Asymmetric Catalytic Vinylogous Addition Reactions Initiated by Meinwald Rearrangement of Vinyl Epoxides

Article abstract of DOI:10.1002/anie.202102054

The first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N′-dioxide/Sc^III complex catalysts. The vinyl epoxides, as masked β,γ-unsaturated aldehydes, via direct vinylogous additions with isatins, 2-alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3-hydroxy-3-substituted oxindoles, α,β-unsaturated aldehydes and spiro-cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual-tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

Full text of DOI:10.1002/anie.202102054

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Asymmetric Catalysis
Hot Paper
Asymmetric Catalytic Vinylogous Addition Reactions Initiated by
Meinwald Rearrangement of Vinyl Epoxides
Jinxiu Xu, Yanji Song, Jun He, Shunxi Dong, Lili Lin, and Xiaoming Feng*
Abstract: The first catalytic asymmetric multiple vinylogous
addition reactions initiated by Meinwald rearrangement of
vinyl epoxides were realized by employing chiral N,N’-dioxide/
ScIII complex catalysts. The vinyl epoxides, as masked b,g-
unsaturated aldehydes, via direct vinylogous additions with
isatins, 2-alkenoylpyridines or methyleneindolinones, provided
a facile and efficient way for the synthesis of chiral 3-hydroxy-
3-substituted oxindoles, a,b-unsaturated aldehydes and spiro-
cyclohexene indolinones, respectively with high efficiency and
stereoselectivity. The control experiments and kinetic studies
revealed that the Lewis acid acted as dual-tasking catalyst,
controlling the initial rearrangement to match subsequent
enantioselective vinylogous addition reactions. A catalytic
cycle with a possible transition model was proposed to
illustrate the reaction mechanism.
Introduction
The chemistry of vinyl epoxides is very attractive for their
easy preparation and multifunctional reactivities in the
synthesis of various bioactive heterocyclic molecules and
natural products.[1,2] Vinyl epoxides are uniquely character-
ized by the connected reactivities of the oxirane ring and the
double bond, which are not offered by either one of them
separately. The well-developed nucleophilic ring-opening
substitutions[3] and formal cycloaddition reactions[4] (Sche-
me 1a) could go through a chiral zwitterionic metal-p-allyl
intermediate to deliver useful chiral b-substituted homoallylic
alcohols[3a–e] and heterocyclic skeletons.[4e–i,n] Besides, the
rearrangements of vinyl epoxides provide access to a number
of functionalized carbon skeletons,[2,5] among them, the
Scheme 1. Reactions about vinyl epoxides.
Meinwald rearrangement[6] has been frequently employed in
total synthesis and attracted widespread attention.[7] Through
Meinwald rearrangement (Scheme 1b), the in situ generated
a-aryl/alkyl b,g-unsaturated aldehydes could react with
nucleophiles at the aldehyde functional group to furnish
homoallylic alcohols, or could isomerize into masked dien-
olates to construct functional aldehydes via transformations
at either a-position or g-position. Several elegant works have
been reported by the Lautens group and others in exploring
their versatile reactivities.[8] To the best of our knowledge, the
catalytic asymmetric vinylogous transformations of vinyl
epoxides upon Meinwald rearrangement remain elusive.
The difficulties exist in the reaction, include: 1) the unstability
of the b,g-unsaturated aldehyde intermediate, which tend to
isomerize into more conjugated but less reactive a,b-
unsaturated aldehydes, 2) the competitive side reactions,[5j,8a]
as well as 3) the difficulty in controlling the chemoselectivity
and stereoselectivity at the same time.
[*] J. X. Xu, Y. J. Song, J. He, Prof. Dr. S. X. Dong, Prof. Dr. L. L. Lin,
Prof. Dr. X. M. Feng
The catalytic asymmetric vinylogous reaction serving as
a powerful tool to construct highly functionalized optically
pure g-functionalized a,b-unsaturated carbonyl compounds
has been widely documented in the last decades.[9] The
enolizable p-extended carbonyl and dienolsilane analogues
were frequently employed in these reactions, but for the a-
substituted b,g or a,b-unsaturated aldehydes, direct vinyl-
ogous additions have been scarcely reported for their
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102054.
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Table 1: Optimization of reaction conditions.
relatively low g-reactivity and intrinsical competition reac-
tions. Only a few successful examples by using chiral amines
catalyst through dienamine intermediates have been reported
by Melchiorre group, Chen group and others.[10] Chiral N,N’-
dioxide-metal complexes[11] developed by our group, have
been proven to be efficient in asymmetric addition reactions
and others. Combining with the unique characters of the
Meinwald rearrangement of vinyl epoxides, we conceived that
the chiral N,N’-dioxide-metal complexes acted as suitable
chiral Lewis acid to control both the Meinwald rearrange-
ment of vinyl epoxides and the subsequent transformations
(Scheme 1c). Herein, we set out to develop efficient chiral
N,N’-dioxide-metal catalytic systems for the asymmetric
Meinwald rearrangement/vinylogous cascade reactions of
vinyl epoxides with isatins, 2-alkenoylpyridines and methyl-
eneindolinones. Vinyl epoxides served as masked vinylogous
enolate species, providing a facile and efficient way for
vinylogous-aldol, vinylogous-Michael and formal [4+2] cyclo-
addition reactions. A number of a,b-unsaturated aldehyde
derivatives and cyclohexene derivatives were obtained in high
efficiency and stereoselectivities, which are truly important
motifs in valuable molecule skeletons.[9,12–13]
Entry[a]
Metal salt
Ligand
R (1)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Mg(OTf)2
Ni(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L-PetBu
L-PetBu
L-PetBu
L-PiPr3
L-PePr3
L-PrPr3
L-PrCy3
L-PrCy3
L-PrCy3
L-PrCy3
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Bn (1b)
Trityl (1c)
Trityl (1c)
trace
23
47
49
61
71
92
95
96
–
2
30
30
21
42
75
87
98
98
9
10[d]
96
Results and Discussion
[a] Unless otherwise noted, all reactions were carried out with metal salt/
ligand (10 mol%, 1.0/1.0), 1 (0.10 mmol) and 2a (3.0 equiv) in THF
(1.0 mL) at 358C for 16 h. [b] Yield of the isolated 3. [c] Determined by
HPLC analysis on a chiral stationary phase. [d] 2a (1.5 equiv), Sc(OTf)3/
L-PrCy3 (2.5 mol%), reacted at 508C for 17 h. Bn=Benzyl, Trityl=Tri-
phenylmethyl, THF=Tetrahydrofuran.
In the initial studies, the Meinwald rearrangement/vinyl-
ogous aldol cascade reaction of isatin 1a with vinyl epoxide
2a was used as model reaction to optimize the reaction
conditions (Table 1). Firstly, various metal salts combined
with N,N’-dioxide L-PetBu were tested in THF at 358C
(entries 1–3). It showed that the complexes of Mg(OTf)2 or
Ni(OTf)2 gave extremely low yields and ee. The complex of
Sc(OTf)3 gave 3-hydroxy-3-substituted oxindole 3a in 47%
yield with 30% ee (entry 3). The low yields are due to the
unproductive loss of 2a, while 1a could be recovered. Then,
the structure of the chiral N,N’-dioxide ligands by coordinat-
ing with Sc(OTf)3 was evaluated (entries 4–7). It was found
that the l-proline-derived L-PrPr3 gave better results than
the l-pipecolic acid derived L-PiPr3 and l-perindopril-
derived L-PePr3 (entry 6 vs. entries 4, 5). Changing the amide
moiety to 2,4,6-cyclohexyl phenyl led to higher yield and ee
(92% yield and 75% ee; entry 7). Comparatively, when chiral
BOX, PyBOX or BINOL ligand was used as the ligand,
moderate yields but low ee values were achieved (See the
Supporting Information for details). N-Protected group (R)
of isatin 1 was another key parameter in influencing the
outcomes of this cascade reaction (entries 7–9). N-Benzyl
isatin 1b significantly improved the enantioselectivity to 87%
ee (entry 8) The more steric N-triphenylmethyl isatin 1c could
afford the 3-hydroxy-3-substituted oxindole 3c in 96% yield
with 98% ee (entry 9). The catalyst loading could be reduced
to 2.5 mol%, and the results were kept if the amount of 2a
reduced to 1.5 equivalent and the reaction temperature
increased to 508C (entry 10).
or electron-donating groups at 5, 6 or 7-positions, could be
smoothly transformed into the corresponding products (3e–
3k) in 86–99% yields with 86–98% ee. While R2 in vinyl
epoxide was phenyl, the corresponding product 3d could be
obtained in 36% yield with 97% ee. The decreased yield was
caused by the steric hindrance between two substrates. The
absolute configuration of product 3c was determined to be
(S,E) by X-ray crystallography analysis.[14]
Encouraged by aboved results, the Meinwald rearrange-
ment/vinylogous Michael reaction of 2-alkenoylpyridine 4
with vinyl epoxide 2 was examined (Scheme 3). By switching
the ligand to L-PrEt2, lowering the temperature to 108C and
adding 5 mol% 3-chlorobenzoic acid, the alkenoylpyridine
4a reacted with vinyl epoxide 2a to deliver the g-function-
alized a,b-unsaturated aldehyde 5a in moderate results.
However, when R2 was phenyl (2b), product 5b was obtained
in 82% yield with 94% ee. The addition of 3-chlorobenzoic
acid could shorten the reaction time, which might be because
it can facilitate the enolization of b,g-unsaturated aldehyde
and release the chiral Lewis acid catalyst. Then, variation of 2-
alkenoylpyridines by reacting with 2b revealed that regard-
less of the electronic nature or position of the substituents on
the b-phenyl (R3) had little effect on the enantioselectivity.
The products 5c–5e could be obtained in 92–94% ee, but
yields were influenced by the steric hindrance and electronic
nature significantly. 2-Naphthyl, 3-thienyl and 3-furyl sub-
stituted substrates were also suitable, affording 5 f–5h in 71–
With the optimized reaction conditions in hand (Table 1,
entry 10), the substrate scope of aldol cascade reactions was
evaluated (Scheme 2). A series of 3-hydroxy-3-substituted
oxindoles were obtained.[12] Isatins with electron-withdrawing
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Scheme 2. Substrate scope of the Meinwald rearrangement/vinylogous
aldol reaction. [a] Unless otherwise noted, all reactions were carried
out with Sc(OTf)3/L-PrCy3 (2.5 mol%, 1.0/1.0), 1 (0.10 mmol) and 2
(0.15 mmol) in THF (1.0 mL) at 508C. E/Z>20:1 in all cases. The
yields were the isolated product. The ee values were determined by
HPLC analysis on a chiral stationary phase. [b] 2a (0.30 mmol). [c]
17:1 E/Z. [d] 10 mol% Sc(OTf)3/L-PrCy3.
Scheme 3. Substrate scope of the Meinwald rearrangement/vinylogous
Michael reaction. [a] All reactions were carried out with Sc(OTf)3/L-
PrEt2 (10 mol%, 1.0/1.2), 3-chlorobenzoic acid (5 mol%), 4
(0.1 mmol) and 2 (0.2 mmol) in THF (1.0 mL) at 108C. E/Z>20:1 in
all cases. The yields were the isolated product. The ee values were
determined by HPLC analysis on a chiral stationary phase. [b] N-
Aminophthalimide (1.0 equiv), EtOH, reflux.
77% yields and 93–94% ee. Moreover, 2-alkenoylpyridines
bearing styryl, alkyl or ester substituent at R3 position were
also tolerated in this reaction system, delivering the products
(5i, 5j and 5k) in 65–93% yields with 90–93% ee. Addition-
ally, substrates bearing 3’-F or 5’-Br group on the pyridine ring
could also form the desired product in acceptable results (5l
and 5m). If pyridyl substituent was replaced by phenyl,
bidentate pyrazolyl or pyridine N-oxide, trace or few desired
products were detected, which indicates that the crucial factor
for the reaction is the higher reactivity caused by the electron-
withdrawing pyridine substituent rather than the bidentate
association by the catalyst (See Supporting Information for
details). The absolute configuration of 5b was assigned to be
(S,E) by X-ray analysis of the single crystal of its hydrazone
derivative 12 prepared by a condensation with N-amino-
phthalimide.[14]
Methyleneindolinones were also applied, which under-
went formal [4+2] cycloaddition reaction after the Meinwald
rearrangement, delivering spiro-cyclohexene indolinone de-
rivatives (Scheme 4). Methyleneindolinones 6 bearing elec-
tron-donating or electron-withdrawing groups at 5’,6’,7’-
positions of indolinone proceeded well to give spiro-cyclo-
hexene indolinones 7a, 7c–k in good yields with excellent d.r.
(92:8–94:6) and ee values (89–98% ee). 7b with a chloro-
substituent at 4’-position was transformed in lower yield and
ee (43% yield and 66% ee), which might be caused by the
increased steric hindrance. With regard to vinyl epoxides 2,
meta- or para-substituted aryl R2 delivered the corresponding
products 7n–7s in 77–92% yields with 91:9–94:6 d.r. and 89–
94% ee. Vinyl epoxides with ortho-substituted phenyl (7l and
7m) transformed in much lower yields. In addition, 2-
naphthyl-substituted vinyl epoxide proceed well to afford 7t
in 88% yield with 94:6 d.r. and 93% ee. Alkyl (cyclohexyl and
methyl) substituted vinyl epoxides were amenable to the
present reaction, delivered spiro-cyclohexene indolinones in
moderate results (7u and 7v). 1,2-Epoxybutene transformed
to the product 7w in 44% yield with 90:10 d.r. and 91% ee.
The absolute configuration of 7a was unambiguously deter-
mined to be (1S,2S,6S) by X-ray crystallographic analysis.[14]
To illustrate the potential synthetic utility of the current
catalytic system, gram-scale synthesis and some transforma-
tions of the products were performed (Scheme 5). The gram
scale synthesis of all the three Meinwald rearrangement/
vinylogous addition reactions performed well. Two consec-
utive reduction of 3-hydroxy-3-substituted oxindoles 3c could
afford 1,5-dihydroxy compound 8 with 74% yield. Ring
closure of 5b under basic condition produced 9 in 64% yield.
Following by a well-established Wittig reaction, the chiral 1,9-
dicarbonyl compound 10 was afforded in 74% yield. Fur-
thermore, oxidation of 7a with mCPBA generated polysub-
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Scheme 5. Gram scale synthesis and further transformations.
benzoic acid and L-PrEt2 could not solely accelerate trans-
formations of vinyl epoxide 2b. These results indicated that
N,N’-dioxide/ScIII complex could suppress the isomerization
of active b,g-unsaturated aldehyde intermediate and accel-
erate the subsequent vinylogous reaction after the Meinwald
rearrangement of vinyl epoxide. On the other hand, more
stable a-aryl a,b-unsaturated aldehyde 14 could not partic-
ipate in the following vinylogous reaction even warming the
reaction temperature to 358C (Scheme 6b).
Kinetic experiments of initial rate kinetic analysis with
reaction of 6a and 2b through the ReactIR instrument
showed first-order dependences of the reaction rate on the
concentration of both 2b and the chiral catalyst (see
Supporting Information for more details). This feature of
kinetics indicates that the process of Meinwald rearrange-
ment is involved in the rate-limiting step. However, the
correlation between the reaction rate and the concentration
of methyleneindolinone 6a showed an inverse relationship
(Scheme 6c). These data implied that the vinylogous step was
more rapid than the rearrangement of vinyl epoxide, although
the pre-coordination of methyleneindolinone 6a to the chiral
scandium(III) center might relax the promotion ability of
Sc(OTf)3/L-PrEt2 complex in the process of Meinwald
rearrangement to some extent, overwhelmed the side reac-
tions as well. In view of that the diastereoselectivity arises
from the second reaction, the chiral catalyst must also be
involved in the following addition transformation. Addition-
ally, the kinetic profile of Meinwald rearrangement/formal
[4+2] cycloaddition reaction showed a zero-order depend-
ence on 3-chlorobenzoic acid (Scheme 6c), so the role of acid
might be to facilitate the enolization of a-aryl b,g-unsaturated
Scheme 4. Substrate scope of the Meinwald rearrangement/formal
[4+2] cycloaddition reaction. [a] Unless otherwise noted, all reactions
were carried out with Sc(OTf)3/L-PrEt2(10 mol%, 1.0/1.2), 3-chloroben-
zoic acid (5 mol%), 6 (0.1 mmol) and 2 (0.2 mmol) in THF (1.0 mL)
at 108C. The yields were the isolated major diastereomer. The d.r.
values were determined by 1H NMR analysis of crude product. The ee
values were determined by HPLC analysis on a chiral stationary phase.
[b] 358C. [c] Sc(OTf)3/L-PiEt2 (10 mol%, 1.0/1.2). [d] 2 (3.0 equiv).
stituted epoxide 11 in 67% yield. All these transformations
could occur smoothly without any erosion of the enantiose-
lectivity, and with excellent diastereoselectivities.[15]
To gain insight into the mechanism of these rearrange-
ment/ vinylogous type cascade reactions, control experiments
and kinetic studies were conducted in the reaction between
methyleneindolinone 6a and vinyl epoxide 2b (Scheme 6).
Since a-aryl b,g-unsaturated aldehydes would isomerize to
more stable conjugate a,b-unsaturated aldehydes,[16] a-aryl
a,b-unsaturated aldehyde 14 which was in fact observed in the
reaction system was selected to explore influencing factors in
Meinwald rearrangement (Scheme 6a). In the presence of
1
Sc(OTf)3, 46% yield of 14 could be determined by H NMR
analysis after 10 min. While in the presence of L-PrEt2/
Sc(OTf)3 complex, the epoxide was consumed quickly but the
transformed components were complex. Besides, 3-chloro-
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Scheme 6. Control experiments and kinetic studies.
aldehyde 13 and release the chiral Lewis acid catalyst for the
second cycle. Furthermore, a linear relationship between the
ee of ligand L-PrEt2 and product 7a was found (see
Supporting Information for more details), implying that
enantiodetermining active catalyst was likely a mono-chiral
N,N’-dioxide-scandium complex.
Based on the above analysis, determination of the
absolute configuration of the products and previous stud-
ies,[8,9,17,18] a possible catalytic cycle with a transition-state
tion. Next, the catalyst-bonded a,b-unsaturated carbonyl
compound 6a and dienolate would occur g-addition reaction.
The dienolate prefers to attack 6a from its b-Si-face (TS-1)
because the Re-face was strongly blocked by the nearby aryl
ring of L-PrEt2. Next, diastereoselective intramolecular
addition reaction performs via TS-2 to yield the desired
product 7a.
mode was proposed (Scheme 7). First, the chiral N,N’-dioxide Conclusion
L-PrEt2 and metal salt coordinated in situ to form chiral metal
complex [Sc*]. Then, with the assistance of [Sc*], vinyl
epoxide 2b smoothly went through Meinwald rearrangement
to form a-aryl b,g-unsaturated aldehyde 13, then isomerized
to its dienolate intermediate Int. with the assistance of acid,
releasing the chiral [Sc*] to undergo enantioselective reac-
The first catalytic asymmetric multiple vinylogous addi-
tion reactions initiated by Meinwald rearrangement of vinyl
epoxides were realized via employing chiral N,N’-dioxide/ScIII
complex catalysts. By reacting with isatins, 2-alkenoylpyr-
idines or methyleneindolinones, a series of chiral 3-hydroxy-
3-substituted oxindoles, a,g-difunctionalized a,b-unsaturated
aldehydes and spiro-cyclohexene indolinones were observed
in good yields with excellent enantioselectivities and diaste-
reoselectivities. Kinetic studies suggested that the process of
Meinwald rearrangement is involved in the rate-limiting step.
The Lewis acid acts as dual-tasking catalyst, controlling the
initial rearrangement step to match subsequent enantioselec-
tive vinylogous addition reactions. Further investigations on
other type reactions of vinyl epoxides are underway.
Acknowledgements
We appreciate the National Natural Science Foundation of
China (No. 21890723 and 21871188) for financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · Meinwald rearrangement ·
Scheme 7. The proposed reaction mechanism.
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[14] Deposition Numbers 2016129 (for 3c), 1997722 (for 7a), and
2031626 (for 12) contain the supplementary crystallographic
data for this paper. These data are provided free of charge by the
joint Cambridge Crystallographic Data Centre and Fachinfor-
Manuscript received: February 9, 2021
Accepted manuscript online: April 7, 2021
Version of record online: && &&
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Angewandte
Research Articles
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Research Articles
Asymmetric Catalysis
J. X. Xu, Y. J. Song, J. He, S. X. Dong,
L. L. Lin, X. M. Feng*
&&&& — &&&&
Asymmetric Catalytic Vinylogous
Addition Reactions Initiated by Meinwald
Rearrangement of Vinyl Epoxides
The first catalytic asymmetric multiple
vinylogous addition reactions initiated by
Meinwald rearrangement of vinyl epox-
ides were realized by employing chiral
N,N’-dioxide/ScIII complexes as catalysts.
Direct vinylogous additions via dienolates
of b,g-unsaturated aldehydes were real-
ized. A series of chiral a,b-unsaturated
aldehydes and spiro-cyclohexene indoli-
nones were synthesized in good yields
with excellent stereoselectivity.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
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These are not the final page numbers!