Organocatalytic domino sequence to asymmetrically access spirocyclic oxindole-α-methylene-γ-lactams

Article abstract of DOI:10.1016/j.tet.2021.132163

An asymmetric allylic alkylation-lactamization domino sequence of 3-aminooxindoles with Morita-Baylis-Hillman carbonates catalyzed by quinidine derivative (β-ICD) was developed. And a series of chiral spirocyclic oxindole-α-methylene-γ-lactams have been facilely prepared in good yields and stereoselectivities. This developed protocol would broaden the utilization of Morita-Baylis-Hillman carbonates in asymmetric construction of spirocyclic oxindoles.

Full text of DOI:10.1016/j.tet.2021.132163

Tetrahedron 89 (2021) 132163
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic domino sequence to asymmetrically access spirocyclic
oxindole-a-methylene-g-lactams
Zhen-Zhen Xie a, Yu-Lun Qian a, Yu Zheng a, Qing-Lan Zhao a, Jun-An Xiao b,
,
c
,
, *
Hao-Yue Xiang a, Kai Chen a **, Hua Yang a
a College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China
b College of Chemistry and Materials Science, Nanning Normal University, Nanning, 530001, Guangxi, PR China
c State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric allylic alkylation-lactamization domino sequence of 3-aminooxindoles with Morita-
Received 8 March 2021
Received in revised form
4 April 2021
Accepted 12 April 2021
Available online 21 April 2021
Baylis-Hillman carbonates catalyzed by quinidine derivative (
b-ICD) was developed. And a series of
chiral spirocyclic oxindole- -methylene- -lactams have been facilely prepared in good yields and ster-
a
g
eoselectivities. This developed protocol would broaden the utilization of Morita-Baylis-Hillman car-
bonates in asymmetric construction of spirocyclic oxindoles.
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric organocatalysis
Allylic alkylation-lactamization
Morita-Baylis-Hillman carbonates
Spirooxindole
1. Introduction
aldehydes [4g,5] or 2-bromoenals [4d,6] which are susceptible to
the attack by N-heterocyclic carbene (NHC) to form a,b-unsaturated
Spirocyclic oxindoles are widely present in an array of natural
products and pharmaceuticals as a major class of optically active
privileged scaffolds [1]. Up to now, enormous efforts have been
made to construct spirocyclic oxindoles with structural complexity
acyl azoliums and subsequently react with various 3-
aminooxindoles or oxindole imines to afford spirocyclic oxindole-
g
-lactams (Scheme 1(a)). In 2012, Jiao’s [5b] and Chi’s [5a] groups
disclosed that NHC-catalyzed [3 þ 2] annulation of -unsaturated
aldehydes with oxindole imines successfully delivered a range of
spirocyclic oxindole-
a,b
and diversity [2]. On the other hand, a-methylene-g-butyrolactams
are important building blocks in organic synthesis, many of which
possess significant biological activities, including anticancer and
anti-inflammatory effects [3]. Consequently, diversity-driven
studies for medicinal studies on the biologically related scaffolds
render it highly attractive and demanding to assemble the spi-
g
-lactams. Thereafter, NHC-catalyzed [3 þ 2]
annulation of 2-bromoenals with 3-aminooxindoles was also re-
ported [4d,6]. Besides, another major synthetic pathway was based
on 3-isothiocyanato oxindoles as nucleophiles (Scheme 1(b)) [4e,7].
Despite these impressive advances, developing new efficient
rocyclic oxindole-
advantage of the synergistic effects of both spirocycilc oxindoles
and -methylene- -butyrolactam scaffolds.
In recent years, a set of asymmetric synthetic strategies to rapid
a
-methylene-
g
-lactam, which might fully take
method to access diversified spirocyclic oxindole-g-lactams is still
extremely attractive and urgent, allowing us to broadly exploit their
medicinal potentials.
a
g
Morita-Baylis-Hillman adduct derivatives (MBHADs), as versa-
tile synthons, offer a wide array of synthetic opportunities in
asymmetric synthesis, especially in organocatalysis [8]. Essentially,
they are prone to being attacked by various nucleophiles to facilely
realize diverse functionalizations [9]. Nevertheless, we noticed that
using Morita-Baylis-Hillman carbonate as Michael acceptors for the
synthesis of spirocyclic oxindole has been rarely exploited. Wang’s
group reported an organocatalytic asymmetric domino reaction of
MBHADs and 3-hydroxyoxindoles promoted by quinidine [10].
construction of spirooxindole scaffold merging with
g
-lactam have
been established [4]. One major method relies on a,b-unsaturated
* Corresponding author.
** Corresponding author. College of Chemistry and Chemical Engineering, Central
South University, Changsha, 410083, PR China.
E-mail addresses: kaichen@csu.edu.cn (K. Chen), hyangchem@csu.edu.cn
(H. Yang).
https://doi.org/10.1016/j.tet.2021.132163
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
Table 1
Optimization of reaction Conditionsa.
Scheme 1. Synthetic Profiles for Spirocyclic Oxindole-g-Lactams.
entry Solvent
cat.
t1/t2 (h) yield(%)b drc
erd
1
2
3
4
5
6
7
8
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhC2H5
C1
C2
C3
C4
C5
C6
C7
23/5
23/5
23/5
23/5
17/6
23/5
23/5
23/5
79
76
97
trace
96
trace
trace
32
53
72
96
91
97
90
trace
86
96
97
87
>20:1 67.0:32.0
>20:1 61.0:39.0
>20:1 87.0:13.0
However, considering the significant difference in the reactivities
between N and O atoms, also, 3-aminooxindoles are expected to
serve as competent reaction partners [11]. Driven by our continued
efforts in the construction of spirooxindoles [12,13], we speculated
that a newly designed domino sequence by using 3-aminooindoles
with MBH carbonates could proceed an allylic alkylation-
e
e
>20:1 89.0:11.0
e
e
e
e
(DHQD)2PYR
(DHQD)2PHAL 23/5
C5
>20:1 77.0:23.0
>20:1 87.5:12.5
>20:1 91.0:9.0
>20:1 87.5:12.5
>20:1 79.0:21.0
>20:1 86.0:14.0
>20:1 83.5:16.5
cyclization process to rapidly assemble spirocyclic oxindole-
methylene- -lactams. Despite an achiral metal-catalyzed stepwise
protocol has been reported by Yoda and co-workers [4h], asym-
metric approach to access optically active spirocyclic oxindole-
methylene- -lactams still remains a synthetic challenge. Herein,
a-
9
10
11
12
13
14
15
16
17
18e
19f
13/6
13/6
13/4
13/4
13/10
17/6
13/5
12/5
15/5
24/5
g
o-xylene C5
CH2Cl2
DMC
THF
DMF
PhCF3
C6F6
C5
C5
C5
C5
C5
C5
C5
C5
a
-
g
e
e
we developed a new asymmetric organocatalytic domino reaction
between 3-aminooxindoles and MBHADs catalyzed by quinidine
derivative (b-ICD), enabling a facile access to enantiopure spi-
>20:1 93.5:6.5
>20:1 94.5:5.5
>20:1 95.0:5.0
>20:1 93.0:7.0
C6F6
C6F6
rooxindoles bearing
(Scheme 1(c)).
