Iron(ii) triflate/N-heterocyclic carbene-catalysed cross-coupling of arylmagnesiums with aryl chlorides and tosylates

Article abstract of DOI:10.1039/c5cc08302h

In comparison to iron(ii) halides, iron(ii) triflate exhibits a greater resistance towards reduction by p-tolylmagnesium bromide. This knowledge has led to the development of an iron(ii) triflate/N-heterocyclic carbene-catalysed cross-coupling system of aryl Grignard reagents with aryl chlorides and tosylates with high efficiency, even surpassing that of previously reported catalyst systems employing strongly coordinating counterions in some cases.

Full text of DOI:10.1039/c5cc08302h

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Iron(II) Triflate/N-Heterocyclic Carbene-Catalysed Cross-Coupling
of Arylmagnesiums with Aryl Chlorides and Tosylates
Yi-Yuan Chua, Hung A. Duong*
98ssReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
In comparison to iron(II) halides, iron(II) triflate exhibits a greater 1b). A metalate mechanism via an Fe(II)/Fe(IV) catalytic cycle
resistance towards reduction by p-tolylmagnesium bromide. This was proposed.7,8 We later realized that an iron(III) tert-
knowledge led to the development of an iron(II) triflate/N- butoxide dimer/NHC catalyst system is also highly effective for
heterocyclic carbene-catalysed cross-coupling of aryl Grignard the cross-coupling reaction.9 Cook et al. recently reported an
reagents with aryl chlorides and tosylates with a high efficiency, FeF3/IPr-catalysed coupling of C-O based aryl electrophiles
even surpassing that of previously reported catalyst systems with aryl Grignard reagents.10
employing strongly coordinating counterions in some cases.
cat. FeYn/SIPr
a.
Ar1-Cl
+
Ar2MgX
Ar1-Ar2
+
Ar2-Ar2
3' (undesired)
1
2
3
Transition metal-catalysed cross-coupling reactions are
amongst the most important synthetic technologies at
present.1 Catalysts based on palladium and nickel are
predominantly used for this purpose. There have been
considerable efforts towards employing iron catalysts as an
alternative due to the crustal abundance, inexpensiveness and
low toxicity profile of this element.2 In particular, iron-
catalysed Kumada reaction for aryl-aryl coupling is of
significant interests since biaryls are ubiquitous in fine
chemicals, agrochemicals, pharmaceuticals and materials.3
However, it is not trivial to control the selectivity of this
reaction since arylmagnesiums can undergo self-coupling
rather readily in the presence of an iron catalyst.4
Nakamura (2007): Y = F
Duong (2014):
Y = OtBu
Ar2MgX
transmetallation
- Ar2-Ar2
reductive elimination
LmFeIIAr2
LmFe(0)
LmFeIIY2
b.
2
inhibited by Y = F or OtBu
Scheme 1. (a) Iron/NHC-catalysed cross-coupling of aryl chlorides and arylmagnesiums.
(b) A proposed mechanism for the reduction of Fe(II) to Fe(0) by arylmagnesiums.
Whereas previous successes rely on the use of strongly
coordinating counterions to attain high selectivity, we
discovered that a combination of Fe(OTf)2/NHC can catalyse
Significant developments have been achieved with
activated substrates such as 2-pyridyl halides or 2-
chlorostyrenes.5 For substrates bearing no activating group,
Nakamura et al. showed that a combination of iron fluorides
and an N-heterocyclic carbene (NHC) ligand can efficiently
facilitate cross-coupling of aryl chlorides and arylmagnesiums
(Scheme 1a).6 The high selectivity obtained was attributed to a
synergistic modulation of the fluoride counterion and the NHC.
Presumably, fluoride strongly coordinates to Fe(II) and
stabilises the iron centre against reduction by arylmagnesiums,
ultimately suppressing the homocoupling pathway (Scheme
the cross-coupling reaction in
a high efficiency, even
surpassing that of the iron fluoride or alkoxide systems in
some cases. A broad array of biaryls can be obtained in good
to excellent yields from the coupling of arylmagnesiums with
aryl chlorides and tosylates under these conditions. We report
herein our findings.
During our investigation on the reduction of different iron
salts with p-tolylmagnesium bromide 2a in the presence of SIPr
as the ligand, we noticed that the reaction of Fe(OTf)2 was
rather sluggish compared to iron halides (Table 3). Heating a
mixture of FeCl2, SIPr (1 equiv) and 2a (30 equiv) in THF at 60
oC led to the quantitative formation of 3a’ within 10 min (entry
1) while the reaction of FeBr2 reached full conversion within 1h
(entry 2). On the other hand, the reduction of Fe(OTf)2
progressed rather slowly and only produced 24% of 3a after 1h
(entry 3). Fe(OTf)3 was more prone to reduction, giving 83% of
3a’ after 1h (entry 4).
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Table 1. Reduction of iron salts with p-tolylmagnesium bromide 2a.
Table 3. Biaryl cross-coupling using Fe(OTf)2/SIPr.a
3a’
3a’
(%)
100
85
Entry
[FeXn]
FeCl2
FeBr2
t (min)
(mmol)a
1
2
10
10
0.10
0.085
0.10
60
100
24
60
0.024
0.039
0.125
3
4
Fe(OTf)2
Fe(OTf)3
120
60
39
83
a Determined by GC using dodecane as an internal standard.
a Conditions: 1.2 equiv ArMgBr, 3 mol% Fe(OTf)2, 3 mol% SIPr, THF (0.3-0.4 M).
Intrigued by the resistance of Fe(OTf)2 towards the
reduction, we investigated the combination of Fe(OTf)2/SIPr as
without compromising the reaction yields. Attempts to lower
the reaction temperature to rt resulted in low conversions
(entry 7). Iron halides displayed only moderate activity (entries
8-9). Notably, reaction with p-tolylmagnesium chloride led to
only 55% yield of 3a (entry 10).
a catalyst for the cross-coupling of chlorobenzene 1a and 2a 11
.
Remarkably, 3a was formed in an excellent yield in the
presence of 3 mol% Fe(OTf)2 and 9 mol% SIPr with little 3a’
observed (Table 2, entry 1). As expected, iron halides in
combination with SIPr only gave low to moderate selectivity
(entries 2-5). Further investigations revealed that other NHC’s
such as IPr and SIMes were not as effective as SIPr (entries 6
and 7). The reaction yield was not affected when the ligand to
metal ratio was reduced to 1:1, albeit together with a slight
increase in the homocoupling product (entry 8).
Table 4. Generation of SIPr in situ from a combination of SIPr.HCl and a base.
Table 2. Fe(OTf)2/SIPr-catalysed cross-coupling of 1a and 2a.
Entry
X
x
y
Base
conv.
(%)a
76
3a
(%)a
33
3a’
(%)a
31
3
(mol%)
1
2
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Cl
3
3
3
3
3
9
9
9
9
3
None
NaH (9)
100
100
100
100
100
30
>99
>99
>99
>99
98
3
NaOtBu (9)
KOtBu (9)
NaOtBu (3)
NaOtBu (1.5)
NaOtBu (9)
NaOtBu (3)
NaOtBu (3)
NaOtBu (3)
5
Entry
NHC
(mol%)
SIPr (9)
SIPr (9)
SIPr (9)
SIPr (9)
SIPr (9)
IPr (9)
conv.
(%)a
100
85
3a
(%)a
>99
68
3a’
(%)a,b
4
[FeXn] (mol%)
4
4
5
7
1
2
3
4
5
6
7
8
Fe(OTf)2 (3)
FeBr2 (3)
6
7b
0.5 1.5
4
18
22
14
25
8
3
3
3
3
9
3
3
3
29
13
16
15
13
FeBr3 (3)
84
62
8
67
55
FeCl2 (3)
93
81
9
10c
Br
79
70
FeCl3 (3)
73
49
OTf
68
55
Fe(OTf)2 (3)
Fe(OTf)2 (3)
Fe(OTf)2 (3)
84
80
a Determined by GC using dodecane as an internal standard. b Reaction was run at
rt. cp-tolylmagnesium chloride was used instead of 2a.
