Chiral 2-aminobenzimidazole as bifunctional catalyst in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles

Article abstract of DOI:10.3390/molecules23061374

The use of readily available chiral trans-cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated;

Full text of DOI:10.3390/molecules23061374

molecules
Article
Chiral 2-Aminobenzimidazole as Bifunctional
Catalyst in the Asymmetric Electrophilic Amination
of Unprotected 3-Substituted Oxindoles
ID
Llorenç Benavent, Alejandro Baeza * and Megan Freckleton
Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain; l.benavent@ua.es (L.B.); mf91@alu.ua.es (M.F.)
* Correspondence: alex.baeza@ua.es; Tel.: +34-965-902-888
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 9 May 2018; Accepted: 5 June 2018; Published: 6 June 2018
Abstract: The use of readily available chiral trans-cyclohexanediamine-benzimidazole derivatives as
bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted
oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained
a dimethylamino moiety (5). With this catalyst under optimized conditions, different oxindoles
containing a wide variety of substituents at the 3-position were aminated in good yields and with
good to excellent enantioselectivities using di-tert-butylazodicarboxylate as the aminating agent.
The procedure proved to be also efficient for the amination of 3-substituted benzofuranones, although
with moderate results. A bifunctional role of the catalyst, acting as Brønsted base and hydrogen bond
donor, is proposed according to the experimental results observed.
Keywords: organocatalysis; electrophilic amination; benzimidazoles; asymmetric catalysis; oxindoles
1. Introduction
Substituted oxindoles containing a chiral center at the C3 position are attractive targets in organic
synthesis since they are recognized as drug candidates and also for their use as intermediates in alkaloid
synthesis. More particularly, the development of efficient methods to prepare 3-aminooxindoles is
of current interest owing to the wide presence of these frameworks in bioactive natural products
and pharmaceutically active compounds [
construction of these oxindoles, asymmetric organocatalyzed electrophilic amination has emerged
as a powerful tool because it is considered a simple and straightforward methodology [ ].
1–5]. Among the different strategies developed for the
6–9
Additional to this, the well-known advantages in the use of organocatalysts must be also taken
into account: they are readily available or simple-to-prepare catalysts, easy to handle, and there is no
risk of metal contamination in the final product [10,11]. For these reasons, it is not surprising that in the
last decade, different studies have successfully described the organocatalytic asymmetric electrophilic
3-amination of oxindoles, giving rise to the desired compounds in high yields and enantioselectivities
and with a broad substrate scope [12–14]. However, most of the works reported so far require the use
of N-protected oxindoles, which implies a tedious protection-deprotection sequence.
In the last years, our research group has been involved in the synthesis and application of benzimidazole
derivatives as bifunctional organocatalysts which activate different active methylene compounds
through hydrogen bond interactions in different asymmetric organocatalyzed transformations [15
More concretely, a few years ago we reported the successful employment of such organocatalysts in the
enantioselective electrophilic amination of 1,3-dicarbonyl compounds [20 21]. Continuing with this research
–19].
,
line, we disclose the application of 2-aminobenzimidazoles as catalysts in the asymmetric electrophilic
amination of 3-substituted unprotected oxindoles (Figure 1).
Molecules 2018, 23, 1374; doi:10.3390/molecules23061374
www.mdpi.com/journal/molecules

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Figure 1. Benzimidazole-based organocatalyst in the asymmetric electrophilic amination of active
methylene compounds.
