Enantioselective [3 + 2] annulation of 4-isothiocyanato pyrazolones and alkynyl ketones under organocatalysis

Article abstract of DOI:10.1039/d0ob02423f

An asymmetric [3 + 2] annulation reaction of 4-isothiocyanato pyrazolones with alkynyl ketones in the presence of an organic catalyst derived from a cinchona alkaloid under mild conditions is realized. This protocol provides unprecedented expeditious access to a wide range of optically active spiro[pyrroline-pyrazolones] with various electronic properties in high yields with good to excellent enantioselectivities.

Full text of DOI:10.1039/d0ob02423f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Enantioselective [3 + 2] annulation of
4-isothiocyanato pyrazolones and alkynyl
ketones under organocatalysis†
Cite this: Org. Biomol. Chem., 2021,
19, 1145
Wenyao Wang, Shiqiang Wei, Xiaoze Bao, Shah Nawaz, Jingping Qu
and
Baomin Wang
*
Received 3rd December 2020,
Accepted 7th January 2021
An asymmetric [3 + 2] annulation reaction of 4-isothiocyanato pyrazolones with alkynyl ketones in the
presence of an organic catalyst derived from a cinchona alkaloid under mild conditions is realized. This
protocol provides unprecedented expeditious access to a wide range of optically active spiro[pyrroline–
pyrazolones] with various electronic properties in high yields with good to excellent enantioselectivities.
DOI: 10.1039/d0ob02423f
rsc.li/obc
is valuable to develop a novel strategy to construct this core
structure efficiently.
Introduction
Pyrazolones and their derivatives, featuring two adjacent nitro-
As part of our research into the asymmetric synthesis and
gen atoms within a pentacyclic heterocycle, have drawn con- modification of pharmaceutically relevant heterocycles,2b,8 very
siderable attention from organic and medicinal chemists recently, we developed a series of 4-isothiocyanato pyrazolones
owing to their important synthetic and pharmaceutical poten- and successfully used them as ambiphilic synthons to react
tial.1 In particular, spiropyrazolones have recently risen to pro- with imines9 and activated alkenes10 for the asymmetric syn-
minence because of their significant medicinal relevance.2 As thesis of a range of spirocyclic pyrazolone derivatives in high
exemplified by the entities in Fig. 1, spiropyrazolone deriva- yields with excellent diastereoselectivity and enantioselectivity.
tives exhibit diverse medicinal potential ranging from antitu- Our results indicated that the readily achieved novel 4-isothio-
mor, antibacterial to analgesic activities and can serve as a cyanato pyrazolones were powerful synthons to construct
type-4-phosphodiesterase inhibitor.2a,3 Thus, the development
of methods that provide efficient access to these core struc-
tures has triggered vast investigation. Over the last few years,
some elegant studies have been published on the asymmetric
synthesis of spiropyrazolones bearing an all-carbon ring.4
However, there exist only a handful of reports on the efficient
synthesis of optically active spiropyrazolones with a five-mem-
bered N-heterocyclic ring,5 especially with the nitrogen atom at
Fig. 1 Biologically active spiropyrazolone derivatives.
the C4 position of the pyrazolone unit.6 For example, in 1994,
Ronald Grigg developed an elegant [3 + 2] annulation of male-
imide with an azomethine ylide for the synthesis of spiro-
pyrazolones (Scheme 1a).6a Later, Javier Agejas reported a two-
step reaction to construct spiro[pyrrolidine–pyrazolones]
(Scheme 1b).6e To date, asymmetric approaches to access these
special chiral spiro[pyrroline–pyrazolones] have been less
explored, especially via a catalytic cascade approach.7 Hence, it
State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences,
School of Chemical Engineering, Dalian University of Technology, Dalian 116024,
People’s Republic of China. E-mail: bmwang@dlut.edu.cn
†Electronic supplementary information (ESI) available: Experimental procedures
and detailed characterization data of all new compounds (PDF). X-ray crystal
details for 4 (CIF). CCDC 2012543. For ESI and crystallographic data in CIF or
Scheme 1 Previous synthesis of spiro[pyrrolidine–pyrazolones] and
other electronic format see DOI: 10.1039/d0ob02423f
our asymmetric [3 + 2] annulation.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1145–1154 | 1145

View Article Online
Paper
Organic & Biomolecular Chemistry
4-nitrogen attached chiral spirocyclic pyrazolones. Aiming to with 37% ee (entry 1), and similar enantioselectivity was
develop a new strategy for the construction of spiro[pyrroline– obtained when quinidine (Q2) was used (entry 2). Encouraged
pyrazolones] with high levels of enantiocontrol, herein, we by these results, further trials of quinine-derived hydrogen-
present the organocatalytic asymmetric Michael/annulation of bonding catalysts (Q3–6) were conducted (entries 3–6). While
4-isothiocyanato pyrazolones and alkynyl ketones with bifunc- all could smoothly catalyze the model reaction, delivering the
tional chiral squaramide as a catalyst, providing spiro[pyrro- spiroannulation product in a high yield, the quinine squara-
line–pyrazolone] core structures in high yields with excellent mide catalyst Q4 exhibited superior stereocontrol, affording
enantioselectivities.
the dispirocyclic product with 90% ee (entry 4). When
N-tosylsulfonamide Q7 was used, very low enantioselectivity
was obtained (entry 7). With Q4 as the most optimal catalyst,
the effect of solvents was investigated (entries 8–14). The
results showed that the enantioselectivity of this annulation
Results and discussion
Initially, the reaction of 4-isothiocyanato pyrazolone 1a and varied less in similar solvents chloroform and 1,2-dichlor-
alkynyl ketone 2a was selected as the model reaction with oethane (entries 8 and 9) but decreased greatly in other sol-
natural quinine (Q1) as the catalyst in dichloromethane (DCM) vents, especially acetonitrile and diethyl ether (entries 11 and
at room temperature (Table 1). The cascade annulation reac- 12). With the initially used DCM as the solvent of choice, the
tion proceeded rapidly to give the product 3aa in 87% yield decrease of the amount of alkynyl ketone from 1.2 to 1.1 equi-
valent improved the isolated yield to 91% and ee to 93% (entry
15). With quinidine squaramide Q8, the enantiomer of 3aa
could also be obtained conveniently in 83% yield with 92% ee.
Table 1 Optimization of the reaction conditionsa
Reducing the catalyst loading or cooling the reaction resulted
in reduced enantioselectivities (entries 17–19).
With the optimal reaction conditions being identified
(Table 1, entry 15), the generality of the annulation reaction
was investigated. First, the scope of 4-isothiocyanato pyrazo-
lones 1 that participated in the asymmetric annulation is
shown in Table 2. Generally, a broad spectrum of 4-isothiocya-
nato pyrazolones reacted well with phenyl alkynyl ketone 2a,
delivering a diverse array of [3 + 2] derivatives in high yields
with excellent stereocontrol. Various electron-donating and
electron-withdrawing substituents such as methyl, methoxyl
and fluorine groups on the phenyl group at the C3 position of
pyrazolones afforded the [3 + 2] annulation products 3ba–3ea
in high yields (86–90%) with excellent enantioselectivities
(86–94% ee). Additionally, this procedure was also applicable
to 4-isothiocyanato pyrazolones with 1-naphthyl (3fa, 89%
Entry
Cat.
Solvent
t [h]
Yieldb [%]
ee [%]
yield, 81% ee) and 2-naphthyl (3ga, 84% yield, 83% ee) at the
C3 position of the pyrazolones. Substrates bearing methyl,
ethyl, isopropyl and cyclopropyl at the C3 position of pyrazo-
lones were also investigated under the standard conditions. It
turned out that all alkyl substituents had no influence on this
reaction affording products 3ia–3ka in good yields (87–91%)
with high enantioselectivities (91–93% ee) except for 3ha,
probably due to the low steric hindrance of the methyl group.
Besides, the N-tert-butyl group at the N1 position of the pyrazo-
lone was also well accommodated to provide the desired
product 3la in 95% yield with 87% ee.
