Organocatalytic oxa/aza-Michael-Michael cascade strategy for the construction of spiro [chroman/tetrahydroquinoline-3,3′-oxindole] scaffolds

Article abstract of DOI:10.1021/ol401595g

A new useful and effective chiral amine-catalyzed oxa-and aza-Michael-Michael cascade methodology for the construction of enantiomerically enriched indolinones spiro-fused with chromans or tetrahydroquinolines is reported. By employing suitable organocatalysts depending on the different Michael donors (Ar-OH/Ar-NHR), the processes offered excellent stereocontrol (dr >20:1, >99% ee) under mild conditions.

Full text of DOI:10.1021/ol401595g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic oxa/aza-Michaelꢀ
Michael Cascade Strategy for the
Construction of Spiro [Chroman/
Tetrahydroquinoline-3,30-oxindole] Scaffolds
Haibin Mao,† Aijun Lin,† Yang Tang,† Yan Shi,† Hongwen Hu,† Yixiang Cheng,† and
Chengjian Zhu*,†,‡
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination
Chemistry, Nanjing University, Nanjing, 210093, China, and Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
cjzhu@nju.edu.cn
Received June 6, 2013
ABSTRACT
A new useful and effective chiral amine-catalyzed oxa- and aza-MichaelꢀMichael cascade methodology for the construction of enantiomerically
enriched indolinones spiro-fused with chromans or tetrahydroquinolines is reported. By employing suitable organocatalysts depending on the
different Michael donors (Ar-OH/Ar-NHR), the processes offered excellent stereocontrol (dr >20:1, >99% ee) under mild conditions.
Spirooxindole,1 chroman,2 and tetrahydroquinoline3
skeletons containing multiple stereogenic centers are pri-
vileged heterocyclic ring systems thatare featured ina large
number of bioactive alkaloids and medicinally relevant
compounds. Furthermore, some sophisticated structures
in which the oxindole core is fused with a chroman/
tetrahydroquinoline moiety at the C3-position were docu-
mented as possessing remarkable biological activities.4
Because of the significant medicinal value and structural
complexities, these intriguing frameworks have emerged as
attractive synthetic targets (Scheme 1a).5 However, the
efficient asymmetric synthetic methodology to construct
these rigid spiroarchitectures with multistereocenters is
deficient. Very recently, Shi and Tu realized the highly
stereoselective synthesis of spiro [tetrahydroquinoline-
2,30-oxindole] derivatives through an isatin-involved
Povarov reaction (Scheme 1b).6 Nevertheless, enantiomeri-
cally enriched spiro [chroman/tetrahydroquinoline-3,30-
oxindole] scaffolds possessing the potential as an important
pharmacophore have not been constructed until now.
Asymmetric organocatalytic domino reactions7 which
proceed consecutively and under the same reaction
† Nanjing University.
‡ Chinese Academy of Sciences.
(1) For selected reviews of spirooxindoles: (a) Lin, H.; Danishefsky,
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K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (c) Zhou, F.; Liu, Y.-L.;
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r
10.1021/ol401595g
XXXX American Chemical Society

in organocatalytic Michaelꢀhemiacetalization cascade re-
actions with carbonyl compounds.9 However, chiral Lewis
base catalyzed oxa-MichaelꢀMichael cascade reactions
of (E)-2-(2-nitrovinyl)phenol derivatives with electron-
deficient olefins are less developed;10 the asymmetric reac-
tions involving (E)-2-(2-nitrovinyl)aniline derivatives have
not even been reported. Inspired by the pioneering work of
Wang on the use of bifunctional tertiary amine-hydrogen-
bond donor catalysts in asymmetric domino reactions,11
and also in conjunction with the construction of spiro
[chroman/tetrahydro-quinoline-3,30-oxindole] skeletons,
herein, we described our results on chiral Lewis base
catalyzed oxa/aza-MichaelꢀMichael cascade sequences
between methyleneindolinones and (E)-2-(2-nitrovinyl)
phenol/aniline derivatives (Scheme 1c).
Scheme 1. Spiro [Chroman/Tetrahydroquinoline-3,30-oxindole]
Scaffold Synthesis
Initial examinations were carried out by using variously
N-protected methyleneindolinones 2and (E)-2-(2-nitrovinyl)-
phenol 3a in the presence of 20 mol % DABCO (Table 1,
entries 1ꢀ4). The preliminary studies revealed that the
reaction efficiency highly depended on the protection form
of the nitrogen. The promising racemic product was
obtained only when Boc was used (Table 1, entry 4).
Inspired by this result, we examined a number of chiral
tertiary amines (1aꢀ1d) and bifunctional tertiary amine-
hydrogen-bond donor catalysts (1eꢀ1h) for the enantio-
induction of the reaction using N-Boc protected methyl-
eneindolinone 2a as the Michael acceptor (Table 1, entries
5ꢀ12). This led to identification of squaramide-cinchona
bifunctional catalyst 1h as the optimal catalyst, which
provided the desired product in 71% yield with 85% ee,
10:1 dr (Table 1, entry 12). To further increase the reaction
diastereo- and enantioselectivity, we focused on varying
reaction parameters including solvent, temperature, and
concentration of the reactants (see Supporting Informa-
tion (SI), Table S1). After investigating these parameters,
the optimized conditions were established to afford spiro
[chroman-3,30-oxindole] 4a in 72% yield with >20:1 dr and
92% ee in CH2Cl2 (0.05 mol/L) at 0 °C (Table S1, entry 11).
With optimized reaction conditions in hand, we exam-
ined an array of N-Boc protected methyleneindolinones 2
and 2-(E)-(2-nitrovinyl)phenol derivatives 3 to explore the
generality of this asymmetric oxa-MichaelꢀMichael cas-
cade reaction. The results are summarized in Scheme 2.
The scope of the reaction could be successfully extended to
N-Boc protected methyleneindolinones with various ester
groups, and high stereoselectivities (>20:1 dr, 92%-98% ee)
were generally achieved (Scheme 2, 4aꢀ4e). Further ex-
ploration of the substrate scope focused on the 2-(E)-(2-
nitrovinyl)phenol derivatives 3 (Scheme 2, 4fꢀ4l). These
results indicated that enantioselectivities were almost
conditions to construct complex frameworks from simple
precursors are characterized by high efficiencies, excellent
stereoselectivities, and environmental friendliness. There-
fore, organocatalytic domino reactions are widely regarded
as powerful tools in contemporary organic synthesis.
Recently, methyleneindolinones were selected to enantio-
selectively construct spirooxindole scaffolds in organo-
catalytic domino reactions and cycloadditions.8 (E)-2-(2-
Nitrovinyl)phenols bearing both a Michael donor and
Michael acceptor were important starting materials for
affording chiral chromene or chroman cores, particularly
(8) For selected examples: (a) Chen, X.-H.; Wei, Q.; Luo, S.-W.;
Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (b)
Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.;
Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48,
7200. (c) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.;Eur.
J. 2010, 16, 2852. (d) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am.
Chem. Soc. 2011, 133, 4672. (e) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend,
B.; Li, Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am.
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Chem. Soc. 2011, 133, 5053. (f) Tan, B.; Hernandez-Torres, G.; Barbas,
C. F. J. Am. Chem. Soc. 2011, 133, 12354. (g) Tan, B.; Candeias, N. R.;
Barbas, C. F. Nat. Chem. 2011, 3, 473. (h) Sun, W.; Zhu, G.; Wu, C.;
Hong, L.; Wang, R. Chem.;Eur. J. 2012, 18, 6737. (i) Duan, S.-W.; Li,
Y.; Liu, Y.-Y.; Zou, Y.-Q.; Shi, D.-Q.; Xiao, W.-J. Chem. Commun.
2012, 48, 5160. (j) Li, G.; Liang, T.; Wojtas, L.; Antilla, J. C. Angew.
Chem., Int. Ed. 2013, 52, 4628. (k) Wang, L.; Shi, X.-M.; Dong, W.-P.;
Zhu, L.-P.; Wang, R. Chem. Commun. 2013, 49, 3458. (l) Shi, Y.; Lin, A.;
Mao, H.; Mao, Z.; Li, W.; Hu, H.; Zhu, C.; Cheng, Y. Chem.;Eur. J.
2013, 19, 1914.
(9) (a) Enders, D.; Wang, C.; Yang, X.; Raabe, G. Adv. Synth.Catal.
2010, 352, 2869. (b) Lu, D.; Li, Y.; Gong, Y. J. Org. Chem. 2010, 75,
6900. (c) Hong, B.-C.; Kotame, P.; Lee, G.-H. Org. Lett. 2011, 13, 5758.
(d) Enders, D.; Yang, X.; Wang, C.; Raabe, G.; Runsik, J. Chem.;
Asian J. 2011, 6, 2255. (e) Hong, B.-C.; Kotame, P.; Liao, J.-H. Org.
Biomol. Chem. 2011, 9, 382. (f) Ramachary, D. B.; Shiva Prasad, M.;
Madhavachary, R. Org. Biomol. Chem. 2011, 9, 2715. (g) Enders, D.;
Urbanietz, G.; Raabe, G. Synthesis 2011, 2011, 1905. (h) Ramachary,
D. B.; Sakthidevi, R.; Shruthi, K. S. Chem.;Eur. J. 2012, 18, 8008. (i)
Ramachary, D. B.; Madhavachary, R.; Prasad, M. S. Org. Biomol.
Chem. 2012, 10, 5825. (j) Enders, D.; Urbanietz, G.; Hahn, R.; Raabe, G.
Synthesis 2012, 44, 773.
(10) Only some examples using R,β-unsaturated aldehydes as sub-
strates based on chiral secondary amines catalysis: (a) Kotame, P.;
Hong, B.-C.; Liao, J.-H. Tetrahedron Lett. 2009, 50, 704. (b) Zhang, X.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening for the Optimal Catalysta
Scheme 2. Synthesis of 4-(Nitromethyl)spiro [Chroman-3,30-
oxindole] Derivatives 4a,b
entry
R1
cat.
t (h)
yield (%)b
drc
ee (%)d
1
H
DABCO
DABCO
DABCO
DABCO
1a
96
96
96
24
24
24
24
24
24
24
24
24
0
ꢀ
ꢀ
2
Ac
0
ꢀ
ꢀ
3
Bn
trace
68
53
82
78
75
68
64
67
71
ꢀ
ꢀ
4
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
ꢀ
ꢀ
5e
6
13:1
>20:1
>20:1
>20:1
9:1
ꢀ10
80
73
63
28
36
56
85
1b
7
1c
8
1d
9
1e
10
11
12
1f
9:1
1g
10:1
10:1
1h
a Unless otherwise noted, the reaction was carried out with
0.20 mmol of 2, 0.10 mmol of 3a, 20 mol % of catalyst 1 (0.02 mmol)
in CH2Cl2 (1 mL) at rt. b Yield of isolated product. c Determined by 1H
NMR analysis of the crude products. d ee values of the major diaster-
eoisomer were determined by chiral HPLC analysis. e The opposite
configuration.
independent of the nature [halides (4hꢀ4j), electron-
donating (4f, 4g, 4l), and electron-withdrawing (4k) groups]
and position (4f, 4l) of the substituent on the aromatic
ring of 3. When a series of methyleneindolinones 2 with
varioussubstituentson the aromatic ring wereemployed as
the substrate, the asymmetric transformation could also be
completedwith excellent stereoselectivities in moderate-to-
good yields (Scheme 2, 4mꢀ4q). Functional groups, such
as fluoro (4m), chloro (4n), and bromo (4o, 4q) groups,
were well tolerated under the reaction conditions. More-
over, the absolute configurations of the stereogenic centers
of product 4j were confirmed by X-ray crystallographic
analysis.12a
a The reaction was carried out with 0.20 mmol of 2, 0.10 mmol of 3,
and 20 mol % of catalyst for 1 h in CH2Cl2 (2.0 mL) at 0 °C. b Yield of
isolated product; ee values were determined by chiral HPLC analysis; dr
was determined by 1H NMR analysis of the crude products, and unless
otherwise noted, dr values of compound 4 were greater than 20:1.
To demonstrate the practical utility of our domino proto-
col, we examined the preparation of 4c on a gram scale (see
(12) (a) CCDC 913217 contains the supplementary crystallographic
data of the product 4j for this paper. (b) CCDC 933342 contains the
supplementary crystallographic data of the product 6g for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
SI). When the reaction was conducted in 4 mmol amounts,
1.27 g of optically pure 4c (64% yield, up to 99% ee) could be
obtained after recrystallization from CH2Cl2/n-hexane.
Org. Lett., Vol. XX, No. XX, XXXX
C

Next, we wished to construct another attractive syn-
thetic target: spiro [tetrahydroquinoline-3,30-oxindole]
skeleton 6 through an asymmetric aza-MichaelꢀMichael
cascade sequence between methyleneindolinones 2 and
N-Ts-2-(E)-(2-nitrovinyl)aniline 5. However, to our surprise,
the enantioselectivity of the reaction employing 1h as the
catalyst under the above optimized conditions was low
(30% ee) though the yield (94%) and diastereoselectivity
(>20:1) remained relatively high. This result spurred us
to seek another catalyst for the purpose of obtaining
enantiomerically enriched spiro [tetrahydroquinoline-3,30-
oxindole]. After screening the catalyst library of Table 1
again, we excitedly found that excellent stereoselectivity
(>20:1 dr and 98% ee) could be achieved in quantitative
yield (96%) when chiral tertiary amine 1b was used.
Inspired by this result, we then evaluated a number of
N-Boc protected methyleneindolinones 2 to determine
the substrate generality of this new catalytic system, and the
results are summarized in Scheme 3. Ester groups did not
substantially impact the yield or stereoselectivity (Scheme 3,
6aꢀ6b). Moreover, both electron-donating and -withdrawing
substituents at different positions on the aromatic ring
afforded the products with 97%ꢀ98% ee and excellent dr
values in good yields (Scheme 3, 6cꢀ6g). In consideration
of employing this new catalyst, the absolute configurations
of the stereogenic centers of the spiro [tetrahydroquinoline-
3,30-oxindole] skeletons were confirmed once again by
X-ray crystallographic analysis (Scheme 3, 6g).12b
Scheme 3. Synthesis of Spiro [Tetrahydroquinoline-3,30-
oxindole] Derivatives 6a,b
In summary, we have developed a convenient and
efficient organocatalytic cascade strategy for the asym-
metric synthesis of spiro [chroman/tetrahydro-quinoline-
3,30-oxindole] skeletons from readily available and simple
starting materials. The oxa-MichaelꢀMichael reaction
sequence catalyzed by a squaramide-tertiary amine pro-
ceeded well under mild conditions to furnish a series of spiro
[chroman-3,30-oxindole] derivatives containing three contig-
uous stereocenters, including one spiro quaternary chiral
center. This straightforward process offered excellent stereo-
control (>20:1 dr and >99% ee) even on a preparative scale.
Significantly, when the sterically hindered chiral tertiary
amine was used as the organocatalyst, the aza-Michaelꢀ
Michael reactions of methyleneindolinones 2 with the ra-
tional designed N-Ts-2-(E)-(2-nitrovinyl)aniline 5 provided
the densely functionalized spiro [tetrahydroquinoline-3,30-
oxindole] derivatives in almost quantitative yields with ex-
cellent stereoselectivities (>20:1 dr and up to 98% ee). Fur-
ther studies on the biological activity of this intriguing class of
spirocyclic compounds are underway in our laboratory.
a The reaction was carried out with 0.20 mmol of 2, 0.10 mmol of 5,
b
and 20 mol % of catalyst 1b in CH2Cl2 (2.0 mL) at 0 °C. Yield of
isolated product; ee values were determined by chiral HPLC analysis; dr
was determined by 1H NMR analysis of the crude products, and dr
values of all 6 compounds were greater than 20:1.
Acknowledgment. We gratefully acknowledge the Na-
tional Natural Science Foundation of China (21172106,
21074054), National Science Fund for Talent Training in
Basic Science (No. J1103310), the National Basic Research
Program of China (2010CB923303), and the Research
Fund for the Doctoral Program of Higher Education of
China (20120091110010) for their financial support.
Supporting Information Available. Representative ex-
perimental procedures, analytical data for all the com-
pounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX