A 1,4-Palladium Migration/Heck Sequence with Unactivated Alkenes: Stereoselective Synthesis of Trisubstituted 1,3-Dienes

Article abstract of DOI:10.1002/adsc.202001589

The palladium-catalyzed cross-coupling of ortho-vinyl aromatic bromides and olefins was achieved through a controllable 1,4-palladium migration/Heck cascade protocol. The reaction represents a mild, efficient and highly stereoselective method for the synthesis of trisubstituted 1,3-dienes, especially for triaryl-substituted ones. (Figure presented.).

Full text of DOI:10.1002/adsc.202001589

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DOI: 10.1002/adsc.202001589
A 1,4-Palladium Migration/Heck Sequence with Unactivated
Alkenes: Stereoselective Synthesis of Trisubstituted 1,3-Dienes
Ze-Jian Xue,a Meng-Yao Li,a Bin-Bin Zhu,a Zhi-Tao He,a,* Chen-Guo Feng,a, b,*
and Guo-Qiang Lina, b,*
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032, People’s Republic of China
E-mail: hezt@sioc.ac.cn; fengcg@sioc.ac.cn; lingq@sioc.ac.cn
The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of
b
Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China
Manuscript received: December 22, 2020; Revised manuscript received: February 9, 2021;
Version of record online: March 3, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001589
ward and efficient approach to the key 1,3-diene
Abstract: The palladium-catalyzed cross-coupling
of ortho-vinyl aromatic bromides and olefins was
achieved through a controllable 1,4-palladium mi-
skeleton[8] (Scheme 1b). Usually, stoichiometric amount
of oxidant is required to recycle the transition metal
catalysts, limiting the substrate scope to that with
gration/Heck cascade protocol. The reaction repre-
relatively robust functional groups. Thus, the develop-
sents a mild, efficient and highly stereoselective
ment of an oxidant-free protocol for cross-coupling
method for the synthesis of trisubstituted 1,3-dienes,
between unactivated terminal alkenes should be impor-
especially for triaryl-substituted ones.
tant and useful.
Recently, we[9] and others[10] have demonstrated aryl
to alkenyl 1,4-palladium migration as a powerful method
Keywords: Palladium migration; Heck reaction;
for generation of stereodefined alkenyl palladium species
diene synthesis
which were applied to some stereoselective cascade
Conjugated dienes are important building blocks or
motifs in organic chemistry for their wide existence in
natural products,[1] numerous potential transformations
to key compounds,[2] and broad applications in material
science like polybutadiene (PB).[3] Especially, due to
the
aggregation-induced
emission
(AIE)
characteristics,[4] triphenyl-substituted 1,3-butadienes
received considerable attention in the development of
advanced electrochemical materials.[5] As the geometry
of the 1,3-butadienes played a critical role in their
optical behaviors,[6] a stereoselective protocol for
efficient construction of this motif is very attractive
and valuable.
Among diverse strategies developed to construct this
structure, the cross-coupling of an alkenyl nucleophile
and an alkenyl electrophile is a reliable method[7]
(Scheme 1a). However, the required prefunctionalization
of the involved two coupling olefin partners often makes
the target synthesis complex and challenging. In contrast,
the coupling between two unactivated alkenes without
the need of pre-transformations of alkenes to alkenyl
nucleophiles or electrophiles has emerged as a straightfor-
Scheme 1. Transition Metal-Catalyzed Synthesis of 1,3-Dienes.
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reactions with unsaturated carbony compounds,[9c] aryl or ligand.[12] Thus, the optimal reaction condition was
alkenyl boronic esters,[9a] 1,3-diene[9b] et al. We wondered determined by using Pd(OAc)2 (5.0 mol%) and (2-
if an unactivated olefin was involved in a 1,4-Pd MeOÀ C6H4)3P (10 mol%) as the catalyst, CsOPiv
°
migration/Heck sequence (Scheme 1c), it would provide (2.0 equiv.) as the base in 1,4-dioxane at 50 C.
a new route to the challenging triaryl-substituted 1,3-
The generality of the 1,4-migration/Heck sequence
dienes. In addition, this oxidant-free process should also with styrene 2a was studied with a number of
be able to provide precise stereo-control over the final brominated terminal olefins 1 and the results were
product. We herein reported our research on the 1,4- summarized in Table 2. The substituent effect on the
palladium migration/Heck cascade reaction with unac- brominated aryl ring was first explored. Both para- and
tivated alkenes.
meta-methyl-substituted arylbromide worked well with
To examine the feasibility of this reaction, terminal
olefin 1a and styrene 2a were used as model substrates,
P(2-MeOÀ C6H4)3 as the ligand and CsOAc as the base
for initial trials (Table 1). Fortunately, medium yield of
coupling product 3a was observed but with obvious
unmigrated Heck coupling product 4 (entry 1). When
CsOAc was switched to CsOPiv, similar yield of 3a and
better selectivity was obtained (entry 2). Then the
influence of reaction temperature on this cascade process
was also examined (entries 3–6). To our delight, lowering
Table 2. Scope of Ortho-Vinyl Aromatic Bromides for the
Coupling Reactions.[a]
°
temperature to 50 C boosted the yield of 3a to 95%
(entry 5). In addition, various bases were tested (entries
7–10). The unique excellent performance from the
carboxylate salts indicated a concerted metalation-depro-
tonation (CMD) mechanism might be involved in CÀ H
activation process.[11] Finally, a set of monophosphate
ligands were evaluated (see SI for details). Only the (2-
MeOÀ C6H4)3P gave a good yield, possibly attributing to
the beneficial effect from o-MeO group as a hemiliable
Table 1. Optimization of the Reaction Conditions.[a]
°
Entry
T/ C
Base
Yield of 3a[b]
3a:4:5[b]
1
2
3
4
5
6
7
8
9
100
100
80
CsOAc
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOAc
KOPiv
Cs2CO3
CsF
53
52
69
90
95
52
76
90
0
86:12:2
91:7:2
92:6:2
94:4:2
94:4:2
94:4:2
94:4:2
90:8:2
nd
60
50
40
50
50
50
50
[a] Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), Pd
(OAc)2 (0.01 mmol), (2-MeOÀ C6H4)3P (0.02 mmol), CsOPiv
10
19
nd
°
(0.40 mmol), 1,4-dioxane (2.0 mL), Ar atmosphere, 50 C,
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), Pd
(OAc)2 (0.01 mmol), (2-MeOÀ C6H4)3P (0.02 mmol), base
(0.40 mmol), 1,4-dioxane (2.0 mL), Ar atmosphere, 7 h.
[b] Determined by GC with dodecane as internal standard.
7 h, unless otherwise noted.
[b]
°
Conducted on a 1 mmol scale at 70 C.
[c]
°
Performed at 70 C.
[d]
°
Performed at 90 C.
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Table 3. Scope of Styrenes for the Coupling Reaction.[a]
styrene, giving the coupling product 3b and 3c in 89%
and 72% yield, respectively. In contrast, the Me
substituent in ortho-position provided no product owing
to the increased steric hindrance. The presence of
electron-donating group like methoxyl in para- (3d) or
meta-position (3e) showed equally good reactivity. While
bromide substitution can be spontaneously consumed via
oxidative addition of palladium catalyst, less reactive
chloride was well tolerated, providing a handle for further
derivation (3f). When the reaction was conducted on
1 mmol scale, slightly elevated temperature was required
for full conversion, giving a comparable yield of 85%.
The scope of substituents on the non-brominated aryl
groups on the olefin 1a was further evaluated (Table 2).
Different from the influence of the methyl group on the
brominated arene, the introduction of Me onto para-
(3g), meta- (3h) or ortho- (3i) position of the phenyl
ring afforded high yields for all cases. Both electron-
donating and electron-withdrawing groups gave over
78% yields (3j–3m). The replacement of the phenyl ring
by other groups was also tested. Naphthyl ring was well
accommodated and gave an excellent yield of 99% (3n).
Acceptable yields were obtained with heteroaromatic
thiophene (3o) or ester group (3p). Although the desired
reaction still took place with alkyl substitutions, a great
amount of by-products were accompanied. For example,
an isolated yield of 24% was observed with isopropyl
group (3q).
[a] Reaction conditions: 1a (0.20 mmol), 2 (0.40 mmol), Pd
(OAc)2 (0.01 mmol), (2-MeOÀ C6H4)3P (0.02 mmol), CsOPiv
°
(0.40 mmol), 1,4-dioxane (2.0 mL), Ar atmosphere, 50 C,
7 h, unless otherwise noted.
[b]
°
Performed at 90 C.
[c]
°
Performed at 70 C.
A set of styrenes as substrates were evaluated and the
results were shown in Table 3. Similarly, the steric
hindrance showed no obvious effect on the coupling:
methyl group at para-, meta- or ortho- positions of the
phenyl ring gave 53–94% yield of the coupling product
(3r–3t). But the methyl group in ortho-position did
suppress the reaction to some extent, due to potential
steric hindrance (3t). Electron-donating group like MeO
(3u) on the para-position of the phenyl ring worked
smoothly, while the electron-withdrawing groups like CN
(3v) and NO2 (3w) gave slightly reduced yield. When
phenyl group was replaced with a naphthyl (3x) or
biphenyl (3y) group, excellent yields were observed for
both cases. Several aliphatic alkenes were tested, but they
showed lower reactivity and usually produced inseparable
isomer mixture. When allyl alcohol was used, which was
supposed to prevent the possible side reaction via
13]
coordination of palladium with the hydroxyl group,[
the desired product 3z was isolated in 50% yield.
Based on previous studies,[9,10] a plausible reaction
pathway for this cascade process was described in
Scheme 2. The reaction started with the oxidative
Scheme 2. The Plausible Reaction Pathway.
addition of palladium catalyst by arylbromide 1a to alkenyl position. The resulting vinyl palladium species
generate Pd(II) species A, which may exchange its D reacts with styrene via the classical Heck pathway to
bromide with PivOÀ anion to facilitate the following offer the product 3a and thus closes the catalytic cycle.
CÀ H activation step through CMD mechanism. Once
In summary, a stereoselective synthetic protocol of
the five-membered palladacycle C generated by the the trisubstituted 1,3-dienes was established by the design
CÀ H activation, it undergoes a formal proton transfer of a 1,4-palladium migration/Heck cascade sequence.
to render a net 1,4-palladium shift from the aryl to A wide range of trisubstituted 1,3-dienes were con-
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stereoselectivity, which is challenging to be obtained
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General procedure for the synthesis of 3: In a 10 mL sealed
tube, a mixture of ortho-vinyl bromobenzene 1 (0.20 mmol,
1.0 equiv.), styrene derivative 2 (0.40 mmol, 2.0 equiv.), Pd-
(OAc)2 (2.2 mg, 0.010 mmol, 5.0 mol%), (2-MeOÀ C6H4)3P
(7.0 mg, 0.020 mmol, 10 mol%) and CsOPiv (94 mg, 2.0 equiv.)
°
in 1,4-dioxane (2.0 mL) was stirred at 50 C under argon for
7 h. After cooling to room temperature, the mixture was filtered
through a celite pad and concentrated under vacuum. The
residue was purified by flash chromatography (elute: hexane) to
afford product 3.
Acknowledgements
This work was supported by The National Natural Science
Foundation of China (21772216, 21871284, 91956113), the
Chinese Academy of Sciences (XDB 20020100 and QYZDY-
SSWSLH026), the Science and Technology Commission of
Shanghai Municipality (18401933500 and 20XD1423400), the
Shanghai Municipal Education Commission (2019-01-07-00-
10-E00072) for financial support.
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