Highly efficient construction of bisspirooxindoles containing vicinal spirocenters through an organocatalytic modified Feist-Bénary reaction

Article abstract of DOI:10.1002/chem.201301175

We have developed an organocatalytic modified Feist-Bénary reaction of cyclic dicarbonyl compounds, isatins and cyclic α-bromo dicarbonyl compounds. This method affords bisspirooxindole-fused dihydrofurans containing two vicinal spiro centers. To the best

Full text of DOI:10.1002/chem.201301175

FULL PAPER
Spiro Compounds
S. Ahadi, H. R. Khavasi,
A. Bazgir* ..................... &&&& — &&&&
Highly Efficient Construction of Biss-
pirooxindoles Containing Vicinal
Spirocenters through an Organocata-
lytic Modified Feist–Bꢀnary Reaction
Crowded spaces! An organocatalytic
modified Feist–Bꢀnary reaction of
cyclic dicarbonyl compounds, isatins,
and cyclic a-bromo dicarbonyls was
developed. This method affords biss-
pirooxindole-fused dihydrofurans con-
taining two vicinal spiro centers (see
scheme; DBU=1,8-diazabicyclo-
AHCTUNGTRENN[GUN 5.4.0]undec-7-ene). Employing cyclic
a-halo dicarbonyl compounds for the
synthesis of bisspirooxindole-fused
dihydrofurans has not been previously
reported.
Chem. Eur. J. 2013, 00, 0 – 0
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DOI: 10.1002/chem.201301175
Highly Efficient Construction of Bisspirooxindoles Containing Vicinal
Spirocenters through an Organocatalytic Modified Feist–Bꢀnary Reaction
[
a]
Somayeh Ahadi, Hamid Reza Khavasi, and Ayoob Bazgir*
Abstract: We have developed an organocatalytic modified Feist–Bꢀnary reaction
of cyclic dicarbonyl compounds, isatins and cyclic a-bromo dicarbonyl compounds.
This method affords bisspirooxindole-fused dihydrofurans containing two vicinal
spiro centers. To the best of our knowledge, employing cyclic a-halo dicarbonyl
compounds for the synthesis of bisspirooxindole-fused dihydrofurans has not been
previously reported.
Keywords: Feist–Bꢀnary reaction ·
fused-ring systems · organocatalysis ·
spiro compounds · synthetic meth-
ods
Introduction
Intramolecular alkylation on the quaternary carbon is one
of the most conventional methods for the synthesis of spiro-
centers. The alkylation can be accomplished either through
Developing effective methods for the construction of spiro-
cyclic frameworks has been a topic of great relevance in or-
ganic synthesis because of the outstanding biological activi-
[3]
direct substitution or through 1,4-addition (Scheme 2).
[1]
ties of this class of compounds. The spirocyclic compounds
are synthesized by: a) alkylation methods, b) transition-
metal-based processes, c) ring-closure methods, d) cycloaddi-
tion strategies, e) radical cyclizations, and f) rearrangement-
based approaches involving cleavage of bridged ring sys-
[2]
tems (Scheme 1).
Scheme 2. Alkylation methods for the spirocenter formation.
Nucleophilic addition and annulation reactions with isatin
electrophiles are major strategies that have been widely uti-
[4]
lized for the synthesis of spirooxindoles. Such compounds
have drawn enormous interest from researchers in the area
of synthetic and medicinal chemistry because they occur in
many natural products and have a wide range of bioactivi-
[
5]
[6]
ty; they can act as progesterone receptor modulators,
[7]
[8]
[9]
anti-HIV, anticancer, antitubercular, and antimalarial
agents,
hibitors of human NK-1 receptor.
[10,11]
[12]
MDM2 inhibitors,
and antimicrobial and in-
[13–15]
For example, com-
pounds i and ii, with the pyrrolidinyl spirooxindole frame-
Scheme 1. The construction of spiro compounds.
work, are known as an inhibitor of acetylcholinesterase and
[16]
as an antitumor agent, respectively (Scheme 3).
