Catalytic Asymmetric Three-component Hydroacyloxylation/ 1,4-Conjugate Addition of Ynamides

Article abstract of DOI:10.1002/asia.202000503

A highly enantioselective three-component hydroacyloxylation/1,4-conjugate addition of ortho-hydroxybenzyl alcohols, ynamides and carboxylic acids was developed under mild reaction conditions in the presence of a chiral N,N′-dioxide/Sc(OTf)₃ complex, which went through in situ generated ortho-quinone methides with α-acyloxyenamides, delivering a range of corresponding chiral α-acyloxyenamides derivatives containing gem(1,1)-diaryl skeletons in moderate to good yields with excellent ee values. The scale-up experiment and further derivation showed the practicality of this catalytic system. In addition, a possible catalytic cycle and transition state model was proposed to elucidate the origin of the stereoselectivity based on X-ray crystal structure of the α-acyloxyenamide intermediate and product.

Full text of DOI:10.1002/asia.202000503

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Catalytic Asymmetric Three-component Hydroacyloxylation/1,4-
Conjugate Addition of Ynamides
Authors: Xiangqiang Li, Mingyi Jiang, Tangyu Zhan, Weidi Cao, and
Xiaoming Feng
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Catalytic Asymmetric Three-component Hydroacyloxylation/1,4-
Conjugate Addition of Ynamides
Xiangqiang Li, [a] Mingyi Jiang, [a] Tangyu Zhan, [a] Weidi Cao,*[a] and Xiaoming Feng*[a]
[a]
X. Q. Li, M. Y. Jiang, T. Y. Zhan, Prof. Dr. W. D. Cao, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 (China)
Homepage: http://www.scu.edu.cn/chem_asl/
E-mail: wdcao@scu.edu.cn; xmfeng@scu.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract:
A
highly
enantioselective
three-component
hydroacyloxylation/1,4-conjugate addition of ortho-hydroxybenzyl
alcohols, ynamides and carboxylic acids was developed under mild
reaction conditions in the presence of a chiral N,N'-dioxide/Sc(OTf)3
complex, which went through in situ generated ortho-quinone methides
with α-acyloxyenamides, delivering a range of corresponding chiral
-acyloxyenamides derivatives containing gem(1,1)-diaryl skeletons
in moderate to good yields with excellent ee values. The scale-up
experiment and further derivation showed the practicality of this
catalytic system. In addition, a possible catalytic cycle and transition
state model was proposed to elucidate the origin of the
stereoselectivity based on X-ray crystal structure of the α-
acyloxyenamide intermediate and product.
Ynamide is a class of alkynes with strong polarized triple bond,[1]
which could form keteniminium dipoles to perform interesting
transformations.[2] Enantioselective catalytic reactions of
ynamides appear recently, but the few examples are limited to
two-component reactions, occurring at the α- or β-position. An
enantioselective nucleophilic β-addition of terminal ynamides to
isatins was reported by Wolf with the use of
bisoxazolidine-Cu(II) complex (Scheme 1a).[3] Ye and coworkers
established organocatalytic intramolecular α-
a chiral
hydroalkoxylation/[1,3] rearrangement of ynamide-containing
racemic alcohols (Scheme 1b),[4a] and desymmetrizing α-, or β-
cycloisomerization of prochiral 4-ynamide cyclohexanones at
high temperature (Scheme 1c)[4b]. The transformation arising at
the two sites of ynamide via three-component reactions[5] will
facilitate molecule complexity with simple experimental
procedures. The hydroacyloxylation of ynamides with carboxylic
acids provides a workable method to synthesize functionalized
α-acyloxyenamides,[6] enabling further transformations into
useful structural motifs shared by numerous biologically active
compounds. Recently, Cui group reported BF3-catalyzed three-
component addition/isomerization cascades from ynamides and
carboxylic acids, involving several types of electrophiles, such
as aldehydes,[7a] aldimines[7b] and ortho-hydroxybenzyl
alcohols.[7c] These reactions afforded amides in the presence of
20-100 mol% catalyst loading. Nevertheless, with regard to
chiral Lewis acid catalyzed asymmetric three-component
reactions of ynamides initiated by the addition of acids, such
processes are difficult due to the compete interaction of each
reactants to the catalyst metal center, including the electron-
withdrawing group at ynamides, the carboxylic acid nucleophile,
and hetero-atoms of the electrophile.
Scheme 1. Asymmetric ynamide-based reactions.
construction method is to take advantage of asymmetric 1,4-
conjugate additions to ortho-quinone methides (o-QMs), which
are a type of versatile species and can be generated in situ from
ortho-hydroxybenzyl alcohols in the presence of an acidic
catalyst.[8] In recent years, organocatalytic 1,4-conjugate
additions of different nucleophiles to o-QMs were reported, such
as boronates, indoles, and alcohols.[9] Our group accomplished
the asymmetric addition of C3-substituted indoles to o-QMs
catalyzed by chiral N,Nʹ-dioxide-metal complexes.[10] Inspired by
these works and in view to the power of chiral Lewis acid
catalysts of N,Nʹ-dioxide-metal complex, being available to
various functional groups and asymmetric catalysis, we initiate
the three-component reaction between ynesulfonamide,
carboxylic acid, and ortho-hydroxybenzyl alcohols. Herein, we
report an enantioselective hydroacyloxylation/1,4-conjugate
Chiral gem(1,1)-diaryl skeletons are prevalent in many natural
products and pharmaceuticals. A direct and effective protocol of
addition cascade in the presence of
a
chiral N,Nʹ-
dioxide/Sc(OTf)3 complex (Scheme 1d).[11] Noteworthy, the
1
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reaction affords sulfonamidopropenyl acetates as the final
product, rather than propanamide derivatives via esterification in
the presence of BF3.
(entry 7). It was worth mentioning that 4 Å MS added in this
reaction played an important role in absorbing the water to
produce ortho-quinone methides from ortho-hydroxybenzyl
alcohols, the reaction couldn’t proceed in the absence of MS
(entry 8). In addition, other representative ligands were also
explored, such as CPA, Box, and Pybox, no desired product 4a
was obtained with the decomposition of ynamide 3a (See SI for
details).
Table 1. Optimization of the reaction conditions. [a]
Table 2. Substrate scope of carboxylic acids. [a]
Entry
R
4
Yield [%]
ee [%]
Entry
Ligand
Solvent
Yield [%][b]
ee [%][c]
1
Ph
4a
4b
4c
4d
4e
4f
80
76
80
80
80
49
50
50
20
46
68
35
95
94
90
92
90
99
90
92
99
96
96
98
1
L3-PiPr2
L3-PrPr2
L3-RaPr2
L3-PiMe2
L3-PiPr3
L3-PiPr3
L3-PiPr3
L3-PiPr3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TCE
40
27
20
trace
40
52
80
0
92
80
92
-
2
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-F3CC6H4
4-MeC6H4
3-O2NC6H4
3-BrC6H4
2-BrC6H4
2-Naphthyl
2-Thiophenyl
Allyl
2
3
3
4
4
5
5
96
95
95
-
6
6
7
4g
4h
4i
7[d]
8[e]
TCE
8
TCE
9
10
11
12
4j
[a] Unless otherwise noted, all the reactions were performed with
ligand/Sc(OTf)3 (1:1, 10 mol%), 1a (0.10 mmol), 2a (0.10 mmol), 3a (0.10
mmol) and 4 Å MS(30 mg) in solvent (1.0 mL) under N2 at 35 °C for 24 hours.
[b] Isolated yield. [c] Determined by chiral HPLC analysis on a chiral stationary
phase. [d] The reaction was performed with 1a (0.12 mmol) for 72 hours. [e]
Without addition of 4 Å molecular sieve (MS).
4k
4l
[a] All the reactions were performed with L3-PiPr3/Sc(OTf)3 (1:1, 10 mol%), 1a
(0.12 mmol), 2 (0.10 mmol), 3a (0.10 mmol) and 4 Å MS (30 mg) in TCE (1.0
mL) under N2 at 35 °C for 72 hours. Isolated yield; ee value was determined
by chiral HPLC analysis on a chiral stationary phase.
