Enantioselective Palladium-Catalyzed Decarboxylative Allylation of β-Keto Esters Assisted by a Thiourea

Article abstract of DOI:10.1055/s-0036-1590869

Enantioselective intramolecular decarboxylative allylation of β-keto esters catalyzed by a palladium bis(phosphine)-thiourea complex is reported. This procedure is not only effective for β-keto esters, but also effective for β-keto amides. An intermolecular variant of the asymmetric decarboxylative allylation is also established. DFT calculations indicate that an outer-sphere mechanism is viable for the decarboxylative allylation of β-keto esters.

Full text of DOI:10.1055/s-0036-1590869

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
H. Qian et al.
Letter
Synlett
Enantioselective Palladium-Catalyzed Decarboxylative Allylation
of β-Keto Esters Assisted by a Thiourea
O
Hua Qian ‡
O
O
O
O
O
Guoxian Gu ‡
Qinghai Zhou
Jiaxiang Lu
X
X
12 examples
Pd2(dba)3 (2.5 mol%)
ZhaoPhos (6.25 mol%)
up to 92% yield
up to 89% ee
Lung Wa Chung*
Xumu Zhang*
(X = OR, NR2)
K2CO3
CH2Cl2
O
O
O
O
Department of Chemistry, South University of Science and
Technology of China, 1088 Xueyuan Blvd, Nanshan District,
Shenzhen, Guangdong 518055, P. R. of China
oscarchung@sustc.edu.cn
OEt
6 examples
OEt
+
Ar
OCO2Me
Ar
zhangxm@sustc.edu.cn
up to 83% yield
up to 78% ee
‡ These two authors contributed equally to this work
Received: 16.06.2017
O
Accepted after revision: 18.07.2017
Published online: 22.08.2017
DOI: 10.1055/s-0036-1590869; Art ID: st-2017-w0477-l
O
O
Pd2(dba)3 (2.5 mol%)
L (6.25 mol%)
O
O
O
OEt
OEt
Abstract Enantioselective intramolecular decarboxylative allylation of
β-keto esters catalyzed by a palladium bis(phosphine)-thiourea com-
plex is reported. This procedure is not only effective for β-keto esters,
but also effective for β-keto amides. An intermolecular variant of the
asymmetric decarboxylative allylation is also established. DFT calcula-
tions indicate that an outer-sphere mechanism is viable for the decar-
boxylative allylation of β-keto esters.
1a
2a
L = (S)-t-BuPHOX, THF, r.t., 2 h, 89% yield, 24% ee
L = L8, hexane/toluene, 30 °C, 48 h, 70% ee
OMe
Key words asymmetric synthesis, β-keto esters, decarboxylative al-
lylation, thioureas, palladium catalysis
O
t-Bu
L8, Ar = 4-F3CC6H4
PAr2
N
The enantioselective formation of all-carbon quaternary
stereocenters remains an interesting but challenging topic
in synthetic organic chemistry.1 For the past two decades,
transition-metal-catalyzed decarboxylative asymmetric al-
lylation of prochiral enolates (the Tsuji allylation reaction)
has emerged as a powerful tool for the synthesis of enantio-
enriched quaternary stereocenters.2
Scheme 1 Enantioselective allylation of β-keto esters developed by Stoltz
Although tremendous efforts have been devoted to the
development of the Tsuji allylation reaction,3–8 the intramo-
lecular decarboxylative asymmetric allylation of β-keto es-
ters remains problematic.9 For example, the Stoltz group re-
ported an elegant example of a palladium-catalyzed proto-
col for the asymmetric Tsuji allylation;9a however, this
allylation reaction was primarily effective for the allylation
of unstabilized ketone enolates. For the allylation of stabi-
lized allyl enol carbonates such as 1a, the ee of the allyla-
tion product 2a was only 24% (Scheme 1). Later, the ee of 2a
was improved to 70% through high-throughput screening of
ligands and solvents.9c Nevertheless, new methods are still
needed for enantioselective intramolecular decarboxylative
allylation of β-keto esters.10
The combination of a transition-metal catalyst and an
organocatalyst through a covalent bond into one bifunc-
tional molecule provides unprecedented opportunities to
achieve challenging transformations.11 Recently, we have
discovered that bis(phosphine)-thiourea (ZhaoPhos) ligated
metal complexes efficiently catalyzed the asymmetric hy-
drogenation of imines and pyridines,12 nitroalkenes,13 α,β-
unsaturated compounds,14 and maleic acid derivatives.15
The hydrogen bonding between the substrate and the
thiourea moiety of the ligand was believed to be crucial for
achieving high enantioselectivity. As part of our continued
effort to extend the application of ZhaoPhos, we propose
that this bis(phosphine)-thiourea ligand can also promote
the enantioselective allylation of β-keto esters (Figure 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
H. Qian et al.
Letter
Synlett
Herein, we report the enantioselective allylation of β-keto
esters catalyzed by a palladium(0) bis(phosphine)-thiourea
complex.
the solvent, whereas the ee of 2a turned out to be negligible
(Table 1, entry 1). Addition of one equivalent of K2CO3 to the
reaction solution proved to be beneficial to the enantiose-
lectivity (32% ee; entry 2). Subsequently, different solvents
were screened for the allylation of 1a. Ethereal solvents
such as THF and 1,2-dimethoxyethane (DME) provided 2a
with 83% ee (entries 3 and 4). Diethyl ether, methyl tert-bu-
tyl ether (MTBE) and 1,4-dioxane gave 2a with low enan-
tioselectivity (25–73% ee; entries 5–7). Use of toluene as
the solvent formed the desired product 2a in 44% ee
(entry 8). Halogenated solvents were also tested and CH2Cl2
turned out to be the choice of solvent, providing 2a with
89% ee (entry 9). Polar solvents such as ethanol, acetoni-
trile, and ethyl acetate gave 2a with low ee (15–66%; entries
13–15). Among the bases examined, K3PO4 gave an ee com-
parable to that with K2CO3 (entry 16). Triethylamine and
BSA did not promote the reaction at all (entries 18 and 19).
The addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
or 1,4-diazabicyclo[2.2.2]octane (DABCO) as base gave 2a
with 84% ee (entries 20 and 21). Overall, these experiments
demonstrated that the use of CH2Cl2 as the solvent and
K2CO3 as the base provided the best results (92% yield, 89%
ee; entry 9).
F3C
CF3
S
N
H
N
O
H
O
O
PPh2
Pd
Fe
PPh2
Figure 1 Proposed interaction of a β-keto ester with Pd-ZhaoPhos
We commenced our study by examining substrate 1a as
a model substrate catalyzed by a 1:2.5 mixture of Pd2(dba)3
(2.5 mol %) and ZhaoPhos in various solvents at room tem-
perature. Substrates 1a–l can be synthesized by deprotona-
tion of β-keto esters with potassium tert-butoxide in tetra-
hydrofuran (THF) at room temperature followed by nucleo-
philic substitution with allyl chloroformate. Initially,
ethereal solvents and halogenated solvents were tested, but
no or trace amount of product 2a was formed. Full conver-
sion was achieved by using nonpolar solvent n-hexane as
Table 1 Screening of Solvents and Basesa
F3C
CF3
O
S
O
O
Pd2(dba)3 (2.5 mol%)
ZhaoPhos (6.25 mol%)
NH
O
O
O
OEt
NH
OEt
base (1 equiv)
PPh2
PPh2
solvent, r.t., 24 h
Fe
1a
2a
(ZhaoPhos)
Entry
Solvent
Base
Yield (%)b
ee (%)c
1
2
n-hexane
n-hexane
THF
none
67
78
95
92
87
81
97
94
92
84
84
81
71
2
32
83
83
73
68
25
44
89
86
84
84
15
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
3
4
DME
5
Et2O
6
MTBE
7
1,4-dioxane
toluene
8
9
CH2Cl2
10
11
12
13
DCE
DCE/THF (1:1)
DCE/DME (1:1)
EtOH
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
H. Qian et al.
Letter
Synlett
Table 1 (continued)
Entry
Solvent
Base
Yield (%)b
ee (%)c
14
15
16
17
18
19
20
21
MeCN
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
K2CO3
K2CO3
K3PO4
TBD
63
48
90
66
82
88
61
42
BSA
N.R.
N.R.
68
N.A.
N. A.
84
Et3N
DBU
DABCO
71
84
a Reaction conditions: substrate 0.30 mmol, Pd2(dba)3 (0.0075 mmol), ZhaoPhos (0.019 mmol), solvent (5 mL), base (0.30 mmol), r.t., 24 h. TBD = 1,5,7-Triaza-
bicyclo-[4.4.0]dec-5-ene. BSA = N,O-Bis(trimethylsilyl)acetamide. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. DABCO = 1,4-Diazobicyclo(2.2.2)octane. N.R. = no
reaction. N.A.= not available.
b Isolated yield.
c The ee was determined by HPLC using a chiral stationary phase.
O
O
Y
O
Pd2(dba)3 (2.5 mol%)
ZhaoPhos (6.25 mol%)
With the optimized conditions in hand, we sought to
study the substrate scope.16 As summarized in Scheme 2,
substrates containing a six-membered ring with ester func-
tionality such as ethyl (2a), methyl (2b), benzyl (2c), and
isopropyl (2d) esters provided the products in good yield
with high enantioselectivity (88–89% ee). When the ester
functionality was changed to phenyl ester, 82% ee was
achieved for the desired allylation product (2f). However,
when the ester group was switched to tert-butyl ester, the
ee of the desired product (2e) turned out to be negligible. In
addition, β-keto esters containing a five-membered ring
(2g) or a seven-membered ring (2h) provided the allylation
product with low enantioselectivity. Meanwhile, the incor-
poration of a heteroatom such as nitrogen (2i) and sulfur
(2j) into the cyclohexanone ring had a detrimental effect on
the ee of the allylation product. Substrate containing a te-
tralone moiety (2k) provided the desired product with di-
minished ee (57%) under the optimized conditions. Finally,
β-keto amide worked well for the asymmetric decarboxyl-
ative allylation reaction, rendering the allylation product 2l
in 57% yield and 88% ee.
O
O
Y
O
X
X
K2CO3 (1 equiv)
CH2Cl2, r.t., 24 h
n
n
1
2
X = OR, NR2
n = 0, 1, 2
Y = CH2, S, NPh
O
O
O
O
O
O
OBn
OEt
OMe
2a
2b
2c
92% yield
89% ee
86% yield
88% ee
86% yield
88% ee
O
O
O
O
O
O
OPh
O
O
2d
2e
2f
86% yield
89% ee
83% yieldc
4 % ee
73% yield
82% ee
O
O
O
O
O
O
OEt
OEt
OBn
We also sought to study the intermolecular decarboxyl-
ative asymmetric allylation of β-keto esters.17,18 To this end,
treatment of ethyl 2-cyclohexanonecarboxylate (3; 1.2
equiv) and cinnamyl methyl carbonate (4a; 1 equiv) with a
catalytic amount of Pd2(dba)3 (2.5 mol%) and ZhaoPhos
(6.25 mol%) in the presence of a stoichiometric amount of
K2CO3 (1.2 equiv) in CH2Cl2 at 40 °C for 24 h provided the
desired allylation product 5 in 83% isolated yield and 76% ee
(5a; Scheme 3).19 As summarized in Scheme 3, a variety of
cinnamyl methyl carbonates were tested and moderate to
good enantioselectivities were observed. Substrates with
electron-donating substituents (4b and 4d) furnished the
products with good ee values. Electron-withdrawing (4c)
and sterically demanding (4e) substituents on the aromatic
N
Bn
2i
2g
2h
88% yield
21% ee
90% yield
3 % ee
61% yield
29% ee
O
O
O
S
O
O
O
OMe
OMe
NBn2
2j
2k
2l
57% yielda
88% ee
78% yield
42% ee
81% yield
57% ee
Scheme 2 Substrate Scope. Reagents and conditions: substrate (0.30
mmol), Pd2(dba)3 (0.0075 mmol), ZhaoPhos (0.019 mmol), solvent (5
mL), r.t. The ee was determined by HPLC using a chiral stationary phase.
a Reaction run for 48 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
H. Qian et al.
Letter
Synlett
According to previous computational studies,2b,20 the
enantioselectivity should be determined by the reductive
elimination step. A mechanistic study on the enantioselec-
tivity of this Pd-catalyzed allylation was performed by DFT
(M06) calculations. Three mechanisms were considered:
inner-sphere, outer-sphere, and three-membered-ring re-
ductive elimination pathways (see the Supporting Informa-
tion for details). TS-RE-O2-Si is the most favorable transi-
tion state for the Si-face of the enolate, which is lower in
free energy than that for the Re-face manifold via TS-RE-
O1-Re by 2.3 kcal/mol (Figure 2, and Figure X1 in the Sup-
porting Information). These computational results are in
good agreement with the experimental observations. Both
transition states can be regarded as following the outer-
sphere pathway.21 TS-RE-O2-Si is an earlier transition state
than TS-RE-O1-Re, due to the longer C–C bond forming in
the former case (2.36 Å). Furthermore, the enolate substrate
forms stronger interactions with the catalyst, and strong
stacking between the thiourea part and one phenyl on the P
ligand were found in TS-RE-O2-Si. Our distortion/interac-
tion analysis22 further supports the conclusion that larger
interaction stabilization between the substrate and catalyst
(18.3 kcal/mol) in TS-RE-O2-Si is a major factor in the ob-
served enantioselectivity.
O
O
O
O
Pd2(dba)3 (2.5 mol%)
ZhaoPhos (6.25 mol%)
OEt
OEt
Ar
Ar
OCO2Me
+
K2CO3 (1.2 equiv)
CH2Cl2, 40 °C
24 h
3 (1.2 equiv)
4 (1 equiv)
5
Ar =
Ar =
Ar =
CF3
5c
OMe
5a
83% yield
76% ee
5b
68% yield
78% ee
75% yield
42% ee
Me
Ar =
Ar =
Ar =
Me
5d
5e
5f
82% yield
78% ee
82% yield
64% ee
79% yield
73% ee
Scheme 3 Intermolecular asymmetric allylation of β-keto ester. Reagents
and conditions: substrate (0.30 mmol), Pd2(dba)3 (0.0075 mmol), Zhao-
Phos (0.019 mmol), K2CO3, solvent (1 mL), 40 °C. The ee was deter-
mined by HPLC using a chiral stationary phase.
ring led to a decrease of the enantioselectivity for the corre-
sponding products.
To gain insight into the mechanism of the intramolecu-
lar asymmetric allylation reaction, a control experiment
was conducted (Scheme 4). Subjecting 1a to a catalytic
1:2.5 mixture of Pd2(dba)3 and ZhaoPhos-Me2 (L1) in CH2Cl2
at r.t. for 24 h led to the formation of allylated product 2a in
96% isolated yield with 15% ee. This result highlights the
key role of the hydrogen bonding donor in the catalyst to
achieve high enantioselectivity.
O
O
O
Pd2(dba)3 (2.5 mol%)
L1 (6.25 mol%)
O
O
O
OEt
OEt
K2CO3 (1 equiv)
CH2Cl2, r.t., 24 h
1a
2a
96% yield
15% ee
F3C
CF3
MeS
N
N
Me
PPh2
Fe
PPh2
Figure 2 Computed structures for the most favorable reductive
elimination transition state for the Re-and Si-face of the enolate at the
M06/6-31G(d)+SDD level with relative energies and key structural pa-
rameters. The three Ph groups attached to the phosphines are simpli-
fied as green balls and hydrogen atoms on one phenyl ring linked to P
are omitted for clarity.
L1
Scheme 4 Control experiment
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
H. Qian et al.
Letter
Synlett
In summary, we have developed a new protocol for the
asymmetric allylation of β-keto esters catalyzed by a palla-
dium bis(phosphine)-thiourea complex. This protocol
works well with both β-keto esters and amides that contain
six-membered rings. An intermolecular variant of this de-
carboxylative allylation is also reported. DFT calculations
indicate that an outer-sphere mechanism is operative for
the allylation of β-keto esters. Further studies to explain the
role of K2CO3 on enantioselectivity, as well as improving the
enantioselectivity and expanding the substrate scope of the
enantioselective decarboxylative allylation, is under way in
our laboratory.
Yano, S.; Hara, S. Synthesis 2017, 49, 1295. (c) Hayashi, T.;
Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53,
113.
(9) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044. (b) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.;
Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. III
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Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2012,
134, 19050. (e) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.;
Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák,
Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.;
White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S.
C.; Stoltz, B. M. Chem. Eur. J. 2011, 17, 14199. (f) Reeves, C. M.;
Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2013,
52, 6718. (g) Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett.
2014, 16, 2314. (h) Craig, I. I R. A.; Loskot, S. A.; Mohr, J. T.;
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Funding Information
We are grateful for a start-up fund from the South University of Sci-
ence and Technology of China (to X. Zhang), and the National Natural
Science Foundation of China (21672096) (to L. W. Chung) and the
Shenzhen Science and Technology Innovation Committee
(KQTD20150717103157174) (to X. Zhang and L. W. Chung) for finan-
(10) An enantioselective Claisen rearrangement of O-allyl β-keto
esters catalyzed by thiourea has been reported, see: Uyeda, C.;
Rötheli, A. R.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2010, 49,
9753.
cial support.
N
oaitn
a
l
N
a
utra
l
S
ecin
c
e
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
6
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2
0
9
6)
(11) Dong, X.-Q.; Zhao, Q.; Li, P.; Chen, C.; Zhang, X. Org. Chem. Front.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590869.
S
u
p
p
ortioInfgrmoaitn
S
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(16) General procedure for decarboxylative allylation of β-keto
esters: A Schlenk tube containing Pd2(dba)3 (7 mg, 0.0076 mol),
ZhaoPhos (16 mg, 0.0184 mmol) and K2CO3 (42 mg, 0.30 mmol)
in degassed anhyd CH2Cl2 (5 mL) was stirred for 15 min under
Ar. Substrate (0.30 mmol) was added last. The resulting mixture
was stirred at r.t. under Ar for 24 h and was concentrated under
vacuum. The residue was then purified by chromatography
with petroleum ether/EtOAc to afford enantioenriched product.
For 2a: Yield: 58 mg (92%); colorless oil; 89% ee. 1H NMR: δ =
5.83–5.67 (m, 1 H), 5.04 (d, J = 13.3 Hz, 2 H), 4.19 (q, J = 7.1 Hz,
2 H), 2.61 (dd, J = 14.0, 6.9 Hz, 1 H), 2.47 (dt, J = 14.9, 4.3 Hz,
3 H), 2.34 (dd, J = 14.0, 7.8 Hz, 1 H), 2.07–1.97 (m, 1 H), 1.82–
1.71 (m, 3 H), 1.50–1.43 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C{1H} NMR: δ = 207.5, 171.4, 133.3, 118.2, 61.2, 60.8, 41.1,
39.3, 35.7, 27.5, 22.4, 14.1. HPLC (Daicel Chiralpak) AD-H
column; hexanes/i-PrOH = 99.5:0.5; flow rate = 0.5 mL/min; UV
detection at 210 nm): tR = 10.512 (tminor), 12.371 (tmajor) min.
(17) For selected examples on asymmetric allylation of β-keto esters
with cinnamyl acetate or cinnamyl carbonates, see: (a) Gavrilov,
K. N.; Zheglov, S. V.; Novikov, I. M.; Lugovsky, V. V.; Zimarev, V.
S.; Mikhel, I. Tetrahedron: Asymmetry 2016, 27, 1260. (b) Savoia,
D.; Alvaro, G.; Fabio, R. D.; Fiorelli, C.; Gualandi, A.; Monari, M.;
Piccinelli, F. Adv. Synth. Catal. 2006, 348, 1883. (c) Gavrilov, K.
N.; Shiryaev, A. A.; Zheglov, S. V.; Bochelyuk, M. S.; Chuchelkin,
I. V.; Tafeenko, V. A.; Chernyshev, V. V.; Zamilatskov, I. A.;
(8) For examples of asymmetric intermolecular allylation of β-keto
esters with allyl acetate, see: (a) Trost, B. M.; Radinov, R.;
Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879. (b) Yoshida, M.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
H. Qian et al.
Letter
Synlett
Mikhel, I. S. Tetrahedron Lett. 2015, 56, 4756. (d) Nemoto, T.;
Masuda, T.; Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70,
7172.
Angew. Chem. Int. Ed. 2014, 53, 6776. (c) Patil, M.; Thiel, W.
Chem. Eur. J. 2012, 18, 10408. (d) Chen, J.-P.; Peng, Q.; Lei, B.-L.;
Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc. 2011, 133, 14180.
(e) Meletis, P.; Patil, M.; Thiel, W.; Frank, W.; Braun, M. Chem.
Eur. J. 2011, 17, 11243.
(18) For asymmetric allylation of β-keto esters with cinnamyl alco-
hols, see: (a) Zhou, H.; Zhang, L.; Xu, C.; Luo, S. Angew. Chem. Int.
Ed. 2015, 54, 12645. (b) Kita, Y.; Kavthe, R. D.; Oda, H.;
Mashima, K. Angew. Chem. Int. Ed. 2016, 55, 1098.
(19) Cinnamyl methyl carbonates were the limiting reagents in the
intermolecular asymmetric allylation reaction.
(20) (a) Bai, D.-C.; Yu, F.-L.; Wang, W.-Y.; Chen, D.; Li, H.; Liu, Q.-R.;
Ding, C.-H.; Chen, B.; Hou, X.-L. Nat. Commun. 2016, 7, 11806.
(b) Huo, X.; Yang, G.; Liu, D.; Liu, Y.; Gridnev, I. D.; Zhang, W.
(21) Considering the Pd-O distance of 2.602 Å, TS-RE-O2-Si can be
classified as a quasi-outer-sphere pathway (with some inner-
sphere character).
(22) (a) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 12664. (b) Ess, D. H.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 10646.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F