Pd-Catalyzed Enantio- and Regioselective Formation of Allylic Aryl Ethers

Article abstract of DOI:10.1021/acs.orglett.7b03247

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.

Full text of DOI:10.1021/acs.orglett.7b03247

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Pd-Catalyzed Enantio- and Regioselective Formation of Allylic Aryl
Ethers
Jianing Xie,†,‡ Wusheng Guo,†,‡ Aijie Cai,† Eduardo C. Escudero-Adan,† 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
S
* Supporting Information
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.
hiral tertiary allylic aryl ethers are important building blocks
in the synthesis of natural products and biologically active
Scheme 2. Pd-Catalyzed Asymmetric Synthesis of Allylic
Scaffolds Featuring Tertiary Carbon Stereocenters
C
compounds such as Ustiloxin D, vitamin E, and products known
as peroxisome proliferator-activated receptor γ (PPARγ)
modulators (Scheme 1).1−3 The asymmetric allylic substitution
Scheme 1. Representatives of Natural Products or
Pharmaceuticals Featuring Chiral Tertiary Aryl Ether
Fragments
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).
recently reported the first regio- and enantioselective synthesis of
α,α-disubstituted allylic N-arylamines based on a Pd-catalyzed
conversion of cyclic carbonate A through a zwitterionic
intermediate B in the 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
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
Received: October 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03247
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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 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
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 °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.
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
Table 1. Selected Data for the Optimization of the Reaction
a
Conditions Towards the Enantioenriched Aryl Ether 2a
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
additive
(equiv)
temp
(°C)
t
b
c
a
entry
L, solv
(h) 2a (%)
er
Scheme 3. Scope in Phenols To Produce Aryl Ethers 2
1
2
3
4
Cs2CO3 (1) L1, THF
Cs2CO3 (2) L1, THF
Cs2CO3 (3) L1, THF
L1, THF
25
25
25
25
25
25
25
25
25
25
25
10
0
12
12
12
12
12
12
12
12
12
12
12
12
36
36
36
36
36
36
36
36
36
36
36
36
19 (53)
67.5:32.5
76:24
44 (35)
56 (18)
87:13
10
d
5
Cs2CO3 (3) L1, THF
Cs2CO3 (3) L1, DCM
Cs2CO3 (3) L1, Tol
53
88.5:11.5
6
0
7
0
8
K3PO4 (3)
K2CO3 (3)
DBU (3)
CsF (3)
L1, THF
L1, THF
L1, THF
L1, THF
0 (75)
9
36 (59)
74:26
10
11
12
13
14
15
16
17
18
19
20
21
0
50
73
76 (10)
0
74.5:25.5
91:9
Cs2CO3 (3) L1, THF
Cs2CO3 (3) L1, THF
Cs2CO3 (3) L2, THF
Cs2CO3 (3) L3, THF
Cs2CO3 (3) L4, THF
Cs2CO3 (3) L5, THF
Cs2CO3 (3) L6, THF
Cs2CO3 (3) L7, THF
Cs2CO3 (3) L8, THF
Cs2CO3 (3) L9, THF
Cs2CO3 (3) L1, THF
Cs2CO3 (3) L1, THF
Cs2CO3 (3) L1, THF
94.5:5.5
0
0
0
0
65
81
0
86:14
78:22
0
0
0
88
85
0
85:15
23:77
0
0
e
22
0
74
68
85
94:6
93:7
95:5
f
23
0
d
24
0
a
Reaction conditions unless otherwise stated: carbonate A (0.20
mmol, 1 equiv), phenol (1.5 equiv), Pd2(dba)3·CHCl3 (2 mol %),
b
a
ligand L (8 mol %), THF (0.20 mL), open to air. Isolated yield of 2a;
Reaction conditions unless stated otherwise: carbonate A (0.20
c
in brackets, the NMR yield of the linear product. Determined by
mmol), phenol partner (1.5 equiv), THF (0.30 mL), Pd2(dba)3·CHCl3
(2 mol %), L1 (8 mol %), Cs2CO3 (3 equiv), 0 °C, 36 h. Isolated
yields are reported. 60 h. 45 h.
d
e
f
HPLC. Using 0.30 mL of THF. Phenol (1.2 equiv). Pd2(dba)3·
b
c
CHCl3 (1.25 mol %), ligand L1 (5 mol %).
B
DOI: 10.1021/acs.orglett.7b03247
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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
Scheme 5. (Z)-Stereoselective Formation of the Linear Allylic
Aryl Ethers 4
a
In order to further amplify the scope of the reaction, we then
systematically varied the cyclic carbonates (Scheme 4) producing
Scheme 4. Scope in Cyclic Carbonates To Produce Allylic Aryl
a
Ethers 3
a
Reaction 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 %
b
c
for L11−L13), rt, 12 h. Determined by 1H NMR. Cs2CO3 (3 equiv)
was added. Reaction conditions for 4a−4f: carbonate (0.20 mmol),
phenol (1.5 equiv), THF (0.20 mL), Pd2(dba)3·CHCl3 (2 mol %),
L12 (8 mol), Cs2CO3 (3 equiv), rt, 12 h. Isolated yields are reported.
(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 the
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 ligand-governed
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 enantioin-
duction.
a
Reaction 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 °C, 36 h. Isolated yields are reported.
b
c
60 h. Using 0.20 mL of THF.
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 deactiva-
tion 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
X-ray diffraction of the product 3e (Scheme 4).
Encouraged by our previous success in (Z)-stereoselective
synthesis of linear allylic amines,9a we also probed the regio- and
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
C
DOI: 10.1021/acs.orglett.7b03247
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2008, 14, 5737. (h) Olson, A. C.; Overman, L. E.; Sneddon, H. F.; Ziller,
J. W. Adv. Synth. Catal. 2009, 351, 3186. (i) Trost, B. M.; Toste, F. D. J.
Am. Chem. Soc. 1998, 120, 815. (j) Austeri, M.; Linder, D.; Lacour, J.
Adv. Synth. Catal. 2010, 352, 3339. (k) Trost, B. M.; Gunzner, J. L.;
Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396. (l) Trost, B.
M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328.
(5) To the best of our knowledge, there is only one known example of
the asymmetric synthesis of tertiary allylic aryl ethers through phenol
nucleophilic substitution. However, this protocol has quite limited
scope, see ref 2a. Controlling the regioselectivity in allylic substitution
with phenols is challenging, see: (a) Goux, C.; Massacret, M.; Lhoste, P.;
Sinou, D. Organometallics 1995, 14, 4585. (b) Trost, B. M.; Toste, F. D.
J. Am. Chem. Soc. 1999, 121, 4545.
(6) For asymmetric synthesis of allylic tertiary alkyl ethers through
allylic substitution with alcohol nucleophiles: (a) Trost, B. M.;
McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702.
(b) Trost, B. M.; Brown, B. S.; McEachern, E. J.; Kuhn, O. Chem. - Eur. J.
2003, 9, 4442. (c) Khan, A.; Khan, S.; Khan, I.; Zhao, C.; Mao, Y.; Chen,
Y.; Zhang, Y. J. J. Am. Chem. Soc. 2017, 139, 10733.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03247.
■
S
Experimental details and spectra for new products (PDF)
Accession Codes
CCDC 1585738 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akleij@iciq.es.
ORCID
(7) Continuous endeavors have been devoted to develop new methods
for the asymmetric synthesis of tertiary aryl ethers, please see, for
example: (a) Forbeck, E. M.; Evans, C. D.; Gilleran, J. A.; Li, P.; Joullie,
́
Wusheng Guo: 0000-0001-5259-3600
Arjan W. Kleij: 0000-0002-7402-4764
Author Contributions
‡These authors contributed equally to this work.
Notes
M. M. J. Am. Chem. Soc. 2007, 129, 14463. (b) Woiwode, T. F.; Rose, C.;
Wandless, T. J. J. Org. Chem. 1998, 63, 9594. (c) Shibatomi, K.;
Kotozaki, M.; Sasaki, N.; Fujisawa, I.; Iwasa, S. Chem. - Eur. J. 2015, 21,
́
14095. (d) Li, P.; Forbeck, E. M.; Evans, C. D.; Joullie, M. M. Org. Lett.
2006, 8, 5105. (e) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org.
Chem. 1998, 63, 9594.
(8) For seminal work using vinyl cyclic carbonates in synthetic
chemistry: Bando, T.; Harayama, H.; Fukazawa, Y.; Shiro, M.; Fugami,
K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1994, 59, 1465.
(9) Selected recent examples including contributions from our
research group: (a) Guo, W.; Martínez-Rodríguez, L.; Kuniyil, R.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Cerca program/Generalitat de Catalunya, ICREA,
and the Spanish Ministerio de Economıa y Competitividad
■
́
Martin, E.; Escudero-Adan
Soc. 2016, 138, 11970. (b) Guo, W.; Martínez-Rodríguez, L.; Martín, E.;
Escudero-Adan, E. C.; Kleij, A. W. Angew. Chem., Int. Ed. 2016, 55,
́
, E. C.; Maseras, F.; Kleij, A. W. J. Am. Chem.
(MINECO) through projects CTQ-2014-60419-R, and the
Severo Ochoa Excellence Accreditation 2014−2018 through
project SEV-2013-0319. We acknowledge the analytical
assistance (HPLC) from the CTAE unit from ICIQ. J.X. thanks
the CSC (2016-06200061) for a predoctoral fellowship.
́
11037. (c) Khan, A.; Zheng, R.; Kan, Y.; Ye, J.; Xing, J.; Zhang, Y. J.
Angew. Chem., Int. Ed. 2014, 53, 6439. (d) Ohmatsu, K.; Imagawa, N.;
Ooi, T. Nat. Chem. 2014, 6, 47. (e) Wang, H.; Lorion, M. M.;
Ackermann, L. ACS Catal. 2017, 7, 3430. (f) Gom
́
ez, J. E.; Guo, W.;
Kleij, A. W. Org. Lett. 2016, 18, 6042.
REFERENCES
■
(10) Cai, A.; Guo, W.; Martínez-Rodríguez, L.; Kleij, A. W. J. Am.
Chem. Soc. 2016, 138, 14194.
(11) (a) Kumar, N.; Leray, I.; Depauw, A. Coord. Chem. Rev. 2016, 310,
1. (b) Awual, M. R.; Yaita, T.; Miyazaki, Y.; Matsumura, D.; Shiwaku, H.;
Taguchi, T. Sci. Rep. 2016, 6, 19937.
(1) For the total synthesis of Ustiloxin D using an allylic tertiary aryl
ether as intermediate: Sawayama, A. M.; Tanaka, H.; Wandless, T. J. J.
Org. Chem. 2004, 69, 8810.
(2) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074.
(b) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain, C. J. Am.
Chem. Soc. 2004, 126, 11966. (c) Trost, B. M.; Shen, H. C.; Dong, L.;
Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276. (d) Trost, B. M.;
Asakawa, N. Synthesis 1999, 1999, 1491. (e) Trost, B. M. J. Org. Chem.
2004, 69, 5813.
(3) Enantioenriched derivatives of tertiary (allylic) aryl ethers are
frequently encountered in pharmaceuticals or used as important
building blocks in synthesis, see: (a) Trost, B. M.; Crawley, M. L.
Chem. Rev. 2003, 103, 2921. Original contributions: (b) Cao, B.; Park,
(12) Hydrogen bond assistance should also be considered, please refer
to ref 9a and ref 10.
(13) Alkali metal cations have strong affinity for oxygen donors, see for
example ref 11.
(14) Enantioenriched chromanes are important fragments in many
drugs and natural products such as vitamin E, Clusifoliol, Siccanin, and
Calanolide A; see ref 2.
(15) The S-containing substrates have the potential to poison the Pd-
catalyst and typically require higher reaction temperatures, see ref 9f.
(16) Enantioenriched compounds with 1,3-benzodioxole fragments
are of interest in pharmaceutical development: Bloom, J. D.; Dutia, M.
D.; Johnson, B. D.; Wissner, A.; Burns, M. G.; Largis, E. E.; Dolan, J. A.;
Claus, T. H. J. Med. Chem. 1992, 35, 3081.
́
H.; Joullie, M. M. J. Am. Chem. Soc. 2002, 124, 520. (c) Tanaka, H.;
Sawayama, A. M.; Wandless, T. J. J. Am. Chem. Soc. 2003, 125, 6864.
(d) Mizuguchi, E.; Achiwa, K. Chem. Pharm. Bull. 1997, 45, 1209.
(e) Pochetti, G.; Mitro, N.; Lavecchia, A.; Gilardi, F.; Besker, N.; Scotti,
E.; Aschi, M.; Re, N.; Fracchiolla, G.; Laghezza, A.; Tortorella, P.;
Montanari, R.; Novellino, E.; Mazza, F.; Crestani, M.; Loiodice, F. J.
Med. Chem. 2010, 53, 4354.
(17) In the presence of L12, the likely formation of the more
nucleophilic CsOPh species further facilitates catalytic turnover.
(4) For the asymmetric synthesis of secondary allylic aryl ethers and
related chemistry, see, for example: (a) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 2000, 122, 11262. (b) Trost, B. M.; Tang, W. J. Am. Chem.
Soc. 2002, 124, 14542. (c) Onitsuka, K.; Okuda, H.; Sasai, H. Adv. Synth.
Catal. 2008, 47, 1454. (d) Kirsch, S. F.; Overman, L. E.; White, N. S. Org.
Lett. 2007, 9, 911. (e) Kim, D.; Reddy, S.; Singh, O. V.; Lee, J. S.; Kong,
S. B.; Han, H. Org. Lett. 2013, 15, 512. (f) Trivedi, R.; Tunge, J. A. Org.
Lett. 2009, 11, 5650. (g) Austeri, M.; Linder, D.; Lacour, J. Chem. - Eur. J.
D
DOI: 10.1021/acs.orglett.7b03247
Org. Lett. XXXX, XXX, XXX−XXX