Catalytic Asymmetric Mannich/Cyclization of 2-Isothiocyanato-1-indanones: An Approach to the Synthesis of Bispirocyclic Indanone-Thioimidazolidine-Oxindoles

Article abstract of DOI:10.1021/acs.orglett.8b01389

This study demonstrates that novel isothiocyanates derived from 1-indanones are useful building blocks in heteroannulation reactions with isatinimines. This convenient Mannich/cyclization cascade reaction serves as a powerful tool for the enantioselective construction of bispirocyclic indanone-thioimidazolidine-oxindoles bearing two adjacent spiro-quaternary stereocenters in good to excellent yields with excellent diastereo- and enantioselectivities. Versatile transformations of the products into other potential bioactive bispirocyclic heterocycles have also been demonstrated.

Full text of DOI:10.1021/acs.orglett.8b01389

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Asymmetric Mannich/Cyclization of 2‑Isothiocyanato-1-
indanones: An Approach to the Synthesis of Bispirocyclic
Indanone−Thioimidazolidine−Oxindoles
Bo-Liang Zhao and Da-Ming Du*
School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
S
* Supporting Information
ABSTRACT: This study demonstrates that novel isothiocya-
nates derived from 1-indanones are useful building blocks in
heteroannulation reactions with isatinimines. This convenient
Mannich/cyclization cascade reaction serves as a powerful
tool for the enantioselective construction of bispirocyclic
indanone−thioimidazolidine−oxindoles bearing two adjacent
spiro-quaternary stereocenters in good to excellent yields with
excellent diastereo- and enantioselectivities. Versatile trans-
formations of the products into other potential bioactive
bispirocyclic heterocycles have also been demonstrated.
ndanones have played an important role in the development
of catalytic asymmetric synthesis; in particular, 1-indanone-
In contemporary organic synthetic chemistry, domino or
cascade reactions have become a new tool in total synthesis5
and one of the most effective ways to synthesize heterocyclic
structural architectures.6 In particular, organocatalytic domino
or cascade reactions have become powerful strategies for the
buildup of chemical and stereochemical diversity with multiple
stereocenters from simple and readily available starting
materials.7 In this process, the design and synthesis of cascade
reagents with high reactivity and high selectivity is one of the
most critical steps. Over the past years, various cascade
reagents for the preparation of chiral compounds with multiple
stereocenters have been introduced. Among them, isothiocya-
nates bearing an electron-withdrawing moiety in the α-position
have proved to be particularly efficient cascade reagents for the
asymmetric synthesis of heterocyclic compounds.
After Seidel et al.’s pioneering application of isothiocyanates
derived from oxazolidinones in organocatalysis,8 isocyanoace-
tates have become irreplaceable building blocks for the
synthesis of numerous important classes of nitrogen hetero-
cyclic compound by the organocatalyzed asymmetric [3 + 2]
cycloadditions with electrophiles. Ever since the report by
Yuan et al. in 2011,9 3-isothiocyanato oxindoles have become
extremely efficient and versatile cascade reagents for the
enantioselective synthesis of spirooxindoles.10 We envisoned
that 2-isothiocyanato 1-indanones might also be used as
cascade reagents. To verify the viability of this concept, we
successfully synthesized and explored the readily accessible 1-
indanone-derived isothiocyanates (Scheme 1a).
I
derived cyclic β-ketoesters are the most commonly used
substrates to verify the asymmetric substitution reaction
strategies.1 However, the reactions of 1-indanone-derivatives
as nucleophilic reagents are limited.2 To the best of our
knowledge, the use of 1-indanone-derived nucleophilic cascade
reagents to trigger the asymmetric cascade reactions have not
been realized until now.
On the other hand, the important heterocyclic skeleton of
spirooxindole is the core framework of many natural products
and bioactive molecules.3 Among them, spirooxindoles
containing two adjacent spiro-quaternary stereocenters and
1-indanone units have shown considerable bioactivities, such as
antitumor, cholinesterase, or acetylcholinesterase (AChE)
inhibitory activities (Figure 1).4 In this context, the
spiroindanone-oxindole architecture present in the biologically
relevant spirooxindole derivatives is worth noticing. Accord-
ingly, the development of efficient methods for the asymmetric
synthesis of spiroindanone−oxindoles could be important in
the future design and discovery of medicinally significant
compounds.
Received: May 2, 2018
Figure 1. Examples of biologically active spiroindanone−oxindoles.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01389
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Isothiocyanate Strategy in the Organocatalyzed
Asymmetric Synthesis of Heterocycles and the Synthetic
Objectives of Our Study
Table 1. Screening of Organocatalysts and Optimization of
Reaction Conditions
a
b
c
d
entry
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
PhMe
THF
cat.
yield (%)
dr (%)
ee (%)
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C1
C1
C1
C1
C1
C1
C1
C1
87
76
83
72
69
79
76
84
90
84
68
80
92
79
80
79
87
92
64
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>99
>99
−95
−95
99
99
>99
85
9
85
98
52
99
10
11
12
13
14
15
16
Given the biological and chemical importance of spiroinda-
none−oxindoles and their analogues, the task of developing a
new approach to this class of compounds was undertaken.
Herein, we present an efficient strategy for the enantioselective
construction of bispirocyclic indanone−thioimidazolidine−
oxindoles (Scheme 1b) bearing two adjacent spiro-quaternary
stereocenters through a squaramide-catalyzed cascade Man-
nich/cyclization reaction between 2-isothiocyanato-1-indanone
1 and isatinimine 2.
We first performed the reaction of 2-isothiocyanato-2,3-
dihydro-1H-inden-1-one 1a with N-Boc isatinimine 2a. To our
delight, in the presence of 5 mol % of squaramide C1 derived
from quinine, the cascade Mannich/cyclization reaction was
completed in CH2Cl2 at room temperature in 12 h and
afforded the desired product 3aa in 87% yield with excellent
diastereoselectivity and enantioselectivity (>25:1 dr, > 99% ee)
(Table 1, entry 1). With the above excellent result in hand, we
evaluated a small library of organocatalysts (Figure 2) for this
cascade process (Table 1, entries 1−11). Some squaramide
catalysts C1−C9 derived from cinchona alkaloid and (1S,2S)-
(+)-1,2-diaminocyclohexane were screened (Table 1, entries
2−9). The opposite enantiomer of the product 3aa was
obtained with lower enantioselectivity when quinidine-derived
squaramides C3 or C4 were used as catalysts (Table 1, entries
3 and 4).
>99
96
98
95
99
99
MeCN
e
17
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
f
18
g
19
99
a
Reaction conditions: 1a (0.1 mmol), 2a (0.11 mmol), catalyst (5
mol %) in 0.5 mL of solvent were stirred at room temperature for 12
b
c
d
1
h. Isolated yield. Determined by H NMR. Determined by chiral
HPLC analysis. The reaction was performed at 0 °C. 10 mol % of
catalyst was used. 2.5 mol % of catalyst was used.
e
f
g
In addition, as a comparison of the used squaramides, the
corresponding quinine-derived thiourea C10 was also
evaluated (Table 1, entry 10). There was a slight decline in
yield and enantioselectivity. There was a significant drop in
yield and enantioselectivity when quinine C11 used as the
catalyst (Table 1, entry 11). As shown in the Table 1, the
squaramide C1 derived from quinine still proved to be the
most efficient catalyst with respect to the yield and
enantioselectivity of this cascade reaction.
To improve the reaction efficiency, further optimization was
carried out using squaramide C1 as the catalyst. The effects of
solvent, reaction temperature, and catalyst loading amount
were investigated (Table 1, entries 12−19). Solvent effects play
important roles in the reactions (Table 1, entries 12−16). The
results show that ClCH2CH2Cl was the best solvent with
respect to both yield and enantioselectivity. However, the
results of the reaction did not improve when the temperature
was lowered to 0 °C (Table 1, entry 17). Subsequently, the
Figure 2. Screened organocatalysts.
effect of catalyst loading amount was tested. An increase in
catalyst loading amount did not further improve the reaction
results (Table 1, entry 18). When the catalyst loading amount
was reduced to 2.5 mol %, the yield of 3aa significantly
declined (Table 1, entry 19). Thus, we use a 5 mol % catalyst
loading.
Following this optimization of the reaction conditions, the
substrate scope of this enantioselective squaramide-catalyzed
Mannich/cyclization cascade reaction was examined for the
synthesis of bispirocyclic indanone−thioimidazolidine−oxin-
doles 3. The results are shown in Scheme 2. Initially, structural
B
DOI: 10.1021/acs.orglett.8b01389
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
this cascade process (3ba, 3fa, 3ea, and 3ha). It is worth
mentioning that nearly a single diastereoisomer of the product
was obtained. Then a variety of isatinimines were tested. When
4-substituted isatinimines were reacted with 1a, no obvious
reaction product was observed, which may be due to large
steric hindrance. Subsequently, various 5-substituted, 6-
substituted, 7-substituted, and 5,7-disubstituted N-Boc-isatini-
mines were examined. All these substrates smoothly underwent
this cascade Mannich/cyclization reaction to afford the desired
spirooxindoles (3ac−am). In addition, we also tested a N-Ph-
isatinimine, which gave the corresponding product 3an with a
dramatic decline of enantioselectivity.
Scheme 2. Substrate Scope
Subsequently, the influence of the N-protecting group of the
isatinimines on the reaction results was investigated. The N-
unprotected, N-methyl-, and N-allylisatinimines all could give
the corresponding products (3ao−aq) with comparable
excellent yields and stereoselectivities to N-benzylisatinimine.
Finally, we tried two isatinimines with p-bromobenzyl and p-
nitrobenzyl N-protecting groups, which afforded their corre-
sponding products in lower yields than N-benzylisatinimine
(3ar and 3as).
The absolute configuration of the type of product was
elucidated by single-crystal X-ray diffraction analysis of 3ia as
(2′S,3″R) (Figure 3), and the configurations of other products
were assigned by analogy.
Figure 3. X-ray structure of 3ia (inclusion of CHC13 molecules).
Remarkably, the derivatization of the major diastereomer of
3aa into other structurally diverse spiroindanone-oxindoles,
such as compounds 4−8 bearing two adjacent spiro-quaternary
stereocenters, could be smoothly realized (for details, see the
Supporting Information). As illustrated in Scheme 3, the Boc
group of 3aa could be easily removed with CF3CO2H,
affording the corresponding product 4. In addition, the
thioimidazolidine moiety of 3aa also could be smoothly
converted into an imidazolidine ring with m-CPBA, which led
a
Reaction conditions: 1 (0.1 mmol), 2 (0.11 mmol), and catalyst C1
(5 mol %) in ClCH2CH2Cl (0.5 mL) were stirred at rt for 24−48 h.
Scheme 3. Further Investigation of Transformation of 3aa
1
The dr of products were determined by H NMR. The ee values of
products were determined by HPLC.
variations were made on the 2-isothiocyanato-1-indanones 1.
We found that the substrates with electron-withdrawing
substituents such as F, Cl, and Br and electron-donating
substituents such as Me and MeO all could react smoothly
with 2a to afford the corresponding products (3ba−ia) in high
yields with excellent enantioselectivities. Compared with
electron-withdrawing substituents, electron-donating substitu-
ents on the aromatic rings of 1-indanones improved the
reaction yield. However, the positions of the substituted group
on the aromatic rings of 1-indanones had little influence on
C
DOI: 10.1021/acs.orglett.8b01389
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to compound 5,11 which is another class of heterocycles now
available for future biological investigation. The Boc group of 4
could also be easily removed with CF3CO2H to afford
compound 6. In addition, the thioimidazolidine moiety of
3aa also could be smoothly converted into a 2-(alkylthio)-
imidazolidine ring as in compounds 7 and 8, which resulted in
the formation of another family of bispirocyclic indanone−
thioimidazolidine−oxindole analogues.
To further highlight the synthetic value of this methodology,
a large-scale experiment was conducted under the optimized
conditions (for details, see the Supporting Information). The
cascade reaction of 1a and 2a on a gram scale performed well,
and the product was obtained in slightly decreased yield (82%)
with the same excellent diastereo- and enantioselectivity
(>25:1 dr, > 99% ee).
In conclusion, we have synthesized a new type of 1-
indanone-derived isothiocyanate cascade reagent and success-
fully applied these in the enantioselective squaramide-catalyzed
cascade Mannich/cyclization reaction for the construction of
bispirocyclic indanone−thioimidazolidine−oxindoles bearing
two adjacent spiro-quaternary stereocenters in good to
excellent yields (up to 95%) with excellent diastereo- and
enantioselectivities (up to >25:1 dr, > 99% ee). In addition, the
practicality of this methodology has been demonstrated by the
synthetic transformations and the resulting novel heterocycles.
H. J. Am. Chem. Soc. 2013, 135, 5356. (c) Wang, X.; Yang, T.; Cheng,
X.; Shen, Q. Angew. Chem., Int. Ed. 2013, 52, 12860. (d) Xu, J.; Hu,
Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T. Adv. Synth. Catal. 2012,
354, 515. (e) Shibatomi, K.; Soga, Y.; Narayama, A.; Fujisawa, I.;
Iwasa, S. J. Am. Chem. Soc. 2012, 134, 9836.
(2) For selected examples, see: (a) Yu, L.; Wu, X.; Kim, M. J.;
Vaithiyanathan, V.; Liu, Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H.
Adv. Synth. Catal. 2017, 359, 1879. (b) Lou, Y.-P.; Zheng, C.-W.; Pan,
R.-M.; Jin, Q.-W.; Zhao, G.; Li, Z. Org. Lett. 2015, 17, 688.
(c) Shirakawa, S.; Wang, L.; He, R.; Arimitsu, S.; Maruoka, K. Chem. -
Asian J. 2014, 9, 1586.
(3) (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. (b) Yu, J.; Shi, F.; Gong, L. Acc. Chem. Res. 2011, 44, 1156.
(c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41,
7247.
(4) For examples, see: (a) Ali, M. A.; Ismail, R.; Choon, T. S.; Yoon,
Y. K.; Wei, A. C.; Pandian, S.; Kumar, R. S.; Osman, H.; Manogaran,
E. Bioorg. Med. Chem. Lett. 2010, 20, 7064. (b) Girgis, A. S. Eur. J.
Med. Chem. 2009, 44, 91.
(5) (a) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167.
(b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
(6) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45,
1278.
(7) For selected reviews of organocatalytic domino or cascade
reactions, see: (a) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem.
́
Rev. 2014, 114, 2390. (b) Toure, B. B.; Hall, D. G. Chem. Rev. 2009,
109, 4439. (c) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38,
2993. (d) Enders, D.; Grondal, C.; Huttl, M. R. Angew. Chem., Int. Ed.
2007, 46, 1570.
ASSOCIATED CONTENT
* Supporting Information
■
(8) Li, L.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2008, 130,
12248.
(9) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan,
W.-C. Org. Lett. 2011, 13, 2472.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01389.
(10) For selected examples on 3-isothiocyanato oxindoles in the
synthesis of spirooxindole molecules, see: (a) Zhao, J.-Q.; Zhou, X.-J.;
Zhou, Y.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2018, 20,
909. (b) Lin, Y.; Liu, L.; Du, D.-M. Org. Chem. Front. 2017, 4, 1229.
(c) Zhao, H.-W.; Tian, T.; Pang, H.-L.; Li, B.; Chen, X.-Q.; Yang, Z.;
Meng, W.; Song, X.-Q.; Zhao, Y.-D.; Liu, Y.-Y. Adv. Synth. Catal.
2016, 358, 2619. (d) Du, D.; Xu, Q.; Li, X.-G.; Shi, M. Chem. - Eur. J.
2016, 22, 4733. (e) Wang, L.; Yang, D.; Li, D.; Liu, X.; Zhao, Q.; Zhu,
R.; Zhang, B.; Wang, R. Org. Lett. 2015, 17, 4260. (f) Zhao, J.-Q.; Wu,
Z.-J.; Zhou, M.-Q.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2015, 17, 5020. (g) Kayal, S.; Mukherjee, S. Org. Lett. 2015, 17, 5508.
(h) Wang, L.; Yang, D.; Li, D.; Wang, R. Org. Lett. 2015, 17, 3004.
(i) Bai, M.; Cui, B.-D.; Zuo, J.; Zhao, J.-Q.; You, Y.; Chen, Y.-Z.; Xu,
X.-Y.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2015, 71, 949. (j) Cai,
H.; Zhou, Y.; Zhang, D.; Xu, J.; Liu, H. Chem. Commun. 2014, 50,
14771. (k) Tan, F.; Lu, L.-Q.; Yang, Q.-Q.; Guo, W.; Bian, Q.; Chen,
J.-R.; Xiao, W.-J. Chem. - Eur. J. 2014, 20, 3415. (l) Liu, X.-L.; Han,
W.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2013, 15, 1246. (m) Cao,
Y.-M.; Shen, F.-F.; Zhang, F.-T.; Wang, R. Chem. - Eur. J. 2013, 19,
1184. (n) Wu, H.; Zhang, L.-L.; Tian, Z.-Q.; Huang, Y.-D.; Wang, Y.-
M. Chem. - Eur. J. 2013, 19, 1747. (o) Han, W.-Y.; Li, S.-W.; Wu, Z.-
J.; Zhang, X.-M.; Yuan, W.-C. Chem. - Eur. J. 2013, 19, 5551.
(p) Kato, S.; Yoshino, T.; Shibasaki, M.; Kanai, M.; Matsunaga, S.
Angew. Chem., Int. Ed. 2012, 51, 7007. (q) Han, Y.-Y.; Chen, W.-B.;
Han, W.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2012, 14,
490.
Experimental details, 1H and 13C spectra of new
compounds, and HPLC chromatograms (PDF)
Accession Codes
CCDC 1839384 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +86 10 68914985. E-mail: dudm@bit.edu.cn.
ORCID
Da-Ming Du: 0000-0002-9924-5117
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National
Postdoctoral Program for Innovative Talents of China (No.
BX201700030) and the Project funded by China Postdoctoral
Science Foundation (No. 2017M620630). We also thank the
Analysis & Testing Center of the Beijing Institute of
Technology.
(11) Grivas, S.; Ronne, E. Acta Chem. Scand. 1995, 49, 225.
REFERENCES
■
(1) (a) Shirakawa, S.; Tokuda, T.i; Kasai, A.; Maruoka, K. Org. Lett.
2013, 15, 3350. (b) Deng, Q.-H.; Bleith, T.; Wadepohl, H.; Gade, L.
D
DOI: 10.1021/acs.orglett.8b01389
Org. Lett. XXXX, XXX, XXX−XXX