Catalytic Asymmetric Addition of Diorganozinc Reagents to Pyrazole-4,5-Diones and Indoline-2,3-Diones

Article abstract of DOI:10.1002/chem.202005081

The catalytic enantioselective diorganozinc additions to cyclic diketones including pyrazolin-4,5-diones and isatins have been developed. In the presence of morpholine-containing chiral amino alcohol ligand, the corresponding chiral cyclic tertiary alcohols were produced in good to excellent yields (up to 97 %) and enantioselectivities (up to 95 % ee). The notable feature of this protocol includes its mild reaction conditions, Lewis acid additives free and broad functional group tolerance.

Full text of DOI:10.1002/chem.202005081

Communication
doi.org/10.1002/chem.202005081
Chemistry—A European Journal
&
Asymmetric Synthesis
Catalytic Asymmetric Addition of Diorganozinc Reagents to
Pyrazole-4,5-Diones and Indoline-2,3-Diones
Rong-Hui Wang,[a] Ya-Ling Li,[a] Hong-Jiao He,[a] You-Cai Xiao,*[a] and Fen-Er Chen*[a, b, c]
tions and good tolerance to many functionalities.[5] However,
Abstract: The catalytic enantioselective diorganozinc addi-
Lewis acid additives are often required for these transforma-
tions to cyclic diketones including pyrazolin-4,5-diones
tions because of the lowered reactivity of ketones
and isatins have been developed. In the presence of mor-
(Scheme 1a).[6] In addition, the substrate scope is mainly limit-
pholine-containing chiral amino alcohol ligand, the corre-
ed to acyclic ketones(Scheme 1b). Walsh’s group reported the
sponding chiral cyclic tertiary alcohols were produced in
first catalytic asymmetric addition of organozinc reagents to
good to excellent yields (up to 97%) and enantioselectivi-
cyclic ketones using bis(sulfonamide) diols as chiral ligand with
ties (up to 95% ee). The notable feature of this protocol
Ti(O-iPr)4.[7] Since then, little progress has been made in this
includes its mild reaction conditions, Lewis acid additives
area. Therefore, the development of effective protocols for the
free and broad functional group tolerance.
enantioselective diorganozinc addition to cyclic ketones is
highly desirable.
Chiral tertiary alcohols represent an important class of frame-
works which has been widely exists in a variety of natural
products and clinical pharmaceuticals.[1] Besides that, They are
also a versatile family of chiral building blocks that are found
wide application in synthetic organic chemistry.[2] Therefore, it
is of great significance to develop asymmetric new methods
for the synthesis of these compounds. In contrast to chiral sec-
ondary alcohols, the asymmetric construction of chiral tertiary
alcohols remains a great challenge in asymmetric synthesis,
due to the less reactive nature of precursors and the decreased
enantioface differentiation between the two substituents at
prochiral carbon center.[3] Nevertheless, various strategies to-
wards the synthesis of these scaffolds have been disclosed in
Scheme 1. Studies of asymmetric diorganozinc additions to aldehydes and
ketones.
the last decades. Among them, the asymmetric nucleophilic
additions to ketones using organometallic reagents represent
one of the most straightforward methods for the production
of chiral tertiary alcohols.[4] Diorganozinc reagents were consid-
Chiral pyrazolones and their derivatives are a unique class of
ered as the reagents of choice due to the mild reaction condi-
five membered heterocyclic compounds, which have been
found diverse applications in medicinal, analytical and dye
chemistry, as well as potential utility as chelating agents, pho-
tographic couplers and synthetic building blocks.[8] Great ef-
forts have been devoted to the synthesis of these structural
motifs.[9] However, the asymmetric version of these transforma-
tions, especially the use of pyrazolin-4,5-diones as a C-4 nucle-
ophile, has been rarely studied (Scheme 2a). In 2018, Enders’s
group reported the first organocatalytic Friedel–Crafts reaction
of pyrazole-4,5-diones with indoles, delivering the indolypyra-
zolone derivatives in medium to good enantioselectivies.[10]
Later on, Mukherjee’s group reported a direct organocatalytic
asymmetric vinylogous aldol reaction of allyl ketones to pyra-
zole-4,5-diones.[11] In 2019, Wu reported a copper-catalyzed
enantioselective alkynylation of pyrazole-4,5-diones with al-
kynes.[12] Very recently, Bhat’s group developed an asymmetric
[3+2] annulation between MBH carbonates derived from isatin
and pyrazole-4,5-diones.[13] Inspired by previous reports on
[a] R.-H. Wang, Dr. Y.-L. Li, H.-J. He, Prof. Y.-C. Xiao, Prof. F.-E. Chen
Sichuan Research Center for Drug Precision Industrial Technology
West China School of Pharmacy
Sichuan University
Chengdu 610041 (P. R. China)
E-mail: xiaoliguo1987@scu.edu.cn
[b] Prof. F.-E. Chen
Engineering Center of Catalysis and Synthesis for Chiral Molecules
Department of Chemistry
Fudan University
Shanghai 200433 (P. R. China)
E-mail: rfchen@fudan.edu.cn
[c] Prof. F.-E. Chen
Shanghai Engineering Center of
Industrial Asymmetric Catalysis for Chiral Drugs
Shanghai 200433 (P. R. China)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202005081.
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Table 1. Optimization of asymmetric dimethylzinc addition to pyrazole-
4,5-dione 1a.[a]
Entry
Ligand
Temp. [8C]
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8[d]
9[e]
10[e]
11
12
13
14
15[f]
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
0
0
0
0
0
0
0
0
À20
À40
0
0
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
THF
51
54
69
94
87
89
92
90
79
74
89
71
90
95
94
0
9
Scheme 2. Asymmetric transformation of pyrazolin-4,5-diones and isatins.
17
37
53
55
82
45
57
27
85
82
80
95
95
asymmetric nucleophilic addition to pyrazole-4,5-diones, we
herein described an asymmetric addition of diorganozinc re-
agents to pyrazole-4,5-diones by the use of chiral amino alco-
hol ligand for the construction of optically pure tertiary alco-
hols (Scheme 2b). In addition, we extended this methodology
to the asymmetric diorganozinc addition to isatin derivatives
(Scheme 2b).
Et2O
EA
EA
0
0
Initially, the asymmetric addition between pyrazole-4,5-dione
1a and dimethylzinc 2a was selected as the model reaction.
First, the reaction was performed with 20 mol% of diamine
ligand L1 in CH2Cl2 with 2 equivalent of Me2Zn at 08C, the de-
sired chiral tertiary alcohol product 3a could be obtained in
moderate yield and low enantioselectivity (Table 1, entry 1).
Changing the chiral ligand L1 to salen ligand L2 resulted in a
better catalytic activity and stereoselectivity (entry 2). Inspired
by the preliminary results, we turned our attention to the use
of different chiral amino alcohol ligands for chiral induction.
We observed that the reactions performed proceed smoothly
to deliver the corresponding product in good to high yields,
albeit with moderate enantioselectivities (entries 3–7). Among
the amino alcohol ligand tested, morpholine-containing ligand
L714 showed the best results in terms of yield and enantiose-
lectivity (entry 7). Meanwhile, ligand loading had obvious ef-
fects on the reaction stereoselectivity. A dramatically decreased
ee was observed with 10 mol% of ligand L7 (entry 8). Next, we
investigated the reaction temperature and it was found that
decreasing the temperature proved to be not beneficial for the
stereoselective control (entries 9–10). Finally, we examined the
effects of various solvents such as toluene, THF, Et2O and ethyl
acetate (EA), and the results indicated EA was the best solvent,
affording the desired product in 95% yield and 95% ee (en-
tries 11–14). It is important to note that reducing the amount
[a] Reaction conditions unless specified otherwise: 1a (0.1 mmol), 2a
(0.2 mmol), ligand (0.02 mmol), solvent (1.0 mL), 18 h. [b] Isolated yield.
[c] The ee values were determined by HPLC. [d] 10 mol% of ligand. [e] re-
action time is 24 h. [f] 1.5 equiv of 2a was used, 24 h.
of Me2Zn to 1.5 equivalent do not influence the yield and
enantioselectivity of this reaction (entry 15).
With the optimal reaction conditions in hand, the scope of
the enantioselective addition of diorganozinc reagents to vari-
ous pyrazole-4,5-diones 1 was explored (Scheme 3). First, the
reactions of 3-methyl pyrazole-4,5-diones with electron-donat-
ing group at 1-aryl proceeded smoothly to afford the chiral ter-
tiary alcohols 3a–3d in excellent yields (90–94%) and enantio-
selectivities (90–95%), while product 3e was obtained in lower
yield and stereoselectivity due to steric effect. In addition,
slightly lower yield and ee (3 f–3i, 88–91%, 81–88% ee) were
generated when substrates bearing electron-withdrawing
group at 1-aryl were applied. 3-ethyl pyrazole-4,5-dione with
different substituents at 1-aryl also worked well in identical re-
action conditions, affording the corresponding products 3j–3n
in up to 92% yield and 94% ee. Next, other substituents at C3-
position of pyrazole-4,5-dione 1 such as isopropyl, tert-butyl
and phenyl were examined, giving the corresponding prod-
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Scheme 3. Substrate scope of the asymmetric diorganozinc additions to pyr-
azole-4,5-dione 1. Reaction conditions: 0.2 mmol of 1, 1.5 equiv of 2,
20 mol% of L7, EA, 08C, 12–24 h.
Scheme 4. Substrate scope of the asymmetric dimethylzinc additions to N-
substituted isatin 4. Reaction conditions: 0.2 mmol of 4, 2.0 equiv of 2,
20 mol% of ent-L7, DCM, À408C, 20–36 h.
ucts 3o–3q in high yields (89–95%) and enantioselectivities
(80–88%). Furthermore, alkyl analogues at C1-position were
also tolerated in this reaction, although a relatively low ee
were obtained (3r-3u, 82–90%, 83–86% ee). Finally, we tested
the Et2Zn addition to prochiral ketone 1. To our delight, the
desired tertiary alcohols 3v–3x bearing ethyl group could be
obtained in moderated yield and enantioselectivity. Our re-
peated attempts to use other diorganozinc reagents were un-
successful, only very low enantioselectivity could be generated
(see details in Supporting Information). The chiral tertiary alco-
hols were assigned to the S-configuration, based on the X-ray
analysis of the single crystal of product 3a.
To further demonstrate the synthetic utility of this methodol-
ogy, we extended the substrate scope to the synthesis of 3-
substituted-3-hydroxy-2-oxindoles, which is present in various
natural products and biological compounds.[15] Arundaphine,
convolutamydine C, maremycin B and paratunamide D are rep-
resentative examples of a growing list of bioactive natural pro-
ducts.[15d] Especially, there are few methods for the catalytic
asymmetric synthesis of chiral 3-hydroxy-3-methyl-2-oxindoles
in previous report.[16] Shibashaki[16d] and Pedro’s group[16e] re-
ported the enantioselective addition of Me2Zn to isatins cata-
lyzed by proline-derived aminodiol and a-hydroxyamides
ligand, respectively, and only moderate ee values were ob-
tained. We performed the reaction between N-substituted isa-
tins 4 and Me2Zn in the presence of DCM at À408C. Most of
the isatin derivatives reacted smoothly with Me2Zn to afford
the corresponding 3-hydroxy-3-methyl-2-oxindoles 5 in excel-
lent yields with excellent enantioselectivities (Scheme 4). For
example, either electron-donating or withdrawing group of the
phenyl ring at N-aryl position were compatible under the opti-
nating groups, such as 1-naphthyl, benzyl, ethyl, et al were
also tolerated in this reaction, providing diverse 3-hydroxy-3-
methyl-2-oxindoles 5g–5l in excellent yield and high enantio-
selectivities. However, when the protecting group was elec-
tron-withdrawing group such as acetyl, the product 5m was
obtained in moderate yield, albeit with high ee. The absolute
configuration of 5 was determined by comparison to reported
literature.[16e]
Next, the effect of substitution on the benzene ring of N-
phenyl protected isatins 4 was evaluated (Table 2). In general,
electron-donating group at different position on the benzene
ring afforded the desired products in higher enantioselectivi-
ties in comparison with the electron-withdrawing group (en-
tries 1–6). Very importantly, we observed that other diorgano-
zinc reagents such as Et2Zn and nBu2Zn were also tolerated in
this reaction, although a slightly lower yields and enantioselec-
tivities were obtained (entries 7–10).
In order to understand the mechanism of this reaction, a
non-linear effect (NLE) study was conducted. The enantiopuri-
ties of the products were evaluated using various chiral amino
ligands L7 with 20%, 40%, 60% and 80% ee, respectively, and
a (+)-NLE was observed in this study (see detailed results in
Supporting Information). Based on the previous report[6f,17] and
the NLE studies, we proposed a plausible catalytic mechanism
of this reaction. As shown in Scheme 5, amino alcohoLL7 is de-
protonated to form a zinc aminoalkoxide species which could
further coordinates to pyrazole-4,5-diones 1. In addition, an-
other molecular of Me2Zn might coordinate with oxygen atom,
mized conditions to give the desired product 5a–5 f in 90– resulting in a si-face attack of Me2Zn through a six-membered
97% yields and 91–94% ee. Other N-substituted electron-do- transition-state. The outcome of the diorganozinc addition of
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Conflict of interest
Table 2. Substrate scope of the asymmetric diorganozinc additions to
substituted isatin 4.[a]
The authors declare no conflict of interest.
Keywords: chiral amino alcohol · diorganozinc addition ·
indoline-2,3-diones · pyrazole-4,5-diones
Entry
R1
R2
R
Yield [%][b]
ee [%][c]
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1
2
3
4
5
6
7
8
9
10
5-Me
5-OMe
5,7-Me2
5-F
5-Cl
6-Cl
H
6-Cl
5-OMe
H
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Ph
Me
Me
Me
Me
Me
Me
Et
Et
Et
nBu
5n, 95
5o, 92
5p, 96
5q, 92
5r, 95
5s, 90
5t, 75
5u, 77
5v, 72
5w, 62
90
88
92
89
76
87
80
79
69
70
[a] Reaction conditions: 0.2 mmol of 4, 2.0 equiv of 2, 20 mol% of ent-L7,
DCM, À408C, 20–36 h. [b] Isolated yields. [c] The ee values were deter-
mined by HPLC.
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Scheme 5. Plausible transition state for the diorganozinc addition to pyra-
zole-4,5-diones.
isatins 4 could also be explained by the similar transition
model.
In conclusion, the asymmetric additions of diorganozinc re-
agents to cyclic ketones including pyrazole-4,5-diones and sub-
stituted isatins were achieved without any additives. In the
presence of a chiral amino alcohol ligand L7 under mild condi-
tions, a wide range of highly functionalized tertiary alcohol
products with pyrazolone and 2-oxindole motifs could be ob-
tained in excellent yields (up to 97% yield) and high to excel-
lent enantioselectivities (up to 95% ee). This methodology pro-
vides an efficient approach for the asymmetric addition of dio-
rganozinc reagents to the challenging cyclic ketones. Studies
toward clarifying the detained reaction mechanism are under
way in our laboratory.
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This work was supported by the Fundamental Research Funds
for the Central Universities (Grants Nos. YJ201853 and
YJ201805) and the National Natural Science Foundation (Grant
No. 21907072).
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Manuscript received: November 24, 2020
Revised manuscript received: December 23, 2020
Accepted manuscript online: January 16, 2021
Version of record online: February 8, 2021
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