Palladium-Catalyzed Enantioselective Reductive Heck Reactions: Convenient Access to 3,3-Disubstituted 2,3-Dihydrobenzofuran

Article abstract of DOI:10.1002/anie.201806372

The first example of highly enantioselective intramolecular hydroarylation of allyl aryl ethers was realized by palladium-catalyzed reductive heck reactions utilizing a new chiral sulfinamide phosphine ligand (N-Me-XuPhos). N-Me-XuPhos can be easily prepared on gram scale from readily available starting materials in a one-pot synthesis approach. A series of optically active 2,3-dihydrobenzofurans bearing a quaternary stereocenter were obtained in good yields and with excellent enantioselectivities. The practicality of this reaction was validated in the straightforward synthesis of CB2 receptor agonists. Moreover, deuterium was efficiently incorporated into the products.

Full text of DOI:10.1002/anie.201806372

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Accepted Article
Title: Palladium-Catalyzed Enantioselective Reductive Heck Reactions:
Convenient Access to 3,3-Disubstituted 2,3-Dihydrobenzofuran
Authors: Junliang Zhang, Zhan-Ming Zhang, Bing Xu, Yanyan Qian,
Lizuo Wu, Yuanqi Wu, Lujia Zhou, and Yu Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806372
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10.1002/anie.201806372
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Palladium-Catalyzed Enantioselective Reductive Heck Reactions:
Convenient Access to 3,3-Disubstituted 2,3-Dihydrobenzofuran
Zhan-Ming Zhang,+ Bing Xu,+ Yanyan Qian, Lizuo Wu, Yuanqi Wu, Lujia Zhou, Yu Liu and Junliang
Zhang*
Abstract: The first example of highly enantioselective intramolecular
hydroarylation of allyl aryl ethers was realized via palladium-
catalyzed reductive heck reactions by utilizing a designed new chiral
sulfonamide phosphine ligand (N-Me-XuPhos). N-Me-XuPhos can
be easily prepared in a gram-scale from readily available starting
materials via a ‘one-pot’ synthesis approach. A series of optically
active 2,3-dihydrobenzofuran bearing a quaternary stereocenter
were obtained in good yields with excellent enantioselectivities. The
practicality of this reaction was validated in the straightforward
synthesis of CB2 receptor agonists. Moreover, deuterium was
efficiently incorporated into the products.
present the first example of highly chemo- and enantioselective
palladium-catalyzed hydroarylation reaction of allyl aryl ethers
with the use a designed new chiral ligand, which providing a
facile access to a series of enantioenriched 3,3-disubstituted
2,3-dihydrobenzofurans bearing an all-carbon quaternary
stereocenter[14] in good yields and high ees (Scheme 1b).
The palladium-catalyzed hydroarylation or reductive Heck
reactions between arylhalides and alkenes is one of the most
powerful and straightforward synthetic tools for the efficient
construction of a variety of cyclic skeletons that constitute key
moiety of bioactive natural products and pharmaceuticals.[1,2] In
1998, Diaz et al. reported the first example of asymmetric
hydroarylation reaction of o-iodophenol-derived allyl ether
(retinoid derivatives: only two examples), delivering the 3,3-
disubstituted 2,3-dihydrobenzofuran in moderate yield with
moderate ee (Scheme 1a).[3] The 3,3-disubstituted 2,3-
dihydrobenzofuran is core motifs in ubiquitous biologically active
alkaloids, and building blocks for the rapid synthesis of multiple
scaffolds, such as DNA-PK inhibitors, Furaquinocin A,
retionoids, CB2 receptor agonists, HCV NS5B inhibitors, and so
on (Figure 1).[3,4] Despite several elegant palladium-catalyzed
asymmetric hydroarylation of various substrates such as
enones, amides, indoles derivatives have been dependently
reported by the groups of Buchwald,[5] Jia,[6] Zhou,[7] de Vries
and Minnaard,[8] and Zhu[9] in past decade (Scheme 1a), the
devolopment of highly enantioselective arylation of o-
iodophenol-derived allyl ethers is still in great demand.
Scheme 1. Pd-catalyzed enantioselective intramolecular reductive Heck
reactions.
Over past few years, we designed and developed a series of
new chiral sulfonamide phosphine ligands such as Ming-Phos,[10]
Xiang-Phos[11] and PC-Phos,[12] which have shown good
performance in asymmetric transition metal catalysis.[13] Inspired
by these success, we wondered whether these chiral ligands
could address the low enantioselectivity issue of asymmetric
hydroarylation of o-iodophenol-derived allyl ethers. Herein, we
Figure 1. Biologically active alkaloids containing 3,3-disubstituted 2,3-
dihydrobenzofuran skeletons.
[*]
Z.-M. Zhang,[+] B. Xu,[+] L. Zhou, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering
East China Normal University, Shanghai 200062, China
E-mail: jlzhang@chem.ecnu.edu.cn
With the use of o-iodophenol-derived allyl ether 1a as the
model substrate and [PdCl(ally)]2 as a precatalyst, a series of
chiral ligands including commercially available chiral ligands
were investigated (Figure 2). The product 2a was obtained in
32% yield and with 68% ee value, when BINAP (L1) was used
as the chiral ligand. Although the sterically bulkier XylBINAP (L2)
led to a better ee (78% ), the yield decreased to 15% yield. The
(R)-DTBM-BIPHEP (L4) with bulky substitutent could deliver
79% ee but in only 19% yield. The other chiral ligands such as
(R)-DM-SEGPHOS (L3), (R)-MOP (L5), iPrPHOX (L6), (R)-(S)-
PPFA (L7), L8 and Binol-derived phosphoramidite (L9) all failed
Y. Qian, L. Wu, Y. Wu, Prof. Dr. Y. Liu
College of Chemistry and Life Science, Advanced Institute of
Materials Science
Changchun University of Technology, Changchun 130012, China
These authors contributed equally to this work.
[+]
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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to improve the enantioselectivity (Figure 2). Meanwhile, chiral
examined as precatalysts under the identical reaction conditions
ligands (Ming-Phoses M1-5, Xiang-Phos X1, PC-Phos PC1)
(Table 1, entries 14–17), among which Pd2(dab)3•CHCl3
developed by our group also gave low ees (Table 1, entries 1–7). exhibited the best enantioselectivity (Table 1, entry 17, 89% ee).
Then, the solvent was further screened with the use of N-Me-
Xu3 as the chiral ligand (Table 1, entries 18–22). By changing
the single solvent to a mixed solvent system (PhMe/MeOH = 1:3)
increased the ee to 92% (Table 1, entry 22). Lowering the
tempearture to 90 ºC further increased the ee to 95% (Table 1,
entry 23). The lower catalyst loading delivered a higher yield
with a lit bit lower enantioselectivity (Table 1, entry 24).
Table 1. Optimization of the reaction conditions. [a]
NMR Yield
Entry
[M]
L
Solvent
(Ee) [%]b,c
53(0)
1
2
[PdCl(ally)]2
[PdCl(ally)]2
M1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
DCE/EtOH = 3:1
MeOH
M2
80(16)
73(19)
70(27)
57(13)
78(5)
3
[PdCl(ally)]2
M3
4
[PdCl(ally)]2
M4
5
[PdCl(ally)]2
M5
6
[PdCl(ally)]2
X1
Figure 2. Screened known ligands
7
[PdCl(ally)]2
PC1
82(27)
64(51)
60(62)
60(68)
66(71)
63(55)
68(84)
72(88)
66(77)
71(88)
73(89)
70(89)
70(78)
67(86)
-
8
[PdCl(ally)]2
Xu1
9
[PdCl(ally)]2
Xu2
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
[PdCl(ally)]2
Xu3
[PdCl(ally)]2
N-Me-Xu1
N-Me-Xu2
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
N-Me-Xu3
[PdCl(ally)]2
[PdCl(ally)]2
Pd(OAc)2
Pd(TFA)2
Pd2(dab)3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
Pd2(dab)3•CHCl3
EtOH
DCE
PhMe
Scheme 2. Gram-scale synthesis of XuPhos and N-Me-XuPhos ligands.
PhMe/MeOH = 1:3
PhMe/MeOH = 1:3
85(92)
82(95)
A related but structurally novel sulfonamide monophosphine
ligands (named XuPhos and N-Me-XuPhos, respectively) were
then designed by merging the moieties of Ming-Phos with the
privileged ligand CyJohnPhos for the corresponding racemic
reaction. Notably, XuPhos and N-Me-XuPhos could be easily
24d,e Pd2(dab)3•CHCl3
PhMe/MeOH = 1:3 90f(93)
[a] Unless otherwise noted. All reactions were carried out with 0.1 mmol of 1a,
10 mol% of catalyst ([Pd] to L = 1:2.2) in 3.0 mL solvent at 100 ºC for 8-20 h.
[b] NMR yield with CH2Br2 as an internal standard. [c] Determined by chiral
HPLC. [d] At 90 ºC. [e] 5 mol% of catalyst ([Pd] to L = 1:1.5) was used. [f]
Isolated yield.
one-pot synthesized in
a gram scale starting from the
dicyclohexyl phosphine borane, that is, the deprotonation of the
dicyclohexyl phosphine borane with nBuLi, subsequent treatment
[15]
with 1,2-dibromobenzene,
then trapped by the chiral Rs-
With optimized conditions in hand, we next examined the
reaction scope of the. The effect of allyl substituents was
examined, and the results are shown in Scheme 3. Excellent
enantioselectivities (90–95%) were exclusively observed for the
new quaternary stereogenic centers generated from all of the
reactions. For example, the aryl allyl ethers bearing diverse
functional groups, such as the halogens (F, Cl), an electron-
withdrawing group (CF3, CO2Et), and electron-donating groups
(Me, OMe) at the para-position of the phenyl ring, generally
react well to furnish the corresponding products 2b–2g in good
yields with 90–95% ees. Further substrate scope investigation
demonstrated that the meta- and ortho-substituent of the phenyl
ring are also compatible to deliver the desired 2h–l in good
sulfinimines, quenched by NH4Cl aq. or MeOTf, followed by the
deprotection with Et2NH. Moderate yields and excellent
diastereoselectivity could be delivered. The structure and
absolute configuration of the ligand was finally confirmed by the
X-ray diffaction analysis of N-Me-Xu3 (Figure 3a). [16] Gratifyingly,
these XuPhos ligands were more effective for enantioselective
induction than Ming-Phos (Table 1, entries 8–10: Xu1-3, 51–
68% ees). Several N-Me-XuPhos without H-bonding site were
next examined (Table 1, entries 11–13), to our delight, N-Me-
Xu3 could give a much higher ee value (Table 1, entry 13, 84%
ee). Inspired by this result, other palladium salts such as
Pd(OAc)2, Pd(TFA)2, Pd2(dab)3 and Pd2(dab)3•CHCl3 were then
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yields with 90–93% ees. For the di- or tri-substituted phenyl ring,
the corresponding products 2m–2q were prepared in 89–96%
yields and with 92–94% ees. The phenyl could be replaced by
other aryl or heteroaryl groups such as 1-naphthyl (2r), 2-
naphthyl (2s), benzo[d][1,3]dioxol-5-yl (2t),1-pyrenyl (2u), 2-
thienyl (2v), 4-dibenzothienyl (2w) as well as 9-phenyl-9H-
carbazol-3-yl (2x), and all of them deliver the corresponding
compounds in good yields with high ees. To our delight, those
substrates with a broad range of simple, bulkyl alkyl and ether
(R1) also worked well to furnish the desired products 2y–2ae in
77–97% yields with 90–93% ees. Moreover, the reaction of 2-
aryl substrate (1af) proceed also well to produce the desired 2af
in 75% yield with 90% ee.
To illustrate the synthetic utility of this new method, a series
of enantioenriched CB2 receptor agonists[4b-d] were prepared in
70-91% yields with 91–95% ees (Scheme 5). A range of para-,
meta- and ortho-substituted benzyl (5a–5g), 1-naphthylmethyl
(5h), 2-naphthylmethyl (5i) are compatible to deliver the desired
products 6a–6i in good yields with 91–95% ees. And the alkyl
substrate 5j also worked well to furnish the desired products 6j
in 91% yield with 94% ee. Meanwhile, ent-6a, the enantiomer of
product 6a was delivered by using the ent-N-Me-Xu3 with
opposite configuration of N-Me-Xu3. To our delight, a gram-
scale reaction deliverd 1.07 g of 6a in 80% yield without loss of
enantioselectivity, indicating the present method is easy to
scale-up. It is noteworthy that the enantiopure 6a (>99% ee) can
be obtained by simple recrystallization (Et2O and n-hexane) of
the crude product. Meanwhile, the absolute configuration of the
product was confirmed by the X-ray diffaction analysis of 6a
(Figure 3b).[16]
Scheme 5. Enantioselective synthesis of a series of CB2 receptor agonists.
Scheme 3. Exploration of the effect of allyl substituents.
Scheme 6. Enantioselective synthesis of D-labeled 2,3-dihydrobenzofuran.
Deuterium labeling is of great value in the reaction
mechanistic study,[17] material science[18] and in particular,
pharmaceuticals, because the incorporation of deuterium atom
can change the absorption, distribution, and toxicological
properties of the drugs, while resist metabolic degradation in the
body and increasing the compound’s half-life.[19] An important
Scheme 4. Exploration of the effect of aryl substituents.
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Figure 3. X-ray crystal structure of N-Me-X3 and 6a.
In summary, we have developed the first highly chemo- and
enantio-selective palladium-catalyzed hydroarylation of allyl aryl
ethers for efficient construction of chiral 2,3-dihydrobenzofuran
bearing an all-carbon quaternary stereocenter through the use of
a well-designed, easily available N-Me-XuPhos ligand. In view
of the high efficiency, operational simplicity, high chemo- and
enantioselectivity, broad substrate scope, and synthetic
applications of the asymmetric synthesis of a series of CB2
receptor agonists, the present method can be expected to find
wide synthetic applications. Moreover, further applications of N-
Me-XuPhos in other transition-metal-catalyzed reactions are
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We gratefully acknowledge the funding support of NSFC
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Keywords: Novel ligand design• Hydroarylation • Palladium •
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10.1002/anie.201806372
Angewandte Chemie International Edition
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Zhan-Ming Zhang,+ Bing Xu,+ Yanyan
Qian, Lizuo Wu, Yuanqi Wu, Lujia Zhou,
Yu Liu and Junliang Zhang*
Page No. – Page No.
Palladium-Catalyzed Enantioselective
Reductive Heck Reactions:
Convenient Access to 3,3-
A highly chemo- and enantioselective intramolecular hydroarylation of allyl aryl ethers
remained a long-standing challenge. Reported herein is the first example of highly
enantioselective intramolecular hydroarylation of allyl aryl ethers via palladium-catalyzed
reductive heck reactions by utilizing a designed new chiral sulfonamide phosphine ligand
(N-Me-XuPhos).
Disubstituted 2,3-Dihydrobenzofuran
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