Iron-catalyzed aryl-aryl cross-couplings with magnesium-derived copper reagents

Article abstract of DOI:10.1002/anie.200462013

(Chemical Equation Presented) Well-matched couples: Functionalized aryl and heteroaryl copper species obtained from the corresponding magnesium derivatives undergo Fe-catalyzed cross-coupling reactions with aryl iodides that bear keto, ester, triflate, or nitrile groups (see scheme).

Full text of DOI:10.1002/anie.200462013

Communications
Biphenyl Synthesis
Iron-Catalyzed Aryl–Aryl Cross-Couplings with
Magnesium-Derived Copper Reagents**
Ioannis Sapountzis, Wenwei Lin, Christiane C. Kofink,
Christina Despotopoulou, and Paul Knochel*
Dedicated to Professor Michael Veith
on the occasion of his 60th birthday
Transition-metal-catalyzed cross-coupling reactions are very
À
powerful C C bond-forming reactions, especially between
C(sp2) centers at which typical SN2 substitutions cannot
operate.[1] Palladium(0) catalysts are the most widely and
reliably used,[1,2] especially if appropriate ligands such as
sterically hindered phosphines are present.[3] Nickel(0) com-
plexes have also found useful applications, but appear to have
[*] Dr. I. Sapountzis, Dipl.-Chem. W. Lin, Dipl.-Chem. C. C. Kofink,
C. Despotopoulou, 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. I.S. thanks Aventis Pharma (Frankfurt
a. M.) for a fellowship. We also thank Chemetall GmbH (Frankfurt),
Wacker Chemie GmbH (Mꢁnchen), BASF AG (Ludwigshafen), and
Bayer Chemicals AG 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.200462013
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Chemie
a less general scope.[4] Following the pioneering work of Kochi
and co-workers,[5] iron catalysts have recently been very
actively investigated for their performance in cross-coupling
reactions.[6] Although highly efficient cross-coupling reactions
could be realized between a range of alkyl magnesium
reagents and aryl halides or aryl sulfonates, iron-catalyzed
cross-coupling between two aryl moieties remained problem-
atic owing to extensive homo-coupling reactions of the aryl
magnesium species.[6,7] We assumed that the homo-coupling
side reaction may arise by the formation of ferrate complexes
with the highly reactive organomagnesium compounds.[7] We
therefore transmetalated the aryl magnesium species to the
corresponding organozinc compounds, which have a lower
tendency to form unstable ate complexes.[8] Unfortunately, no
iron-catalyzed cross-coupling reaction of aryl zinc reagents
with aryl halides could be observed under various reaction
conditions.
Table 2: Fe-catalyzed cross-coupling between functionalized aryl copper
reagents 1 and aryl iodides 3 to give 4.
Entry Aryl copper 1[a] Aryl iodide 3
Product 4
Yield
[%][b]
1
2
3
PhCu
93
80
86
1a
3a
4a
PhCu
1a
3b
3c
4b
4c
PhCu
1a
4
5
6
75
68
86
We therefore turned our attention to other organometallic
species and found that organocopper compounds[9] of type 1,
prepared by the reaction of functionalized aryl magnesium
chlorides 2[10] with CuCN·2LiCl,[11] react with functionalized
aryl halides 3 in the presence of catalytic amounts of
[Fe(acac)3] (10 mol%) in DME/THF (3:2) between 25 and
1b
1c
1d
3a
3d
3a
4d
4e
4 f
808C, leading to polyfunctional biphenyls of type
4
(Scheme 1, Table 1 and Table 2).
7
8
9
76
72
58
1e
1d
3a
3e
4g
4h
Scheme 1. Fe-catalyzed cross-coupling of copper reagents 1 with aryl
iodides 3. FG1 =CO2Et, OMe, OTf; FG2 =CO2Et, COPh, COMe, CN,
CONR2.
1e
3 f
4i
Table 1: Cross-coupling of 2-substituted benzophenones with
PhCu(CN)MgCl in the presence of [Fe(acac)3].
10
11
50
62
1d
1 f
3b
3g
4j
Entry
X
Conversion [%][a]
1
2
3
4
5
I
Br
Cl
OTf
OTs
100 (<5)[b], (55)[c]
86 (93)[d]
75 (77)[d]
35 (100)[e]
0
4k
[a] The copper reagent is better represented as ArCu(CN)MgCl. [b] Yield
of analytically pure products.
[a] Conversion after 30 min (determined by GC). [b] Conversion in the
absence of [Fe(acac)3] after 30 min. [c] Conversion after 48 h in the
absence of [Fe(acac)3]. [d] Conversion after 18 h. [e] Conversion after 2 h
in THF.
Remarkably, by using organocopper reagents 1, the
amount of homo-coupling is decreased, and the cross-
coupling reaction occurs readily. The nature of the leaving
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group of the electrophilic aromatic reagent 3 is also important
(Table 1). Thus, the reaction of PhCu(CN)MgCl (1a) with 2-
iodobenzophenone (3a) is complete within 30 min at 258C. In
the absence of [Fe(acac)3], less than 5% of biphenyl 4a is
observed after 30 min, and a conversion of approximately
54% only is observed after 48 h (Table 1, entry 1). The
corresponding bromide (2-bromobenzophenone; Table 1,
entry 2) also reacts fast, but after 30 min leads only to 86%
conversion. A reaction time of 18 h only slightly improves the
conversion (93%). Similarly, 2-chlorobenzophenone does not
lead to complete conversion (75% after 30 min, but only 77%
after 18 h). A significantly slower conversion is observed with
a triflate substituent (X = OTf), but no reaction is observed
with a tosylate (X = OTs) as leaving group. The fact that 2-
chlorobenzophenone is converted indicates that the mecha-
nism of the reaction does not involve a halogen–copper
exchange reaction.[12,13] Interestingly, the reactivity of aryl
copper with aryl halides is the opposite to that observed for
the FeIII-catalyzed reaction with alkyl magnesium species, for
which aryl iodides are poorer substrates than aryl bromides or
chlorides.[7]
We then investigated the reaction scope and noticed a
remarkable functional-group compatibility and chemoselec-
tivity. The reaction of PhCu(CN)MgCl (1a) is especially fast
with 2-iodobenzophenone (3a) (30 min) and the correspond-
ing ketone 4a was obtained in 93% yield (Table 2, entry 1). 4-
Iodobenzophenone (3b) reacts at 258C within 4 h to give the
desired ketone 4b in 80% yield (Table 2, entry 2). Remark-
ably, a methyl ketone, such as 2-iodophenyl methyl ketone
(3c) undergoes iron-catalyzed cross-coupling without any
competitive deprotonation of the methyl ketone or addition
to the carbonyl function. Func-
Scheme 2. Comparison between 2-, 3-, and 4-substituted substrates in
the iron-catalyzed cross-coupling.
considerably. Thus, 4-iodoanisole leads only to some con-
version at 808C after 12 h. We also compared the cross-
coupling rate between 2-, 3-, and 4-substituted ethyl iodo-
benzoate (3g–i) with PhCu(CN)MgCl in the presence of
[Fe(acac)3] (10 mol%). Interestingly, the 2- and 4-substituted
iodobenzoates 3g and 3i react five times faster than the 3-
substituted ester 3h (Scheme 2). This may indicate that the
slow step of the cross-coupling is the nucleophilic attack of the
catalytically active species to the benzoates 3g–i.[14]
Heterocyclic copper compounds are also suitable reagents
for this cross-coupling reaction. Thus, organocopper reagents
1g and 1h react under standard conditions with the iodides 3 f
and 3e to furnish functionalized indole 4o and pyridine 4p,
respectively (Scheme 3).
tionalized
aryl
magnesium
reagents that bear an ester
group at C2 or C4, such as 1b,
1c, or 1d also undergo cross-
coupling within a few hours,
leading to the expected products
4d–f in 68–86% yield (Table 2,
entries 4–6). Thereby, the steri-
cally hindered functionalized
2,2’-substituted biphenyl 4d is
prepared in 75% yield (Table 2,
entry 4).
