Palladium-catalyzed domino Heck/cyanation: Synthesis of 3-cyanomethyloxindoles and their conversion to spirooxoindoles

Article abstract of DOI:10.1016/j.tet.2010.09.056

3′-Alkyl-3-cyanomethyloxindoles, prepared by a palladium-catalyzed domino Heck/cyanation, were efficiently converted to spiropyrrolidinyl-, spiropiperidinyl- and spirocyclopropyl-oxindoles. The so-obtained spirooxindoles bearing three diversity points wer

Full text of DOI:10.1016/j.tet.2010.09.056

Tetrahedron 66 (2010) 8911e8921
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed domino Heck/cyanation: synthesis of
3-cyanomethyloxindoles and their conversion to spirooxoindoles
,
Stéphanie Jaegli a, Jean-Pierre Vors b, Luc Neuville a, Jieping Zhu a
*
a Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette cedex, France
b Bayer CropScience SA, 14-20 rue Pierre Baizet, 69009 Lyon, France
a r t i c l e i n f o
a b s t r a c t
30-Alkyl-3-cyanomethyloxindoles, prepared by a palladium-catalyzed domino Heck/cyanation, were
efficiently converted to spiropyrrolidinyl-, spiropiperidinyl- and spirocyclopropyl-oxindoles. The
so-obtained spirooxindoles bearing three diversity points were further functionalized via selective
N-acylation, N-alkylation, N-sulfonylation, SNAr reaction and BuchwaldeHartwig N-arylation reaction to
reach diverse set of heterocycles.
Article history:
Received 26 July 2010
Received in revised form 14 September 2010
Accepted 15 September 2010
Available online 21 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Spirooxindoles
Domino reaction
Heck reaction
Cyanation
Heterocycle
1. Introduction
we describe herein the synthesis of spiropyrrolidinyl-, spiropiper-
idinyl- and spirocyclopropyl-oxindoles using 6 as common starting
materials.
The 3,30-spirocyclooxindole skeleton is found in a growing
number of natural or synthetic products presenting various bi-
ological activities.1 In particular, the spiropyrrolidinyloxindole, due
to its presence in a large number of bioactive alkaloids, such as
spirotryprostatin A2 (1) and horsfiline3 (2, Fig. 1), to just name
a few, is being considered as a privileged structure in medicinal
chemistry. The intense research work has led to the development of
promising anticancer drug candidates.4 In addition, the potential of
synthetic spiropiperidinyl- or spirocyclopropyl-oxindoles as leads
in the development of effective pharmaceuticals and agrochemicals
has also been recognized. For example, cyclopropyloxindole 3 was
reported to exhibit potent antiviral activity,5 whereas compound 4
or 5 have been reported to behave as pain killer6 or to have in-
secticidal activities,7 respectively.
N
O
H
H
O
Me
N
N
MeO
O
O
N
H
N
H
MeO
Spirotryprostatin A (1)
(-) Horsfiline (2)
R2
N
c-octyl
N
N
F
Cl
We have been interested in the synthesis of oxindoles featuring
a key palladium-catalyzed cyclization processes.8 One such reaction
that we developed is the intramolecular domino Heck/cyanation
sequence allowing ready access to diversely functionalized 3-alkyl-
3-cyanomethyl-2-oxindoles 6.9e11 As a continuation of this work,
O
R1
O
O
N
N
Me
N
H
3
4
5
N
O
Cl
R3
CN
R2
O
N
R1
6
* Corresponding authors. Tel.: þ33 1 69 82 31 31/44 75; fax: þ 33 1 69 07 72 47;
e-mail addresses: neuville@icsn.cnrs-gif.fr (L. Neuville), zhu@icsn.cnrs-gif.fr (J. Zhu).
Fig. 1. Natural and synthetic 3,30-spirooxindoles.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.056

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S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
2. Results and discussion
(3 mol %), K4[Fe(CN)6] (0.22 equiv), Na2CO3 (1.0 equiv), DMF, 120 ꢀC]
to give key intermediate 13 in 70% yield. At this stage, all attempts
to selectively reduce the nitrile group without affecting the nitro
function failed.14 On the contrary, selective reduction of the nitro
group was easily achieved using iron in refluxing water and the
newly formed aniline was protected as a tert-butylcarbamate fur-
nishing compound 14 in 83% yield over two steps. Reduction of the
nitrile group (NaBH4/CoCl2$6H2O)15 followed by protection of the
resulting primary amine as an allylcarbamate provided 15.
O-deprotection of compound 15 was best achieved using HF$Pyr
leading to alcohol 16 in 85% yield. The same reaction performed in
the presence of TBAF provided 16 (38%) together with a significant
amount of tertiary alcohol 17 (20%). The formation of 17 can be
account for by the retro-aldol followed by oxidation of enolate by
residual oxygen in the solvent.16 Pyrrolidine ring closure was finally
achieved in two steps: treatment of 16 with methanesulfonyl
chloride (MsCl, Et3N, CH2Cl2) afforded the corresponding mesylate,
which without purification, was cyclized upon treatment with NaH
in THF to afford the spirooxindole 17 in 81% yield.
2.1. Preparation of spiropyrrolidinyloxindoles
Among all 3,30-spirocyclooxindoles known in literature, the
spiropyrrolidinyloxindoles have attracted the most attention and
considerable efforts are continuously being made to prepare them.
Having recently successfully synthesized horsfiline9b and in a view
of biological evaluation of this class of spirocycle, we decided to
prepare more analogues using the same methodology. Orthogonally
protected 5-amino-spiro[3,30-pyrrolidin]-oxindole 7 (Scheme 1)
was targeted as convenient platform as the three nitrogenpresent in
this heterocycle could be used as diversity entries for parallel
synthesis.
O2N
I
OTBS
2-Chloro-N-methyl
O2N
pyridinium iodide,
NH2
OTBS
8
9
+
n-Bu3N, toluene
N
H
O
HO2C
°
90 C, 60%
Selective removal of three N-protective groups in spirooxindole
7 was next evaluated (Fig. 2). Treatment of 7 under mild acidic
conditions (TFA, CH2Cl2, rt) afforded the aniline 18 in 84% yield.
N-Allyloxy carbamate was selectively cleaved under Guibe’s con-
ditions (n-Bu3SnH, Pd(PPh3)4 cat.)17 affording compound 19 in
excellent yield (95%). On the other hand, heating a solution of 7 in
I
10
OTBS
OTBS
NaHMDS, MOMCl
THF, 0°C-rt.
O2N
O2N
N
OMOM
N
O
57% (95%)
MOM
I
I
11
12
OTBS
CN
Alloc
N
Pd(OAc)2 (3%),
1. Fe, FeSO4, H2O, reflux.
K4Fe(CN)6 Na2CO3
O2N
BocHN
O
DMF, 120°C
70%
2. Boc2O, THF,rt
83%
N
O
N
MOM
13
7
MOM
AllocHN
OTBS
TBSO
1. CoCl2, NaBH4
MeOH, rt.
HCl conc.,
CN
Pd(PPh3)4 (8
TFA, CH2Cl2,
0°C-rt.
BocHN
BocHN
H2O/THF
mol%), Bu3SnH,
AcOH, CH2Cl2, rt.
(1/1), 65°C.
O
O
N
2. AllocCl,
NaHCO3/DCM, rt
78%
N
MOM
Alloc
N
H
Alloc
MOM
N
N
15
14
H2N
BocHN
O
H2N
O
AllocHN
HO
O
1. MsCl, Et3N,
CH2Cl2, rt.
N
N
N
H
HF.Pyr, THF
BocHN
MOM
MOM
20, 51%
18, 84%
19, 95%
O
°
0
C then rt.
2. NaH, THF,
N
85%
°
0 C then rt.
MOM
F3C
81%
16
Alloc
N
Alloc
N
R1
O
O
R2
AllocHN
HO
Alloc
N
HN
HN
O
BocHN
BocHN
O
N
O
N
O
MOM
MOM
N
N
R3
21 (76%)
22 (94%)
MOM
17
MOM
7
Alloc
N
N
Scheme 1. Synthesis of 5-amino-spiro[3,30-pyrrolidin]-oxindole platform 7.
NO2
H
N
H
N
Our synthesis began with the coupling of 4-nitro-2-iodoani-
line12 8 with carboxylic acid 99b under Mukaiyama’s conditions.13
Protection of the amide proved to be rather difficult because the
para nitro group strongly reduced the nucleophilicity of the nitro-
gen. However, deprotonation of 10 with NaHMDS in THF followed
by addition of MOMCl furnished a clean mixture of N-alkylated and
O-alkylated products in a 1.3/1 ratio. The O-alkylated compound
was unstable on silica during flash chromatography and was
hydrolyzed back to the starting material 10. Thus, the N-MOM
intermediate 12 was obtained in a 95% yield based on recovered
starting material (Scheme 1).
O
O
N
N
O2N
MOM
MOM
23 (60%)
24 (35%)
O2N
O
SO2CF3
N
N
N
BocHN
BocHN
BocHN
O
O
O
N
N
N
MOM
MOM
MOM
25 (84%)
26 (68%)
27 (60%)
The properly functionalized amide was submitted to our pre-
viously established Heck/cyanation reaction conditions [Pd(OAc)2
Fig. 2. Functionalized spiropyrrolidinyloxindoles.

S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
8913
a mixed solvent H2O/THF (v/v¼1/1) in the presence of concd HCl at
65 ꢀC afforded double N-deprotected oxindole 20.
1. CH2(CO2Et)2
1. CH2O, piperidine,
pyridine, 75 °C
HO2C
CO2Et
NaH, DMF
0-100 °C
Br
Various derivatives prepared from compound 18 and 19 are
given in Fig. 2. Acylation, sulfonylation [RCOCl or RSO2Cl, Et3N,
DCM, rt] or alkylation [p-NO2eBnBr, TBAI, Cs2CO3, DMF, rt] of 18
and 19 under classic conditions furnished compound 21, 22, and
25e27 in good to excellent yields. The SNAr reaction between
18 and 1-fluoro-2-nitrobenzene (t-BuOK, DMSO) provided com-
pounds 23 in moderate yield. Palladium-catalyzed N-arylation of 18
with with 1-bromo-4-nitrobenzene [Pd(OAc)2 (10 mol %), BINAP
(20 mol %), Cs2CO3 Toluene, 90 ꢀC]18 afforded compound 24 in
which the alloc group was converted to allyl group.19
O
O
O
2.KOH, EtOH/H2O
4 °C, 63%
2. KOH, EtOH/H2O
4 °C, 61%
O
30
29
O
O
4-chloro-2-iodoaniline
2-Chloro-N-methyl
pyridinium iodide
HO2C
O
Cl
O
n-Bu3N, toluene
100 °C, 64%
N
H
O
31
I
32
O
O
O
Pd(OAc)2 (3 mol%)
O
NaH, SEMCl,
THF, 0 °C-rt
K4Fe(CN)6
CN
Cl
2.2. Preparation of spiropiperidinyloxindoles
Cl
K2CO3, DMF
O
120 °C, 68%
O
92%
N
N
In order to expand the structural diversity of our analogues,
we envisaged the construction of spiropiperidinyloxindoles. Clas-
sical route to spiropiperidinyloxindoles involves treatment of
oxindole with bis(2-chloroethylmethylamine) under basic condi-
tions followed by a three step protection/deprotection procedure.20
SEM
SEM
I
33
34
H
N
CHO
CN
CoCl2, NaBH4
MeOH, rt.
HCl (3N), THF
reflux
Cl
Cl
O
O
Recent alternative strategies rely on intramolecular a-arylation of
53% (91%)
55%
N
amides as initially reported by Hartwig21 or dearomatization of
N
SEM
SEM
N-arylisonicotinamides22
36
35
In analogy to the pyrrolidine series, we thought that the con-
struction of spiropiperidinyloxindoles could be achieved starting
from a 3-functionalized-3-cyanomethyl-oxindole (Fig. 3). Direct
Scheme 2. Synthesis of the spiropiperidinyloxindole 36.
solution of 35 with NaBH4/CoCl2$6H2O provided directly the spi-
ropiperidine 36 in a 55% yield. Under these conditions, a sequence
of reduction of nitrile to primary amine, intramolecular conden-
sation of aldehyde and amine to iminium salt and its reduction
occurred to deliver the desired compound. It is also noteworthy
that under these conditions, reduction of nitrile function went
faster than that of aldehyde, a pre-condition in order for the present
reductive cyclization process to proceed effectively.
For the derivatization of 36, we decided to focus our efforts in the
introduction of diversity on the nitrogen of the oxindole. Compound
36 was first reductively alkylated with 4-chloro-cinnamaldehyde26
to give compound 37 in a 75% yield. The SEM group was next
cleaved in two steps: treatment of 37 with dimethylaluminium
chloride furnished the N-hydroxymethylated intermediate that was
hydrolyzed to 38 under basic conditions (MeOH, Et3N, reflux,
Scheme 3). Diverse substituents were then introduced on the
oxindole nitrogen of 38 (Fig. 4). Acylation [RCOCl, Et3N, DCM, rt]
provided rather unstable imide 39aeb prone to deacylation in
deuterated chloroform. Alkylation under classic conditions [RBr,
NaH, THF, rt] furnished compound 39ceg. The thiooxindole 39h was
prepared from 38 by its reaction with Lawesson’s reagent in
refluxing xylene in a moderate 25% yield.27 We also applied an
N-cyclopropylation method recently developed in our group [Cu
(OAc)2/BiPy, Na2CO3, DCE, 70 ꢀC, air] and obtained compound 39i in
reductive cyclization of u-oxo nitrile derivative 28b seemed to be an
attractive route even if, to the best of our knowledge, such cyclization
starting from a 3,30-disubstituted oxindole has not been reported
so far.
NH
FG= OH
O
FG
N
H
CN
O
NH
N
H
FG= CHO
28a FG = OH
28b FG = CHO
O
N
H
Fig. 3. 3-Functionalized-3-cyanomethyl-oxindoles as precursor of spiropyrrolidinyl-
and spiropiperidinyl-oxindoles.
The synthesis of 5-chloro-spiro[3,40-piperidin]-oxindole 36,
presenting again three points of diversity, is depicted in Scheme 2.
The carboxylic acid 31 was prepared in four steps from diethyl
malonate and bromomethyldioxolane 29 in 41% overall yield. Thus
monoalkylation of diethyl malonate with 29 followed by saponifi-
cation gave mono acid 30.23 Subsequent Knoevenagel condensation
between 30 and formaldehyde gave, after hydrolysis of the ethyl
ester, the carboxylic acid 31. Coupling between this acid and the 4-
chloro-2-iodoaniline24 was best realized here again in the presence
of Mukaiyama’s reagent to afford the amide 32. N-protection of 32
under standard conditions (NaH, SEMCl, 0 ꢀC then rt) furnished the
tertiary amide 33 in a 92% yield. As expected, Palladium-catalyzed
domino Heck/cyanation provided uneventfully the key oxindole 34
in a 68% yield. Piperidine ring formation was next evaluated. Re-
duction of nitrile to primary amine proceeded smoothly. However,
attempts to realize the intramolecular reductive aminoalkylation of
the resulting amino acetal under a variety of acidic conditions failed
to afford the desired spiropiperidinyl oxindole.25 The acetal func-
tion was found to be noticeably stable in this case. Alternatively,
heating to reflux a THF solution of 34 in the presence of HCl (3 N)
afforded aldehyde 35 in 91% yield (based on conversion) without
touching the N-SEM function. Gratefully, treatment of a methanol
Cl
H
N
N
4-Chloro
cinnamaldehyde,
Cl
Cl
O
O
NaBH3CN, AcOH,
MeOH, rt. 75%
N
N
SEM
SEM
36
37
Cl
N
1. Me2AlCl,
CH2Cl2, -78 °C-rt
Cl
O
2. Et3N/MeOH (1:2)
reflux, 2-10 days.
72%
N
H
38
Scheme 3. Synthesis of oxindole 38.

8914
S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
R1
N
R1
N
R1
N
OTBS
CN
OMs
CN
1. TBAF, AcOH, THF, rt
2. MsCl, Et3N, DCM, rt.
R
R
O
O
Cl
Cl
Cl
Cl
Cl
N
N
O
O
O
O
O
MOM
MOM
Cl
N
N
N
R = NO2, 13
R = NO2, 40, 83%
R = NHBoc, 14
R = NHBoc, 41, 71%
N
N
O
O
H
CN
39a 33%a
R1
39b 41%a
39c 70%b
R1
NC
H
10
4
9
R1
N
R
R
NaH, THF
N
N
O
O
N
0 °C then rt
N
Cl
Cl
MOM
MOM
O
R = NO2, 42a/42b, 50% (2/1)
R = NHBoc, 43a/43b, 87% (2/1)
Cl
N
N
N
Scheme 4. Synthesis of spirocyclopropyloxindoles.
CF3
F
39d 80%b
R1
39e 34%b
39f 31%b
R1
3. Conclusion
R1
N
N
N
In conclusion, we demonstrated that 3-alkyl-3-cyanomethylox-
indole, easily accessible through a palladium-catalyzed domino
intramolecular Heck/cyanation sequence, is a versatile intermediate
for the elaboration of spirocyclooxindoles. The so-obtained spi-
ropyrrolidinyl-, spiropiperidinyl-, or spirocyclopropyloxindoles
bearing three diversity points were further functionalized via
N-acylation, N-alkylation, N-sulfonylation, SNAr reaction and the
BuchwaldeHartwig N-arylation to reach diverse set of spiroox-
indoles. Evaluation of their bioactivities, especially as agrochemi-
cals, is ongoing.
Cl
Cl
Cl
NO2
Cl
O
S
O
N
N
H
N
39i 64%d
39h 25%c
39g 68%b
R1
N
R1= (E)-3-(4-chlorophenyl)prop-2-en
O
N
4. Experimental section
4.1. General
39j 21%e
OMe
Proton NMR (1H NMR) spectra were recorded at 500 MHz on
a Bruker AC-500 spectrometer. Carbon NMR (13C NMR) spectra
were recorded at 75 MHz on a Bruker AC-300 spectrometer. 1H
Fig. 4. Synthesized spiropiperidinyloxindoles 39. aCondition: 38 (1.0 equiv), RCOCl
(1.2 equiv), Et3N (1.2 equiv), CH2Cl2, rt. bCondition: 38 (1.0 equiv), RX (2.0 equiv), NaH
60% (2.0 equiv), THF, 0 ꢀC. cCondition: 38 (1.0 equiv), Lawesson’s reagent (1.2 equiv),
xylene, 140 ꢀC. dCondition: 38 (1.0 equiv), Cu(OAc)2 (1.0 equiv), bipyridine (1.0 equiv),
cyclopropyl boronic acid (2.5 equiv), Na2CO3 (2.0 equiv), DCE, air, 70 ꢀC. eCondition: 38
(1.0 equiv), p-methoxyiodobenzene (1.0 equiv), K2CO3 (2 equiv), CuI (0.1 equiv), N,N-
dimethylenediamine (0.2 equiv), CH3CN, reflux.
NMR and 13C NMR chemical shifts (
d
) are reported in parts per
million (ppm) relative to residual solvent signals in CDCl3 (
d
¼7.26,
77.16). Melting points (mp) were recorded using Büchi B-540
melting point apparatus. Infrared spectra were recorded on a Per-
kineElmer Spectrum BX FT-IR spectrometer. Mass spectra were
obtained from an AEI MS-9 spectrometer using positive electron
spray (ESþ). Flash chromatography was performed using SDS silica
64% yield.28a Finally, a copper-catalyzed N-arylation29 [4-iodo-ani-
sole, CuI, N,N-dimethylethylenediamine, K2CO3, CH3CN, refux]30a
afforded compound 39j.
gel 60 (35e70 mm). Preparative thin layer chromatography (pre-
parative TLC) was carried out on 20ꢁ20 cm glass support plates
with a layer thickness of 0.5 mm (SDS Silica gel 60 F254). All reagents
were obtained from commercial suppliers. Organic solvents were
routinely dried and/or distilled prior to use. When needed, solvents
were degazed using freeze-drying. All reactions were performed
under an argon atmosphere unless otherwise stated.
2.3. Spirocyclopropyloxindoles
Different strategies to access spirocyclopropyloxindoles have
been developed including alkylation of oxindole enolate with
dibromoethane.5b,31 Based on this process, 3-cyanomethyloxindole
has recently been converted to spirocyclopropyl oxindole through
a one-pot double alkylation process.32 This result prompted us to
apply such alkylation strategy starting from the already available
intermediates 13 and 14.
In the event, oxindoles 13 and 14 were O-deprotected and con-
verted to their mesylated derivatives 40 and 41 in 83 and 71% overall
yields, respectively (Scheme 4). Simple treatment of intermediate 40
with sodium hydride provided diastereomeric spirocyclopropyl-
oxindoles 42a and 42b in a 2:1 diastereomeric ratio in 50% yield.
Reaction was much cleaner with the NHBoc derivative 41 leading to
spirocyclopropyloxindoles 43a and 43b (dr¼2:1) in 87% yield. In both
cases, diastereoisomers were separated by flash chromatography on
silica gel. The unambiguous attribution of their relative configuration
was based on anisotropic effects of the nitrile and carbonyl groups
on the chemical shifts of H4 and H10, respectively, and by comparison
with literature data of known spirocyclopropyloxindoles.32,33
4.2. Spiropyrrolidinyloxindoles synthesis
4.2.1. 2-((tert-Butyldimethylsilyloxy)methyl)-N-(2-iodo-4-nitro-phe-
nyl)acrylamide (10). To a solution of 2-chloro-1-methylpyridinium
iodide (13.94 g, 54.5 mmol, 2.4 equiv) in toluene (45 mL) were
added 2-((tert-butyldimethylsilyloxy)methyl)acrylic acid 9 (9.83 g,
45.4 mmol, 2.0 equiv), n-Bu3N (26.0 mL, 109.0 mmol, 4.8 equiv) and
2-iodo-4-nitroaniline (6.0 g, 22.7 mmol, 1.0 equiv). After being
stirred at 100 ꢀC under argon atmosphere for 16 h, the reaction
mixture was quenched with saturated aqueous NH4Cl and extrac-
ted with EtOAc. The combined organic layers were washed with
brine, dried (Na2SO4). The crude was concentrated under reduced
pressure, dissolved in THF/H2O (8/1) (40 mL) and LiOH (1.0 g,
23.8 mmol) was added. The mixture was stirred at room temper-
ature for 6 h, diluted with EtOAc and extracted. The combined

S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
8915
organic layers were washed with brine, dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography (SiO2,
Heptane/EtOAc: 100/0 to 100/5) to give the corresponding anꢂil1ide
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated. The residue was purified by flash chromatogra-
phy (SiO2, Heptane/EtOAc: 9/1 to 4/1) to give the compound 14
10 (6.31 g, 60%) as a yellow solid. Mp 89e91 ꢀC. IR (CHCl3, cm
)
n
(1.46 g, 88%) as white solid. Mp 127e129 ꢀC. IR (CHCl3, cmꢂ1
) n
3386, 3082, 2953, 2928, 2884, 1686, 1530, 1496, 1348, 1096. 1H NMR
3338, 2931, 2857, 1714, 1540, 1497, 1367, 1338, 1229, 1161, 1104. 1H
NMR (CDCl3, 500 MHz)
(CDCl3, 500 MHz)
d
8.96 (br s, 1H), 8.68 (d, J¼2.6 Hz, 1H), 8.59 (d,
d
7.60 (d, J¼2.0 Hz, 1H), 7.25 (dd, J¼2.0,
J¼9.2 Hz, 1H), 8.24 (dd, J¼2.6, 9.2 Hz, 1H), 6.25 (s, 1H), 5.77 (s, 1H),
8.5 Hz, 1H), 6.99 (d, J¼8.5 Hz, 1H), 6.49 (s, 1H), 5.13 (d, J¼11.0 Hz,
1H), 5.09 (d, J¼11.0 Hz, 1H), 3.91 (d, J¼9.6 Hz, 1H), 3.80 (d, J¼9.6 Hz,
1H), 3.32 (s, 3H), 2.97 (d, J¼16.7 Hz, 1H), 2.81 (d, J¼16.7 Hz, 1H), 1.51
4.55 (s, 2H), 0.93 (s, 9H), 0.15 (s, 6H). 13C NMR (CDCl3, 75 MHz)
d
164.9, 144.4, 143.6, 142.0, 134.4, 124.7, 124.1, 120.7, 87.7, 63.2, 26.0,
18.0, ꢂ4.9. HRMS (m/z, ESIþ) calcd for C16H23N2O4NaSiI: 485.0370,
(s, 9H), 0.80 (s, 9H), 0.00 (2 s, 6H). 13C NMR (CDCl3, 75 MHz)
d 175.8,
found 485.0370.
152.7, 137.5, 134.6, 128.4, 119.8, 116.2, 115.6, 110.1, 80.6, 71.5, 66.7,
56.3, 52.0, 28.3 25.6, 21.7, 18.1, ꢂ5.6. HRMS (m/z, ESIþ) calcd for
C24H37N3O5NaSi ([MþNa]þ): 498,2400, found 498,2402.
4.2.2. 2-((tert-Butyldimethylsilyloxy)methyl)-N-(2-iodo-4-nitro-
phenyl)-N-(methoxymethyl)acrylamide (12). To a solution of anilide
10 (5.0 g, 10.8 mmol, 1.0 equiv) in THF (100 mL) at 0 ꢀC, was added
dropwise a 0.5 M solution of NaHMDS in THF (43.2 mL, 21.6 mmol,
2.0 equiv). The reaction mixture turned dark and was further stir-
red for 30 min at 0 ꢀC. MOMCl (2.46 mL, 32.4 mmol, 3.0 equiv) was
added dropwise at 0 ꢀC before reaction was allowed to reach room
temperature. After being stirred for an additional 1 h, the reaction
mixture was quenched with water and extracted with EtOAc. The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated. The residue was purified by flash chromatogra-
phy (SiO2, Heptane/EtOAc: 100/0 to 100/5) to give starting material
10 (2.0 g, 40%) and compound 12 (3.12 g, 57%) as a yellow oil. IR
4.2.5. tert-Butyl 3-(2-(allyloxycarbonylamino)ethyl)-3-((tert-butyldi-
methylsilyloxy)methyl)-1-(methoxymethyl)-2-oxoindolin-5-ylcarba-
mate(15). To asolution ofoxindole 14 (1.45 g, 3.05mmol,1.0equiv) in
MeOH (30 mL) were added CoCl2$6H2O (1.44 g, 6.10 mmol, 2.0 equiv)
and portion wise NaBH4 (1.15 g, 30.0 mmol, 10.0 equiv) over 45 min.
After being further stirred for 1 h, the reaction mixture was quenched
by slow addition of HCl (2 N, 50 mL) and washed with EtOAc. The
aqueous phase was basified with NaOH (2 N) and extracted with
EtOAc. The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was taken in a 1/1 mixture of
CH2Cl2/NaHCO3 saturated (30 mL) and AllocCl (0.36 mL, 3.37 mmol,
1.1 equiv) was added. After being stirred at room temperature over-
night, the reaction mixture was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4) and concen-
trated. The residue was purified by flash chromatography (SiO2,
Heptane/EtOAc: 9/1 to 7/3) to give the compound 15 (1.34 g, 78%) as
(CHCl3, cmꢂ1
1H NMR (CDCl3, 500 MHz) (rotamers)
(m, 1H), 7.46 (d, J¼7.7 Hz, 1H), 5.83e5.00 (m, 3H), 4.62 (d, J¼9.0 Hz,
1H), 4.48 (d, J¼9.0 Hz, 1H), 4.26 (br s, 1H), 3.40 (s, 3H), 0.91 (s, 9H),
0.08 (s, 6H). Due to the sever presence of rotamers the 13C NMR was
poorly resolved. HRMS (m/z, ESIþ) calcd for C18H27N2O5NaSiI:
529.0632, found 529.0616.
)
n
3093, 2950, 2928, 2855,1671,1524,1256,1110,1086.
8.72 (d, J¼2.3 Hz, 1H), 8.21
d
a white foam. IR (CHCl3, cmꢂ1
1495,1450,1137,1233,1162,1114.1H NMR (CDCl3, 500 MHz)
)
n
3327, 2930, 2856, 1703, 1610, 1537,
7.42 (m,
d
1H), 7.16 (d, J¼8.4 Hz, 1H), 6.92 (d, J¼8.4 Hz, 1H), 6.44 (br s, 1H),
5.89e5.81 (m,1H), 5.24 (d, J¼17.2 Hz,1H), 5.17 (dd, J¼1.2,10.4 Hz,1H),
5.07 (AB, J¼10.9 Hz, 2H), 4.71 (br s,1H), 4.45 (d, J¼5.4 Hz, 2H), 3.81 (s,
2H), 3.30 (s, 3H), 3.05e2.90 (m, 2H), 2.12e2.04 (m, 2H), 1.51 (s, 9H),
4.2.3. 2-(3-((tert-Butyldimethylsilyloxy)methyl)-1-(methoxymethyl)-
5-nitro-2-oxoindolin-3-yl)acetonitrile (13). To a degassed solution of
iodoanilide 12 (3.10 g, 6.12 mmol, 1.0 equiv) in DMF (30 mL) were
added K4Fe(CN)6$3H2O (0.57 g, 1.35 mmol, 0.22 equiv), Na2CO3
(0.65 g, 6.12 mmol, 1.0 equiv) and Pd(OAc)2 (41.0 mg, 0.18 mmol,
0.03 equiv). After being stirred at 120 ꢀC under argon atmosphere for
4 h, the reaction mixture was quenched with water and extracted
with EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (SiO2, Heptane/EtOAc: 10/0 to 10/2) to give oxindole
0.72 (s, 9H), ꢂ0.10 (2s, 6H). 13C NMR (CDCl3, 75 MHz)
d 178.8, 155.8,
152.8, 138.0, 134.2, 132.9, 130.5, 118.5, 117.5, 115.3, 109.5, 80.4, 71.4,
68.2, 65.4, 56.3, 54.5, 37.1, 32.4, 28.4, 25.6,18.1, ꢂ5.6. HRMS (m/z, ESIþ)
calcd for C28H45N3O7NaSi: 586.2924, found 586.2928.
4.2.6. tert-Butyl 3-(2-(allyloxycarbonylamino)ethyl)-3-(hydroxyme-
thyl)-1-(methoxymethyl)-2-oxoindolin-5-ylcarbamate (16). To a so-
lution of compound 15 (1.0 g, 1.77 mmol, 1.0 equiv) in THF (35 mL)
at 0 ꢀC was added dropwise HF$Pyr (2.5 mL). The reaction was
stirred at room temperature for 12 h and poured into Et2O/NaHCO3
saturated at 0 ꢀC, and extracted with Et2O. The combined organic
layers were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by flash chromatography (SiO2, Heptane/
EtOAc: 2/1 to 1/1) to give the compound 16 (0.68 g, 85%) as white
13 (1.73 g, 70%) as a yellow oil. IR (CHCl3, cmꢂ1
) n 2950, 2930, 2885,
1736, 1617, 1523, 1488, 1336, 1098. 1H NMR (CDCl3, 500 MHz)
d
8.35e8.33 (m, 2H), 7.22 (d, J¼8.9 Hz,1H), 5.22 (d, J¼11.1 Hz,1H), 5.16
(d, J¼11.1 Hz, 1H), 3.96 (d, J¼9.7 Hz,1H), 3.80 (d, J¼9.7 Hz,1H), 3.35 (s,
3H), 3.08 (d, J¼16.8 Hz,1H), 2.91 (d, J¼16.8 Hz,1H), 0.80 (s, 9H), ꢂ0.02
(2s, 6H). 13C NMR (CDCl3, 75 MHz)
d 175.8, 147.7, 144.0, 128.8, 126.5,
120.1, 115.5, 110.1, 71.8, 66.4, 56.7, 52.1, 25.6, 21.6, 18.1, ꢂ5.6. HRMS
(m/z, ESIþ) calcd for C19H27N3O5NaSi: 428.1618, found 428.1607.
solid. Mp 125e127 ꢀC. IR (CHCl3, cmꢂ1
1702, 167, 1537, 1494, 1335, 1235, 1216, 1156, 1062. 1H NMR (CDCl3,
500 MHz)
) n 3323, 3015, 2976, 2933,
4.2.4. tert-Butyl
methyl)-1-(methoxymethyl)-2-oxoindolin-5-ylcarbamate
3-((tert-butyldimethylsilyloxy)methyl)-3-(cyano-
(14). To
d
7.45 (s, 1H), 7.15 (d, J¼8.4 Hz, 1H), 6.94 (d, J¼8.4 Hz, 1H),
6.75 (s, 1H), 5.88e5.80 (m, 1H), 5.23 (d, J¼17.1 Hz, 1H) 5.16 (d,
J¼10.4 Hz, 1H), 5.07 (AB, J¼10.9 Hz, 2H), 4.81 (br s, 1H), 4.44 (d,
J¼4.6 Hz, 2H), 3.78 (m, 2H), 3.28 (s, 3H), 3.02e2.88 (m, 2H), 2.71 (br
s, 1H), 2.20 (m, 1H), 2.04 (m, 1H), 1.50 (s, 9H). 13C NMR (CDCl3,
a suspension of compound 13 (1.50 g, 3.70 mmol,1.0 equiv) in water
(37 mL) were added iron (2.10 g, 37 mmol, 10.0 equiv), FeSO4$7H2O
(1.03 g, 3.70 mmol, 1.0 equiv) and the reaction was heated at reflux
for 14 h. The reaction mixture was cooled to room temperature,
filtered on Celite and extracted with CH2Cl2. The combined organic
layers were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by flash chromatography (SiO2, Heptane/
EtOAc: 9/1 to 7/3) to give the corresponding aniline (1.30 g, 94%). To
a solution of this aniline (1.30 g, 3.46 mmol, 1.0 equiv) in THF
(35 mL) was added Boc2O (0.91 g, 4.16 mmol, 1.2 equiv) and the
reaction was stirred at room temperature for 15 h. The reaction
mixture was quenched with water and extracted with EtOAc. The
75 MHz)
d 179.2, 155.9, 153.1, 137.8, 134.5, 132.8, 129.6, 119.3, 117.6,
115.1, 110.0, 80.6, 71.3, 67.4, 65.5, 56.2, 54.2, 37.0, 32.6, 28.4. HRMS
(m/z, ESIþ) calcd for C22H31N3O7Na: 472.2060, found 472.2079.
4.2.7. Allyl 5-(tert-butoxycarbonylamino)-1-(methoxymethyl)-2-oxo-
spiro[indoline-3,30-pyrrolidine]-10-carboxylate (7). To a solution of
compound 16 (0.65 g, 1.45 mmol, 1.0 equiv) in CH2Cl2 (29 mL) at 0 ꢀC
were added Et3N (0.81 mL, 5.82 mmol, 4.0 equiv) and MsCl (0.45 mL,
5.82 mmol, 4.0 equiv). After being stirred at room temperature for

8916
S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
16 h, the reaction mixture was quenched with saturated aqueous
NH4Cl and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated to furnish
crude mesylated compound. The crude was taken in THF (25 mL) and
NaH 60% (116 mg, 2.9 mmol, 2.0 equiv) was added in small portion at
1.0 equiv) in THF/H2O (1/1) (4 mL) was added three drops of concd
HCl. After being stirred at reflux overnight, the reaction mixture
was quenched with NaOH 2 N and extracted with EtOAc. The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated. The residue was purified by flash chromatogra-
phy (SiO2, CH2Cl2/MeOH: 100/8) to give the compound 20 (11 mg,
0
ꢀC. After being stirred at 0 ꢀC for 1 h, the reaction mixture was
carefully quenched with saturated aqueous NH4Cl and extracted
with EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (SiO2, Heptane/EtOAc: 2/1 to 1/1) to give the
51%) as light yellow oil. IR (CHCl3, cmꢂ1
1433, 1410, 1323, 1214, 1130. 1H NMR (CDCl3, 500 MHz) (rotamers)
) n 3231, 2935, 1692, 1494,
d
8.55 (dl, 1H), 6.72 (d, J¼8.2 Hz, 1H), 6.58e6.56 (m, 2H), 6.01e5.88
(m, 1H), 5.38e5.10 (m, 2H), 4.66e4.60 (m, 2H), 3.90e3.86 (m, 1H),
3.81e3.75 (m, 2H), 3.65e3.61 (m, 1H), 2.45e2.39 (m, 1H),
compound 7 (0.51 g, 81%) as white foam. IR (CHCl3, cmꢂ1
)
n
3315,
2978, 2935, 1702, 1697, 1571, 1498, 1445, 1334, 1231, 1158, 1086. 1H
NMR (CDCl3, 500 MHz) (rotamers) 7.41 and 7.32 (2m, 1H), 7.25 and
2.09e2.04 (m, 1H). 13C NMR (CDCl3, 75 MHz) (rotamers)
d 179.7 and
d
179.2, 154.7 and 154.6, 142.4 and 142.2, 134.1 and 133.7, 133.1 and
132.9, 132.1 and 131.8, 117.4, 114.7 and 114.6, 110.7 (2C), 66.0, 54.3
and 54.1, 53.6 and 52.6, 45.6 and 45.2, 36.3 and 35.4. HRMS (m/z,
ESIþ) calcd for C15H17N3O3Na: 310.1168, found 310.1178.
7.15 (2d, J¼7.9 Hz,1H) 6.95 and 6.93 (2d, J¼7.9 Hz,1H), 6.71 (br s,1H),
6.01e5.85 (m, 1H), 5.33 and 5.22 (2d, J¼17.2 Hz, 1H), 5.25 and 5.15
(2d, J¼10.4 Hz, 1H), 5.09 (s, 2H), 4.64 and 4.59 (2d, J¼4.9 Hz, 2H),
3.93e3.77 (m, 2H), 3.80 (m,1H), 3.64 (m, 1H), 3.29 (s, 3H), 2.40e2.34
(m, 1H), 2.19e2.07 (m, 1H), 1.49 (s, 9H). 13C NMR (CDCl3, 75 MHz)
4.3. Spiropiperidinyloxindoles synthesis
(rotamers)
d 178.4 and 178.1, 154.6 and 154.5, 153.05 and 153.00,
136.65 and 136.60, 134.7, 133.0 and 132.9, 131.9 and 131.5, 119.4 and
119.2,117.4, 114.5,109.9, 80.6, 71.5, 66.0, 56.2, 54.6 and 54.2, 53.3 and
52.3, 45.7 and 45.3, 36.5 and 35.8, 28.3. HRMS (m/z, ESIþ) calcd for
C22H29N3O6Na: 454.1954, found 454.1960.
4.3.1. 2-((1,3-Dioxolan-2-yl)methyl)-N-(4-chloro-2-iodophenyl)ac-
rylamide (32). Following the same procedure as for the synthesis of
compound 10, using compound 31 and 4-chloro-2-iodoaniline, fur-
nished compound 32 (64%) as white solid. Mp 58e60 ꢀC. IR (CHCl3,
cmꢂ1
1127, 1030. 1H NMR (CDCl3, 500 MHz)
)
n
3386, 3298, 2956, 2884, 1679, 1626, 1568, 1504, 1376, 1288,
8.26 (br s, 1H), 8.18 (d,
4.2.8. Allyl 5-amino-1-(methoxymethyl)-2-oxospiro[indoline-3,30-pyr-
rolidine]-10-carboxylate (18). To a solution of compound 7 (150.0 mg,
0.35 mmol, 1.0 equiv) in CH2Cl2 (3.5 mL) at 0 ꢀC, was added TFA
(0.26 mL, 3.5 mmol, 10.0 equiv). After being stirred at room tem-
perature for 1 h, the reaction mixture was quenched with saturated
aqueous NaHCO3 solution and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography (SiO2,
CH2Cl2/MeOH: 9/1) to give the compound 18 (98 mg, 84%) as yellow
d
J¼8.9 Hz, 1H), 7.77 (d, J¼2.3 Hz, 1H), 7.32 (dd, J¼2.3, 8.9 Hz, 1H), 6.10
(s, 1H), 5.65 (s, 1H), 5.08 (t, J¼4.5 Hz, 1H), 4.02 (m, 2H), 3.88 (m, 2H),
2.82 (d, J¼4.5 Hz, 2H). 13C NMR (CDCl3, 75 MHz)
d 166.3, 139.6, 137.9,
137.4, 130.0, 129.1, 124.2, 122.9, 103.2, 90.0, 65.1, 36.9. HRMS (m/z,
ESIþ) calcd for C13H13NO335ClINa: 415.9526, found 415.9532.
4.3.2. 2-[(1,3-Dioxolan-2-yl)methyl]-N-(4-chloro-2-iodophenyl)-N-
[(2-(trimethylsilyl)ethoxy)methyl]-acrylamide (33). Following the
same procedure as for the synthesis of compound 11, using com-
pound 32 and SEMCl, furnished compound 33 (92%) as colourless
oil. IR (CHCl3, cmꢂ1
1133, 1085. 1H NMR (CDCl3, 500 MHz) (rotamers)
1H), 6.63 (dd, J¼2.1, 8.1 Hz, 1H) 6.59 (m, 1H), 6.01e5.87 (m, 1H), 5.35
and 5.27 (2d, J¼17.1 Hz,1H), 5.24 and 5.18 (2d, J¼10.4 Hz,1H), 5.08 (s,
2H), 4.65 and 4.61 (2 m, 2H), 3.92e3.87 (m, 1H), 3.81e3.75 (m, 2H),
3.64 (m, 1H), 3.30 (s, 3H), 2.46e2.38 (m, 1H), 2.12e2.02 (m, 1H). 13C
) n 3356, 2942, 1702, 1697, 1497, 1410, 1349, 1229,
d
6.85 (d, J¼8.1 Hz,
oil. IR (CHCl3, cmꢂ1
)
n
3015, 2952, 2888,1660,1627,1468,1248,1217,
1066, 1031, 834, 749. 1H NMR (CDCl3, 500 MHz) (rotamers)
d
7.87
(m, 1H), 7.33 (m, 1H), 7.22 (d, J¼8.4 Hz, 1H), 5.93e4.97 (m, 4H), 4.55
(m, 1H), 3.98 (s, 2H), 3.85 (s, 2H), 3.77e3.32 (m, 2H), 2.76e2.36 (m,
2H), 0.89 (m, 2H), 0.01 (s, 9H). Due to the presence of sever
rotamers the 13C NMR was poorly resolved. HRMS (m/z, ESIþ) calcd
for C19H27NO4Si35ClNa: 546.0340, found 546.0317.
NMR (CDCl3, 75 MHz) (rotamers)
d 177.4, 154.6, 142.7, 133.0 and
132.9, 132.8, 132.4, 117.4, 114.8 and 114.7, 110.5, 110.4, 71.5, 65.9, 56.1,
54.6 and 54.3, 53.3 and 52.3, 45.7 and 45.2, 36.6 and 35.7. HRMS (m/z,
ESIþ) calcd for C17H21N3O4Na: 354.1430, found 354.1430.
4.3.3. 2-[3-((1,3-Dioxolan-2-yl)methyl)-5-chloro-2-oxo-1-((2-(tri-
methylsilyl)ethoxy)methyl)indolin-3-yl]acetonitrile (34). Following
the same procedure as for the synthesis of compound 12, using
compound 33 furnishedꢂc1ompound 34 (68%) as white solid. Mp
4.2.9. tert-Butyl 1-(methoxymethyl)-2-oxospiro[indoline-3,30-pyrro-
lidine]-5-ylcarbamate (19). To a solution of compound 7 (100.0 mg,
0.23 mmol,1.0 equiv) in CH2Cl2 (4 mL) were added AcOH (0.060 mL,
1.03 mmol, 4.5 equiv), Pd(PPh3)4 (21.4 mg, 0.018 mmol, 0.08 equiv)
67e69 ꢀC. IR (CHCl3, cm
) n 2952, 2892, 2250, 1725, 1673, 1485,
and dropwise n-Bu3SnH (135
mL, 0.46 mmol, 2.0 equiv). After being
1432, 1337, 1248, 1083, 858, 836. 1H NMR (CDCl3, 500 MHz)
d 7.41
stirred at room temperature for 1 h, the reaction mixture was
quenched with saturated aqueous NaHCO3 solution and extracted
with CH2Cl2. The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (SiO2, CH2Cl2/MeOH: 100/1) to give the compound
(d, J¼1.9 Hz, 1H),7.32 (dd, J¼1.9, 8.4 Hz, 1H), 7.07 (d, J¼8.4 Hz, 1H),
5.14 (s, 2H), 4.77 (dd, J¼3.4, 6.5 Hz, 1H), 3.78e3.67 (m, 4H), 3.60 (m,
2H), 2.88 (d, J¼16.6 Hz, 1H), 2.65 (d, J¼16.6 Hz, 1H), 2.35e2.26 (m,
2H), 0.91 (t, J¼7.3 Hz, 2H), 0.03 (s, 9H). 13C NMR (CDCl3, 75 MHz)
d
176.6, 140.6, 129.6, 129.5, 128.8, 124.3, 115.7, 111.4, 100.7, 70.0, 66.4,
19 (77 mg, 95%) as yellow oil. IR (CHCl3, cmꢂ1
)
n
3308, 2933, 1711,
1608, 1539, 1498, 1367, 1338, 1238, 1161, 1099, 1077. 1H NMR (CDCl3,
500 MHz)
64.6, 47.1, 39.1, 26.6, 17.8, ꢂ1.4. HRMS (m/z, ESIþ) calcd for
C20H27N2O4Si35ClNa: 445.1326, found 445.1335.
d
7.47 (d, J¼2.2 Hz, 1H), 7.14 (dd, J¼2.2, 8.3 Hz, 1H), 6.91
(d, J¼8.3 Hz,1H), 6.90 (br s, 1H), 5.10 (s, 2H), 3.50e3.41 (m, 2H), 3.35
(d, J¼12.0 Hz, 1H), 3.29 (s, 3H), 3.08 (d, J¼12.0 Hz, 1H), 2.35e2.25
(m, 1H), 2.17e2.11 (m, 1H), 1.49 (s, 9H). 13C NMR (CDCl3, 75 MHz)
4.3.4. 2-[5-Chloro-2-oxo-3-(2-oxoethyl)-1-((2-(trimethylsilyl)eth-
oxy)methyl)indolin-3-yl]acetonitrile (35). A solution of compound
34 (2.0 g, 4.72 mmol, 1.0 equiv) in a 1/2 mixture of HCl 3 N/THF
(24 mL) was heated at 65 ꢀC overnight. The reaction was quenched
with NaOH 2 N and extracted with EtOAc. The combined organic
layers were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by flash chromatography (SiO2, Hept/
AcOEt: 85/15) to give the compound 35 (0.95 g, 53%) as colourless
d
181.5, 153.1, 136.9, 134.7, 132.9, 118.6, 114.2, 109.6, 80.5, 71.3, 59.3,
56.2, 54.8, 48.4, 39.0, 28.4. HRMS (m/z, ESIþ) calcd for C18H26N3O4:
348.1923, found 348.1933.
4.2.10. Allyl 5-amino-2-oxospiro[indoline-3,30-pyrrolidine]-10-car-
boxylate (20). To a solution of compound 7 (25.0 mg, 0.075 mmol,
oil. IR (CHCl3, cmꢂ1
) n 3441, 3021, 2953,1725, 1612,1486, 1434,1333,

S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
8917
1249, 1219, 1081, 860, 837, 756. 1H NMR (CDCl3, 500 MHz)
d
9.53 (s,
8.2 Hz, 1H), 6.85 (d, J¼8.2 Hz, 1H), 6.56 (d, J¼15.9 Hz, 1H), 6.33 (td,
J¼6.6, 15.9 Hz, 1H), 3.35 (d, J¼6.6 Hz, 2H), 3.00 (m, 2H), 2.78 (m, 2H),
1H), 7.37 (d, J¼2.0 Hz, 1H), 7.35 (dd, J¼2.0, 8.3 Hz, 1H), 7.11 (d,
J¼8.3 Hz,1H), 5.22 (d, J¼11.1 Hz,1H), 5.17 (d, J¼11.1 Hz,1H), 3.69 (dt,
J¼8.3, 16.7 Hz, 1H), 3.60 (dt, J¼8.3, 16.7 Hz, 1H), 3.37 (d, J¼18.5 Hz,
1H) 3.17 (d, J¼18.5 Hz, 1H), 2.90 (d, J¼16.6 Hz, 1H), 2.60 (d,
J¼16.6 Hz, 1H), 0.94 (t, J¼8.3 Hz, 2H), 0.02 (s, 9H). 13C NMR (CDCl3,
2.01 (m, 2H), 1.94 (m, 2H). 13C NMR (CDCl3, 75 MHz)
d 181.8, 138.5,
136.7, 135.4, 133.1, 132.0, 128.7, 127.7, 127.5, 127.3, 124.2, 110.5, 61.1,
48.4, 45.7, 33.0. HRMS (m/z, ESIþ) calcd for C21H21N2O35Cl2: 387.1017,
found 387.1026.
75 MHz)
d 195.8, 176.1, 140.8, 129.8, 129.5, 129.1, 123.5, 115.2, 111.7,
70.1, 66.5, 48.3, 45.8, 26.3, 17.8, ꢂ1.4. HRMS (m/z, ESIþ) calcd for
4.4. Spirocyclopropyloxindoles synthesis
C18H23N2O3Si35ClNa: 401.1064, found 401.1076.
4.4.1. 2-(3-(Hydroxymethyl)-1-(methoxymethyl)-5-nitro-2-oxo-
indolin-3-yl)acetonitrile. To a solution of compound 13 (250 mg,
0.62 mmol, 1.0 equiv) in THF (6 mL) and AcOH (0.8 mL) at 0 ꢀC
was slowly added TBAF (1 M in THF) (0.80 mL, 0.81 mmol,
1.3 equiv). After being stirred at room temperature overnight, the
reaction mixture was quenched with saturated aqueous NaHCO3
solution and extracted with EtOAc. The combined organic layers
were washed with brine, dried (Na2SO4) and concentrated. The
residue was purified by flash chromatography (SiO2, Hept/AcOEt:
4/1 to 1/1) to give the 2-(3-(hydroxymethyl)-1-(methox-
ymethyl)-5-nitro-2-oxoindolin-3-yl)acetonitrile (154 mg, 85%) as
4.3.5. 5-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-
3,40-piperidin]-2-one (36). To a solution of oxindole 35 (800 mg,
2.12 mmol, 1.0 equiv) in MeOH (14 mL) were added CoCl2$6H2O
(1.0 g, 4.24 mmol, 2.0 equiv), and portion wise NaBH4 (800 mg,
21.2 mmol, 10.0 equiv) over 45 min. After being further stirred for
30 min, the reaction mixture was quenched by slow addition of HCl
(2 N, 20 mL) and washed with EtOAc. The aqueous phase was ba-
sified with NaOH (2 N) and extracted with EtOAc. The combined
organic layers were washed with brine, dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography (SiO2,
CH2Cl2/MeOH: 10/0 to 10/1) to give the compound 36 (428 mg,
sticky yellow solid. IR (CHCl3, cmꢂ1
) n 3479, 2927, 1730, 1617,
55%) as colourless oil. IR (CHCl3, cmꢂ1
1485, 1430, 1335, 1247, 1090. 1H NMR (CDCl3, 500 MHz)
)
n
3055, 2924, 1714, 1610,
7.39 (d,
1522, 1487, 1337, 1276, 1101, 1080. 1H NMR (CDCl3, 500 MHz)
d
d
8.33 (m, 2H), 7.26 (d, J¼9.3 Hz, 1H), 5.22 (AB, J¼11.1 Hz, 2H),
J¼1.9 Hz, 1H), 7.24 (dd, J¼1.9, 8.3 Hz, 1H), 6.97 (d, J¼8.3 Hz, 1H), 5.12
(s, 2H), 3.52 (t, J¼8.3 Hz, 2H), 3.37 (m, 2H), 3.06 (m, 2H), 2.22 (br s,
1H), 1.84 (m, 2H), 1.75 (m, 2H), 0.89 (t, J¼8.2 Hz, 2H), ꢂ0.05 (s, 9H).
4.00 (d, J¼10.9 Hz, 1H), 3.94 (d, J¼10.9 Hz, 1H), 3.36 (s, 3H), 3.10
(d, J¼16.9 Hz, 1H), 2.99 (d, J¼16.9 Hz, 1H). 13C NMR (CDCl3,
75 MHz)
d 176.3, 147.7, 144.1, 128.0, 126.7, 119.8, 115.4, 110.4, 71.8,
13C NMR (CDCl3, 75 MHz)
d
179.7, 139.6, 135.7, 128.1, 127.8, 124.0,
65.4, 56.6, 51.6, 21.5. HRMS (m/z, ESIþ) calcd for C13H13N3O5Na:
110.6, 69.1, 65.9, 46.0, 41.1, 33.4, 17.7, ꢂ1.4. HRMS (m/z, ESIþ) calcd
314.0753, found 314.0755.
for C18H28N2O2Si35Cl: 367.1609, found 367.1596.
4.4.2. [3-(Cyanomethyl)-1-(methoxymethyl)-5-nitro-2-oxoindolin-
3-yl]methyl methanesulfonate (40). To a solution of 2-(3-(hydroxy-
methyl)-1-(methoxymethyl)-5-nitro-2-oxoindolin-3-yl)acetonitrile
(100 mg, 0.34 mmol, 1.0 equiv) in CH2Cl2 (7 mL) at 0 ꢀC were added
4.3.6. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-((2-(trimethylsilyl)
ethoxy)methyl)spiro[indoline-3,40-piperidin]-2-one (37). To a solution
of 36 (400 mg, 1.09 mmol, 1.0 equiv) and p-chlorocinammaldehyde
(217 mg, 1.31 mmol, 1.2 equiv) in 7 mL dry MeOH was added 0.1 mL
of acetic acid. After been stirred for 15 min at rt, NaCNBH3 (82 mg,
1.31 mmol,1.2 equiv) was added and reaction mixture was stirred for
15 h. Reaction was quenched with saturated aqueous NaHCO3 and
extracted with EtOAc. The combined organic layers were washed
with brine, dried (Na2SO4) and concentrated. The residue was puri-
fied by flash chromatography (SiO2, Hept/acetone: 9/1) to give the
Et3N (100 mL, 0.68 mmol, 2.0 equiv) and MsCl (48 mL, 0.61 mmol,
1.8 equiv). After being stirred at room temperature overnight, the
reaction mixture was quenched with saturated aqueous NH4Cl so-
lution and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated. The residue
was purified by flash chromatography (SiO2, Hept/AcOEt: 1/2) to give
thecompound40 (122 mg, 97%) asyellow oil. IR (CHCl3, cmꢂ1
)
n
2919,
compound 37 (423 mg, 75%) as white foam. IR (CHCl3, cmꢂ1
)
n
2948,
1737, 1618, 1524, 1488, 1338, 1176. 1H NMR (CDCl3, 500 MHz)
d 8.38
1714, 1609, 1486, 1332, 1248, 1214, 1086. 1H NMR (CDCl3, 500 MHz)
(m, 2H), 7.29 (d, J¼9.3 Hz, 1H), 5.22 (s, 3H), 4.62 (d, J¼10.2 Hz, 1H),
3.94 (d, J¼10.2 Hz, 1H), 3.36 (s, 3H), 3.10 (d, J¼16.8 Hz, 1H), 3.00 (s,
d
7.38e7.36 (m, 6H), 7.02 (d, J¼8.3 Hz, 1H), 6.56 (d, J¼15.9 Hz, 1H),
6.33 (td, J¼6.7,15.8 Hz,1H), 5.15 (s, 2H), 3.55 (t, J¼8.2 Hz, 2H), 3.34 (d,
J¼6.7 Hz, 2H), 3.01 (m, 2H), 2.80 (m, 2H), 1.96 (m, 4H), 0.92 (t,
3H), 2.99 (d, J¼16.8 Hz, 1H). 13C NMR (CDCl3, 75 MHz)
d 174.0, 147.5,
144.3, 127.3, 126.2, 120.2, 114.4, 110.8, 72.1, 69.4, 56.7, 49.7, 37.7, 22.3.
HRMS (m/z, ESIþ) calcd for C14H15N3O7NaS: 392.0528, found
392.0534.
J¼8.2 Hz, 2H), ꢂ0.03 (s, 9H). 13C NMR (CDCl3, 75 MHz)
d 179.8, 142.1,
139.6, 135.6, 135.4, 133.1, 131.8, 128.7, 128.1, 127.8, 127.5, 123.9, 110.6,
69.1, 65.9, 61.1, 48.4, 45.4, 33.3, 17.7, ꢂ1.5. HRMS (m/z, ESIþ) calcd for
C27H35N2O2Si35Cl2Na: 517.1845, found 517.1848.
4.4.3. 10-(Methoxymethyl)-50-nitro-20-oxospiro(cyclopropane-1,30-
indoline)-2-carbonitrile (42a/42b). To a solution of compound 40
(60 mg, 0.16 mmol, 1.0 equiv) in THF (3 mL) was added NaH (60% in
mineral oil) (13 mg, 0.32 mmol, 2.0 equiv). After being stirred at
room temperature overnight, the reaction mixture was quenched
with saturated aqueous NH4Cl solution and extracted with EtOAc.
The combined organic layers were washed with brine, dried
(Na2SO4) and concentrated. The residue was purified by preparative
TLC (SiO2, Hept/AcOEt: 1/1) to give the compound 42a (15 mg, 34%)
as colourless oil and the compound 42b (7 mg, 16%) as white solid.
4.3.7. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)spiro[indoline-3,40-pi-
peridin]-2-one (38). To a solution of 37 (150 mg, 0.29 mmol, 1 equiv)
in 6 mL dry CH2Cl2 at ꢂ78 ꢀC was added dropwise Me2AlCl 1 M in
hexane (1.75 mL, 1.75 mmol, 6 equiv). After being stirred at ꢂ78 ꢀC
for 1 h, the reaction mixture was allowed to reach rt. After being
further stirred for 2 h, reaction was cautiously quenched at 0 ꢀC with
saturated aqueous NaHCO3 and diluted with CH2Cl2. After vigorous
stirring for 1 h, reaction was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried (Na2SO4) and con-
centrated. The crude residue was dissolved in 3 mL Et3N/MeOH
(ratio 1:2) and heated at reflux for 5 days. Solvents were concen-
trated and residue was purified by preparative TLC (SiO2, Hept/ace-
tone: 2/1) to give 38 (81 mg, 72%) as a pale yellow solid. Mp
Data for compound 42a: IR (CHCl3, cmꢂ1
) n 2935, 1736, 1619, 1523,
1488, 1378, 1340, 1277, 1231, 1187, 1103. 1H NMR (CDCl3, 500 MHz)
d
8.36 (dd, J¼2.1, 8.8 Hz, 1H), 8.12 (d, J¼2.1 Hz, 1H), 7.29 (d, J¼8.8 Hz,
1H), 5.25 (s, 2H), 3.40 (s, 3H), 2.63 (dd,1H, J¼7.2, 9.5 Hz,1H), 2.30 (dd,
J¼5.4, 9.5 Hz, 1H), 2.14 (dd, J¼5.4, 7.2 Hz, 1H).13C NMR (CDCl3,
75e77 ꢀC. IR (CHCl3, cmꢂ1
1090. 1H NMR (CDCl3, 500 MHz)
1H), 7.34 (d, J¼8.7 Hz, 2H), 7.30 (d, J¼8.7 Hz, 2H), 7.20 (dd, J¼2.0,
)
n
3192, 2825, 1706, 1621, 1479, 1327, 1215,
8.75 (br s, 1H), 7.36 (d, J¼1.9 Hz,
75 MHz) d 173.5, 147.8, 144.1, 125.8, 124.9, 117.0, 115.8, 110.1, 72.2,
d
56.9, 31.6, 22.2, 16.3. HRMS (m/z, ESIþ) calcd for C13H11N3O4Na:
296.0647, found 296.0610.

8918
S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
Data for compound 42b: Mp 157e159 ꢀC. IR (CHCl3, cmꢂ1
1736, 1619, 1523, 1488, 1378, 1340, 1277, 1231, 1187, 1103. 1H NMR
(CDCl3, 500 MHz)
)
n
2935,
5.17 (d, J¼10.4 Hz, 1H), 5.10 (s, 2H), 4.63e4.58 (m, 2H), 3.95e3.88
(m, 1H), 3.83e3.77 (m, 2H), 3.65 (d, J¼10.9 Hz, 1H), 3.31 (s, 3H),
2.44e2.37 (m, 1H), 2.19e2.07 (m, 1H), 1.53e1.48 (m, 1H), 1.09e1.04
(m, 2H), 0.85e0.83 (m, 2H). 13C NMR (CDCl3, 75 MHz). Rotamer 1:
d
8.32 (dd, J¼2.0, 8.7 Hz, 1H), 7.79 (d, J¼2.0 Hz,
1H), 7.26 (d, J¼8.7 Hz,1H), 5.28 (AB, J¼11.0 Hz, 2H), 3.40 (s, 3H), 2.53
(dd, J¼7.7, 9.1 Hz, 1H), 2.35 (dd, J¼5.6, 7.7 Hz, 1H), 2.21 (dd, J¼5.6,
d
178.3, 171.9, 154.6, 137.2, 134.4, 132.9, 131.9, 120.5, 117.4, 115.5,
9.1 Hz, 1H). 13C NMR ((CD3)2CO, 75 MHz)
d
172.3, 148.2, 143.7, 127.7,
109.8, 71.5, 66.0, 56.2, 54.6, 53.2, 45.7, 36.5, 15.5, 7.9. Rotamer 2:
d
125.0, 116.2,115.5,109.8, 71.7, 55.8, 31.7, 22.0,15.8. HRMS (m/z, ESIþ)
177.9, 171.9, 154.6, 137.2, 134.4, 132.8, 131.5, 120.2, 117.4, 115.3, 109.8,
71.5, 66.0, 56.2, 54.2, 52.2, 45.2, 35.7, 15.5, 7.9. HRMS (m/z, ESIþ)
calcd for C21H25F3N3O5Na: 422.1692, found 422.1678.
calcd for.C13H11N3O4Na: 296.0647, found 296.0641.
4.4.4. tert-Butyl-2-cyano-10-(methoxymethyl)-20-oxospiro[cyclopro-
pane-1,30-indoline]-50-ylcarbamate (43a/43b). Following the same
procedure as for the synthesis of compound 42a/42b using com-
pound 41 (80 mg, 0.18 mmol) furnished compound 43a (36 mg, 58%)
as white solid and compound 43b (18 mg, 29%) as colouꢂrl1ess oil.
4.5.4. Allyl
amido)spiro[indoline-3,30-pyrrolidine]-10-carboxylate (22). Prepared
following general procedure A. Colourless oil. IR (CHCl3, cmꢂ1
3311, 2937, 1703, 1673, 1547, 1494, 1444, 1408, 1324, 1167, 1126, 1065,
1017. 1H NMR (CDCl3, 500 MHz) Rotamer 1:
8.39 (br s, 1H), 7.98 (d,
1-(methoxymethyl)-2-oxo-5-(4-(trifluoromethyl)benz-
)
n
Data for compound 43a: Mp>200 ꢀC. IR (CHCl3, cm
)
n
3330,
d
2934, 1714, 1606, 1537, 1495, 1455, 1367, 1336, 1238, 1160. 1H NMR
J¼7.8 Hz, 2H), 7.72 (d, J¼7.8 Hz, 2H), 7.68 (d, J¼8.4 Hz, 1H), 7.54 (s,
1H), 7.05 (d, J¼8.4 Hz, 1H), 5.98e5.90 (m, 1H), 5.32 (d, J¼17.1 Hz, 1H),
5.20 (d, J¼10.6 Hz,1H), 5.11 (s, 2H), 4.62e4.57 (m, 2H), 3.95e3.86 (m,
1H), 3.82e3.77 (m, 2H), 3.65 (d, J¼11.3 Hz, 1H), 3.32 (s, 3H),
(CDCl3, 500 MHz)
d
7.47 (dd, J¼1.9, 8.3 Hz,1H), 7.15 (d, J¼1.9 Hz,1H),
7.07 (d, J¼8.3 Hz, 1H), 6.54 (br s, 1H), 5.15 (s, 2H), 3.34 (s, 3H), 2.47
(dd, J¼7.1, 9.4 Hz, 1H), 2.14 (dd, J¼5.1, 9.4 Hz, 1H), 1.92 (dd, J¼5.1,
6.9 Hz,1H),1.5 (s, 9H). 13C NMR (CDCl3, 75 MHz)
d
173.4,152.7,137.8,
2.44e2.39 (m, 1H), 2.21e2.14 (m, 1H). Rotamer 2: d 8.39 (br s, 1H),
134.3, 124.1, 119.6, 116.4, 112.6, 110.2, 80.6, 71.8, 56.3, 37.8, 28.2, 21.6,
15.2. HRMS (m/z, ESIþ) calcd for C18H21N3O4Na: 366.1430, found
366.1427.
7.98 (d, J¼7.8 Hz, 2H), 7.72 (d, J¼7.8 Hz, 2H), 7.66 (s, 1H), 7.51 (d,
J¼8.5 Hz, 1H), 7.03 (d, J¼8.5 Hz, 1H), 5.90e5.84 (m, 1H), 5.24 (d,
J¼17.4 Hz,1H), 5.15 (d, J¼10.6 Hz,1H), 5.09 (s, 2H), 4.57e4.53 (m, 2H),
3.95e3.86 (m,1H), 3.82e3.77 (m, 2H), 3.65 (d, J¼11.3 Hz, 1H), 3.31 (s,
3H), 2.44e2.39 (m,1H), 2.14e2.05 (m,1H). 13C NMR (CDCl3, 75 MHz).
Data for compound 43b: Mp 157e159 ꢀC. IR (CHCl3, cmꢂ1
)
n
3330,
2934, 1714, 1606, 1537, 1495, 1455, 1367, 1336, 1238, 1160. 1H NMR
(CDCl3, 500 MHz)
d
7.33 (br s, 1H), 7.03 (d, J¼8.4 Hz, 1H), 6.96 (dd,
Rotamer 1:
(d, J¼35 Hz), 127.6, 125.7 (d, J¼4 Hz), 123.5 (d, J¼272 Hz), 121.2, 117.5,
116.1, 110.0, 71.5, 66.0, 56.3, 54.6, 53.2, 45.7, 36.5. Rotamer 2: 177.7,
d 178.1, 164.6, 154.6, 138.1, 138.0, 133.9, 133.7, 132.8, 131.8
J¼1.8, 8.4 Hz, 1H), 6.52 (d, J¼1.8 Hz, 1H), 5.19 (AB, J¼10.9 Hz, 2H),
3.36 (s, 3H), 2.38 (dd, J¼7.7, 9.0 Hz, 1H), 2.20 (dd, J¼5.1, 7.7 Hz, 1H),
2.05 (dd, J¼5.1, 9.0 Hz, 1H), 1.50 (s, 9H). 13C NMR (CDCl3, 75 MHz)
d
164.6, 154.6, 138.1, 138.0, 133.8, 133.2, 132.6, 131.8 (d, J¼35 Hz), 127.6,
125.7 (d, J¼4 Hz), 123.5 (d, J¼272 Hz), 121.2, 117.5, 115.9, 110.0, 71.5,
66.0, 56.3, 54.2, 52.2, 45.2, 35.7. HRMS (m/z, ESIþ) calcd for
C25H24N3O5F3Na: 526.1566, found 526.1570.
d
172.0, 152.8, 137.7, 134.5, 126.3, 118.9, 115.6, 110.5, 110.3, 80.9, 71.9,
56.5, 32.3, 28.8, 21.6, 15.7. HRMS (m/z, ESIþ) calcd for
C18H21N3O4Na: 366.1430, found 366.1424.
4.5. Functionalization of spiropyrrolidinyloxindoles and
spiropiperidinyloxindoles
4.5.5. Allyl 1-(methoxymethyl)-5-(2-nitrophenylamino)-2-oxospiro
[indoline-3,30-pyrrolidine]-10-carboxylate (23). To a solution of 18
(20.0 mg, 0.06 mmol, 1.0 equiv) in 0.3 mL DMSO were added
4.5.1. General procedure A, acylation/sulfonylation. To a solution of
the amine containing oxindole (1.0 equiv) and Et3N (1.2 equiv) in
dry CH2Cl2 (0.1 M) was added dropwise at 0 ꢀC the corresponding
acyl chloride or sulfonyl chloride (1.2 equiv). Reaction mixture was
stirred at 0 ꢀC or rt until full conversion of the starting amine. Re-
action was quenched with saturated aqueous NH4Cl and extracted
with CH2Cl2 or EtOAc. The combined organic layers were washed
with brine, dried (Na2SO4) and concentrated.
2-nitrofluorobenzene (6.5 mL, 0.06 mmol, 1.0 equiv) and t-BuOK
(14.9 mg, 0.13 mmol, 2.0 equiv). After stirring at rt overnight,
reaction mixture was diluted and extracted with EtOAc. The
combined organic layers were washed with brine, dried (Na2SO4)
and concentrated. The residue was purified by preparative TLC
(Hept/EtOAc: 1/2) to afford compound 27 (16.4 mg, 60%) as
a bright orange oil. IR (CHCl3, cmꢂ1
)
n
3345, 2938, 1720, 1702,
1613, 1573, 1494, 1407, 1341, 1259, 1225, 1188, 1145, 1079. 1H NMR
(CDCl3, 500 MHz) (rotamers)
d
9.42 (br s, 1H), 8.21 (d, J¼8.5 Hz,
4.5.2. General procedure B, alkylation. To a solution of the amine
(1.0 equiv) in dry THF (0.1 M) at 0 ꢀC was added portion wise NaH
60% (2.0 equiv). After being stirred at 0 ꢀC for 10 min, the corre-
sponding halogenated compound (2.0 equiv) was added and re-
action stirred at rt until complete conversion. Reaction was
quenched with saturated aqueous NH4Cl and extracted with CH2Cl2
or EtOAc. The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated.
1H), 7.35 (m, 1H), 7.24 (m, 1H), 7.14e7.10 (m, 2H), 7.05e7.02 (m,
1H), 6.77 (dd, J¼7.5 Hz, 1H), 6.00e5.88 (m, 1H), 5.33e5.25 (m,
1H), 5.21e5.14 (m, 1H), 5.16 (s, 2H), 4.66e4.57 (m, 2H), 3.97e3.90
(m, 1H), 3.87e3.75 (m, 2H), 3.73e3.66 (m, 1H), 3.36 (s, 3H),
2.51e2.46 (m, 1H), 2.20e2.12 (m, 1H). 13C NMR (CDCl3, 75 MHz)
(rotamers)
d 177.9 and 177.7, 154.5 and 154.4, 143.6, 139.2 and
139.1, 135.9 and 135.8, 134.6 and 134.5, 133.3, 133.0 and 132.8,
126.7, 125.9, 120.3 and 120.2, 117.5; 117.4, 115.6 and 115.5, 110.7,
71.6, 66.1, 56.4, 54.7 and 54.3, 53.3 and 52.3, 45.7 and 45.1, 36.5
and 35.8. HRMS (m/z, ESIþ) calcd for C23H24N4O6Na: 475.1594,
found 475.1591.
4.5.3. Allyl 5-(cyclopropanecarboxamido)-1-(methoxymethyl)-2-oxo-
spiro[indoline-3,30-pyrrolidine]-10-carboxylate (21). Prepared follow-
ing general procedure A. Colourless oil. IR (CHCl3, cmꢂ1
)
n
3312, 3010,
2940, 2887, 1702, 1682, 1609, 1548, 1493, 1445, 1407, 1331, 1227, 1187,
1086. 1H NMR (CDCl3, 500 MHz). Rotamer 1:
7.69 (br s,1H), 7.57 (m,
4.5.6. 10-Allyl-1-(methoxymethyl)-5-(4-nitrophenylamino)spiro[in-
doline-3,30-pyrrolidin]-2-one (24). To a solution of 18 (20.0 mg,
0.06 mmol, 1.2 equiv) in 0.6 mL dry toluene were added p-nitro-
bromobenzene (10.2 mg, 0.05 mmol, 1.0 equiv), Cs2CO3 (23.0 mg,
0.07 mmol,1.4 equiv), Pd(OAc)2 (1.4 mg, 0.006 mmol, 0.1 equiv) and
BINAP (7.5 mg, 0.012 mmol, 0.2 equiv) and reaction mixture was
heated at 90 ꢀC for 3 h. After cooling, water was added and reaction
mixture was extracted with EtOAc. The combined organic layers
were washed with brine, dried (Na2SO4) and concentrated. The
d
1H), 7.31 (d, J¼7.9 Hz, 1H), 6.97 (d, J¼7.9 Hz, 1H), 6.00e5.93 (m, 1H),
5.35 (d, J¼17.3 Hz, 1H), 5.24 (d, J¼11.1 Hz, 1H), 5.10 (s, 2H), 4.66e4.63
(m, 2H), 3.95e3.88 (m, 1H), 3.83e3.77 (m, 2H), 3.65 (d, J¼10.9 Hz,
1H), 3.31 (s, 3H), 2.44e2.37 (m, 1H), 2.19e2.07 (m, 1H),1.53e1.48 (m,
1H), 1.09e1.04 (m, 2H), 0.85e0.83 (m, 2H).
Rotamer 2:
d
7.69 (br s, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.41 (m, 1H),
6.99 (d, J¼7.8 Hz, 1H), 5.93e5.86 (m, 1H), 5.26 (d, J¼17.9 Hz, 1H),

S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
8919
residue was purified by preparative TLC (CH2Cl2/MeOH: 9/1) to
afford compound 24 (8.6 mg, 35%) as an orange solid. Mp
117.5, 61.1, 48.2, 45.3, 33.9, 15.2, 11.5. HRMS (m/z, ESIþ) calcd for
C25H25N2O235Cl2: 455.1293, found 455.1315.
106e108 ꢀC. IR (CHCl3, cmꢂ1
)
n
3323, 2936, 1715, 1590, 1488, 1321,
1307, 1182, 1100. 1H NMR (CDCl3, 500 MHz)
d
8.10 (d, J¼9.1 Hz, 2H),
4.5.11. (E)-5-Chloro-1-(2-chloroisonicotinoyl)-10-(3-(4-chlorophenyl)
allyl)spiro[indoline-3,40-piperidin]-2-one (39b). Prepared following
general procedure A. Title compound rapidly decomposed. Colour-
7.46 (d, J¼1.9 Hz, 1H), 7.15 (dd, J¼1.9, 8.2 Hz, 1H), 7.02 (d, J¼8.2 Hz,
1H), 6.83 (d, J¼9.1 Hz, 2H), 6.26 (br s, 1H), 5.99e5.91 (m, 1H), 5.26
(d, J¼17.2 Hz, 1H), 5.16 (d, J¼10.2 Hz, 1H), 5.13 (s, 2H), 3.35 (s, 3H),
3.35e3.32 (m,1H), 3.27e3.22 (m, 2H), 3.15e3.08 (m,1H), 2.88e2.78
(m, 2H), 2.44e2.39 (m, 1H), 2.21e2.13 (m, 1H). 13C NMR (CDCl3,
less oil. IR (CHCl3, cmꢂ1
)
n
2927, 2822, 1761, 1704, 1478, 1371, 1338,
1296, 1264, 1148, 1104. 1H NMR (CDCl3, 500 MHz)
d
8.54 (d, J¼5.0 Hz,
1H), 7.99 (d, J¼8.6 Hz, 1H), 7.38 (d, J¼1.8 Hz, 1H), 7.36 (dd, J¼1.8,
8.6 Hz, 1H), 7.31e7.27 (m, 6H), 6.51 (d, J¼15.6 Hz, 1H), 6.27 (m, 1H),
3.27 (d, J¼5.2 Hz, 1H), 2.83 (m, 2H), 2.76 (m, 2H), 2.00 (m, 4H).
75 MHz) d 180.2, 150.9, 139.6, 138.3, 135.3, 134.5, 126.3, 123.0, 119.3,
118.1, 113.0, 110.0, 71.6, 63.6, 58.1, 56.4, 53.9, 53.1, 37.5. ESI (þ) m/z
409.1 [MþH].
4.5.12. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-((2-chloropyridin-
4-yl)methyl)spiro[indoline-3,40-piperidin]-2-one (39c). Prepared fol-
4.5.7. tert-Butyl 10-(cyclopropanecarbonyl)-1-(methoxymethyl)-2-oxo-
spiro[indoline-3,30-pyrrolidine]-5-ylcarbamate (25). Prepared follow-
lowing general procedure B. Colourless oil. IR (CHCl3, cmꢂ1
)
n
2921,
2823, 1710, 1594, 1487, 1427, 1351, 1169, 1086. 1H NMR (CDCl3,
500 MHz)
ing general procedure A. Colourless oil. IR (CHCl3, cmꢂ1
)
n
3292, 2933,
1714, 1609, 1540, 1499, 1454, 1366, 1339, 1236, 1159, 1092. 1H NMR
(CDCl3, 500 MHz). Rotamer 1:
d
8.32 (d, J¼5.1 Hz, 1H), 7.40 (d, J¼2.0 Hz, 1H), 7.33 (d,
d
7.47 (d, J¼1.6 Hz, 2H), 7.11 (dd, J¼1.6,
J¼8.5 Hz, 2H), 7.28 (d, J¼8.5 Hz, 2H), 7.18 (dd, J¼2.0, 8.3 Hz, 1H), 7.16
(s,1H), 7.04 (d, J¼5.1 Hz,1H), 6.56 (d, J¼17.4 Hz, 1H), 6.55 (d, J¼8.3 Hz,
1H), 6.35 (m, 1H), 4.85 (s, 2H), 3.38 (m, 2H), 3.06 (m, 2H), 2.86 (m,
8.5 Hz, 1H), 6.95 (d, J¼8.5 Hz, 1H), 6.61 (br s, 1H), 5.12 (s, 2H),
4.20e4.15 (m,1H), 4.07e4.02 (m, 2H), 3.91e3.86 (m, 1H), 3.32 (s, 3H),
2.50e2.45 (m, 1H), 2.33e2.27 (m, 1H), 1.76e1.71 (m, 1H), 1.50 (s, 9H),
2H), 2.07 (m, 4H). 13C NMR (CDCl3, 75 MHz)
d 179.4, 152.3, 150.2,
1.07e1.03 (m, 2H), 0.85e0.82 (m, 2H). Rotamer 2:
d
7.33 (m, 1H), 7.25
148.0, 139.5, 135.7, 135.1, 133.3, 132.0, 128.7, 128.6, 128.0, 127.6 (2C),
124.4,122.3, 120.5, 109.3, 61.0, 48.3, 45.1, 42.1, 33.0. HRMS (m/z, ESIþ)
calcd for C27H25N3O35Cl3: 512.1063, found 512.1043 and calcd for
C27H25N3O35Cl237Cl: 514.1034, found 514.1030.
(d, J¼1.4 Hz, 1H), 7.00 (d, J¼8.3 Hz, 1H), 6.57(br s, 1H), 5.12 (s, 2H),
4.00e3.95 (m, 1H), 3.91e3.86 (m, 2H), 3.77 (m, 1H), 3.30 (s, 3H),
2.44e2.39 (m, 1H), 2.12e2.07 (m, 1H), 1.54e1.47 (m, 1H), 1.50 (s, 9H),
1.07e1.03 (m, 2H), 0.78e0.75 (m, 2H). 13C NMR (CDCl3, 75 MHz).
Rotamer 1:
d
178.6, 172.4, 153.1, 136.7, 134.8, 132.1, 119.6, 114.6, 110.0,
177.7,
4.5.13. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-(4-(trifluoro-
methyl)benzyl)spiro[indoline-3,40-piperidin]-2-one (39d). Prepared
80.7, 71.6, 56.3, 54.8, 53.6, 45.8, 36.6, 28.4,12.7, 7.9. Rotamer 2:
d
172.3, 153.0, 136.5, 134.7, 131.3, 119.3, 114.5, 109.9, 80.6, 71.4, 56.2,
54.3, 51.8, 45.5, 35.3, 28.4, 12.6, 7.7. HRMS (m/z, ESIþ) calcd for
C22H29N3O5Na: 438.2029, found 438.2026.
following general procedure B. Colourless oil. IR (CHCl3, cmꢂ1
) n
2938, 2821, 1707, 1608, 1486, 1322, 1166, 1124, 1110, 1066. 1H NMR
(CDCl3, 500 MHz)
d
7.57 (d, J¼8.1 Hz, 2H), 7.37e7.27 (m, 7H), 7.14 (dd,
J¼2.0, 8.3 Hz, 1H), 6.58 (d, J¼8.2 Hz, 1H), 6.55 (d, J¼15.9 Hz, 1H), 6.33
(td, J¼6.7, 15.8 Hz, 1H), 4.92 (s, 2H), 3.34 (d, J¼6.7 Hz, 2H), 3.02 (m,
4.5.8. tert-Butyl
fonyl)spiro[indoline-3,30-pyrrolidine]-5-ylcarbamate (26). Prepared
following general procedure A. Colourless oil. IR (CHCl3, cmꢂ1
3329, 2977, 2936, 1720, 1713, 1698, 1537, 1500, 1450, 1389, 1367,
1337, 1225, 1158, 1093, 1051. 1H NMR (CDCl3, 500 MHz)
7.46 (d,
1-(methoxymethyl)-2-oxo-10-(trifluoromethylsul-
2H), 2.80 (m, 2H), 1.98 (m, 4H). 13C NMR (CDCl3, 75 MHz)
d 179.5,
)
n
140.0, 139.7, 136.0, 135.4, 133.2, 132.1, 130.2 (d, J¼32 Hz), 128.7, 128.1,
127.8, 127.6, 127.4, 127.1, 126.0 (d, J¼4 Hz), 124.2, 123.9 (d, J¼270 Hz),
109.6, 61.1, 48.5, 45.2, 43.1, 33.2. HRMS (m/z, ESIþ) calcd for
C29H26N2OF335Cl2: 545.1374, found 543.1379 and calcd for
C29H26N2OF335Cl37Cl: 547.1345, found 547.1378.
d
J¼2.0 Hz,1H), 7.22 (dd, J¼2.0, 8.4 Hz,1H), 6.99 (d, J¼8.4 Hz,1H), 6.50
(br s, 1H), 5.10 (AB, J¼10.9 Hz, 2H), 4.11e4.07 (m, 1H), 3.98e3.93 (m,
1H), 3.89 (d, J¼10.4 Hz, 1H), 3.77 (d, J¼10.4 Hz, 1H), 3.32 (s, 3H),
2.50e2.43 (m, 1H), 2.37e2.30 (m, 1H), 1.52 (s, 9H). 13C NMR (CDCl3,
4.5.14. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-(4-fluorobenzyl)
spiro[indoline-3,40-piperidin]-2-one (39e). Prepared following gen-
75 MHz)
d 177.2, 152.9, 136.7, 134.9, 129.6, 119.8, 114.4, 110.3, 80.9,
71.6, 56.3, 56.2, 52.9, 48.2, 36.7, 28.3. HRMS (m/z, ESIþ) calcd for
eral procedure B. Colourless oil. IR (CHCl3, cmꢂ1
)
n
3044, 2919, 2825,
1709, 1608, 1510, 1486, 1427, 1342, 1223, 1197. 1H NMR (CDCl3,
500 MHz)
C19H24N3O6NaSF3: 502.1236, found 502.1253.
d
7.34 (d, J¼1.7 Hz, 1H), 7.32 (d, J¼8.6 Hz, 2H), 7.28 (d,
4.5.9. tert-Butyl 1-(methoxymethyl)-10-(4-nitrobenzyl)-2-oxospiro[in-
J¼8.6 Hz, 2H), 7.20 (dd, J¼5.3, 8.5 Hz, 2H), 7.14 (dd, J¼1.7, 8.2 Hz,
1H), 7.00 (dd, J¼8.6 Hz, 2H), 6.61 (d, J¼8.2 Hz, 1H), 6.55 (d,
J¼15.9 Hz, 1H), 6.33 (td, J¼6.6, 15.9 Hz, 1H), 4.84 (s, 2H), 3.35 (m,
2H), 3.03 (m, 2H), 2.80 (m, 2H), 1.98 (m, 4H). 13C NMR (CDCl3,
doline-3,30-pyrrolidine]-5-ylcarbamate (27). Prepared following gen-
eral procedure B. Yellow oil. IR (CHCl3, cmꢂ1
)
n
3320, 2933, 1712,
1606, 1519, 1493, 1343, 1232, 1159, 1092. 1H NMR (CDCl3, 500 MHz)
(rotamers) 8.21 (m, 2H), 7.81 (m, 1H), 7.66 (m, 2H), 7.05 (m, 1H),
d
125 MHz)
d
179.1, 162.6 (d, J¼246 Hz), 140.2, 136.0, 135.4, 133.2,
6.91 (d, J¼8.0 Hz, 1H), 6.48 (br s, 1H), 5.09 (s, 2H), 3.95e3.78 (m, 2H),
3.29 (s, 3H), 3.25e3.17 (m, 1H), 2.97e2.70 (m, 3H), 2.44e2.40 (m,
1H), 2.17e2.13 (m, 1H), 1.55 (s, 9H). 13C NMR (CDCl3, 125 MHz)
132.0, 131.4, 128.8 (d, J¼22 Hz), 128.7, 127.9, 127.7, 127.6 (2C), 124.1,
115.8 (d, J¼8 Hz), 109.2, 61.1, 48.4, 45.2, 42.8, 33.1. HRMS (m/z, ESIþ)
calcd for C28H26N2OF35Cl2: 495.1406, found 495.1396 and calcd for
C28H26N2OF35Cl37Cl: 497.1377, found 497.1398.
(rotamers) d 180.1, 152.9, 147.2, 136.4, 134.7, 129.3, 123.8, 118.6, 115.2,
109.5, 80.6, 71.6, 64.0, 58.5, 56.2, 54.1, 53.3, 37.3, 28.4. HRMS (m/z,
ESIþ) calcd for C25H31N4O6: 483.2244, found 483.2239.
4.5.15. (E)-5-Chloro-1-(4-chlorobenzyl)-10-(3-(4-chlorophenyl)allyl)
spiro[indoline-3,40-piperidin]-2-one (39f). Prepared following gen-
4.5.10. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-(cyclopro-
eral procedure B. Colourless oil. IR (CHCl3, cmꢂ1
)
n
2930, 2822,
panecarbonyl)spiro[indoline-3,40-piperidin]-2-one
(39a). Prepared
following general procedure A. Colourless oil. IR (CHCl3, cmꢂ1
2938, 2823, 2358, 2340,1748,1697,1474,1389,1318,1290,1252,1143,
1103. 1H NMR (CDCl3, 500 MHz)
1709, 1608, 1486, 1427, 1340, 1170, 909. 1H NMR (CDCl3, 500 MHz)
)
n
d
7.36 (d, J¼1.7 Hz, 1H), 7.33 (d, J¼8.5 Hz, 2H), 7.28 (d, J¼8.5 Hz,
2H), 7.24 (m, 2H), 7.21 (s, 1H), 7.15 (dd, J¼2.0, 8.3 Hz, 1H), 7.10 (m,
1H), 6.60 (d, J¼8.3 Hz, 1H), 6.56 (d, J¼15.9 Hz, 1H), 6.34 (dt, J¼6.6,
15.9 Hz, 1H), 4.84 (s, 2H), 3.35 (d, J¼6.6 Hz, 2H), 3.04 (m, 2H), 2.82
d
8.08 (d, J¼8.7 Hz, 1H), 7.34e7.25
(m, 6H), 6.55 (d, J¼15.8 Hz, 1H), 6.34 (td, J¼6.6, 15.8 Hz, 1H), 3.36 (d,
J¼6.6 Hz, 2H), 3.14 (m, 1H), 2.96 (m, 2H), 2.87 (m, 2H), 2.02 (m, 4H),
(m, 2H), 2.00 (m, 4H). 13C NMR (CDCl3, 125 MHz)
d 179.5, 140.1,
1.27 (m, 2H), 1.10 (m, 2H, H). 13C NMR (CDCl3, 75 MHz)
d
180.1, 175.2,
137.7, 136.0, 135.4, 134.8, 133.2, 132.1, 130.2, 128.7, 128.0, 127.8,
127.6, 127.2, 125.1, 124.1, 109.7, 61.1, 48.4, 45.2, 43.0, 33.1. HRMS
137.7, 135.3, 135.1, 133.2, 132.1, 130.4, 128.8, 128.2, 127.6 (2C), 123.2,

8920
S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
(m/z, ESIþ) calcd for C28H26N2O35Cl3: 511.1111, found 511.1127 and
1170. 1H NMR (CDCl3, 500 MHz)
d
7.38 (d, J¼1.8 Hz, 1H), 7.32 (d,
calcd for C28H26N2O35Cl237Cl: 513.1128, found 513.1103.
J¼8.5 Hz, 2H), 7.28 (d, J¼8.5 Hz, 2H), 7.26 (d, J¼8.8 Hz, 2H), 7.17 (dd,
J¼1.8, 8.3 Hz, 1H), 7.02 (d, J¼8.8 Hz, 2H), 6.69 (d, J¼8.3 Hz, 1H), 6.55
(d, J¼15.9 Hz, 1H), 6.35 (dt, J¼6.6, 15.9 Hz, 1H), 3.85 (s, 3H), 3.35 (d,
J¼6.6 Hz, 2H), 3.08 (m, 2H), 2.85 (m, 2H), 2.06 (m, 4H). 13C NMR
4.5.16. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-(4-nitrobenzyl)
spiro[indoline-3,40-piperidin]-2-one (39g). Prepared following gen-
eral procedure B. Colourless oil. IR (CHCl3, cmꢂ1
)
n
2936, 2822,1709,
(CDCl3, 125 MHz) d 178.9, 159.2, 141.6, 135.6, 135.2, 133.3, 128.7,
1068, 1530, 1486, 1427, 1348, 1170, 1088. 1H NMR (CDCl3, 500 MHz)
128.0, 127.8 (2C), 127.7, 127.6, 126.6, 124.0, 114.9, 110.2, 61.0, 55.6,
48.2, 44.9, 33.1. HRMS (m/z, ESIþ) calcd for C28H27N2O235Cl2:
493.1450, found 493.1435.
d
8.14 (d, J¼8.1 Hz, 1H), 8.09 (s, 1H), 7.56 (d, J¼7.8 Hz, 1H), 7.51 (dd,
J¼7.8, 8.1 Hz, 1H), 7.38 (d, J¼2.0 Hz, 1H), 7.33 (d, J¼8.5 Hz, 2H), 7.28
(d, J¼8.5 Hz, 2H), 7.16 (dd, J¼2.0, 8.3 Hz, 1H), 6.59 (d, J¼8.3 Hz, 1H),
6.55 (d, J¼15.9 Hz, 1H), 6.34 (dt, J¼6.2, 15.9 Hz, 1H), 4.97 (s, 2H),
3.35 (d, 2J¼6.2 Hz, 2H), 3.04 (m, 2H), 2.82 (m, 2H), 2.01 (m, 4H). 13C
Acknowledgements
NMR (CDCl3, 75 MHz)
d 179.5, 148.6, 139.6, 137.8, 136.0, 135.3,
Financial support from the CNRS and Bayer Cropscience
(doctoral fellowship to S.J.) is gratefully acknowledged.
133.2, 133.0, 132.1, 130.1, 128.7, 128.3, 127.8, 127.6 (2C), 124.3,
122.9, 121.9, 109.4, 61.1, 48.4, 45.2, 42.8, 33.2. HRMS (m/z, ESIþ)
calcd for C28H26N3O335Cl2: 522.1351, found 522.1359 and calcd for
C28H26N3O335Cl37Cl: 524.1322, found 524.1348.
Supplementary data
Copies of NMR spectra. Supplementary data associated with this
article can be found in online version at doi:10.1016/j.tet.2010.09.056.
These data include MOL files and InChIKeys of the most important
compounds described in this article.
4.5.17. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)spiro [indoline-3,40-
piperidine]-2-thione (39h). To a solution of compound 38 (20.0 mg,
0.052 mmol, 1.0 equiv) in 0.5 mL xylene was added Lawesson’s
reagent (25 mg, 0.062 mmol, 1.2 equiv) and the reaction mixture
was heated at 140 ꢀC for 12 h. After solvent evaporation, crude
residue was purified by flash chromatography (SiO2, Hept/acetone:
9/1) to give the thioamide 39h (5.2 mg, 25%) as a yellow glue. IR
References and notes
1. For recent reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 12,
2209e2219; (b) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127e139;
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Howley, P.M.; Koehler, A.N.; Hayakawa, H.; Neumann, C.S.; Schreiber, S.L.
WO2008/144507 A2, 2008. (i) Eastwood, P.R.; Gonzalez Rodriguez, J.;
Vidal Juan, B.; Aguilar Izquierdo, N. (Almirall) WO2009/124692 A1, 2009.
2. (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832e835; (b) Cui, C. B.;
Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651e12666.
(CHCl3, cmꢂ1
1336, 1236, 1162. 1H NMR (CDCl3, 500 MHz)
)
n
3058, 2939, 2820, 1618, 1593, 1490, 1470, 1454,
9.68 (br s, 1H), 7.68
d
(m, 1H), 7.34e7.26 (m, 5H), 6.94 (d, J¼8.3 Hz, 1H), 6.57 (d, J¼15.7 Hz,
1H), 6.34 (m, 1H), 3.37 (d, J¼6.6 Hz, 2H), 2.65 (m, 2H), 2.36 (m, 2H),
1.64 (m, 4H). HRMS (m/z, ESIþ) calcd for C21H21N2S35Cl2: 403.0803,
found 403.0802.
4.5.18. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-cyclopropylspiro
[indoline-3,40-piperidin]-2-one (39i). A solution of Cu(OAc)2 (11.7 mg,
0.064 mmol, 1.0 equiv) and bipyridine (10.0 mg, 0.064 mmol,
1.0 equiv) in 0.4 mL DCE was added to a solution of 38 (25 mg,
0.064 mmol, 1.0 equiv), cyclopropyl boronic acid (14.0 mg,
0.16 mmol, 2.5 equiv) and Na2CO3 (13.6 mg, 0.13 mmol, 2.0 equiv) in
0.2 mL DCE. Resulting reaction mixture was heated at 70 ꢀC for 1 h
30 min. Reaction was quenched with water, acidified with dilute HCl
and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated. The residue
was purified by flash chromatography (SiO2, CH2Cl2/MeOH: 100/1)
to give the compound 39i (8.5 mg, 31%) as colourless oil and starting
3. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991, 56,
6527e6530.
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Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130e10131; (c)
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Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49,
3432e3435; (d) Shangary, S.; Qin, D.; McEachern, D.; Liu, M.; Miller, R. S.; Qiu, S.;
Nikolovska-Coleska, Z.; Ding, K.; Wang, G.; Chen, J.; Bernard, D.; Zhang, J.; Lu, Y.;
Gu, Q.; Shah, R. B.; Pienta, K. J.; Ling, X.; Kang, S.; Guo, M.; Sun, Y.; Yang, D.;
Wang, S. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 3933e3938.
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Pharmaceutica) WO2006/130416 A2, 2006.
material 38 (12 mg, 48%) IR (CHCl3, cmꢂ1
1608, 1485, 1374, 1332. H NMR (CDCl3, 500 MHz)
)
n
2923, 2848, 2364, 1716,
7.33e7.27 (m,
1
d
5H), 7.24 (dd, J¼2.0, 8.3 Hz), 7.02 (d, J¼8.3 Hz, 1H), 6.53 (d, J¼15.9 Hz,
1H), 6.34 (m, 1H), 3.33 (m, 2H), 3.01 (m, 2H), 2.76 (m, 2H), 2.61 (m,
1H), 1.90 (m, 4H), 1.06 (m, 2H), 0.87 (m, 2H). 13C NMR (CDCl3,
75 MHz)
d
180.1, 141.7, 135.5, 135.3, 133.2, 132.1, 129.7, 128.7, 128.5,
7. Hughes, D.J.; Worthington, P.A.; Russell, C.A.; Clarke, E.D.; Peace, J.E.; Ashton,
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Maienfisch, P. (Syngenta) WO 2003/106457, 2003.
127.65,127.58,123.7,110.2, 61.0, 48.3, 44.8, 33.0, 22.1, 6.0. HRMS (m/z,
ESIþ) calcd for C24H25N2O35Cl2: 427.1344, found 427.1343.
8. (a) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351e4354; (b)
Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927e4930; (c)
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(b) Yasui, Y.; Takemoto, Y. Chem. Rec. 2008, 8, 386e394; (c) Kamisaki, H.; Yasui, Y.;
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4.5.19. (E)-5-Chloro-10-(3-(4-chlorophenyl)allyl)-1-(4-methoxy-
phenyl)spiro[indoline-3,40-piperidin]-2-one (39j). To
solution of oxindole 38 (25 mg, 0.065 mmol, 1.0 equiv) and
p-methoxyiodobenzene (15.0 mg, 0.065 mmol,1 equiv) in 0.6 mL of
acetonitrile were successively added K2CO3 (18 mg, 0.13 mmol,
2 equiv), CuI (1.2 mg, 0.0065 mmol, 0.1 equiv) and dimethylene-
a degassed
diamine (1.5 mL, 0.013 mmol, 0.2 equiv) and the reaction mixture
was heated at reflux for 20 h. After cooling, reaction was quenched
with HCl 1 M and extracted with EtOAc. The combined organic
layers were washed with brine, dried (Na2SO4) and concentrated.
The residue was purified by flash chromatography (SiO2, CH2Cl2/
MeOH: 100/5) to give the compound 39j (6.7 mg, 21%) as colourless
11. For recently developed synthetic methodologies to 3,3-disubstituted oxindoles,
see: (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548e14549; (b)
Tang, S.; Peng, P.; Zhong, P.; Li, J. H. J. Org. Chem. 2008, 73, 5476e5480; (c)
oil. IR (CHCl3, cmꢂ1
) n 2926, 2850,1720, 1607,1514,1481, 1298,1250,

S. Jaegli et al. / Tetrahedron 66 (2010) 8911e8921
8921
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