a-methylene-g-butyrolactam moieties
a
Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol, 2.0
equiv), 2a (0.10 mmol, 1.0 equiv), and catalyst (0.02 mmol, 20 mol %) in solvent
(0.5 mL) and stirred at room temperature for the specified time (t1). After that,
TsOH$H2O (0.15 mmol, 1.5 equiv) was added to the mixture and then heated at
50 ꢀC for the specified time (t2). TLC was used to monitor the reaction progress, and
time t1 and t2 were given based on the consumption of starting material 2a and the
formation of product 3aa, respectively.
2. Results and discussion
2.1. Optimization of the reaction conditions
b
Isolated yield.
In order to verify our speculation, we initiated our studies on a
reaction of MBH carbonate 1a and 3-aminooxindole 2a by using a
series of cinchona alkaloid derivatives as the catalyst in toluene
(Table 1). It is worth mentioning that a one-pot process was
designed to realize the domino sequence by sequentially pro-
ceeding the organocatalytic allylic alkylation and acid-promoted
lactamization and deprotection. Various readily available alka-
c
Determined by 1H NMR analysis.
d
Determined by HPLC on a chiral stationary phase.
Reaction was carried out in C6F6 (0.25 mL) with C5 (0.01 mmol, 10 mol%) as
e
catalyst.
f
Reaction was carried out in C6F6 (0.10 mL) with C5 (0.01 mmol, 10 mol%) as
catalyst.
loids including quinine, quinidine, cinchonine, cinchonidine and
isocupreidine ( -ICD) were tested to catalyze this reaction as
shown in Table 1 (entries 1e5). To our delight, upon using -ICD
b-
catalyst, a series of solvents were then screened, where similar
results were achieved except DMF (Table 1, entries 10e16). Inter-
estingly, upon using perfluorobenzene (C6F6) as the solvent, an
obvious improvement in enantioselectivity was observed (Table 1,
b
b
(C5) as catalysts, the target product 3aa was successfully achieved
in high yield with excellent diastereoselectivity and good enan-
tioselectivity (Table 1, entry 5). Except for C4, the other alkaloids
(C1, C2, & C3) were able to effectively promote the reaction to
deliver the target product, albeit with lower enantiomeric ratios
(er) in a slightly longer reaction time. However, two cinchona-
derived bifunctional organocatalysts (C6 & C7) were unable to
afford the desired product (Table 1, entries 6e7). Besides, cinchona
alkaloids (DHQD)2PYR and (DHQD)2PHAL have been tested, but
giving inferior results (Table 1, entries 8e9). Using C5 as the optimal
entry 17), which might be attributed to its
p-p interaction or
electrostatic interaction with substrates or catalysts [14]. Subse-
quently, using C6F6 as an additive rather than a solvent was also
examined (See Supporting Information, Table S2), and it was found
that the er value was enhanced when increasing the amount of C6F6
in ethylbenzene as the solvent, but still worse than the results by
using C6F6 as the solvent. Encouraged by these promising results,
we then investigated the amount of C6F6 and the catalyst loading.
2

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
To our delight, in the presence of 10 mol% catalyst C5, 3aa was
ultimately obtained in excellent yield (97%) with excellent stereo-
selectivity (>20:1 dr, 95.0:5.0 er) (Table 1, entry 18).
plausible adduct formed in the first step were unable to be
observed (see Supporting Information). To be noted, the enantio-
selectivity was also perfectly maintained by replacing methyl group
with ethyl group (Scheme 2, 3aa, bottom).
aUnless otherwise noted, reaction was carried out using 1a
(0.10 mmol, 1.0 equiv), 2 (0.20 mmol, 2.0 equiv), and catalyst C5
(0.01 mmol, 10 mol%) in C6F6 (0.25 mL) and stirred at room tem-
perature for the specified time (t1). After that, TsOH$H2O
(0.15 mmol, 1.5 equiv) was added to the mixture and then heated at
50 ꢀC for the specified time (t2). bIsolated yields, dr value was
determined by 1H NMR analysis, er value was determined by HPLC
2.2. Scope and limitations of substrates
After obtaining the optimal conditions in hand, we turned our
attention to investigate the functional group tolerance (Scheme 2).
Initially, various MBH carbonates (Scheme 2, 1a-1n) with different
substituents were evaluated under the standard conditions. The
results showed that electron-donating or electron-withdrawing
groups on different positions of the phenyl ring were found suit-
able for this reaction (Scheme 2, 3aa-3ka). However, introducing a
fluoro group onto the para- or ortho-position of the phenyl ring
would obviously decrease the corresponding yield (Scheme 2, 3ca
& 3ha), presumably due to the strong electron-withdrawing effect
of fluorine atom. Besides, the corresponding products were ob-
tained in good yields with good enantioselectivities and excellent
diastereoselectivities. Encouragingly, spirocyclic lactam product 3la
was also obtained in excellent yield and enantioselectivity
(>99.5:0.5 er), upon using MBH carbonate bearing a naphthyl ring,
though an elongated reaction time was required. In addition, the
furyl-substituted MBH carbonate displayed satisfactory reactivity,
giving the product 3ma in 81% yield with 92.0:8.0 er. Alkyl
substituted MBH carbonate 1o was prepared and subjected to the
optimal reaction conditions, but the desired product and the
c
on a chiral stationary phase. After single run of recrystallization.
dStructure and stereochemistry were confirmed by X-ray analysis
and circular dichroism spectroscopy.
The absolute configuration was successfully confirmed by X-ray
crystallography and circular dichroism spectroscopy (See details in
Supporting Information). The crystallography data of racemic
mixtures demonstrate that the plausible configurations should be
(3R, 30R) or (3S, 30S). To figure out the dominant enantiomer in this
asymmetric reaction, the CD spectrum of 3ia was also determined.
As shown in Fig. S1 (See Supporting Information), the comparison
between experimental and predicted CD spectra suggests that the
dominant configuration of the product 3ia can be assigned to be
(3R, 30R) (Supporting Information. Fig. S2). These results can be also
supported by Wang’s work [10], in which the absolute configura-
tion of similar spirooxindoles bearing
a-methylene-g-butyr-
olactone motifs was confirmed to be (C3R, C30R) by X-ray analysis.
Subsequently, various substituted 3-aminooxindoles (2b-2f)
were also examined in the protocol. The results are listed in Scheme
3. It was found that electron-donating substituents on the phenyl
ring of 3-aminooxindole were well tolerated, giving the corre-
sponding products 3ab-3ae in good to excellent yields with
excellent diastereoselectivities and good enantioselectivities. The
presence of a fluoro group severely affected the yield, and the
desired product 3af was furnished in moderate yield, albeit with
comparable stereoselectivity. However, the stereoselectivity was
markedly sabotaged upon replacing Bn with Me, which might be
attributed to the change of steric effect (see Supporting
Information).
aUnless otherwise noted, reaction was carried out using 1a
(0.10 mmol, 1.0 equiv), 2 (0.20 mmol, 2.0 equiv), and catalyst C5
Scheme 2. Scope of Morita-Baylis-Hillman Carbonates 1a,b
.
Scheme 3. Scope of 3-Aminooxindoles 2a,b
.
3

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
spirocyclic oxindole-
a
-methylene-
g
-lactams were obtained in
good to excellent yields with excellent diastereoselectivitie and
good enantioselectivities. Moreover, this strategy would broaden
the library of spirooxindole heterocycles, paving the way to the
diversity-driven investigation on the biological activities of diffi-
cultly accessible heterocycles.
4. Experimental section
Unless otherwise noted, all solvents and reagents were pur-
chased from commercial suppliers and used without further puri-
fication. Flash chromatography was carried out on silica gel
(200e300 mesh). 1H NMR spectra were recorded at 400 MHz. The
chemical shifts were recorded in ppm relative to tetramethylsilane
and with the solvent resonance as the internal standard. Data were
reported as follows: chemical shift, multiplicity (s, single; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad), coupling
constants (Hz), integration. 13C NMR data were collected at
100 MHz with complete proton decoupling. Chemical shifts were
reported in ppm from the tetramethylsilane with the solvent
resonance as an internal standard. Infrared spectra (IR) were
measured by FT-IR apparatus. ECD spectra was recorded with JASCO
J-815 spectrometer. High resolution mass spectroscopy (HRMS)
was recorded on TOF MS ES þ Mass spectrometer and acetonitrile
was used to dissolve the sample. MBH Carbonates 1a-1n were
prepared according to the reported protocols [15], and 3-
aminooxindole derivatives 2 were prepared according to the liter-
ature procedure with minor modifications [4h].
Scheme 4. Scale-up Experiment and Transformation of the Spirooxindole Compound.
Scheme 5. Plausible Mechanism.
(0.01 mmol, 10 mol%) in C6F6 (0.25 mL) and stirred at room tem-
perature for the specified time (t1). After that, TsOH$H2O
(0.15 mmol, 1.5 equiv) was added to the mixture and then heated at
50 ꢀC for the specified time (t2). bIsolated yields, dr value was
determined by 1H NMR analysis, er value was determined by HPLC
on a chiral stationary phase.
To further testify the scalability of this protocol, a scale-up
experiment of 1g and 2a was performed as shown in Scheme 4a.
Satisfyingly, the corresponding product 3ga was obtained in 78%
yield with 89.0:11.0 er and >20:1 dr, while the enantiopurity of 3ga
was improved to 96.5:3.5 er through a single run of recrystalliza-
tion. To demonstrate the synthetic utility of the resulting spi-
rocyclic oxindole, the transformations of product 3aa (96.5:3.5 er)
were conducted (Scheme 4b). Pleasingly, the double-bond shifting
product 4 can be effectively obtained in a moderate yield (62%)
without eroding enantioselectivity (96.0:4.0 er) in the presence of
NaH. Further experiments showed that compound 3aa could un-
dergo Michael addition with nitromethane in the presence of DBU,
successfully delivering the corresponding derivate 5 in an excellent
yield (91%) and enantioselectivity (98.5:1.5 er).
4.1. General procedures
4.1.1. General procedures for the synthesis of 3-aminooxindoles 2
To a suspension of 3-(hydroxyimino)-1-methylindolin-2-ones
[16] (2 mmol, 1 equiv.) in methanol (4 mL) was added Pd/C (10%
palladium on carbon) (10 wt%). The mixture was stirred under a
hydrogen atmosphere at room temperature for 10 h. Thereafter, the
vessel was evacuated and backfilled with Ar three times. Then di-
tert-butyl dicarbonate (2.2 mmol, 1.2 equiv.) was added and the
reaction mixture was stirred at room temperature for additional
4e9 h. After completion of the reaction (confirmed by TLC analysis),
Pd/C was removed by filtration. The obtained filtrate was concen-
trated to dryness and the resulting residue was purified by flash
column chromatography (EA/PE ¼ 1/4) on silica gel to yield the
crude substrates. Finally, the corresponding products can be further
purified through recrystallization over hexanes and CH2Cl2. The
data of the known compounds 2 were consistent with the previ-
ously reports [17]. Characterization data of new compounds 2c, 2d
and 2f are provided herein.
On the basis of our experimental results and the absolute
configuration of the product 3, a possible reaction mechanism is
tentatively proposed in Scheme 5. Initially, a SN2’ attack of cinchona
4.1.2. General experimental procedure for the synthesis of spirocy-
clic lactams 3
To a solution of MBH carbonates 1 (0.2 mmol, 2.0 equiv.) and 3-
aminooxindoles 2 (0.1 mmol, 1.0 equiv.) in hexafluorobenzene
alkaloids (b-ICD) on the MBHAD 1a followed by an intermolecular
Michael addition of the enolized 2a gives the asymmetric allylic
alkylation product Int-1. Subsequently, acid-promoted depro-
tection and lactamization would facilely afford the desired spi-
rooxindole 3aa (Scheme 5).
(C6F6) was added b-ICD (0.01 mmol, 10 mol%). The reaction mixture
was stirred at room temperature until the TLC analysis showed the
complete consumption of starting materials 2 (11e36 h). Subse-
quently, 1.5 equiv. of TsOH$H2O was added and stirred at 50 ꢀC
(preheated). After the completion of the reaction, the resulting
residue was purified by column chromatography (EA/PE ¼ 2/3) to
3. Conclusion
In conclusion, we have established an organocatalytic protocol
of 3-aminooxindole with Morita-Baylis-Hillman carbonates to
afford the corresponding chiral spirocyclic oxindole-a-methyl-g-
lactams 3.
assemble novel chiral spirocyclic oxindole-a-methylene-g-lactam
skeleton. In this protocol, the asymmetric allylic alkylation-
lactamization domino sequence was effectively realized by
4.1.3. General procedures for the synthesis of 4
A suspension of compound 3aa (38 mg, 1.0 mmol) in dry DMSO
employing
b-ICD as the catalyst in perfluorobenzene. The resulting
(1.0 mL) with vigorous stirring was cooled to 0 ꢀC, then sodium
4

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
hydride was added (4 mg, 0.2 mmol) under argon atmosphere. The
mixture was stirred at 30 ꢀC for overnight and quenched with
1.0 mL water under 0 ꢀC. The mixture was extracted with EtOAc,
dried over anhydrous Na2SO4 and concentrated in vacuo. The res-
idue was purified by column chromatography on silica gel (EA/
PE ¼ 2/3) to give the desired compound 4 (62%, 96.0:4.0 er).
