Design, Synthesis, and Resolution of Spirocyclic Bisoxindole-Based C2-Symmetric Diols

Article abstract of DOI:10.1021/acs.joc.0c01155

A new type of spirocyclic bisoxindole-based C2-symmetric diols (SBIDOLs) was designed and synthesized. A series of racemic SBIDOL derivatives (6a-6g) were readily synthesized from commercially available 2-halo-5-methoxyanilines 1 (X = Cl or Br) through N-mono alkylation, acylation, oxidation, double intramolecular Friedel-Crafts reaction, and demethylation reactions. The optical resolution of racemic 6b was achieved via fractional crystallization of their bis-l-menthoxycarboxylates. Further modifications of SBIDOLs were investigated, leading to 5,5′-diaryl SBIDOL derivatives (11a and 11b) through Pd-catalyzed Suzuki coupling and DM-SBIDOL 12 by Pd/C-catalyzed hydrogenative dechlorination reactions.

Full text of DOI:10.1021/acs.joc.0c01155

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Article
Design, Synthesis and Resolution of Spirocyclic
Bisoxindoles Based C2-Symmetric Diols
Guodong Sun, Zhongqing Wang, Zhonghua Luo, YiCao Lin, Zhuofei Deng, Ridong Li, and Jiancun Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01155 • Publication Date (Web): 21 Jul 2020
Downloaded from pubs.acs.org on July 21, 2020
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Design, Synthesis and Resolution of Spirocyclic Bisoxindoles Based C2-
Symmetric Diols
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⧺
Guodong Sun†, ‡, ‖, Zhongqing Wang§,├,‖,*, Zhonghua Luo§, Yicao Lin§, Zhuofei Deng§, Ridong Li , Jiancun Zhang†,*
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†
State Key laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Heath, Chinese Academy
of Sciences, 190 Kaiyuan Road, Guangzhou, 510530, P. R. China
‡University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, P. R. China
§
State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma Co., Ltd, Dongguan 523871, P.
R. China
├
School of Pharmacy, Xiangnan University, Chenzhou 423000 Hunan, China, Xiangnan University, Chenzhou
423000, China
⧺
Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center,
Beijing 100191, PR China
*E-mail:wangzhongqing@hec.cn
*E-mail:zhang_jiancun@gibh.ac.cn
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TOC Graphic:
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This work:
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R
new C2-symmetric diols
N
N
electronic & steric tunability
hemilable coordinating ability
divergent & facile synthesis
O
O
OH
OH
R
s
b i
d
ol
3,3'- piro i[ ndoline]-2,2'- ione-4,4'-di
SBIDOL
ABSTRACT
A new type of spirocyclic bisoxindoles based C2-symmetric diols (SBIDOLs) was designed and synthesized. A
series of racemic SBIDOL derivatives (6a~6g) were readily synthesized from commercially available 2-halo-5-
methoxyanilines 1 (X=Cl or Br) through N-mono alkylation, acylation, oxidation, double intramolecular Friedel-
Crafts reaction and demethylation reactions. The optical resolution of racemic 6b was achieved via fractional
crystallization of their bis-L-menthoxycarboxylates. Further modifications of SBIDOLs were investigated leading to
5, 5’- diaryl SBIDOL derivatives (11a and 11b) through Pd-catalyzed Suzuki coupling and DM-SBIDOL 12 by
Pd/C catalyzed hydrogenative dechlorination reactions.
KEYWORDS
synthesis, resolution, C2-symmetric diols, spirocyclic bisoxindoles
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INTRODUCTION
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Due to their unique structures, spirocyclic bisoxindoles have attracted great attention and a host of methods have
thus been developed for their syntheses in the past decades.1 The synthesis of racemic spirocyclic bisoxindoles
through a PIFA [PhI-(TFA)2]-promoted intramolecular oxidative coupling from N1, N3-diarylmalonamides was
firstly reported by Du and Zhao in 2012.1a A catalytic asymmetric version of the above reaction was later developed
by Gong and co-workers in 2014 (Scheme 1A).1b Recently, an elegant regioselective and enantioselective synthesis
of enantioenriched spirocyclic bisoxindoles via a copper(I)-catalyzed intramolecular asymmetric double C-arylation
was reported by Cai and co-workers (Scheme 1B).1c
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Scheme 1. Reported Synthesis of Spirocyclic Bisoxindoles and Design of SBIDOL (This Work)
A: Du, Zhao and Gong
6R3
7
B: Cai and co-workers
5
R1
1
N
Cu(I)-catalyzed intramolecular
asymmetric double C-arylation
hypervalent iodine reagents-promoted
intramolecular oxidative coupling
O
O
O
O
R4
R3
R4
R3
4
2
O
O
3
N
R1
N
R2
N
R1
N
R2
4'
N
I
I
R2
R4
spirocyclic bis-oxindoles
racemate or chiral
C: SPINOL
This work:
introduce two OHs
R
new C2-symmetric diols
N
N
OH
OH
electronic & steric tunability
hemilable coordinating ability
divergent & facile synthesis
O
O
OH
OH
R
SPINOL
s
b i
d
ol
3,3'- piro i[ ndoline]-2,2'- ione-4,4'-di
SBIDOL
Despite the readiness of the synthesis of spirocyclic bis-oxindoles, their use as chiral ligand scaffolds in
asymmetric catalysis was rarely explored.2g We envisioned that a new type of C2-symmetric diol (SBIDOL, Scheme
1, this work) could be achieved when the two hydroxyl groups were introduced to both 4 and 4’ positions of the
spirocyclic bisoxindoles as shown in Scheme 1. Since the end of the last century, a variety of spirocyclic C2-
symmetric diols2 have been developed. Among them, SPINOL (Scheme 1C, below left), first synthesized by Birman
et al. 2a, has gained much attention in the field of asymmetric catalysis lately and has been extensively studied by
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Zhou and coworkers3. We reason that the SBIDOL might be a worthy chiral backbone for asymmetric catalysis, due
to the great structural similarity of SBIDOL and SPINOL. Moreover, there are other interesting properties of
SBIDOL: (1) the shorter C-N bond length and the existence of two C=O bonds4 adjacent to the spiro center may
affect the dihedral angles, which are a key factor for reactivity and enantioselectivity in asymmetric catalysis for the
axially chiral ligands; (2) the presence of amide NH provides an anchor for ready modifications thus offers more
diversity. Herein, we report our efforts on the synthesis of this new type of C2-symmetric diols based on the
spirocyclic bisoxindoles skeletons.
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RESULTS AND DISCUSSION
Inspired by the synthetic methods of spirocyclic bis-oxindoles and SPINOL, we chose commercially available 2-
halo-5-methoxyanilines 1 (X= Cl or Br) as the starting materials. The annilines underwent N-mono alkylation,
acylation, oxidation, double intramolecular Friedel-Crafts reaction and demethylation to afford a series of racemic
SBIDOL derivatives (6a~6g). The overall synthetic route is illustrated in Scheme 2.
Scheme 2. The Synthetic Route of Racemic SBIDOL Derivatives 6a~6g.
method A
: for
2a
2b
and
1. paraformaldehyde,MeONa
,MeOH,reflux
2. NaBH4, 0 °C~rt
OMe
OMe
X
X
O
O
DCM,Et3N
0 °C~rt
O
O
HN
R
H2N
+
MeO
N
R
N
R
OMe
method B
: for
2c,2d,2f
2g
and
Cl
Cl
RBr, NaH,THF,0 °C~reflux
method C 2e
54% ~ 91%
X
X
: for
2a~2g
3a~3g
1
1. cyclohexanone,Toluene
,reflux
2. NaBH4, 0 °C~rt
gram-scale
gram-scale
X=Cl, Br
81% ~ 99%
X
X
R
R
X
X
N
N
N
N
O
O
Eaton's reagent
DCE, 60 °C
DCM,BBr3
0 °C~rt
AcOH,CrO3
80 °C
O
O
O
O
OMe
OMe
OH
OH
MeO
N
R
N
R
OMe
60%~82%
52%~94%
53% ~ 78%
O
R
R
4a~4g
gram-scale
X
X
5a~5g
rac-6a~6g
6a
, X=Br, R=Me
, X=Cl, R=Me
, X=Cl, R=n-Pr
, X=Cl, R=i-Pr
, X=Cl, R=Cy
6b
6c
6d
6e
6f
, X=Cl, R=n-Octyl
6g
, X=Cl, R=(S)-2-methylbutyl
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First, the N-mono alkylations of 1 were carried out at gram-scale by three methods: method A (paraformaldehyde,
MeONa/MeOH, reflux then NaBH4) for 2a and 2b; method B (RBr/NaH, THF) for 2c, 2d, 2f and 2g; and method C
(cyclohexanone, toluene, reflux then NaBH4) for 2e. Notably, all these three methods were efficient, and seven
aniline derivatives with different alkyls were obtained in 81%~ 99% yields, without any over-alkylated products
observed. The corresponding N1,N3-dialkylmalonamides 3a~3g were obtained with malonyl chloride in the presence
of Et3N. We found that the addition sequence5 in this acylation step was critical for clean transformation and high
yield. The direct transformation of the malonamides to their corresponding oxomalonamides seems to be
challenging, as there are only limited reported examples.6 Although Zhang and co-workers developed a direct
oxidative reaction for the synthesis of vicinal tricarbonyl amides with PIFA,6a low yields were obtained in our
cases.7 Fortunately, CrO3 was found to be an efficient reagent to achieve the direct oxidations6b and the desired
products 4a~4g were obtained in moderate to good yields (53%~78%). Next, we focused our attention to the key
double intramolecular Friedel−Crafts reaction step. Initially, we tried to perform this reaction with PPA in DCE at
reflux and full conversion could be achieved. However, the high viscosity of PPA makes it difficult to workup at
larger scales. Therefore, Eaton’s reagent8, an ideal alternative for PPA, was investigated. Gladly, the reactions went
smoothly to afford the desired sprocyclic products (5a~5g, 60%~82%) at a lower temperature (60 °C). Notably, the
halo atom is critical for the regioselectivity, as it blocks one of the possible reaction sites of the Friedel−Crafts
reaction. The subsequent demethylations were carried out with BBr3 in DCM to give the racemic 7, 7’-halo SBIDOL
derivatives 6a~6g in 52%~94% yields. Interestingly, Compound 6g with a chiral side chain on its nitrogen atoms
was obtained as a pair of inseparable diastereomers with a ratio of about 1:2 (by chiral HPLC).
