Visible-Light-Promoted Iron-Catalyzed C(sp2)–C(sp3) Kumada Cross-Coupling in Flow

Article abstract of DOI:10.1002/anie.201906462

A continuous-flow, visible-light-promoted method has been developed to overcome the limitations of iron-catalyzed Kumada–Corriu cross-coupling reactions. A variety of strongly electron rich aryl chlorides, previously hardly reactive, could be efficiently coupled with aliphatic Grignard reagents at room temperature in high yields and within a few minutes’ residence time, considerably enhancing the applicability of this iron-catalyzed reaction. The robustness of this protocol was demonstrated on a multigram scale, thus providing the potential for future pharmaceutical application.

Full text of DOI:10.1002/anie.201906462

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Accepted Article
Title: Visible light-promoted Fe-catalyzed Csp2-Csp3 Kumada cross-
coupling in flow
Authors: Xiao-Jing Wei, Irini Abdiaj, Carlo Sambiagio, Chenfei Li, Eli
Zysman-Colman, Jesus Alcazar, and Timothy Noel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906462
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10.1002/anie.201906462
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COMMUNICATION
Visible-Light-Promoted Iron-Catalyzed Csp2-Csp3 Kumada Cross-
Coupling in Flow
Xiao-Jing Wei,[a] Irini Abdiaj,[b] Carlo Sambiagio,[a] Chenfei Li, [c] Eli Zysman-Colman,[c] Jesús Alcꢀzar,*[b]
Timothy Noꢁl*[a]
temperatures and/or long reaction times.[14] Despite further
Abstract: A continuous-flow, visible light-promoted method has been
notable advancements in the field of Fe-catalyzed cross-
developed to overcome the limitations of Fe-catalyzed Kumada-
Corriu cross-couplings. A variety of strongly electron-rich aryl
chlorides, previously hardly reactive, could be efficiently coupled with
aliphatic Grignard reagents at room temperature, in high yields and
within a few minutes residence time, considerably enhancing the
applicability of this Fe-catalyzed reaction. The robustness of this
protocol was demonstrated on the multi-gram scale, providing the
potential for future pharmaceutical application.
Over the past three decades, transition metal-catalyzed cross-
coupling reactions have emerged as one of the most important
classes of C-C bond-forming reactions.[1] One of the oldest and
most important transformations is the coupling of aryl halides with
Grignard reagents. This chemistry has been extensively studied
using Pd[2] and Ni[3] catalysis since its first discovery by Kumada
and Corriu in 1972.[4] Despite the efficiency of these reactions,
these metals are toxic and expensive, and more and more
research has been devoted to the development of efficient
Scheme 1. Csp2-Csp3 bond formation via Kumada-Corriu cross-couplings.
catalytic methods using cheap, Earth-abundant and non-toxic
alternative catalysts.[5] In this regard, iron catalysis has been
couplings,[15] to date the coupling of electron-rich aryl chlorides
with aliphatic Grignard reagents remains challenging and the
number of reports is still considerably limited.
[7]
extensively investigated.[6]
In 2002, based on pioneering
studies by, among others, Kharasch,[8] Kochi,[9] and Cahiez,[10]
Fürstner developed the first efficient Fe-catalyzed Kumada-Corriu
coupling between aryl chlorides and alkyl Grignard reagents.[11]
Key to this advancement was the use of N-methyl-2-pyrrolidone
(NMP) as a co-solvent in the reaction. This method provided a
very attractive alternative to the Pd/Ni-catalyzed reaction, as aryl
chlorides could be more efficiently employed as starting materials
instead of aryl bromides and iodides (Scheme 1).[12] Nonetheless,
this protocol and subsequent ones,[13] are limited to electron-
deficient aryl chlorides, triflates, and tosylates, and to primary
Very recently Alcázar and co-workers developed visible light-
promoted
Pd/Ni-catalyzed
Negishi
cross-couplings,
demonstrating the advantage of irradiation on this type of cross-
coupling reaction.[16] Inspired by these results, and following our
continuous interest in metal-catalyzed couplings in flow,[17] herein
we report a light-promoted Fe-catalyzed Kumada-Corriu coupling
for Csp2-Csp3 bond-formation in continuous-flow.[18] Considering
the present limitations on the scope of aryl chlorides reaction
partners typical for this reaction, this method allows the
broadening of the substrate scope under very mild and scalable
conditions.
aliphatic
Grignard
reagents.