Subsequently, the scope of alkynyl ketones 2 was investi-
gated (Table 2). Alkynyl ketones 2 bearing various electron-
donating groups at the para- and meta-positions on the aro-
matic ring such as methoxy and methyl were amenable for the
[3 + 2] annulation reactions, providing the corresponding
desired products (3ab–3ad) in high yields (88–91%) with high
enantioselectivities (91–93% ee). Besides, alkynyl ketones 2
bearing electron-withdrawing halogens such as F and Br pro-
ceeded smoothly, affording products (3ae–3ag) in high yields
1
2
3
4
5
6
7
8
Q1
Q2
Q3
Q4
Q5
Q6
Q7
Q4
Q4
Q4
Q4
Q4
Q4
Q4
Q4
Q8
Q4
Q4
Q4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
Toluene
CH3CN
Et2O
THF
1,4-Dioxane
DCM
DCM
DCM
DCM
DCM
0.5
0.5
0.5
0.5
1
1
1.5
1
1
1
1
1
1.5
1.5
0.5
0.5
0.5
0.5
3
87
88
89
88
85
93
86
89
90
91
86
89
86
90
91
83
87
90
86
37
−21
86
90
80
71
13
82
89
55
33
15
27
45
93
−92
89
92
82
9
10
11
12
13
14
15f
16f
17c, f
18d, f
19e, f
a Unless otherwise noted, the reaction was performed on a 0.1 mmol
scale with 1a (1.0 equiv.), 2a (1.2 equiv.), and a catalyst (10 mol%) in a
solvent (1 mL). b Isolated yield. c Catalyst (5 mol%). d The reaction was
carried out at 0 °C. e The reaction was carried out at −20 °C. f The
amount of 2a was 1.1 equiv.
1146 | Org. Biomol. Chem., 2021, 19, 1145–1154
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Generality of the asymmetric [3 + 2] annulation reactiona
the presence of 10 mol% of Q4 in DCM; the reaction also
worked well without any loss in the efficiency and stereochemi-
cal outcome of the reaction (Scheme 2). The desired product
3aa could be obtained in 86% yield with excellent enantio-
selectivity (90% ee).
Next, the versatility of spiro[pyrroline–pyrazolones] 3 was
analyzed. As shown in Scheme 3, 3af could be further trans-
formed into spiro[2H-pyrrole-pyrazolone] derivative 4 in 91%
yield with 89% ee through direct methylation. The absolute
configuration of the product was unambiguously determined
to be R by X-ray crystallographic analysis of a single crystal of
4. To obtain the pyrrolin-2-one derivatives, 3aa was directly
subjected to an oxidation reaction with mCPBA in THF, and
pyrrolin-2-thione could be converted into pyrrolin-2-one,
giving compound 5 in 85% yield with 91% ee.
Based on the result and previously reported dual activation
mode,10,11 a plausible working model was proposed, as shown
in Scheme 4. 4-Isothiocyanato pyrazolone 1a was deprotonated
to form the enamine tautomer of 4-isothiocyanato pyrazo-
lone,12 and alkynyl ketone 2a was activated via double hydro-
gen bonding. Then, the Michael addition/cyclization of 1a and
alkynyl ketone 2a gave the product 3aa.
Scheme 2 Gram-scale synthesis of 3aa.
a The reactions were conducted with 1 (0.2 mmol) and Q4 (10 mol%)
in DCM (2.0 mL) at rt for 5 minutes. Then alkynyl ketones 2
(0.22 mmol) were added into the reaction mixture. The yields of the
isolated products are given. The ee was determined by chiral HPLC.
b The reaction time was 1 h. c The reaction time was 72 h.
(90–91%) with high enantioselectivities (89–93% ee). It turned
out that the electronic properties of alkynyl ketones had no
pronounced influence on the yields and stereoselectivities. In
addition, asymmetric [3 + 2] annulation of alkynyl ketones
with a heteroaryl substituent or a naphthyl substituent pro-
ceeded smoothly, delivering the corresponding chiral products
in 89% yield with 93% ee and 93% yield with 91% ee (3ah and
3ai), respectively. The aliphatic alkynyl ketone was also accom-
modated, providing 4aj in 81% yield with 87% ee. Changing
terminal alkynones to internal α,β-ynones had no obvious
effect on the enantioselectivity of the annulation product
(3ak–3ao). Due to the conjugate and steric effects of aryl with
alkynones, the reactivity of α,β-ynones was suppressed (3ak–
3ao) and the reaction time was prolonged to 72 h, but the
enantioselectivities remained high (85–94% ee).
Scheme 3 Diversification of 3af and 3aa.
To confirm the practicability of the [3 + 2] annulation
process, the gram-scale synthesis of compound 3aa was facilely
Scheme 4 Proposed transition state working model for the [3 + 2]
achieved. 1a (2.5 mmol) and 2a (2.75 mmol) were treated in annulation.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1145–1154 | 1147

View Article Online
Paper
Organic & Biomolecular Chemistry
hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1
tmajor = 15.2 min, tminor = 12.7 min).
,
Conclusions
In summary, we have developed an asymmetric [3 + 2] annula-
Compound ent-3aa. Yellow solid (35.0 mg, 83% yield). Mp
tion reaction between 4-isothiocyanato pyrazolones and 110.9–113.5 °C; [α]8D = −12.50 (c 0.12, CH2Cl2), 1H NMR
alkynyl ketones for the first time in the presence of an organo- (400 MHz, chloroform-d) δ 8.37 (s, 1H), 8.00–7.90 (m, 4H),
catalyst. This reaction provided an efficient protocol for the 7.76–7.67 (m, 2H), 7.63–7.54 (m, 1H), 7.45 (dtd, J = 8.1, 5.4, 3.3
enantioselective synthesis of spiro[pyrroline–pyrazolones] in Hz, 7H), 7.28 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H); 13C NMR
high yields with excellent enantioselectivities and allows the (101 MHz, chloroform-d) δ 196.9, 151.6, 146.7, 141.2, 137.3,
use of a wide range of 4-isothiocyanato pyrazolones while toler- 135.8, 134.4, 132.0, 130.1, 129.4, 129.2, 129.0, 128.8, 126.4,
ating a considerable degree of variations of alkynyl ketones 126.1, 119.0, 78.8; the enantiomeric excess was determined to
under mild conditions.
be −92% (determined by HPLC using a chiral AD-H column,
hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1
tmajor = 18.4 min, tminor = 14.0 min).
,
Compound 3ba. Yellow solid (78.7 mg, 90% yield). Mp
111.5–114.5 °C, [α]2D3 = −4.8 (c 0.25, CH2Cl2); 1H NMR
(400 MHz, chloroform-d) δ 8.44 (s, 1H), 7.93 (t, J = 7.5 Hz, 4H),
7.61–7.52 (m, 2H), 7.47–7.38 (m, 5H), 7.32–7.25 (m, 2H), 7.24
(s, 1H), 7.02 (s, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, chloro-
form-d) δ 196.8, 189.6, 164.9, 151.7, 146.7, 141.2, 139.2, 137.3,
135.8, 134.4, 132.8, 130.1, 129.4, 129.2, 128.9, 128.8, 126.6,
126.4, 123.3, 118.9, 78.9, 21.5. HRMS (ESI) m/z calcd for
C26H19N3O2S ([M + H]+) 438.1271, found 438.1286; the enantio-
meric excess was determined to be 94% (determined by HPLC
using a chiral AD-H column, hexane/2-propanol = 7/3, λ =
Experimental
General information
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification.
Column chromatography was performed on silica gel
(200–300 mesh). Enantiomeric excesses (ee) were determined
by HPLC using the corresponding commercial chiral columns
as stated at 30 °C with a UV detector at 254 nm. Optical
rotations were reported as follows: [α]TD (c g per 100 mL,
solvent). All 1H NMR and 19F NMR spectra were recorded on
Bruker Avance II 400 MHz and Bruker Avance III 471 MHz
spectrometers, respectively, 13C NMR spectra were recorded on
a Bruker Avance II 101 MHz spectrometer or a Bruker Avance
III 126 MHz spectrometer with chemical shifts reported in
ppm (in CDCl3, with TMS as an internal standard). The data
254 nm, 30 °C, 0.8 mL min−1, tmajor = 14.8 min, tminor
=
12.6 min).
