Cobalt(II)-catalyzed cross-coupling of polyfunctional aryl copper reagents with aryl bromides and chlorides

Article abstract of DOI:10.1002/anie.200500099

(Chemical Equation Presented) Polyfunctionalized biphenyl and heteroaromatic compounds were formed in the presence of [Co(acac)₂], Bu₄Nl, and 4-fluorostyrene (3) through a smooth cross-coupling reaction between organocopper reagents 1, prepared by the transmetalation of functionalized aryl magnesium halides with CuCN·2 LiCl, and aryl halides 2 that bear electron-withdrawing substituents. acac = acetylacetonate, DME = 1,2-dimethoxyethane, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

Full text of DOI:10.1002/anie.200500099

Angewandte
Chemie
Cross-Coupling Reactions
reactions,[15] was not effective alone,[16] but in combination
with Bu4NI a conversion of 100% was reached within 21 h.
The use of DMPU[17] as a cosolvent also led to a considerable
rate improvement. A conversion of 100% was now observed
after 15 min at 808C, with the desired product 3a formed as
the sole product. Under optimized reaction conditions (1a
(1 equiv), 2a (1.7 equiv), [Co(acac)2] (7.5 mol%), Bu4NI
(1 equiv), 4 (20 mol%)), the ester 3a was isolated in 77%
yield (Scheme 1).
Cobalt(ii)-Catalyzed Cross-Coupling of
Polyfunctional Aryl Copper Reagents with
Aryl Bromides and Chlorides**
Tobias J. Korn and Paul Knochel*
There are now a number of efficient experimental procedures
available for palladium- and nickel-catalyzed cross-coupling
reactions of aromatic organometallic reagents with aryl
halides.[1,2] However, the high cost of palladium and the
required phosphine ligands, as well as the high toxicity of
nickel catalysts, led us to explore the use of alternative metals
for such coupling reactions. Following the pioneering work of
Kochi and co-workers and others,[3] we found recently that
functionalized aryl copper reagents smoothly undergo cross-
coupling with aryl iodides in the presence of [Fe(acac)3] as the
catalyst.[4] In contrast to the elegant method of Fꢀrstner and
co-workers,[5] in our case only aryl iodides could be used; aryl
bromides and chlorides did not react.
Scheme 1. The CoII-catalyzed cross-coupling reaction of 2a with ethyl
2-bromobenzoate (1a) under optimized conditions. acac=acetylaceto-
nate, DME=1,2-dimethoxyethane, DMPU=1,3-dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone.
To extend the scope of this cross-coupling reaction, we
examined other metal salts as catalysts. We reported recently
the cobalt(ii)-catalyzed cross-coupling of allylic chlorides with
dialkyl zinc reagents[6] and of heteroaromatic chlorides with
aromatic and heteroaromatic Grignard reagents.[7] Other
cobalt-catalyzed reactions have also been discovered recently
by the research groups of Cahiez,[8] Oshima,[9] and Gosmini.[10]
Preliminary experiments showed that [Co(acac)2] catalyzes
efficiently the cross-coupling of aryl copper derivatives with
aryl bromides and chlorides; the reaction is therefore
complementary to the recently reported iron-catalyzed pro-
cess.[4] As a test reaction, we examined the coupling of ethyl 2-
bromobenzoate (1a; 1 equiv) with the phenylcopper reagent
2a (3 equiv),[11] which was prepared by the reaction of
PhMgCl with CuCN·2LiCl[12] in a 2:1 mixture of DME/THF
at 808C. In the absence of the catalyst, no reaction was
observed after 4 h; the desired product 3a was only detected
after 24 h.[13] When [Co(acac)2] (10 mol%) was added, a
conversion of 46% was observed after 15 min; however, the
conversion increased to just 49% within the next 4 h of
reaction time. A significant improvement was observed upon
the addition of Bu4NI (3 equiv),[14] which led to a conversion
of 81% after 21 h. The addition of 4-fluorostyrene (4;
20 mol%), which was known to promote cross-coupling
The additives Bu4NI and styrene 4 were still required in
the polar solvent mixture containing DMPU, as only partial
conversion was observed in their absence. We studied the
scope of the reaction and found that a broad range of aryl
copper reagents of type 2 reacted with a variety of aryl
bromides with electron-withdrawing substituents. Thus, the 4-
methoxyphenylcopper reagent 2b underwent a smooth cross-
coupling reaction with 1a at 808C to afford the desired
biphenyl derivative 3b in 79% yield (Table 1, entry 2). Aryl
copper species with electron-withdrawing substituents dis-
played lower reactivity. However, 2c underwent the coupling
with the reactive compound 1b at 808C to give ketone 3c in
62% yield (Table 1, entry 3). Similarly, the bromo diester 1c
reacted with various aryl copper derivatives of low reactivity,
such as 2d or 2e; in these cases the cross-coupling products 3d
and 3e were isolated in 65 and 54% yield, respectively
(Table 1, entries 4 and 5). The heterocyclic copper reagent 2 f
reacted rapidly with 1b at 808C to give the substituted
pyridine 3 f in 62% yield (Table 1, entry 6). As mentioned
above, aryl copper compounds with an electron-donating
substituent displayed high reactivity in these cross-coupling
reactions. Thus, 2b reacted with 1b within 1 h at room
temperature (89% yield; Table 1, entry 7). 4-Bromobenzo-
phenone (1d) also underwent complete conversion at 258C
within 7.5 h (73% yield; Table 1, entry 8). However, 3-
bromobenzophenone (1e) reacted only slowly in the desired
cross-coupling; the expected product 3i was obtained in 25%
yield after 24 h at room temperature (Table 1, entry 9).
Interestingly, the corresponding cyano-substituted aryl
copper derivatives 2g–i reacted smoothly with 1b to provide
ketones 3j–l in 74–90% yield (Table 1, entries 10–12). A
methyl ketone is an especially sensitive functionality, which
can be readily deprotonated by numerous organometallic
species. Remarkably, we found that 2-bromoacetophenone
(1 f) reacted smoothly with various aryl copper reagents to
[*] Dipl.-Chem. T. J. Korn, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG), and Merck Research Laboratories
(MSD) for financial support. T.J.K. thanks the DFG and the CNRS for
a fellowship. We also thank Chemetall and BASF for generous gifts
of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500099
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Table 1: [Co(acac)2]-catalyzed reaction of aryl copper derivatives 2 with aryl bromides 1 to give products 3.
Entry
Aryl bromide 1
Aryl copper reagent 2[a]
Product 3
Conditions [8C, h]
Yield [%][b]
1
2
1a
1a
2a: R=H
2b: R=OMe
3a: R=H
3b: R=OMe
80, 0.25
80, 0.25
77
79
3
1b
2c
3c
80,3
62
4
5
1c
1c
2d: R=F
2e: R=CO2Et
3d: R=F
3e: R=CO2Et
80, 0.5
80, 18
65
54
6
7
1b
2 f
3 f
80, 16
62
89
1b
2b
3g
RT, 1
8
9
1d
1e
2b
2b
3h
3i
RT, 7.5
RT, 24
73
25
10
1b
2g
3j
RT, 0.5
90
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Table 1: (Continued)
Entry Aryl bromide 1
Aryl copper reagent 2[a]
Product 3
Conditions [8C, h]
Yield [%][b]
11
1b
1b
2h
3k
RT, 0.5
80
74
12
2i
3l
RT, 2.5
13
14
1 f
1 f
2b: R=OMe
2g: R=CN
3m: R=OMe
3n: R=CN
RT, 0.5
RT, 1
90
77
15
1 f
2j
3o
RT, 15
83
16
17
1 f
2k
3p
3q
RT, 0.25
RT, 0.25
70
42
PhCu
1g
2a
[a] The copper reagent is better represented as ArCu(CN)MgCl. [b] Yield of analytically pure product. RT=room temperature.
give the polyfunctional ketones 3m–p in 70–90% yield
(Table 1, entries 13–16). An unexpected reactivity difference
was observed between the 9-phenanthrylcopper reagent 2k
and the 1-naphthylcopper reagent 2j. Whereas 2k reacted
with 1 f within 15 min at room temperature, 2j required a
reaction time of 15 h at the same temperature (Table 1,
entries 15 and 16). Finally, we found a remarkable compat-
ibility of the reaction conditions with an aldehyde function-
ality. Thus, 2-bromobenzaldehyde (1g) reacted readily with
2a to provide 2-phenylbenzaldehyde (3q) in 42% yield
(Table 1, entry 17).
phenone (5) with the aryl copper compounds 2a, 2b, and 2h
proceeded smoothly at 258C within 15 min to 1.5 h under our
typical reaction conditions and furnished the expected
ketones 3r, 3g, and 3k in almost quantitative yield
(Scheme 2).
In further experiments to establish the scope of this
method, we investigated the cross-coupling of bromoketones
6a,b with heterocyclic substituents. An efficient cross-cou-
pling reaction took place with 2h, as well as with the
heteroaromatic copper reagents 2 f and 2l; the products 7a–
c were formed in 74–88% yield (Scheme 3).
The excellent reactivity of aryl bromides with electron-
withdrawing substituents led us to examine cross-coupling
reactions with aryl chlorides. The reaction of 2-chlorobenzo-
In summary, we have shown that [Co(acac)2] catalyzes the
cross-coupling of functionalized aryl copper reagents with a
variety of chloro- and bromoaryl ketones and bromoaryl
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for 0.5 h at room temperature, then quenched with a saturated,
aqueous solution of NH4Cl/NH3 (9:1; 50 mL). The organic phase was
washed a second time with a saturated, aqueous solution of NH4Cl/
NH3 (9:1; 50 mL), and the combined aqueous 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. Purification by flash chromatography on
silica gel (pentane/diethyl ether 4:1) furnished 3j as a light-yellow
solid (256 mg, 0.90 mmol, 90%; m.p.: 91.4–92.38C).
Received: January 11, 2005
Published online: April 12, 2005
Keywords: cobalt · cross-coupling · Grignard reagents ·
heterocycles · organocopper compounds
Scheme 2. Cobalt-catalyzed cross-coupling reactions of 2-chlorobenzo-
.
phenone (5) with aryl copper compounds: a) 5 (1 equiv), 2 (1.7 equiv),
[Co(acac)2] (7.5 mol%), DME/THF/DMPU (3:2:1), 4 (20 mol%),
Bu4NI (1 equiv).
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Scheme 3. Cobalt-catalyzed cross-coupling reactions of heterocycle-
substituted bromoaryl ketones 6 with heteroaryl and aryl copper
compounds: a) 6 (1 equiv), 2 (1.7 equiv), [Co(acac)2] (7.5 mol%),
DME/THF/DMPU (3:2:1), 4 (20 mol%), Bu4NI (1 equiv).
esters in a DME/THF/DMPU solvent mixture in the presence
of the promoters 4-fluorostyrene and Bu4NI. The reaction
leads to polyfunctional biphenyl derivatives and heterocyclic
analogues. The remarkable functional-group compatibility of
organocopper reagents with esters, ketones, and even alde-
hydes should make this cross-coupling method especially
attractive for multistep syntheses, as it should be possible to
avoid the extensive use of protecting groups.
Experimental Section
Typical procedure: 3j: 4-Bromobenzonitrile (309 mg, 1.70 mmol) was
added to iPrMgCl·LiCl (1.73 mL, 1.70 mmol, 0.98m in THF) at
À208C in a 25-mL Schlenk tube equipped with a magnetic stirring bar
and a septum. The reaction mixture was warmed to 08C and stirred at
this temperature for 2 h.
A solution of CuCN·2LiCl (1.9 mL,
1.9 mmol, 1m in THF) was then added, and the mixture was stirred
for an additional 10 min. DME (6.0 mL), DMPU (2.0 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-bromobenzophenone (261 mg,
1.00 mmol) were then added, and the reaction mixture was stirred
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