Iron-Catalyzed Cross-Coupling of Alkynyl and Styrenyl Chlorides with Alkyl Grignard Reagents in Batch and Flow

Article abstract of DOI:10.1002/chem.201904480

Transition-metal-catalyzed cross-coupling chemistry can be regarded as one of the most powerful protocols to construct carbon–carbon bonds. While the field is still dominated by palladium catalysis, there is an increasing interest to develop protocols that utilize cheaper and more sustainable metal sources. Herein, we report a selective, practical, and fast iron-based cross-coupling reaction that enables the formation of Csp?Csp³ and Csp²?Csp³ bonds. In a telescoped flow process, the reaction can be combined with the Grignard reagent synthesis. Moreover, flow allows the use of a supporting ligand to be avoided without eroding the reaction selectivity.

Full text of DOI:10.1002/chem.201904480

DOI: 10.1002/chem.201904480
Communication
&
Catalysis
Iron-Catalyzed Cross-Coupling of Alkynyl and Styrenyl Chlorides
with Alkyl Grignard Reagents in Batch and Flow
Yuchao Deng+,[a, b] Xiao-Jing Wei+,[a] Xiao Wang,[c] Yuhan Sun,[b, d] and Timothy Noꢀl*[a]
dustry, alternatives for palladium are currently of high inter-
Abstract:
Transition-metal-catalyzed
cross-coupling
est.[5] Amongst potential candidates, earth-abundant first row
transition metals provide arguably the highest likelihood to re-
place palladium due to their reduced cost and low toxicity.[6] In
this regard, iron has received substantial attention as it is a
metal with minimum safety concern and it provides many cat-
alytic options as its oxidation states range from ÀII to +VI.[7]
However, despite the great potential to cover essentially all rel-
evant catalytic transformations in organic synthesis, reality is
different and iron proves to be notorious to tame, hindering
its widespread adoption.[8]
chemistry can be regarded as one of the most powerful
protocols to construct carbon–carbon bonds. While the
field is still dominated by palladium catalysis, there is an
increasing interest to develop protocols that utilize cheap-
er and more sustainable metal sources. Herein, we report
a selective, practical, and fast iron-based cross-coupling re-
action that enables the formation of CspÀCsp3 and Csp2À
Csp3 bonds. In a telescoped flow process, the reaction can
be combined with the Grignard reagent synthesis. More-
over, flow allows the use of a supporting ligand to be
avoided without eroding the reaction selectivity.
While the classical Sonogashira reaction enables the efficient
coupling between aryl halides and terminal alkynes,[9] metal-
catalyzed Csp–Csp3 couplings are very rare (Scheme 1). Cahiez
et al. found that alkyl–alkynyl cross-coupling can be achieved
using copper catalysis and slow addition of the Grignard cou-
pling partner.[10] A cobalt-enabled coupling between bromoal-
kynes and organozinc halide nucleophiles was described by
Gosmini and co-workers. The groups of Nakamura[11] and Hu[12]
developed iron-catalyzed protocols to couple alkyl bromides
and iodides with alkynyl Grignard reagents.[13] In search of syn-
thetically useful Fe-catalyzed cross-coupling reactions,[14] we
Transition-metal-catalyzed cross-coupling reactions serve as
one of the most powerful protocols to construct carbon–
carbon and carbon–heteroatom bonds in a variety of biologi-
cally active molecules,[1] natural products,[2] and functional ma-
terials.[3] To date, the workhorse of cross-coupling chemistry
has been palladium, which in combination with suitable li-
gands allowed high catalytic efficiency to be enacted for a
wide variety of electrophile–nucleophile combinations.[4] How-
ever, due to the scarcity and increasing cost of palladium and
the stringent heavy metal regulations in the pharmaceutical in-
[a] Y. Deng,+ X.-J. Wei,+ Prof. Dr. T. Noꢀl
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
[b] Y. Deng,+ Prof. Dr. Y. Sun
School of Physical Science and Technology
ShanghaiTech University, Shanghai, 201210 (P. R. China)
[c] Prof. X. Wang
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210023 (P. R. China)
[d] Prof. Dr. Y. Sun
Shanghai Advanced Research Institute
Chinese Academy of Sciences, Shanghai, 201210 (P. R. China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201904480.
ꢁ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Scheme 1. Established metal-catalyzed Csp–Csp3 coupling reactions and re-
action design of an Fe-based protocol to enable the Csp–Csp3 and Csp2–
Csp3 coupling.
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describe herein our efforts to develop a robust protocol to action produces only a limited amount of product along with
cross-couple both styrenyl and alkynyl chlorides with alkyl unidentified byproducts (Table 1, entry 8).[16]
Grignard reagents by using an Fe catalyst and an NHC
With optimal conditions in hand, we probed the generality
ligand.[15] This method provides a set of conditions that are of his protocol for the coupling of alkynyl chlorides with
both practical and widely applicable in CspÀCsp3 and Csp2À Grignard reagents (Figure 1). Various alkynyl chlorides with
Csp3 bond-forming reactions. Interestingly, the Fe-based cou-
pling reaction could be translated to flow and was combined
with an inline generation of Grignard reagents. Furthermore,
the flow strategy allowed the reaction to be carried out under
mild conditions whilst avoiding the use of an NHC ligand, thus
simplifying the overall process.
Initial cross-coupling experiments started with 1-chloro-2-
phenylacetylene as a benchmark substrate and cyclohexyl-
magnesium chloride in ethereal solvents at 08C (Table 1). With
Table 1. Optimization of the reaction conditions for the iron-catalyzed
cross-coupling between alkynyl chlorides and alkyl Grignard reagents.[a]
Figure 1. Scope of the iron-catalyzed cross-coupling between alkynyl chlo-
rides and alkyl Grignard reagents. Reaction conditions: 0.5 mmol 1,
0.6 mmol R’MgCl, 1 mol% [Fe(acac)3], 2 mol% SIPr-HCl in 2.5 mL THF at 08C.
Entry Catalyst
Ligand T [8C] Conv. (5)[a] 2a [%][b] 2a“ [%][b] 2a’’ [%][b]
1[c]
2
3
4
5
6
7
8
FeCl3·6H2O –
FeCl3·6H2O –
FeCl2·4H2O –
0
0
0
0
0
0
r.t.
0
88
100
32
90
71
100
100
81
66
80
27
77
69
97
91
12
5
12
1
3
–
1
6
–
18
8
4
10
2
2
[a] 2 mol% [Fe(acac)3] and 4 mol% SIPr-HCl.
[Fe(acac)3]
–
electron-neutral (2a, 2c, 2d), -withdrawing (2b), and -donating
groups (2e) underwent efficient cross-coupling with cyclohex-
ylmagnesium chloride (89–96% yields). 1-Chloro-2-phenylacet-
ylene could be efficiently coupled with a diverse set of aliphat-
ic Grignard reagents, including phenylmagnesium chloride
(2 f), propylmagnesium chloride (2g), methylmagnesium chlo-
ride (2h), (trimethylsilyl)methylmagnesium chloride (2i), and
cyclopentyl magnesium chloride (2j) (81–93% yields). Also
Grignard reagents decorated with medicinally important scaf-
folds, such as N-methylpiperidine (2k), can be tolerated (99%
yield). Finally, also alkylated alkynyl chlorides and aromatic
Grignard reagents (2l) can be coupled in this protocol furnish-
ing the targeted product in 90% isolated yield.
[Fe(acac)3] L1
[Fe(acac)3] L2
[Fe(acac)3] L2
3
–
–
–
[a] Standard reaction conditions: 1 (0.5 mmol), cyclohexylmagnesium chlo-
ride (1.0m in THF, 0.6 mmol), THF (1.9 mL, 0.2m), Fe catalyst (1 mol%) and
SIPr-HCl (2 mol%). [b] Conversion and yields were determined by GCMS.
[c] Et2O instead of THF.
Expanding the substrate scope to involve styrenyl chlorides
FeCl3·6H2O as the iron source, the use of THF as a solvent was in this Fe-catalyzed cross-coupling protocol permitted us to
preferred over Et2O (Table 1, entries 1 and 2). In both cases, forge Csp2ÀCsp3 bonds as well (Figure 2). Interestingly, for
substantial amounts of byproducts were observed resulting most substrates, the reaction could be completed at room
from homocoupling (2a’) and reduction (2a’’). Switching to an temperature without adding any supporting ligand. b-Chloro-
FeCl2·4H2O catalyst resulted in a diminished reactivity (Table 1, styrene can be rapidly and efficiently coupled with assorted ali-
entry 3). A higher selectivity and reactivity for the desired phatic (4a–g, 90–96% yield) and aromatic (4h) (97% yield)
cross-coupled product (2a) was observed using [Fe(acac)3] Grignard nucleophiles. The protocol is easily scalable without
(Table 1, entry 4). However, the highest selectivities were ob- reduced efficiency (4 f, 8 mmol, 90% yield). b-Chlorostyrenes
tained when catalyst complexes arising from [Fe(acac)3] and bearing electron-neutral (4i–l), -donating (4m–q), and -with-
NHC ligands were used, with the SIPr ligand providing the drawing groups (4r) at the ortho-, meta- and para-positions
best results in terms of reaction efficiency and selectivity. are readily tolerated (89–97% yield). The reaction does not dis-
(Table 1, entries 5 and 6). A lower selectivity was observed play a great sensitivity to steric hindrance, as both naphthyl
when the reaction temperature was raised to room tempera- substrates (4s,t, 91–94% yields) and a-substituted b-chloro-
ture (Table 1, entry 7). In the absence of an iron catalyst, the re- styrenes (4u,v, 94% yield) were efficiently coupled with cyclo-
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Grignard reagents low and to use cheap organohalides as
starting materials.[17] For the preparation of the Grignard re-
agent, we filled an open column with magnesium according to
the procedure reported by Alcazar et al.[18] Over this magnesi-
um packed-bed reactor, a solution of alkyl or aryl halide was
directed and the generated Grignard reagent was merged with
the reagents required for the Fe-catalyzed cross-coupling
transformation (Table 2).[19] The combined reaction mixture was
fed to a capillary microreactor (perfluoroalkoxy alkane, PFA;
750 mm ID). The coupling between b-chlorostyrene and n-pen-
Table 2. Telescoped organomagnesium bromide synthesis and iron-cata-
lyzed cross-coupling in flow. For detailed reaction conditions, see the
Supporting Information.
Figure 2. Scope of the iron-catalyzed cross-coupling between styrenyl chlo-
rides and alkyl Grignard reagents. Reaction conditions: 0.5 mmol 3,
0.6 mmol R’MgCl, 1 mol% [Fe(acac)3]. in 2.5 mL THF at room temperature.
[a] 3 mol% [Fe(acac)3] and 6 mol% SIPr-HCl was added. [b] Scale-up experi-
ment on an 8 mmol scale. [c] Scale-up experiment on an 4.7 mmol scale.
[d] The Z/E ratio of starting material 3x was 91:9 and of product 4x was
88:12.
hexylmagnesium chloride. Double functionalization was also
possible, albeit at a slightly diminished yield (4w, 57% yield).
The reaction was stereoselective in all cases and even the
cross-coupled product derived from (Z)- b-chlorostyrene was
obtained in good yield and with retained stereoselectivity (4x,
93% yield).
Next, we investigated the possibility to telescope both the
Grignard reagent synthesis and the iron-catalyzed cross-cou-
pling transformation in a single, streamlined continuous-flow
process. The combination of these two individual steps allows
the safe control of the exotherm of the Grignard reagent syn-
thesis,[16] to keep the total inventory of potentially hazardous
[a] [Fe(acac)3] (1 mol%), electrophile (0.31m), room temperature.
[b] [Fe(acac)3] (2 mol%), electrophile (0.33m), room temperature.
[c] [Fe(acac)3] (2 mol%), electrophile (0.33m), 08C. [d] [Fe(acac)3] (1 mol%),
electrophile (based on the concentration of the Grignard reagent), 08C.
[e] Residence time denotes the time spent in the capillary microreactor.
[f] Homocoupling compound was determined by GCMS.
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sponding cross-coupled product in 95% isolated yield, requir-
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styrene and 1-chloro-2-phenylacetylene can be reacted with in
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Csp2–Csp3 linkages. The protocol utilizes an NHC ligand to effi-
ciently couple alkynyl chlorides and alkyl Grignard reagents,
while no supporting ligand is needed for the functionalization
of styrenyl chlorides. Interestingly, the Fe-based cross-coupling
reaction can be translated to flow and be combined with the
synthesis of Grignard reagents in a single, uninterrupted con-
tinuous process. A salient feature of the flow protocol is that
the use of an NHC ligand can be avoided for the Csp–Csp3
coupling without compromising the reaction selectivity, which
is attributed to the improved temperature control in a micro-
reactor.
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Acknowledgements
X.J.W. and T.N. would like to acknowledge the European Union
for a Marie Curie ITN Grant (Photo4Future, grant number
641861). Y.D. stay at Eindhoven University of Technology was
financially supported by the China Scholarship Council.
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Conflict of interest
The authors declare no conflict of interest.
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Keywords: catalysis
Grignard reagents · iron
· cross-coupling · flow chemistry ·
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Manuscript received: September 27, 2019
Accepted manuscript online: October 1, 2019
Version of record online: && &&, 0000
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Communication
COMMUNICATION
&
Catalysis
Y. Deng, X.-J. Wei, X. Wang, Y. Sun,
T. Noꢀl*
&& – &&
Iron-Catalyzed Cross-Coupling of
Alkynyl and Styrenyl Chlorides with
Alkyl Grignard Reagents in Batch and
Flow
A broadly applicable Fe-catalyzed
out under mild conditions in very short
reaction times in batch. The use of flow
allows for the process integration of the
Grignard reagent synthesis and the Fe-
based cross-coupling chemistry.
cross-coupling of alkynyl and styrenyl
chlorides with alkyl Grignard reagents is
reported (see scheme). The reaction dis-
plays a broad scope and can be carried
Chem. Eur. J. 2019, 25, 1 – 5
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