Chiral Bifunctional Thiosquaramides as Organocatalysts in the Synthesis of Enantioenriched 3,3-Disubstituted Oxindoles

Article abstract of DOI:10.1002/ejoc.201901327

Four novel chiral bifunctional thiosquaramides have been prepared from cyclopentyl dithiosquarates and diamines derived from natural l-Valine and l-tert-Leucine. The novel thiosquaramides have been tested as organocatalyst in the nitro-Michael addition of 3-substituted oxindoles to different β-aryl-substituted nitroalkenes. The reaction occurred easily in high yields and excellent stereoselectivities, showing that the novel organocatalysts are much more effective than their thioureas and squaramides homologs.

Full text of DOI:10.1002/ejoc.201901327

DOI: 10.1002/ejoc.201901327
Full Paper
Asymmetric Organocatalysis
Chiral Bifunctional Thiosquaramides as Organocatalysts in the
Synthesis of Enantioenriched 3,3-Disubstituted Oxindoles
Patricia Rodríguez-Ferrer,[a] Daniel Naharro,[a] Alicia Maestro,[a] José M. Andrés*[a] and
Rafael Pedrosa*[a]
Abstract: Four novel chiral bifunctional thiosquaramides have substituted nitroalkenes. The reaction occurred easily in high
been prepared from cyclopentyl dithiosquarates and diamines yields and excellent stereoselectivities, showing that the novel
derived from natural L-Valine and L-tert-Leucine. The novel thio- organocatalysts are much more effective than their thioureas
squaramides have been tested as organocatalyst in the nitro- and squaramides homologs.
Michael addition of 3-substituted oxindoles to different ꢀ-aryl-
Introduction
ployed electrophile used in organocatalyzed conjugate addi-
tions and the possibilities of transformations of the nitro func-
tionality in the final products. The synthesis of enantioenriched
3,3-disubstituted oxindoles has received a lot of attention,[11]
but the most studied organocatalyzed transformation refers to
the Michael addition of 3-substituted oxindoles to nitroolefins
catalyzed by bifunctional thioureas. In that way, bifunctional
thioureas bearing as chiral appendage cinchona alkaloids,[12]
1,2-cyclohexanediamine,[13] and 1,2-diphenyl ethylenedi-
amine[14] have been used with high effectiveness.
Organocatalyst such as guanidines,[15] phosphoramides,[16]
aminoindanol,[17] phase-transfer catalysts,[18] chiral secondary
amines,[19] or bifunctional squaramides derived from 1,2-cyclo-
hexane diamine,[20] and quinine[21] have been also used to pro-
mote the same stereoselective addition. Chiral bifunctional
thioureas have been also employed in enantioselective addi-
tions of 3-substituted oxindoles to maleimides,[22] and unsatu-
rated ketones or sulfones.[23]
Since the explosion of organocatalysis twenty years ago, a lot
of small metal-free molecules able to promote stereoselective
transformations have been developed. Among them, bifunc-
tional organocatalysts that activate both the nucleophile by a
basic appendage, and the electrophile by H-bond formation
behave as very efficient catalysts. The catalytic activity of these
structures is dependent on the strength of the formed
hydrogen bond, and the stereoselectivity on the nature of the
chiral appendage. Searching for the modification of the acidity
of the catalysts, chiral ureas,[1] thioureas,[2] and squaramides,[3]
have been the most common organocatalysts used in different
stereoselective transformations.
Thiosquaramides are known more than fifty years ago,[4] and
they have more acidic character than squaramides. They are
more soluble than squaramides in non-polar solvents as a con-
sequence of less self-aggregation, and they have been calcu-
lated to be better organocatalysts than thioureas or squar-
amides.[5] They have been used as anion transporters,[6] or in
the formation of complex transition metal derivatives,[7] but
only very recently it has described a general synthesis of these
substrates and used as organocatalysts.[8] Our interest in devel-
oping bifunctional organocatalysts[9] led us to consider the
preparation of novel bifunctional thiosquaramides and study if
they were able to promote enantioselective additions of
3-substituted oxindoles to nitrostyrenes.
Now we report on the synthesis of novel bifunctional chiral
thiosquaramides with diamines derived from (
L)-valine and
(L
)-tert-leucine (Th-sq-Ia,b and Th-sq-IIa,b, Figure 1), and their
unprecedented application as organocatalysts in the stereo-
selective synthesis of 3,3-disubstituted oxindoles with two
The selection of oxindole derivatives as nucleophiles was
motivated by the interest of the addition products as biological
active substrates,[10] and nitrostyrene because it is the most em-
[a] Instituto CINQUIMA and Departamento de Química Orgánica,
Facultad de Ciencias, Universidad de Valladolid,
Paseo de Belén 7, 47011 Valladolid, Spain
E-mail: jmandres@qo.uva.es
pedrosa@qo.uva.es
http://sintesisasimetrica.blogs.uva.es/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901327.
Figure 1. Organocatalysts used in this work.
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quaternary-tertiary stereocenters. Known thioureas (Th-Ia,b)[24]
and squaramides (sq-Ia,b)[25] have also tested in the same reac-
tion for comparative purposes.
Table 1. Screening of the catalysts and optimization of the reaction condi-
tions.
Results and Discussion
The synthesis of thiosquaramides was carried out in two steps
from cyclopentyl dithiosquarate 1[8a] as summarized in
Scheme 1. The reaction of dithiosquarate with 0.9 equivalents
of benzylamine or 3,5-bis(trifluoromethyl)benzylamine, in di-
chloromethane (DCM) at room temperature, lead to the mono-
displacement derivatives 2[8a] and 3, respectively, in good
yields. These hemidithiosquarates were transformed into the
final chiral bifunctional thiosquaramides (Th-sq-Ia,b, and Th-
sq-IIa,b) in moderate to good yields by reaction with 1.1 equiv-
Entry R1
Catalyst
Solvent Time
[h]
Product
[%][a]
dr[b]
er[c]
1
Me
Th-sq-Ia
Th-sq-Ia
Th-sq-Ia
Th-sq-Ia
Th-sq-Ia
Th-sq-Ia
Th-Ia
Th-Ib
sq-Ia
sq-Ib
Th-sq-Ib
Th-sq-IIa DCM
Th-sq-IIb DCM
Th-sq-Ia
Th-sq-Ib
Th-sq-IIb DCM
Th-sq-IIb DCM
THF
2
7aa (92)
7aa (84)
7aa (58)
7aa (97)
7aa (99)
7aa (98)
7aa (99)
7aa (67)
7aa (99)
7aa (62)
7aa (81)
7aa (82)
7aa (76)
7ba (80)
7ba (98)
7ba (95)
7ba (87)
7ca (67)
7da (96)
89:11
87:13
85:15
91:9
90:10
93:7
84:16
78:22
85:15
82:18
87:13
93:7
86:14
95:5
93:7
94:6
92:8
93:7
93:7
92:8
96:4
97:3
98:2
87:11
88:12
85:15
92:8
96:4
95:5
97:3
97:3
99:1
99:1
97:3
68:32
89:11
2
3
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
PhMe
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
4
4
2
2
5
2
1
1
alents of diamines[26] derived from natural
L-Valine and L-tert-
5[d]
6[e]
7
Leucine in DCM at room temperature. It is interesting to note
that, contrary to the very well-known synthesis of unsymmetri-
cally substituted squaramides, in our case it was not possible
to alter the order of incorporation of two different amines to
the thiosquaramides nucleus because the reaction of dithio-
8
9
10
11
12
13
14
15
16
17[f]
18
19
3
1.5
0.5
1
squarate 1 with the diamine derived from L-Valine leading to
the monosubstitution compound 4 did not work (Scheme 1).
We initiated a study to calibrate the activity of the novel
thiosquaramides against their thioureas (Th-Ia,b) and squaram-
ides (sq-Ia,b) homologs taken as reaction model the conjugate
addition of 3-phenyl-substituted oxindoles (5a–d) to trans-ꢀ-
nitrostyrene (6a) (Table 1). First, we focused our attention on
the identification of the best reaction conditions by using 3-
phenyl-1-methyl-substituted oxindole 5a as nucleophile, and
5 mol-% of thiosquaramide Th-sq-Ia as catalysts. The reaction
occurred easily at room temperature in THF yielding the addi-
tion product 7aa in excellent yield and good stereoselection
(entry 1 in Table 1), and similar results were obtained when the
DCM
DCM
1
1
Bn
Bn
Bn
0.5
2.5
2
Boc Th-sq-Ia
Th-sq-Ia
DCM
DCM
71:29
81:19
H
1
[a] Values refer to pure isolated compound. [b] Measured by HPLC. [c] Deter-
mined by HPLC on a chiral column, and correspond to the major diastereoiso-
mer. [d] Reaction at –20 °C. [e] Reaction at –78 °C. [f] Reaction performed
with 1 mol-% of catalyst Th-sq-IIb.
The effectiveness of all the catalysts was then tested under
reaction was carried out in toluene, although at expenses of the best experimental conditions (r.t., 5 mol-% of catalyst, DCM)
increase the reaction time (entry 2). The same reaction in (entries 7–13 in Table 1). From these data it is possible to con-
chloroform gave the addition product maintaining the stereo- clude that catalysts derived from
selectivity in much lower yield (entry 3), but the best yield, sq-Ia) are more diastereoselective, but less enantioselective
diastereo- and enantioselection were obtained in DCM (entry than those derived from -tert-Leucine (Th-Ib, sq-Ib, and Th-sq-
L-Valine (Th-Ia, sq-Ia, and Th-
L
4). Only a slight increase in the enantioselectivity was observed Ib) (compare entries 7, 9, 11, and 12 vs. 8, 10, 4 and 13, respec-
when the temperature was lowered to –20 °C (entry 5) or –78 °C tively), and that thiosquaramides are, in general, more effective
(entry 6).
catalysts than thioureas or squaramides in this reaction.
Scheme 1. Synthesis of thiosquaramides.
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To study the influence of the substituent on the nitrogen
atom we reacted different substituted oxindoles (5b–d) with
trans-ꢀ-nitrostyrene in the presence of thiosquaramides as the
best catalysts (entries 14–19). Interestingly, unsubstituted ox-
indole 5d easily reacted leading to 7da, but with lower stereo-
control than the methyl-substituted substrate 5a (compare en-
tries 19 and 4). The same fact was observed for the reaction of
N-Boc-substituted derivative 5c, in that case, the addition prod-
uct 7ca was obtained in moderate yield and very poor stereo-
control (entry 18). On the contrary, the reaction of N-benzyl-
substituted oxindole 5b was the most stereoselective reaction,
independently of the thiosquaramide used as catalyst (entries
14–16). Interestingly, only a slight increase in the reaction time
and lowering diastereoselectivity was observed when the ratio
of catalyst Th-sq-IIb can be decreased to 1 mol-% (entry 17).
Table 2. Scope of the reaction for different substituted N-benzyloxindoles
with nitroolefins.
Entry[a]
Reagents
Time
[h]
Product
[%][b]
dr[c]
er[c]
The influence in the reaction of the electronic nature of the
substituent at the oxindole and nitroolefin aromatic rings was
studied by using different 3-aryl-1-benzyl-5-substituted oxind-
oles 5b–l as nucleophiles, ꢀ-aryl nitroolefins 6a–f as electro-
philes and Th-sq-IIb as the best catalyst at room temperature
(Table 2). The electronic character of the nitroolefin has little or
no influence on the addition process. Both nitrostyrenes bear-
ing electron-withdrawing- (6b, c) or donating groups (6d) be-
have in a similar way that the parent nitrostyrene (6a), yielding
the addition products in excellent yield (81–97 %) and stereo-
selection (dr 92:8–94:6, er 97:3–99:1; compare entries 1–3 in
Table 2 vs. entry 16 in Table 1). The reaction of the naphthyl
derivative 6e was slower, although maintaining the excellent
yield and stereoselectivity (entry 4 in Table 2), but the furyl
nitroolefin 6f led to the addition product 7bf in good enantio-
selection and moderate yield and diastereoselectivity (entry 5).
1
2
3
4
5
6
7
5b/6b
5b/6c
5b/6d
5b/6e
5b/6f
5e/6a
5f/6a
5f/6a
5g/6a
5g/6a
5h/6a
5h/6a
5i/6a
5j/6a
5j/6a
5k/6a
5l/6a
5m/6a
0.5
2
0.5
5
7bb (81)
7bc (97)
7bd (81)
7be (98)
7bf (73)
7ea (84)
7fa (95)
7fa (95)
7ga (92)
7ga (82)
7ha (91)
7ha (72)[e]
7ia (71)
7ja (96)
7ja (98)
7ka (98)
7la (63)
7ma (83)
94:6
93:7
92:8
93:7
84:16
89:11
88:12
92:8
99:1
99:1
97:3
98:2
97:3
98:2
97:3
97:3
95:5
97:3
93:7
1
0.5
0.5
3
0.5
3
0.5
0.5
0.5
0.5
3
0.5
0.5
27
8[d]
9
86:14
90:10
82:18
10[d]
11
12[e]
13
14
15[d]
16
17
18[f]
97:3[e] 97:3[e]
97:3
99:1
91:9
97:3
98:2
> 99: < 1
95:5
60:40
81:19
90:10
99:1
79:21
The effect of a substituent at the aromatic ring in the oxind-
ole was studied by reacting compounds 5e–i, with a substitu-
ent at C-5, and the C-7 substituted oxindole 5j, with nitro-
styrene 6a (entries 6–15 in Table 2). Interestingly, the presence
of a methyl group (5e) or a halogen (5f–h) at C-5 in the oxind-
ole nucleus does not modify the reactivity of the nucleophile,
although decreased the diastereoselection maintaining the ex-
cellent enantioselectivity (entries 6, 7, 9, and 11 in Table 2). To
demonstrate the interest of the process, the reaction of 5h with
6a was tenfold scaled up with similar results, but increasing the
stereoselection to 97:3 dr and 97:3 er, after recrystallization of
7ha (entry 12 in Table 2). On the other hand, the stereoselec-
tion was recovered to excellent levels when the reaction was
carried out at low temperature (–40 °C) for longer reaction
times (entries 8, 10). The only exception to that general behav-
ior corresponds to 5-methoxy oxindole 5i, which gave the addi-
tion product 7ia in lower yield although very good diastereo-
and enantioselection (entry 13).
[a] The reactions were carried out with 0.15 mmol of oxindole, 0.30 mmol of
nitroalkene, and 5 mol-% of catalysts in 0.2 mL of DCM. [b] Values refer to
pure compounds after column chromatography. [c] Measured by HPLC on a
chiral column. [d] The reaction was carried out at –40 °C. [e] The reaction
was scaled up to 1.5 mmol of nucleophile, and yield, dr, and er were deter-
mined after recrystallization. [f] The reaction was carried out with 20 mol-%
of catalyst.
at C-3 easily reacted with nitrostyrene yielding 7ka in good
diastereoselectivity and excellent yield and enantioselection
but 5l, with an electron-donating (MeO) group at the same po-
sition gave the addition product 7la with total stereoselectivity
in moderate yield (entries 16, 17 in Table 2).
The absolute stereochemistry of the major enantiomer was
determined as (R,R) by XR-diffraction analysis for 7ha[27] (Fig-
ure 2), and extended for all the addition products by analogy.
Furthermore, in an attempt to increase the scope of the proc-
ess we study the reaction of the less acidic 3-methyl-substituted
oxindole 5m with nitrostyrene. As expected, the reaction was
really slow (120 h) when 5 mol-% of catalyst was used, but it
was completed in 24 h with good yield, moderate diastereo-
selection (dr 79:21), and excellent enantioselection (er 95:5) by
increasing the ratio of catalyst Th-sq-IIb to 20 mol-% (entry 18
Oxindole 5j, with an electron-withdrawing substituent at
C-7 also reacted easily with nitrostyrene, but yielding 7ja in
very poor diastereoselection. Fortunately, both the diastereo-
and enantioselectivity were improved at low temperature (com-
pare entries 14 and 15 in Table 2). On the contrary, the elec-
tronic nature of a substituent at C-4 in the aryl group attached in Table 2). As an example of the synthetic utility of the reaction
to C-3 in the oxindole plays an important role in the reaction. we have prepared, in two steps, the enantioenriched spiroox-
Thus, compound 5k with a 4′-trifluromethyl phenyl substituent indolyl lactam 8, with two contiguous quaternary-tertiary
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Experimental Section
General: New compounds were characterized by 1H NMR
(500 MHz), 13C NMR (126 MHz), high-resolution mass spectrometry
(Agilent 5973, ESI-QTOF), IR spectroscopy (Perkin-Elmer Spectrum
One FT-IR spectrometer), and elemental analysis (Elemental Analysis
Center of the Complutense University of Madrid, using a Perkin
Elmer 2400 CHN). Chemical shifts for protons and carbons are re-
ported in ppm from TMS with the residual CHCl3 resonance for
protons, and carbon resonance of the solvent for carbons as internal
references. Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad), coupling constants in Hertz, and integration.
Specific rotations (concentration given in g per 100 mL) were meas-
ured on a Perkin–Elmer 341 digital polarimeter using a 5-mL cell
with a 1-dm path length, and sodium lamp. Melting points were
obtained with open capillary tubes and are uncorrected. TLC analy-
sis was performed on glass-backed plates coated with silica gel 60
and an F254 indicator, and visualized by either UV irradiation or by
staining with phosphomolybdic acid solution, and Column chroma-
tography was carried out using silica gel (230–240 mesh).
Figure 2. ORTEP representation of the structure of 7ha determined by X-ray
diffraction analysis. The thermal ellipsoids are shown at 50 % probability.
stereocenters as summarized in Scheme 2. This compound class
has recently received a great synthetic interest[28] because of
their important biological properties.[29]
Chiral HPLC analysis was performed on a JASCO HPLC system
(JASCO PU-2089 pump and UV-2075 UV/Vis detector) and on Hew-
lett–Packard 1090 Series II instrument equipped with a quaternary
pump, using a Chiralpak IA, Lux-amylose-1 and Lux-i-Amylose-1 an-
alytical columns (250 × 4.6 mm). UV detection was monitored at
220 or at 254 nm.
Commercially available organic and inorganic compounds were
used without further purification. Solvents were dried and stored
over microwave-activated 4 Å molecular sieves. Known compounds
1,[8a] 2,[8a] 5a–b, d, l,[31] 5c,[32] 5e,[33] 5m,[34] and 5n[35] have been
prepared as described in the literature.
Scheme 2. Two steps synthesis of spirooxindolyl lactam 8.
3-{[3,5-Bis(trifluoromethyl)benzyl]amino}-4-(cyclopentoxy)-
cyclobut-3-ene-1,2-dithione (3): To a solution of 1 (1.20 g,
4.25 mmol, 1.0 equiv.) in dry CH2Cl2 (20 mL) was added 3,5-bis(tri-
fluoromethyl)benzylamine (0.42 mL, 3.83 mmol, 0.90 equiv.) at 0 °C
and the resulting solution was stirred for 15 min at that tempera-
ture, and then 15 min at room temperature. The solution was trans-
ferred to a silica gel column and quickly eluted with CH2Cl2 to afford
3 (1.18 g, 2.68 mmol, 70 %) as an amorphous yellow solid¸ m.p.
84–85 °C. The compound exists as a mixture of two rotamers in
A solution of 5n and trans-ꢀ-nitrostyrene (6a) in DCM was
stirred at r.t. for 24 h in the presence of 20 mol-% of Th-sq-
IIb leading to the addition product 7na in good yield (82 %),
moderate diastereoselectivity (dr 79:21), and excellent enantio-
selection (ee 94:6). The major diastereoisomer was isolated by
flash chromatography, and transformed into spirooxindolyl
lactam 8 (83 %) by reduction of the nitro group with Zn/
HOAc,[30] and in situ lactamization. HPLC on a chiral phase
shown that compound 8 was obtained with the same enantio-
meric ratio than 7na, showing that no epimerization occurred
during the reduction–lactamization process.
1
DMSO at room temperature in a ratio 0.61:0.37. Major rotamer: H
NMR (500 MHz, [D6]DMSO) δ = 10.14 (t, J = 6.0 Hz, 1H), 8.10 (s, 1H),
8.04 (s, 2H), 6.34 (m, 1H), 4.76 (d, J = 6.0 Hz, 2H), 2.00–1.84 (m, 4H),
1.77–1.57 (m, 4H) ppm. Minor rotamer: 1H NMR (500 MHz,
[D6]DMSO) δ = 10.07 (t, J = 6.0 Hz, 1H), 8.10 (s, 1H), 8.04 (s, 2H),
6.29 (m, 1H), 5.37 (d, J = 6.0 Hz, 2H), 2.00–1.84 (m, 4H), 1.77–1.57
Conclusions
(m, 4H) ppm. 13C NMR (126 MHz, [D6]DMSO) δ = 217.9, 217.7, 206.8,
2
206.8, 183.5, 182.8, 176.1, 173.8, 141.1, 141.0, 130.9 (q, JC-F
=
We have prepared four novel thiosquaramides in two steps by
sequential transamination of cyclopentyl dithiosquarate with
benzylamine or 3,5-bis(trifluoromethyl)benzylamine, and chiral
2
32.9 Hz), 130.9 (q, JC-F = 32.9 Hz), 129.5 (m), 129.2 (m), 123.7 (q,
1JC-F = 272.8 Hz), 122.0 (m), 87.9, 87.8, 47.5, 45.5, 35.4, 34.2, 34.1,
23.7, 23.5, 23.4 ppm. IR (ATR): ν = 3242, 2964, 1693, 1514, 1415,
˜
diamines derived from L-Valine or L-tert-Leucine. These thio-
6 8 1 c m – 1 . H R M S ( E S I - QTO F ) m / z : [ M + H ] + C a l c d. for
squaramides have been tested as organocatalysts in the stereo-
selective addition of 3-substituted oxindoles to different trans-
ꢀ-aryl nitroolefins. The reported data show that the nitro-
Michael addition occurred in high yield and diastereoselectivity,
and excellent enantioselection. The novel organocatalysts pro-
vide much better results than their thiourea or squaramide
counterparts. The described strategy has been applied as a key
step in the synthesis of an example of enantioenriched biologi-
cally active spirooxindolyl lactam.
C18H15F6NNaOS2 462.0391, found 462.0395.
(S)-3-(Benzylamino)-4-{[1-(dimethylamino)-3-methylbutan-2-
yl]amino}cyclobut-3-ene-1,2-dithione (Th-sq-Ia): To a solution of
2 (300 mg, 0.99 mmol) in anhydrous CH2Cl2 (4 mL) was added drop-
wise a solution of (S)-N1,N1,3-trimethylbutane-1,2-diamine[26]
(142 mg, 1.09 mmol, 1.1 equiv.) in anhydrous CH2Cl2 (0.5 mL) at
0 °C and the resulting solution was stirred for 5 min at that tempera-
ture, and then 36 h at room temperature. The solvent was removed
under vacuum and immediately purified by flash column chroma-
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tography (CH2Cl2/MeOH: 50:1) to afford catalyst Th-sq-Ia as a brown
2.23 (br, 6H), 0.91 (s, 9H) ppm. 13C NMR (126 MHz, [D6]DMSO) δ =
solid (206 mg, 0.60 mmol, 60 %); m.p. 129–130 °C. [α]2D3 = –94.3 (c = 205.5, 205.5, 171.4, 171.0, 141.7, 131.0 (q, 2JC-F = 32.6 Hz), 129.5 (m),
0.30, CHCl3). 1H NMR (500 MHz, [D6]DMSO) δ = 9.02 (br, 1H), 8.57
129.0 (m), 123.7 (q, 1JC-F = 273.0 Hz) 122.1 (m), 59.2, 58.8, 45.6, 45.3,
(br, 1H), 7.43–7.30 (m, 5H), 5.36 (d, J = 13.2 Hz, 1H), 5.26 (d, J = 34.4, 26.4 ppm. IR (ATR): ν = 3242, 3162, 2964, 1707, 1575, 1476, 704,
˜
13.2 Hz, 1H), 5.18 (br, 1H), 2.57 (br, 1H), 2.39 (br, 1H), 2.25 (br, 6H),
1.85 (br, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H) ppm.
13C NMR (126 MHz, [D6]DMSO) δ = 204.4, 204.0, 171.3, 170.5, 137.9,
129.3, 128.6, 128.3, 61.1, 55.5, 46.5, 45.6, 31.2, 19.4, 17.1 ppm. IR
681 cm–1. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd. for C21H26F6N3S2
498.1467, found 498.1485.
General Procedure for the Synthesis of Oxindoles 5f–k: The syn-
thesis of these compounds was carried out in two steps as de-
scribed previously.[31] To a cooled solution (0 °C) of the correspond-
ing benzylisatin (17.0 mmol) in THF (55 mL) was added a solution
of the corresponding arylmagnesium bromide in Et2O (20.4 mmol,
1.2 equiv.) under nitrogen atmosphere. The mixture was warmed to
(ATR): ν = 3170, 2958, 1703, 1569, 1453, 732, 696 cm–1. HRMS (ESI-
˜
QTOF) m/z: [M + H]+ Calcd. for C28H26N3S2 348.1559, found
348.1563.
(S)-3-(Benzylamino)-4-{[1-(dimethylamino)-3,3-dimethylbutan-
2-yl]amino}cyclobut-3-ene-1,2-dithione (Th-sq-Ib): To a solution room temperature and stirred for 30 min. The reaction was
of 2 (300 mg, 0.99 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (4 mL)
quenched with MeOH (20 mL) and aqueous solution of NH4Cl
was added dropwise a solution of (S)-N1,N1,3,3-tetramethylbutane- (20 mL), and extracted with EtOAc (3 × 20 mL). The organic layer
1,2-diamine[26] (157 mg, 1.09 mmol, 1.1 equiv.) in dry CH2Cl2 was washed with brine, dried with anhydrous MgSO4, and concen-
(0.5 mL) at 0 °C and the resulting solution was stirred for 5 min at
trated under reduced pressure to give an orange oil. The com-
that temperature, and then 36 h at room temperature. The solvent pounds were purified by flash column chromatography on silica gel
was removed under vacuum and immediately purified by flash col-
umn chromatography (CH2Cl2/MeOH: 50:1) to afford catalyst Th-sq-
Ib as a brown solid (182 mg, 0.505 mmol, 51 %); m.p. 138–139 °C.
[α]2D3 = –77.3 (c = 0.30, CHCl3). 1H NMR (500 MHz, [D6]DMSO) δ =
8.85 (br, 1H), 8.51 (br, 1H), 7.43–7.32 (m, 5H), 5.36 (d, J = 14.3 Hz,
1H), 5.28 (d, J = 14.2 Hz, 1H), 5.06 (br, 1H), 2.48 (m, 2H), 2.18 (br,
6H), 0.91 (s, 9H) ppm. 13C NMR (126 MHz, [D6]DMSO) δ = 204.5,
204.0, 171.4, 170.4, 137.9, 129.3, 128.7, 128.3, 59.3, 58.7, 46.5, 45.6,
(CH2Cl2/pentane, 1:1 to CH2Cl2 to CH2Cl2/MeOH, 9:1) affording the
corresponding 3-hydroxy-3-arylindolin-2-ones.
A mixture of the corresponding 3-hydroxy-3-arylindolin-2-one
(17.0 mmol) in 95 mL of HOAc, and SnCl2 (34.0 mmol, 2 equiv.) was
stirred at 110 °C for 2 h and then cooled to room temperature. After
elimination of the HOAc under vacuum, the residue was diluted
with EtOAc. The solution was successively washed with water, an
aqueous solution of NaHCO3, brine, and dried with MgSO4. The
mixture was purified by flash chromatography on silica gel (hexane/
EtOAc, 8:1 to 4:1) to give the final compounds as white solids.
34.4, 26.4 ppm. IR (ATR): ν = 3172, 2958, 1704, 1569, 1477, 727,
˜
696 cm–1. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd. for C19H28N3S2
362.1719, found 362.1721.
1-Benzyl-5-fluoro-3-phenylindolin-2-one (5f): Compound 5f was
obtained according to the general procedure using 1-benzyl-5-
fluoroindoline-2,3-dione[36] (4.34 g, 17.0 mmol). Purification by flash
column chromatography on silica gel (hexane/EtOAc: 8:1 to 4:1) af-
forded the pure compound as a white solid (3.08 g, 9.7 mmol, 57 %);
(S)-3-{[3,5-Bis(trifluoromethyl)benzyl]amino}-4-{[1-(dimethyl-
amino)-3-methylbutan-2-yl]amino}cyclobut-3-ene-1,2-dithione
(Th-sq-IIa): To a solution of 3 (439 mg, 1.0 mmol) in dry CH2Cl2
(4 mL) was added dropwise a solution of (S)-N1,N1,3-trimethylbu-
tane-1,2-diamine[26] (143 mg, 1.1 mmol, 1.1 equiv.) in dry CH2Cl2
(0.5 mL) at 0 °C and the resulting solution was stirred for 5 min at
that temperature, and then 20 h at room temperature. The solvent
was removed under vacuum and immediately purified by flash col-
umn chromatography (CH2Cl2/MeOH: 50:1) to afford catalyst Th-sq-
1
m.p. 118–119 °C. H NMR (500 MHz, CDCl3) δ = 7.40–7.25 (m, 8H),
7.24–7.19 (m, 2H), 6.93–6.87 (m, 2H), 6.73- 6.66 (m, 1H), 4.99 (d, J =
15.7 Hz, 1H), 4.89 (d, J = 15.7 Hz, 1H), 4.70 (s, 1H) ppm. 13C NMR
(126 MHz, CDCl3) δ = 175.7, 159.31 (d, 1JC-F = 241.0 Hz), 139.4, 136.1,
3
135.6, 130.5 (d, JC-F = 8.5 Hz), 129.1, 128.9, 128.4, 127.9, 127.8,
IIa as a brown solid (290 mg, 0.6 mmol, 60 %) m.p. 123–124 °C.
¸
2
2
127.3, 114.64 (d, JC-F = 23.4 Hz), 113.16 (d, JC-F = 24.8 Hz), 109.7
[α]2D3 = –24.0 (c = 0.20, CHCl3). 1H NMR (500 MHz, [D6]DMSO) δ =
9.13 (br, 1H), 8.77 (br, 1H), 8.16 (s, 2H), 8.05 (s, 1H), 5.54 (d, J =
15.1 Hz, 1H), 5.48 (d, J = 15.1 Hz, 1H), 5.19 (br, 1H), 2.64 (br, 1H),
2.50 (br, 1H), 2.30 (br, 6H), 1.87–1.85 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H),
0.87 (d, J = 6.8 Hz, 3H) ppm. 13C NMR (126 MHz, [D6]DMSO) δ =
205.2, 203.8, 171.4, 171.1, 141.6, 131.0 (q, 2JC-F = 33.1 Hz), 129.3 (m),
3
(d, JC-F = 8.1 Hz), 52.3, 44.1 ppm. IR (ATR): ν = 3065, 3031, 2919,
˜
2869, 1709, 1614, 1489, 1456, 799, 741, 695, 649 cm–1. HRMS (ESI-
QTOF) m/z: [M + Na]+ Calcd. for C21H16FNNaO 340.1108, found
340.1110.
1-Benzyl-5-chloro-3-phenylindolin-2-one (5g): Compound 5g
was obtained according to the general procedure using 1-benzyl-
5-chloroindoline-2,3-dione[37] (4.62 g, 17.0 mmol). Purification by
flash column chromatography on silica-gel (hexane/EtOAc: 8:1 to
4:1) afforded the pure compound as white solid (2.27 g, 6.8 mmol,
40 %); m.p. 149–150 °C. 1H NMR (500 MHz, CDCl3) δ = 7.39–7.27 (m,
8H), 7.22–7.19 (m, 2H), 7.17 (ddd, J = 8.3, 2.1, 0.8 Hz, 1H), 7.15–7.13
(m, 1H), 6.69 (d, J = 8.3 Hz, 1H), 4.99 (d, J = 15.6 Hz, 1H), 4.89 (d,
J = 15.6 Hz, 1H), 4.69 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3) δ =
175.6, 142.1, 136.0, 135.5, 130.6, 129.1, 128.9, 128.4, 128.3, 128.2,
1
123.7 (q, JC-F = 272.9 Hz), 121.9 (m), 60.9, 55.5, 45.3, 31.2, 19.3,
17.2 ppm. IR (ATR): ν = 3237, 3166, 2964, 1702, 1575, 1462, 704,
˜
681 cm–1. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd. for C20H24F6N3S2
484.1310, found 484.1328.
(S)-3-{[3,5-Bis(trifluoromethyl)benzyl]amino}-4-{[1-(dimethyl-
amino)-3,3-dimethylbutan-2-yl]amino}cyclobut-3-ene-1,2-dithi-
one (Th-sq-IIb): To a solution of 3 (439 mg, 1.0 mmol) in dry CH2Cl2
(4 mL) was added dropwise a solution of (S)-N1,N1,3,3-tetramethyl-
butane-1,2-diamine[26] (159 mg, 1.1 mmol, 1.1 equiv.) in dry CH2Cl2
(0.5 mL) at 0 °C and the resulting solution was stirred for 5 min at
that temperature, and then 3.5 h at room temperature. The solvent
was removed under vacuum and immediately purified by flash col-
umn chromatography (MeOH/CH2Cl2, 1:50) to afford catalyst Th-sq-
IIb as a brown solid (348 mg, 0.70 mmol, 70 %); m.p. 164–165 °C
127.9, 127.8, 127.3, 125.5, 110.1, 52.1, 44.1 ppm. IR (ATR): ν = 3063,
˜
3034, 2921, 2871, 1709, 1604, 1487, 1453, 1428, 743, 697, 663, cm–1
.
HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C21H16ClNNaO 356.0813,
found 356.0814.
1-Benzyl-5-bromo-3-phenylindolin-2-one (5h): Compound 5h
[α]2D3 = –22.0 (c = 0.10, CHCl3). 1H NMR (500 MHz, [D6]DMSO) δ = was obtained according to the general procedure using 1-benzyl-
9.02 (br, 1H), 8.71 (br, 1H), 8.16 (s, 2H), 8.08 (s, 1H), 5.55 (d, J =
15.0 Hz, 1H), 5.47 (d, J = 15.0 Hz, 1H), 5.06 (br, 1H), 2.48 (m, 2H),
5-bromoindoline-2,3-dione[38] (5.37 g, 17.0 mmol). Purification by
flash column chromatography on silica gel (hexane/EtOAc: 8:1 to
Eur. J. Org. Chem. 2019, 6539–6549
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4:1) afforded the pure compound as a white solid (3.34 g, 8.8 mmol,
cedure, using oxindole 5a, nitrostyrene 6a and catalyst Th-sq-Ia at
52 %); m.p. 173–174 °C. 1H NMR (500 MHz, CDCl3) δ = 7.39–7.27 (m, - 78 °C. The crude reaction mixture was purified by flash chromatog-
10H), 7.20 (m, 2H), 6.65 (d, J = 8.3 Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H),
4.88 (d, J = 15.7 Hz, 1H), 4.70 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
δ = 175.5, 142.6, 136.0, 135.4, 131.2, 131.0, 129.1, 128.9, 128.4, 128.2,
raphy (hexane/EtOAc: 8:1 to 4:1) leading to compound 7aa as an
inseparable mixture of diastereoisomers. White solid (55 mg,
0.147 mmol, 98 %). [α]2D3 = +130.5 [(c = 1.00, CHCl3) (dr = 93:7, 96 %
ee for the major diastereomer)]. 1H NMR for major diastereomer
127.9, 127.8, 127.3, 115.5, 110.7, 52.0, 44.0 ppm. IR (ATR): ν = 3059,
˜
3034, 2921, 2871, 1709, 1600, 1483, 1453, 713, 697 cm–1. HRMS (ESI- (500 MHz, CDCl3) δ = 7.70 (dt, J = 8.3, 1.1 Hz, 2H), 7.48–7.38 (m,
QTOF) m/z: [M + Na]+ Calcd. for C21H16BrNNaO 400.0307, found 4H), 7.29–7.23 (m, 1H), 7.14–7.08 (m, 1H), 7.07–7.01 (m, 3H), 6.84–
400.0316.
6.79 (m, 2H), 6.64 (dd, J = 8.3, 1.1 Hz, 1H), 5.00 (dd, J = 12.8, 12.1 Hz,
1H), 4.83 (dd, J = 15.3, 12.1 Hz, 1H), 4.74 (dd, J = 16.0, 12.7 Hz, 1H),
2.70 (s, 3H) ppm. 13C NMR for major diastereomer (101 MHz, CDCl3)
δ = 175.3, 144.6, 135.6, 133.4, 129.4, 129.2, 128.7, 128.4, 128.1, 127.7,
127.7, 126.7, 126.1, 122.3, 108.8, 76.0, 59.7, 50.7, 25.9 ppm. IR (ATR):
1-Benzyl-5-methoxy-3-phenylindolin-2-one (5i): Compound 5i
was obtained according to the general procedure using 1-benzyl-
5-methoxyindoline-2,3-dione[37] (4.54 g, 17.0 mmol). Purification by
flash column chromatography on silica gel (hexane/EtOAc: 8:1 to
4:1) afforded the pure compound as a white solid (4.20 g,
ν = 3060, 2923, 1709, 1610, 1552, 1493, 699 cm–1. HPLC: Lux-
˜
Amylose-1 column, hexane/isopropanol = 90:10, 1.0 mL/min, λ =
254 nm. Dr 93:7. Major diastereoisomer: tr = 14.72 min (minor
enantiomer), tr = 17.66 min (major enantiomer) (er 98:2). Minor dia-
stereoisomer: tr = 12.17 min (major enantiomer), tr = 16.67 min
(minor enantiomer) (er 77:23). HRMS (ESI-QTOF) m/z: [M + Na]+
Calcd. for C23H20N2NaO3 395.1366, found 395.1384.
1
12.75 mmol, 75 %); m.p. 127–128 °C. H NMR (400 MHz, CDCl3) δ =
7.38–7.19 (m, 10H), 6.78–6.75 (m, 1H), 6.74–6.69 (m, 1H), 6.65 (d, J =
8.5 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.86 (d, J = 15.7 Hz, 1H), 4.67
(s, 1H), 3.70 (s, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ = 175.8, 156.1,
137.0, 136.8, 136.0, 130.2, 129.0, 128.8, 128.5, 127.6, 127.6, 127.3,
112.9, 112.3, 109.6, 55.7, 52.5, 44.0 ppm. IR (ATR): ν = 3063, 3034,
˜
2917, 2833, 1700, 1600, 1491, 793, 734, 697 cm–1. HRMS (ESI-QTOF)
(R)-1-Benzyl-3-[(R)-2-nitro-1-phenylethyl]-3-phenylindolin-2-
one (7ba): Product 7ba was obtained from oxindole 5b, nitrostyr-
ene 6a and catalyst Th-sq-IIb. The crude reaction mixture was puri-
fied by flash chromatography (hexane/EtOAc: 8:1 to 4:1) leading to
compound 7ba as an inseparable mixture of diastereoisomers.
White solid, (63 mg, 0.142 mmol, 98 %). [α]2D3 = +86.5 [(c = 1.00,
m/z: [M + Na]+ Calcd. for C22H19NNaO2 352.1308, found 352.1313.
1-Benzyl-3-phenyl-7-(trifluoromethyl)indolin-2-one (5j): Com-
pound 5j was obtained according to the general procedure using 1-
benzyl-7-(trifluoromethyl)indoline-2,3-dione[39] (5.19 g, 17.0 mmol).
Purification by flash column chromatography on silica gel (hexane/
EtOAc: 8:1 to 4:1) afforded the pure compound as a white solid
(2.19 g, 5.95 mmol, 35 %); m.p. 178–179 °C. 1H NMR (500 MHz,
CDCl3) δ = 7.60 (d, J = 8.1 Hz, 1H), 7.40–7.30 (m, 4H), 7.29–7.24 (m,
2H), 7.23–7.18 (m, 3H), 7.16–7.10 (m, 3H), 5.28 (d, J = 16.9 Hz, 1H),
5.20 (d, J = 16.9 Hz, 1H), 4.72 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
δ = 177.0, 141.7, 136.3, 136.0, 131.6, 129.1, 129.0, 128.5, 128.3, 128.0,
1
CHCl3) (dr = 94:6, 98 % ee for the major diastereomer)]. H NMR for
major diastereomer (500 MHz, CDCl3) δ = 7.74–7.69 (m, 2H), 7.48–
7.41 (m, 3H), 7.30–7.21 (m, 4H), 7.18–7.04 (m, 5H), 6.97–6.92 (m, 2H),
6.53–6.47 (m, 1H), 6.42 (dd, J = 7.8, 1.4 Hz, 2H), 5.06 (dd, J = 12.4,
12.4 Hz, 1H), 4.96 (dd, J = 15.1, 12.2 Hz, 1H), 4.80 (d, J = 15.7 Hz,
1H), 4.77 (dd, J = 15.4, 12.5 Hz, 1H), 4.28 (d, J = 16.1 Hz, 1H) ppm.
13C NMR for major diastereomer (101 MHz, CDCl3) δ = 175.5, 143.8,
136.3, 134.7, 134.0, 129.4, 129.4, 129.3, 128.6, 128.5, 128.4, 128.3,
127.6, 127.3, 127.2, 126.4, 126.2, 122.4, 110.4, 76.8, 59.6, 50.7,
3
1
126.9, 126.6 (q, JC-F = 6.2 Hz) 125.8, 123.4 (q, JC-F = 271.7 Hz),
2
122.2, 112.9 (q, JC-F = 32.0 Hz), 50.7, 45.6 ppm. IR (ATR): ν = 3038,
˜
2925, 1725, 1591, 1495, 1453, 697 cm–1. HRMS (ESI-QTOF) m/z: [M
43.9 ppm. IR (ATR): ν = 3065, 2923, 1710, 1610, 1552, 1489, 695 cm–1
.
+ Na]+ Calcd. for C22H16F3NNaO 390.1076, found 390.1083.
˜
HPLC: Lux-i-Amylose-1 column, hexane/isopropanol = 90:10,
1.0 mL/min, λ = 254 nm. Dr 94:6. Major diastereoisomer: tr =
20.42 min (minor enantiomer), tr = 48.82 min (major enantiomer)
(er 99:1). Minor diastereoisomer: tr = 26.10 min (major enantiomer),
tr = 28.92 min (minor enantiomer) (er 80:20). HRMS (ESI-QTOF) m/z:
[M + Na]+ Calcd. for C29H24N2NaO3 471.1679, found 471.1685.
1-Benzyl-3-[4-(trifluoromethyl)phenyl]indolin-2-one (5k): Com-
pound 5k was obtained according to the general procedure using
1-benzylindoline-2,3-dione[40] (4.03 g, 17.0 mmol). Purification by
flash column chromatography on silica gel (hexane/EtOAc: 8:1 to
4:1) afforded the pure compound as a white solid (3.25 g,
1
8.84 mmol, 52 %); m.p. 145–146 °C. H NMR (500 MHz, CDCl3) δ =
tert-Butyl (R)-3-[(R)-2-Nitro-1-phenylethyl]-2-oxo-3-phenylind-
oline-1-carboxylate (7ca):[15,18] Product 7ca was obtained accord-
ing to the general procedure, from oxindole 5c, nitrostyrene 6a and
catalyst Th-sq-Ia. The crude reaction mixture was purified by flash
chromatography (hexane/EtOAc: 8:1 to 4:1) leading to compound
7ca as an inseparable mixture of diastereoisomers. Colorless oil
(46 mg, 0.10 mmol, 67 %). [α]2D3 = +36.6 (c = 1.00, CHCl3) [(dr =
71:29, 36 % ee for the major diastereomer)]. Lit.[15] [α]D23 = +242.7
7.61 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.33–7.23 (m, 5H),
7.24 (dt, J = 7.9, 1.0 Hz, 1H), 7.15 (m, 1H), 7.05 (td, J = 7.6, 0.9 Hz,
1H), 6.83 (ddd, J = 7.8, 1.0, 0.5 Hz, 1H), 4.99 (d, J = 15.6 Hz, 1H), 4.90
(d, J = 15.6 Hz, 1H), 4.77 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
δ = 175.2, 143.6, 140.7, 135.7, 129.9 (q, 2JC-F = 32.5 Hz), 128.9, 128.9,
3
1
128.8, 127.9, 127.8, 127.4, 125.9 (q, JC-F = 3.7 Hz), 124.0 (q, JC-F
=
273.8 Hz), 109.5, 51.7, 44.1 ppm. IR (ATR): ν = 3038, 2925, 1704,
˜
1608, 1491, 1466, 734, 697 cm–1. HRMS (ESI-QTOF) m/z: [M + Na]+
1
(c = 0.5, CHCl3) [dr 98:2, ee 89 % for (R,R)-enantiomer]. H NMR for
Calcd. for C22H16F3NNaO 390.1076, found 390.1080.
major diastereomer (400 MHz, CDCl3) δ = 7.69 (dt, J = 7.7, 1.3 Hz,
1H), 7.59 (ddq, J = 9.5, 8.4, 1.3 Hz, 3H), 7.45–7.38 (m, 4H), 7.16–7.11
(m, 1H), 7.06–7.01 (m, 3H), 6.77 (dt, J = 6.9, 1.2 Hz, 2H), 4.94 (t, J =
12.6, 12.2 Hz, 1H), 4.87 (dd, J = 12.1, 3.1 Hz, 1H), 4.77 (dd, J =
12.7, 3.1 Hz, 1H), 1.43 (s, 9H) ppm. 13C NMR for major diastereomer
(101 MHz, CDCl3) δ = 173.9, 148.3, 141.0, 135.4, 132.8, 129.6, 129.3,
128.8, 128.6, 128.4, 128.0, 127.9, 126.6, 125.7, 124.2, 115.7, 84.2, 75.8,
General Procedure for the Enantioselective Michael Addition:
A mixture of oxindole 5a–n (0.15 mmol), catalyst (0.0075 mmol,
0.05 equiv.) and nitroolefins 6a–f (0.3 mmol, 2 equiv.) in 0.2 mL of
DCM was stirred at r.t. in Wheaton vial until consumption of the
starting material (monitored by 1H-NMR). After solvent removal un-
der reduced pressure, the crude mixture was purified by flash col-
umn chromatography to afford the corresponding product. The
enantiomeric excess was determined by chiral-phase HPLC analysis
using mixtures of hexane/2-propanol as eluent.
60.1, 50.8, 27.8 ppm. IR (ATR): ν = 3973, 1784, 1709, 1610, 1551,
˜
1468, 741, 695 cm–1. HPLC: Lux-Amylose-1 column, hexane/isoprop-
anol = 98:2, 0.5 mL/min, λ = 254 nm. Dr 71:29. Major diastereoiso-
(R)-1-Methyl-3-[(R)-2-nitro-1-phenylethyl]-3-phenylindolin-2- mer: tr = 26.47 min (minor enantiomer), tr = 36.19 min (major
one (7aa): Product 7aa was obtained according to the general pro- enantiomer) (er 68:32). Minor diastereoisomer: tr = 25.22 min (major
Eur. J. Org. Chem. 2019, 6539–6549
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Full Paper
enantiomer), tr = 60.22 min (minor enantiomer) (er 58:42). HRMS
(ESI-QTOF) m/z: [M + Na]+ Calcd. for C27H26N2NaO5 481.1734, found
481.1752.
16.1 Hz, 1H) ppm. 13C NMR for major diastereomer (101 MHz, CDCl3)
δ = 175.3, 158.7 (d, JC-F = 242.1 Hz), 139.8, 135.7, 134.0 (d, J =
63.4 Hz), 129.4, 129.3, 128.8, 128.7, 128.7, 128.5, 128.5, 127.4, 127.3,
1
2
2
127.1, 126.4, 115.9 (d, JC-F = 23.0 Hz), 114.1 (d, JC-F = 24.7 Hz),
(R)-3-[(R)-2-Nitro-1-phenylethyl]-3-phenylindolin-2-one
(7da):[16] Product 7da was obtained according to the general proce-
dure, by reacting oxindole 5d, nitrostyrene 6a and catalyst Th-sq-Ia.
The crude reaction mixture was purified by flash chromatography
(hexane/EtOAc: 8:1 to 4:1) leading to compound 7da as an insepara-
ble mixture of diastereoisomers. Colorless oil (52 mg, 0.144 mmol,
96 %). [α]2D3 = +137.7 [(c = 0.70, CHCl3) (dr = 81:19, 78 % ee for the
major diastereomer)]. 1H NMR for major diastereomer (500 MHz,
CDCl3) δ = 7.98 (br, 1H), 7.69–7.62 (m, 2H), 7.43–7.39 (m, 4H), 7.28–
7.22 (m, 1H), 7.12–7.08 (m, 1H), 7.04–6.99 (m, 3H), 6.86 (dd, J = 8.3,
1.3 Hz, 2H), 6.75 (dt, J = 7.8, 0.8 Hz, 1H), 5.00 (t, J = 12.8, 12.0 Hz,
1H), 4.83 (dd, J = 15.2, 12.1Hz, 1H), 4.74 (dd, J = 15.9, 12.7Hz, 1H)
ppm. 13C NMR for major diastereomer (101 MHz, CDCl3) δ = 177.5,
141.7, 135.7, 133.5, 129.5, 129.2, 128.9, 128.4, 128.2, 128.0, 127.8,
3
111.0 (d, JC-F = 8.0 Hz), 76.4, 60.1, 50.5, 44.0 ppm. IR (ATR): ν =
˜
3060, 2923, 1705, 1601, 1552, 1489, 1452, 737, 695 cm–1. HPLC: Lux-
i-Amylose-1 column, hexane/isopropanol = 95:5, 1.0 mL/min, λ =
254 nm. Dr 92:8. Major diastereoisomer: tr = 27.45 min (minor
enantiomer), tr = 89.04 min (major enantiomer) (er 97:3). Minor dia-
stereoisomer: tr = 44.99 min (major enantiomer), tr = 48.64 min
(minor enantiomer) (er 67:32). HRMS (ESI-QTOF) m/z: [M + Na]+
Calcd. for C29H23FN2NaO3 489.1585, found 489.1587.
(R)-1-Benzyl-5-chloro-3-[(R)-2-nitro-1-phenylethyl]-3-phenyl-
indolin-2-one (7ga): Product 7ga was obtained according to the
general procedure, using oxindole 5g, nitrostyrene 6a and catalyst
Th-sq-IIb at - 40 °C. The crude reaction mixture was purified by
flash chromatography (hexane/EtOAc: 8:1 to 4:1) leading to com-
pound 7ga as an inseparable mixture of diastereoisomers. White
solid (59 mg, 0.12 mmol, 82 %). [α]2D3 = +11.0 [(c = 0.40, CHCl3) (dr =
127.6, 126.4, 122.4, 110.7, 76.3, 60.0, 50.4 ppm. IR (ATR): ν = 3210,
˜
2923, 1709, 1618, 1552, 1473, 737, 695 cm–1. HPLC: Chiralpak IA
column, hexane/isopropanol = 95:5, 1.0 mL/min, λ = 254 nm. Dr
81:19. Major diastereoisomer: tr = 29.99 min (major enantiomer),
tr = 37.08 min (minor enantiomer) (er 89:11). Minor diastereoisomer:
tr = 32.50 min (major enantiomer), tr = 34.73 min (minor enantio-
mer). (er 68:32). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for
C22H18N2NaO3 381.1210, found 381.1219.
1
90:10, 94 % ee for the major diastereomer)]. H NMR for major dia-
stereomer (500 MHz, CDCl3) δ = 7.71–7.63 (m, 2H), 7.50–7.43 (m,
2H), 7.43–7.39 (m, 2H), 7.30–7.24 (m, 2H), 7.18–7.11 (m, 3H), 7.07
(dd, J = 8.3, 6.8 Hz, 2H), 7.01–6.94 (m, 2H), 6.44–6.35 (m, 3H), 5.03
(t, J = 12.3, 12.2 Hz, 1H), 4.95 (dd, J = 14.9, 12.1 Hz, 1H), 4.78 (d, J =
16.1 Hz, 1H), 4.76 (dd, J = 15.0, 12.4 Hz, 1H), 4.26 (d, J = 16.0 Hz,
1H) ppm. 13C NMR for major diastereomer (101 MHz, CDCl3) δ =
175.1, 142.4, 135.6, 134.2, 133.6, 129.8, 129.4, 129.3, 129.2, 128.7,
128.7, 128.5, 128.5, 127.9, 127.4, 127.4, 127.0, 126.4, 111.3, 76.4, 59.9,
(R)-1-Benzyl-5-methyl-3-[(R)-2-nitro-1-phenylethyl]-3-phenyl-
indolin-2-one (7ea): Product 7ea was obtained according to the
general procedure, using oxindole 5e, nitrostyrene 6a and catalyst
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7ea as
an inseparable mixture of diastereoisomers. White solid (58 mg,
0.13 mmol, 84 %). [α]2D3 = +31.0 [(c = 0.10, CHCl3) (dr = 89:11, 96 %
ee for the major diastereomer)]. 1H NMR for major diastereomer
(500 MHz, CDCl3) δ = 7.73–7.70 (m, 2H), 7.44 (dd, J = 8.5, 6.8 Hz,
2H), 7.39 (d, J = 7.3 Hz, 1H), 7.27–7.22 (m, 2H), 7.12 (td, J = 7.6,
2.2 Hz, 3H), 7.09–7.04 (m, 3H), 6.98–6.92 (m, 2H), 6.41 (dd, J = 7.3,
1.7 Hz, 2H), 6.38 (d, J = 8.0 Hz, 1H), 5.07 (dd, J = 12.6, 12.1 Hz, 1H),
4.96 (dd, J = 15.0, 12.1, 1H), 4.78 (d, J = 15.5 Hz, 1H), 4.78 (dd, J =
15.1, 12.6 Hz, 1H), 4.26 (d, J = 16.1 Hz, 1H), 2.48 (s, 3H) ppm. 13C
NMR for major diastereomer (126 MHz, CDCl3) δ = 175.4, 141.5,
136.5, 134.8, 134.1, 132.0, 129.8, 129.4, 129.2, 128.5, 128.4, 128.3,
128.3, 127.6, 127.3, 127.1, 126.8, 126.4, 110.1, 76.9, 59.7, 50.5, 43.9,
50.5, 44.0 ppm. IR (ATR): ν = 3061, 2919, 1709, 1605, 1552, 1485,
˜
737, 695 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/isoprop-
anol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 90:10. Major diastereoiso-
mer: tr = 23.42 min (minor enantiomer), tr = 71.87 min (major
enantiomer) (er 97:3). Minor diastereoisomer: tr = 37.62 min (minor
enantiomer), tr = 40.14 min (major enantiomer) (er 71:29). HRMS
(ESI-QTOF) m/z: [M + H]+ Calcd. for C29H24ClN2O3 483.1470, found
483.1478.
(R)-1-Benzyl-5-bromo-3-[(R)-2-nitro-1-phenylethyl]-3-phenyl-
indolin-2-one (7ha): Product 7ha was obtained according to the
general procedure, using oxindole 5h (1.5 mmol), nitrostyrene 6a
(3.0 mmol) and catalyst Th-sq-IIb (0.075 mmol). The crude reaction
mixture was purified by flash chromatography (hexane/EtOAc: 8:1
to 4:1) and recrystallized from hexane/ethyl acetate leading to com-
pound 7ha as a mixture of diastereoisomers. White solid (568 mg,
1.08 mmol, 72 %). [α]2D3 = +26.6 [(c = 1.0, CHCl3) (dr = 97:3, 94 % ee
for the major diastereomer)]. 1H NMR for major diastereomer
(500 MHz, CDCl3) δ = 7.72–7.64 (m, 2H), 7.54 (d, J = 1.9 Hz, 1H),
7.46 (dd, J = 8.3, 6.7 Hz, 2H), 7.38 (dd, J = 8.3, 1.9 Hz, 1H), 7.28–7.24
(m, 2H), 7.14 (td, J = 7.5, 6.8, 1.7 Hz, 3H), 7.07 (dd, J = 8.2, 6.8 Hz,
2H), 7.01–6.95 (m, 2H), 6.42–6.37 (m, 2H), 6.35 (d, J = 8.4 Hz, 1H),
21.4 ppm. IR (ATR): ν = 2923, 1705, 1601, 1552, 1497, 728, 695 cm–1
.
˜
HPLC: Lux-i-Amylose-1 column, hexane/isopropanol = 95:5, 1.0 mL/
min, λ = 254 nm. Dr 89:11. Major diastereoisomer: tr = 22.79 min
(minor enantiomer), tr = 68.45 min (major enantiomer) (er 98:2).
Minor diastereoisomer: tr = 31.77 min (minor enantiomer), tr =
34.18 min (major enantiomer) (er 86:14). HRMS (ESI-QTOF) m/z: [M
+ Na]+ Calcd. for C30H26N2NaO3 485.1836, found 485.1844.
(R)-1-Benzyl-5-fluoro-3-[(R)-2-nitro-1-phenylethyl]-3-phenylind- 5.02 (dd, J = 12.2, 12.2 Hz, 1H), 4.95 (dd, J = 14.9, 12.3 Hz, 1H), 4.78
olin-2-one (7fa): Product 7fa was obtained according to the gen-
eral procedure, using oxindole 5f, nitrostyrene 6a and catalyst Th-
sq-IIb at - 40 °C. The crude reaction mixture was purified by flash
(d, J = 12.2 Hz, 1H), 4.75 (dd, J = 14.9, 12.3 Hz, 1H), 4.26 (d, J =
12.1 Hz, 1H) ppm. 13C NMR for major diastereomer (126 MHz, CDCl3)
δ = 175.0, 142.9, 135.6, 134.1, 133.6, 132.4, 129.5, 129.3, 129.1, 128.8,
chromatography (hexane/EtOAc: 8:1 to 4:1) leading to compound 128.7, 128.6, 128.5, 127.4, 127.4, 127.0, 126.4, 115.1, 111.8, 76.4, 59.8,
7fa as an inseparable mixture of diastereoisomers. White solid
50.5, 44.0 ppm. IR (ATR): ν = 3060, 2923, 1714, 1606, 1552, 1481,
˜
(66 mg, 0.14 mmol, 95 %). [α]D23 = +77.6 [(c = 1.00, CHCl3) (dr = 92:8,
737, 695 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/isoprop-
1
94 % ee for the major diastereomer)]. H NMR for major diastereo- anol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 97:3. Major diastereoisomer:
mer (500 MHz, CDCl3) δ = 7.70–7.66 (m, 2H), 7.48–7.43 (m, 2H),
7.42–7.38 (m, 1H), 7.28–7.24 (m, 1H), 7.20 (dd, J = 8.0, 2.5 Hz, 1H),
tr = 25.77 min (minor enantiomer), tr = 82.82 min (major enantio-
mer) (er 97:3). Minor diastereoisomer: tr = 39.92 min (minor enantio-
7.16–7.11 (m, 3H), 7.10–7.06 (m, 2H), 7.01–6.95 (m, 3H). 6.43–6.38 mer), tr = 44.28 min (major enantiomer) (er 91:9). HRMS (ESI-QTOF)
(m, 3H), 5.02 (dd, J = 12.1, 12.0, 1H), 4.96 (dd, J = 14.5, 12.0 Hz, 1H),
m/z: [M + Na]+ Calcd. for C29H23BrN2NaO3 549.0784, found
4.79 (d, J = 16.2 Hz, 1H), 4.75 (dd, J = 14.3, 12.0 Hz, 1H), 4.26 (d, J = 549.0786.
Eur. J. Org. Chem. 2019, 6539–6549
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6545
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(R)-1-Benzyl-5-methoxy-3-[(R)-2-nitro-1-phenylethyl]-3-phenyl-
indolin-2-one (7ia): Product 7ia was obtained according to the
general procedure, using oxindole 5i, nitrostyrene 6a and catalyst
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7ia as an
inseparable mixture of diastereoisomers. White solid (51 mg,
1H), 4.28 (d, J = 16.1 Hz, 1H) ppm. 13C NMR for major diastereomer
2
(126 MHz, CDCl3) δ = 174.8, 143.8, 134.4, 133.5, 130.7 (q, JC-F
=
32.8 Hz), 129.9, 129.3, 128.8, 128.6, 128.6, 128.4, 128.2, 127.3, 126.5,
3
1
126.4, 126.1 (q, JC-F = 3.8 Hz), 126.1, 123.8 (q, JC-F = 271.8 Hz),
122.8, 110.7, 76.5, 59.5, 50.8, 44.0 ppm. IR (ATR): ν = 2923, 1709,
˜
1605, 1547, 1377, 762, 695 cm–1. HPLC: Lux-i-Amylose-1 column,
0.11 mmol, 71 %). [α]2D3 = +70.8 [(c = 0.90, CHCl3) (dr = 97:3, 98 % hexane/isopropanol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 90:10. Major
ee for the major diastereomer)]. 1H NMR for major diastereomer
(500 MHz, CDCl3) δ = 7.75–7.69 (m, 2H), 7.47–7.42 (m, 2H), 7.40–
7.35 (m, 1H), 7.28–7.23 (m, 1H), 7.12 (dd, J = 8.2, 6.9 Hz, 3H), 7.09–
7.05 (m, 2H), 7.03 (d, J = 2.5 Hz, 1H), 7.00–6.96 (m, 2H), 6.78 (dd, J =
8.6, 2.5 Hz, 1H), 6.40 (dd, J = 7.9, 1.4 Hz, 2H), 6.38 (d, J = 8.6 Hz,
1H), 4.95 (dd, J = 12.4, 12.3 Hz, 1H), 4.91 (dd, J = 15.0, 12.1 Hz, 1H),
4.78 (d, J = 16.1 Hz, 1H), 4.75 (dd, J = 15.3, 12.5 Hz, 1H), 4.24 (d, J =
16.0, 1H), 3.87 (s, 3H) ppm. 13C NMR for major diastereomer
(101 MHz, CDCl3) δ = 175.2, 155.6, 137.3, 136.3, 134.8, 134.0, 129.4,
129.3, 128.6, 128.6, 128.5, 128.4, 128.3, 127.6, 127.1, 126.4, 114.3,
diastereoisomer: tr = 30.29 min (minor enantiomer), tr = 109.47 min
(major enantiomer) (er 98:2). Minor diastereoisomer: tr = 29.11 min
(major enantiomer), tr = 60.22 min (minor enantiomer) (er 72:28).
HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C30H23F3N2NaO3
539.1553, found 539.1549.
(R)-1-Benzyl-3-(4-methoxyphenyl)-3-[(R)-2-nitro-1-phenyleth-
yl]indolin-2-one (7la): Product 7la was obtained according to the
general procedure, using oxindole 5l, nitrostyrene 6a and catalyst
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7la as an
inseparable mixture of diastereoisomers. White solid (45 mg,
0.095 mmol, 63 %). [α]2D3 = +125.2 [(c = 0.20, CHCl3) (dr = 99:1,
> 99 % ee for the major diastereomer)]. 1H NMR for major diastereo-
mer (500 MHz, CDCl3) δ = 7.66–7.61 (m, 2H), 7.48–7.39 (m, 1H),
7.28–7.21 (m, 3H), 7.17–7.10 (m, 1H), 7.13–7.05 (m, 4H), 6.94 (ddd,
J = 14.6, 7.7, 1.8 Hz, 4H), 6.50–6.45 (m, 1H), 6.44–6.39 (m, 2H), 5.05
(dd, J = 12.4, 12.3 Hz, 1H), 4.90 (dd, J = 15.1, 12.1 Hz, 1H), 4.80 (d,
J = 16.0 Hz, 1H), 4.80 (dd, J = 15.7, 12.7 Hz, 1H), 4.27 (d, J = 16.1 Hz,
1H), 3.82 (s, 3H) ppm. 13C NMR for major diastereomer (101 MHz,
CDCl3) δ = 175.8, 159.7, 143.8, 134.7, 134.1, 130.0, 129.3, 128.8,
128.6, 128.3, 128.3, 128.1, 127.5, 127.1, 126.4, 126.1, 122.3, 114.6,
112.8, 110.6, 76.7, 60.0, 55.9, 50.5, 44.0 ppm. IR (ATR): ν = 3065, 2923,
˜
1705, 1601, 1556, 1493, 695 cm–1. HPLC: Lux-i-Amylose-1 column,
hexane/isopropanol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 97:3. Major
diastereoisomer: tr = 48.98 min (minor enantiomer), tr = 165.11 min
(major enantiomer) (er 99:1). Minor diastereoisomer: tr = 89.55 min
(major enantiomer), tr = 106.69 min (minor enantiomer) (er 86:14).
HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C30H26N2NaO4 501.1785,
found 501.1783.
(R)-1-Benzyl-3-[(R)-2-nitro-1-phenylethyl]-3-phenyl-7-(trifluoro-
methyl)indolin-2-one (7ja): Product 7ja was obtained according
to the general procedure, from oxindole 5j, nitrostyrene 6a and
catalyst Th-sq-IIb at - 40 °C. The crude reaction mixture was purified
by flash chromatography (hexane/EtOAc: 8:1 to 4:1) leading to com-
pound 7ja as an inseparable mixture of diastereoisomers. White
solid (76 mg, 0.147 mmol, 98 %). [α]2D3 = +71.0 [(c = 0.10, CHCl3)
(dr = 81:19, 94 % ee for the major diastereomer)]. 1H NMR for major
diastereomer (500 MHz, CDCl3) δ = 7.71 (ddd, J = 8.2, 3.4, 1.3 Hz,
1H), 7.66–7.61 (m, 2H), 7.60 (dd, J = 7.6, 1.3 Hz, 1H), 7.48–7.43 (m,
2H), 7.30–7.24 (m, 2H), 7.16–7.11 (m, 2H), 7.11–7.06 (m, 1H), 7.06–
7.02 (m, 3H), 6.89–6.84 (m, 2H), 6.48–6.42 (m, 2H), 4.99 (dd, J = 12.1,
10.6 Hz, 1H), 4.97 (dd, J = 11.5, 10.6 Hz, 1H), 4.81 (dd, J = 12.1,
11.5 Hz, 1H), 4.81 (d, J = 17.6 Hz, 1H), 4.70 (d, J = 17.3 Hz, 1H) ppm.
13C NMR for major diastereomer (101 MHz, CDCl3) δ = 176.8, 135.6,
133.2, 130.7, 129.8, 129.7, 129.5, 129.0, 128.8, 128.7, 128.5, 128.4,
110.3, 76.8, 59.0, 55.3, 50.8, 43.9 ppm. IR (ATR): ν = 2965, 1709, 1605,
˜
1543, 1510, 1489, 762, 699 cm–1. HPLC: Lux-i-Amylose-1 column,
hexane/isopropanol = 85:15, 1.0 mL/min, λ = 254 nm. Dr 99:1. Major
diastereoisomer: tr = 23.35 min (minor enantiomer), tr = 103.72 min
(major enantiomer) (er > 99: < 1). Minor diastereoisomer: tr =
32.53 min (major enantiomer), tr = 60.55 min (minor enantiomer)
(er 70:30). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C30H26N2NaO4
501.1785, found 501.1789.
(S)-1-Benzyl-3-methyl-3-[(R)-2-nitro-1-phenylethyl]indolin-2-
one (7ma):[13a] Product 7ma was obtained as a mixture 79:21 of
diastereoisomers (48 mg, 0.125 mmol, 83 %) according to the gen-
eral procedure, using oxindole 5m, nitrostyrene 6a and catalyst Th-
sq-IIb (0.03 mmol, 0.2 equiv.). The major diastereoisomer was iso-
lated by flash chromatography (hexane/EtOAc: 8:1 to 4:1) as a color-
less oil. [α]2D3 = –102.0 [(c = 0.30, CHCl3) (90 % ee for the major
diastereomer)]. 1H NMR for major diastereomer (500 MHz, CDCl3)
δ = 7.23 (m, 1H), 7.20–7.11 (m, 7H), 7.07 (td, J = 7.5, 1.1 Hz, 1H),
6.90 (m, 2H), 6.65 (dd, J = 7.9, 1.6 Hz, 2H), 6.53 (dd, J = 8.1, 1.0 Hz,
1H), 5.14 (dd, J = 12.7, 4.3 Hz, 1H), 4.98 (dd, J = 12.7, 11.3 Hz, 1H),
4.88 (d, J = 15.8 Hz, 1H), 4.44 (d, J = 15.8 Hz, 1H), 4.08 (dd, J =
11.4, 4.4 Hz, 1H), 1.57 (s, 3H) ppm. 13C NMR for major diastereomer
(101 MHz, CDCl3) δ = 178.1, 142.6, 135.0, 135.0, 130.6, 128.9, 128.8,
128.7, 128.3, 128.2, 127.3, 126.7, 123.5, 122.6, 109.7, 76.4, 50.7, 50.0,
3
1
128.2, 127.7 (q, JC-F = 6.3 Hz), 126.5, 126.5, 125.0, 122.9 (q, JC-F
272.4 Hz), 121.8, 113.7 (q, 2JC-F = 32.8 Hz), 76.4, 58.2, 50.5, 45.8 ppm.
IR (ATR): ν = 2977, 1734, 1597, 1556, 1452, 1443, 733, 695 cm–1
=
.
˜
HPLC: Lux-i-Amylose-1 column, hexane/isopropanol = 97:3, 1.0 mL/
min, λ = 254 nm. Dr 81:19. Major diastereoisomer: tr = 27.19 min
(minor enantiomer), tr = 79.48 min (major enantiomer) (er 97:3).
Minor diastereoisomer: tr = 24.30 min (minor enantiomer), tr =
25.51 min (major enantiomer) (er 67:33). HRMS (ESI-QTOF) m/z:
[M + Na]+ Calcd. for C30H23F3N2NaO3 539.1553, found 539.1562.
(R)-1-Benzyl-3-[(R)-2-nitro-1-phenylethyl]-3-[4-(trifluorometh-
yl)phenyl]indolin-2-one (7ka): Product 7ka was obtained accord-
ing to the general procedure, using oxindole 5k, nitrostyrene 6a
and catalyst Th-sq-IIb. The crude reaction mixture was purified by
flash chromatography (hexane/ethyl acetate: 8:1 to 4:1) leading to
compound 7ka as an inseparable mixture of diastereoisomers.
White solid (76 mg, 0.147 mmol, 98 %). [α]2D3 = +66.0 [(c = 0.10,
CHCl3) (dr = 90:10, 96 % ee for the major diastereomer)]. 1H NMR
for major diastereomer (500 MHz, CDCl3) δ = 7.84 (d, J = 8.3 Hz,
2H), 7.68 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 7.1, 1.6 Hz, 1H), 7.28–7.21
(m, 3H), 7.12–7.04 (m, 5H), 6.93–6.88 (m, 2H), 6.53–6.49 (m, 1H),
6.43–6.38 (m, 2H), 5.03 (dd, J = 12.5, 12.2Hz, 1H), 4.92 (dd, J = 15.1,
12.1 Hz, 1H), 4.74 (d, J = 15.9 Hz, 1H), 4.67 (dd, J = 15.6, 12.6 Hz,
43.7, 21.7 ppm. IR (ATR): ν = 2923, 1709, 1610, 1552, 1489, 1456,
˜
728, 695 cm–1. HPLC: Lux-Amylose-1 column, hexane/isopropanol =
90:10, 1.0 mL/min, λ = 254 nm. Major diastereoisomer: tr =
21.07 min (minor enantiomer), tr = 29.53 min (major enantiomer)
(er 95:5). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C24H22N2NaO3
409.1523, found 409.1526.
Ethyl 2-{(S)-1-Benzyl-3-[(R)-2-nitro-1-phenylethyl]-2-oxoindolin-
3-yl}acetate (7na): Product 7na was obtained as a mixture 79:21
of diastereoisomers (56 mg, 0.123 mmol, 82 %) according to the
general procedure, using oxindole 5n, nitrostyrene 6a and catalyst
Th-sq-IIb (0.03 mmol). The major diastereoisomer was isolated by
Eur. J. Org. Chem. 2019, 6539–6549
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flash chromatography (hexane/EtOAc: 8:1 to 4:1) as a white solid; (er 99:1). Minor diastereoisomer: tr = 31.56 min (major enantiomer),
m.p 206–207 °C from hexane/EtOAc. [α]2D3 = –32.7 [(c = 0.40, CHCl3) tr = 88.51 min (minor enantiomer) (er 86:14). HRMS (ESI-QTOF) m/z:
1
(88 % ee for the major diastereomer)]. H NMR for major diastereo- [M + Na]+ Calcd. for C30H23F3N2NaO3 539.1553, found 539.1555.
mer (500 MHz, CDCl3) δ = 7.26–7.16 (m, 7H), 7.09–7.04 (m, 2H),
(R)-1-Benzyl-3-[(R)-1-(4-methoxyphenyl)-2-nitroethyl]-3-phenyl-
6.92–6.89 (m, 4H), 6.55 (d, J = 7.8 Hz, 1H), 4.96 (dd, J = 12.8, 4.4 Hz,
indolin-2-one (7bd): Product 7bd was obtained according to the
1H), 4.88 (dd, J = 12.8, 11.0 Hz, 1H), 4.80 (d, J = 15.8 Hz, 1H), 4.54
general procedure, using oxindole 5b, nitrostyrene 6d and catalyst
(d, J = 15.8 Hz, 1H), 3.99 (dd, J = 11.0, 4.4 Hz, 1H), 3.90 (m, 1H), 3.80
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
(m, 1H), 3.16 (d, J = 16.0 Hz, 1H), 3.02 (d, J = 16.0 Hz, 1H), 0.94 (t,
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7bd as
J = 7.1 Hz, 3H) ppm. 13C NMR for major diastereomer (101 MHz,
an inseparable mixture of diastereoisomers. White solid (58 mg,
CDCl3) δ = 177.0, 168.7, 144.1, 135.3, 134.0, 129.2, 128.6, 128.5,
0.12 mmol, 81 %). [α]2D3 = +74.0 [(c = 0.60, CHCl3) (dr = 92:8, 94 %
128.3, 128.1, 127.4, 127.0, 123.3, 122.4, 109.6, 76.1, 60.8, 51.8, 50.0,
ee for the major diastereomer)]. 1H NMR for major diastereomer
44.2, 39.2, 13.8 ppm. IR (ATR): ν = 2923, 1701, 1610, 1556, 1489,
˜
(500 MHz, CDCl3) δ = 7.70 (dd, J = 8.3, 1.4 Hz, 2H), 7.43 (td, J = 7.5,
1468, 1456, 699 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/iso-
6.8, 1.5 Hz, 3H), 7.39–7.37 (m, 1H), 7.28–7.23 (m, 2H), 7.17–7.12 (m,
propanol = 90:10, 1.0 mL/min, λ = 254 nm. Major diastereoisomer:
1H), 7.10–7.05 (m, 2H), 6.86–6.81 (m, 2H), 6.65–6.60 (m, 2H), 6.51
tr = 42.97 min (minor enantiomer), tr = 56.29 min (major enantio-
(dd, J = 7.8, 1.3 Hz, 1H), 6.44–6.40 (m, 2H), 5.00 (dd, J = 12.3, 12.3 Hz,
mer) (er 94:6). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for
1H), 4.90 (dd, J = 15.2, 12.3 Hz, 1H), 4.90 (d, J = 16.1Hz, 1H), 4.75
C27H26N2NaO5 481.1734, found 481.1736.
(dd, J = 15.2, 12.3 Hz, 1H), 4.25 (d, J = 16.1 Hz, 1H), 3.74 (s, 3H) ppm.
13C NMR for major diastereomer (101 MHz, CDCl3) δ = 175.6, 159.5,
143.9, 136.4, 134.6, 130.5, 129.4, 129.2, 128.4, 128.4, 127.6, 127.4,
127.2, 126.5, 126.2, 125.8, 122.4, 113.8, 110.4, 77.0, 59.7, 55.0, 50.1,
(R)-1-Benzyl-3-[(R)-1-(4-chlorophenyl)-2-nitroethyl]-3-phenyl-
indolin-2-one (7bb): Product 7bb was obtained according to the
general procedure, using oxindole 5b, nitrostyrene 6b and catalyst
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7bb as
an inseparable mixture of diastereoisomers. White solid (59 mg,
0.12 mmol, 81 %). [α]2D3 = +86.1 [(c = 0.70, CHCl3) (dr = 94:6, 98 %
ee for the major diastereomer)]. 1H NMR for major diastereomer
(500 MHz, CDCl3) δ = 7.71–7.66 (m, 2H), 7.46–7.41 (m, 3H), 7.41–
7.36 (m, 1H), 7.32–7.25 (m, 2H), 7.20–7.15 (m, 3H), 7.06 (d, J = 8.7 Hz,
2H), 6.86 (d, J = 8.6 Hz, 2H), 6.58–6.55 (m, 1H), 6.48 (dd, J = 7.5,
2.0 Hz, 2H), 4.99 (dd, J = 12.3, 12.2 Hz, 1H), 4.92 (dd, J = 14.8,
12.2 Hz, 1H), 4.89 (d, J = 16.0 Hz, 1H), 4.75 (dd, J = 14.8, 12.3 Hz,
1H), 4.26 (d, J = 16.0 Hz, 1H) ppm. 13C NMR for major diastereomer
(101 MHz, CDCl3) δ = 175.3, 143.8, 136.0, 134.5, 134.4, 132.6, 130.7,
129.6, 129.3, 128.6, 127.5, 127.4, 126.9, 126.5, 126.2, 122.5, 110.5,
43.9 ppm. IR (ATR): ν = 2915, 1709, 1610, 1552, 1514, 1468, 741,
˜
691, 649 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/isoprop-
anol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 92:8. Major diastereoisomer:
tr = 51.15 min (minor enantiomer), tr = 54.42 min (major enantio-
mer) (er 97:3). Minor diastereoisomer: tr = 35.17 min (major enantio-
mer), tr = 64.61 min (minor enantiomer) (er 73:27). HRMS (ESI-QTOF)
m/z: [M + Na]+ Calcd. for C30H26N2NaO4 501.1785, found 501.1787.
(R)-1-Benzyl-3-[(R)-1-(naphthalen-2-yl)-2-nitroethyl]-3-phenyl-
indolin-2-one (7be): Product 7be was obtained according to the
general procedure, using oxindole 5b, nitrostyrene 6e and catalyst
Th-sq-IIb. The crude reaction mixture was purified by flash chroma-
tography (hexane/EtOAc: 8:1 to 4:1) leading to compound 7be as
an inseparable mixture of diastereoisomers. Yellow oil (73 mg,
0.147 mmol, 98 %). [α]2D3 = +39.7 [(c = 0.90, CHCl3) (dr = 93:7, 96 %
ee for the major diastereomer)]. 1H NMR for major diastereomer
(500 MHz, CDCl3) δ = 7.81–7.76 (m, 3H), 7.62 (d, J = 8.2 Hz, 1H),
7.56–7.40 (m, 8H), 7.32–7.25 (m, 2H), 6.97 (dd, J = 8.8, 1.8 Hz, 1H),
6.87 (t, J = 7.5 Hz, 1H), 6.49–6.41 (m, 3H), 6.12 (dd, J = 7.9, 1.3 Hz,
2H), 5.17 (dd, J = 12.2, 11.5 Hz, 1H), 5.17 (dd, J = 12.2, 10.8 Hz, 1H),
4.85 (d, J = 16.6 Hz, 1H), 4.85 (dd, J = 11.5, 10.8 Hz, 1H), 4.13 (d, J =
16.1 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ = 175.5, 143.9, 136.4,
134.2, 133.2, 133.1, 131.6, 129.5, 129.4, 129.3, 128.5, 128.3, 128.1,
128.0, 127.6, 127.5, 127.3, 127.0, 126.4, 126.3, 126.3, 126.2, 126.0,
76.6, 59.3, 50.1, 44.0 ppm. IR (ATR): ν = 2923, 1714, 1610, 1552,
˜
1489, 1464, 728, 695 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/
isopropanol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 94:6. Major dia-
stereoisomer: tr = 42.50 min (minor enantiomer), tr = 48.72 min
(major enantiomer) (er 99:1). Minor diastereoisomer: tr = 28.10 min
(major enantiomer), tr = 59.88 min (minor enantiomer) (er 77:23).
HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C29H23ClN2NaO3
505.1293, found 505.1289.
(R)-1-Benzyl-3-{(R)-2-nitro-1-[4-(trifluoromethyl)phenyl]ethyl}-
3-phenylindolin-2-one (7bc): Product 7bc was obtained according
to the general procedure, using oxindole 5b, nitrostyrene 6c and
catalyst Th-sq-IIb. The crude reaction mixture was purified by flash
chromatography (hexane/EtOAc: 8:1 to 4:1) leading to compound
7bc as an inseparable mixture of diastereoisomers. White solid
(75 mg, 0.145 mmol, 97 %). [α]2D3 = +51.0 [(c = 0.10, CHCl3) (dr =
93:7, 98 % ee for the major diastereomer)]. 1H NMR for major dia-
stereomer (500 MHz, CDCl3) δ = 7.71–7.67 (m, 2H), 7.45 (ddd, J =
7.7, 6.6, 1.5 Hz, 3H), 7.41–7.38 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.29
(dd, J = 4.3, 1.5 Hz, 1H), 7.28–7.25 (m, 1H), 7.19–7.14 (m, 1H), 7.12–
7.05 (m, 4H), 6.60–6.56 (m, 1H), 6.56–6.52 (m, 2H), 5.04 (dd, J = 12.2,
122.5, 110.5, 77.0, 59.6, 50.9, 43.9 ppm. IR (ATR): ν = 3060, 2919,
˜
1709, 1609, 1552, 1489, 728, 695 cm–1. HPLC: Lux-i-Amylose-1 col-
umn, hexane/isopropanol = 95:5, 1.0 mL/min, λ = 254 nm. Dr 93:7.
Major diastereoisomer: tr = 54.60 min (minor enantiomer), tr =
90.02 min (major enantiomer) (er 98:2). Minor diastereoisomer: tr =
50.23 min (major enantiomer), tr = 111.32 min (minor enantiomer)
(er 78:22). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C33H26N2NaO3
521.1836, found 521.1836.
(R)-1-Benzyl-3-[(R)-1-(furan-2-yl)-2-nitroethyl]-3-phenylindolin-
10.9 Hz, 1H), 5.04 (dd, J = 16.5, 10.9 Hz, 1H), 4.78 (dd, J = 16.5, 2-one (7bf): Product 7bf was obtained according to the general
12.1 Hz, 1H), 4.78 (d, J = 15.9 Hz, 1H), 4.30 (d, J = 15.9 Hz, 1H) ppm.
procedure, using oxindole 5b, nitrostyrene 6f and catalyst Th-sq-
13C NMR for major diastereomer (101 MHz, CDCl3) δ = 175.2, 143.7, IIb. The crude reaction mixture was purified by flash chromatogra-
2
138.3, 135.9, 134.5, 130.5 (q, JC-F = 32.6 Hz), 129.8, 129.4, 128.7,
phy (hexane/EtOAc: 8:1 to 4:1) leading to compound 7bf as an in-
separable mixture of diastereoisomers. White solid (48 mg,
0.11 mmol, 73 %). [α]2D3 = +144.3 [(c = 0.60, CHCl3) (dr = 84:16, 94 %
3
128.6, 127.5, 127.5, 126.7, 126.5, 126.2, 125.2 (q, JC-F = 3.7 Hz),
1
125.2, 124.5 (q, JC-F = 271.9 Hz), 122.6, 110.5, 76.4, 59.2, 50.3,
1
44.1 ppm. IR (ATR): ν = 2927, 1709, 1610, 1556, 1489, 1468, 749,
ee for the major diastereomer)]. H NMR (500 MHz, CDCl3) δ = 7.61
˜
695 cm–1. HPLC: Lux-i-Amylose-1 column, hexane/isopropanol = (d, J = 7.6 Hz, 2H), 7.45–7.21 (m, 9H), 7.03 (d, J = 2.0 Hz, 1H), 6.93
97:3, 1.0 mL/min, λ = 254 nm. Dr 93:7. Major diastereoisomer: tr = (dd, J = 6.6, 3.0 Hz, 2H), 6.64 (d, J = 7.8 Hz, 1H), 6.10 (dd, J = 3.3,
69.64 min (minor enantiomer), tr = 75.63 min (major enantiomer)
1.8 Hz, 1H), 5.96 (d, J = 3.3 Hz, 1H), 5.09 (dd, J = 12.6, 10.8 Hz, 1H),
Eur. J. Org. Chem. 2019, 6539–6549
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[5]
[6]
T. Lu, S. E. Wheeler, Chem. Eur. J. 2013, 19, 15141.
5.09 (dd, J = 12.6, 11.4 Hz, 1H), 4.84 (d, J = 15.8 Hz, 1H), 4.66 (dd,
J = 11.4, 10.7 Hz, 1H), 4.58 (d, J = 15.8 Hz, 1H) ppm. 13C NMR
(101 MHz, CDCl3) δ = 175.8, 148.5, 143.3, 142.5, 135.9, 135.0, 129.3,
129.2, 128.6, 128.5, 127.5, 127.4, 127.4, 127.1, 126.1, 122.4, 110.2,
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110.0, 109.5, 75.0, 58.8, 44.6, 44.1 ppm. IR (ATR): ν = 2919, 1714,
˜
1610, 1547, 1489, 745, 695 cm–1. HPLC: Lux-i-Amylose-1 column,
hexane/isopropanol = 97:3, 1.0 mL/min, λ = 254 nm. Dr 84:16. Major
diastereoisomer: tr = 46.00 min (minor enantiomer), tr = 199.72 min
(major enantiomer) (er 97:3). Minor diastereoisomer: tr = 75.12 min
(major enantiomer), tr = 79.92 min (minor enantiomer) (er 64:36).
HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C27H22N2NaO4 461.1472,
found 461.1475.
[7]
[8]
(3S,5′R)-1-Benzyl-5′-phenylspiro[indoline-3,4′-piperidine]-2,2′-
dione (8): A mixture of Zn powder (340 mg, 5.2 mmol, 20 equiva-
lents) and 7na (119 mg, 0.26 mmol) in HOAc (1.8 mL) was heated
at 70 °C overnight. When the reaction was finished, the mixture was
filtered through a pad of celite and the filtrate was concentrated
under vacuum. The mixture was redissolved in DCM and then an
aqueous solution of NaHCO3 was added until basic pH. The product
was extracted with DCM (3 × 10 mL). The organic layer was washed
with brine, dried with anhydrous MgSO4, and concentrated under
reduced pressure. The compound was purified by flash column
chromatography on silica gel (EtOAc/MeOH, 40:1 to 15:1) affording
compound 8 as a white solid (83 mg, 0.216 mmol, 83 %); m.p 166–
168 °C. [α]2D3 = –131.7 [(c = 1.00, CHCl3) (88 % ee for the major
diastereomer)]. 1H NMR for major diastereomer (500 MHz, CDCl3)
δ = 7.53 (dd, J = 7.4, 1.4 Hz, 1H), 7.28 (br s, 1H), 7.24 (m, 1H), 7.19
(td, J = 7.7, 1.3 Hz, 1H), 7.16–7.03 (m, 6H), 6.77 (d, J = 7.2 Hz, 2H),
6.46 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 7.4 Hz, 2H), 5.03 (d, J = 16.0 Hz,
1H), 4.25 (d, J = 16.0 Hz, 1H), 4.01 (t, J = 11.9 Hz, 1H), 3.77–3.62 (m,
2H), 3.21 (d, J = 17.5 Hz, 1H), 2.44 (d, J = 17.5 Hz, 1H). 13C NMR for
major diastereomer (126 MHz, CDCl3) δ = 176.6, 170.3, 142.8, 135.7,
134.7, 129.0, 128.6, 128.5, 128.5, 128.1, 127.1, 126.3, 124.3, 123.0,
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[17]
109.8, 51.3, 45.2, 44.5, 43.8, 39.3 ppm. IR (ATR): ν = 3240, 3060, 3037,
˜
2923, 1709, 1664, 1614, 758, 728, 695 cm–1. HPLC: Lux-Amylose-1
column, hexane/isopropanol = 90:10, 1.0 mL/min, λ = 254 nm. tr =
47.04 min (major enantiomer), tr = 106.17 min (minor enantiomer)
(er 94:6). HRMS (ESI-QTOF) m/z: [M + Na]+ Calcd. for C25H22N2NaO2
405.1573, found 405.1577.
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Acknowledgments
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Authors thank Junta de Castilla y León (Projects FEDER-
VA115P17, and VA149G18) for financial support. The aid in the
X-ray diffraction determination provided by Dr. R. García Rodrí-
guez is also acknowledged.
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Keywords: Asymmetric catalysis · Michael addition ·
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Received: September 6, 2019
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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim