Enantioselective Syntheses of C2-Symmetric Pyrazolones and Diones via One-Pot Organo-/Iodine Sequential Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c02330

The catalytic diastereo- and enantioselective syntheses of C2-symmetric axially chiral 1,4-dicarbonyl derivatives with 2,3-quaternary stereocenters were achieved by utilizing an organo-/iodine binary catalytic strategy. The reactions proceeded well under

Full text of DOI:10.1021/acs.orglett.1c02330

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Letter
Enantioselective Syntheses of C2‑Symmetric Pyrazolones and Diones
via One-Pot Organo-/Iodine Sequential Catalysis
Kai-Xiang Feng, Cheng-Ke Tang, Qiao-Yu Shen, Ai-Bao Xia,* Li-Sha Huang, Zhan-Yu Zhou,
Xing Zhang, Xiao-Hua Du, and Dan-Qian Xu*
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ABSTRACT: The catalytic diastereo- and enantioselective syntheses of C2-symmetric axially chiral 1,4-dicarbonyl derivatives with
2,3-quaternary stereocenters were achieved by utilizing an organo-/iodine binary catalytic strategy. The reactions proceeded well
under mild conditions without metals or strong bases.
C2-symmetric axially chiral frameworks constitute important
structural motifs in a number of natural products and
biologically active molecules.1 Moreover, they act as core
scaffolds in many privileged organocatalysts and ligands.2
Many efforts have been devoted to the enantio- and
diastereoselective synthesis of C2-symmetric axially chiral
biaryl backbones because of the wide range of applications of
these motifs, and numerous novel and practical routes have
been established.2,3 However, to the best of our knowledge, the
catalytic enantio- and diastereoselective construction of the C2-
symmetric axially chiral alkyl skeleton with contiguous
quaternary stereocenters is more challenging and considerably
less explored than that of well-developed C2-symmetric axially
chiral biaryl architectures, likely due to the relatively low
atropisomerization barrier around the C2-symmetric axis
(Scheme 1, a).
1,4-Dicarbonyl molecules are found in a wide range of
biologically active compounds,4 and their synthetic utility has
been effectively demonstrated.5 Consequently, the enantio-
and diastereoselective syntheses of 1,4-dicarbonyl moieties
have attracted considerable attention.6 However, methods for
the catalytic asymmetric construction of C2-symmetric axially
chiral 1,4-dicarbonyl derivatives remain underdeveloped.7
Current chiral construction strategies include (1) the indirect
single-electron transfer (SET) oxidative coupling of preformed
chiral enolates, a process that generally needs a strong base and
a metal oxidant but exhibits only moderate diastereoselectivi-
ties;5b,8 (2) the direct asymmetric organocatalytic oxidative
homocoupling of aldehydes with a metal oxidant;9 (3) the
direct asymmetric homodialkylation of bisoxindoles with a
base;10 and (4) the metal-catalyzed double Michael
addition.5c,11 For example, in 2011, Thomson’s group
developed a process for the efficient CuCl2-promoted oxidative
coupling of preformed chiral lithium enolates to construct
enantioselective C2-symmetric 1,4-diketones (Scheme 1, b1).5b
In 2018, Jørgensen and co-workers presented a novel
methodology for the direct organocatalytic stereoselective
oxidative homocoupling of α-substituted aldehydes via open-
shell intermediates with Ag2CO3 as an oxidant to construct
chiral C2-symmetric 1,4-dialdehydes (Scheme 1, b2).9
However, the reported cases suffered from the multistep
preparation of chiral starting substrates, low diastereoselectivity
and/or enantioselectivity, narrow substrate scope, and require-
ment of stoichiometric amounts of strong bases and metal
oxidants. Therefore, developing general and effective catalytic
Received: July 12, 2021
https://doi.org/10.1021/acs.orglett.1c02330
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Design of Organo-/Iodine Sequential Catalysis
Table 1. Screening of Reaction Conditions
for C2-Symmetric Axially Chiral Compounds
b
c
d
entry
cat.
oxidant
solvent
yield (%) ee (%)
dr
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70
75
55
91
75
99
35
76
78
88
98
85
90
99
95
75
96
95
63
30
76
66
75
−61
−66
−83
25
−66
−82
72
85
62
84
90
85
85
90
92
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
methods to construct novel C2-symmetric axially chiral alkyl
derivatives is interesting and urgent.