Spirocyclic lactam (3ba). White solid (42 mg, yield 90%) from
20
34 mg of 2a; er 92.5:7.5; [
247e248 ꢀC; IR (neat)
1H NMR (d6-DMSO, 400 MHz)
a
]
¼ ꢁ44.9 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3165, 1706, 1611, 1172, 1009, 729, 496 cmꢁ1
;
d
8.89 (s, 1H), 7.79 (dd, J ¼ 8.8, 0.8 Hz,
1H), 7.52 (d, J ¼ 8.4 Hz, 2H), 7.32e7.28 (m, 1H), 7.25e7.19 (m, 4H),
6.96 (d, J ¼ 8.4 Hz, 2H), 6.64 (d, J ¼ 8.0 Hz, 1H), 6.56 (dd, J ¼ 7.2,
0.8 Hz, 2H), 6.12 (d, J ¼ 3.6 Hz 1H), 5.23 (d, J ¼ 2.8 Hz, 1H), 4.91 (d,
4.1.4. General procedures for the synthesis of 5
The reaction was performed according a reported literature [18].
To a solution of compound 3aa (38 mg, 0.1 mmol) in anhydrous
J ¼ 12.0 Hz, 1H), 4.75 (t, J ¼ 3.2 Hz, 1H), 4.43 (d, J ¼ 16.0 Hz, 1H); 13
C
{1H} NMR (d6-DMSO, 100 MHz)
d 175.2, 170.1, 143.3, 142.5, 135.7,
133.7, 132.3, 131.9, 130.5, 128.8, 127.7, 127.5, 126.8, 124.9, 123.6,
122.0, 115.7109.8, 67.6, 55.4, 55.1, 43.2; HRMS (TOF-ESI) m/z [M þ
Na]þ calcd for C25H19BrN2NaOþ2 481.0522, found 481.0498; HPLC
analysis (CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV
254 nm) tR ¼ 21.0 min (minor), 24.0 min (major).
nitromethane (0.332 mL, 6.2 mmol) was added DBU (3
mL,
0.02 mmol). The mixture was stirred at rt. for 16 h. The solvent was
evaporated under reduced pressure and the crude mixture was
purified by column chromatography on silica gel (EA/PE ¼ 2/3) to
give the desired compound 5 (91%, 98.5:1.5 er).
Spirocyclic lactam (3ca). White solid (25 mg, yield 63%) from
20
34 mg of 2a; er 93.0:7.0; [
201e202 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ15.0 (c ¼ 0.05 in CH2Cl2); m.p.
D
4.2. Characterization data of compound 2,3aa-3ma, 3 ab-3af, 4
and 5
n
3196, 1698, 1612, 1342, 1171, 755, 455 cmꢁ1
7.55 (dd, J ¼ 7.2, 0.8 Hz, 1H), 7.24e7.10
;
d
(m, 5H), 7.03e6.99 (m, 2H), 6.90 (t, J ¼ 8.8 Hz, 2H), 6.73 (s, 1H), 6.49
(d, J ¼ 7.6 Hz, 1H), 6.44 (d, J ¼ 7.2 Hz, 2H), 6.34 (d, J ¼ 3.6 Hz, 1H),
5.35 (d, J ¼ 2.8 Hz, 1H), 4.98 (d, J ¼ 16.0 Hz, 1H), 4.46 (t, J ¼ 3.2 Hz,
1H), 4.16 (d, J ¼ 16.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz)
3-Aminooxindole (2c). White solid (684 mg, yield 97%) from
533 mg of 1-benzyl-3-(hydroxyimino)-7-methylindolin-2-one
which was prepared according the literature without purified [3]
m.p. 212e213 ꢀC; IR (neat)
594 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
(m, 4H), 6.94e6.93 (m, 2H), 5.47 (br s, 1H), 5.27e5.16 (m, 3H), 2.23
(s, 3H) 1.46 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz)
175.8, 155.7,
n
3362, 1728, 1503, 1159, 923, 726,
7.31e7.28 (m, 2H), 7.25e7.18
d
172.76 (d, JC-F ¼ 387.4 Hz), 162.78 (d, JC-F ¼ 247.4 Hz), 143.3, 140.3,
d
134.6, 131.7 (d, JC-F ¼ 8.1 Hz), 129.1 (d, JC-F ¼ 3.2 Hz), 128.6, 127.5,
127.0, 126.5, 123.6 (d, JC-F ¼ 24.3 Hz), 118.1, 115.6 (d, JC-F ¼ 21.4 Hz),
109.7, 67.8, 56.6, 44.0; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for
d
140.8, 137.4, 133.0, 128.9, 127.7, 127.2, 125.8, 123.0, 122.3, 120.0, 80.5,
C
25H19FN2NaOþ2 421.1323, found 421.1307; HPLC analysis (CHIR-
53.4, 45.4, 28.3, 18.7; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for
ALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
C
21H24N2NaOþ3 375.1679, found 375.1679.
tR ¼ 17.5 min (major), 20.1 min (minor).
3-Aminooxindole (2d). White solid (667 mg, yield 91%) from
561 mg of 1-benzyl-3-(hydroxyimino)-5,7-dimethylindolin-2-one
Spirocyclic lactam (3da). White solid (38 mg, yield 93%) from
20
34 mg of 2a; er 93.0:7.0; [
234e235 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
d
a
]
¼ ꢁ24.9 (c ¼ 0.05 in CH2Cl2); m.p.
D
which was prepared according the literature without purified [3]
n
3350, 1716, 1609, 1360, 1173, 762, 545 cmꢁ1
7.54 (d, J ¼ 6.8 Hz, 1H), 7.20e7.13 (m,
;
m.p. 206e207 ꢀC; IR (neat)
n
3352, 1727, 1516, 1339, 1159, 920,
693 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
7.32e7.29 (m, 2H), 7.25e7.17
(m, 3H), 7.09 (s, 1H), 6.77 (s, 1H), 5.20e5.16 (m, 4H), 2.26 (s, 3H),
2.20 (s, 3H), 1.48 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz)
175.6,
d
3H), 7.08 (t, J ¼ 7.6 Hz,1H), 6.96 (d, J ¼ 8.4 Hz,1H), 6.75 (d, J ¼ 8.8 Hz,
3H), 6.44 (d, J ¼ 7.2 Hz, 1H), 6.37 (d, J ¼ 7.2 Hz, 2H), 6.32 (d,
J ¼ 3.2 Hz, 1H), 5.37 (d, J ¼ 2.4 Hz, 1H), 5.05 (d, J ¼ 15.6 Hz, 1H), 4.45
(t, J ¼ 3.2 Hz, 1H), 4.13 (d, J ¼ 16.0 Hz, 1H), 3.78 (s, 3H); 13C{1H} NMR
d
155.7, 138.3, 137.4, 133.5, 132.6, 128.8, 127.7, 127.2, 125.8, 123.1, 119.7,
80.6, 53.5, 45.3, 28.3, 20.7, 18.5; HRMS (TOF-ESI) m/z [M þ Na]þ
calcd for C22H26N2NaO3þ 389.1836, found 389.1831.
(CDCl3, 100 MHz)
d 174.9, 171.2, 159.6, 143.3, 140.6, 134.6, 131.1,
130.4, 128.5, 127.33, 127.26, 126.5, 125.1, 123.8, 123.4, 118.0, 114.0,
3-Aminooxindole (2f). White solid (606 mg, yield 85%) from
541 mg of 1-benzyl-7-fluoro-3-(hydroxyimino)indolin-2-one
which was prepared according the literature without purified [3]
109.7, 68.0, 56.8, 55.1, 44.0; HRMS (TOF-ESI) m/z [M þ Na]þ calcd
for
C
26H22N2NaOþ3 433.1523, found 433.1520; HPLC analysis
(CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
m.p. 72e73 ꢀC; IR (neat)
n
3346, 2976, 1707, 1352, 1158, 959,
7.39e7.37 (m, 2H), 7.32e7.27
tR ¼ 21.0 min (minor), 22.5 min (major).
770 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
Spirocyclic lactam (3ea). White solid (31 mg, yield 79%) from
20
(m, 3H), 7.23e7.14 (m, 1H), 6.98e6.96 (m, 2H), 5.29 (br s, 1H),
34 mg of 2a; er 93.0:7.0; [
240e241 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ ꢁ23.4 (c ¼ 0.05 in CH2Cl2); m.p.
D
5.15e4.97 (m, 3H), 1.46 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz)
n
3172, 1701, 1612, 1345, 1172, 817, 757 cmꢁ1
;
d
174.3, 155.5, 147.4 (d, JC-F ¼ 244.4 Hz), 136.7, 129.8, 129.4 (d, JC-
¼ 8.6 Hz), 128.6, 127.7, 123.6 (d, JC-F ¼ 6.2 Hz), 120.3, 117.3 (d, JC-
¼ 19.5 Hz), 80.8, 53.9, 45.8, 28.2; HRMS (TOF-ESI) m/z [M þ Na]þ
d
7.53 (d, J ¼ 6.8 Hz, 1H), 7.21e7.13 (m,
3H), 7.09e7.02 (m, 4H), 6.93 (d, J ¼ 8.0 Hz, 2H), 6.43e6.40 (m, 3H),
6.35 (d, J ¼ 3.2 Hz, 1H), 6.29 (s, 1H), 5.38 (d, J ¼ 2.4 Hz, 1H), 5.02 (d,
F
F
calcd for C20H21FN2NaO3þ 379.1428, found 379.1442.
J ¼ 15.9 Hz,1H), 4.46 (s,1H), 4.13 (d, J ¼ 16.0 Hz,1H), 2.35 (s, 3H); 13
C
Spirocyclic lactam (3aa). White solid (37 mg, yield 97%) from
34 mg of 2a, er 95.0:5.0; White solid (36 mg, yield 95%) from 34 mg
{1H} NMR (CDCl3, 100 MHz)
d 174.9, 170.9, 143.3, 140.3, 138.0, 134.6,
130.4, 130.2, 129.9, 129.3, 128.5, 127.3, 127.2, 126.5, 123.7, 123.4,
118.1, 109.7, 67.9, 57.2, 44.0, 21.3; HRMS (TOF-ESI) m/z [M þ Na]þ
calcd for C26H22N2NaOþ2 417.1573, found 417.1567; HPLC analysis
(CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
tR ¼ 17.7 min (major), 19.1 min (minor).
of 2a (replacing methyl group with ethyl group), er 95.5:4.5;
20
[
a
]
¼ ꢁ16.5 (c ¼ 0.05 in CH2Cl2); m.p. 138e139 ꢀC; IR (neat)
n
D
3220, 1712, 1611, 1354, 1174, 736, 455 cmꢁ1 1H NMR (CDCl3,
;
400 MHz)
d
7.55 (d, J ¼ 6.6 Hz, 1H), 7.32 (t, J ¼ 7.3 Hz, 1H), 7.23e7.11
(m, 5H), 7.08e7.01 (m, 5H), 6.41 (d, J ¼ 7.6 Hz 1H), 6.35 (d, J ¼ 7.2 Hz,
2H), 6.29 (d, J ¼ 3.2 Hz, 1H), 5.35 (d, J ¼ 2.4 Hz, 1H), 4.96 (d,
J ¼ 16.0 Hz, 1H), 4.47 (s, 1H), 4.13 (d, J ¼ 16.0 Hz, 1H); 13C{1H} NMR
Spirocyclic lactam (3fa). White solid (39 mg, yield 85%) from
20
34 mg of 2a; er 88.5:11.5; [
165e166 ꢀC; IR (neat)
552 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
a
]
¼ þ55.1 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3060, 1705, 1613, 1465, 1343, 1753,
(CDCl3, 100 MHz)
d
174.9, 171.1, 143.3, 140.3, 134.7, 133.3, 130.4,
d
7.56 (d, J ¼ 6.8 Hz, 2H), 7.44
130.0, 128.6, 128.3, 127.3, 127.2, 126.4, 123.7, 123.4, 118.1, 109.8, 67.9,
57.4, 44.0; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for C25H20N2NaOþ2
403.1417, found 403.1397; HPLC analysis (CHIRALCEL IA, hexane/i-
PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm) tR ¼ 15.6 min (major),
18.2 min (minor).
(d, J ¼ 8.0 Hz, 1H), 7.22e7.08 (m, 7H), 6.52e6.48 (m, 3H), 6.35e6.34
(m, 2H), 5.24e2.22 (m, 2H), 5.50 (d, J ¼ 16.0 Hz, 1H), 4.19 (d,
J ¼ 16.0 Hz,1H); 13C{1H} NMR (CDCl3,100 MHz)
d 174.8,143.0,134.8,
134.1, 132.7, 130.4, 129.7, 128.6, 127.7, 127.3, 127.1, 126.5, 126.3, 125.2,
123.3, 118.6, 109.6, 67.5, 54.3, 44.1; HRMS (TOF-ESI) m/z [M þ Na]þ
5

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
calcd for C25H19BrN2NaOþ2 481.0522, found 481.0522; HPLC analysis
(CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
tR ¼ 14.6 min (major), 21.0 min (minor).