Electron-neutral
(e.g.
chlorobenzene) and electron-rich aryl chlorides could only later
be successfully employed in the reaction when N-heterocyclic
carbene (NHC) ligands were used, but still required high
At the beginning of our study, we treated model substrates
chlorobenzene (1a) and n-propylmagnesium bromide (2a) with 1
[a]
X.-J. Wei, Dr. C. Sambiagio, Dr. T. Noël
Department of Chemical Engineering and Chemistry
Micro Flow Chemistry and Synthetic Methodology
Eindhoven University of Technology
Den Dolech 2, 5612 AZ Eindhoven (The Netherlands)
E-mail: t.noel@tue.nl
Homepage: www.noelresearchgroup.com
I. Abdiaj, Dr. J. Alcázar
Discovery Sciences, Janssen Research and Development
Jannsen-Cilag, S.A.
Jarama 75A, 45007 Toledo (Spain)
E-mail: jalcazar@its.jnj.com
C. Li, Dr..E. Zysman-Colman
Organic Semiconductor Center, EaStCHEM School of Chemistry
University of St Andrews,
St Andrews, Fife, KY16 9ST (UK).
mol% FeCl2∙4H2O and
2
mol% 3-bis(2,6-diisopropyl-
phenyl)imidazolinium chloride (SIPr∙HCl) as ligand under
irradiation of blue LED (450 nm) at 20 oC. To our delight, n-
propylbenzene 3aa was obtained in 76% yield using a residence
time of 20 minutes, while the reaction without light only furnished
5% of 3aa (Table 1, entries 1-2). This shows that visible light
indeed significantly accelerates the Kumada cross-coupling. At 25
oC the reaction proceeded more efficiently, giving 84% yield (entry
3). Different iron halides such as FeF3 or FeCl3 gave moderate to
good yield, while the use of Fe(acac)3 (acac = acetylacetonate)
resulted in an excellent 89% yield of 3aa (entries 4-6). Increasing
the catalyst loading (2%) and concentration resulted in 98% yield
within only 15 minutes residence time (entry 7). Control
[b]
[c]
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10.1002/anie.201906462
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10). Interestingly, when cyclohexylmagnesium chloride (CyMgCl)
2b was employed in the reaction, full conversion was achieved
within only 5 minutes residence time (entry 11). This reagent was
thus selected for further studies.
experiments in the absence of Fe or NHC gave no product, while
the reaction in the dark under these conditions only produced 11%
of 3aa (entries 8-
With the optimal conditions in hand, the scope of this trans-
formation was investigated (Scheme 2). Unfunctionalized aryl
chlorides in the coupling with Grignard 2b already show large
differences in yields between irradiation and non-irradiation
conditions (3ab-3cb, 83-91% vs 27-51%). Substrates containing
a fluorine or methyl moiety also reacted smoothly, giving 88-99%
yield under irradiation (3db-3eb). Furthermore, functionalization
with one or two strongly electron-donating methoxy groups,
including at very challenging ortho positions, also resulted in high
isolated yields of compounds 3fb-3jb (61-93%). It has to be noted
that for compounds 3ib and 3jb, 5% Fe(acac)3 and 10% NHC
were required to reach full conversion within 20 minutes residence
time. The strong electron-donating groups –NMe2 and –NHMe
were also tolerated in the reaction and furnished 3kb and 3lb in
high yields (82-96%). The presence of a free NH moiety in 3lb is
particularly noteworthy, as it avoids the introduction of protecting
groups. Unprotected NH functionalities in medicinally relevant[7c]
indoles and pyrrolopyridines were also successfully tolerated
(3mb-3nb, 91%). Other functionalized heterocyclic chlorides,
Table 1. Optimization of reaction conditions.[a]
Entry
1[b,c]
2[b,c,d]
3[b]
Cat.
FeCl2.4H2O
FeCl2.4H2O
FeCl2.4H2O
FeF3
R
RT (min)
20
Yield (%)
76 (3aa)
5 (3aa)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
n-Propyl (2a)
Cyclohexyl (2b)
20
20
84 (3aa)
45 (3aa)
73 (3aa)
89 (3aa)
98 (3aa)
0 (3aa)
4[b]
20
5[b]
FeCl3
20
6[b]
Fe(acac)3
Fe(acac)3
/
20
7
15
8
15
such
as
2-methylquinoline,
2-methoxypyridine,
2-
9[e]
10[d]
Fe(acac)3
Fe(acac)3
Fe(acac)3
15
0 (3aa)
methyltiopyrimidine, and benzofuran chlorides were reacted with
2b in modest to good yields (3ob-3rb, 45-84%).
15
11 (3aa)
96 (3ab)
11
5
[a]Reaction conditions: Feed 1: Chlorobenzene 1a (2 mmol), Fe(acac)3 (0.04
mmol), tetrahydrofuran (THF, 5 mL). Feed 2: Grignard reagent (3 mmol),
SIPr∙HCl (0.08 mmol), THF, 25 °C, 24 W blue LED. RT = residence time. GC
yields are reported. [b] Fe(acac)3 (0.02 mmol), SIPr∙HCl (0.04 mmol), [c]T = 20
oC. [d] No light; [e] No ligand.
Scheme 2. Substrate scope. Reaction conditions: Feed 1: 1 (2 mmol, 1.0 equiv.), Fe(acac)3 (0.04 mmol), THF 5 mL. Feed 2: 2b (1.5 equiv.), SIPr∙HCl (0.08 mmol),
25 oC, RT: 5 minutes, 24 W blue LED. GC/LC yield. Isolated yield reported in brackets. [a] RT = 2 min; [b] Fe(acac)3 (5 mol%), SIPr∙HCl (10 mol%); [c] Grignard reagent
(2.5 equiv.); [d] RT = 15 min; [e] RT = 1 min; [f] RT = 20 min. Scope of Grignard reagents, reaction conditions: Feed 1: 1 (2 mmol, 1.0 equiv.), Fe(acac)3 (5 mol%).
Feed 2: 3 (1.5 equiv.), SIPr∙HCl (15 mol%), 25 oC, RT: 20 minutes, [g]Fe(acac)3 (2 mol%), SIPr∙HCl (4 mol%), [h] Fe(acac)3 (10 mol%), SIPr∙HCl (30 mol%) in batch
with 34 W blue LED irradiation at 45 oC for 4 hours; [i]40 oC. [j] 0.3 equiv. of iPrMgBr was added as additive in Feed 2 in advance. [k] 2d (2.0 equiv).
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10.1002/anie.201906462
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Next, we studied the reactivity of different Grignard reagents. A
few generally less reactive alkyl Grignard reagents, such as n-
propylmagnesium
and
(trimethylsily)methylmagnesium
chlorides,[19] were successfully employed in the coupling with
electron-rich or heterocyclic aryl chlorides, affording good isolated
yields of the coupling products 3ha-3nc (55-95%). Encouraged
by these results, some new Grignard reagents decorated with
medicinally important moieties, such as tetrahydropyrane and N-
methylpiperidine[20] were prepared[21] and tested in the reaction.
Compounds 3hd-3he, featuring electron-rich or heteroaromatic
moieties, were obtained under mild reaction conditions in 70-95%
yield.[22] As expected, most of these compounds were only
obtained in trace amounts in the absence of light. Finally, the
scalability of this protocol was demonstrated on a multi-gram
scale synthesis of unprotected indole 3mb (Scheme 3). With only
5 minutes residence time, after running continuously for 2.5 hours,
11.36 gram of 3mb were isolated (95%), with the space-time yield
reaching 454 mg/h·mL.
Figure 1. a) Batch reaction profiles for the coupling of CyMgCl 2b with
chlorobenzene 1a and b) p-chloroanisole 1h with or without blue light irradiation;
c) reaction profiles for the coupling with chloroindole 1m with or without light,
and in light on/off experiment
Scheme 3. Reaction scale-up. Feed 1: 1m (9.06 g, 60 mmol), Fe(acac)3
(423.6 mg, 2 mol%), THF (150 mL); Feed 2: 2b (150 mL, 1.0 M in THF, 2.5
equiv.), SIPr∙HCl, (1.02 g, 4 mol%); 25 oC, residence time = 5 minutes.
Despite the recent interest in Fe-catalyzed cross-couplings, the
elucidation of their mechanism is not straightforward.[23] The
current mechanistic understanding of Fe-catalyzed Kumada
coupling using -hydrogen-containing Grignard reagents[24]
supports an initial reduction of Fe(III) to a lower oxidation states
species [Fered] by the Grignard, leading to FeXn or Fe(MgX)n
intermediates. Different oxidation states for [Fered] have been
24-25]
suggested, ranging from Fe(-II) to Fe(+I).[15d,
This initial
necessary step is followed by a rate-determining oxidative
addition of the aryl chloride, and a transmetalation with further
Grignard reagent, or vice versa. The final reductive elimination is
suggested to be fast and restore the [Fered] species.[11b, 25]
We performed some experiments to understand the effect of
irradiation in this reaction. Kinetic profiles for the coupling of
chlorobenzene 1a and p-chloroanisole 1h with CyMgCl 2b with
and without irradiation showed a clear beneficial effect of light on
the rate of the reaction. In particular, the effect of irradiation is
much more pronounced for the coupling of electron-rich 1h than
for chlorobenzene 1a (Figure 1 a-b).This might suggest an effect
of light in facilitating the oxidative addition, although other effects
cannot as yet be excluded. A strong effect of light was also
observed for the coupling with chloroindole 1m, which results in
almost no reaction in the absence of light. Light on/off
experiments on this reaction show that light is needed during the
whole process (Figure 1c), so its role in the mere generation of an
active catalytic species (off-cycle) can be excluded.
Figure 2: In-line UV-Vis analysis of the reaction between CyMgCl 2b and
chloroindole 1m; Top: 0.01 M in THF, Bottom: 0.1 M.
In-line UV-Vis analysis of the reaction between CyMgCl 2b and
chloroindole 1m (under irradiation) was performed at low
concentration (0.01 M) to study the first step of the reaction
(Figure 2, top). Upon addition of 2b and 1m to a solution of
Fe/NHC in THF, the characteristic absorption band of Fe(acac)3
(ca. 450 nm) immediately disappeared, and a broad, stable band
in the visible range (450-600 nm) appears after ca. 30 min. This
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band remained almost unchanged for the following 100 min.
Similar results were obtained without irradiation (see ESI).
Keywords: cross-coupling • iron catalysis • photocatalysis •
Kumada coupling • flow chemistry
The same experiment under more concentrated conditions (0.1
M, Figure 2, bottom) also showed the disappearance of Fe(acac)3
and the formation of the large band at 450-600 nm upon addition
of Grignard and chloroindole. Under such conditions, this band
appeared and disappeared quickly, and a new weak band at 
450 nm briefly appeared after a short time. After turning the light
on, the same band appeared with a much higher intensity. Full
conversion was observed within several minutes from this event.
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cycle process) is not particularly influenced by light, which is
instead essential during the real catalytic process (Figure 1c).
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accelerated coupling of unactivated and electron-rich aryl
chlorides with alkylmagnesium compounds in continuous-flow
conditions. The use of blue light was demonstrated to
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Acknowledgements
X.-J.W., I.A., J.A., and T.N. would like to acknowledge the
European Union for a Marie Curie ITN Grant (Photo4Future,
Grant No. 641861). C.S. acknowledges the European Union for a
Marie Curie European post-doctoral fellowship (FlowAct, Grant
No. 794072). We would like to thank the Engineering and Physical
Sciences Research Council for financial support (EP/M02105X/1).
C. L. thanks the Prof. & Mrs Purdie Bequests Scholarship and
AstraZeneca for his PhD Studentship. Finally, we thank Dr. J. P.
Hofmann for useful discussion.
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[24] Reactions with Grignard reagents without -hydrogens might
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Seidel, R. Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008,
130, 8773-8787.
[25] a) J. Kleimark, A. Hedström, P.-F. Larsson, C. Johansson, P.-
O. Norrby, ChemCatChem 2009, 1, 152-161; b) J. Kleimark,
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[26] As the spectroscopic studies could not be accurately
performed under the typical reaction conditions, and no well-
defined Fe species were employed for such investigations
(reaction components were reacted in-situ with the catalyst
precursor), the proposed catalytic cycle is not certain. Under
such conditions, a variety of Fe species might be present in
solution with different coordination, ligand environment and/or
oxidation state, likely very dynamic under the reaction
conditions. Different mechanistic pathways might also be
possible, such as for example the excitation of a Fe species,
which then acts as a photoredox catalyst; see: R. Kancherla,
K. Muralirajan, A. Sagadevan, M. Rueping, Trends Chem.,
10.1016/j.trechm.2019.03.012.
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10.1002/anie.201906462
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Xiao-Jing Wei, Irini Abdiaj, Carlo
Sambiagio, Chenfei Li, Eli Zysman-
Colman, Jesús Alcꢀzar,* Timothy Noꢁl*
Page No. – Page No.
Visible-Light-Promoted Iron-
Catalyzed Csp2-Csp3 Kumada Cross-
Coupling in Flow
Text for Table of Contents
Iron shines in the spotlight: An accelerated, visible-light-promoted iron-catalyzed Kumada cross-coupling is reported. The coupling of electron-
rich aryl chlorides with aliphatic Grignard reagents, normally very challenging in the absence of light, could here be performed in high yields. The
use of flow allowed for full conversion in a matter of minutes and scalability to multigram scale.
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