Also,
Grignard
reagents that bear an electron-
donating group (e.g. 1e) react
well to furnish the ketone 4g in
76% yield (Table 2, entry 7).
Scheme 3. Cross-coupling of heterocyclic copper reagents.
Various aryl iodides that bear
electron-withdrawing substitu-
ents at C4 (such as a cyanide
(3e), an amide (3 f), or a ketone (3b)) undergo smooth cross-
coupling and lead to the products 4h–j in 50–70% yield
(Table 2, entries 8–10). Remarkably, copper reagent 1 f, which
bears a triflate group, reacts with ethyl 2-iodobenzoate 3g to
furnish biphenyl 4k in 62% yield (Table 2, entry 11).
We noticed that the presence of an electron-withdrawing
substituent at the aryl iodide accelerates the cross-coupling
reaction and that donor substituents slow down the reaction
In summary, we have shown that the Fe-catalyzed cross-
coupling reaction between functionalized heteroaryl and aryl
copper reagents derived from the corresponding organo-
magnesium reagents proceeds readily with functionalized aryl
iodides.[15] The electron-poor electrophilic iodides undergo
the cross-coupling reaction more readily. This new procedure
presents an economical way (ꢀ 3 times cheaper than Pd-
catalyzed reactions) to perform aryl–aryl cross-couplings.
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Experimental Section
Typical procedure (4h): A 25-mL Schlenk tube equipped with a
magnetic stirring bar and a septum was charged with ethyl 4-
iodobenzoate (855 mg, 3.10 mmol) and DME (5 mL), and the
solution was cooled to À208C. iPrMgCl (3.3 mL, 3.0 mmol, 0.90m in
THF) was then added, and the reaction mixture was stirred at this
temperature for 15 min. Subsequently, a solution of CuCN·2LiCl
(2.8 mL, 2.8 mmol, 1.0m in THF) was added, and the reaction mixture
was stirred for an additional 10 min. A solution of 4-iodobenzonitrile
(3e) (229 mg, 1.00 mmol) and [Fe(acac)3] (35 mg, 0.10 mmol) dis-
solved in DME (3 mL) was added in one portion, and the reaction
mixture was heated at 808C for 3 h. The reaction mixture was
quenched with saturated aqueous NH4Cl and was extracted with
CH2Cl2 (3 ꢀ 40 mL). The organic fractions were washed with satu-
rated aqueous NH4Cl/NH3 (9:1) (50 mL) and brine (50 mL), dried
over Na2SO4, filtered, and the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/Et2O 9:1) furnished
4h as a colorless solid (181 mg, 72%).
Received: September 16, 2004
Published online: December 30, 2004
Keywords: cross-coupling · homogeneous catalysis · iron ·
.
copper · magnesium
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[14] We submitted the substituted iodoesters 3g–i to Pd-and Ni-
catalyzed cross-coupling and found that in the case of Pd
catalysis, 4-iodoester 3i reacts significantly faster than 3g and
3h, whereas under Ni catalysis, the 3-iodoester 3h is the fastest.
These results indicate that the mechanism of Ni-, Pd- and Fe-
catalyzed cross-coupling reactions is significantly different, as
electronic and steric effects of the substituents affect them
differently (see Supporting Information for details).
[15] Interestingly, copper reagents made from aryl lithium species
can also be used. The reaction proceeds at a similar rate
(somewhat faster). The occurrence of an I–Cu exchange reaction
is minimized with this type of copper species (ArCu(CN)Li).
[16] A patent application for this and related crossing-coupling
reactions has been filed.
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