Organocatalytic vinylogous Mannich reaction of trimethylsiloxyfuran with isatin-derived benzhydryl-ketimines

Article abstract of DOI:10.1039/c6ob01359g

A family of chiral quaternary 3-aminooxindole butenolides has been synthesized by BINOL-derived phosphoric acid-catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such a vinylogous Mannich-type reaction was found to produce diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The configurational assignment of the obtained products was safely performed by chemical correlation. A computational study of the transition state allowed rationalizing the obtained stereochemical outcome, highlighting the possible binding modes of the catalyst-imine-nucleophile transition complex.

Full text of DOI:10.1039/c6ob01359g

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Page 1 of 9
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DOI: 10.1039/C6OB01359G
Organocatalytic Vinylogous Mannich Reaction of Trimethylsiloxyfuran
with Isatin-derived Benzhydryl-Ketimines
Giulia Rainoldi,a Alessandro Sacchetti,b Alessandra Silvani*,a and Giordano Lesmaa
aDipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, Milano, 20133, Italy.
bDipartimento di Chimica, Materiali ed Ing. Chimica ‘Giulio Natta’, Politecnico di Milano, p.zza Leonardo da Vinci
32, Milano, 20133, Italy.
Abstract
A family of chiral quaternary 3-aminooxindole butenolides have been synthesized, by BINOL-derived phosphoric acid-
catalyzed addition of trimethylsiloxyfuran to isatin-derived ketimines. Such vinylogous Mannich-type reaction was
found to produce the diastereoisomeric butenolides in good yields and in most cases high enantiomeric excesses. The
configurational assignment of the obtained products was safely performed by chemical correlation. A computational
study of the transition state allowed to rationalize the obtained stereochemical outcome, highlighting the possible
binding modes of the catalyst-imine-nucleophile transition complex.
Introduction
Optically active -amino--unsaturated carbonyl compounds, particularly those bearing the -butenolide skeleton, are
receiving considerable attention due to their broad application in the synthesis of biologically active compounds. The
butenolide ring is in fact one of the most ubiquitous structures found in natural products and its incorporation into more
complex heterocyclic architectures has continuously attracted the attention from a pharmaceutical point of view.1
The vinylogous Mannich-type reaction of imines with a dienolate equivalent, such as trimethylsiloxyfuran (TMSOF), is
a useful mean to prepare -butenolide derivatives bearing an amine functionality.2 Metal complexes and organocatalysts
promote efficiently asymmetric vinylogous Mannich (AVM) reactions of aldimines, affording optically active -amino-
-unsaturated carbonyl compounds in high yields and enantiomeric excesses. With regard to catalytic methods, a
milestone was placed in 2006 by Hoveyda,3,4 who reported the first highly diastereo- and enantioselective protocol for
such reaction. The AVM was catalyzed by a silver salt and an easily accessible chiral phosphine, and only aromatic
aldimines were employed. More recently, a new Ag(I)-monophosphine complex was developed by Xu, displaying wide
aldimine versatility, excellent yield and diastereoselectivity, and moderate enantioselectivity.5 Among organocatalytic,
metal-free methods, a iodine-substituted chiral phosphoric acid was demonstrated by Akiyama to efficiently catalyze
the AVM of aliphatic as well aromatic aldimines.6
Application of the vinylogous Mannich-type reaction to ketimines is more challenging, due to the lower reactivity of
ketimines compared with aldimines and to the steric challenge inherent in the stereocontrolled formation of a quaternary
stereocenter consecutive with a bulky tertiary one. To date, there are only few reports on the AVM of TMSOF with
ketimines, to give chiral -amino--unsaturated carbonyl compounds having a quaternary carbon center. Besides the
successful Ag-catalyzed process, applied by Hoveyda7 also to -ketimine esters, relevant is the contribution from
Nakamura,8 who reported a Cinchona alkaloid amide/copper (II) catalyzed diastereo- and enantioselective Mannich
reaction of ketimines. Quite recently, the strictly related Cinchona alkaloid amide/zinc (II) system was also developed
by the same author,9 and applied to the similar Mannich reaction employing -butenolide instead of TMSOF as
nucleophile. Given the relevance of chiral -amino--unsaturated carbonyl compounds having a quaternary carbon
center, the development of novel stereoselective methods for the construction of this attractive framework in an
asymmetric manner is highly desirable.
As part of our interest in the asymmetric synthesis of 3,3-disubstituted oxindole derivatives and related spiro-
compounds,10 we recently turned our attention to BINOL-derived phosphoric acids as useful chiral Brønsted acid
catalysts for the Biginelli reaction applied to isatin, allowing the synthesis of spiro(indoline-pyrimidine)-diones
derivatives.11 Chiral Brønsted acid catalysts have recently emerged as a new class of environmentally benign chiral
catalysts for a number of enantioselective reactions.12 Herein, our ongoing interest was extended to the asymmetric
preparation of quaternary 3-aminooxindole butenolides, which can be considered an intriguing combination of
pharmacologically interesting -butenolide and oxindole motifs. A racemic preparation of such compounds in excellent
yields and diastereoselectivities was realized by Deng,13 employing AgOAc as the catalyst. A highly practical, sulfinyl
amine chiral auxiliary-based approach was also recently developed,14 based on a simple Lewis acid mediated
diastereoselective vinylogous Mannich process.
At the best of our knowledge, no organocatalytic methods employing TMSOF have been reported for the preparation of
such scaffolds. Only a related AVM was recently realized, based on a bifunctional quinidine-derived catalyst and 3,4-
dichlorofuran-2(5H)-one as the nucleophile.15 Herein, we report the BINOL-derived phosphoric acid-catalyzed
asymmetric synthesis of quaternary 3-aminooxindole butenolides via a vinylogous Mannich-type reaction, consisting in
the enantioselective addition of TMSOF to isatin-derived ketimines (Scheme 1).

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DOI: 10.1039/C6OB01359G
Results and discussion
We began our investigation using N-diphenylmethyl ketimine 1a, obtained as the only product in the reaction between
C,C-diphenyl-methanamine and N-benzyl-isatin (Scheme 1), and two well-known isatin-derived ketimines, 2 and 3.
Scheme 1. Synthesis of isatin-based N-benzydryl ketimines 1.
Reaction of 1a, 2 and 3 with TMSOF, initially carried out at room temperature, using THF as the solvent and 10 mol %
of catalyst 4a, proved to be completely ineffective. Reasoning that the addition of a protic cosolvent to the reaction
mixture could be essential for the onset of the catalytic cycle, we repeated the reaction by adding MeOH (1% vol). In
such conditions, all three ketimines proved to be reactive, affording the corresponding 3-aminooxindole butenolides
with variable yields, up to 84% (Table 1, entries 1-3). We assumed that probably the protic cosolvent suppresses the
undesired retroaddition reaction by rapidly converting the silylated butenolide ring into the final product, while also
enabling the isolation of the adduct formed under conditions of kinetic control.16 In addition, we can also suppose that,
in absence of a protic source, the catalytic BINOL-derived phosphoric acid might be converted to the corresponding O-
silylated BINOL-phosphate, evidently not able to promote the AVM reaction as the phosphoric acid form.17
Ketimine 1a, performing to the best, was then chosen for subsequent conditions and catalyst screening, also in the light
of the potential greater versatility of the obtained products, due to the easy removal of the protective diphenyl-methyl
group. The temperature proved to be a key parameter for the asymmetric induction of this reaction. At room
temperature (entry 1), the reaction proceeds to give 5 as a 75/25 mixture of the 5a and 5b diastereoisomers, each of
which with a negligible enantiomeric excess. Upon lowering the reaction temperature (entries 4-7), we noticed a
substantial maintenance of the obtained yields, with a collapse of diastereoselectivity and an overall improvement of the
o
enantioselectivity for both 5a and 5b diastereoisomers. In particular, carrying out the reaction at - 40 C, both
diastereoisomers could be recovered in almost equal quantities (80% overall yield, 5a/5b 52:48), showing excellent
enantioselectivities (ee 5a 90%, ee 5b 92%). Changing the solvent to toluene (entry 8) or dichloromethane (entry 9)
entailed a significant negative effect on the chemical conversion, demonstrating that the originally chosen THF was the
optimal solvent for this reaction. Screening of more hindered catalysts 4b-e, aimed to evaluate the impact of the 3,3'-
substitution, and of octahydro-BINOL-based 4f was performed (entries 10-14). Increasing the size of the 3,3'-substitents
on the phosphoric acid proved detrimental for the chemical conversion, with only catalysts 4b and 4f able to afford
product 5, with maintenance of the same level of diastereo- and lower enantioselectivity with respect to catalyst 4a, and
in definitely decreased yields.
Table 1. Optimization of the asymmetric AVM reaction.a
entry R (ketimine) catalyst solvent temp., time yield %b dr (5a:5b)c ee % 5ad ee % 5bd
1
2
3
4
5
6
CH(Ph)2
p-MeO-C6H5
Boc
THF
THF
THF
rt, 10 min
rt, 20 min
rt, 8h
84
60
15
87
85
80
75:25
61:39
51:49
69:31
57:43
52:48
0
2
25
10
7
4a
4a
4a
4a
4a
4a
5
CH(Ph)2
CH(Ph)2
CH(Ph)2
THF 0 oC, 40 min
1
31
69
92
THF
- 20 oC, 1h
- 40 oC, 7h
47
90
THF

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DOI: 10.1039/C6OB01359G
7
CH(Ph)2
CH(Ph)2
CH(Ph)2
CH(Ph)2
CH(Ph)2
CH(Ph)2
CH(Ph)2
CH(Ph)2
THF
- 78 oC, 48h
68
35
27
50
nr
51:49
53:47
55:45
57:43
-
90
89
90
57
-
92
93
93
66
-
4a
4a
4a
4b
4c
4d
4e
4f
8
Toluene - 40 oC, 48h
CH2Cl2 - 40 oC, 48h
9
10
11
12
13
14
THF
THF
THF
THF
THF
- 40 oC, 48h
- 40 oC, 48h
- 40 oC, 48h
- 40 oC, 48h
- 40 oC, 48h
nr
-
-
-
nr
-
-
-
41
50:50
67
78
a Reactions were performed with 0.12 mmol of ketimine and 0.14 mmol of TMSOF, in 1.2 mL of solvent; MeOH was
c
used as additive (1% vol). bIsolated yield. Determined by 1H NMR (from integration of olefinic protons). dDetermined
by chiral HPLC analysis. nr = no reaction.
o
After having established 4a as the catalyst of choice and to work in THF at - 40 C as the optimal conditions, the
substrate scope of the AVM reaction was surveyed, by evaluating differently N-substituted isatins and the presence of
substituents at 5- or 6-position of the isatin nucleus. (Table 2).
Table 2. Substrate scope of the asymmetric AVM reaction catalyzed by 4a.a
entry R1
R2 yield %b
drc
ee % 5a-13ad ee % 5b-13bd
1 (1a) Bn
H
H
H
H
H
80
78
81
79
81
45
42
65
68
5a:5b 52:48
6a:6b 63:37
7a:7b 55:45
8a:8b 55:45
9a:9b 47:53
10a:10b 72:28
11a:11b 70:30
12a:12b 70:30
13a:13b 62:38
90
80
91
84
4
92
88
68
89
96
15
74
42
31
2 (1b)
H
3 (1c) Me
4 (1d) PMB
5 (1e) Tr
6 (1f) Bn 5-F
7 (1g) Bn 5-Cl
8 (1h) Bn 6-Br
9 (1i) Me 6-Br
1
26
31
32
a Reactions were performed with 0.12 mmol of ketimine and 0.14 mmol of TMSOF, in 1.2 mL of solvent; MeOH was
b
c
1
used as additive (1% vol). Isolated yield. Determined by H NMR (from integration of olefinic protons); for relative
d
and absolute configurational assignment of diastereoisomeric products, see below. Determined by chiral HPLC
analysis.
In general, all isatins readily undergo this reaction, to afford the desired products 5-13 in moderate to high yields, with a
good degree of enantioselectivity (entries 1-5). The presence of a halogen substituent on the oxindole (entries 6-9)
results in a lowering of yield and enantiomeric excess, with a slight increase of diastereoselectivity.
Since diastereoisomers 7a and 7b (entry 3) proved to be readily separable by flash chromatography, we selected them
for the determination of absolute and relative stereochemistry. However, neither of them proved to be suitable for X-ray
analysis. Thus, starting from the major 7a, we performed a chemical correlation based on the literature compound 14, as
depicted in Scheme 2. From NMR and []D comparison of compound 15, derived from 14, and compound 15', derived
from 7a, the (R,R) anti configuration could be safely assigned to 7a.

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DOI: 10.1039/C6OB01359G
Scheme 2. Chemical correlations for the configurational assignment of 7a and 7b.
For the configurational assignment of minor diastereoisomer 7b, still we relied on a chemical correlation, performing on
both 7a and 7b the same reaction to give the silyl enol ether derivative 16. Since 16 was obtained as opposite
enantiomer starting from 7a and 7b, we could assign the (S,R) syn configuration to 7b.
In order to propose a possible explanation of the stereochemical outcome, a preliminary investigation of the transition
state organization was performed by means of computational tools. The theoretical study of this reaction is complicated
by a number of factors, namely, the size of the system, the possible approach endo or exo of the nucleophile, with
respect to both the re and si face of the imine and the several competing H-bonding possibilities in the assembly of the
transition state. We were aware that also the E/Z geometry of the imine might play an important role in the
enantioselection. However, since NMR analysis of starting imine 1c showed the presence of a major isomer (9:1) and
theoretical DFT calculations indicated the Z-1c imine more stable than the corresponding E isomer by 4.38 kcal/mol, we
decided to consider only the Z geometry in our further studies.
In accordance with the enantioselectivity of the reaction, in the proposed model18 the major enantiomer (3R,2’R)-7a is
achieved through TS-A, whereas TS-C would lead to the diastereoisomeric (3S,2’R)-7b. To support this hypothesis, we
calculated the energy for TS-C and TS-D at the B3LYP/6-31G(d) level (see SI for details).19 TS-C resulted to be lower
in energy for 0.6 kcal/mol at 233 K, with respect to TS-D , in agreement with the measured 68% ee. In such favored
TS-C, the 2-hydroxyfuran is coordinated to the catalyst 4a through the OH hydrogen and it prefers to assume the endo
orientation with respect to the imine as the third component (the opposite exo orientation is present in TS-D). The same
considerations apply to TS-A (favored) and TS-B. The orientation of the imine is less significant, probably due to the
great steric hindrance around both faces of the imine double bond.
Figure 1. Possible binding modes of the catalyst 4a - 2-hydroxyfuran - imine 1c transition complex.
Conclusions

Page 5 of 9
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In summary, an organocatalytic approach for the asymmetric synthesis of quaternary 3-aminooxindole butenolides has
been developed. The method exploits the vinylogous Mannich reaction of TMSOF with variDoOusI: 10is.1a0t3in9/-Cd6eOriBv0e1d359G
benzhydryl-ketimines, affording diastereoisomeric products in good yields and in most cases high enantiomeric
excesses. The obtained products, containing a quaternary stereocenter consecutive with a bulky tertiary one, are suitable
for further transformations, as demonstrated in the performed chemical correlation study. The stereochemical outcome
was also rationalized by means of a computational study, which allowed to propose the most favoured binding modes of
reaction components in the transition state.
Experimental section
General Information
All commercial materials (Aldrich, Fluka) were used without further purification. All solvents were of reagent grade or
HPLC grade. All reactions were carried out under a nitrogen atmosphere unless otherwise noted. All reactions were
monitored by thin layer chromatography (TLC) on precoated silica gel 60 F254; spots were visualized with UV light or
by treatment with ninhydrin solution in ethanol. Products were purified by flash chromatography (FC) on silica gel 60
(230–400 mesh). 1H NMR spectra and 13C NMR spectra were recorded on 300 and 400 MHz spectrometers. Chemical
shifts are reported in parts per million relative to the residual solvent. 13C NMR spectra have been recorded using the
APT pulse sequence. Multiplicities in 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, m =
multiplet, br s = broad singlet. High-resolution MS spectra were recorded with a Waters Micromass Q-ToF micro TM
mass spectrometer, equipped with an ESI source. Chiral HPLC analysis was performed on Jasco PU-2080 (UV Detector
and binary HPLC pump) at 254 nm. Chiralcel ODH and AD columns were purchased from Daicel Chemical
Industries®. Optical rotator power [α]T was measured with a Jasco P-1030 polarimeter, endowed with a cell of 1 dm
D
pathlength and 1 mL capacity. The light used has a wavelength of 589 nm (Sodium D line). All the N-substituted
isatins20 and BINOL-derived phosphoric acids21 were synthetized according to reported literature.
General procedure A for the synthesis of isatins-derived benzhydryl imines (GP-A)
To a suspension of appropriate substituted isatin (1.5 mmol) in absolute EtOH (5 mL), under a nitrogen atmosphere,
benzhydryl amine (1.5 mmol) was added in one portion and the mixture was refluxed for 24 hours. The reaction was
cooled to room temperature and stirred for 2 hours.
3-(Benzhydrylimino)-1-benzylindolin-2-one (1a)
Prepared according to GP-A using 1-benzyl isatin. The desired product 1a was collected by filtration; yield: 494 mg,
1
82%; yellow foam; H NMR (300 MHz, CDCl3, 9:1 mixture of imine isomers) δ 7.87 (s, 0.9H), 7.77 (d, J = 7.5 Hz,
0.9H), 7.61-7.46 (m, 4H), 7.45-7.14 (m, 12.1H), 7.05 (t, J = 7.5 Hz, 0.9H), 6.98 (t, J = 7.5 Hz, 0.1H), 6.75 (d, J = 7.8
Hz, 0.1H), 6.66 (d, J = 7.8 Hz, 0.9H), 6.56 (s, 0.1H), 4.97 (s, 0.2H), 4.89 (s, 1.8H); 13C NMR (75 MHz, CDCl3) δ 158.9,
151.8, 144.6 and 143.0 (1C), 144.2 (2C), 135.3, 133.3 and 132.7 (1C), 128.9-127.1 (15C), 123.2, 122.9 and 122.5 (1C),
122.0, 110.3 and 109.3 (1C), 69.9 and 65.5 (1C), 43.9 and 43.5 (1C); HRMS (ESI) calcd for C28H22N2NaO+ [MNa]+
425.1624, found 425.1632.
3-(Benzhydrylimino)indolin-2-one (1b)
Prepared according to GP-A using isatin. The desired product was collected by filtration; yield: 407 mg, 87%; yellow
1
foam; H NMR (300 MHz, CDCl3, 4:1 mixture of imine isomers) δ 8.83 (m, br, 0.2H), 7.98 (m, br, 0.8H), 7.83-7.69
(m, 2H), 7.52 (d, br, J = 7.8 Hz, 3.2H), 7.46 (d, br, J = 7.7 Hz, 0.8H), 7.38-7.13 (m, 7H), 7.06 (t, J = 7.5 Hz, 0.8H), 7.00
(t, J = 7.5 Hz, 0.2H), 6.92 (d, J = 7.6 Hz, 0.2H), 6.78 (d, J = 7.6 Hz, 0.8H), 6.53 (s, br, 0.2H); 13C NMR (75 MHz,
CD2Cl2+1%DMSO-d6) δ 160.9, 153.6, 144.8 (2C), 143.8, 133.8 and 133.2 (1C), 128.9-127.2 (10C), 122.8, 122.7, 122.5,
111.8 and 110.8 (1C), 69.9 and 65.1 (1C); HRMS (ESI) calcd for C21H16N2NaO+ [MNa]+ 335.1155, found 335.1144.
3-(Benzhydrylimino)-1-methylindolin-2-one (1c)
Prepared according to GP-A using 1-methyl isatin. The desired product was collected by filtration; yield: 367 mg, 75%;
1
yellow foam; H NMR (400 MHz, CD2Cl2, 9:1 mixture of imine isomers) δ 7.83 (s, 0.9H), 7.78 (d, br, J = 7.5 Hz,
0.9H), 7.76 (d, br, J = 7.5 Hz, 0.1H), 7.57 (d, br, J = 7.7 Hz, 3.6H), 7.52 (d, br, J = 7.8 Hz, 0.4H), 7.47 (dt, J = 7.8 and
1.5 Hz, 0.9H), 7.46 (dt, J = 7.7 and 1.5 Hz, 0.1H), 7.41-7.24 (m, 6H), 7.16 (dt, J = 7.6, 1.0 Hz, 0.9H), 7.06 (dt, J =
7.8, 1.0 Hz, 0.1H), 6.92 (d, br, J = 7.8 Hz, 0.1H), 6.86 (d, br, J = 7.8 Hz, 0.9H), 6.57 (s, 0.1H), 3.27 (s, 0.3H), 3.22 (s,
2.7H); 13C NMR (101 MHz, CD2Cl2) δ 158.9, 152.3, 145.7 and 143.3 (1C), 144.4 (2C), 133.5 and 132.9 (1C), 128.6-
127.3 (10C), 122.9, 122.5, 121.7, 109.2 and 108.4 (1C), 69.7 and 65.4 (1C), 26.0 and 25.5 (1C); HRMS (ESI) calcd for
C22H18N2NaO+ [MNa]+ 349.1311, found 349.1322.
3-(Benzhydrylimino)-1-(4-methoxybenzyl)indolin-2-one (1d)
Prepared according to GP-A using 1-4-methoxybenzyl isatin. The desired product was collected by filtration; yield: 486
mg, 75%; yellow foam; 1H NMR (400 MHz, CD2Cl2, 9:1 mixture of imine isomers) δ 7.88 (s, br, 0.9H), 7.79 (d, br, J =
7.6 Hz, 0.9H), 7.76 (d, br, J = 7.7 Hz, 0.1H), 7.59 (d, br, J = 7.4 Hz, 3.6H), 7.54 (d, br, J = 7.4 Hz, 0.4H), 7.44-7.23
(m, 9H), 7.12 (t, J = 7.6, 0.9H), 7.03 (t, J = 7.7, 0.1H), 6.88 (d, br, J = 8.0, 2H), 6.84 (d, br, J = 7.8, 0.1H), 6.78 (d, br, J
= 7.8, 0.9H), 6.57 (s, br, 0.1H), 4.93 (s, 0.2H), 4.87 (s, 1.8H), 3.80 (s, 3H). 13C NMR (101 MHz, CD2Cl2) δ 159.9,
159.4, 152.9, 145.5, 145.0 (2C), 144.0, 134.0 and 133.4 (1C), 129.4-127.6 (12C), 123.7 and 123.3 (1C), 122.6, 122.7,
+
114.8 (2C), 110.9 and 110.0 (1C), 70.5 and 66.1 (1C), 55.9, 43.9 and 43.5 (1C); HRMS (ESI) calcd for C29H24N2NaO2
[MNa]+ 455.1730, found 455.1742.
3-(Benzhydrylimino)-1-tritylindolin-2-one (1e)

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Prepared according to GP-A using 1-trityl isatin. The desired product was collected by filtration; yield: 498 mg, 60%;
DOI: 10.1039/C6OB01359G
1
pale yellow foam; H NMR (300 MHz, CDCl3, 9:1 mixture of imine isomers) δ 7.82-7.69 (m, 1.9H), 7.61-7.37 (m,
10H), 7.35-7.17 (m, 15H), 7.04-6.83 (m, 2H), 6.50 (s, br, 0.1H), 6.38 (d, J = 7.8 Hz, 0.1H), 6.16 (d, J = 7.8 Hz, 0.9H);
13C NMR (101 MHz, CDCl3) δ 160.3, 151.8, 145.3, 144.5 (2C), 141.9 (3C), 131.6 and 131.2 (1C), 129.6-126.9 (25C),
123.4, 122.6, 122.2 and 122.8 (1C), 117.2 and 115.7 (1C), 74.7, 69.7 and 64.4 (1C); HRMS (ESI) calcd for
C40H30N2NaO+ [MNa]+ 577.2250, found 577.2239.
3-(Benzhydrylimino)-1-benzyl-5-fluoroindolin-2-one (1f)
Prepared according to GP-A using 5-fluoro-1-benzyl isatin. The desired product was collected by filtration; yield: 428
mg, 68%; yellow foam; 1H NMR (400 MHz, CD2Cl2, 9:1 mixture of imine isomers) δ 7.88 (s, 0.9H), 7.63-7.50 (m, 4H),
7.47-7.26 (m, 11H), 7.07 (dt, J = 8.0, 2.8 Hz, 1H), 6.75 (dd, J = 8.0, 4.2 Hz, 0.1H), 6.68 (dd, J = 8.0, 3.9 Hz, 0.9H),
6.50 (s, 0.1H), 4.99 (s, 0.2H), 4.93 (s, 1.9H). 13C NMR (101 MHz, CD2Cl2) δ 160.1 (d, J = 241.6Hz, 1C), 159.4, 152.4,
144.8 (2C), 143.7 and 141.5 (1C), 135.9, 131.0-127.8 (15C), 123.8 (d, J = 8.5Hz, 1C), 120.3 (d, J = 24.0Hz) and 119.6
(d, J = 24.0Hz) (1C), 116.0 (d, J = 24.0Hz) and 110.3 (d, J = 24.0Hz) (1C), 111.6 (d, J = 7.1Hz) and 111.0 (d, J =
7.1Hz) (1C), 70.6 and 66.4 (1C), 44.5 and 44.2 (1C); HRMS (ESI) calcd for C28H21FN2NaO+ [MNa]+ 443.1530, found
443.1515.
3-(Benzhydrylimino)-1-benzyl-5-chloroindolin-2-one (1g)
Prepared according to GP-A using 5-chloro-1-benzyl isatin. The desired product was collected by filtration; yield: 458
mg, 70%; yellow foam; 1H NMR (400 MHz, CD2Cl2, 19:1 mixture of imine isomers) δ 7.86 (s, br, 0.95H), 7.81 (d, br, J
= 1.6 Hz, 0.95H), 7.78 (d, br, J = 1.6 Hz, 0.05H), 7.60 (d, br, J = 7.5 Hz, 3.8H), 7.55 (d, br, J = 7.5 Hz, 0.2H), 7.46-7.26
(m, 12H), 6.76 (d, J = 8.5 Hz, 0.05H), 6.69 (d, J = 8.5 Hz, 0.95H), 6.53 (s, br, 0.05H), 5.00 (s, 0.1H), 4.93 (s, 1.9H); 13
C
NMR (101 MHz, CD2Cl2) δ 158.4, 151.2, 144.1 (2C), 143.3, 135.1, 132.9 and 132.3 (1C), 130.4-127.1 (16C), 123.3,
122.4, 111.3 and 110.6 (1C), 70.0 and 65.9 (1C), 43.9 and 43.6 (1C); HRMS (ESI) calcd for C28H21ClN2NaO+ [MNa]+
459.1234, found 459.1245.
3-(Benzhydrylimino)-1-benzyl-6-bromoindolin-2-one (1h)
Prepared according to GP-A using 6-bromo-1-benzyl isatin. The desired product was collected by filtration; yield: 562
mg, 78%; yellow foam; 1H NMR (400 MHz, CD2Cl2, 85:15 mixture of imine isomers) δ 7.83 (s, 0.85H), 7.68 (d, J = 7.7
Hz, 0.85H), 7.66-7.50 (m, 4.15H), 7.47-7.25 (m, 11.85H), 7.19 (dd, J = 7.8 and 1.2 Hz, 0.15H), 6.99 (d, J = 1.2 Hz,
0.15H), 6.93 (s, br, 0.85H), 6.51 (s, br, 0.15H), 4.98 (s, 0.3H), 4.91 (s, 1.7H); 13C NMR (101 MHz, CD2Cl2) δ 158.6,
151.2, 145.9, 144.1 (2C), 135.0, 128.9-125.7 (17C), 123.4, 120.9, 113.5 and 112.7 (1C), 70.1 and 65.8 (1C), 43.9 and
43.6 (1C); HRMS (ESI) calcd for C28H21BrN2NaO+ [MNa]+ 503.0729, found 503.0713.
3-(Benzhydrylimino)-6-bromo-1-methylindolin-2-one (1i)
Prepared according to GP-A using 6-bromo-1-methyl isatin. The desired product was collected by filtration; yield: 424
mg, 70%; yellow foam; 1H NMR (400 MHz, CD2Cl2, 85:15 mixture of imine isomers) δ 7.78 (s, br, 0.85H), 7.66 (d, J =
7.8 Hz, 0.85H), 7.61-7.46 (m, 4.15H), 7.44-7.19 (m, 7H), 7.10 (s, br, 0.15H), 7.03 (s, br, 0.85H), 6.48 (s, br, 0.15H),
3.25 (s, 0.45H), 3.20 (s, 2.55H); 13C NMR (101 MHz, CD2Cl2) δ 159.2, 152.1, 147.3, 144.8 (2C), 131.1-123.9 (13C),
121.3, 113.5 and 112.7 (1C), 70.6 and 66.3 (1C), 26.9 and 26.4 (1C); HRMS (ESI) calcd for C22H17BrN2NaO+ [MNa]+
427.0416, found 427.0411.
General procedure B for the asymmetric organocatalyzed synthesis of compounds 5-13 (GP-B)
To a solution of isatin-derived imine 1a-i (0.12 mmol, 1eq) and trimethylsilyloxyfuran (TMSOF) (0.14 mmol, 1.16eq)
in tetrahydrofuran (1 mL) cooled to -40 °C, a solution of catalyst (R)-4a (10% mol) in MeOH (25 µL) and
tetrahydrofuran (200 µL) was slowly added. The resulting mixture was stirred at the same temperature for 7 hours. The
reaction was quenched by adding NaHCO3 saturated aq. (1 mL) and the product was extracted with EtOAc (2 x 5 mL).
The combined organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure.
The residue was purified by FC, as indicated below.
3-(Benzhydrylamino)-1-benzyl-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (5a,b)
Prepared according to GP-B using 3-(benzhydrylimino)-1-benzylindolin-2-one (1a); FC: n-Hexane:EtOAc, 7:3; yield:
47 mg, 80%; pale orange solid; 1H NMR (300 MHz, CDCl3, mixture of diasteroisomers syn:anti, 48:52) δ 7.83 (dd, J =
5.8 and 1.7 Hz, 0.52H), 7.43-7.13 (m, 15H), 7.10 (dd, J = 5.9 and 1.5 Hz, 0.48H), 7.08-6.91 (m, 2.48H), 6.87 (td, J =
7.6 and 1.0 Hz, 0.52H), 6.65 (d, J = 7.8 Hz, 0.48H), 6.59 (d, J = 7.8 Hz, 0.52H), 6.25 (dd, J = 5.8, 1.9 Hz, 0.52H), 5.97
(dd, J = 5.9, 2.2 Hz, 0.48H), 5.48 (t, br, J = 1.8 Hz, 0.48H), 5.26 (t, br, J = 1.7 Hz, 0.52H), 4.81 (d, J = 15.9 Hz, 0.52H),
4.73 (s, br, 0.48H), 4.72 (s, br, 0.52H), 4.65 (d, J = 15.4 Hz, 0.48H), 4.25 (d, J = 15.9 Hz, 0.52H), 4.10 (d, J = 15.4 Hz,
0.48H), 3.03-2.41 (m, br, 1H); 13C NMR (101 MHz, CDCl3, mixture of diasteroisomers syn:anti, 48:52) δ 176.0 and
174.3 (1C), 165.0 and 163.2 (1C), 152.4 and 151.1 (1C), 143.6 and 143.3 (2C), 142.2 and 141.8 (1C), 135.5 and 135.3
(1C), 130.1 and 129.9 (1C), 128.8-1258(17C), 124.2 and 123.9 (1C), 122.9 and 122.1 (1C), 109.6 and 109.5 (1C), 86.1
and 85.2 (1C), 68.1 and 67.3 (1C), 63.0 and 62.3 (1C), 43.9; HRMS (ESI) calcd for C32H26N2NaO3+ [MNa]+ 509.1836,
found 509.1828; enantiomeric excess: syn 92%, anti 90%, determined by HPLC (Chiracel-AD, n-hexane:isopropanol =
1:1, flow rate 0.6 mL/min): tR = 10.33 min (anti, minor), tR = 11.75 min (syn, major); tR = 14.27 min (syn, minor), tR =
66.85 min (anti, major).
3-(Benzhydrylamino)-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (6a,b)
Prepared according to GP-B using 3-(benzhydrylimino)indolin-2-one (1b); FC: dichlorometane:MeOH, 99:1; yield: 37
1
mg, 78%; pale yellow solid; H NMR (300 MHz, CDCl3+1% CD3OD, mixture of diasteroisomers syn:anti, 37:63) δ

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7.73 (d, br, J = 5.8 Hz, 0.63H), 7.32-6.82 (m, 15H), 6.81-6.62 (m, 1.37H), 6.16 (dd, J = 5.9 and 1.9 Hz, 0.63H), 5.92
DOI: 10.1039/C6OB01359G
(dd, J = 5.8 and 1.9 Hz, 0.37H), 5.34 (t, br, J = 1.8 Hz, 0.37H), 5.16 (t, br, J = 1.8 Hz, 0.63H), 4.64 (s, 0.37H), 4.62 (s,
0.63H); 13C NMR (75 MHz, CDCl3+1% CD3OD, mixture of diasteroisomers syn:anti, 37:63) δ 178.1, 172.6 and 172.3
(1C), 153.1 and 151.7 (1C), 143.6 and 143.4 (2C), 142.6 and 142.0 (1C), 129.9-121.6 (15C), 110.3, 86.0 and 85.2 (1C),
66.0 and 64.8 (1C), 62.9 and 62.2 (1C); HRMS (ESI) calcd for C25H20N2NaO3+ [MNa]+ 419.1366, found 419.1354;
enantiomeric excess: syn 88%, anti 80%, determined by HPLC (Chiracel-AD, n-hexane:isopropanol = 4:1, flow rate 0.7
mL/min): tR = 10.58 min (syn, minor), tR = 11.38 min (syn, major), tR = 13.61 min (anti, minor), tR = 63.13 min (anti,
major).
3-(Benzhydrylamino)-1-methyl-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (7a) and (7b)
Prepared according to GP-B using 3-(benzhydrylimino)-1-methylindolin-2-one (1c); FC: n-Hexane:EtOAc, 7:3.
1
(7a) yield: 22 mg, 45%; orange foam; [α]20D –24.6 (c 0.2, CHCl3); H NMR (400 MHz, CDCl3, anti diasteroisomer) δ
7.88 (dd, J = 5.6 and 1.5 Hz, 1H), 7.43-7.13 (m, 10H), 6.97 (t, J = 7.6 Hz, 1H), 6.87- 6.80 (m, 2H), 6.70 (d, J = 7.6 Hz,
1H), 6.27 (dd, J = 5.6 and 1.5 Hz, 1H), 5.16 (t, J = 1.5 Hz, 1H), 4.68 (s, br, 1H), 2.81 (s, 3H), 2.71-2.45 (m, br, 1H); 13
C
NMR (101 MHz, CDCl3) δ 175.7, 171.8, 152.6, 144.5, 143.3, 141.9, 130.2, 128.5-126.8 (11C), 124.0, 123.1, 122.1,
108.5, 85.1, 67.0, 62.2, 26.1; HRMS (ESI) calcd for C26H22N2NaO3+ [MNa]+ 433.1523, found 433.1529; enantiomeric
excess: 91%, determined by HPLC (C-ODH, n-hexane:isopropanol = 4:1, flow rate 0.7 mL/min): tR = 5.51 min (minor),
tR = 15.34 min (major).
(7b) yield: 19 mg, 36%; orange foam; [α]20D + 115.2 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3, syn diasteroisomer) δ
7.42-7.07 (m, 11H), 7.03 (t, br, J = 7.8 Hz, 1H), 6.94-6.86 (m, 2H), 6.64 (d, br, J = 7.8 Hz, 1H), 5.93 (dd, J = 5.9, 2.0
Hz, 1H), 5.41 (s, 1H), 4.64 (s, 1H), 3.21-2.74 (m, br, 1H), 2.68 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.2, 172.1,
151.2, 143.6, 143.5, 141.4, 130.0, 128.4-127.1 (10C), 125.7, 123.9, 123.7, 122.9, 108.6, 86.0, 67.9, 63.1, 25.9; HRMS
(ESI) calcd for C26H22N2NaO3+ [MNa]+ 433.1523, found 433.1531; enantiomeric excess: 68%, determined by HPLC
(C-AD, n-hexane:isopropanol = 4:1, flow rate 0.7 mL/min): tR = 11.28 min (major), tR = 13.51 min (minor).
3-(Benzhydrylamino)-1-(4-methoxybenzyl)-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (8ab)
Prepared according to GP-B using 3-(benzhydrylimino)-1-(4-methoxybenzyl)indolin-2-one (1d); FC: n-Hexane:EtOAc,
1
7:3; yield: 51 mg, 79%; H NMR (300 MHz, CDCl3, mixture of diasteroisomers syn:anti, 45:55) δ 7.73 (d, J = 4.9 Hz,
0.55H), 7.32-6.74 (m, 17.45H), 6.63 (d, br, J = 7.8 Hz, 0.45H), 6.58 (d, br, J = 7.8 Hz, 0.55H), 6.20 (d, br, J = 5.8 Hz,
0.55H), 5.93 (d, br, J = 5.9 Hz, 0.45H), 5.45 (s, br, 0.45H), 5.31 (s, br, 0.55H), 4.80-4.64 (m, 1.55H), 4.56 (d, J = 14.7
Hz, 0.45H), 4.15 (d, J = 15.8 Hz, 0.55H), 3.99 (d, J = 14.7 Hz, 0.45H), 3.75 (s, 3H), 3.34-2.47 (m, br, 1H); 13C NMR
(75 MHz, CDCl3, mixture of diasteroisomers syn:anti, 45:55) δ 175.2 and 174.0 (1C), 172.0 and 171.6 (1C), 159.2,
152.2 and 151.1 (1C), 143.5 and 143.4 (1C), 142.9, 141.6, 130.2 and 129.9 (1C), 128.8-127.2 (14C), 125.7 and 124.2
(1C), 122.8 and 122.2 (1C), 122.4, 114.2, 111.3, 109.6 and 109.5 (1C), 86.0 and 84.8 (1C), 68.0 and 67.3 (1C), 63.0
and 62.6 (1C), 55.3, 43.4 and 43.3 (1C); HRMS (ESI) calcd for C33H28N2NaO4+ [MNa]+ 539.1941, found 539.1950;
enantiomeric excess: syn 89%, anti 84%, determined by HPLC (Chiracel-AD, n-hexane:isopropanol = 9:1, flow rate 1.0
mL/min): tR = 30.00 min (anti minor), tR = 40.25 min (syn major), tR = 42.46 min (syn minor), tR = 112.89 min (anti
major).
3-(Benzhydrylamino)-3-(5-oxo-2,5-dihydrofuran-2-yl)-1-tritylindolin-2-one (9ab)
Prepared according to GP-B using 3-(benzhydrylimino)-1-tritylindolin-2-one (1e); FC: n-Hexane:EtOAc, 4:1; yield:
64mg, 81%; pale orange solid; 1H NMR (400 MHz, CDCl3, mixture of diasteroisomers syn:anti, 53:47) δ 7.81 (dd, J =
5.9 and 1.5 Hz, 0.47H), 7.67-6.99 (m, 23H), 6.95 (d, br, J = 7.7 Hz, 0.47H), 6.88 (t, br, J = 7.7 Hz, 0.47H), 6.81-6.86
(m, 3.06H), 6.55 (dd, J = 5.9 and 1.5 Hz, 0.53H), 6.41-6.27 (m, 2H), 6.22 (dd, J = 5.8 and 1.9 Hz, 0.47H), 5.83 (dd, J =
5.9 and 2.2 Hz, 0.53H), 5.35 (t, br, J = 1.7 Hz, 0.53H), 5.24 (t, br, J = 1.7 Hz, 0.47H), 4.60 (s, br, 0.53H), 4.17 (s, br,
0.47H), 3.47-2.32 (m, br, 1H); 13C NMR (101 MHz, CDCl3, mixture of diasteroisomers syn:anti, 53:47) δ 178.6 and
175.6 (1C), 172.0 and 171.4 (1C), 153.0 and 151.7 (1C), 144.1 and 144.0 (1C), 143.5 and 143.4 (1C), 143.3 and 143.2
(1C), 142.2 and 141.9 (3C), 129.2, 129.3-126.9 (26C), 126.5 and 125.4 (1C), 125.2, 123.9 and 123.2 (1C), 122.4 and
121.0 (1C), 116.0 and 115.8 (1C), 86.5 and 85.2 (1C), 75.4 and 75.2 (1C), 68.8 and 68.4 (1C), 62.9 and 62.6 (1C);
+
HRMS (ESI) calcd for C44H34N2NaO3 [MNa]+ 661.2462, found 661.2455; enantiomeric excess: syn 96%, anti 4%,
determined by HPLC (Chiracel-AD, n-hexane:isopropanol = 17:1, flow rate 0.7 mL/min): tR = 15.85 min (anti minor),
tR = 24.13 min (syn minor), tR = 27.90 min (anti major), tR = 33.83 min (syn major).
3-(Benzhydrylamino)-1-benzyl-5-fluoro-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (10ab)
Prepared according to GP-B using 3-(benzhydrylimino)-1-benzyl-5-fluoroindolin-2-one (1f); FC: n-Hexane:EtOAc,
1
7:3; 29 mg, yield: 45%; pale orange solid; H NMR (300 MHz, CDCl3, mixture of diasteroisomers syn:anti, 28:72) δ
7.81 (d, br, J = 4.9 Hz, 0.72H), 7.52-6.76 (m, 16.56H), 6.69 (d, br, J = 7.8 Hz, 0.72H), 6.57-6.42 (m, 1H), 6.25 (d, br, J
= 5.8 Hz, 0.72H), 5.99 (d, br, J = 5.8 Hz, 0.28H), 5.42 (s, br, 0.28H), 5.21 (s, br, 0.72H), 4.81 (d, J = 15.7 Hz, 0.72H),
4.72-4.60 (m, 1.28H), 4.30 (d, J = 15.7 Hz, 0.72H), 4.11 (d, J = 15.7 Hz, 0.28H), 3.01-2.66 (m, br, 1H); 13C NMR (75
MHz, CDCl3, mixture of diasteroisomers syn:anti, 28:72) δ 175.8 and 174.1 (1C), 158.9 (d, J = 239.9Hz) and 158.1 (d,
J = 244.0Hz) (1C), 152.1 and 150.8 (1C), 143.3 and 142.9 (1C), 142.1 and 141.8 (1C), 139.3 and 138.7 (1C), 135.1 and
134.9 (1C), 128.9- 127.1 (16C), 125.3 and 124.6 (1C), 124.4 and 124.0 (1C), 116.6-116.1 (m, 1C), 114.9 (d, J =
26.2Hz) and 113.8 (d, J = 22.8Hz) (1C), 110.0 (d, J = 8.7Hz) (1C), 85.8 and 84.8 (1C), 68.3 and 67.7 (1C), 63.1 and
62.5 (1C), 44.0; HRMS (ESI) calcd for C32H25FN2NaO3+ [MNa]+ 527.1741, found 527.1752; enantiomeric excess: syn
15%, anti 1%, determined by HPLC (C-ODH, n-hexane:isopropanol = 4:1, flow rate 0.7 mL/min): tR = 25.91 min (syn
major), tR = 32.60 min (syn minor), tR = 35.53 min (anti major), tR = 57.56 min (anti minor).

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3-(Benzhydrylamino)-1-benzyl-5-chloro-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (11ab)
Prepared according to GP-B using 3-(benzhydrylimino)-1-benzyl-5-chloroindolin-2-one (1g); FC:DnO-IH: 1e0x.1a0n39e/:CE6tOOBA0c13,59G
7:3; yield: 27 mg, 42%; pale orange solid; 1H NMR (400 MHz, CDCl3, mixture of diasteroisomers syn:anti, 3:7) δ 7.83
(dd, J = 5.8, 1.2 Hz, 0.7H), 7.46-6.98 (m, 16.6H), 6.92 (d, , J = 2.0 Hz, 0.7H) 6.54 (d, J = 8.4 Hz, 0.3H), 6.50 (d, J = 8.4
Hz, 0.7H), 6.29 (dd, J = 5.8, 1.7 Hz, 0.7H), 6.06 (dd, J = 5.8, 1.9 Hz, 0.3H), 5.44 (t, J = 1.5 Hz, 0.3H), 5.24 (t, J = 1.5
Hz, 0.7H), 4.84 (d, J = 15.8 Hz, 0.7H), 4.76-4.62 (m, 1.3H), 4.34 (d, J = 15.8 Hz, 0.7H), 4.14 (d, J = 15.8 Hz, 0.3H),
3.11-2.68 (m, br, 1H); 13C NMR (101 MHz, CDCl3, mixture of diasteroisomers syn:anti, 3:7) δ 176.4 and 174.7 (1C),
172.2 and 172.0 (1C), 152.7 and 151.5 (1C), 143.8-142.1 (3C), 135.7 and 135.6 (1C), 130.7 and 130.5 (1C), 129.6 to
126.8 (17C), 126.6 and 125.2 (1C), 125.1 and 124.8 (1C), 111.1, 86.5 and 85.4 (1C), 68.9 and 68.3 (1C), 63.8 and 63.3
(1C), 44.8 and 44.7 (1C); HRMS (ESI) calcd for C32H25ClN2NaO3+ [MNa]+ 543.1446, found 543.1454; enantiomeric
excess: syn 74%, anti 26%, determined by HPLC (C-AD, n-hexane:isopropanol = 9:1 to 3:7, flow rate 1.0 mL/min): tR
= 18.02 min (syn major), tR = 19.84 min (anti major), tR = 37.38 min (syn minor), tR = 57.02 min (anti minor).
3-(Benzhydrylamino)-1-benzyl-6-bromo-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (12ab)
Prepared according to GP-B using 3-(benzhydrylimino)-1-benzyl-6-bromoindolin-2-one (1h); FC: n-Hexane:EtOAc,
7:3; yield: 44 mg, 65%; orange solid; 1H NMR (400 MHz, CDCl3, mixture of diasteroisomers 3:7) δ 7.83 (d, br, J = 5.6
Hz, 0.7H), 7.46-7.02 (m, 14.6H), 7.01-6.94 (m, 2H), 6.86 (d, br, J = 7.9 Hz, 0.7H ), 6.79 (s, br 0.3H), 6.74 (s, br, 0.7H),
6.26 (dd, J = 5.6, 1.5 Hz, 0.7H), 6.00 (dd, J = 5.8, 1.9 Hz, 0.3H), 5.44 (s, br, 0.3H), 5.22 (s, br, 0.7H), 4.79 (d, J = 15.8
Hz, 0.7H), 4.72- 4.58 (m, 1.3H), 4.25 (d, J = 15.8 Hz, 0.7H), 4.08 (d, J = 15.8 Hz, 0.3H), 3.10-2.69 (m, br, 1H). 13C
NMR (101 MHz, CDCl3, mixture of diasteroisomers syn:anti, 3:7) δ 176.6 and 174.9 (1C), 172.3 and 172.0 (1C), 152.8
and 151.4 (1C), 145.5-142.2 (4C), 135.6 and 135.4 (1C), 129.7 to 127.6 (15C), 126.5 and 125.7 (1C), 125.0 and 124.9
(1C), 124.6 and 124.4 (1C), 123.6 and 123.5 (1C), 113.5, 86.4 and 85.4 (1C), 68.5 and 67.9 (1C), 63.8 and 63.1 (1C),
44.7; HRMS (ESI) calcd for C32H25BrN2NaO3+ [MNa]+ 587.0941 found 587.0944. enantiomeric excess: syn 42%, anti
31%, determined by HPLC (C-AD, n-hexane:isopropanol = 9:1, flow rate 1.0 mL/min): tR = 16.04 min (anti minor), tR
= 17.91 min (syn major), tR = 24.31 min (syn minor), tR = 63.35 min (anti major).
3-(Benzhydrylamino)-6-bromo-1-methyl-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (13a) and (13b)
Prepared according to GP-B using 3-(benzhydrylimino)-6-bromo-1-methylindolin-2-one (1i); FC: n-Hexane:EtOAc,
7:3.
(13a) yield: 25 mg, 42%; orange foam; [α]20D – 18.4 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3, anti diasteroisomer) δ
7.84 (dd, J = 5.8, 1.9 Hz, 1H), 7.24-7.10 (m, 8H), 7.06 (d, br, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.88-6.80 (m,
3H), 6.25 (dd, J = 5.8, 1.9 Hz, 1H), 5.12 (s, br, 1H), 4.61 (s, 1H), 2.78 (s, 3H), 2.72-2.06 (m, br, 1H); 13C NMR (75
MHz, CDCl3) δ 175.5, 171.6, 152.3, 145.7, 142.8, 141.6, 128.3-127.1 (11C), 125.0, 124.3, 124.1, 121.9, 112.1, 84.6,
+
66.9, 62.3, 26.2; HRMS (ESI) calcd for C26H21BrN2NaO3 [MNa]+ 511.0628, found 511.0637; enantiomeric excess: anti
32%, determined by HPLC (C-ODH, n-hexane:isopropanol = 4:1, flow rate 0.7 mL/min): tR = 23.33 min (major), tR =
75.68 min (minor).
(13b) yield: 15 mg, 26%; orange foam; [α]20D – 2.82 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3, syn diasteroisomer) δ
7.44-7.03 (m, 11H), 7.01-6.90 (m, 2H), 6.80 (d, J = 1.4 Hz, 1H), 5.97 (dd, J = 5.8, 2.0 Hz, 1H), 5.39 (s, br, 1H), 4.62 (s,
1H), 2.68 (s, 3H), 2.16-1.77 (m, br, 1H); 13C NMR (75 MHz, CDCl3) δ 173.8, 171.7, 150.9, 144.9, 142.8, 140.9, 128.3-
126.9 (11C), 125.8, 124.2, 123.9, 122.5, 112.2, 85.5, 67.8, 63.4, 26.1; HRMS (ESI) calcd for C26H21BrN2NaO3+ [MNa]+
511.0628, found 511.0633; enantiomeric excess: syn 31%, determined by HPLC (C-ODH, n-hexane:isopropanol = 4:1,
flow rate 0.7 mL/min): tR = 14.81 min (major), tR = 23.13 min (minor).
Post-transformation reactions
3-Amino-1-methyl-3-(5-oxotetrahydrofuran-2-yl)indolin-2-one (15)
To a solution of Mannich adduct 14 (100 mg, 0.29 mmol) in EtOAc (3 mL), 10% Pd/C (10% w/w) was added. The
reaction mixture was degassed in vacuo, placed under an atmosphere of H2 (g), stirred at rt and the conversion was
monitored by TLC. The mixture was filtered through a pad of Celite eluting with EtOAc (10 mL) and the solvent was
concentrated in vacuo. The crude residue was dissolved in dry MeOH (1 mL) followed by the dropwise addition of HCl
solution (0.5 mL, 4M HCl in dioxane) and the resulting mixture was stirred at room temperature for 4h. After
quenching with saturated aq NaHCO3 (2 mL), and dilution with CH2Cl2 (2 mL), the aqueous phase was extracted with
CH2Cl2 (3 x 5 mL). The combined organic layer was washed with saturated aq NaHCO3, dried over anhydrous Na2SO4
and the solvent was removed under reduce pressure. The crude was subjected to FC (dichlorometane:MeOH, 95:5)
giving the desired product 15, as a white foam (65 mg, 91% overall yield).
[α]20D – 83.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.46 (d, br, J = 7.8 Hz, 1H), 7.36 (t, br, J = 7.6 Hz, 1H), 7.09
(t, br, J = 7.7 Hz, 1H), 6.86 (d, br, J = 7.8 Hz, 1H), 4.62 (dd, br, J = 7.8 and 5.9 Hz, 1H), 3.21 (s, 3H), 2.58-2.33 (m,
4H), 1.88 (m, br, 2H); 13C NMR (75 MHz, CDCl3) δ 177.7, 176.6, 143.7, 130.1, 128.2, 124.8, 123.2, 108.7, 82.4, 62.1,
+
28.0, 26.5, 21.7; HRMS (ESI) calcd for C13H14N2NaO3 [MNa]+ 269.0897, found 269.0908.
3-Amino-1-methyl-3-(5-oxotetrahydrofuran-2-yl)indolin-2-one (15’)
Palladium hydroxide (20 wt.% on carbon, 12 mg) was added to a solution of vinylogous Mannich-adduct 7a (82 mg,
0.20 mmol) in MeOH (1 mL). The reaction mixture was degassed in vacuo, placed under an atmosphere of H2 (g),
stirred at rt and the conversion was monitored by TLC. The mixture was filtered through a pad of Celite eluting with
MeOH (10 mL), and the solvent was concentrated in vacuo. The crude was subjected to FC (dichlorometane:MeOH,
95:5) to give 15' as a white foam (47 mg, 96%).

Page 9 of 9
Organic & Biomolecular Chemistry
1
13
[α]20D – 90.6 (c 1.3, CHCl3); H NMR (300 MHz, CDCl3) and C NMR (75 MHz, CDCl3) were identical to those of
View Article Online
DOI: 10.1039/C6OB01359G
compound 15. HRMS (ESI) calcd for C13H14N2NaO3 [MNa]+ 269.0897, found 269.0879.
+
3-(Benzhydrylamino)-1-methyl-3-(5-((triisopropylsilyl)oxy)furan-2-yl)indolin-2-one (16)
To a solution of 3-(benzhydrylamino)-1-methyl-3-(5-oxo-2,5-dihydrofuran-2-yl)indolin-2-one (7a or 7b) (60 mg, 0.15
mmol) in anhydrous dichloromethane (1.5 mL) cooled to 0 °C, anhydrous trimethylamine (0.15 mmol, 1eq) and
TIPSOTf (0.17 mmol, 1.1 eq) were added. The solution was stirred at the same temperature for 1 hour (monitored by
TLC). The reaction was quenched by adding water (1.5 mL). The organic phase was separated, dried over anhydrous
Na2SO4 and the solvent was evaporated in vacuo to give 16 as a viscous oil.
Compound (R)-16 from 7a:
Yield: 72 mg, 98%; [α]20D – 33.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.33-7.10 (m, 12H), 6.90 (t, J = 7.4 Hz,
1H), 6.69 (d, J = 7.7 Hz, 1H), 6.13 (d, br, J = 2.9 Hz, 1H), 5.04 (d, br, J = 2.9 Hz, 1H), 4.79 (s, 1H), 3.07-2.95 (m, br,
1H), 2.72 (s, 3H), 1.22 (hept, J = 7.8 Hz, 3H), 1.04 (d, J = 7.8 Hz,18H); 13C NMR (75 MHz, CDCl3) δ 175.7, 157.1,
144.2, 143.4, 142.5, 141.1, 128.1-126.9 (12C), 123.1, 122.2, 109.7, 109.0, 84.3, 71.7, 62.6, 25.2, 17.5 (6C), 12.2 (3C);
HRMS (ESI) calcd for C35H42N2NaO3Si+ [MNa]+ 589.2857, found 589.2866.
Compound (S)-16 from 7b:
1
Yield: 69 mg, 95%; [α]20D + 31.8 (c 0.9, CHCl3); H NMR (300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3) were
identical to those of compound (R)-16; HRMS (ESI) calcd for C35H42N2NaO3Si+ [MNa]+ 589.2857, found 589.2869.
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