Compound 3ca. Yellow solid (75.2 mg, 86% yield). Mp
121.5–124.5 °C; [α]D20 = −11.33 (c 0.07, CH2Cl2); 1H NMR
(400 MHz, chloroform-d) δ 8.43 (s, 1H), 7.99–7.88 (m, 4H),
7.62–7.51 (m, 3H), 7.42 (q, J = 7.3 Hz, 4H), 7.25 (s, 1H), 7.20 (d,
J = 8.1 Hz, 2H), 7.02 (s, 1H), 2.37 (s, 3H); 13C NMR (101 MHz,
chloroform-d) δ 196.8, 189.7, 164.9, 151.7, 146.6, 142.7, 141.4,
137.4, 135.8, 134.4, 130.1, 130.1, 129.2, 128.8, 126.3, 126.2,
126.1, 118.9, 78.9, 21.7; HRMS (ESI) m/z calcd for C25H18N3O2S
([M + H]+) 438.1271, found 438.1286; the enantiomeric excess
was determined to be 92% (determined by HPLC using a
chiral AD-H column, hexane/2-propanol = 7/3, λ = 254 nm,
1
for H NMR are recorded as follows: chemical shift (δ, ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br = broad singlet, dd = double doublet, coupling constants in
Hz, integration). HRMS (ESI) was performed with an HRMS/
MS instrument (LTQ Orbitrap XLTM).
General procedure for the synthesis of compounds 3
A tube equipped with a magnetic stir bar was charged with 30 °C, 0.8 mL min−1, tmajor = 11.3 min, tminor = 10.1 min).
4-isothiocyanato pyrazolone 1 (0.2 mmol), Q4 (0.02 mmol), Compound 3da. Yellow solid (80.6 mg, 89% yield). Mp
and DCM (2 mL). After stirring for 5 min, alkynyl ketone 2 124.5–125.5 °C; [α]2D0 = +35.00 (c 0.12, CH2Cl2); 1H NMR
(0.22 mmol) was added in one portion. The reaction was moni- (400 MHz, chloroform-d) δ 8.52 (s, 1H), 7.94 (dd, J = 16.2, 8.0
tored by TLC. After 0.5–1 h, the mixture was purified by Hz, 4H), 7.63 (dd, J = 9.0, 2.7 Hz, 2H), 7.58 (d, J = 7.3 Hz, 1H),
column chromatography on silica gel (unless otherwise noted, 7.43 (q, J = 8.0 Hz, 4H), 7.25 (d, J = 3.0 Hz, 1H), 7.06 (d, J = 4.5
petroleum ether/EtOAc = 8 : 1 was used as the eluent) directly Hz, 1H), 6.92 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H); 13C NMR
to give the product 3.
(101 MHz, chloroform-d) δ 196.8, 189.7, 164.8, 162.5, 151.3,
Compound 3aa. Yellow solid (77.1 mg, 91% yield). Mp 146.6, 141.4, 137.4, 135.8, 134.4, 130.1, 129.1, 128.7, 127.9,
111.5–114.5 °C; [α]D20 = +35.00 (c 0.30, CH2Cl2), 1H NMR 126.2, 121.6, 118.9, 114.9, 79.0, 55.5; HRMS (ESI) m/z calcd for
(400 MHz, chloroform-d) δ 8.06 (s, 1H), 8.02 (s, 1H), 7.99 (dd, J C26H19N3O3S ([M + H]+) 454.1220, found 454.1237; the enantio-
= 4.4, 1.4 Hz, 2H), 7.97 (s, 1H), 7.75 (dd, J = 8.0, 1.6 Hz 2H), meric excess was determined to be 87% (determined by HPLC
7.63 (t, J = 7.4 Hz, 1H), 7.51–7.46 (m, 7H), 7.30 (t, J = 7.5 Hz, using a chiral AD-H column, hexane/2-propanol = 7/3, λ =
1H), 7.17 (s, 1H); 13C NMR (101 MHz, chloroform-d) δ 196.8, 254 nm, 30 °C, 0.8 mL min−1, tmajor = 17.2 min, tminor
=
189.7, 164.9, 151.6, 146.6, 141.3, 137.3, 135.8, 134.4, 131.9, 14.5 min).
130.1, 129.4, 129.2, 128.9, 128.8, 126.4, 126.1, 118.9, 78.9;
Compound 3ea. Yellow solid (77.6 mg, 88% yield). Mp
HRMS (ESI) m/z calcd for C25H17N3O2S ([M + H]+) 424.1114, 124.5–126.5 °C; [α]2D0 = +10.88 (c 0.22, CH2Cl2); 1H NMR
found 424.1114; the enantiomeric excess was determined to be (400 MHz, chloroform-d) δ 8.68 (s, 1H), 7.90 (dd, J = 12.5, 7.8
93% (determined by HPLC using a chiral AD-H column, Hz, 4H), 7.69 (dd, J = 8.9, 5.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H),
1148 | Org. Biomol. Chem., 2021, 19, 1145–1154
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
7.42 (q, J = 8.4 Hz, 4H), 7.25 (s, 1H), 7.10 (t, J = 8.6 Hz, 2H), Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.93 (s,
7.06 (s, 1H); 19F NMR (470 MHz, CDCl3) δ −107.12; 13C NMR 1H), 2.59–2.33 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H); 13C NMR
(101 MHz, chloroform-d) δ 196.8, 189.7, 164.9, 164.7 (d, J = (101 MHz, chloroform-d) δ 197.3, 189.7, 165.1, 158.8, 146.9,
254.5 Hz), 150.7, 146.8, 141.1, 137.2, 135.7, 134.5, 130.1, 129.2, 139.7, 137.4, 135.7, 134.5, 130.0, 129.1, 128.8, 126.1, 118.9,
128.8, 128.4 (d, J = 8.8 Hz), 126.5, 125.3 (d, J = 3.4 Hz), 118.9, 80.0, 22.2, 10.0; HRMS (ESI) m/z calcd for C21H17N3O2S ([M +
116.7 (d, J = 22.3 Hz), 78.8; HRMS (ESI) m/z calcd for H]+) 376.1114, found 376.1126; the enantiomeric excess was
C25H18N3O2FS ([M + H]+) 442.1020, found 442.1034, the enan- determined to be 91% (determined by HPLC using a chiral
tiomeric excess was determined to be 86% (determined by AD-H column, hexane/2-propanol = 7/3, λ = 254 nm, 30 °C,
HPLC using a chiral AD-H column, hexane/2-propanol = 7/3, λ 0.8 mL min−1, tmajor = 13.0 min, tminor = 9.3 min).
= 254 nm, 30 °C, 0.8 mL min−1, tmajor = 17.8 min, tminor
13.8 min).
=
Compound 3ja. Yellow solid (67.7 mg, 87% yield). Mp
88.0–89.0 °C; [α]D18 = −168.04 (c 0.51, CH2Cl2); 1H NMR
Compound 3fa. Yellow solid (84.2 mg, 89% yield). Mp (400 MHz, chloroform-d) δ 8.95 (s, 1H), 7.93 (d, J = 7.0 Hz, 2H),
158.5–160.0 °C; [α]D19 = +16.00 (c 0.62, CH2Cl2); 1H NMR 7.82 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.8
(400 MHz, chloroform-d) δ 8.98 (d, J = 8.6 Hz, 1H), 8.41 (s, 1H), Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.95 (s,
8.01 (d, J = 7.7 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 1H), 2.72 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.23 (d,
Hz, 1H), 7.87 (d, J = 6.9 Hz, 2H), 7.70–7.62 (m, 1H), 7.63–7.53 J = 7.0 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 197.2,
(m, 3H), 7.53–7.46 (m, 3H), 7.40 (t, J = 7.7 Hz, 2H), 7.31 (t, J = 189.8, 165.2, 161.9, 146.6, 140.2, 137.4, 135.7, 134.5, 130.1,
7.5 Hz, 1H), 7.15 (s, 1H); 13C NMR (101 MHz, chloroform-d) δ 130.0, 129.1, 128.8, 126.1, 118.9, 80.1, 29.6, 20.9, 20.3; HRMS
196.8, 189.6, 164.5, 152.4, 146.6, 141.2, 137.4, 135.8, 134.3, (ESI) m/z calcd for C22H19N3O2S ([M + H]+) 390.1271, found
134.2, 132.6, 130.4, 130.0, 129.3, 129.2, 128.7, 128.4, 127.5, 390.1282; the enantiomeric excess was determined to be 93%
126.7, 126.4, 125.5, 125.3, 125.1, 119.0, 80.3; HRMS (ESI) m/z (determined by HPLC using a chiral AD-H column, hexane/
calcd for C29H19N3O2S ([M + H]+) 474.1271, found 474.1284; 2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor
the enantiomeric excess was determined to be 81% (deter- 10.8 min, tminor = 8.5 min).