[
a] S. Ahadi, H. R. Khavasi, Dr. A. Bazgir
Department of chemistry, Shahid Beheshti University
Tehran 1983963113 (Iran)
Fax : (+98)21-22431661
E-mail: a_bazgir@sbu.ac
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301175.
Scheme 3. Bioactive spirooxindoles.
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Bisspirooxindoles with Vicinal Spirocenters
FULL PAPER
As a privileged scaffold, di-
hydrofuran is a ubiquitous sub-
unit in many natural products
with remarkable biological ac-
tivities and its derivatives are
widely applied in the pharma-
[17]
ceutical industry.
Therefore,
the synthesis of new heterocy-
cles containing both spirooxin-
dole and dihydrofuran moieties
may result in the development
of new drug candidates. Where-
as spirooxindoles fused to dihy-
drofuran have attracted atten-
Scheme 6. Reaction of 3-bromo-4-hydroxycoumarin (1), isatins 2, and 1,3-indandione (3).
[18]
tion,
bisspiro compounds in-
[22–26]
corporating both spirooxindole and dihydrofuran motifs or
bisspiro compounds containing a dihydrofuran moiety have
seldom been described. Very recently, the formation of dis-
pirodihydrofuranyl oxindoles from activated cyclic electro-
philes, amines, and dimethyl acetylenedicarboxylate
ed.
Very recently, we also described a modified Feist–
Bꢀnary reaction for the convenient synthesis of spiro-
(indeno[1,2-b]furan)triones by using cyclic a-bromo dike-
tone (Scheme 5).
A
H
U
G
R
N
N
ACHTUNGTRENNUNG
[27]
According to the above reports and as a continuation of
(
DMAD) through Huisgen dipolar additions has been re-
our previous work on the development of new methods for
[19]
[28–30]
ported. In 2007, Barba and co-workers achieved the syn-
thesis of 2,3-bis(spiro-2-indanyl-1,3-dione)indeno[1,2-b]
through electrochemical reduction of 2,2-dibromo-1,3-indan-
spirooxindole synthesis,
we herein report the first three-
A
H
U
T
N
U
G
component organocatalytic modified Feist–Bꢀnary reaction
of 3-bromo-4-hydroxycoumarin (1), isatins 2, and 1,3-indan-
dione (3) for the construction of two vicinal spirocenters in
a bisspirooxindole-containing furoindoline moiety. To our
surprise, the expected product 5 was not obtained and only
product 4 was isolated in a good yield (Scheme 6).
[20]
dione (Scheme 4).
Interrupted Feist–Bꢀnary dihydrofuran synthesis is a
base-catalyzed reaction of a-halogen ketones and b-dicar-
bonyl compounds.
[21]
Recently, improved tandem reactions
initiated by the reaction of stabilized carbanions on electro-
philes followed by a cyclization step have been report-
Results and Discussion
Our study commenced with a three-component reaction of
1
, N-methyl isatin (2a), and 3 as a model reaction in the
presence of various bases and solvents (Table 1). Screening
of the solvent revealed that acetic acid is the most suitable
reaction media, providing 1’’-methyl-4’H-dispiro(chromane-
3
,2’-indeno
in 91% isolated yield in presence of 30 mol% 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU; entry 4). It was found
ACHTUNGTRENNUNG[ 1,2-b]furan-3’,3’’-indoline)-2,2’’,4,4’-tetraone (4a)
AHCTUNGTRENNUNG
that when the amount of DBU was increased from 10 to 20,
and 30 mol%, the isolated yield increased from 70 to 74 and
9
1%, respectively; further increases in the amount of DBU
Scheme 4. Previous works for the synthesis of bisspiro compounds.
did not improve the yield (entry 7). It should be mentioned
that when the reaction was carried out in the absence of
DBU the yield of the product was low (entry 9). When this
reaction was carried out with other bases such as, NEt3,
Cs CO , K CO , NH OAc, or pyridine, the yield of the ex-
2
3
2
3
4
pected product was reduced. Furthermore, it was found that
lower reaction temperature led to lower yield (entry 8).
With optimal conditions in hand, we extended the reac-
tion to various isatins 2 (Scheme 7). Reasonable yields were
obtained by using N-alkyl isatins, however, when this reac-
tion was carried out with N-H isatins, the expected products
were obtained in only trace amounts.
