Iron-catalyzed direct arylation through an aryl radical transfer pathway

Article abstract of DOI:10.1021/ja910687u

(Figure Presented) A general and efficient iron-catalyzed direct arylation of benzene and hetereoaryl derivatives using a cost-effective and environmentally benign catalyst is described. The reaction is performed under neat conditions and can proceed at room temperature.

Full text of DOI:10.1021/ja910687u

Published on Web 01/19/2010
Iron-Catalyzed Direct Arylation through an Aryl Radical Transfer Pathway
Fr e´ d e´ ric Vall e´ e, James J. Mousseau, and Andr e´ B. Charette*
Department of Chemistry, UniVersit e´ de Montr e´ al, P.O. Box 6128, Station Downtown, Montr e´ al,
Qu e´ bec, Canada, H3C 3J7
Received December 18, 2009; E-mail: andre.charette@umontreal.ca
Biaryl compounds are omnipresent in Nature as well as in
numerous biologically active compounds, including antibiotics and
Table 1. Iron-Catalyzed Direct Arylation of Benzene with Various
a
1
Aryl and Heteroaryl Iodides
various receptor inhibitors, and have been used to treat hypertension
as well as bipolar disorders. Consequently, they have attracted much
2
pharmaceutical interest, as well as in other areas including material
3
,4
and supramolecular sciences.
Figure 1. Various ways to prepare biaryl compounds.
The recent application of transition metals to direct functional-
ization processes has opened an opportunistic new class of
5
carbon-carbon bond forming reactions. Owing to the ubiquity of
C-H bonds, the possibility of directly introducing a new func-
tionality via a direct C-H bond transformation is a highly attractive
6
strategy in synthesis. Although several Rh, Pd, and Ru catalysts
have proven to be highly effective in such direct coupling
7
processes, the development of new, cost-effective, and environ-
mentally benign catalysts for the aforementioned transformations
8
remains a significant challenge. Iron has recently emerged as a
promising alternative as a catalyst for direct C-C bond forming
reactions due to their low cost, toxicity, and offer attractive industrial
9
,10
possibilities in terms of sustainable chemistry (Figure 1).
While Fe catalysis has been investigated in the field of cross
11
coupling reactions, the envisaged direct arylation of arenes poses
a challenge and often requires stoichiometric quantities of iron
1
2
reagents. In addition, Nakamura recently described the elegant
use of an Fe catalyst to perform directed arylation reactions.
However, drawbacks of these contributions are that they require
not only a directing group, but also a large excess of Grignard
9
reagent in conjunction with a stoichiometric amount of Zn salts.
Herein, we report our efforts toward the development of a high
yielding, mild, iron-catalyzed direct arylation of unactivated arenes
with aryl iodides without the addition of a stoichiometric amount
of metal reagent or the requirement of a directing group.
Our optimization studies determined that a mixture of 4-iodot-
oluene (1 equiv), benzene (100 equiv), KOt-Bu (2 equiv), Fe(OAc)
2
a
2
Reaction conditions: 1 (1 equiv), benzene (100 equiv), Fe(OAc) (5
(5 mol %), and bathophenanthroline (10 mol %) at a relatively mild
mol %), bathophenanthroline (10 mol %), KOt-Bu (2 equiv), 80 °C,
b
c
8
0 °C provided the desired tolyl biphenyl in 86% yield (Table 1,
2
0 h. Reaction performed at 125 °C. Reaction performed at rt for
13
d
entry 3). Interestingly the catalyst proved to be particularly
60 h. Reaction performed at 90 °C.
1
514 9 J. AM. CHEM. SOC. 2010, 132, 1514–1516
10.1021/ja910687u  2010 American Chemical Society

C O M M U N I C A T I O N S
efficient, as even a catalyst loading of 0.5 mol % furnished the
product in 76% yield (GC) when performed at 125 °C.
Recently, Bolm and Buchwald reported that reactions catalyzed
3
with FeCl may be positively affected by trace quantities of other
1
4
With the optimal conditions in hand, we explored the scope of our
method using commercially available aryl iodides as coupling partners
for benzene. Gratifyingly, the reaction was found to be quite general.
The reactions proceeded cleanly, and biaryls 3 were obtained in
moderate to excellent yields (Table 1). In a few cases, trace amounts
of biphenyl resulting from the coupling of two benzene molecules were
detected, although this side product could be readily removed.
Unsubstituted aryl iodides provided the biaryl products in good to
excellent yields (entries 1, 2). 4-Iodotoluene reacted well under the
standard reaction conditions, although 4-bromotoluene was found to
be less effective (entries 3, 4) and 4-chlorotoluene proved unreactive.
metals, particularly Cu. Cognizant of this possibility, we inves-
tigated whether a catalytic amount of Cu could influence the reaction
outcome. Fe(OAc)
with 4-iodotoluene (Table 3). These findings suggest that the purity
of Fe(OAc) does not play a crucial role in the success of the
transformation. Indeed, using Fe(OAc) with high purity (99.995%,
entry 1) yielded improved results with respect to reagent grade
Fe(OAc) (97%, entry 2). Both CuOAc and Cu(OAc) were
2
was examined in the direct coupling of benzene
2
2
2
2
ineffective as catalysts (entries 3, 4). Furthermore, using Fe in
conjunction with Cu proved to be detrimental, providing 57% and
48% yields with CuOAc and Cu(OAc)
2
respectively (entries 5, 6).
2
-Iodotoluene gave a very good yield when the reaction was performed
a
Table 3. Direct Arylation in Presence of Fe and Cu Catalysts
at 125 °C (entry 5). Electron-rich iodides were exceptionally effective
partners (entries 6-8). These species proved to be even effective at
rt, as moderate yields were obtained with slightly prolonged reaction
times. Electron-poor substrates were operative but provided slightly
lower yields (entries 9-10), even iodides bearing enolizable centers
b
entry
catalyst
purity (%)
commercial source yield(%)
c
1
2
3
4
5
6
Fe(OAc)2
Fe(OAc)
99.995
Aldrich
Strem
Strem
Strem
98 (87)
91
6
2
97
99
97
Cu(OAc)
Cu(OAc)
2
9
(entry 9). Both F and Cl substitutions were tolerated (entries 11, 12).
Fe(OAc)
Fe(OAc)
2
+ Cu(OAc) 99.995 + 99 Aldrich Strem 57
+ Cu(OAc) 99.995 + 97 Aldrich Strem 48
Gratifyingly, pyridyl and pyrazyl iodides provided the corresponding
heterobiaryls with excellent results (entries 13-15).
2
2
a
Reaction conditions: 1 (1 equiv), benzene (100 equiv), cat. (5 mol
Next, the coupling of different arene derivatives was examined.
They combined with aryl iodides to afford the corresponding biaryl
products in moderate to good yields (Table 2). Toluene provided a
mixture of regioisomers favoring the o- position over the m- and
p- positions with a moderate overall yield (Table 2, entry 1). PhTMS
also provided a mixture of regioisomers, favoring the p- position
over the m- and o- positions with a low overall yield, (entry 2).
p-Xylene reacted successfully with 1c furnishing 5c in 81% yield
%
), bathophenanthroline (10 mol %), KOt-Bu (2 equiv), 80 °C, 20 h.
Yield determined by GCMS analysis using an internal standard.
Yield of isolated product.
b
c
Scheme 1. Effect of Radical Inhibitors
(
entry 3). Interestingly, hindered 4d reacted with 1c to afford 5d
in moderate yield (entry 4). Even 4f reacted with both 1c and 1f
giving the corresponding products in moderate yields.
To gain some understanding of the reaction, a KIE of 1.04 was
determined. This result suggested that the C-H bond breaking event
was not rate limiting. This was surprising and prompted us to consider
a possible radical pathway, which is known to exhibit such low values
in radical aromatic substitutions. This was indeed supported by
experiments performed in the presence of radical scavengers. Galvi-
noxyl and TEMPO (1 equiv) completely inhibited the reaction (Scheme
Table 2. Iron-Catalyzed Direct Arylation of Arene Derivatives with
a
Various Aryl Iodides
15
1). Other experiments (Table 4) demonstrated that tBuOK is likely
less important in the radical transformation as has been reported (entry
16
2)
and that a metal-free version of the reaction using AIBN was
possible; however, it was far less efficient (entry 3).
Due to the results shown in Tables 3 and 4 and Scheme 1, we
believe that a plausible mechanistic pathway could be analogous
to that reported in a metal-catalyzed living radical polymerization
1
7
reaction (Figure 2). The Fe-catalyzed radical direct coupling is
believed to proceed via reversible activation of the aryl-halogen
bond by via a one-electron oxidation of the metal center to form
an initiating radical species and an oxidized metallo-intermediate.
This intermediate is then transformed into the biaryl product via
radical addition onto an arene (possibly precoordinated to Fe) and
III
proximal abstraction of a halogen atom from the Fe complex.
This regenerates the active form of the catalyst as well as HI that
can be quenched by tBuOK. Although we cannot rule out a more
prominent role of tBuOK, the presence of tBuOH is observed in
the reaction mixture. As in the metal-catalyzed living radical
polymerization, the reaction would rely on creating a dynamic
equilibrium between a low concentration of growing radicals and
a large amount of dormant species, which cannot propagate and/or
self-terminate. As a result, side reactions are limited, and the process
of direct coupling is efficient. Such a mechanism would explain
a
2
Reaction conditions: 1 (1 equiv), arene (100 equiv), Fe(OAc) (5
mol %), bathophenanthroline (10 mol %), KOt-Bu (2 equiv), 130 °C,
0 h. Yield determined as a mixture of isomers.
b
2
J. AM. CHEM. SOC. 9 VOL. 132, NO. 5, 2010 1515

C O M M U N I C A T I O N S
the increased efficiency of electron-rich species, as they could
the Canada Research Chair Program, the Canada Foundation for
Innovation, and the Universit e´ de Montr e´ al. J.J.M. is grateful to
FQRNT for a doctoral scholarship.
15
stabilize radical intermediates, providing a positive ꢀ-effect. This
may explain the preference for o-substitution in toluene, due to
the formation of a tertiary radical stabilized though additional
hyperconjugation. In addition, the observed ratios are consistent
Supporting Information Available: Experimental procedures,
sample spectra, and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
5
with aryl radical substitutions onto toluene.
a
Table 4. Direct Arylation in Presence of Fe and AIBN
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6
426.
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