Asymmetric Catalytic Formal 1,4-Allylation of β,γ-Unsaturated α-Ketoesters: Allylboration/Oxy-Cope Rearrangement

Article abstract of DOI:10.1002/anie.201905533

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ-unsaturated α-ketoesters has been realized by employing a chiral Ni^II/N,N′-dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy-Cope rearrangement sequence, providing a facile and rapid route to γ-allyl-α-ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2-allylboration products provided insight into the mechanism of the subsequent oxy-Cope rearrangement reaction: substrate-induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition-state model is proposed as the origin of high chirality transfer during the oxy-Cope rearrangement.

Full text of DOI:10.1002/anie.201905533

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Asymmetric Catalytic Formal 1,4-Allylation of β,γ-Unsaturated α-
Ketoesters via Allylboration/Oxy-Cope Rearrangement
Authors: Qiong Tang, Kai Fu, Peiran Ruan, Shunxi Dong, Zhishan Su,
Xiaohua Liu, and Xiaoming Feng
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905533
Angew. Chem. 10.1002/ange.201905533
Link to VoR: http://dx.doi.org/10.1002/anie.201905533
http://dx.doi.org/10.1002/ange.201905533

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetric Catalytic Formal 1,4-Allylation of ,-Unsaturated -
Ketoesters via Allylboration/Oxy-Cope Rearrangement
Qiong Tang, Kai Fu, Peiran Ruan, Shunxi Dong,* Zhishan Su, Xiaohua Liu and Xiaoming Feng*
Abstract: A highly enantioselective formal conjugate allyl addition of
allylboronic acids to ,-unsaturated -ketoesters has been realized
II
by employing a chiral Ni /N,N-dioxide complex as the catalyst. This
transformation proceeded via allylboration/oxy-Cope rearrangement
tandem process, providing a facile and rapid route to -allyl--
ketoesters with moderate to good yields (65–92%) and excellent ee
values (90–99% ee). The isolation of 1,2-allylboration products
enabled us to get insight into the mechanism of subsequent oxy-
Cope rearrangement reaction: substrate-induced chiral transfer and
chiral Lewis acid accelerated process. Based on the experimental
investigations and DFT calculations, a rare boat-like transition-state
model was proposed to elucidate the origin of high chirality transfer
during the oxy-Cope rearrangement.
Introduction
Transition-metal-catalyzed conjugate addition of allylic metal
reagents to ,-unsaturated carbonyl compounds is one of the
most powerful methods for constructing new C-C bonds.[1]
Asymmetric 1,4-allylation are much less developed, although
racemic version[2-8] of such process has been accomplished with
allylsilicon,[2] allyltin,[3] allylcopper,[4] allyltantalum,[5] allylbarium,[6]
allylindium[7] and others[8] for many years. The challenging
problem was to control both regio- (1,2 or 1,4 addition of
electrophiles; - or -addition of allylic reagents) and
stereoselectivity of the reaction. In this context, Snapper
developed copper(II)-catalyzed enantioselective Hosomi–
Sakurai conjugate silylallylation of cyclic unsaturated ketoesters
(Scheme 1a).[9] Our group reported catalytic asymmetric
conjugate allylation of coumarins with tetraallyltin.[10] However,
only simple allyl reagents without substituents were investigated
in these cases.
Benefit from bench stability and high selectivity exhibited in a
range of reactions, allylboron species have been widely used in
modern organic synthesis.[11] Morken and co-workers described
the first example of asymmetric catalytic conjugate allylation of
allylboronic acid pinacol ester to dialkylidene ketones with the
use of either Ni(0) or Pd(0) complex as the catalyst (Scheme
1b).[12] In 2016, the Hoveyda group established a catalytic
enantioselective conjugate addition of alkylidene malonates with
in-situ generated (pin)B-substituted allylcopper compounds
(Scheme 1c).[13] The formation of allyl metal species and metal-
 complexation might be the key to deliver -selective 1,4-
Scheme 1. Conjugate allyl addition of unsaturated carbonyl compounds.
addition products. On the other hand, allylboronic acid and their
ester typically undergo -addition with aldehydes, ketones and
imines to afford homoallylic alcohols and amines.[14-16] In pi
[17]
wo
wherein they reported a direct allylation of
quinones with allylboronates probably via allylation/oxy-Cope
rearrangement[18]/oxidation sequence, we envisioned that this
protocol was potentially used in the enantioselective formal
conjugate allylation of unsaturated carbonyl compounds. As
depicted in Scheme 1d, if asymmetric 1,2-allylboration of enone
is realized, the chirality transfer of allylation product 3 could
afford enantioenriched 1,4-allylation product 4 in a subsequent
oxy-Cope rearrangement[18-19] through a well-defined cyclic
transition state. Herein, we wish to disclose our effort alone this
line. Chiral Lewis acid catalyst of NiII/N,N-dioxide complex[20]
was found to be highly efficient for the titled reaction, supplying
-allyl--ketoesters with moderate to good yields (65–92%) and
excellent ee values (90–99% ee) and E-selectivity. Moreover,
1,2-allylboration products could also be isolated in high yields
and diastereo- and enantioselectivities, which enabled us to
probe the detailed reaction pathway of oxy-Cope rearrangement.
[*]
Q. Tang, Dr. K. Fu, P. R. Ruan, Prof. Dr. S. X. Dong, Prof. Dr. Z. S.
Su, Prof. Dr. X. H. Liu, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu
610064 (China)
E-mail: dongs@scu.edu.cn; xmfeng@scu.edu.cn
Homepage: http://chem.scu.edu.cn/chem-asl/
Results and Discussion
At the outset of this study, we chose methyl (E)-2-oxy-4-
phenylbut-3-enoate (1a) and (E)-[3-(4-methoxyphenyl)allyl]-
boronic acid (2a) as the model substrates to optimize the
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
reaction conditions (Table 1).[21] Firstly, a variety of metal salts
combined with L3-PiPr2 were tested in DCM at 35 C (entries
1–5). It was found that many typically Lewis acids, except
Cu(OTf)2, could promote the reaction, among which Ni(OTf)2
provided very promising results, giving the formal 1,4-allylation
product -allyl--ketoester 4aa in 48% yield with 71% ee (entry
5). Encouraged by these results, various chiral N,N-dioxide
ligands coordinating with Ni(OTf)2 were evaluated (entries 5–
10). Compared with L3-PiPr2 derived from S-pipecolinic acid, L-
proline-derived L3-PrPr2 and L-ramipril-based L3-RaPr2
displayed a higher activity, yielding the desired product with
85% and 86% yields, respectively (entry 5 vs entries 6 and
the efficiency of other N,N-dioxide ligands derived from L-
ramipril were further screened (entries 8–10). It was found that
the amide units of the ligands showed an appreciable influence
on both reactivity and enantioselectivity. With less sterically
constrained amide (L3-RaEt2 or L3-RaPh), both yields and ee
values decreased dramatically (entries 8–9). Meanwhile, upon
changing the ligand to slightly sterically encumbered L3-RaPr3,
no better result was achieved (84% yield and 62% ee; entry 10).
With Ni(OTf)2/L3-RaPr2 as the catalyst, we set out to further
optimize other reaction parameters. Surprisingly, performing the
reaction at 0 C mainly provided -selective 1,2-allylboration
product 3aa. To our delight, 3aa could convert to 4aa smoothly
7).[22] Since L3-RaPr2 was superior in terms of enantioselectivity, with a higher enantioselectivity (92% ee) when the reaction
mixture was stirred at 35 C for a period of 48 h (entry 11).
Notably, further lowering the temperature to 20 C, the 1,2-
allylboration product 3aa was exclusively formed, and no
Table 1. Optimization of the reaction conditions.[a]
rearrangement product 4aa was detected. Transformation of 3aa
was conducted at 35 C for 48 h, supplying -allyl--ketoester
4aa with as high as 95% ee in 86% yield (entry 12). It should be
noted that the rearrangement process could be shortened to 12
h when the second step was performed at 80 C and 1,2-
dicholorethane was used as the solvent, equally good
enantiomeric excess (96% ee) and slightly lower yield (79% vs
86%) was obtained (entry 13). The absolute configurations of
allylboration product 3aa and formal allyl conjugate addition
product 4aa were determined to be (2R,3S)-3aa and (S,E)-4aa
respectively by X-ray crystallographic analysis.[23]
With the optimized reaction conditions (Table 1, entry 12) in
hand, the substrate scope was evaluated (Table 2). Firstly, a
Entry
1
Metal salt
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
Mg(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ligand
L3-PiPr2
L3-PiPr2
L3-PiPr2
L3-PiPr2
L3-PiPr2
L3-PrPr2
L3-RaPr2
L3-RaEt2
L3-RaPh
L3-RaPr3
L3-RaPr2
L3-RaPr2
L3-RaPr2
Yield (%)[b]
ee (%)[c]
--
range of ,-unsaturated -ketoesters 1 were examined with allyl
boronic acid 2a. The substrates regardless of electronic nature
and the position of substituents at the aromatic ring were
compatible in current system (entries 1–22), affording the
corresponding products in moderate to good yields (65–92%)
with high to excellent enantioselectivities (90–99% ee).
Generally, the -aryl substituted unsaturated -ketoesters with
substituent at the ortho-position of the aromatic ring gave better
enantioselectivities, while yields ranged from 71-86% (entries 1–
6). Besides, heteroaromatic substituted 1g and 1n, as well as
ring-condensed substituted 1h were also suitable substrates,
offering the desired products 4ga, 4na and 4ha in 71–84% yield
with high ee values (93-99% ee, entries 7, 8 and 15). More
sterically hindered 2,6-dichloro-substituted substrate 1i provided
a slightly lower yield and enantioselectivity (65% yield and 90%
ee, entry 9). The steric hindrance and electronic properties
resulting from the incorporation at the meta- and para-positions
of the aromatic ring on the keto esters had a very limited effect
on the efficiency of the reaction. Good yields (67–92%) with
excellent enantioselectivities (92–99% ee) were obtained
(entries 10–23). Notably, the catalytic system was also suitable
for -alkenyl substituted 1w, affording the expected 1,4-addition
product 4wa in 68% yield with 97% ee (entry 24). The aliphatic
substrate 1y was investigated as well, however, only 1,2-
allylboration product 3ya was obtained in 70% yield, 82:18 d.r.
and 76% ee for major diastereomers (entry 25). Moreover,
heating the solution of compound 3ya in toluene at higher
temperature (110 C) did not lead to the desired rearrangement
product and the starting material 3ya was recovered.
trace
80
53
41
48
85
86
57
56
84
83
86
79
2
0
3
13
58
71
65
84
34
21
62
92
95
96
4
5
6
7
8
9
10
11[d]
12[e]
13[f]
[a] All reactions were carried out with metal salt/ligand (1:1, 10 mol%), 1a
(0.10 mmol), 2a (0.15 mmol) in DCM (0.5 mL) at 35 C for 48 h. [b] Yield of
isolated product 4aa. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Stirred at 0 C for 60 h and then at 35 C for another 48 h. [e]
Stirred at 20 C for 72 h and then at 35 C for another 48 h. [f] Stirred at
20 C for 72 h in DCE and then at 80 C for 12 h. Abbreviation: PMP =
para-methoxyphenyl, DCM = dichloromethane. DCE = dichloromethane
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 2. Substrate scope with ,-unsaturated--ketoesters 1.[a]
Entry
1
1: R1
4
Yield (%)[b]
86
ee (%)[c]
95 (S,E)
98
1a: C6H5
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
2
1b: 2-FC6H4
1c: 2-ClC6H4
1d: 2-F3CC6H4
1e: 2-MeC6H4
1f: 2-MeOC6H4
1g: 2-thienyl
1h: 2-naphthyl
1i: 2,6-Cl2C6H3
1j: 3-FC6H4
83
3
76
98
Scheme 2. Substrate scope with respect to the allyl boronic acids.
4
74
98
5
71
97
adducts 4kb-4ke (66–86% yields and 96–99% ee). It was
noteworthy that the terminal substituted allyl groups in the
products were E-configuration. However, when (E)-dec-2-en-1-
ylboronic acid (2f) was used as the substrate, only 1,2-
allylboration product 3kf (99% yield, 89:11 d.r. and 96% ee for
major diastereomers) was obtained even at an elevated
temperature (70 C) in DCE. We also performed the oxy-Cope
rearrangement of 3kf in toluene at a higher temperature (120 C)
however, no reaction occurred and the starting material 3kf was
recovered. Moreover, the addition of KH (2 equiv) or KHMDS (2
equiv) didn t promote the anionic oxy-Cope rearrangement of
3kf. It seems that the aromatic substituted group at -position of
allylboronic acid is crucial for the oxy-Cope rearrangement.
6
86
97
7
72
97
8
84
99
9
65
90
10
11
12
14
15
16
17
18
19
20
21
22
4ja
84
99
1k: 3-ClC6H4
1l: 3-F3CC6H4
1m: 3-MeOC6H4
1n: 3-thienyl
1o: 3,4-Cl2C6H3
1p: 4-FC6H4
1q: 4-ClC6H4
1r: 4-BrC6H4
1s: 4-F3CC6H4
1t: 4-MeC6H4
1u: 4-PhC6H4
4ka
4la
92
97
76
97
4ma
4na
4oa
4pa
4qa
4ra
4sa
4ta
4ua
88
98
71
93
Table 3. Representative substrates of the 1,2-allylboration reaction.[a]
83
98
74
98
85
99
74
99
entry
1: R1
3
Yield (%)[b]
d.r.
ee (%)[c]
97
90
97
1
2
3
4
5
6
1a: C6H5
3aa
3ca
3ha
3ka
3qa
3ta
93
86
89
99
87
93
97:3
98:2
95:5
96:4
96:4
98:2
84
97
1c: 2-ClC6H4
1h: 2-naphthyl
1k: 3-ClC6H4
1q: 4-ClC6H4
1t: 4-MeC6H4
97
80
93
97
23
4va
67
92
1v:
98
24
4wa
3ya
68
70
97
76
1w:
98
25[d]
1y: cyclohexyl
97
[a] All reactions were carried out with Ni(OTf)2/L3-RaPr2 (1:1, 10 mol%), 1
(0.10 mmol), 2a (0.15 mmol) in DCM (0.5 mL) at 20 C for 72 h and then at
35 C for 48 h. [b] Yield of isolated product. [c] Determined by HPLC analysis
on a chiral stationary phase. [d] With 82:18 d.r.
7
3va
3kb
75
89
>99:1
>99:1
97
98
1v:
8[d]
1k: 3-ClC6H4
Subsequently, substrate scope with respect to the allyl
boronic acids was examined. As depicted in Scheme 2, the
reactions proceeded smoothly with representative allyl boronic
acids 2b–2e, and good results were obtained for the conjugate
[a] All reactions were carried out with Ni(OTf)2/L3-RaPr2 (1:1, 10 mol%), 1
(0.10 mmol), 2a (0.15 mmol) in DCM (0.5 mL) at 20 C for 72 h. [b] Yield of
isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] 2b was used.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
We also investigated the generality of the 1,2-allylboration
reaction with representative substrates. As shown in Table 3,
performing the reactions at 20 C enabled us to isolate the
homoallylic alcohols 3. Excellent outcomes (75–99% yield, 95:5–
>99:1 d.r. and 97–98% ee) were obtained for all selected
substrates.
Scheme 4, the allylboration product 3aa (97:3 d.r. and 97% ee)
was isolated and subjected into different conditions. It was found
that oxy-Cope rearrangement of 3aa to 4aa occurred smoothly
at 35 C without a catalyst (condition a), and a full conversion
could be obtained after 72 h. The addition of Ni(OTf)2 could
accelerate the rearrangement (condition b). The rate was further
enhanced in the presence of Ni(OTf)2/L3-RaPr2 (60% yield after
16 h; condition c). Notably, the enantioselectivity of the
rearrangement product 4aa is as high as the starting material.
And the ee value of the remained 3aa did not change during the
reaction (for details, see SI). These results indicated that the
high degree of enantiocontrol in oxy-Cope rearrangement was
exerted by the efficient chiral transfer of 3aa, rather than dictated
by Ni(OTf)2/L3-RaPr2. In addition, we also conducted the
reaction of 3aa with 32:68 d.r. and 97% ee/0% ee. The erosion
of enantioselectivity was probably attributed to the
transformation of another two diastereomers (2R,3R) and
(2S,3S)-3aa to racemic 4aa.
Scheme 3. Gram-scale asymmetric synthesis and transformations of 4ka.
To evaluate the synthetic potential of the catalytic system,
gram-scale synthesis of 4ka was performed. ketoester 1k (5.0
mmol) reacted smoothly with 2a (7.5 mmol) under the optimized
reaction conditions, supplying the desired product 4ka in 91%
yield (1.701 g) with 98% ee (Scheme 3a). Further
transformations of 4ka were carried out. When 4ka was treated
with 1.05 equivalents of BH3•THF in the presence of (R)-Me-
CBS oxazaborolidine at 0 C, the carbonyl group was reduced
while the ester group retained, and the corresponding product
alcohol 5 was isolated in 92% yield with 96:4 d.r. and 99% ee.[24]
In contrast, when 4ka was reduced by 5 equivalents of NaBH4 in
a mixed solvent of MeOH and H2O (3:1, v/v) at 35 C, both
carbonyl groups were reduced, affording the diol product 6 in 99%
yield with 66:34 d.r. and 99% ee (for details, see SI).
Subsequent oxidation of 6 gave the aldehyde product 7 in 98%
yield with 98% ee (Scheme 3b).
Figure 1. Energy profiles for oxy-Cope rearrangement of 2R,3S-3aa.
To further understand the mechanism of the oxy-Cope
rearrangement of 3aa, DFT calculations were performed at the
B3LYP-D3(BJ)/6-311g**(SMD, CH2Cl2) theoretical level. Four
isomers of 3aa (2R,3S-3aa, 2S,3S-3aa, 2R,3R-3aa and 2S,3R-
3aa) were optimized, and the corresponding transition states in
the rearrangement reactions were located (for details, see SI).
Resulting from the repulsion from the bulky -CO2CH3 group, the
styryl moiety in 3aa preferred to be cis-arrangement with -OH
g oup with th H1…O2 i t nc of 2.350~2.368 Å (Figu 2).
For 2R,3S-3aa, the chair-like transition state (2R,3S-TS-C)
associated with (R,E)-4aa was energetically less favorable than
the boat-like transition state 2R,3S-TS-B associated with (S,E)-
4aa by 0.8 kJ mol-1 (see Figure 1). However, in order to
construct a chair-like six-member ring, 2R,3S-3aa had to rotate
C-C bond via a less stable conformer 2R,3S-3aa-I (G = 7.3
kJ/mol), which existed in a much less amount than that of more
stable 2R,3S-3aa. Additionally, the process of oxy-Cope
Scheme 4. Oxy-Cope rearrangement of compound 3aa to product 4aa.
In order to gain insight into the oxy-Cope rearrangement, a
series of control experiments were performed. As shown in
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
Asymmetry 1991, 879–880; f) M. J. Wu, C. C. Wu, P.-C. Lee,
Tetrahedron Lett. 1992, 33, 2547–2548; g) M.-J. Wu, J.-Y. Yeh,
Tetrahedron 1994, 50, 1073–1082; h) P. H. Lee, K. Lee, S.-Y. Sung, S.
Chang, J. Org. Chem. 2001, 66, 8646–8649 and references therein; i)
C. E. Davis, B. C. Duffy, R. M. Coates, J. Org. Chem. 2003, 68, 6935–
6943; j) L.-W. Xu, M.-S. Yang, H.-Y. Qiu, G.-Q. Lai, J.-X. Jiang, Synth.
Commun. 2008, 38, 1011–1019; k) J. A. Hilf, M. S. Holzwarth, S. D.
Rychnovsky, J. Org. Chem. 2016, 81, 10376–10382.
rearrangement was irreversible due to the tautomerization of the
productive diene to
a
more stable ketone ester 4aa.
Consequently, the reaction pathway via boat-like transition state
was more favorable for 2R,3S-3aa,[25-26] (for details, see SI). In
contrast, 2S,3S-3aa and 2R,3R-3aa, preferred to proceed
through generally accepted chair-like transition states (2S,3S-
TS-C) and (2R,3R-TS-C) to yield the (R,E)-4aa and (S,E)-4aa
respectively (see Figure S3).
[3]
[4]
a) A. Hosomi, H. Iguchi, M. Endo, H. Sakurai, Chem. Lett. 1979, 8,
977–980; b) D. R. Williams, R. J. Mullins, N. A. Miller, Chem. Commun.
2003, 2220–2221; c) A. M. Dumas, E. Fillion, Org. Lett. 2009, 11,
1919–1922.
Conclusion
a) H. O. House, J. M. Wilkins, J. Org. Chem. 1978, 43, 2443–2454; b) B.
H. Lipshutz, E. L. Ellsworth, S. H. Dimock, R. A. J. Smith, J. Am. Chem.
Soc. 1990, 112, 4404–4410; c) B. H. Lipshutz, C. Hackmann, J. Org.
Chem. 1994, 59, 7437–7444; d) D. R. Williams, W. S. Kissel, J. J. Li,
Tetrahedron Lett. 1998, 39, 8593–8596.
In
summary,
an
efficient
tandem
reaction
asymmetric
of ,-
allylboration/oxy-Cope
rearrangement
unsaturated -ketoesters with allylboronic acids was developed
by using a chiral NiII/N,N-dioxide complex catalyst. This protocol
provided an alternative efficient strategy for formal conjugate
allyl addition to unsaturated compounds. The corresponding
chiral -allyl--ketoester products were obtained in moderate to
good yields with excellent ee values. The intermediates,
allylboration products, could be isolated in good results as well.
In addition, a rare boat-like transition-state model was proposed
to elucidate efficient chiral transfer in the subsequent oxy-Cope
rearrangement based on the experimental investigations and
theoretical calculations. Further studies on the utility of this
method and the reaction mechanism are in progress.
[5]
a) A. Takuwa, Y. Nishigaichi, H. Iwamoto, Chem. Lett. 1991, 20, 1013–
1016; b) I. Shibata, T. Kano, N. Kanazawa, S. Fukuoka, A. Baba,
Angew. Chem. Int. Ed. 2002, 41, 1389–1392; Angew. Chem. 2002, 114,
1447–1450.
[6]
[7]
A. Yanagisawa, S. Habaue, K. Yasue, H. Yamamoto, J. Am. Chem.
Soc. 1994, 116, 6130–6141 and references therein.
a) L. Wang, X. Sun, Y. Zhang, Synth. Commun. 1998, 28, 3263–3267;
b) S. Araki, T. Horie, M. Kato, T. Hirashita, H. Yamamura, M. Kawai,
Tetrahedron Lett. 1999, 40, 2331–2334; c) P. H. Lee, H. Ahn, K. Lee,
S.-Y. Sunga, S. Kimb, Tetrahedron Lett. 2001, 42, 37–39; d) P. H. Lee,
K. Lee, S. Kim, Org. Lett. 2001, 3, 3205–3207; e) P. H. Lee, D.
Seomoon, S. Kim, K. Nagaiah, S. V. Damle, K. Lee, Synthesis 2003,
2003, 2189–2193.
[8]
For examples using other allylic reagents, see: a) T. Ooi, Y. Kondo, K.
Maruoka, Angew. Chem. Int. Ed. 1997, 36, 1183–1185; Angew. Chem.
1997, 109, 1231–1233; b) M. Hojo, H. Harada, H. Ito, A. Hosomi, Chem.
Commun. 1997, 2077–2078; c) H. M. S. Kumar, B. V. S. Reddy, P. T.
Reddy, J. B. Yadav, Tetrahedron Lett. 1999, 40, 5387–5388; d) C.
Schneider, O. Reese, Synthesis 2000, 2000, 1689–1694; e) H. Ito, T.
Nagahara, K. Ishihara, S. Saito, H. Yamamoto, Angew. Chem. Int. Ed.
2004, 43, 994–997; Angew. Chem. 2004, 116, 1012–1015; f) S. K.
Mandal, S. Jana, S. C. Roy, Tetrahedron Lett. 2005, 46, 6115–6117; g)
S. Hanessian, E. Mainetti, F. Lecomte, Org. Lett. 2006, 8, 4047–4049;
h) K.-H. Shen, J.-T. Liu, Y.-R. Wu, C.-F. Yao, Synth. Commun. 2007,
37, 3677–3687; i) M. B. Shaghafi, B. L. Kohn, E. R. Jarvo, Org. Lett.
2008, 10, 4743–4746; j) J. D. Waetzig, E. C. Swift, E. R. Jarvo,
Tetrahedron 2009, 65, 3197–3201; k) L.-M. Zhao, S.-Q. Zhang, F. Dou,
R. Sun, Org. Lett. 2013, 15, 5154–5157; l) D.-F. Li, K. Liu, Y.-X. Jiang,
Y. Gu, J.-R. Zhang, L.-M. Zhao, Org. Lett. 2018, 20, 1122–1125.
M. Shizuka, M. L. Snapper, Angew. Chem. Int. Ed. 2008, 47, 5049–
5051; Angew. Chem. 2008, 120, 5127–5129.
Experimental Section
Ni(OTf)2 (0.01 mmol), L3-RaPr2 (0.01 mmol) and ,-unsaturated--
ketoester 1 (0.10 mmol) were dissolved in 0.5 mL of DCM. The mixture
was stirred at 35 C for 30 min and then cooled to 20 C. Allyl boronic
acid 2 (0.15 mmol) was added and the reaction mixture was stirred at
20 °C for 72 h. Then, the reaction was warmed to 35 C and stirred at
this temperature for another 48 h. The reaction mixture was directly
subjected to column chromatography on silica gel and eluted with
p t ol um th ‒ th l c t t (v/v 8:1) to ffo th co pon ing
product 4.
[9]
Acknowledgements
[10] Y. L. Kuang, X. H. Liu, L. Chang, M. Wang, L. L. Lin, X. M. Feng, Org.
Lett. 2011, 13, 3814–3817.
We appreciate the National Natural Science Foundation of
China (Nos. 21772127 and 21432006) for financial support.
[11] C. Diner, K. J. Szabó, J. Am. Chem. Soc. 2017, 139, 2–14.
[12] For racemic example, see: a) J. D. Sieber, S. Liu, J. P. Morken, J. Am.
Chem. Soc. 2007, 129, 2214–2215; for asymmetric examples, see: b) J.
D. Sieber, J. P. Morken, J. Am. Chem. Soc. 2008, 130, 4978–4983; c) L.
A. Brozek, J. D. Sieber, J. P. Morken, Org. Lett. 2011, 13, 995–997.
[13] a) X. Li, F. Meng, S. Torker, Y. Shi, A. H. Hoveyda, Angew. Chem. Int.
Ed. 2016, 55, 9997–10002; Angew. Chem. 2016, 128, 10151–10156;
for other examples of conjugate allyl addition, see: b) Y. Yanagida, R.
Yazaki, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50,
7910–7914; Angew. Chem. 2011, 123, 8056–8060; c) F. Meng, X. Li, S.
Torker, Y. Shi, X. Shen, A. H. Hoveyda, Nature 2016, 537, 387–393; d)
Y. Huang, S. Torker, X. Li, J. del Pozo, A. H. Hoveyda, Angew. Chem.
Int. Ed. 2019, 58, 2685–2691; Angew. Chem. 2019, 131, 2711–2717.
[14] a) J. L. Y. Chen, H. K. Scott, M. J. Hesse, C. L. Willis, V. K. Aggarwal, J.
Am. Chem. Soc. 2013, 135, 5316–5319; b) M. Hesse, S. Essafi, C.
Keywords: ll l o onic ci • mm t ic c t l i • nic l •
ng m nt • t n m ction
[1]
For selected reviews, see: a) A. Alexakis, J. E. Bäckvall, N. Krause, O.
Pàmies, M. Diéguez, Chem. Rev. 2008, 108, 2796–2823; b) T.
Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem. Soc.
Rev. 2009, 38, 1039–1075; c) T. Thaler, P. Knochel, Angew. Chem. Int.
Ed. 2009, 48, 645–648; Angew. Chem. 2009, 121, 655–658.
[2]
a) A. Hosomi, H. Sakurai, J. Am. Chem. Soc. 1977, 99, 1673–1675; b)
G. Majetich, A. Casares, D. Chapman, M. Behnke, J. Org. Chem. 1986,
51, 1745–1753; c) M. Hayashi, T. Mukaiyama, Chem. Lett. 1987, 16,
1719–1722; d) L. F. Tietze, M. Ruther, Chem. Ber. 1990, 123, 1387–
1395; e) Y.-S. Hon, F. L. Chen, Y.-P. Huang, T.-J. Lu, Tetrahedron:
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
Watson, J. Harvey, D. Hirst, C. Willis, V. K. Aggarwal, Angew. Chem.
Int. Ed. 2014, 53, 6145–6149; Angew. Chem. 2014, 126, 6259–6263.
[15] a) R. Wada, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2004, 126, 8910–8911; b) S. Lou, P. N. Moquist, S. E. Schaus, J. Am.
Chem. Soc. 2006, 128, 12660–12661; c) M. Raducan, R. Alam, K. J.
Szabó, Angew. Chem. Int. Ed. 2012, 51, 13050–13053; Angew. Chem.
2012, 124, 13227–13230; d) Y. Cui, Y. Yamashita, S. Kobayashi, Chem.
Commun. 2012, 48, 10319–10321; e) Y. Cui, W. Li, T. Sato, Y.
Yamashita, S. Kobayashi, Adv. Synth. Catal. 2013, 355, 1193–1205; f)
J. L. Y. Chen, V. K. Aggarwal, Angew. Chem. Int. Ed. 2014, 53, 10992–
10996; Angew. Chem. 2014, 126, 11172–11176; g) R. Alam, T.
Vollgraff, L. Eriksson, K. J. Szabó, J. Am. Chem. Soc. 2015, 137,
11262–11265.
J. Guo, Y. Xia, L. L. Lin, X. M. Feng, Angew. Chem. Int. Ed. 2016, 55,
4054–4058; Angew. Chem. 2016, 128, 4122–4126; f) J. Li, L. L. Lin, B.
W. Hu, P. F. Zhou, T. Y. Huang, X. H. Liu, X. M. Feng, Angew. Chem.
Int. Ed. 2017, 56, 885–888; Angew. Chem. 2017, 129, 903–906; g) H. F.
Zheng, Y. Wang, C. R. Xu, X. Xu, L. L. Lin, X. H. Liu, X. M. Feng, Nat.
Commun. 2018, 9, 1968–1974; h) Y. H. Zhou, L. L. Lin, X. H. Liu, X. Y.
Hu, Y. Lu, X. Y. Zhang, X. M. Feng, Angew. Chem. Int. Ed. 2018, 57,
9113–9116; Angew. Chem. 2018, 130, 9251–9254; i) Y. S. Chen, S. X.
Dong, X. Xu, X. H. Liu, X. M. Feng, Angew. Chem. Int. Ed. 2018, 57,
16554–16558; Angew. Chem. 2018, 130, 16792 –16796.
[21] Firstly, allyl-Bpin was examined in the current catalytic system.
However, no reaction occurred. All the unsuccessful substrates we
tested were collected as scope limitation in SI, Page 4.
[16] For selected examples, see: a) R. Wada, T. Shibuguchi, S. Makino, K.
Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687–
7691; b) S. Lou, P. N. Moquist, S. E. Schaus, J. Am. Chem. Soc. 2007,
129, 15398–15404; c) E. M. Vieira, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2011, 133, 3332–3335; d) D. L. Silverio, S. Torker, T.
Pilyugina, E. M. Vieira, M. L. Snapper, F. Haeffner, A. H. Hoveyda,
Nature 2013, 494, 216–221; e) Q. Y. Tan, X. Q. Wang, Y. Xiong, Z. M.
Zhao, L. Li, P. Tang, M. Zhang, Angew. Chem. Int. Ed. 2017, 56, 4829–
4833; Angew. Chem. 2017, 129, 4907–4911.
[22] We do not have a clear-cut explanation for such difference in the
activity of catalysts derived from amino acids.
[23] CCDC 1893622 and 1889596 (3aa and 4aa) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[24] In sharp contrast, when (S)-Me-CBS oxazaborolidine was used, much
lower diastereoselectivity was obtained (92% yield with 99% ee and
53:47 d.r.).
[25] In ref 18k, the group of Davies described an oxy-Cope rearrangement
[17] a) H.-P. Deng, D. Wang, K. J. Szabó, J. Org. Chem. 2015, 80, 3343–
3348 and references therein. In this work, the author tried to observe
the intermediate, allylboration product by monitoring the reaction with
1H NMR, however, this attempt was proved to be fruitless. In addition,
the similar reaction had been disclosed by employing allyltin, allylnickel,
t ifluo o il l n ll l-indium species, see selected examples: (b) Y.
Naruta. J. Am. Chem. Soc. 1980, 102, 3774–3783; c) L. S. Hegedus, B.
R. Evans, D. E. Korte, E. L. Waterman, K. Sjoberg. J. Am. Chem. Soc.,
1976, 98, 3901–3909; d) E. Hagiwara, Y. Hatanaka, K.-i. Gohda, T.
Hiyama, Tetrahedron Lett. 1995, 36, 2773–2776; e) S. Araki, N.
Katsumura, Y. Butsugan, J. Organomet. Chem. 1991, 415, 7–24.
[18] For selected reviews, see: a) L. A. Paquette, Tetrahedron 1997, 53,
13971–14020; b) H. M. L. Davies, Y. Lian, Acc. Chem. Res. 2012, 45,
923–935; for selected examples of Cope rearrangement, see: c) R. J.
Felix, D. Weber, O. Gutierrez, D. J. Tantillo, M. R. Gagne, Nat. Chem.
2012, 4, 405–409; d) B. T. Parr, H. M. L. Davies, Angew. Chem. Int. Ed.
2013, 52, 10044–10047; Angew. Chem. 2013, 125, 10228–10231; e)
W.-B. Liu, N. Okamoto, E. J. Alexy, A. Y. Hong, K. Tran, B. M. Stoltz, J.
Am. Chem. Soc. 2016, 138, 5234–5237; f) X. Gao, M. Xia, C. Yuan, L.
Zhou, W. Sun, C. Li, B. Wu, D. Zhu, C. Zhang, B. Zheng, D. Wang, H.
Guo, ACS Catal. 2019, 9, 1645–1654; g) C. Apel, S. S. Hartmann, D.
Lentz, M. Christmann, Angew. Chem. Int. Ed. 2019, 58, 5075–5079;
Angew. Chem. 2019, 131, 5129–5133; for selected examples of aza-
Cope and representative Claisen rearrangement, see: h) M.
Hiersemann, Eur. J. Org. Chem. 2001, 2001, 483–491; i) B. T. Parr, Z.
Li, H. M. L. Davies, Chem. Sci. 2011, 2, 2378–2382; j) J.
Mahatthananchai, J. Kaeobamrung, J. W. Bode, ACS Catal. 2012, 2,
494–503; k) B. T. Parr, H. M. L. Davies, Nat. Commun. 2014, 5, 4455–
4466; l) B. T. Parr, H. M. L. Davies, Org. Lett. 2015, 17, 794–797; m) S.
Ri c hoff J. M i n J. Kȁ tn W. F R. P t Angew. Chem. Int.
Ed. 2018, 57, 1404–1408; Angew. Chem. 2018, 130, 1418–1422.
[19] A similar pathway was proposed by Majetich and co-workers in 1986
process of a similar compound obtained from rhodium-catalyzed
reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols.
However, chair-like T.S. rather than boat-like T.S. was proposed based
on experimental studies. A rationale for this difference is probably
attributed to the influence of configuration of the starting materials of
rearrangements.
[26] For examples involving boat-like transition-state, see: a) C. Ullenius, P.
W. Ford, J. E. Baldwin, J. Am. Chem. Soc. 1972, 94, 5910–5911; b) J.
E. Baldwin, C. Ullenius, J. Am. Chem. Soc. 1974, 96, 1542–1547; c) D.
Sperling, H.-U. Reißig, J. Fabian, Liebigs Ann. Recueil 1997, 2443–
2449.
when they reported
a conjugate allyl addition of enone using
trimethylallylsilane and fluoride catalysis, however, the subsequently
control experiment studies indicated that the 1,2-addition/anionic oxy-
Cope rearrangement mechanism was deemed unlikely, for details, see
ref. 2b.
[20] For selected reviews of N,N-dioxide, see: a) X. H. Liu, L. L. Lin, X. M.
Feng, Acc. Chem. Res. 2011, 44, 574–587; b) X. H. Liu, L. L. Lin, X. M.
Feng, Org. Chem. Front. 2014, 1, 298–302; c) X. H. Liu, H. F. Zheng, Y.
Xia, L. L. Lin, X. M. Feng, Acc. Chem. Res. 2017, 50, 2621–2631; d)X.
H. Liu, S. X. Dong, L. L. Lin, X. M. Feng, Chin. J. Chem. 2018, 36, 791–
797; for selected examples of 3,3-sigmatropic rearrangement catalyzed
by metal salt/N,N-dioxide complex, see: e) Y. B. Liu, X. H. Liu, H. P. Hu,
This article is protected by copyright. All rights reserved.

10.1002/anie.201905533
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Qiong Tang, Kai Fu, Peiran Ruan,
Shunxi Dong*, Zhishan Su, Xiaohua Liu
and Xiaoming Feng*
Page No. – Page No.
Asymmetric Catalytic Formal 1,4-
Allylation
of ,-Unsaturated
-
A
highly efficient catalytic asymmetric allylboration/oxy-Cope rearrangement
tandem reaction of ,-unsaturated -ketoesters with allylboronic acids has been
realized by employing
NiII/N,N-dioxide complex as the catalyst. This
Ketoesters via Allylboration/Oxy-
Cope Rearrangement
a
transformation provided a facile and rapid route to formal allyl conjugate addition
products chiral -allyl--ketoesters in good results.
This article is protected by copyright. All rights reserved.