2. Results and Discussion
Firstly, the search for the optimal conditions was performed by choosing the model reaction
between commercial available unprotected 3-methyl-2-oxindole (1a) and di-t-butylazodicarboxylate
(2a), using 10 mol % of catalyst loading. Different parameters such as benzimidazole derivative
(Figure 2), solvent, and temperature were examined (Table 1). The model reaction was not
serendipitously selected because, to the best of our knowledge, only a few articles describe the
successful enantioselective amination of such an unprotected oxindole [14
the table, among the different benzimidazole derivatives tested ( ) at room temperature and using
toluene as solvent (Table 1, entries 1–6), catalyst bearing a dimethylamino moiety—which has
,22–24]. As observed in
4–9
5
previously shown its efficiency for the amination of 1,3-dicarbonyl compounds [20]—provided the best
results in terms of enantioselectivity (Table 1, entry 2). With the best catalyst at hand, other solvents
were evaluated (Table 1, entries 7–11) without observing an improvement in the ee of the amination
product 3aa. However, in the case of using hexane as solvent, similar results to those obtained in
toluene were achieved (Table 1, entry 10). Therefore, both solvents were tested in a reaction performed
at 0 ◦C for 72 h (Table 1, entries 12 and 13). Whereas the enantioselectivity in toluene increased up
to 81% without detriment to conversion, a significant drop in the optical purity of 3aa was observed
in hexane, probably due to the lower solubility of the reagents and catalyst in this solvent at lower
temperatures. Attempts to further increase the ee of 3aa by lowering the reaction temperature were
unsuccessful, probably for the same solubility reasons (Table 1, entries 14 and 15). It is also important
to remark that the concentration barely affects the results observed for the best conditions. However,
reducing the catalyst amount (5 mol %) resulted in a dramatic drop of enantioselectivity.
Figure 2. Benzimidazole-derived organocatalysts tested.

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Table 1. Optimal condition screening a.
◦
Conv. (%) b
Entry
Catalyst Solvent
Temp. ( C)
ee (%) c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4
5
6
7
8
9
5
5
5
5
5
5
5
5
5
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
Et2O
25
25
25
25
25
25
25
25
25
90
80
80
92
40
87
80
85
75
81
79
89
82
56
59
13
73
57
5
rac.
3
56
66
50
73
5
81
51
71
70
THF
C6H14
MeOH
PhMe
C6H14
PhMe
PhMe
25
25
0 d
0 d
−20 d
−78 e
a
Unless otherwise stated, general conditions were 1a (0.15 mmol), 2a (1.1 equiv.), organocatalyst (10 mol %) in
toluene (1 mL) at the corresponding temperature for 24 h. Conversions determined by 1H NMR from the crude
reaction mixture. Determined by chiral HPLC analysis (Daicel Chiralcel OD-H, see Materials and Methods section
for details). The reaction was run for 72 h. The reaction was run for 96 h.
b
c
d
e
Next, we decided to evaluate the influence of the azodicarboxylate reagent. Thus, diethyl (2b
)
and diisopropyl (2c) derivatives were allowed to react with oxindole 1a under the best conditions
(Scheme 1). As depicted, none of them improved upon the results obtained with 2a.
Scheme 1. Influence of azodicarboxylate reagent.
Finally, the last parameter evaluated was the presence of a protecting group on the oxindole.
We selected the Boc group due to its ease of removal. Surprisingly, the reaction produced the expected
amination product in good yields but with low enantioselectivity (Scheme 2).
Scheme 2. Influence of the N-Boc protecting group.

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Once all the parameters which can have an effect in the reaction outcome were studied, the scope of
the asymmetric benzimidazole organocatalyzed electrophilic amination was evaluated. As previously
5
mentioned, good yields and enantioselectivities were achieved with 3-methyloxindole (1a) (Table 2,
entry 1). Similar results were obtained with the 5-bromo analogue 1b (Table 2, entry 2). Surprisingly,
when 3-phenyloxindole (1c) was employed, a slight drop in both yield and enantioselectivity was
observed (Table 2, entry 3). Better results, especially in term of ee values, were obtained with
3-allyloxindole (3d) and ester derivative 3e, reaching 84% and 85% ee, respectively (Table 2, entries 4
and 5). Next, a series of 3-benzyl-substituted oxindoles were evaluated. Thus, 3-benzyloxindole (3e
)
was firstly tested giving rise to good yield and enantioselectivity in compound 3fa (Table 2, entry 6).
Surprisingly, excellent enantioselectivity was achieved when a 3-PMB-oxindole (3g) was employed
(Table 2, entry 7). Encouraged by this result, a couple of para-substituted benzyl oxindoles were
synthesized and tested (Table 2, entries 8 and 9). As can be observed in the table, the introduction
of a NO2 group produced the amination product 3ha with good yields and enantioselectivity.
In contrast, we were pleased to discover that the presence of CF3 gave rise to the product 3ia with
perfect enantioselectivity.
Table 2. Reaction scope a.
