Stereospecific Iron-Catalyzed Carbon (sp2)-Carbon (sp2) Cross-Coupling of Aryllithium with Vinyl Halides

Article abstract of DOI:10.1021/acs.orglett.1c01318

We present herein an efficient synthetic protocol involving iron-catalyzed cross-coupling of organolithium compounds with vinyl halides as key coupling partners. More than 30 examples were obtained with moderate to good yields and high stereoselectivities. The practicality of this method is evidenced by a gram-scale synthesis. In addition, a preliminary mechanistic investigation was also performed.

Full text of DOI:10.1021/acs.orglett.1c01318

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Letter
Stereospecific Iron-Catalyzed Carbon (sp2)−Carbon (sp2) Cross-
Coupling of Aryllithium with Vinyl Halides
Peng Chen, Zhi-Yong Wang, Xiao-Shui Peng,* and Henry N.C. Wong*
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ABSTRACT: We present herein an efficient synthetic protocol
involving iron-catalyzed cross-coupling of organolithium compounds
with vinyl halides as key coupling partners. More than 30 examples
were obtained with moderate to good yields and high stereo-
selectivities. The practicality of this method is evidenced by a gram-
scale synthesis. In addition, a preliminary mechanistic investigation
was also performed.
ransition-metal-catalyzed cross-coupling reactions target-
ing to selective C−C bond formation enable the facile
C(sp3)−C(sp3) bonds, consequently providing valuable
alternatives to existing methodologies by demonstrating for
the first time that organolithium reagents could be employed as
cross-coupling partners in iron-catalyzed cross-coupling
procedures.19a Soon after, iron-catalyzed C(sp2)−C(sp2)
bonds and other C−C bond cross-coupling reactions were
also realized in good yields.19b,c Furthermore, highly practical
and efficient iron-catalyzed C(sp2)−C(sp2) oxidative homo-
coupling reactions of alkenyllithium and aryllithium reagents
were also achieved, leading to the formation of symmetric 1,3-
butadienes and biaryls in moderate to good yields,
respectively.19d,e
Vinyl arenes are privileged scaffolds frequently found in
bioactive natural products, pharmaceuticals, and polymers.20
Metal-catalyzed cross-coupling methods are also among the
most deployed synthetic methodologies for the realization of
substituted styrenes. As shown in Scheme 1, while such
reactions are usually dominated by palladium,21 nickel,22 and
cobalt23 catalysts, an iron-catalyzed Kumada process was also
reported in 2011.24 Herein, we report the stereoselective
construction of vinyl arenes under a mild iron-catalyzed cross-
coupling process between aryllithium compounds and vinyl
halides.
T
preparation of structurally diversified molecules and facilitate
the development of modern drugs and organic materials.1−4
Traditionally, catalysis by palladium, ruthenium, and nickel has
been commonly used in the cross-coupling reactions involving
many organometallic reagents.1,5−10 However, because of their
intrinsic limitations such as high reactivities and low
selectivities, the direct application of organolithium reagents
in cross-coupling reactions has not been fully explored and still
remains an enormous challenge, despite that organolithium
reagents are either commercially available or easily accessible
through direct metalation or halogen-lithium exchange
processes. Early studies by Murahashi and co-workers
pioneered the palladium-catalyzed cross-coupling procedure
involving alkyllithium/aryllithium reagents and alkenyl halides
in 1970s.11 Feringa and co-workers developed some elegant
palladium-based catalytic systems to directly generate C−C
bonds by using organolithium compounds as cross-coupling
partners.12 Moreover, they also disclosed for the first time
palladium catalytic systems for alkenyllithium or lithium
acetylides as cross-coupling partners.12g−j However, iron has
attracted a great deal of interest toward the catalysis of cross-
coupling reactions because of its low cost, low toxicity, earth-
abundance, as well as its novel reactivity as compared with
those analogous reactions with precious metals (i.e., palla-
dium). Accordingly, the development of iron-catalyzed cross-
coupling reactions is expectedly undergoing an explosive
growth.13 In 1971, Kochi demonstrated that simple iron salts
were able to catalyze the stereoselective generation of C−C
As shown in Table 1, we commenced the preliminary
screening on this cross-coupling reaction by reacting p-
anisyllithium 2, freshly prepared by treatment of 4-
bromoanisole with t-BuLi, with (E)-2-iodovinylbenzene 1a in
the presence of various commonly used iron catalysts in
toluene. Without any iron catalyst or ligand, no reaction
bonds.14 Subsequently, the research groups of Fu
̈
rstner,
Received: April 16, 2021
Published: May 19, 2021
Nakamura, Bedford, and Cahiez have all contributed
significantly to iron-catalyzed cross-coupling reactions.15−18
In 2016, our group exploited an efficient iron-catalyzed cross-
coupling reaction under mild conditions, involving organo-
lithium compounds and a variety of organic bromides. Our
examples included the formation of C(sp2)−C(sp3) bonds and
https://doi.org/10.1021/acs.orglett.1c01318
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4385−4390
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attempted (entries 9, 10, and 14), no significant improvement
was realized. We then examined several NHC ligands (entry
13), Buchwald ligands, and other commonly used phosphine-
containing, amine-containing monodentate as well as bidentate
ligands (entries 11, 12; see Table S3 in the Supporting
Information). Relevant results showed that Xphos was a better
ligand for this reaction. Moreover, lower loading of iron
catalyst (5 mol %) was found to reduce slightly the overall
transformation efficiency (entry 15). Eventually, the best
condition was found to be Fe(acac)2 and Xphos, in which 74%
of 3a was obtained (entry 14; other details can be found in the
Supporting Information).
Scheme 1. Transition-Metal-Catalyzed Cross-Coupling
Reactions to Form a C−C Bond
With the optimized reaction condition in hand, the substrate
scope of the iron-catalyzed cross-coupling reaction of 2 with
(E)-vinyl iodides 1 was further examined. The results are
shown in Scheme 2. Gratifyingly, vinyl iodides with both
a,b
Scheme 2. Scope of (E)-Vinyl Iodides
a b
,
Table 1. Optimization of Reaction Conditions
c
entry
Fe
ligand
Li
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-
-
-
-
-
-
-
-
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
17
48
38
48
50
45
60
trace
52
64
67
55
74
FeCl2
FeCl3
FeBr2
FeBr3
Fe(acac)2
Fe(acac)3
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
-
XPhos
XPhos
BrettPhos
MePhos
SIPr-HBF4
XPhos
XPhos
Et2O
a
Reaction conditions: Fe(acac)2 (0.02 mmol), Xphos (0.02 mmol), 1
(0.2 mmol), in 2.0 mL of toluene under Ar, added a solution of 2 in
Et2O over 2 h by a syringe pump at 0 °C, then at 23 °C for 6 h.
toluene
toluene
toluene
toluene
toluene
b
Isolated yield.
d
57
a
electron-donating groups, such as t-butyl (viz. 1b) and n-butyl
(viz. 1c), and electron-deficient aromatic ring, for example, the
pharmaceutically useful trifluoromethylvinyl iodide 1d,
smoothly underwent this coupling reaction to generate the
desired stilbenes in moderate to good yields (3b, 3c, and 3d).
Moreover, ortho-, meta-, and para-methylphenylvinyl iodides
(1e, 1f, and 1g) were also studied, generating 3e, 3f, and 3g,
respectively, with 3g notably being isolated in excellent yield
(82%). Meanwhile, stilbene 3k was also afforded with good
yield. The steric hindrance exerted by one ortho-methyl group
was found to be less obvious than that shown by two ortho-
methyl groups (3e vs 3j). Fluorine-substituted phenylvinyl
iodides 1h and 1i successfully underwent the cross-coupling
with excellent chemoselectivity and moderate to good yields,
affording the corresponding fluorinated stilbenes 3h and 3i.
Reaction conditions: To a solution of compound 1a (0.2 mmol),
iron catalyst (10 mol %) and ligand (10 mol %) in toluene (2.0 mL)
was added a solution of 2 (c = 0.2 mmol/mL) in Et2O over 2 h by a
syringe pump at 0 °C. Isolated yield. The equiv of 2. 5 mol %
Fe(acac)2 and 5 mol % Xphos were used.
b
c
d
occurred (entry 1). With iron catalysts, cross-coupling product
3a, together with some homocoupling products, were
observed. Subsequently, several iron catalysts were screened
(entries 2−7), and the highest yield among these entries was
50% when Fe(acac)2 was used. It is noteworthy that with 3.0
equiv of 2, all starting materials were consumed, and the yield
was improved to 60% (entry 8). However, a further increase of
the amount of 2 to 4.0 equiv led to a decrease of the yield of 3a
to 48%. Although different solvents were respectively
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a b
,
Table 2. Substrate Scope
R1
R2
R3
X
Ar
product
yield (%)
H
H
H
H
H
H
H
H
H
H
H
Me
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
BnOCH2
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
I
I
I
I
I
I
I
I
I
I
I
Br
I
Br
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
72
81
62
60
62
55
72
56
57
46
42
32
54
4-MeC6H4
4-EtC6H4
4-tBuC6H4
4-iPrC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
BnO(CH2)4
3, 5-(MeO)2 C6H3
Ph
4-MeO-3,5-(Me)2C6H2
Ph
3,4-(OCH2O)C6H3
4-MeOC6H4
3,5-(MeO)2 C6H3
Ph
Me
H
Ph
4-MeOC6H4
4-MeOC6H4
c
2-naphthyl
H
62
a
Reaction conditions: Fe(acac)2 (0.02 mmol), Xphos (0.02 mmol), 4 (0.2 mmol), in 2.0 mL toluene under Ar, added a solution of 5 in Et2O over 2
b
c
1
h by a syringe pump at 0 °C, then at 23 °C for 6 h. Isolated yield. The Z/E ratio was determined by H NMR, Z/E > 10:1.
Nevertheless, 4-chlorine-, 4-bromine-, and 4-iodo-phenylvinyl
iodides were chemoselectively incompatible with this protocol.
Furthermore, alkylvinyl iodides 1l, 1m, and 1n were
successfully employed, as exemplified by the generation of
products 3l, 3m, and 3n in 55%−76% yields, respectively. The
application of conjugated olefin 1o as substrate was also
feasible and furnished the desired product 3o in 68% yield. It
was also uncovered that the sterically hindered (1-iodovinyl)-
cyclopentane 1p formed the corresponding coupling product
3p in 52% yield. In addition, compounds 3r and 3s were
formed with high yields, when the reactions were carried out
by allowing iodomethylenecyclohexane (1r) or iodomethyle-
necycloheptane (1s) to react with 2. A benzyloxymethylvinyl
iodide 1q was also examined, and as a result, 3q was obtained
in 40% yield. To our delight, freshly prepared (E)-β-3-
thienylvinyl iodide (1t) also successfully furnished the
corresponding product 3t. In addition, the application of this
protocol to couple the stanolone derivative 1u with 2
successfully led to the desired product 3u, albeit in only 45%
yield.
On the basis of the scope of various vinyl iodides 1 in
Scheme 2, we further explored the scope of this protocol by
coupling vinyl halides 4 with aryllithiums 5 (Table 2). Under
the standard condition, aryllithiums 5 bearing electron-
donating alkyl groups such as Me, Et, t-Bu, and i-Pr underwent
the cross-coupling reaction smoothly with (E)-1-(2-iodovinyl)-
3-methoxybenzene (4a) to afford stilbenes 6a−6e in good to
excellent yields. In addition, 4 containing electron-donating
groups coupled with different aryllithiums, resulting in the
formation of products 6f−6k in good yields as well. To our
delight, the sterically hindered tetrasubstituted 2-bromo-3-
methylbut-2-ene (4l), also furnished successfully the corre-
sponding product 6l in 32% yield. In order to explore the
reaction diversity, two examples with Z-alkenyl halides were
investigated. Experimental results showed that both com-
pounds reacted under our optimized condition to give 6m and
6n, respectively. Moreover, regardless of yields, it is interesting
to note that a very small percentage of isomerization was found
in the latter two cases, which lends support to our hypothesis
that this reaction might likely go through a nonradical pathway.
To demonstrate the synthetic utility of our work, we
attempted to carry out the reaction at a larger scale of 1 g, as
can be seen in Scheme 3. Two typical scale-up reactions in
approximately 1 g scale provided the corresponding stilbenes
in satisfactory yields.
Scheme 3. Gram-Scale Reactions
In order to gain a better mechanistic understanding of the
reaction, additional studies were performed on the basis of our
previous work (Scheme 4).19c Thus, the reaction of 4m was
carried out and monitored very carefully, but only a small
amount of isomerization product 3a was observed (Z/E > 7:1).
Moreover, good cross-coupling result was also obtained for
(Z)-2-(2-bromovinyl)naphthalene (4n), leading to the for-
mation of high Z/E ratio product 6n in 62% yield (Z/E >
10:1). Additionally, a radical clock experiment of 1n was also
performed. The results indicated that no ring-opening products
were observed, therefore hinting at the absence of transient
radical intermediates. These observations suggested that
radical pathways were not likely to be involved in this reaction
(for other details, please see Supporting Information).
In summary, we have demonstrated an efficient highly
stereospecific Fe(II)-catalyzed cross-coupling process by using
organolithium reagents and vinyl halides. More than 30
examples were obtained with moderate to good yields. The
reaction could be scaled up to gram scale. This method
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Research Grants Council (Hong Kong) (RGC) in the form of
GRF (CUHK14304819, CUHK14309216, CUHK14303815,
and 403012), and the Innovation and Technology Commis-
sion (Hong Kong) in the form of subsidy to the State Key
Laboratory of Synthetic Chemistry, the open grant to CUHK-
Shenzhen from the State Key Laboratory of Synthetic
Chemistry, Direct Grant from CUHK, and the University
Development Fund Grants from The Chinese University of
Hong Kong, Shenzhen.
Scheme 4. Control Experiments
DEDICATION
■
This work is dedicated to the memory of Professor Klaus
Hafner.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01318.
Experimental procedures and compound characteriza-
tion (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xiao-Shui Peng − Department of Chemistry, and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong SAR, China; School of Science and
Engineering, The Chinese University of Hong Kong
(Shenzhen), Shenzhen 518172, China; orcid.org/0000-
0001-9528-8470; Email: xspeng@cuhk.edu.cn
Henry N.C. Wong − Department of Chemistry, and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong SAR, China; School of Science and
Engineering, The Chinese University of Hong Kong
(Shenzhen), Shenzhen 518172, China; orcid.org/0000-
0002-3763-3085; Email: hncwong@cuhk.edu.hk
Authors
Peng Chen − Department of Chemistry, and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong SAR, China
Zhi-Yong Wang − Department of Chemistry, and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong SAR, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01318
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by grants from National Natural
Science Foundation of China (NSFC) (21971219, 21672181),
■
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