SIMes (9)
SIPr (3)
20
16
13
7
100
>99
a Determined by GC using dodecane as an internal standard. b Determined based
Similar to the iron fluoride and alkoxide catalyst systems, a
broad range of biaryls can be accessed in high yields in the
presence of 3 mol% Fe(OTf)2, 3 mol% SIPr.HCl and 3 mol%
NaOtBu at 60 oC (Table 5, condition A). In comparison to
previous systems that normally require 3 mol% of iron salt and
9 mol% of the carbene precursor, the significantly lower
loadings of the expensive carbene ligand employed in the
current system is rather attractive. In the case of highly
electron-rich chloroindole (3i) or deactivated Grignard reagent
on 2a.
The combination of 3 mol% Fe(OTf)2 and 3 mol% SIPr
indeed catalysed the reactions of aryl Grignard reagents with
aryl chlorides bearing electron-donating and electron-
withdrawing groups in good to excellent yields (Table 3).
We further investigated the generation of SIPr in situ from
the air-stable precursor SIPr.HCl (Table 4). While the reaction
yield dropped significantly in the absence of an added base
(entry 1), strong bases such as NaH, NaOtBu or KOtBu was
found to efficiently promote catalyst generation (entries 2-4).
An excellent yield of 2a can be obtained using 3 mol% Fe(OTf)2,
3 mol% SIPr.HCl and 3 mol% base (entry 5). Notably, the
reaction could be run at as low as 0.5 mol% Fe(OTf)2 (entry 6)
(
3k), a 3:1 ligand to metal ratio helped improve the reaction
yields significantly (condition B). Similarly, for highly activated
p-(trifluoromethyl)chlorobenzene 3m), less decomposition
was observed with more added ligand. For chlorobenzene and
chloropyridine, high yields of the cross-coupled products (3a
(
,
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3j and, 3l) could be obtained at 0.5 mol% Fe(OTf)2, 1.5 mol%
SIPr.HCl and 1.5 mol% NaOtBu (condition C).
We then turned our attention to aryl tosylates, a highly
attractive class of compounds for cross-coupling due to their
Overall, the reaction tolerated electron-rich and electron- ease of access from broadly abundant and inexpensive
deficient substituents on both coupling partners. In particular, phenols. Cook et al. recently reported the first iron-catalysed
even highly deactivated 3-(trifluoromethyl)phenylmagnesium cross-coupling of C-O based aryl electrophiles with aryl
bromide (3k) can be coupled with chlorobenzene in 79% yield. Grignard reagents employing 10 mol% FeF3 and 20 mol%
Challenging
π
-electron rich aromatic systems such as 4- IPr.HCl.10 A large excess of the organomagnesiums (ca. 3-4
chlorostyrene 3f or 3-chloroindole 3i were arylated in very equiv relative to aryl tosylates) was, however, required to
good yields.9 The sterically hindered ortho, ortho’- obtain high conversions. We found that a combination of 3
disubstituted biphenyls 3n and 3o were formed under our mol% Fe(OTf)2, 9 mol% IPr.HCl and 9 mol% NaOtBu could
conditions in 77% and 99% yields, respectively.
enable efficient coupling of aryl tosylates and arylmagnesiums
(Table 6). A variety of biaryls featuring electron-donating or
electron-withdrawing substituents were successfully prepared
in good yields employing only 1.2 equiv of the Grignard
reagent. Running the reaction at diluted conditions (0.06 M)
helped improve the yields of the desired products. In the case
of highly electron-rich 4-chloro-N,N-dimethylaniline (3t) and
sterically hindered ortho-substituted aryl chlorides (3u and 3v),
5 mol% of the iron catalyst was needed to achieve good
conversions. A significant amount of phenol was observed in
Table 5. Cross-coupling of aryl chlorides and arylmagnesiums using
Fe(OTf)2/SIPr.HCl/NaOtBu.
1.2 equiv ArMgBr (2)
cat. Fe/SIPr.HCl/NaOtBu
Cl
conditions Aa, Bb or Cc
THF, 60 oC
R2
R1
R1
1
3
Me
Me
Me
the
(trifluoromethyl)phenyl tosylate (3q) and 1-naphthyl tosylate
3s), resulting in only moderate yields of the cross-coupled
reactions
of
highly
electron-deficient
3-
(
3b
3c
A: 99%
3a
products.
MeO
F
A: 91%
A: 99%
C: 95%
Table 6. Cross-coupling of aryl tosylates and arylmagnesiums.
Me
Me
Bn
N
Me
3g
A: 82%
3f
A:92%d
Me
Me
Me
N
TBSO
3i
B: 84%
3j
A: 61%
C: 73%
3h
A: 86%
N
Me
OMe
F
CF3
3l
A: 99%
C: 97%
3k
B: 79%
3d
A: 81%
OMe
Me
Me
NMe2
F3C
Me
OMe
3o
A: 99%
3m
B: 79%
3n
A: 76%
a Condition A: 3 mol% Fe(OTf)2, 3 mol% SIPr.HCl, 3 mol% NaOtBu, THF (0.3-0.4 M),
60 oC. b Condition B: 3 mol% Fe(OTf)2, 9 mol% SIPr.HCl, 9 mol% NaOtBu, THF (0.3-
c
0.4 M), 60 oC. Condition C: 0.5 mol% Fe(OTf)2, 1.5 mol% SIPr.HCl, 1.5 mol%
NaOtBu, THF (0.6-0.7 M), 60 oC. d Reaction was run at 0.08 M.
The reaction is compatible with a range of functional
groups including ether, alkene, tertiary amines and silyl-
protected phenol. Attempts to couple aryl chlorides
incorporating a methyl ester or a pivalate group have thus far
only resulted in decomposition of the starting materials.
a Conditions: 5 mol% Fe(OTf)2, 15 mol% SIPr.HCl, 15 mol% NaOtBu, THF (0.06 M),
60 oC.
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3
4
5
(a) J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177; (b)
V. F. Slagt, A. H. M. de Vries, J. G. de Vries, R. M. Kellogg, Org.
Proc. Res. Dev. 2010, 14, 30; (c) C. Ivica, Synthesis of Biaryls,
Elsevier Ltd: Oxford, 2004.
To probe the relative reactivity of aryl chlorides and
tosylates, we performed a competitive iron-catalysed reaction
between p-chlorotoluene 1e (1 equiv) and phenyl tosylate 4a
(1 equiv) with p-anisylmagnesium bromide (1 equiv). A poor
selectivity was obtained (see supporting information for more
details).
(a) T. Nagano, T. Hayashi, Org. Lett., 2005,
Cahiez, C. Chaboche, F. Mahuteau-Betzer, M. Ahr, Org. Lett.,
2005, , 1943; (c) G. Cahiez, A. Moyeux, J. Buendia, C.
7, 491; (b) G.
7
Duplais, J. Am. Chem. Soc., 2007, 129, 13788.
The high efficiency of Fe(OTf)2/NHC is rather remarkable in
comparison to previous catalyst systems employing strongly
coordinating counterions.6,9,10,12 It is in particular interesting to
note the ability of Fe(OTf)2 to resist reduction the by Grignard
reagents.13 Presumably, a mechanism for the transmetallation
of arylmagnesiums with iron(II) halides could involve initial
coordination of the main group element to the halogen, which
facilitates removal of the halogen from the iron centre and the
transfer of the carbon nucleophile (Scheme 2).14 Possibly, this
assistance is diminished in the case of a non-coordinating
counterion such as triflate, rendering the reduction of Fe(OTf)2
by 2a less facile. Further studies are needed to evaluate this
possibility and to better understand the effect observed.
For Fe-catalysed cross-coupling of arylmagnesiums with aryl
halides containing an activating group, see: (a) A. Furtsner, A.
Leitner, Angew. Chem. Int. Ed. 2002, 41, 609; (b) A. Furtsner,
A. Leitner, A.; A. Mendez, H. Krause, J. Am. Chem. Soc. 2002,
124, 13856; (c) O. M. Kuzmina, A. K. Steib, D. Flubacher, P.
Knochel, Org. Lett. 2012, 14, 4818; (d) O. M. Kuzmina, A. K.
Steib, J. T. Markiewicz, D. Flubacher, P. Knochel, P. Angew.
