Highly Stereoselective Synthesis of 1,3-Dienes through an Aryl to Vinyl 1,4-Palladium Migration/Heck Sequence

Article abstract of DOI:10.1002/anie.201801963

An efficient aryl to vinyl 1,4-palladium migration/Heck sequence was developed for the stereoselective synthesis of 1,3-dienes. High stereoselectivity was observed not only for 1,3-dienes bearing two similar aryl groups at terminal positions, but also for

Full text of DOI:10.1002/anie.201801963

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Accepted Article
Title: Highly Stereoselective Synthesis of 1,3-Dienes via Aryl to Vinylic
1,4-Palladium Migration/Heck Sequence
Authors: Tian-Jiao Hu, Meng-Yao Li, Qian Zhao, Chenguo Feng, and
Guo-Qiang Lin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801963
Angew. Chem. 10.1002/ange.201801963
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10.1002/anie.201801963
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Metal Migration
Highly Stereoselective Synthesis of 1,3-Dienes via Aryl to Vinylic 1,4-
Palladium Migration/Heck Sequence**
Tian-Jiao Hu, Meng-Yao Li, Qian Zhao, Chen-Guo Feng* and Guo-Qiang Lin*
1, 3-Dienes are frequently incorporated in complex natural
products[1] and biologically active molecules.[2] Moreover, they are
also versatile synthetic precursors for a variety of important organic
transformations.[3] Consequently, numerous methods have been
developed for the efficient synthesis of these useful 1,3-diene
compounds.[4] Among them, the transition-metal catalyzed direct
cross-coupling of two different alkenes via the activation of alkenyl
C-H bond is a straightforward and atom-efficient approach, and
received tremendous research interest.[5] Despite the advancements,
the stereochemical control of two double bonds remains to be a
challenge in this area, especially for the coupling of two terminal
olefins.[6]
Currently, two strategies are often used to solve this
stereoselectivity problem. The first is to mainly rely on the inherent
steric properties of the reaction substrates (Scheme 1a).[7] For
example, good stereoselectivity was observed for the palladium-
catalyzed cross-coupling of α-methyl styrene derivatives with
acrylates. Sometimes, the inherent minor difference is sufficient to
offer a better stereoselectivity by applying a suitable ligand.[7e-f]
However, it would become almost impossible to achieve
considerable stereoselectivity when olefin substrates bear similar
substituents. Another challenge in this case is to reverse the
selectivity for structurally unfavored products. These problems were
partially solved by introducing a directing group (Scheme 1b).
Excellent stereoselectivities were obtained with various heteroatom
substituents, including ester,[8] amide,[9] alcohol,[10] and phosphate[11]
Obviously, this strategy is not suitable for substrates without a
heteroatom directing group. In addition, the stereoselectivity cannot
be switched to the unfavored isomer due to the nature of the
directing group. Therefore, new strategies to address these unsolved
problems are still highly desirable.
[13]
Based on the pioneering work by Dyker,[12] Larock
and
Miura,[14] 1, 4-migration of transition metals has become a useful
synthetic tool to enable the remote functionalization of C-H bonds
and bring new chemical accessibility and selectivity.[15] As one of
the most studied transitional metal in this field, 1,4-palladium
migration was usually applied in the intramolecular
functionalization,[16] and limited success was achieved in the more
elusive intermolecular process.[17] The biggest obstacle lies in
controlling the extraneous functional reagents to react on the new
migrated site rather than the originally generated one. Recently, we
disclosed an efficient intermolecular aryl to vinylic 1, 4-palladium
migration/borylation sequence for the stereospecific synthesis of tri-
substituted olefins.[18] As part of our ongoing research program
aimed at expanding the utility of this discovery, we became
interested in developing this as a new strategy for the stereoselective
synthesis of 1,3-dienes which are problematic targets according to
the existing methods (Scheme 1c).
.
[]
T.-J. Hu, M.-Y. Li, Prof. C.-G. Feng, Prof. G.-Q. Lin
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, Chinese Academy of
Sciences, Shanghai 200032 (China)
E-mail: fengcg@sioc.ac.cn
Prof. C.-G. Feng
Innovation Research Institute of Traditional Chinese
Medicine, Shanghai University of Traditional Chinese
Medicine, Shanghai 200032 (China)
Dr. Q. Zhao
Jiangsu Key Laboratory of Chiral Drug Development,
Jiangsu Aosaikang Pharmaceutical CO., LTD.
Nanjing, 211112 (China)
[] This work was supported by the National Natural Science
Foundation of China (21472212, 21772216), the Strategic
Priority Research Program of the Chinese Academy of
Sciences
(XDB
20020100),
the
973
Program
(2015CB856600) and The Key Research Program of
Frontier Science (QYZDY-SSW-SLH026). We thank Dr.
Han-Qing Dong (Arvinas, Inc.) for his help in the
preparation of this manuscript.
Scheme 1. Stereoselectivity control in the transition-metal catalyzed
direct cross-coupling of two different olefins
Our investigation began with examination of the coupling of
terminal olefin 1aa and methyl acrylate 2a using Pd(OAc)2 as
precatalyst and PPh3 as ligand. To our delight, the direct Heck
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
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10.1002/anie.201801963
Angewandte Chemie International Edition
process was efficiently inhibited, and the desired diene 3aa via the
1,4-palladium migration/Heck sequence was successfully generated
in 28% yield (Table, entry 1). The low yield was attributed to
several side reactions, including the dehalogenation and
dimerization of 1aa. The reaction yield could be improved by using
triarylphosphine ligand bearing electron-donating MeO or Me group
at the para-position of the phenyl ring (entries 2 and 3). A
significant improvement was achieved with ortho-MeO substituted
triarylphosphine ligand (entry 6), which may be explained by that
the o-MeO substituents as hemilabile supporting ligands would
induce the generation of active monomeric palladium
intermediates.19 Interestingly, the catalytic activity was almost
completely suppressed when the ortho-MeO group was switched to
the ortho-Me group, probably due to the increased steric hindrance
(entry 7). Bisphosphine ligands were also effective, but failed to
bring better results (entries 8 and 9). The base also played an
important role for this reaction, affecting the migration efficiency,
the E/Z ratio and yield of the desired product (entries 10-12). A
profound increase of the direct Heck product 4 by using CsF
highlighted the importance of carboxylate anion (AcO- or PivO-) for
this migration sequence, most likely for the C-H activation step
(entry 12).[20] Slightly increasing the amount of 2a to 1.5 equivalents
could further improve the reaction yield, but more 2a had a
deleterious effect on the catalytic activity (entries 13-14).
As for the synthesis of 1,3-dienes bearing gem-diaryl
substituents at the terminal site, it is usually difficult to efficiently
discriminate two similar aryl groups and achieve good
stereoselectivity when introducing any substitutions to the double
bond. With the optimized reaction conditions in hand, we started to
apply this method for the stereoselective synthesis of 1,3-dienes
having two different aryl groups at the terminal site (Scheme 2). As
expected, the corresponding double bonds were generated in a
stereospecific way for all the tested examples. High reaction yields
were obtained when electron-donating or mild electron-withdrawing
groups were introduced to the phenyl ring A at different positions.
Stronger electron-withdrawing CF3 group led to obvious drop in
reaction yield (3af). In addition, the replacement of phenyl ring A
by naphthyl (3aj), pyridyl (3ak) and thienyl (3al) groups also
proceeded well. Variation of substituents at the phenyl ring B also
found a beneficial effect from election-donating groups and a
reverse effect from electron-withdrawing groups. A variety of
acrylates (3ca-3ce), as well as acrylamide (3cf), acrolein (3cg) and
ethyl vinyl ketone (3ch) were accommodated in this reaction,
providing the desired products in high reaction yields. Acrylonitrile
(3ci) and diethylvinylphosphonate (3cj) were also competent
coupling partners, albeit in reduced yields. The reaction
stereochemistry of 3ah was confirmed to be (2E, 4E) by the X-ray
structure analysis, which is in accordance with our predicted
stereoselectivity[21]
.
Table 1: Optimization of reaction conditions.[a]
[a] Reactions conditions: 1aa (0.30 mmol), 2a (0.33 mmol, 1.1 equiv),
Pd(OAc)2 (0.015 mmol), ligand (0.03 mmol) and base (0.60 mmol) in
solvent (6 mL) at 100 oC for 3 h unless otherwise noted. [b] Combined
1
yield of two isomers and determined by H NMR spectroscopy using
CH2Br2 as an internal standard. [c] 2E/2Z = (2E)-3aa/(2Z)-3aa and
determined by 1H NMR. [d] ligand (0.015 mmol) was used. [e] 2a (1.5
equiv) was added. [f] 2a (2 equiv) was added.
Scheme 2. Stereoselective synthesis of 1,3-dienes bearing gem-
diaryl substitutions via 1,4-palladium migration/Heck sequence.
Reactions conditions: 1 (0.30 mmol), 2 (0.45 mmol), Pd(OAc)2 (0.015
2
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10.1002/anie.201801963
Angewandte Chemie International Edition
mmol), L5 (0.03 mmol) and CsOAc (0.60 mmol) in THF (6 mL) at 100
oC for 3 h unless otherwise noted. Yields are given for the isolated
major isomer. The (2E)-3/(2Z)-3 ratio was determined by 1H NMR
analysis of crude products and given in parenthesis. [a] Combined
isolated yield of (2E)-3 and (2Z)-3. [b] The (2E)-3/(2Z)-3 ratio is not
determined. [c] 2 (0.60 mmol), Pd(OAc)2 (0.03 mmol), L5 (0.06 mmol)
were added.
gram-scale reaction was also carried out to demonstrate the
practicability of this reaction [Eq. (3)].
The replacement of the phenyl ring A by alkyl groups also
proved to be feasible. Various olefins bearing different linear alkyl
chains or a branched iso-propyl group successfully went through the
1,4-migration/Heck sequence (Scheme 3). The double bond at 4-
position of the resulting esters was in complete Z-configuration,
providing a complementary method in this field because most
previous approaches generated the favourable E-geometry.[7b-f]
In order to gain some preliminary understanding of the reaction
mechanism, an intermolecular KIE experiment was carried out and
kH/kD = 3.2 was observed [Eq. (4)], which is in accordance with the
data for 1,4-palladium migration/borylation sequence.[18] This
indicates that the C−H bond cleavage should be involved in the rate
determining step of the catalytic cycle. Notably, some d2-1ea
molecules might go through an intramolecular deuterium shift to the
aryl ring simultaneously as previously reported.[18,22]
Scheme 3. Stereoselective synthesis of 1,3-dienes bearing gem-
alkylaryl substitutions via 1,4-palladium migration/Heck sequence.
Moreover, replacing the phenyl ring A by an ester group was
also tested, which would stereoselectively generate multi-substituted
muconate derivatives. In this case, the electronic properties of two
coupling partners would facilitate the homo-coupling process and
made the palladium migration/Heck sequence much more
challenging. Fortunately, the desired dienes were produced
smoothly in acceptable reaction yields, albeit accompanied by a
significant amount of homo-coupling products as expected.
Different from the (Z, E)-muconate derivatives obtained by previous
method,[8b] this approach stereospecifically generated products in (E,
E) stereochemistry.
In conclusion, gem-disubstituted ethylenes could undergo
stereoselective cross-coupling with electron-deficient olefins via an
efficient 1,4-palladium migration/Heck sequence. Owing to the
novel directing mode, this method could provide the desired
products with new stereoselectivities, which are inaccessible by
previous conventional methods.The practicality of this reaction is
highlighted by the broad substrate scope, the easy product
transformation and the preparative reaction scale. In addition, this
work represents the first aryl to vinylic 1,4-palladium
migration/Heck reaction, and we expect that our results would
encourage more efforts to discover intermolecular transformations
via controlled metal migration mechanism.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: cross-coupling · palladium· alkenylation · C-H
functionalization · metal migration
Scheme 4 Stereoselective synthesis of (E,E)-muconate derivatives
via 1,4-palladium migration/Heck sequence.
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Further chemical transformations were demonstrated in Scheme
5. The resulting methyl (E)-5,5-diphenylpenta-2,4-dienoate 3aa can
easily be converted to the corresponding acid 5 by hydrolysis [Eq.
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more potential utility of these 1,3-diene moieties. In addition, a
3
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10.1002/anie.201801963
Angewandte Chemie International Edition
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Cambridge
Crystallographic
Data
Centre
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www.ccdc.cam.ac.uk/data_request/cif.
[22] A possible reaction mechanism was provided in the supporting
information.
[10] Cross-couplings of two terminal olefins with an alcohol directing
group, see: Q.-J. Liang, C. Yang, F.-F. Meng, B. Jiang, Y.-H. Xu, T. -
4
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10.1002/anie.201801963
Angewandte Chemie International Edition
Layout 2:
Metal Migration
Tian-Jiao Hu, Meng-Yao Li, Qian Zhao,
Chen-Guo Feng* and Guo-Qiang Lin*
__________ Page – Page
Highly Stereoselective Synthesis of 1,3-
Dienes via Aryl to Vinylic 1,4-Palladium
Migration/Heck Sequence
An efficient aryl to vinylic 1,4-palladium/Heck sequence has been developed for the
stereoselective synthesis of 1,3-dienes. High stereoselectivities were observed not
only for 1,3-dienes bearing two similar aryl groups at terminal positions, but also for
those with unfavourable configuration by previous methods.
5
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