=
mined by HPLC using a chiral AD-H column, hexane/2-propa-
nol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor = 16.6 min, 99.0–102.0 °C; [α]1D8 = −96.10 (c 0.41, CH2Cl2); 1H NMR
tminor = 14.1 min). (400 MHz, chloroform-d) δ 8.80 (s, 1H), 7.95 (d, J = 7.0 Hz, 2H),
Compound 3ka. Yellow solid (69.7 mg, 90% yield). Mp
Compound 3ga. Yellow solid (79.5 mg, 84% yield). Mp 7.79 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8
110.5–112.5 °C; [α]D20 = +42.33 (c 0.15, CH2Cl2); 1H NMR Hz, 2H), 7.37 (t, J = 8.2 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.97 (d,
(400 MHz, chloroform-d) δ 8.23 (s, 1H), 8.03–7.95 (m, 6H), 7.85 J = 1.5 Hz, 1H), 1.59 (tt, J = 8.0, 5.1 Hz, 1H), 1.16–1.04 (m, 4H);
(dd, J = 18.5, 9.1 Hz, 3H), 7.64–7.40 (m, 8H), 7.29 (t, J = 7.4 Hz, 13C NMR (101 MHz, chloroform-d) δ 197.4, 189.7, 164.9, 159.7,
1H), 7.16 (s, 1H); 13C NMR (101 MHz, chloroform-d) δ 196.9, 146.8, 139.8, 137.4, 135.8, 134.5, 130.1, 129.1, 128.8, 128.7,
189.6, 164.9, 151.5, 146.7, 141.2, 137.3, 135.8, 134.7, 134.4, 126.0, 118.8, 80.2, 10.0, 9.8, 9.4; HRMS (ESI) m/z calcd for
132.8, 130.0, 129.4, 129.3, 129.2, 128.8, 128.3, 127.8, 127.2, C22H17N3O2S ([M + H]+) 388.1114, found 388.1128; the enantio-
127.1, 126.4, 126.3, 122.2, 118.9, 78.8; HRMS (ESI) m/z calcd meric excess was determined to be 92% (determined by HPLC
for C29H19N3O2S ([M + H]+) 474.1271, found 474.1284; the using a chiral AD-H column, hexane/2-propanol = 7/3, λ =
enantiomeric excess was determined to be 83% (determined 254 nm, 30 °C, 0.8 mL min−1, tmajor = 16.2 min, tminor
=
by HPLC using a chiral AD-H column, hexane/2-propanol = 7/ 10.3 min).
3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor = 21.4 min, tminor
14.8 min).
=
Compound 3la. Yellow oil (76.6 mg, 95% yield). [α]D8
=
+56.14 (c 0.61, CH2Cl2); 1H NMR (400 MHz, chloroform-d) δ
Compound 3ha. Yellow solid (59.9 mg, 83% yield). Mp 7.98–7.90 (m, 2H), 7.63–7.55 (m, 3H), 7.38–7.32 (m, 3H),
115.5–116.5 °C; [α]2D0 = −152.50 (c 0.20, CH2Cl2); 1H NMR 7.41–7.30 (m, 3H), 7.04 (s, 1H), 1.58 (s, 9H); 13C NMR
(400 MHz, chloroform-d) δ 8.17 (s, 1H), 8.01–7.92 (m, 2H), 7.85 (101 MHz, chloroform-d) δ 196.8, 189.8, 166.4, 149.2, 146.7,
(dd, J = 8.7, 1.2 Hz, 2H), 7.67–7.58 (m, 1H), 7.49 (t, J = 7.8 Hz, 141.7, 136.0, 134.2, 131.1, 130.1, 129.7, 129.2, 128.7, 125.6,
2H), 7.47–7.38 (m, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.96 (s, 1H), 79.5, 59.9, 28.2; HRMS (ESI) m/z calcd for C23H22N3O2S ([M +
2.18 (s, 3H); 13C NMR (101 MHz, chloroform-d) δ 197.3, 189.7, H]+) 404.1427, found 404.1428; the enantiomeric excess was
165.0, 154.8, 147.1, 139.4, 137.3, 135.7, 134.5, 130.0, 129.1, determined to be 87% (determined by HPLC using a chiral
128.8, 126.1, 118.9, 80.0, 14.2; HRMS (ESI) m/z calcd for IC-H column, hexane/2-propanol = 7/3, λ = 254 nm, 30 °C,
C20H15N3O2S ([M + H]+) 362.0958, found 362.0969; the enantio- 0.8 mL min−1, tmajor = 9.8 min, tminor = 13.2 min).
meric excess was determined to be 82% (determined by HPLC
Compound 3ab. Yellow solid (78.7 mg, 90% yield). Mp
using a chiral AD-H column, hexane/2-propanol = 7/3, λ = 215.0–217.0 °C; [α]2D0 = −10.69 (c 0.29, CH2Cl2); 1H NMR
254 nm, 30 °C, 0.8 mL min−1, tmajor = 10.8 min, tminor
=
(400 MHz, acetone-d6) δ 10.20 (s, 1H), 8.01 (dd, J = 8.7, 1.2 Hz,
9.3 min).
2H), 7.86 (dd, J = 7.6, 2.1 Hz, 2H), 7.84–7.81 (m, 2H), 7.78 (s,
Compound 3ia. Yellow solid (68.3 mg, 91% yield). Mp 1H), 7.62–7.57 (m, 3H), 7.56–7.50 (m, 3H), 7.45 (t, J = 8.0 Hz,
95.0–97.0 °C; [α]1D9 = −151.11 (c 0.36, CH2Cl2); 1H NMR 1H), 7.32 (t, J = 7.5 Hz, 1H), 2.41 (s, 3H); 13C NMR (101 MHz,
(400 MHz, chloroform-d) δ 8.77 (s, 1H), 7.93 (d, J = 7.0 Hz, 2H), acetone-d6) δ 205.3, 197.4, 189.8, 165.6, 151.8, 147.5, 141.4,
7.82 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 138.6, 1378.0, 136.4, 134.9, 131.6, 130.0, 129.9, 129.3, 129.1,
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1145–1154 | 1149

View Article Online
Paper
Organic & Biomolecular Chemistry
128.7, 127.0, 126.0, 125.9, 118.7, 79.4, 20.5; HRMS (ESI) m/z 502.0227; the enantiomeric excess was determined to be 89%
calcd for C26H19N3O2S ([M + H]+) 438.1271, found 438.1276; (determined by HPLC using a chiral AD-H column, hexane/
the enantiomeric excess was determined to be 91% (deter- 2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor
mined by HPLC using a chiral AD-H column, hexane/2-propa- 19.1 min, tminor = 15.7 min).
=
nol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor = 14.6 min,
tminor = 13.0 min).
Compound 3ag. Yellow solid (90.2 mg, 90% yield). Mp
97.0–98.0 °C; [α]D20 = −40.65 (c 1.23, CH2Cl2); 1H NMR
Compound 3ac. Yellow solid (79.5 mg, 91% yield). Mp (400 MHz, chloroform-d) δ 8.74 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H),
110.0–111.0 °C; [α]D20 = −11.43 (c 0.14, CH2Cl2); 1H NMR 7.73 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 8.4
(400 MHz, chloroform-d) δ 8.27 (s, 1H), δ 7.96 (d, J = 8.1 Hz, Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 6.9 Hz, 4H), 7.24 (s,
2H), 7.89 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H), 7.46 (m, 1H), 6.99 (s, 1H); 13C NMR (101 MHz, chloroform-d) δ 196.5,
5H), 7.27 (d, J = 8.8 Hz, 3H), 7.10 (s, 1H), 2.41 (s, 3H); 13C NMR 188.9, 164.9, 151.6, 146.5, 141.7, 137.2, 134.4, 132.1, 132.0,
(101 MHz, chloroform-d) δ 197.1, 189.1, 165.0, 151.6, 147.0, 131.5, 129.9, 129.5, 129.3, 128.9, 126.5, 126.1, 118.9, 79.1;
145.6, 140.7, 137.4.0, 133.4, 131.9, 130.2, 129.5, 129.4, 129.2, HRMS (ESI) m/z calcd for C25H16BrN3O2S ([M + H]+) 504.0204,
129.0, 126.4, 126.1, 119.0, 78.8, 21.9; HRMS (ESI) m/z calcd for found 504.0196; the enantiomeric excess was determined to be
C26H19N3O2S ([M + H]+) 438.1271, found 438.1276; the enantio- 91% (determined by HPLC using a chiral AD-H column,
meric excess was determined to be 91% (determined by HPLC hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1
using a chiral AD-H column, hexane/2-propanol = 7/3, λ = tmajor = 19.7 min, tminor = 12.1 min).
,
254 nm, 30 °C, 0.8 mL min−1, tmajor = 18.1 min, tminor
=
Compound 3ah. Yellow solid (76.4 mg, 89% yield). Mp
120.0–121.0 °C; [α]2D1 = +4.17 (c 0.24, CH2Cl2); 1H NMR
12.5 min).
Compound 3ad. Yellow solid (79.7 mg, 88% yield). Mp (400 MHz, acetone-d6) δ 10.19 (s, 1H), 8.07 (dd, J = 4.9, 1.1 Hz,
235.0–236.0 °C; [α]1D9 = −49.75 (c 0.40, CH2Cl2); 1H NMR 1H), 8.02 (s, 1H), 8.00 (d, J = 4.0 Hz, 1H), 7.89 (s, 1H),
(400 MHz, acetone-d6) δ 10.17 (s, 1H), 8.00 (t, J = 7.6 Hz, 4H), 7.86–7.79 (m, 3H), 7.60–7.56 (m, 3H), 7.58–7.49 (m, 2H), 7.32
7.84 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.61–7.54 (m, 3H), 7.53 (t, (t, J = 7.4 Hz, 1H), 7.29 (dd, J = 4.9, 3.9 Hz, 1H); 13C NMR
J = 8.0 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 9.0 Hz, 2H), (101 MHz, acetone-d6) δ 205.3, 196.8, 181.2, 165.5, 151.7,
3.92 (s, 3H); 13C NMR (101 MHz, acetone-d6) δ 205.3, 197.7, 146.6, 143.6, 141.9, 138.0, 136.5, 136.2, 131.6, 129.9, 129.3,
188.1, 165.7, 164.6, 151.9, 147.8, 140.9, 138.0, 132.0, 131.6, 129.1, 128.7, 126.0, 125.9, 118.7, 79.2; HRMS (ESI) m/z calcd
129.9, 129.4, 129.3, 129.1, 126.0, 125.9, 118.7, 114.0, 79.4, 55.3; for C23H15N3O2S2 ([M + H]+) 430.0678, found 430.0684; the
HRMS (ESI) m/z calcd for C26H19N3O3S ([M + H]+) 454.1220, enantiomeric excess was determined to be 93% (determined
found 454.1228; the enantiomeric excess was determined to be by HPLC using a chiral AD-H column, hexane/2-propanol = 7/
93% (determined by HPLC using a chiral AD-H column, 3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor = 18.9 min, tminor
=
hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1
tmajor = 23.5 min, tminor = 16.8 min).
,
14.9 min).
Compound 3ai. Yellow solid (88.0 mg, 93% yield). Mp
Compound 3ae. Yellow solid (80.3 mg, 91% yield). Mp 230.0–231.0 °C; [α]1D8 = −39.35 (c 0.31, CH2Cl2); 1H NMR
108.0–110.0 °C; [α]D17 = −23.33 (c 0.42, CH2Cl2); 1H NMR (400 MHz, acetone-d6) δ 10.21 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H),
(400 MHz, chloroform-d) δ 8.59 (s, 1H), 7.97 (dd, J = 8.8, 5.4 8.20 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.02 (t, J = 7.0
Hz, 2H), 7.90 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 6.9 Hz, 2H), 7.46 Hz, 3H), 7.88–7.84 (m, 3H), 7.71 (t, J = 7.7 Hz, 1H), 7.65–7.57
(d, J = 7.3 Hz, 1H), 7.44–7.38 (m, 4H), 7.26 (t, J = 7.4 Hz, 1H), (m, 5H), 7.52 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H); 13C
7.09 (t, J = 8.5 Hz, 2H), 7.05 (s, 1H); 19F NMR (377 MHz, chloro- NMR (101 MHz, acetone-d6) δ 205.4, 197.4, 191.7, 165.6,
form-d) δ −102.42; 13C NMR (101 MHz, chloroform-d) δ 196.6, 151.8, 148.6, 142.4, 138.0, 134.5, 134.1, 133.0, 133.0, 131.6,
188.3, 166.5 (d, J = 257.4 Hz), 165.0, 151.6, 146.7, 141.2, 137.3, 130.7, 30.0, 129.3, 129.1, 128.6, 128.5, 126.7, 126.1, 125.9,
132.9 (d, J = 9.8 Hz), 132.2 (d, J = 2.9 Hz), 132.0, 129.4, 129.2, 125.8, 124.5, 118.8, 79.3; HRMS (ESI) m/z calcd for
128.9, 126.5, 126.1, 118.9, 116.1 (d, J = 22.2 Hz), 79.0; HRMS C29H19N3O2S ([M + H]+) 474.1271, found 474.1279; the enan-
(ESI) m/z calcd for C25H16FN3O2S ([M + H]+) 442.1020, found tiomeric excess was determined to be 91% (determined by
442.1025; the enantiomeric excess was determined to be 93% HPLC using a chiral AD-H column, hexane/2-propanol = 7/3,
(determined by HPLC using a chiral AD-H column, hexane/ λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor = 20.1 min, tminor
=
2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor
15.0 min, tminor = 11.3 min).
=
23.7 min).
Compound 3aj. Yellow solid (73.0 mg, 81% yield). Mp
Compound 3af. Yellow solid (91.4 mg, 91% yield). Mp 161.3–163.5 °C; [α]5D = +55.00 (c 0.16, CH2Cl2); 1H NMR
114.0–116.0 °C; [α]D17 = +14.17 (c 0.15, CH2Cl2); 1H NMR (400 MHz, chloroform-d) δ 8.26 (s, 1H), 7.95–7.82 (m, 2H),
(400 MHz, chloroform-d) δ 8.13 (s, 1H), 7.93 (d, J = 7.5 Hz, 2H), 7.62–7.53 (m, 2H), 7.49–7.33 (m, 6H), 7.26 (d, J = 7.4 Hz, 2H),
7.72 (d, J = 7.2 Hz, 2H), 7.56 (dd, J = 17.1, 7.6 Hz, 2H), 7.24 (s, 1H), 7.23–7.12 (m, 3H), 3.57 (dt, J = 18.1, 7.5 Hz, 1H),
7.52–7.37 (m, 7H), 7.29 (d, J = 7.5 Hz, 1H), 7.18–7.05 (m, 1H); 3.40 (dt, J = 18.1, 7.5 Hz, 1H), 2.95 (t, J = 7.6 Hz, 2H); 13C NMR
13C NMR (101 MHz, chloroform-d) δ 195.6, 189.4, 164.7, 151.4, (151 MHz, chloroform-d) δ 195.9, 164.5, 151.2, 146.2, 146.0,
146.0, 145.3, 138.6, 137.3, 133.6, 132.8, 131.9, 131.1, 129.3, 140.6, 137.3, 132.0, 129.4, 129.3, 129.0, 128.5, 126.5, 126.2,
129.2, 128.9, 127.4, 126.4, 126.2, 120.7, 118.9, 78.3; HRMS 126.0, 118.9, 77.8, 44.0, 29.5; HRMS (ESI) m/z calcd for
(ESI) m/z calcd for C25H16BrN3O2S ([M + H]+) 502.0219, found C27H22N3O2S ([M + H]+) 452.1427, found 452.1423; the enantio-
1150 | Org. Biomol. Chem., 2021, 19, 1145–1154
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
meric excess was determined to be 87% (determined by HPLC (determined by HPLC using a chiral AD-H column, hexane/
using a chiral AD-H column, hexane/2-propanol = 7/3, λ = 2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1, tmajor
=
254 nm, 30 °C, 0.8 mL min−1, tmajor = 31.9 min, tminor
=
20.3 min, tminor = 13.7 min).
Compound 3ao. Yellow solid (45.0 mg, 48% yield). Mp
26.7 min).