3m
3n
3o
3p
3n
3n
3n
3n
Previous works have demonstrated that iodine is not only a
“metal-like” compound with mild Lewis acid characteristics but
also an efficient radical donor, and iodide can be oxidized to
molecular iodine.12 On the basis of those concepts, our group
developed an innovative organo-/iodine binary catalyst system
to synthesize structurally and stereochemically diverse spiro
compounds.13 In 2015, Bisai and co-workers developed a novel
KOtBu- and I2-promoted protocol to synthesize a structurally
diverse range of racemic dimeric 2-oxindoles with low
diastereoselectivities via SET oxidation and the radical-based
homocoupling pathway (Scheme 1, c).7c Inspired by the above
works and as a part of our ongoing research projects on
applications of organo/iodine binary catalytic strategies in
asymmetric catalysis, herein, we report the first efficient
method for the construction of C2-symmetric axially chiral
pyrazolones and diones via chiral hydrogen bonding and
molecular iodine sequential catalysis without transition metals
and strong bases (Scheme 1, d).
The designed sequential catalytic reaction of isoxazole
nitroolefin 1a and pyrazolone 2a was initially examined in
the presence of the chiral hydrogen bonding catalyst 3a,
molecular iodine, H2O2, and CH2Cl2 (Table S0).14 The
desired product 4aa was selectively obtained with 70% yield,
76% ee, and >99:1 dr (Table 1, entry 1). Given this
encouraging result, a series of squaramide, urea, and thiourea
catalysts were next tested (entries 2−16). Evidence from the
screening of the squaramide catalysts 3b−3g (entries 2−7)
showed that squaramide architectures provided 35% to 99%
yield, 25% to −83% ee, and all >99:1 dr. Urea catalysts gave
76%−99% yields and 62%−90% enantiomeric excesses with
excellent diastereoselectivities (entries 8−15). The best results
e
f
g
90
88
h
a
Reaction conditions: 1a (0.24 mmol, 1.2 equiv), 2a (0.2 mmol), and
organocatalyst 3 (4.0 mol %) in solvent (2.0 mL), r.t., 48 h; then I2
(0.1 mmol, 50 mol %), H2O2 (2.0 equiv, 30% aqueous), r.t., 3 min.
b
c
Isolated yield. Enantiomeric excess was determined through HPLC
d
1
analysis by using a Chiralcel IC-H. dr was determined through H
NMR analysis. I2 (40 mol %). I2 (30 mol %). I2 (20 mol %). I2 (10
mol %).
e
f
g
h
were achieved when the catalyst 3n, which delivered 4aa in
99% yield, >99:1 dr, and 90% ee (entry 14), was used. The
thiourea catalyst 3p was further screened and still provided 4aa
with 75% yield, 85% ee, and >99:1 dr (entry 16). Finally,
iodine loadings of 40 mol % to 10 mol % were screened
(entries 17−20). The iodine loading of 30 mol % was the
better choice and gave 4aa in 95% yield with 92% ee and >99:1
dr (entry 18).