1H), 5.38 (d, J ¼ 3.2 Hz, 1H), 4.98 (d, J ¼ 16.0 Hz, 1H), 4.43 (t,
J ¼ 3.2 Hz, 1H), 4.18 (d, J ¼ 16.0 Hz, 1H); 13C{1H} (CDCl3, 100 MHz)
d
174.6, 170.6, 143.2, 139.6, 135.7, 134.6, 132.8, 131.6, 130.7, 130.2,
Spirocyclic lactam (3ga). White solid (40 mg, yield 96%) from
128.7, 128.6, 127.5, 126.8, 126.5, 123.7, 123.6, 122.5, 118.5, 109.9, 67.6,
56.8, 44.1 HRMS (TOF-ESI) m/z [M
Na]þ calcd for
C
25H19BrN2NaOþ2 481.0522, found 481.0523; HPLC analysis (CHIR-
20
34 mg of 2a; er 91.5:8.5; [
217e218 ꢀC; IR (neat)
1H NMR (DMSO-d6, 400 MHz)
a
]
¼ ꢁ30.1 (c ¼ 0.05 in CH2Cl2); m.p.
þ
D
n
3187, 1700, 1489, 1343, 1173, 822, 690 cmꢁ1
8.85 (s, 1H), 7.74 (d, J ¼ 6.8 Hz, 1H),
;
d
ALCEL IG, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
7.34 (d, J ¼ 8.4 Hz, 2H), 7.27e7.23 (m, 1H), 7.19e7.13 (m, 4H), 6.97 (d,
J ¼ 8.4 Hz, 2H), 6.60 (d, J ¼ 8.0 Hz, 1H), 6.52 (d, J ¼ 6.8 Hz, 2H), 6.07
(d, J ¼ 3.6 Hz, 1H), 5.18 (d, J ¼ 2.8 Hz, 1H), 4.85 (d, J ¼ 16.0 Hz, 1H),
4.72 (t, J ¼ 2.8 Hz, 1H), 4.38 (d, J ¼ 16.4 Hz, 1H); 13C{1H} NMR
tR ¼ 36.0 min (minor), 43.9 min (major).
Spirocyclic lactam (3la). White solid (41 mg, yield 95%) from
20
34 mg of 2a; er 99.5:0.5; [
242e243 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
d
a
]
¼ þ27.3 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3193, 1700, 1612, 1341, 1173, 755, 478 cmꢁ1
7.84e7.79 (m, 2 H), 7.75e7.72 (m, 2H),
;
(DMSO-d6, 100 MHz)
d
175.2, 170.2, 143.2, 142.6, 135.7, 133.4, 133.3,
132.0, 130.5, 128.9, 128.7, 127.64, 127.56, 126.8, 125.0, 123.6, 115.7,
7.45 (t, J ¼ 7.6 Hz, 1H), 7.33e7.29 (m, 1H), 7.24e7.17 (m, 2H),
7.14e7.09 (m, 1H), 7.04e7.00 (m, 2H), 6.87 (t, J ¼ 7.6 Hz, 2H), 6.77 (s,
1H), 6.43 (d, J ¼ 3.2 Hz, 1H), 6.17 (d, J ¼ 8.0 Hz, 1H), 6.01 (d,
J ¼ 7.6 Hz,1H), 5.43 (t, J ¼ 3.2 Hz,1H), 5.36 (d, J ¼ 2.8 Hz,1H), 4.83 (d,
J ¼ 16.0 Hz, 1H), 3.98 (d, J ¼ 16.0 Hz, 1H) 13C{1H} NMR (CDCl3,
109.7, 67.7, 55.0, 43.1; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for
C
25H19ClN2NaOþ2 437.1027, found 437.1017; HPLC analysis (CHIR-
ALCEL IG, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
tR ¼ 32.2 min (major), 34.9 min (minor).
Spirocyclic lactam (3ha). White solid (30 mg, yield 75%) from
100 MHz) d 175.0, 170.9, 143.3, 141.7, 134.3, 133.6, 132.6, 130.44,
20
34 mg of 2a; er 92.0:8.0; [
188e189 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ ꢁ17.4 (c ¼ 0.05 in CH2Cl2); m.p.
130.40, 128.9, 128.7, 128.3, 128.1, 127.0, 125.9, 125.7, 125.6, 125.5,
123.7, 123.4, 121.9, 119.2, 109.9, 68.1, 51.2, 43.9; HRMS (TOF-ESI) m/z
[M þ Na]þ calcd for C29H22N2NaOþ2 453.1573, found 453.1563; HPLC
analysis (CHIRALCEL OD-H, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV
254 nm) tR ¼ 20.7 min (major), 44.9 min (minor).
D
n
3189, 1710, 1462, 1175, 797, 733, 550 cmꢁ1
;
d
7.53 (q, J ¼ 7.2 Hz, 2H), 7.31e7.27 (m,
1H), 7.19e7.06 (m, 6H), 6.89e6.84 (m, 2H), 6.47 (d, J ¼ 7.6 Hz, 3H),
6.31 (d, J ¼ 3.2 Hz, 1H), 5.30 (d, J ¼ 2.4 Hz, 1H), 5.02e4.95 (m, 2H),
4.19 (d, J ¼ 16.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz)
d
174.8,
Spirocyclic lactam (3ma). White solid (30 mg, yield 81%) from
20
170.7, 163.0, 160.6, 142.9, 140.2, 134.8, 131.7 (d, JC-F ¼ 2.9 Hz), 130.3,
34 mg of 2a; er 92.0:8.0; [
196e197 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ27.3 (c ¼ 0.05 in CH2Cl2); m.p.
D
129.7 (d, JC-F ¼ 8.4 Hz), 128.6, 127.3, 127.0, 126.5, 124.5 (d, JC-
n
3263, 1711, 1611, 1347, 1174, 735, 547 cmꢁ1
;
¼ 3.5 Hz), 124.3, 123.5, 120.9 (d, JC-F ¼ 13.3 Hz), 117.9, 115.0 (d, JC-
d
7.47 (d, J ¼ 7.2 Hz, 1H), 7.23e7.21 (m,
F
¼ 22.5 Hz), 109.6, 67.3, 48.3, 44.0; HRMS (TOF-ESI) m/z [M þ Na]þ
5H), 7.14 (t, J ¼ 7.2 Hz, 1H), 6.90e6.83 (m, 2H), 6.59 (d, J ¼ 8.0 Hz,
1H), 6.44 (s, 1H), 6.33e6.30 (m, 2H), 6.25 (d, J ¼ 2.8 Hz, 1H), 5.51 (d,
J ¼ 2.4 Hz, 1H), 5.00 (d, J ¼ 15.9 Hz, 1H), 4.63 (s, 1H), 4.36 (d,
F
calcd for C25H19FN2NaOþ2 421.1323, found 421.1300; HPLC analysis
(CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
tR ¼ 14.2 min (major), 18.3 min (minor).
J ¼ 15.9 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz)
d 174.5, 170.1, 148.7,
Spirocyclic lactam (3ia). White solid (32 mg, yield 81%) from
143.2, 142.6, 138.4, 134.9, 130.5, 128.7, 127.5, 127.2, 127.1, 123.8,
123.5,118.6, 110.7, 109.9,109.7, 66.5, 50.6, 44.1; HRMS (TOF-ESI) m/z
[M þ Na]þ calcd for C23H18N2NaOþ3 393.1210, found 393.1202; HPLC
analysis (CHIRALCEL IG, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV
254 nm) tR ¼ 33.7 min (major), 48.4 min (minor).
20
34 mg of 2a; er 97.0:3.0 [
271e272 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ15.1 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3175, 2919, 1707, 1341, 945, 752, 487 cmꢁ1
;
d
7.55 (d, J ¼ 7.2 Hz, 1H), 7.49 (d,
J ¼ 7.6 Hz, 1H), 7.23e7.12 (m, 5H), 7.09e7.03 (m, 3H), 6.62 (s, 1H),
6.42 (d, J ¼ 7.6 Hz, 1H), 6.36e6.31 (m, 3H), 5.24 (d, J ¼ 2.4 Hz, 1H),
5.05 (d, J ¼ 16.0 Hz, 1H), 4.85 (t, J ¼ 2.8 Hz, 1H), 4.10 (d, J ¼ 15.9 Hz,
Spirocyclic lactam (3 ab). White solid (39 mg, yield 99%) from
20
35 mg of 2b; er 91.5:8.5; [
262e263 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ ꢁ29.4 (c ¼ 0.05 in CH2Cl2); m.p.
D
1H), 1.62 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz)
d
175.2, 171.0,
n
3267, 1979, 1712, 1495, 1159, 922, 694 cmꢁ1
7.36e7.27 (m, 3H), 7.10e6.97 (m, 7H),
;
143.2, 141.9, 138.2, 134.7, 132.4, 130.9, 130.4, 130.2, 128.7, 128.1,
128.0, 127.2, 126.5, 126.4, 124.0, 123.3, 118.3, 109.8, 67.9, 52.6, 44.1,
19.4; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for C26H22N2NaOþ2
417.1573, found 417.1555; HPLC analysis (CHIRALCEL IA, hexane/i-
PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm) tR ¼ 12.0 min (major),
15.6 min (minor).
d
6.66 (s, 1H), 6.47e6.23 (m, 4H), 5.37 (s, 1H), 4.94 (d, J ¼ 15.6 Hz, 1H),
4.47 (s, 1H), 4.11 (d, J ¼ 15.6 Hz, 1H), 2.37 (s, 3H); 13C{1H} NMR
(CDCl3, 100 MHz)
d 174.9, 171.0, 140.9, 140.4, 134.8, 133.5, 133.1,
130.7, 130.0, 128.6, 128.3, 127.3, 127.2, 126.5, 124.4, 118.0, 109.5, 68.0,
57.4, 44.0, 21.2; HRMS (TOF-ESI) m/z [M þ Na]þ calcd for
Spirocyclic lactam (3ja). White solid (39 mg, yield 98%) from
C
26H22N2NaOþ2 417.1573, found 417.1556; HPLC analysis (CHIRALCEL
20
34 mg of 2a; er 90.0:10.0; [
225e226 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ15.1 (c ¼ 0.05 in CH2Cl2); m.p.
IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm) tR ¼ 11.3 min
D
n
2919, 1699, 1462, 1175, 936, 755, 621 cmꢁ1
;
(major), 17.1 min (minor).
d
7.54 (d, J ¼ 7.2 Hz, 1H), 7.22e7.10 (m,
Spirocyclic lactam (3ac). White solid (36 mg, yield 91%) from
20
6H), 6.99 (t, J ¼ 8.0 Hz, 1H), 6.80e6.75 (m, 3H), 6.50e6.49 (m, 3H),
6.33 (s,1H), 5.36 (s,1H), 4.95 (d, J ¼ 15.9 Hz,1H), 4.46 (s,1H), 4.19 (d,
35 mg of 2c; er 89.5: 10.5; [
236e237 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ24.7 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
2919, 1703,1447, 1183, 1025, 732, 482 cmꢁ1
;
J ¼ 16.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz)
d
174.7, 170.8, 162.6
d
7.44 (d, J ¼ 6.8 Hz, 1H), 7.35 (t,
(d, JC-F ¼ 246.8 Hz), 143.3, 139.9, 135.9 (d, JC-F ¼ 7.5 Hz), 134.7, 130.6,
130.0 (d, JC-F ¼ 8.1 Hz), 128.6, 127.4, 127.0, 126.5, 125.7, 123.7, 123.6,
118.4, 116.8 (d, JC-F ¼ 22.1 Hz), 115.4 (d, JC-F ¼ 21.0 Hz). 109.8, 67.7,
J ¼ 7.2 Hz, 1H), 7.23 (d, J ¼ 7.6 Hz, 1H), 7.12e7.00 (m, 7H), 6.45 (s,
1H), 6.34 (d, J ¼ 3.2 Hz, 1H), 6.22 (d, J ¼ 7.2 Hz, 2H), 5.37 (d,
J ¼ 3.2 Hz, 1H), 5.12 (d, J ¼ 17.2 Hz, 1H), 4.53e4.83 (m, 2H), 2.02 (s,
56.8, 44.0; HRMS (TOF-ESI) m/z [M
þ
Na]þ calcd for
3H); 13C{1H} NMR (CDCl3, 100 MHz)
d 175.8, 170.9, 141.5, 140.4,
C
25H19FN2NaOþ2 421.1323, found 421.1334; HPLC analysis (CHIR-
136.8, 134.4, 133.4, 130.2, 128.7, 128.6, 128.4, 128.0, 126.7, 125.0,
123.5, 121.8, 120.4, 118.0, 67.2, 57.7, 45.2, 18.5; HRMS (TOF-ESI) m/z
[M þ Na]þ calcd for C26H22N2NaOþ2 417.1573, found 417.1557; HPLC
analysis (CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV
254 nm) tR ¼ 13.5 min (major), 15.2 min (minor).
ALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV 254 nm)
tR ¼ 16.5 min (major), 17.7 min (minor).