Scheme 5. Feist–Bꢀnary reaction and our former work.
Chem. Eur. J. 2013, 00, 0 – 0
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A. Bazgir et al.
Table 1. Optimization of the reaction.
The structure of dispiro(indene-furochromene-indoline)te-
traone 4a was confirmed by single-crystal X-ray analysis
(
Figure 1).
[
a]
Entry
Solvent
CH CN
EtOH
Temp. [8C]
Base ([mol%])
Yield [%]
1
2
3
4
5
6
7
8
9
3
reflux
reflux
reflux
reflux
reflux
reflux
reflux
90
reflux
reflux
reflux
reflux
reflux
reflux
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (20)
DBU (10)
DBU (40)
DBU (30)
–
65
45
50
91
84
70
91
81
67
80
76
80
78
81
2
H O
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
10
11
12
13
14
Py (1equiv)
Figure 1. X-ray crystal structure of 4a.
K
2
CO
CsCO
NEt
NH
3
(30)
(30)
(30)
OAc (30)
3
3
4
When the reaction was carried out with 3-bromo-4-hy-
[
A] Reaction time=48 h.
droxy-6-methyl-2H-pyran-2-one (6) as a cyclic a-bromo di-
1
ketone, TLC analysis and H NMR spectra of the reaction
mixture showed a combination of starting materials and nu-
merous products; the desired product 7 was obtained in
only trace amounts (Scheme 8).
Scheme 8. Use of 3-bromo-4-hydroxy-6-methyl-2H-pyran-2-one (6) in the
reaction.
We have not established an exact mechanism for the for-
mation of 4, however, a reasonable possibility is shown in
Scheme 9. Initially, salt 8 is formed in situ by acid–base reac-
tion of DBU and HOAc. A hydrogen bond then forms be-
tween isatin 2 and 8, thus activating the isatin, which then
[27]
reacts with 3 by Knoevenagel condensation. The Michael
addition of 3-bromo-4-hydroxycoumarins 1 to intermediate
9
affords intermediate 10. Subsequently, nucleophilic attack
[31]
of DBU on 10 produces intermediate 12 and bromo-pyri-
midoazepinium 11 as the source of Br . Finally, the reaction
+
of 11 and 12 affords intermediate 13, which subsequently
undergoes annulation to give the product 4 (Scheme 9).
+
Mechanistically, it is clear that Br acts as a leaving group
and the reaction proceeds via intermediate 13. To clarify the
proposed mechanism, 2-bromo-1H-indene-1,3(2H)-dione
(
14) was used as cyclic a-bromo diketone instead of 1. In
this way, we investigated the reaction of 14, N-methyl isatin
2a), and 4-hydroxycoumarin (15) under the same reaction
conditions and obtained the corresponding product 4a in
(
Scheme 7. Synthesis of dispiro(indene-furochromene-indoline)tetraones
4
.
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Bisspirooxindoles with Vicinal Spirocenters
FULL PAPER
Scheme 11. Synthesis of dispiro(indene-furopyran-indoline)tetraones 7.
cordingly, we investigated the reaction of 2-hydroxynaphtha-
lene-1,4-dione (17), 14, and isatins 2 under the same reac-
tion conditions and obtained the desired dispiro(indene-
furo ACHUTNGRNEGUN[ 3,2-c]pyranindoline)tetraones 18a–c in good isolated
yields (Scheme 12).
Scheme 9. Proposed reaction mechanism.
84% yield (Scheme 10). The structure of 4a obtained in this
way was confirmed by single-crystal X-ray analysis (see the
Supporting Information).
Scheme 12. Synthesis
of
dispiro(indene-furo AHCTUNGTRENNUN[G 3,2-c]pyranindoline)te-
traones 18.
Scheme 10. Reaction of 2-bromoindandione (14), N-methylisatin (2a),
and 4-hydroxycoumarin (15).
