Stereoselective synthesis of conjugated trienes: Via 1,4-palladium migration/Heck sequence

Article abstract of DOI:10.1039/d0cc06452a

Conjugated trienes are ubiquitous structures in natural products and organic functional molecules. An efficient 1,4-palladium migration/Heck sequence was developed for the highly stereoselective synthesis of trisubstituent 1,3,5-trienes, which were found

Full text of DOI:10.1039/d0cc06452a

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Xue, M. Li, B.
Zhu, Z. He, C. Feng and G. Lin, Chem. Commun., 2020, DOI: 10.1039/D0CC06452A.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC06452A
COMMUNICATION
Stereoselective Synthesis of Conjugated Trienes via 1,4-Palladium
Migration/Heck Sequence
Ze-Jian Xue,a Meng-Yao Li,a Bin-Bin Zhu,a Zhi-Tao He,*a Chen-Guo Feng*ab and Guo-Qiang Lin*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
ABSTRACT: Conjugated trienes are ubiquitous structures in natural
products and organic functional molecules. An efficient 1,4-
palladium migration/Heck sequence was developed for the highly
stereoselective synthesis of trisubstituent 1,3,5-trienes, which
were found to undergo easy E/Z isomerization in the light.
pathway I:
direct mode via oxidative addition
R3
R3
R1
[Pd0]
R1
Y
R1
[PdII]
R4
R4
X
R2
R2
R2
Y = H or Metal
coupling step
alkenyl palladium
intermediate
R1
R1
1,4-Pd migration
[Pd0]
[PdII]
Br
Natural products containing conjugated trienic units, which are
often produced as a means of chemical defense, constitute an
important class of molecules and possess interesting biological
activities.1 Due to the extended p-electron system in trienes
decrease the energy gap between the ground and excited
states, they have also found applications in the optoelectronic
materials.2 As a consequence, the development of new
methods for the stereocontrolled construction of this π-
conjugated system has attracted considerable research
interest.3,4,5
Although the Wittig or the Horner-Wadsworth-Emmons
olefinations traditionally were used in the construction of
conjugated trienes,3 transition-metal-catalyzed reactions now
have become a more popular choice, owing to a number of
synthetic advantages like the easier accessibility of starting
material, the better functional group tolerance of reaction
conditions and the increased flexibility in stereochemical
control.4,5 Among those methods, the cross-coupling of alkenyl
halides with various dienyl reagents through alkenyl palladium
intermediates is particularly useful for the modular assemble
of trienes in a stereocontrolled fashion (Scheme 1, pathway
I).4 However, this strategy was often hampered by the
difficulties in the preparation of alkenyl halides with a specific
geometry.6 Therefore, an alternative strategy for the
generation of alkenyl palladium with controlled geometry in
double bond is desirable.
Ar
Ar
pathway II:
indirect mode via 1,4-Pd migration (this work)
Scheme 1 Stereoselective Synthesis of Conjugated Trienes via Alkenyl Palladium
Palladium migration is found to bring new reactivity for the
original reagents, and applied in some synthetic
transformations that are inaccessible by conventional
methods.7 Recently, we8 and others9 have demonstrated aryl
to alkenyl 1,4-palladium migration as a reliable method for the
generation of stereodefined alkenyl palladium species, which
was applied in some stereoselective synthesis of olefins.
During our study, we found that the generated alkenyl
palladium can undergo Heck reaction with active electro-
withdrawing olefins.8c As a continuation of this work, we
herein report a reaction with 1,3-dienes for the stereoselective
synthesis of conjugated trienes (Scheme 1, pathway II).
We started our investigations by optimizing the coupling
of terminal olefin 1a and phenyl butadiene 2a using Pd(OAc)2
as the precatalyst and PPh3 as the ligand (Table 1). To our
delight, the desired triene 3a was obtained in 67% yield under
our initial conditions (entry 4). While electron-withdrawing (4-
CF3Ph)3P gave a decreased yield,(entry 2), electron-donating
(4-MeOPh)3P showed marginal effect on the reaction yield
(entry 3). However, the use of (4-MeOPh)3P as ligand boosted
the formation of 3a to 97% yield (entry 1), which may be
ascribe to the beneficial effect from o-MeO group as a
hemiliable ligand.10 Normally, carboxylate salts played as
internal bases for proton abstraction in the C-H activation via
concerted metalation deprotonation (CMD) mechanism.11 In
the screening of base, all the tested carboxylate salts were
competent for this transformation, and CsOPiv proved to be
the best one (entry 1 vs entries 5 and 6).12 The reaction also
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, China.
b. Innovation Research Institute of Traditional Chinese Medicine, Shanghai
University of Traditional Chinese Medicine, Shanghai, 201203, China.
†Electronic Supplementary Information (ESI) available: CCDC 2030783. See
DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
Table 1 Optimization of the Reaction Conditionsa
Table 2 Substrate Scope of Vinyl Bromidesa,b,c
View Article Online
DOI: 10.1039/D0CC06452A
R2
Ph
Ph
R2
Ph
Ph
Pd(OAc)2, P(2-MeOPh)3
CsOPiv, 1,4-dioxane
Pd(OAc)2, (2-MeOPh)3P
Br
H
Ph
Ph
Br
CsOPiv, 1,4-dioxane
70 , 7 h, dark
℃
R1
R1
70
℃, 7 h, dark
1a
2a
3a
1
2a
3
Ph
Ph
Ph
Ph
Ph
Ph
entry
Deviation from standard conditions
yield(%)b
H
H
H
none
1
2
97
37
63
67
87
85
45
13
85
90
86
67
42
86
Me
Me
3a
3b
3c
, 94%
, 98%
H
, 85%
(4-CF3Ph)3P instead of (2-MeOPh)3P
(4-MeOPh)3P instead of (2-MeOPh)3P
Ph3P instead of (2-MeOPh)3P
Ph
Ph
Ph
Ph
Ph
Ph
3
H
H
4
MeO
OMe
3e
Cl
c
5
KOPiv instead of CsOPiv
3d
3f
[X-ray]
, 71%
, 84%
, 72%
Me
6
CsOAc instead of CsOPiv
Me
Me
Ph
Ph
7
CsF instead of CsOPiv
Ph
H
H
H
8
Cs2CO3 instead of CsOPiv
THF instead of 1,4-dioxane
1,3-dioxolane instead of 1,4-dioxane
MeCN instead of 1,4-dioxane
DMF instead of 1,4-dioxane
DCE instead of 1,4-dioxane
DME instead of 1,4-dioxane
9
c
3g
3h
3i
, 91%
, 82% (94%)
, 80%
Cl
F
F3C
10
11
12
13
14
Ph
Ph
Ph
H
H
H
3j
3k
3l
, 91%
, 81%
, 65%
MeO
S
Ph
Ph
Ph
H
H
H
aReaction conditions: 1a (0.20 mmol), 2a (0.40 mmol, 2 equiv), base (0.40
mmol, 2 equiv), Pd(OAc)2 (0.01 mmol, 5 mol %), Ligand (0.02 mmol, 10 mol
%), solvent (2 mL), sealed tube, in dark, Ar atmosphere, 70 oC, 7 h.
bDetermined by GC using dodecane as an internal standard.
3m
3n
3o
, 92%
, 81%
, 97%
MeO2C
NC
Ph
Ph
Ph
H
H
H
proceeded well in a variety of solvents, especially with ethers
and MeCN (entries 9-14).
3p
3q
3r
, 43%
, 95%
, 37%
With the optimized reaction conditions in hand, the scope of
the palladium-catalyzed 1,4-migration/Heck sequence for the
synthesis of 1,3,5-triene was investigated (Table 2). The
substituent effect on the bromide-containing phenyl ring was
first examined. The methodology boded well with Me groups
in both para- (3b) and meta-positions (3c) of bromide. The
reaction was blocked if the Me group was switched to the
ortho-position, which may be explained by the increased steric
encumbrance. The presence of electron donating group such
as MeO in both para- (3d) and meta-positions (3e) of bromide
did not affect the reactivity. Chloride was tolerated in this
methodology (3f), and the absolute configuration of the
corresponding product was confirmed by X-ray diffraction.13
Next, the phenyl group of 1a was replaced with various groups
to investigate the generality of this transformation.
Introduction of Me onto the para- (3g), meta- (3h) or ortho-
(3i) position of the phenyl ring afforded high yields. When
electron donating group such as MeO (3m) was introduced to
the para position of phenyl ring, good yield was obtained. The
mild electron-withdrawing halides (F and Cl) were tolerated
well in this methodology. It is interesting that the CF3 group
afforded high yield (3l). Replacing the phenyl ring by a
naphthyl group (3n) is also compatible, giving a high yield of
97%. When phenyl ring was replaced by the heteroaromatic ri-
ng like thio-
aReaction conditions: 1 (0.20 mmol), 2a (0.40 mmol, 2 equiv), Pd(OAc)2 (0.01
mmol, 5 mol %), (2-MeOPh)3P (0.02 mmol, 10 mol %), CsOPiv (0.40 mmol, 2
equiv), 1,4-dioxane (2 mL), in dark, Ar atmosphere, 70 oC, 7 h. bIsolated yield.
cPerformed at 90 ℃. cWith olefin 1g (1.37g, 5 mmol) as starting material.
phene, high yield was obtained (3o). The phenyl group also can
be replaced by several nonaryclic groups (3p-3q), albeit with a
significant amount of source material recovery for cyano (3q)
and alkyl (3r) substitutions.
Next, the substituent effect on 1,3-dienes were examined
(Table 3). At first, various 1,3-dienes with different aryl
substitutions on the terminal site were tested. Electron-
donating groups such as Me (3s) and MeO (3t) on the para-
position of the phenyl ring showed a marginal effect on the
reaction outcome, and excellent reaction yields were
observed. The electron withdrawing group like F (3v) and Cl
(3w) were tolerated but the yields decreased. Polyene
molecules bearing N,N-dimethylaniline as donating group have
been widely studied for nonlinear optical properties.14 It is also
tolerated in this methodology with medium yield (3u). While
switching the phenyl ring to furanyl group (3x) gave excellent
reaction yield, alky substitutions made the reaction rather
sluggish and much source material was recovered (3y and 3z).
Notably, the gram scale reaction with 5 mmol of olefin 1g
proceeded very well, affording triene 3g in 94% yield, which is
better than the small-scale trial.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
Notes and references
View Article Online
DOI: 10.1039/D0CC06452A
Table 3 Substrate Scope of Dienesa,b
1
(a) M. Sugita, Y. Natori, N. Sueda, K. Furihata, H. Seto and N.
Ōtake, J. Antibiot., 1982, 35, 1474; (b) M. Avignon-Tropis, J.
M. Berjeaud, J. R. Pougny, I. Fréchard-Ortuno, D. Guillerm
and G. Linstrumelle, J. Org. Chem., 1992, 57, 651; (c) G. A.
Molander and F. Dehmel, J. Am. Chem. Soc., 2004, 126,
10313; (d) C. Thirsk and A. Whiting, J. Chem. Soc., Perkin
Trans. 1, 2002, 999; (e) J. P. Knowles, V. E. O'Connor and A.
Whiting, Org. Biomol. Chem., 2011, 9, 1876; (f) S. BouzBouz
and J. Cossy, Org. Lett., 2004, 6, 3469.
(a) R. E. Martin and F. Diederich, Angew. Chem. Int. Ed. Engl.,
1999, 38, 1350; (b) S.V. Vasyluk, O.O. Viniychuk, Y.M.
Poronik, Y.P. Kovtun, M.P. Shandura, V.M. Yashchuk and O.D.
Kachkovsky, J. Mol. Struct., 2011, 990, 6; (c) J. M. Kauffman
and G. Moyna, J. Org. Chem., 2003, 68, 839.
Ph
R4
Ph
Pd(OAc)2, P(2-MeOPh)3
CsOPiv, 1,4-dioxane
R3
R4
Br
R3
70
℃, 7 h, dark
1a
2
3
Ph
Ph
Ph
Ph
Me
Cl
OMe
N
3s
3t
3u
, 43%
, 98%
, 68%
c
, 90%
2
Ph
Ph
O
F
c
3v
3w
3x
, 90%
, 76%
Ph
Ph
nPentyl
3
4
(a) B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863;
(b) R. J. Petroski and R. J. Bartelt, J. Agric. Food. Chem., 2007,
55, 2282; (c) Y. Leblanc, B. J. Fitzsimmons, R. Zamboni and J.
Rokach, J. Org. Chem., 1988, 53, 265.
Me
3y
3z
, 31%
, 55%
(a) G. Dumonteil, M.-A. Hiebel and S. Berteina-Raboin,
Catalysts, 2018, 8, 115; (b) S. E. Denmark and S. Fujimori, J.
Am. Chem. Soc., 2005, 127, 8971; (c) N. J. McAlpine, L. Wang
and B. P. Carrow, J. Am. Chem. Soc., 2018, 140, 13634; (d) V.
T. Nguyen, H. T. Dang, H. H. Pham, V. D. Nguyen, C. Flores-
Hansen, H. D. Arman and O. V. Larionov, J. Am. Chem. Soc.,
2018, 140, 8434; (e) H. Takayama and T. Suzuki, J. Chem.
Soc., Chem. Commun., 1988, 1044; (f) L. Crombie, M. A.
Horsham and S. R. M. Jarrett, J. Chem. Soc., Perkin Trans. 1,
1991, 1511; (g) E. Li, H. Zhou, V. Östlund, R. Hertzberg and C.
Moberg, New J. Chem., 2016, 40, 6340; (h) D. Brandt, V.
Bellosta and J. Cossy, Org. Lett., 2012, 14, 5594; (i) A.
Torrado, B. Iglesias, S. López and A. R. de Lera, Tetrahedron,
1995, 51, 2435; (j) T. He, P. Gao, S. Fang, Y. Chi and Y. Chen,
Tetrahedron Lett., 2017, 58, 4832.
(a) M. Mato, C. García-Morales and A. M. Echavarren, ACS
Catal., 2020, 10, 3564; (b) M. S. Hadfield and A.-L. Lee, Chem.
Commun., 2011, 47, 1333; (c) N. Kim and R. A. Widenhoefer,
Chem. Sci., 2019, 10, 6149; (d) Z. Huang and E.-i. Negishi,
Org. Lett., 2006, 8, 3675; (e) H. Zhang, X. Wu, Y. Wei and C.
Zhu, Org. Lett., 2019, 21, 7568.
aReaction conditions: 1a (0.20 mmol), 2 (0.40 mmol, 2 equiv), Pd(OAc)2
(0.01 mmol, 5 mol %), (2-MeOPh)3P (0.02 mmol, 10 mol %), CsOPiv (0.40
mmol, 2 equiv), 1,4-dioxane (2 mL), in dark, Ar atmosphere, 70 ℃, 7 h.
bIsolated yield. cPerformed at 90 oC
It is worth mentioning that the obtained trienes would
undergo isomerization in the light. If a solution of 3g in CDCl3
was exposed in the light for 6 hours, the ratio of two E/Z
isomers reached an equilibration of 1:1 (Eq 1). This
phenomenon was also invested in the exposure of 20 W white
LED. The charted curve of the kinetic process was roughly
corresponded to the first-order reversible reaction.15
5
Me
Me
Ph
sunlight, CDCl3
rt, 6 h
Ph
Ph
(1)
6
7
S. K. Stewart and A. Whiting, Tetrahedron Lett., 1995, 36,
3929.
3c 3g
/
= 1 : 1
Me
3g
3c
3g
(a) S. Ma and Z. Gu, Angew. Chem. Int. Ed., 2005, 44, 7512;
(b) F. Shi and R. C. Larock, Top. Curr. Chem., 2010, 292, 123;
(c) A. Rahim, J. Feng and Z. Gu, Chin. J. Chem., 2019, 37, 929.
(a) M.-Y. Li, P.-B. Han, T.-J. Hu, D. Wei, G. Zhang, A.-J. Qin, C.-
G. Feng, B. Tang and G.-Q. Lin, iscience, 2020, 23, 100966; (b)
D. Wei, T.-J. Hu, C.-G. Feng and G.-Q. Lin, Chin. J. Chem.,
2018, 36, 743; (c) T.-J. Hu, M.-Y. Li, Q. Zhao, C.-G. Feng and
G.-Q. Lin, Angew. Chem. Int. Ed., 2018, 57, 5871; (d) T.-J. Hu,
G. Zhang, Y.-H. Chen, C.-G. Feng and G.-Q. Lin, J. Am. Chem.
Soc., 2016, 138, 2897.
(a) Q. Wang, R. Chen, J. Lou, D. H. Zhang, Y.-G. Zhou and Z.
Yu, ACS Catal., 2019, 9, 11669; (b) H. Zhang, Y. Yu and X.
Huang, Org. Biomol. Chem., 2020, 18, 5115; (c) R. Rocaboy
and O. Baudoin, Org. Lett., 2019, 21, 1434.
8
In summary, a stereoselective synthesis of trisubstituent
1,3,5-trienes has been realized by the 1,4-palladium
migration/Heck sequence. A wide range of trisubstituted 1,3,5-
trienes were produced by this transformation in medium to
excellent yields. It is noteworthy that the substrates bearing
two similar aryl groups at terminal positions can be obtained in
high stereoselectivity, which are difficult to be prepared by
traditional methods. In addition, we found that the obtained
trienes can undergo easy E/Z isomerization in the light.
9
10 M. Wakioka, Y. Nakamura, M. Montgomery and F. Ozawa,
Organometallics, 2015, 34, 198.
11 L. Ackermann, Chem. Rev., 2011, 111, 1315.
12 (a) L. Wang and B. P. Carrow, ACS Catal., 2019, 9, 6821; (b) D.
Lapointe and K. Fagnou, Chem. Lett., 2010, 39, 1119.
13 CCDC 2030783 (3f) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
Conflicts of interest
The authors declare no competing financial interest.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
14 (a) B. J. Coe, J. A. Harris, I. Asselberghs, K. Wostyn, K. Clays,
A. Persoons, B. S. Brunschwig, S. J. Coles, T. Gelbrich, M. E.
Light, M. B. Hursthouse and K. Nakatani, Adv. Funct. Mater.,
2003, 13, 347; (b) F. Dumur, C. R. Mayer, E. Dumas, F.
Miomandre, M. Frigoli and F. Sécheresse, Org. Lett., 2008,
10, 321; (c) D. Roberto, R. Ugo, S. Bruni, E. Cariati, F. Cariati,
P. Fantucci, I. Invernizzi, S. Quici, I. Ledoux and J. Zyss,
Organometallics, 2000, 19, 1775.
View Article Online
DOI: 10.1039/D0CC06452A
15 See Supplementary Information for details.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
Stereoselective Synthesis of Conjugated Trienes via 1,4-Palladium MigratiDoOnI:/1H0.e10c3k9/D0CC06452A
Sequence
Ze-Jian Xue, Meng-Yao Li, Bin-Bin Zhu, Zhi-Tao He, Chen-Guo Feng and Guo-Qiang Lin
An efficient 1,4-palladium migration/Heck sequence was developed for the highly stereoselective synthesis of conjugated trienes.