Article https://doi.org/10.

1038/s41467-024-49870-1

Chemo-, regio- and stereoselective access to

polysubstituted 1,3-dienes via Nickel-
catalyzed four-component reactions
Received: 22 March 2024 Shanglin Chen1,5, Ya-Nan Wang2,5, Jinhui Xie1, Wangyang Li 1, Mingxing Ye1,
Xingxing Ma1, Kai Yang 1, Shijun Li 3, Yu Lan 2,3 & Qiuling Song 1,4
Accepted: 21 June 2024

1,2-Difunctionalization of alkynes offers a straightforward approach to access

Check for updates polysubstituted alkenes. However, simultaneous multi-component cascade
1234567890():,;
1234567890():,;

transformations including difunctionalization of two alkynes with both syn-

and anti-selectivity in one catalyst system is undeveloped and proves to be a
significant challenge. Herein, we report a Nickel-catalyzed four-component
reaction to access polysubstituted 1,3-dienes using two terminal alkynes, aryl
boroxines, and perfluoroalkyl iodides, wherein the reaction forms three new
C-C bonds in a single vessel and serve as a modular strategy to access poly-
substituted 1,3-dienes with excellent chemoselectivity, good regioselectivity
and exclusive stereoselectivity. Control experiments reveal the plausible
reaction mechanism and DFT calculations explain the cause for the formation
of this unusual four-component reaction. Furthermore, we successfully
incorporate two biologically active units into 1,2,3,4-tetrasubstituted 1,3-
dienes, which greatly increases the diversity of molecular scaffolds and brings
more potential values to medicinal chemistry, the synthetic utility of our
protocol is further demonstrated by the late-stage transformations.

Transition-metal-catalyzed 1,2-difunctionalization of alkynes repre-
sents an intriguing and prevailing tactic for the efficient construction
of diverse valuable polysubstituted alkenes1–10 and their synthetic
applications widely extend to pharmaceuticals, agrochemicals, natural
products as well as material sciences11–15, thus stimulating great atten-
tion in the chemical community. In the past decade, the development
of various coupling partners greatly increases organic molecular
complexity and facilitates reaction diversification13,16,17. Among them,
organoboron reagents are attractive and valuable synthons owing to
their air stability, non-toxicity, abundance, readily accessible, and
broad availability in versatile transformations13,18–20. Hence, transition-
metal-catalyzed 1,2-difunctionalization of alkynes involving organo-
boron reagents13,17,21 has been proven to be one of the most versatile
and powerful tools for the efficient construction of diverse chemical
bonds recently. Based on the mechanism, this type of transformation
could be divided into radical addition/cross-coupling tactic and car-
bometallation/cross-coupling platform3,5,16, and both of them are
known strategies for the synthesis of value densely substituted alkenes
(Fig. 1a). On the one hand, migratory insertion of alkyne with orga-
nometallic species generating from organoboron reagents enables the
carbometallation procedure, forming alkenyl-metal intermediates
which are further trapped by external electrophiles13, thus affording
the syn-difunctionalization of alkynes, and the successful transition-
metal catalysis3,5,13 which could promote such reactions includes Ni22,
Rh23,24, Pd25,26, etc. (Fig. 1a, left). In this process, the use of directing
group-containing5,13,25–28 or electronically biased alkynes5,13,29–31 have

1
Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, Fujian, China.
2
Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University,
Chongqing, China. 3College of Chemistry and Institute of Green Catalysis, Zhengzhou University, Zhengzhou, China. 4School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan, China. 5These authors contributed equally: Shanglin Chen, Ya-Nan Wang.
e-mail: ylan@zzu.edu.cn; qsong@fzu.edu.cn

Nature Communications | (2024)15:5479 1

Article
been critical to control regioselectivity, yet the success of syn-
difunctionalization of accessible unsymmetrical alkynes with com-
plete regioselectivity is full of challenges. On the other hand, on
account of steric factors of vinyl radicals in the coupling step, radical
addition/cross-coupling platform favors anti-addition3,5,13, which typi-
cally transforms into a stereodefined anti-difunctionalization of
alkynes by utilizing the commercially available organoboron com-
pounds as nucleophilic reagents32–39, and recent feasible catalysts for
this transformation are Pd32–36, Ni37,38, Cu39 etc. (Fig. 1a, right). However,
the combination of feasible alkenyl radicals with a more reactive
intermediate generated in a reaction system instead of well-studied
nucleophilic reagents under transition-metal-catalysis is scarce, and
further exploration is still needed. Herein, it should be noted that the
above-mentioned three-component difunctionalization protocols
were generally used for the assembly of polysubstituted alkenes with
syn- or anti-selectivity respectively, which limit to install two units into
one alkyne to render the corresponding product, yet the integration of
two alkynes with two accessible coupling reagents in a single vessel to
deliver value-added polysubstituted 1,3-dienes with excellent stereo-
specificity in one catalytic system via a four-component reaction has
not been disclosed, thus remaining a vast challenge.
Given the rapid development of the combination of radical
chemistry with transition-metal-catalyzed transformations15, we envi-
sioned that the carbometallation platform should be possibly com-
bined with radical-promoted platform to render a four-component
process, in details, alkyne undergoes migratory insertion into
nucleophilic aryl-metal species with syn-selectivity to lead to the cor-
responding alkenyl-metal intermediate, concurrently, radical-
mediated platform enables radical addition of perfluoroalkyl halides
to another alkyne with anti-selectivity to generate a very active vinyl
radical, the corresponding alkenyl-metal intermediate could trap the
above-mentioned newly generated alkenyl radical intermediate fol-
lowed by reductive elimination to facilitate cascade four-component
reactions (Fig. 1b).
Seeking to achieve the above-mentioned hypothesis about the
cascade difunctionalization of two alkynes, we need to face several
inherent challenges (Fig. 1b): (1) How to make a breakthrough for
conventional three-component difunctionalization reaction from
similar accessible starting materials34? Intermolecular multi-
component reaction processes using similar starting materials are
more challenging inherently, as the radical-mediated three-compo-
nent background reaction acting as the competing reaction greatly
hampers the success of our design. At the same time, on account of
massive competitive reactions that exist in current multi-component
reactions (Such as well-studied three-component reaction, Atom
Transfer Radical Addition reaction (ATRA), Radical addition reaction
(RA), and Alkyne Insertion reaction (AI)), the capability to efficiently
suppress the potential competitive reactions and achieve the specifi-
city of our expected multi-component reaction is full of hurdles. (2)
Selective control has always been a formidable challenge in multi-
component reactions40–52. There is only one regioselectivity involved in
reported three-component difunctionalization32–39 of alkynes, yet in
our hypothesis, we pursue to simultaneously enable syn-
difunctionalization as well as anti-difunctionalization of alkynes in
one catalytic system to afford both syn-controlled alkene unit and anti-
controlled alkene unit, therefore, how to precisely regulate the chemo-
and regioselectivity of two alkynes in a single pot without the directing
groups13,25–28 and the use of electronically biased13,29–31 alkynes will be a
great challenge. (3) How to afford the expected polysubstituted 1,3-
dienes with challenging and intriguing stereospecificity? If successful,
this strategy would achieve a four-component reaction with cascade
1,2-functionalization of two alkynes in one catalyst system, make a
breakthrough for a well-developed three-component difunctionaliza-
tion reaction from accessible starting materials34 and offer an
Nature Communications | (2024)15:5479
https://doi.org/10.1038/s41467-024-49870-1
opportunity to lead to the modular assembly of value-added, appeal-
ing as well as structurally diversified fluorinated polysubstituted 1,3-
dienes.
1,2,3,4-Tetrasubstituted 1,3-dienes, one of the most complicated
and traditionally not-easy-to-accessible conjugated dienes, are widely
found in natural products due to their unique biological activity53 and
possess unique structural complexity as well as a great diversity of
stereoisomers (include (1E, 3E), (1E, 3Z), (1Z, 3Z), (1Z, 3E)), to the best of
our knowledge, the synthesis of such polysubstituted substituted 1,3-
dienes with excellent regioselectivity and exclusive stereoselectivity
has been limited53–59 so far and still remains a formidable challenge.
Therefore, the exploration of a simple and practical method for the
preparation of 1,2,3,4-tetrasubstituted conjugate dienes is highly
desired58. Herein, we report an Nickel-catalyzed four-component
reaction via chemo-, regio-, stereoselective cascade difunctionaliza-
tions of two alkynes to access polysubstituted 1,3-dienes (Fig. 1c),
which includes simultaneous syn-difunctionalization and anti-
difunctionalization of alkynes in one catalytic system, gratifyingly,
this strategy also provides an opportunity to build structurally diverse
1,2,3,4-tetrasubstituted 1,3-dienes by utilizing the readily accessible
starting materials and cheap transition-metal catalyst in a single
operation. Moreover, this reaction features mild reaction conditions,
good functional group tolerance, excellent chemoselectivity, good
regioselectivity as well as exclusive stereoselectivity.
Results
Reaction conditions optimization
To validate our initial hypothesis and solve the aforementioned chal-
lenges, we began our research by using methyl 4-ethynylbenzoate 1,
perfluorobutyl iodide 2, and 4-methoxyaryl boroxine 3 as the model
substrates. We guess that this unusual, appealing, and more challen-
ging multi-component intermolecular cross-coupling reaction could
be achieved using the proper catalytic system, as the palladium cata-
lysts show excellent performance in previous radical-mediated multi-
component difunctionalization reactions32–36, thus promoting us to
have an attempt to utilize them at first. To our delight, when we used
4 mol% Pd(PPh3)Cl2 or Pd(PPh3)4 as the metal catalyst (Table 1, entries
1–4), the polysubstituted 1,3-diene 5 could be successfully obtained
with good regioselectivity and exclusive stereoselectivity albeit in poor
yield, indicating that we indeed enabled cascade difunctionalization of
alkynes in one catalytic system. It was worth noting that poly-
substituted alkene 4 was the dominant byproduct in this reaction
condition, which greatly affected the success of our designed reaction.
After extensive and time-consuming condition evaluations regarding
palladium catalysts (Please see Supplementary Table 1 for more
details), no satisfactory outcomes could be obtained, and this reaction
tendency was exclusively dominated by conventional three-
component reaction or simply afforded the desired product 5 in
poor yields, which forced us to examine different metal catalyst sys-
tems. In order to realize our initial assumption, Fe60 and Cu61,62 catalysts
were further assessed since they also showed good performance in the
difunctionalization of alkynes in previous reports, (Table 1, entries
5–15), however, neither polysubstituted alkenes 4 nor polysubstituted
1,3-dienes 5 were detected in the system, suggesting that these metal
catalysts were not compatible with our designed reaction. None-
theless, the above unsatisfactory results did not discourage us, and we
subsequently focused on a Nickel-catalyzed system based on the
known reactions37,38. We pleasingly found that the nitrogen ligands
performed better than the phosphine ligands in the Nickel-catalyzed
reaction system (Table 1, entries 16–21), moreover, polysubstituted 1,3-
diene 5 began to become the primary product and only a trace amount
of polysubstituted alkene 4 was obtained, this result revealed that the
nickel catalytic system is more favorable for four-component reaction
instead of classical three-component reaction, thus promoted us to
2
Article https://doi.org/10.1038/s41467-024-49870-1

a
Migratory Insertion Platform Radical-mediated Platform

Ar Ar R R
Mn-cat. R-X Mn-cat. ArB(OR)2
+ ArB(OR)2 + R-X
Mn R Mn+2 Ar

Syn-selectivity Two C-C Bonds Anti-selectivity Two C-C Bonds

Limited to directing group-containing or electronically biased alkynes Most example of accessible organboron reagent

Few example of alkenyl metal intermediate trapping reactive alkenyl radical Limited examples of alkenyl radical combine with newly generated reactive intermediate

Synthesis of polysubstituted alkenes with syn-selectivity Synthesis of polysubstituted alkenes anti-selectivity

b

Ar
+ ArB(OR)2 Mn+1-cat.
Ar
Mn+1

radical trapping
reductive
R elimination R
Mn-cat. ?
+ R-X
three C-C bonds formed

unexpected product

R R
R

Ar
Ar X
3-component ATRA RA AI

Challenge:
How to avoid the backgroung three-component reaction and supress the competitive reactions? (chemoselectivity)
How to afford the syn- and anti-controlled alkene units without directing group? (regioselectivity)
How to achieve the stereospecific synthesis of polysubstituted 1,3-dienes? (stereoselectivity)

accessible starting materials

Ar mild reaction condition
Ar O Ar Ni
B B Rf inexpensive metal catalyst
+ + Rf-I + O O
B excellent chemoselectivity

Ar good regioselectivity
four-component reaction
exclusive stereoselectivity

Fig. 1 | Background and our strategy. a Previous arts on transition-metal- alkynes (this work). 3-component = three-component reaction, ATRA = atom
catalyzed 1,2-difunctionalization of alkynes (three-component reaction, well-stu- transfer radical addition reaction, RA = radical addition reaction, AI = alkyne inser-
died). b Our design (four-component reaction, unknown). c Synthesis of poly- tion reaction.
substituted 1,3-dienes via nickel-catalyzed four-component reaction with two

utilize nickel catalysts to optimize the reaction conditions for this
unusual cascade four-component reaction.
Subsequently, by evaluation of metal catalysts and ligands, we
found that Ni(PCy3)2Cl2 and dtbpy emerged as lead catalysts and
superior ligands in our catalytic system (Table 2, entries 1–7; please see
Supplementary Table 5 and Table 6 for more details). Notably, no
desired 1,3-diene 5 was detected when we used Cs2CO332,33 or K3PO436,37
as the base (Table 2, entries 8-9), which could effectively promote
nickel-catalyzed or palladium-catalyzed three-component 1,2-difunc-
tionalization of alkynes involving organoboron reagent in previous
works. Upon the replacement of aryl boroxine with the corresponding
potassium trifluoroborate or pinacol ester, the desired product 5 could
not be obtained (Table 2, entries 10, 11), to our surprise, aryl boronic
acid could get relatively good results in 60 oC (Table 2, entry 12), while
it still remained room for further advancement. Pleasingly, using DMA
and DME as mixed solvents to our reaction system, outperformed the
single solvent system (Table 2, entries 13, 14). This phenomenon defi-
nitely prompted us to investigate more mixed solvent systems and
diverse proportions of mixed solvent, yet it was regretful that no better
outcomes were achieved in these experiments (Please see the Sup-
plementary Table 7 for more details). Encouraged by the above results,
we further carefully screened the temperatures and concentrations
(Table 2, entries 15, 16, see the Supplementary Table 9 and Table 12 for
more details), and eventually the optimal condition for this reaction
was listed as entry 2 with 71% isolated yield, additionally, when the
reaction was scaled up to 1 mmol scale, the target product 5 was
obtained in decent yield without significant erosion of the efficiency
(Table 2, entry 2). By comparison, a dramatic decrease was observed
when the reaction was performed in the absence of a nickel catalyst,
ligand, or base (Table 2, entries 18–20), further indicating that they are
essential to carry out this multi-component reaction system. In parti-
cular, it should be noted that only a small amount of byproduct
polysubstituted alkene 4 was detected in this whole process, thus
revealing that the Ni-catalyzed system was indeed suitable catalytic
system for our designed reaction and we successfully modulated the
reaction from conventional three-component reaction transform into
unusual four-component reaction under mild condition.
Substrate scopes
With the optimal reaction condition in hand (Table 2, entry 2), we next
implemented to examine the substrate scope of this cascade four-
component reaction (Fig. 2). At the outset, we explored the substrate
with different substituents on the para position of the aromatic
alkynes. To our delight, no matter that they were hydrogen, methyl,

Nature Communications | (2024)15:5479 3

Article https://doi.org/10.1038/s41467-024-49870-1

H H Ar O Ar t t
B B Ni(PCy3)2Cl2 (10 mol%) Ar Bu Bu
C4F9I L7 (15 mol%), K2CO3 (2.0 equiv) C4F9
O O
B H
DMA:DME = 1:1 (0.2 M) 45 oC, 72 h
Ar H N N
1' 1' 2 3 L7

Alkyne

Ar
C4F9
H Me Et t
Bu MeS MeO TMS
H

Ar = 4-MeOC6H4 6, 65% 7, 61% 8, 60% 9, 60% 10, 61% 11, 56% 12, 62%

F
Cl

F Cl Br NC MeOC OHC

13, 64% 14, 64% 15, 66% 16, 66% 17, 52% 18, 60% 19, 65% 20, 52%

Multi-substituted alkynes
Me MeO MeO
S O

HF2C HF2CO F3CO MeO

O
Me OMe OMe

21, 55% 22, 70% 23, 70% 24, 52% 25, 61% 26, 50% 27, 35% 28, 56%

Fig. 2 | Substrate scope of catalytic cascade difunctionalizations of alkynes. 72 h. Unless otherwise stated, all desired polysubstituted 1,3-dienes were obtained
Reaction conditions: the reaction was carried out with alkyne 1’ (0.27 mmol), 2 with regioselectivity greater than 95:5 and the regioselectivity was detected by 1H
(0.8 mmol), 3 (0.067 mmol), Ni(PCy3)2Cl2 (10 mol%), dtbpy (15 mol%), K2CO3 NMR analysis of desired products or GC analysis of desired products. DMA = N, N-
(0.4 mmol, 2.0 equiv) in the 1 mL of mixed solvent (DMA:DME = 1:1) at 45 oC for dimethylacetamide, DME = 1,2-dimethoxyethane.

ethyl, tert-butyl, methylthio, methoxy, and trimethylsilyl groups, the
corresponding products (6–12) were all smoothly delivered in mod-
erate yields with excellent regioselectivity and exclusive stereo-
selectivity. Then we evaluated the different halogen-substituted
aromatic alkynes and found that they were compatible to our reaction,
as well in spite of their positions on the aromatic rings (13–17).
Meanwhile, the general electron-withdrawing groups such as ester,
cyano, ketone, aldehyde, difluoromethyl, difluoromethoxy as well as
trifluoromethoxy group were all tolerated with our system and the
target products (5) and (18–23) were obtained in good outcomes.
Heteroaromatic and polysubstituted alkynes including thiophene-
substituted, disubstituted and trisubstituted alkynes (24–28) were also
suitable substrate for our multi-component reaction and worked
smoothly and delivered the desired polysubstituted 1,3-dienes in
moderate yields. Unfortunately, alkyl-substituted alkyne and 1,3-enyne
were not suitable substrates for our current reaction system to access
expected polysubstituted 1,3-dienes, and two molecules of different
terminal alkynes were also not compatible with our current strategy
owing to poor chemoselectivity of radical addition process and
migratory insertion process (Please see the Supplementary 7.4 for
more details).
Encouraged by the above results, we next explored the scope of
aryl boroxines under our optimal reaction condition, and the results
were summarized in Fig. 3. We turned our attention to the reaction of
various aryl boroxine 3’ with methyl 4-ethynylbenzoate 1 and per-
fluorobutyl iodide 2. It was worth noting that the poor outcomes with
certain aryl boroxines resulting from the standard reaction conditions
could be rectified by elevating the reaction temperature from 45 oC to
50 oC (29, 33, 43-44, 54-59). To our delight, this change not only
prompted the reaction to proceed smoothly, but also maintained the
excellent regioselectivity and exclusive stereoselectivity of the
expected polysubstituted 1,3-dienes. It was found that this cascade
difunctionalization reaction exhibited good functional group toler-
ance, a wide range of the para-, meta- and ortho-substituents on aryl
boroxines were examined, both electron-neutral and electron-
donating groups, demonstrated good compatibility, and the corre-
spondingly desired products were obtained in moderate to good
yields with excellent chemoselectivity, exclusive regio- and stereo-
selectivity (29–40), upon treatment with our standard reaction con-
dition. Furthermore, general halogen-substituted aryl boroxines were
also good candidates in our reaction and rendered the desired
halogen-substituted 1,2,3,4-tetrasubstituted dienes (42–45), which
could be used for further elaborations. Gratifyingly, the success of this
four-component reaction could be extended to alkyl boroxine as well
and the desired polysubstituted 1,3-diene 41 was procured in moderate
yield. Moreover, this four-component reaction was also applicable to
diverse (hetero) aryl boroxines and polysubstituted aryl boroxines,
which successfully transform into our desired products (46–53) in
moderate to good yields. A diminished yield was observed for ortho-
substituted aryl boroxine (40), which might be attribute to steric
hindrance.
To further demonstrate the generality of this cascade four-
component reaction, we examined the substrate scope of radical
precursors (Fig. 3). Concretely, the 1,2,3,4-tertasubstituted 1,3-dienes
(54–59) could be obtained in moderate yields with excellent
regioselectivity and exclusive stereoselectivity by increasing the
reaction temperature to 50 oC. The absolute structures of products
58 and 59 were determined by X-ray crystallographic analysis, which
revealed that we indeed achieve the cascade syn- and anti-
difunctionalization of two terminal alkynes in one catalytic system
and successfully access the structurally diverse 1,2,3,4-tertasub-
stituted conjugated 1,3-dienes from readily accessible starting
materials, inexpensive metal catalyst and available nitrogen ligand in
a single step under mild condition. Notably, 1,4-diiodoper-
fluorobutane which possesses reaction sites was also a good sub-
strate for our system reaction and the desired polysubstituted 1,3-
diene 57 was afforded in moderate yield. Furthermore, we also
examined a variety of non-fluoroalkyl radical precursors in our cur-
rent catalytic system, yet they were unable to afford the desired
products (Please see Supplementary 7.5 for more details).

