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Pd-Catalyzed Enantio- and Regioselective Formation of Allylic Aryl
Ethers
Jianing Xie,†,‡ Wusheng Guo,†,‡ Aijie Cai,† Eduardo C. Escudero-Adán,† and Arjan W. Kleij*,†,§
†

Institute of Chemical Research of Catalonia (ICIQ), the Barcelona Institute of Science and Technology, Av. Països Catalans
16, 43007 – Tarragona, Spain
§
Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 – Barcelona, Spain
Supporting Information Placeholder

ABSTRACT: A general methodology for the synthesis of enantioenriched tertiary allylic aryl ethers through Pd-catalyzed decarboxylative reactions of vinyl cyclic carbonates and phenols is presented. Switching of the regioselectivity toward the formation of linear
products by a judicious choice of the ligand is also reported.

Chiral tertiary allylic aryl ethers are important building blocks
in the synthesis of natural products and biologically active compounds such as Ustiloxin D, Vitamin E and products known as
peroxisome proliferator-activated receptor γ (PPAR) modulators (Scheme 1).1-3 The asymmetric allylic substitution with
phenols as nucleophiles represents the most versatile and
straightforward method toward the synthesis of sterically hindered tertiary allylic aryl ethers. The synthesis of enantioenriched secondary allylic aryl ethers through phenol nucleophilic
substitution has been well-established.4 However, the regioselective synthesis of sterically congested tertiary allylic aryl
ethers featuring a tertiary carbon stereocenter through allylic
substitution is still a huge challenge.5-7 Seminal work from Trost
illustrated the use of an intramolecular strategy2a-d to give rise
to the desired aryl ethers, avoiding the formation of regioisomers, though only focused on the preparation of chromanes and
with limitations in substitution diversity (Scheme 2, eq 1).
Scheme 1. Representatives of Natural Products or Pharmaceuticals Featuring Chiral Tertiary Aryl Ether Fragments

Transition-metal-catalyzed decarboxylative transformation
of vinyl cyclic carbonates has proven to be a versatile method
toward the formation of various allylic scaffolds. 8,9 Our group
recently reported the first regio- and enantioselective synthesis
of α,α-disubstituted allylic N-arylamines based on a Pd-catalyzed

Table 1. Selected Data for the Optimization of the Reaction
Conditions towards the Enantioenriched Aryl Ether 2aa
Scheme 2. Pd-Catalyzed Asymmetric Synthesis of Allylic
Scaffolds Featuring Tertiary Carbon Stereocenters

cationic species,11 we envisaged that, in the presence of a phosphoramidite ligand, the presence of suitable metal cations
would help to direct the nucleophilic attack toward the internal
carbon center of the Pd-allyl intermediate C rather than the less
hindered terminal one (Scheme 2, eq 3).12

Scheme 3. The Scope in Phenols to Produce Aryl Ethers 2a

entry

additive
(equiv)

L, solv

temp

t

2a

(o C)

(h)

erc

(%)b

1

Cs2CO3 (1)

L1, THF

25

12

19 (53)

67.5:32.5

2

Cs2CO3 (2)

L1, THF

25

12

44 (35)

76:24

3

Cs2CO3 (3)

L1, THF

25

12

56 (18)

87:13

4

-

L1, THF

25

12

10

-

5d

Cs2CO3 (3)

L1, THF

25

12

53

88.5:11.5

6

Cs2CO3 (3)

L1, DCM

25

12

0

-

7

Cs2CO3 (3)

L1, Tol

25

12

0

-

8

K3PO4 (3)

L1, THF

25

12

0 (75)

-

9

K2CO3 (3)

L1, THF

25

12

36 (59)

74:26

10

DBU (3)

L1, THF

25

12

0

-

11

CsF (3)

L1, THF

25

12

50

74.5:25.5

12

Cs2CO3 (3)

L1, THF

10

12

73

91:9

13

Cs2CO3 (3)

L1, THF

0

36

76 (10)

94.5:5.5

14

Cs2CO3 (3)

L2, THF

0

36

0

-

15

Cs2CO3 (3)

L3, THF

0

36

0

-

16

Cs2CO3 (3)

L4, THF

0

36

65

86:14

17

Cs2CO3 (3)

L5, THF

0

36

81

78:22

18

Cs2CO3 (3)

L6, THF

0

36

0

-

19

Cs2CO3 (3)

L7, THF

0

36

88

85:15

20

Cs2CO3 (3)

L8, THF

0

36

85

23:77

21

Cs2CO3 (3)

L9, THF

0

36

0

-

22e

Cs2CO3 (3)

L1, THF

0

36

74

94:6

23f

Cs2CO3 (3)

L1, THF

0

36

68

93:7

24d

Cs2CO3 (3)

L1, THF

0

36

85

95:5

a

Reaction conditions unless otherwise stated: carbonate A (0.20 mmol, 1
equiv), phenol (1.5 equiv), Pd2(dba)3·CHCl3 (2 mol %), ligand L (8 mol %),
THF (0.20 mL), open to air. bIsolated yield of 2a, in brackets the NMR yield
of the linear product. cDetermined by HPLC. dUsing 0.30 mL of THF.
e
Phenol (1.2 equiv). fPd2(dba)3•CHCl3 (1.25 mol %), ligand L1 (5 mol %).

conversion of cyclic carbonate A through a zwitterionic intermediate B in presence of phosphoramidite ligand L1 (Scheme
2, eq 2, path a, L1 inset in Scheme 2).10 We expected that the
synthesis of enantioenriched tertiary aryl ether 2a would be feasible by changing the nucleophile from aniline to phenol under
the similar reaction conditions; thus, the reaction of carbonate
A and phenol was performed, but unfortunately only 25% of the
aryl ether 2a was isolated. Notably, substantial amount of undesired linear product (Scheme 2, eq 2, path b) was formed.
Considering the strong interaction between oxygen and metal

aReaction

conditions unless stated otherwise: carbonate A (0.20
mmol), phenol partner (1.5 equiv), THF (0.30 mL),
Pd2(dba)3•CHCl3 (2 mol %), L1 (8 mol %), Cs2CO3 (3 equiv), 0 oC,
36 h. Isolated yields are reported. b60 h. c45 h.

In order to check our working hypothesis, we chose the reaction of cyclic carbonate A and phenol as a model reaction (Table
1). Cs2CO3 was first examined as the metal cation source with
the use of L1 (inset in Scheme 2).13 We were pleased to find
that the addition of three equivalents of Cs2CO3 led to appreciable product formation (2a, 56% yield) with an er of 87:13 (Table 1, entries 1‒3). The control reaction in the absence of
Cs2CO3 only gave rise to 10% of product, suggesting the crucial
role of the Cs salt (Table 1, entry 4). The reactions performed
at lower concentration or the use of other solvents/potassium
salts13 did not improve the results significantly (Table 1, entries
5‒9). No reaction was observed in the presence of DBU suggesting that basicity is probably not a key parameter (Table 1,
entry 10). The use of CsF (Table 1, entry 11) showed a similar
outcome (cf., entry 3) further confirming the key role of the Cs
cation in this reaction.13 Lowering the reaction temperature to 0
o
C significantly improved the yield (76%) and enantioselectivity (Table 1, entries 12‒13, er = 94.5:5.5) despite the requirement of longer reaction times. The attempt to improve the enantioselectivity with other phosphoramidite ligands L2‒L9 was
not successful (Table 1, entries 14‒21). A lower amount of phenol (Table 1, entry 22) or catalyst loading (Table 1, entry 23)
gave slightly inferior results. Performing the reaction under diluted conditions gave 2a in 85% yield with an er of 95:5 (Table

1, entry 24), and these optimized reaction conditions were then
applied to investigate the scope of these allylic etherifications.

Scheme 5. (Z)-Stereoselective Formation of the Linear Allylic Aryl Ethers 4a

Scheme 4. The Scope in Cyclic Carbonates to Produce Allylic Aryl Ethers 3a

aReaction

aReaction

conditions unless stated otherwise: carbonate (0.20
mmol), phenol (1.5 equiv), THF (0.30 mL), Pd2(dba)3•CHCl3 (2
mol %), L1 (8 mol %), Cs2CO3 (3 equiv), 0 oC, 36 h. Isolated yields
are reported. b60 h. cUsing 0.20 mL of THF.

Various substituted phenols proved to be suitable reaction
partners to produce a range of allylic tertiary aryl ethers 2
(Scheme 3) in good yields and appreciable enantioinduction
(generally er >90:10). Various para-substitutions on the phenol
reagents including electron –withdrawing and –donating groups
were endorsed, and meta- (2i-2k, 2m, 2n) and ortho-substituted
phenols (2l, 2o) also showed good reactivity. It is worth noting
that the introduction of two vinyl fragments in the aryl ether
product is feasible as exemplified by the successful isolation of
product 2o; this kind of product has potential in the synthesis of
highly functionalized enantioenriched chromanes through olefin metathesis reactions.14
In order to further amplify the scope of the reaction, we then
systematically varied the cyclic carbonates (Scheme 4) producing allylic aryl ethers 3. Various aromatic substituents in the vinyl cyclic carbonate, including those having para- or meta-substitutions, were tolerated. The sulfur-containing substrate allowed to produce compound 3e without noticeable deactivation
of the palladium catalyst (see also product 2h).15 The aryl ether
with bulky naphthyl group (3c, 3d) could be obtained through
requiring longer reaction times. The methyl-substituted cyclic
carbonate also proved to be reactive albeit with lower enantioselectivity (3k), while the bulky cyclohexyl–substituted carbonate showed no reactivity. The installation of a heterocycle
in the aryl ether was feasible (3m),16 whereas attempts to install
substituents on the vinyl group failed (3n). The absolute configuration of these tertiary aryl ethers (S) was deduced by the Xray diffraction of the product 3e (Scheme 4).

conditions for the optimization toward linear aryl ether
4a: carbonate A (0.20 mmol), phenol (1.5 equiv), THF (0.20 mL),
Pd2(dba)3•CHCl3 (2 mol %), L (4 mol % for L10 and L14; 8 mol
% for L11-L13), rt, 12 h. bDetermined by 1H NMR. cCs2CO3 (3
equiv) was added. Reaction conditions for 4a-4f: carbonate (0.20
mmol), phenol (1.5 equiv), THF (0.20 mL), Pd 2(dba)3•CHCl3 (2
mol %), L12 (8 mol ), Cs2CO3 (3 equiv), rt, 12 h. Isolated yields
are reported.

Encouraged by our previous success in (Z)-stereoselective
synthesis of linear allylic amines,9a we also probed the regioand stereoselective synthesis of highly functionalized linear allylic aryl ethers through a six-membered palladacyclic intermediate9a in the presence of suitable ligand. We first chose the reaction of phenol and cyclic carbonate A in THF at rt as a model
reaction (Scheme 5). The use of L10 led to an appreciable yield
of the linear product 4a (57%) while the branched product 2a
was not observed (Table in Scheme 5). Further screening of ligands (L11-L14) suggested that L12 is the best ligand for the
selective formation of linear allylic aryl ether 4a (88% yield).
In contrast, only a small amount of the branched product 2a
(<9%) was observed suggesting that a judicious choice of the
ligand is crucial to control the regioselectivity. Interestingly, the
formation of branched product was further suppressed by the
addition of Cs2CO3 and the yield of the linear product was improved to 98% indicating a subtle role of Cs2CO3 in this ligandgoverned process.17 It is worth noting that the use of ligands
L10‒L14 gave rise to product 4a with excellent stereoselectivity (Z/E >99:1), while the stereoselectivity in linear allylic
amine formation strongly depended on the ligand utilized indicating the different reactivity of anilines and phenols.9a With the
conditions optimized, the formation of linear allylic aryl ethers
4b‒f was then investigated (Scheme 5) and showed in all cases
good yields and excellent stereoselectivity. The (Z)-configuration of all the linear products was supported by 1H-selective 1D
NOESY NMR analysis (see SI for details).
In summary, we here present a general method for the synthesis of otherwise synthetically challenging enantioenriched tertiary allylic aryl ethers through Pd-catalyzed decarboxylative

reaction of vinyl cyclic carbonate and phenol type nucleophiles.
The addition of Cs2CO3 proved to be crucial toward the formation of sterically hindered branched products. A judicious
choice of the ligand switches the regioselectivity toward the (Z)stereoselective formation of highly functionalized linear products. This mild protocol is characterized by a fair scope in reaction partners, overall good yields and appreciable enantio-induction.

 ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxx.
Experimental details and spectra for new products (PDF),
X-ray data for compound 3e (CIF)

 AUTHOR INFORMATION
Corresponding Author
* akleij@iciq.es

Author Contributions
‡These

authors contributed equally to this work.

ORCID
Wusheng Guo: 0000-0001-5259-3600
Arjan W. Kleij: 0000-0002-7402-4764
Notes

The authors declare no competing financial interest.

 ACKNOWLEDGMENT
We thank the Cerca program/Generalitat de Catalunya, ICREA,
and the Spanish Ministerio de Economía y Competitividad
(MINECO) through projects CTQ-2014–60419-R, and the Severo
Ochoa Excellence Accreditation 2014–2018 through project SEV2013–0319. We acknowledge the analytical assistance (HPLC)
from the CTAE unit from ICIQ. J.X thanks the CSC (201606200061) for a predoctoral fellowship.

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