Selective Kumada biaryl cross-coupling reaction enabled by an iron(iii) alkoxide-N-heterocyclic carbene catalyst system

Article abstract of DOI:10.1039/c4cc02930e

A catalyst system comprising Fe₂(O^tBu)₆ and an N-heterocyclic carbene ligand enables efficient syntheses of (hetero)biaryls from the reactions of aryl Grignard reagents with a diverse spectrum of (hetero)aryl chlorides. Amongst the alkoxide and amide counterions investigated, tert-butoxide was the most effective in inhibiting the homocoupling of arylmagnesiums. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02930e

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Selective Kumada biaryl cross-coupling reaction
enabled by an iron(III) alkoxide–N-heterocyclic
carbene catalyst system†
Cite this:DOI: 10.1039/c4cc02930e
Received 21st April 2014,
Accepted 6th June 2014
Yi-Yuan Chua and Hung A. Duong*
DOI: 10.1039/c4cc02930e
www.rsc.org/chemcomm
A catalyst system comprising Fe2(OtBu)6 and an N-heterocyclic fluoride strongly coordinates to the iron centre and inhibits
carbene ligand enables efficient syntheses of (hetero)biaryls from the formation of a ferrate complex that is responsible for the
the reactions of aryl Grignard reagents with a diverse spectrum of homocoupling pathway.
(hetero)aryl chlorides. Amongst the alkoxide and amide counterions
We hypothesized that, similar to fluoride, alkoxide and amide
investigated, tert-butoxide was the most effective in inhibiting the ancillary ligands may induce cross-coupling selectivity in the iron-
homocoupling of arylmagnesiums.
catalysed reaction. Alkoxides, for example, are known to form strong
bonds with the early and middle first-row transition metals through
Biaryls are ubiquitous in fine chemicals, agrochemicals, pharma- ionic bonding, which is reinforced by p-donation.8 In fact, these
ceuticals and materials.1 A common method to prepare biaryls is via ligands have permitted the isolation of a wide range of metal
the palladium- or nickel-catalyzed cross-coupling reactions.2 There complexes,8 including those of iron.9 We envisioned that, in contrast
are, however, some major economic and ecological disadvantages to fluoride, the properties of alkoxides and amides could be altered
associated with the use of these metals. Palladium is a precious for fine tuning of the iron centre. In this report, we disclose an iron
metal whose supply fluctuates while nickel has high toxicity, which alkoxide/NHC catalyst system that promotes the selective biaryl
taints its use in consumer goods and healthcare products. The cross-coupling (Scheme 1b). The scope of the reaction encompasses
search for alternative catalysts based on cheap and environmentally a diverse spectrum of (hetero)aryl chlorides, leading to the synthesis
benign metals is thus an increasingly important task. Iron, being the of a broad array of valuable (hetero)biaryls.
most abundant metal in the earth’s crust (4.7% by weight) with low
toxicity, is an excellent candidate for these purposes.
We set out to explore the influence of strongly basic counter-
ions on the catalytic activity of an iron catalyst in the cross-
A major challenge in the development of iron-catalysed Kumada coupling reaction of chlorobenzene 1a and p-tolylmagnesium
reaction for biaryl cross-coupling is the propensity of aryl Grignard bromide 2a (Table 1). A combination of 3 mol% FeBr3, 9 mol%
reagents to undergo homocoupling reaction.3 A number of efficient
catalyst systems have been developed for the cross-coupling of aryl-
magnesiums with aryl halides bearing an activating group. Examples
include coupling of p-electron deficient N-heteroaryl (pseudo)-
halides at the a-carbon (i.e. 2-pyridyl),4 and of chlorostyrenes
utilizing olefin as an activating substituent (Scheme 1a).5 To date,
the only catalyst system facilitating selective cross-coupling of non-
activated aryl halides and aryl Grignard reagents was that reported
by Nakamura et al. A combination of iron(III) fluoride and an
N-heterocyclic carbene (NHC) ligand was found to suppress the
homocoupling reaction (Scheme 1b).6,7 It was proposed that
Institute of Chemical and Engineering Sciences (ICES), Agency for Science,
Technology and Research (A*STAR), 8, Biomedical Grove, Neuros, #07-01,
Singapore 138665. E-mail: duong_hung@ices.a-star.edu.sg; Fax: +65 6464 2102;
Tel: +65 6799 8519
† Electronic supplementary information (ESI) available: Full experimental proce-
dures, compound characterisation and copies of NMR spectra. See DOI: 10.1039/
Scheme 1 Selective Kumada biaryl cross-coupling under iron catalysis.
c4cc02930e
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Table 1 Effects of counterions and ligands on the iron-catalysed Kumada
biaryl cross-couplinga
Table 2 Scope of aryl Grignard reagents in the iron-catalysed Kumada
biaryl cross-couplinga
Entry Aryl Grignard
Biaryl
Yield (%)
99
b,d
Entry Fe source Ligand
Base
Conv.b (%) 3ab,c 3a0
1e
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr2
FeCl3
Fe(OTf)3
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
NaOtBu
NaOtBu
NaOtBu
NaOMe
NaHMDS
KOtBu
90
100
100
61
77
100
87
58
83
86
90
88
47
22
13
16
7
21
19
19
13
16
4
2
3 f
4
1
5
6
7
8
93
100
100
97
52
100
26
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
None
9
10g
11h
12i
13g
14g
15g
16g
17g
Fe2(OtBu)6 SIPrꢀHCl
Fe2(OtBu)6 SIPrꢀHCl
Fe2(OtBu)6 SIPrꢀHCl
Fe2(OtBu)6 SIPrꢀHCl
100
24
2
92
9
76
97
76
97
6
4
Fe(OEt)3
SIPrꢀHCl
NaOEt
56
39
14
56
32
8
7
10
6
Fe2(OtBu)6 IPrꢀHCl
NaOtBu
Fe2(OtBu)6 SIMesꢀHCl NaOtBu
3
4
82
87
Fe2(OtBu)6 None
NaOtBu
o1
Trace
9
a
Conditions: a mixture of an iron catalyst (3 mol%), L (9 mol%) and
base (18 mol%) in THF was stirred at rt for 1 h. After addition of 1a and
2a (1.2 equiv.), the mixture was heated at 80 1C for 16 h. Determined
b
c
by GC using dodecane as an internal standard. The yield of 3a was
d
calculated based on 1a. 3a0: 4,4-dimethylbiphenyl, the yield of 3a0
e
f
was calculated based on 2a. 9 mol% base was used. 27 mol% base
was used. 1.5 mol% iron catalyst, 9 mol% L and 9 mol% base were
used. 1 mol% iron catalyst, 6 mol% L and 6 mol% base were used.
g
h
i
1.5 mol% iron catalyst, 6 mol% L and 6 mol% base were used.
5
89
SIPrꢀHCl and 9 mol% NaOtBu resulted in 77% yield of 3a together
with a significant amount of the homocoupling product 4,40-dimethyl-
biphenyl 3a0 (Table 1, entry 1). Complete conversions of 1a could be
achieved at a higher loading of NaOtBu (entries 2 and 3) with the
optimal selectivity attained at 18 mol% of the base (entry 2). Other
base additives including NaOMe (entry 4), NaHMDS (entry 5)
and KOtBu (entry 6) were all less effective towards promoting
the selective formation of 3a.
6b
94
7
76 (91)c
Reaction conditions: 1.5 mol% Fe2(OtBu)6, 9 mol% SIPrꢀHCl and
a
b
9
mol% NaOtBu, 1.2 equiv. of ArMgBr. 2.5 mol% Fe2(OtBu)6,
c
15 mol% SIPrꢀHCl and 15 mol% NaOtBu were used. Yield in brackets
10
Amongst the iron precursors studied (entries 7–10), Fe2(OtBu)6
is determined by GC.
(1.5 mol%) gave the best result. An excellent yield of 3a was obtained
with little homocoupling (entry 10). Lowering the catalyst loading to
1 mol% (entry 11), decreasing the amount of SIPr relative to iron to reports that bulky alkoxides disrupt the formation of multimetallic
2 : 1 (entry 12), or running the reaction in the absence of NaOtBu species, which is formed through alkoxo bridges between two or
(entry 13) resulted in an incomplete conversion of 1a. A combination three metals,8b and could lead to highly reactive low coordinate
of ‘‘Fe(OEt)3’’11 and NaOEt was detrimental to the conversion and metal centers.9a,b
selectivity (entry 14). The presence of SIPr proved to be critical to the
Similar to fluoride,6b tert-butoxide was found to significantly
successful heterocoupling as other NHC ligands such as IPr and hinder the reduction of Fe(III) to Fe(0) by aryl Grignard reagents,
SIMes resulted in low yields of 3 (entries 15–17). Notably, the activity which may explain its ability to suppress the homocoupling
of the iron catalyst system was sensitive to the steric properties of reaction. While a complete reduction of FeBr3 to Fe(0) was
both alkoxide and NHC ligands. This is in agreement with previous observed when a mixture of FeBr3 (1 equiv.), SIPr (3 equiv.) and
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Table 3 Scope of aryl chlorides in the iron-catalyzed Kumada biaryl cross-couplinga
Entry
1b
Aryl chloride
Biaryl, yield (%)
Entry
11
Aryl chloride
Biaryl, yield (%)
3a, 99
3q, (trace)c
2
3
3h, 94
3i, 82
12
13
3r, (23)c
3s, 85
4
5
3j, 92
14
15
3t, 92
3u, 80
3k, 98
6
7
3l, 85
16
17
3v, 62
3w, 80
3m, 81
8
9
3n, 89
18
3x, 65
3o, 79
3p, 90
19
3y, 63
3z, 53
10b
20d
a
b
Reaction conditions: 2.5 mol% Fe2(OtBu)6, 15 mol% SIPrꢀHCl and 15 mol% NaOtBu, 1.2 equiv. of 2a. 1.5 mol% Fe2(OtBu)6, 9 mol% SIPrꢀHCl
and 9 mol% NaOtBu were used. Yield in brackets was determined by GC analysis. 4-Anisylmagnesium bromide was used instead of
c
d
p-tolylmagnesium bromide.
2a (10 equiv.) was heated at 80 1C for 1 h, only 13% of 3a0 was obtained with 1.5 mol% of the iron catalyst. In the case of
was obtained from the reaction of Fe2(OtBu)6 under similar the acetal 3g (entry 7), the yield was determined to be 91%
conditions.12
by GC analysis. After purification manipulations involving
Under the optimized conditions, high yielding syntheses of column chromatography and recrystallization, 3g was isolated
biaryls were achieved with a number of arylmagnesiums differ- in 76% yield.
ing in electronic and steric properties (Table 2). In most cases
A range of (hetero)aryl chlorides was evaluated in the reaction
except 2f (entry 6), complete conversion of the aryl chlorides with p-tolylmagnesium bromide (Table 3). In general, 2.5 mol%
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of Fe2(OtBu)6 was needed to ensure the complete conversion
The financial support for this work was provided by ‘‘GSK-EDB
of 1. Aryl chlorides featuring either electron-donating or electron- Singapore Partnership for Green and Sustainable Manufacturing’’
withdrawing substituents were efficiently converted to the corres- and the Institute of Chemical and Engineering Sciences (ICES),
ponding biaryl compounds (entries 1–8). The reaction tolerated Agency for Science, Technology and Research (A*STAR), Singapore.
ortho-, meta- and para-substituted aryl chlorides.
Chlorostyrenes constitute a valuable class of substrate for
the Kumada reaction since the alkene moiety offers various
opportunities for further functionalization. Yet, their p-electron rich
Notes and references
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nature renders them deactivated in cross-coupling reactions. In
addition, their potential to undergo side reactions such as carbome-
tallation and dimerization could further complicate the problem.13
Recently, Jacobi von Wangelin et al. successfully developed an iron
catalyst system to couple a range of chlorostyrenes with aryl Grignard
reagents.5 In the presence of the current iron alkoxide catalyst system,
biaryls resulting from the reaction of chlorostyrenes such as 1i and 1j
could be obtained in very good yields (entries 9 and 10). Notably, the
reaction of 1i was unproductive under the conditions developed by
Jacobi von Wangelin et al.5
R. M. Kellogg, Org. Process Res. Dev., 2010, 14, 30; (c) C. Ivica,
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A. Fu¨rstner, Acc. Chem. Res., 2008, 41, 1500(b) C. Bolm, J. Legros, I. L. Paih
and L. Zani, Chem. Rev., 2004, 104, 6217; (c) S. Enthaler, K. Junge and
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evaluated p-electron rich heterocyclic substrates (Table 3,
entries 11–15). While 2-chlorothiophene 1k failed to convert
to any appreciable extent as indicated by GC analysis (entry 11),
reaction of 2-chlorobenzofuran 1l resulted in mainly decomposition
(entry 12). Interestingly, chloroindoles could be reacted with orga-
nomagnesiums at either the pyrrole ring (entries 13 and 14) or the
benzenoid (entry 15) to give arylated indoles in very good yields.
A number of important developments in the iron-catalyzed
cross-coupling of aryl Grignard reagents with p-electron deficient
N-heteroaryl halides have been reported.4 However, the scope
of these reactions thus far is exclusive to coupling at the activated
a-carbon (e.g. 2-pyridyl). The ability to access other substituted
products is highly desirable considering the importance of pyridines
and quinolines in biologically active compounds.14 In the presence
of the alkoxide-based iron catalyst, a-, b-, or g-arylated pyridines can
all be prepared in moderate to good yields (Table 2, entries 16–18).
In addition, the reaction of 2-chloroquinoline 1s led to the isolation
of 3y in 63% yield. 4-Chloroquinoline 1t, which was previously a
challenging substrate for iron catalysis,4g,h,15 could be cross-coupled
with 4-anisylmagnesium bromide to give 3z in 53% yield.
`
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tional groups, including fluoro (Table 2, entry 4; Table 3, entries 4
10 Fe2(OtBu)6 was prepared from FeCl3 and NaOtBu according to: J. Spandl,
M. Kusserow and I. Bru¨dgam, Z. Anorg. Allg. Chem., 2003, 629, 968.
and 14), silyl-protected phenol (Table 3, entry 6), tertiary amines 11 Ferric oxide was obtained from Strem chemicals. The actual complex
is Fe5(m5-O)(OEt)13, according to B. J. O’Keefe, S. M. Monnier,
M. A. Hillmyer and W. B. Tolman, J. Am. Chem. Soc., 2001, 123, 339.
12 See ESI† for more details.
(Table 2, entry 5 and Table 3, entry 7), and acetal (Table 2, entry 7).
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´
122, 978; (b) J. R. Cabrero-Antonino, A. Leyva-Perez and A. Corma,
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the alkoxide and amide counterions investigated, tert-butoxide was
the most effective in inhibiting the homocoupling of arylmagne-
siums, and enabled efficient synthesis of a broad array of (hetero)-
biaryls. Further studies to gain insights into the origin of the
observed selectivity, and to apply the current findings in developing
new iron-catalysed reactions are now underway in our laboratory.
14 (a) M. E. Welsch, S. A. Snyder and B. R. Stockwell, Curr. Opin. Chem.
Biol., 2010, 14, 347; (b) S. D. Roughley and A. M. Jordan, J. Med.
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15 A. K. Steib, O. M. Kuzmina, S. Fernandez, D. Flubacher and
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