New organocatalytic asymmetric synthesis of highly substituted chiral 2-oxospiro-[indole-3,4'- (1',4'-dihydropyridine)] derivatives

Article abstract of DOI:10.3390/molecules200915807

Herein, we report our preliminary results concerning the first promising asymmetric synthesis of highly functionalized 2-oxospiro-[indole-3,4'-(1',4'-dihydropyridine)] via the reaction of an enamine with isatylidene malononitrile derivatives in the presen

Full text of DOI:10.3390/molecules200915807

Molecules 2015, 20, 15807-15826; doi:10.3390/molecules200915807
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
New Organocatalytic Asymmetric Synthesis of
Highly Substituted Chiral 2-Oxospiro-[indole-3,4′-
(1′,4′-dihydropyridine)] Derivatives
Fernando Auria-Luna †, Eugenia Marqués-López †, Somayeh Mohammadi †, Roghayeh Heiran †
and Raquel P. Herrera *
Laboratorio de Organocatálisis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis
Química y Catálisis Homogénea (ISQCH), CSIC-Universidad de Zaragoza, C/Pedro Cerbuna 12,
E-50009 Zaragoza, Spain; E-Mails: 588861@unizar.es (F.A.-L.); mmaamarq@unizar.es (E.M.-L.);
somayeh_babamohamadi@yahoo.com (S.M.); somaieheiran@gmail.com (R.H.)
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: raquelph@unizar.es;
Tel.: +34-976-761-190.
Academic Editor: Derek J. McPhee
Received: 17 July 2015 / Accepted: 21 August 2015 / Published: 31 August 2015
Abstract: Herein, we report our preliminary results concerning the first promising asymmetric
synthesis of highly functionalized 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)] via the
reaction of an enamine with isatylidene malononitrile derivatives in the presence of a chiral
base organocatalyst. The moderate, but promising, enantioselectivity observed (30%–58%
ee (enantiomeric excess)) opens the door to a new area of research for the asymmetric
construction of these appealing spirooxindole skeletons, whose enantioselective syntheses
are still very limited.
Keywords: chiral base; enamine; isatylidene malononitrile; 1,4-dihydropyridine;
enantioselective; isatin; organocatalysis; spirooxindole; 2-oxospiro-[indole-3,4′-
(1′,4′-dihydropyridine)]

Molecules 2015, 20
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1. Introduction
In the last few years, the development of new synthetic methods leading to spirooxindoles has aroused
remarkable interest [1–6]. This structural motif can be found in natural and non-natural products, and
its relevance is in part due to its challenging architecture, but also because many of these scaffolds
exhibit interesting biological activity (Figure 1) [7–12]. Moreover, the potential of isatins to act both as
an electrophile and as a nucleophile in many reactions and their easy availability have made them
valuable building blocks in organic synthesis, attracting the attention of many scientists [13–15].
Figure 1. Representative structures of biologically-active spirooxindoles.
Moreover, 1,4-dihydropyridine derivatives are a significant class of heterocyclic compounds frequently
found in natural products, and many of them also exhibit pharmacological properties [16–20]. As in
other drugs, the role of the stereochemistry at C-4 can disclose both qualitative and quantitative
differences in the biological activity. Thus, the control of the stereoselectivity in these chiral centers
becomes an inspiring task of research, and therefore, there is growing interest for the development of
enantioselective methods. Additionally, the generation of quaternary carbon centers is a very active
and challenging area of investigation [21–28].
Thus, combining the interest and biological importance of spirooxindoles and 1,4-dihydropyridines
and the search for new analogues with novel synergic properties, together with the increasing concern
for sustainability, which makes essential the continuous search for new efficient catalytic procedures,
encouraged us to explore a new route for the asymmetric synthesis of 2-oxospiro-[indole-3,4′-(1′,4′-
dihydropyridine)] via asymmetric organocatalysis [29–34].
2. Results and Discussion
2.1. Hypothesis of Work
As part of our ongoing research program about the synthesis of new chiral isatin derivatives, we
focused our attention on 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)], in particular on its racemic

Molecules 2015, 20
15809
synthesis reported by Perumal [35] and Yan [36]. Both groups used the same multicomponent strategy
employing Et3N under reflux of EtOH (Scheme 1a). However, it is remarkable that Dabiri and Bazgir’s
group obtained pyrano-fused spirooxindoles [37], instead of dihydropyridine-fused spirooxindoles,
under very similar conditions [38,39].
a) Previous work
Ar
N
ROOC
O
COOR
COOR
NH2
CN
Et3N
ROOC
NH2
Ar
NC
CN
+
+
+
O
EtOH
O
N
H
N
H
Ar
N
Ar
NH
ROOC
ROOC
NC
ROOC
CN
O
ROOC
ROOC
NH
CN
N
ROOC
Ar
CN
N
O
O
N
H
H2
N
N
H
H
b) Our work
EtOOC
Ar
N
H2N
NC
NC
CN
O
COOEt
COOEt
Organocat*
+
*
Ar
EtOOC
N
H
O
N
R'
N
R'
R
3
R
1
2
2-oxospiro-[indole-3,4'-
(1',4'-dihydropyridines)]
Scheme 1. (a) Multicomponent synthesis of racemic 2-oxospiro-[indole-3,4′-(1′,4′-
dihydropyridines)] and the mechanistic hypothesis in previous work; (b) enantioselective
organocatalytic synthesis of enantioenriched 2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridines)]
3 in our work.
The authors invoked a mechanism wherein a basic medium, isatin and malononitrile, condenses
to give an intermediate that reacts with the enamine formed from the acetylenedicarboxylate and
the amine (Scheme 1a). Based on this previous work and our experience with Brønsted bases as
organocatalysts [40–42], we envisioned that a chiral organic base could promote this appealing and
controversial reaction, starting directly from the preformed intermediates, enamines 1 and isatylidene
malononitriles 2, to give enantioenriched spirooxindoles 3 (Scheme 1b).
2.2. Synthesis of Starting Materials: Enamines 1 and Isatylidene Malononitriles 2
For this purpose, we firstly synthesized four different enamines 1a–d in one synthetic step, as
described in Scheme 2 [43,44].

Molecules 2015, 20
15810
Scheme 2. Preparation of the enamines 1a–d.
The synthesis of three differently-protected isatylidene malononitriles 2a–c was also accomplished
(Scheme 3), since the protection of the isatins has been found to be important in the reactivity and
enantioselectivity of different processes [13–15].
Scheme 3. Synthesis of the N-protected 2-(2-oxoindolin-3-ylidene)malononitriles 2a–c.
The syntheses are performed in two steps: first, with the protection of the isatin 6 and, then,
a Knoevenagel condensation with malononitrile, affording very good yields for each step, after
column chromatography.
2.3. Screening
To test the viability of our hypothesis, we studied the efficiency of different organocatalysts I–VIII
(Figure 2) in a model reaction between enamine 1a and isatylidene malononitrile 2a (Table 1).
Figure 2. Model organocatalysts tested (I–VIII).

Molecules 2015, 20
Table 1. Screening of catalysts I–VIII for the synthesis of chiral spirooxindole 3aa.
15811
Entry Cat. a (mol %) 1a (mmol) 2a (mmol) MeCN (mL) t (d) yield (%) b ee c (%) d
1
2
3
4
5
6
7
8
I (10)
II (30)
0.2
0.12
0.12
0.2
0.1
0.06
0.06
0.1
1
0.3
0.3
1
5
5
5
5
5
5
5
5
15
3
Rac. e
4
III (30)
IV (30)
V (30)
16
77
35
38
30
n.r. f
Rac. e
5
0.2
0.1
1
5
VI (30)
VII (30)
VIII (30)
0.2
0.1
1
Rac. e
42
0.2
0.1
1
0.2
0.1
1
n.d. g
a Catalyst; b isolated yields after column chromatography; c enantiomeric excess; d determined by chiral HPLC
e
f
analysis (Daicel Chiralpak IB, Hex:EtOAc 6:4, 1 mL·min−1); racemic mixture; no reaction observed;
g not determined.
As shown in Table 1, although the best reactivity was obtained with quinine (IV) (Entry 4), the most
promising ee value was found with thiourea VII, known as Takemoto’s catalyst [45–50] (Entry 7).
Interestingly, phosphoric acid VIII did not promote the reaction as expected, since the presence of a
Brønsted base is believed to be crucial for the activation of this system, as previously reported [35,36]
(Entry 8).
The influence of the substituents of the aromatic ring in the enamine component 1, over the reactivity
and enantioselectivity of the process, was then considered in its reaction with benzyl-protected
isatylidene malononitrile 2a (Scheme 4).
Scheme 4. Effect of the substituents in the phenyl ring of the enamines 1a–d.

Molecules 2015, 20
15812
The results suggest a clear influence of the electronic effects of the enamine ring 1 in both the reactivity
and the enantioselectivity of the process, although the pattern of correlation is not clear at this point.
Thus, while better reactivity was afforded with enamine 1c (71% yield), the best enantioselectivity was
reached with the dimethoxy substituted enamine 1a (42% ee). In addition, untreatable reaction crude
was observed with enamine 1d.
Moreover, since the protecting group of the isatin scaffold can be relevant in the process, two
additional protecting groups (allyl and ethyl) were tested in the reaction with enamine 1b (Scheme 5).
Scheme 5. Influence of the protecting group on isatylidene malononitrile 2.
Although the enantioselectivity of the process was similar in the three cases, the reactivity was
slightly higher with the firstly used, i.e., benzyl-protected isatylidene malononitrile 2a.
Interestingly, an X-ray diffraction structure of compound 3bb was obtained, and it is shown as
evidence of the high complexity and functionalization of final target products (Figure 3) [51]. This
structure is in agreement with the kind of molecules obtained by groups of Perumal and Yan through
their multicomponent approaches [35,36].
Figure 3. X-ray structure of adduct 3bb.
Taking into account the above-mentioned results, summarized in Figure 4, we continued testing
different key parameters, such as catalyst loading, concentration and solvent, with enamine 1a and

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15813
isatylidene malononitrile 2a, which afford the best value of enantioselectivity in the final product
(42% ee) using 30 mol % of catalyst VII (Table 2).
Figure 4. Summary of the comparative studies of (a) differently-substituted enamine 1 and
(b) differently protected isatylidene malononitrile 2.
Table 2. Additional screening of the reaction.
OMe
COOEt
NC
CN
COOEt
HN
H2N
NC
OMe
COOEt
N
VII
MeO
+
O
Solvent, r.t., 5 days
N
*
COOEt
O
Ph
2a
OMe
1a
N
3aa
Ph
Entry VII (mol %)
Solvent (mL)
MeCN (1)
yield (%) a ee (%) b
1
2
30
20
10
30
30
30
30
30
30
30
30
25
29
55
12
31
13
29
49
48
42
23
11
46
14
20
16
14
26
16
MeCN (1)
3
MeCN (1)
4
MeCN (0.5)
EtOH (0.5)
EtOAc (0.5)
THF (0.5)
5
6
7
8
Toluene (0.5)
CH2Cl2 (0.5)
9
10
CHCl3 (0.5)
a
b
Isolated yields after column chromatography; determined by chiral HPLC analysis (Daicel Chiralpak IB,
Hex:EtOAc 6:4, 1 mL·min−1).

Molecules 2015, 20
15814
We firstly analyzed the effect of the catalyst loading (Entries 1–3), and no improvement was found
lowering the amount of catalyst to 20 and 10 mol %. Then, we concentrated the reaction medium,
getting slightly improved results (Entry 4). The exploration of the solvents (Entries 4–10), which was
performed at the latter concentration, showed MeCN to be the best solvent in this case (Entry 4). As a
conclusion, the best reaction conditions of those explored in this work were found to be 30 mol % of
catalyst VII and 0.5 mL of MeCN as the solvent (Entry 4).
2.4. Scope of the Reaction
With the aim of exploring the generality of this reaction, various isatylidene malononitrile derivatives
2aa′–ad′ were studied under the optimized reaction conditions [52] (Scheme 6).
OMe
COOEt
NC
COOEt
CN
O
HN
H2N
NC
OMe
COOEt
MeO
N
VII (30 mol%)
+
R
MeCN, 15 ºC
5 days
N
Bn
*
COOEt
O
R
OMe
1a
N
3aaa'-aad'
2aa': R = 5-Br
2ac': R = 5-Cl
2ab': R = 5,7-diMe 2ad': R = 5-NO2
Bn
OMe
OMe
H2N
NC
H2N
NC
OMe
N
OMe
COOEt
N
COOEt
Br
Me
*
*
COOEt
O
COOEt
3aaa'
48% ee
82% yield
3aab'
30% ee
40% yield
O
N
N
Bn
Bn
Me
OMe
OMe
H2N
NC
H2N
NC
OMe
COOEt
OMe
COOEt
N
N
Cl
O2N
*
*
COOEt
COOEt
3aac'
30% ee
71% yield
3aad'
58% ee
65% yield
O
O
N
N
Bn
Bn
Scheme 6. Scope of the organocatalyzed synthesis of 2-oxospiro-[indole-3,4′-(1′,4′-
dihydropyridines)] 3aaa′–aad′.
The final adducts 3aaa′–aad′ were obtained with moderate to good yield (40%–82%) and with
moderate enantioselectivity (30%–58% ee). The results suggest the dependence of the reactivity of the

Molecules 2015, 20
15815
process with the electronic properties of the aromatic ring of the isatin, since derivative 2ab′ (40% yield),
with two methyl groups in its structure, was less reactive than those bearing an electron-withdrawing
group in their structures (2aa′, 2ac′ and 2ad′ (65%–82% yield)) or the one without substituent
(2a (55% yield)). In contrast, the enantioselectivity of the process seems to be independent of the
electronic environment in the isatin skeleton.
2.5. Mechanism of the Reaction
Based on the previous reported mechanism for the non-asymmetric version of this reaction [35,36]
and our experimental results, we propose the tentative mechanism depicted in Scheme 7.
Scheme 7. Plausible reaction mechanism. (A) Michael addition; (B) Intramolecular
cyclization; (C) Tautomerization.
Initially, isatylidene malononitrile 2 would undergo a Michael addition with the enamine 1 in a
concomitant coordination of both species with the catalyst VII (A). Then, an intramolecular nucleophilic
addition of the NH to a nitrile group would close the piperidine ring in the intermediate (B). Final
product 3 would be formed after a subsequent tautomerization of the intermediate (C) (Scheme 7).
Although at this stage, we cannot ensure the bifunctional role for the catalyst in this system [53,54], the
experimental results suggest that the presence of both moieties in the skeleton, thiourea and Brønsted
base seems to be crucial for the success of this process. Additional studies are actually ongoing in our lab
in order to shed light on the mechanism and with the aim of improving the enantiomeric excess values
obtained so far.

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3. Experimental Section
3.1. General Experimental Methods
Purification of reaction products was carried out by flash chromatography using silica gel
(0.063–0.200 mm). Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F
plates. 1H-NMR spectra were recorded at 300 and 400 MHz; 13C-APT-NMR spectra were recorded at
75 and 100 MHz; CDCl3 as the solvent. Chemical shifts were reported in the δ scale relative to residual
CHCl3 (7.26 ppm) for 1H-NMR and to the central line of CDCl3 (77.0 ppm) for 13C-APT-NMR.
3.2. Materials
All commercially available solvents and reagents were used as received. Catalyst I, II and III were
synthesized following our reported protocol [55], and the NMR spectra (1H-NMR and 13C-APT-NMR)
for them are consistent with values previously reported in the literature: I [56], II [57] and III [56].
3.3. Synthesis and Physical, Analytical and Spectral data of Starting Materials (1 and 2) and the Final
Compound (3)
3.3.1. Synthesis of E-Enamines 1a–d
To a mixture of diethyl 2-butynedioate 5 (5 mmol) in 40 mL of CH2Cl2, the appropriated aniline 4a–d
(10 mmol) was added at room temperature. The reaction vessel was covered with foil in order to
prevent the decomposition of 5. The reaction mixture was stirred 24 h at room temperature. Then, the
solvent was evaporated under vacuum, and the reaction crude was purified by column chromatography
(SiO2, Hex:EtOAc 85:15) (see Scheme 2).
Diethyl 2-(2,4-Dimethoxyphenylamino)fumarate (1a): Following the general procedure, compound 1a
1
was obtained as a yellow oil in a 55% yield. H-NMR (400 MHz, CDCl3) δ 1.06 (t, 3H, J = 7.1 Hz),
1.21 (t, 3H, J = 7.1 Hz), 3.69 (s, 3H), 3.72 (s, 3H), 4.07 (q, 2H, J = 7.1 Hz), 4.11 (q, 2H, J = 7.1 Hz),
5.22 (s, 1H), 6.30 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz), 6.38 (d, 1H, J = 2.6 Hz), 6.70 (d, 1H, J = 8.7 Hz),
9.41 (s, 1H). 13C-APT-NMR (100 MHz, CDCl3) δ 13.8 (1C), 14.4 (1C), 55.5 (1C), 55.5 (1C), 59.7 (1C),
61.7 (1C), 91.0 (1C), 98.2 (1C), 103.8 (1C), 122.3 (1C), 122.9 (1C), 149.2 (1C), 152.5 (1C), 157.6 (1C),
164.2 (1C), 169.8 (1C).
Diethyl 2-(4-Methoxyphenylamino)fumarate (1b): Following the general procedure, Compound 1b was
obtained as a yellow oil in a 60% yield [58].
Diethyl 2-(4-tert-Butylphenylamino)fumarate (1c): Following the general procedure, compound 1c was
1
obtained as a yellow oil in a 57% yield. H-NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J = 7.1 Hz), 1.20
(t, 3H, J = 7.1 Hz), 1.20 (s, 9H), 4.06 (q, 2H, J = 7.1 Hz), 4.10 (q, 2H, J = 7.1 Hz), 5.24 (s, 1H), 6.77
13
(dt, 2H, J = 8.4 Hz, J = 1.8 Hz), 7.20 (dt, 2H, J = 8.6 Hz, J = 2.0 Hz), 9.57 (s, 1H). C-APT-NMR
(100 MHz, CDCl3) δ 13.6 (1C), 14.4 (1C), 31.4 (3C), 34.3 (1C), 59.8 (1C), 61.9 (1C), 92.8 (1C), 120.9
(2C), 125.9 (2C), 137.8 (1C), 147.3 (1C), 148.9 (1C), 164.4 (1C), 169.6 (1C).

Molecules 2015, 20
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Diethyl 2-(4-(Trifluoromethyl)phenylamino)fumarate (1d): Following the general procedure, compound
1d was obtained as a yellow oil in a 59% yield. 1H-NMR (400 MHz, CDCl3) δ 1.16 (t, 3H, J = 7.1 Hz),
1.31 (t, 3H, J = 7.1 Hz), 4.21 (q, 4H, J = 7.1 Hz), 5.54 (s, 1H), 6.94 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H,
J = 8.4 Hz), 9.72 (s, 1H). 13C-APT-NMR (100 MHz, CDCl3) δ 13.7 (1C), 14.3 (1C), 60.3 (1C), 62.4 (1C),
97.0 (1C), 120.0 (2C), 126.3 (q, 2C, J = 3.79 Hz), 143.5 (1C), 146.8 (1C), 163.9 (1C), 169.2 (1C).
3.3.2. Synthesis of Isatylidene Malononitriles 2a–c and 2aa′–ad′
Protection of Isatin (6)
To a mixture of the protecting reagent RBr (0.2 mmol) and K2CO3 (0.138 g) in MeCN (10 mL),
isatin (6) was added (0.147 g) at room temperature. After that, the reaction mixture was stirred 24 h at
reflux. Then, the solvent was evaporated under vacuum, and the reaction crude was purified by column
chromatography (SiO2, Hex:EtOAc 8:2), giving rise to the corresponding product 7 (see Schemes 3
and 8).
Scheme 8. Synthesis of isatylidene malononitriles 2aa′–ad′, starting from isatins 6a′–d′.
Knoevenagel Condensation
To a mixture of 7 (1 mmol) in EtOH (10 mL), malononitrile (66 mg) was added. After that, the mixture
was heated 24 h at reflux. Then, the solvent was evaporated under vacuum, and the reaction crude was
purified by column chromatography (SiO2, Hex:EtOAc 8:2), giving rise to the corresponding product 2
(see Schemes 3 and 8).
The NMR spectra are consistent with the values previously published for 2a [59], 2b [60]
and 2c [61].
2-(1-Allyl-2-oxoindolin-3-ylidene)malononitrile (2b): Following the general procedure starting from
1
isatin (6), compound 2b was obtained as a black solid in a 77% overall yield. H-NMR (400 MHz,
CDCl3) δ 4.38 (dt, 2H, J = 5.5 Hz, J = 1.6 Hz), 5.29–5.31 (m, 1H), 5.33–5.34 (m, 1H), 5.83 (ddt, 1H,
J = 17.3 Hz, J = 10.1 Hz, J = 5.5 Hz), 6.86–6.90 (m, 1H), 7.16 (dt, 1H, J = 7.8 Hz, J = 0.9 Hz),
7.56 (dt, 1H, J = 7.8 Hz, J = 1.2 Hz), 8.15 (d, 1H, J = 7.9 Hz).

Molecules 2015, 20
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2-(1-Benzyl-5-bromo-2-oxoindolin-3-ylidene)malononitrile (2aa′): Following the general procedure
starting from isatin 6a′, compound 2aa′ was obtained as a black solid in a 74% yield. 1H-NMR (400 MHz,
CDCl3) δ 4.91 (s, 2H), 6.68 (d, 2H, J = 8.5 Hz), 7.27–7.38 (m, 5H), 7.57 (dd, 1H, J = 8.5 Hz, J = 1.9 Hz),
8.21 (d, 1H, J = 1.8 Hz). 13C-APT-NMR (100 MHz, CDCl3) 44.3 (1C), 84.3 (1C), 110.2 (1C), 111.8 (1C),
112.1 (1C), 116.5 (1C), 119.6 (1C), 127.4 (2C), 128.5 (1C), 129.2 (3C), 133.6 (1C), 140.0 (1C), 144.9
(1C), 147.9 (1C), 162.0 (1C).
2-(1-Benzyl-5,7-dimethyl-2-oxoindolin-3-ylidene)malononitrile (2ab′): Following the general procedure
starting from isatin 6b′, compound 2ab′ was obtained as a black solid in a 55% yield. 1H-NMR (400 MHz,
CDCl3) δ 2.22 (s, 3H), 2.29 (s, 3H), 5.16 (s, 2H), 7.05 (br s, 1H), 7.15 (d, 2H, J = 6.8 Hz), 7.26–7.38
13
(m, 3H), 7.86 (br s, 1H). C-APT-NMR (100 MHz, CDCl3) δ 18.5 (1C), 20.6 (1C), 45.3 (1C), 81.8
(1C), 111.0 (1C), 112.6 (1C), 119.2 (1C), 121.4 (1C), 125.2 (1C), 125.6 (2C), 127.8 (1C), 129.1 (2C),
133.8 (1C), 136.0 (1C), 142.3 (1C), 142.7 (1C), 148.8 (1C), 163.9 (1C).
2-(1-Benzyl-5-chloro-2-oxoindolin-3-ylidene)malononitrile (2ac′): Following the general procedure
starting from isatin 6c′ [62,63], compound 2ac′ was obtained as a black solid in a 57% yield. 1H-NMR
(300 MHz, CDCl3) δ 4.91 (s, 2H), 6.72 (d, 1H, J = 8.5 Hz), 7.27–7.39 (m, 5H), 7.42 (dd, 1H, J = 8.5 Hz,
J = 2.1 Hz), 8.08 (d, 1H, J = 2.0 Hz). 13C-APT-NMR (75 MHz, CDCl3) δ 44.3 (1C), 84.3 (1C), 110.2
(1C), 111.7 (1C), 111.8 (1C), 119.2 (1C), 126.4 (1C), 127.4 (2C), 128.5 (1C), 129.2 (2C), 129.6 (1C),
133.7 (1C), 137.1 (1C), 144.5 (1C), 148.1 (1C), 162.2 (1C).
2-(1-Benzyl-5-nitro-2-oxoindolin-3-ylidene)malononitrile (2ad′): Following the general procedure starting
1
from isatin 6d′ [64,65], compound 2ad′ was obtained as a red solid in a 46% yield. H-NMR
(400 MHz, CDCl3) δ 5.00 (s, 2H), 6.94 (d, 1H, J = 8.8 Hz), 7.29–7.41 (m, 5H), 8.40 (dd, 1H, J = 8.8 Hz,
J = 2.2 Hz), 8.99 (d, 1H, J = 2.1 Hz). 13C-APT-NMR (100 MHz, CDCl3) δ 44.8 (1C), 86.4 (1C), 109.8
(1C), 110.5 (1C), 111.3 (1C), 118.2 (1C), 122.0 (1C), 127.5 (2C), 128.9 (1C), 129.4 (2C), 132.5 (1C),
133.0 (1C), 144.0 (1C), 146.8 (1C), 150.1 (1C), 162.5 (1C).
3.3.3. General Procedure for the Synthesis of Spirooxindoles 3
To a mixture of catalyst VII (30 mol %, 12.4 mg) and enamine 1a (0.2 mmol, 65 mg), in MeCN
(0.5 mL), the isatin derivative 2 (0.1 mmol) was added. The reaction mixture was stirred 5 days at the
indicated temperature. Then, the solvent was evaporated under vacuum, and the reaction crude was
purified by column chromatography (SiO2, Hex:EtOAc 85:15), giving rise to the corresponding final
adduct 3 (see Figure 4, Table 2 (Entry 4), and Scheme 6).
Diethyl 2′-Amino-1-benzyl-3′-cyano-1′-(2,4-dimethoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′,6′-
dicarboxylate (3aa): Following the general procedure (at room temperature), compound 3aa was
obtained as a brown solid in a 55% yield. The ee of the product was determined to be 46% by HPLC
using a Daicel Chiralpak IB column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 251 nm):
τmajor = 27.9 min; τminor = 16.3 min. 1H-NMR (400 MHz, CDCl3) δ 0.73 (t, 3H, J = 7.1 Hz), 1.03 (t, 3H,
J = 7.1 Hz), 3.62–3.74 (m, 1H), 3.84 (s, 3H), 3.84–3.93 (m, 3H), 3.96 (s, 3H), 4.28 (s, 2H), 4.79 (d, 1H,
J = 15.7 Hz), 5.16 (d, 1H, J = 15.7 Hz), 6.50–6.55 (m, 2H), 6.67 (d, 1H, J = 7.7 Hz), 7.00–7.07 (m, 1H),

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7.15 (dt, 1H, J = 7.7 Hz, J = 1.2 Hz), 7.22–7.36 (m, 4H), 7.39 (dd, 1H, J = 7.3 Hz, J = 1.1 Hz), 7.48–7.50
13
(m, 2H). C-APT-NMR (75 MHz, CDCl3) δ 13.4 (1C), 13.6 (1C), 44.6 (1C), 55.7 (1C), 56.3 (1C),
60.7 (1C), 61.8 (1C), 62.3 (1C), 99.7 (1C), 103.6 (1C), 104.7 (1C), 109.0 (1C), 116.4 (1C), 118.5 (1C),
123.0 (1C), 124.3 (1C), 127.5 (1C), 127.7 (2C), 128.6 (2C), 128.7 (1C), 132.2 (1C), 135.3 (1C), 135.7
(2C), 142.0 (1C), 144.6 (1C), 151.5 (1C), 158.3 (1C), 162.4 (1C), 162.7 (1C), 164.0 (1C), 178.0 (1C).
Diethyl 2′-Amino-1-benzyl-3′-cyano-1′-(4-methoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′,6′-
dicarboxylate (3ba): Following the general procedure (at room temperature), compound 3ba was
obtained as a brown solid in a 65% yield. The ee of the product was determined to be 30% by HPLC
using a Daicel Chiralpak IC column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 254 nm):
τ
major = 6.7 min; τminor = 10.9 min. 1H-NMR (400 MHz, CDCl3) δ 0.64 (t, 3H, J = 7.1 Hz), 1.00 (t, 3H,
J = 7.1 Hz), 3.57–3.65 (m, 1H), 3.85 (s, 3H), 3.87–3.92 (m, 3H), 4.28 (s, 2H), 4.83 (d, 1H, J = 15.7 Hz),
5.11 (d, 1H, J = 15.7 Hz), 6.70 (d, 1H, J = 7.7 Hz), 6.96–6.98 (m, 2H), 7.05 (dt, 1H, J = 7.6 Hz,
J = 0.8 Hz), 7.17 (dt, 1H, J = 7.7 Hz, J = 1.3 Hz), 7.26 (tt, 1H, J = 7.3 Hz, J = 1.2 Hz), 7.31–7.40 (m,
5H), 7.47–7.49 (m, 2H). 13C-APT-NMR (75MHz, CDCl3) δ 13.3 (1C), 13.5 (1C), 44.5 (1C), 55.6 (1C),
60.7 (1C), 62.0 (1C), 62.2 (1C), 103.7 (1C), 109.0 (1C), 114.9 (2C), 118.2 (1C), 123.1 (1C), 124.1 (1C),
127.1 (1C), 127.5 (1C), 127.7 (2C), 128.7 (2C), 128.9 (1C), 131.7 (2C), 135.0 (1C), 135.7 (2C), 142.3
(1C), 144.1 (1C), 151.2 (1C), 160.9 (1C), 162.4 (1C), 164.0 (1C), 177.8 (1C).
Diethyl 2′-Amino-1-benzyl-1′-(4-tert-butylphenyl)-3′-cyano-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′,6′-
dicarboxylate (3ca): Following the general procedure (at room temperature), compound 3ca was
obtained as a brown solid in a 71% yield. The ee of the product was determined to be 26% by HPLC
using a Daicel Chiralpak IA column (n-hexane:EtOAc 70:30, flow rate 1 mL·min−1, λ = 254 nm):
τmajor = 10.6 min; τminor = 18.2 min. 1H-NMR (400 MHz, CDCl3) δ 0.64 (t, 3H, J = 7.1 Hz), 0.85 (t, 3H,
J = 7.1 Hz), 1.34 (s, 9H), 3.61 (dq, 1H, J = 10.8 Hz, J = 7.1 Hz), 3.82–3.92 (m, 3H), 4.27 (s, 2H),
4.84 (d, 1H, J = 15.7 Hz), 5.11 (d, 1H, J = 15.7 Hz), 6.71 (d, 1H, J = 7.7 Hz), 7.06 (dt, 1H, J = 7.4 Hz,
J = 0.8 Hz), 7.17 (dt, 1H, J = 7.7 Hz, J = 1.3 Hz), 7.26 (tt, 1H, J = 7.3 Hz, J = 1.2 Hz), 7.32–7.41 (m,
5H), 7.47–7.52 (m, 4H). 13C-APT-NMR (100 MHz, CDCl3) δ 13.3 (2C), 31.2 (3C), 35.0 (1C),
44.6 (1C), 60.7 (1C), 61.9 (1C), 62.3 (1C), 103.7 (1C), 109.0 (1C), 118.3 (1C), 123.1 (1C), 124.1 (1C),
126.8 (2C), 127.6 (1C), 127.7 (2C), 128.7 (2C), 128.9 (1C), 130.0 (2C), 132.1 (1C), 135.0 (1C),
135.7 (2C), 142.3 (1C), 143.9 (1C), 151.0 (1C), 154.2 (1C), 162.4 (1C), 164.0 (1C), 177.8 (1C).
Diethyl 1-Allyl-2′-amino-3′-cyano-1′-(4-methoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′,6′-
dicarboxylate (3bb): Following the general procedure (at room temperature), compound 3bb was
obtained as a brown solid in a 61% yield. The ee of the product was determined to be 30% by HPLC
using a Daicel Chiralpak IC column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 254 nm):
τmajor = 7.8 min; τminor = 13.7 min. 1H-NMR (400 MHz, CDCl3) δ 0.79 (t, 3H, J = 7.1 Hz), 0.99 (t, 3H,
J = 7.1 Hz), 3.73–3.81 (m, 1H), 3.85 (s, 3H), 3.86–3.93 (m, 3H), 4.21 (s, 2H), 4.22–4.27 (m, 1H),
4.53–4.61 (m, 1H), 5.25–5.29 (m, 1H), 5.42–5.48 (m, 1H), 5.86–5.96 (m, 1H), 6.86 (d, 1H, J = 6.8 Hz),
6.95–6.99 (m, 2H), 7.09 (dt, 1H, J = 7.5 Hz, J = 0.9 Hz), 7.26 (dt, 1H, J = 7.7 Hz, J = 1.3 Hz),
13
7.34–7.41 (m, 3H). C-APT-NMR (75 MHz, CDCl3) δ 13.4 (1C), 13.5 (1C), 42.9 (1C), 49.4 (1C),
55.7 (1C), 60.8 (1C), 62.0 (1C), 103.5 (1C), 108.9 (2C), 114.9 (1C), 117.9 (1C), 118.1 (1C), 123.1

Molecules 2015, 20
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(1C), 124.0 (1C), 127.0 (1C), 128.9 (1C), 131.3 (1C), 131.7 (2C), 134.9 (1C), 142.2 (1C), 144.0 (1C),
151.1 (1C), 160.9 (1C), 162.4 (1C), 163.9 (1C), 177.4 (1C).
Diethyl 2′-Amino-3′-cyano-1-ethyl-1′-(4-methoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′,6′-
dicarboxylate (3bc): Following the general procedure (at room temperature), compound 3bc was
obtained as a brown solid in a 49% yield. The ee of the product was determined to be 32% by HPLC
using a Daicel Chiralpak IC column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 254 nm):
τ
major = 9.9 min; τminor = 16.5 min. 1H-NMR (400 MHz, CDCl3) δ 0.76 (t, 3H, J = 7.1 Hz), 0.98 (t, 3H,
J = 7.1 Hz), 1.33 (t, 3H, J = 7.2 Hz), 3.68–3.78 (m, 2H), 3.83 (s, 3H), 3.84–3.95 (m, 4H), 4.24 (s, 2H),
6.84 (d, 1H, J = 7.8 Hz), 6.94–6.97 (m, 2H), 7.06 (t, 1H, J = 7.5 Hz), 7.25–7.29 (m, 1H), 7.32–7.38 (m,
3H). 13C-RMN (100 MHz, CDCl3) δ 12.5 (1C), 13.4 (1C), 13.5 (1C), 35.1 (1C), 55.6 (1C), 60.7 (1C),
62.0 (1C), 64.7 (1C), 108.1 (1C), 114.9 (2C), 118.0 (1C), 123.0 (1C), 124.1 (1C), 127.1 (1C), 129.0
(1C), 131.7 (2C), 135.3 (1C), 142.1 (1C), 144.1 (1C), 151.0 (1C), 160.9 (1C), 162.5 (1C), 164.0 (1C),
177.2 (1C).
Diethyl 2′-Amino-1-benzyl-5-bromo-3′-cyano-1′-(2,4-dimethoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-
pyridine]-5′,6′-dicarboxylate (3aaa′): Following the general procedure (at 15 °C), compound 3aaa′
was obtained as a brown solid in an 82% yield. The ee of the product was determined to be 48% by HPLC
using a Daicel Chiralpak IB column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 256.4 nm):
τmajor = 41.7 min; τminor = 15.9 min. 1H-NMR (300 MHz, CDCl3) δ 0.66 (t, 3H, J = 7.1 Hz), 0.96 (t, 3H,
J = 7.2 Hz), 3.49–3.66 (m, 1H), 3.77 (s, 3H), 3.77–3.85 (m, 3H), 3.89 (s, 3H), 4.21 (br s, 2H), 4.71
(d, 1H, J = 15.7 Hz), 5.10 (d, 1H, J = 15.7 Hz), 6.44 (t, 1H, J = 9.8 Hz), 6.45 (t, 1H, J = 9.8 Hz), 6.60
(d, 1H, J = 7.8 Hz), 6.94–7.00 (m, 1H), 7.08 (dt, 1H, J = 7.7 Hz, J = 1.3 Hz), 7.18–7.34 (m, 4H), 7.42
13
(br d, 2H, J = 7.4 Hz). C-RMN (75 MHz, CDCl3) δ 13.4 (1C), 13.6 (1C), 44.6 (1C), 55.7 (1C),
55.7 (1C), 60.7 (1C), 61.8 (1C), 62.3 (1C), 99.6 (1C), 103.5 (1C), 104.7 (1C), 109.0 (1C), 116.3 (1C),
118.5 (1C), 123.0 (1C), 124.3 (1C), 127.7 (2C), 128.7 (2C), 128.7 (1C), 132.2 (1C), 135.3 (1C), 135.7
(1C), 141.9 (1C), 144.7 (1C), 151.5 (1C), 158.3 (1C), 162.4 (1C), 162.7 (1C), 164.0 (1C), 178.0 (1C).
Diethyl 2′-Amino-1-benzyl-3′-cyano-1′-(2,4-dimethoxyphenyl)-5,7-dimethyl-2-oxo-1′H-spiro[indoline-
3,4′-pyridine]-5′,6′-dicarboxylate (3aab′): Following the general procedure (at 15 °C), compound 3aab′
was obtained as a brown solid in a 40% yield. The ee of the product was determined to be 30% by HPLC
using a Daicel Chiralpak IB column (n-hexane:EtOAc 60:40, flow rate 1 mL·min−1, λ = 257 nm):
τmajor = 43.9 min; τminor = 22.4 min. 1H-NMR (400 MHz, CDCl3) δ 0.91 (t, 3H, J = 7.1 Hz), 1.03 (t, 3H,
J = 7.2 Hz), 2.20 (s, 3H), 2.29 (s, 3H), 3.84–4.01 (m, 4H), 3.84 (s, 3H), 3.97 (s, 3H), 4.26 (br s, 2H),
5.04 (d, 1H, J = 16.8 Hz), 5.35 (d, 1H, J = 16.9 Hz), 6.48–6.55 (m, 2H), 6.75 (s, 1H), 7.090 (s, 1H),
13
7.21–7.42 (m, 6H). C-RMN (100 MHz, CDCl3) δ 13.6 (1C), 13.6 (1C), 18.6 (1C), 21.0 (1C), 45.9
(1C), 55.7 (1C), 56.2 (1C), 60.8 (1C), 61.8 (1C), 66.8 (1C), 99.7 (1C), 104.7 (1C), 116.5 (1C), 118.9 (1C),
119.0 (1C), 123.4 (1C), 126.3 (1C), 127.0 (2C), 128.7 (2C), 132.2 (1C), 132.3 (1C), 133.3 (1C), 136.3
(1C), 138.0 (1C), 144.3 (1C), 151.4 (1C), 158.3 (1C), 162.6 (1C), 162.7 (1C), 164.2 (1C), 179.2 (1C).
Diethyl 2′-Amino-1-benzyl-5-chloro-3′-cyano-1′-(2,4-dimethoxyphenyl)-2-oxo-1′H-spiro[indoline-3,4′-
pyridine]-5′,6′-dicarboxylate (3aac′): Following the general procedure (at 15 °C), compound 3aac′
was obtained as a red solid in a 71% yield. The ee of the product was determined to be 30% by HPLC

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using a Daicel Chiralpak IB column (n-hexane:iPrOH = 70:30, flow rate 1 mL·min−1, λ = 244.1 nm):
τmajor = 42.5 min; τminor = 22.9 min. 1H-NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J = 7.1 Hz), 1.03 (t, 3H,
J = 7.1 Hz), 3.77–3.96 (m, 4H), 3.84 (s, 3H), 3.99 (s, 3H), 4.33 (br s, 2H), 4.73 (d, 1H, J = 15.8 Hz),
13
5.18 (d, 1H, J = 15.8 Hz), 6.49–6.59 (m, 3H), 7.09–7.12 (m, 1H), 7.24–7.47 (m, 7H). C-RMN
(75 MHz, CDCl3) δ 13.6 (1C), 13.6 (1C), 44.7 (1C), 55.7 (1C), 55.7 (1C), 60.8 (1C), 60.9 (1C), 61.9
(1C), 99.5 (1C), 102.7 (1C), 104.6 (1C), 110.0 (1C), 115.8 (1C), 118.3 (1C), 124.9 (1C), 127.6 (2C),
128.1 (1C), 128.6 (1C), 128.7 (2C), 132.1 (1C), 135.2 (1C), 137.0 (1C), 140.2 (1C), 144.9 (1C), 151.5
(1C), 158.4 (1C), 162.2 (1C), 162.8 (1C), 163.7 (1C), 177.6 (1C).
Diethyl 2′-Amino-1-benzyl-3′-cyano-1′-(2,4-dimethoxyphenyl)-5-nitro-2-oxo-1′H-spiro[indoline-3,4′-
pyridine]-5′,6′-dicarboxylate (3aad′): Following the general procedure (at 15 °C), compound 3aad′
was obtained as a red solid in a 65% yield. The ee of the product was determined to be 58% by HPLC
using a Daicel Chiralpak IB column (n-hexane:EtOAc 70:30, flow rate 1 mL·min−1, λ = 262.6 nm):
τ
major = 62.9 min; τminor = 35.6 min. 1H-NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J = 7.1 Hz), 0.96 (t, 3H,
J = 7.2 Hz), 3.75–3.94 (m, 4H), 3.78 (s, 3H), 4.03 (s, 3H), 4.30 (br s, 2H), 4.77 (d, 1H, J = 15.8 Hz),
5.16 (d, 1H, J = 15.8 Hz), 6.49–6.52 (m, 3H), 6.66 (d, 1H, J = 8.7 Hz), 7.17–7.42 (m, 6H), 8.06 (dd,
13
1H, J = 2.3 Hz, J = 8.6 Hz), 8.22 (d, 1H, J = 2.3 Hz). C-APT-RMN (75 MHz, CDCl3) δ 13.6 (1C),
13.6 (1C), 45.9 (1C), 55.7 (1C), 56.4 (1C), 61.2 (1C), 62.0 (1C), 63.1 (1C), 99.6 (1C), 102.1 (1C),
104.7 (1C), 108.7 (1C), 115.4 (1C), 118.0 (1C), 120.2 (1C), 126.0 (1C), 127.6 (2C), 127.6 (1C), 128.9
(2C), 132.0 (1C), 134.6 (1C), 136.3 (1C), 143.8 (1C), 145.3 (1C), 147.4 (1C), 151.6 (1C), 158.6 (1C),
161.9 (1C), 163.0 (1C), 163.6 (1C), 178.3 (1C).
4. Conclusions
In summary, we have developed an organocatalytic approach for the chiral formation of
2-oxospiro-[indole-3,4′-(1′,4′-dihydropyridine)] derivatives under mild conditions and operational
simplicity. Final adducts were reached with promising results of enantioselectivity for the first time.
Further mechanistic studies are required in order to understand and to prove the role of the used
catalyst in this process. Moreover, additional studies with the aim of improving the enantioselectivity
of the method are actively on-going in our laboratory.
Acknowledgments
We thank the Ministry of Economy and Competitivity (MINECO, Project CTQ2013-44367-C2-1-P);
the University of Zaragoza (JIUZ-2014-CIE-07) and the Government of Aragon (Research Group E-104)
for financial support of our research.
Author Contributions
F.A.-L., S.M. and R.H. performed the experiments. E.M.-L. and R.P.H. designed the experiments and
wrote the paper. All authors took part in data analysis and discussion. All authors read and approved the
final manuscript.

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Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available.
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