Yield (%) b
Entry
1
3
ee (%) c
1a
1
78
81
(R1 = Me, R2 = H)
1b
2
3
84
61
80
70
(R1 = Me, R2 = Br)
1c
(R1 = Ph, R2 = H)
1d
4
87
84
(R1 = Allyl, R2 = H)
1e
5
6
71
83
85
70
(R1 = CH2CO2Et, R2 = H)
1f
(R1 = Bn, R2 = H)

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Table 2. Cont.
Yield (%) b
Entry
1
3
ee (%) c
1g
7
8
9
75
93
(R1 = p-MeOBn, R2 = H)
1h
79
76
80
99
(R1 = p-NO2Bn, R2 = H)
1i
(R1 = p-CF3Bn, R2 = H)
a
Unless otherwise stated, general conditions were
1 (0.15 mmol), 2a (1.1 equiv.), 5 (10 mol %) in the corresponding
toluene (1 mL) at 0
º
C for 72 h. b Isolated yield after column chromatography. c Determined by chiral HPLC analysis
(see Materials and Methods section for details).
After having evaluated the scope of the methodology with different oxindoles and for the sake of
comparison, we decided to test 5-methyl-3-phenylbenzofuranone under the optimal reaction conditions
(Scheme 3). As depicted, lower enantioselectivity was achieved with this substrate when compared
with the oxindole analogue (see Table 2, entry 3).
Scheme 3. Enantioselective organocatalyzed electrophilic amination of benzofuranone 10.
Concerning a possible reaction mechanism, there is some experimental evidence that needs
to be considered before hypothesizing a possible catalytic cycle. Firstly, when comparing some
optical rotation values obtained from the amination products
3 with those described previously in the
literature, we could conclude that catalyst possessing an (R,R)-absolute configuration produced the
5
corresponding (R)-products. Secondly, from the results obtained in the catalyst screening, it can be
deduced that the dimethylamino moiety is essential for achieving good enantioselectivities, since all the
catalysts lacking such a group produced low ee values. Finally, the fact that N-Boc-protected oxindole
gave rise to the amination product in high yields but as racemic mixtures (Scheme 2) led us to think
there might be another type of influence besides the possible steric hindrance. With all these data in
hand, we hypothesize the following catalytic cycle (Figure 3), assuming the bifunctional role of catalyst
5
: Organocatalyst 5, acting firstly as a Brønsted base, through the guanidine or dimethylamino moiety,
could deprotonate the 3-substituted oxindole. Once the enolate is formed, the guanidine moiety can
stablish hydrogen bond interactions not only with the enolate but also with the N–H bond from the
amide group of oxindole, as depicted in intermediate
can activate the diazocarboxylate by another hydrogen bond interaction (intermediate
A
. Next, the protonated dimethylamino group
), forming
B

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a close transition state in which the enolate reacts through the Re-face, affording the corresponding
(R)-amination product and releasing the catalyst.
Figure 3. Proposed reaction mechanism.
3. Materials and Methods
All reagents were purchased from commercial sources and used without further purification.
Substrates which were not commercially available were synthesized according to known literature
procedures (see Supporting Information for details). NMR spectra were performed on a Bruker AC-300
or Bruker Avance-400 (Bruker Corporation, Karlsruhe, Germany) using CDCl3 as solvent and TMS
as internal standard unless otherwise stated. Optical rotations were measured on a Jasco P-1030
Polarimeter with a 5 cm cell (c given in g/100 mL). Enantioselectivities were determined by HPLC
analysis (Agilent 1100 Series HPLC) equipped with a G1315B diode array detector and a Quat Pump
G1311A (Agilent Technologies, Palo Alto, CA, United States) equipped with the corresponding Daicel
chiral column; the retention time of the major enantiomer is highlighted in bold. HRMS were measured
using HPLC–HRMS (ESI) equipment (Agilent 1100 Series LC/MSD Trap SL, Agilent Technologies).
Analytical TLC was performed on Merck silica gel plates and the spots were visualized with UV light
at 254 nm (Merck Millipore, Billerica, MA, USA). Flash chromatography employed Merck silica gel 60
(0.040–0.063 mm) (Merck Millipore, Billerica, MA, USA).
