Enantioselective Cascade Reaction of α-Cyano Ketones and Isatylidene Malononitriles: Asymmetric Construction of Spiro[4H-pyran-oxindoles]

Article abstract of DOI:10.1002/ejoc.201600432

α-Cyano ketones have been employed for the first time as Michael donors in the construction of chiral spiro compounds. By using only 2 mol-% of a chiral multifunctional organocatalyst, chiral spiro[4H-pyran-oxindole] derivatives were prepared in yields of 97–99 % with enantioselectivities of 76–97 % ee. This method provides a new approach to the synthesis of chiral spirocyclic oxindoles.

Full text of DOI:10.1002/ejoc.201600432

DOI: 10.1002/ejoc.201600432
Full Paper
Asymmetric Catalysis
Enantioselective Cascade Reaction of α-Cyano Ketones and
Isatylidene Malononitriles: Asymmetric Construction of
Spiro[4H-pyran-oxindoles]
[
a]
[a]
[a]
[a]
Jin Xie, Wei-Long Xing, Feng Sha, and Xin-Yan Wu*
Abstract: α-Cyano ketones have been employed for the first prepared in yields of 97–99 % with enantioselectivities of 76–
time as Michael donors in the construction of chiral spiro com- 97 % ee. This method provides a new approach to the synthesis
pounds. By using only 2 mol-% of a chiral multifunctional or- of chiral spirocyclic oxindoles.
ganocatalyst, chiral spiro[4H-pyran-oxindole] derivatives were
Introduction
ployed in the construction of chiral spiro compounds. As there
is continued interest in the enantioselective construction of chi-
The spirooxindole structure is commonly found in many alka-
[11]
ral 3,3-disubstituted 2-oxindoles,
we sought to use α-cyano
[
1]
loids and pharmaceutical molecules. Enormous effort has
been made towards the synthesis of these spiro compounds
because of their outstanding biological activity and wide range
of biomedical applications. Spiro[4H-pyran-oxindole] deriva-
tives, which belong to the spirooxindole family of compounds,
have various biological activities such as anticancer, antifungal,
ketones as the Michael donor in an organocatalytic tandem re-
action to provide chiral spirooxindoles. Herein, we report the
first enantioselective cascade reaction of α-cyano ketones with
isatylidene malononitriles to construct new spiro[4H-pyran-ox-
indole] derivatives.
[
2]
[
3]
and antibacterial properties. Because of the importance of
such compounds, their construction has attracted great interest.
However, the enantioselective synthesis of spiro[4H-pyran-ox-
indole] derivatives is rarely described. In 2010, Yuan first re-
ported an enantioselective synthesis of spiro[4H-pyran-ox-
indoles] by using a domino Knoevenagel/Michael/cyclization re-
action sequence between isatins, malononitrile, and 1,3-di-
Results and Discussion
Initially, the enantioselective cascade reaction of α-cyanoaceto-
phenone (1a) with N-benzyl isatylidene malononitrile (2a) was
used as a model to screen chiral organocatalysts (Figure 1). The
reactions were performed with 2 mol-% of the catalyst and
[
4]
[5–8]
carbonyl compounds. Several research groups
then devel-
1
mol-% of piperidine in CH Cl at 0 °C, and the results are
2 2
oped asymmetric tandem reactions for the synthesis of
spiro[4H-pyran-oxindole] compounds. In those reports, di-
carbonyl or ꢀ-hydroxyl-α,ꢀ-unsaturated carbonyl compounds
were used as the Michael donor, and the exploration of differ-
ent Michael donors for use in an asymmetric tandem reaction
to provide new chiral spiro[4H-pyran-oxindole] derivatives is
still in demand.
summarized in Table 1. We began by using chiral bifunctional
tertiary amine-thiourea organocatalysts C1–C6, and to our de-
light, the cascade reaction afforded spiro product 3aa in excel-
lent yields with moderate enantioselectivities (Table 1, En-
tries 1–6). Cinchona-derived thioureas gave similar results, and
the absolute configuration of the product was controlled by
the chiral backbone of these catalysts (Table 1, Entries 3–6).
α-Cyano ketones are good nucleophiles for the construction Quinidine-derived organocatalysts that contain different
of chiral cyclic compounds. In recent years, α-cyano ketones hydrogen-bonding donors were then examined. Surprisingly,
have been widely employed as 1,3-bis(nucleophile)s to form squaramide C7 and sulfamide C8 afforded poor enantioselectiv-
[
9]
chiral pyran derivatives. Moreover, α-cyano ketones have ities of the product (Table 1, Entries 7 and 8). However, quin-
been used as 1,1-bis(nucleophile)s in enantioselective [4+1] an- idine-derived organocatalysts that contain multiple hydrogen-
[
12]
nulation reactions to produce five-membered ring com- bonding donors
pounds.
provided improved enantioselectivities
[
10]
However, α-cyano ketones have never been em- (Table 1, Entries 9–13 vs. 4). In particular, the preparation of
spiro compound 3aa was achieved in 99 % yield with 72 % ee
[
a] Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology,
Shanghai 200237, P. R. China
in the presence of catalyst C10. To test the chirality match be-
tween a quinidine backbone and a 1,2-diphenylethanediamine,
tertiary amine-thiourea-sulfamide C14 was examined in the
model reaction. However a lower enantioselectivity was the re-
sult (Table 1, Entry 14 vs. 9). The results also indicate that the
absolute configuration of the product is better controlled by
E-mail: xinyanwu@ecust.edu.cn
http://webmanage.ecust.edu.cn/s/230/t/262/a/57293/info.jspy
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600432.
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Figure 1. Structures of the chiral organocatalysts screened (Ts = p-tolylsulfonyl, Ms = methylsulfonyl, Ns = p-nitrophenylsulfonyl).
the quinidine backbone than the 1,2-diphenylethanediamine
scaffold. Considering all of these results, we selected organocat-
alyst C10 for use in our further investigations of the cascade
reaction.
Table 1. Screening of the chiral organocatalysts for the cascade reaction.[a]
Next, the effects of additives were surveyed (Table 2, En-
tries 1–11). In the absence of a base, the cascade reaction pro-
vided low yield with a low enantioselectivity (Table 2, Entries 1
vs. 2). The addition of a primary amine such as benzylamine
could promote the reaction rate as well as the chemical yield
Yield [%][b]
ee [%][c]
Entry
Catalyst
Time [h]
(
Table 2, Entries 3 vs. 1). As expected, the existence of an achiral
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
99
99
99
99
99
99
99
99
99
99
99
99
99
99
26
–45
–49
48
44
–47
–3
3
51
72
60
63
49
34
tertiary amine had a negative effect on the stereoselectivity
(Table 2, Entry 4). These results indicate that a secondary amine
is more suitable than a primary or tertiary amine (Table 2, En-
tries 5–11 and 2 vs. 3 and 4). Among all of the secondary
amines that were screened, morpholine provided the best en-
antioselectivity (82 % ee, Table 2, Entry 6).
C9
In the presence of catalyst C10 and morpholine, the effect of
the solvent was examined (Table 2, Entries 12–19). The cascade
reaction in halogenated solvents such as dichloromethane,
chloroform, and 1,2-dichloroethane provided better enantiose-
lectivities than those obtained by carrying out the reaction in
other solvents such as toluene, ethereal solvents, ethyl acetate,
and CH CN (Table 2, Entries 6, 12, and 13 vs. 14–19). From these
results, CH Cl was chosen as the solvent to optimize the other
reaction conditions.
10
11
12
13
14
C10
C11
C12
C13
C14
[a] The cascade reactions were performed with 1a (0.11 mmol), 2a
(0.1 mmol), a catalyst (0.002 mmol), and piperidine (0.001 mmol) in CH Cl
(2 mL) at 0 °C. [b] Isolated yield of a mixture of enantiomers after column
2
2
3
2
2
chromatography is reported. [c] The enantiomeric excess values of the prod-
uct were determined by chiral HPLC analysis.
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Table 2. Screening of the additives and solvents.[a]
Table 3. Optimization of the reaction conditions.[a]
Entry Additive
Solvent
Time [h] Yield [%][b]
ee
Entry 1a [equiv.]
Conc. [
M
]
Time [h]
Yield [%][b]
ee [%][c]
%][
c]
[
1
2
3
4
5
6
7
1.0
1.1
1.3
1.1
1.1
1.1
1.1
0.05
0.05
0.05
0.025
0.10
0.05
0.05
1.5
1.0
0.8
2.0
0.5
1.25
2.0
99
99
99
99
99
99
99
82
82
82
81
75
81
80
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
–
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2.0
0.5
1.0
1.5
0.5
1.0
1.0
0.5
1.0
3.0
2.0
0.5
0.5
0.7
1.0
1.5
1.0
1.5
1.5
79
99
98
97
98
99
97
99
99
99
99
99
99
99
99
99
99
99
99
49
72
52
27
57
82
81
75
78
54
51
80
80
56
80
73
40
58
43
piperidine
benzylamine
DIPEA
pyrrolidine
morpholine
thiomorpholine
piperazine
1-phenylpiperazine
(3S)-iPr-morpholine CH
(3R)-iPr-morpholine CH
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
[
d]
[
[
d]
e]
[
2
a] Unless otherwise noted, the cascade reactions were performed with 1a,
a (0.1 mmol), catalyst C10 (0.002 mmol), and morpholine (0.001 mmol) in
CH Cl at 0 °C. [b] Isolated yield of an enantiomeric mixture after column
2
2
0
1
2
3
4
5
6
7
8
9
chromatography is reported. [c] The enantiomeric excess values of the prod-
uct were determined by chiral HPLC analysis. [d] Morpholine (0.5 mol-%) was
used. [e] C10 (1 mol-%) and morpholine (0.5 mol-%) were used.
CHCl
3
1,2-DCE
toluene
[
d]
Et
MTBE
THF
EtOAc
CH CN
2
O
Table 4. The effect of N-substituent of isatylidene malononitrile.[a]
[
d]
[
d]
3
[
(
a] The cascade reactions were performed with 1a (0.11 mmol), 2a
0.1 mmol), C10 (0.002 mmol), and additive (0.001 mmol) in solvent (2 mL)
at 0 °C. [b] Isolated yield of an enantiomeric mixture after column chromatog-
raphy is reported. [c] The enantiomeric excess values of the product were
determined by chiral HPLC analysis. [d] DIPEA = N,N-diisopropylethylamine,
Entry
R1
Time [h]
Yield [%][b]
ee [%][c]
1
,2-DCE = 1,2-dichloroethane, MTBE = methyl tert-butyl ether, and THF =
tetrahydrofuran.
1
2
3
4
5
6
7
8
Me
Et
allyl
MOM[
Bn
1.0
1.0
1.0
1.0
1.0
1.0
3.0
1.0
1.5
1.3
1.0
1.5
99 (3ab)
98 (3ac)
99 (3ad)
99 (3ae)
99 (3aa)
99 (3af)
98 (3ag)
99 (3ah)
99 (3ai)
96 (3ab)
98 (3ab)
99 (3ab)
88
83
83
82
82
79
11
64
76
70
90
88
d]
Further reaction conditions, which include the ratio of sub-
strate 1a to 2a, the concentration of the substrate, and the
catalyst loading, were optimized (Table 3). These factors were
determined to impact the reaction rate and enantioselectivities
but not the chemical yields. The product could be produced in
[
d]
PMB
[d]
Tr
Ac
H
Me
Me
Me
9
10[
e]
[f]
1
1
1
2
99 % yield with 80 % ee by using only 1 mol-% of catalyst C10
[g]
(
Table 3, Entry 7).
[
(
a] Unless otherwise noted, the cascade reactions were performed with 1a
0.11 mmol), isatylidene malononitrile (0.1 mmol), catalyst C10 (0.002 mmol),
Under the optimal reaction conditions (0.05
malononitrile 2 in CH Cl , 1.1 equiv. of α-cyano ketone 1, 2 mol-
M isatylidene
2
2
2 2
and morpholine (0.001 mmol) in CH Cl (2 mL) at 0 °C. [b] Isolated yield of
an enantiomeric mixture after column chromatography is reported. [c] The
enantiomeric excess values were determined by chiral HPLC analysis.
%
of C10, and 1 mol-% of morpholine at 0 °C), isatylidene malo-
nonitriles with different N-substituents were employed
Table 4). All of the substrates exhibited good reactivity and
[
d] MOM = methoxymethyl, PMB = p-methoxybenzyl, and Tr = triphenyl-
(
methyl. [e] The reaction was carried out at 25 °C. [f] The reaction was carried
out at –10 °C. [g] The reaction was carried out at –25 °C.
provided excellent yields, and the substituents on the nitrogen
atom were found to have an impact on the stereoselectivity of
the reaction. The low steric hindrance of an N-alkyl substituent
increased the enantioselectivity of the product (Table 4, En-
Next, we investigated the scope of both substrates by using
tries 1–7). However, an N-acetyl-substituted substrate provided N-methyl isatylidene malononitriles as the electrophile in the
inferior enantioselectivity (Table 4, Entry 8). Notably, isatylidene reaction at –10 °C (Table 5). The results indicate that all of the
malononitrile with a free NH group could smoothly undergo examined substrates provided excellent chemical yields (97–
the cascade reaction, although the enantioselectivity of the re- 99 %) with enantioselectivities that varied from 76 to 97 % ee.
action was 76 % ee (Table 4, Entry 9). When the reaction was The α-cyano ketones that have an electron-rich substituent at
carried out at –10 °C, the enantioselectivity improved to the 4-position of its phenyl group provided better enantiose-
90 % ee (Table 4, Entry 11).
lectivities than those obtained by α-cyano ketones that have
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an electron-withdrawing group at the 4-position of the phenyl
substituent (Table 5, Entries 2 and 3 vs. 6–8). Compared with a
4-methoxyphenyl-substituted compound, the corresponding 3-
and 2-substituted substrates provided lower enantioselectivi-
ties, most likely the result of different stereoelectronic effects
(
Table 5, Entries 3–5). The enantioselectivity differences that re-
sult from different dimethoxy substrates are related to the posi-
tions of OMe (Table 5, Entries 9 and 10). Notably, heterocyclic
and polycyclic α-cyano ketones provided excellent enantiose-
lectivities (Table 5, Entries 11–13). The substituents at the 5-,
6
-, and 7-position of the isatylidene malononitrile derivatives
played a minimal role in the enantioselectivity results (91–
7 % ee, Table 5, Entries 14–26). Although substrate 2o exhib-
9
ited low reactivity under the standard reaction conditions as
well as low solubility in CH Cl , spirooxindole 3co was prepared
in 97 % yield with 92 % ee in 12 h (Table 5, Entry 19).
2
2
Figure 2. X-ray crystal structure of 3cq.
To prove the importance of the chiral tertiary amine scaffold
of the organocatalyst, chiral organocatalyst C15, which contains
multiple hydrogen-bonding donors, was employed in the cas-
cade reaction under the typical reaction condition. Because of
the absence of the chiral tertiary amine scaffold, the racemic
product was obtained in 50 % yield after 24 h (Scheme 1). This
result suggests that the reaction rate and stereochemistry are
mostly controlled by the tertiary amine moiety of the chiral
organocatalyst.
Table 5. Substrate scope of the enantioselective cascade reaction.[a]
Entry Ar
R2
Time [h] Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
C
6
H
5
H
H
H
H
H
H
H
H
H
H
H
H
1.0
2.0
2.0
1.5
1.5
1.0
2.0
1.0
1.5
1.5
1.5
1.0
1.0
1.0
1.5
1.0
1.0
1.0
12.0
1.0
1.0
1.0
1.0
1.0
1.0
0.75
98 (3ab)
99 (3bb)
99 (3cb)
99 (3db)
99 (3eb)
99 (3fb)
98 (3gb)
99 (3hb)
99 (3ib)
99 (3jb)
99 (3kb)
99 (3lb)
99 (3mb)
99 (3cj)
98 (3ck)
99 (3cl)
99 (3cm)
99 (3cn)
97 (3co)
99 (3cp)
99 (3cq)
99 (3cr)
99 (3cs)
99 (3ct)
99 (3cu)
99 (3cv)
90
91
95
90
76
85
86
83
94
88
90
93
92
93
93
95
91
94
92
96
97
94
94
94
93
92
4-MeC
6
H
4
4-MeOC
3-MeOC
2-MeOC
4-FC
4-ClC
4-BrC
3,4-(MeO)
3,5-(MeO)
2-thienyl
2-furyl
6
H
H
H
4
4
4
6
6
6
H
4
6
H
4
Scheme 1. Control reaction catalyzed by chiral organocatalyst C15 that has
multiple hydrogen-bond donors.
6
H
4
2
2
C
C
6
H
H
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
6
3
It is known that pyranotriazolopyrimidine derivatives are
[13]
found in many bioactive compounds such as antimicrobial,
[
14]
[15]
antigenotoxic,
and antitumor substances.
Therefore, con-
2-naphthyl
H
verting the cascade product into a pyranotriazolopyrimidine
was investigated. As expected, spiro[4H-pyran-oxindole] 3cq
could be easily transformed into compound 4 in high yield with
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
4-MeOC
6
6
6
6
6
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
4
4
4
4
5-Me
5-MeO
5-F
5-Cl
5-Br
6-Me
6-Cl
6-Br
7-Me
7-F
7-Cl
7-Br
7-CF
3
[
a] The cascade reactions were performed with 1 (0.11 mmol), isatylidene
malononitrile (0.1 mmol), catalyst C10 (0.002 mmol), and morpholine
0.001 mmol) in CH Cl (2 mL) at –10 °C. [b] Isolated yield of enantiomeric
(
2
2
mixture after column chromatography is reported. [c] The enantiomeric ex-
cess values were determined by chiral HPLC analysis.
The absolute configuration of product 3cq was determined
as (S) by X-ray crystal structrure analysis (Figure 2). The configu-
rations of the other spiro[4H-pyran-oxindole] derivatives 3 were
assigned by analogy.
Scheme 2. Transformation of spiro[4H-pyran-oxindole] 3cq.
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high enantioselectivity. Furthermore, compound 4 could un- 127.0, 125.0, 124.2, 116.1, 115.0, 110.3, 88.2, 57.9, 50.1, 44.6 ppm. IR
(
1
9
KBr): ν˜ = 3455, 3321, 3178, 3061, 2205, 1714, 1670, 1611, 1487,
dergo a reaction with benzohydrazide to afford chiral spiro-
indoline-3,10′-pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine] 5 in
8 % yield with 95 % ee (Scheme 2).
468, 1406, 1357, 1321, 1312, 1265, 1191, 1148, 1102, 1080, 1032,
[
7
–
1
75, 910, 845, 738 cm . HRMS (ESI): calcd. for C H N NaO [M +
27
18
4
2
+
Na] 453.1327; found 453.1320. HPLC analysis (AD-H column; λ =
2
2
54 nm; n-hexane/iPrOH, 70:30, flow rate: 0.9 mL min– ): t =
1
R
5.21 min (major), 27.99 min (minor).