Nature Communications | (2024)15:5479 4

 Table 1 | Initial attempt and optimization conditions regarding metal catalysts and ligands
Article

Nature Communications | (2024)15:5479

entry [M] ligand base 4 yield (%)e 5 yield (%)e
1a Pd(PPh3)2Cl2 - K2CO3 71 26
2a Pd(PPh3)4 - K2CO3 72 29
3a Pd(PCy3)2Cl2 - K2CO3 14 14
4a Pd(CN)2Cl2 - K2CO3 6 21
5b FeBr2 - Cs2CO3 nd nd
6b FeCl2 - Cs2CO3 nd nd
7b Fe(acac)3 - Cs2CO3 nd nd
8b Fe(OTf)2 - Cs2CO3 nd nd
9b Fe(OAc)2 - Cs2CO3 nd nd
10c CuI or Cu(CH3CN)4BF6 L1 K2CO3 nd nd
11c CuI or Cu(CH3CN)4BF6 L2 K2CO3 nd nd
12c CuI or Cu(CH3CN)4BF6 L3 K2CO3 nd nd
13c CuI or Cu(CH3CN)4BF6 L4 K2CO3 nd nd
14c CuI or Cu(CH3CN)4BF6 L5 K2CO3 nd nd
15c CuI or Cu(CH3CN)4BF6 L6 K2CO3 nd nd
16d NiBr2·DME L1 K2CO3 5 36
17d NiBr2·DME L2 K2CO3 8 3
18d NiBr2·DME L3 K2CO3 8 32
19d NiBr2·DME L4 K2CO3 nd nd
20d NiBr2·DME L5 K2CO3 nd nd
a b
Reaction conditions: the reaction was carried out with 1 (0.25 mmol), 2 (0.8 mmol), 3 (0.067 mmol), palladium catalyst (4 mol%), K2CO3 (2.0 equiv) in 2 mL of mixed solvent (DCM:H2O = 5:1) at 50 °C for 12 h. Reaction conditions: the reaction was carried out with 1
(0.25 mmol), 2 (0.8 mmol), 3 (0.067 mmol), iron catalyst (10 mol%), Cs2CO3 (1.5 equiv) in 2 mL 1,4-dioxane at 80 °C for 12 h. cReaction conditions: the reaction was carried out with 1 (0.25 mmol), 2 (0.8 mmol), 3 (0.067 mmol), copper catalyst (10 mol%), ligand
(10 mol%), K2CO3 (3.0 equiv) in 2 mL toluene at 80 °C for 12 h. dReaction conditions: the reaction was carried out with 1 (0.25 mmol), 2 (0.8 mmol), 3 (0.067 mmol), nickel catalyst (10 mol%), ligand (15 mol%), K2CO3 (2.0 equiv) in 2 mL DMA at 70 °C for 24 h. eYields
were determined by gas chromatography (GC) using n-dodecane as the internal standard. Unless otherwise stated, the desired polysubstituted 1,3-dienes were obtained with regioselectivity greater than 95:5 (the ratio of 5:5’ was greater than 95:5), and the
regioselectivity was detected by 1H NMR analysis of desired products or GC analysis of desired products. M = Metal catalysts, L = Ligand, nd = not detected.

5
https://doi.org/10.1038/s41467-024-49870-1
 Table 2 | Reaction condition optimizations regarding nickel-catalyzed system. a
Article

Nature Communications | (2024)15:5479

entry [Ni] ligand base solvent 5 yield (%)b
1 Ni(PCy3)2Cl2 L1 K2CO3 DMA: DME (1:1) 71
2 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) 81(71)c(65)d
3 Ni(PCy3)2Cl2 L8 K2CO3 DMA: DME (1:1) 68
4 Ni(PCy3)2Cl2 L9 K2CO3 DMA: DME (1:1) 70
5 Ni(PCy3)2Cl2 L10 K2CO3 DMA: DME (1:1) trace
6 Ni(PCy3)2Cl2 L11 K2CO3 DMA: DME (1:1) trace
7 Ni(PCy3)2Br2 L7 K2CO3 DMA: DME (1:1) 51
8 Ni(PCy3)2Cl2 L7 Cs2CO3 DMA: DME (1:1) nd
9 Ni(PCy3)2Cl2 L7 K3PO4 DMA: DME (1:1) nd
10 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) nde
11 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) tracef
12 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) 63g
13 Ni(PCy3)2Cl2 L7 K2CO3 DMA 56
14 Ni(PCy3)2Cl2 L7 K2CO3 DME 25
15 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) 71h
16 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) 68i
17 Ni(PCy3)2Cl2 L7 K2CO3 DMA: DME (1:1) 76j
18 - L7 K2CO3 DMA: DME (1:1) nd
19 Ni(PCy3)2Cl2 - K2CO3 DMA: DME (1:1) <5
20 Ni(PCy3)2Cl2 L7 - DMA: DME (1:1) nd
a
The reaction was carried out with 1 (0.27 mmol), 2 (0.8 mmol), 3 (0.067 mmol), Ni catalyst (10 mol%), ligand (15 mol%), K2CO3 (2.0 equiv) in 1 mL of mixed solvent (DMA: DME = 1:1) at 45 °C for 72 h. bYields were determined by gas chromatography (GC) using n-
dodecane as the internal standard. cIsolated yield. d1 mmol scale reaction. eArBF3K was used. fArBpin was used. gArB(OH)2 was used, and the reaction was carried out at 60 oC. h50 °C. i40 °C. j2 mL of mixed solvent (DMA: DME = 1:1). Unless otherwise stated, the
desired polysubstituted 1,3-dienes were obtained with regioselectivity greater than 95:5 (the ratio of 5:5’ was greater than 95:5) and (1Z, 3E)/(1E, 3Z) of desired polysubstituted 1,3-dienes were greater than 95:5, and the ratio of Z/E and regioselectivity were detected
by 1H NMR analysis of desired products or GC analysis of desired products, the polysubstituted alkene 4 was obtained with the yield lower than 10%. nd, not detected.

6
https://doi.org/10.1038/s41467-024-49870-1
Article https://doi.org/10.1038/s41467-024-49870-1

H H Ar O Ar t t
B B Ar Bu Bu
Ni(PCy3)2Cl2 (10 mol%)
C4F9I O O L7 (15 mol%), K2CO3 (2.0 equiv) C4F9
B H
DMA:DME = 1:1 (0.2 M) 45 oC, 72 h
Ar H N N
L7
1 1 2 3'
= 4-MeO2CC6H4

Aryl boroxine

Ar
C4F9
i t
H Me Pr Bu TMS O O MeS
H a
29, 68% 30, 70% 31, 70% 32, 71% 33, 71%a 34, 64% 35, 68%

OMe
MeO
O

Me O Ph F Cl Br

36, 60% 37, 65% 38, 63% 39, 62% 40, 36% 41, 40% 42, 40% 43, 42%a 44, 45%a

Me O
N
n
I S O O O O

Me
n = 1, 52, 46%
45, 50% 46, 71% 47, 30% 48, 30% 49, 50% 50, 50% 51, 47%
n = 2, 53, 57%

Radical precursor

Ar Ar Ar Ar Ar
Rf C3F7 CF(CF3)2 C6F13 C4F8I
H H H H H
H H H H H

Ar = 4-MeSC6H4 54, 65%a 55, 65%a 56, 62%a 57, 50%a

Ar Ar
C8F17 C10F21
H H
H H

58, 59%a 59, 56%a

CCDC 2289202 CCDC 2289200

Fig. 3 | Substrate scope of aryl boroxines and radical precursors. Reaction
conditions: the reaction was carried out terminal alkyne (0.27 mmol), per-
fluorobutyl iodine or perfluoroalkyl iodide (0.8 mmol), aryl boroxines
(0.067 mmol), Ni(PCy3)2Cl2 (10 mol%), dtbpy (15 mol%), K2CO3 (2.0 equiv) in 1 mL
of mixed solvent (DMA:DME = 1:1) at 45 oC for 72 h. Unless otherwise stated, all
desired polysubstituted 1,3-dienes were obtained with regioselectivity greater than
95:5; and the regioselectivity was detected by 1H NMR analysis of desired products
or GC analysis of desired products. aThe reaction was carried out in 50 oC. DMA = N,
N-dimethylacetamide, DME = 1,2-dimethoxyethane.

To further showcase the high functional group compatibility and Downstream applications and transformations
broad substrate scope of our current transformation, we applied this To exemplify the synthetic utility of the current method, a series of
strategy to the late-stage functionalization of bioactive compounds transformations on compound 45 were performed in Fig. 5. At the
and drug molecules (Fig. 4). It is noteworthy that this multi-component outset, we tried to convert the reactive C-I bond of polysubstituted 1,3-
reaction performed well with aromatic alkynes derived from Borneol, dienes which derived from aryl boroxines (Fig. 5a). In the presence of 3-
Adamantanemethanol, Galactopyranose, Gemfibrozil, L-Menthol, Ibu- ethynylanisole, CuI and Pd(PPh3)2Cl2, polysubstituted 1,3-diene 45 was
profen and Cholesterol (60–66), affording the expected poly- smoothly transformed into compound 67 via the Sonogashira cross-
substituted 1,3-dienes bearing two complex molecular scaffolds in coupling reaction in excellent yield. Successively, several other Pd-
moderate yields with excellent regioselectivity and exclusive stereo- catalyzed cross-coupling reactions with 1,3-diene 45 were also applic-
selectivity, these scarce structures probably bring more potential able. For instance, compound 45 could experience the Heck cross-
values to medicinal chemistry. In addition, the carbon-carbon double coupling and Suzuki cross-coupling to access correspondingly pro-
bond was also compatible with our reaction system (66), thus further ducts 68 and 69, which bear three ester groups and could be easily
confirming the good compatibility of this four-component reaction. delivered to diverse valuable functional groups if required.

Nature Communications | (2024)15:5479 7

Article https://doi.org/10.1038/s41467-024-49870-1

H H Ar O Ar t t
Ar Bu Bu
B B Ni(PCy3)2Cl2 (10 mol%)
C4F9I L7 (15 mol%), K2CO3 (2.0 equiv) C4F9
O O
H
B DMA:DME = 1:1 (0.2 M) 45 oC, 72 h
Ar H N N
L7
1' 1' 2 3

drug molecules
O
Ar O O
O
C4F9 O O
H O
O
H O O
O

Ar = 4-MeOC6H4
from Borneol from Adamantane from Galactopyranose
60, 60% 61, 65% 62, 50%

O O
O

from Gemfibrozil O
63, 36%
from L-Menthol
64, 65% H
O O
H H
O O
from Cholesterol
from Ibuprofen 66, 66%
65, 62%

Fig. 4 | Modification of natural products and drug molecules. Reaction condi- polysubstituted 1,3-dienes were obtained with regioselectivity greater than 95:5,
tions: the reaction was carried out with 1’ (0.27 mmol), 2 (0.8 mmol), 3 and the regioselectivity was detected by 1H NMR analysis of desired products or GC
(0.067 mmol), Ni(PCy3)2Cl2 (10 mol%), dtbpy (15 mol%), K2CO3 (2.0 equiv) in 1 mL of analysis of desired products. DMA = N, N-dimethylacetamide, DME = 1,2-
mixed solvent (DMA:DME = 1:1) at 45 oC for 72 h, Unless otherwise stated, all desired dimethoxyethane.

a OMe MeO
O
O OMe
OMe

Sonogashira Heck Cross-coupling

Cross-coupling
I

67, 90%a 68, 95%b

C4F9
H
CO2Et
H
EtO2C B(OH)2 = 4-MeO2CC6H4 N
H

Suzuki Cross-coupling N
45 Buchwald-Hartwig
Cross-coupling

69, 62%c 49, 92%d

b
I
I I

CO2H
= =
MePPh3Br PCC DIBAL-H
C4F9 NaOH
C4F9 H C4F9
H f e H
71, 85% 70, 90% H
H H
= 4-MeO2CC6H4
72, 90%g 73, 86%h
45

Fig. 5 | Downstream applications and transformations. a convert the reactive C-I
bond derived from aryl boroxines. b transform the ester groups originated from
accessible terminal alkynes. Reaction condition: a45 (0.05 mmol), 3-ethynylanisole
(3.0 equiv), PdCl2(PPh3)2 (10 mol%), CuI (5 mol%) in Et3N and THF at rt for 12 h. b45
(0.05 mmol), methyl acrylate (5.0 equiv), Pd(tBu3P)2 (10 mol%), and N,
N-dicyclohexylmethylamine (2.0 equiv) in THF at 50 oC for 12 h. c45 (0.05 mmol), (4-
Ethoxycarbonylphenyl)boronic acid (1.5 equiv), Pd(PPh3)2Cl2 (10 mol%), Na2CO3
(2.0 equiv) in THF and H2O at 80 oC for 12 h. d45 (0.05 mmol), Pd(OAc)2 (5 mol%),
Xantphos (10 mol%), Cs2CO3 (4.0 equiv) in 1,4-dioxane at 100 oC for 12 h. e45
(0.05 mmol), DIBAL-H (10 equiv) in THF at −78 oC for 6 h. f70 (0.05 mmol), PCC (2.4
equiv) in DCM at rt for 4 h. g71 (0.05 mmol), MePPh3Br (3.0 equiv), K2CO3 (4.0
equiv) in 1,4-dioxane at 80 oC for 12 h. h45 (0.05 mmol), NaOH (20 equiv) in MeOH
and THF at 80 oC for 8 h. DIBAL-H = diisobutylaluminium hydride, PCC = pyridinium
chlorochromate.

Nature Communications | (2024)15:5479 8

Article https://doi.org/10.1038/s41467-024-49870-1

I
w/o Ni catalyst H
H
5
C4F9
a H H C4F9
Ar O Ar not detected 74, trace 75, trace
B B
C4F9I w/o Ligand
O O
B 5 74 75
Ar <5% major major
1 1 2 3
w/o K2CO3
5 74 75
= 4-MeO2CC6H4 Ar = 4-MeOC6H4 not detected not detected not detected

b H H Ar O Ar Ni(PCy3)2Cl2 (10 mol%) Ar

B B
dtbpy (15 mol%), K2CO3 (2.0 equiv) C4F9
C4F9I O O H
B DMA:DME = 1:1 (0.2 M), 45 oC, 72 h
H
Ar TEMPO (5.0 equiv)
5, not detected
1 1 2 3

H H Ar O Ar C4F9 C4F9
c B B
C4F9I O O (5.0 equiv)
B Ph Ph
Ph Ph Ph Ph
Ar "standard conditions"
76, minor 77, major
1 1 2 3
detected by GCMS

d Ar O Ar
H H
B B Ni(dtbpy)Cl2 (10 mol%) Ar
K2CO3 (2.0 equiv) C4F9
C4F9I O O
B H
DMA:DME = 1:1 (0.2 M), 45 oC, 72 h
Ar H

1 1 2 3
5, 81% yielda

e Ar
H H Ar O Ar
B B Ni(dtbpy)Cl2 (10 mol%)
C4F9
PCy3 (10 mol%), K2CO3 (2.0 equiv) H
C4F9I O O
B H
DMA:DME = 1:1 (0.2 M), 45 oC, 72 h
Ar
5, 81% yielda
1 1 2 3

Fig. 6 | Mechanism investigations. a In the control experiments, metal catalysis, e To explore the role of PCy3. a Yields were determined by gas chromatography
ligand, and base are essential for this catalytic cycle. b Radical inhibition reactions (GC) using n-dodecane as the internal standard. TEMPO = 2,2,6,6-tetra-
using TEMPO. c Radical trapping reactions using 1,1-Diphenylethylene. d Standard methylpiperidinyloxy, PCy3 = tricyclohexyl phosphine, DMA = N, N-dimethylaceta-
reaction condition using Ni(II) complex. dtbpy = 4,4′-di-tert-butyl-2,2′-dipyridyl. mide, DME = 1,2-dimethoxyethane.

Furthermore, a new C-N bond was forged from compound 45 and
carbazole through Pd-catalyzed Buchwald-Hartwig cross-coupling
reaction and compound 49 delivered in 92% yield (Fig. 5a). Subse-
quently, we were dedicated to transforming the ester groups origi-
nated from accessible terminal alkynes into diverse functional groups
(Fig. 5b). For example, the ester group of 45 could groups (Fig. 5b, left).
For example, the ester group of 45 could be successfully reduced to
the corresponding benzyl alcohol 70 in the presence of DIBAL-H, and
then alcohol 70 was transformed into aldehyde compound 71 through
a one-step efficient oxidation reaction in excellent yield. Next, the
Wittig-type reaction enabled the formation of styrene 72 in 90% yield
from aldehyde 71 and MePPh3Br in basic conditions. Last but not least,
we also successfully access the 1,2,3,4-tetrasubstituted 1,3-diene car-
boxylic acid compounds 73 via hydrolysis of 45 under mild conditions
with great outcome (Fig. 5b, right).
Mechanism investigations
To shed light on the potential reaction pathways, several control
experiments were carried out to explore the mechanism of this four-
component reaction (Fig. 6). First of all, no expected product 5 was
detected and only a trace amount of alkenes 74 and 75 were obtained
in the lack of Ni catalyst, indicating that nickel catalyst is essential for
the generation of radicals and could be responsible for the process of
syn-difunctionalization of the alkyne (Fig. 6a, top). Then, in the
absence of bipyridine ligands, a dramatically decreased in the yield of
compound 5 was observed and a substantial amount of fluoroalkylated
alkene 74 and perfluoroalkylated alkenyl iodide 75 were detected,
which revealed that the auxiliary effect of ligands on transition-metal
catalysis significantly affects the process of trapping the newly gen-
erated fluoroalkylated alkenyl radical by Nickel species (Fig. 6a, mid-
dle). Crucially, the absence of base even inhibited the generation of
radicals, this evidence illustrated that the transmetallation process was
the initiation step of this process (Fig. 6a, bottom). Subsequently,
when 2,2,6,6-tetramethy-1-pioerdinyloxy (TMEPO) was added to our
catalytic system, the formation of compound 5 was significantly sup-
pressed (Fig. 6b); when a stoichiometric amount of 1,1-diphenylethy-
lene was added to the reaction, the perfluoroalkyl radical was
successfully trapped, this result suggested that radical process could
be involved in our transformation (Fig. 6c). Moreover, in recent years,
ligand relay catalysis platform63–67 has become a novel catalytic pattern
in the construction of novel chemical bonds, the feasibility of ligand
exchange could potentially improve the catalytic efficiency and get the
satisfied results. As nitrogen ligand and phosphine ligand existed in
our current reaction system, we guessed that whether our reaction

Nature Communications | (2024)15:5479 9

Article
NiIIX2
Ar
L
Ar
VII Rf NiILX
H
Ar
LNiI
ILNiIII XAT
III
V LNiIAr
Rf RfI
H
VI Rf II
1 RfI
III Rf
1 process between Ni(I)-aryl intermediate CP4 and perfluorobutyl iodine
III
III
LI Ni Ar
path c
ILNiII
III
Ar
VIII Rf
V H
1
path b
Fig. 7 | Proposed reaction mechanism. XAT = halogen atom transfer, L = ligand,
X = halogen atom.
system probably underwent the process of ligand exchange to facil-
itate this unusual four-component reaction, yet further experiment
indicated that dtbpy plays a leading role in our reaction system and
excludes the ligands relay catalytic process (Fig. 6a, d and e).
On the basis of the previous literatures on Nickel-catalyzed
difunctionalization of alkynes37,38 and our observations, herein, three
proposed reaction pathways of this four-component cascade reaction
are described in Fig. 7. First of all, with the assistance of the base, aryl
boroxine 3 and Ni(I) species undertake transmetallation process to
render LNiIAr species I in situ. The species I could undergo regiose-
lective syn-1,2-migratory insertion of alkyne 1 to afford alkenyl-Ni(I)
intermediate II, which facilitates Rf-I to generate Rf·radical via XAT
(halogen atom transfer) process to lead to alkenyl-Ni (II) intermediate
V. Then, perfluoroalkyl radical undergoes radical addition to alkyne 1
to render the intermediate III, and the newly generated alkenyl radical
III could be captured by intermediate V to form crucial Ni(III) species
VI which followingly undergoes reductive elimination to access the
desired fluoroalkylated polysubstituted 1,3-dienes VII (Fig. 7, Path a). In
addition, with further studies on the transition-metal-catalyzed 1,2-
difunctionalization of alkynes involving organoboron reagents13 and
transition-metal-catalyzed functionalization of π conjugated
compounds68–72, we propose another possible reaction pathway. After
a similar transmetallation process, the LNiIAr species I mediates the
XAT process of Rf-I 2 to deliver Rf·radical along with ILNiIIAr (inter-
mediate IV), and the intermediate III smoothly form from the same
radical addition process as preceding Path a, simultaneously, another
alkyne 1 undergoes critical migratory insertion into intermediate IV to
deliver intermediate V, which traps the newly generated vinyl radical
III to render the Ni(III) species VI, further reductive elimination ren-
ders the desired fluoroalkylated polysubstituted 1,3-dienes VII along
with the regeneration of LNiI species, thus finishing the entire catalytic
cycle (Fig. 7, Path b). Finally, according to Nevado’s work34,35,37,38, we
also propose the third possible pathway as follows. In this pathway,
intermediate IV generated from XAT process could recombine with
the newly generated fluoroalkylated alkenyl radical III to render
Nature Communications | (2024)15:5479
https://doi.org/10.1038/s41467-024-49870-1
Ar alkenyl-Ni(III) intermediate VIII, which occurs critical migratory
O
B
O
insertion of alkyne 1 to afford Ni(III) species VI and subsequent
B B
reductive elimination completes the catalytic system and delivers the
O Ar desired 1,2,3,4-tetrasubstituted 1,3-diene VII (Fig. 7, Path c).
3
To gain further insights on the possible mechanism of this reac-
base
Ar O Ar tion and verify the feasibility of these above-mentioned reaction
B B
pathways, theoretical investigation was performed at M06/6-311 + G(d,
O O
B p)(SDD for Ni, K and I)/ SMDDCM//M06/6-31 G(d)(SDD for Ni, K and I)/
baseX SMDDCM level (Fig. 8). The combination of K2CO3, aryl boroxine 3, and
Ni(I)-iodide CP16 results the generation of complex CP1, which is much
1 stable comparing with simple Ni(I)-iodide CP16. Therefore, CP1 was set
Ar
to relative zero in calculated free energy profiles. Based on complex
path a
I CP1, which undergoes a transmetallation process via transition state
TS2 to achieve aryl transfer with a free energy barrier of 22.5 kcal/mol.
2 After the release of boron carbonate CP3, the Ni(I)-arylintermediate
CP4 is formed with an endothermic energy of 15.2 kcal/mol, regardless
Rf of the driving force from the crystallization process. Then, an XAT
XAT
2 occurs via the transition state TS5 affording a Ni(II)-iodide inter-
mediate CP7 with the release of perfluoroalkyl radical. The computa-
tional results showed that this process is quite fast with a free energy
barrier of only 6.5 kcal/mol. The generated perfluoroalkyl radical could
ILNiIIAr react with terminal alkyne 1 via radial addition transition state TS8 to
IV form a perfluoroalkylated alkenyl radical CP9 with a free energy barrier
of 9.9 kcal/mol. The formation of perfluoroalkylated alkenyl radical
CP9 is exergonic by 26.4 kcal/mol probably attributed to the genera-
tion of a new C-C covalent bond. Meanwhile, another terminal alkyne 1
could undergoes migratory insertion into Ni-C(aryl) bond via transi-
tion state TS10 with a free energy barrier of 12.6 kcal/mol. The gen-
eration of Ni(II)-alkenyl intermediate CP11 is also exergonic by
31.6 kcal/mol indicating an irreversible process. The combination of
newly generated radical CP9 and Ni(II)-alkenyl intermediate CP11
results in a Ni(III)-bialkenyl intermediate CP13 via radical trapping
transition state TS12 with a free energy barrier of 15.1 kcal/mol. The
expected polysubstituted 1,3-diene product can be afforded through
further reductive elimination from this Ni(III)-bialkenyl intermediate
CP13. Computational results showed that the energy barrier of the step
is only 7.4 kcal/mol. Finally, active species CP1 can be regenerated with
the ion exchange with K2CO3 and coordination of aryl boroxine
(Fig. 8a). Hence, we successfully verify the feasibility of proposed Path
b and reveal that this four-component reaction indeed achieves syn-
difunctionalization and anti-difunctionalization of respective alkynes
by a set of metal catalyst and ligand. At the same time, the origins of
good regioselectivity without the use of directing group-containing3,5,13
or electronically biased3,5,13 alkynes were elaborately elucidated by
subsequent calculation. (Please see the Supplementary Fig 28 for more
details)
Furthermore, we have also investigated the competitive pathways
(Path a and Path c) proposed in Fig. 7. As shown in Fig. 8b, when Ni(I)-
aryl is formed, alkyne insertion could take place via transition state
TS18. The calculated free energy barrier is 16.1 kcal/mol, which is much
higher than that of XAT with 2. Therefore, the formation of per-
fluoroalkyl radical CP6 and Ni(II) intermediate CP7 is the major path-
way, thus the Path a is ruled out. As shown in Fig. 8c, the calculated free
energy barrier of radical addition with perfluoroalkylated alkenyl
radical CP9 onto CP7 via transition state TS21 is 2.6 kcal/mol higher
than that of alkyne insertion via transition state TS10. Hence, the
generation of Ni(III)-alkenyl-aryl intermediate CP22 is unfavorable,
which could derive to the formation of polysubstituted alkenes and
return to the well-known three-component reaction, this result also led
us to exclude the Path c. Notably, in our theoretical calculation, we
found that the rate of alkyne insertion is faster than that of radical
addition, so 1,2,3,4-tetrasubstituted 1,3-dienes could be found as a
primary product rather than trisubstituted alkenes, thus well explain-
ing that the success of modulating the reaction from conventional
10
Article https://doi.org/10.1038/s41467-024-49870-1

a
Ar
O B
Ar B C4F9
O
O B K H
IH
O Ph
Ar I
O t
N Ni Ar Bu
C4F9
N Ni O
N 24.4 N
K
N Cp7 + TS8 N
= Ar = OMe
DG 22.5 21.7 1 N
CP3 2 N
kcal/mol TS2 TS5 I
Ph Ar H t
Bu
15.2 14.5
CP4 CP6 + CP7 I C4F9 N Ni
N Ph Ar
N Ni Ar Cp9 I
N Ni Ar H
0.0 C4F9 + 0.7
N
N N Ni
CP1 Ar 1 TS10
Ar Ph
N I Ar
O B B
Ar B O O -11.9 Ph H
O N Ni
K K CP7 -28.4 C4F9
O B B B
Ar O O I N
O TS12 Ph
Ar O I CP9 Ph
O I N Ni Ar
N Ni O CP3 O C4F9
N -43.5 -40.2 Ph
K Ar
N K TS14
CP11 -47.6
Ar
CP13 Ph K I
Ar I H Ar
I
B O N Ni H CP15 C4F9 O
O
B Ar Ph N Ni
O N -89.9 K
Ph C4F9I N Ni O
B O N Ph
N Ni I CP16
Ar Ph N
1 2 3
N -107.4
C4F9 K2CO3
CP17
-114.0
Alkyne Radical 3
insertion trapping CP1

trans- Radical Alkyne Radical Reductive Regenerated

metallation SET addition insertion trapping elimination catalyst

b C4F9 c
I Ar
IH I I
Ar H H
N Ni Ar
N Ni Ar C4F9 + N Ni
N N Ni
C4F9I Ph Ph
N Ph N
CP6 + CP7 I N
TS5 TS10 CP11
XAT DG= -0.7 AI DG = -31.6
DG‡ = 6.5 DG‡ = 12.6
N Ni Ar N Ni Ar
AI Ar RAT I I
N Ar H N
CP4 H CP7
Ph N Ni Ar N Ni Ar
N Ni N Ni
Ph Ph N H N
N N Ph Ph H
TS18 TS19 Ph
CP9 C4F9
DG‡ = 16.1 DG = -29.3 C4F9
C4F9
TS21 CP22
DG‡ = 15.2 DG = -13.8

Fig. 8 | The calculated results at M06/6-311 + G(d, p)(SDD for Ni, K and I)/ species. c The comparing pathways between the radical trapping and alkyne
SMDDCM//M06/6-31 G(d) (SDD for Ni, K and I)/SMDDCM. a The free energy profile insertion for the Ni(II)-aryl species. AI = alkyne insertion, RAT = radical trapping,
for the Nickel-catalyzed four-component cascade difunctionalization of alkynes. XAT = halogen atom transfer.
b The comparing pathways between the XAT and alkyne insertion for the Ni(I)-aryl

three-component reaction transforms into unusual and challenging cascade difunctionalization reaction and density functional theory
four-component reaction in our catalytic system. (DFT) calculations further verify the feasibility of the proposed
In summary, we report a Nickel-catalyzed four-component reac- mechanism as well as explain why our reaction tends to an unusual
tion involving two terminal alkynes, aryl boroxine, and perfluoroalkyl four-component reaction rather than the well-established three-com-
iodides, which provide a simple and flexible platform to access poly- ponent reaction from similar starting materials. Further application
substituted 1,3-dienes via unusual cascade difunctionalization. Herein, and the selectivity of different alkynes owing to greater challenges in
we successfully combine the carbometallation/cross-coupling plat- our reaction system will be explored by our laboratory in the future.
form and radical addition/cross-coupling platform in one operation,
which utilizes cheap nickel catalyst and accessible starting materials to Methods
render the more complicated fluorinated 1,2,3,4-tetrasubstituted General procedure for the synthesis of polysubstituted 1,3-
conjugated dienes and proposes the possible reaction mechanism dienes
under our catalytic system with both anti-difunctionalization and syn- To an oven-dried 10 mL Young’s Tube vial equipped with a magnetic
difunctionalization of two terminal alkynes. This protocol features stir bar was added L7 (0.03 mmol, 8.0 mg, 15 mol%), Ni(PCy3)2Cl2
mild conditions, wide substrate compatibility, simple execution, (0.02 mmol, 13.8 mg, 10 mol%), terminal alkynes (0.27 mmol, 1.35
excellent chemoselectivity, good regioselectivity, and exclusive ste- equiv), boroxine (0.067 mmol, 27 mg), K2CO3 (0.4 mmol, 56 mg, 2.0
reoselectivity. The late-stage transformations demonstrate the syn- equiv), The vial was introduced in a argon-filled atmosphere, then
thetic application of our current strategy and offer a facile route to perfluoroalkyl iodides (0.8 mmol, 4.0 equiv), anhydrous DMA (0.5 mL,
access an array of versatile 1,2,3,4-tetrasubstituted 1,3-dienes. 0.2 M) and anhydrous DME (0.5 mL, 0.2 M) were added. Next, the
Mechanistic experiments reveal the possible mechanism of this reaction mixture was stirred at 45 °C (or 50 °C) in an oil bath at

Nature Communications | (2024)15:5479 11

Article
660 rpm for 72 h. After the reaction was completed, the reaction
mixture was extracted with EtOAc, and the combined organic layers
were dried over Na2SO4, filtered, and concentrated under reduced
pressure. The product was purified by column chromatography over
silica gel for each substrate.
Data availability
Data relating to the materials and methods, optimization studies,
experimental procedures, NMR spectra, and mass spectrometry are
available in the Supplementary Information. Source data are provided
in this paper. Crystallographic data for the structures reported in this
Article have been deposited at the Cambridge Crystallographic Data
Center, under deposition numbers 2289202 (58) and 2289200 (59).
Copies of the data can be obtained free of charge via https://www.ccdc.
cam.ac.uk/structures/. Data can also be obtained from the corre-
sponding author upon request. Source data are provided with
this paper.
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Acknowledgements
Financial support from the National Key R&D Program of China
(2023YFF0723900 to Q.S.), National Natural Science Foundation of
China (21931013 and 22271105 to Q.S.), Natural Science Foundation of
Fujian Province (2022J02009 to Q.S.) and Open Research Fund of
School of Chemistry and Chemical Engineering, Henan Normal Uni-
versity (to Q.S.) are gratefully acknowledged.
Author contributions
Q.S. designed and directed the project. S.C. performed the experiments
and developed the reactions. J.X., W.L., M.Y., X.M., and K.Y. helped
collect some experimental data; Y.L. and S.L. directed the DFT calcula-
tions, and Y.W. conducted the DFT calculations. Q.S., Y.L., and S.C.
wrote the manuscript. All authors discussed the results and commented
on the manuscript.
Competing interests
The authors declare no competing interests.
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