Organocatalytic enantioselective construction of multi-functionalized spiro oxindole dienes

Article abstract of DOI:10.1039/c4ob00545g

A diastereo- and enantio-selective domino Michael-cyclization- tautomerization reaction of isatylidene malononitriles with α,α- dicyanoalkenes catalyzed by a cinchona alkaloid-derived bifunctional thiourea catalyst has been developed. A series of multi-functionalized spiro oxindole diene derivatives have been obtained in good to excellent yields (up to 97%) with good to excellent enantioselectivities (up to 96%) as well as good diastereoselectivities (up to 7.9=1). In addition, an anomalous temperature effect on the enantioselectivity has also been studied for this transformation. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00545g

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Organocatalytic enantioselective construction of
multi-functionalized spiro oxindole dienes†
Cite this: Org. Biomol. Chem., 2014,
12, 4372
Xiao-Fei Huang, Ya-Fei Zhang, Zheng-Hang Qi, Nai-Kai Li, Zhi-Cong Geng, Kun Li
and Xing-Wang Wang*
A diastereo- and enantio-selective domino Michael-cyclization–tautomerization reaction of isatylidene
malononitriles with α,α-dicyanoalkenes catalyzed by a cinchona alkaloid-derived bifunctional thiourea
catalyst has been developed. A series of multi-functionalized spiro oxindole diene derivatives have been
obtained in good to excellent yields (up to 97%) with good to excellent enantioselectivities (up to 96%) as
well as good diastereoselectivities (up to 7.9 : 1). In addition, an anomalous temperature effect on the
enantioselectivity has also been studied for this transformation.
Received 12th March 2014,
Accepted 26th April 2014
DOI: 10.1039/c4ob00545g
www.rsc.org/obc
access multifunctionalized spiro oxindoles with diene moieties
remain less explored. Therefore, the development of efficient
Introduction
Spirocyclic oxindole scaffolds bearing a spirocyclic quaternary catalytic systems is in high demand.
stereocenter at the C-3 position are privileged structural
Although prepared more than a century ago,11 α,α-dicyano-
motifs, which are prevalent in numerous natural products and alkenes were first applied as successful vinylogous donors
biologically active molecules.1 Recently, a large number of in asymmetric synthetic chemistry in 2005.12,13 Shortly after-
chiral spirocyclic oxindoles have been reported as important wards, a series of highly enantioselective Michael addition
molecular probes for studying biological activities toward reactions of α,α-dicyanoalkenes and α,β-unsaturated com-
different cellular processes.2 As a result of their importance, pounds were disclosed.14 A non-asymmetric version of functio-
various synthetic protocols catalyzed by either chiral tran- nalized spirocyclic oxindoles by one-pot tandem reactions of
sition-metal complexes or chiral organocatalysts have been alkylidene malononitriles with isatylidene malononitriles was
developed to achieve optically active spirocyclic oxindole com- reported by Perumal’s group15 in 2010. Based on these litera-
pounds.3 Among these procedures, one-pot domino transform- ture reports, we envisioned that α,α-dicyanoolefins could be
ation is especially attractive, as it permits the stereoselective used as a versatile building block for the construction of
formation of several bonds catalyzed by a single catalyst in a chiral spiro oxindole compounds. Herein, we present
single operation without the necessity to isolate the intermedi- our study on an organocatalyzed asymmetric Michael-cycliza-
ates.4 In 2009, Melchiorre and co-workers reported enantio- tion–tautomerization process between isatylidene malono-
selective synthesis of multistereogenic spiro oxindole nitriles and α,α-dicyanoalkenes at relatively high temperature,
hexanones via [4 + 2] domino double Michael additions.5 which furnished
a series of multi-functionalized spiro
Since then, more intriguing spirocyclic oxindole skeletons oxindole dienes in good to excellent yields with good
have been constructed by asymmetric organocatalytic domino diastereoselectivities as well as good to excellent enantio-
reactions.6 Our group has also synthesized a series of spiro- selectivities.
cyclic oxindoles through organocatalyzed domino [4 + 2] type7 or
[5 + 1] type8 double Michael addition, Michael/reduction/cycli-
zation9 and Michael-aldol10 additions. However, to the best of
Results and discussion
our knowledge, efficient catalytic stereoselective methods to
In a preliminary study, the model reaction of isatylidene malono-
nitrile 1a and 2-cyclohexylidene malononitrile 2 catalyzed by
different organic catalysts 3a–m was carried out in toluene at
room temperature, and the results are summarized in Table 1.
When cinchona alkaloid derivatives 3a–3c were employed as
the catalysts, only 17–26% ees were observed (entries 1–3).
Bifunctional thiourea catalysts 3d–3g with different stereogenic
structures were also investigated (entries 4–7), and the results
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China. E-mail: wangxw@suda.edu.cn; Fax: +86 (0)512 65880378;
Tel: +86 (0)512 65880378
†Electronic supplementary information (ESI) available: Characterization data
and HPLC chromatograms for all compounds. CCDC 951552. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00545g
4372 | Org. Biomol. Chem., 2014, 12, 4372–4385
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Table 1 Evaluation of model substrates and catalysts of the asymmetric cascade Michael-cyclization–tautomerization between 1a, 5a–10a and 2a
Entry
Cat.
Substrate
Time (h)
Product
Yieldb (%)
eec (%)
drd
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3m
3m
3m
3m
3m
3m
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = H/1a
R = Me/5a
R = Bn/6a
R = Allyl/7a
R = Bz/8a
R = MOM/9a
R = Ac/10a
1
1.75
1.75
24
6
4
4
1.5
0.5
3
12
2
2.5
2
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
95
93
92
94
95
96
97
94
97
94
95
97
96
89
95
89
91
98
93
17
17
26
−30
9
2.7 : 1
4.0 : 1
1.6 : 1
3.5 : 1
4.9 : 1
3.6 : 1
2.1 : 1
4.0 : 1
2.4 : 1
1.9 : 1
4.9 : 1
1.2 : 1
2.1 : 1
2.1 : 1
2.1 : 1
2.1 : 1
3.6 : 1
2.4 : 1
5.7 : 1
−24
52
22
35
54
30
70
72
65
62
63
77
76
72
9
10
11
12
13
14
15
16
17
18
19
1.5
2
2.5
3.5
4g
a Unless noted otherwise, reactions were carried out with 1a, 5a–10a (0.1 mmol), 2 (0.12 mmol), and 3 (20 mol%), in toluene (1.0 mL) at room
temperature. b Isolated yield. c,d Determined by chiral HPLC, the ee of the major diastereomer.
revealed that quinine-based bifunctional thiourea catalyst 3g 12, 13 vs. 7, 10). In terms of both reactivity and stereo-
performed better and the desired product 4a was isolated in selectivity, 3m proved to be the best catalyst (entries 12 vs. 13).
97% yield with 2.1 : 1 dr and 52% ee (entry 7). Subsequently,
Having identified the optimal catalyst, we proceeded to
more cinchona alkaloid based bifunctional catalysts 3h–3k study the influence of different N-protecting groups of the oxin-
were tested in this reaction (entries 8–11), among which 3g dole moiety (entries 14–19). When substrates 5a–10a bearing
and 3j proved to be the best performers in terms of enantio- different substituents such as –methyl, –benzyl, –allyl, –Bz,
selectivities (entries 7, 10 vs. 8, 9, 11). This may be attributed –MOM and –Ac groups were tested, the desired products 4e–4g
to the increase in acidity of the thiourea due to the presence of were furnished in excellent yields with slightly higher enantio-
electron-withdrawing
1,3-bis(trifluoromethyl)phenyl
and selectivities and diastereoselectivities than those of 4b–4d
p-nitrophenyl groups, respectively. Inspired by these findings, (entries 17–19 vs. entries 14–16). Generally, taking into
hydroquinine-derived thioureas 3l and 3m were synthesized account stereoselectivity, the reaction with the substrate 10a
and examined for this transformation. To our delight, the bearing a –Ac protecting group was demonstrated to be a
desired product 4a was obtained in 97% and 96% yields with suitable model for further optimization of the reaction
1.2 : 1 and 2.1 : 1 drs, 70% and 72% ees, respectively (entries conditions.
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With the optimal model substrate and catalyst in hand, ination of reactant concentration revealed that the reaction did
other parameters were further optimized, including the reac- not work better in either more concentrated or dilute mixtures
tion solvent, additive, concentration, temperature and catalyst in comparison with 0.1 M of substrate 10a (entries 14, 16, 17).
loading. The results are summarized in Table 2. Although the The enantioselectivity was slightly improved in anhydrous
reaction between 10a and 2 proceeded smoothly in a wide m-xylene without sacrificing the yield and stereoselectivity
range of solvents, the enantioselectivities were found to vary (entry 18, 96% yield, 90% ee, 5.7 : 1 dr). Encouraged by these
dramatically (entries 1–15). The desired product 4g was furn- results, additives were tested in this reaction, including 3 Å,
ished in 93% yield with 5.3 : 1 dr, 48% ee in acetonitrile 4 Å, 5 Å and 13× molecular sieves, which gave rise to better
(entry 4), whereas no desired product was detected in DMF results including excellent yields (90–95%), good diastereo-
and ethanol (entries 2 and 3). Thus relatively polar solvents are selective ratios (5.7 : 1 to 6.1 : 1) and excellent enantioselectivities
not favorable for this transformation. However, the reaction (92–93%) (entries 19–22). Overall, the 3 Å molecular sieve was
proceeded smoothly in less polar solvents, such as DCM, proved to be the optimal additive, as the desired product 4g
CHCl3, THF, Et2O, and MTBE, which produced the desired was obtained in 94% yield, 93% ee and 5.7 : 1 dr (entry 19).
product 4g in 49–93% yields with 4.6 : 1–10.1 : 1 drs and A study on the effect of reaction temperature (entries 23–29)
32–70% ees (entries 5–9). Subsequently, aromatic hydrocarbon revealed that when it was decreased to −5 °C, only a trace
solvents were tested, such as ethylbenzene, xylene, o-xylene, amount of 4g was detected even after the reaction time was
p-xylene, m-xylene, and mesitylene (entries 10–15). Overall, prolonged to 48 h (entry 23). Interestingly, 4g was obtained in
m-xylene was found to be the optimal solvent, which gave rise high yield (97%) with a slightly increased enantioselectivity
to 4g in 93% yield, 86% ee and 6.1 : 1 dr (entry 14). The exam- (94% ee) at 50 °C within 0.7 h (entry 26 vs. entries 19, 24 and 25).
Table 2 Optimization of the reaction conditions for the asymmetric cascade Michael-cyclization–tautomerization between 10 and 2a
Entry
Solvent
Additive
Temp. (°C)
Time (h)
Yieldb (%)
eec (%)
drd
1
2
3
4
5
6
7
8
Toluene
DMF
EtOH
CH3CN
DCM
CHCl3
THF
Et2O
MTBE
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
−5
10
40
50
60
80
100
50
50
3.5
4.0
0.5
5.0
5.0
5.0
3.5
3.0
3.5
20
3.0
3.0
3.0
3.0
20
93
<5
<5
93
76
49
91
95
92
87
91
92
95
93
94
87
92
96
94
90
95
93
<10
87
95
97
96
95
88
97
95
72
nd
nd
48
32
47
69
69
70
27
80
71
78
86
67
76
77
90
93
93
92
92
nd
87
93
94
92
90
75
94
90
5.7 : 1
nd
nd
5.3 : 1
10.1 : 1
5.7 : 1
5.3 : 1
4.6 : 1
4.6 : 1
7.3 : 1
6.7 : 1
6.1 : 1
6.7 : 1
6.1 : 1
5.7 : 1
5.7 : 1
5.3 : 1
5.7 : 1
5.7 : 1
5.7 : 1
5.7 : 1
6.1 : 1
nd
9
10
11
12
13
14
15
16e
17f
18g
19g
20g
21g
22g
23g
24g
25g
26g
27g
28g
29g
30g,h
31g,i
Ethylbenzene
Xylene
o-Xylene
p-Xylene
m-Xylene
Mesitylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
m-Xylene
12
—
—
2.0
3.0
2.0
2.0
5.0
5.0
48
3 Å
4 Å
5 Å
13X
3 Å
3 Å
3 Å
3 Å
3 Å
3 Å
3 Å
3 Å
3 Å
22
6.7 : 1
5.7 : 1
5.7 : 1
5.3 : 1
4.9 : 1
4 : 1
1.3
0.7
0.7
0.5
1.0
1.5
3.5
6.7 : 1
5.7 : 1
a Unless noted otherwise, reactions were carried out with 10a (0.1 mmol), 2 (0.12 mmol), and 3m (20 mol%), in the corresponding solvent
(1.0 mL) at room temperature. b Isolated yield. c,d Determined by chiral HPLC, the ee of the major diastereomer. e [10a] = 0.05 M. f [10a] = 0.2 M.
g Anhydrous solvent was used. h 10 mol% 3m was used. i 5 mol% 3m was used.
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When the temperature was further elevated, the ee and dr
values slightly dropped (entries 27–29). Thus, 50 °C was
selected as the optimal reaction temperature.
Table 3 Substrate scope for the reaction of the asymmetric cascade
Michael-cyclization–tautomerizationa
Finally, the feasibility to reduce the catalyst loading was
also studied (entries 30 and 31). When the reaction was con-
ducted in the presence of 10 mol% 3m, 4g was isolated in 97%
yield, 94% ee and 6.7 : 1 dr after the reaction time was pro-
longed to 1.5 h. In addition, when the catalyst loading was
further decreased to 5 mol%, the reaction evidently became
sluggish and the values of enantio- and diastereo-selectivities
also somewhat dropped (entry 31). Thus, the optimal reaction
conditions for the Michael-cyclization–tautomerization reac-
tion between 10 and 2 were finally established as the reaction
being performed at 50 °C, with a substrate concentration of
0.1 M in the presence of 10 mol% catalyst 3m and 3 Å mole-
cular sieves as additives.
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Substrate
Product
drd
1
2
3
4
5
6
7
8
R1 = H/10a
1.5
1.2
1.3
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
0.3
0.3
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
97
92
53
92
94
93
66
92
96
94
95
91
88
93
94
93
86
96
91
94
94
91
94
92
91
80
70
75
6.7 : 1
3.2 : 1
4.2 : 1
6.7 : 1
5.7 : 1
6.1 : 1
6.4 : 1
6.1 : 1
7.1 : 1
7.2 : 1
6.2 : 1
7.9 : 1
1.9 : 1
2.0 : 1
R1 = 4-Cl/10b
R1 = 4-Br/10c
R1 = 5-F/10d
R1 = 5-Cl/10e
R1 = 5-Br/10f
R1 = 5-NO2/10g
R1 = 5-CH3/10h
R1 = 5-OCH3/10i
R1 = 6-Cl/10j
R1 = 6-Br/10k
R1 = 5,6-F2/10l
R1 = H/10a
Having established the optimal reaction conditions, we
further explored the substrate scope of the 3m catalyzed
9
10
11
12
13e
14e, f
cascade
Michael-cyclization–tautomerization
sequence
between isatylidene malononitriles 10a–10l and 2-cyclohexyli-
dene malononitrile 2, and the results are summarized in
Table 3. The cascade approach was applicable to isatylidene
malononitriles bearing various substituents, and the desired
products were isolated in moderate to excellent yields
(53–97%), moderate to good diastereoselectivities (3.2 : 1 to
7.9 : 1) and good to excellent enantioselectivities (80–96%)
(entries 1–12). The steric hindrance and electronic properties
of the substituents on the phenyl rings of the oxindole back-
bones seemed to have somewhat influenced the reactivities
and diastereoselectivities of the reactions. Notably, substrates
10b and 10c with substituents (–Cl or –Br) at the 4-position of
oxindole backbones led to the isolation of the desired products
4h and 4i in distinctively different yields (92 and 53%) with
excellent enantioselectivities (93 and 86%) and moderate dia-
stereoselectivities (3.2 : 1 and 4.2 : 1), respectively (entries 2
and 3). In comparison, all reactions involving substrates 10d–
10l bearing substituents (–F, –Cl, –Br, –NO2, –Me, –OMe) at
5- or 6-positions of oxindole backbones completed in less than
4s
4s
R1 = H/10a
a Reactions were performed with 10 (0.2 mmol), 2 (0.24 mmol), 40 mg
3 Å MS and 10 mol% catalyst 3m in 2.0 mL m-xylene at 50 °C.
b Isolated yield. c Determined by HPLC analysis, the ee of the major
diastereomer. d Determined by 1H NMR of crude products. e 2′ was
used as a reactant. f Catalyst 3l was used as a catalyst.
Scheme 1 The asymmetric cascade Michael-cyclization–tautomeriza-
tion between 10a and 11a.
2 h, which furnished the desired products 4j–4r in 66–95% with 62% ee (Scheme 1). Apparently, the above established
yields with 5.7 : 1 to 7.9 : 1 drs and 91–96% ees (entries 4–12). reaction conditions were not suitable for this transformation.
For the substrate 10g bearing a strong electron-withdrawing In order to improve both reactivity and enantioselectivity, the
–NO2 group, the corresponding reaction gave the desired reaction parameters were then further optimized, including
product 4m in good dr (6.4 : 1) and excellent ee (94%), various N-protecting groups of substrates, catalysts, solvents
although the yield dropped to 66% (entries 7 vs. 4–6 and and additives, and the results are summarized in Table 4.
8–12). Furthermore, 2-cyclopentylidene malononitrile 2′ was When substrates 10a and 5a–7a, 9a bearing different N-protect-
also tested for this transformation, and the reaction proceeded ing groups such as –Ac, –Me, –Bn, –allyl, and –MOM reacted
very fast (within 0.3 h) and produced the expected product 4s with 11a in the presence of catalyst 3m in toluene, the corres-
in 70% ee and 1.9 : 1 dr (entry 13). A better result of 75% ee ponding products 12a–12e were obtained in excellent yields
and 2 : 1 dr was obtained when catalyzed by 3l (entry 14). This (93–98%) with low to moderate enantioselectivities (13–69%
finding suggests that the substrate 2 bearing a six-membered ee, entries 1–5). Based on these results, the N-methyl group
ring is more favorable for this transformation (entry 1 vs. turned out to be the optimal protecting group of the substrate
entries 13 and 14).
5a, and the reaction furnished the desired product 12b in 93%
In order to further explore the substrate scope, the cascade yield with 69% ee after 3 h of reaction (entry 2). After the
reaction between 10a and 2-(1-phenylethylidene)malononitrile screening of different catalysts (entries 6–8), solvents (entries
11a was investigated under otherwise identical reaction con- 9–13), and additives (entries 14 and 15), the best result (91%
ditions, and the desired product 12a was isolated in 75% yield yield, 70% ee) was obtained in the presence of 10 mol% cata-
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Table 4 Optimization of reaction conditions for the asymmetric cascade Michael-cyclization–tautomerization between 5a–7a, 9a–10a and 11aa
Entry
Substrate
Cat.
Solvent
Product
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
R = Ac/10a
R = Me/5a
R = Bn/6a
R = Allyl/7a
R = MOM/9a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
R = Me/5a
3m
3m
3m
3m
3m
3f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
o-Xylene
p-Xylene
m-Xylene
Mesitylene
Toluene
Toluene
12a
12b
12c
12d
12e
12b
12b
12b
12b
12b
12b
12b
12b
12b
12b
3
93
93
95
96
98
89
92
91
95
92
94
91
89
94
91
47
69
46
44
13
−22
37
63
67
48
24
63
66
63
70
0.7
1.2
1.2
1
4
3g
3l
1.3
0.7
1.2
1.2
2
1.2
1.2
0.5
0.5
9
3m
3m
3m
3m
3m
3m
3m
10
11
12
13
14d
15e
a Unless noted otherwise, reactions were carried out with 5a–7a, 9a–10a (0.1 mmol), 11a (0.12 mmol), cat. 3 (10 mol%), and in the corresponding
solvent (1.0 mL) at room temperature. b Isolated yield. c Determined by chiral HPLC. d 20 mg 3 Å MS was used as an additive. e 20 mg 4 Å MS was
used as an additive.
lyst 3m with 20 mg of 4 Å MS after 0.5 h of reaction at room such an abnormal phenomenon in the field of organocata-
temperature in toluene (Table 1, entry 15).
lysis.17 However, to the best of our knowledge, no study has
Intriguingly, it was found that the reaction temperature reported that the desired product was obtained in racemic
largely influenced the enantioselectivity of this transformation form at relatively low temperature, whereas higher enantio-
(Fig. 1). When the reaction was performed at −20 and −40 °C, selectivity can be obtained at higher temperature. In this
respectively, the product was obtained in racemic form. instance, we also observed that when the reaction temperature
However, when the temperature was elevated from 0 °C to was further elevated to over 70 °C, the enantioselectivity of the
100 °C, the ee values increased from 34% to 95% (Fig. 1). It is desired product was still moved up, albeit the yield dramati-
generally accepted that lowered temperature will be preferred cally decreased, which may be due to the decomposition of the
for achieving higher enantioselectivity, whereas elevated temp- product at relatively high temperature.18 In terms of both the
erature will significantly reduce the enantioselectivity for organo- isolated yield and the enantioselectivity of the desired product,
catalysis.16 Only recently, some publications have reported 70 °C was selected as the appropriate reaction temperature for
this transformation. The product 12b was obtained in 87%
yield with 89% ee under the optimal reaction conditions.
The substrate scope was further explored for the enantio-
selective domino Michael-cyclization–tautomerization reaction
between 5 and 11. As shown in Table 5, for substrates 11
bearing either electron-donating or electron-withdrawing
groups at o-, m-, or p-positions of the phenyl ring, the corres-
ponding products 12f–12s were obtained in 57–93% yields
with 79–95% ees (entries 2–15). Both the electronic and steric
properties of the substituents on phenyl rings of substrates 11
influence the catalytic outcomes of this transformation. For
substrates 11b–11e bearing halogen substituents (–F, –Cl, –Br
or –I) at the 4-positions of the phenyl rings, the enantio-
selectivities of the desired products 12f–12i decreased from
95% to 81% following the sequence –F, –Cl, –Br and –I, while
their yields decreased from 91% to 72% (entries 2–5). When
Fig. 1 The influence of temperature on the domino reaction of 5a and
the –F substituent was installed at p-, m-, and o-positions of
11a. Unless noted otherwise, reactions were carried out with 5a
the phenyl rings, respectively, the ee values of the corres-
(0.1 mmol), 11a (0.12 mmol), cat. 3m (10 mol%), 20 mg 4 Å MS and in
ponding products dropped from 95% to 83% (entries 2 vs. 8
toluene (1.0 mL) for 0.5 h. −40 °C for 24 h; −20 °C for 10 h; 0 °C for 2 h.
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Table 5 Substrate scope in the reaction of the asymmetric cascade
Michael-cyclization–tautomerization between 5 and 11a
Scheme 2 Gram-scale asymmetric synthesis of 4p.
Yieldb eec
Entry Substrate 11
Substrate 5
Product (%)
(%)
1
2
3
4
5
6
7
8
R1 = H/11a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
R2 = H/5a
12b
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
12s
12t
87
91
81
79
72
93
87
93
73
92
92
72
74
61
57
90
72
76
72
89
95
85
82
81
84
80
89
86
83
95
83
88
79
93
92
74
78
76
R1 = 4-F/11b
R1 = 4-Cl/11c
R1 = 4-Br/11d
R1 = 4-I/11e
R1 = 4-NO2/11f
R1 = 4-CF3/11g
R1 = 3-F/11h
R1 = 3-Cl/11i
R1 = 2-F/11j
9
10
11
12
13
14
15
16
17
18
19
R1 = 3,4-F2/11k
R1 = 4-CH3/11l
R1 = 4-OCH3/11m R2 = H/5a
R1 = 4-Ph/11n
R1 = 2-furan/11o
R1 = 4-F/11b
R1 = 4-F/11b
R1 = 4-F/11b
R1 = 4-F/11b
R2 = H/5a
R2 = H/5a
R2 = 5-F/5b
Fig. 2 X-ray crystal structure of the chiral compound 4p.
R2 = 5-OCH3/5c 12u
R2 = 6-Cl/5d
R2 = 7-F/5e
12v
12w
a Reactions were performed with 11 (0.2 mmol), 5 (0.24 mmol), 40 mg
4 Å MS and 10 mol% catalyst 3m in 2.0 mL toluene at 70 °C. b Isolated
yield. c Determined by chiral HPLC analysis.
Scheme 3 A one-pot, three-component reaction for synthesis of 4g.
vs. 10). Notably, the reactions with substrates bearing strong
electron-withdrawing groups (–F, –NO2 and –CF3) proceeded
smoothly within 0.5 h and furnished desired products in more
than 90% yields with good to excellent enantioselectivities
(80–95% ees, entries 2, 6–11). In contrast, reactions of sub-
strates 11l–11n bearing –Me, –OMe and –Ph groups afforded
the desired products 12p–12r in lower yields of 61–74% yields
with decreased ees of 79–88% (entries 12–14). In addition,
heteroatoms are tolerated in this catalytic system, as 11o bearing
a furyl group was transformed to the corresponding product
12s in 57% yield with 93% ee (entry 15). Isatylidene malononi-
triles 5b–5e were also investigated for this transformation
under otherwise identical reaction conditions, which afforded
the desired products 12t–12w in 72–90% yields with 74–92%
ee (entries 16–19). The catalytic outcomes implied that the
substituents on the oxindole backbones played important
roles in predominating the reactivity and enantioselectivity.
A gram-scale synthesis of 4p was performed in the presence
of 10 mol% of catalyst 3m, and led to 1.19 g of the desired
product in 95% yield with 6.3 : 1 dr and 92% ee (Scheme 2).
After recrystallization from dichloromethane and petroleum
ether, optically active 4p (98% ee, >99 : 1 dr) was obtained,
0.72 g in 57% yield. Single crystals of 4p were obtained from
dichloromethane and isopropanol, and the configuration of
the two contiguous stereo centers was unambiguously deter-
mined by X-ray diffraction analysis (Fig. 2).19
Fig. 3 Proposed reaction mechanism.
A
one-pot, three-component approach involving isatin
derivative 13, malononitrile 14, and 2 was investigated, which
proceeded smoothly under optimal reaction conditions, and
produced the desired product 4g in 90% yield with 5.9 : 1 dr
and 89% ee (Scheme 3).
A plausible mechanism is proposed as shown in Fig. 3. The
deprotonation of 2-cyclohexylidene malononitrile 2 by bifunc-
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tional organocatalyst 3m generates the nucleophilic anion, chiral column with 2-propanol–hexane as the eluent. Infrared
which may form an ion pair with protonated 3m. At the same spectra were obtained on a Varian-1000 FT-IR spectrometer.
time, isatylidene malononitriles 10 would be concertedly acti- Optical rotations were measured at 589 nm (Na D line) on an
vated by mono- or bis-hydrogen bonding(s) between the Autopol IV automatic polarimeter. X-ray data were recorded on
thiourea moieties and carbonyl groups of oxindole backbones. a Rigaku Mercury CCD/AFC diffractometer. Optical rotations
Michael addition, subsequently, takes place from the Re-face are reported as follows: [α]rDt (c in g per 100 mL, solvent).
attack of 10. The resulting intermediate B undergoes an intra-
General procedure for the preparation of 4g–4s. 20 mg of
molecular nucleophilic addition on the –CN group to form an activated 3 Å molecular sieve powders (3 Å MS) was added to a
imine C, which upon isomerization generates the corres- solution of 10 (0.2 mmol), 2 or 2′ (0.24 mmol), and organocata-
ponding spirocyclic oxindole dienes 4 in a one-pot fashion.
lyst 3m (10 mol%) in anhydrous m-xylene (2 mL). The reaction
mixture was stirred at 50 °C for a suitable reaction time until
complete consumption of 10 (monitored by TLC). The solvent
was evaporated, and the residue was purified by flash column
silica gel chromatography (DCM–EA = 20/1–10/1) to provide
Conclusions
In summary, we have developed an asymmetric domino the corresponding products 4g–4s. Yields and spectral and
Michael-cyclization–tautomerization reaction between isatyli- analytical data for compounds 4g–4s are as follows:
dene malononitriles with α,α-dicyanoalkenes catalyzed by a
1-Acetyl-3′-amino-2-oxo-6′,7′-dihydro-2′H-spiro[indoline-3,1′-
cinchona alkaloid-derived bifunctional thiourea at a relatively naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile (4g): white solid,
high reaction temperature. A series of multi-functionalized 97% yield, 6.7 : 1 dr, 94.0% ee; the enantiomeric excess was
spiro oxindole dienes were synthesized in good to excellent determined by HPLC on a Daicel Chiralpak AD-H with hexane–
yields (up to 97%) with good diastereoselectivities (up to i-PrOH (90 : 10) as the eluent. Flow: 1.0 mL min−1; λ = 254 nm:
7.9 : 1) and good to excellent enantioselectivities (up to 96%). tmajor = 15.196 min; tminor = 13.407 min (major). tmajor
=
In addition, the temperature effect on the reaction outcomes 14.213 min; tminor = 18.1517 min (minor). [α]2D5: +26.0 (c 0.50 in
has also been investigated, which revealed that the desired CH3COCH3). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J = 8.1
product was obtained in racemic form at relatively low temp- Hz, 1H), 7.67 (s, 2H), 7.55 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 7.5 Hz,
erature, whereas high enantioselectivity was observed at rela- 1H), 7.03 (d, J = 9.3 Hz, 1H), 5.98 (s, 1H, major), 5.86 (s, 1H,
tively high temperature. Further interpretation of the minor), 3.05 (d, J = 9.3 Hz, 1H), 2.70 (s, 3H, major), 2.55 (s, 3H,
temperature effect, expansion of the reaction system, as well as minor), 2.19–2.13 (m, 1H), 1.98–1.87 (m, 1H), 1.68–1.61 (m,
biological evaluations of the resulting spiro compounds are 2H), 1.51–1.47 (m, 1H), 0.44 (q, J = 11.4 Hz, 1H). 13C NMR
ongoing in our laboratory.
(75 MHz, DMSO-d6) δ 173.37, 170.15, 141.65, 140.58, 131.30,
126.38, 124.74, 124.56, 121.33, 116.21, 115.37, 110.39, 109.83,
81.67, 55.27, 42.44, 38.06, 26.72, 24.51, 23.44, 20.09; IR (film)
νmax: 3551.2, 3410.0, 3337.3, 3225.1, 2940.6, 2215.5, 1753.8,
1732.2, 1655.9, 1639.8, 1600.9, 1465.8, 1370.5, 1336.1, 1269.9,
1180.4, 1018.0, 881.7, 754.2, 594.6 cm−1; ESI-MS: [M + Na]+ m/z
Experimental section
General information
Unless otherwise noted, all reagents were purchased from = 406.1; HRMS: m/z [M + Na]+ calcd for C22H17N5NaO2:
commercial suppliers and used without further purification. 406.1274; found: 406.1265.
Toluene and m-xylene were freshly distilled from sodium.
1-Acetyl-3′-amino-4-chloro-2-oxo-6′,7′-dihydro-2′H-spiro-
Column chromatography purifications were performed using [indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile
300–400 mesh silica gel. 1H and 13C NMR spectra were (4h): white solid, 93% yield, 3.2 : 1 dr, 93.0% ee. The enantio-
recorded on a Varian Inova-400 spectrometer. The solvent for meric excess was determined by HPLC on a Daicel Chiralpak
NMR is CDCl3 or DMSO-d6, unless otherwise noted. Chemical IA with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1.0 mL
shifts are reported in delta (δ) units in parts per million (ppm) min−1; λ = 254 nm: tmajor = 13.080 min; tminor = 10.221 min
relative to the singlet (0 ppm) for tetramethylsilane (TMS). (major). tmajor = 14.324 min; tminor = 16.994 min (minor). [α]2D5:
Data are reported as follows: chemical shift, multiplicity (s = +190.8 (c 0.50 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
single, d = doublet, t = triplet, m = multiplet, dd = doublet of δ 8.28 (d, J = 8.4 Hz, 1H, minor), 8.23 (d, J = 8.4 Hz, 1H, major),
doublets), coupling constants (Hz), and integration. 13C NMR 7.63 (t, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.46 (s, 2H), 5.86 (s, 1H),
spectra were recorded on 100 MHz or 75 MHz. Chemical shifts 3.86 (d, J = 10.2 Hz, 1H), 2.70 (s, 3H, minor), 2.55 (s, 3H,
are reported in parts per million relative to the central line of major), 2.24–2.16 (m, 1H), 2.11–2.01 (m, 1H), 1.76–1.73 (m,
the multiplet at 77.0 ppm for CDCl3, 39.5 ppm for DMSO. 1H) 1.51–1.40 (m, 2H), 1.02 (q, J = 12.0 Hz, 1H). 13C NMR
Mass spectra were carried out using an Agilent 6120 Quadru- (75 MHz, DMSO-d6) δ 169.27, 169.12, 142.22, 139.10, 132.51,
pole LC/MS system with an ESI resource. High-resolution mass 130.69, 127.74, 124.98, 121.64, 118.40, 115.20, 114.68, 110.70,
spectra (HRMS) for all the compounds were determined on a 109.96, 82.29, 57.47, 41.90, 33.37, 26.08, 24.25, 23.91, 20.53;
Micromass GCT-TOF mass spectrometer with an ESI resource. IR (film) νmax: 3555.9, 3471.8, 3414.9, 3230.5, 2953.3, 2217.5,
High performance liquid chromatography (HPLC) was per- 1767.6, 1721.3, 1638.5, 1615.9, 1439.5, 1369.7, 1271.8, 1255.6,
formed on an Agilent 1200 Series chromatograph using a 1168.5, 1177.5, 1033.4, 790.5, 619.6, 598.3 cm−1; ESI-MS:
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[M + Na]+ m/z = 440.1; HRMS: m/z [M + Na]+ calcd for 129.48, 124.81, 123.63, 123.50, 122.74, 117.44, 114.55, 109.40,
C22H16ClN5NaO2: 440.0885; found: 440.0866. 109.09, 80.89, 54.52, 41.64, 37.38, 26.08, 23.89, 22.79, 19.43; IR
1-Acetyl-3′-amino-4-bromo-2-oxo-6′,7′-dihydro-2′H-spiro- (film) νmax: 3550.4, 3423.9, 3361.5, 2939.6, 2215.2, 1762.7,
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 1728.6, 1639.6, 1600.9, 1470.3, 1372.5, 1321.6, 1293.6, 1200.5,
(4i): white solid, 53% yield, 4.2 : 1 dr, 86% ee. The enantio- 1176.7, 1020.6, 834.5, 613.1 cm−1; ESI-MS: [M + Na]+ m/z =
meric excess was determined by HPLC on a Daicel Chiralpak 440.1; HRMS: m/z [M + Na]+ calcd for C22H16ClN5NaO2:
IA with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1.0 mL 440.0885; found: 440.0873.
min−1; λ = 254 nm: tmajor = 14.314 min; tminor = 11.090 min
1-Acetyl-3′-amino-5-bromo-2-oxo-6′,7′-dihydro-2′H-spiro-
(major). tmajor = 15.972 min; tminor = 17.647 min (minor). [α]2D5: [indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile
+170.2 (c 0.50 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6) (4l): white solid, 93% yield, 6.1 : 1 dr, 94% ee. The enantio-
δ 8.32 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), meric excess was determined by HPLC on a Daicel Chiralpak
7.42 (s, 2H), 5.82 (s, 1H), 3.98–3.94 (m, 1H), 2.67 (s, 3H, AD-H with hexane–i-PrOH (95 : 5) as the eluent. Flow: 1 mL
minor), 2.49 (s, 3H, major), 2.23–1.91 (m, 2H), 1.77–1.40 (m, min−1; λ = 254 nm: tmajor = 29.007 min; tminor = 35.805 min
3H), 0.98 (q, J = 12.3 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) (major). tmajor = 30.981 min; tminor = 26.179 min (minor). [α]2D5:
δ 169.29, 169.23, 142.60, 139.10, 132.53, 131.47, 124.91, 121.53, −10.8 (c 0.50 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
119.77, 119.07, 115.18, 115.12, 110.80, 109.99, 82.28, 57.35, δ 8.13 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.68 (s, 2H),
41.97, 33.17, 26.15, 24.26, 23.93, 20.58; IR (film) νmax: 3559.9, 6.96 (s, 1H), 5.94 (s, 1H, major), 5.78 (s, 1H, minor), 2.98 (d, J =
3461.3, 3417.9, 3210.5, 2207.5, 1777.6, 1731.6, 1639.7, 1625.1, 8.1 Hz, 1H), 2.62 (s, 3H, major), 2.46 (s, 3H, minor), 2.12–2.06
1432.5, 1359.2, 1261.8, 1245.4, 1162.3, 1174.9, 1032.4, 779.5, (m, 1H), 1.99–1.80 (m, 1H), 1.59–1.54 (m, 2H), 1.42 (s, 1H),
612.6 cm−1; ESI-MS: [M + Na]+ m/z = 484.0; HRMS: m/z [M + 0.40 (q, J = 11.4 Hz, 1H). 13C NMR (75 MHz, DMSO-d6)
Na]+ calcd for C22H16BrN5NaO2: 484.0380; found: 484.0375.
1-Acetyl-3′-amino-5-fluoro-2-oxo-6′,7′-dihydro-2′H-spiro- 123.39, 118.12, 117.88, 114.90, 109.77, 109.47, 81.26, 54.82,
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 42.05, 37.78, 26.47, 24.28, 23.17, 19.81; IR (film) νmax
δ 172.27, 169.84, 141.21, 139.78, 134.12, 126.71, 125.15, 124.03,
:
(4j): white solid, 92% yield, 6.7 : 1 dr, 96.0% ee. The enantio- 3550.9, 3416.1, 3229.6, 2938.7, 2213.7, 1760.6, 1728.9,
meric excess was determined by HPLC on a Daicel Chiralcel 1638.4, 1617.8, 1467.3, 1371.7, 1294.4, 1258.5, 1175.8, 1020.2,
OD-H with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1.0 mL 827.5, 607.9 cm−1; ESI-MS: [M + Na]+ m/z = 484.0; HRMS: m/z
min−1; λ = 254 nm: tmajor = 18.765 min; tminor = 9.889 min [M
(major). tmajor = 13.112 min; tminor = 10.731 min (minor). [α]2D5: 484.0380.
+29.2 (c 0.50 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
(1-Acetyl-3′-amino-5-nitro-2-oxo-6′,7′-dihydro-2′H-spiro-
+
Na]+ calcd for C22H16BrN5NaO2: 484.0366; found:
δ 8.29 (q, J = 5.2 Hz, 1H), 7.73 (s, 2H), 7.48–7.42 (m, 1H), 6.74 [indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile
(dd, J = 8.4, 2.4 Hz, 1H), 6.01 (s, 1H, major), 5.86 (s, 1H, (4m): white solid, 66% yield, 6.4 : 1 dr, 94% ee. The enantio-
minor), 3.06 (d, J = 4.2 Hz, 1H), 2.70 (s, 3H, major), 2.55 (s, 3H, meric excess was determined by HPLC on a Daicel Chiralpak
minor), 2.20–2.13 (m, 1H), 1.99–1.92 (m, 1H), 1.70–1.62 (m, AD-H with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1 mL
2H), 1.57–1.48 (m, 1H), 0.46 (q, J = 12.0 Hz, 1H). 13C NMR min−1; λ = 254 nm: tmajor = 17.141 min; tminor = 23.685 min
1
(75 MHz, DMSO-d6) δ 172.26, 169.40, 158.81 (d, JC,F = 242 (major). tmajor = 31.506 min; tminor = 21.701 min (minor). [α]2D5:
3
Hz), 140.81, 136.51, 124.80, 123.60, 122.56 (d, JC,F = 8 Hz), −4.6 (c 0.25 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
2
2
117.64, 117.43 (d, JC,F = 12 Hz), 114.61, 111.25 (d, JC,F = 26 δ 8.51 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 7.81 (s, 2H), 7.77 (d, J =
Hz), 109.47, 109.08, 80.93, 54.61, 41.63, 37.37, 26.03, 23.89, 2.1 Hz, 1H), 6.06 (s, 1H, major), 5.89 (s, 1H, minor), 3.12 (d, J =
22.79, 19.44; IR (film) νmax: 3424.7, 3349.5, 3226.7, 2939.5, 10.5 Hz, 1H), 2.74 (s, 3H, major), 2.58 (s, 3H, minor), 2.24–2.13
2216.2, 1760.7, 1722.3, 1642.3, 1479.0, 1372.6, 1291.1, 1256.3, (m, 1H), 1.98–1.90 (m, 1H), 1.73–1.49 (m, 3H), 0.47 (q, J = 11.4
1174.3, 1021.3, 837.9, 587.3 cm−1; ESI-MS: [M + Na]+ m/z = Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 172.02, 169.61,
424.1; HRMS: m/z [M + H]+ calcd for C22H17FN5O2: 402.1366; 145.07, 144.18, 140.66, 127.23, 125.32, 123.38, 121.83, 119.15,
found: 402.1358.
116.41, 114.46, 109.23, 109.00, 80.84, 54.33, 41.54, 37.44,
1-Acetyl-3′-amino-5-chloro-2-oxo-6′,7′-dihydro-2′H-spiro- 26.19, 23.86, 22.71, 19.39; IR (film) νmax: 3557.5, 3467.4,
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 3414.2, 3222.6, 2939.6, 2214.9, 1765.9, 1737.7, 1651.0, 1617.4,
(4k): white solid, 94% yield, 5.7 : 1 dr, 91% ee. The enantio- 1531.5, 1470.4, 1344.1, 1288.8, 1171.9, 1020.8, 849.6, 758.2,
meric excess was determined by HPLC on a Daicel Chiralpak 613.5 cm−1; ESI-MS: [M + Na]+ m/z = 451.1; HRMS: m/z
AD-H with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1 mL [M + Na]+ calcd for C22H16N6NaO4: 451.1125; found: 451.1111.
min−1; λ = 254 nm: tmajor = 11.493 min; tminor = 13.122 min
1-Acetyl-3′-amino-5-methyl-2-oxo-6′,7′-dihydro-2′H-spiro-
(major). tmajor = 12.114 min; tminor = 10.608 min (minor). [α]2D5: [indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile
−4.8 (c 0.50 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6) (4n): white solid, 92% yield, 6.1 : 1 dr, 91% ee. The enantio-
δ 8.29 (d, J = 8.7 Hz, 1H), 7.76 (s, 2H), 7.68 (d, J = 8.4 Hz, 1H), meric excess was determined by HPLC on a Daicel Chiralpak
6.91 (s, 1H), 6.02 (s, 1H, major), 5.80 (s, 1H, minor), 3.06 (d, J = AD-H with hexane–i-PrOH (90 : 10) as the eluent. Flow: 0.8 mL
8.1 Hz, 1H), 2.70 (s, 3H, major), 2.53 (s, 3H, minor), 2.20–1.98 min−1; λ = 254 nm: tmajor = 14.045 min; tminor = 16.056 min
(m, 2H), 1.71–1.51 (m, 3H), 0.45 (q, J = 11.4 Hz, 1H). 13C NMR (major). tmajor = 14.782 min; tminor = 13.431 min (minor). [α]2D5:
(75 MHz, DMSO-d6) δ 171.98, 169.46, 140.82, 139.00, 130.86, +49.8 (c 0.5 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
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δ 8.15 (d, J = 8.4 Hz, 1H), 7.66 (s, 2H), 7.38 (d, J = 8.1 Hz, 1H), (4q): white solid, 95% yield, 6.2 : 1 dr, 91% ee. The enantio-
6.79 (s, 1H), 5.99 (s, 1H, major), 5.86 (s, 1H, minor), 3.04 (d, J = meric excess was determined by HPLC on a Daicel Chiralpak
9.0 Hz, 1H), 2.69 (s, 3H, major), 2.65 (s, 3H, minor), 2.41 (s, AD-H with hexane–i-PrOH (90 : 10) as the eluent. Flow: 1 mL
3H, minor), 2.30 (s, 3H, major), 2.20–2.14 (m, 1H), 1.99–1.92 min−1; λ = 254 nm: tmajor = 10.897 min; tminor = 9.276 min
(m, 1H), 1.67–1.54 (m, 2H), 1.56–1.51 (m, 1H), 0.47 (q, J = 11.4 (major). tmajor = 15.524 min; tminor = 28.433 min (minor). [α]2D5:
Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 172.82, 169.38, +45.6 (c 0.25 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6)
141.04, 137.77, 134.79, 131.11, 124.14, 124.06, 120.78, 115.47, δ 8.39 (s, 1H), 7.70 (s, 2H), 7.62 (d, J = 7.2 Hz, 1H), 6.97 (d, J =
114.76, 109.81, 109.26, 81.08, 54.69, 41.86, 37.46, 26.04, 23.88, 8.1 Hz, 1H), 6.00 (s, 1H, major), 5.86 (s, 1H, minor), 3.05 (d, J =
22.81, 20.50, 19.50; IR (film) νmax: 3550.9, 3431.3, 3358.9, 9.0 Hz, 1H), 2.70 (s, 3H, major), 2.54 (s, 3H, minor), 2.19–2.08
2937.0, 2213.0, 1759.9, 1718.5, 1640.8, 1597.6, 1485.2, 1372.8, (m, 1H), 1.98–1.94 (m, 1H), 1.69–1.61 (m, 2H), 1.54–1.47 (m,
1325.8, 1308.3, 1266.2, 1194.4, 1020.3, 828.4, 631.1, 1H), 0.46 (q, J = 11.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6)
586.3 cm−1; ESI-MS: [M + Na]+ m/z = 420.1; HRMS: m/z [M + δ 172.17, 169.63, 141.05, 140.80, 128.67, 125.83, 124.55,
Na]+ calcd for C23H19N5NaO2: 420.1431; found: 420.1421.
1-Acetyl-3′-amino-5-methoxy-2-oxo-6′,7′-dihydro-2′H-spiro- 54.58, 41.55, 37.32, 26.07, 23.89, 22.81, 19.44; IR (film) νmax
123.77, 123.56, 120.10, 118.40, 114.69, 109.51, 109.15, 81.02,
:
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 3555.7, 3416.8, 3228.7, 2937.7, 2214.5, 1762.2, 1730.2, 1638.4,
(4o): white solid, 96% yield, 7.1 : 1 dr, 94% ee. The enantio- 1596.5, 1470.9, 1417.4, 1371.5, 1332.9, 1295.9, 1282.0, 1255.8,
meric excess was determined by HPLC on a Daicel Chiralpak 1197.7, 1178.2, 1024.9, 929.0, 879.3, 760.9, 610.5 cm−1
;
AD-H with hexane–i-PrOH (85 : 15) as the eluent. Flow: 1 mL ESI-MS: [M + Na]+ m/z = 484.0; HRMS: m/z [M + Na]+ calcd for
min−1; λ = 254 nm: tmajor = 9.484 min; tminor = 11.625 min C22H16BrN5NaO2: 484.0380; found: 484.0371.
(major). tmajor = 12.416 min; tminor = 10.249 min (minor). [α]2D5:
1-Acetyl-3′-amino-5,6-difluoro-2-oxo-6′,7′-dihydro-2′H-spiro-
−7.8 (c 0.5 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6) [indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile
δ 8.18 (d, J = 8.7 Hz, 1H), 7.68 (s, 2H), 7.13 (d, J = 8.1 Hz, 1H), (4r): white solid, 91% yield, 7.9 : 1 dr, 80% ee. The enantio-
6.50 (s, 1H), 5.97 (s, 1H, major), 5.84 (s, 1H, minor), 3.81 (s, meric excess was determined by HPLC on a Daicel Chiralpak
3H, minor), 3.72 (s, 3H, major), 3.03 (d, J = 7.8 Hz, 1H), 2.66 (s, IA with hexane–i-PrOH (95 : 5) as the eluent. Flow: 1 mL min−1
;
3H), 2.17–2.11 (m, 1H), 1.96 (s, 1H), 1.62–1.46 (m, 3H), 0.46 (q, λ = 254 nm: tmajor = 12.455 min; tminor = 13.528 min (major).
J = 11.1 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 172.65, tmajor = 15.896 min; tminor = 14.696 min (minor). [α]2D5: +18.8
169.20, 156.30, 141.07, 133.24, 124.27, 124.05, 122.00, 116.73, (c 0.5 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6) δ 8.24–8.18
114.64, 113.81, 111.03, 109.70, 109.20, 80.92, 54.78, 54.66, (m, 1H), 7.67 (s, 2H, major), 7.43 (s, 2H, minor), 6.92 (t, J = 9.3
41.82, 37.43, 25.94, 23.91, 22.82, 19.49; IR (film) νmax: 3430.1, Hz, 1H), 5.98 (s, 1H, major), 5.82 (s, 1H, minor), 3.01 (d, J = 8.7
2937.9, 2213.8, 1760.5, 1703.6, 1639.9, 1595.4, 1486.3, 1373.6, Hz, 1H), 2.65 (s, 3H, major), 2.45 (s, 3H, minor), 2.15–2.09 (m,
1295.1, 1271.9, 1183.8, 1015.6, 834.9, 603.9 cm−1; ESI-MS: [M + 1H), 1.93–1.87 (m, 1H), 1.61–1.57 (m, 2H), 1.45 (s, 1H), 0.46 (q,
Na]+ m/z
C23H19N5NaO3: 436.1380; found: 436.1369.
=
436.1; HRMS: m/z [M
+
Na]+ calcd for J = 11.7 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 171.85,
169.37, 151.54, 148.27, 148.07, 145.01, 144.84, 140.56, 138.88,
1-Acetyl-3′-amino-6-chloro-2-oxo-6′,7′-dihydro-2′H-spiro- 136.80, 136.69, 125.08, 124.76, 123.34, 117.18, 114.58, 113.57,
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 113.29, 109.35, 109.02, 106.42, 106.09, 80.96, 54.45, 41.58,
(4p): white solid, 94% yield, 7.2 : 1 dr, 92% ee. The enantio- 37.32, 25.94, 23.88, 22.70, 19.40. IR (film) νmax: 3556.8, 3476.9,
meric excess was determined by HPLC on a Daicel Chiralpak 3415.9, 3353.3, 3230.6, 2938.0, 2217.9, 1760.8, 1728.0, 1638.1,
AD-H with hexane–i-PrOH (85 : 15) as the eluent. Flow: 1 mL 1619.7, 1494.8, 1446.5, 1376.6, 1275.6, 1220.1, 1167.2, 1012.1,
min−1; λ = 254 nm: tmajor = 6.969 min; tminor = 6.026 min 877.0, 792.6, 623.2 cm−1; ESI-MS: [M + Na]+ m/z = 442.1;
(major). tmajor = 9.379 min; tminor = 15.758 min (minor). [α]2D5: HRMS: m/z [M + Na]+ calcd for C22H15F2N5NaO2: 442.1086;
+25.6 (c 0.5 in CH3COCH3). 1H NMR (300 MHz, DMSO-d6) found: 442.1093.
δ 8.26 (s, 1H), 7.71 (s, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.04 (d, J =
1′-Acetyl-6-amino-2′-oxo-3,3a-dihydrospiro[indene-4,3′-indo-
7.5 Hz, 1H), 6.00 (s, 1H, major), 5.88 (s, 1H, minor), 3.06 (d, J = line]-5,5,7(2H)-tricarbonitrile (4s): white solid, 90% yield,
7.2 Hz, 1H), 2.71 (s, 3H, major), 2.56 (s, 3H, minor), 2.20–2.14 2.0 : 1 dr, 75% ee. The enantiomeric excess was determined by
(m, 1H), 1.99–1.95 (m, 1H), 1.67–1.51 (m, 3H), 0.46 (q, J = 11.1 HPLC on a Daicel Chiralpak IA with hexane–i-PrOH (90 : 10) as
Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 172.35, 169.73, the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor = 12.268 min;
141.10, 140.91, 135.10, 125.86, 125.69, 124.65, 123.88, 119.80, tminor = 11.104 min (major). tmajor = 15.394 min; tminor
=
115.77, 114.79, 109.63, 109.25, 81.13, 54.64, 41.75, 37.47, 13.979 min (minor). [α]2D5: −37.6 (c 0.5 in CH3COCH3). 1H NMR
26.17, 24.00, 22.92, 19.55; IR (film) νmax: 3424.6, 3359.2, (300 MHz, DMSO-d6) δ 8.22 (t, J = 8.1 Hz, 1H), 7.96 (s, 2H,
3223.7, 2939.1, 2214.1, 1761.3, 1728.9, 1640.7, 1600.6, 1472.2, major), 7.76 (s, 2H, minor), 7.62–7.44 (m, 1H), 7.34 (t, J = 7.5
1423.0, 1372.1, 1333.9, 1295.5, 1282.2, 1258.2, 1177.9, 934.9, Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H) 5.70 (s, 1H, major), 5.58 (s,
880.5, 615.7 cm−1; ESI-MS: [M + Na]+ m/z = 440.1; HRMS: m/z 1H, minor), 3.70–3.52 (m, 1H), 2.67 (s, 3H, major), 2.54 (s, 3H,
[M
440.0865.
+
Na]+ calcd for C22H16ClN5NaO2: 440.0885; found: minor), 2.34–2.12 (m, 2H), 1.96–1.87 (m, 1H, major), 1.61–1.58
(m, 1H, minor), 1.21–1.11 (m, 1H, minor), 0.69–0.62 (m, 1H,
1-Acetyl-3′-amino-6-bromo-2-oxo-6′,7′-dihydro-2′H-spiro- major). 13C NMR (75 MHz, DMSO-d6) δ 172.45, 170.76, 169.61,
[indoline-3,1′-naphthalene]-2′,2′,4′(8′H,8a′H)-tricarbonitrile 169.44, 143.52, 142.49, 140.07, 139.52, 131.69, 130.75, 130.66,
4380 | Org. Biomol. Chem., 2014, 12, 4372–4385
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125.78, 125.49, 124.08, 123.97, 123.29, 122.76, 120.97, 120.37, DMSO-d6) δ 8.33 (s, 2H), 7.55–7.43 (m, 4H), 7.39 (d, J = 8.4 Hz,
115.64, 115.10, 114.61, 110.46, 109.86, 109.65, 109.25, 77.45, 2H), 7.25–7.17 (m, 2H), 5.58 (s, 1H), 3.24 (s, 3H). 13C NMR
76.60, 54.37, 53.87, 45.98, 43.02, 42.37, 30.53, 30.03, 26.03, (75 MHz, DMSO-d6) δ 171.48, 148.56, 144.06, 138.36, 135.87,
25.90, 24.63; IR (film) νmax: 3543.4, 3472.1, 3418.1, 3221.4, 134.07, 131.86, 129.62, 129.00, 124.61, 124.44, 124.30, 116.73,
2938.4, 2848.4, 2215.2, 1756.2, 1725.6, 1644.6, 1586.9, 1465.9, 112.31, 110.81, 110.45, 76.67, 54.26, 43.97, 27.23; IR (film)
1371.2, 1312.0, 1268.6, 1178.8, 1018.1, 755.7, 593.7 cm−1
ESI-MS: [M + Na]+ m/z = 392.1; HRMS: m/z [M + Na]+ calcd for 1645.9, 1609.1, 1571.9, 1489.5, 1470.1, 1374.9, 1349.4, 1095.5,
;
νmax: 3477.5, 3433.9, 3311.4, 3222.4, 3203.0, 2205.1, 1713.8,
C21H15N5NaO2: 392.1118; found: 392.1119.
1014.8, 921.5, 892.6, 835.5, 792.8, 753.7, 626.2 cm−1; ESI-MS:
General procedure for the preparation of 12b, 12f– [M + Na]+ m/z = 434.1; HRMS: m/z [M + Na]+ calcd for
12w. 20 mg of activated 4 Å molecular sieve powders (4 Å MS) C23H14ClN5NaO: 434.0779; found: 434.0769.
was added to a solution of 5 (0.2 mmol), 11 (0.24 mmol), and
5-Amino-3-(4-bromophenyl)-1′-methyl-2′-oxospiro[cyclo-
the organocatalyst 3m (10 mol%) in anhydrous toluene (2 mL). hexa-[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12h): brown
The reaction mixture was stirred at 70 °C for 30 min. The solid, 79% yield, 82% ee. The enantiomeric excess was deter-
solvent was evaporated, and the residue was purified by flash mined by HPLC on a Daicel Chiralpak AD-H with hexane–
column silica gel chromatography (DCM–EA = 20/1–10/1) to i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm:
provide the corresponding products 12b, 12f–12w. Yields and tmajor = 14.490 min; tminor = 18.062 min. 1H NMR (300 MHz,
spectral and analytical data for compounds 12b, 12f–12w are DMSO-d6) δ 8.34 (s, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.55–7.45 (m,
as follows:
2H), 7.32 (d, J = 7.8 Hz, 2H), 7.24–7.17 (m, 2H), 5.58 (s, 1H),
5-Amino-1′-methyl-2′-oxo-3-phenylspiro[cyclohexa[2,4]diene- 3.29 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 171.46, 148.58,
1,3′-indoline]-4,6,6-tricarbonitrile (12b): brown solid, 87% 144.05, 138.47, 136.24, 131.92, 129.87, 124.60, 124.30, 122.72,
yield, 89% ee. The enantiomeric excess was determined by 116.74, 112.25, 110.81, 110.42, 76.63, 54.28, 43.97, 27.24; IR
HPLC on
a
Daicel Chiralpak AD-H with hexane–i-PrOH (film) νmax: 3557.1, 3480.8, 3414.6, 3312.1, 3223.2, 3203.8,
2205.4, 1714.0, 1645.6, 1610.5, 1573.0, 1488.6, 1470.4, 1373.6,
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
10.019 min; tminor = 14.573 min. 1H NMR (300 MHz, DMSO-d6) 1348.6, 1074.7, 1011.1, 921.2, 833.6, 792.7, 754.0, 621.9 cm−1
;
δ 8.30 (s, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.47–7.36 (m, 6H), ESI-MS: [M + Na]+ m/z = 478.0; HRMS: m/z [M + Na]+ calcd for
7.25–7.17 (m, 2H), 5.54 (s, 1H), 3.24 (s, 3H). 13C NMR (75 MHz, C23H14BrN5NaO: 478.0274; found: 478.0276.
DMSO-d6) δ 171.62, 148.47, 144.05, 139.47, 137.02, 131.81,
5-Amino-3-(4-iodophenyl)-1′-methyl-2′-oxospiro[cyclohexa-
129.42, 128.94, 127.70, 124.73, 124.27, 116.86, 111.81, 110.89, [2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12i): brown solid,
110.43, 77.09, 54.27, 44.04, 27.23; IR (film) νmax: 3551.5, 72% yield, 81% ee. The enantiomeric excess was determined
3481.0, 3432.7, 3303.5, 3220.9, 2204.6, 1709.8, 1638.6, 1615.9, by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH
1564.5, 1470.5, 1375.7, 1351.7, 756.6, 690.9, 623.9, 541.4 cm−1
;
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
ESI-MS: [M + Na]+ m/z = 400.1; HRMS: m/z [M + H]+ calcd for 15.617 min; tminor = 20.182 min. 1H NMR (300 MHz, DMSO-d6)
C23H16N5O: 378.1349; found: 378.1340.
δ 8.32 (s, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.52–7.42 (m, 2H),
7.22–7.14 (m, 4H), 5.54 (s, 1H), 3.22 (s, 3H). 13C NMR (75 MHz,
5-Amino-3-(4-fluorophenyl)-1′-methyl-2′-oxospiro[cyclohexa-
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12f): brown solid, DMSO-d6) δ 171.46, 148.58, 144.04, 138.68, 137.76, 136.56,
91% yield, 95% ee. The enantiomeric excess was determined 131.85, 129.84, 124.60, 124.30, 116.75, 112.12, 110.82, 110.42,
by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH 95.90, 76.60, 54.28, 43.97, 27.25; IR (film) νmax: 3557.2,
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
3480.7, 3411.9, 3233.1, 2205.1, 1722.2, 1638.2, 1616.4, 1573.7,
11.517 min; tminor = 15.334 min. 1H NMR (300 MHz, DMSO-d6) 1487.6, 1471.0, 1372.9, 1349.8, 1259.6, 1091.9, 1005.9, 927.0,
δ 8.33 (s, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.47–7.40 (m, 3H), 824.0, 751.5, 616.1 cm−1; ESI-MS: [M + Na]+ m/z = 526.0;
7.28–7.17 (m, 4H), 5.55 (s, 1H), 3.24 (s, 3H). 13C NMR (75 MHz, HRMS: m/z [M + Na]+ calcd for C23H14IN5NaO: 526.0135;
1
DMSO) δ 171.56, 162.83 (d, JC,F = 259 Hz), 148.49, 144.04, found: 526.0115.
3
138.45, 133.46, 131.83, 129.97 (d, JC,F = 8 Hz), 128.63, 124.68,
5-Amino-1′-methyl-3-(4-nitrophenyl)-2′-oxospiro[cyclohexa-
2
124.30, 116.82, 115.90 (d, JC,F = 20 Hz), 111.86, 110.85, [2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12j): brown solid,
110.43, 76.91, 54.25, 44.00, 27.23; IR (film) νmax: 3481.4, 93% yield, 84% ee. The enantiomeric excess was determined
3431.7, 3412.5, 3303.8, 3216.2, 2204.6, 1712.3, 1642.9, 1618.9, by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH
1609.7, 1565.0, 1511.9, 1470.7, 1375.9, 1351.4, 1239.9, 1155.7, (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
893.0, 841.7, 790.5, 756.3, 684.5, 633.6, 496.2 cm−1; ESI-MS: 26.216 min; tminor = 36.952 min. 1H NMR (300 MHz, DMSO-d6)
[M + Na]+ m/z = 418.1; HRMS: m/z [M + Na]+ calcd for δ 8.48 (s, 2H), 8.27 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H),
C23H14FN5NaO: 418.1075; found: 418.1059.
5-Amino-3-(4-chlorophenyl)-1′-methyl-2′-oxospiro[cyclohexa- 13C NMR (75 MHz, DMSO-d6) δ 171.29, 148.85, 147.97, 144.10,
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12g): brown 143.39, 137.90, 131.98, 129.32, 129.21, 128.62, 125.73, 124.36,
7.56–7.47 (m, 2H), 7.26–7.13 (m, 2H), 5.77 (s, 1H), 3.25 (s, 3H).
solid, 81% yield, 85% ee. The enantiomeric excess was deter- 124.18, 116.58, 114.24, 110.70, 110.50, 76.02, 54.31, 43.89,
mined by HPLC on a Daicel Chiralpak AD-H with hexane– 27.27; IR (film) νmax: 3480.6, 3413.5, 3236.9, 2205.1, 1722.9,
i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: 1639.7, 1615.4, 1573.5, 1519.6, 1471.0, 1372.5, 1346.9, 1260.5,
tmajor = 13.614 min; tminor = 17.267 min. 1H NMR (300 MHz, 1092.3, 894.6, 851.8, 753.2, 697.5, 618.6 cm−1
; ESI-MS:
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[M + Na]+ m/z = 445.1; HRMS: m/z [M + Na]+ calcd for by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH
C23H14N6O3: 445.1020; found: 445.1030.
(80 : 20) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
5-Amino-1′-methyl-2′-oxo-3-(4-(trifluoromethyl)phenyl)- 19.460 min; tminor = 26.822 min. 1H NMR (300 MHz, DMSO-d6)
spiro-[cyclohexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile δ 8.24 (s, 2H), 7.53 (t, J = 5.7 Hz, 1H), 7.46 (d, J = 5.1 Hz, 2H),
(12k): brown solid, 87% yield, 80% ee. The enantiomeric 7.31–7.21 (m, 5H), 5.55 (s, 1H), 3.24 (s, 3H). 13C NMR (75 MHz,
1
excess was determined by HPLC on a Daicel Chiralpak AD-H DMSO-d6) δ 171.44, 159.53 (d, JC,F = 245 Hz), 146.98, 144.07,
with hexane–i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1
;
134.69, 131.90, 131.66 (d, JC,F = 8 Hz), 130.89, 125.22, 125.08
3
1
2
2
λ = 254 nm: tmajor = 11.832 min; tminor = 16.842 min. H NMR (d, JC,F = 15 Hz), 124.40 (d, JC,F = 17 Hz), 124.33, 116.42
(400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.80 (d, J = 8.4 Hz, 2H), (d, JC,F = 8 Hz), 116.08, 113.77, 110.78, 110.47, 77.99, 54.17,
3
7.60 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.27–7.19 (m, 43.85, 27.27. IR (film) νmax: 3478.2, 3434.2, 3308.0, 3224.0,
2H), 7.03–6.94 (m, 1H), 5.69 (s, 1H), 3.25 (s, 3H). 13C NMR 2207.3, 1711.7, 1640.2, 1615.1, 1568.1, 1488.4, 1470.2, 1376.7,
(75 MHz, DMSO-d6) δ 13C NMR (75 MHz, DMSO-d6) δ 171.39, 1352.0, 1221.5, 1086.0, 893.6, 753.8, 686.2, 620.5 cm−1
;
148.74, 144.09, 141.05, 138.33, 131.93, 129.44, 129.33, 128.71, ESI-MS: [M + Na]+ m/z = 418.1; HRMS: m/z [M + Na]+ calcd for
128.63, 125.96, 125.90, 125.73, 124.49, 124.33, 116.69, 113.43, C23H14FN5NaO: 418.1075; found: 418.1085.
110.76, 110.47, 107.92, 76.32, 54.28, 43.95, 27.25. IR (film)
5-Amino-3-(3,4-difluorophenyl)-1′-methyl-2′-oxospiro[cyclo-
νmax: 3556.9, 3480.5, 3413.9, 3235.3, 2206.8, 1722.5, 1638.5, hexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12o): brown
1616.5, 1573.9, 1492.6, 1471.6, 1325.1, 1169.9, 1126.5, 1067.6, solid, 92% yield, 95% ee. The enantiomeric excess was deter-
1017.2, 852.1, 753.2, 620.4 cm−1; ESI-MS: [M + Na]+ m/z = mined by HPLC on a Daicel Chiralpak AD-H with hexane–
468.1; HRMS: m/z [M + Na]+ calcd for C24H14F3N5NaO: i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm:
468.1043; found: 468.1030.
tmajor = 10.206 min; tminor = 18.180 min. 1H NMR (400 MHz,
DMSO-d6) δ 8.35 (s, 2H), 7.55–7.44 (m, 4H), 7.25–7.18 (m, 3H),
5-Amino-3-(3-fluorophenyl)-1′-methyl-2′-oxospiro[cyclohexa-
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12l): brown solid, 5.62 (s, 1H), 3.23 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
93% yield, 89% ee. The enantiomeric excess was determined δ 171.41, 148.65, 144.06, 137.54, 134.42, 131.87, 129.31,
by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH 128.61, 124.94, 124.57, 124.39, 124.31, 118.19, 117.98, 117.26,
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
117.04, 116.74, 112.73, 110.74, 110.41, 76.44, 54.07, 43.94,
1
8.777 min; tminor = 19.323 min. H NMR (300 MHz, DMSO-d6) 27.06. IR (film) νmax: 3480.7, 3433.9, 3304.1, 3218.9, 2205.6,
δ 8.34 (s, 2H), 7.53–7.44 (m, 3H), 7.26–7.18 (m, 5H), 5.64 (s, 1713.7, 1641.9, 1610.5, 1565.7, 1520.2, 1470.9, 1433.9, 1376.3,
1H), 3.24 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 171.46, 1350.9, 1303.2, 1276.4, 1087.3, 900.0, 830.1, 770.1, 756.7,
1
3
162.37 (d, JC,F = 243 Hz), 148.63, 144.07, 139.26 (d, JC,F
=
685.9, 639.5 cm−1; ESI-MS: [M + Na]+ m/z = 436.1; HRMS: m/z
Na]+ calcd for C23H13F2N5NaO: 436.0980; found:
123.97, 116.75, 116.27 (d, JC,F = 20 Hz), 114.64 (d, JC,F = 22 436.0985.
Hz), 112.77, 110.80, 110.44, 76.57, 54.24, 43.97, 27.24; IR (film) 5-Amino-1′-methyl-2′-oxo-3-p-tolylspiro[cyclohexa[2,4]diene-
3
8 Hz), 138.26, 131.88, 131.02 (d, JC,F = 8 Hz), 124.58, 124.34, [M
+
2
2
νmax: 3479.7, 3434.3, 3414.1, 3304.8, 3221.8, 2205.3, 1711.0, 1,3′-indoline]-4,6,6-tricarbonitrile (12p): brown solid, 72%
1638.2, 1616.4, 1565.2, 1488.2, 1470.7, 1444.2, 1346.7, 1351.2, yield, 83% ee. The enantiomeric excess was determined by
1265.3, 1086.7, 899.1, 781.9, 755.5, 694.1, 630.6 cm−1; ESI-MS: HPLC on
a
Daicel Chiralpak AD-H with hexane–i-PrOH
[M + Na]+ m/z = 418.1; HRMS: m/z [M + Na]+ calcd for (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
C23H14FN5NaO: 418.1075; found: 418.1086.
12.556 min; tminor = 20.131 min. 1H NMR (300 MHz, DMSO-d6)
=
5-Amino-3-(3-chlorophenyl)-1′-methyl-2′-oxospiro[cyclohexa- δ 8.26 (s, 2H), 7.52–7.43 (m, 2H), 7.30–7.10 (m, 6H), 5.48 (s,
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12m): brown 1H), 3.24 (s, 3H), 2.32 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
solid, 73% yield, 86% ee. The enantiomeric excess was deter- δ 171.66, 148.39, 144.04, 139.37, 138.95, 134.20, 131.78,
mined by HPLC on a Daicel Chiralpak AD-H with hexane– 129.47, 127.60, 124.83, 124.25, 116.92, 111.13, 110.93, 110.41,
i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: 77.24, 54.25, 44.04, 27.22, 21.23; IR (film) νmax: 3557.2, 3480.7,
tmajor = 8.383 min; tminor = 19.869 min. 1H NMR (300 MHz, 3413.9, 3311.5, 3204.5, 2206.7, 1714.3, 1645.1, 1609.1, 1572.6,
DMSO-d6) δ 8.38 (s, 2H), 7.56–7.42 (m, 5H), 7.35 (d, J = 6.0 Hz, 1488.8, 1470.1, 1373.1, 1349.9, 1084.8, 892.7, 825.5, 789.7,
1H), 7.26–7.18 (m, 2H), 5.66 (s, 1H), 3.25 (s, 3H). 13C NMR 756.4, 684.1, 625.7 cm−1; ESI-MS: [M + Na]+ m/z = 414.1;
(75 MHz, DMSO-d6) δ 171.43, 148.63, 144.07, 139.02, 138.01, HRMS: m/z [M + Na]+ calcd for C24H17N5NaO: 414.1325; found:
133.65, 131.86, 130.85, 129.30, 127.52, 126.50, 124.56, 124.31, 14.1325.
116.71, 112.93, 110.79, 110.42, 76.45, 54.24, 43.93, 27.25; IR
5-Amino-3-(4-methoxyphenyl)-1′-methyl-2′-oxospiro[cyclo-
(film) νmax: 3557.2, 3480.6, 3412.9, 3232.6, 2208.2, 1714.9, hexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12q): brown
1636.9, 1614.8, 1557.9, 1548.8, 1489.2, 1470.9, 1378.0, 1344.8, solid, 74% yield, 88% ee. The enantiomeric excess was deter-
1260.0, 1125.9, 1095.4, 1039.9, 788.2, 750.3, 692.3, 617.3 cm−1
;
mined by HPLC on a Daicel Chiralpak AD-H with hexane–
ESI-MS: [M + Na]+ m/z = 434.1; HRMS: m/z [M + Na]+ calcd for i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm:
C23H14ClN5NaO: 434.0779; found: 434.0765.
tmajor = 17.709 min; tminor = 21.768 min. 1H NMR (300 MHz,
DMSO-d6) δ 8.24 (s, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.44 (d, J =
5-Amino-3-(2-fluorophenyl)-1′-methyl-2′-oxospiro[cyclohexa-
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12n): brown solid, 7.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.24–7.17 (m, 2H), 6.97 (d,
92% yield, 83% ee. The enantiomeric excess was determined J = 8.4 Hz, 2H), 5.45 (s, 1H), 3.77 (s, 3H), 2.24 (s, 3H). 13C NMR
4382 | Org. Biomol. Chem., 2014, 12, 4372–4385
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(75 MHz, DMSO-d6) δ 171.72, 160.24, 148.37, 144.02, 139.01, = 436.1; HRMS: m/z [M + Na]+ calcd for C23H13F2N5NaO:
131.75, 129.29, 129.07, 124.90, 124.25, 117.00, 114.28, 110.95, 436.0980; found: 436.0993.
110.41, 77.32, 55.65, 54.25, 44.08, 27.20; IR (film) νmax: 3551.3,
5-Amino-3-(4-fluorophenyl)-5′-methoxy-1′-methyl-2′-oxo-
3485.7, 3413.2, 3306.6, 3197.7, 2206.7, 1713.6, 1645.1, 1614.8, spiro[cyclohexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile
1567.8, 1515.9, 1469.9, 1375.5, 1349.9, 1259.8, 1035.9, 892.6, (12u): brown solid, 72% yield, 74% ee. The enantiomeric
791.1, 772.7, 685.3, 623.3 cm−1; ESI-MS: [M + Na]+ m/z = 430.1; excess was determined by HPLC on a Daicel Chiralpak AD-H
HRMS: m/z [M + Na]+ calcd for C24H17N5NaO2: 430.1274; with hexane–i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ
found: 430.1267.
= 254 nm: tmajor = 11.702 min; tminor = 19.917 min. 1H NMR
5-Amino-3-(biphenyl-4-yl)-1′-methyl-2′-oxospiro[cyclo-hexa- (300 MHz, DMSO-d6) δ 8.32 (s, 2H), 7.45–7.41 (m, 2H), 7.25 (t,
[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12r): brown solid, J = 8.7 Hz, 2H), 7.19–7.10 (m, 2H), 7.02 (s, 1H), 5.54 (s, 1H), 3.74
61% yield, 79% ee. The enantiomeric excess was determined (s, 3H), 3.21 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 171.09,
1
by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH 162.90 (d, JC,F = 245 Hz), 156.38, 148.33, 138.61, 137.34,
3
2
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
133.42, 129.99 (d, JC,F = 8 Hz), 125.80, 116.78, 115.86 (d, JC,F
17.870 min; tminor = 29.426 min. 1H NMR (300 MHz, DMSO-d6) = 22 Hz), 115.62, 111.85, 111.70, 110.97, 110.88, 110.79, 76.92,
δ 8.33 (s, 2H), 7.71 (t, J = 8.4 Hz, 4H), 7.56–7.35 (m, 7H), 55.99, 54.47, 44.00, 27.26; IR (film) νmax: 3564.7, 3414.7,
7.26–7.18 (m, 2H), 5.59 (s, 1H), 3.26 (s, 3H). 13C NMR (75 MHz, 3230.9, 2207.8, 1715.0, 1639.5, 1619.3, 1601.4, 1506.7, 1495.5,
DMSO-d6) δ 171.61, 148.59, 144.09, 141.07, 139.70, 139.11, 1384.4, 1367.2, 1289.9, 1232.8, 1161.9, 1032.2, 841.1, 808.1,
136.07, 131.82, 129.44, 128.33, 127.07, 124.78, 124.31, 116.95, 625.9 cm−1; ESI-MS: [M + Na]+ m/z = 448.1; HRMS: m/z [M +
111.84, 110.92, 110.42, 107.91, 77.02, 54.33, 44.10, 27.24; Na]+ calcd for C24H16FN5NaO2: 448.1180; found: 448.1197.
IR (film) νmax: 3415.1, 3230.9, 2204.6, 1722.3, 1639.0, 1613.5,
5-Amino-6′-chloro-3-(4-fluorophenyl)-1′-methyl-2′-oxo-spiro-
(12v):
1573.3, 1488.5, 1470.9, 1372.3, 1348.9, 1259.3, 1091.9, 1006.9, [cyclohexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile
848.4, 758.4, 697.6, 616.8 cm−1; ESI-MS: [M + Na]+ m/z = 476.1; brown solid, 76% yield, 78% ee. The enantiomeric excess was
HRMS: m/z [M + Na]+ calcd for C29H19N5NaO: 476.1482; found: determined by HPLC on a Daicel Chiralpak AD-H with hexane–
476.1466.
i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm:
5-Amino-3-(furan-2-yl)-1′-methyl-2′-oxospiro[cyclohexa-[2,4]- tmajor = 13.826 min; tminor = 26.548 min. 1H NMR (300 MHz,
diene-1,3′-indoline]-4,6,6-tricarbonitrile (12s): brown solid, DMSO-d6) δ 8.33 (s, 2H), 7.45–7.39 (m, 4H), 7.25 (t, J = 8.4 Hz,
57% yield, 93% ee. The enantiomeric excess was determined 3H), 5.54 (s, 1H), 3.25 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
1
by HPLC on a Daicel Chiralpak AD-H with hexane–i-PrOH δ 171.63, 146.90 (d, JC,F = 196 Hz), 138.63, 136.46, 133.35,
(70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: tmajor
=
129.99 (d, JC,F = 8 Hz), 125.75, 123.98, 123.45, 116.68, 115.90
3
13.131 min; tminor = 20.500 min. 1H NMR (300 MHz, DMSO-d6) (d, JC,F = 22 Hz), 111.33, 111.00, 110.71, 110.63, 76.99, 54.02,
δ 8.33 (s, 2H), 7.76 (s, 1H), 7.53 (t, J = 5.4 Hz, 1H), 7.41 (d, J = 43.83, 27.47; IR (film) νmax: 3467.9, 3419.3, 2209.9, 1722.8,
5.4 Hz, 1H), 7.25–7.17 (m, 2H), 6.91 (s, 1H), 6.61 (s, 1H), 5.79 1639.8, 1608.1, 1506.9, 1374.7, 1237.6, 1161.4, 1106.1, 1072.4,
(s, 1H), 3.23 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 171.47, 902.8, 842.3, 815.8, 613.4 cm−1; ESI-MS: [M + Na]+ m/z = 452.1;
148.95, 148.84, 144.47, 144.06, 131.87, 127.86, 124.66, 124.29, HRMS: m/z [M + Na]+ calcd for C23H13ClFN5NaO: 452.0685;
117.01, 112.42, 110.69, 110.48, 110.35, 108.65, 73.75, 53.85, found: 452.0692.
2
43.86, 27.28; IR (film) νmax: 3485.9, 3431.3, 3304.9, 3227.1,
5-Amino-7′-fluoro-3-(4-fluorophenyl)-1′-methyl-2′-oxo-spiro-
2208.3, 1709.3, 1637.9, 1611.7, 1573.4, 1558.5, 1487.5, 1470.7, [cyclohexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12w):
1376.7, 1351.8, 1264.8, 1162.5, 1015.5, 898.9, 750.9, 665.7, brown solid, 72% yield, 76% ee. The enantiomeric excess was
618.4 cm−1; ESI-MS: [M + Na]+ m/z = 390.1; HRMS: m/z [M + determined by HPLC on a Daicel Chiralpak AD-H with hexane–
Na]+ calcd for C21H13N5NaO2: 390.0961; found: 390.0973.
i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm:
5-Amino-5′-fluoro-3-(4-fluorophenyl)-1′-methyl-2′-oxospiro- tmajor = 12.393 min; tminor = 23.977 min. 1H NMR (300 MHz,
[cyclohexa[2,4]diene-1,3′-indoline]-4,6,6-tricarbonitrile (12t): DMSO-d6) δ 8.33 (s, 2H), 7.44–7.39 (m, 3H), 7.33–7.20 (m, 4H),
brown solid, 90% yield, 92% ee. The enantiomeric excess was 5.55 (s, 1H), 3.40 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
determined by HPLC on a Daicel Chiralpak AD-H with hexane– δ 171.31, 148.24, 138.63, 133.37, 130.66, 130.04, 129.93,
i-PrOH (70 : 30) as the eluent. Flow: 1 mL min−1; λ = 254 nm: 127.49, 125.48, 120.68, 119.62, 116.67, 116.05, 115.76, 111.35,
tmajor = 9.558 min; tminor = 16.551 min. 1H NMR (300 MHz, 110.67, 76.96, 54.41, 43.99, 29.52; IR (film) νmax: 3479.9, 3432.5,
DMSO-d6) δ 8.31 (s, 2H), 7.41–7.37 (m, 3H), 7.24–7.18 (m, 4H), 3303.4, 3219.1, 2205.4, 1714.5, 1641.4, 1564.4, 1510.9, 1489.3,
5.50 (s, 1H), 3.20 (s, 3H). 13C NMR (75 MHz, DMSO-d6) 1475.3, 1369.7, 1261.3, 1239.6, 1131.3, 1059.0, 859.9, 840.5, 784.3,
1
1
δ 171.28, 162.88 (d, JC,F = 244 Hz), 159.02 (d, JC,F = 238 Hz), 731.7, 634.9 cm−1; ESI-MS: [M + Na]+ m/z = 436.1; HRMS: m/z
148.20, 140.51, 138.85, 133.38, 130.05 (d, JC,F = 8 Hz), 126.00 [M + Na]+ calcd for C23H13F2N5NaO: 436.0980; found: 436.0997.
3
3
2
(d, JC,F = 9 Hz), 118.33 (d, JC,F = 23 Hz), 116.70, 115.89 (d,
2JC,F = 20 Hz), 112.29 (d, 2JC,F = 26 Hz), 111.62 (d, 3JC,F = 8 Hz),
111.16, 110.72, 110.61, 77.07, 54.44, 43.84, 27.41; IR (film)
νmax: 3556.8, 3471.9, 3440.7, 3414.3, 3308.4, 3223.8, 2205.3,
Acknowledgements
1714.1, 1644.3, 1618.5, 1571.5, 1491.5, 1364.2, 1269.0, 1242.0, We are grateful for financial support of the National Natural
1157.7, 841.9, 818.9, 687.0, 623.5 cm−1; ESI-MS: [M + Na]+ m/z Science Foundation of China (21272166), the Program for New
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