With the optimized reaction conditions in hand, the scope of
isoxazole nitroolefins 1 and pyrazolones 2 was investigated
(Scheme 2). Different groups substituting for isoxazole
nitroolefins 1 were first examined and provided 4aa−4ar in
moderate to high yields (70%−95%) with high to excellent
enantioselectivities (84%−96% ee) and excellent diastereose-
lectivities (>99:1 dr). Electron-rich (MeO and Me) groups
B
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a
Scheme 2. Substrate Scopes for Isoxazole Nitroolefins and Pyrazolones
a
Reaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), and organocatalyst 3n (4.0 mol %) in CH2Cl2 (2.0 mL), r.t., 48 h; then I2 (0.06 mmol, 30 mol
%), H2O2 (2.0 equiv, 30% aqueous), r.t., 3 min.
a
Scheme 3. Substrate Scopes for Nitroolefins and Pyrazolones
a
Reaction conditions: 2 (0.2 mmol), 5 (0.24 mmol), and organocatalyst 3g (3.0 mol %) in CH2Cl2 (2.0 mL), r.t., 6 h; then I2 (50 mol %), H2O2
(2.0 equiv, 30% aqueous), r.t., 3 min.
(1b−1f) and electron-poor (F, Cl, Br, and NO2) groups (1g−
1o) on the phenyl group were well tolerated. Additionally, the
naphthyl-substituted isoxazole nitroolefin 1p and the heter-
oatom-substituted isoxazole nitroolefin 1q underwent the
sequential catalytic reaction to produce the desired products
4ap and 4aq in good yields (74% and 83%) with high
enantioselectivities (96% and 87% ee) and excellent diaster-
eoselectivities (>99:1 dr). Notably, in the case of the aliphatic
isoxazole nitroolefin 1r, the sequence also proceeded smoothly
to present 4ar in 78% yield with 88% ee and 99:1 dr. Next, the
generality of pyrazolones was studied. A variety of substituent
groups, such as Me, Et, Pr, and i-Pr groups, were tolerated well
at the 5-position of pyrazolones, and when the steric hindrance
of substituents increased, the yields of 4aa and 4ba−4bc
decreased slightly but still presented 90%−92% ee and >99:1
dr. Remarkably, the cyclopropyl-bearing pyrazolone was
converted into 4bd with 98% yield, 90% ee, and >99:1 dr.
Moreover, aromatic groups carrying pyrazolones at the 2-
position showed good compatibility with the organo-/iodine
sequential catalytic system to give products 4ca−4cc with
80%−87% yields, 97%−99% ee, and >99:1 dr. On the scale of
2.0 mmol, the desired product 4aa was achieved in 95% yield,
with >99:1 dr and 90% ee.14
The reactions of pyrazolones 2 and nitroolefins 5 were
further studied to evaluate the one-pot organo-/iodine
sequential catalytic system well. Having identified the best
reaction conditions (Table S1),14 the scope of various
nitroolefins 5 was investigated (Scheme 3). This asymmetric
reaction advanced smoothly to give the desired products 6.
The substrates (5a−5l) with electron-donating and electron-
withdrawing functional groups on the phenyl were well
tolerated. The desired products 6aa−6al were achieved with
72%−95% yields, 92%−99% ee, and >99:1 dr. The
disubstituted aromatic ring substrate could furnish 6am with
62% yield, 92% ee, and >99:1 dr. Notably, the reactions of 2a
with 2-naphthyl-, 2-furyl-, and 2-thienyl-substituted nitroolefins
offered 6an−6ap in 79%−95% yields with 95%−98% ee and
>99:1 dr. The stereochemistry of 6ab was assigned to (2S,
11R, 21S, 30R) by using X-ray crystallographic analysis.14
Then, the generality of pyrazolones 2 was further investigated.
The reaction proceeded efficiently with alkyl substituents (Me,
Et, Pr, and i-Pr) on the 5-position of pyrazolones, providing
C
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corresponding products 6 with high yields (87%−96%) and
excellent stereoselectivities (92%−95% ee, all >99:1 dr, 6ba−
6bc). Aryl substituents, such as Ph, 4-MeOC6H4, 4-FC6H4, and
4-BrC6H4, were tolerated at the 5-position of pyrazolones to
furnish 6bd−6bg with 80%−93% yields and excellent stereo-
selectivities (95% ee, >99:1 dr). Next, a representative range of
pyrazol-5-ones with diverse substituents (Me, F, Cl, Br, and
NO2) on the N-aryl group were tested and afforded products
6ca−6cf in 79%−97% yields with 86%−98% ee and >99:1 dr.
Moreover, the aliphatic i-Pr-substituted pyrazol-5-one provided
6cg in 84% yield with 80% ee and >99:1 dr.
iodine radical.15 The chiral environment of intermediate A-1
was retained. Finally, the intermediate A-1 rapidly underwent
radical-based homocoupling to furnish 4aa. The excellent
diastereoselectivity might be mainly attributed to the high ee
and dr values of intermediate A and the high equilibrium ratio
of the chiral diastereomer A-1 during the dimerization.
Subsequently, HI was oxidized to I2 by H2O2 for the next cycle.
In conclusion, a novel method for the one-pot catalytic
construction of C2-symmetric axially chiral alkyl skeletons via
asymmetric organo-/iodine sequential catalysis was developed.
The current transformation allowed the synthesis of C2-
symmetric axially chiral pyrazolones and diones with a broad
substrate scope with high yields (up to 99%), enantioselectiv-
ities (up to 99% ee), and excellent diastereoselectivities (up to
>99:1 dr) under mild conditions without the use of metals and
strong bases. The sequential catalytic protocol might be
conducted via Michael addition, hydrogen atom abstraction,
and then radical-based homocoupling.
Encouraged by the obtained results, the performance of the
highly challenging dicarbonyl compound 1,3-cyclohexanedione
was further investigated (Scheme 4). Delightedly, under the
Scheme 4. Substrate Scopes for Isoxazole Nitroolefins and
a
1, 3-Cyclohexanedione
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02330.
General procedures, product characterization, copies of
NMR spectra, HPLC chromatograms, and crystallo-
graphic data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 4aa−4cc, 6aa−6cg, 8aa−8ah, and A (ZIP)
a
Reaction conditions: 1 (0.45 mmol), 7 (0.3 mmol), organocatalyst
3m (10.0 mol %), and Na2CO3 (10.0 mol %) in CH2Cl2 (2.0 mL),
−5 °C, 48 h; then I2 (50 mol %), H2O2 (2.0 equiv, 30% aqueous), r.t.,
3 min.
Accession Codes
CCDC 2015866 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
optimized reaction conditions (Table S2),14 all reactions
smoothly delivered the corresponding products 8aa−8ah in
50%−70% yields with 84%−95% ee and >99:1 dr.
A proposed sequential catalysis mechanism is depicted
(Scheme 5) on the basis of the absolute configuration of the
product and the control experiments (Table S3).14 In the
organocatalytic Michael reaction, the activated pyrazolone 2a
attacked the simultaneously activated isoxazole nitroolefin 1a
from the Re-face to deliver the adduct A via the transition state
(TS). In the I2-catalyzed oxidative homocoupling step, iodine
and H2O2 produced the iodine radical; then, the stable C(sp3)-
H precursor A was transformed into an organic 3° radical A-1
intermediate through hydrogen atom abstraction by a reactive
AUTHOR INFORMATION
■
Corresponding Authors
Ai-Bao Xia − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China; orcid.org/0000-0003-0990-0470;
Email: xiaaibao@zjut.edu.cn
Dan-Qian Xu − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
Scheme 5. Proposed Reaction Mechanism
D
https://doi.org/10.1021/acs.orglett.1c02330
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China; orcid.org/0000-0003-0152-0860; Email: chrc@
zjut.edu.cn
Authors
Kai-Xiang Feng − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
Cheng-Ke Tang − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China; orcid.org/0000-0002-3685-7757
Qiao-Yu Shen − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
Li-Sha Huang − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
Zhan-Yu Zhou − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
Xing Zhang − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
Xiao-Hua Du − Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou 310014, P. R.
China
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Dimerization of 2-Oxindoles Promoted by KOtBu-I2: Total Synthesis
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financially supported by Zhejiang Key Laboratory of Green
Pesticides and Cleaner Production Technology.
■
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