Chem. Int. Ed. 2013, 52, 4945; (e) Gülak, S. Jacobi von
Wangelin, A. Angew. Chem. Int. Ed. 2012, 51, 1357; (f)
Kuzmina, O. M.; Steib, A. K.; Markiewicz, J. T.; Flubacher, D.;
Knochel, P. Angew. Chem. Int. Ed. 2013, 52, 4945; (g)
Kuzmina, O. M.; Steib, A. K.; Fernandez, S. Boudot, W.;
Markiewicz, J. T.; Knochel, P. Chem. Eur. J. 2015, 21, 8242.
(a) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc. 2007,
129, 9844; (b) T. Hatakeyama, S. Hashimoto, K. Ishizuka, M.
Nakamura, J. Am. Chem. Soc. 2009, 131, 11949.
6
7
For mechanistic studies on iron/NHC-catalysed C-C bond
cross-coupling reactions, see: (a) J. A. Przyojski, K. P.
Veggeberg, H. D. Arman, J. I. Tonzetich, ACS Catal. 2105, 5,
5938; (b) X. Wang, J. Zhang, L. Wang, L. Deng,
Organometallics 2015, 34, 2775; (c) Y. Liu, J. Xiao, L. Wang, Y.
Song, L. Deng, Organometallics 2015, 34, 599.
Scheme 2. A possible mechanism for the transmetallation of iron(II) halides and
aryl Grignard reagents.
8
For further mechanistic discussions on iron-catalysed C-C
bond cross-coupling reactions, see: (a) M. Jin, L.Adak, M.
Nakamura, J. Am. Chem. Soc. 2015, 137, 7128; (b) R. B.
Bedford, Acc. Chem. Res. 2015, 48, 1485; (c) A. Hedstrçm, Z.
Izakian, I. Vreto, C.-J. Wallentin, P.-O. Norrby, Chem. Eur. J.
2015, 21, 5946; (d) R. B. Bedford, P. B. Brenner, E. Carter, P.
M. Cogswell, M. F. Haddow, J. N. Harvey, D. M. Murphy, J.
Nunn, C. H. Woodall, Angew. Chem., Int. Ed. 2014, 53, 1804;
(e) S. L. Daifuku, M. H. Al-Afyouni, B. E. R. Snyder, J. L.
Kneebone, M. L. Neidig, J. Am. Chem. Soc. 2014, 136, 9132;
(f) C. J. Adams, R. B. Bedford, E. Carter, N. J. Gower, M. F.
Haddow, J. N. Harvey, M. Huwe, M. Å. Cartes, S. M. Mansell,
C. Mendoza, D. M. Murphy, E. C. Neeve, J. Nunn J. Am.
Conclusions
In conclusion, the non-coordinating triflate counterion was
found to significantly slow down the reduction of the iron
centre by arylmagnesiums. In comparison to previously
reported iron catalyst systems, Fe(OTf)2/NHC exhibited
comparable or better catalytic efficiency in the cross-coupling
of aryl Grignard reagents with aryl chlorides and tosylates.
Chem. Soc. 2012, 134
Hashimoto, Y. Kondo, Y. Fujiwara, H. Seike, H. Takaya, T.
Tamada, T. Ono, M. Nakamura, J. Am. Chem. Soc. 2010, 132
10674; (h) D. Noda, Y. D. Sunada, T. Hatakeyama, M.
Nakamura, H. Nagashima J. Am. Chem. Soc. 2009, 131, 6078;
(i) A. Fürstner, R. Martin, H. Krause, G. Seidel, R. Goddard, C.
W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773; and
references therein.
, 10333; (g) T. Hatakeyama, T.
Acknowledgements
,
The financial support for this work was provided by “GSK-EDB
Singapore Partnership for Green and Sustainable
Manufacturing” and the Institute of Chemical and Engineering
Sciences (ICES), Agency for Science, Technology and Research
(A*STAR), Singapore.
9
Y.-Y. Chua, H. A. Duong, Chem. Commun. 2014, 50, 8424.
10 T. Agrawal, S. P. Cook, Org. Lett. 2014, 16, 5080.
11 We found that better results were obtained with freshly
prepared Grignard reagents. Therefore, all the
arylmagnesiums used in this study was freshly prepared prior
to use.
References
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13 This may suggest a mechanism involving the intermediacy of
ate-complexes (see reference 6b). Further evidence is the
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14 J. F. Hartwig, Organotransition Metal Chemistry: From
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