Spirocyclic lactam (3ka). White solid (43 mg, yield 94%) from
20
34 mg of 2a; er 93.5:6.5; [
194e195 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ þ11.7 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3193, 1704, 1612, 1347, 1173, 758, 553 cmꢁ1
7.55e7.52 (m, 1H), 7.44e7.42 (m, 1H),
;
Spirocyclic lactam (3ad). White solid (32 mg, yield 78%) from
20
d
37 mg of 2d; er 91.5:8.5; [
252e253 ꢀC; IR (neat)
1H NMR (DMSO-d6, 400 MHz)
a
]
¼ þ14.2 (c ¼ 0.05 in CH2Cl2); m.p.
D
7.23 (dd, J ¼ 6.4, 1.2 Hz, 1H), 7.20e7.13 (m, 5H), 7.07 (t, J ¼ 8.0 Hz,
n
2856,1984,1706,1448,1153, 929, 747 cmꢁ1
8.83 (s, 1H), 7.44 (s, 1H), 7.40e7.36
;
1H), 7.00 (d, J ¼ 7.6 Hz, 1H), 6.50 (t, J ¼ 6.4 Hz, 4H), 6.37e6.35 (m,
d
6

Z.-Z. Xie, Y.-L. Qian, Y. Zheng et al.
Tetrahedron 89 (2021) 132163
(m, 1H), 7.27 (t, J ¼ 8.0 Hz, 2H), 7.14e7.06 (m, 3H), 7.04e6.97 (m,
2H), 6.84 (s, 1H), 6.29 (d, J ¼ 5.6 Hz, 2H), 6.06 (s, 1H), 5.16 (s, 1H),
4.92 (d, J ¼ 17.2 Hz, 1H), 4.67e4.61 (m, 2H), 2.31 (s, 3H), 1.91 (s, 3H);
Acknowledgements
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21576296, 21776318,
81703365, 22003077), Natural Science Foundation of Hunan
Province (2018JJ3868, 2017JJ3401) and Central South University.
13C{1H} NMR (DMSO-d6, 100 MHz)
d 176.3, 170.3, 142.9, 139.0, 137.7,
134.4, 134.3, 132.6, 130.2, 129.0, 128.9, 128.8, 128.6, 127.0, 125.4,
123.4, 119.6, 115.4, 67.4, 56.4, 44.5, 20.9, 18.1; HRMS (TOF-ESI) m/z
[M þ Na]þ calcd for C27H24N2NaOþ2 431.1730, found 431.1712; HPLC
analysis (CHIRALCEL IA, hexane/i-PrOH ¼ 80/20, 0.8 mL/min, UV
254 nm) tR ¼ 10.5 min (major), 13.7 min (minor).
Appendix A. Supplementary data
Spirocyclic lactam (3ae). White solid (39 mg, yield 95%) from
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132163.
20
37 mg of 3e; er 94.0:6.0; [
210e211 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ ꢁ31.7 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3322, 1982, 1700, 1458, 1177, 940, 696 cmꢁ1
;
d
7.33 (t, J ¼ 7.2 Hz, 1H), 7.21e7.05 (m,
References
8H), 6.80 (s, 1H|), 6.69 (d, J ¼ 8.4 Hz, 1H), 6.35e6.30 (m, 4H), 5.37 (d,
J ¼ 2.0 Hz, 1H), 4.93 (d, J ¼ 16.0 Hz, 1H), 4.45 (s, 1H), 4.10 (d,
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20
36 mg of 3f; er 85.0:15.0; [
230e231 ꢀC; IR (neat)
1H NMR (CDCl3, 400 MHz)
a
]
¼ ꢁ15.0 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
2920, 1716, 1484, 1188, 971, 694, 459 cmꢁ1
;
d
7.34e7.29 (m, 3H), 7.22 (t, J ¼ 7.2 Hz,
2H), 7.14e7.00 (m, 6H), 6.56e6.36 (m, 4H), 5.40 (s, 1H), 4.87 (d,
J ¼ 15.6 Hz, 1H), 4.47e4.42 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz)
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d
174.5, 170.8, 147.2 (d, JC-F ¼ 246.8 Hz), 139.7, 135.9, 132.9, 130.3,
129.9, 128.7, 128.6, 128.4, 127.1, 126.5, 124.2 (d, JC-F ¼ 6.3 Hz), 119.7,
118.7,118.6 (d, JC-F ¼ 23.9 Hz),118.5, 67.8, 57.6, 45.4; HRMS (TOF-ESI)
m/z [M þ Na]þ calcd for C25H19FN2NaOþ2 421.1323, found 421.1309;
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Spirocyclic lactam (4). White solid (24 mg, yield 62%) from 38 mg
20
of 3aa; er 96.0:4.0; [
252e253 ꢀC; IR (neat)
1H NMR (d6-DMSO, 400 MHz)
a
]
¼ ꢁ32.2 (c ¼ 0.05 in CH2Cl2); m.p.
D
n
3357, 2920, 1707, 1079, 798, 691, 450 cmꢁ1
;
d
8.95 (s, 1H), 7.32 (t, J ¼ 7.6 Hz, 1H),
7.29e7.18 (m, 7H), 7.07 (t, J ¼ 7.2 Hz, 1H), 6.97 (d, J ¼ 7.2 Hz, 2H),
6.87 (d, J ¼ 8.0 Hz, 1H), 6.83 (d, J ¼ 7.2 Hz, 2H), 4.97 (d, J ¼ 16.0 Hz,
1H), 4.77 (d, J ¼ 16.0 Hz, 1H), 1.86 (s, 3H); 13C{1H} NMR (d6-DMSO,
100 MHz) d 174.1, 173.4, 150.1, 143.5, 135.8, 132.6, 132.0, 130.5, 129.3,
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20
of 3aa; er 98.5:1.5; [
236e237 ꢀC; IR (neat)
1H NMR (d6-DMSO, 400 MHz)
a
n
]
¼ ꢁ22.8 (c ¼ 0.05 in CH2Cl2); m.p.
D
3379, 1709, 1363, 1175, 987, 748, 591 cmꢁ1
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d
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DMSO, 100 MHz)
128.85, 128.7, 128.6, 128.0, 127.4, 126.7, 124.7, 123.4, 109.7, 73.2, 67.5,
56.8, 43.0, 27.4; HRMS (TOF-ESI) m/z [M
K]þ calcd for
26H23KN3Oþ4 480.1320, found 480.1353; HPLC analysis (CHIRALCEL
d 177.8, 175.8, 143.3, 135.6, 134.0, 130.3, 128.87,
þ
C
IG, hexane/i-PrOH ¼ 80/30, 1.0 mL/min, UV 254 nm) tR ¼ 28.1 min
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Declaration of competing interest
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8