General Procedure for the Asymmetric Amination of 3-Substituted Oxindoles
◦
In an open-air tube at room temperature (25 C), the corresponding 3-substituted oxindole
(0.10 mmol) was added to a solution of organocatalyst
5 (10 mol %) in toluene (1 mL). After 5 min,
the mixture was introduced into a cooling bath at 0 ◦C and after 2 min, di-tert-butylazodicarboxilate
(0.11 mmol, 1.1 eq.) was added in one portion. The reaction was then allowed to react for 3 days.
After this time, water (5 mL) and ethyl acetate (5 mL) were added, and the aqueous layer was then
re-extracted twice (2
×
10 mL). The combined organic phases were dried (MgSO4) and evaporated
under reduced pressure. Finally, the reaction crude was purified by column chromatography on silica
gel or TLC preparative using hexane/ethylacetate mixtures as eluent.

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Di-tert-butyl (R)-1-(3-methyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3aa) [23]. Colorless oil;
[α]D28 = −7.66 (c = 1.0, CHCl3, 81% ee). 1H-NMR (300 MHz, CDCl3) δH = 8.31 (s, 1H), 7.79 (d,
J = 7.3 Hz, 1H), 7.20 (dd, J = 10.9, 4.3 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.82 (s, 1H), 1.53 (d, J = 5.7 Hz,
12H), 1.20 (s, 9H); 13C-NMR (75 MHz, CDCl3) δC = 180.35, 156.21, 153.14, 139.34, 133.55, 128.16, 124.05,
123.02, 109.89, 82.54, 81.24, 66.11, 28.25, 27.78, 23.55; chiral HPLC analysis: Chiralcel OD-H column,
Hexane/iPrOH 95 : 05, flow rate = 1 mL/min, λ = 240 nm, retention times: 7.2, 8.3 min.
Di-tert-butyl 1-(1-(tert-butoxycarbonyl)-3-methyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3aa’) [25].
1
Colorless oil; H NMR (300 MHz, CDCl3) ) δH = 7.90 (d, J = 7.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
7.32 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.65 (s, 1H), 1.65 (s, 9H), 1.53 (d, J = 3.4 Hz, 12H),
1.14 (s, 9H); 13C-NMR (101 MHz, CDCl3) δC = 176.27, 156.24, 152.87, 149.24, 137.97, 128.44, 124.98,
123.69, 114.65, 84.33, 81.52, 65.81, 28.22, 28.11, 27.66, 24.38; chiral HPLC analysis: Chiralcel IA column,
Hexane/iPrOH 90 : 10, flow rate = 1 mL/min, λ = 240 nm, retention times: 12.7, 18.1 min.
1
Diethyl 1-(3-methyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3ab) [23]. Colorless oil; H-NMR
(300 MHz, CDCl3) δH = 8.45 (s, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.35 (s, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.05
(t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 4.30 (dd, J = 13.5, 6.9 Hz, 2H), 4.00 (d, J = 6.8 Hz, 2H), 1.55
(s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.04 (s, 3H); 13C-NMR (101 MHz, CDCl3) δC = 179.59, 157.09, 154.20,
139.39, 132.56, 128.51, 124.18, 123.14, 109.84, 66.27, 62.83, 62.28, 22.95, 14.52, 13.98; chiral HPLC analysis:
Chiralcel AD-H column, Hexane/iPrOH 90 : 10, flow rate = 1 mL/min,
19.3, 33.2 min.
λ = 240 nm, retention times:
Diisopropyl (R)-1-(3-methyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3ac) [23]. Colorless oil; [α]D28 = −3.64
1
(c = 1.0, CHCl3, 60% ee); H-NMR (300 MHz, CDCl3) δH = 8.44 (s, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.20 (t,
J = 7.3 Hz, 1H), 7.06 (dd, J = 13.4, 5.8 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 5.05 (dt, J = 12.4, 6.2 Hz, 1H), 4.73 (dt,
J = 12.1, 6.0 Hz, 1H), 1.54 (s, 3H), 1.33 (dd, J = 6.2, 1.6 Hz, 6H), 1.08 (d, J = 6.1 Hz, 3H), 0.89 (bs, 3H); 13C-NMR
(101 MHz, CDCl3) δC = 179.69, 156.88, 153.76, 139.38, 132.93, 128.42, 124.19, 123.09, 109.73, 70.81, 70.08, 66.12,
23.09, 22.04, 21.91, 21.65, 21.48; chiral HPLC analysis: Chiralcel AD-H column, Hexane/iPrOH 90 : 10, flow
rate = 1 mL/min, λ = 240 nm, retention times: 14.2, 18.7 min.
Di-tert-butyl (R)-1-(5-bromo-3-methyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3ba) [24]. Yellow
solid; [α]
28 = +18.64 (c = 1.0, CHCl3, 80% ee); 1H-NMR (300 MHz, CDCl3) δH = 8.80 (s, 1H), 7.93 (s,
D
1H), 7.32 (dd, J = 8.1, 1.8 Hz, 2H), 6.96–6.68 (m, 2H), 1.54 (m, 12H), 1.25 (s, 9H); 13C-NMR (101 MHz,
CDCl3) δC = 178.15, 155.91, 152.78, 138.07, 131.16, 127.33, 124.07, 111.19, 82.77, 81.46, 66.89, 28.24, 27.87,
14.12; chiral HPLC analysis: Chiralcel OD-H column, Hexane/iPrOH 95 : 05, flow rate = 0.8 mL/min,
λ = 240 nm, retention times: 10.6, 12.4 min.
Di-tert-butyl (R)-1-(2-oxo-3-phenylindolin-3-yl)-hydrazine-1,2-dicarboxylate (3ca) [24]. White solid;
1
[α]D28 = −60.38 (c = 1.0, CHCl3, 70% ee); H NMR (300 MHz, CDCl3): δH = 8.25 (s, 1H), 8.09 (d,
J = 7.3 Hz, 1H), 7.65–7.57 (m, 2H), 7.30–7.27 (m, 3H), 7.25 (s, 1H), 7.15 (t, J = 7.4 Hz, 1H), 6.82 (d,
J = 7.6 Hz, 1H), 6.26 (bs, 1H), 1.32 (s, 9H), 1.21 (s, 9H); 13C-NMR (101 MHz, CDCl3) δC = 177.89,
154.81, 153.48, 140.03, 133.71, 130.59, 129.43, 128.65, 128.59, 128.15, 126.94, 122.64, 109.90, 82.76,
80.83, 72.64, 28.04, 27.81; chiral HPLC analysis: Chiralcel OD-H column, Hexane/iPrOH 90 : 10,
flow rate = 1 mL/min, λ = 240 nm, retention times: 5.9, 9.0 min.
28
Di-tert-butyl 1-(3-allyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3da). Yellow oil; [
α
]
D
=
−
11.47
(c = 1.0, CHCl3, 84% ee); 1H-NMR (300 MHz, CDCl3) δH = 7.93 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.20
(t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.71 (m, 2H), 5.42–5.24 (m, 1H), 4.97 (dd, J = 19.9, 13.6 Hz
2H), 2.70 (d, J = 7.5 Hz, 2H), 1.54 (s, 9H), 1.22 (s, 9H); 13C-NMR (101 MHz, CDCl3) δC = 177.84, 156.13,
153.12, 139.88, 130.16, 128.36, 124.69, 123.00, 120.13, 109.35, 82.67, 81.39, 68.86 40.71, 28.26, 27.82; HRMS
(ESI-MS) calculated for C32H44N4NaO4: 571.3260, found: 571.3310; chiral HPLC analysis: Chiralcel
,

Molecules 2018, 23, 1374
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AD-H column, Hexane/iPrOH 90 : 10, flow rate = 1 mL/min,
16.1 min.
λ
= 240 nm, retention times: 10.1,
Di-tert-butyl-1-[3-(2-ethoxy-2-oxoethyl)-2-oxoindolin-3-yl]-hydrazine-1,2-dicarboxylate (3ea). Yellow oil;
28
1
[
α
]
=
−
1.53 (c = 1.0, CHCl3, 85% ee); H-NMR (300 MHz, CDCl3) δH = 8.06 (s, 1H), 7.74 (d,
D
J = 7.4 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.86–6.66 (m, 2H), 3.95 (q, J = 7.1 Hz,
2H), 3.08 (d, J = 14.2 Hz, 1H), 2.90 (d, J = 14.1 Hz, 1H), 1.54 (s, 9H), 1.24 (s, 9H), 1.04 (t, J = 7.1 Hz, 3H);
13C-NMR (101 MHz, CDCl3) δC = 168.30, 155.89, 152.80, 140.29, 129.70, 128.96, 125.33, 122.91, 109.67,
82.91, 81.56, 66.66, 60.95, 41.32, 28.27, 27.85, 13.83; HRMS (ESI-MS) calculated for C34H48N4NaO8:
663.3370, found: 663.3375; chiral HPLC analysis: Chiralcel AD-H column, Hexane/iPrOH 70 : 30,
flow rate = 1 mL/min, λ = 240 nm, retention times: 8.4, 11.9 min.
Di-tert-butyl (R)-1-(3-benzyl-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3fa) [24]. White solid;
[α]D28 = −7.83 (c = 1.0, CHCl3, 70% ee); 1H-NMR (300 MHz, CDCl3) δH = 7.95 (dd, J = 5.3, 3.2 Hz, 1H),
7.26 (s, 1H), 7.11 (dd, J = 5.6, 3.2 Hz, 2H), 7.06–6.88 (m, 4H), 6.71 (d, J = 7.0 Hz, 2H), 6.44 (dd, J = 5.5,
3.1 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.15 (d, J = 12.1 Hz, 1H), 1.58 (s, 9H), 1.23 (d, J = 2.6 Hz, 9H);
13C-NMR (101 MHz, CDCl3) δC = 177.66, 156.33, 152.80, 139.96, 132.90, 130.45, 128.41, 127.39, 126.75,
124.88, 122.81, 109.06, 82.69, 81.47, 69.96, 42.19, 28.29, 27.82; chiral HPLC analysis: Chiralcel AD-H
column, Hexane/iPrOH 90 : 10, flow rate = 1 mL/min, λ = 240 nm, retention times: 8.9, 10.6 min.
Di-tert-butyl (R)-1-(3-(4-methoxybenzyl)-2-oxoindolin-3-yl)-hydrazine-1,2-dicarboxylate (3ga) [24]. Yellow
28
oil; [α
]
D
=
−
102.12 (c = 1.0, CHCl3, 93% ee); 1H-NMR (300 MHz, CDCl3) δH = 7.97–7.88 (m, 1H), 7.11
(d, J = 4.1 Hz, 3H), 6.80 (s, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.1 Hz, 2H), 6.46 (s, 1H), 3.69 (s,
3H), 3.29 (d, J = 12.2 Hz, 1H), 3.10 (d, J = 12.1 Hz, 1H), 1.57 (s, 9H), 1.22 (s, 9H); 13C-NMR (101 MHz,
CDCl3) δC = 177.67, 158.40, 156.29, 153.12, 131.42, 128.37, 124.81, 122.79, 112.84, 109.11, 82.66, 81.47,
69.93, 55.02, 41.36, 28.28, 27.83; chiral HPLC analysis: Chiralcel AD-H column, Hexane/iPrOH 90 : 10,
flow rate = 1 mL/min, λ = 240 nm, retention times: 13.1, 15.9 min.
Di-tert-butyl-1-[3-(4-nitrobenzyl)-2-oxoindolin-3-yl]-hydrazine-1,2-dicarboxylate (3ha). Red oil; [α]D28 = −32.43
(c = 1.0, CHCl3, 80% ee); 1H-NMR (300 MHz, CDCl3) δH = 7.97 (dd, J = 5.2, 3.3 Hz, 1H), 7.84 (d, J = 8.8 Hz,
2H), 7.14 (dd, J = 5.6, 3.2 Hz, 2H), 6.94 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.46 (dd, J = 5.5, 3.1 Hz, 1H), 3.40 (d,
J = 11.9 Hz, 1H), 3.22 (d, J = 11.9 Hz, 1H), 1.57 (s, 9H), 1.22 (s, 9H); 13C-NMR (101 MHz, CDCl3) δC = 177.18,
156.42, 152.93, 147.01, 140.96, 139.71, 131.34, 129.02, 124.92, 123.21, 122.52, 109.46, 83.06, 81.81, 69.57, 41.88,
28.28, 27.81; HRMS (ESI-MS) calculated for C25H30N4O6: 482.2165, found: 480.2332; chiral HPLC analysis:
Chiralcel AD-H column, Hexane/iPrOH 90 : 10, flow rate = 1 mL/min,
28.6 min.
λ = 240 nm, retention times: 18.9,
Di-tert-butyl (R)-1-[02-oxo-3-(4-(trifluoromethyl)benzyl)-indolin-3-yl]hydrazine-1,2-dicarboxylate (3ia) [24].
28
Yellow oil; [
α
]
D
=
−
98.62 (c = 1.0, CHCl3, 99% ee); 1H-NMR (300 MHz, CDCl3) δH = 8.01–7.86 (bs, 1H),
7.40 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.15–7.09 (m, 2H), 6.98 (s, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.43 (bs, 1H),
3.34 (d, J = 12.0 Hz, 1H), 3.18 (d, J = 12.0 Hz, 1H), 1.57 (s, 9H), 1.22 (s, 9H); 13C-NMR (101 MHz, CDCl3)
δC = 177.32, 156.36, 152.98, 139.85, 137.24, 130.76, 130.24, 128.75, 124.84, 124.22, 122.98, 109.33, 82.88,
81.67, 69.67, 41.87, 28.27, 27.80; chiral HPLC analysis: Chiralcel AD-H column, Hexane/iPrOH 95 : 05
,
flow rate = 1 mL/min, λ = 240 nm, retention times: rt = 16.2, 20.4 min.
Di-tert-butyl (R)-1-(5-methyl-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)-hydrazine-1,2-dicarboxylate (11a).
28
Colorless oil; [
α
]
=
−
23.86 (c = 1.0, CHCl3, 55% ee); 1H-NMR (300 MHz, CDCl3) δH = 7.88 (s, 1H),
D
7.57 (dd, J = 6.7, 2.9 Hz, 2H), 7.36–7.32 (m, 3H), 7.23–7.13 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.28 (s, 1H),
2.47 (s, 3H), 1.34 (s, 9H), 1.29 (s, 9H); 13C-NMR (101 MHz, CDCl3) δC = 174.61, 154.62, 153.21, 150.91,
133.92, 132.85, 130.84, 130.13, 129.27, 129.02, 128.46, 128.31, 127.55, 110.73, 110.36, 83.85, 81.18, 71.45,
28.01, 27.78, 21.46; HRMS (ESI-MS) calculated for C40H47N2NaO6: 674.3332, found: 674.2301; chiral

Molecules 2018, 23, 1374
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HPLC analysis: Chiralcel AD-H column, Hexane/iPrOH 70 : 30, flow rate = 1 mL/min,
retention times: 7.4, 16.9 min.
λ
= 240 nm,
4. Conclusions
In summary, in this work we have described the use of readily available chiral trans-
cyclohexanediamine-benzimidazole derivative ( ) as an organocatalyst for the asymmetric electrophilic
5
amination of 3-substituted oxindoles employing di-t-butylazodicarboxylate as the aminating agent.
In general, for this challenging transformation, which avoids the need for protection of the oxindole
substrate, the amination products were obtained in good yields and with enantioselectivities
varying from good to high when 10 mol % of catalyst was employed. On the contrary, moderate
enantioselectivities were achieved with benzofuranone derivatives. Finally, according to some
experimental finds and assuming the bifunctional role of the catalyst, a possible catalytic cycle has
been postulated. However, a more comprehensive study of the reaction mechanism is necessary.
Supplementary Materials: The following are available online. General remarks and as well as NMR spectra and
HPLC charts of amination compounds are provided.
Author Contributions: A.B. conceived and designed the experiments; L.B., A.B. and M.F. performed the
experiments and analyzed the data; A.B., L.B. and M.F. wrote the paper.
Acknowledgments: Financial support from the Spanish Ministerio de Economía, Industria y Competitividad
(CTQ2015-66624-P) and the University of Alicante (VIGROB-173, VIGROB-285, UAUSTI17-06, UADIF17-27) is
acknowledged. M.F. thanks the University of Edinburgh for an ERASMUS fellowship.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3aa–3ia are available from the authors.
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