Enantioselective Synthesis of Chromenes via a Palladium-Catalyzed Asymmetric Redox-Relay Heck Reaction

Article abstract of DOI:10.1002/asia.201701504

A palladium-catalyzed asymmetric redox-relay Heck reaction of 4H-chromenes and arylboronic acids has been successfully developed. The reaction proceeded in moderate to good yields with good to high enantioselectivities. The resulting product is an advanced intermediate of bio-active compound BW683C.

Full text of DOI:10.1002/asia.201701504

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Enantioselective Synthesis of Chromenes by the Palladium-
Catalyzed Asymmetric Redox-Relay Heck Reaction
Authors: Ze-Zhen Jiang, Ang Gao, Hao Li, Di Chen, Chang-Hua Ding,
Bin Xu, and Xue-Long Hou
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10.1002/asia.201701504
Chemistry - An Asian Journal
COMMUNICATION
Enantioselective Synthesis of Chromenes by the Palladium-
Catalyzed Asymmetric Redox-Relay Heck Reaction
Ze-Zhen Jiang,[a,b] Ang Gao,[b] Hao Li,[a,b] Di Chen,[b] Chang-Hua Ding,*[b] Bin Xu,*[a] and Xue-Long
Hou*[b]
Dedication ((optional))
Abstract:
A palladium-catalyzed asymmetric redox-relay Heck
reaction of 4H-chromenes and arylboronic acids has been
successfully developed. The reaction proceeded in moderate to
good yields with good to high enantioselectivities. The resulting
product is an advanced intermediate of bio-active compound
BW683C.
Figure 1. Chromene and chroman rings in bio-active compounds.
Chromene and chroman rings are key heterocycles present in a
variety of natural occurring products and bio-active molecules
such as (S)-Candenatenin E,[1a] Hilgartene,[1b] BW683C,[1c] and
tephrowatsin E[1d] (Figure 1). Thus the development of efficient
synthetic methods to access these motifs has received a
tremendous amount of attention, and many strategies have been
reported.[2] However, the catalytic asymmetric synthesis of 2H-
chromene derivatives are limited. The main strategies are based
on the enantioselective addition of aryl boronates to in-situ
generated pyrylium ions,[3] the intramolecular asymmetric
Brønsted acid-catalyzed allylic etherification,[4] and the 6-endo-
trig Pd-catalyzed asymmetric allylic substitution.[5] You’s group
reported an iridium-catalyzed asymmetric allylic etherification
and the subsequent Ru-catalyzed ring-closing metathesis
reaction for enantioselective synthesis of chromene.[6] In spite of
these significant advancement, some problems exit such as the
limitation of intramolecular approach[4,5] or the need of multiple
step reactions.[6] Therefore, the development of new approaches
to this important motifs is still in great demand. In connection
with our studies on palladium-catalyzed asymmetric Heck
reaction,[7] we envisioned that the enantioselective Heck of 4H-
chromene would provide an attractive access to optically active
chromenes. While Pd-catalyzed intermolecular Heck reaction
has been well developed,[8-10] the alkenes suitable for the
asymmetric intermolecular Heck reaction are limited. Cyclic
alkenes such as 2,3-dihydrofuran and 3,4-dihydro-2H-pyran are
most commonly used substrates in asymmetric Heck reaction.
Surprisingly, the report of using their analogue, 4H-chromene,
as substrate for asymmetric Heck reaction is not available so far.
Herein, we reported our preliminary results to this end.
Initially, we examined the Heck reaction of 4H-chromene (1a)
with phenyl trifluoromethanesulfonate in the presence of two
catalyst systems which show high efficiency in the Mizoroki-
Heck reaction (eq 1).[11] Unfortunately, 2-phenyl-2H-chromene
(3a) was obtained in very low yield and an extensive
optimization of reaction conditions couldn’t lead to a better result.
Then, the Pd-catalyzed oxidative Heck reaction between 4H-
chromene (1a) with phenyl boronic acid (1a) was conducted in
the presence of catalytic Pd(OAc)2 (eq 2).[12] The yield of 3a was
also very low and the extensive exploration couldn’t improve the
reaction. Inspired by the Pd-catalyzed redox-relay Heck reaction
of Sigman group,[10] Pd(CH3CN)2Cl2 and PyrOx L1 were used as
the catalyst for the reaction of 4H-chromene (1a) with phenyl
boronic acid (2a) (eq 3). Pleasingly, the reaction afforded
product 3a in 20% yield with 96% ee (eq 3 and entry 1, table 1).
It is noted that alkenols are usually used as substrates in the Pd-
catalyzed redox-relay Heck reaction.[10] The result herein
represents a new application of the catalyst system in the Pd-
catalyzed intermolecular Heck reaction. The promising results
promoted us to carry out further investigations. Studies on the
influence of reaction temperature indicated that performing the
reaction at higher temperature afforded a better yield of 3a but
lower enantioselectivity (entries 1–4, table 1). When the reaction
was conducted at a temperature of 80 °C, enantioselectivity of
product 3a was significantly reduced to 40% ee (entry 4, table 1).
Control experiments revealed the importance of the presence of
oxygen because only 5% of 3a was observed when the reaction
was carried out under argon (entry 5 vs entry 3, table 1).
Absence of 3 Å MS also led to a yield decrescence of 3a (entry
6 vs entry 3, table 1). The yield of 3a was increased significantly
from 29% to 61%, whereas the enantioselectivity was also
increased from 91% to 93%, when the reaction was run by using
12 mol% of Cu(OTf)2 (entry 7 vs entry 2, table 1). Performing the
reaction using 20 mol% of Cu(OTf)2 didn’t afforded better results
[a]
[b]
Z.-Z. Jiang, H. Li, Prof. Dr. B. Xu
Department of Chemistry, Innovative Drug Research Center
Shanghai University
Shanghai 200444, China
E-mail: xubin@shu.edu.cn
Z.-Z. Jiang, A. Gao, H. Li, D. Chen, Dr. C.-H. Ding, Prof. Dr. X.-L.
Hou
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Lingling Road, Shanghai 200032, China
E-mail: dingch@sioc.ac.cn; xlhou@sioc.ac.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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(entry 8 vs entry 7, table 1). Switching the ratio of 1a/2a from
100/120 to 150/100 further increased the yield of 3a to 81%
while the enantioselectivity was unchanged (entries 9 vs entry 7,
Table 1). A solvent screen showed the reaction proceeded well
in DMF and DMSO (entries 10 and 11, Table 1), but the reaction
did not proceed in toluene (entry 12, table 1). Other solvents,
such as CH3CN and THF, gave inferior results (entries 13 and
14, Table 1). Use of other bidentate nitrogen ligands L2-L4
didn’t improve the reaction (entries 15–17, Table 1) [for more
optimization of reaction conditions, such as the effect of
palladium salt, copper salt, and ligand on the reaction, see
Supporting Information].
arylboronic acids 2, leading to the corresponding allylic
alkylation products 3 in 49–88% yields with 57–95% ee. The
reaction tolerated various substituents at the para, meta, or
ortho positions of the phenyl group of boronic acid 2 (entries 2–
8). The substituent at the ortho-position of the phenyl ring of
arylboronic acid 3d showed a diminished effect on the yield and
enantioselectivity of the reaction (entry 4). The reaction of
arylboronic acid 2f, bearing bromide as substituent which is
suitable for further transformation, could be used to provide 2H-
chromene 3f in 53% yield with 93% ee (entry 6). The reaction
also worked well for arylboronic acid 2g with ester group on the
phenyl ring, affording the corresponding product 3g in 49% yield
with 95% ee (entry 7). The presence of bulky groups such as 1-
naphtyl or 2-naphthyl at the boronic acids 2 had little influence
on the reaction (entries 9 and 10). A halide atom as a
substituent at the 6-position of 4H-chromene 1 exerted limited
effects on the enantioselectivity (entries 11–13). Notably, the
reaction of 4H-chromene 1d with boronic acid 2k provided 2H-
chromene 3m with 93% ee, which has been reported to be
transformed into BW683C by the Pt-catalyzed hydrogenation.[6]
A methyl groups as a substituent at the 6- and 7- positions of
4H-chromene 1 have negative effects on the enantioselectivity
(entries 14 and 15). However, substantial amounts of unknown
side product were observed for the arylboronic acids with an
electron-withdrawing group on the aromatic ring, thus resulting
in a poorer yield of the Heck product, although with high ee
value (entries 7, 16-18). The absolute configuration of product 3f
was determined to be (R) by comparison of optical rotation to
that of literature[6].
Table 1. Optimization of Reaction Conditions for Pd-Catalyzed Asymmetric
Redox-Relay Heck Reaction of 4H-Chromene (1a) and Phenylboronic Acid
(2a)[a]
entry
Ligand
Cu(OTf)2 (mol%)
Solvent
T
yield/%[b]
ee/%[c]
(oC)
1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
6
DMAc[g]
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
rt
20
29
80
71
5
96
91
87
40
87
87
93
93
93
95
89
--
2
6
40
60
80
60
60
40
40
40
40
40
40
40
40
40
40
40
3
6
Table 2. Substrate Scope for Palladium-Catalyzed Asymmetric Redox-Relay
Heck Reaction of 4H-Chromenes 1 and Arylboronic Acids 2[a]
4
6
5[d]
6[e]
7
6
6
72
61
62
81
52
67
nr
12
20
12
12
12
12
12
12
12
12
12
entry
1
R (1)
Ar (2)
yield (3,%)[b]
81 (3a)
76 (3b)
84 (3c)
51 (3d)
80 (3e)
53 (3f)
ee (%)[c]
93
8
9[f]
10
11
12
13
14
15
16
17
H (1a)
Ph (2a)
2
H (1a)
p-Me-C6H4 (2b)
m-Me-C6H4 (2c)
o-Me-C6H4 (2d)
p-F-C6H4 (2e)
p-Br-C6H4 (2f)
p-MeOCO-C6H4 (2g)
p-MeO-C6H4 (2h)
1-naphthyl (2i)
2-naphthyl (2j)
p-MeO-C6H4 (2h)
p-MeO-C6H4 (2h)
p-Cl-C6H4 (2k)
p-MeO-C6H4 (2h)
p-MeO-C6H4 (2h)
91
DMSO
toluene
CH3CN
THF
3
H (1a)
94
4
H (1a)
83
5
79
76
84
80
11
5
H (1a)
92
42
71
61
76
6
H (1a)
93
DMAc
DMAc
DMAc
7
H (1a)
49 (3g)
88 (3h)
63 (3i)
95
8
H (1a)
82
9
H (1a)
91
[a] Entries 1-8: molar ratio of 1a/2a/[Pd]/L = 100/120/6/13. [b] Isolated yield.
[c] Determined by chiral HPLC. [d] under argon instead of O2. [e] in the
absence of 3 Å MS. [f] entries 9-17 molar ratio of 1a/2a = 150/100. [g] DMAc:
dimethylacetamide
10
11
12
13
14
15
H (1a)
70 (3j)
92
6-F (1b)
6-Br (1c)
6-Cl (1d)
6-Me (1e)
7-Me (1f)
84 (3k)
71 (3l)
85
85
62 (3m)
71 (3n)
62 (3o)
92
With the above optimum conditions established, the substrate
scope of this Pd-catalyzed asymmetric redox-relay Heck
reaction was examined (eq 4 and Table 2). In general, the
reaction proceeded smoothly for a variety of 4H-chromene 1 and
83
66
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0.026 mmol), Cu(OTf)2 (8.6 mg, 0.024 mmol) and 3Å MS (30 mg) were
added into the dry Schlenk tube. The flask was evacuated via vacuum
and refilled with O2 three times, then DMAc (2 mL) was added using a
syringe. The resulting mixture was stirred for 30-40 minutes. Then, 4H-
Chromenes 1 (0.3 mmol, 1.5 equiv) and aryl boronic acid 2 (0.2 mmol,
1.0 equiv) were added. The resulting mixture was stirred for another 18 h
to 24 h at 40 °C. After the reaction was completed, the reaction mixture
was diluted with EtOAc (2 mL) and H2O (5 mL). The aqueous phase was
extracted with EtOAc (3×5 mL). The organic phase was dried with
anhydrous Na2SO4 and then filtered through a 0.5 inch plug of silica gel
(eluting with EtOAc) to remove the solid. The crude reaction mixture was
concentrated under reduced pressure. The resulting crude product was
purified by flash column silica gel chromatography (eluting with petroleum
ether/ethyl acetate 100/1) to provide product 3.
16
17
18
H (1a)
H (1a)
H (1a)
p-CF3-C6H4 (2l)
p-CN-C6H4 (2m)
p-Ac-C6H4 (2n)
21 (3p)
37 (3q)
45 (3r)
93
91
92
[a] Molar ratio of 1/2/Pd(CH3CN)2Cl2/L1/Cu(OTf)2 = 150:100:6:13:12. [b]
Isolated yield. [c] Determined by chiral HPLC.
In conclusion, we have realized
a palladium-catalyzed
asymmetric redox-relay Heck reaction of 4H-chromenes and
arylboronic acids in moderate to good yields with good to high
enantioselectivities. The resulting products contain core
structure of many natural products and bio-active compound.
The usefulness of the method is demonstrated by the product
3m reported to be converted into BW683C.[6] Further studies of
extension of the method and applications in organic synthesis
are in progress.
Acknowledgements
Financial support by National Natural Science Foundation of
China (NSFC) (21372242, 21472214, 21532010, 21421091), the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20030100), the NSFC and the Research Grants
Council of Hong Kong Joint Research Scheme (21361162001),
the Technology Commission of Shanghai Municipality, and the
Croucher Foundation of Hong Kong is acknowledged.
Experimental Section
General procedure for the palladium-catalyzed asymmetric redox-
relay Heck reaction of 4H-chromenes 1 and arylboronic acids 2:
A 10 mL dry Schlenk tube equipped with a stir bar was flame dried and
flushed with argon. Pd(CH3CN)2Cl2 (3.1 mg, 0.012 mmol), L1 (7.1 mg,
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Keywords: palladium • redox-relay Heck reaction • asymmetric
catalysis • 4H-chromene • boronic acid
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Entry for the Table of Contents (Please choose one layout)
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Ze-Zhen Jiang, Ang Gao, Hao Li,
Chang-Hua Ding,* Bin Xu,* and Xue-
Long Hou*
Page No. – Page No.
Enantioselective Synthesis of
Chromenes by the Palladium-
Catalyzed Asymmetric Redox-Relay
Heck Reaction
A palladium-catalyzed asymmetric redox-relay Heck reaction of 4H-chromenes and
arylboronic acids has been successfully developed. The reaction proceeded in
moderate to good yields with good to high enantioselectivities. The resulting
product is an advanced intermediate of bio-active compound BW683C.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.