Conclusion
Encouraged by this success, we attempted to synthesize
6
7
’-methyl-dispiro(indene-furo
by using 14. Interestingly, dispiro(indene-furoCAHTUNGTRENNUNG
A
H
U
G
R
N
U
G
We have developed an organocatalytic cascade Knoevena-
gel–Michael alkylation reaction of 1,3-dicarbonyl com-
pounds, cyclic a-bromo diketones, and isatins for the synthe-
sis of bisspirooxindoles containing two vicinal spirocenters.
Prominent among the advantages of this method are novel-
ty, simplicity, good yields, and the straightforward work-up
procedures employed.
nindoline)tetraones 7a–c were isolated in good yields by the
reaction of 14, 2, and 16 (Scheme 11). Surprisingly, we found
that the reaction also proceeds very efficiently with NH
isatin, affording the desired product 7c in good yield.
Naphthalene-1,4-dione derivatives are known to possess a
wide spectrum of biological applications such as antibacteri-
al, antifungal, antiinflammatory, anticancer, antidiabetic and
[32]
antimalarial activities. Considering the very important bi-
ologically activities of molecules containing the naphtha-
lene-1,4-dione scaffold, we hypothesized that the integration
of a naphthalene-1,4-dione moiety with a spirooxindole-
fused dihydrofuran may result in the discovery of novel
drug candidates with unknown biologically activities. Ac-
Experimental Section
General methods: Melting points were determined with a melting point
Thermo Scientific 9100 apparatus and are uncorrected. IR spectra were
1
taken with a Bomem FT-IR MB spectrometer. H NMR spectra were re-
corded with a 300 MHz Bruker DRX Avance spectrometer. Chemical
Chem. Eur. J. 2013, 00, 0 – 0
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A. Bazgir et al.
shifts are expressed in parts per million downfield from tetramethylsilane
as an internal standard. Elemental C, H and N analyses were performed
with a Heraeus CHN-O-Rapid analyzer. MS spectra were recorded with
a Shimadzu QP 1100EX mass spectrometer operating at an ionization
potential of 70 eV.
1’’-Benzyl-4’H-dispiro(indene-2,2’-furo
1,2’’,3,4’-tetraone (4c): Yield: 74%; cream powder; m.p. 2458C; H NMR
ACHTUNGTRENUNNG[ 3,2-c]chromene-3’,3’’-indoline)-
1
3
(300 MHz, [D
2H; CH ), 6.92 (d,
Ar), 7.23–7.28 (m, 1H; H-Ar), 7.40–7.47 (m, 5H; H-Ar), 7.79–7.93 (m,
H; H-Ar), 8.09–8.23 ppm (m, 5H; H-Ar); IR (KBr): n˜ =1745, 1723,
6
]DMSO): d=4.79 and 5.06 (AB system, JAHCTUNTGENRNUG
3
2
JACHTUNGTRENNUNG
3
All chemicals were purchased from Merck or Aldrich and were used
À1
+
[
33]
1643 cm ; MS (EI, 70 eV): m/z (%): 528 (83) [M] , 434 (96), 390 (96),
without further purification. 3-Bromo-4-hydroxycoumarin
bromo-1H-indene-1,3(2H)-dione
and 2-
[34]
286 (35), 104 (87), 91 (100); elemental analysis calcd (%) for C33
C 75.42, H 3.64, N 2.67; found: C 75.32, H 3.57, N 2.58.
6
H19NO :
were prepared by reported proce-
dures.
1
3
5’’-Bromo-1’’-methyl-4’H-dispiro(indene-2,2’-furo
ACHTUNGERTNNUNG[ 3,2-c]chromene-3’,3’’-
Due to very low solubility of the products 4, 7 and 18, no C NMR data
were obtained for these products.
indoline)-1,2’’,3,4’-tetraone (4d): Yield: 90%; white powder; m.p. 2428C
1
(
JACHTUNGTRENNUNG
dec); H NMR (300 MHz, [D
6
]DMSO): d=2.80 (s, 3H; CH
(H,H)=8.3 Hz, 1H; H-Ar), 7.45 (brs, 1H; H-Ar), 7.49–7.68 (m, 4H;
H-Ar), 7.85–7.98 ppm (m, 5H; H-Ar); IR (KBr): n˜ =1769, 1734, 1642,
3
), 6.84 (d,
X-ray crystallography: The X-ray diffraction measurements were made
a STOE IPDS-II diffractometer with graphite-monochromated
MoKa radiation. Cell constants and an orientation matrix for data collec-
3
with
À1
+
1
600 cm ; MS (EI, 70 eV): m/z (%): 531 (56) [M] , 470 (87), 454 (100),
tion were obtained by least-squares refinement of diffraction data from
998 unique reflections for 4a. Data were collected at a temperature of
98(2) K to a maximum 2q value of 51.988 and in a series of w scans in 18
oscillations and integrated using the Stoe X-AREA software package.