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With the racemic SBIDOL derivatives in hand, the optical resolutions of these compounds were investigated and
6b was selected as an example. Employing the resolution method for SPINOL,2a we tried L-menthyl chloroformate
as the chiral resolving agent. Gratifyingly, the resulting diastereomers of bis-L-menthoxycarboxylates (7 and 8,
Scheme 3) were easily separated by fractional crystallization9 from hexane, affording 32% and 36% of the
enantiomerically pure diastereomer of 7 and 8, respectively. After hydrazinolysis, the pure (S)-6b and (R)-6b were
obtained in almost quantitative yields with 97% ee and 99% ee, respectively. (Scheme 3) The absolute configuration
of compound (R)-6b was determined by single-crystal X-ray diffraction. (see Supporting Information)
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Scheme 3. The Optical Resolution of Racemic 6b.
5
6
7
8
9
Cl
Cl
O
Me
O
O
Me
O
O
N
Et3N, DMAP
DCM, 0 °C~rt
N
+
rac-6b
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O
Cl
O
O
O
O
O
O
O
O
O
+
O
O
O
N
N
Me
Me
Cl
Cl
fractional crystallization
7
32%
8
36%
Cl
Cl
N
Me
Me
N
N2H4.H2O
THF, reflux
O
O
OH
OH
O
O
OH
OH
+
N
N
Me
Me
Cl
(R)-6b
99% yield, 99% ee
Cl
(S)-6b
99% yield, 97% ee
Scheme 4. The Divergent Utilities of (R)-6b.
Cl
Cl
Cl
I
Ar
I
Me
1, Pd(PPh3)4,Na2CO3
DME/H2O, N2, 80 oC
Me
Me
N
N
N
N
NIS
MOMCl,NaH
O
O
OH
OH
O
O
O
O
OH
OH
OMOM
OMOM
(A) (R)-6b
CH3OH, 0 °C~r.t.
82%
2, HCl(37%),dioxane
100 oC
DMF, 0 °C~r.t.
85%
N
N
Me
Me
Me
I
Ar
I
11a
11b
87 % for
99 % for
Cl
Cl
Cl
9
11
10
11a
11b
, Ar= 2-naphthalenyl
, Ar= 9-anthracenyl
Me
N
N
Pd/C, H2 (2 MPa)
O
O
OH
OH
(B) (R)-6b
NaHCO3,CH3OH
60 °C
Me
92 %
12 (DM-SBIDOL)
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Further modification of SBIDOL was also investigated as shown in Scheme 4. First, (R)-6b was treated with NIS
in MeOH to give the diiodide 9 as a sole product. Upon protection with MOM, compound 10 was subjected to a Pd-
catalyzed Suzuki coupling with ArB(OH)2 followed by deprotection in one pot to afford the 5, 5’- diaryl SBIDOL
derivatives 11a and 11b in 87% and 99% yield, respectively.(Scheme 4A) In addition, the chlorine atoms in (R)-6b
molecule could be readily removed by catalytic hydrogenation with Pd/C at 2MPa of H2 to give DM-SBIDOL 12 in
92% yield (Scheme 4B).
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CONCLUSION
In conclusion, we have successfully designed and synthesized of a new type of C2-symmetric diols (SBIDOLs)
based on the spirocyclic bisoxindole skeletons. Seven racemic SBIDOL derivatives (6a~6g) were synthesized from
commercially available 2-halo-5-methoxyanilines 1 (X=Cl or Br) through N-mono alkylation, acylation, oxidation,
double intramolecular Friedel-Crafts reaction and demethylation. The optical resolution of racemic 6b was achieved
via fractional crystallization of its bis-L-menthoxycarboxylates. In addition, further transformations to 5,5’- diaryl
SBIDOL derivatives 11a and 11b through Pd-catalyzed Suzuki coupling and to DM-SBIDOL 12 by Pd/C catalyzed
hydrogenative dechlorination were investigated demonstrating the potential of diverse modification of SBIDOLs.
Further applications of SBIDOLs as chiral ligands in various reactions are ongoing in our group.
EXPERIMENTAL SECTION
General. Eaton’s reagent (7.7/92.3 % by weight of P2O5/ MeSO3H) was purchased from Alfa-Aesar and used
directly. If no special treatments are indicated, all reagents and solvents were used without further purification.
NMR spectra were measured on a Bruker Avance 400 spectrometer or 600 spectrometer in solvents indicated;
1
chemical shifts are reported in units (ppm) by assigning TMS resonance in the H spectrum as 0.00 ppm, CDCl3
resonance in the 13C spectrum as 77.0 ppm. Coupling constants are reported in Hz with multiplicities denoted as
singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m (multiplets), and etc. HRMS were
performed on Fourier Transform Ion Cyclotron Resonance Mass Spectrometer. Analytical HPLC for liquid phase
was carried out on an Agilent HPLC workstation. Melting points were measured using a melting point instrument
and are uncorrected. Analytical thin layer chromatography TLC was performed on Huanghai HSGF 254 silica gel
plates (0.2 ± 0.03 mm thick) with fluorescent indicator 254 nm. Silica gel 60 H (200-300 mesh), manufactured by
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Qingdao Haiyang Chemical Group Co. (China), was used for general chromatography. Optical rotations were
measured using a 1 mL cell with a 1 dm path length on a Jasco P-1030 polarimeter and are reported as follows: [α]2D0
(c in g per 100 mL solvent).
9
Typical experimental procedure for compounds 2a and 2b (2b as an example). 20 g 2-chloro-5-
methoxyaniline 2b (126.9 mmol, 1 eq) and 19 g paraformaldehyde (634.5 mmol, 5 eq) was added in 120 mL
methanol at room temperature, 34 g MeONa (189 mmol, 1.5 eq, 30% in methanol) was added and the mixture was
stirred for 2 h at reflux (oil bath) to give an imine intermediate. The mixture was then reacted with 9.6 g NaBH4
(254 mmol, 2 eq) at 0 °C, and then warmed to room temperature for an additional 2 h. The reaction mixture was
then quenched with water, and the solvent was evaporated on a rotary evaporator to give a residue that was diluted
with CH2Cl2 then washed with water. Evaporation of the solvent gave a residue that was purified on a silica gel
column chromatography using hexane and EA (20:1) as an eluent.
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2-bromo-5-methoxy-N-methylaniline (2a). The product was isolated by flash chromatography (hexane:EA=
20:1) as a yellow oil (8.5 g, 80 %); Rf = 0.36 (hexane). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.5 Hz, 1H), 6.27
– 6.15 (m, 2H), 4.37 (s, 1H), 3.81 (s, 3H), 2.90 (d, J = 5.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 160.5,
146.8, 132.4, 102.4, 100.9, 97.6, 55.4, 30.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C8H11BrNO) 216.0019,
found: 216.0018.
2-chloro-5-methoxy-N-methylaniline (2b). The product was isolated by flash chromatography (hexane:EA=
1
20:1) as a yellow oil (18.7 g, 86 %); Rf = 0.34 (hexane). H NMR (400 MHz, CDCl3) δ 7.14 (dd, J = 7.7, 1.1 Hz,
1H), 6.28 – 6.13 (m, 2H), 4.33 (s, 1H), 3.79 (s, 3H), 2.88 (d, J = 5.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
159.7 (s), 145.8 (s), 129.1 (s), 111.2 (s), 101.5 (s), 97.4 (s), 55.31 (s), 30.3 (s). HRMS (ESI-TOF) m/z: [M+H]+
calcd. for (C8H11ClNO) 172.0524, found: 172.0530.
Typical experimental procedure for compounds 2c, 2d, 2f and 2g (2d as an example). Under N2 protection,
2.9 g NaH (60% dispersion in mineral oil, 72.3 mmol, 1.2eq) was suspended in 90 mL dry THF, then the mixture
was cooled to 0 °C, a solution of 2-chloro-5-methoxyaniline (9.5g, 60.3 mmol, 1 eq) in 35mL THF was added
slowly via a dropping funnel over 30 min. The mixture was warmed to room temperature for 1 h, and then 2-
bromopropane (8.94g, 72.3 mmol, 1.2eq) was added slowly. When the addition was over, the mixture was stirred at
reflux (oil bath) for 1 h. The reaction mixture was then quenched with 50 mL water, and extracted with EA (2 × 50
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mL). The organic layer was separated and concentrated to give a residue that was purified on a silica gel column
chromatography using hexane and EA (20:1) as an eluent.
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8
9
2-chloro-5-methoxy-N-propylaniline (2c). The product was isolated by flash chromatography (hexane:EA=
100:1) as a yellow oil (13.1 g, 93 %); Rf = 0.41 (hexane). 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.6 Hz, 1H),
6.20 (d, J = 2.7 Hz, 1H), 6.16 (dd, J = 8.6, 2.8 Hz, 1H), 4.27 (s, 1H), 3.76 (s, 3H), 3.09 (t, J = 7.1 Hz, 2H), 1.74 –
1.62 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 145.0, 129.2, 111.2, 101.5, 97.9,
55.3, 45.4, 22.4, 11.6. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C10H15ClNO) 200.0837, found: 200.0837.
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2-bromo-N-isopropyl-5-methoxyaniline (2d). The product was isolated by flash chromatography (hexane:EA=
100:1) as a yellow oil (10.1 g, 84 %); Rf = 0.42 (hexane). 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.6 Hz, 1H),
6.22 (d, J = 2.7 Hz, 1H), 6.15 (dd, J = 8.6, 2.8 Hz, 1H), 4.10 (s, 1H), 3.76 (s, 3H), 3.60 (dd, J = 12.0, 6.4 Hz, 1H),
1.24 (d, J = 6.3 Hz, 6H). 13C {1H} NMR (151 MHz, CDCl3) δ 159.6, 144.0, 129.4, 111.3, 101.2, 98.4, 55.4, 44.2,
22.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C10H15ClNO) 200.0837, found: 200.0841.
2-chloro-5-methoxy-N-octylaniline (2f). The product was isolated by flash chromatography (hexane:EA= 100:1)
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as a yellow oil (11.7 g, 99 %); Rf = 0.47 (hexane). H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 1H), 6.25 –
6.11 (m, 2H), 4.23 (s, 1H), 3.76 (s, 3H), 3.11 (dd, J = 12.2, 6.9 Hz, 2H), 1.71 – 1.59 (m, 2H), 1.39 – 1.19 (m, 10H),
0.99 – 0.80 (m, 3H). 13C {1H} 13C NMR (101 MHz, CDCl3) δ 159.7, 145.0, 129.2, 111.2, 101.4, 97.9, 55.3, 43.7,
31.8, 29.4, 29.2, 27.1, 22.7, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C15H25ClNO) 270.1619, found:
270.1611.
(S)-2-chloro-5-methoxy-N-(2-methylbutyl)aniline (2g). The product was isolated by flash chromatography
(hexane:EA= 100:1) as a yellow oil (2.39 g, 81 %); Rf = 0.44 (hexane). [α]2D0 +11.0; 1H NMR (400 MHz, CDCl3) δ
7.12 (d, J = 8.6 Hz, 1H), 6.20 (d, J = 2.7 Hz, 1H), 6.16 (dd, J = 8.6, 2.8 Hz, 1H), 4.34 (d, J = 0.9 Hz, 1H), 3.76 (s,
3H), 2.99 (ddd, J = 19.5, 12.3, 6.6 Hz, 2H), 1.72 (dq, J = 13.2, 6.7 Hz, 1H), 1.57 – 1.40 (m, 1H), 1.24 (tt, J = 14.9,
7.6 Hz, 1H), 1.01 – 0.90 (m, 6H). 13C {1H} NMR (101 MHz, CDCl3) δ 159.7, 145.1, 129.2, 101.3, 97.9, 55.3, 49.6,
34.3, 27.3, 17.5, 11.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C12H19ClNO) 228.1150, found: 228.1142.
Typical experimental procedure for compound 2e. To a 250ml round-bottomed flask equipped with a Dean-
Stark trap was added cyclohexanone (24.5 g, 250.6 mmol, 5eq), 2-chloro-5-methoxyaniline (7.9 g, 50.1 mmol, 1eq)
and 100 mL toluene, the mixture was stirred for 22 h at reflux (oil bath) to give an imine intermediate. The solvent
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was removed and switched to ethanol (100 mL). NaBH4 (5.7 g, 150.4 mmol, 3eq) was added portion wise at 0 °C,
and then warmed to room temperature for an additional 16 h. The reaction was then quenched with water, and the
solvent was evaporated on a rotary evaporator to give a residue that was diluted with CH2Cl2 then washed with
water. Evaporation of the solvent gave a residue that was purified on a silica gel column chromatography using
hexane and EA (20:1) as an eluent.
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2-bromo-N-cyclohexyl-5-methoxyaniline (2e). The product was isolated by flash chromatography (hexane:EA=
100:1) as a colorless oil (9.7 g, 81 %); Rf = 0.47 (hexane). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 1H),
6.22 (d, J = 2.7 Hz, 1H), 6.14 (dd, J = 8.7, 2.8 Hz, 1H), 4.19 (d, J = 6.6 Hz, 1H), 3.75 (s, 3H), 3.32 – 3.18 (m, 1H),
2.04 (d, J = 9.9 Hz, 2H), 1.82 – 1.70 (m, 2H), 1.69 – 1.60 (m, 1H), 1.45 – 1.14 (m, 5H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.6, 143.9, 129.4, 111.4, 101.0, 98.5, 55.4, 51.5, 33.1, 25.9, 24.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for (C13H19ClNO) 240.1150, found: 240.1147.
Typical experimental procedure for compounds 3a~3g (3a as an example). Under N2 protection, to a 100 mL
round-bottomed flask was added malonyl dichloride (1.7 g, 12 mmol, 1 eq) and 30 mL dry CH2Cl2, the mixture was
cooled to 0 °C. Then the solution of 2a (5.2 g, 24 mmol, 2 eq) was added in drop wise followed by Et3N (3.1 g, 30
mmol, 2.5 eq) was added in drop wise via a syringe. When the addition was over the mixture was stirred for an
additional 2 h. The reaction was then quenched with 30 mL water. The organic layer was separated and concentrated
to give a residue that was purified on a silica gel column chromatography using hexane and EA (2:1) as an eluent.
N1, N3-bis(2-bromo-5-methoxyphenyl)-N1,N3-dimethylmalonamide (3a). The product was isolated by flash
chromatography (hexane:EA= 2:1) as a white solid (4.0 g, 66 %). Rf = 0.38 (hexane:EA= 2:1); mp 180.5 °C ;
Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.38 (m, 2H),
7.07 – 6.48 (m, 4H), 3.84 – 3.76 (m, 6H), 3.15 (d, J = 17.3 Hz, 6H), 2.97 – 2.82 (m, 2H). 13C {1H} NMR (151 MHz,
CDCl3) δ 167.0, 166.7, 160.1, 159.9, 142.7, 142.6, 134.0, 133.8, 116.9, 116.2, 115.4, 115.2, 113.4, 112.6, 55.8,
55.8, 41.6, 41.2, 35.9, 35.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C19H21Br2N2O4) 498.9863, found: 498.9859.
N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dimethylmalonamide (3b). Brown solid (11.0 g, 54 %,
recrystallized from ethanol); Rf = 0.30 (hexane:EA= 2:1); mp 141.1-142.5 °C; Mixture of two rotamers in
chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 26.0, 8.9 Hz, 2H), 7.12 – 6.16 (m,
4H), 3.80 (d, J = 4.0 Hz, 6H), 3.16 (d, J = 15.6 Hz, 6H), 3.07 – 2.73 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
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167.1 (s), 159.3 (s), 141.0 (s), 130.6 (s), 123.3 (s), 116.4 (s), 114.9 (s), 55.8 (s), 40.8 (s), 35.8 (s). HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C19H21Cl2N2O4) 411.0873, found: 411.0869.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dipropylmalonamide (3c). The product was isolated by flash
chromatography (hexane:EA= 2:1) as a yellow oil (2.6 g, 77 %). Rf = 0.66 (hexane:EA= 2:1); Mixture of two
rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.21 (m, 2H), 7.00 – 6.40 (m,
4H), 4.00 – 3.83 (m, 2H), 3.79 (d, J = 8.4 Hz, 6H), 3.27 – 3.13 (m, 2H), 2.96 – 2.78 (m, 2H), 1.68 – 1.39 (m, 4H),
0.89 (dt, J = 11.8, 7.4 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 167.0, 166.7, 159.0, 158.9, 139.8, 130.8, 130.7,
124.4, 123.7, 116.7, 116.2, 116.1, 115.2, 55.8, 50.0, 42.1, 41.7, 20.8, 11.3. HRMS (ESI-TOF) m/z: [M+H]+ calcd.
for (C23H29Cl2N2O4) 467.1499, found: 467.1507.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-diisopropylmalonamide (3d). The product was isolated by flash
chromatography (hexane:EA= 2:1) as a yellow solid (3.8 g, 91 %); Rf = 0.56 (hexane:EA= 2:1); mp 134.8-136.2 °C ;
Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.23 (m, 2H),
6.94 – 6.29 (m, 4H), 4.77 (hept, J = 6.7 Hz, 2H), 3.81 (d, J = 4.1 Hz, 6H), 3.03 – 2.66 (m, 2H), 1.20 (dd, J = 40.4,
6.6 Hz, 6H), 0.92 (dd, J = 11.0, 6.9 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 166.8, 166.4, 158.7, 158.5, 137.1,
137.0, 130.7, 130.5, 126.0, 125.4, 118.0, 117.2, 116.0, 114.8, 55.7, 48.3, 48.0, 43.4, 43.1, 21.7, 19.1. HRMS (ESI-
TOF) m/z: calcd. for [M+H]+ (C23H29Cl2N2O4) 467.1499, found: 467.1505.
N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dicyclohexylmalonamide (3e). The product was isolated by flash
chromatography (hexane:EA= 2:1) as a brown solid (4.2 g, 74 %); Rf = 0.68 (hexane:EA= 2:1) mp 191.3-192.5 °C ;
Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.21 (m, 2H),
6.99 – 6.27 (m, 4H), 4.50 – 4.34 (m, 2H), 3.81 (d, J = 1.1 Hz, 6H), 3.01 – 2.62 (m, 2H), 2.02 – 1.50 (m, 10H), 1.45 –
1.06 (m, 6H), 1.02 – 0.68 (m, 4H). 13C{1H} NMR (151 MHz, CDCl3) δ 166.7, 166.4, 158.7, 158.4, 137.5, 137.3,
130.6, 130.4, 126.1, 125.4, 118.1, 117.4, 115.9, 114.8, 56.3, 55.9, 55.8, 55.7, 43.3, 42.9, 32.0, 29.6, 25.7, 25.4.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C29H37Cl2N2O4) 547.2125, found: 547.2120.
N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dioctylmalonamide (3f). The product was isolated by flash
chromatography (hexane:EA= 4:1) as a yellow oil(9.5 g, 71 %); Rf = 0.90 (hexane:EA= 2:1); Mixture of two
rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.16 (m, 2H), 6.96 – 6.33 (m,
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4H), 3.95 – 3.80 (m, 2H), 3.79 – 3.68 (m, 6H), 3.18 (ddd, J = 15.5, 10.6, 5.4 Hz, 2H), 2.92 – 2.72 (m, 2H), 1.63 –
1.09 (m, 24H), 0.80 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 170.1, 166.9, 166.6, 159.1, 158.9,
141.1, 139.9, 131.0, 130.8, 130.7, 124.6, 124.4, 123.8, 116.8, 116.3, 116.1, 115.2, 114.8, 55.8, 55.7, 48.8, 48.5, 48.3,
42.2, 41.7, 31.8, 29.3, 29.2, 27.8, 27.6, 27.0, 26.9, 22.6, 22.2, 14.1. HRMS (ESI-TOF) m/z: calcd. for [M+H]+
(C33H49Cl2N2O4) 607.3064, found: 607.3054.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-bis((S)-2-methylbutyl)malonamide (3g). The product was isolated
by flash chromatography (hexane:EA= 4:1) as a yellow solid(3.4 g, 73 %); Rf = 0.80 (hexane:EA= 2:1) mp 103.6-
105.3 °C ; Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.30 (ddd,
J = 10.9, 9.0, 3.0 Hz, 2H), 7.01 – 6.43 (m, 4H), 3.87 (ddd, J = 13.5, 8.2, 5.3 Hz, 2H), 3.82 – 3.75 (m, 6H), 3.21 –
3.01 (m, 2H), 2.96 – 2.81 (m, 2H), 1.65 – 1.30 (m, 4H), 1.22 – 1.04 (m, 2H), 1.00 (t, J = 8.0 Hz, 2H), 0.95 – 0.73
(m, 10H). 13C{1H} NMR (151 MHz, CDCl3) δ 167.4, 167.2, 159.0, 158.8, 140.2, 140.0, 139.9, 130.7, 124.3, 124.2,
123.6, 116.8, 116.6, 116.4, 116.2, 115.9, 115.8, 115.2, 115.1, 55.7, 55.6, 54.1, 53.5, 53.4, 42.5, 42.1, 42.0, 33.4,
33.3, 27.2, 26.6, 17.1, 16.9, 16.8, 11.3, 11.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C27H37Cl2N2O4) 523.2125,
found: 523.2130.
Typical experimental procedure for compounds 4a~4g (4a as an example). To a 50 mL round-bottomed flask
compound 3a (2.0 g 4 mmol, 1 eq) was dissolved in 20 mL AcOH, and then CrO3 (1.4 g 14 mmol, 3.5 eq) was
added in one portion. The mixture was heated at 80 °C (oil bath) for 2h then was cooled to room temperature. The
solvent was removed under vacuum and the residue was added 30 mL water and 30 mL CH2Cl2. The organic layer
was separated and concentrated to give a residue that was purified on a silica gel column chromatography using
hexane and EA (4:1) as an eluent.
N1, N3-bis(2-bromo-5-methoxyphenyl)-N1,N3-dimethyl-2-oxomalonamide (4a). The product was isolated by
flash chromatography (hexane:EA= 4:1) as a white solid(1.6 g, 78 %); Rf = 0.20 (hexane:EA= 6:1); mp 144.1-145.4;
Mixture of two rotamers in chloroform at ambient temperature. 1H 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.39 (m,
2H), 7.20 – 6.70 (m, 4H), 3.84 – 3.71 (m, 6H), 3.41 – 3.21 (m, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 181.2,
180.6, 180.1, 164.7, 164.0, 159.7, 159.4, 140.6, 140.5, 140.4, 140.3, 134.0, 133.9, 116.8, 116.5, 115.6, 112.8, 112.1,
55.9, 55.8, 36.1, 35.9, 35.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C19H19Br2N2O5) 512.9655, found: 512.9661.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dimethyl-2-oxomalonamide (4b). The product was isolated by
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flash chromatography (hexane:EA= 4:1) as a yellow solid(6.2 g, 60 %); Rf = 0.22 (hexane:EA= 6:1) mp 132.5-134.0
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°C; Mixture of two rotamers in chloroform at ambient temperature. H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.9
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Hz, 2H), 7.18 – 7.11 (m, 2H), 6.85 – 6.74 (m, 2H), 3.79 (s, 6H), 3.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
180.2 (s), 164.8 (s), 158.9 (s), 138.8 (s), 130.8 (s), 123.1 (s), 116.4 (s), 114.4 (s), 55.8 (s), 35.5 (s). HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C19H19Cl2N2O5) 425.0666, found: 425.0670.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dipropyl-2-oxomalonamide (4c). The product was isolated by flash
chromatography (hexane:EA= 4:1) as a yellow solid(4.3 g, 63 %); Rf = 0.48 (hexane:EA= 6:1); mp 132.7-134.1 °C;
Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.21 (m, 2H),
7.15 – 6.75 (m, 4H), 4.31 – 3.94 (m, 2H), 3.87 – 3.69 (m, 6H), 3.46 – 3.19 (m, 2H), 1.69 – 1.51 (m, 4H), 1.06 – 0.86
(m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 180.3, 164.8, 158.7, 137.2, 130.8, 123.6, 116.2, 116.0, 55.8, 49.3, 20.2,
11.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C23H27Cl2N2O5) 481.1292, found: 481.1299.
N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-diisopropyl-2-oxomalonamide (4d). The product was isolated by
flash chromatography (hexane:EA= 4:1) as a yellow solid(3.4 g, 53 %); Rf = 0.36 (hexane:EA= 6:1); mp 122.2-
123.5 °C; Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.20
(m, 2H), 7.06 – 6.62 (m, 4H), 4.66 – 4.28 (m, 2H), 3.77 (dd, J = 18.7, 5.8 Hz, 6H), 1.43 – 1.08 (m, 12H). 13C{1H}
NMR (151 MHz, CDCl3) δ 181.9, 181.2, 180.2, 165.2, 165.1, 164.5, 164.3, 163.4, 158.5, 158.4, 158.2, 136.0,
135.4, 130.9, 130.8, 130.7, 130.6, 126.1, 125.9, 125.8, 125.7, 125.6, 125.5, 117.5, 117.2, 116.9, 116.7, 116.6, 116.5,
116.4, 116.2, 115.6, 115.2, 55.9, 55.8, 55.7, 55.6, 51.9, 51.7, 51.6, 51.5, 50.6, 23.3, 23.2, 21.0, 20.7, 20.5, 20.0, 19.8,
19.1, 18.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C23H27Cl2N2O5) 481.1292, found: 481.1295.
N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dicyclohexyl-2-oxomalonamide (4e). The product was isolated by
flash chromatography (hexane:EA= 4:1) as a yellow solid(1.7 g, 64 %); Rf = 0.44 (hexane:EA= 6:1); mp 82.3-83.5
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2H), 7.04 – 6.60 (m, 4H), 4.36 – 4.05 (m, 2H), 3.83 – 3.72 (m, 6H), 2.39 – 1.88 (m, 4H), 1.87 – 1.46 (m, 8H), 1.43 –
1.25 (m, 6H), 1.07 (ddd, J = 34.3, 19.1, 8.0 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 181.9, 181.4, 181.2, 180.2,
165.2, 164.4, 164.1, 163.4, 158.5, 158.5, 158.4, 158.3, 158.1, 135.9, 135.8, 135.5, 134.6, 134.5, 130.9, 130.8, 130.7,
130.6, 130.5, 130.4, 126.3, 126.0, 125.8, 125.7, 125.6, 117.8, 117.6, 117.2, 116.8, 116.7, 116.5, 116.3, 116.1, 115.5,
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115.4, 115.0, 59.9, 59.4, 59.2, 59.0, 58.8, 58.1, 55.9, 55.8, 55.7, 55.6, 33.6, 33.3, 31.6, 31.1, 30.8, 30.5, 30.4, 29.3,
29.0, 28.9, 25.8, 25.7, 25.6, 25.5 25.4, 25.3, 24.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C29H35Cl2N2O5)
561.1918, found: 561.1894.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-dioctyl-2-oxomalonamide (4f). The product was isolated by flash
chromatography (hexane:EA= 6:1) as a white solid(4.5 g, 72 %); Rf = 0.76 (hexane:EA= 6:1); mp 78.8-80.0 °C;
Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 9.0 Hz,
2H), 6.45 (d, J = 9.0 Hz, 2H), 4.09 (t, J = 7.7 Hz, 4H), 3.54 (s, 6H), 1.72 (dtd, J = 20.9, 13.3, 7.4 Hz, 4H), 1.46 –
1.20 (m, 20H), 0.87 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 153.7, 141.5, 132.3, 116.2,
107.7, 107.0, 58.8, 55.6, 42.2, 31.8, 29.5, 29.4, 29.2, 26.5, 22.6, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for
(C33H47Cl2N2O5) 621.2857, found: 621.2863.
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N1, N3-bis(2-chloro-5-methoxyphenyl)-N1,N3-bis((S)-2-methylbutyl)-2-oxomalonamide (4g). The product was
isolated by flash chromatography (hexane:EA= 6:1) as a white solid(3.2 g, 72 %); Rf = 0.65 (hexane:EA= 6:1); mp
120.8-122.3 °C; Mixture of two rotamers in chloroform at ambient temperature. 1H NMR (400 MHz, CDCl3) δ 7.42
– 7.22 (m, 2H), 7.19 – 6.75 (m, 4H), 4.21 – 3.97 (m, 2H), 3.82 – 3.71 (m, 6H), 3.38 – 3.13 (m, 2H), 1.54 (ddd, J =
17.5, 9.5, 5.4 Hz, 2H), 1.44 – 1.08 (m, 4H), 1.05 – 0.80 (m, 12H). 13C{1H} NMR (151 MHz, CDCl3) δ 180.7, 180.2,
165.2, 165.0, 164.5, 164.4, 158.6, 158.4, 137.7, 137.4, 137.0, 130.9, 130.8, 124.1, 123.5, 116.6, 116.4, 116.1, 116.0,
115.9, 115.7, 55.8, 55.7, 54.1, 53.3, 52.5, 33.0, 32.9, 27.3, 27.2, 26.6, 17.1, 17.0, 16.9, 11.2. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for (C27H35Cl2N2O5) 537.1918, found: 537.1925.
Typical experimental procedure for compounds 5a~5g (5a as an example). To a 50 mL round-bottomed flask
compound 4a (2.0 g 3.9 mmol, 1 eq) was dissolved in 20 mL 1, 2-DCE, and then Eaton’s reagent (6.0 g, 3 eq w/w)
was added. The mixture was heated at 60 °C (oil bath) for 2h then was cooled to 0°C. Water (20 mL) was added to
quench the reaction. The solvent was removed under vacuum and the residue was extracted with EA (2 × 50 mL).
The organic layer was separated and concentrated to give the crude product. 20 mL hexane and EA mixture (1:1)
was added to the above obtained crude product, the slurry was warmed to reflux for 1h then was cooled to 0°C for
30min. The pure 5a was collected by filtration, and washed with 10 mL hexane, then dried under vacuum at 50°C.
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7,7'-dibromo-4,4'-dimethoxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (5a). The product was obtained by
crystallization from hexane and EA mixture (1:1). Rf = 0.39 (hexane:EA= 4:1); Gray solid, 0.95 g, 66 %; mp 235.2-
236.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 9.0 Hz, 2H), 6.42 (d, J = 9.0 Hz, 2H), 3.63 (s, 6H), 3.56 (s,
6H). 13C {1H} NMR (151 MHz, CDCl3) δ 171.9, 154.2, 143.2, 135.5, 116.1, 107.9, 94.1, 58.7, 56.0, 30.4. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for (C19H17Br2N2O4) 494.9550, found: 494.9558.
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7,7'-dichloro-4,4'-dimethoxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (5b). The product was obtained by
crystallization from hexane and EA mixture (1:1). Rf = 0.37 (hexane:EA= 4:1); Brown solid, 4.7 g, 82 %; mp 236.5-
238.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 9.0 Hz, 2H), 3.62 (s, 6H), 3.57 (s, 6H).
13C {1H} NMR (101 MHz, CDCl3) δ 171.7 (s), 153.7 (s), 141.8 (s), 132.3 (s), 115.7 (s), 108.1 (s), 107.3 (s), 58.8
(s), 56.0 (s), 30.2 (s). HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C19H17Cl2N2O4) 407.0560, found: 407.0563.
7,7'-dichloro-4,4'-dimethoxy-1,1'-dipropyl-3,3'-spirobi[indoline]-2,2'-dione (5c). The product was obtained by
crystallization from hexane and EA mixture (1:1). Rf = 0.57 (hexane:EA= 4:1); Gray solid, 2.86 g, 73 %; mp 177.9-
179.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 9.0 Hz, 2H), 4.08 (t, J = 7.5 Hz, 4H),
3.54 (s, 6H), 1.88 – 1.66 (m, 4H), 0.99 (t, J = 7.4 Hz, 6H). 13C {1H} NMR (101 MHz, CDCl3) δ 171.6, 153.6, 141.3,
132.2, 116.0, 107.5, 106.9, 58.7, 55.5, 43.4, 22.6, 10.7. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C23H25Cl2N2O4)
463.1186, found: 463.1183.
7,7'-dichloro-1,1'-diisopropyl-4,4'-dimethoxy-3,3'-spirobi[indoline]-2,2'-dione (5d). The product was obtained
by crystallization from hexane and EA mixture (1:1). Rf = 0.64 (hexane:EA= 4:1); White solid, 1.6 g, 62 %; mp
227.3-228.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 9.0 Hz, 2H), 6.44 (d, J = 9.0 Hz, 2H), 5.31 (dt, J = 13.5,
6.7 Hz, 2H), 3.56 (s, 6H), 1.61 (d, J = 6.8 Hz, 6H), 1.51 (d, J = 6.8 Hz, 6H). 13C {1H} NMR (151 MHz, CDCl3) δ
172.1, 153.6, 141.7, 132.7, 116.8, 107.5, 106.8, 106.8, 59.4, 55.7, 55.7, 55.6, 55.6, 47.7, 20.0, 20.0, 19.5, 19.4.
HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C23H25Cl2N2O4) 463.1186, found: 463.1191.
7,7'-dichloro-1,1'-dicyclohexyl-4,4'-dimethoxy-3,3'-spirobi[indoline]-2,2'-dione (5e). The product was obtained
by crystallization from hexane and EA mixture (1:1). Rf = 0.80 (hexane:EA= 4:1); Gray solid, 0.56 g, 74 %; mp
205.6-206.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J = 16.7, 9.0 Hz, 2H), 6.52 – 6.36 (m, 2H), 4.88 (t, J = 11.6
Hz, 2H), 3.57 (d, J = 12.5 Hz, 6H), 2.58 – 2.15 (m, 4H), 2.02 – 1.58 (m, 10H), 1.47 – 1.11 (m, 6H). 13C {1H} NMR
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(151 MHz, CDCl3) δ 172.1, 153.6, 141.9, 132.7, 116.9, 107.6, 106.9, 59.5, 55.7, 29.5, 29.2, 26.3, 26.2, 25.3. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for (C29H33Cl2N2O4) 543.1812, found: 543.1806.
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7,7'-dichloro-4,4'-dimethoxy-1,1'-dioctyl-3,3'-spirobi[indoline]-2,2'-dione (5f). The product was obtained by
crystallization from hexane and EA mixture (1:1). Rf = 0.86 (hexane:EA= 4:1); White solid, 3.0 g, 77 %; mp 126.7-
128.2 °C; 1H 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 9.0 Hz, 2H), 6.45 (d, J = 9.0 Hz, 2H), 4.09 (t, J = 7.7 Hz,
4H), 3.54 (s, 6H), 1.72 (dtd, J = 20.9, 13.3, 7.4 Hz, 4H), 1.46 – 1.20 (m, 20H), 0.87 (t, J = 6.8 Hz, 6H). 13C {1H}
NMR (101 MHz, CDCl3) δ 171.6, 153.7, 141.5, 132.3, 116.2, 107.7, 107.0, 58.8, 55.7, 42.2, 31.8, 29.5, 29.4, 29.2,
26.5, 22.6, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C33H45Cl2N2O4) 603.2751, found: 603.2761.
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7,7'-dichloro-4,4'-dimethoxy-1,1'-bis((S)-2-methylbutyl)-3,3'-spirobi[indoline]-2,2'-dione (5g). The product was
obtained by crystallization from hexane and EA mixture (1:1). Rf = 0.46 (hexane:EA= 4:1); Gray solid, 0.27 g, 60 %;
mp 156.3-157.5 °C; A pair of inseparable diastereomers, about 1:1.5 by HPLC. 1H NMR (400 MHz, CDCl3) δ 7.19
(d, J = 9.0 Hz, 2H), 6.47 (d, J = 9.0 Hz, 2H), 4.05 – 3.86 (m, 4H), 3.54 (s, 6H), 2.09 – 1.92 (m, 2H), 1.52 (dt, J =
13.4, 7.3 Hz, 2H), 1.31 – 1.11 (m, 7H), 0.94 (dt, J = 13.8, 7.1 Hz, 13H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.0,
153.7, 141.7, 132.5, 115.8, 115.8, 107.7, 107.7, 106.9, 106.9, 58.9, 58.8, 55.7, 55.6, 47.9, 47.7, 35.5, 35.4, 26.5,
26.4, 16.0, 16.0, 11.4, 11.2. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C27H33Cl2N2O4) 519.1812, found: 519.1807.
Typical experimental procedure for compounds 6a~6g (6a as an example). To a 50 mL round-bottomed flask
compound 5a (0.5 g, 1mmol, 1 eq) was dissolved in 10 mL CH2Cl2, and then the mixture was cooled to 0°C. BBr3
(1.25 g, 5 mmol, 5 eq) was added slowly via a syringe under the protection of N2 gas. The mixture was then warmed
to room temperature and stirred until the starting material was completely disappeared. Upon reaction completion,
water (10 mL) was added slowly to quench the reaction. The solvent was removed under vacuum and the residue
was extracted with EA (2 × 20 mL). The organic layer was separated and concentrated to give the crude product that
was purified on a silica gel column chromatography using hexane and EA (2:1) as an eluent.
7,7'-dibromo-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (6a). The product was isolated by
flash chromatography (hexane:EA= 1:1) as a white solid(0.38 g, 81 %); Rf = 0.22 (hexane:EA= 2:1); mp 264.8-
266.2 °C; 1H NMR (400 MHz, MeOD) δ 7.29 (d, J = 8.9 Hz, 2H), 6.42 (d, J = 8.9 Hz, 2H), 3.62 (s, 6H). 13C {1H}
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NMR (101 MHz, MeOD) δ 174.33, 153.90, 144.37, 136.41, 115.80, 113.63, 93.02, 60.37, 30.80. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C17H13Br2N2O4) 466.9237, found: 466.9242.
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7,7'-dichloro-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (6b). The product was isolated by
flash chromatography (hexane:EA= 1:1) as a white solid(3.5 g, 94 %); Rf = 0.20 (hexane:EA= 2:1); mp 340.2-341.0
°C; 1H NMR (400 MHz, MeOD) δ 7.10 (d, J = 8.9 Hz, 2H), 6.44 (d, J = 8.9 Hz, 2H), 3.58 (s, 6H). 13C {1H} NMR
(151 MHz, MeOD) δ 174.1, 153.4, 142.8, 133.2, 115.2, 113.0, 107.4, 60.4, 30.5. HRMS (ESI-TOF) m/z: [M+H]+
calcd. for (C17H13Cl2N2O4) 379.0247, found: 379.0250.
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7,7'-dichloro-4,4'-dihydroxy-1,1'-dipropyl-3,3'-spirobi[indoline]-2,2'-dione (6c). The product was isolated by
flash chromatography (hexane:EA= 1:1) as a gray solid (1.1 g, 61 %); Rf = 0.34 (hexane:EA= 2:1); mp 292.2-293.5
°C; 1H NMR (400 MHz, MeOD) δ 7.11 (d, J = 8.9 Hz, 2H), 6.45 (d, J = 8.9 Hz, 2H), 4.15 – 3.99 (m, 4H), 1.78 (dq, J
= 14.3, 7.0 Hz, 4H), 0.99 (t, J = 7.4 Hz, 6H). 13C {1H} NMR (101 MHz, MeOD) δ 172.9, 152.1, 141.0, 131.9, 114.2,
111.5, 105.4, 59.0, 43.3, 22.4, 9.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C21H21Cl2N2O4) 435.0873, found:
435.0869.
7,7'-dichloro-1,1'-diisopropyl-4,4'-dihydroxy-3,3'-spirobi[indoline]-2,2'-dione (6d). The product was isolated by
flash chromatography (hexane:EA= 2:1) as a white solid(1.2 g, 52 %); Rf = 0.44 (hexane:EA= 2:1); mp 337.6-339.2
°C; 1H NMR (400 MHz, MeOD) δ 7.09 (d, J = 8.9 Hz, 2H), 6.42 (d, J = 8.9 Hz, 2H), 5.44 – 5.29 (m, 2H), 1.55 (dd, J
= 18.2, 6.8 Hz, 12H). 13C {1H} NMR (151 MHz, MeOD) δ 174.6, 153.4, 142.7, 133.5, 116.2, 112.7, 106.7, 61.1,
54.8, 20.2, 19.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C21H21Cl2N2O4) 435.0873, found: 435.0865.
7,7'-dichloro-1,1'-dicyclohexyl-4,4'-dihydroxy-3,3'-spirobi[indoline]-2,2'-dione (6e). The product was isolated
by flash chromatography (hexane:EA= 2:1) as a gray solid(0.65 g, 56 %); Rf = 0.52 (hexane:EA= 2:1); mp 292.3-
293.9 °C; 1H NMR (400 MHz, MeOD) δ 7.08 (d, J = 8.9 Hz, 2H), 6.41 (d, J = 8.9 Hz, 2H), 4.94 (t, J = 10.9 Hz, 2H),
2.50 – 2.19 (m, 4H), 2.04 – 1.76 (m, 9H), 1.68 (d, J = 12.4 Hz, 2H), 1.43 – 1.18 (m, 6H). 13C {1H} NMR (151 MHz,
MeOD) δ 174.6, 153.5, 142.9, 133.6, 116.4, 112.7, 106.8, 61.3, 57.3, 30.8, 30.0, 27.4, 27.3, 26.5. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C27H29Cl2N2O4) 515.1499 found: 515.1492.
7,7'-dichloro-4,4'-dihydroxy-1,1'-dioctyl-3,3'-spirobi[indoline]-2,2'-dione (6f). The product was isolated by flash
chromatography (hexane:EA= 2:1) as a white solid(0.62 g, 65 %); Rf = 0.64 (hexane:EA= 2:1); mp 209.4-210.2 °C;
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1H NMR (400 MHz, MeOD) δ 7.10 (d, J = 8.9 Hz, 2H), 6.43 (d, J = 8.9 Hz, 2H), 4.09 (t, J = 7.5 Hz, 4H), 1.86 –
1.65 (m, 4H), 1.46 – 1.24 (m, 20H), 0.89 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (151 MHz, MeOD) δ 174.1, 153.6,
142.4, 133.3, 115.7, 112.9, 106.8, 60.4, 43.2, 33.0, 30.5, 30.4, 30.3, 27.5, 23.7, 14.5. HRMS (ESI-TOF) m/z:
[M+H]+ calcd. for (C31H41Cl2N2O4) 575.2438 found: 575.2434.
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7,7'-dichloro-4,4'-dihydroxy-1,1'-bis((S)-2-methylbutyl)-3,3'-spirobi[indoline]-2,2'-dione (6g). The product was
isolated by flash chromatography (hexane:EA= 2:1) as a gray solid (0.2 g, 81 %); Rf = 0.48 (hexane:EA= 2:1); mp
242.5-243.4 °C; A pair of inseparable diastereomers, about 1:2 by HPLC. 1H NMR (400 MHz, MeOD) δ 7.11 (d, J =
8.9 Hz, 2H), 6.45 (d, J = 8.9 Hz, 2H), 4.05 – 3.82 (m, 4H), 2.01 (dt, J = 14.8, 5.5 Hz, 2H), 1.58 (ddd, J = 17.9, 12.1,
6.0 Hz, 2H), 1.21 (dt, J = 15.4, 8.4 Hz, 2H), 1.03 – 0.87 (m, 12H). 13C{1H} NMR (151 MHz, MeOD) δ 173.1, 173.0,
152.2, 152.1, 141.2, 132.0, 114.1, 114.0, 111.5, 105.4, 105.4, 59.0, 35.3, 26.3, 26.2, 15.2, 15.1, 10.2, 10.1. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for (C25H29Cl2N2O4) 491.1499 found: 491.1493.
Typical experimental procedure for the optical resolution of 6b. Under N2 protection, to a 250 mL round-
bottomed flask rac-6b (4.5 g, 11.9 mmol, 1 eq) was suspended in 50 mL dry CH2Cl2, followed by Et3N (4.5 g, 44
mmol, 3.7 eq) and DMAP (145 mg 1.2 mmol, 0.1eq). The mixture was stirred at room temperature to give a solution
then was cooled to 0 °C. L-menthyl chloroformate (7.0 g, 32 mmol, 2.7 eq) was added in drop wise via a 20 mL
syringe. When the addition was over the mixture was slowly warmed to room temperature and stirred for an
additional 5 h. The reaction was then quenched with 50 mL water. The organic layer was separated and concentrated
to give a residue that was purified on a silica gel column chromatography using hexane and EA (6:1) as an eluent.
The mixture of compound 7 and 8 was obtained as colorless oil (7.4 g, 83.8%). The oil was dissolved in 40 mL
hexane, and the mixture was stirred at room temperature to give a white solid, which was filtered and washed with
20 mL hexane to give compound 8. The mother liquor contained a small amount of 8 and all of the uncrystalized
diastereomer 7 was concentrated to give a residue, which was dissolved in 25 mL hexane and kept at 5 °C for 5 days
in a refrigerator. Colorless cubes were crystalized out, which were collected by filtration and washed with 10 mL
cold hexane to give compound 7.
(R)-7,7'-dichloro-1,1'-dimethyl-2,2'-dioxo-3,3'-spirobi[indoline]-4,4'-diyl
bis((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl) dicarbonate (7) Rf = 0.65 (hexane:EA= 6:1); Colorless cubes, 2.8 g, 32 %; mp 148.2-149.8 °C;
[α]2D0 -139.5, (c = 0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.22 (m, 2H), 7.01 (d, J = 9.1 Hz, 2H), 4.38 (td,
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J = 10.9, 4.4 Hz, 2H), 3.65 (s, 6H), 2.02 (d, J = 11.7 Hz, 2H), 1.66 (d, J = 12.3 Hz, 4H), 1.61 – 1.52 (m, 2H), 1.50 –
1.24 (m, 4H), 1.06 – 0.83 (m, 18H), 0.63 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 170.2, 150.9,
145.5, 141.7, 132.5, 118.8, 116.5, 112.3, 79.8, 58.4, 46.7, 40.4, 34.0, 31.3, 30.4, 25.8, 23.1, 21.9, 20.9, 16.0. HRMS
(ESI-TOF) m/z: [M+H]+ calcd. for (C39H49Cl2N2O8) 743.2860 found: 743.2868.
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(S)-7,7'-dichloro-1,1'-dimethyl-2,2'-dioxo-3,3'-spirobi[indoline]-4,4'-diyl
bis((1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl) dicarbonate (8) Rf = 0.68 (hexane:EA= 6:1) White powder, 3.2 g, 36 %; mp 185.3-186.5 °C; [α]
20 +91.5, (c = 0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.21 (m, 2H), 6.94 (d, J = 9.0 Hz, 2H), 4.38 (td, J =
D
10.9, 4.3 Hz, 2H), 3.67 (s, 6H), 1.91 (dtd, J = 13.8, 6.9, 2.4 Hz, 2H), 1.68 (d, J = 11.3 Hz, 6H), 1.48 – 1.30 (m, 4H),
1.08 – 0.82 (m, 18H), 0.78 (t, J = 6.8 Hz, 6H). 13C {1H} NMR (151 MHz, CDCl3) δ 170.2, 151.0, 145.3, 141.8,
132.7, 119.5, 117.2, 112.6, 79.7, 58.1, 46.9, 40.0, 33.9, 31.2, 30.3, 26.1, 23.2, 21.9, 20.7, 16.3. HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C39H49Cl2N2O8) 743.2860 found: 743.2865.
To a 100ml round-bottomed flask compound 7 (1.5 g, 2 mmol, 1 eq) was dissolved in 30 mL THF, and N2H4.H2O
(1.0 g, 20 mmol, 10 eq) was added. The mixture was heated at reflux (oil bath) for 1 h. Then the mixture was
concentrated to give a residue, which was purified by silica gel column chromatography (hexane: EA=2:1) to give
enatiomerically pure compound (R)-6b in quantitative yield. Compound (S)-6b was obtained in the similar
operation from compound 8.
(R)-7,7'-dichloro-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione ((R)-6b). White solid, 0.76 g,
yield 99%. [α]2D0 -74.0, (c = 0.5, MeOH). Enantiometric excess: 99 %, determined by HPLC (Chiral ND(2)
column(250 × 4.6mm), hexane/EtOH 80:20, flow rate 0.5 mL/min, tR= 9.42 min, tS = 11.50 min, λ = 210 nm).
(S)-7,7'-dichloro-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione ((S)-6b). White solid, 0.6 g,
yield 99%. [α]2D0 +65.0, (c = 0.5, MeOH). Enantiometric excess: 97 %, determined by HPLC (Chiral ND(2)
column(250 × 4.6mm), hexane/EtOH 80:20, flow rate 0.5 mL/min, tR= 9.42 min, tS = 11.50 min, λ = 210 nm).
Experimental procedure for the synthesis of compound 9. To a 250 mL round-bottomed flask, (R)-6b (2.7 g,
7.1 mmol, 1 eq) was dissolved in 150 mL MeOH. The mixture was cooled to 0 °C and NIS (4.0 g 17.8 mmol, 2.5eq)
was added in portion wise. The mixture was stirred for 0.5 h then warmed to room temperature for an additional 0.5
h. The reaction was then quenched with 20 mL saturated Na2S2O3 aqueous solution. Methanol was removed under
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vacuum, and the residue was extracted with 100 mL EA. The organic layer was separated and concentrated to give a
residue that was purified on a silica gel column chromatography using hexane and EA (3:1, with 1%MeOH) as an
eluent.
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(R)-7,7'-dichloro-4,4'-dihydroxy-5,5'-diiodo-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (9). Rf
= 0.61
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(hexane:EA= 2:1) Gray solid, 3.7 g, 82%. [α]D +118.0, (c = 0.5, MeOH). H NMR (400 MHz, DMSO) δ 10.98 (s,
1H), 9.40 (s, 1H), 7.65 (s, 2H), 3.41 (s, 6H). 13C {1H} NMR (151 MHz, DMSO) δ 179.5 (s), 170.6 (s), 151.5 (s),
141.6 (s), 139.9 (s), 115.7 (s), 107.5 (s), 81.1 (s), 59.3 (s), 29.7 (d, J = 39.7 Hz). HRMS (ESI-TOF) m/z: [M+H]+
calcd. for (C17H11Cl2I2N2O4) 630.8180 found: 630.8168.
Experimental procedure for the synthesis of compound 10. To a 100 mL round-bottomed flask, NaH (60% oil
dispersion, 127mg, 3.2 mmol, 4 eq) was suspended in 25 mL DMF. The mixture was cooled to 0 °C and 9 (500 mg
0.8 mmol, 1 eq) in 10ml DMF was added in drop wise. The mixture was stirred for 0.5 h then MOMCl (255 mg 3.2
mmol, 4 eq) was added in drop wise. The mixture was warmed to room temperature for an additional 1 h. The
reaction was then quenched with 30 mL water and extracted with 100 mL EA. The organic layer was separated and
concentrated to give a residue that was purified on a silica gel column chromatography using hexane and EA (10:1)
as an eluent.
(R)-7,7'-dichloro-5,5'-diiodo-4,4'-bis(methoxymethoxy)-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (10). Rf
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= 0.27 (hexane:EA= 6:1) White solid, 482 mg, 85%. [α]D +83.7, (c = 0.5, CH2Cl2). H NMR (400 MHz, CDCl3) δ
7.72 (s, 2H), 4.74 (dd, J = 17.4, 4.7 Hz, 4H), 3.61 (s, 6H), 3.27 (s, 6H). 13C {1H} NMR (151 MHz, CDCl3) δ 170.6
(s), 152.3 (s), 142.7 (s), 141.8 (d, J = 16.6 Hz), 122.3 (s), 112.8 (s), 99.7 (s), 82.7 (s), 57.8 (s), 30.4 (s). HRMS (ESI-
TOF) m/z: [M+H]+ calcd. for (C21H19Cl2I2N2O6) 718.8704 found: 718.8711.
Typical experimental procedure for the synthesis of compound 11a and 11b. Under N2 protection, 10 (100
mg, 139 μmol, 1 eq), ArB(OH)2 (556 μmol, 4 eq), Na2CO3 (77.5 mg, 730 μmol, 5 eq), Pd(PPh3)4 (16 mg, 13.9μmol,
0.1eq ) was added to a mixture of 6 mL DME and 2 mL water. The mixture was heated at 80 °C (oil bath) for 5 h.
Then the mixture was cooled to room temperature and concentrated to give a residue. The obtained residue was
dissolved in 5 mL 1,4-dioxane and 5 mL 37% HCl aq and heated at 100 °C (oil bath) for 2 h. Then the mixture was
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cooled to room temperature and extracted with 30 mL EA. The organic layer was separated and concentrated to give
a residue that was purified on a silica gel column chromatography using hexane and EA (4:1) as an eluent.
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(R)-7,7'-dichloro-4,4'-dihydroxy-1,1'-dimethyl-5,5'-di(naphthalen-2-yl)-3,3'-spirobi[indoline]-2,2'-dione (11a).
Rf = 0.22 (hexane:EA= 2:1) White solid, 76.5 mg, 87%. [α]2D0 +414.4, (c = 0.5, EA). 1H NMR (400 MHz, DMSO) δ
9.32 (s, 2H), 8.03 – 7.79 (m, 8H), 7.58 – 7.45 (m, 6H), 7.34 (s, 2H), 3.56 (s, 6H). 13C{1H} NMR (101 MHz, DMSO)
δ 171.5 (s), 171.5 (s), 148.9 (s), 148.9 (s), 140.7 (s), 140.7 (s), 133.5 (s), 133.1 (s), 132.6 (s), 132.1 (s), 128.2 – 127.5
(m), 127.4 (s), 127.1 (s), 126.9 (s), 126.1 (d, J = 5.3 Hz), 117.3 (s), 106.2 (s), 59.3 (s), 29.7 (s). HRMS (ESI-TOF)
m/z: [M+H]+ calcd. for (C37H25Cl2N2O4) 631.1186 found: 631.1170.
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(R)-5,5'-di(anthracen-9-yl)-7,7'-dichloro-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (11b).
Rf = 0.23 (hexane:EA= 2:1) White solid, 100.4 mg, 99%. [α]2D0 +194.4, (c = 0.5, EA). 1H NMR (400 MHz, DMSO)
δ 9.16 (t, J = 19.6 Hz, 2H), 8.98 – 8.79 (m, 4H), 8.03 (s, 2H), 7.85 – 7.58 (m, 10H), 7.57 – 7.39 (m, 3H), 7.31 – 7.15
(m, 2H), 3.57 (d, J = 7.4 Hz, 6H). 13C{1H} NMR (151 MHz, DMSO) δ 171.6 (t, J = 4.6 Hz), 149.9 (dd, J = 14.5, 7.8
Hz), 133.1 (dd, J = 31.2, 13.1 Hz), 132.7 – 132.1 (m), 132.1 (s), 131.8 – 130.9 (m), 130.3 (d, J = 5.8 Hz), 130.1 (d, J
= 8.4 Hz), 129.5 – 128.9 (m), 128.8 (s), 128.6 (s), 127.2 (s), 127.1 (s), 127.1 – 126.4 (m), 126.0 (d, J = 12.6 Hz),
125.7 (s), 124.5 (dd, J = 22.4, 11.1 Hz), 123.3 (d, J = 13.2 Hz), 122.9 (d, J = 16.7 Hz), 115.9 – 115.4 (m), 105.2 (d, J
= 2.9 Hz), 59.2 (d, J = 9.6 Hz), 39.9 (s), 39.7 (d, J = 21.0 Hz), 39.5 (s), 39.4 (s), 39.2 (s), 39.1 (s), 39.1 – 38.9 (m),
29.8 (d, J = 9.5 Hz). HRMS (ESI-TOF) m/z: [M+H]+ calcd. for (C45H29Cl2N2O4) 731.1499 found: 731.1504.
Experimental Procedure for the synthesis of compound 12. To a 250ml autoclave, (R)-6b (500 mg, 1.3 mmol,
1 eq) was dissolved in 50 mL MeOH, followed by Pd/C (100mg, 0.2eq) and NaHCO3 (244 mg, 2.9 mmol, 2.2eq).
The mixture was degassed three times and recharged with H2 gas (2 MPa) then was warmed to 60 °C (oil bath) for
24 h. The reaction mixture was concentrated to give a residue that was purified on a silica gel column
chromatography using hexane and EA (1:1) as an eluent.
(R)-4,4'-dihydroxy-1,1'-dimethyl-3,3'-spirobi[indoline]-2,2'-dione (12). Rf = 0.16 (hexane:EA= 1:1) White solid,
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337 mg, yield 92%. [α]D -43.2, (c = 0.5, MeOH). H NMR (400 MHz, MeOD) δ 9.45 (s, 2H), 7.14 (t, J = 8.0 Hz,
2H), 6.57 (d, J = 7.6 Hz, 2H), 6.43 (d, J = 8.2 Hz, 2H), 3.16 (s, 6H). 13C {1H} NMR (151 MHz, MeOD) δ 171.7 (s),
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152.8 (s), 146.5 (s), 129.7 (s), 111.6 (s), 110.8 (s), 100.2 (s), 58.7 (s), 26.8 (s). HRMS (ESI-TOF) m/z: [M+H]+
calcd. for (C17H15N2O4) 311.1026 found: 311.1020.
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ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra of all new compounds and HPLC spectra for compounds 5g, 6g, (R)-6b and (S-
6b) (PDF). X-ray structure information for (R)-6b (CIF). This material is available free of charge via the internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Authors
E-mail: wangzhongqing@hec.cn.
E-mail: zhang_jiancun@gibh.ac.cn.
Author Contributions
‖G.S. and Z.W. contributed equally to this work.
Notes.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Guangzhou Science and Technology Project (201707020046). We also
gratefully acknowledge financial support from the State Key Laboratory of Anti-Infective Drug Development
(Sunshine Lake Pharma Co., Ltd), (N0. 2015DQ780357). We gratefully thank Zhongjian Zhong (HEC pharm Co.,
Inc.) for NMR assistance, Baolei Luan and Yanling Liu (both HEC pharm Co., Inc.) for HPLC and optical rotation
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assistance. We also gratefully thank professor Lei Zhang (South China University of Technology) for X-ray
crystallographic analysis.
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REFERENCES
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(4) We believe that the amide C=O bonds in SBIDOLs may also provide weak coordination with the metals when
SBIDOLs are used as a ligand for metal-catalyzed reactions. (Ligands with similar amide C=O bonds please see:
Arshad. N.; Hashim. J.; Kappe. C.-O. Synthesis of Bisquinolone-Based Mono- and Diphosphine Ligands of the Aza-
BINAP Type. J. Org. Chem. 2008, 73, 4755.)
(5) We found that the best addition sequence is: first, the malonyl chloride was dissolved in DCM, followed by the
aniline derivatives and finally Et3N was added in drop wise.
(6) (a) Liu, Y.; Zhang, Z.; Wan, Y.; Zhang, G.; Li, Z.; Bi, J.; Ma, N.; Liu, T.; Liu, Q. Oxidation of β-Ketoamides:
The Synthesis of Vicinal Tricarbonyl Amides. J. Org. Chem. 2017, 82, 3901. (b) Malmberg, W.; Voß, J.;
Weinschneider, S. Preparation of New Vicinal Tricarbonyl Compounds and Some of Their Sulfur Analogs. Liebigs
Annalen der Chemie, 1983, 10, 1694.
(7) We also tried to directly synthesize compound 5 from 3 with PIFA as described in ref 1a, however, only trace
amount of the products were obtained.
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(8) Eaton, P.; Carlson, G.; Lee, J. Phosphorus Pentoxide-methanesulfonic Acid. Convenient Alternative to
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Polyphosphoric Acid. J. Org. Chem. 1973, 38, 4071.
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(9) Small amount of compounds 7 and 8 could also be separated by silica gel column chromatography (hexane: EA
=6:1). Compound 7 is more polar than 8.
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