We commenced the three-component hydroacyloxylation/1,4-
conjugate addition with ortho-hydroxybenzyl alcohol 1a, carboxylic
acid 2a and ynamide 3a as the model substrates to optimize the
reaction conditions. Initially, various metal salts, such as Ni(II),
Mg(II), Al(III), Sc(III), Yb(III) were screened. It was interesting to
find that only Sc(OTf)3 could promote this reaction and provide
the desired product 4a in 40% yield with 92% ee (Table 1, entry
1, see the SI for details). The examination of the chiral backbone
of N,Nʹ-dioxide ligands upon coordination with Sc(OTf)3 showed
that L-piperidine acid-derived L3-PiPr2 was superior to L-proline-
derived L3-PrPr2 and L-ramipril acid-derived L3-RaPr2 in terms of
enantioselectivity and reactivity (Table 1, entry 1 vs. entries 2
and 3). Meanwhile, the steric hindrance of amide units of the
ligands had a significant influence on the enantioselectivity and
yield. Better results (40% yield, 96% ee) were obtained when
using L3-PiPr3 with larger steric hindrance (Table 1, entry 5 vs.
entries 1 and 4). If the reaction was carried out in CHCl2CHCl2
instead of CH2Cl2, the yield could be increased to 52% with
slightly reduced ee value (Table 1, entry 6, 95% ee). To further
improve the yield, the ratio between 1a, 2a and 3a was explored.
In view of the erosion of ortho-quinone methides under acidic
conditions, the amount of 1a was increased (1a:2a:3a = 1.2:1:1)
and afforded 4a in 80% yield and 95% ee with prolonged time
With the optimized reaction conditions in hand, the substrate
scope was examined. Firstly, a series of carboxylic acids 2b–2l
were investigated. As shown in Table 2, 2b–2i bearing different
substituent groups on the phenyl ring could be transformed into
the corresponding products 4b–4i smoothly with excellent
enantioselectivities. Nevertheless, both the electronic property
and position of the substituents have a significant impact on the
yields. Generally, the benzoic acid 2b–2e with electron-
withdrawing group on the para-position of the phenyl ring gave
higher yields (76–80%) than that with electron donating group
(2f, 49% yield). With the bromo- substituent closing to the
carboxyl group, the yields decreased obviously (entry 3, 8 and 9).
Other aromatic carboxylic acids, such as 2-naphthalene formic
acid 2j and 2-thiophenoic acid 2k afforded the corresponding
products 4j and 4k in moderate yields and excellent
enantioselectivities (46–68% yields, 96% ee). Aliphatic acid 2l
was also tolerated in this reaction and showed excellent
enantioselectivity, albeit with low yield (entry 12, 35% yield, 98%
ee).
2
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Next, a range of ortho-hydroxybenzyl alcohols 1b–1e with
different halogen substituents at the 4- or 5-position of phenol
ring were investigated (Table 3), and give the corresponding
products 4m–4p in good yields and excellent ee values (70–
80% yields, 90–96% ee), however, the decreased yield and ee
value of 4q was obtained (56% yield, 85% ee) when 5-methyl
substituted 1f was used as the substrate. The ortho-
hydroxybenzyl alcohols 1g–1j bearing variety of substituents on
the phenyl ring were applicable as well and produced 4r–4u in
46–70% yields with 90–96% ee.
Encouraged by these results, we turned attention to the scope
of ynamides (Scheme 2). Switching the N-methyl group to other
aliphatic protecting groups, such as benzyl, allyl, propargyl, and
3-butenyl, the desired products 4v-4y could be obtained in
moderate yields with excellent enantioselectivities (38–58%
yields, 96–99% ee). N-methanesulfonyl protecting ynamide 3f
was also compatible in this process and afforded 4z in 46% yield
and 94% ee.
To show the synthetic utility of the methodology, a gram-scale
synthesis of 4m was performed. As shown in Scheme 3a, 1b
(3.0 mmol) reacted with 2b (2.50 mmol) and 3a (2.50 mmol)
smoothly under the optimized reaction conditions, the desired
product 4m was obtained in 77% yield (1.02 g) with 92% ee
value. Furthermore, the product 4o underwent acyl migration to
form 5 in 85% yield in the presence of dimethylaminopyridine
(DMAP) without loss of enantioselectivity. Upon treatment of 5
with KN(TMS)2 in THF, chroman-2-one 6 was furnished in good
yield and enantioselectivity (Scheme 3b, 78% yield, 90% ee).[12]
Table 3. Substrate scope of o-QMs. [a]
Entry
R1
R2
H
4
Yield [%]
84
ee [%]
92
1
2
3
4
5
6
7
8
9
5-F
5-Cl
5-Br
4-Cl
5-Me
H
4m
4n
4o
4p
4q
4r
H
72
90
H
70
90
H
80
96
H
56
85
4-Me
4-F
4-Cl
3-F
46
90
H
4s
4t
70
93
H
59
92
H
4u
48
96
[a] All the reactions were performed with L3-PiPr3/Sc(OTf)3 (1:1, 10 mol%), 1
(0.12 mmol), 2b (0.10 mmol), 3a (0.10 mmol) and 4 Å MS (30 mg) in TCE (1.0
mL) under N2 at 35 °C for 72 hours. Isolated yield; ee value was determined
by chiral HPLC analysis on a chiral stationary phase.
Scheme 2. Substrate scope of ynamides. [a]
Scheme 3. a) Gram-scale synthesis of 4m. b) Transformation of the product
4o. c) Control experiment.
To gain insight into the reaction mechanism, the control
experiment was conducted. When the pre-prepared enamide 7[12]
was subjected to react with 1a under the standard conditions, 4a
could be obtained in 67% yield and 95% ee within 24 hours,
along with the complete conversion of
suggesting the reaction involved
7
the
(Scheme 3c),
process of
hydroacyloxylation of ynamide. The reduced yield (67%)
compared with the result of AMCR process (80%) may arise
from the decomposition of 7, which exhibited the advantage of
three-component reaction under this catalytic system.
Based on these results and our previous works,[13] a plausible
reaction catalytic cycle is presented in Scheme 4. Initially, the
L3-PiPr3/Sc(OTf)3 complex coordinates with 1a and facilitates the
dehydration to give the ortho-quinone methide A. The Re face of
o-QM A is strongly shielded by the neighboring 2,4,6-triisopropyl
group of the ligand L3-PiPr3. Therefore, the acyloxyenamide B
[a] All the reactions were performed with L3-PiPr3/Sc(OTf)3 (1:1, 10 mol%), 1a
(0.12 mmol), 2b (0.10 mmol), 3 (0.10 mmol) and 4 Å MS (30 mg) in the TCE
(1.0 mL) under N2 at 35 °C for 72 h. Isolated yield; ee value was determined
by chiral HPLC analysis on a chiral stationary phase.
3
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which was formed through hydroacyloxylation of ynamide 3a
with carboxylic acid, attacks o-QM A from its Si face to afford the
intermediate C with S-configuration, subsequent intramolecular
1,5-proton shift produced the desired product 4 (path a), which
was different from the previous result that acyl migration
occurred if Sc(OTf)3 or BF3 was used (path b),[7c] indicating N,Nʹ-
dioxide ligand L3-PiPr3 played a key role in this process. The
reason is not clear at this stage, a possible explanation may be
that the larger steric hindrance of ligand L3-PiPr3 tends to allow
the migration of smaller size of proton rather than acyl group.
[3]
[4]
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Scheme 4. The proposed catalytic cycle.
In conclusion, we developed a highly catalytic asymmetric
three-component hydroacyloxylation/1,4-conjugate addition of
ortho-hydroxybenzyl alcohols, ynamides and carboxylic acids
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with
a chiral N,N'-dioxide/Sc(OTf)3 complex catalyst. This
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protocol provided a facile and efficient access to gem(1,1)-diaryl
substituted α-acyloxyenamides with a broad substrate scope
under mild reaction conditions. Furthermore, the synthetic
application was conducted to demonstrate valuable utility. A
plausible catalytic cycle and transition state were proposed to
explain the reaction mechanism. Further development of
asymmetric ynamide-based three-component reaction is
ongoing in our group.
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Acknowledgements
We appreciate the National Natural Science Foundation of
China (Nos. 21890723 and 21801174) for financial support.
Keywords: α-acyloxyenamides • asymmetric catalysis •
conjugate addition • three-component reactions • ynamide
[12] CCDC 1984972 and 1973996 (intermediate B), contains the
supplementary crystallographic data for this paper. The absolute
configuration of 6 was determined to be (1S,2S) by its analogue’s (6)
(CCDC 1984972) X-ray single-crystal analysis. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk./ data_request/cif.
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4
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
The catalytic asymmetric three-component 1,4-conjugate addition of in situ generated ortho-quinone methides with α-acyloxyenamides
derived from ynamides and carboxylic acids was achieved under mild reaction conditions by using chiral N,N'-dioxide-Sc(OTf)3
complex as catalyst, affording a variety of chiral -acyloxyenamides derivatives containing gem(1,1)-diaryl skeletons in moderate to
good yields with excellent enantioselectivities.
5
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