The data were corrected for Lorentz and Polarizing effects. The struc-
tures were solved by direct methods and refined on F2 by full-matrix
least-squares procedure. All hydrogen atoms were added at ideal posi-
tions and constrained to ride on their parent atoms, with Uiso(H)=
2
90 (22), 104 (96), 76 (52); elemental analysis calcd (%) for
4
C
27
H
14BrNO
’’-Methyl-5’’-nitro-4’H-dispiro(indene-2,2’-furo
doline)-1,2’’,3,4’-tetraone (4e): Yield: 78%; brick-red powder; m.p>
6
: C 61.38, H 2.67, N 2.65; found: C 61.30, H 2.63, N 2.71.
2
1
ACHTUNGTRNE[UNNG 3,2-c]chromene-3’,3’’-in-
[
35]
1
2
J
708C; H NMR (300 MHz, [D
6
3
]DMSO): d=2.92 (s, 3H; CH ), 7.12 (d,
3
A
H
U
G
R
N
U
G
3
5
H; H-Ar), 8.16 (brs, 1H; H-Ar), 8.26 ppm (d, J
A
H
U
G
R
N
U
G
À1
Ar); IR (KBr): n˜ =1728, 1651, 1604 cm ; elemental analysis calcd (%)
1
.2Ueq. All refinements were performed by using the X-STEP32 crystal-
for C27
’’-Bromo-1’’-ethyl-4’H-dispiro(indene-2,2’-furo
doline)-1,2’’,3,4’-tetraone (4 f): Yield: 87%; brick-red powder; m.p.>
H
14
N
2
O
8
: C 65.59, H 2.85, N, 5.67; found: C 65.53, H 2.80, N 5.58.
[
36]
lographic software package. Complete crystallographic data for com-
pound 4a has been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication No. CCDC-929571. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
5
ACHTUNGTRNE[UNNG 3,2-c]chromene-3’,3’’-in-
1
3
2
708C; H NMR (300 MHz, [D
6
]DMSO): d=0.64 (t, J ACHUTNTGRENNUG( H,H)=6.7 Hz,
3
3
H; CH ), 3.31–3.38 (m, 1H; CH), 3.50–3.57 (m, 1H; CH), 6.87 (d, J-
3
AHCTUNGTRENNUNG
General procedure for the synthesis of 4:
A
mixture of isatins
1.0 mmol), 1,3-indandione (1.0 mmol), and 3-bromo-4-hydroxycoumarin
1 mmol) in HOAc (2 mL) in the presence of DBU (30 mol%) was
heated to reflux for 48 h. Upon completion of the reaction (TLC), the
mixture was evaporated under vacuum. Methanol (3 mL) was added and
the precipitated product was filtered and washed with methanol (2 mL)
to afford the pure product 4.
(
(
À1
+
n˜ =1762, 1736, 1642, 1598 cm ; MS (EI, 70 eV): m/z (%): 545 (96) [M] ,
68 (96), 390 (74), 293 (35), 104 (100), 76 (65); elemental analysis calcd
%) for C28 16BrNO : C 62.01, H 2.97, N 2.58; found: C 62.11, H 2.93, N
4
(
H
6
2
.65.
1
’’-Ethyl-5’’-nitro-4’H-dispiro(indene-2,2’-furo ACHUTNRGNENUG[ 3,2-c]chromene-3’,3’’-indo-
line)-1,2’’,3,4’-tetraone (4g): Yield: 77%; brick-red powder; m.p.>
1
’’-Methyl-4’H-dispiro(indene-2,2’-furo
A
H
U
G
E
N
N
[3,2-c]chromene-3’,3’’-indoline)-
,2’’,3,4’-tetraone (4a): Yield: 95%; cream powder; m.p. 2408C (dec);
1
3
2
708C; H NMR (300 MHz, [D
6
]DMSO): d=0.72 (t, J ACHUTNTGRENNUG( H,H)=6.9 Hz,
1
3
3
H; CH ), 3.42–3.52 (m, 1H; CH), 3.54–3.67 (m, 1H; CH), 7.16 (d, J-
3
1
3
H NMR (300 MHz, [D
6
]DMSO): d=2.83 (s, 3H; CH3), 6.82 (d, J-
AHCTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(H,H)=7.8 Hz, 1H; H-Ar), 7.01–7.06 (m, 1H; H-Ar), 7.16 (d, 3J
ACHTUNGTRNENUNG( H,H)=
7
.3 Hz, 1H; H-Ar), 7.55–7.63 (m, 3H; H-Ar), 7.85–7.97 ppm (m, 6H; H-
1
1
H; H-Ar), 8.21–8.24 ppm (m, 1H; H-Ar); IR (KBr): n˜ =1734, 1659,
À1
Ar); IR (KBr): n˜ =1763, 1732, 1643 cmÀ1; MS (EI, 70 eV): m/z (%): 449
607 cm ; elemental analysis calcd (%) C28
16 2 8
H N O : C 66.14, H 3.17, N
+
(
(
3
29) [M] , 376 (58), 290 (29), 104 (100), 76 (56); elemental analysis calcd
5.51; found: C 66.09, H 3.24, N 5.58.
General procedure for the synthesis of 7 and 18: A mixture of isatins
1.0 mmol), CÀH acid (1.0 mmol), and 2-bromo-1H-indene-1,3(2H)-dione
%) for C27
.07.
Crystal data for 4a: C27
H
15NO
6
: C 72.16, H 3.36, N 3.12; found: C 72.10, H 3.41, N
(
À1
H
15NO
6
(CCDC-929571); M=449.40 gmol
;
(1 mmol) in HOAc (2 mL) in the presence of DBU (30 mol%) was
heated to reflux for 48 h. Upon completion of the reaction (TLC), the
mixture was evaporated under vacuum. Methanol (3 mL) was added and
the precipitated product was filtered and washed with methanol (2 mL)
to afford the pure product.
monoclinic system; space group P21/c; a=9.8897(13) ꢂ, b=
3
2
4
0
3.0963(19) ꢂ, c=11.1997(14) ꢂ, b=95.518(10)8; V=2546.3(5) ꢂ ; Z=
À3
À1
;
1
cald =1.172 gcm
; m ACHTUNRTGENNUNG( Mo-Ka)=0.084 mm ; crystal dimension of
.27ꢃ0.26ꢃ0.19 mm. The structure was solved by using SHELXS. The
structure refinement and data reduction was carried out with SHELXL
1
1
’’,6’-Dimethyl-4’H-dispiro(indene-2,2’-furo
,2’’,3,4’-tetraone (7a): Yield: 72%; brick-red powder; m.p.>2708C;
ACHTUNGTRNENUNG[ 3,2-c]pyran-3’,3’’-indoline)-
of the X-Step32 suite of programs. Non-hydrogen atoms were refined
2
anisotropically by full matrix least-squares on F values to final R
1
=
1
H NMR (300 MHz, [D
6
]DMSO): d=2.35 (s, 3H; CH
3
), 2.79 (s, 3H;
0
.0927, wR
2
=0.2045 and S=0.938 with 308 parameters using 4998 inde-
3
CH
3
), 6.77 (d, J
A
H
U
G
R
N
U
G
pendent reflection (q range=2.54–25.998). Hydrogen atoms were located
from the expected geometry and were not refined.
(
m, 2H; H-Ar), 7.23–7.24 (m, 1H; H-Ar), 7.51–7.54 (m, 1H; H-Ar),
À1
7
.81–7.93 ppm (m, 3H; H-Ar); IR (KBr): n˜ =1727, 1639 cm ; MS (EI,
+
1
’’-Ethyl-4’H-dispiro(indene-2,2’-furo
A
H
U
G
E
N
N
[3,2-c]chromene-3’,3’’-indoline)-
70 eV): m/z (%): 413 (38) [M] , 369 (52), 340 (71), 104 (100), 76 (59); el-
1
,2’’,3,4’-tetraone (4b): Yield: 80%; brick-red powder; m.p. 2578C;
emental analysis calcd (%) C24
69.65, H 3.30, N 3.31.
6
H15NO : C 69.73, H 3.66, N 3.39; found: C
1
3
H NMR (300 MHz, [D
), 3.30–3.39 (m, 1H; CH
(H,H)=7.72 Hz, 1H; H-Ar), 7.02 (t, J
6
]DMSO): d=0.59 (t,
J
A
H
U
T
E
N
G
3
CH
3
2
), 3.50–3.60 (m, 1H; H-Ar), 6.89 (d, J-
1’’-Ethyl-6’-methyl-4’H-dispiro(indene-2,2’-furo
ACHTUNGTNERNUNG[ 3,2-c]pyran-3’,3’’-indo-
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
U
G
line)-1,2’’,3,4’-tetraone (7b): Yield: 68%; brown powder; m.p.>2708C;
3
3
1
3
(
d,
J
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(H,H)=7.38, 1H; H-Ar), 7.27 (t,
J
A
H
U
G
E
N
N
(H,H)=7.70 Hz, 1H; H-Ar),
H NMR (300 MHz, [D ]DMSO): d=0.57 (t,
JACHTUNGTRENNUNG
6
7
3
.54–7.67 (m, 3H; H-Ar), 7.85–7.90 (m, 2H; H-Ar), 7.94–7.97 ppm (m,
3
3
À1
H; H-Ar); IR (KBr): n˜ =1761, 1729, 1646, 1602 cm ; MS (EI, 70 eV):
Ar), 7.03 (brs, 2H; H-Ar), 7.24 (m, 1H; H-Ar), 7.55–7.57 (m, 2H; H-
Ar), 7.81–7.83 (m, 1H; H-Ar), 7.94 ppm (brs, 2H, H-Ar); IR (KBr): n˜ =
1733, 1698, 1678 cm ; elemental analysis calcd (%) C H NO : C 70.25,
+
m/z (%): 466 (30) [M] , 390 (100), 290 (78), 104 (96), 76 (70); elemental
analysis calcd (%) for C28
À1
H
17NO
6
: C 72.57, H 3.31, N 3.06; found: C
2
5
17
6
7
2.66, H 3.37, N 3.01.
H 4.01, N 3.28; found: C 70.31, H 3.97, N 3.23.
&
6
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Bisspirooxindoles with Vicinal Spirocenters
FULL PAPER
5
’’-Bromo-6’-methyl-4’H-dispiro(indene-2,2’-furo
A
H
U
G
R
N
U
G
b) M. M.-C. Lo, C. S. Neumann, S. Nagayama, E. O. Perlstein, S. L.
Schreiber, J. Am. Chem. Soc. 2004, 126, 16077–16086.
[9] V. V. Vintonyak, K. Warburg, H. Kruse, S. Grimme, K. Hubel, D.
Rauth, H. Waldmann, Angew. Chem. 2010, 122, 6038–6041; Angew.
Chem. Int. Ed. 2010, 49, 5902–5905.
line)-1,2’’,3,4’-tetraone (7c): Yield: 60%; cream powder; m.p.>2708C;
1
H NMR (300 MHz, [D
6
]DMSO): d=1.89 (s, 3H; CH
1
7
1
2
H; H-Ar), 7.25–7.32 (m, 3H; H-Ar), 7.35–7.43 (m, 2H; H-Ar), 7.76–
.78 (m, 3H; H-Ar), 10.70 ppm (s, 1H; NH); IR (KBr): n˜ =1740,
À1
712 cm ; elemental analysis calcd (%) for C23
.53, N 2.93; found: C 57.85, H 2.60, N 2.85.
[10] B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana, S. H.
Ang, S. Y. Leong, J. Tan, J. Wong, S. Keller-Maerki, C. Fischli, A.
