A general and efficient method to access tetracyclic spirooxindole derivatives

Article abstract of DOI:10.1002/ejoc.201403292

An efficient, simple, and convenient synthetic procedure for the synthesis of tetracyclic spirooxindole derivatives, starting from N-protected isatins and 2-fluoropyridine, was successfully developed. It enables the facile formation of a new class of spirooxindoles in which the oxindole core is fused with various heterocycles at the C-3 position.

Full text of DOI:10.1002/ejoc.201403292

Job/Unit: O43292
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Date: 04-12-14 15:35:59
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FULL PAPER
DOI: 10.1002/ejoc.201403292
A General and Efficient Method to Access Tetracyclic Spirooxindole
Derivatives
[
a]
[b]
[b]
[c,d]
Abderrahman El Bouakher, Stéphane Massip, Christian Jarry, Yves Troin,
Isabelle Abrunhosa-Thomas,[ and Gérald Guillaumet*
c,d]
[a]
Keywords: Anionic condensation / Reduction / Cyclization / Selective deprotection / Tetracyclic spirooxindole / Spiro
compounds
An efficient, simple, and convenient synthetic procedure for
the synthesis of tetracyclic spirooxindole derivatives, starting
from N-protected isatins and 2-fluoropyridine, was success-
fully developed. It enables the facile formation of a new class
of spirooxindoles in which the oxindole core is fused with
various heterocycles at the C-3 position.
Introduction
Spiroheterocycles are of great interest due to their con-
formational restriction, which is associated with their broad
range of physical and biochemical properties.[ In particu-
lar, polycyclic spirooxindole systems have emerged as at-
tractive synthetic targets because of their prevalence in a
number of biologically active compounds and natural prod-
1]
[
2]
ucts. A survey of the literature showed that the biological
potential can be related to the framework of the spiro
[
3]
ring. For example, the simplest tricyclic skeleton, horsfi-
line (Ia; Figure 1), in which the oxindole moiety is linked
with a pyrrolidine, is an alkaloid found in the plant Horsfil-
dea superb Warb and used in traditional herbal medicine
for its antitumor activity. Two other spirooxindole alkaloids
of the same type also used as antitumor compounds are
coerulescine (Ib) from the blue canary grass Phalaris coeru-
[
4]
lescens and elacomine (II) from Elaeagnus commutate.
Spirobrassinin (III) and its analogues are a particular
class of spirooxindole phytoalexins, isolated from the plant
family Cruciferae, which exhibit potent antitumor, antimi-
[
5]
crobial, and oviposition stimulant biological activities,
whereas compound IV was characterized as a hit com- Figure 1. Spirooxindoles with interesting biological activities.
pound for new inhibitors of β-secretase (BCAE-1) involved
in Alzheimer’s disease, and compound V (XEN 907), con-
[
a] Institut de Chimie Organique et Analytique,
[
6]
Université d’Orléans, UMR CNRS 7311,
4
5067 Orléans Cedex, France
nected to a dihydrobenzofuran unit, displayed strong anal-
E-mail: gerald.guillaumet@univ-orleans.fr
www.icoa.fr
[
7]
gesic activity.
[
[
[
b] Université Bordeaux Segalen, CNRS FRE 3396,
Pharmacochimie,
Spirocyclic oxindoles fused with piperidine systems are
used as an antimalarial agent (cipargamine, NITD-609, VI;
1
46 Rue Léo Saignat, 33000 Bordeaux, France
[
8]
Figure 1) or for the treatment of anemia (HIF PHD 1–3,
c] Clermont Université, ENSCCF, Institut de Chimie de
Clermont-Ferrand (ICCF),
BP 10448, 63000 Clermont-Ferrand, France
d] CNRS, UMR 6296, Institut de Chimie de Clermont-Ferrand
[
9]
VII), whereas compound VIII, in which the spirooxindole
unit is fused with a cyclopropane system, was shown to be
a potent HIV-1 non-nucleoside reverse transcriptase inhibi-
(
ICCF),
BP 80026, 63171 Aubiere, France
[10]
tor.
E-mail: yves.troin@ensccf.fr
Thus, many methods have appeared in the literature, all
directed towards the synthesis of this highly valuable struc-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403292.
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G. Guillaumet et al.
FULL PAPER
tural motif.[3] In this context, we focused our efforts on the tive in a key step. Intermediates of this kind and their syn-
[
13]
development of a general route for the synthesis of biolo- thetic potential have been extensively described, and have
gically active polycyclic spirooxindoles fused with five-, generally been obtained through the addition of a nucleo-
six-, or seven-membered heterocycle systems, condensed in phile to a carbonyl group in the indole 3-position. In our
each case with a pyridine core (Figure 2).
case, we decided to use 2-fluoropyridine, selective ortho-
[
14]
lithiation of which with LDA efficiently furnished the re-
sulting 3-lithio derivative. Condensation of this with N-pro-
tected isatins 2 or 3 afforded compounds 4 and 5, respec-
tively, in good yields. Dehydroxylation of compounds 4 and
5
was achieved in two steps by treatment with SOCl and
2
[
15]
pyridine in dichloromethane at 0 °C for 2 h
and then
with zinc dust in a THF/AcOH mixture at room tempera-
[
16]
ture for 3 h
to afford compounds 8 and 9, our pivotal
structures, in good yields (Scheme 1).
Figure 2. Targeted molecules.
We wish to describe our results here. All products were
Spirooxindoles Containing Five-, Six-, or Seven-Membered
Heterocycles Incorporating Amine Functions
obtained from derivatives 4 or 5 as common starting mate-
[
11]
rials, themselves prepared from N-substituted isatins 2
and 3,
[
12]
conveniently prepared in turn from commercial
Alkylation of compounds 8 and 9 variously with diodo-
methane, dibromomethane, 1,2-dibromoethane, or 1,3-di-
bromopropane in the presence of potassium hydroxide in
isatin (Scheme 1). Three series of new spirooxindole deriva-
tives were efficiently synthesized (Figure 2), containing a
five-, six-, or seven-membered heterocycle with
[
17]
DMF
gave the corresponding alkylated products 10
(95%), 11 (75%), 12 (70%), and 13 (90%) (Scheme 2).
*
*
*
an amine function (in the first series)
an ether function (in the second series)
an amide function (in the third series).
Scheme 2. Spirooxindoles 14–19. (i) KOH, DMF, dihaloalkane (di-
iodomethane for 10, 1,2-dibromoethane for 11, 1,3-dibromoprop-
ane for 12, and dibromethane for 13), room temp., 2 h; (ii) but-
ylamine or 4-methoxybenzylamine, dioxane, microwaves, 200 °C,
3
h.
S 2 substitution and S Ar cyclization were achieved in
N
N
[
18]
a one-step
fashion by treatment with butylamine or 4-
methoxybenzylamine under microwave irradiation condi-
tions (200 °C, 3 h.), and allowed the convenient synthesis of
a series of spirooxindoles 14–19 in good yield (Table 1).
N-Deprotection of compound 15 was next envisaged, by
Scheme 1. Synthesis of compounds 8 and 9. (i) (a) 4-methoxybenzyl
chloride, K CO , KI, DMF, 120 °C, 4 h; (b) 1-bromopentane,
NaH, DMF, room temp., 12 h; (ii) 2-fluoropyridine, LDA, THF,
2
78 °C, 4 h, then 2 or 3, –78 °C to room temp., 6 h; (iii) SOCl ,
2
3
[
19]
standard procedures.
No reaction at all was achieved
with the use of TFA at room temperature during 12 h, TFA
–
pyridine, CH
h.
2
Cl
2
, 0 °C, 2 h; (iv) Zn, THF/AcOH (7:3), room temp., at 100 °C for 1 h, or H /Pd-C in methanol at room tempera-
2
3
ture over 4 h (Table 2). However, when the reaction was car-
ried out with TFA in dichloromethane in the presence of
10 equiv. of triflic acid, at room temperature overnight, N-
deprotected product 20 was obtained in excellent yield
[
20]
(90%).
Results and Discussion
Selective deprotection of compounds 18 and 19 was con-
One straightforward method for the synthesis of these ducted with trifluoroacetic acid at 100 °C over 30 min un-
products is to use a 3-substituted 3-hydroxyindole deriva- der microwave conditions and furnished compounds 21 and
2
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A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
Table 1. Synthesis of compounds 14–19.
Scheme 3. Selective deprotection of compounds 18 and 19.
Spirooxindoles Containing Five-, Six-, or Seven-Membered
Heterocycles Incorporating Ether Functions
To extend the methodology we decided to prepare spiro-
oxindoles of type 24, in which the oxindole core was fused
with a tetrahydrofuran system. Hydroxymethylation of
compound 8 at the C-3 position was performed in THF at
room temperature in the presence of 10 equiv. of paraform-
aldehyde and 4 equiv. of diisopropylamine for 12 h to give
[
21]
compound 23 in a quantitative yield.
However, all
attempts to transform compound 23 into 24 by S Ar cycli-
N
[
22]
zation in basic medium
were not successful, with only
compound 8 being obtained by a retro-aldol process
Scheme 4).
(
In the face of such failure, we went back to the first ap-
proach, starting from compounds 4 and 5. Treatment of 4
with sodium methoxide in methanol for 12 h furnished 25
95% yield); likewise, 5 led to 26 in a similar yield (96%).
Dehydroxylation of compounds 25 and 26 was achieved, as
described previously, in two steps, firstly by treatment with
(
SOCl and pyridine in dichloromethane at 0 °C for 2 h to
2
give 27 and 28 (75 and 70% yield, respectively), and then
by treatment with zinc dust in a THF/AcOH mixture at
room temperature for 3 h to afford compounds 29 and 30
in near quantitative yield (Scheme 5).
Table 2. Attempted PMB removal.
Hydrolysis of compounds 29 and 30 was carried out with
HCl (3 n) in a H O/dioxane mixture (1:1) at 80 °C over
2
[
23]
1
2 h, with the corresponding pyridones 31 and 32 being
isolated in good yields. Further treatment of intermediates
1 and 32 with chloroiodomethane in DMF at room tem-
perature in the presence of Cs CO for 12 h afforded the
3
2
3
cyclized compounds 24 and 33 in 80% and 81% yields,
respectively (Scheme 5). The structure of compound 33 was
confirmed by X-ray diffraction (Figure 3). Finally, N-de-
protected product 34 was obtained in good yield (87%) by
use of TFA and 10 equiv. of triflic acid in dichloromethane
at room temperature overnight.
Entry
Conditions
Result
s.m.[a]
s.m.
1
2
3
4
TFA, 12 h, r.t.
TFA, 1 h, microwaves, 100 °C
, Pd-C, P = 1 atm, MeOH, 4 h, r.t.
H
2
s.m.
TFA, triflic acid 10 equiv., CH
2
Cl
2
, 12 h, r.t. 20 (90%)
The corresponding six- and seven-membered hetero-
cycles 41 and 42 were prepared from compound 8 by treat-
ment with sodium hydride, followed by alkylation with
methyl bromoacetate or methyl 3-bromopropionate at 0 °C
[a] s.m.: starting material, CH
2
Cl /dichloromethane.
2
2
2
in excellent yields (95% and 98% respectively; for 2 h[25] to afford 35 (98%) or 36 (80%). Saponification
Scheme 3). Under these conditions no deprotection of the of the corresponding esters was carried out with NaOH
lactam function was observed.
(2 n) in MeOH at room temperature overnight to give 37
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Scheme 4. Attempts to cyclize compound 23.
chloroformate in the presence of triethylamine at 0 °C in
THF for 0.5 h. Reduction of these anhydrides with NaBH4
in EtOH at ambient temperature overnight afforded the
alcohols 39 and 40 in very good yields (Scheme 6). Finally,
compounds 39 and 40 were cyclized in THF at 150 °C in
the presence of 1 equiv. of NaH under microwave irradia-
tion conditions for 2 h to give compounds 41 and 42 in
[
22]
good yields after purification (Scheme 6).
Scheme 5. Synthesis of spirooxindoles 24, 33, and 34. (i) MeONa,
2 2 2
MeOH, reflux, 12 h; (ii) SOCl , pyridine, CH Cl , 0 °C, 2 h;
Scheme 6. Synthesis of spirooxindoles 41 and 42. (i) Methyl bromo-
(
8
iii) Zn, THF/AcOH, room temp., 3 h; (iv) HCl (3 n), dioxane,
acetate or methyl 3-bromopropionate, NaH, THF, 0 °C, 2 h;
0 °C, 12 h; (v) chloroiodomethane, Cs
2 3
CO , DMF, room temp.,
(
ii) NaOH (2 n), MeOH, room temp., 12 h; (iii) (a) ethyl chloro-
formate, Et N, THF, 0 °C, 0.5 h; (b) NaBH , EtOH, room temp.,
2 h; (iv) NaH, THF, 150 °C, microwaves, 2 h.
1
2 h; (vi) TFA, triflic acid, CH Cl , room temp., 12 h.
2
2
3
4
1
Attempts to reduce ester 35 directly to alcohol 39 with
LiAlH (0.5 or 1 equiv.) were unsuccessful, with a mixture
4
of compounds 43 and 39 being obtained (Scheme 7). Com-
pound 43, the main compound obtained in both cases, was
the result of molecular trapping of the alcohol on the tran-
sient iminium ion. The relative stereochemistry was deter-
mined by X-ray diffraction (Figure 4) and is in accordance
with compounds obtained by the same methodology.[
26]
Figure 3. ORTEP view of compound 33[24] (two positions of the
disordered lateral chain C22 and C23 have been omitted to allow
better visibility of the chemical structure).
and 38 in quantitative yields, and the resulting acids were
transformed into mixed anhydrides by treatment with ethyl Scheme 7. Reduction of ester 35 with LiAlH .
4
4
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A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
tain the N-deprotected product 50 in an excellent yield of
7%.
9
Alternatively, compound 45 was N-deprotected by use of
TFA at 100 °C under microwave irradiation conditions for
0 min to give 53 in excellent yield. Treatment of 53 with
methyl chloroformate or methyl bromoacetate in the pres-
ence of triethylamine furnished a crude product that was
then cyclized under microwave irradiation conditions at
00 °C for 1 h to afford 54 or 55 in good yields after purifi-
cation (Scheme 9).
3
1
Figure 4. ORTEP view of compound 43.[24]
Spirooxindoles Containing Five- or Six-Membered
Heterocycles Incorporating Amide Functions
Scheme 9. Synthesis of spirooxindoles 54 and 55. (i) TFA, 100 °C,
microwaves, 30 min; (ii) methyl chloroformate or methyl bromo-
3
acetate, Et N, THF, room temp., 12 h, then 100 °C, microwaves, 1 h.
Compounds 8 and 9 were also employed in the synthesis
of spirooxindoles containing five- or six-membered N-het-
erocycles incorporating lactam functions. Treatment of
compounds 8 and 9 with butylamine or 4-methoxybenzyla-
mine in dioxane at 180 °C for 3 h under microwave irradia-
Conclusions
We have developed a synthetic route to new spirooxind-
tion conditions led to substitution of the fluorine atom by oles fused with five-, six-, or seven-membered heterocycle
[
18]
the amine group and afforded 44 and 45 in good yields. moieties. A library of a wide variety of original tetracyclic
These were converted into 46, 47, and 48 by treatment with spirooxindoles was obtained in moderate to good yields by
methyl chloroformate or methyl bromoacetate in THF at starting from two key intermediates: 3-(2-fluoropyridin-
0
°C in the presence of 2 equiv. of NaH for 2 h. Finally, 3-yl)-3-hydroxy-1-[(4-methoxyphenyl)methyl]indolin-2-one
compounds 46, 47, and 48 were cyclized in methanol in (4) and 3-(2-fluoropyridin-3-yl)-3-hydroxy-1-pentylindolin-
the presence of Et N at 100 °C under microwave irradiation 2-one (5). This method opens the way to a general synthesis
3
conditions for 2 h to give compounds 49, 50, and 51 in good of tetracyclic spirooxindole systems, major skeletons for
to excellent yields after purification (Scheme 8). As in the designing biologically active compounds. Further studies
case of compound 20, use of triflic acid (10 equiv., TFA, and investigation of the properties of these molecules are
CH Cl , room temperature, overnight) was necessary to ob- currently in progress in our laboratory.
2
2
Experimental Section
General: Microwave-assisted reactions were carried out with a
Biotage Initiator Microwave synthesis instrument with internal
temperatures measured with an IR sensor. The reactions were mon-
itored by thin-layer chromatography (TLC) analysis on silica gel
(
60 F254) plates. Spots were visualized with UV light at 254 nm
and 356 nm. Column chromatography was performed with silica
gel 60 (230–400 mesh, 0.040–0.063 mm). Melting points (m.p.) were
obtained with a melting point apparatus with a digital thermome-
1
ter in open capillary tubes and are reported without correction. H
1
3
and C NMR spectra were recorded with a Bruker DPX 400 MHz
instrument in CDCl or [D ]DMSO. The chemical shifts are re-
3
6
ported in parts per million (δ scale), and all coupling constant (J)
values are in Hertz [Hz]. The following abbreviations are used to
explain the multiplicities: s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet) and dd (doublet of doublets). IR absorption
spectra were obtained with a Perkin–Elmer Paragon 1000 PC spec-
trometer, and values are reported in cm . HRMS was performed
with a Maxis Bruker 4G instrument, and spectra were recorded
with a time-of-flight mass spectrometer fitted with an electrospray
(ESI).
Scheme 8. Synthesis of spirooxindoles 49–52. (i) Butylamine or 4-
methoxybenzylamine, dioxane, 180 °C, microwaves, 3 h; (ii) methyl
chloroformate or methyl bromoacetate, NaH, THF, 0 °C, 2 h;
–
1
(
iii) MeOH, Et
CH Cl , room temp., 12 h.
3
N, 100 °C, microwaves, 2 h; (iv) TFA, triflic acid,
2
2
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G. Guillaumet et al.
FULL PAPER
General Method to Prepare Compounds 4 and 5: 2-Fluoropyridine
9.7 g, 0.1 mol) was added slowly to a cold (–75 °C) solution of
lithium diisopropylamide, which had been prepared previously by
treatment of diisopropylamine (10.1 g, 0.1 mol) with butyllithium
26.8 Hz), 121.8 (d, J = 4.3 Hz), 123.6, 124.4, 126.9, 128.7 (2 CH),
129.5, 130.7, 140.8 (d, J = 3.2 Hz), 142.0, 148.0 (d, J = 15.1 Hz),
159.02 (d, J = 240.2 Hz), 159.3, 172.4 ppm. IR (ATR diamond): ν˜
= 2935, 2837, 1732, 1605, 1512, 1488, 1467, 1424, 1380, 1271, 1244,
(
–
1
(
62.5 mL, 0.1 mol) in THF (250 mL) at 0 °C for 30 min. The re-
sulting yellow mixture was stirred at –78 °C for 4 h before addition
of compound 2 (26.7 g, 0.1 mol) or 3 (21.7 g, 0.1 mol) in THF found 383.0955.
75 mL) solution. Stirring was continued at –78 °C for 6 h, before
hydrolysis with an aqueous solution of NH Cl at room tempera-
1175, 1113, 1034, 938, 925, 824, 805, 755, 706, 684, 668, 638 cm .
HRMS (ESI): calcd. for C21 16ClFN
H
2 2
O
[M + H]+ 383.0957;
(
3
-Chloro-3-(2-fluoropyridin-3-yl)-1-pentylindolin-2-one (7): Yellow
4
1
oil; yield 76 %. H NMR (CDCl
7
2
3
, 400 MHz): δ = 0.93 (t, J =
.1 Hz, 3 H), 1.31–1.52 (m, 4 H), 1.72–1.89 (m, 2 H), 3.71–3.97 (m,
H), 6.96 (d, J = 7.9 Hz, 1 H), 7.04 (td, J = 7.5, 0.8 Hz, 1 H), 7.12
ture. The aqueous phase was extracted with ethyl acetate, and the
organic phase was washed with water and brine, dried with anhy-
drous sodium sulfate, and filtered. The filtrate was concentrated in
vacuo, and the residue was purified by column chromatography
(
dd, J = 7.5, 1.0 Hz, 1 H), 7.32–7.41 (m, 2 H), 8.17–8.23 (m, 1
13
H), 8.51 (ddd, J = 9.8, 7.6, 1.9 Hz, 1 H) ppm. C NMR (CDCl
3
,
(petroleum ether/EtOAc 7:3) to give product 4 or 5.
100 MHz): δ = 13.9, 22.3, 26.7, 28.9, 40.8, 64.0 (d, J = 6.3 Hz),
3
-(2-Fluoropyridin-3-yl)-3-hydroxy-1-(4-methoxybenzyl)indolin-2- 109.3, 119.9 (d, J = 26.8 Hz), 121.7 (d, J = 4.3 Hz), 123.4, 124.5
1
one (4): M.p. 94 °C; yield 65%. H NMR (CDCl
3
, 400 MHz): δ =
(d, J = 1.1 Hz), 129.6, 130.7, 140.7 (d, J = 3.2 Hz), 142.4, 147.9 (d,
3
1
7
2
.81 (s, 3 H), 3.98 (s, 1 H), 4.81 (d, J = 15.5 Hz, 1 H), 5.05 (d, J = J = 15.2 Hz), 159.0 (d, J = 240.3 Hz), 172.1 ppm. IR (ATR dia-
5.5 Hz, 1 H), 6.82 (d, J = 7.9 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 2 H), mond): ν˜ = 2952, 2933, 2867, 1709, 1609, 1602, 1489, 1466, 1421,
.01 (t, J = 7.5 Hz, 1 H), 7.09 (d, J = 6.7 Hz, 1 H), 7.22–7.31 (m,
H), 7.33 (d, J = 8.6 Hz, 2 H), 8.15 (d, J = 4.8 Hz, 1 H), 8.40
1369, 1356, 1296, 1240, 1162, 1144, 1094, 1025, 924, 902, 826, 812,
758, 742, 727, 711 cm . HRMS (ESI): calcd. for C18H18ClFN O
2
–
1
13
, 100 MHz): [M + H]+ 333.1164; found 333.1162.
General Method to Prepare Compounds 8 and 9: Compound 6
3.82 g, 10 mmol) or 7 (3.33 g, 10 mmol) was dissolved in tetra-
hydrofuran (70 mL) and acetic acid (30 mL), and zinc dust (3.27 g,
0 mmol) was added. The reaction mixture was stirred at ambient
(
ddd, J = 9.6, 7.6, 1.9 Hz, 1 H) ppm. C NMR (CDCl
δ = 43.8, 55.3, 74.6 (d, J = 5.3 Hz), 110.1, 114.3 (2ϫCH), 121.6
d, J = 4.2 Hz), 122.9 (d, J = 28.2 Hz), 123.5, 124.4, 127.0, 128.7,
3
(
1
1
(
28.8, 129.3, 130.4, 138.6 (d, J = 4.4 Hz), 143.1, 147.8 (d, J =
4.9 Hz), 159.2, 159.3 (d, J = 239.0 Hz), 175.9 ppm. IR (ATR dia-
5
mond): ν˜ = 3306, 2838, 1719, 1609, 1576, 1513, 1487, 1245, 1174,
temperature for 3 h and filtered. The filtrate was concentrated in
vacuo to dryness. The residue was dissolved in ethyl acetate, washed
with saturated aqueous ammonium chloride solution and brine,
dried with anhydrous sodium sulfate, filtered, and concentrated in
vacuo to dryness to afford pure compound 8 or 9, each in quantita-
tive yield.
–
1
1
065, 1028, 835, 749, 676, 649 cm . HRMS (ESI): calcd. for
+
C
21
H
17FN
2
O
3
[M + H] 365.1296; found 365.1294.
3
9
6
1
7
7
-(2-Fluoropyridin-3-yl)-3-hydroxy-1-pentylindolin-2-one (5): M.p.
1
3
2 °C; yield 70%. H NMR (CDCl , 400 MHz): δ = 0.94 (t, J =
.9 Hz, 3 H), 1.34–1.49 (m, 4 H), 1.66–1.83 (m, 2 H), 3.61–3.73 (m,
H), 3.81–3.88 (m, 1 H), 4.15 (s, 1 H), 6.94 (d, J = 7.8 Hz, 1 H),
.03 (td, J = 7.5, 0.8, Hz, 1 H), 7.09 (d, J = 6.1 Hz, 1 H), 7.25–
.27 (m, 1 H), 7.36 (td, J = 7.7, 1.4 Hz, 1 H), 8.11–8.13 (m, 1
3
-(2-Fluoropyridin-3-yl)-1-(4-methoxybenzyl)indolin-2-one (8): M.p.
1
133 °C. H NMR (CDCl
3
, 400 MHz): δ = 3.81 (s, 3 H), 4.88 (d, J
=
15.5 Hz, 1 H), 4.91 (s, 1 H), 5.02 (d, J = 15.3 Hz, 1 H), 6.85 (d,
13
3
H), 8.35 (ddd, J = 9.6, 7.6, 1.8 Hz, 1 H) ppm. C NMR (CDCl ,
J = 7.8 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.02 (t, J = 7.5 Hz, 1
H), 7.13 (d, J = 7.2 Hz, 1 H), 7.18–7.26 (m, 2 H), 7.32 (d, J =
1
1
1
00 MHz): δ = 13.9, 22.4, 26.8, 29.0, 40.0, 74.6 (d, J = 5.3 Hz),
09.1, 121.6 (d, J = 4.2 Hz), 123.0, 123.3, 124.5, 129.5, 130.4, 138.5,
43.4, 147.0 (d, J = 14.8 Hz), 159.3 (d, J = 240.6 Hz), 175.8 ppm.
8
5
.6 Hz, 2 H), 7.59 (ddd, J = 9.4, 7.4, 1.9 Hz, 1 H), 8.20 (d, J =
.1 Hz, 1 H) ppm. C NMR (CDCl , 100 MHz): δ = 34.6, 46.5 (d,
3
13
IR (ATR diamond): ν˜ = 3336, 2956, 2931, 2871, 1702, 1609, 1487,
J = 2.7 Hz), 55.3, 109.5, 114.2 (2ϫCH), 119.7 (d, J = 30.3 Hz),
21.8 (d, J = 4.3 Hz), 123.0, 124.4, 127.4, 127.6, 128.7, 128.8
2ϫCH), 140.9 (d, J = 4.8 Hz), 143.3, 146.9 (d, J = 14.7 Hz), 159.2,
–
1
1
430, 1361, 1241, 1140, 1121, 1099, 926, 860, 750, 695, 676 cm .
1
(
+
HRMS (ESI): calcd. for C18
15.1502.
2 2
H19FN O [M + H] 315.1503; found
3
1
1
1
61.9 (d, J = 239.8 Hz), 174.5 ppm. IR (ATR diamond): ν˜ = 2913,
184, 2050, 1980, 1710, 1612, 1603, 1511, 1491, 1437, 1303, 1244,
General Method to Prepare Compounds 6 and 7: Thionyl chloride
4.1 mL, 56.7 mmol) was added dropwise to a solution of
hydroxyindole 4 (13.76 g,37.8 mmol) or 5 (11.87 g,37.8 mmol) and
pyridine (6.2 mL, 75.6 mmol) in CH Cl (80 mL), cooled to 0 °C
in a round-bottomed flask. The reaction solution was stirred at
°C for 2 h. Water (60 mL) was then added, and the mixture was
extracted with CH Cl (3ϫ 100 mL). The combined extracts were
washed with brine and then dried with MgSO prior to concentra-
–
1
173, 1120, 1104, 1028, 928, 825, 787, 760, 727, 687 cm . HRMS
(
+
(
ESI): calcd. for C21
H
17FN
2
O
2
[M + H] 349.1347; found 349.1346.
1
2
2
3-(2-Fluoropyridin-3-yl)-1-pentylindolin-2-one (9): M.p. 85 °C. H
NMR (CDCl , 400 MHz): δ = 0.93 (t, J = 7.1 Hz, 3 H), 1.32–1.46
3
0
(m, 4 H), 1.68–1.81 (m, 2 H), 3.71–3.89 (m, 2 H), 4.82 (s, 1 H),
2
2
6.94 (d, J = 7.9 Hz, 1 H), 7.04 (td, J = 7.5, 0.8 Hz, 1 H), 7.14 (d,
J = 7.4 Hz, 1 H), 7.18 (ddd, J = 7.2, 4.9, 1.7 Hz, 1 H), 7.33 (ddd,
4
tion. Purification by column chromatography (petroleum ether/ J = 7.9, 2.0, 1.0 Hz, 1 H), 7.56 (ddd, J = 9.4, 7.4, 1.9 Hz, 1 H),
1
3
EtOAc, 8:2) afforded chlorooxindole 6 (10.85 g) or 7 (9.56 g), each
as an oil.
8.18 (ddd, J = 4.9, 1.8, 1.2 Hz, 1 H) ppm. C NMR (CDCl3,
100 MHz): δ = 13.9, 22.3, 27.0, 29.0, 40.4, 46.5 (d, J = 2.7 Hz),
1
08.7, 119.8 (d, J = 30.3 Hz), 121.8 (d, J = 4.3 Hz), 122.7, 124.5
3
-Chloro-3-(2-fluoropyridin-3-yl)-1-(4-methoxybenzyl)indolin-2-one
1
(d, J = 1.0 Hz), 127.6, 128.7, 140.8 (d, J = 4.9 Hz), 143.8, 146.8 (d,
J = 14.7 Hz), 161.9 (d, J = 239.7 Hz), 174.34 ppm. IR (ATR dia-
mond): ν˜ = 2923, 2859, 1712, 1600, 1488, 1466, 1432, 1260, 1239,
(6): Yellow oil; yield 75%. H NMR (CDCl
3
, 400 MHz): δ = 3.81
(s, 3 H), 4.95 (d, J = 15.5 Hz, 1 H), 5.05 (d, J = 15.5 Hz, 1 H),
6
7
7
1
7
5
.83 (d, J = 7.9 Hz, 1 H), 6.91 (d, J = 8.7 Hz, 2 H), 7.02 (td, J =
.5, 0.6, Hz, 1 H), 7.11 (dd, J = 7.4, 0.8 Hz, 1 H), 7.25 (dd, J =
.8, 1.1 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.39 (ddd, J = 7.4, 4.9,
–
1
1
183, 1105, 994, 900, 875, 866, 849, 789, 752, 732, 670 cm . HRMS
+
(
2
ESI): calcd. for C18H19FN O [M + H] 299.1554; found 299.1553.
.7 Hz, 1 H), 8.24 (dd, J = 3.5, 1.4 Hz, 1 H), 8.55 (ddd, J = 9.8, General Method to Prepare Compounds 10–13: A solution of 8 or
.6, 1.8 Hz, 1 H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 44.1,
9 (2 mmol) and a dihaloalkane (4 mmol) in DMF (4 mL) was de-
gassed and bubbled with argon under ice-cooling. Powdered KOH
3
5.3, 64.2 (d, J = 6.2 Hz), 110.2, 114.3 (2 CH), 119.7 (d, J =
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
(
4 mmol) was added to the solution in one portion, and the reac-
tion mixture was stirred at room temperature for 2 h, diluted with
O, and extracted with ethyl acetate. The organic layer was
washed with H O and brine and dried with Na SO , and the sol-
3
NMR (CDCl , 100 MHz): δ = 14.0, 22.3, 27.0, 29.1, 40.6, 54.4, (d,
J = 5.4 Hz), 67.1, 108.8, 121.0 (d, J = 28.0 Hz), 121.7 (d, J =
4.3 Hz), 123.0, 124.3 (d, J = 5.2 Hz), 129.4, 129.6, 139.7 (d, J =
4.6 Hz), 143.4, 147.0 (d, J = 15.6 Hz), 161.0 (d, J = 240.2 Hz),
174.4 ppm. IR (ATR diamond): ν˜ = 2930, 2860, 1710, 1611, 1488,
1433, 1363, 1255, 1122, 1103, 909, 873, 812, 749, 729, 694,
H
2
2
2
4
vents were evaporated. The residue was purified on a silica gel col-
umn (petroleum ether/EtOAc, 9:1 to 7:3) to give compounds 10–
1
–
1
+
3 in good to excellent yields.
673 cm . HRMS (ESI): calcd. for C19
91.0816; found 391.0815.
2
H20BrFN O [M + H]
3
3
2
=
-(2-Fluoropyridin-3-yl)-3-(iodomethyl)-1-(4-methoxybenzyl)indolin-
1
-one (10): Yellow oil; yield 95%. H NMR (CDCl
3
, 400 MHz): δ
General Method to Prepare Compounds 14–19: In a 5 mL micro-
wave reaction vial, compound 10, 11, 12, or 13 (0.30 mmol,
1 equiv.) was dissolved in 1,4-dioxane (1.8 mL), and the appropri-
3.80 (s, 3 H), 3.95 (d, J = 9.7 Hz, 1 H), 4.15 (d, J = 9.7 Hz, 1
H), 4.94 (d, J = 15.4 Hz, 1 H), 5.03 (d, J = 15.4 Hz, 1 H), 6.86–
6
4
.90 (m, 3 H), 7.08 (td, J = 7.6, 1.0 Hz, 1 H), 7.22 (ddd, J = 7.5, ate amine (10 equiv.) was then added, after which the vial was se-
.8, 1.8 Hz, 1 H), 7.23–7.32 (m, 1 H), 7.33 (dd, J = 7.6, 1.3 Hz, 1 aled. The reaction mixture was subjected to microwave irradiation
H), 7.38 (d, J = 8.6 Hz, 2 H), 7.85 (ddd, J = 9.7, 7.6, 1.8 Hz, 1 H), with stirring at 200 °C for 3 h. After the system had cooled down
.17 (dt, J = 4.8, 1.6 Hz, 1 H) ppm. 13C NMR (CDCl
, 100 MHz): to room temperature, 1,4-dioxane was removed under reduced pres-
δ = 7.2 (d, J = 4.6 Hz), 44.0, 53.9 (d, J = 5.4 Hz), 55.3, 109.8, 114.2 sure. The residue was then purified by column chromatography on
2 CH), 121.1 (d, J = 27.9 Hz), 121.8 (d, J = 4.3 Hz), 123.2, 124.0 silica gel (petroleum ether/EtOAc, 9:1 to 7:3) to provide the ex-
8
3
(
(
(
1
=
d, J = 5.4 Hz), 127.3 (d, J = 1.6 Hz), 129.1 (2 CH), 129.4, 130.4
d, J = 2.0 Hz), 139.5 (d, J = 4.5 Hz), 143.0, 147.0 (d, J = 15.4 Hz),
59.2, 160.9 (d, J = 240.2 Hz), 175.0 ppm. IR (ATR diamond): ν˜
pected products.
1
Ј-Butyl-1-(4-methoxybenzyl)-1Ј,2Ј-dihydrospiro[indoline-3,3Ј-
1
pyrrolo[2,3-b]pyridin]-2-one (14): Yellow oil; yield 85%. H NMR
CDCl , 400 MHz): δ = 1.01 (t, J = 7.4 Hz, 3 H), 1.49 (dq, J =
4.6, 7.3 Hz, 2 H), 1.63–1.75 (m, 2 H), 3.36–3.46 (m, 1 H), 3.63–
.70 (m, 1 H), 3.77 (d, J = 9.3 Hz, 1 H), 3.82 (s, 3 H), 4.01 (d, J =
2931, 2836, 1711, 1610, 1573, 1512, 1486, 1466, 1432, 1303, 1246,
(
3
–1
1
177, 1103, 910, 835, 789, 748, 728, 694, 648 cm . HRMS (ESI):
1
3
+
2 2
calcd. for C22H18FIN O [M + H] 489.0470; found 489.0468.
3
-(2-Bromoethyl)-3-(2-fluoropyridin-3-yl)-1-(4-methoxybenzyl)- 9.3 Hz, 1 H), 4.81 (d, J = 15.3 Hz, 1 H), 5.05 (d, J = 15.3 Hz, 1
1
indolin-2-one (11): Yellow oil; yield 75 %. H NMR (CDCl
3
,
H), 6.39 (dd, J = 7.1, 5.3 Hz, 1 H), 6.77 (dd, J = 7.2, 1.5 Hz, 1 H),
400 MHz): δ = 2.79–2.88 (m, 1 H), 2.95–3.09 (m, 2 H), 3.22–3.15 6.85 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 7.01 (td, J =
(m, 1 H), 3.81 (s, 3 H), 4.90 (d, J = 15.3 Hz, 1 H), 5.02 (d, J =
7.6, 0.9 Hz, 1 H), 7.17 (dd, J = 7.4, 0.7 Hz, 1 H), 7.22 (td, J = 7.7,
1
5.3 Hz, 1 H), 5.02 (d, J = 15.3 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 1.2 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 2 H), 7.98 (dd, J = 5.3, 1.5 Hz,
1
3
H), 7.03 (t, J = 7.3 Hz, 1 H), 7.12 (d, J = 6.9 Hz, 1 H), 7.22–7.28
3
1 H) ppm. C NMR (CDCl , 100 MHz): δ = 14.0, 20.3, 29.6, 43.6,
(
m, 2 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.93 (ddd, J = 9.7, 7.6, 1.8 Hz, 45.1, 54.0, 55.3, 59.3, 109.3, 112.5, 114.3 (2ϫCH), 123.3, 123.4,
1
1
1
1
H), 8.17 (dd, J = 3.5, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl
00 MHz): δ = 26.0, 38.9, 43.9, 53.5 (d, J = 4.7 Hz), 55.3, 109.7,
3
,
124.7, 127.9, 128.6, 128.8 (2 ϫ CH), 130.1, 133.8, 141.9, 147.9,
159.2, 162.6, 177.7 ppm. IR (ATR diamond): ν˜ = 2956, 2929, 2858,
14.3 (2 CH), 121.7 (d, J = 4.2 Hz), 122.2 (d, J = 27.8 Hz), 123.3, 1713, 1608, 1574, 1512, 1486, 1465, 1302, 1273, 1246, 1175, 1106,
–
1
23.5 (d, J = 3.3 Hz), 127.4, 128.9 (2 CH), 129.0, 130.1, 138.9 (d,
1061, 924, 838, 748, 656 cm . HRMS (ESI): calcd. for C26
27 3 2
H N O
J = 4.6 Hz), 142.7, 146.7 (d, J = 15.5 Hz), 159.3, 160.9 (d, J =
[M + H]+ 414.2176; found 414.2180.
2
1
9
40.8 Hz), 176.1 ppm. IR (ATR diamond): ν˜ = 3299, 2932, 1740,
1
[
(
Ј-Butyl-1-(4-methoxybenzyl)-2Ј,3Ј-dihydro-1ЈH-spiro[indoline-3,4Ј-
587, 1507, 1468, 1455, 1430, 1366, 1325, 1263, 1194, 1178, 1061,
1
1,8]naphthyridin]-2-one (15): Yellow oil; yield = 90%. H NMR
CDCl , 400 MHz): δ = 1.02 (t, J = 7.3 Hz, 3 H), 1.42–1.52 (m, 2
H), 1.70–1.78 (m, 2 H), 2.14–2.19 (m, 2 H), 3.49–3.55 (m, 1 H),
-(3-Bromopropyl)-3-(2-fluoropyridin-3-yl)-1-(4-methoxybenzyl)- 3.65–3.75 (m, 1 H), 3.80 (s, 3 H), 3.81–3.85 (m, 1 H), 4.04–4.11 (m,
–
1
68, 823, 809, 798, 785 cm . HRMS (ESI): calcd. for
+
3
23 2 2
C H20FN O [M + H] 455.0765; found 455.0761.
3
1
indolin-2-one (12): Yellow oil; yield 70 %. H NMR (CDCl
3
,
1 H), 4.91 (q, J = 15.4 Hz, 2 H), 6.34 (dd, J = 7.4, 4.9 Hz, 1 H),
400 MHz): δ = 1.41–1.56 (m, 1 H), 1.67–1.79 (m, 1 H), 2.46–2.58 6.62 (dd, J = 7.4, 1.8 Hz, 1 H), 6.85 (d, J = 7.9 Hz, 1 H), 6.88 (d,
(
m, 2 H), 3.30–3.39 (m, 2 H), 3.80 (s, 3 H), 4.94 (d, J = 15.3 Hz, 1
J = 8.7 Hz, 2 H), 7.01–7.09 (m, 2 H), 7.22 (td, J = 7.7, 1.5 Hz, 1
1
3
H), 4.99 (d, J = 15.3 Hz, 1 H), 6.87 (d, J = 7.9 Hz, 1 H), 6.90 (d, H), 7.27 (d, J = 8.7 Hz, 2 H), 7.27 (d, J = 8.7 Hz, 1 H) ppm.
J = 8.7 Hz, 2 H), 6.99–7.07 (m, 2 H), 7.19–7.30 (m, 2 H), 7.34 (d, NMR (CDCl , 100 MHz): δ = 14.2, 20.4, 29.3, 30.7, 42.8, 43.2,
J = 8.6 Hz, 2 H), 8.00 (ddd, J = 9.7, 7.6, 1.8 Hz, 1 H), 8.14 (ddd, 48.7, 50.2, 55.3, 109.2, 111.3, 114.2 (2 CH), 115.2, 123.0, 124.0,
J = 4.9, 1.8, 1.2 Hz, 1 H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 128.0, 128.2, 128.6 (2 CH), 134.5, 135.0, 142.4, 147.4, 155.4, 159.1,
6.7, 33.1, 34.4, 43.8, 52.5 (d, J = 4.6 Hz), 55.3, 109.4, 114.2 (2
C
3
3
2
179.1 ppm. IR (ATR diamond): ν˜ = 2928, 2870, 2323, 1709, 1609,
CH), 121.6 (d, J = 4.2 Hz), 123.1 (d, J = 27.7 Hz), 123.1, 123.3 (d,
J = 2.7 Hz), 127.7, 128.7, 129.0 (2 CH), 131.0, 139.0 (d, J = 4.8 Hz),
1593, 1488, 1464, 1351, 1304, 1279, 1196, 1178, 1165, 1140, 930,
–
1
919, 900, 871, 764, 750, 694 cm . HRMS (ESI): calcd. for
1
1
1
6
4
42.9, 146.4 (d, J = 15.4 Hz), 159.2, 160.9 (d, J = 241.0 Hz),
77.0 ppm. IR (ATR diamond): ν˜ = 2932, 1708, 1610, 1574, 1512,
486, 1465, 1429, 1303, 1245, 1176, 1103, 1031, 806, 748, 645,
27 29 3 2
C H N O
[M + H]+ 428.2333; found 428.2337.
9
3
Ј-Butyl-1-(4-methoxybenzyl)-6Ј,7Ј,8Ј,9Ј-tetrahydrospiro[indoline-
,5Ј-pyrido[2,3-b]azepin]-2-one (16): Yellow oil; yield 68 %. H
1
31 cm–1. HRMS (ESI): calcd. for C24
71.0974; found 471.0901.
2 2
H22BrFN O
[M + H]+
NMR (CDCl
3
, 400 MHz): δ = 1.02 (t, J = 7.4 Hz, 3 H), 1.41–1.56
(
m, 2 H), 1.65–1.85 (m, 2 H), 1.94–2.04 (m, 2 H), 2.08–2.15 (m, 1
3
-(Bromomethyl)-3-(2-fluoropyridin-3-yl)-1-pentylindolin-2-one (13): H), 2.19–2.30 (m, 1 H), 3.45–3.54 (m, 2 H), 3.73–3.89 (m, 2 H),
1
Yellow oil; yield 90%. H NMR (CDCl
6.9 Hz, 3 H), 1.50–1.31 (m, 4 H), 1.74–1.81 (m, 2 H), 3.78–3.85 (dd, J = 7.6, 1.7 Hz, 1 H), 6.84 (d, J = 7.7 Hz, 1 H), 6.88 (d, J =
m, 2 H), 4.04 (d, J = 10.0 Hz, 1 H), 4.32 (d, J = 10.0 Hz, 1 H), 8.6 Hz, 2 H), 6.97 (t, J = 7.4 Hz, 1 H), 7.12–7.21 (m, 2 H), 7.30 (d,
3
, 400 MHz): δ = 0.94 (t, J
3.80 (s, 3 H), 4.94 (s, 2 H), 6.49 (dd, J = 7.6, 4.6 Hz, 1 H), 6.74
=
(
6
1
3
.96 (dd, J = 8.1, 1.0 Hz, 1 H), 7.10 (td, J = 7.6, 1.0 Hz, 1 H), 7.21
J = 8.9 Hz, 2 H), 8.03 (dd, J = 4.6, 1.7 Hz, 1 H) ppm. C NMR
(CDCl , 100 MHz): δ = 14.2, 20.7, 24.8, 30.7, 33.5, 43.3, 50.6, 51.9,
55.3, 55.9, 109.1, 114.2, 114.3, 121.6, 122.8, 124.5, 127.7, 128.2,
(ddd, J = 7.6, 4.8, 1.9 Hz, 1 H), 7.32–7.43 (m, 2 H), 7.82 (ddd, J
3
1
3
=
9.7, 7.6, 1.8 Hz, 1 H), 8.16 (dt, J = 4.8, 1.6 Hz, 1 H) ppm.
C
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
G. Guillaumet et al.
concentrated in vacuo. The residue was purified by column
FULL PAPER
128.7 (2 CH), 137.4, 139.0, 141.2, 145.2, 159.1, 161.7, 179.3 ppm.
1
IR (ATR diamond): ν˜ = 2928, 2857, 1704, 1608, 1557, 1512, 1483,
chromatography (EtOAc). Yellow oil; yield 90%. H NMR (CDCl
3
,
1
7
465, 1434, 1372, 1246, 1223, 1196, 1174, 1032, 953, 879, 797, 763, 400 MHz): δ = 1.01 (t, J = 7.3 Hz, 3 H), 1.38–1.57 (m, 2 H), 1.63–
–
1
45, 670, 667 cm . HRMS (ESI): calcd. for C28
H
31
N
3
O
2
[M +
1.94 (m, 2 H), 2.09–2.16 (m, 1 H), 2.18–2.24 (m, 1 H), 3.50–3.56
+
H] 442.2489; found 442.2489.
(m, 1 H), 3.67–3.85 (m, 2 H), 3.97–4.04 (m, 1 H), 6.36 (dd, J = 7.4,
4
1
1
1
1
.9 Hz, 1 H), 6.74 (dd, J = 7.4, 1.7 Hz, 1 H), 6.96 (d, J = 7.8 Hz,
1
Ј-Butyl-1-pentyl-1Ј,2Ј-dihydrospiro[indoline-3,3Ј-pyrrolo[2,3-b]pyr-
H), 7.00–7.12 (m, 2 H), 7.19–7.27 (m, 1 H), 8.05 (dd, J = 4.9,
1
3
idin]-2-one (17): Yellow oil; yield 80 %. H NMR (CDCl ,
1
3
3
.8 Hz, 1 H), 9.09 (s, 1 H) ppm. C NMR (CDCl 100 MHz): δ =
4
1
1
00 MHz): δ = 0.93 (t, J = 6.9 Hz, 3 H), 0.99 (t, J = 7.3 Hz, 3 H),
.33–1.43 (m, 4 H), 1.44–1.52 (m, 2 H), 1.64–1.71 (m, 2 H), 1.72–
.81 (m, 2 H), 3.35–3.42 (m, 1 H), 3.60–3.76 (m, 2 H), 3.73 (d, J
4.1, 20.4, 29.3, 30.6, 42.8, 48.7, 50.8, 110.1, 111.3, 115.0, 123.0,
24.2, 128.3, 135.0, 135.3, 140.5, 147.1, 155.2, 181.7 ppm. IR (ATR
diamond): ν˜ = 3180, 3077, 2956, 2926, 2871, 1699, 1616, 1502,
1
6
=
9.3 Hz, 1 H), 3.81–3.88 (m, 1 H), 3.95 (d, J = 9.3 Hz, 1 H), 6.37
dd, J = 7.1, 5.3 Hz, 1 H), 6.76 (dd, J = 7.2, 1.6 Hz, 1 H), 6.92 (d,
J = 7.8 Hz, 1 H), 7.03 (td, J = 7.6, 0.8 Hz, 1 H), 7.17 (dd, J = 7.4,
.8 Hz, 1 H), 7.28–7.32 (m, 1 H), 7.95 (dd, J = 5.3, 1.5 Hz, 1 H)
470, 1427, 1387, 1353, 1294, 1191, 1169, 1041, 798, 786, 729, 684,
(
–
1
+
21 3 2
66 cm . HRMS (ESI): calcd. for C19H N O [M + H] 308.1757;
found 308.1754.
0
13
ppm. C NMR (CDCl
3
, 100 MHz): δ = 14.0 (2 CH
7.1, 29.0, 29.6, 40.3, 45.1, 53.9, 59.3, 108.5, 112.4, 123.1, 123.4,
24.7, 128.6, 130.0, 134.0, 142.2, 147.8, 162.6, 177.4 ppm. IR (ATR
3
), 20.2, 22.3, General Method to Prepare Compounds 21–22: In a 5 mL micro-
2
1
wave reaction vial, compound 18 or 19 (0.40 mmol, 1 equiv.) was
dissolved in trifluoroacetic acid (2 mL). The reaction mixture was
subjected to microwave irradiation with stirring at 100 °C for
30 min. After the system had cooled down to room temperature,
trifluoroacetic acid was removed under reduced pressure. The resi-
due was then purified by column chromatography on silica gel (pe-
diamond): ν˜ = 2955, 2929, 2859, 1713, 1606, 1487, 1464, 1354,
–1
1324, 1281, 1137, 1098, 750, 686, 648 cm . HRMS (ESI): calcd.
+
for C23
29 3
H N O [M + H] 364.2383; found 364.2386.
1
[
4
,1Ј-Bis(4-methoxybenzyl)-1Ј,2Ј-dihydrospiro[indoline-3,3Ј-pyrrolo-
troleum ether/EtOAc/Et
3
N 7:3:1 to 0:10:1) to provide the expected
1
2,3-b]pyridin]-2-one (18): Yellow oil; yield 75%. H NMR (CDCl
00 MHz): δ = 3.61 (d, J = 9.4 Hz, 1 H), 3.80 (s, 3 H), 3.81 (s, 3
H), 3.91 (d, J = 9.4 Hz, 1 H), 4.51 (d, J = 14.9 Hz, 1 H), 4.79 (d, 1-(4-Methoxybenzyl)-1Ј,2Ј-dihydrospiro[indoline-3,3Ј-pyrrolo[2,3-b]-
3
,
product in excellent yield.
1
J = 15.3 Hz, 1 H), 4.91 (d, J = 14.8 Hz, 1 H), 5.01 (d, J = 15.3 Hz, pyridin]-2-one (21): M.p. 176 °C; yield 95 %. H NMR (CDCl
H), 6.46 (dd, J = 7.2, 5.2 Hz, 1 H), 6.79–6.83 (m, 2 H), 6.89 (dd, 400 MHz): δ = 3.81 (s, 3 H), 3.85 (d, J = 9.3 Hz, 1 H), 4.21 (d, J
J = 8.6, 6.7 Hz, 4 H), 6.98 (td, J = 7.6, 1.0 Hz, 1 H), 7.10 (dd, J = = 9.3 Hz, 1 H), 4.81 (d, J = 15.3 Hz, 1 H), 4.98 (s, 1 H), 5.04 (d, J
.5, 1.4 Hz, 1 H), 7.19 (td, J = 7.7, 1.3 Hz, 1 H), 7.28 (d, J = = 15.3 Hz, 1 H), 6.51 (dd, J = 7.3, 5.2 Hz, 1 H), 6.82–6.90 (m, 2
.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 8.03 (dd, J = 5.3, 1.5 Hz, H), 6.90 (d, J = 8.6 Hz, 2 H), 7.02 (td, J = 7.5, 1.0 Hz, 1 H), 7.22
H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 43.6, 48.7, 53.8, 55.3 (td, J = 7.6, 1.2 Hz, 2 H), 7.31 (d, J = 8.6 Hz, 2 H), 7.96 (dd, J =
), 58.8, 109.3, 113.0, 114.0 (2 CH), 114.3 (2ϫCH), 123.3,
23.5, 124.6, 127.8, 128.6, 128.7 (2 CH), 129.3 (2 CH), 129.3, 130.5, 54.4, 55.3, 55.8, 109.3, 114.1, 114.3 (2 CH), 123.4, 123.6, 123.6,
33.6, 141.9, 147.9, 158.9, 159.2, 162.4, 177.6 ppm. IR (ATR dia- 127.9, 128.7, 128.8 (2 CH), 130.9, 133.5, 141.9, 148.0, 159.2, 164.1,
3
,
1
7
8
1
3
1
3
(2 CH
3
3
5.2, 1.6 Hz, 1 H) ppm. C NMR (CDCl , 100 MHz): δ = 43.6,
1
1
mond): ν˜ = 2930, 2835, 1713, 1608, 1575, 1511, 1486, 1464, 1379, 177.6 ppm. IR (ATR diamond): ν˜ = 3151, 2915, 1708, 1608, 1592,
–
1
1
307, 1273, 1244, 1178, 1031, 917, 749, 643 cm . HRMS (ESI):
1508, 1486, 1463, 1441, 1379, 1362, 1250, 1121, 1108, 944, 930,
+
–1
calcd. for C30
H
27
N
3
O
3
[M + H] 478.2125; found 478.2127.
907, 809, 776, 760, 674 cm . HRMS (ESI): calcd. for C22
[
19 3 2
H N O
M + H]+ 358.1550; found 358.1554.
1
[
(
3
1
,1Ј-Bis(4-methoxybenzyl)-2Ј,3Ј-dihydro-1ЈH-spiro[indoline-3,4Ј-
1
1,8]naphthyridin]-2-one (19): Yellow oil; yield 78 %. H NMR
CDCl , 400 MHz): δ = 2.08–2.23 (m, 2 H), 3.42–3.48 (m, 1 H), naphthyridin]-2-one (22): M.p. 193 °C; yield 98 %. H NMR
.80 (s, 3 H), 3.83 (s, 3 H), 3.86–4.40 (m, 1 H), 4.88 (d, J = 15.4 Hz, (CDCl , 400 MHz): δ = 2.11–2.27 (m, 2 H), 3.58–3.69 (m, 1 H),
H), 4.95 (d, J = 15.3 Hz, 1 H), 5.09 (d, J = 15.2 Hz, 1 H), 6.41 3.80 (s, 3 H), 4.09–4.15 (m,1 H), 4.88 (d, J = 15.4 Hz, 1 H), 4.93
1-(4-Methoxybenzyl)-2Ј,3Ј-dihydro-1ЈH-spiro[indoline-3,4Ј-[1,8]-
1
3
3
(
dd, J = 7.4, 4.9 Hz, 1 H), 6.69 (dd, J = 7.4, 1.8 Hz, 1 H), 6.85 (d, (d, J = 15.3 Hz, 1 H), 6.46 (dd, J = 7.4, 5.3 Hz, 1 H), 6.78 (dd, J
J = 8.0 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 = 7.4, 1.7 Hz, 1 H), 6.84–6.92 (m, 3 H), 6.98 (s, 1 H), 7.09 (ddd, J
H), 6.98–7.09 (m, 2 H), 7.22 (td, J = 7.6, 1.9 Hz, 1 H), 7.26 (d, J = 14.0, 7.5, 1.3 Hz, 2 H), 7.21–7.31 (m, 3 H), 7.86 (dd, J = 5.3,
1
3
=
1
8.6 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 2 H), 8.08 (dd, J = 4.9, 1.8 Hz,
H) ppm. 13C NMR (CDCl
100 MHz): δ = 30.7, 42.0, 43.3, 50.3, 43.4, 49.2, 55.3, 109.5, 112.4, 114.3 (2 CH), 116.5, 123.2, 123.9,
), 109.2, 112.0, 113.9 (2 CH), 114.2 (2ϫCH), 127.8, 128.7 (2 CH), 133.4, 137.1, 142.4, 143.9, 154.8, 159.2,
15.3, 123.0, 124.0, 128.0, 128.2, 128.6 (2 CH), 128.7, 128.9 (2 CH), 178.3 ppm. IR (ATR diamond): ν˜ = 3150, 2928, 1706, 1610, 1593,
30.8, 134.4, 135.2, 142.3, 147.4, 155.5, 158.7, 159.1, 178.9 ppm. 1512, 1486, 1464, 1414, 1349, 1295, 1250, 1200, 1171, 1123, 1067,
3
1.7 Hz, 1 H) ppm. C NMR (CDCl , 100 MHz): δ = 30.3, 26.6,
3
5
1
1
0.8, 55.3 (2 CH
3
–
1
IR (ATR diamond): ν˜ = 2930, 2834, 1706, 1610, 1563, 1510, 1487
944, 931, 905, 817, 761, 744, 721, 674, 647 cm . HRMS (ESI):
1
6
380, 1352, 1301, 1279, 1245, 1173, 1032, 952, 808, 750, 674, 644,
21 cm . HRMS (ESI): calcd. for C31H N O [M + H] 492.2282;
29 2 3
calcd. for C23
21 3 2
H N O
[M + H]+ 372.1707; found 372.1709.
–1
+
Preparation of 3-(2-Fluoropyridin-3-yl)-3-(hydroxymethyl)-1-(4-
methoxybenzyl)indolin-2-one (23): Paraformaldehyde (2.00 g,
found 492.2284.
Preparation of 1Ј-Butyl-2Ј,3Ј-dihydro-1ЈH-spiro[indoline-3,4Ј- 67 mmol) and diisopropylamine (3.77 mL, 26.8 mmol) were added
[
(
0
1,8]naphthyridin]-2-one (20): Trifluoromethanesulfonic acid
0.22 mL, 2.5 mmol) was added to a stirred solution of 15 (0.1 g,
.25 mmol) in dichloromethane (2 mL) and trifluoroacetic acid
at 0 °C to a solution of 3-(2-fluoropyridin-3-yl)-1-(4-meth-
oxybenzyl)indolin-2-one (8; 2.53 g, 6.70 mmol) in THF (20.0 mL).
The reaction mixture was stirred at room temperature for 12 h,
(2 mL). The reaction mixture was stirred at ambient temperature followed by the addition of ammonium chloride solution (10.0 mL)
for 12 h and concentrated in vacuo. The residue was basified with
saturated aqueous sodium hydrogen carbonate and extracted with
ethyl acetate. The organic phase was washed with water and brine,
dried with anhydrous sodium sulfate, and filtered. The filtrate was
and ethyl acetate (100 mL). The organic layer was washed with
water and brine, dried with Na SO , and filtered. The filtrate was
concentrated to dryness in vacuo to give the title compound after
purification by column chromatography (petroleum ether/EtOAc,
2
4
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
–1
5
3
4
:5). M.p. 110 °C; yield 99%. 1H NMR (CDCl
.12 (d, J = 7.9 Hz, 1 H), 3.79 (s, 3 H), 4.05–4.17 (m, 1 H), 4.35–
.46 (m, 1 H), 4.95 (d, J = 15.4 Hz, 1 H), 5.02 (d, J = 15.4 Hz, 1
3
, 400 MHz): δ =
925, 881, 813, 773, 747, 709, 684, 662, 640 cm . HRMS (ESI): calcd.
for C22 19ClN
[M + H]+ 395.1157; found 395.1156.
H
2 3
O
3
-Chloro-3-(2-methoxypyridin-3-yl)-1-pentylindolin-2-one (28): Yel-
, 400 MHz): δ = 0.96 (t, J =
.1 Hz, 3 H), 1.37–1.55 (m, 4 H), 1.74–1.85 (m, 2 H), 3.65 (s, 3 H),
.69–3.80 (m, 1 H), 3.82–3.93 (m, 1 H), 6.91 (d, J = 7.9 Hz, 1 H),
.99 (dd, J = 5.4, 1.6 Hz, 2 H), 7.06 (dd, J = 7.5, 5.0 Hz, 1 H), 7.33
ddd, J = 7.9, 6.4, 2.6 Hz, 1 H), 8.16 (dd, J = 5.0, 1.8 Hz, 1 H),
H), 6.85 (d, J = 7.9 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.95–7.05
m, 1 H), 7.03–7.06 (m, 1 H), 7.22 (td, J = 7.7, 1.4 Hz, 1 H), 7.25–
.29 (m, 1 H), 7.32 (d, J = 8.6 Hz, 2 H), 8.07–8.33 (m, 2 H) ppm.
1
low oil; yield 70%. H NMR (CDCl
3
(
7
3
6
7
13
C NMR (CDCl
3
, 100 MHz): δ = 43.7, 54.6 (d, J = 4.5 Hz), 55.3,
6
5.0, 109.8, 114.1, 114.3 (2 CH), 120.6 (d, J = 28.3 Hz), 121.6 (d,
(
8
J = 4.1 Hz), 123.1, 123.7 (d, J = 2.0 Hz), 127.4, 128.7 (2 CH),
1
3
3
.38 (dd, J = 7.5, 1.8 Hz, 1 H) ppm. C NMR (CDCl , 100 MHz):
1
1
28.9, 129.1, 140.5 (d, J = 4.7 Hz), 142.9, 146.6 (d, J = 15.3 Hz),
59.2, 161.3 (d, J = 240.3 Hz), 177.2 ppm. IR (ATR diamond): ν˜
δ = 14.0, 22.4, 27.1, 29.0, 40.6, 53.3, 65.8, 108.5, 116.9, 119.5, 122.8,
23.9, 130.0, 130.5, 138.3, 142.7, 147.2, 159.3, 173.2 ppm. IR (ATR
diamond): ν˜ = 2953, 2930, 2870, 1728, 1610, 1583, 1487, 1464,
428, 1401, 1354, 1258, 1157, 1139, 1114, 1014, 945, 793, 773, 749,
2 2
07, 685, 660 cm . HRMS (ESI): calcd. for C19H21ClN O [M +
1
=
1
3300, 2931, 1708, 1610, 1574, 1513, 1487, 1466, 1432, 1304, 1246,
–
1
177, 1120, 908, 723, 695 cm . HRMS (ESI): calcd. for
1
7
+
C
22
H
19FN
2
O
3
[M + H] 379.1452; found 379.1451.
General Method to Prepare Compounds 25 and 26: Compound 4 or 5
8.97 mmol) was added to a solution of sodium methoxide (8.0 mL,
5.9 mmol, 4.0 equiv., 25% in methanol) in methanol (60 mL). The
–
1
+
H] 345.1364; found 345.1361.
(
3
General Method to Prepare Compounds 29 and 30: See general
method to prepare compounds 8 and 9.
reaction mixture was heated at reflux under argon for 12 h and then
diluted with ethyl acetate and water. The organic layer was washed
with water and brine and dried with sodium sulfate. The solvent was
1-(4-Methoxybenzyl)-3-(2-methoxypyridin-3-yl)indolin-2-one (29):
M.p. 135 °C. H NMR (CDCl , 400 MHz): δ = 3.81 (s, 3 H), 3.82
1
3
removed at reduced pressure to give 25 or 26 after purification by (s, 3 H), 4.82 (d, J = 15.4 Hz, 1 H), 4.85 (s, 1 H), 5.08 (d, J =
column chromatography (petroleum ether/EtOAc, 7:3).
15.3 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 6.87–6.92 (m, 3 H), 6.97
td, J = 7.5, 0.7 Hz, 1 H), 7.06 (d, J = 7.4 Hz, 1 H), 7.20 (t, J =
(
3
-Hydroxy-1-(4-methoxybenzyl)-3-(2-methoxypyridin-3-yl)indolin-2-
1
7.7 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 2 H), 7.44 (dd, J = 7.3, 1.8 Hz,
one (25): M.p. 152 °C; yield 95%. H NMR (CDCl
=
1
J = 8.7 Hz, 2 H), 6.95–7.01 (m, 2 H), 7.07 (d, J = 7.2 Hz, 1 H),
7
3
, 400 MHz): δ
3.59 (s, 3 H), 3.81 (s, 3 H), 3.86 (br. s, 1 H), 4.77 (d, J = 15.3 Hz,
H), 5.03 (d, J = 15.3 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 6.90 (d,
1
3
1
1
1
1
3
H), 8.14 (dd, J = 5.0, 1.9 Hz, 1 H) ppm. C NMR (CDCl ,
00 MHz): δ = 43.5, 47.9, 53.5, 55.3, 108.9, 114.1 (2 CH), 116.9,
20.1, 122.5, 124.0, 128.0, 128.1, 128.7, 129.0 (2 CH), 138.8, 143.4,
45.2, 159.1, 161.9, 175.8 ppm. IR (ATR diamond): ν˜ = 2953, 1707,
.25 (td, J = 7.8, 1.1 Hz, 1 H), 7.37 (d, J = 8.7 Hz, 2 H), 8.08 (dd,
1
3
1610, 1585, 1513, 1487, 1465, 1438, 1412, 1348, 1304, 1273, 1246,
1
for C22
J = 7.4, 1.8 Hz, 1 H), 8.12 (dd, J = 4.9, 1.5 Hz, 1 H) ppm.
C
–
1
177, 1111, 1028, 906, 874, 749, 726, 655 cm . HRMS (ESI): calcd.
NMR (CDCl
2 CH), 116.9, 122.8, 123.0, 124.2, 127.8, 129.1 (2 CH), 129.8,
30.0, 135.8, 143.6, 145.5, 159.2, 160.1, 176.7 ppm. IR (ATR dia-
mond): ν˜ = 3319, 3015, 2952, 1702, 1611, 1518, 1489, 1468, 1436,
3
, 100 MHz): δ = 43.6, 53.4, 55.3, 75.5, 109.2, 114.4
[M + H]+ 361.1547; found 361.1546.
20 2 3
H N O
(
1
3-(2-Methoxypyridin-3-yl)-1-pentylindolin-2-one (30): M.p. 87 °C.
H NMR (CDCl , 400 MHz): δ = 0.94 (t, J = 7.0 Hz, 3 H), 1.37–
1
3
1
7
406, 1315, 1248, 1186, 1176, 1028, 1007, 972, 957, 821, 788, 758,
42, 709, 666, 629 cm . HRMS (ESI): calcd. for C22H N O [M
20 2 4
1.47 (m, 4 H), 1.72–1.80 (m, 2 H), 3.64–3.77 (m, 1 H), 3.80–3.90
(m, 1 H), 3.88 (s, 3 H), 4.78 (s, 1 H), 6.84–6.92 (m, 2 H), 6.99 (t, J
= 7.5 Hz, 1 H), 7.08 (d, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.7 Hz, 1 H),
–1
+
+
H] 377.1496; found 377.1493.
7
.40 (dd, J = 7.3, 1.7 Hz, 1 H), 8.12 (dd, J = 5.0, 1.8 Hz, 1 H) ppm.
3
-Hydroxy-3-(2-methoxypyridin-3-yl)-1-pentylindolin-2-one (26):
1
3
1
C NMR (CDCl , 100 MHz): δ = 14.0, 22.4, 27.2, 29.1, 40.2, 47.7,
M.p. 104 °C; yield 96%. H NMR (CDCl
J = 7.0 Hz, 3 H), 1.32–1.51 (m, 4 H), 1.62–1.83 (m, 2 H), 3.58–
.69 (m, 1 H), 3.73 (s, 3 H), 3.79–3.91 (m, 1 H), 3.85 (s, 1 H), 6.90
3
, 400 MHz): δ = 0.95 (t,
3
5
1
1
8
3.5, 108.2, 116.9, 120.4, 122.3, 124.1, 128.1, 128.9, 138.5, 143.7,
46.0, 161.9, 175.6 ppm. IR (ATR diamond): ν˜ = 2953, 2930, 1709,
3
610, 1586, 1487, 1464, 1411, 1355, 1306, 1186, 1155, 1092, 1019,
(d, J = 7.8 Hz, 1 H), 6.98 (ddd, J = 12.5, 7.5, 2.9 Hz, 2 H), 7.08
–
1
22 2 2
97, 780, 748, 727, 698 cm . HRMS (ESI): calcd. for C19H N O
(dd, J = 7.3, 0.9 Hz, 1 H), 7.32 (td, J = 7.7, 1.3 Hz, 1 H), 8.05 (dd,
+
1
3
[M + H] 311.1754; found 311.1752.
J = 7.4, 1.9 Hz, 1 H), 8.10 (dd, J = 5.0, 1.9 Hz, 1 H) ppm.
C
3
NMR (CDCl , 100 MHz): δ = 14.0, 22.4, 27.2, 29.1, 40.3, 53.3,
General Method to Prepare Compounds 31 and 32: Aqueous HCl
solution (3 m, 20 mL) was added to a solution of 29 or 30
7
1
2
1
5.5, 108.4, 116.9, 122.8, 123.0, 124.3, 129.8, 130.1, 135.8, 143.9,
45.4, 160.0, 176.5 ppm. IR (ATR diamond): ν˜ = 3302, 3063, 2930,
870, 1699, 1611, 1588, 1490, 1463, 1449, 1402, 1359, 1210, 1179,
(
5.3 mmol) in 1,4-dioxane (20 mL). The reaction mixture was
heated at 80 °C overnight. The solution was basified to pH = 8
with NaOH solution (1 n) and extracted with ethyl acetate. The
–1
119, 1065, 1013, 962, 948, 787, 772, 749, 685 cm . HRMS (ESI):
+
22 2 3
calcd. for C19H N O [M + H] 327.1703; found 327.1702.
combined organic layers were dried with MgSO
to yield 31 or 32, each as a white solid, after purification by column
chromatography (CH Cl /MeOH, 95:5).
4
and concentrated
General Method to Prepare Compounds 27 and 28: See general
method to prepare compounds 6 and 7.
2
2
3
-Chloro-1-(4-methoxybenzyl)-3-(2-methoxypyridin-3-yl)indolin-2-one 1-(4-Methoxybenzyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)indolin-2-one
1
1
(
(
27): Yellow oil; yield 75%. H NMR (CDCl
s, 3 H), 3.82 (s, 3 H), 4.90 (d, J = 15.3 Hz, 1 H), 5.03 (d, J =
5.4 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 15.6 Hz, 1 H), 6.21 (t, J = 6.7 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 1 H),
.96–7.01 (m, 2 H), 7.08 (dd, J = 7.5, 5.0 Hz, 1 H), 7.25 (ddd, J = 6.86 (d, J = 8.6 Hz, 2 H), 6.97 (t, J = 7.4 Hz, 1 H), 7.09 (dd, J =
.8, 7.0, 2.1 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 8.17 (dd, J = 5.0, 6.5, 1.9 Hz, 1 H), 7.15–7.21 (m, 2 H), 7.38 (dd, J = 7.8, 4.2 Hz, 3
3
, 400 MHz): δ = 3.48
(31): M.p. 210 °C; yield 65%. H NMR (CDCl
3
, 400 MHz): δ =
3.77 (s, 3 H), 4.83 (d, J = 15.5 Hz, 1 H), 4.82 (s, 1 H), 5.11 (d, J =
1
6
7
1
1
1
1
1
13
13
.8 Hz, 1 H), 8.41 (dd, J = 7.5, 1.8 Hz, 1 H) ppm. C NMR (CDCl
3
,
H), 12.73 (s, 1 H) ppm. C NMR (CDCl
3
, 100 MHz): δ = 43.4,
00 MHz): δ = 43.9, 53.4, 55.3, 65.9, 109.3, 114.2 (2 CH), 116.9,
48.2, 55.2, 106.4, 109.0, 114.1 (2 CH), 122.4, 123.9, 128.0, 128.1,
19.3, 123.0, 123.7, 127.7, 129.2 (2 CH), 129.9, 130.5, 138.4, 142.4, 128.4, 128.7, 128.8 (2 CH), 134.0, 140.4, 143.6, 159.0, 163.7,
47.2, 159.3, 159.4, 173.4 ppm. IR (ATR diamond): ν˜ = 2951, 2836, 175.7 ppm. IR (ATR diamond): ν˜ = 2918, 1980, 1702, 1642, 1610,
728, 1610, 1513, 1487, 1464, 1401, 1304, 1246, 1177, 1163, 1031,
1513, 1486, 1351, 1318, 1253, 1221, 1175, 1052, 1031, 953, 922,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
G. Guillaumet et al.
The residue was purified by column chromatography (petroleum
FULL PAPER
–1
7
94, 764, 698, 657, 646 cm . HRMS (ESI): calcd. for C21
18 2 3
H N O
M + H]+ 347.1390; found 347.1387.
ether/EtOAc 3:7). M.p. 246 °C; yield 87%. H NMR ([D
1
[
6
]DMSO,
4
00 MHz): δ = 4.72 (d, J = 9.4 Hz, 1 H), 4.85 (d, J = 9.4 Hz, 1 H),
3
1
7
2
1
2
2
1
-(2-Oxo-1,2-dihydropyridin-3-yl)-1-pentylindolin-2-one (32): M.p.
30 °C; yield 70%. H NMR (CDCl 400 MHz): δ = 0.93 (t, J =
3
.0 Hz, 3 H), 1.31–1.48 (m, 4 H), 1.70–1.85 (m, 2 H), 3.33–4.11 (m,
H), 4.83 (s, 1 H), 6.23 (t, J = 6.7 Hz, 1 H), 6.89 (d, J = 7.8 Hz,
1
6.88 (dd, J = 7.3, 5.1 Hz, 1 H), 6.96 (d, J = 7.8 Hz, 1 H), 7.00 (td,
J = 7.6, 1.0 Hz, 1 H), 7.19 (dd, J = 7.5, 1.2 Hz, 1 H), 7.23 (dd, J
=
7.3, 1.7 Hz, 1 H), 7.28 (td, J = 7.7, 1.3 Hz, 1 H), 8.07 (dd, J =
1
3
5
.1, 1.7 Hz, 1 H), 10.70 (s, 1 H) ppm. C NMR ([D
100 MHz): δ = 56.6, 77.1, 110.4, 118.0, 122.9 (2 C), 124.5, 129.6,
32.3, 133.4, 142.5, 148.3, 168.6, 178.2 ppm. IR (ATR diamond):
ν˜ = 3068, 3023, 2796, 1711, 1618, 1471, 1458, 1366, 1235, 1213,
6
]DMSO,
H), 7.00 (t, J = 7.5 Hz, 1 H), 7.19–7.25 (m, 2 H), 7.28–7.33 (m,
H), 12.81 (s, NH) ppm. 1 C NMR (CDCl
3
3
100 MHz): δ = 14.0,
1
2.4, 27.0, 29.1, 40.2, 47.6, 106.5, 108.2, 122.3, 124.2, 128.0, 128.8,
29.0, 133.8, 139.9, 143.9, 164.0, 175.6 ppm. IR (ATR diamond):
1
6
149, 1096, 1014, 981, 929, 866, 852, 810, 742, 731, 718, 698, 642,
03 cm . HRMS (ESI): calcd. for C14H N O [M + H] 239.0815;
10 2 2
ν˜ = 2960, 2924, 2855, 1714, 1644, 1621, 1607, 1567, 1488, 1463,
–
1
+
1
7
351, 1309, 1254, 1197, 1179, 1165, 1091, 955, 929, 920, 810, 797,
–
1
found 239.0819.
General Method To Prepare Compounds 35 and 36: A solution of 3-
2-fluoropyridin-3-yl)-1-(4-methoxybenzyl)indolin-2-one (8; 1.00 g,
.10 mmol) and either methyl bromoacetate (0.44 mL, 4.60 mmol)
64, 754, 733, 724, 696, 640 cm . HRMS (ESI): calcd. for
[M + H]+ 297.1598; found 297.1594.
18 20 2 2
C H N O
(
3
General Method to Prepare Compounds 24 and 33: Cs
4
2 3
CO (1.3 g,
mmol) and chloroiodomethane (2.22 mL, 3 mmol) was added to
or methyl bromopropionate (4.60 mmol) in THF (20.0 mL) was de-
gassed by bubbling argon through it. Sodium hydride (0.19 g,
a solution of 31 or 32 (2 mmol) in DMF (5 mL). The reaction
mixture was stirred at room temperature overnight and then diluted
with ethyl acetate and water. After decantation, the aqueous phase
was extracted twice with ethyl acetate. The combined organic layers
were washed with water and brine and dried with sodium sulfate.
The solvent was removed under reduced pressure, and the residue,
after purification by column chromatography (petroleum ether/
EtOAc, 8:2 to 5:5), afforded 24 or 33, each as a white solid.
4
2
.60 mmol) was added at 0 °C. The mixture was stirred at 0 °C for
h and quenched with ammonium chloride solution. The mixture
was poured into water (150 mL) and extracted with ethyl acetate
200 mL). The organic layer was washed with water, dried with so-
(
dium sulfate, and filtered. The filtrate was concentrated in vacuo
to dryness. The residue was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 8:2) to afford 35 or 36.
1
Ј-(4-Methoxybenzyl)-2H-spiro[furo[2,3-b]pyridine-3,3Ј-indolin]-2Ј-
1
Methyl 2-[3-(2-Fluoropyridin-3-yl)-1-(4-methoxybenzyl)-2-oxo-
indolin-3-yl]acetate (35): White oil; yield 98%. H NMR (CDCl
one (24): M.p. 80 °C; yield 80%. H NMR (CDCl
3
, 400 MHz): δ =
1
3
,
3
5
7
.81 (s, 3 H), 4.76 (d, J = 9.1 Hz, 1 H), 4.81 (d, J = 15.3 Hz, 1 H),
.03 (d, J = 15.3 Hz, 1 H), 5.04 (d, J = 9.1 Hz, 1 H), 6.81 (dd, J =
.3, 5.1 Hz, 1 H), 6.87–6.93 (m, 3 H), 7.02–7.10 (m, 2 H), 7.14 (dd,
400 MHz): δ = 3.41 (d, J = 16.2 Hz, 1 H), 3.49 (s, 3 H), 3.66 (d, J
=
16.2 Hz, 1 H), 3.81 (s, 3 H), 4.90 (d, J = 15.5 Hz, 1 H), 5.08 (d,
J = 15.5 Hz, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 6.89 (d, J = 8.7 Hz,
2 H), 7.03 (td, J = 7.6, 0.8 Hz, 1 H), 7.17 (ddd, J = 7.5, 4.8, 1.8 Hz,
1
J = 7.4, 0.8 Hz, 1 H), 7.24–7.29 (m, 1 H), 7.31 (d, J = 8.7 Hz, 2
H), 8.15 (dd, J = 5.1, 1.7 Hz, 1 H) ppm. 1 C NMR (CDCl
3
3
,
H), 7.22 (td, J = 7.8, 1.1 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.38
1
1
1
2
1
7
00 MHz): δ = 43.8, 53.4, 55.3, 56.5, 77.4, 109.6, 114.3 (2 CH),
(
d, J = 7.5 Hz, 1 H), 7.71 (ddd, J = 9.8, 7.7, 1.8 Hz, 1 H), 8.14 (dt,
17.4, 122.1, 123.6, 123.8, 127.6, 128.8 (2 CH), 129.3, 131.9, 132.8,
42.1, 148.7, 159.3, 169.6, 176.6 ppm. IR (ATR diamond): ν˜ =
913, 2323, 2162, 2050, 1709, 1660, 1612, 1558, 1514, 1492, 1426,
274, 1247, 1206, 1172, 1121, 1027, 931, 905, 867, 827, 788, 760,
1
3
J = 4.8, 1.5 Hz, 1 H) ppm. C NMR (CDCl
3
, 100 MHz): δ = 39.2
d, J = 5.1 Hz), 44.0, 51.5 (d, J = 5.6 Hz), 51.8, 55.3, 109.6, 114.2
2 CH), 121.7 (d, J = 4.3 Hz), 122.2 (d, J = 27.4 Hz), 123.0, 124.0
(
(
–
1
(d, J = 5.8 Hz), 127.7 (2 CH), 128.8, 128.9, 130.3, 139.2 (d, J =
4.7 Hz), 143.3, 146.6 (d, J = 15.6 Hz), 159.1, 161.2 (d, J =
18 2 3
48, 672, 659, 629 cm . HRMS (ESI): calcd. for C22H N O [M
+
+
H] 359.1390; found 359.1394.
2
1
1
40.3 Hz), 169.6, 176.5 ppm. IR (ATR diamond): ν˜ = 2952, 2837,
713, 1610, 1574, 1513, 1487, 1466, 1431, 1352, 1294, 1246, 1199,
177, 1127, 11031, 1014, 886, 827, 750, 731, 695, 648 cm . HRMS
1
Ј-Pentyl-2H-spiro[furo[2,3-b]pyridine-3,3Ј-indolin]-2Ј-one (33):
1
M.p. 109 °C; yield 81%. H NMR (CDCl
J = 7.0 Hz, 3 H), 1.32–1.47 (m, 4 H), 1.72–1.79 (m, 2 H), 3.69–
3
, 400 MHz): δ = 0.93 (t,
–
1
+
(
2 4
ESI): calcd. for C24H21FN O [M + H] 421.1558; found 421.1558.
3
6
.89 (m, 2 H), 4.72 (d, J = 9.1 Hz, 1 H), 4.98 (d, J = 9.1 Hz, 1 H),
.80 (dd, J = 7.4, 5.1 Hz, 1 H), 6.96 (d, J = 7.9 Hz, 1 H), 7.08 (ddd,
Methyl 3-[3-(2-Fluoropyridin-3-yl)-1-(4-methoxybenzyl)-2-oxo-
indolin-3-yl]propanoate (36): White oil; yield 80 %. H NMR
(CDCl , 400 MHz): δ = 1.96–2.06 (m, 1 H), 2.19–2.27 (m, 1 H),
3
2.64–2.77 (m, 2 H), 3.59 (s, 3 H), 3.80 (s, 3 H), 4.89 (d, J = 15.3 Hz,
1 H), 5.04 (d, J = 15.3 Hz, 1 H), 6.86 (d, J = 7.9 Hz, 1 H), 6.90 (d,
J = 8.6 Hz, 2 H), 6.97–7.04 (m, 2 H), 7.21 (td, J = 7.8, 1.5 Hz, 1
H), 7.25–7.27 (m, 1 H), 7.35 (d, J = 8.6 Hz, 2 H), 8.03 (ddd, J =
1
J = 8.7, 5.2, 1.3 Hz, 2 H), 7.15 (dd, J = 7.4, 0.9 Hz, 1 H), 7.35 (td,
1
3
J = 7.7, 1.3 Hz, 1 H), 8.12 (dd, J = 5.1, 1.6 Hz, 1 H) ppm.
NMR (CDCl , 100 MHz): δ = 14.0, 22.3, 27.1, 29.0, 40.5, 56.4,
7.4, 108.8, 117.3, 122.1, 123.9, 123.9, 129.3, 132.1, 132.7, 142.5,
C
3
7
1
2
1
6
48.6, 168.6, 176.3 ppm. IR (ATR diamond): ν˜ = 3059, 2955, 2930,
858, 1694, 1610, 1599, 1490, 1465, 1422, 1355, 1315, 1228, 1183,
1
3
160, 1115, 1102, 1088, 994, 948, 867, 789, 754, 724, 711, 685, 9.5, 7.7, 1.6 Hz, 1 H), 8.14 (d, J = 4.8 Hz, 1 H) ppm. C NMR
–1
+
54 cm . HRMS (ESI): calcd. for C19
H
20
N
2
O
2
[M + H] 309.1598; (CDCl
3
, 100 MHz): δ = 28.4, 30.6, 43.8, 51.7, 52.2 (d, J = 4.5 Hz),
found 309.1602.
Preparation of 2H-Spiro[furo[2,3-b]pyridine-3,3Ј-indolin]-2Ј-one
34): Trifluoromethanesulfonic acid (1.24 mL, 10 equiv.) was added
to a stirred solution of 1Ј-(4-methoxybenzyl)-2H-spiro[furo[2,3-b]-
pyridine-3,3Ј-indolin]-2Ј-one (32; 0.50 g, 1.4 mmol) in dichloro-
methane (5 mL) and trifluoroacetic acid (5 mL). The reaction mix-
ture was stirred at ambient temperature for 12 h and concentrated
in vacuo. The residue was basified with saturated aqueous sodium
hydrogen carbonate and extracted with ethyl acetate. The organic
phase was washed with water and brine, dried with anhydrous so-
dium sulfate, and filtered. The filtrate was concentrated in vacuo.
55.2, 109.5, 114.2 (2 CH), 121.6 (d, J = 4.2 Hz), 122.9 (d, J =
2
1
1
7.8 Hz), 123.1, 123.5 (d, J = 2.5 Hz), 127.6, 128.8, 128.9 (2 CH),
30.4, 139.0 (d, J = 4.7 Hz), 143.0, 146.5 (d, J = 15.4 Hz), 159.2,
60.9 (d, J = 241.0 Hz), 172.8, 176.7 ppm. IR (ATR diamond): ν˜
(
=
2951, 2837, 1709, 1610, 1574, 1513, 1486, 1466, 1430, 1349, 1302,
2
6
4
46, 1175, 1102, 1029, 022, 906, 827, 805, 750, 730, 693, 646,
–
1
+
32 cm . HRMS (ESI): calcd. for C25
35.1715; found 435.1713.
2 4
H23FIN O [M + H]
General Method To Prepare Compounds 37 and 38: NaOH (2 n,
2 mL) was added to a mixture of 35 or 36 (1 mmol) in MeOH
(15 mL). The solution was stirred at room temperature for 12 h,
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
and then the solvent was removed. The residue was dissolved in
146.45 (d, J = 15.5 Hz), 159.2, 161.1 (d, J = 240.7 Hz), 178.0 ppm.
IR (ATR diamond): ν˜ = 2923, 1730, 1709, 1610, 1431, 1414, 1579,
H
2
O (10 mL), and the mixture was acidified to pH = 1 with aque-
ous HCl (10 %). Extractions were performed with CH Cl
0 mL), and the combined organic layers were concentrated in
vacuo to give 37 or 38 in quantitative yield.
2
2
(3 ϫ 1514, 1486, 1379, 1342, 1246, 1221, 1201, 1177, 1103, 1068, 953,
–
1
2
938, 895, 803, 787, 752, 744, 696, 659, 648, 633 cm . HRMS (ESI):
calcd. for C23
H
2 3
21FN O
[M + H]+ 393.1609; found 393.1607.
2
-[3-(2-Fluoropyridin-3-yl)-1-(4-methoxybenzyl)-2-oxoindolin-3-yl]- 3-(2-Fluoropyridin-3-yl)-3-(3-hydroxypropyl)-1-(4-methoxybenzyl)-
1
1
acetic Acid (37): White oil. H NMR (CDCl
(
3
, 400 MHz): δ = 3.50 indolin-2-one (40): White oil; yield 75 %. H NMR (CDCl
3
,
s, 2 H), 3.81 (s, 3 H), 4.93 (d, J = 15.5 Hz, 1 H), 5.02 (d, J =
400 MHz): δ = 1.16–1.25 (m, 1 H), 1.34 (s, 1 H), 1.39–1.47 (m, 1
1
7
5.4 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 2 H), H), 2.36–2.55 (m, 2 H), 3.58–3.62 (m, 2 H), 3.81 (s, 3 H), 4.90 (d,
.04 (t, J = 7.6 Hz, 1 H), 7.21 (dt, J = 6.9, 4.2 Hz, 2 H), 7.32 (d, J J = 15.3 Hz, 1 H), 5.03 (d, J = 15.3 Hz, 1 H), 6.85 (d, J = 7.8 Hz,
=
8.5 Hz, 3 H), 7.77 (ddd, J = 9.6, 7.7, 1.6 Hz, 1 H), 8.16 (d, J = 1 H), 6.89 (d, J = 8.6 Hz, 2 H), 6.97–7.07 (m, 2 H), 7.20 (dd, J =
.4 Hz, 1 H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 39.5, 44.1,
7.6, 1.6 Hz, 1 H), 7.22–7.28 (m, 1 H), 7.35 (d, J = 8.6 Hz, 2 H),
1.1 (d, J = 5.2 Hz), 55.3, 110.0, 114.3 (2 CH), 121.8, 121.9, 123.5, 8.02 (ddd, J = 9.7, 7.6, 1.9 Hz, 1 H), 8.14 (dt, J = 4.9, 1.5 Hz, 1
4
5
1
3
1
3
23.9 (d, J = 4.9 Hz), 127.1, 128.8 (2 CH), 129.2, 130.1, 139.0 (d,
3
H) ppm. C NMR (CDCl , 100 MHz): δ = 26.7, 32.1, 43.8, 52.8
J = 4.4 Hz), 142.7, 146.9 (d, J = 14.7 Hz), 159.2, 160.9 (d, J =
(d, J = 4.4 Hz), 55.3, 62.4, 109.4, 114.2 (2 CH), 121.6 (d, J =
4.2 Hz), 123.0, 123.3 (t, J = 2.8 Hz), 123.6, 127.7, 128.5, 129.0 (2
2
1
6
4
40.8 Hz), 172.0, 177.5 ppm. IR (ATR diamond): ν˜ = 2939, 2835,
722, 1611, 1467, 1247, 1196, 1115, 1020, 983, 930, 813, 757, CH), 131.3, 139.1 (d, J = 4.9 Hz), 143.1, 146.3 (d, J = 15.4 Hz),
64 cm–1. HRMS (ESI): calcd. for C23
07.1402; found 407.1399.
H
19FN
O
[M + H]+ 159.1, 160.97 (d, J = 241.2 Hz), 177.3 ppm. IR (ATR diamond): ν˜
2
4
= 3429, 2933, 1708, 1609, 1575, 1513, 1486, 1466, 1428, 1348, 1302,
–
1
1
244, 1177, 1124, 807, 749, 645 cm . HRMS (ESI): calcd. for
3
-[3-(2-Fluoropyridin-3-yl)-1-(4-methoxybenzyl)-2-oxoindolin-3-yl]-
[M + H]+ 407.1765; found 407.1766.
24 2 3
C H23FN O
1
propanoic Acid (38): M.p. 133 °C. H NMR (CDCl
1.93–2.08 (m, 1 H), 2.24 (ddd, J = 16.5, 11.1, 5.2 Hz, 1 H), 2.68
dtd, J = 24.3, 13.2, 5.1 Hz, 2 H), 3.79 (s, 3 H), 4.89 (d, J = 15.3 Hz,
3
, 400 MHz): δ
General Method To Prepare Compounds 41 and 42: In a 5 mL mi-
crowave reaction vial, compound 39 or 40 (0.30 mmol, 1 equiv.)
was dissolved in THF (2 mL), NaH (1.1 equiv.) was then added,
degassing was performed, and the vial was sealed. The reaction
mixture was subjected to microwave irradiation with stirring at
=
(
1
2
8
H), 5.03 (d, J = 15.3 Hz, 1 H), 6.86–6.91 (m, 2 H), 6.95–7.05 (m,
H), 7.15–7.30 (m, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 8.02 (t, J =
1
3
.0 Hz, 1 H), 8.15 (d, J = 4.7 Hz, 1 H), 9.05 (s, 1 H) ppm.
, 100 MHz): δ = 28.3, 30.3, 43.9, 52.1 (d, J = 4.5 Hz),
5.7, 109.6, 114.3 (2 CH), 121.7 (2 C), 122.8 (d, J = 27.5 Hz), 123.5
d, J = 2.2 Hz), 127.5, 128.9, 129.0 (2 CH), 130.3, 139.1 (d, J =
C
150 °C for 2 h. After the system had cooled down to room tempera-
NMR (CDCl
5
(
3
ture, the THF was removed under reduced pressure. The residue
was then purified by column chromatography on silica gel (petro-
leum ether/EtOAc, 8:2 to 5:5) to provide the expected product.
4
2
1
1
.6 Hz), 142.9, 146.5 (d, J = 15.1 Hz), 159.2, 160.86 (d, J =
41.5 Hz), 176.8, 177.4 ppm. IR (ATR diamond): ν˜ = 2914, 1730,
709, 1610, 1431, 1342, 1306, 1246, 1222, 1201, 1186, 1177, 1167,
1
-(4-Methoxybenzyl)-2Ј,3Ј-dihydrospiro[indoline-3,4Ј-pyrano[2,3-b]-
1
pyridin]-2-one (41): White oil; yield 78 %. H NMR (CDCl
00 MHz): δ = 2.23–2.38 (m, 2 H), 3.81 (s, 3 H), 4.54–4.61 (m, 1
H), 4.87 (d, J = 15.3 Hz, 1 H), 4.96 (d, J = 15.3 Hz, 1 H), 5.18–
3
,
–
1
127, 950, 938, 803, 787, 760, 752, 697, 659, 649, 633 cm . HRMS
4
+
(ESI): calcd. for C24
2 4
H21FN O [M + H] 421.1558; found 421.1558.
5
7
1
6
1
.03 (m, 1 H), 6.78 (dd, J = 7.5, 4.7 Hz, 1 H), 6.84–6.93 (m, 4 H),
General Method To Prepare Compounds 39 and 40: Triethylamine
.01–7.10 (m, 2 H), 7.20–7.35 (m, 3 H), 8.18 (dd, J = 4.7, 1.8 Hz,
(
(
0.58 mmol, 1.2 equiv.) was added to a solution of 37 or 38
0.48 mmol) in THF (8 mL). The mixture was cooled to –10 °C.
1
3
3
H) ppm. C NMR (CDCl , 100 MHz): δ = 31.8, 43.4, 48.1, 55.3,
2.7, 109.4, 114.3 (2 CH), 116.8, 117.7, 123.3, 123.8, 127.8, 128.7,
28.8 (2 CH), 133.7, 137.8, 142.6, 148.1, 159.2, 161.3, 178.5 ppm.
Ethyl chloroformate (0.53 mmol, 1.1 equiv.) was added, and the
solution was stirred at the same temperature for 0.5 h. The precipi-
tate was filtered off and washed with THF (2ϫ 2 mL). The com-
bined filtrates were concentrated in vacuo to give a crude oil, which
IR (ATR diamond): ν˜ = 2921, 2361, 2323, 1705, 1610, 1577, 1513,
1
9
487, 1466, 1434, 1378, 1353, 1273, 1244, 1170, 1103, 1051, 1030,
63, 920, 839, 798, 774, 750, 694, 673, 646 cm . HRMS (ESI):
–
1
was used for further experiments without any purification. NaBH
20 mg, 0.53 mmol) was added at room temperature to a stirred
4
[M + H]+ 373.1547; found 373.1548.
20 3 3
calcd. for C23H N O
(
solution of the mixed anhydride (0.48 mmol) in dry EtOH (5 mL).
The resulting solution was stirred overnight. TLC (petroleum ether/
EtOAc, 5:5) indicated the reaction was complete. The reaction mix-
ture was concentrated in vacuo to give a residue, which was ex-
tracted with EtOAc (3ϫ 10 mL), washed with brine (3ϫ 5 mL),
dried with sodium sulfate, and concentrated in vacuo to give a resi-
due, which was purified by column chromatography (petroleum
ether/EtOAc, 5:5) to give 39 or 40.
1-(4-Methoxybenzyl)-3Ј,4Ј-dihydro-2ЈH-spiro[indoline-3,5Ј-oxepino-
[2,3-b]pyridin]-2-one (42): M.p. 120 °C; yield 90 %. 1H NMR
(CDCl , 400 MHz): δ = 1.99–2.20 (m, 2 H), 2.24–2.38 (m, 1 H),
3
2.39–2.64 (m, 1 H), 3.80 (s, 3 H), 4.16–4.32 (m, 1 H), 4.67–4.77 (m,
1 H), 4.94 (d, J = 15.3 Hz, 1 H), 5.02 (d, J = 15.3 Hz, 1 H), 6.85
(d, J = 7.8 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.95 (dd, J = 7.7,
4.7 Hz, 1 H), 7.00 (td, J = 7.6, 0.9 Hz, 1 H), 7.19 (td, J = 7.8,
1.1 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 2 H), 7.36 (dd, J = 7.7, 1.9 Hz,
1
H), 7.74 (dd, J = 7.5, 0.6 Hz, 1 H), 8.16 (dd, J = 4.7, 1.8 Hz, 1
3
-(2-Fluoropyridin-3-yl)-3-(2-hydroxyethyl)-1-(4-methoxybenzyl)-
1
3
1
H) ppm. C NMR (CDCl
3
, 100 MHz): δ = 26.5, 37.4, 43.3, 55.3,
indolin-2-one (39): M.p. 180 °C; yield 80 %. H NMR (CDCl
00 MHz): δ = 2.20 (s, 1 H), 2.39–2.59 (m, 1 H), 2.76–2.83 (m, 1
H), 3.50–3.65 (m, 2 H), 3.80 (s, 3 H), 4.97 (q, J = 15.4 Hz, 2 H),
3
,
5
1
1
1
8
5.7, 72.0, 109.4, 114.3 (2 CH), 120.1, 122.9, 126.0, 127.2, 127.8,
4
28.2, 128.7 (2 CH), 133.2, 139.4, 141.2, 146.9, 159.2, 165.8,
78.4 ppm. IR (ATR diamond): ν˜ = 2917, 1702, 1607, 1515, 1485,
440, 1297, 1280, 1250, 1199, 1178, 1109, 1041, 1028, 905, 870,
6
7
7
8
4
.85 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 7.01 (td, J =
.6, 0.9 Hz, 1 H), 7.15 (d, J = 7.4 Hz, 1 H), 7.15–7.27 (m, 2 H),
–
1
18, 757, 745, 677, 642, 633 cm . HRMS (ESI): calcd. for
.34 (d, J = 8.7 Hz, 2 H), 7.93 (ddd, J = 9.7, 7.7, 1.8 Hz, 1 H),
[M + H]+ 387.1703; found 387.1708.
.11–8.17 (m, 1 H) ppm. 1 C NMR (CDCl
3
C
24
H
22
N
2
O
3
3
, 100 MHz): δ = 38.1,
3.9, 52.30 (d, J = 4.8 Hz), 55.3, 58.8, 109.6, 114.2 (2 CH), 121.69
3a-(2-Fluoropyridin-3-yl)-8-(4-methoxybenzyl)-3,3a,8,8a-tetrahydro-
2H-furo[2,3-b]indole (43): LiAlH (9 mg, 0.238 mmol) was added to
a cold (0 °C) solution of 35 (0.2 g, 0.476 mmol) in THF (10 mL).
(d, J = 4.2 Hz), 122.8 (d, J = 27.7 Hz), 123.2, 123.5 (d, J = 4.0 Hz),
4
127.5, 128.7, 128.9 (2 CH), 131.3, 139.3 (d, J = 4.8 Hz), 142.5,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
G. Guillaumet et al.
FULL PAPER
The mixture was stirred at 0 °C for 1 h and then treated with brine
cautiously until the evolution of H had ceased. The residue was
purified by column chromatography on silica gel (petroleum ether/
bromopropionate (0.6 mmol) in THF (2 mL) was degassed by bub-
bling argon through it. Sodium hydride (25 mg, 0.6 mmol) was
added at 0 °C. The mixture was stirred at 0 °C for 2 h and quenched
with ammonium chloride solution. The mixture was poured into
water (15 mL) and extracted with ethyl acetate (20 mL). The or-
ganic layer was washed with water, dried with sodium sulfate, and
filtered. The filtrate was concentrated in vacuo to dryness. The resi-
due was purified by column chromatography on silica gel (petro-
leum ether/EtOAc, 9:1 to 7:3) to afford compounds 46–48.
2
1
EtOAc, 8:2) to give 43. M.p. 102 °C; yield 65%. H NMR (CDCl
00 MHz): δ = 2.52–2.57 (m, 1 H), 2.73–2.80 (m, 1 H), 3.68 (ddd,
J = 11.4, 8.7, 4.7 Hz, 1 H), 3.82 (s, 3 H), 4.19 (t, J = 7.8 Hz, 1 H),
.51 (d, J = 15.4 Hz, 1 H), 4.56 (d, J = 15.4 Hz, 1 H), 5.69 (s, 1
H), 6.46 (d, J = 7.8 Hz, 1 H), 6.73 (t, J = 7.4 Hz, 1 H), 6.89 (d, J
8.6 Hz, 2 H), 7.07–7.17 (m, 3 H), 7.32 (d, J = 8.5 Hz, 2 H), 7.69
3
,
4
4
=
1
3
(ddd, J = 9.7, 7.6, 1.8 Hz, 1 H), 8.11 (d, J = 4.8 Hz, 1 H) ppm.
C
Methyl 2-{3-[2-(Butylamino)pyridin-3-yl]-1-(4-methoxybenzyl)-2-
3
NMR (CDCl , 100 MHz): δ = 39.9 (d, J = 3.8 Hz), 48.3, 55.3, 57.7
1
oxoindolin-3-yl}acetate (46): Yellow oil; yield 50 %. H NMR
(d, J = 5.8 Hz), 67.3, 101.9 (d, J = 3.2 Hz), 106.3, 114.0 (2 CH),
(
CDCl
H), 1.65–1.74 (m, 2 H), 3.00 (d, J = 16.9 Hz, 1 H), 3.38–3.53 (m,
H), 3.43 (s, 3 H), 3.78 (s, 3 H), 4.47 (d, J = 16.9 Hz, 1 H), 4.86
d, J = 15.6 Hz, 1 H), 4.92 (d, J = 15.6 Hz, 1 H), 6.41 (dd, J = 7.7,
3
, 400 MHz): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.41–1.56 (m, 2
118.0, 121.5 (d, J = 4.2 Hz), 142.4, 126.0 (d, J = 27.5 Hz), 128.8 (2
CH), 129.0, 129.9, 130.5, 138.8 (d, J = 5.3 Hz), 145.8 (d, J =
5.1 Hz), 150.3, 158.8, 161.1 (d, J = 240.6 Hz) ppm. IR (ATR dia-
mond): ν˜ = 2993, 2953, 2858, 2831, 1980, 1601, 1575, 1486, 1420,
2
(
1
4
7
.8 Hz, 1 H), 6.78–6.88 (m, 3 H), 6.95 (dd, J = 7.7, 1.7 Hz, 1 H),
.14 (t, J = 7.4 Hz, 1 H), 7.20 (dd, J = 7.3, 1.0 Hz, 1 H), 7.24–7.33
1
7
+
384, 1354, 1227, 1078, 958, 94, 924, 876, 863, 849, 823, 804, 761,
–1
3 2
52, 671, 644, 622 cm . HRMS (ESI): calcd. for C23H21FN O [M
1
3
(
m, 3 H), 7.39 (s, 1 H), 8.08 (dd, J = 4.8, 1.6 Hz, 1 H) ppm.
C
+
H] 377.1660; found 377.1655.
3
NMR (CDCl , 100 MHz): δ = 14.0, 20.6, 31.6, 36.7, 41.9, 43.8,
Further elution furnished compound 39 (20% yield).
51.7, 53.6, 55.2, 110.0, 111.9, 114.1 (2 CH), 116.9, 122.7, 125.1,
1
1
1
1
27.5, 128.7 (2 CH), 128.9, 129.8, 136.0, 143.2, 147.2, 157.8, 159.1,
70.8, 178.7 ppm. IR (ATR diamond): ν˜ = 3306, 2955, 2930, 2871,
738, 1691, 1610, 1587, 1513, 1488, 1466, 1420, 1347, 1303, 1247,
General Method To Prepare 44 and 45: In a 5 mL microwave reac-
tion vial, compound 8 or 9 (0.60 mmol, 1 equiv.) was dissolved in
1
,4-dioxane (2 mL). The appropriate amine (10 equiv.) was then
–
1
197, 1175, 1032, 1000, 881, 761, 748, 730, 685 cm . HRMS (ESI):
added, after which the vial was sealed. The reaction mixture was
subjected to microwave irradiation with stirring at 180 °C for 3 h.
After the system had cooled down to room temperature, 1,4-diox-
ane was removed under reduced pressure. The residue was then
purified by column chromatography on silica gel (petroleum ether/
EtOAc, 9:1 to 7:3) to give 44 or 45.
[M + H]+ 474.2387; found 474.2389.
31 3 4
calcd. for C28H N O
Methyl 3-[2-(4-Methoxybenzylamino)pyridin-3-yl]-2-oxo-1-pentyl-
indoline-3-carboxylate (47): Yellow oil; yield = 50%. H NMR
1
(
CDCl
H), 1.78–1.91 (m, 2 H), 3.79 (s, 3 H), 3.81 (s, 3 H), 4.05 (t, J =
.4 Hz, 2 H), 4.61 (d, J = 5.7 Hz, 2 H), 4.92 (s, 1 H), 6.68 (dd, J =
3
, 400 MHz): δ = 0.92 (t, J = 6.9 Hz, 3 H), 1.32–1.43 (m, 4
7
3
-[2-(Butylamino)pyridin-3-yl]-1-(4-methoxybenzyl)indolin-2-one
1
7.2, 5.1 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2 H), 7.15 (t, J = 7.0 Hz, 1
H), 7.21–7.31 (m, 3 H), 7.36 (d, J = 8.2 Hz, 1 H), 7.45 (dd, J =
(
44): Yellow oil; yield 70%. H NMR (CDCl
t, J = 7.3 Hz, 3 H), 1.34–1.51 (m, 2 H), 1.52–1.72 (m, 2 H), 3.27–
.55 (m, 2 H), 3.79 (s, 3 H), 4.80 (d, J = 15.4 Hz, 1 H), 4.81 (s, 1
H), 4.95 (d, J = 15.4 Hz, 1 H), 5.73 (s, 1 H), 6.53 (dd, J = 7.4,
3
, 400 MHz): δ = 0.96
(
3
1
3
7.2, 1.9 Hz, 2 H), 8.20 (dd, J = 5.0, 1.8 Hz, 1 H) ppm. C NMR
(
CDCl , 100 MHz): δ = 13.9, 22.2, 29.0, 29.3, 42.7, 44.8, 55.2, 56.2,
3
9
1
8.1, 109.7, 112.2, 112.4, 113.7 (2 CH), 120.0, 120.4, 122.2, 124.8,
28.8 (2 CH), 132.1, 132.2, 138.6, 139.3, 147.1, 152.7, 156.7,
5
7
.0 Hz, 1 H), 6.82–6.94 (m, 3 H), 7.02 (dd, J = 7.4, 1.3 Hz, 1 H),
.11 (td, J = 7.5, 0.7 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1 H), 7.18–1.31
13
158.5 ppm. IR (ATR diamond): ν˜ = 3430, 2955, 1776, 1611, 1582,
3
(m, 3 H), 8.14 (dd, J = 5.0, 1.7 Hz, 1 H) ppm. C NMR (CDCl ,
1
7
4
566, 1465, 1440, 1420, 1301, 1235, 1205, 1175, 1115, 1092, 931,
70, 734 cm . HRMS (ESI): calcd. for C28
74.2387; found 474.2390.
1
1
1
00 MHz): δ = 14.0, 20.3, 31.7, 41.8, 43.4, 47.9, 55.2, 109.6, 112.5,
14.2 (2 CH), 116.8, 123.0, 125.6, 126.4, 127.5, 128.7, 128.8 (2 CH),
35.6, 143.7, 147.0, 158.2, 159.2, 176.2 ppm. IR (ATR diamond):
–
1
+
31 3 4
H N O [M + H]
ν˜ = 3344, 2955, 2929, 2869, 1695, 1610, 1578, 1512, 1488, 1465,
Methyl 2-{3-[2-(4-Methoxybenzylamino)pyridin-3-yl]-2-oxo-1-pent-
ylindolin-3-yl}acetate (48): Yellow oil; yield 55 %. H NMR
1
6
438, 1303, 1342, 1280, 1246, 1176, 1031, 900, 797, 749, 730, 657,
05 cm . HRMS (ESI): calcd. for C25H N O [M + H] 402.2176;
27 3 2
1
–1
+
(
3
CDCl , 400 MHz): δ = 0.89 (t, J = 6.9 Hz, 3 H), 1.27–1.42 (m, 3
found 402.2176.
H), 1.56–1.75 (m, 2 H), 3.02 (d, J = 16.7 Hz, 1 H), 3.44 (s, 3 H),
3.62–3.71 (m, 2 H), 3.83 (s, 3 H), 4.36 (d, J = 16.7 Hz, 1 H), 4.52
(dd, J = 14.3, 4.1 Hz, 1 H), 4.69 (dd, J = 14.3, 5.9 Hz, 1 H), 6.46
(dd, J = 7.7, 4.8 Hz, 1 H), 6.87–6.94 (m, 3 H), 7.02 (dd, J = 7.7,
1.7 Hz, 1 H), 7.16 (td, J = 7.4, 0.6 Hz, 1 H), 7.21 (dd, J = 7.4,
3
-[2-(4-Methoxybenzylamino)pyridin-3-yl]-1-pentylindolin-2-one
1
(
45): Yellow oil; yield 65%. H NMR (CDCl
t, J = 6.9 Hz, 3 H), 1.27–1.39 (m, 4 H), 1.55–1.68 (m, 2 H), 3.57–
.75 (m, 2 H), 3.82 (s, 3 H), 4.56 (dd, J = 14.0, 3.9 Hz, 1 H), 4.64
3
, 400 MHz): δ = 0.89
(
3
(
dd, J = 14.0, 6.4 Hz, 1 H), 4.75 (s, 1 H), 6.01 (s, 1 H), 6.57 (dd, J 1.2 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2 H), 7.38 (td, J = 7.7, 1.4 Hz, 1
1
3
=
1
7.4, 5.0 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 7.9 Hz,
H), 7.05 (dd, J = 7.4, 1.4 Hz, 1 H), 7.13 (td, J = 7.5, 0.8 Hz, 1 (CDCl
H), 7.64 (s, 1 H), 8.08 (dd, J = 4.8, 1.6 Hz, 1 H) ppm. C NMR
3
, 100 MHz): δ = 14.0, 22.3, 26.6, 29.0, 37.0, 40.5, 45.5, 51.6,
H), 7.21 (d, J = 7.4 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.37 (t, J
53.4, 55.3, 109.1, 112.4, 113.8 (2 CH), 117.2, 122.5, 125.3, 128.0 (2
CH), 130.0, 132.2, 136.0, 143.4, 147.1, 157.3, 158.5, 170.6,
178.3 ppm. IR (ATR diamond): ν˜ = 3299, 2953, 2870, 1740, 1670,
13
=
7.7 Hz, 1 H), 8.15 (dd, J = 5.0, 1.7 Hz, 1 H) ppm. C NMR
(
CDCl , 100 MHz): δ = 13.9, 22.3, 27.0, 29.0, 40.2, 45.7, 47.8, 55.3,
3
1
(
(
1
8
[
08.9, 113.0, 113.9 (2 CH), 117.2, 122.8, 125.6, 126.4, 128.7, 129.1 1610, 1586, 1586, 1509, 1491, 1466, 1365, 1303, 1244, 1196, 1174,
–
1
2 CH), 131.9, 135.6, 144.0, 145.9, 157.8, 158.6, 175.9 ppm. IR
ATR diamond): ν˜ = 3337, 2929, 2859, 1694, 1611, 1592, 1508,
1174, 1153, 1138, 1036, 927, 909, 771, 755, 730, 648, 605 cm .
HRMS (ESI): calcd. for C29
488.2544.
33 3 4
H N O
[M + H]+ 488.2544; found
465, 1412, 1361, 1301, 1277, 1244, 1198, 1173, 1154, 1094, 933,
–1
29 3 2
69, 750, 728, 697, 673 cm . HRMS (ESI): calcd. for C26H N O
General Method To Prepare 49, 51, and 52: In a 5 mL microwave
reaction vial, compound 46, 47, or 48 (0.30 mmol, 1 equiv.) was
M + H]+ 416.2333; found 416.2331.
General Method To Prepare 46, 47, and 48: A solution of 44 or 45
0.3 mmol) and either methyl bromoacetate (0.6 mmol) or methyl
dissolved in methanol (2 mL) in the presence of Et
The reaction mixture was subjected to microwave irradiation with
3
N (0.5 mL).
(
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
stirring at 100 °C for 2 h. After the system had cooled down to
room temperature, the solvent was removed under reduced pres-
sure. The residue was then purified by column chromatography on
silica gel (petroleum ether/EtOAc, 8:2 to 7:3) to give 49, 51, or 52.
1
400 MHz): δ = 1.02 (t, J = 7.3 Hz, 3 H), 1.44–1.62 (m, 2 H), 1.70–
1.92 (m, 2 H), 2.98 (d, J = 15.9 Hz, 1 H), 3.11 (d, J = 15.9 Hz, 1
H), 4.31 (t, J = 7.6 Hz, 2 H), 6.87 (dd, J = 7.5, 4.9 Hz, 1 H), 6.98
(d, J = 7.8 Hz, 1 H), 7.04–7.13 (m, 3 H), 7.29 (td, J = 7.7, 1.2 Hz,
1
3
H), 8.32 (dd, J = 4.8, 1.7 Hz, 1 H), 9.06 (s, 1 H) ppm. C NMR
CDCl , 100 MHz): δ = 14.0, 20.4, 29.9, 39.4, 40.8, 50.0, 110.7,
18.5, 120.5, 123.4, 123.7, 129.4, 131.2, 134.7, 140.3, 147.6, 152.1,
1Ј-Butyl-1-(4-methoxybenzyl)-1ЈH-spiro[indoline-3,4Ј-[1,8]naphthyr-
(
3
1
idine]-2,2Ј(3ЈH)-dione (49): Yellow oil; yield 95 %. H NMR
CDCl , 400 MHz): δ = 1.03 (t, J = 7.4 Hz, 3 H), 1.45–1.55 (m, 2
H), 1.73–1.87 (m, 2 H), 2.94 (d, J = 15.9 Hz, 1 H), 3.13 (d, J =
1
1
1
8
(
3
67.4, 178.9 ppm. IR (ATR diamond): ν˜ = 2918, 1710, 1609, 1513,
487, 1466, 1431, 1304, 1247, 1176, 1029, 1014, 1029, 1014, 957,
1
6
0
5.9 Hz, 1 H), 3.81 (s, 3 H), 4.21–4.46 (m, 2 H), 4.91 (s, 2 H), 6.80–
.92 (m, 4 H), 7.01 (dd, J = 7.6, 1.7 Hz, 1 H), 7.05 (dd, J = 7.5,
.7 Hz, 1 H), 7.14 (d, J = 6.7 Hz, 1 H), 7.22–7.28 (m, 3 H), 8.32
–
1
19 3 2
01, 750, 730, 648, 632 cm . HRMS (ESI): calcd. for C19H N O
[
M + H]+ 322.1550; found 322.1550.
(
dd, J = 4.8, 1.7 Hz, 1 H) ppm. 13C NMR (CDCl
3
, 100 MHz): δ = Preparation of 3-(2-Aminopyridin-3-yl)-1-pentylindolin-2-one (53):
4.0, 20.4, 30.0, 39.7, 40.9, 43.5, 49.5, 55.3, 109.9, 114.3 (2 CH), In a 5 mL microwave reaction vial, compound 45 (0.4 g, 0.96 mmol,
1
1
1
2
1
6
4
18.5, 120.8, 123.4, 127.4, 128.7 (2 CH), 129.2, 130.9, 134.5, 142.0,
47.6, 152.2, 159.2, 167.2, 176.5 ppm. IR (ATR diamond): ν˜ =
956, 2931, 2871, 1713, 1679, 1610, 1585, 1487, 1465, 1446, 1378,
359, 1271, 1247, 1221, 1032, 1013, 913, 874, 780, 747, 730, 685,
1 equiv.) was dissolved in trifluoroacetic acid (2.5 mL). The reac-
tion mixture was subjected to microwave irradiation with stirring
at 100 °C for 30 min. After the system had cooled down to room
temperature, trifluoroacetic acid was removed under reduced pres-
sure. The residue was then purified by column chromatography on
62, 641 cm–1. HRMS (ESI): calcd. for C27
42.2125; found 442.2127.
27 3 3
H N O
[M + H]+
silica gel (petroleum ether/EtOAc 5:5) to give 53 in excellent yield.
1
M.p. 157 °C; yield 98%. H NMR (CDCl
3
, 400 MHz): δ = 0.91 (t,
1
Ј-(4-Methoxybenzyl)-1-pentylspiro[indoline-3,3Ј-pyrrolo[2,3-b]pyr-
J = 6.8 Hz, 3 H), 1.32–1.41 (m, 4 H), 1.67–1.75 (m, 2 H), 3.68–
.80 (m, 2 H), 4.78 (s, 1 H), 6.75 (dd, J = 7.5, 6.1 Hz, 1 H), 7.01
d, J = 8.0 Hz, 1 H), 7.15–7.26 (m, 2 H), 7.43–7.53 (m, 2 H), 7.77
1
idine]-2,2Ј(1ЈH)-dione (51): Yellow oil; yield 70%. H NMR
CDCl , 400 MHz): δ = 0.93 (t, J = 7.1 Hz, 3 H), 1.32–1.47 (m, 4
H), 1.75–1.80 (m, 2 H), 3.69–3.88 (m, 2 H), 3.80 (s, 3 H), 5.04 (s,
3
(
3
(
(
1
3
3
dd, J = 6.1, 1.6 Hz, 1 H), 8.46 (s, 2 H) ppm. C NMR (CDCl ,
2
6
H), 6.82 (dd, J = 7.4, 0.7 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2 H),
.93 (dd, J = 7.3, 5.3 Hz, 1 H), 6.93 (dd, J = 7.3, 5.3 Hz, 1 H), 7.03
1
1
00 MHz): δ = 13.9, 22.3, 27.0, 28.9, 40.6, 47.2, 109.7, 112.3, 121.7,
23.4, 123.7, 125.6, 129.9, 135.5, 141.5, 144.0, 155.8, 173.9 ppm.
(dd, J = 7.6, 0.8 Hz, 1 H), 7.15 (dd, J = 7.3, 1.6 Hz, 1 H), 7.38 (td,
IR (ATR diamond): ν˜ = 3393, 3100, 2933, 1709, 1660, 1610, 1490,
1
6
J = 7.8, 1.2 Hz, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 8.27 (dd, J = 5.3,
467, 1361, 1195, 1176, 1133, 1095, 799, 778, 752, 721, 698,
1
.6 Hz, 1 H) ppm. 13C NMR (CDCl
3
, 100 MHz): δ = 14.0, 22.3,
–
1
+
21 3
31 cm . HRMS (ESI): calcd. for C18H N O [M + H] 296.1757;
2
1
1
1
7.0, 28.8, 40.8, 42.8, 55.2, 61.6, 109.3, 114.0 (2 CH), 118.8, 122.9,
23.2, 123.8, 127.1, 128.4, 129.4 (2 CH), 129.8, 131.3, 144.8, 148.4,
58.2, 159.0, 171.3, 171.7 ppm. IR (ATR diamond): ν˜ = 2931, 2870,
732, 1708, 1607, 1593, 1513, 1487, 1464, 1450, 1336, 1303, 1256,
found 296.1755.
General Method To Prepare 54 and 55: Either methyl bromoacetate
(2.53 mmol) or methyl bromopropionate (2.53 mmol) was added to
175, 1137, 1106, 1092, 946, 931, 783, 805, 752, 694, 640 cm . a solution of compound 53 (0.5 g, 1.69 mmol) and Et N (1 mL) in
3
–
1
1
+
HRMS (ESI): calcd. for C27
H
27
N
3
O
3
[M + H] 442.2125; found THF (9 mL). The reaction solution was stirred at room tempera-
ture for 12 h. The solvent was removed in vacuo to give a crude
442.2128.
oil. The crude oil was dissolved in methanol (5 mL) in the presence
1
Ј-(4-Methoxybenzyl)-1-pentyl-1ЈH-spiro[indoline-3,4Ј-[1,8]naphthyr-
of triethylamine (0.5 mL). The reaction mixture was subjected to
microwave irradiation with stirring at 100 °C for 1 h. After the sys-
tem had cooled down to room temperature, the solvent was re-
moved under reduced pressure. The residue was then purified by
column chromatography on silica gel (petroleum ether/EtOAc, 4:6)
to give 54 or 55 in good yield.
1
idine]-2,2Ј(3ЈH)-dione (52): Yellow oil; yield 85%. H NMR
CDCl , 400 MHz): δ = 0.93 (t, J = 6.9 Hz, 3 H), 1.32–1.45 (m, 4
H), 1.63–1.85 (m, 2 H), 2.86 (d, J = 15.8 Hz, 1 H), 3.18 (d, J =
(
3
1
1
5.8 Hz, 1 H), 3.71–3.85 (m, 2 H), 3.81 (s, 3 H), 5.44 (d, J =
3.9 Hz, 1 H), 5.54 (d, J = 13.9 Hz, 1 H), 6.80 (d, J = 6.8 Hz, 1
H), 6.91–6.85 (m, 4 H), 6.92 (d, J = 7.9 Hz, 1 H), 7.03 (dd, J =
7
8
.6, 1.7 Hz, 1 H), 7.29 (td, J = 7.8, 1.2 Hz, 1 H), 7.56 (d, J = 1-Pentylspiro[indoline-3,3Ј-pyrrolo[2,3-b]pyridine]-2,2Ј(1ЈH)-dione
.7 Hz, 2 H), 8.33 (dd, J = 4.9, 1.7 Hz, 1 H) ppm. 13C NMR (54): M.p. 190 °C; yield 60%. H NMR (CDCl
1
3
, 400 MHz): δ =
(
CDCl
3
, 100 MHz): δ = 13.9, 22.3, 27.1, 29.0, 39.8, 40.4, 43.2, 49.6,
0.93 (t, J = 7.0 Hz, 3 H), 1.35–1.45 (m, 4 H), 1.71–1.84 (m, 2 H),
3.81 (t, J = 7.4 Hz, 2 H), 6.89–7.04 (m, 3 H), 7.07 (t, J = 7.9 Hz,
1 H), 7.21 (dd, J = 7.5, 1.6 Hz, 1 H), 7.40 (td, J = 7.7, 1.4 Hz, 1
5
1
1
1
1
5.2, 109.1, 113.6 (2 CH), 118.8, 121.1, 123.2, 123.5, 129.1, 130.1,
30.4 (2 CH), 131.1, 134.6, 141.9, 147.4, 151.7, 158.8, 167.4,
76.2 ppm. IR (ATR diamond): ν˜ = 2931, 2871, 2248, 1711, 1682,
609, 1585, 1511, 1487, 1465, 1444, 1378, 1359, 1321, 1245, 1175,
033, 909, 891, 848, 810, 780, 753, 77, 685, 646, 632 cm . HRMS 118.7, 123.3, 123.6, 124.0, 126.8, 129.9, 132.3, 144.7, 147.7, 158.2,
ESI): calcd. for C28
1
3
H), 8.28 (dd, J = 5.3, 1.6 Hz, 1 H), 10.90 (s, 1 H) ppm. C NMR
(CDCl , 100 MHz): δ = 14.0, 22.3, 27.0, 28.8, 40.8, 62.3, 109.3,
3
–1
+
(
H
29
N
3
O
3
[M + H] 456.2282; found 456.2284.
171.1, 172.6 ppm. IR (ATR diamond): ν˜ = 3207, 2927, 2859, 1740,
1
9
682, 1599, 1482, 1462, 1429, 1306, 1255, 1202, 1172, 1150, 1125,
Preparation of 1Ј-Butyl-1ЈH-spiro[indoline-3,4Ј-[1,8]naphthyridine]-
–
1
76, 952, 804, 786, 760, 666, 644, 628 cm . HRMS (ESI): calcd.
2,2Ј(3ЈH)-dione (50): Trifluoromethanesulfonic acid (0.22 mL,
for C19
19 3 2
H N O
[M + H]+ 322.1550; found 322.1554.
2.5 mmol) was added to a stirred solution of 49 (0.1 g, 0.23 mmol)
in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The re-
action mixture was stirred at ambient temperature for 12 h and
concentrated in vacuo. The residue was basified with saturated
aqueous sodium hydrogen carbonate and extracted with ethyl acet-
ate. The organic phase was washed with water and brine, dried with
anhydrous sodium sulfate, and filtered. The filtrate was concen-
1-Pentyl-1ЈH-spiro[indoline-3,4Ј-[1,8]naphthyridine]-2,2Ј(3ЈH)-
dione (55): M.p. 220 °C; yield 70%. H NMR (CDCl , 400 MHz):
3
δ = 0.93 (t, J = 6.9 Hz, 3 H), 1.27–1.50 (m, 4 H), 1.64–2.01 (m, 2
H), 2.85 (d, J = 16.3 Hz, 1 H), 3.12 (d, J = 16.3 Hz, 1 H), 3.68–
3.93 (m, 2 H), 6.91 (dd, J = 7.6, 5.0 Hz, 1 H), 6.97 (d, J = 7.8 Hz,
1 H), 7.11–7.04 (m, 2 H), 7.29 (d, J = 5.9 Hz, 1 H), 7.36 (td, J =
1
trated in vacuo. The residue was purified by column chromatog-
7.8, 1.1 Hz, 1 H), 8.39 (dd, J = 5.0, 1.6 Hz, 1 H), 10.33 (s, 1 H)
1
13
raphy (EtOAc) to give 50. Yellow oil; yield 97%. H NMR (CDCl
3
,
ppm. C NMR (CDCl
3
, 100 MHz): δ = 13.9, 22.3, 27.1, 29.0, 39.1,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 04-12-14 15:35:59
Pages: 15
G. Guillaumet et al.
FULL PAPER
4
1
3
1
7
0.4, 50.1, 109.2, 119.1, 119.1, 123.4, 123.6, 129.4, 131.3, 135.0,
42.1, 147.8, 151.5, 168.2, 176.3 ppm. IR (ATR diamond): ν˜ =
047, 2959, 2898, 1697, 1608, 1589, 1500, 1452, 1430, 1406, 1332,
276, 1231, 1189, 1136, 1124, 1097, 998, 971, 945, 860, 794, 780,
E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. M.
Plouffe, K. Henson, T. Wagner, E. A. Winzeler, F. Petersen, R.
Brun, V. Dartois, T. T. Diagana, T. H. Keller, J. Med. Chem.
2010, 53, 5155–5164.
[
9] P. Vachal, S. Miao, J. M. Pierce, D. Guiadeen, V. J. Colandrea,
M. J. Wyvratt, S. P. Salowe, L. M. Sonatore, J. A. Milligan, R.
Hajdu, A. Gollapudi, C. A. Keohane, R. B. Lingham, S. M.
Mandala, J. A. DeMartino, X. Tong, M. Wolff, D. Steinhuebel,
G. R. Kieczykowski, F. J. Fleitz, K. Chapman, J. Athanaso-
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–
1
21 3 2
55, 693, 658, 645 cm . HRMS (ESI): calcd. for C20H N O [M
+
+
H] 336.1707; found 336.1710.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the H and C NMR spectra.
1
13
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Received: October 2, 2014
Published Online: ᭿
14
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43292
/KAP1
Date: 04-12-14 15:35:59
Pages: 15
A General and Efficient Route to Tetracyclic Spirooxindole Derivatives
Spiro Compounds
A. El Bouakher, S. Massip, C. Jarry,
Y. Troin, I. Abrunhosa-Thomas,
G. Guillaumet* ................................ 1–15
A General and Efficient Method to Access
Tetracyclic Spirooxindole Derivatives
Keywords: Anionic condensation
/ Re-
duction / Cyclization / Selective deprotec-
tion / Tetracyclic spirooxindole / Spiro
compounds
Tetracyclic spirooxindoles were easily pre-
pared from N-protected isatins and 2-
fluoropyridine, leading to fused C-3 ox-
indole heterocycles in good yields.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15