Conclusions
(
S)-2′-Amino-1-methyl-2-oxo-6′-phenylspiro[indoline-3,4′-
In summary, we have developed the first organocatalytic enan- pyran]-3′,5′-dicarbonitrile (3ab): White solid (34.6 mg, 98 % yield,
2
0
1
tioselective Michael/cyclization cascade reaction sequence be- 90 % ee); m.p. 218.5–220.9 °C. [α] = +33.1 (c = 0.295, DMSO). H
D
tween α-cyano ketones and isatylidene malononitriles. In the NMR (300 MHz, [D ]DMSO): δ = 7.81 (d, J = 6.9 Hz, 2 H), 7.75 (s, 2
6
H), 7.64–7.512 (m, 4 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.23–7.15 (m, 2 H),
presence of 2 mol-% of tertiary amine catalyst C10, which con-
tains multiple hydrogen-bonding donors, all of the correspond-
ing spirooxindoles were obtained in excellent yields (97–99 %)
with good-to-excellent enantioselectivities (76–97 % ee) within
3
1
1
2
1
+
.23 (s, 3 H) ppm. 13C NMR (75 MHz, [D ]DMSO): δ = 174.9, 160.1,
6
59.9, 143.0, 132.3, 130.5, 130.4, 129.6, 128.9, 128.1, 125.2, 123.8,
17.0, 115.4, 109.4, 87.3, 53.6, 49.9, 26.7 ppm. IR (KBr): ν˜ = 3432,
245, 2193, 2125, 1663, 1496, 1470, 1370, 1309, 1263, 1152, 1052,
026, 1003, 827, 762 cm . HRMS (ESI): calcd. for C H N NaO [M
Na] 377.1014; found 377.1012. HPLC analysis (AD-H column; λ =
2
h, with the exception of product 3co. The method established
–1
21
14
4
2
herein represents a new protocol for the asymmetric construc-
tion of spiro[4H-pyran-oxindole] derivatives.
+
–1
2
9
54 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
R
.64 min (minor), 14.45 min (major).
(
3
S)-2′-Amino-1-ethyl-2-oxo-6′-phenylspiro[indoline-3,4′-pyran]-
′,5′-dicarbonitrile (3ac): White solid (36.2 mg, 98 % yield,
Experimental Section
General Methods: The 1H and 13C NMR spectroscopic data were
2
0
1
83 % ee); m.p. 213.2–215.3 °C. [α] = +52.5 (c = 0.305, DMSO). H
NMR (300 MHz, [D ]DMSO): δ = 7.81 (d, J = 7.2 Hz, 2 H), 7.74 (s, 2
H), 7.66–7.52 (m, 4 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.23–7.16 (m, 2 H),
3
D
recorded with a Bruker 300 or Bruker 400 spectrometer. The chemi-
6
cal shifts of the 1H NMR spectra were referenced to tetramethyl-
1
3
.80 (q, J = 6.9 Hz, 2 H), 1.17 (t, J = 6.9 Hz, 3 H) ppm. C NMR
silane (δ = 0.00 ppm) when CDCl was used as the solvent. When
3
(75 MHz, [D ]DMSO): δ = 174.6, 160.0, 159.7, 141.9, 132.3, 130.9,
[
D ]DMSO was used as the NMR solvent, the chemical shifts were
6
6
1
30.4, 129.6, 128.9, 128.0, 125.4, 123.6, 117.0, 115.3, 109.4, 87.3, 53.7,
referenced to the residual solvent signal [δ = 2.50 ppm for
13
49.7, 34.8, 12.5 ppm. IR (KBr): ν = 3400, 3190, 2636, 2256, 2122,
1
C H N NaO [M + Na] 391.1171; found 391.1178; HPLC analysis
(
(
CD )(CHD )SO]. The C NMR spectra were referenced to the carbon
˜
3
2
–
1
655, 1052, 1027, 998, 825, 777 cm . HRMS (ESI): calcd. for
signals of the solvent (δ = 77.0 ppm for CDCl and 39.52 ppm for
3
+
[
D ]DMSO). IR spectra were recorded on a Nicolet Magna-I 550 spec-
22 16
4
2
6
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
trometer. High resolution mass spectrometry was carried out with
an electrospray ionization time-of-flight (ESI-TOF) mass spectrome-
ter. Optical rotations were measured on a WZZ-2A digital polarime-
ter at the wavelength of the sodium D line (589 nm). HPLC analysis
was performed on equipment by Waters, which included a Daicel
Chiralpak AD-H column and a Daicel Chiralpak AS-H column. Tolu-
ene, THF, ether, and MTBE were freshly distilled from sodium-benzo-
–
1
0
.9 mL min ): t = 8.77 min (minor), 13.96 min (major).
R
(
3
8
S)-1-Allyl-2′-amino-2-oxo-6′-phenylspiro[indoline-3,4′-pyran]-
′,5′-dicarbonitrile (3ad): White solid (38.0 mg, 99 % yield,
20
1
3 % ee); m.p. 203.9–204.3 °C. [α]D = +24.2 (c = 0.317, DMSO). H
NMR (300 MHz, [D ]DMSO): δ = 7.84–7.76 (m, 4 H), 7.64–7.54 (m, 4
H), 7.41 (t, J = 7.5 Hz, 1 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.06 (d, J =
6
phenone. Ethyl acetate, CH Cl , CHCl , ClCH CH Cl, and CH CN were
2
2
3
2
2
3
7.5 Hz, 1 H), 5.90–5.80 (m, 1 H), 5.27–5.15 (m, 2 H), 4.41 (s, 2 H) ppm.
freshly distilled from CaH . Thin layer chromatography was per-
13
2
C NMR (75 MHz, [D ]DMSO): δ = 174.8, 160.2, 159.8, 142.1, 132.3,
6
formed on silica gel plates (10–40 μm). Column chromatography
was performed on silica gel (300–400 mesh) and eluted with ethyl
1
1
31.0, 130.5, 130.3, 129.6, 128.9, 128.1, 125.3, 123.8, 117.1, 116.5,
15.5, 110.0, 87.3, 53.7, 50.0, 42.0 ppm. IR (KBr): ν = 3421, 3008,
˜
[
16]
[17]
[18]
[19]
acetate and CH Cl . Catalysts C1,
C2,
C3–C7,
and C8
2
2
2261, 2193, 2123, 2003, 1717, 1669, 1607, 1489, 1464, 1410, 1355,
1
were prepared according to literature procedures. For the prepara-
tion and characterization of the chiral catalysts C9–C15,
Supporting Information.
–1
308, 1237, 1199, 1148, 1053, 1026, 1006, 821, 777, 760 cm . HRMS
[
20]
see the
+
(ESI): calcd. for C H N NaO [M + Na] 403.1171; found 403.1163.
23 16 4 2
HPLC analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30;
flow rate: 0.9 mL min ): t = 10.39 min (minor), 17.34 min (major).
–
1
General Procedure for the Cascade Reaction of α-Cyano Ket-
R
ones with Isatylidene Malononitriles: To a solution of α-cyano (S)-2′-Amino-1-(methoxymethyl)-2-oxo-6′-phenylspiro[indoline-
ketone 1 (0.11 mmol), catalyst C10 (1.3 mg, 0.002 mmol), and mor- 3,4′-pyran]-3′,5′-dicarbonitrile (3ae): White solid (38.3 mg, 99 %
2
0
pholine (0.08 μL, 0.001 mmol) in CH Cl (2 mL) was added isatylid- yield, 82 % ee); m.p. 206.8–207.5 °C. [α] = +21.6 (c = 0.320, DMSO).
2
2
D
1
ene malononitrile 2 (0.1 mmol) at –10 °C, and the resulting mixture
H NMR (300 MHz, [D ]DMSO): δ = 7.84–7.80 (m, 4 H), 7.67–7.58 (m,
6
was stirred at this temperature until the reaction reached comple- 4 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.24 (t, J = 8.4 Hz, 2 H), 5.20 (s, 2 H),
3.27 (s, 3 H) ppm. 13C NMR (75 MHz, [D ]DMSO): δ = 175.7, 160.2,
159.8, 141.3, 132.4, 130.4, 130.1, 129.5, 129.0, 128.1, 125.5, 124.3,
tion (monitored by TLC). The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
6
(
CH Cl /EtOAc, 6:1) to give the desired product 3.
117.1, 115.5, 110.4, 87.1, 71.2, 55.8, 53.7, 50.5 ppm. IR (KBr): ν =
2
2
˜
3
1
408, 3263, 2921, 2819, 2255, 2195, 2127, 1724, 1664, 1470, 1408,
(
S)-2′-Amino-1-benzyl-2-oxo-6′-phenylspiro[indoline-3,4′-
–1
344, 1313, 1151, 1122, 1051, 1024, 1002 824, 775, 760 cm . HRMS
pyran]-3′,5′-dicarbonitrile (3aa): White solid (42.5 mg, 99 % yield,
8
NMR (300 MHz, CDCl ): δ = 7.77 (d, J = 8.1 Hz, 2 H), 7.52–7.25 (m,
1
5
1
+
2
0
1
(ESI): calcd. for C22
H N NaO [M + Na] 407.1120; found 407.1118.
16 4 3
2 % ee); m.p. 206.8–208.3 °C. [α] = +30.7 (c = 0.358, DMSO). H
D
HPLC analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30;
3
–
1
flow rate: 0.9 mL min ): t = 11.28 min (minor), 13.15 min (major).
R
0 H), 7.15 (t, J = 7.8 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.31 (s, 2 H),
.01 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 175.3, 160.1, 159.4,
(S)-2′-Amino-1-(4-methoxybenzyl)-2-oxo-6′-phenylspiro[ind-
oline-3,4′-pyran]-3′,5′-dicarbonitrile (3af): White solid (45.8 mg,
3
42.2, 134.5, 132.2, 130.6, 129.9, 129.2, 128.9, 128.7, 127.9, 127.8,
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
0
9
9 % yield, 79 % ee), m.p. 209.2–211.1 °C. [α] = +19.1 (c = 0.383, H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
D
1
–1
DMSO). H NMR (300 MHz, [D ]DMSO): δ = 7.86–7.79 (m, 4 H), 7.65–
0.9 mL min ): t = 14.07 min (minor), 16.48 min (major).
6
R
7
.54 (m, 4 H), 7.33 (d, J = 8.1 Hz, 3 H), 7.17 (t, J = 7.5 Hz, 1 H), 6.98
(
S)-2′-Amino-6′-(4-methoxyphenyl)-1-methyl-2-oxospiro[ind-
(d, J = 7.8 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 2 H), 4.95 (s, 2 H), 3.71 (s, 3
oline-3,4′-pyran]-3′,5′-dicarbonitrile (3cb): White solid (37.9 mg,
9
DMSO). H NMR (300 MHz, [D ]DMSO): δ = 7.80 (d, J = 8.1 Hz, 2 H),
7
3
1
1
3
9
13
H) ppm. C NMR (75 MHz, [D ]DMSO): δ = 175.3, 160.3, 159.9, 158.7,
1
1
6
20
9 % yield, 95 % ee); m.p. 217.7–220.5 °C. [α] = +40.9 (c = 0.320,
D
42.0, 132.3, 130.7, 130.2, 129.6, 129.0, 128.6, 128.1, 127.4, 125.4,
23.8, 117.1, 115.5, 114.0, 110.1, 87.3, 55.1, 53.8, 50.0, 42.9 ppm. IR
1
6
.71 (s, 2 H), 7.51–7.40 (m, 2 H), 7.22–7.11 (m, 4 H), 3.84 (s, 3 H),
(
1
KBr): ν˜ = 3394, 2255, 2128, 1660, 1513, 1309, 1250, 1181, 1151,
.22 (s, 3 H) ppm. 13C NMR (75 MHz, [D ]DMSO): δ = 175.1, 162.2,
–
1
6
052, 1029, 1000, 824, 763 cm . HRMS (ESI): calcd. for
59.9, 159.7, 143.0, 130.6, 130.3, 129.9, 125.1, 123.7, 121.5, 117.1,
15.8, 114.3, 109.3, 85.4, 55.6, 53.7, 49.9, 26.7 ppm. IR (KBr): ν˜ =
341, 3000, 2910, 2149, 1652, 1440, 1405, 1318, 1239, 1019, 952,
+
C H N NaO [M + Na] 483.1433; found 483.1446. HPLC analysis
28
20
4
3
(
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
–1
0
.9 mL min ): t = 20.22 min (minor), 29.03 min (major).
R
–1
02, 777, 759, 708 cm . HRMS (ESI): calcd. for C H N NaO [M +
22
16
4
3
+
(
S)-2′-Amino-2-oxo-6′-phenyl-1-tritylspiro[indoline-3,4′-pyran]-
Na] 407.1120; found 407.1119. HPLC analysis (AD-H column; λ =
254 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
14.89 min (minor), 18.95 min (major).
–
1
3
1
′,5′-dicarbonitrile (3ag): White solid (57.2 mg, 98 % yield,
R
2
0
1
1
%
e
e
)
;
m
.
p
.
2
3
9
.
6
–
2
4
0
.
7
°
C
.
[
α
]
D
=
+
6
.
2
(
c
=
0
.
4
8
5
,
D
M
S
O
)
.
H
NMR (300 MHz, [D ]DMSO): δ = 7.82–7.76 (m, 4 H), 7.61–7.58 (m, 3
6
(
S)-2′-Amino-6′-(3-methoxyphenyl)-1-methyl-2-oxospiro[ind-
H), 7.52–7.44 (m, 7 H), 7.30–7.18 (m, 9 H), 7.10–7.00 (m, 2 H), 6.30
oline-3,4′-pyran]-3′,5′-dicarbonitrile (3db): White solid (37.9 mg,
9
DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.73 (s, 2 H), 7.52–7.36
1
3
(
d, J = 7.5 Hz, 1 H) ppm. C NMR (75 MHz, [D ]DMSO): δ = 176.3,
20
6
9 % yield, 90 % ee); m.p. 247.6–248.6 °C. [α] = +71.2 (c = 0.32,
D
1
1
5
7
60.2, 159.7, 142.4, 141.5, 132.3, 130.9, 130.0, 129.6, 128.9, 128.6,
28.1, 127.8, 127.0, 125.1, 123.4, 117.5, 115.8, 115.8, 87.4, 74.4, 54.4,
0.4 ppm. IR (KBr): ν˜ = 3426, 2253, 2126, 1657, 1052, 1023, 998, 827,
1
6
13
(m, 5 H), 7.22–7.15 (m, 3 H), 3.82 (s, 3 H), 3.23 (s, 3 H) ppm. C NMR
(100 MHz, [D ]DMSO): δ = 174.9, 159.8, 159.7, 159.2, 143.0, 130.7,
6
–1
+
61 cm . HRMS (ESI): calcd. for C H N NaO [M + Na] 605.1953;
3
9
26
4
2
1
1
2
1
7
30.5, 130.3, 130.2, 125.1, 123.7, 120.2, 118.0, 116.9, 115.3, 113.3,
09.3, 87.4, 55.5, 53.7, 49.9, 26.7 ppm. IR (KBr): ν˜ = 3348, 3297, 3180,
920, 2205, 1701, 1666, 1597, 1461, 1413, 1368, 1310, 1268, 1239,
151, 1128, 1089, 1034, 1019, 990, 937, 910, 852, 794, 772,
found 605.1940. HPLC analysis (AD-H column; λ = 254 nm; n-hex-
–
1
ane/iPrOH, 90:10; flow rate: 0.9 mL min ): t = 13.42 min (minor),
R
1
6.07 min (major).
–
1
+
49 cm . HRMS (ESI): calcd. for C H N NaO [M + Na] 407.1120;
(
S)-1-Acetyl-2′-amino-2-oxo-6′-phenylspiro[indoline-3,4′-
22 16
4
3
found 407.1114. HPLC analysis (AD-H column; λ = 254 nm; n-hex-
ane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 9.03 min (minor),
1
pyran]-3′,5′-dicarbonitrile (3ah): White solid (38.1 mg, 99 % yield,
–
1
1
6
4 % ee); m.p. 211.2–213.3 °C. [α] 2D 0 = +26.2 (c = 0.318, DMSO). H
R
2.27 min (major).
NMR (300 MHz, [D ]DMSO): δ = 8.17 (d, J = 8.1 Hz, 1 H), 7.95 (s, 2
6
H), 7.85 (d, J = 6.3 Hz, 2 H), 7.70–7.59 (m, 4 H), 7.52 (t, J = 7.5 Hz, 1
(
S)-2′-Amino-6′-(2-methoxyphenyl)-1-methyl-2-oxospiro[ind-
1
3
H), 7.40 (t, J = 7.2 Hz, 1 H), 2.65 (s, 3 H) ppm. C NMR (75 MHz,
D ]DMSO): δ = 176.5, 170.4, 160.6, 160.0, 139.3, 132.6, 130.6, 129.4,
oline-3,4′-pyran]-3′,5′-dicarbonitrile (3eb): White solid (38.1 mg,
99 % yield, 76 % ee); m.p. 227.5–230.2 °C. [α] = +41.4 (c = 0.320,
DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.62–7.54 (m, 3 H), 7.50–
7
H), 3.22 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 174.7,
1
120.5, 119.0, 117.1, 114.6, 112.3, 109.3, 90.9, 56.0, 53.6, 49.7,
2
1
1
[
20
6
D
1
2
1
29.0, 128.2, 126.5, 125.7, 116.8, 116.1, 115.2, 108.8, 87.0, 53.9, 51.0,
1
6
6.3 ppm. IR (KBr): ν˜ = 3422, 3012, 2988, 2262, 2120, 1653, 1047,
.42 (m, 3 H), 7.24–7.14 (m, 3 H), 7.09 (t, J = 7.2 Hz, 1 H), 3.85 (s, 3
–
1
025, 1001, 828, 776 cm . HRMS (ESI): calcd. for C H N O [M +
13
2
2
15
4
3
6
+
H] 383.1144; found 383.1136. HPLC analysis (AD-H column; λ =
60.1, 159.0, 157.0, 142.9, 133.4, 130.7, 130.5, 130.3, 124.8, 123.7,
–
1
2
8
54 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
R
.87 min (minor), 10.34 min (major).
6.6 ppm. IR (KBr): ν˜ = 3403, 3280, 3169, 2928, 2842, 2198, 1701,
612, 1594, 1494, 1472, 1439, 1409, 1370, 1354, 1313, 1285, 1243,
(
S)-2′-Amino-2-oxo-6′-phenylspiro[indoline-3,4′-pyran]-3′,5′-di-
–
1
167, 1144, 1111, 1017, 936, 909, 799, 763 cm . HRMS (ESI): calcd.
carbonitrile (3ai): White solid (33.7 mg, 99 % yield, 76 % ee); m.p.
+
2
0
1
for C22
H N NaO [M + Na] 407.1120; found 407.1114. HPLC analy-
16 4 3
2
14.4–217.0 °C. [α] = +27.1 (c = 0.283, DMSO). H NMR (300 MHz,
D
sis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
0
[
D ]DMSO): δ = 10.89 (s, 1 H), 7.80 (d, J = 7.2 Hz, 2 H), 7.69 (s, 2 H),
6
–
1
.9 mL min ): t = 9.81 min (minor), 15.28 min (major).
R
7
7
.66–7.55 (m, 3 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H),
.11 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR
(S)-2′-Amino-6′-(4-fluorophenyl)-1-methyl-2-oxospiro[indoline-
(
75 MHz, [D ]DMSO): δ = 176.6, 159.9, 159.7, 141.6, 132.3, 131.4, 3,4′-pyran]-3′,5′-dicarbonitrile (3fb): White solid (37.2 mg, 99 %
6
1
5
1
30.2, 129.6, 128.9, 128.0, 125.5, 123.1, 117.2, 115.5, 110.3, 87.6, 53.9, yield, 85 % ee); m.p. 249.4–251.7 °C. [α]20 = +46.8 (c = 0.310, DMSO).
D
1
0.3 ppm. IR (KBr): ν˜ = 3415, 3005, 2919, 2597, 2134, 1970, 1902,
H NMR (400 MHz, [D ]DMSO): δ = 7.92–7.87 (m, 2 H), 7.73 (s, 2 H),
6
–
1
657, 1439, 1407, 1317, 1243, 1022, 954, 901, 777, 709 cm . HRMS 7.53 (d, J = 7.2 Hz, 1 H), 7.45 (t, J = 8.8 Hz, 3 H), 7.22–7.15 (m, 2 H),
+
13
(
ESI): calcd. for C20H13N O [M + H] 341.1039; found 341.1034.
3.23 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 174.9, 164.0
(d, JC,F = 249.4 Hz), 159.8, 159.1, 143.0, 130.9 (d, JC,F = 8.7 Hz), 130.4
(d, JC,F = 8.8 Hz), 126.1 (d, JC,F = 3.0 Hz), 125.2, 123.7, 116.9, 116.3,
4
2
6
HPLC analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30;
–1
flow rate: 0.9 mL min ): t = 8.78 min (minor), 10.78 min (major).
R
1
3
9
16.0, 115.3, 109.3, 87.4, 53.7, 49.9, 26.7 ppm. IR (KBr): ν˜ = 3441,
(
S)-2′-Amino-1-methyl-2-oxo-6′-(p-tolyl)spiro[indoline-3,4′-
002, 2906, 2592, 2142, 1970, 1655, 1441, 1400, 1316, 1241, 1014,
pyran]-3′,5′-dicarbonitrile (3bb): White solid (36.4 mg, 99 % yield,
9
NMR (300 MHz, [D ]DMSO): δ = 7.72–7.69 (m, 4 H), 7.52–7.37 (m, 4
–
1
52, 901, 784, 706 cm . HRMS (ESI): calcd. for C H FN NaO [M +
1 % ee); m.p. 219.7–223.1 °C. [α] D2 = +51.2 (c = 0.307, DMSO). H
0
1
21 13
4
2
+
Na] 395.0920; found 395.0901. HPLC analysis (AD-H column; λ =
2
1
6
–1
54 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
13
R
H), 7.22–7.15 (m, 2 H), 3.22 (s, 3 H), 2.38 (s, 3 H) ppm. C NMR
75 MHz, [D ]DMSO): δ = 175.0, 160.1, 159.9, 143.0, 142.6, 130.6,
0.66 min (minor), 16.76 min (major).
(
6
1
4
1
30.3, 129.4, 127.9, 126.7, 125.1, 123.8, 117.1, 115.5, 109.4, 86.6, 53.6,
(S)-2′-Amino-6′-(4-chlorophenyl)-1-methyl-2-oxospiro[indoline-
9.9, 26.7, 21.2 ppm. IR (KBr): ν˜ = 3376, 2953, 2737, 2261, 2125, 3,4′-pyran]-3′,5′-dicarbonitrile (3gb): White solid (37.9 mg, 98 %
–
1
20
648, 1048, 1024, 995, 827, 781, 712 cm . HRMS (ESI): calcd. for yield, 86 % ee); m.p. 257.1–258.9 °C. [α] = +43.2 (c = 0.324, DMSO).
D
+
1
C H N O [M + H] 369.1352; found 369.1345. HPLC analysis (AD-
H NMR (300 MHz, [D ]DMSO): δ = 7.84 (d, J = 7.8 Hz, 2 H), 7.75 (s,
22
17
4
2
6
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
2
7
H), 7.68 (d, J = 7.5 Hz, 2 H), 7.53 (d, J = 6.0 Hz, 1 H), 7.44 (t, J =
.2 Hz, 1 H), 7.22–7.17 (m, 2 H), 3.23 (s, 3 H) ppm. C NMR (75 MHz,
HRMS (ESI): calcd. for C H N NaO S [M + Na] 383.0579; found
19
12
4
2
1
3
383.0570. HPLC analysis (AS-H column; λ = 254 nm; n-hexane/iPrOH,
70:30; flow rate: 0.9 mL min ): t = 17.04 min (minor), 21.85 min
–
1
[D ]DMSO): δ = 174.9, 159.8, 159.0, 143.0, 137.0, 130.4, 130.0, 129.1,
6
R
1
28.4, 125.3, 123.8, 118.9, 117.0, 115.2, 109.4, 87.8, 53.7, 49.9,
(major).
2
1
C H
C H
6.7 ppm. IR (KBr): ν˜ = 3458, 2996, 2914, 2152, 1649, 1440, 1401,
–
1
(S)-2′-Amino-6′-(furan-2-yl)-1-methyl-2-oxospiro[indoline-3,4′-
pyran]-3′,5′-dicarbonitrile (3lb): White solid (34.0 mg, 99 % yield,
318, 1239, 1024, 951, 902, 784, 706 cm . HRMS (ESI): calcd. for
3
3
5
7
+
ClN NaO2 [M + Na] 411.0625; found 411.0630; calcd. for
2
1
13
4
2
0
1
+
93 % ee) m.p. 245.3–248.2 °C. [α]
D
= +182.0 (c = 0.287, DMSO). H
ClN NaO [M + Na] 413.0595; found 413.0598. HPLC analy-
21
13
4
2
NMR (400 MHz, [D ]DMSO): δ = 8.07 (s, 1 H), 7.73 (s, 2 H), 7.49–7.41
6
sis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
0
1
3
–1
(m, 2 H), 7.23–7.15 (m, 3 H), 6.83 (s, 1 H), 3.22 (s, 3 H) ppm. C NMR
100 MHz, [D ]DMSO): δ = 174.9, 159.4, 149.5, 147.4, 143.4, 143.1,
.9 mL min ): t = 13.21 min (minor), 22.12 min (major).
R
(
6
(S)-2′-Amino-6′-(4-bromophenyl)-1-methyl-2-oxospiro[indoline-
1
4
30.3, 130.3, 125.1, 123.7, 116.8, 115.9, 114.4, 112.9, 109.3, 83.4, 53.6,
9.5, 26.7 ppm. IR (KBr): ν˜ = 3358, 3184, 2917, 2846, 2371, 2200,
3
,4′-pyran]-3′,5′-dicarbonitrile (3hb): White solid (42.8 mg, 99 %
2
0
yield, 83 % ee); m.p. 264.6–265.2 °C. [α] = +34.9 (c = 0.361, DMSO).
D
1710, 1666, 1598, 1467, 1366, 1329, 1225, 1190, 1125, 1097, 1015,
942, 902, 885, 833, 760, 730 cm . HRMS (ESI): calcd. for
C H N NaO [M + Na] 367.0807; found 367.0790. HPLC analysis
1
H NMR (400 MHz, [D ]DMSO): δ = 7.83–7.74 (m, 6 H), 7.53 (d, J =
–1
6
7
.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.22–7.15 (m, 2 H), 3.23 (s, 3
+
19
12
4
3
13
H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 174.8, 159.8, 159.1,
1
1
1
6
(AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
43.0, 132.0, 130.4, 130.0, 128.7, 126.0, 125.2, 123.7, 116.9, 115.2,
–1
0
.9 mL min ): t = 10.96 min (minor), 12.02 min (major).
R
09.3, 87.8, 62.8, 53.7, 49.9, 26.7 ppm. IR (KBr): ν˜ = 3401, 2258, 2127,
–
1
651, 1066, 1032, 997, 827, 780, 717 cm . HRMS (ESI): calcd. for (S)-2′-Amino-1-methyl-6′-(naphthalen-2-yl)-2-oxospiro[ind-
7
8
9
1
+
C H
BrNaN O [M + Na] 455.0120; found 455.0119; calcd. for
oline-3,4′-pyran]-3′,5′-dicarbonitrile (3mb): White solid (39.9 mg,
2
1
13
4 2
+
20
C H
BrNaN O [M + Na] 457.0100; found 457.0110. HPLC analy- 99 % yield, 92 % ee); m.p. 260.3–261.7 °C. [α]
D
= +42.8 (c = 0.336,
]DMSO): δ = 8.46 (s, 1 H), 8.11 (d, J =
8.8 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.85
21
13
4 2
1
sis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate: DMSO). H NMR (400 MHz, [D
6
–1
0
.9 mL min ): t = 14.31 min (minor), 25.61 min (major).
R
(
dd, J = 8.8 Hz, J = 1.6 Hz, 1 H), 7.78 (s, 2 H), 7.70–7.61 (m, 2 H),
1 2
(
[
S)-2′-Amino-6′-(3,4-dimethoxyphenyl)-1-methyl-2-oxospiro-
indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3ib): White solid
7
7
1
1
1
2
1
.57 (d, J = 7.2 Hz, 1 H), 7.46 (dt, J = 8.0 Hz, J = 0.8 Hz, 1 H), 7.24–
1 2
.17 (m, 2 H), 3.25 (s, 3 H) ppm. 13C NMR (100 MHz, [D ]DMSO): δ =
2
0
6
(41.0 mg, 99 % yield, 94 % ee); m.p. 253.3–254.1 °C. [α] = +87.5
D
75.0, 160.2, 160.0, 143.0, 134.2, 131.9, 130.5, 130.3, 129.0, 128.9,
28.6, 128.6, 127.8, 127.4, 126.9, 125.2, 124.0, 123.8, 117.0, 115.5,
09.4, 87.8, 53.7, 50.0, 26.7 ppm. IR (KBr): ν˜ = 3346, 3168, 2920,
201, 1707, 1663, 1625, 1492, 1468, 1413, 1370, 1302, 1238, 1151,
1
(c = 0.345, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.72 (s, 2 H),
6
7
3
1
1
4
1
8
4
.49–7.41 (m, 3 H), 7.39 (s, 1 H), 7.22–7.12 (m, 3 H), 3.84 (s, 3 H),
1
3
.81 (s, 3 H), 3.23 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ =
6
75.1, 159.9, 159.6, 152.0, 148.5, 143.0, 130.6, 130.2, 125.1, 123.7,
21.7, 121.4, 117.0, 115.9, 111.4, 110.8, 109.3, 85.4, 55.8, 55.7, 53.7,
9.9, 26.6 ppm. IR (KBr): ν˜ = 3429, 3167, 2903, 2194, 1704, 1662,
599, 1473, 1410, 1347, 1311, 1242, 1206, 1163, 1143, 1060, 932,
–
1
126, 1019, 897, 869, 827, 768, 744, 680 cm . HRMS (ESI): calcd. for
+
C H N NaO [M + Na] 427.1171; found 427.1179. HPLC analysis
25
16
4
2
(
0
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
–
1
.9 mL min ): t = 12.93 min (minor), 17.84 min (major).
–1
+
R
59, 749, 671 cm . HRMS (ESI): calcd. for C H N NaO [M + Na]
2
3
18
4
4
37.1226; found 437.1205. HPLC analysis (AD-H column; λ = 254 nm;
(
S)-2′-Amino-6′-(4-methoxyphenyl)-1,5-dimethyl-2-oxospiro-
–
1
n-hexane/iPrOH, 80:20; flow rate: 0.9 mL min ): t = 34.56 min (ma-
jor), 39.70 min (minor).
R
[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cj): White solid
20
(
(
39.7 mg, 99 % yield, 93 % ee); m.p. 259.3–259.7 °C. [α] = +75.7
D
1
c = 0.332, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.80 (d, J =
(
[
S)-2′-Amino-6′-(3,5-dimethoxyphenyl)-1-methyl-2-oxospiro-
indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3jb): White solid
6
9.2 Hz, 2 H), 7.66 (s, 2 H), 7.31 (s, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.12
2
0
(d, J = 8.8 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1 H), 3.84 (s, 3 H), 3.20 (s, 3
(41.4 mg, 99 % yield, 88 % ee); m.p. 232.5–234.4 °C. [α] = +56.3
D
H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, [D ]DMSO): δ = 175.0,
1
(c = 0.340, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.73 (s, 2 H),
6
6
162.1, 159.8, 159.5, 140.6, 132.9, 130.8, 130.4, 129.8, 125.5, 121.5,
7
6
.51 (d, J = 7.2 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.23–7.15 (m, 2 H),
.97 (s, 2 H), 6.76 (s, 1 H), 3.80 (s, 6 H), 3.23 (s, 3 H) ppm. 1 C NMR
3
117.1, 115.8, 114.3, 109.0, 85.5, 55.6, 53.9, 50.0, 26.6, 20.6 ppm. IR
(
1
1
KBr): ν˜ = 3305, 3184, 2926, 2840, 2205, 1708, 1674, 1629, 1605,
(100 MHz, [D ]DMSO): δ = 174.9, 160.5, 159.8, 159.5, 143.0, 131.1,
6
515, 1452, 1417, 1358, 1327, 1312, 1258, 1182, 1156, 1116, 1067,
1
5
2
1
7
30.4, 130.3, 125.1, 123.7, 116.9, 115.2, 109.3, 106.0, 103.9, 87.5, 55.6,
3.7, 49.9, 26.7 ppm. IR (KBr): ν˜ = 3424, 3300, 3168, 2967, 2917,
192, 1704, 1665, 1630, 1603, 1492, 1469, 1412, 1350, 1315,
247, 1208, 1162, 1144, 1094, 1060, 1025, 927, 857, 817, 753,
–
1
026, 930, 845, 801, 777, 749, 700 cm . HRMS (ESI): calcd. for
+
C H N NaO [M + Na] 421.1277; found 421.1276. HPLC analysis
23 18
4
3
(
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
–
1
–1
+
0.9 mL min ): t = 10.70 min (minor), 15.36 min (major).
03 cm . HRMS (ESI): calcd. for C H N NaO [M + Na] 437.1226;
R
2
3
18
4
4
found 437.1233. HPLC analysis (AD-H column; λ = 254 nm; n-hex-
(
S)-2′-Amino-5-methoxy-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
–
1
ane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 8.42 min (minor),
R
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3ck): White solid
1
1.31 min (major).
S)-2′-Amino-1-methyl-2-oxo-6′-(thiophen-2-yl)spiro[indoline-
,4′-pyran]-3′,5′-dicarbonitrile (3kb): White solid (35.6 mg, 99 %
20
(40.4 mg, 98 % yield, 93 % ee); m.p. 237.8–237.9 °C. [α] = +136.2
D
1
(
3
(c = 0.345, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.80 (d, J =
9.2 Hz, 2 H), 7.66 (s, 2 H), 7.17 (d, J = 2.4 Hz, 1 H), 7.12 (d, J = 8.8 Hz,
6
2
0
yield, 90 % ee); m.p. 233.8–234.2 °C. [α] = +50.3 (c = 0.300, DMSO). 2 H), 7.07 (d, J = 8.4 Hz, 1 H), 6.99 (dd, J = 8.4 Hz, J = 2.4 Hz, 1
D
1
2
1
13
H NMR (400 MHz, [D ]DMSO): δ = 8.02 (d, J = 4.8 Hz, 1 H), 7.95 (d,
H), 3.84 (s, 3 H), 3.77 (s, 3 H), 3.19 (s, 3 H) ppm. C NMR (100 MHz,
6
J = 3.6 Hz, 1 H), 7.78 (s, 2 H), 7.50–7.42 (m, 2 H), 7.31 (t, J = 4.0 Hz,
1
[D ]DMSO): δ = 174.8, 162.1, 159.8, 159.6, 156.4, 136.3, 131.9, 129.8,
6
H), 7.21–7.15 (m, 2 H), 3.23 (s, 3 H) ppm. 1 C NMR (100 MHz, 121.6, 117.1, 115.8, 114.8, 114.2, 111.9, 109.8, 85.4, 55.7, 55.6, 53.8,
3
[
D ]DMSO): δ = 175.0, 159.5, 153.9, 143.0, 132.8, 131.7, 131.1, 130.4, 50.3, 26.7 ppm. IR (KBr): ν˜ = 3349, 3299, 3170, 3013, 2917, 2849,
6
1
2
1
30.3, 128.4, 125.1, 123.8, 116.9, 115.5, 109.4, 83.8, 53.6, 49.8,
2197, 1697, 1664, 1626, 1605, 1513, 1495, 1452, 1410, 1358, 1299,
–1
6.7 ppm. IR (KBr): ν˜ = 3354, 3188, 2921, 2851, 2369, 1660, 1627, 1288, 1264, 1176, 1153, 1031, 1012, 841, 810, 780, 724 cm . HRMS
–
1
+
467, 1408, 1291, 1161, 1110, 1091, 1054, 937, 872, 780, 728 cm .
(ESI): calcd. for C H N NaO [M + Na] 437.1226; found 437.1228.
23 18 4 4
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
HPLC analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30;
(AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
–1
–1
flow rate: 0.9 mL min ): t = 17.15 min (minor), 22.61 min (major).
0.9 mL min ): t = 17.10 min (minor), 22.47 min (major).
R
R
(
S)-2′-Amino-5-fluoro-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
(S)-2′-Amino-6-chloro-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cl): White solid
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cp): White solid
2
0
20
(
(
39.8 mg, 99 % yield, 95 % ee); m.p. 262.2–262.8 °C. [α] = +33.6 (41.4 mg, 99 % yield, 96 % ee); m.p. 254.4–255.1 °C. [α] = +63.0
D
D
1
1
c = 0.335, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.80 (d, J =
(c = 0.340, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.80 (d, J =
6
6
9
7
4
.2 Hz, 2 H), 7.74 (s, 2 H), 7.57 (dd, J = 7.6 Hz, J = 2.4 Hz, 1 H),
8.4 Hz, 2 H), 7.75 (s, 2 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.35 (s, 1 H), 7.24
(d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 3.23 (s, 3
1
2
.29 (dt, J = 8.8 Hz, J = 2.8 Hz, 1 H), 7.18 (dd, J = 8.8 Hz, J =
1
2
1
2
.4 Hz, 1 H), 7.13 (d, J = 9.2 Hz, 2 H), 3.84 (s, 3 H), 3.22 (s, 3 H) ppm.
H) ppm. 13C NMR (100 MHz, [D ]DMSO): δ = 175.2, 162.2, 159.9,
6
1
3
C NMR (100 MHz, [D ]DMSO): δ = 175.1, 162.2, 160.4, 159.9 (d,
144.5, 134.8, 129.9, 129.3, 126.7, 123.4, 121.4, 116.9, 115.7, 114.3,
6
JC,F = 5.9 Hz), 158.1, 139.3 (d, JC,F = 1.4 Hz), 132.3 (d, JC,F = 8.0 Hz),
29.9, 121.5, 117.0, 116.7 (d, JC,F = 23.3 Hz), 115.8, 114.3, 113.3 (d,
JC,F = 25.6 Hz), 110.4 (d, JC,F = 8.0 Hz), 84.8, 55.6, 53.3, 50.3,
109.9, 84.8, 55.6, 53.2, 49.6, 26.9 ppm. IR (KBr): ν = 3304, 3173, 2919,
˜
1
2204, 1704, 1663, 1601, 1513, 1489, 1415, 1371, 1296, 1259, 1181,
–
1
1148, 1114, 1073, 1029, 914, 868, 846, 806, 725 cm . HRMS (ESI):
calcd. for C22H153 ClN NaO3 [M + Na] 441.0730; found 441.0727;
5
+
2
1
1
6.8 ppm. IR (KBr): ν = 3295, 3166, 2208, 1704, 1667, 1603, 1509,
˜
4
37
+
494, 1462, 1414, 1357, 1317, 1300, 1268, 1258, 1176, 1149, 1118,
calcd. for C H
ClN NaO3 [M + Na] 443.0700; found 443.0727.
22
15 4
–
1
032, 927, 883, 845, 819, 789, 768, 693 cm . HRMS (ESI): calcd. for
HPLC analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30;
+
–1
C H FN NaO [M + Na] 425.1026; found 425.1022. HPLC analysis flow rate: 0.9 mL min ): t = 14.10 min (minor), 16.48 min (major).
22
15
4
3
R
(
0
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
(
S)-2′-Amino-6-bromo-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
–1
.9 mL min ): t = 10.90 min (minor), 15.43 min (major).
R
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cq): White solid
2
0
(
S)-2′-Amino-5-chloro-6′-(4-methoxyphenyl)-1-methyl-2-oxo- (46.1 mg, 99 % yield, 97 % ee); m.p. 265.8–266.7 °C. [α] = +20.3
D
1
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cm): White solid
(c = 0.380, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.80 (d, J =
6
2
0
(
(
41.6 mg, 99 % yield, 91 % ee); m.p. 249.4–250.7 °C. [α] = +95.1 8.8 Hz, 2 H), 7.76 (s, 2 H), 7.50–7.37 (m, 3 H), 7.13 (d, J = 8.8 Hz, 2
D
1
13
c = 0.341, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.81 (d, J =
H), 3.84 (s, 3 H), 3.23 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO):
6
6
8
1
.4 Hz, 2 H), 7.74 (s, 3 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 8.4 Hz,
δ = 175.1, 162.2, 159.9, 159.9, 144.6, 129.9, 129.7, 127.0, 126.3, 123.2,
121.4, 116.9, 115.7, 114.3, 112.6, 84.7, 55.6, 53.1, 49.7, 26.9 ppm. IR
H), 7.13 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 3.23 (s, 3 H) ppm. 13
C
NMR (100 MHz, [D ]DMSO): δ = 174.9, 162.2, 160.0, 159.9, 141.9, (KBr): ν˜ = 3311, 3175, 2918, 2204, 1705, 1671, 1606, 1511, 1415,
6
1
8
1
1
32.5, 130.2, 129.9, 127.8, 125.5, 121.5, 117.0, 115.8, 114.2, 110.9, 1364, 1320, 1298, 1261, 1178, 1148, 1121, 1092, 1066, 1031, 945,
–
1
4.6, 55.6, 53.1, 50.1, 26.8 ppm. IR (KBr): ν = 3341, 3291, 3166, 2195,
9 1 0 , 8 7 0 , 8 4 3 , 8 0 2 , 7 2 1 c m . H R M S ( E S I ) : c a l c d . f or
˜
79
+
706, 1664, 1607, 1513, 1478, 1409, 1347, 1298, 1258, 1180, 1156,
C H
BrN NaO [M + Na] 485.0225; found 485.0229; calcd. for
BrN NaO [M + Na] 487.0205; found 487.0218. HPLC analy-
22
15 4 3
–1
35
81
+
028, 822, 737 cm . HRMS (ESI): calcd. for C H
ClN NaO [M + C H
2
2
15
37
4
3
22 15 4 3
+
Na] 441.0730; found 441.0729; calcd. for C H
Na] 443.0700; found 443.0698. HPLC analysis (AD-H column; λ =
ClN NaO3 [M +
sis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
2
2
15
4
+
–1
0.9 mL min ): t = 13.64 min (minor), 14.93 min (major).
R
–
1
2
1
54 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
R
(
[
S)-2′-Amino-6′-(4-methoxyphenyl)-1,7-dimethyl-2-oxospiro-
indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cr): White solid
0.29 min (minor), 15.57 min (major).
2
0
(
S)-2′-Amino-5-bromo-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
(39.5 mg, 99 % yield, 94 % ee); m.p. 243.0–243.4 °C. [α] = +27.0
(c = 0.331, DMSO). H NMR (400 MHz, CDCl ): δ = 7.72 (d, J = 8.8 Hz,
D
1
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cn): White solid
3
2
0
(
(
45.7 mg, 99 % yield, 94 % ee); m.p. 237.9–239.0 °C. [α] = +56.2 2 H), 7.16–7.03 (m, 3 H), 6.87 (d, J = 8.8 Hz, 2 H), 5.44 (d, J = 10.8 Hz,
c = 0.380, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.84 (d, J =
D
1
13
2 H), 3.81 (s, 3 H), 3.56 (s, 3 H), 2.59 (s, 3 H) ppm. C NMR (100 MHz,
6
2
8
.0 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 2 H), 7.75 (s, 2 H), 7.63 (dd, J =
CDCl ): δ = 176.3, 162.6, 159.8, 159.7, 141.0, 134.5, 131.0, 129.9,
124.2, 123.2, 121.5, 121.0, 116.6, 115.7, 114.2, 86.6, 58.2, 55.6, 49.7,
1
3
.0 Hz, J = 2.0 Hz, 1 H), 7.14 (t, J = 8.8 Hz, 3 H), 3.84 (s, 3 H), 3.22
2
13
(
1
s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 174.8, 162.2, 160.0, 30.7, 19.2 ppm. IR (KBr): ν˜ = 3305, 3186, 2925, 2212, 2194, 1710,
6
59.9, 142.3, 133.0, 132.9, 129.9, 128.2, 121.6, 117.0, 115.8, 115.5, 1695, 1673, 1631, 1604, 1512, 1452, 1416, 1360, 1328, 1313, 1258,
–
1
1
3
14.2, 111.4, 84.6, 55.6, 53.1, 50.1, 26.8 ppm. IR (KBr): ν˜ = 3340, 3303, 1182, 1154, 1116, 1030, 929, 844, 800, 777, 748 cm . HRMS (ESI):
+
171, 2916, 2204, 1706, 1660, 1604, 1511, 1482, 1413, 1348, 1302,
calcd. for C H N NaO [M + Na] 421.1277; found 421.1273. HPLC
23 18 4 3
–
1
1
261, 1178, 1153, 1093, 1032, 832, 725 cm . HRMS (ESI): calcd. for analysis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow
7
8
9
1
+
–1
C H
C H
BrN NaO [M + Na] 485.0225; found 485.0227; calcd. for rate: 0.9 mL min ): t = 13.33 min (minor), 16.35 min (major).
2
2
15
4
3
R
+
BrN NaO [M + Na] 487.0205; found 487.0210. HPLC analy-
22
15
4 3
(
S)-2′-Amino-7-fluoro-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
sis (AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
0
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cs): White solid
–1
.9 mL min ): t = 10.21 min (minor), 15.03 min (major).
20
R
(
39.9 mg, 99 % yield, 94 % ee); m.p. 252.3–252.7 °C. [α] = +23.6
D
1
(
[
S)-2′-Amino-6′-(4-methoxyphenyl)-1,6-dimethyl-2-oxospiro- (c = 0.335, DMSO). H NMR (400 MHz, CDCl ): δ = 7.72 (d, J = 8.8 Hz,
indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3co): White solid
3
2 H), 7.14–7.12 (m, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.51 (s, 2 H), 3.82
2
0
13
(40.0 mg, 97 % yield, 92 % ee); m.p. 236.9–237.4 °C. [α] = +71.3 (s, 3 H), 3.50 (d, J = 1.6 Hz, 3 H) ppm. C NMR (100 MHz, CDCl3):
D
1
(c = 0.160, CH Cl ). H NMR (400 MHz, [D ]DMSO): δ = 7.79 (d, J = δ = 175.4, 162.8, 160.0, 159.9, 148.0 (d, JC,F = 244.3 Hz), 132.9 (d,
2
2
6
8
2
.8 Hz, 2 H), 7.63 (s, 2 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 9.2 Hz,
JC,F = 2.2 Hz), 130.1 (d, JC,F = 8.7 Hz), 129.9, 125.0 (d, JC,F = 5.8 Hz),
H), 6.79 (d, J = 2.4 Hz, 1 H), 6.71 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 121.3, 121.1 (d, JC,F = 2.9 Hz), 118.8 (d, JC,F = 19.7 Hz), 116.3, 115.5,
1
2
1
3
H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.21 (s, 3 H) ppm. C NMR (100 MHz,
D ]DMSO): δ = 175.7, 162.1, 161.2, 159.8, 159.4, 144.4, 129.8, 125.9,
114.3, 85.8, 57.4, 55.7, 50.5, 29.8 (d, JC,F = 5.1 Hz) ppm. IR (KBr): ν =
˜
[
3307, 3184, 2923, 2190, 1722, 1704, 1673, 1626, 1604, 1512, 1462,
1413, 1363, 1325, 1310, 1254, 1178, 1150, 1121, 1025, 845, 781,
6
1
4
1
1
22.3, 121.6, 117.1, 115.9, 114.3, 108.2, 96.6, 85.8, 55.6, 55.6, 54.1,
9.4, 26.7 ppm. IR (KBr): ν = 3334, 3298, 2928, 2834, 2312, 2208,
–
1
+
737 cm . HRMS (ESI): calcd. for C H FN NaO [M + Na] 425.1026;
˜
22 15 4 3
668, 1631, 1598, 1510, 1458, 1413, 1373, 1295, 1258, 1181, 1151,
found 425.1026. HPLC analysis (AD-H column; λ = 254 nm; n-hex-
–
1
–1
121, 1088, 1025, 859, 844, 792, 696 cm . HRMS (ESI): calcd. for ane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 12.12 min (minor),
R
+
C H N NaO [M + Na] 437.1226; found 437.1226. HPLC analysis 15.86 min (major).
23
18
4
4
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Full Paper
+
(
S)-2′-Amino-7-chloro-6′-(4-methoxyphenyl)-1-methyl-2-oxo- [M + Na] 541.0487; found 541.0485. HPLC analysis (AD-H column;
–1
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3ct): White solid
(
λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t =
41.4 mg, 99 % yield, 94 % ee); m.p. 257.7–258.0 °C. [α] = +44.0 12.74 min (major), 15.70 min (minor).
R
2
0
D
1
(c = 0.348, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.82–7.79 (m,
6
(
S)-6-Bromo-8′-(4-methoxyphenyl)-1-methyl-2-oxo-2′-phenyl-
spiro[indoline-3,10′-pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyr-
imidine]-9′-carbonitrile (5): To a solution of compound 4 (49.3 mg,
4
3
H), 7.53 (d, J = 6.4 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 7.23–7.11 (m,
1
3
H), 3.84 (s, 3 H), 3.54 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO):
6
δ = 175.6, 162.3, 159.9, 159.8, 138.6, 133.6, 132.3, 129.9, 125.1, 124.6,
21.4, 116.9, 115.6, 114.8, 114.3, 84.8, 55.6, 53.4, 49.8, 30.0 ppm. IR
KBr): ν = 3325, 3189, 2922, 2846, 2202, 1716, 1664, 1605, 1459,
0
.095 mmol) in anhydrous ethyl acetate (1 mL) were added benzo-
1
(
1
(
4
4
hydrazide (19.4 mg, 0.143 mmol) and acetic acid (1 mL). The reac-
tion mixture was heated at reflux for 5 h, whereupon the reaction
reached completion (monitored by TLC). After the mixture was con-
centrated under reduced pressure, the residue was purified by col-
umn chromatography to give the desired product 5 (43.8 mg, 78 %
yield, 95 % ee) as a white solid; m.p. 330.9–332.7 °C. [α] = –122.3
c = 0.320, CH Cl ). H NMR (400 MHz, [D ]DMSO): δ = 9.80 (s, 1 H),
.00–7.97 (m, 2 H), 7.88 (d, J = 9.2 Hz, 2 H), 7.63 (d, J = 1.6 Hz, 1 H),
.54–7.47 (m, 4 H), 7.28 (dd, J = 8.0 Hz, J = 1.6 Hz, 1 H), 7.17 (d,
J = 8.8 Hz, 2 H), 3.86 (s, 3 H), 3.43 (s, 3 H) ppm. C NMR (100 MHz,
˜
–
1
406, 1327, 1260, 1180, 1143, 1108, 1020, 837, 745 cm . HRMS
3
5
+
ESI): calcd. for C22H15 ClN NaO [M + Na] 441.0730; found
41.0725; calcd. for C H
4 3
3
7
ClN NaO [M + Na]+ 443.0700; found
2
2
15 4 3
43.0689. HPLC analysis (AD-H column; λ = 254 nm; eluent: n-hex-
20
D
–
1
ane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 12.07 min (minor),
1
1
R
(
8
2
2
6
4.34 min (major).
7
(
S)-2′-Amino-7-bromo-6′-(4-methoxyphenyl)-1-methyl-2-oxo-
1
2
13
spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cu): White solid
2
0
[D ]DMSO): δ = 173.8, 165.8, 162.3, 161.5, 153.0, 150.9, 145.4, 142.0,
131.4, 130.1, 129.8, 129.2, 128.9, 127.2, 127.1, 126.1, 123.5, 121.8,
(
(
46.1 mg, 99 % yield, 93 % ee); m.p. 246.2–247.4 °C. [α] = +21.7
c = 0.380, DMSO). H NMR (400 MHz, [D ]DMSO): δ = 7.82–7.78 (m,
6
D
1
6
1
15.8, 114.4, 112.3, 97.3, 84.7, 55.6, 49.4, 27.2 ppm. IR (KBr): ν˜ =
4
7
H), 7.60 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 7.2 Hz, 1 H), 7.13 (d, J =
.6 Hz, 3 H), 3.84 (s, 3 H), 3.55 (s, 3 H) ppm. C NMR (100 MHz,
1
3
2953, 2920, 2840, 2349, 2313, 2213, 1725, 1634, 1603, 1504, 1455,
1
9
409, 1364, 1324, 1265, 1234, 1175, 1125, 1086, 1062, 1022, 968,
36, 887, 837, 725, 684, 603 cm . HRMS (ESI): calcd. for
C H BrN O [M + H] 591.0780; found 591.0773. HPLC analysis
AD-H column; λ = 254 nm; n-hexane/iPrOH, 70:30; flow rate:
[D ]DMSO): δ = 175.8, 162.3, 159.9, 159.8, 140.0, 135.6, 133.9, 129.9,
6
–
1
1
4
1
7
4
4
26.7, 125.5, 125.1, 121.4, 116.9, 115.7, 114.3, 102.1, 84.8, 55.6, 53.4,
9.8, 30.2 ppm. IR (KBr): ν˜ = 3315, 3173, 2920, 2850, 2373, 2210,
707, 1664, 1601, 1409, 1299, 1256, 1180, 1153, 1100, 1020, 830,
+
30 20
6 3
(
–
1
–
1
79
+
+
0.9 mL min ): t = 35.77 min (minor), 90.32 min (major).
81, 715 cm . HRMS (ESI): calcd. for C H
BrN NaO [M + Na]
R
2
2
15
4
3
8
1
85.0225; found 485.0227; calcd. for C H
BrN NaO [M + Na]
2
2
15
4 3
87.0205; found 487.0205. HPLC analysis (AD-H column; λ = 254 nm;
Acknowledgments
–
1
n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 11.66 min (mi-
R
nor), 14.53 min (major).
The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant number
(
S)-2′-Amino-6′-(4-methoxyphenyl)-1-methyl-2-oxo-7-(trifluoro-
2
1102043), the Science and Technology Commission of Shang-
methyl)spiro[indoline-3,4′-pyran]-3′,5′-dicarbonitrile (3cv):
hai Municipality (grant number 15ZR1409200), and the Funda-
White solid (45.0 mg, 99 % yield, 92 % ee); m.p. 227.8–229.2 °C.
2
0
1
[
α] = +54.8 (c = 0.377, DMSO). H NMR (400 MHz, [D ]DMSO): δ = mental Research Funds for the Central Universities.
D
6
7
3
1
1
.92–7.80 (m, 6 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H),
1
3
.84 (s, 3 H), 3.38 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ =
6
Keywords: Organocatalysis · Asymmetric catalysis · Domino
reactions · Spiro compounds · Nitrogen heterocycles
76.3, 162.3, 160.2, 160.0, 140.6, 133.4, 129.9, 128.0 (q, JC,F = 5.1 Hz),
23.9, 123.4 (q, JC,F = 269.8 Hz), 121.3, 116.7, 115.5, 114.3, 111.4 (q,
JC,F = 3.2 Hz), 84.5, 55.6, 53.1, 48.7, 29.3 (q, JC,F = 5.8 Hz) ppm. IR
KBr): ν = 3349, 3301, 3172, 2916, 2199, 1706, 1661, 1598, 1515,
(
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˜
1
7
4
451, 1322, 1302, 1262, 1185, 1152, 1121, 1081, 1053, 1023, 827,
–1
+
99, 752 cm . HRMS (ESI): calcd. for C H F N NaO [M + Na]
2
3
15
3
4
3
75.0994; found 475.0999. HPLC analysis (AD-H column; λ = 254 nm;
–
1
n-hexane/iPrOH, 70:30; flow rate: 0.9 mL min ): t = 9.02 min (mi-
R
nor), 10.80 min (major).
Ethyl (S,E)-N-[6-Bromo-3′,5′-dicyano-2′-(4-methoxyphenyl)-1-
methyl-2-oxospiro(indoline-3,4′-pyran)-6′-yl]formimidate (4): A
mixture of product 3cq (46.3 mg, 0.1 mmol), triethyl orthoformate
(0.75 mL), and acetic acid (0.25 mL) was heated at reflux for 2 h,
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whereupon the reaction reached completion (monitored by TLC).
After the mixture was concentrated under reduced pressure, the
residue was purified by column chromatography to give the desired
2
0
product 4 (49.3 mg, 95 % yield, 95 % ee) as a colorless oil. [α]
=
D
1
+
54.8 (c = 0.414, CH Cl ). H NMR (400 MHz, CDCl ): δ = 8.35 (s, 1
2 2 3
H), 7.75 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.23 (d, J =
8
2
.0 Hz, 1 H), 7.11 (s, 1 H), 6.97 (d, J = 8.4 Hz, 2 H), 4.44 (t, J = 6.4 Hz,
H), 3.85 (s, 3 H), 3.30 (s, 3 H), 1.38 (t, J = 6.8 Hz, 3 H) ppm. 13
[3] For selected examples of the biological activities of spiro[4H-pyran-ox-
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Kidwai, A. Jain, V. Nemaysh, R. Kumar, P. M. Luthra, Med. Chem. Res. 2013,
22, 2717–2723; c) K. Parthasarathy, C. Praveen, C. Balachandran, P. Sent-
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C
NMR (100 MHz, CDCl ): δ = 173.8, 162.6, 160.5, 160.4, 158.1, 144.4,
3
1
8
2
1
29.7, 128.3, 126.9, 126.3, 124.7, 121.5, 115.1, 114.2, 114.1, 112.8,
5.0, 78.1, 65.0, 55.5, 51.2, 27.1, 13.7 ppm. IR (KBr): ν˜ = 2955, 2921,
851, 2307, 2215, 1725, 1659, 1601, 1513, 1460, 1367, 1261, 1207,
–
1
181, 1022, 836, 725 cm . HRMS (ESI): calcd. for C H BrN NaO
2
5
19
4
4
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[
Received: June 6, 2016
Published Online: ■
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Full Paper
Asymmetric Catalysis
J. Xie, W.-L. Xing, F. Sha,
X.-Y. Wu* ............................................ 1–11
Enantioselective Cascade Reaction
of α-Cyano Ketones and Isatylidene
Malononitriles: Asymmetric Con-
struction of Spiro[4H-pyran-oxind-
oles]
α-Cyano ketones have been used for ole] derivatives were prepared in ex-
the first time as Michael donors in the cellent yields with good-to-excellent
construction of chiral spiro com- enantioselectivities. This method pro-
pounds. In the presence of only 2 mol- vides a new approach to the synthesis
%
of a chiral multifunctional organo- of chiral spirocyclic oxindoles.
catalyst, chiral spiro[4H-pyran-oxind-
DOI: 10.1002/ejoc.201600432
Eur. J. Org. Chem. 0000, 0–0
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11
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim