Ligand-Free Iron-Catalyzed Carbon (sp2)-Carbon (sp2) Oxidative Homo-Coupling of Alkenyllithiums

Article abstract of DOI:10.1021/acs.orglett.8b03893

A new strategy was developed for the efficient synthesis of di-, tetra-, and hexa-substituted 1,3-butadienes. This one-pot procedure involves lithium-iodine exchange to generate the corresponding vinyllithium intermediates. A subsequent iron-catalyzed ligand-free oxidative homo-coupling eventually led to the formation of 1,3-butadienes in acceptable to excellent isolated yields.

Full text of DOI:10.1021/acs.orglett.8b03893

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ligand-Free Iron-Catalyzed Carbon (sp2)−Carbon (sp2) Oxidative
Homo-Coupling of Alkenyllithiums
Zhuliang Zhong,†,∥ Zhi-Yong Wang,†,∥ Shao-Fei Ni,§ Li Dang,*,§ Hung Kay Lee,† Xiao-Shui Peng,*,†,‡
and Henry N. C. Wong*,†,‡
†Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong SAR, China
‡Shenzhen Center of Novel Functional Molecules, Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10,
Second Yuexing Road, Shenzhen 518507, P. R. China
§Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong
Province, Shantou University, Shantou, Guangdong 515063, P. R. China
S
* Supporting Information
ABSTRACT: A new strategy was developed for the efficient synthesis of di-, tetra-, and hexa-
substituted 1,3-butadienes. This one-pot procedure involves lithium−iodine exchange to
generate the corresponding vinyllithium intermediates. A subsequent iron-catalyzed ligand-
free oxidative homo-coupling eventually led to the formation of 1,3-butadienes in acceptable
to excellent isolated yields.
ron is one of the most abundant metals on earth and
consequently one of the most inexpensive and environ-
diversified 1,3-butadiene species, such as polycyclic or acyclic
multisubstituted 1,3-butadienes (Scheme 1b).
I
mentally friendly ones.1 Iron-based catalysts have been actively
investigated for oxidative coupling reactions of Grignard
reagents (Scheme 1a).2 Although oxidative homo-coupling of
Upon a lithium−iodine exchange between the vinyl iodide 1a
and t-BuLi, the resulting vinyllithium moiety 2a was subjected to
an iron-catalyzed oxidative homo-coupling. On the basis of the
reports of iron-mediated oxidative homo-coupling of vinyl-
lithium,3 a stoichiometric amount of FeCl3 was employed at the
beginning, forming the desired 1,3-butadiene (3a) in 86% yield
(Table 1, entry 1). Various iron salts were uncovered to give the
same result in lower or slightly lower yields than FeCl3, such as
FeF3 (56%), FeBr3 (52%), Fe(acac)3 (70%), FeF2 (25%), FeCl2
(82%), and FeBr2 (38%) (Table 1, entries 2−7). Next, we
turned our attention to the use of catalytic amounts of FeCl3. In
the absence of an oxidant, decreasing loading of FeCl3 led to a
lower yield of 3a (Table 1, entry 8). Several commonly used
oxidants were examined for this iron-catalyzed oxidative homo-
coupling of vinyllithium (Table 1, entries 9−11). Considering
the reaction yields and environmental friendly issue, di-tert-butyl
peroxide (DTBP) was chosen as an oxidant in 86% yield (Table
1, entry 11). Although Et3N was reported to be a successful
additive in FeCl2-catalyzed homo-coupling involving organo-
lithium,7 it was not suitable for our reaction system (Table 1,
entry 12). Changing the solvents or temperature led to no
significant improvement to yields. Furthermore, we were able to
reduce the catalyst loading to 5 mol % and shortened the
reaction time to 30 min without sacrificing the yield (Table 1,
entry 13). Due to the fact that vinyllithium was destroyed during
the addition procedure with a syringe and that FeCl3 can be
dissolved well in THF, we chose to add a solution of FeCl3 in
Scheme 1. Iron-Catalyzed Oxidative Homo-Coupling of
Organometallic Reagents
vinyllithium using a stoichiometric amount of FeCl3 has been
reported since 1969,3 efficient methods for iron-catalyzed
oxidative coupling involving lithium reagents remain elusive.
Conjugated 1,3-diene motifs appear in many biologically active
natural products4 and participate in a variety of useful chemical
syntheses.5 In connection with our continuing interest in iron-
catalyzed coupling reactions of lithium reagents,6 herein we
reported an efficient iron-catalyzed oxidative homo-coupling of
alkenyllithiums, generated through either direct lithium−halide
exchange or cyclization of acetylenic lithium reagents, affording
Received: December 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03893
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
be well tolerated on the aromatic rings with 64−73% yields (3e−
i). Meanwhile, disubstituted aryl substrates and heteroaryl
substrates were tested in 59−79% yields (3j−n). Notably, alkyl-
substituted diene 3o was isolated in excellent yield (98%).
Additionally, various polycyclic dienes (3p−t), especially a
dimer of natural product derivative (3t), were obtained in
acceptable to high yields (47−77%).
As organolithiums were well used in cyclization to form new
carbon−carbon bonds,8 we next employed cyclization of
acetylenic alkyllithium to in situ generated vinyllithium species,
which then underwent oxidative homo-coupling to generate
polycyclic all-substituted 1,3-butadienes. As can be seen in
Scheme 3, 1,3-butadienes with two 5- or 4-membered rings
Table 1. Optimization of the Reaction Conditions
b
entry iron salt (mol %)
additive
time (min) yield (%)
1
2
3
4
5
6
7
8
FeCl3 (100)
FeF3 (100)
FeBr3 (100)
Fe(acac)3 (100)
FeF2 (100)
FeCl2 (100)
FeBr2 (100)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl2 (10)
FeCl3 (5)
none
none
none
none
none
none
none
none
60
60
60
60
60
60
60
60
60
60
60
60
30
30
86
56
52
70
25
82
38
29
41
84
86
33
86
94
Scheme 3. Tandem Anionic Cyclization/Iron-Catalyzed
9
O2 (balloon)
a b
,
Homo-Coupling from Acetylenic Alkyl Iodides
10
11
12
13
14
DCE (1.0 equiv)
DTBP (1.0 equiv)
Et3N (1.0 equiv)
DTBP (1.0 equiv)
DTBP (1.0 equiv)
c
FeCl3 (5)
a
Reaction condition: a solution of vinyllithium (0.2 mmol) was added
to a mixture of iron salts, additive (if applicable) in THF (1.0 mL) at
b
c
rt. GC-MS analysis. To a solution of vinyllithium (0.2 mmol) were
added a solution of FeCl3 in THF (0.1 mL) and additive.
THF to vinyllithium. Gratifyingly, this optimization increased
the yield of diene 3a to 94% (Table 1, entry 14), and the isolated
yield reached 91% (Scheme 2).
After the establishment of an acceptable optimal reaction
condition, we turned our attention to examine the substrate
scope of this oxidative homo-coupling. As shown in Scheme 2,
homo-couplings of electron-deficient aryl groups were slightly
disfavored, leading to 49−58% yields (3b−d). Electron-
donating groups, such as methyl, n-butyl, and methoxyl, can
Scheme 2. Iron-Catalyzed Homo-Coupling from Alkenyl
a b
,
Iodides
a
b
Reaction condition: 4 (0.2 mmol), t-BuLi (0.44 mmol). Isolated
c
yields. t-BuLi (0.4 mmol).
could be easily obtained in satisfactory yields (6a,b). In contrast,
butadiene 6c with two 6-membered rings was formed in low
yield because of allene formation.8 With electron-deficient aryl
groups, the homo-couplings were slightly disfavored in 46−56%
yields (6d−f). In particular, an aryl substrate with a stronger
electron-withdrawing moiety CF3 gave rise to diene 6g in a
much lower yield (30%). Several electron-rich aryl groups were
suitable for this reaction, providing the corresponding 1,3-
butadienes (6i−o) in good yields (60−76%). However,
substrate 4h, featuring an ortho-methoxy group on the phenyl
a
b
Reaction condition: 1 (0.2 mmol), t-BuLi (0.44 mmol). Isolated
yields.
B
DOI: 10.1021/acs.orglett.8b03893
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Letter
ring, gave 6h in only 43% yield. This could be attributed to the
steric hindrance effect. Moreover, electron-rich aryl groups were
also able to provide 1,3-butadienes containing two 4-membered
rings in moderate yields (6t,u). Unfortunately, this oxidative
coupling process still suffers from lower yields under current
conditions when aromatic groups were replaced by alkyl, silyl, or
alkenyl groups (6p−s).
Scheme 5. Scale-Up Syntheses and Transformation of
Butadienes
Finally, several acetylenic phenyl iodides 7 were allowed to
generate butadienes 8 with two fluorene rings (Scheme 4). To
Scheme 4. Tandem Anionic Cyclization/Iron-Catalyzed
a b
,
Homo-Coupling from Acetylenic Phenyl Iodides
In order to obtain mechanistic insights of this transformation,
several control experiments were carried out (Table 2).
a
Table 2. Control Experiments
b
entry
iron (mol %)
oxidant
time (min)
yield (%)
1
2
3
none
Fe (100)
Fe (10)
DTBP (1.0 equiv)
none
DTBP (1.0 equiv)
60
60
60
25
0
25
a
b
a
Reaction condition: 7 (0.2 mmol), t-BuLi (0.44 mmol). Isolated
Reaction condition: a solution of vinyllithium 2a (0.2 mmol) was
added to a mixture of iron and oxidant (if applicable) in THF (1.0
mL) at rt. GC-MS analysis.
c
yields. t-BuLi (0.4 mmol).
b
our delight, acetylenic phenyl iodides were able to undergo this
tandem cyclization/oxidative coupling in higher yields than
those of the corresponding acetylenic alkyl iodides, probably due
to the stabilization of vinyllithium with the fluorene motif.
To demonstrate the practicality of this protocol, we carried
out the coupling reaction with substrates 1a (5 mmol, 1.15 g)
and 4a (5 mmol, 1.42 g) on a gram-scale reaction to afford diene
compounds 3a and 6a in 80 and 64% yield, respectively (Scheme
5). Diene 3a and its derivatives were rather useful in organic
synthesis, for example, in Diels−Alder reaction9 and Mc-
Cormack cycloaddition.10 Subsequent treatment of polycyclic
diene 6a with a Lewis acid led to an intramolecular Friedel−
Crafts cyclization, forming the highly substituted indene 9a.11
Diene 8a and its derivatives were applied to construct the
corresponding dispirocycles bearing high fluorescence quantum
yields, which were expected to be applicable in the field of
optoelectronics.12
It is worth noting that butadienes with bulky substituents
show axial chirality because of hindered rotation around the
C2−C3 bond.13 Fortunately, single crystals of diene products
(6b, 6n, and 8b) were obtained from hexane or hexane/ethyl
acetate (Schemes 3 and 4), whose X-ray diffraction analysis
revealed that the torsion angle of C1−C2−C3−C4 was
95.698(337), 80.275(318), and 69.432(227)°, respectively.
Indeed, the current protocol for preparing nonplanar butadienes
could help open up avenues for the synthesis and application of
various axially chiral 1,3-butadienes.
Experiments in entry 1 (Table 2) and entry 8 (Table 1) showed
that both catalyst and oxidant were necessary for this reaction
condition. One equivalent of FeCl2 also worked well (Table 1,
entry 6), but iron powder (1.0 equiv) did not work (Table 2,
entry 2) in this oxidative homo-coupling. Moreover, a catalytic
amount of iron power and stoichiometric oxidant failed to
initiate the catalytic cycle (Table 2, entry 3 vs entry 1).
Therefore, we proposed Fe(I) as the lowest oxidation state in
this homo-coupling. Since 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and 1,1-diphenylethylene (DPE) were known to
interact directly with organolithium reagents,6a these radical
scavengers were not suitable if this reaction involves a radical
pathway. Furthermore, radical clock experiments14 with cyclo-
propyl substrate 4q to diene 6q did not generate ring-opening
products, which partially supported that the catalytic cycle of
this transformation did not involve radical species.
On the basis of these experimental results and literature
reports,15 we propose herein a plausible mechanism of oxidative
homo-coupling in Scheme 6. At the beginning, catalytic amounts
of FeCl3 and vinyllithium reagents generate the tetra-
coordinated complex A, which readily undergoes a reductive
elimination of the homo-coupling product to form Fe(I)
complex B.16 In the presence of DTBP, Fe(I) complex B
would be oxidized to Fe(III) complex C. Subsequently, complex
C would regenerate the reactive complex A with two more
molecules of vinyllithium, thus completing the catalytic cycle. In
C
DOI: 10.1021/acs.orglett.8b03893
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Scheme 6. Proposed Mechanism for Iron-Catalyzed
Oxidative Homo-Coupling
ACKNOWLEDGMENTS
■
Grants from the National Natural Science Foundation of China
(Project No. 21672181), Shenzhen Science and Technology
Innovation Committee (JCYJ20160608151520697), NSFC/
RGC Joint Research Scheme (N_CUHK451/13), Research
Grants Council (GRF Projects 403012/CUHK14309216/
CUHK14303815 and CRF PolyU C5023-14G), Innovation
and Technology Commission (a grant to the State Key
Laboratory of Synthetic Chemistry and GHP/004/16GD),
and Direct Grant (2018/2019) from CUHK are gratefully
acknowledged.
REFERENCES
■
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observed (see Figure S5 in the Supporting Information), which
partially supports the proposed mechanism.
In summary, we have developed an iron-catalyzed oxidative
homo-coupling of vinyllithiums for the efficient synthesis of di-,
tetra-, and hexa-substituted 1,3-butadienes. This reaction
system, involving inexpensive and environmentally friendly
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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obtained free of charge via www.ccdc.cam.ac.uk/data_request/
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: ldang@stu.edu.cn.
*E-mail: xspeng@cuhk.edu.hk.
*E-mail: hncwong@cuhk.edu.hk.
ORCID
Vanthuyne, N.; Joulin, B.; Naubron, J.-V.; Cismas,̧ C.; Terec, A.; Varga,
R. A.; Roussel, C.; Roncali, J.; Grosu, I. J. Org. Chem. 2009, 74, 9062−
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Li Dang: 0000-0003-2666-7607
Henry N. C. Wong: 0000-0002-3763-3085
Author Contributions
∥Z.Z., Z.-Y.W.: These authors contributed equally.
Notes
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The authors declare no competing financial interest.
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