Regiocontrolled Reductive Vinylation of Aliphatic 1,3-Dienes with Vinyl Triflates by Nickel Catalysis

Article abstract of DOI:10.1021/jacs.1c00142

The regiocontrolled functionalization of 1,3-dienes has become a powerful tool for divergent synthesis, yet it remains a long-standing challenge for aliphatic substrates. Herein, we report a reductive approach for a branch-selective 1,2-hydrovinylation of aliphatic 1,3-dienes with R-X electrophiles, which represents a new selectivity pattern for diene functionalization. Simple butadiene, aromatic 1,3-dienes, and highly conjugated polyene were also tolerated. The combination of Ni(0) and the phosphine-nitrile ligand generally resulted in >20:1 regioselectivity with the retention of the geometry of the C3-C4 double bonds. This reaction proceeds with a broad substrate scope, and it allows for the conjugation of two biologically active units to form more complex polyene molecules, such as tetraene and pentaene as well as heptaene.

Full text of DOI:10.1021/jacs.1c00142

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Regiocontrolled Reductive Vinylation of Aliphatic 1,3-Dienes with
Vinyl Triflates by Nickel Catalysis
Xiaobo Pang, Zhen-Zhen Zhao, Xiao-Xue Wei, Liangliang Qi, Guang-Li Xu, Jicheng Duan,
Xue-Yuan Liu, and Xing-Zhong Shu*
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ABSTRACT: The regiocontrolled functionalization of 1,3-dienes has become a powerful tool for divergent synthesis, yet it remains
a long-standing challenge for aliphatic substrates. Herein, we report a reductive approach for a branch-selective 1,2-hydrovinylation
of aliphatic 1,3-dienes with R−X electrophiles, which represents a new selectivity pattern for diene functionalization. Simple
butadiene, aromatic 1,3-dienes, and highly conjugated polyene were also tolerated. The combination of Ni(0) and the phosphine−
nitrile ligand generally resulted in >20:1 regioselectivity with the retention of the geometry of the C3−C4 double bonds. This
reaction proceeds with a broad substrate scope, and it allows for the conjugation of two biologically active units to form more
complex polyene molecules, such as tetraene and pentaene as well as heptaene.
he transition-metal-catalyzed hydrofunctionalization of
1,3-dienes has emerged as a promising method to
be in equilibrium during the reactions. These properties of
diene chemistry make it particularly challenging to control the
selectivity. Previous studies have shown that the selectivity is
closely dependent on the electronic and steric nature of the
diene substrate.7 Therefore, to date, the majority of reports on
highly selective transformations have focused on the reactions
of aromatic 1,3-dienes.1−28 The use of aliphatic dienes typically
results in a complex mixture of 1,2- and 1,4-adducts and Z-/E-
isomers, except for cyclic29,30 and highly sterically hindered
substrates.7,9,13,16,19 A general method to account for the
selective hydrocarbonation of common aliphatic 1,3-dienes is
still to be developed.
T
produce value-added molecules.1−6 In particular, hydro-
carbonation reactions offer straightforward access to alkene-
containing building blocks with high regio- and stereochemical
diversity. Generally, the reactions of 1,3-dienes with
nucleophiles afford 1,2-addition products with branch
selectivity, which is a major advance in this field (Scheme
1(1a)).7−18 However, there are very few reports on the
Scheme 1. 1,2-Hydrocarbonation of 1,3-Dienes
Herein, we report a branch-selective 1,2-hydrovinylation of
aliphatic 1,3-dienes by a nickel-catalyzed reductive vinylation
reaction (Scheme 1(3)). Aliphatic dienes with diverse steric
properties and simple butadiene and aromatic derivatives were
all tolerated. The success of this effort depends on the use of
phosphine−nitrile ligands, which have rarely been used in the
area of transition-metal catalysis.31 It thus offers an approach to
skipped dienes (1,4-dienes) with a scope that is comple-
mentary to the established methodologies.22,23,29,30,32−39
Skipped dienes are key structural elements found in various
natural products,40−42 and the importance of this class of
compounds has spurred the development of many useful
methods,32 including the coupling of 1,3-dienes with
alkenes29,30,33−38 or vinyl electrophiles.22,23 These reactions
provide very efficient access to linear 1,4-addition products. As
part of our ongoing studies on reductive vinylation
coupling of R−X electrophiles with dienes, which typically
results in linear selectivity (Scheme 1(1b)).19−24 The discovery
of novel selectivity patterns would provide new opportunities
for research in this field, but it remains largely unexplored.25−28
The reactions of 1,3-dienes typically involve the intermedi-
acy of η3-π-allyl species (Scheme 1(2)).5 The unsymmetrical
metal-π-allyl complexes could be attacked at either C2 or C4,
resulting in the 1,2- or 1,4-addition products. Moreover, the Z-
and E-isomers may be formed since these intermediates may
Received: January 5, 2021
Published: March 16, 2021
https://dx.doi.org/10.1021/jacs.1c00142
J. Am. Chem. Soc. 2021, 143, 4536−4542
© 2021 American Chemical Society
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Communication
reactions,43−47 we wondered whether 1,3-dienes could couple
with vinyl triflates to offer new selectivity profiles for skipped
diene synthesis.
We began our investigation by studying the reaction of diene
1a with vinyl triflate 2a (Table 1). After numerous trials, we
essential role. The reactions worked well in the presence of Si−
H (entries 1, 5, and 6); by contrast, the reactions with
i
HCO2Na, HCO2H, or PrOH were completely ineffective
(entries 7−9), even though they are frequently employed in
Ni/Pd-catalyzed hydrocarbonation reactions.48 The reactions
with the metal reductant afforded no desired product (entry
10). Control experiments revealed that the Ni catalyst and
PMHS were all required for the vinylation of 1,3-dienes (entry
11). The reaction of vinyl bromide did not yield any desired
product, and the use of vinyl iodide gave 3a in 35% yield with a
7:1 regioselectivity (entries 12 and 13).
a
Table 1. Optimization of the Reaction Conditions
The ligands had a substantial effect on the reaction (Table
1). Although nitrogen ligands have found broad applications in
the reductive hydrofunctionalization of alkenes,49 they gave
either no or low yields of the desired product (L1−L4). In
these cases, most of the vinyl triflate was recovered, and diene
1a was reacted to form a mixture of 1,2-/1,4-hydrogenation
products in 87% yield for L1 and approximately 20% yield for
L2/L4. While no reaction was observed in the presence of
phosphine ligand L5 or L6, the use of phosphine−nitrile ligand
L7 gave a promising result. The reaction efficiency appeared to
be governed by the electronic and steric nature of the ligands.
The use of electron-rich L8 improved the yield to 75% and
gave a ratio of 3a/4a of >20:1, whereas its electron-poor
counterpart, L10, yielded trace amounts of 3a. More sterically
hindered L9 increased the yield (97%) further. Bis(2-
cyanophenyl) phenylphosphine (L11) gave a low yield of
the desired product. No reaction was observed when the cyano
group was placed at either the meta or para position (L12 or
L13). Further studies revealed that the combination of
Ni(COD)2 and L7 gave tetrameric complex A, which clearly
shows the essential role of the cyano group at the ortho
position.50 The reaction using this complex gave results
comparable to those from standard conditions (see 3n in Table
2).
With the optimal reaction conditions in hand, we studied the
scope of the reaction for 1,3-dienes (Table 2). The less
sterically hindered aliphatic 1,3-dienes, such as those bearing
linear alkyl chains,51 which have proved to be very challenging
with respect to the control of selectivity,7 worked well to afford
skipped dienes 3b and 3c with regioisomeric ratios of >20:1.
The reaction of cyclohexanyl diene afforded 3d in high yield.
Polyenes [1,3,12-henicosatriene (3e) and 6,10-dimethyl-
undeca-1,3,9-triene (3f)] were selectively vinylated to afford
the skipped trienes. The presence of acidic amide (3g) and
alcohol (3h) groups was tolerated. 1,3-Dienes derived from
amino acid (3i), α-oxyacid (3j), and ferrocenecarboxylic acid
(3k) were coupled well. Butadiene is one of the highest volume
bulk chemicals in the world, and its functionalization is of
considerable interest. Reported methods for the hydro-
vinylation of 1,3-butadienes generally yield the 1,4-addition
products.33−38 Alternatively, our method offers access to the
1,2-adducts (3l and 3m). When aromatic substrates were
employed, ligand L7 was required to give high yields of the
desired products. Under these conditions, aromatic 1,3-dienes,
bearing electron-neutral (3n), electron-rich (3o−3q) and
electron-poor (3r) arenes, were all coupled well. Heteroaryl
substrates (3s and 3t) and multisubstituted 1,3-dienes (3u and
3v) were tolerated.
a
Reaction conditions: 1a (0.1 mmol) and 2a (0.18 mmol) were used;
the yields and the ratio of 3a/4a were determined by GC analysis
using dodecane as an internal standard. bIsolated yields obtained from
c
1a (0.2 mmol) and 2a (0.36 mmol) are given in parentheses. Et3N
(2.5 equiv) was used instead of CsF. KOH (2.5 equiv) was used
instead of CsF.
d
determined that the combination of Ni(COD)2, L9 and
polymethylhydrosiloxane (PMHS) gave the best result,
affording 3a in 94% isolated yield with >20:1 regioselectivity
(entry 1). The use of Ni(II) precatalysts also gave good results
(entries 2−4), but they required remarkably long induction
periods (details in Scheme S3). The hydride source plays an
The substrate scope of the reaction with vinyl triflates is
shown in Table 3. Regioisomeric ratios of >20:1 were obtained
for all of the cases studied. Cyclic vinyl triflates, ranging from
five- to eight-membered rings, were coupled with 1a to afford
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a
a
Table 2. Scope of the Reaction with 1,3-Dienes
Table 3. Scope of the Reaction with Vinyl Triflates
a
Conditions as shown in Table 1, entry 1; diene 1 (0.2 mmol) was
used; reactions were run for 48 h, and isolated yields are given; only E
isomers were observed; the regioisomeric and diastereomeric ratios
1
were determined by H NMR and 13C NMR, respectively; 1-tosyl-
1,2,3,6-tetrahydropyridin-4-yl triflate (2b) was used for volatile
b
molecules and for the purpose of isolation. TBAF (0.2 mmol) was
c
added after 48 h to cleave the O−Si bond formed in situ. The dr
d
value was determined by HPLC. The dr value was not assigned.
a
Conditions are the same as shown in Table 1, entry 1; diene 1a (0.2
eButadiene (0.4 mmol), vinyl triflate (2.0 equiv), PMHS (1.25 equiv),
and CsF (1.0 equiv) were used; 1,2-/1,4-addition ratio of 9:1. fL7 was
used. gComplex A (2 mol %) was used instead of Ni(COD)2 and L7.
mmol) was used; reactions were run for 48 h, and isolated yields are
given; only E-isomers were observed; the regioisomeric and
diastereomeric ratios were determined by H NMR and 13C NMR,
1
b
c
respectively. The dr value was not assigned. TBAF (0.2 mmol) was
added after 48 h to cleave the O−Si bond formed in situ. dDiene 1a (4
mmol) was used; the reaction was run for 72 h.
target products 3w−y in good yields. A larger ring-sized
substrate, cyclododecenyl triflate, afforded triene 3z in
moderate yield. Cyclic vinyl triflates, with substituents at the
3- and 4-positions, afforded respective products 3aa−ae in
good to high yields. Nonaromatic heterocycles are key
structural motifs found in various pharmaceuticals; however,
their introduction through C−C bonds is challenging. Our
method provides a way of producing nonaromatic heterocycle-
containing polyenes, such as the trienes of 3-piperideine (3af),
3,6-dihydro-2H-pyran (3ag), and 3,6-dihydro-2H-thiopyran
(3ah). The reaction could be run on the gram scale without a
loss of efficiency (3af). A benzene-fused substrate, 3,4-
dihydronaphthalenyl triflate, was also tolerated (3ai). Besides
cyclic substrates, acyclic vinyl triflates also coupled well (3aj−
ap). Functionalities, including silyl ether (3aa), alcohols (3ab
and 3ap), ketal (3ac), ester (3ad, 3al and 3ao), heterocycles
(3af−ah) and amide (3am), were tolerated. However, fully
substituted vinyl triflate was not found to be effective (3aq).
The modification of biologically active molecules offers a
promising approach to altering the pharmacological profiles of
compounds. This method allows for the conjugation of two
biologically active units into one polyene52 (Scheme 2). For
example, vinyl triflates derived from (+)-nootkatone 5 and
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a
The formed vinyl−Ni(II)−OTf may undergo migratory
insertion, followed by protonation with Si−H, to afford the
desired products (the reductive Heck reaction pathway).53,54 If
this is the case, then Si−H should have little or no effect on the
regioselectivity. However, in the absence of Si−H, the reaction
of vinyl triflate 2k with diene 1n and Ni(0) (1.0 equiv) gave
only linear products 15 and 16, without any branch adduct
observed (Scheme 4(1)).55 Moreover, because alkyl−NiX can
Scheme 2. Modification of Biologically Active Molecules
Scheme 4. Insight into the Migratory Insertion of the Diene
a
Conditions as shown in Table 1, entry 1; 1a/9 (0.2 mmol) and
triflates (0.36 mmol) were used; reactions were run for 60 h, and
isolated yields are given; the regioisomeric and diastereomeric ratios
1
b
were determined by H NMR and 13C NMR, respectively. The dr
value was not assigned.
testosterone 7 were coupled with geraniol-derived triene 1a to
afford pentaene 6 and tetraene 8 in moderate yields. Highly
conjugated polyene, retinol-derived 9, was coupled with 7 at
the terminal alkene moiety to afford heptaene 10 with good
regioselectivity.
be terminated by various hydride/proton sources,48 such as
HCO2Na, HCO2H, and PrOH, we expected that the reaction
i
The reaction can be initiated by NiH, which is usually
generated from Ni(II) and Si−H.49 It is also possible that the
reaction begins with Ni(0) and R−X.53,54 Our control
experiments indicate that the latter might be involved in this
reaction. (1) The Ni(0) catalyst was found to work more
efficiently than the Ni(II), and the latter required a long
induction period (Scheme S3). (2) Vinyl triflates showed
higher activity toward Ni(0) than aliphatic dienes and Si−H.
For example, under standard conditions, vinyl triflate 2c
reacted well to form vinyl−H 12 in 38% yield, whereas
aliphatic diene 1a remained intact even after 48 h (Scheme
3(1)). (3) For cases in which the reaction started with diene
1n and Si−H, a mixture of 1,2-/1,4-addition products and Z-/
E-isomers was afforded (Scheme 3(2)). Such selectivity is not
consistent with that observed for the hydrovinylation products.
with these reagents instead of Si−H would also yield the
desired product. However, none of these reactions proceeded
(Table 1, entries 7−9). These results suggest that Si−H should
react with Ni before the migratory insertion step, which very
likely forms the vinyl−Ni(II)−H intermediate.56−59 The
presence of CsF may facilitate this process.60,61
On the basis of the above-mentioned results and the
previous reports, we tentatively propose a catalytic cycle for the
reductive vinylation of 1,3-dienes (Scheme 5). Oxidative
Scheme 5. Proposed Mechanism
Scheme 3. Insight into the Initial Step of This Reaction
addition of vinyl−OTf to Ni(0) affords R−Ni(II)−OTf,
which undergoes transmetalation with Si−H to afford an R−
Ni(II)−H intermediate.56−59 The migratory insertion of the
1,3-diene into the vinyl−Ni(II)H bond, followed by C−H
reductive elimination, affords the desired product.62,63
Alternatively, the insertion of a 1,3-diene into a vinyl
Ni(II)−H bond may also result in the desired product via
the intermediacy of an allyl−Ni(II)−vinyl species (Scheme
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S4).64 Our control experiments suggest that the former process
might be favored. The reactions of E-18 and Z-18 exclusively
afforded E-19 and Z-19 in 75 and 71% yields, respectively
(Scheme 4(2)). Retention of the geometry of the C3−C4
double bond was also observed when aliphatic substrate 1a was
used (Scheme S2). These results suggest that the reaction may
not proceed through the intermediacy of a π-allylnickel
species.7,64
In conclusion, we have developed a new hydrovinylation
reaction of 1,3-dienes with vinyl triflates and thereby
established a method for producing skipped dienes with a
scope that is complementary to that of established method-
ologies. This reaction demonstrates a new selectivity pattern
for diene functionalization, namely, branch-selective 1,2-
addition with R−X electrophiles. It also offers a method to
account for the regiocontrolled hydrocarbonation of common
aliphatic 1,3-dienes, which has been a long-standing challenge
in this field. Work on the further expansion of the scope of
coupling partners is in progress in our laboratory.
Jicheng Duan − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Xue-Yuan Liu − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0002-8862-9924
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00142
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
for their financial support (21772072 and 22071084). We are
grateful to Prof. Wei Yu (Lanzhou University) for helpful
discussions.
ASSOCIATED CONTENT
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■
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00142.
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Accession Codes
CCDC 2067720 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Xing-Zhong Shu − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0002-0961-1508; Email: shuxingzh@
lzu.edu.cn
Authors
Xiaobo Pang − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Zhen-Zhen Zhao − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Xiao-Xue Wei − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Liangliang Qi − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
Guang-Li Xu − State Key Laboratory of Applied Organic
Chemistry (SKLAOC), College of Chemistry and Chemical
Engineering, Lanzhou University, Lanzhou 730000, China
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Communication
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