Highly enantioselective synthesis of spiro[cyclohexanone-oxindoles] and spiro[cyclohexanone-pyrazolones] by asymmetric cascade [5+1] double Michael reactions

Article abstract of DOI:10.1002/ejoc.201101529

The asymmetric catalytic synthesis of naturally occurring and biologically active spiro compounds is a challenge for modern chemical methodology. Here we report the construction of spiro compounds through cascade [5+1] double Michael reactions between divinyl ketones and N-unprotectedoxindoles or N-phenyl-protected pyrazolones catalyzed by a combination of the easily available 9-amino-9-deoxy-epi-quinine with N-Boc-D-phenylglycine. The desired multistereogenic spiro[cyclohexanone-oxindoles and -pyrazolones] were obtained with high yields (up to 98 %) andstereoselectivities (up to >20:1 dr, 99 % ee). An efficient approach to spiro compounds through cascade [5+1] double Michael reactions between divinyl ketones and oxindoles or N-protected pyrazolones in the presence of 9-amino-9-deoxy-epi-quinine and N-Boc-D-phenylglycine is reported. Multistereogenic spiro[cyclohexanone- oxindoles and -pyrazolones] are obtained with high yields (up to 98 %) and stereoselectivities (up to >20:1 dr, 99 % ee). Copyright

Full text of DOI:10.1002/ejoc.201101529

FULL PAPER
DOI: 10.1002/ejoc.201101529
Highly Enantioselective Synthesis of Spiro[cyclohexanone-oxindoles] and
Spiro[cyclohexanone-pyrazolones] by Asymmetric Cascade [5+1] Double
Michael Reactions
Bin Wu,[a] Jian Chen,[a] Mei-Qiu Li,[a] Jin-Xin Zhang,[a] Xiao-Ping Xu,[a] Shun-Jun Ji,*[a]
and Xing-Wang Wang*[a]
Keywords: Spiro compounds / Nitrogen heterocycles / Organocatalysis / Enantioselectivity / Michael addition
The asymmetric catalytic synthesis of naturally occurring and
biologically active spiro compounds is a challenge for mod- quinine with N-Boc-
combination of the easily available 9-amino-9-deoxy-epi-
-phenylglycine. The desired multi-
D
ern chemical methodology. Here we report the construction
of spiro compounds through cascade [5+1] double Michael
reactions between divinyl ketones and N-unprotected
oxindoles or N-phenyl-protected pyrazolones catalyzed by a
stereogenic spiro[cyclohexanone-oxindoles and -pyrazol-
ones] were obtained with high yields (up to 98%) and
stereoselectivities (up to Ͼ20:1 dr, 99% ee).
Introduction
Oxindoles[1] and pyrazolones[2] are two important types
of structural motif, constituting core structural elements
common in a large number of biologically active naturally
occurring products and a series of pharmaceutically active
compounds. Chitosenine (Figure 1), for instance, exhibits
short-lived inhibitory activity of ganglionic transmission in
vivo in rats and rabbits,[3] whereas NITD609 kills the blood
stages of Plasmodium falciparum and Plasmodium vivax.[4]
Strychnofoline inhibits mitosis in a number of cell lines[5]
and aspidophylline A can reverse drug resistance in resist-
ant KB cells.[6] Among the natural pyrazoline derivatives,
the p38 inhibitor in Figure 1 is very important for treatment
of inflammation[7] and the depicted HIV-1 integrase inhibi-
tor[7–8] and hydantoin have been reported to display specific
activities against bacteria.[9] Thanks to the broad biological
activities and structural complexity of spirocyclic oxindole
and pyrazolone compounds, the development of syntheti-
cally effective protocols for such compounds is of consider-
able topical interest.[10]
Figure 1. Naturally occurring and biologically active oxindole and
pyrazoline derivatives.
Spiro[cyclohexanone-1,3Ј-indoline] and spiro[cyclohexa-
none-1,5Ј-pyrazolone] compounds, which are intriguing
combinations of multistereogenic cyclohexanone and
oxindole or pyrazolone motifs, are promising subsets with
potential bioactivities. The asymmetric synthesis of the two
classes of compounds involves the stereocontrolled instal-
lation of a spiro quaternary chiral carbon center, which has
been a challenging goal for synthetic chemists.[11] In ad-
dition, another urgent goal for synthetic chemists is to find
effective and sustainable methodologies to construct the
multistereogenic centers of these complex structures in one-
pot fashion and in a catalytic way.[12] Over the past decade,
asymmetric organocatalysis, as a new and powerful meth-
odology, has grown rapidly and become one of the most
active and attractive research fields in organic chemistry.[13]
Notably, organocatalytic cascade reactions are viewed as
powerful tools for the synthesis of such spirocyclic oxindole
and pyrazolone compounds.[14]
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou 215123, P. R. China
Fax: +86-512-65880378
E-mail: wangxw@suda.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101529.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1318–1327

Synthesis of Spiro[cyclohexanone-oxindoles and -pyrazolones]
After Melchiorre and co-workers, in 2009, has pioneer- with excellent enantioselectivities, catalyzed by a combina-
ingly achieved the organocatalytic synthesis of spiro[cy- tion of a cinchona-based chiral primary amine and a
clohexanone-oxindoles] through a [4+2] tandem iminium BINOL-phosphoric acid (Scheme 1, Eq. iii).
and enamine catalytic sequence,[15] Gong’s,[16] Wang’s,[17]
and our group[18] sequentially reported that the multi-
stereogenic structures of spiro[cyclohexanone-oxindoles]
can be constructed through asymmetric formal [4+2] cyclo-
additions or [4+2] domino double Michael additions cata-
lyzed by Brønsted acid/Lewis base bifunctional organocata-
lysts or primary amine catalysts. Recently, Barbas III’s
group presented a remarkable organocatalytic methodology
for the construction of bispiro-oxidoles containing three
quaternary stereocenters in a cascade approach with use of
a single multifunctional organocatalyst,[19] followed by an
enantioselective synthesis of spiro[cyclopentene-oxindoles]
through a phosphane-catalyzed [3+2] cycloaddition reac-
tion.[20] During this period, more asymmetric organocata-
lytic methodologies for the construction of the intriguing
Scheme 1. Reported models for asymmetric cascade [5+1] double
Michael additions of divinyl ketones with active methylene pronu-
cleophiles.
spirocyclic oxindole skeletons in the presence of primary
amines, secondary amines, or Brønsted acid/Lewis base bi-
functional organocatalysts were successfully developed.
They include a cascade Michael/Michael/aldol reaction[21]
or a domino Michael/Michael/Michael/aldol reaction for
Here we disclose that [5+1] double Michael additions be-
tween divinyl ketones and N-unprotected oxindoles or N-
phenyl-protected pyrazolones can be efficiently catalyzed by
amine-modified cinchona alkaloids and α-amino acid deriv-
atives to afford the desired multistereogenic spiro[cy-
clohexanone-oxindoles] and spiro[cyclohexanone-pyrazol-
ones] in moderate to high yields and with good to excellent
diastereoselectivities and enantioselectivities.
spiro[cyclohexenecarbaldehyde-oxindoles],[22]
a Michael/
ketone aldol/dehydration domino reaction for spiro[cy-
clohexenone-oxindoles],[17] a formal [2+2+2] annulation for
spiro[cyclohexanol-oxindoles] and spiro[cyclopiperidine-
oxindoles],[23] a Knoevenagel/Michael cyclization for spi-
ro[4H-pyran-oxindoles],[24] and direct asymmetric intermo-
lecular aldol reaction for spiro[cyclooxazolidinethione-
oxindoles].[25] On the other hand, there are only a few
literature reports for the organocatalytically asymmetric
synthesis of spiropyrazolone derivatives. In 2011, Rios et al.
reported that spiro[cyclohexenecarbaldehyde-pyrazolones]
bearing three or four contiguous chiral centers could be
Results and Discussion
Encouraged by previous success in establishing primary
synthesized in a highly enantioselective manner through amine salts in asymmetric iminium ion catalysis, we began
domino Michael/Michael/aldol/dehydration sequences be- the investigation by testing the model reaction between N-
tween pyrazolones and enals[26] or between unsaturated unprotected oxindole 2a (Table 1) and dienone 3a catalyzed
pyrazolones, enolizable aldehydes, and enals catalyzed by by primary amine 1a (20 mol-%) and with TFA (40 mol-%)
secondary amine catalysts.[27]
as additive in toluene at 40 °C. To our delight, the enantio-
To the best of our knowledge, divinyl ketones as latent mer 4a was formed in 33% yield, with a good diastereo-
electrophilic acceptors, aided by asymmetric organocatal- selectivity and 67% ee (Table 1, Entry 1). Use of the
ysis, have only come to be exploited this year. Our group pseudoenantiomer 1b under the same conditions afforded
reported that a thiourea-modified cinchona alkaloid and a compound 4a in 46% yield and with 88% ee (Table 1, En-
base catalyzed stepwise [5+1] cyclizations of divinyl ketones try 2). Subsequently, a range of reaction conditions with
with nitromethane, furnishing optically active 4-nitrocy- primary amine 1b (20 mol-%) were further investigated to
clohexanones with good yields, excellent diastereoselectivi- improve the catalytic efficacy. When different benzoic acid
ties, and high enantioselectivities (Scheme 1, Eq. i).[28] Yan derivatives were used, no obvious improvements in enantio-
and co-workers,[29] and later Lattanzi’s group,[30] disclosed selectivities were observed (Table 1, Entries 3–5 vs. 2). In-
that 9-amino-9-deoxy-epi-quinine and quinine efficiently creasing the amount of dienone 3a relative to that of ox-
catalyze double-conjugate additions of malononitrile to di- indole 2a was found to improve the yield of 4a considerably,
enones. Various 3,4,4,5-tetrasubstituted cyclohexanones with the best result (91% yield, 91% ee) obtained when two
were prepared with good yields and diastereoselectivities equivalents of 3a were used in the reaction (Table 1,
and excellent enantioselectivities (Scheme 1, Eq. ii). Other- Entry 8).
Asymmetric counterion-directed
catalysis
wise, highly enantioselective [5+1] double Michael reactions (ACDC)[32] has been recognized as an efficient strategy for
of N-Boc- or N-CO2Et-protected oxindoles as active meth- enantioselective transformations, and so we turned our at-
ylene pronucleophiles with dienones were developed by tention to chiral acids such as Boc-l-proline (Boc = tert-
Wang’s group[31] to access spirocyclic oxindole derivatives butyloxycarbonyl), Boc-l-Phg-OH, and Boc-d-Phg-OH as
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S.-J. Ji, X.-W. Wang et al.
FULL PAPER
Table 1. Screening studies of the asymmetric cascade [5+1] double still the best choice for this transformation (Table 1, En-
Michael addition between oxindole 2a and dienone 3a.[a]
tries 14–17 vs. 13). Finally, we established optimized reac-
tion conditions for the cascade [5+1] double Michael reac-
tion between divinyl ketone 3a and N-unprotected oxindole
2a: a 1:2 molar ratio of 2a to 3a, a 20 mol-% catalyst load-
ing of 1b with 40 mol-% N-Boc-d-Phg-OH as additive, and
toluene as the reaction solvent at 40 °C for 72 hours.
With the optimized reaction conditions to hand, we next
proceed to examine the generality of the reaction, and the
results are summarized in Table 2. A variety of substituents
on dienones and N-unprotected oxindoles were tolerated
well in this catalytic system, with the desired products being
Table 2. Asymmetric cascade [5+1] double Michael additions be-
tween N-unprotected oxindoles 2 and dienones 3.[a]
Entry
Additive
Solvent Time Yield[b]
dr[c]
ee[d]
[h]
[%]
[%]
1[e]
2
3
4
5
TFA
TFA
PhMe
PhMe
PhMe
DCM
DCM
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
CHCl3
THF
60
36
40
36
36
72
72
72
40
40
40
72
72
72
72
72
72
33
46
61
48
56
57
61
91
50
52
56
66
92
88
85
67
72
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
6:1
67
88
90
88
90
90
90
91
86
93
94
94
94
89
85
87
89
4-O2NC6H4COOH
4-FC6H4COOH
2-IC6H4COOH
TFA
6
Entry
R1, R2
R3
Yield[b]
[%]
dr[c]
ee[d][e]
[%]
7[f]
8[g]
9
TFA
TFA
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ph (3a)
4-MeOC6H4 (3b)
4-MeC6H4 (3c)
4-iPrC6H4 (3d)
4-FC6H4 (3e)
3-ClC6H4 (3f)
4-ClC6H4 (3g)
4-CF3C6H4 (3h)
2-BrC6H4 (3i)
2,4-Cl2C6H3 (3j)
1-naphthyl (3k)
2-thienyl (3l)
Ph (3a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
4a/92
4b/97
4c/75
4d/75
4e/83
4f/84
4g/70
4h/78
4i/69
4j/61
4k/53
4l/67
4m/79
4n/96
4o/92
4p/63
4q/98
4r/91
4s/98
4t/86
4u/94
4v/74
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
13:1
94
92
90
90
92
92
90
72
73
90
77
96
96
97
90
96
96
99
92
97
91
94
Boc-l-proline
Boc-l-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
10
11
12
13[g]
14[g]
15[g]
16[g]
17[g]
19:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
13:1
EtOAc
Ͼ20:1
H (2a)
H (2a)
H (2a)
[a] Reactions were performed with 2a (0.25 mmol), 3a (0.3 mmol),
catalyst 1b (20 mol-%), and additive (40 mol-%), in solvent
(1.0 mL) at 40 °C. [b] Isolated yields. [c] Determined by chiral
4-Cl (2b)
4-Br (2c)
5-Br (2d)
5-Cl-7-Me (2e)
5-F (2f)
6-Br (2g)
5-Cl (2h)
7-CF3 (2i)
5,6-(F)2 (2j)
H (2a)
1
HPLC or H NMR spectroscopy. [d] Determined by chiral HPLC.
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
10:1
[e] With catalyst 1a. [f] With 3a (0.375 mmol). [g] With 3a
(0.5 mmol).
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
9:1
additives. To our delight, the introduction of N-Boc-d-
phenylglycine (40 mol-%) and 1b (20 mol-%), established as
an organocatalyst system for Michael additions by Mel-
chiorre and co-workers,[33] resulted in the best enantiomeric
excess (94% ee) for the reaction (Table 1, Entry 11). Again,
when two equivalents of dienone 3a were used, the reaction
led to the desired product in the highest yield (92%) within
72 hours, albeit with the same stereoselectivity (Table 1, En-
Ͼ20:1
1.1:1
Ph, 4-ClC6H4 (3m)
[a] Unless otherwise noted, the reactions were performed with 2
(0.25 mmol), 3 (0.5 mmol), catalyst 1b (20 mol-%), and Boc-d-Phg-
OH (40 mol-%) in toluene (1 mL) at 40 °C for 72 h. [b] Isolated
yields. [c] Determined by chiral HPLC. [d] Determined by chiral
HPLC. [e] Absolute configurations were determined by comparing
the specific rotations of 4a and 4s with those reported in the litera-
try 13). Other solvents were also examined, but toluene was ture.[15]
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Eur. J. Org. Chem. 2012, 1318–1327

Synthesis of Spiro[cyclohexanone-oxindoles and -pyrazolones]
obtained in moderate to high yields (53–98%) and with ex- Table 3. Screening studies of the asymmetric cascade [5+1] double
Michael addition between pyrazolone 5a and dienone 3a.[a]
cellent enantioselectivities (72–99% ees). For divinyl
ketones with different substituents on the phenyl groups
(3a–j), electronic and steric properties had some effects on
the reactivities (61–97% yields) and stereoselectivities (72–
94% ees), although the diastereoselectivities (Ͼ20:1) could
be retained in all cases (Table 2, Entries 1–10). Generally,
the presence of electron-donating substituents on the dien-
ones resulted in products with higher yields and enantio-
selectivities, whereas that of electron-withdrawing substitu-
ents on the dienones resulted in products with lower yields
and enantioselectivities. The sterically hindered dienone
substrates 3i–k, with ortho-substituents on their phenyl or
naphthyl groups, turned out to be less reactive for this
transformation, as evidenced by lower yields (Table 2, En-
tries 9–11). Pleasingly, the double Michael addition between
dienone 3l, bearing thiophen-2-yl groups, and oxindole 2a
performed very well to afford the desired product 4l in good
yield (67%) and with excellent diastereo- and enantio-
selectivities (Ͼ20:1 dr, 96% ee, Table 2, Entry 12). On the
other hand, double Michael additions between the N-un-
protected oxindole derivatives 2b–j and 3a were also investi-
gated and were seen to afford the products in moderate to
high yields (63–98%) and with excellent enantioselectivities
(90–99% ee values, Table 2, Entries 13–21). Notably, the
electronic and steric properties of the N-unprotected ox-
indoles with different positional substituents on the indole
ring had slight influence on the reactivities and stereoselec-
tivities. Furthermore, the unsymmetrical divinyl ketone 3m
was also examined for this transformation and provided the
desired product 4v in 74% yield with inferior diastereoselec-
tivity (1.1:1 dr) but good enantioselectivity (Table 2, En-
try 22).
Entry
Additive
Solvent Yield[b]
[%]
dr[c]
6a/6aЈ
ee[d]
[%]
1
2
3
4
5
6
7
8
TFA
TFA
benzoic acid
PhMe
DCM
PhMe
71
68
54
44
50
79
75
73
69
65
6:1
1:1
3:1
19:1
Ͼ20:1
8:1
13:1
7:1
71
89
77
34
53
69
72
84
84
89
(R)-BINOL-phosphoric acid PhMe
(S)-BINOL-phosphoric acid PhMe
Boc-l-Phg-OH
Boc-l-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
Boc-d-Phg-OH
PhMe
CHCl3
PhMe
PhMe
CHCl3
9[e]
10
6:1
4:1
[a] Reactions were performed with 5a (0.1 mmol), 3a (0.12 mmol),
catalyst 1b (20 mol-%), and acid (40 mol-%) in solvent (1.0 mL) at
room temp. for 48 h. [b] Isolated yields. [c] Determined by chiral
HPLC. [d] Determined by chiral HPLC. [e] With 5a (0.1 mmol) and
3a (0.2 mmol) for this reaction.
We next further examined the double Michael additions
between pyrazolones and dienones assisted by the estab-
lished catalytic method. The initial screening results are
shown in Table 3. When pyrazolone 5a (Table 3) was treated catalyst 1b (20 mol-%) and N-Boc-d-phenylglycine (40 mol-
with dienone 3a in the presence of catalyst 1b (20 mol-%) %) in CHCl3 at room temp. for 48 hours.
and TFA (40 mol-%) in toluene at room temp. for 48 hours,
Having established the optimal reaction conditions, we
the desired spirocyclic compound 6a was obtained in 71% decided to explore the substrate scope and limitations of
yield, with a moderate diastereoselective ratio and enantio- this protocol for the double Michael additions of divinyl
selectivity (6:1 dr, 71% ee, Table 3, Entry 1). Several chiral ketones 3a–g and 3i–m with N-phenyl-protected pyrazolone
or achiral acids, such as benzoic acid, (R)- or (S)-BINOL- 5a. The results are shown in Table 4. For the dienone sub-
phosphoric acids, and l- or d-Boc-Phg-OHs, were then strates, both electron-donating and electron-withdrawing
screened as additives for this reaction. The (R)-BINOL- substituents on phenyl groups were tolerated, with the de-
phosphoric acid as additive improved the diastereoselective sired products being obtained in moderate yields (47–70%)
ratio sharply (19:1 dr), albeit with a large loss of enantio- and with moderate to good diastereoselectivity ratios
selectivity (34% ee, Table 3, Entry 4). N-Boc-d-phenylgly- (3:1Ǟ20:1 drs) and good enantioselectivities (81–97% ee
cine as additive proved to be effective in terms of both reac- values, Table 4, Entries 1–9). Intriguingly, dienones 3e–g
tivity and stereoselectivity (73% yield, 7:1 dr and 84% ee, and 3m, bearing meta- and para-halogen substituents (F, Cl,
Table 3, Entry 8). Increasing the amount of 3a had only a Br) on their phenyl groups, furnished the desired products
slight influence on the reactivity (Table 3, Entry 9). In with good to excellent enantioselectivities (90–98% ees), but
CHCl3 as the reaction medium the reaction gave the final with varying levels of diastereoselectivity (3:1Ǟ20:1 drs,
product with a higher enantioselectivity, though the dia- Table 4, Entries 5–8). Dienone 3l, bearing thiophen-2-yl
stereoselectivity was somewhat decreased (Table 3, En- groups, was also suitable for this reaction, giving the desired
tries 10 vs. 8). The optimal conditions chosen for the cas- product 6j in 52% yield, 1:2 dr, and 81% ee (Table 4, En-
cade [5+1] double Michael reactions between divinyl try 10). In contrast, the dienone substrates 3i and 3j, with
ketones and N-phenyl-protected pyrazolones were therefore ortho-substituents, proved ineffective for these transforma-
Eur. J. Org. Chem. 2012, 1318–1327
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1321

S.-J. Ji, X.-W. Wang et al.
FULL PAPER
tions were monitored by thin-layer chromatography (TLC) on silica
gel precoated glass plates (0.2Ϯ0.03 mm thickness, GF-254, par-
ticle size 0.01–0.04 mm). Chromatograms were visualized by fluo-
rescence quenching with UV light at 254 nm. Flash column
chromatography was performed with silica gel (particle size 0.04–
tions, probably due to the effects of steric hindrance
(Table 4, Entries 11–12).
Table 4. Asymmetric cascade [5+1] double Michael additions be-
tween pyrazolone 5a and dienones 3.[a]
1
0.05 mm). H and 13C NMR spectra were recorded in CDCl3 with
Varian Inova-300 or -400 NMR spectrometers. Chemical shifts (δ,
ppm) are relative to the resonance of the deuterated solvent as the
internal standard (CDCl3, δ = 7.26 ppm for proton NMR, δ =
77.00 ppm for carbon NMR). Coupling constants (J) are given in
Hz. Chiral HPLC was performed with an Agilent 1200 Series chro-
matograph and a Chiralcel OD-H (0.46 cm ϫ25 cm) or Chi-
ralpak AD-H (0.46ϫ25 cm2) column.
General Procedure for the Asymmetric Double Michael Addition Re-
actions between Oxindoles and Dienones: An oxindole
2
(0.25 mmol), a dienone 3 (0.5 mmol), catalyst 1b (20 mol-%), and
N-Boc-d-Phg-OH (40 mol-%) were stirred in toluene (1.0 mL) un-
der air at 40 °C for 72 h. The reaction mixture was then directly
subjected to flash column chromatography on silica gel (petroleum
ether/ethyl acetate 5:1 as eluent) to afford the corresponding prod-
uct 4.
Entry
R
Yield[b]
[%]
dr[c]
6/6Ј
ee[d][e]
[%]
General Procedure for the Asymmetric Double Michael Addition Re-
actions between Pyrazolones and Dienones: Pyrazolone 5a
(0.1 mmol), a dienone 3 (0.12 mmol), catalyst 1b (20 mol-%), and
N-Boc-d-Phg-OH (40 mol-%) were stirred in CHCl3 (1.0 mL) un-
der air at room temp. for 48 h. The reaction mixture was then di-
rectly subjected to flash column chromatography on silica gel (pe-
troleum ether/ethyl acetate 5:1 as eluent) to afford the correspond-
ing product 6.
1
2
3
4
5
6
7
8
9
Ph (3a)
4-MeOC6H4 (3b)
4-MeC6H4 (3c)
4-iPrC6H4 (3d)
4-FC6H4 (3e)
3-ClC6H4 (3f)
4-ClC6H4 (3g)
4-BrC6H4 (3m)
3,5-(MeO)2C6H3 (3k)
2-thienyl (3l)
6a/65
6b/47
6c/53
6d/53
6e/60
6f/52
6g/47
6h/70
6i/56
6j/52
n.r.[f]
n.r.[f]
4:1
3:1
4:1
7:1
7:1
Ͼ20:1
Ͼ20:1
3:1
3:1
1:2
89
84
88
81
90
95
97
92
84
81
–
2,6-Diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione (4a): 92%
yield, Ͼ20:1 dr, 94% ee. The enantiomeric excess was determined
by HPLC with a Daicel Chiralpak AD-H and n-hexane/iPrOH
(85:15) as the eluent. Flow rate: 0.75 mLmin–1, λ = 210 nm: tminor
= 20.547 min, tmajor = 13.983 min. [α]2D5 = –110.8 (c = 0.96 in
CHCl3) {ref.:[15] [α]rDt = –112.9 (c = 0.96 in CHCl3), 2S,6S enanti-
omer, 98% ee}. 1H NMR (300 MHz, CDCl3): δ = 7.82 (s, 1 H),
7.18–7.15 (m, 3 H), 6.94–6.79 (m, 8 H), 6.64 (t, J = 7.5 Hz, 1 H),
6.45 (d, J = 7.5 Hz, 1 H), 6.10 (d, J = 7.5 Hz, 1 H), 3.88 (t, J =
14.1 Hz, 1 H), 3.72–3.67 (m, 1 H), 3.62–3.51 (m, 2 H), 2.90 (dd, J
= 15.0, 4.6 Hz, 1 H), 2.64 (d, J = 14.7 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 42.1, 42.9, 45.7, 46.9, 56.1, 109.5, 121.5,
126.1, 127.4, 127.6, 127.8, 128.1, 128.2, 128.3, 128.4, 129.6, 130.2,
138.2, 140.1, 181.0, 211.5 ppm. HRMS (ESI): calcd. for
C25H21NO2 [M + H]+ 367.1572; found 367.1683.
10
11
12
2-BrC6H4 (3i)
2,4-Cl2C6H3 (3j)
–
–
–
[a] Unless otherwise noted, the reactions were performed with 5a
(0.1 mmol), 3 (0.12 mol), catalyst 1b (20 mol-%), and Boc-d-Phg-
OH (40 mol-%) in CHCl3 (1 mL) at room temp. for 48 h. [b] Iso-
lated yields. [c] Determined by chiral HPLC. [d] Determined by chi-
ral HPLC. [e] The absolute configurations of the products were not
determined. [f] n.r.: no reaction.
Conclusions
In conclusion, we have developed an efficient methodol-
ogy for the construction of enantiomerically enriched spiro-
[cyclohexanone-oxindoles] and spiro[cyclohexanone-pyraz-
olones] through cascade [5+1] Michael/Michael addition re-
actions between divinyl ketones and either N-unprotected
oxindoles or N-phenyl-protected pyrazolones, catalyzed by
combinations of cinchona-based chiral primary amines and
α-amino acid derivatives. The final products were obtained
in moderate to high yields and with good to excellent dia-
stereoselectivities and enantioselectivities. Further expan-
sion of the substrate scope of this catalytic system, as well
as biological evaluations of the resulting spiro compounds,
are in progress in our laboratories.
2,6-Bis(4-methoxyphenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4b): 97% yield, Ͼ20:1 dr, 92% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ =
210 nm: tminor = 35.457 min, tmajor = 25.954 min. [α]2D5 = –213.4 (c
1
= 1.10 in CHCl3). H NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H),
6.97 (t, J = 7.5 Hz, 1 H), 6.85–6.71 (m, 7 H), 6.56–6.48 (m, 3 H),
6.22 (d, J = 7.3 Hz, 1 H), 3.89 (t, J = 15.0 Hz, 1 H), 3.75–3.68 (m,
4 H), 3.61–3.59 (m, 5 H), 2.90 (dd, J = 17.4, 7.5 Hz, 1 H), 2.66
(dd, J = 15.0, 1.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
42.5, 43.3, 44.9, 46.1, 55.2, 55.4, 56.4, 109.5, 113.4, 113.6, 121.5,
126.1, 127.2, 128.0, 129.4, 130.4, 130.6, 132.4, 140.4, 158.6, 158.9,
181.0, 211.9 ppm. HRMS (EI): calcd. for C27H25NO4 [M]+
427.1784; found 427.1787.
2,6-Bis(4-methylphenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4c): 75% yield, Ͼ20:1 dr, 90% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 0.75 mLmin–1, λ = 210 nm:
Experimental Section
General: Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. Reac-
1322
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1318–1327

Synthesis of Spiro[cyclohexanone-oxindoles and -pyrazolones]
tminor = 30.468 min, tmajor = 13.824 min. [α]2D5 = –193.1 (c = 1.14 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.01–6.94
(m, 3 H), 6.81–6.68 (m, 7 H), 6.53 (d, J = 7.5 Hz, 1 H), 6.18 (d, J
= 7.5 Hz, 1 H), 3.92 (t, J = 14.1 Hz, 1 H), 3.75 (dd, J = 13.8,
14.1 Hz, 1 H), 3.71–3.67 (m, 2 H), 3.49 (dd, J = 16.2, 5.4 Hz, 1 H),
2.97 (dd, J = 16.2, 6.9 Hz, 1 H), 2.67 (dd, J = 15.6, 2.7 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.9, 42.5, 45.3, 45.9,
56.1, 109.9, 122.0, 125.7, 128.4, 128.5, 128.7, 129.8, 130.1, 133.3,
3.3 Hz, 1 H), 3.66–3.58 (m, 2 H), 2.92 (dd, J = 18.0, 7.5 Hz, 1 H), 133.6, 136.4, 138.2, 140.2, 140.3, 180.1, 210.5 ppm. HRMS (EI):
2.70 (dd, J = 15.3, 3.0 Hz, 1 H), 2.28 (s, 3 H), 2.11 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.2, 21.3, 42.4, 43.2, 45.3, 46.7,
56.2, 109.5, 121.5, 126.2, 128.1, 128.3, 128.9, 129.6, 130.0, 130.0,
130.4, 135.5, 136.8, 137.2, 140.4, 181.1, 211.9 ppm. HRMS (ESI)
calcd. for C27H25NO2 [M + H]+ 395.1885; found 395.1964.
calcd. for C25H19Cl2NO2 [M]+ 435.0793; found 435.0797.
2,6-Bis(2,4-dichlorophenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-di-
one (4j): 61% yield, Ͼ20:1 dr, 90% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralcel OD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 6.138 min, tmajor = 8.268 min. [α]2D5 = –23.1 (c = 1.09 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.63 (s, 1 H), 7.45–7.31
(m, 3 H), 7.23 (s, 1 H), 7.08–6.95 (m, 3 H), 6.69 (d, J = 7.8 Hz, 1
H), 6.62 (t, J = 7.5 Hz, 1 H), 5.89 (d, J = 7.5 Hz, 1 H), 4.58 (dd,
J = 13.5, 6.6 Hz, 1 H), 4.17–4.09 (m, 1 H), 3.96–3.75 (m, 2 H), 2.63
(d, J = 15.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 38.7,
41.8, 42.3, 43.4, 53.8, 109.5, 119.6, 122.15, 124.9, 127.8, 128.7,
128.8, 129.6, 129.7, 130.2, 133.7, 133.8, 134.4, 135.7, 137.0, 137.4,
138.6, 140.0, 180.6, 209.9 ppm. HRMS (ESI): calcd. for
C25H17Cl4NO2 [M + H]+ 503.0013; found 503.0086.
2,6-Bis(4-isopropylphenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4d): 75% yield, Ͼ20:1 dr, 90% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
210 nm: tminor = 8.209 min, tmajor = 6.819 min. [α]2D5 = –148.3 (c =
0.99 in CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.17 (s, 1 H),
7.04 (d, J = 8.1 Hz, 2 H), 6.92 (t, J = 7.5 Hz, 1 H), 6.82–6.77 (m,
6 H), 6.64 (t, J = 7.5 Hz, 1 H), 6.48 (d, J = 7.5 Hz, 1 H), 6.06 (d,
J = 7.5 Hz, 1 H), 3.90 (t, J = 14.1 Hz, 1 H), 3.75–3.55 (m, 3 H),
2.91–2.81 (m, 2 H), 2.71–2.62 (m, 2 H), 1.19 (d, J = 6.9 Hz, 6 H),
1.05 (d, J = 6.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
23.9, 24.1, 33.7, 33.9, 42.3, 43.2, 45.3, 46.7, 56.1, 109.4, 121.4,
126.1, 126.2, 126.4, 128.0, 128.4, 129.6, 130.5, 135.7, 137.7, 140.3,
147.7, 148.3, 180.9, 211.9 ppm. HRMS (ESI): calcd. for
C31H33NO2 [M + H]+ 451.2511; found 451.2589.
2,6-Bis(2-thienyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione (4l):
67% yield, Ͼ20:1 dr, 96% ee. The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (80:20) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 15.901 min, tmajor = 16.724 min. [α]2D5 = –98.6 (c = 1.05 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.18 (d, J
= 4.5 Hz, 1 H), 7.10 (t, J = 7.5 Hz, 1 H), 6.94–6.87 (m, 2 H), 6.80
(t, J = 7.5 Hz, 1 H), 6.72–6.58 (m, 4 H), 6.20 (d, J = 7.5 Hz, 1 H),
4.25 (dd, J = 13.5, 4.2 Hz, 1 H), 3.93–3.79 (m, 3 H), 2.89–2.75 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.5, 42.8, 43.3, 44.4,
55.9, 109.9, 122.1, 124.4, 124.8, 125.6, 125.8, 126.4, 127.0, 127.2,
128.8, 130.0, 140.9, 141.4, 142.8, 180.5, 209.4 ppm. HRMS (ESI):
calcd. for C21H17NO2S2 [M + H]+ 379.0701; found 379.0775.
2,6-Bis(4-fluorophenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4e): 83% yield, Ͼ20:1 dr, 92% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 26.878 min, tmajor = 17.434 min. [α]2D5 = –115.9 (c = 1.03 in
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 8.42 (s, 1 H), 7.03 (t, J
= 7.5 Hz, 1 H), 6.89–6.76 (m, 7 H), 6.66 (t, J = 8.4 Hz, 2 H), 6.58
(d, J = 7.5 Hz, 1 H), 6.34 (d, J = 7.5 Hz, 1 H), 3.89 (t, J = 14.7 Hz,
1 H), 3.74–3.69 (m, 2 H), 3.52 (dd, J = 16.2, 5.7 Hz, 1 H), 2.98
(dd, J = 16.2, 6.6 Hz, 1 H), 2.67 (dd, J = 15.6, 1.8 Hz,1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 42.1, 42.8, 45.0, 45.9, 56.4, 109.7,
114.8, 115.1, 115.2, 115.4, 121.9, 125.7, 128.6, 129.8, 129.9, 130.0,
130.9, 131.0, 133.6, 133.7, 135.6, 135.6, 140.3, 180.8, 211.0 ppm.
HRMS (ESI): calcd. for C25H19F2NO2H [M + H]+ 403.1384; found
403.1464.
4Ј-Chloro-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4m): 79% yield, 13:1 dr, 96% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 17.084 min, tmajor = 19.319 min. [α]2D5 = –94.8 (c = 0.98 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.15–7.13
(m, 2 H), 7.09–7.00 (m, 6 H), 6.89–6.83 (m, 4 H), 6.31 (dd, J = 6.6,
2.1 Hz, 1 H), 4.36 (dd, J = 14.7, 2.1 Hz, 1 H), 4.21 (dd, J = 14.7,
2.7 Hz, 1 H), 4.04–3.89 (m, 2 H), 2.86 (dd, J = 17.1, 2.7 Hz, 1 H),
2.50 (dd, J = 17.1, 2.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 40.4, 40.5, 42.4, 44.9, 60.3, 108.3, 123.9, 127.1, 127.4, 127.6,
128.1, 128.3, 128.4, 129.8, 130.9, 133.5, 137.4, 138.5, 142.7, 180.4,
211.6 ppm. HRMS (EI): calcd. for C25H20ClNO2 [M]+ 401.1183;
found 401.1183.
2,6-Bis(3-chlorophenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4f): 83% yield, Ͼ20:1 dr, 92% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 14.092 min, tmajor = 9.943 min. [α]2D5 = –130.5 (c = 1.23 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.33 (s, 1 H), 7.27–7.14
(m, 2 H), 7.06–7.01 (m, 2 H), 6.95–6.76 (m, 6 H), 6.59 (d, J =
7.5 Hz, 1 H), 6.35 (d, J = 7.5 Hz, 1 H), 3.89 (t, J = 14.4 Hz, 1 H),
3.71–3.67 (m, 2 H), 3.52 (dd, J = 15.9, 5.1 Hz, 1 H), 2.98 (dd, J =
15.9, 6.6 Hz, 1 H), 2.69 (dd, J = 15.3, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 41.7, 42.4, 45.4, 46.3, 55.9, 109.9, 122.0,
125.7, 126.6, 127.3, 127.7, 127.9, 128.7, 128.8, 129.4, 129.5, 129.6,
129.8, 133.9, 134.1, 140.0, 140.3, 141.7, 180.1, 210.3 ppm. HRMS
(EI): calcd. for C25H19Cl2NO2 [M]+ 435.0793; found 435.0797.
4Ј-Bromo-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4n): 96% yield, 10:1 dr, 97% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 18.684 min, tmajor = 21.760 min. [α]2D5 = –68.7 (c = 0.92 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.18–7.16
(m, 2 H), 7.09–7.01 (m, 7 H), 6.88–6.78 (m, 3 H), 6.35 (d, J =
7.8 Hz, 1 H), 4.50 (d, J = 14.7 Hz, 1 H), 4.28–4.10 (m, 2 H), 3.98
(t, J = 17.1 Hz, 1 H), 2.90 (d, J = 15.3 Hz, 1 H), 2.60 (dd, J = 17.1,
2.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.9, 40.4,
42.8, 45.0, 60.6, 108.9, 119.8, 127.3, 127.6, 127.8, 128.1, 128.2,
2,6-Bis(4-chlorophenyl)spiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4g): 70% yield, Ͼ20:1 dr, 90% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
210 nm: tminor = 26.415 min, tmajor = 19.801 min. [α]2D5 = –207.6 (c
1
= 0.98 in CHCl3). H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1 H), 128.4, 128.7, 129.9, 137.4, 138.4, 138.6, 143.1, 180.6, 211.7 ppm.
7.16 (d, J = 8.4 Hz, 2 H), 7.06–6.97 (m, 3 H), 6.87–6.78 (m, 5 H),
6.57 (d, J = 7.5 Hz, 1 H), 6.39 (d, J = 7.5 Hz, 1 H), 3.87 (t, J =
HRMS (EI): calcd. for C25H20BrNO2 [M]+ 445.0677; found
445.0669.
Eur. J. Org. Chem. 2012, 1318–1327
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1323

S.-J. Ji, X.-W. Wang et al.
FULL PAPER
5Ј-Bromo-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
(4o): 92% yield, Ͼ20:1 dr, 90% ee. The enantiomeric excess was 210 nm: tminor = 17.998 min, tmajor = 10.655 min. [α]2D5 = –104.6 (c
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
= 1.14 in CHCl3) {ref.:[15] [α]rDt = –107.1 (c = 1.05 in CHCl3), 2S,6S
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
enantiomer, 94% ee}. H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1
1
210 nm: tminor = 16.478 min, tmajor = 10.423 min. [α]2D5 = –119.9 (c
H), 7.41–7.32 (m, 1 H), 7.28–7.27 (m, 2 H), 7.05–6.99 (m, 3 H),
1
= 0.91 in CHCl3). H NMR (300 MHz, CDCl3): δ = 8.10 (s, 1 H), 6.95–6.88 (m, 5 H), 6.46 (d, J = 8.4 Hz, 1 H), 5.99 (d, J = 1.6 Hz,
7.28–7.25 (m, 3 H), 7.11–7.02 (m, 4 H), 6.93–6.88 (m, 4 H), 6.43
(d, J = 8.2 Hz, 1 H), 6.11 (d, J = 1.5 Hz, 1 H), 3.93 (t, J = 14.4 Hz, 3.65–3.59 (m, 2 H), 2.93 (dd, J = 17.6, 7.2 Hz, 1 H), 2.71 (dd, J =
1 H), 3.74–3.60 (m, 3 H), 2.94 (dd, J = 17.4, 6.9 Hz, 1 H), 2.71
16.0, 3.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.8,
(dd, J = 15.3, 2.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.7, 45.5, 46.8, 56.4, 110.4, 126.5, 126.9, 127.3, 127.5, 128.0, 128.1,
41.9, 42.8, 45.6, 47.0, 56.4, 110.8, 114.3, 127.6, 128.0, 128.3, 128.4, 128.3, 128.4, 129.5, 131.9, 137.7, 138.6, 140.0, 180.7, 210.9 ppm.
1 H), 3.92 (t, J = 14.4 Hz, 1 H), 3.72 (dd, J = 14.0, 4.0 Hz, 1 H),
128.5, 129.4, 129.6, 131.0, 132.3, 137.8, 139.2, 139.7, 180.4, HRMS (ESI): calcd. for C25H20ClNO2 [M + H]+ 401.1183; found
211.0 ppm. HRMS (EI): calcd. for C25H20BrNO2 [M]+ 445.0677;
found 445.0669.
401.1251.
2,6-Diphenyl-7Ј-trifluoromethylspiro[cyclohexane-1,3Ј-indoline]-
2Ј,4-dione (4t): 86% yield, 9:1 dr, 97% ee. The enantiomeric excess
was determined by HPLC with a Daicel Chiralpak AD-H and n-
hexane/iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ =
210 nm: tminor = 17.871 min, tmajor = 9.827 min. [α]2D5 = –74.6 (c =
1.01 in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H),
5Ј-Chloro-7Ј-methyl-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-
2Ј,4-dione (4p): 63% yield, Ͼ20:1 dr, 96% ee. The enantiomeric ex-
cess was determined by HPLC with a Daicel Chiralpak AD-H and
n-hexane/iPrOH (85:15) as the eluent. Flow rate: 0.75 mLmin–1, λ
= 210 nm: tminor = 14.832 min, tmajor = 11.355 min. [α]2D5 = –86.7 (c
1
= 0.39 in CHCl3). H NMR (300 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.30–7.27 (m, 2 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.06–6.98 (m, 4 H),
7.27–7.25 (m, 4 H), 7.04–6.79 (m, 7 H), 5.80 (s, 1 H), 3.91 (t, J = 6.95 (d, J = 6.4 Hz, 2 H), 6.86 (d, J = 7.2 Hz, 2 H), 6.75 (t, J =
14.7 Hz, 1 H), 3.72–3.55 (m, 2 H), 3.10 (dd, J = 14.1, 6.6 Hz, 1 H), 7.6 Hz, 1 H), 6.12 (d, J = 7.6 Hz, 1 H), 3.97 (t, J = 14.4 Hz, 1 H),
2.91 (dd, J = 12.0, 1.5 Hz, 1 H), 2.70 (dd, J = 15.3, 3.0 Hz, 1 H),
3.80–3.71 (m, 2 H), 3.68–3.63 (m, 1 H), 2.92 (dd, J = 15.6, 4.0 Hz,
1.98 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.0, 42.9, 1 H), 2.74 (dd, J = 15.2, 3.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
45.5, 46.0, 47.1, 56.6, 106.7, 120.0, 123.9, 126.8, 127.5, 128.0, 128.3,
128.3, 128.4, 129.3, 129.6, 137.6, 138.0, 139.8, 183.9, 211.0 ppm.
HRMS (EI): calcd. for C25H22ClNO2 [M]+ 415.1339; found
415.1343.
CDCl3): δ = 41.9, 42.7, 42.8, 45.7, 46.9, 55.1, 111.8, 121.2, 124.9,
124.9, 127.6, 127.7, 128.0, 128.1, 128.1, 128.2, 128.4, 128.6, 129.6,
137.4, 137.7, 139.9, 180.1, 210.6 ppm. HRMS (ESI): calcd. for
C26H20F3NO2 [M + H]+ 435.1446; found 435.1519.
5Ј-Fluoro-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4q): 98% yield, Ͼ20:1 dr, 96% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
210 nm: tminor = 21.978 min, tmajor = 10.895 min. [α]2D5 = –99.7 (c =
0.99 in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H),
7.44–7.32 (m, 2 H), 7.26–7.25 (m, 2 H), 7.06–6.99 (m, 3 H), 6.94–
6.89 (m, 4 H), 6.67 (td, J = 8.8, 2.4 Hz, 1 H), 6.46 (dd, J = 8.4,
4.4 Hz, 1 H), 5.78 (dd, J = 8.4, 2.0 Hz, 1 H), 3.92 (t, J = 14.8 Hz,
1 H), 3.73 (dd, J = 14.0, 3.6 Hz, 1 H), 3.68–3.62 (m, 2 H), 2.91
5Ј,6Ј-Difluoro-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-di-
one (4u): 94% yield, Ͼ20:1 dr, 91% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 1 mL min–1, λ =
210 nm: tminor = 27.231 min, tmajor = 10.017 min. [α]2D5 = –96.6 (c =
1.12 in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.44 (s, 1 H),
7.43–7.33 (m, 1 H), 7.30–7.27 (m, 2 H), 7.07–7.02 (m, 3 H), 6.94–
6.88 (m, 4 H), 6.39 (dd, J = 9.6, 6.4 Hz, 1 H), 5.78 (dd, J = 10.0,
7.6 Hz, 1 H), 3.91 (t, J = 14.8 Hz, 1 H), 3.72–3.64 (m, 2 H), 3.60–
3.56 (m, 1 H), 2.87 (dd, J = 16.0, 4.4 Hz, 1 H), 2.71 (dd, J = 15.6,
(dd, J = 18.4, 7.6 Hz, 1 H), 2.71 (dd, J = 15.6, 3.2 Hz, 1 H) ppm. 3.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.8, 42.7,
13C NMR (100 MHz, CDCl3): δ = 41.7, 42.6, 45.5, 46.6, 56.3,
109.7, 109.8, 113.6, 113.8, 114.3, 114.6, 127.2, 127.3, 127.7, 128.0,
128.1, 128.3, 128.9, 129.3, 131.6, 131.7, 135.9, 137.5, 139.5, 180.8,
210.8 ppm. HRMS (ESI): calcd. for C25H20FNO2 [M + H]+
385.1478; found 385.1551.
45.7, 46.9, 56.1, 99.3, 99.6, 115.5, 115.7, 125.7, 127.4, 127.7, 128.1,
128.2, 128.5, 128.6, 128.7, 129.1, 129.5, 137.6, 139.6, 139.7, 181.0,
210.7 ppm. HRMS (EI): calcd. for C25H19F2NO2 [M]+ 403.1384;
found 403.1459.
2-(4-Chlorophenyl)-6-phenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-
dione (4v): 74% yield, 1.1:1 dr, 94% ee. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AD-H and n-hex-
ane/iPrOH (85:15) as the eluent. Flow rate: 0.75 mL min–1, λ =
210 nm: tminor = 36.349 min, tmajor = 14.685 min. [α]2D5 = –102.8 (c
6Ј-Bromo-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-dione
(4r): 91% yield, Ͼ20:1 dr, 99% ee. The enantiomeric excess was de-
termined by HPLC with a Daicel Chiralpak AD-H and n-hexane/
iPrOH (85:15) as the eluent. Flow rate: 1 mLmin–1, λ = 210 nm:
tminor = 28.473 min, tmajor = 10.701 min. [α]2D5 = –119.4 (c = 0.94 in
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1 H), 7.26–7.21
(m, 2 H), 7.06–7.00 (m, 4 H), 6.93–6.87 (m, 4 H), 6.83 (dd, J = 8.4,
1
= 0.97 in CHCl3). H NMR (400 MHz, CDCl3, trans and cis): δ =
8.18 (s, 1 H), 8.11 (s, 1 H), 7.22–7.16 (m, 5 H), 7.02–6.96 (m, 7 H),
6.93–6.92 (m, 2 H), 6.89–6.87 (m, 4 H), 6.83–6.78 (m, 3 H), 6.72
1.2 Hz, 1 H), 6.72 (d, J = 1.2 Hz, 1 H), 5.91 (d, J = 8.0 Hz, 1 H), (t, J = 7.6 Hz, 1 H), 6.56 (t, J = 8.0 Hz, 2 H), 6.37 (d, J = 7.2 Hz,
3.93 (t, J = 14.0 Hz, 1 H), 3.74 (dd, J = 10.0, 3.6 Hz, 1 H), 3.68–
3.60 (m, 2 H), 2.91 (dd, J = 14.8, 4.0 Hz, 1 H), 2.71 (dd, J = 15.6,
3.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.9, 42.8,
45.5, 46.9, 55.8, 112.8, 121.7, 124.4, 127.4, 127.5, 127.8, 128.2,
128.3, 128.4, 129.1, 129.5, 137.8, 139.9, 141.4, 180.5, 211.0 ppm.
HRMS (ESI): calcd. for C25H20BrNO2 [M + H]+ 445.0677; found
445.0747.
1 H), 6.16 (d, J = 7.2 Hz, 1 H), 4.15–4.05 (m, 1 H), 3.97–3.86 (m,
1 H), 3.78–3.66 (m, 4 H), 3.63–3.50 (m, 2 H), 3.00–2.95 (m, 2 H),
2.73–2.66 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3, trans and
cis): δ = 41.7, 41.8, 42.5, 44.8, 45.5, 45.8, 46.6, 55.8, 60.0, 60.5,
109.5, 121.5, 121.6, 125.6, 125.7, 127.3, 127.5, 127.9, 128.1, 128.2,
129.3, 129.6, 129.7, 129.8, 130.5, 132.9, 133.2, 136.5, 137.6, 138.2,
139.7, 140.1, 140.2, 180.5, 210.8, 210.9 ppm. HRMS (ESI): calcd.
for C25H20ClNO2 [M + H]+ 401.1183; found 401.1187.
5Ј-Chloro-2,6-diphenylspiro[cyclohexane-1,3Ј-indoline]-2Ј,4-di-
one (4s): 98% yield, Ͼ20:1 dr, 92% ee. The enantiomeric excess was 3Ј-Methyl-1Ј,2,6-triphenyl-1H-spiro[cyclohexane-1,4Ј-pyrazole]-
determined by HPLC with a Daicel Chiralpak AD-H and n-hex- 4,5Ј(4H)-dione (6a): 65% yield, 4.0:1 dr, 89% ee. The enantiomeric
1324
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1318–1327

Synthesis of Spiro[cyclohexanone-oxindoles and -pyrazolones]
excess was determined by HPLC with a Daicel Chiralpak AD-H 10.5 Hz, 1 H), 2.62 (d, J = 16.2 Hz, 1 H), 1.76 (s, 3 H) ppm. 13C
and n-hexane/iPrOH (80:20) as the eluent. Flow rate: 1 mLmin–1,
NMR (75 MHz, CDCl3): δ = 14.2, 41.2, 42.4, 43.2, 47.6, 61.8,
115.9, 115.9, 116.1, 116.2, 120.0, 120.2, 126.2, 129.0, 129.1, 129.2,
λ = 210 nm: tminor = 12.957 min, tmajor = 16.371 min. [α]2D5 = –36.1
1
(c = 1.24 in CHCl3). H NMR (300 MHz, CDCl3): δ = 7.48–7.39 129.2, 129.5, 129.6, 133.4, 136.9, 137.0, 160.2, 163.7, 172.9,
(m, 2 H), 7.34–7.25 (m, 4 H), 7.25–7.13 (m, 9 H), 4.05–3.81 (m, 2
H), 3.66 (d, J = 14.4 Hz, 1 H), 3.38 (dd, J = 16.2, 4.8 Hz, 1 H),
2.99 (dd, J = 16.5, 9.6 Hz, 1 H), 2.69–2.55 (m, 1 H), 1.67 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.9, 40.8, 41.5, 42.6,
44.4, 62.1, 120.0, 125.8, 127.5, 127.8, 127.9, 128.3, 128.8, 128.9,
129.2, 136.8, 137.4, 138.7, 160.8, 175.0, 209.5 ppm. HRMS (ESI):
calcd. for C27H24N2O2 [M + H]+ 408.1838; found 408.1925.
207.3 ppm. HRMS (EI): calcd. for C27H22F2N2O2 [M]+ 444.1649;
found 444.1651.
2,6-Bis(3-chlorophenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclohexane-
1,4Ј-pyrazole]-4,5Ј(4H)-dione (6f): 52% yield, Ͼ20:1 dr, 95% ee. The
enantiomeric excess was determined by HPLC with a Daicel Chi-
ralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow rate:
1 mLmin–1, λ = 210 nm: tminor = 11.498 min, tmajor = 13.416 min.
1
2,6-Bis(4-methoxyphenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclo- [α]2D5 = –64.0 (c = 0.97 in CHCl3). H NMR (300 MHz, CDCl3): δ
hexane-1,4Ј-pyrazole]-4,5Ј(4H)-dione (6b): 47 % yield, 3:1 dr,
84% ee. The enantiomeric excess was determined by HPLC with a
Daicel Chiralpak AD-H and n-hexane/iPrOH (85:15) as the eluent.
= 7.39 (d, J = 7.8 Hz, 2 H), 7.29–7.19 (m, 5 H), 7.14–7.04 (m, 4
H), 6.97–6.91 (m, 2 H), 3.86–3.69 (m, 2 H), 3.52 (d, J = 14.4 Hz,
1 H), 3.22 (dd, J = 16.2, 4.5 Hz, 1 H), 2.94–2.80 (m, 1 H), 2.57 (d,
J = 16.5 Hz, 1 H), 1.68 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.4, 41.9, 42.2, 47.8, 48.0, 61.3, 121.0, 125.6, 125.7, 126.0,
Flow rate: 1 mLmin–1, λ = 210 nm: tminor = 13.801 min, tmajor
=
28.255 min. [α]2D5 = –42.5 (c = 1.13 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.45–7.30 (m, 4 H), 7.14–7.05 (m, 5 H), 6.83–6.71 (m, 126.1, 126.6, 127.8, 128.9, 129.1, 129.4, 130.5, 135.0, 135.2, 136.8,
4 H), 3.94 (t, J = 14.1 Hz, 1 H), 3.77 (d, J = 6.6 Hz, 1 H), 3.70 (s, 137.1, 139.5, 160.1, 172.9, 206.7 ppm. HRMS (EI): calcd. for
6 H), 3.44 (d, J = 13.8 Hz, 2 H), 2.53 (d, J = 14.1 Hz, 2 H), 2.06
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 29.6, 42.5,
47.5, 55.1, 55.2, 62.0, 113.9, 114.1, 120.0, 120.2, 125.5, 125.7, 128.2,
128.6, 129.5, 137.0, 137.1, 159.1, 160.6, 173.2, 208.1 ppm. HRMS
(EI): calcd. for C29H28N2O4 [M]+ 468.2049; found 468.2049.
C27H22Cl2N2O2 [M]+ 476.1058; found 476.1052.
2,6-Bis(4-chlorophenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclohexane-
1,4Ј-pyrazole]-4,5Ј(4H)-dione (6g): 47 % yield, Ͼ20:1 dr, 97% ee.
The enantiomeric excess was determined by HPLC with a Daicel
Chiralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow
3Ј-Methyl-2,6-bis(4-methylphenyl)-1Ј-phenyl-1H-spiro[cyclohexane-
1,4Ј-pyrazole]-4,5Ј(4H)-dione (6c): 53% yield, 4:1 dr, 88% ee. The
enantiomeric excess was determined by HPLC with a Daicel Chi-
ralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow rate:
1 mLmin–1, λ = 210 nm: tminor = 21.284 min, tmajor = 14.782 min.
rate: 1 mL min–1, λ = 210 nm: tminor = 44.419 min, tmajor
=
23.212 min. [α]2D5 = –116.7 (c = 0.91 in CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H), 7.36–7.26 (m, 4 H),
7.19–7.16 (m, 3 H), 7.07–7.03 (m, 4 H), 3.92–3.76 (m, 2 H), 3.60
(d, J = 14.1 Hz, 1 H), 3.27 (dd, J = 16.2, 4.2 Hz, 1 H), 3.00–2.91
(m, 1 H), 2.61 (d, J = 16.2 Hz, 1 H), 1.74 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.7, 40.2, 40.8, 41.7, 43.2, 61.7, 119.6,
[α]2D5 = –44.5 (c = 1.04 in CHCl3). H NMR (300 MHz, CDCl3): δ
1
= 7.52–7.42 (m, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 7.19–7.01 (m, 9
H), 4.01–3.79 (m, 2 H), 3.63 (d, J = 13.8 Hz, 1 H), 3.47–3.30 (m, 122.8, 124.0, 125.9, 128.8, 129.0, 129.1, 134.1, 134.7, 136.6, 136.8,
1 H), 2.90 (dd, J = 15.9, 8.4 Hz, 1 H), 2.64–2.50 (m, 1 H), 2.31–
143.3, 159.9, 174.4, 208.3 ppm. HRMS (EI): calcd. for
2.19 (m, 6 H), 1.62 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ C27H22Cl2N2O2 [M]+ 476.1085; found 476.1068.
= 15.9, 21.1, 41.7, 42.6, 44.2, 48.3, 62.0, 120.0, 125.7, 127.2, 127.7,
2,6-Bis(4-bromophenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclohexane-
127.8, 128.9, 129.4, 129.7, 133.9, 134.7, 135.8, 137.9, 161.1, 175.1,
209.8 ppm. HRMS (EI): calcd. for C29H28N2O2 [M]+ 436.2151;
found 436.2150.
1,4Ј-pyrazole]-4,5Ј(4H)-dione (6h): 70% yield, 3:1 dr, 92% ee. The
enantiomeric excess was determined by HPLC with a Daicel Chi-
ralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow rate:
1 mLmin–1, λ = 210 nm: tminor = 59.231 min, tmajor = 28.282 min.
2,6-Bis(4-isopropylphenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclo-
hexane-1,4Ј-pyrazole]-4,5Ј(4H)-dione (6d): 53 % yield, 7:1 dr,
81% ee. The enantiomeric excess was determined by HPLC with a
Daicel Chiralpak AD-H and n-hexane/iPrOH (80:20) as the eluent.
1
[α]2D5 = –49.7 (c = 0.94 in CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.44–7.33 (m, 8 H), 7.25–7.18 (m, 1 H), 7.10–7.07 (m, 4 H), 3.92
(t, J = 14.1 Hz, 2 H), 3.45 (dd, J = 13.8, 3.0 Hz, 2 H), 2.54 (d, J =
14.4 Hz, 2 H), 2.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 14.1, 41.9, 47.4, 47.4, 47.7, 61.2, 120.0, 122.3, 122.5, 126.1, 128.8,
Flow rate: 1 mLmin–1, λ = 210 nm: tminor = 19.609 min, tmajor
=
14.179 min. [α]2D5 = –62.7 (c = 0.99 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.40–7.38 (m, 2 H), 7.32–7.25 (m, 3 H), 7.16–7.08 (m, 132.1, 136.3, 136.7, 138.8, 149.6, 150.7, 157.8, 159.8, 172.6,
3 H), 7.06–7.03 (m, 5 H), 3.90–3.78 (m, 1 H), 3.70–3.58 (m, 1 H),
3.36–3.29 (m, 1 H), 2.99–2.83 (m, 1 H), 2.79–2.73 (m, 1 H), 2.62
(d, J = 15.9 Hz, 1 H), 2.43–2.25 (m, 1 H), 2.11–2.00 (m, 1 H), 1.67
(s, 3 H), 1.21 (d, J = 6.9 Hz, 6 H), 1.09 (d, J = 6.3 Hz, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.9, 23.9, 24.1, 30.0, 33.9, 40.8,
41.5, 42.3, 43.7, 62.2, 120.3, 125.9, 126.7, 127.1, 127.8, 127.8, 128.0,
128.9, 134.0, 136.0, 137.4, 148.9, 161.1, 175.2, 210.0 ppm. HRMS
(EI): calcd. for C33H36N2O2 [M]+ 492.2777; found 492.2776.
206.7 ppm. HRMS (EI): calcd. for C25H22Br2N2O2 [M]+ 564.0048;
found 564.0020.
2,6-Bis(3,5-dimethoxyphenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclo-
hexane-1,4Ј-pyrazole]-4,5Ј(4H)-dione (6i): 56% yield, 3:1 dr, 84% ee.
The enantiomeric excess was determined by HPLC with a Daicel
Chiralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow
rate: 1 mL min–1, λ = 210 nm: tminor = 13.551 min, tmajor
=
28.736 min. [α]2D5 = –44.9 (c = 1.04 in CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.63 (d, J = 7.8 Hz, 2 H), 7.36 (t, J = 8.4 Hz, 2 H),
7.16 (t, J = 6.6 Hz, 1 H), 6.36–6.24 (m, 6 H), 3.89–3.79 (m, 2 H),
3.66 (s, 6 H), 3.60 (s, 6 H), 3.37 (dd, J = 16.8, 5.4 Hz, 2 H), 2.87
(dd, J = 16.5, 9.0 Hz, 1 H), 2.61 (dd, J = 16.5, 2.7 Hz, 1 H), 1.70
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0, 40.8, 41.7,
42.5, 43.3, 45.0, 55.4, 55.5, 55.5, 61.6, 99.8, 100.3, 105.3, 106.0,
106.2, 119.5, 125.7, 129.0, 129.2, 137.6, 139.2, 141.1, 161.3, 175.4,
209.4 ppm. HRMS (EI): calcd. for C31H32N2O6 [M]+ 528.2260;
found 528.2261.
2,6-Bis(4-fluorophenyl)-3Ј-methyl-1Ј-phenyl-1H-spiro[cyclohexane-
1,4Ј-pyrazole]-4,5Ј(4H)-dione (6e): 60% yield, 7:1 dr, 90% ee. The
enantiomeric excess was determined by HPLC with a Daicel Chi-
ralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow rate:
1 mLmin–1, λ = 210 nm: tminor = 29.911 min, tmajor = 21.142 min.
1
[α]2D5 = –41.6 (c = 1.24 in CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.46–7.41 (m, 2 H), 7.35–7.30 (m, 2 H), 7.19–7.09 (m, 5 H), 7.02–
6.97 (m, 2 H), 6.92–6.87 (m, 2 H), 3.98–3.77 (m, 2 H), 3.63–3.47
(m, 1 H), 3.27 (dd, J = 13.5, 4.5 Hz, 1 H), 2.97 (dd, J = 16.2,
Eur. J. Org. Chem. 2012, 1318–1327
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1325

S.-J. Ji, X.-W. Wang et al.
FULL PAPER
[5]
O. Dideberg, J. Lamotte-Brasseur, L. Dupont, H. Campsteyn,
M. Vermeire, L. Angenot, Acta Crystallogr., Sect. B 1977, 33,
1796–1801.
G. Subramaniam, O. Hiraku, M. Hayashi, T. Koyano, K. Ko-
miyama, T.-S. Kam, J. Nat. Prod. 2007, 70, 1783–1789.
a) Y. L. Janin, Bioorg. Med. Chem. 2007, 15, 2479–2513; b)
M. T. Gutierrez-Lugo, C. J. Bewley, J. Med. Chem. 2008, 51,
2606–2612; c) I. R. Matthews, PCT Int. Appl. WO 46679
(2005).
S. Bondock, R. Rabie, H. A. Etman, A. A. Fadda, Eur. J. Med.
Chem. 2008, 43, 2122–2129.
E. Szymanska, K. Kiec-Kononowicz, A. Bialecka, A. Kas-
prowicz, Farmaco Ed. Sci. 2002, 57, 39–44.
3Ј-Methyl-1Ј-phenyl-2,6-bis(2-thienyl)-1H-spiro[cyclohexane-1,4Ј-
pyrazole]-4,5Ј(4H)-dione (6j): 52% yield, 1:2 dr, 81% ee. The enan-
tiomeric excess was determined by HPLC with a Daicel Chi-
ralpak AD-H and n-hexane/iPrOH (85:15) as the eluent. Flow rate:
1 mLmin–1, λ = 210 nm: tminor = 16.944 min, tmajor = 21.412 min.
[α]2D5 = +107.9 (c = 0.81 in CHCl3, dark sample). 1H NMR
(300 MHz, CDCl3): δ = 7.51 (d, J = 8.1 Hz, 1 H), 7.36–7.30 (m, 3
H), 7.19–7.09 (m, 3 H), 6.93–6.84 (m, 4 H), 4.17–3.86 (m, 2 H),
3.81–3.57 (m, 2 H), 2.79–2.65 (m, 2 H), 2.17 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.1, 29.6, 42.5, 47.5, 55.1, 62.0,
114.0, 114.1, 120.0, 120.2, 125.7, 128.2, 128.6, 128.8, 129.5, 130.5,
137.0, 159.2, 160.6, 173.2, 208.1 ppm. HRMS (EI): calcd. for
C23H20N2O2S2 [M]+ 420.0966; found 420.0964.
[6]
[7]
[8]
[9]
[10]
a) K. C. Nicolaou, S. A. Snyder, Proc. Natl. Acad. Sci. USA
2004, 101, 11929–11936; b) J. T. Mohr, M. R. Krout, B. M.
Stoltz, Nature 2008, 455, 323–332; c) E. J. Sorensen, H. M. L.
Davies, Chem. Soc. Rev. 2009, 38, 2969–3276.
For selected examples on the synthesis of spirocycles: a) M.
Sannigrahi, Tetrahedron 1999, 55, 9007–9071; b) T.-L. Liu, Z.-
Y. Xue, H.-Y. Tao, C.-J. Wang, Org. Biomol. Chem. 2011, 9,
1980–1986; c) T.-L. Liu, Z.-L. He, Q.-H. Li, H.-Y. Tao, C.-J.
Wang, Adv. Synth. Catal. 2011, 353, 1713–1719; d) T.-L. Liu,
Z.-L. He, H.-Y. Tao, Y.-P. Cai, C.-J. Wang, Chem. Commun.
2011, 47, 2616–2618; e) T.-L. Liu, Z.-L. He, C.-J. Wang, Chem.
Commun. 2011, 47, 9600–9602.
For recent reviews on natural product synthesis with the aid of
organocatalysis, see: a) E. Marques-Lopez, R. P. Herrear, M.
Christmann, Nat. Prod. Rep. 2010, 27, 1138–1167; b) C. Gron-
dal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–168.
For selected books on organocatalysis, see: a) A. Berkessel, H.
Gröger, Asymmetric Organocatalysis, Wiley-VCH, Weinheim,
Germany, 2004; b) P. I. Dalko, Enantioselective Organocata-
lysis, Wiley-VCH, Weinheim, Germany, 2007; c) B. List, Asym-
metric Organocatalysis, Springer-Verlag, Berlin, Heidelberg,
Germany, 2010; d) For selected reviews on organocatalysis, see:
B. List, Acc. Chem. Res. 2004, 37, 548–557; e) P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248; Angew. Chem. Int. Ed.
2004, 43, 5138–5175; f) S. Mukherjee, J. W. Yang, S. Hoffmann,
B. List, Chem. Rev. 2007, 107, 5471–5569; g) D. W. C. MacMil-
lan, Nature 2008, 455, 304–308; h) A. Dondoni, A. Massi, An-
gew. Chem. 2008, 120, 4716; Angew. Chem. Int. Ed. 2008, 47,
4638–4660; i) P. Melchiorre, M. Marigo, A. Carlone, G. Bar-
toli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed.
2008, 47, 6138–6171; j) S. Bertelsen, K. A. Jørgensen, Chem.
Soc. Rev. 2009, 38, 2178–2189; k) A. G. Doyle, E. N. Jacobsen,
Chem. Rev. 2007, 107, 5713–5743; l) C. F. Barbas III, Angew.
Chem. 2008, 120, 44; Angew. Chem. Int. Ed. 2008, 47, 42–47;
m) A. N. R. Alba, X. Companyó, R. Rios, Chem. Soc. Rev.
2010, 39, 2018–2033.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra and HPLC traces for the
determination of the enantiomeric excess for compounds 4 and
compounds 6.
[11]
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC) (21072145), the Foundation
for the Authors of National Excellent Doctoral Dissertations of
PR China (200931), and the Natural Science Foundation of Jiangsu
Province of China (BK2009115). This project was funded also by
the Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).
[12]
[13]
[1] For selected examples, see: a) H. Venkatesan, M. C. Davis, Y.
Altas, J. P. Snyder, D. C. Liotta, J. Org. Chem. 2001, 66, 3653–
3661; b) H. Lin, S. J. Danishefsky, Angew. Chem. 2003, 115,
38; Angew. Chem. Int. Ed. 2003, 42, 36–51; c) C. Marti, E. M.
Carreira, Eur. J. Org. Chem. 2003, 2209–2219; d) M. M.-C. Lo,
C. S. Neumann, S. Nagayama, E. O. Perlstein, S. L. Schreiber,
J. Am. Chem. Soc. 2004, 126, 16077–16086; e) G. C. Bignan, K.
Battista, P. J. Connolly, M. J. Orsini, J. C. Liu, S. A. Middleton,
A. B. Reitz, Bioorg. Med. Chem. Lett. 2005, 15, 5022–5066; f)
C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902;
Angew. Chem. Int. Ed. 2007, 46, 8748–8758; g) B. M. Trost,
M. K. Brennan, Synthesis 2009, 3003–3025; h) S. Ma, X. Q.
Han, S. Krishnan, S. C. Virgil, B. M. Stoltz, Angew. Chem.
2009, 121, 8181; Angew. Chem. Int. Ed. 2009, 48, 8037–8041; i)
S. Kotha, A. C. Deb, K. Lahiri, E. Manivannan, Synthesis
2009, 165–193.
[2] For selected examples, see: a) G. Mariappan, B. P. Saha, N. R.
Bhuyan, P. R. Bharti, D. Kumar, J. Adv. Pharm. Technol. Res.
2010, 1, 260–267; b) R. Ma, J. Zhu, J. Liu, L. Chen, X. Shen,
H. Jiang, J. Li, Molecules 2010, 15, 3593–3601; c) A. Kimata,
H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta, T. Suzuki,
N. Miyata, J. Med. Chem. 2007, 50, 5053–5056; d) K. Sujatha,
G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal, M.
Rajendran, Bioorg. Med. Chem. Lett. 2009, 19, 4501–4503; e)
S. M. Sondhi, M. Dinodia, J. Singh, R. Rani, Curr. Bioact.
Compd. 2007, 3, 91–108; f) J. Elguero, P. Goya, N. Jagerovic,
A. M. S. Silva, Targets Heterocycl. Systems. 2002, 6, 52–98.
[3] a) S. Sakai, N. Aimi, K. Yamaguchi, H. Ohhira, K. Hori, J.
Haginiwa, Tetrahedron Lett. 1975, 16, 715–718; b) S. Sakai, N.
Aimi, K. Yamaguchi, E. Yamanaka, J. Haginiwa, J. Chem. Soc.
Perkin Trans. 1 1982, 1257–1262.
[4] M. Rottmann, C. McNamara, B. K. Yeung, M. C. Lee, B. Zou,
B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B.
Cohen, K. R. Spencer, G. E. González-Páez, S. B. Lakshmina-
rayana, A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H. P.
Beck, R. Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller,
D. A. Fidock, E. A. Winzeler, T. T. Diagana, Science 2010, 329,
1175–1180.
[14]
[15]
For selected reviews on organocascade reaction, see: a) D. En-
ders, M. R. M. Huttl, C. Grondal, G. Raabe, Nature 2006, 441,
861–863; b) D. Enders, C. Grondal, M. R. M. Hüttl, Angew.
Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570–
1581; c) X. Yua, W. Wang, Org. Biomol. Chem. 2008, 6, 2037–
2046; d) A. N. Alba, X. Companyo, M. Viciano, R. Rios, Curr.
Org. Chem. 2009, 13, 1432–1474.
G. Bencivenni, L. Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciai-
oli, M. P. Song, G. Bartoli, P. Melchiorre, Angew. Chem. 2009,
121, 7336; Angew. Chem. Int. Ed. 2009, 48, 7200–7203.
Q. Wei, L.-Z. Gong, Org. Lett. 2010, 12, 1008–1011.
L.-L. Wang, L. Peng, J.-F. Bai, Q.-C. Huang, X.-Y. Xu, L.-X.
Wang, Chem. Commun. 2010, 46, 8064–8066.
Y.-B. Lan, H. Zhao, Z.-M. Liu, G.-G. Liu, J.-C. Tao, X.-W.
Wang, Org. Lett. 2011, 13, 4866–4870.
B. Tan, N. R. Candeias, C. F. Barbas III, Nat. Chem. 2011, 3,
473–477.
B. Tan, N. R. Candeias, C. F. Barbas III, J. Am. Chem. Soc.
2011, 133, 4672–4675.
[16]
[17]
[18]
[19]
[20]
[21]
X. Companyó, A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moy-
ano, R. Rios, Chem. Commun. 2010, 46, 6953–6955.
1326
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1318–1327

Synthesis of Spiro[cyclohexanone-oxindoles and -pyrazolones]
[22]
[23]
[24]
[29] X. M. Li, B. Wang, J. M. Zhang, M. Yan, Org. Lett. 2011, 13,
374–377.
[30] C. D. Fusco, A. Lattanzi, Eur. J. Org. Chem. 2011, 3728–3731.
[31] L.-L. Wang, L. Peng, J.-F. Bai, L.-N. Jia, X.-Y. Luo, Q.-C. Hu-
ang, X.-Y. Xu, L.-X. Wang, Chem. Commun. 2011, 47, 5593–
5595.
[32] a) N. J. A. Martin, B. List, J. Am. Chem. Soc. 2006, 128, 13368–
13369; b) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299;
Angew. Chem. Int. Ed. 2006, 45, 4193–4195; c) X. W. Wang, B.
List, Angew. Chem. 2008, 120, 1135; Angew. Chem. Int. Ed.
2008, 47, 1119–1122; d) X. W. Wang, C. M. Reisinger, B. List,
J. Am. Chem. Soc. 2008, 130, 6070–6071.
[33] a) G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri,
P. Melchiorre, Org. Lett. 2007, 9, 1403–1406; b) F. Pesciaioli,
F. D. Vincentiis, P. Galzerano, G. Bencivenni, G. Bartoli, A.
Mazzanti, P. Melchiorre, Angew. Chem. 2008, 120, 8831; An-
gew. Chem. Int. Ed. 2008, 47, 8703–8706.
K. Jiang, Z. J. Jia, X. A. Yin, L. Wu, Y. C. Chen, Org. Lett.
2010, 12, 2766.
K. Jiang, Z.-J. Jia, S. Chen, L. Wu, Y.-C. Chen, Chem. Eur. J.
2010, 16, 2852–2855.
W.-B. Chen, Z.-J. Wu, Q.-L. Pei, L.-F. Cun, X.-M. Zhang, W.-
C. Yuan, Org. Lett. 2010, 12, 3132–3135.
[25] a) W.-B. Chen, Z.-J. Wu, J. Hu, L.-F. Cun, X.-M. Zhang, W.-
C. Yuan, Org. Lett. 2011, 13, 2472–2475; b) X. Jiang, Y. Cao,
Y. Wang, L. Liu, F. Shen, R. Wang, J. Am. Chem. Soc. 2010,
132, 15328–15333.
[26] A.-N. R. Alba, A. Zea, G. Valero, T. Calbet, M. Fontbardia,
A. Mazzanti, A. Moyano, R. Rios, Eur. J. Org. Chem. 2011,
1318–1325.
[27] A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyanoa, R. Rios,
Org. Biomol. Chem. 2011, 9, 6519–6523.
[28] B. Wu, G.-G. Liu, M.-Q. Li, Y. Zhang, S.-Y. Zhang, J.-R. Qiu,
X.-P. Xu, S.-J. Ji, X.-W. Wang, Chem. Commun. 2011, 47, 3992–
3994.
Received: October 19, 2011
Published Online: January 4, 2012
Eur. J. Org. Chem. 2012, 1318–1327
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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