Cobalt(II)-catalyzed cross-coupling between polyfunctional arylcopper reagents and aryl fluorides or tosylates

Article abstract of DOI:10.1021/ol0529142

Organocopper compounds prepared by the transmetalation of functionalized arylmagnesium halides with CuCN-2LiCI undergo smooth cross-coupling reactions with aryl fluorides and tosylates bearing a carbonyl function in the ortho position in the presence of C

Full text of DOI:10.1021/ol0529142

ORGANIC
LETTERS
2006
Vol. 8, No. 4
725-728
Cobalt(II)-Catalyzed Cross-Coupling
between Polyfunctional Arylcopper
Reagents and Aryl Fluorides or
Tosylates
Tobias J. Korn, Matthias A. Schade, Stefan Wirth, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13, Haus F, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received December 1, 2005
ABSTRACT
Organocopper compounds prepared by the transmetalation of functionalized arylmagnesium halides with CuCN
‚2LiCl undergo smooth cross-
coupling reactions with aryl fluorides and tosylates bearing a carbonyl function in the ortho position in the presence of Co(acac)2 (7.5 mol %),
Bu4NI (1 equiv), and 4-fluorostyrene (20 mol %) as promoters in DME/THF/DMPU leading to polyfunctional aromatics or heterocycles.
Transition-metal catalyzed cross-coupling reactions between
arylmetals and aryl halides is an actively investigated field
in organometallic chemistry. Commonly, palladium and
nickel complexes are very active catalysts, and efficient
experimental procedures are now available.1 Although aryl
iodides, bromides, and, nowadays, even chlorides2 have
found widespread applications, aryl fluorides3 and tosylates4
are by far less used electrophiles. By following the pioneering
work of Kochi and others,5 we recently found that Fe(acac)3
catalyzes cross-coupling reactions between arylcoppers and
aryl iodides.6 In contrast to the elegant work of Fu¨rstner,7
aryl iodides are the only electrophiles reacting with aryl-
coppers. However, the cross-coupling between functionalized
(4) Selected examples: (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu,
H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. (b) Netherton, M. R.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910. (c) Huang, X.; Anderson,
K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653. (d) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126,
3058, and references therein. (e) Limmert, M. E.; Roy, A. H.; Hartwig, J.
F. J. Org. Chem. 2005, 70, 9364, and references therein.
(5) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b)
Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502. (c) See also:
Molander, G.; Rahn, B.; Shubert, D. C.; Bonde, S. E. Tetrahedron Lett.
1983, 24, 5449. (d) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199. (e)
Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901. (f) Hojo,
M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A. Angew.
Chem., Int. Ed. 2001, 40, 621. (g) Nakamura, M.; Hirai, A.; Nakamura, E.
J. Am. Chem. Soc. 2000, 122, 978. (h) Ho¨lzer, B.; Hoffmann, R. W. Chem.
Commun. 2003, 732. (i) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem.
2004, 2081.
(1) (a) Metal Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b)
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-Interscience: New York, 2002. (c) Transition Metals for
Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 2004.
(2) For a review on Pd-catalyzed cross-coupling reactions with aryl
chlorides, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
(3) Selected examples: (a) Dankwardt, J. W. J. Organomet. Chem. 2005,
690, 932, and references therein. (b) Bahmanyar, S.; Borer, B. C.; Kim, Y.
M.; Kurtz, D. M.; Yu, S. Org. Lett. 2005, 7, 1011. (c) Saeki, T.; Takashima,
Y.; Tamao, K. Synlett 2005, 1771. (d) Ackermann, L.; Born, R.; Spatz, J.
H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216.
(6) Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.; Knochel,
P. Angew. Chem., Int. Ed. 2005, 44, 1654.
10.1021/ol0529142 CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/14/2006

arylcopper reagents and aryl bromides or chlorides could be
efficiently performed by using Co(acac)2.8 The high reactivity
of cobalt catalysts for various C-C bond-forming reactions
has been recently reported by Cahiez,9 Oshima,10 Gosmini,11
and us.12 Interestingly, Fu¨rstner has shown that aryl triflates
and tosylates can be successfully used in iron-catalyzed cross-
coupling reactions with alkylmagnesium reagents.7b,c We
wish now to report that cobalt-catalyzed aryl-aryl cross-
coupling between aryl fluorides or tosylates and arylcopper
reagents occurs readily. In preliminary experiments, we have
examined the coupling of 2-fluorobenzophenone (1a;
1 equiv) with 4-methoxyphenylcopper (2a; 3 equiv),13 which
was prepared by the reaction of 4-methoxyphenylmagnesium
bromide with CuCN‚2LiCl14 in a 3:2:1 DME/THF/DMPU
mixture at room temperature (2 h) with Co(acac)2
(7.5 mol %), 4-fluorostyrene (4; 20 mol %),15 and Bu4NI
(1 equiv),16 as a catalytic system leading to the desired
product 3a in 98% yield (Scheme 1).17
Table 1. Cobalt-Catalyzed Cross-Coupling of Aryl Fluorides
Scheme 1. Co(II)-Catalyzed Cross-Coupling between
4-Methoxyphenylcopper (2a) and 2-Fluorobenzophenone (1a)
To explore the scope of this cross-coupling, we have
examined the reactions of various arylcopper reagents of type
2 with aryl fluorides bearing electron-withdrawing substit-
(7) (a) For a review on iron-catalyzed reactions, see: Bolm, C.; Legros,
J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217. (b) Fu¨rstner, A.;
Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856.
(c) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609. (d)
Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308. (e) Scheiper,
B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org. Chem. 2004, 69,
3943. (f) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem.
Soc. 2004, 126, 3686. (g) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(h) Martin, R.; Fu¨rstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955. (i)
Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J. W.; Hird, M. Chem.
Commun. 2004, 2822. (j) Fu¨rstner, A.; Martin, R.; Majima, K. J. Am. Chem.
Soc. 2005, 127, 12236. (k) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer,
F.; Ahr, M. Org. Lett. 2005, 7, 1943. (l) Nagano, T.; Hayashi, T. Org. Lett.
2005, 7, 491. (m) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Hird, M.
Chem. Commun. 2005, 4161.
(8) Korn, T. J.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 2947.
(9) (a) Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159. (b)
Avedissian, H.; Be´rillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998,
39, 6163.
(10) (a) For a review, see: Shinokubo, H.; Oshima, K. Eur. J. Org. Chem.
2004, 2081. (b) Fujioka, T.; Nakamura, T.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2002, 4, 2257. (c) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2002, 41, 4137. (d) Wakabayashi, K.; Yorimitsu, H.; Oshima, K.
J. Am. Chem. Soc. 2001, 123, 5374. (e) Ohmiya, H.; Tsuji, T.; Yorimitsu,
H.; Oshima, K. Chem.-Eur. J. 2004, 10, 5640. (f) Ikeda, Y.; Nakamura,
T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514. (g)
Mizutani, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 3959. (h)
Ohmiya, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2004, 33, 1240. (i)
Ohmiya, H.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005, 44,
2368. (j) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
2005, 44, 3488.
a The copper reagent is better represented by ArCu(CN)MgX (X ) Br,
Cl). b Yield of analytically pure product.
726
Org. Lett., Vol. 8, No. 4, 2006

Scheme 2 Co-Catalyzed Diarylation between 1g and the
Arylcopper Compounds 2b and 2d
Table 2. Cobalt-Catalyzed Cross-Coupling of Aryl Tosylates
uents. 2-Fluorobenzophenone (1a) reacts even faster with
3,4-dichlorophenylcopper (2b) (room temperature, 0.5 h), and
the corresponding ketone 3b is obtained in 87% yield (entry
2 of Table 1). Interestingly, functionalized fluorobenzo-
phenones undergo the cobalt-catalyzed cross-coupling reac-
tion as well. Thus, the fluorobenzophenone derivative 1b
bearing a pivalate substituent reacts with arylcopper 2c at
room temperature within 16 h to give the polyfunctional
ketone 3c in 72% yield (entry 3). The reaction between
copper reagent 2c and more electron-rich fluoroketones,
which are substituted with an OMe group (1c) or a NMe2
group (1d) in the para position, proceeds much faster (3 h
instead of 16 h), and the coupling products 3d and 3e are
isolated in 95-98% yield (entries 4 and 5). Remarkably,
arylcoppers bearing an electron-withdrawing cyano substitu-
ent in the meta (2d) or para position (2e) give the fastest
reactions and react within 15 min at room temperature with
the fluorobenzophenones 1b and 1c to give the ketones 3f
and 3g18 in 52 and 87% yield, respectively (entries 6 and
7).
a The copper reagent is better represented by ArCu(CN)MgX (X ) Br,
Cl). b Yield of analytically pure product.
Elevated temperatures are required for the coupling of
heterocyclic copper reagents with fluoroketones. 3-Benzo-
[b]thienylcopper (2f) smoothly undergoes the cross-coupling
with 2-fluorobenzophenone (1a) at 80 °C yielding the desired
product 3h in 94% yield (entry 8). Similarly, 3-thienylcopper
(11) (a) Gomes, P.; Gosmini, C.; Pe´richon, J. Org. Lett. 2003, 5, 1043.
(b) Gomes, P.; Gosmini, C.; Pe´richon, J. Synthesis 2003, 1909. (c) Amatore,
M.; Gosmini, C.; Pe´richon, J. Eur. J. Org. Chem. 2005, 989.
(12) Korn, T. J.; Knochel, P. Synlett 2003, 1892.
(13) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135. (b)
Taylor, R. J. K. Organocopper Reagents; Oxford University Press: Oxford,
1994. (c) Krause, N. Modern Organocopper Chemistry; Wiley-VCH:
Weinheim, Germany, 2002.
(14) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(18) Typical procedure for the synthesis of 3g: A 25 mL Schlenk tube,
equipped with a magnetic stirring bar and a septum, was charged with
i-PrMgCl‚LiCl (2.63 mL, 3.15 mmol, 1.2 M in THF) and cooled to -20
°C, and 4-bromobenzonitrile (544 mg, 2.99 mmol) was added. The reaction
mixture was warmed to 0 °C and stirred at this temperature for 2 h.
Subsequently, a solution of CuCN‚2LiCl (3.2 mL, 3.2 mmol, 1.0 M in THF)
was added. After stirring for an additional 10 min, DME (6 mL), DMPU
(2 mL), Bu4NI (370 mg, 1.00 mmol), 4-fluorostyrene (25 mg, 0.20 mmol),
Co(acac)2 (19.3 mg, 0.075 mmol), and (2-fluorophenyl)(4-methoxyphenyl)-
methanone (230 mg, 1.00 mmol) were added. The reaction mixture was
stirred for 15 min at room temperature and quenched with saturated
NH4Cl(aq)/NH3 (9:1) (50 mL). The organic phase was washed a second time
with saturated NH4Cl(aq)/NH3 (9:1) (50 mL), and the combined aq phases
were extracted with EtOAc (3 × 40 mL). The combined organic phases
were washed with brine (50 mL), dried over MgSO4, and filtered, and the
solvent was evaporated in vacuo. Flash chromatographical purification on
silica gel (pentane/diethyl ether ) 4:1) furnished 3g as a colorless solid
(271 mg, 0.87 mmol, 87%, mp: 120.8-122.9 °C).
(15) Piber, M.; Jensen, A. E.; Rottla¨nder, M.; Knochel, P. Org. Lett.
1999, 1, 1323.
(16) (a) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095. (b) Nguefack, J.-F.; Bollit, V.; Sinou, D. Tetrahedron Lett.
1996, 37, 5527. (c) Powell, N. A.; Rychnovsky, S. D. Tetrahedron Lett.
1996, 37, 7901. (d) Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999,
549. (e) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T.
H.; O¨ fele, K.; Beller, M. Chem.-Eur. J. 1997, 3, 1357. (f) Jensen, A. E.;
Knochel, P. J. Org. Chem. 2002, 67, 79.
(17) No full conversion is observed if only 1.7 or 2 equiv of copper
reagent is used. In the absence of the cobalt catalyst, no product was detected
even after 2 days.
Org. Lett., Vol. 8, No. 4, 2006
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(2g) reacts with 1d, providing ketone 3i in 42% yield (entry
9). Finally, even an alkyl-substituted ketone such as 1e and
ethyl 2-fluorobenzoate (1f) react with the electron-rich
arylcopper reagents 2h and 2a at 80 °C yielding ketones 3j
and 3k in 71 and 51% yield, respectively (entries 10 and
11).
Remarkably, a 2-fold cobalt-catalyzed cross-coupling is
possible with the pentafluorinated benzophenone 1g. Thus,
the reactions between 1g and arylcoppers 2b and 2d proceed
smoothly at room temperature within 30 min and furnish
the expected ketones 3l and 3m in acceptable yields (39-
50%, Scheme 2).19
Aryl tosylates are easily available from phenols. They are
more stable and less expensive than the corresponding
triflates and are therefore very attractive reagents for cross-
couplings. We have found that Co-catalyzed aryl-aryl cross-
coupling reactions between aryl tosylates and arylcopper
reagents proceed readily. Thus, various copper reagents such
as 2a or 2i undergo a cross-coupling efficiently with tosylate
5a furnishing the corresponding ketones 3a and 3n after 3 h
at room temperature in 82 and 78% yield, respectively
(entries 1 and 2 of Table 2). Interestingly, an alkoxy
substituent accelerates the Co-catalyzed reaction and the
ketones 3o and 3p are obtained in 78-96% yield after only
15 min at room temperature (entries 3 and 4).
an elevated reaction temperature and a longer reaction time.
Thus, the reaction between 2k and tosylate 5a proceeds at
80 °C (48 h), furnishing the ketone 3q in 54% yield (entry
5).
Finally, 3-thienylcopper (2g) smoothly undergoes the
cross-coupling with 5b at 80 °C within 15 min yielding the
desired product 3r in 74% yield (entry 6).
In summary, we have shown that Co(acac)2 catalyzes the
cross-coupling between functionalized arylcopper compounds
and various aryl fluorides and tosylates in a DME/THF/
DMPU mixture leading to polyfunctional biphenyls. The
presence of the promoters 4-fluorostyrene and Bu4NI is
crucial for the success of the reaction. Extension of the
reaction scope and further mechanistic studies are currently
being investigated in our laboratories.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
Merck Research Laboratories (MSD) for financial sup-
port. T.J.K. thanks the DFG and CNRS for a fellowship
(KN 347/5-2). We also thank Chemetall GmbH (Frankfurt)
and BASF AG (Ludwigshafen) for the generous gift of
chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The presence of ortho substituents in the copper reagent,
such as two methyl groups as in mesitylcopper (2k), requires
(19) A mixture of mono- and 2-fold cross-coupling products is obtained,
if only 3 equiv of the arylcopper reagents 2b or 2d are used.
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