Compound 3ak. Yellow solid (78.8 mg, 79% yield). Mp 161.3–163.5 °C; [α]5D = +55.00 (c 0.16, CH2Cl2); 1H NMR
104.0–105.0 °C; [α]D18 = +38.67 (c 0.15, CH2Cl2); 1H NMR (400 MHz, chloroform-d) δ 8.03–7.86 (m, 3H), 7.68–7.56 (m,
(400 MHz, chloroform-d) δ 8.14 (s, 1H), 8.07 (d, J = 7.0 Hz, 2H), 2H), 7.55–7.37 (m, 5H), 7.29 (t, J = 7.1 Hz, 1H), 7.27 (s, 1H),
7.93 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 6.1 Hz, 2H), 7.58–7.52 (m, 7.24 (d, J = 2.3 Hz, 3H), 7.17 (t, J = 6.7 Hz, 1H), 3.64 (dt, J =
1H), 7.51–7.41 (m, 7H), 7.30 (t, J = 7.4 Hz, 1H), 7.20 (td, J = 6.1, 17.3, 7.8 Hz, 1H), 3.50 (dt, J = 17.4, 7.4 Hz, 1H), 3.02 (t, J = 7.6
2.5 Hz, 1H), 7.17–7.09 (m, 4H); 13C NMR (101 MHz, chloro- Hz, 2H), 1.83 (s, 3H); 13C NMR (101 MHz, chloroform-d) δ
form-d) δ 195.6, 189.4, 164.7, 151.4, 146.0, 145.3, 138.6, 137.3, 198.9, 197.4, 165.4, 158.4, 141.9, 140.5, 137.2, 132.0, 129.5,
133.6, 132.8, 131.9, 131.1, 129.3, 129.2, 128.9, 127.4, 126.4, 129.2, 128.6, 128.5, 128.4, 126.5, 126.1, 125.9, 119.0, 80.8, 44.7,
126.2, 120.7, 118.9, 78.3; HRMS (ESI) m/z calcd for 29.8, 11.6; HRMS (ESI) m/z calcd for C28H24N3O2S ([M + H]+)
C31H21N3O2S ([M + H]+) 500.1427, found 500.1434; the enantio- 466.1584, found 466.1578; the enantiomeric excess was deter-
meric excess was determined to be 85% (determined by HPLC mined to be 93% (determined by HPLC using a chiral AD-H
using a chiral AD-H column, hexane/2-propanol = 7/3, λ = column, hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL
254 nm, 30 °C, 0.8 mL min−1, tmajor = 13.9 min, tminor
=
min−1, tmajor = 14.9 min, tminor = 16.4 min).
12.1 min).
The procedure for the synthesis of compounds 4
Compound 3al. Yellow solid (78.6 mg, 76% yield). Mp
114.0–115.0 °C; [α]2D0 = +25.59 (c 0.17, CH2Cl2); 1H NMR To a solution of 3af (50.1 mg, 0.1 mmol, 1.0 equiv.) in THF
(400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.08 (dd, J = 8.6, 5.5 (2.0 mL) were added K2CO3 (16.6 mg, 0.12 mmol, 1.2 equiv.)
Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.78–7.69 (m, 2H), 7.44 (td, J = and iodomethane (17.0 mg, 0.12 mmol, 1.2 equiv.) in
7.7, 2.0 Hz, 6H), 7.28 (t, J = 7.5 Hz, 1H), 7.19 (h, J = 4.2 Hz, 1H), sequence. The reaction mixture was stirred at rt for 6 h. The
7.11 (d, J = 4.4 Hz, 4H), 7.07 (t, J = 8.6 Hz, 2H); 19F NMR solvent was evaporated, and then the crude mixture was puri-
(470 MHz, CDCl3) δ −102.23; 13C NMR (101 MHz, chloroform- fied by silica gel column chromatography (EtOAc/petroleum
d) δ 197.0, 190.0, 166.5 (d, J = 257.3 Hz), 166.0, 152.7, 152.6, ether = 1/5) to give 4 as a light yellow solid (47.0 mg, 91%
142.2, 137.1, 132.7, 132.7, 132.2 (d, J = 2.3 Hz), 131.9, 131.1, yield). Mp 150–153 °C; [α]1D7 = +31.00 (c 0.20, CH2Cl2); 1H NMR
129.5, 129.3, 129.3, 128.6 (d, J = 58.8 Hz), 127.3, 126.6, 126.2, (400 MHz, chloroform-d) δ 7.94 (d, J = 8.1 Hz, 2H), 7.57 (d, J =
119.4, 116.2 (d, J = 22.1 Hz), 80.4; HRMS (ESI) m/z calcd for 7.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.46 (s, 1H), 7.43 (t, J = 8.1
C31H20N3O2S ([M + H]+) 518.1333, found 518.1337; the enantio- Hz, 3H), 7.41–7.27 (m, 5H), 7.26–7.21 (m, 1H), 2.62 (s, 3H); 13
C
meric excess was determined to be 91% (determined by HPLC NMR (101 MHz, chloroform-d) δ 189.4, 177.8, 164.2, 157.4,
using a chiral AD-H column, hexane/2-propanol = 7/3, λ = 152.8, 143.9, 139.7, 137.8, 133.5, 132.1, 131.2, 130.4, 129.1,
254 nm, 30 °C, 0.8 mL min−1, tmajor = 11.3 min, tminor
9.9 min).
=
129.0, 128.9, 127.5, 126.1, 125.9, 119.2, 119.1, 90.0, 14.4;
HRMS (ESI) m/z calcd for C26H18BrN3O2S ([M + H]+) 518.0361,
Compound 3am. Yellow solid (87.0 mg, 80% yield). Mp found 518.0354; the enantiomeric excess was determined to be
124.0–125.0 °C; [α]1D4 = +10.88 (c 0.62, CH2Cl2); 1H NMR 89% (determined by HPLC using a chiral AD-H column,
(400 MHz, chloroform-d) δ 8.46 (s, 1H), 8.23 (q, J = 8.7 Hz, 4H), hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL min−1
7.91 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 6.8 Hz, 2H), 7.51–7.43 (m, tmajor = 13.5 min, tminor = 12.4 min).
5H), 7.31 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.18–7.08
,
The procedure for the synthesis of compounds 5
(m, 4H); 13C NMR (101 MHz, chloroform-d) δ 196.5, 190.1,
165.9, 154.0, 152.4 150.8, 141.4, 139.9, 137.0, 132.1, 131.4, To a solution of 3aa (42.3 mg, 0.1 mmol, 1.0 equiv.) in THF
130.7, 129.5, 129.5, 129.3, 128.8, 127.9, 127.3, 126.7, 126.1, (1.0 mL) was added 85% mCPBA (21.3 mg, 0.105 mmol, 1.05
124.1, 119.3, 80.6; HRMS (ESI) m/z calcd for C31H20N4O4S ([M equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 5 h
+ H]+) 545.1278, found 545.1286; the enantiomeric excess was and then the mixture was diluted with DCM (10 mL). The reac-
determined to be 94% (determined by HPLC using a chiral tion was quenched with saturated NaHCO3 aqueous (2 mL).
AD-H column, hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, The organic phase was separated and washed with saturated
0.8 mL min−1, tmajor = 16.0 min, tminor = 19.0 min).
NaHCO3 aqueous and brine, dried over Na2SO4, and concen-
Compound 3an. Yellow solid (62.0 mg, 66% yield). Mp trated. The crude mixture was purified by silica gel column
117.5–119.8 °C; [α]D8 = −36.67 (c 0.50, CH2Cl2); 1H NMR chromatography (EtOAc/petroleum ether = 1/3) to give 5 as a
(400 MHz, chloroform-d) δ 8.43 (s, 1H), 8.01–7.86 (m, 4H), white solid (34.6 mg, 85% yield). Mp 150–153 °C; [α]D17
=
7.75–7.64 (m, 2H), 7.52–7.40 (m, 7H), 7.29 (t, J = 7.5 Hz, 1H), −50.00 (c 0.10, CH2Cl2); 1H NMR (400 MHz, chloroform-d) δ
1.79 (s, 3H); 13C NMR (101 MHz, chloroform-d) δ 197.7, 189.9, 7.96 (d, J = 7.5 Hz, 2H), 7.88 (d, J = 6.9 Hz, 2H), 7.76 (d, J = 7.1
165.9, 154.1, 152.5, 142.5, 141.0, 137.2, 134.4, 132.1, 131.3, Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.51–7.36 (m, 8H), 7.27 (t, J =
129.6, 129.3, 128.6, 126.6, 126.4, 119.0, 81.5, 11.4; HRMS (ESI) 7.4 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H); 13C NMR (101 MHz,
m/z calcd for C26H19N3O2SCl ([M + H]+) 472.0881, found chloroform-d) δ 188.4, 170.4, 166.3, 152.6, 145.9, 138.9, 137.5,
472.0879; the enantiomeric excess was determined to be 92% 135.9, 134.2, 131.7, 129.8, 129.7, 129.2, 129.2, 129.1, 128.8,
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1145–1154 | 1151

View Article Online
Paper
Organic & Biomolecular Chemistry
126.2, 126.1, 118.9, 71.5; HRMS (ESI) m/z calcd for C25H17N3O3
([M + H]+) 408.1343, found 408.1343; the enantiomeric excess
was determined to be 91% (determined by HPLC using a
chiral AD-H column, hexane/2-propanol = 7/3, λ = 254 nm,
30 °C, 0.8 mL min−1, tmajor = 25.4 min, tminor = 15.1 min).
M. Rubin and A. N. Maslivets, Diastereoselective synthesis
of indolindiones by formal [5 + 1] double michael cyclo-
addition to 4-cinnamoylpyrrolediones, Eur. J. Org. Chem.,
2015, 2739–2744; (c) S. Wu, Y. Li, G. Xu, S. Chen, Y. Zhang,
N. Liu, G. Dong, C. Miao, H. Su, W. Zhang and C. Sheng,
Novel spiropyrazolone antitumor scaffold with potent
activity: Design, synthesis and structure–activity relation-
ship, Eur. J. Med. Chem., 2016, 115, 141–147;
(d) B. Mohammed, T. Oualid, N. Fatiha, C.-B. Nouredine,
B. Khaldoun and M. S. S. Artur, Advances in spirocyclic
hybrids: Chemistry and medicinal actions, Curr. Med.
Chem., 2018, 25, 3748–3767; (e) C. Chen and L. He,
Advances in research of spirodienone and its derivatives:
Biological activities and synthesis methods, Eur. J. Med.
Chem., 2020, 203, 112577.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Fundamental Research Funds for the Central
Universities (No. DUT18LAB16) for supporting this work.
4 (a) A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and
R. Rios, Highly enantioselective cascade synthesis of spiro-
pyrazolones, Org. Biomol. Chem., 2011, 9, 6519–6523;
(b) J.-X. Zhang, N.-K. Li, Z.-M. Liu, X.-F. Huang, Z.-C. Geng
and X.-W. Wang, Enantioselective synthesis of unsymmetri-
Notes and references
1 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, The com-
binatorial synthesis of bicyclic privileged structures or pri-
vileged substructures, Chem. Rev., 2003, 103, 893–930;
(b) F. Manetti, M. Magnani, D. Castagnolo, L. Passalacqua,
M. Botta, F. Corelli, M. Saddi, D. Deidda and A. De Logu,
Ligand-based virtual screening, parallel solution-phase and
microwave-assisted synthesis as tools to identify and syn-
thesize new inhibitors of mycobacterium tuberculosis,
ChemMedChem, 2006, 1, 973–989; (c) G. Varvounis,
cal
diaryl-substituted
spirocyclohexanonepyrazolones
through a cascade [4 + 2] double michael addition, Adv.
Synth. Catal., 2013, 355, 797–808; (c) P. Chauhan,
S. Mahajan, C. C. J. Loh, G. Raabe and D. Enders,
Streocontrolled construction of six vicinal stereogenic
centers on spiropyrazolones via organocascade Michael/
Michael/1,2-addition reactions, Org. Lett., 2014, 16, 2954–
2957; (d) P. Sun, C.-Y. Meng, F. Zhou, X.-S. Li and J.-W. Xie,
Organocatalytic asymmetric one-pot sequential reaction:
Synthesis of highly substituted spirocyclohexanepyrazo-
lones with six contiguous stereogenic carbons, Tetrahedron,
2014, 70, 9330–9336; (e) B. Han, W. Huang, W. Ren, G. He,
J.-h. Wang and C. Peng, Asymmetric synthesis of cyclo-
hexane-fused drug-like spirocyclic scaffolds containing six
contiguous stereogenic centers via organocatalytic cascade
reactions, Adv. Synth. Catal., 2015, 357, 561–568;
(f) J.-H. Li, T.-F. Feng and D.-M. Du, Construction of spiro-
cyclopropane-linked heterocycles containing both pyrazo-
lones and oxindoles through Michael/alkylation cascade
reactions, J. Org. Chem., 2015, 80, 11369–11377;
(g) M. Amireddy and K. Chen, Organocatalytic one-pot
asymmetric synthesis of functionalized spiropyrazolones
via a Michael-aldol sequential reaction, RSC Adv., 2016, 6,
77474–77480; (h) D. Hack, A. B. Dürr, K. Deckers,
P. Chauhan, N. Seling, L. Rübenach, L. Mertens, G. Raabe,
F. Schoenebeck and D. Enders, Asymmetric synthesis of
spiropyrazolones by sequential organo- and silver catalysis,
Angew. Chem., Int. Ed., 2016, 55, 1797–1800; (i) J.-H. Li,
H. Wen, L. Liu and D.-M. Du, Diastereo- and enantio-
selective synthesis of spiro-pyrrolidine-pyrazolones by
squaramide-catalyzed cascade aza-Michael/Michael reac-
tions, Eur. J. Org. Chem., 2016, 2492–2499; ( j) L. Wang,
S. Li, P. Chauhan, D. Hack, A. R. Philipps, R. Puttreddy,
K. Rissanen, G. Raabe and D. Enders, Asymmetric, three-
component, one-pot synthesis of spiropyrazolones and 2,5-
chromenediones from aldol condensation/NHC-catalyzed
Chapter
2
pyrazol-3-ones. Part IV: Synthesis and
applications, Adv. Heterocycl. Chem., 2009, 98, 143–224;
(d) V. Hadi, Y.-H. Koh, T. W. Sanchez, D. Barrios,
N. Neamati and K. W. Jung, Development of the next gene-
ration of HIV-1 integrase inhibitors: Pyrazolone as a novel
inhibitor scaffold, Bioorg. Med. Chem. Lett., 2010, 20, 6854–
6857; (e) S. Fustero, M. Sánchez-Roselló, P. Barrio and
A. Simón-Fuentes, From 2000 to mid-2010: A fruitful
decade for the synthesis of pyrazoles, Chem. Rev., 2011,
111, 6984–7034; (f) P. Chauhan, S. Mahajan and D. Enders,
Asymmetric synthesis of pyrazoles and pyrazolones employ-
ing the reactivity of pyrazolin-5-one derivatives, Chem.
Commun., 2015, 51, 12890–12907; (g) S. Liu, X. Bao and
B. Wang, Pyrazolone: A powerful synthon for asymmetric
diverse derivatizations, Chem. Commun., 2018, 54, 11515–
11529.
2 (a) M. S. Chande, P. A. Barve and V. Suryanarayan,
Synthesis and antimicrobial activity of novel spirocom-
pounds with pyrazolone and pyrazolthione moiety,
J. Heterocycl. Chem., 2007, 44, 49–53; (b) V. Kumar, K. Kaur,
G. K. Gupta and A. K. Sharma, Pyrazole containing natural
products: Synthetic preview and biological significance,
Eur. J. Med. Chem., 2013, 69, 735–753.
3 (a) X. Han, W. Yao, T. Wang, Y. R. Tan, Z. Yan,
J. Kwiatkowski and Y. Lu, Asymmetric synthesis of spiropyr-
azolones through phosphine-catalyzed [4 + 1] annulation,
Angew. Chem., Int. Ed., 2014, 53, 5643–5647;
(b) P. S. Silaichev, V. O. Filimonov, P. A. Slepukhin,
1152 | Org. Biomol. Chem., 2021, 19, 1145–1154
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
annulation reactions, Chem. – Eur. J., 2016, 22, 5123–5127;
(k) S. R. Yetra, S. Mondal, S. Mukherjee, R. G. Gonnade and
A. T. Biju, Enantioselective synthesis of spirocyclohexadie-
nones by NHC-catalyzed formal [3 + 3] annulation reaction
of enals, Angew. Chem., 2016, 128, 276–280; (l) J.-Y. Liu,
J. Zhao, J.-L. Zhang and P.-F. Xu, Quaternary carbon center
forming formal [3 + 3] cycloaddition reaction via bifunc-
tional catalysis: Asymmetric synthesis of spirocyclohexene
pyrazolones, Org. Lett., 2017, 19, 1846–1849; (m) W. Yang,
W. Sun, C. Zhang, Q. Wang, Z. Guo, B. Mao, J. Liao and
H. Guo, Lewis-base-catalyzed asymmetric [3 + 3] annulation
8 (a) H. Yoshida, H. Yanai, Y. Namiki, K. Fukatsu-Sasaki,
N. Furutani and N. Tada, Neuroprotective effects of edara-
vone: A novel free radical scavenger in cerebrovascular
injury, CNS Drug Rev., 2006, 12, 9–20; (b) Y. Sarrafi,
M. Hamzehloueian, K. Alimohammadi and S. Yeganegi,
Experimental and theoretical approaches to [1,5]-prototro-
pic generation of an azomethine ylide and a 1,3-dipolar
cycloaddition for novel spiropyrrolidine oxindoles syn-
thesis, J. Mol. Struct., 2012, 1030, 168–176; (c) L. Zou,
B. Wang, H. Mu, H. Zhang, Y. Song and J. Qu, Development
of tartaric acid derived chiral guanidines and their appli-
cation to catalytic enantioselective α-hydroxylation of
β-dicarbonyl compounds, Org. Lett., 2013, 15, 3106–3109;
(d) G. Zhu, B. Wang, X. Bao, H. Zhang, Q. Wei and J. Qu,
Catalytic asymmetric construction of spiro[pyrrolidine-2,3′-
oxindole] scaffolds through chiral phosphoric acid-cata-
lyzed 1,3-dipolar cycloaddition involving 3-amino oxi-
ndoles, Chem. Commun., 2015, 51, 15510–15513; (e) Q. Wei,
G. Zhu, H. Zhang, J. Qu and B. Wang, 1,3-Dipolar cyclo-
addition of azomethine ylides involving 3-aminooxindoles:
Versatile construction of dispiro[pyrrolidine-2,3′-oxindole]
scaffolds, Eur. J. Org. Chem., 2016, 5335–5339; (f) G. Zhu,
S. Wu, X. Bao, L. Cui, Y. Zhang, J. Qu, H. Chen and
B. Wang, Asymmetric [3 + 2] cycloaddition of 3-amino oxi-
ndole-based azomethine ylides with α,β-ynones: A straight-
forward approach to spirooxindoles incorporating 2,5-dihy-
dropyrroles and pyrroles, Chem. Commun., 2017, 53, 4714–
4717; (g) G. Zhu, S. Liu, S. Wu, L. Peng, J. Qu and B. Wang,
Assembly of indolenines, 3-amino oxindoles, and aldehydes
into indolenine-substituted spiro[pyrrolidin-2,3′-oxindoles]
via 1,3-dipolar cycloaddition with divergent diastereo-
selectivities, J. Org. Chem., 2017, 82, 4317–4327; (h) G. Zhu,
Q. Wei, H. Chen, Y. Zhang, W. Shen, J. Qu and B. Wang,
Asymmetric [3 + 2] cycloaddition of 3-amino oxindole-based
azomethine ylides and α,β-enones with divergent diastereo-
control on the spiro[pyrrolidine-oxindoles], Org. Lett., 2017,
19, 1862–1865; (i) S. Wu, G. Zhu, S. Wei, H. Chen, J. Qu and
B. Wang, Organocatalytic [3 + 2] cycloaddition of oxindole-
based azomethine ylides with 3-nitrochromenes: A facile
approach to enantioenriched polycyclic spirooxindole-chro-
mane adducts, Org. Biomol. Chem., 2018, 16, 807–815.
reaction
of
Morita–Baylis–Hillman
carbonates:
Enantioselective synthesis of spirocyclohexenes, ACS Catal.,
2017, 7, 3142–3146; (n) J. Zheng, S.-B. Wang, C. Zheng and
S.-L. You, Asymmetric synthesis of spiropyrazolones by
Rhodium-catalyzed C(sp2)−H functionalization/annulation
reactions, Angew. Chem., 2017, 129, 4611–4615.
5 (a) Q. Chen, J. Liang, S. Wang, D. Wang and R. Wang, An
asymmetric approach toward chiral multicyclic spirooxin-
doles from isothiocyanato oxindoles and unsaturated pyra-
zolones by a chiral tertiary amine thiourea catalyst, Chem.
Commun., 2013, 49, 1657–1659; (b) B.-D. Cui, S.-W. Li,
J. Zuo, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan, Quinine-cata-
lyzed asymmetric domino Michael-cyclization reaction for
the synthesis of spirocyclic oxindoles bearing two spiro
quaternary centers and three consecutive stereocenters,
Tetrahedron, 2014, 70, 1895–1902; (c) L. Liu, Y. Zhong,
P. Zhang, X. Jiang and R. Wang, Core scaffold-inspired
stereoselective synthesis of spiropyrazolones via an organo-
catalytic Michael/cyclization sequence, J. Org. Chem., 2012,
77, 10228–10234.
6 (a) M. F. Aly, G. M. El-Nagger, T. I. El-Emary, R. Grigg,
S. A. M. Metwally and S. Sivagnanam, X=Y-ZH compounds
as potential 1,3-dipoles.: Part 41. Azomethine ylide for-
mation from the reactions of α-amino acids and esters with
alloxan (strecker degradation) and with 1-phenyl-3-methyl-
pyrazolin-4,5-dione, Tetrahedron, 1994, 50, 895–906;
(b) E. D. Phillips, S. C. Hirst, M. W. D. Perry and
J. Withnall, [3 + 2] cycloaddition reactions of 4-alkyl-3-
hydroxy-2H-pyrazolo[4,3-C]isoquinolinium inner salts,
J. Org. Chem., 2003, 68, 8700–8703; (c) U. Uršič, U. Grošelj,
A. Meden, J. Svete and B. Stanovnik, Diastereoselective syn-
thesis of dimethyl(4r*,4a’r*,7a’R*)-1-aryl-6′-benzoyl-4a’-
methyl-5-oxo-1,4′,4a’,5,5′,6′-hexahydro-spiro[pyrazole-4,7′-
pyrrolo[3,4-c]pyridazine]-3′,7a’(1′η)-dicarboxylates,
9 X. Bao, S. Wei, X. Qian, J. Qu, B. Wang, L. Zou and G. Ge,
Asymmetric construction of a multi-pharmacophore-con-
taining dispirotriheterocyclic scaffold and identification of
a human carboxylesterase 1 inhibitor, Org. Lett., 2018, 20,
3394–3398.
Synthesis, 2009, 217–226; (d) L. Guideri, R. Noschese and
F. Ponticelli, Tetrahydropyridinium bromide: Useful 10 S. Wei, X. Bao, W. Wang, S. Nawaz, Q. Dai, J. Qu and
synthon to functionalized pyrrolidines, J. Heterocycl. Chem.,
2012, 49, 297–302; (e) J. Agejas and L. Ortega, Synthesis of
spirocyclic pyrazolones by oxidative C-N bond formation,
J. Org. Chem., 2015, 80, 6509–6514.
B. Wang, Enantioselective construction of dispirotrihetero-
cycles featuring a 4-aminopyrazolone motif through a
cascade Michael/cyclization process, Chem. Commun., 2020,
56, 10690–10693.
7 L. Wang, D. Yang, D. Li, X. Liu, Q. Zhao, R. Zhu, B. Zhang 11 (a) A. G. Doyle and E. N. Jacobsen, Small-molecule H-bond
and R. Wang, Catalytic asymmetric [3 + 2] cyclization reac-
tions of 3-isothiocyanato oxindoles and alkynyl ketones via
an in situ generated magnesium catalyst, Org. Lett., 2015,
17, 4260–4263.
donors in asymmetric catalysis, Chem. Rev., 2007, 107,
5713–5743; (b) J. P. Malerich, K. Hagihara and V. H. Rawal,
Chiral squaramide derivatives are excellent hydrogen bond
donor catalysts, J. Am. Chem. Soc., 2008, 130, 14416–14417.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 1145–1154 | 1153

View Article Online
Paper
Organic & Biomolecular Chemistry
12 (a) A. R. Katrizky, P. Barczynski and D. L. Ostercamp,
Mechanisms of heterocycle ring formation. Part 5. A
carbon-13 nuclear magnetic resonance study of pyrazoli-
none synthesis by the reaction of β-ketoesters with substi-
tuted hydrazines, J. Chem. Soc., Perkin Trans. 2, 1987, 969–
975; (b) V. Bobošík, A. Piklerová and A. Martvoň, Synthesis
and stability of 2-oxoisothiocyanates, Collect. Czech. Chem.
Commun., 1983, 48, 3421–3425.
1154 | Org. Biomol. Chem., 2021, 19, 1145–1154
This journal is © The Royal Society of Chemistry 2021