficient nickel-
catalyzed cross-coupling between aryl and heteroaryl bro-
mides, chlorides or sulfonates (1) and arylzinc reagents (2),
using very small amounts of nickel salts (0.05 mol %) and
(1) ) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Tsuji, J.
Transition Metal Reagents and Catalysts: InnoVations in Organic Synthesis;
Wiley: Chichester, 1995. (c) Cross-Coupling Reactions. A Practical Guide.
Top. Curr. Chem. 2002, 219. (d) Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998.
(4) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302.
(5) (a) Rieke R. D. Science 1989, 246, 1260. (b) Burns, T. P.; Rieke, R.
D. J. Org. Chem. 1987, 52, 3674. (c) Lee, J.; Velarde-Ortiz, R.; Guijarro,
A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428.
(6) (a) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem., Int.
Ed. 2004, 43, 1017. (b) Gong, L.-Z.; Knochel, P. Synlett 2005, 267.
(7) ) (a) Percec, V.; Bac, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
1060. (b) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024.
(c) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513. (d) Galland, J.-C.;
Savignac, H.; Genet, J.-P. Tetrahedron Lett. 1999, 40, 2323. (e) Inada, K.;
Miyara, N. Tetrahedron 2000, 56, 8657. (f) Percec, V.; Golding, G. M.;
Smidrkal, J.; Weihold, O. J. Org. Chem. 2004, 69, 3447-3452.
(2) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(3) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
5223. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (d) Tamaru, J.; Ochiai,
H.; Nakamura, T.; Yoshida, Z. Tetrahedron Lett. 1986, 27, 955. (e) Qian,
M.; Negishi, E. Tetrahedron Lett. 2005, 46, 2927. (f) Zeng, X.; Zeng, F.;
Negishi, E. Org. Lett. 2004, 6, 3245. (g) Zeng, X.; Qian, M.; Hu, Q.; Negishi,
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10.1021/ol051615+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/07/2005

ligands (diethyl phosphite and DMAP, 0.2 mol % each) at
room temperature in THF, using N-ethylpyrrolidinone (NEP)
as cosolvent (Scheme 1).
(EtO)2P(O)H (0.2 mol %) and DMAP (0.2 mol %) at 25 °C
to give the cross-coupling product 3a in 79% yield after 2 h
(entry 1, Table 1). Similarly, the reaction of 2a with ethyl
3-bromobenzoate (1b) furnished the expected product 3b in
91% yield (entry 2) within a 6 h reaction time. We have
noticed that electron-rich arylzinc reagents react especially
well with aryl bromides under our conditions. Thus, the
cross-coupling of ethyl 4-bromobenzoate (1c) with 2a
provided the biphenyl 3c in 87% yield within a 6 h reaction
time (entry 3). Aryl bromides, bearing a ketone function,
are compatible with the mild cross-coupling conditions, and
4-bromobenzophenone reacted smoothly with 2a leading to
the ketone 3d in 73% yield within a 3 h reaction time (entry
4). 4-Bromo-acetophenone (1h) reacted with 2b within 2.5
h affording the methyl ketone 3g in 77% yield (entry 8).
Electron-poor aryl chlorides are also suitable electrophiles
under the reaction conditions we are advocating. Thus, the
reaction of 2a with ethyl 4-chlorobenzoate gave the expected
product 3c within 48 h at 25 °C in 83% yield (entry 5).
Heterocyclic halides such as 3-bromopyridine (1f) reacted
with 2a within 2 h at 25 °C, leading to the pyridine 3e in
81% yield. Scaling up the reaction using 20 mmol (1f)
provided the cross-coupling product 3e in a comparable yield
of 82%. By using 3-chloropyridine, the same cross-coupling
reaction required 12 h and gave 3e in 68% yield (entry 6).
The presence of an electron-withdrawing group allowed
cross-coupling of 2-chloropyridine derivatives. Thus, the
reaction of methyl 6-chloronicotinate (1g) with 3-methoxy-
phenylzinc bromide (2b) furnished the pyridine 3f in 74%
yield after 24 h (entry 7). 3-Pyridylzinc bromide displayed
a reduced reactivity and reacted with 2-bromobenzophenone
only at 50 °C, giving the ketone 3h in 76% yield within a 3
h reaction time (entry 9). Various substituted arylzinc
reagents such as 2d or 2e reacted with 5-bromopyrimidine
(1f), leading to the products 3i (82%) and 3j (60%). In the
case of an electron-deficient arylzinc halide (2e) the reaction
had to be performed at 50 °C within a 24 h reaction time
(entries 10 and 11). Aryl nonaflates proved especially
convenient substrates for the cross-coupling reaction as they
were usually easier to purify and more reactive than the aryl
triflates.12 Thus, the reaction of the zinc reagent 2f with the
nonaflate 1k provided the quinoline 3k in 88% yield (entry
12). 2-Zincated N-methylpyrrole (2g) obtained from the
corresponding lithium reagent13 and ZnBr2 underwent a
smooth cross-coupling with 3-bromopyridine (1f) at 70 °C
leading to â-nicotyrine 3l in 62% yield (entry 13), a natural
product with insecticidal activity14 (Scheme 2).
Scheme 1. Ni-Catalyzed Cross-Coupling Reaction of Arylzinc
Derivatives with Aryl Halides and Sulfonates
In preliminary studies, we investigated the cross-coupling
reaction between 4-methoxyphenylzinc bromide and 4-bro-
motoluene and found that the reaction took place in the
presence of 0.05 mol % of NiCl2 at room temperature without
a ligand when N-methylpyrrolidinone was used as a cosolvent
(THF-NMP 5:2). Other polar solvents such as DMSO,
DMAC, DMPU or Et3N were not effective as cosolvents.
Having examined various N-substituted pyrrolidinones, we
observed that N-(2-methoxyethyl)- and especially N-eth-
ylpyrrolidinone (NEP) gave much better results than with
NMP (88% conversion in the presence of NEP within 6 h
against 44% for NMP). We have further optimized the
cosolvent ratio and found that 8:1 THF-NEP mixture gives
the best results. We next screened this reaction with a broad
number of ligands such as phosphines, diphosphines, phos-
phites and various N-heterocycles. Surprisingly, from all the
ligands checked, diethyl phosphite gave the highest reaction
rate and the minimum amount of the arylzinc homocoupling
product. Interestingly, triphenylphosphine, also enhanced the
coupling rate but did not inhibit the reaction even when
present at 25-fold higher levels than Ni catalyst. Ratios of
NiCl2-(EtO)2P(O)H greater than 4:1 led to slower reaction
rates and extensive homocoupling. Other dialkyl and diaryl
phosphites were much less efficient.
We have also observed that the addition of 4-(dimethyl-
amino)pyridine (DMAP)10 in equimolar ratio to the ligand
amount provides a further rate acceleration, whereas DMAP
itself as a ligand showed poor results. The optimized
conditions allowed us to perform a broad range of cross-
coupling reactions within 1-20 h at room temperature (Table
1). Thus, 4-methoxyphenylzinc bromide (2a, 1.2 equiv),
obtained from the corresponding arylmagnesium reagent11
by a transmetalation with ZnBr2, reacted with 3-bromo-1-
fluorobenzene (1a) in the presence of NiCl2 (0.05 mol %),
Other arylzinc bromides such as 2h or 2i having a
trifluoromethyl- or a 1,3-dioxolane group provided the
corresponding biphenyls 3m-o in 68-94% yields (entries
14-16). Finally, for the cross-coupling of triflate 1l, we
probed the effect of the nature of the halide in the arylzinc
component. Thus, the cross-coupling reaction after the
transmetalation of 1-naphthylmagnesium bromide with ZnCl2
(8) (a) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999, 121,
5819. (b) Bo¨hm, V. P. W.; Weskamp, T.; Gsto¨ttmayr, C. W. K.; Herrmann,
W. A. Angew. Chem., Int. Ed. 2000, 39, 1602. (c) Quesnelle, C. A.;
Familoni, O. B.; Snieckus, V. Synlett 1994, 349. (d) Tucker, C. E.; de Vries,
J. G. Top. Catal. 2002, 19, 111. (e) Ackermann, L.; Born, R. Angew. Chem.,
Int. Ed. 2005, 44, 2444-2447.
(9) For Ni-catalyzed cross-coupling reactions, using other organometal-
lics, see: (a) Han, J. W.; Tokunaga, N.; Hayashi, T. Synlett 2002, 871. (b)
Shirakawa, E.; Yamasaki, K.; Hiyama, T. Synthesis 1998, 1544. (c) Terao,
J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc.
2002, 124, 4222. (d) Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.;
Kambe, N. AdV. Synth. Cat. 2004, 346, 905. (e) Percec, V.; Bae, J.-Y.;
Hill, D. H. J. Org. Chem. 1995, 60, 6895-6903.
(11) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(12) Rottla¨nder, M.; Knochel, P. J. Org. Chem. 1998, 63, 203.
(13) Brittain, J. M.; Jones, R. A.; Arques, J. S.; Saliente, T. A. Synth.
Commun. 1982, 12, 231.
(10) Steglich, W.; Hoefle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981.
(14) Mu¨ller, G. B.; Georgies, S. V. J. Org. Chem. 1989, 54, 2476.
4872
Org. Lett., Vol. 7, No. 22, 2005

Table 1. Cross-Coupling Products of Type 3, Obtained by a Nickel-Catalyzed Cross-Coupling between Aryl Halides and Sulfonates
with Functionalized Arylzinc Compounds in the Presence of (EtO)2P(O)H and DMAP
a Reaction time at 25 °C. b Yield of analytically pure product. c Reaction time and yield, obtained by using 3-chloropyridine as a substrate. d Reaction
performed at 50 °C. e Reaction performed at 70 °C. f Yield obtained by using 1-naphthylzinc chloride as a reagent. g 20 mmol scale reaction.
Org. Lett., Vol. 7, No. 22, 2005
4873

(EtO)2P(O)H and the role of DMAP in the ligand complex
is not yet clear, and the reaction mechanism is currently under
further investigation in our laboratory.
Scheme 2. Synthesis of â-Nicotyrine
In summary, we have developed an efficient Ni-catalyzed
cross-coupling reaction of arylzinc halides with aryl bro-
mides, triflates and activated chlorides, using very small
amount of NiCl2 (0.05 mol %) with (EtO)2P(O)H and DMAP
(0.2 mol % each) as ligands. The reaction scope is broad
and most of the cross-couplings proceed at room temperature.
or ZnBr2 proceeded with practically the same yields (77-
79%, entry 17).
In many cases, our cross-coupling reaction can be per-
formed with even much lower catalyst loadings. For instance,
the cross-coupling between 4-methoxyphenylzinc bromide
and ethyl 4-bromobenzoate or 5-bromopyrimidine were
complete at room temperature in the presence of NiCl2
(0.0025 mol %), (EtO)2P(O)H (0.01 mol %), DMAP (0.01
mol %) catalyst after 24 h. In these cases, even nickel that
was present as an admixture in commercial ZnBr2 (about 1
ppm, measured by atomic absorption spectroscopy method)
caused the formation of significant amounts of the cross-
coupling products. The source of such high efficiency of
Acknowledgment. We thank the Fond der Chemischer
Industrie, Lanxess (Leverkusen), Chemetall GmbH (Frank-
furt), Degussa AG (Frankfurt), BASF AG (Ludwigshafen)
for the generous gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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