Goh, E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. Plouffe,
K. Henson, T. Wagner, E. A. Winzeler, F. Petersen, R. Brun, V. Dar-
tois, T. T. Diagana, T. H. Keller, J. Med. Chem. 2010, 53, 5155–5164.
[11] a) M. Rottmann, C. McNamara, B. K. S. Yeung, M. C. S. Lee, B.
Zhou, B. Russell, P. Seitz, D. M. Plouffe, N. V. Dharia, J. Tan, S. B.
Cohen, K. R. Spencer, G. E. Gonzalez-Paez, S. B. Lakshminarayana,
A. Goh, R. Suwanarusk, T. Jegla, E. K. Schmitt, H.-P. Beck, R.
Brun, F. Nosten, L. Renia, V. Dartois, T. H. Keller, D. A. Fidock,
E. A. Winzeler, T. T. Diagana, Science 2010, 329, 1175–1180;
b) S. H. Ang, P. Crastel, S. Y. Leong, L. J. Tan, W. L. J. Wong,
B. K. S. Yeung, B. Zou (Novartis AG), Us Patent 2009/0275560A1,
1
1
’’-Methyldispiro(indene-2,2’-naphtho ACHTNUGTRENNUN[G 2,3-b]furan-3’,3’’-indoline)-
,2’’,3,4’,9’-pentaone (18a): Yield: 83%; cream powder; m.p.>2708C;
1
H NMR (300 MHz, [D
6
3
]DMSO): d=2.81 (s, 3H; CH ), 6.87 (d, J-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(H,H)=7.7 Hz, 1H; H-Ar), 7.01–7.06 (m, 1H; H-Ar), 7.27–7.32 (m, 2H;
3
H-Ar), 7.38 (d,
1
8
J
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(H,H)=7.4 Hz, 1H; H-Ar), 7.58 (d,
H; H-Ar), 7.80–7.89 (m, 4H; H-Ar), 7.96 (m, 2H; H-Ar), 8.12–
.14 ppm (m, 1H; H-Ar); IR (KBr): n˜ =1778, 1732, 1689, 1645 cm ; MS
(
(
EI, 70 eV): m/z (%): 461 (28), 433 (21), 388 (35), 290 (12), 104 (100), 76
59); elemental analysis calcd (%) for C28 : C 72.88, H 3.28, N
H
15NO
6
3
.04; found: C 72.82, H 3.34, N 3.11.
5
’’-Bromo-1’’-methyldispiro(indene-2,2’-naphtho ACHUNTGRNENUG[ 2,3-b]furan-3’,3’’-indo-
2
009; c) J.-J. Liu, Z. Zhang (Hoffmann La Roche AG) spiroindoli-
line)-1,2’’,3,4’,9’-pentaone (18b): Yield: 80%; yellow powder; m.p.>
1
none derivatives: PCT Int. Appl. WO 2008/055812, 2008.
[12] K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S. S. Qiu, Shang-
ary, W. Gao, D. Qin, J. Stukey, K. Krajewski, P. P. Roller, S. Wang, J.
Med. Chem. 2006, 49, 3432–3435.
2
708C; H NMR (300 MHz, [D
6
]DMSO): d=2.48 (s, 3H; CH
), 6.88 (d,
(H,H)=7.96 Hz, 1H; H-Ar),
.69–7.67 (m, 1H; H-Ar), 7.75 (brs, 1H; H-Ar), 7.82–7.88 (m, 4H; H-
3
3
J ACHTUNGTRENNUNG( H,H)=5.78 Hz, 1H; H-Ar), 7.51 (d, J ACHTUNGTRENNUNG
7
Ar), 7.98 (brs, 2H; H-Ar), 8.12 ppm (brs, 1H; H-Ar); IR (KBr): n˜ =
1
C
À1
[13] T. Okita, M. Isobe, Tetrahedron 1994, 50, 11143–11152.
715, 1675, 1648, 1609 cm
14BrNO
’’-Nitrodispiro(indene-2,2’-naphtho
,2’’,3,4’,9’-pentaone (18c): Yield: 61%; brown powder; m.p.>2708C;
; elemental analysis calcd (%) for
[
14] P. Rosemmond, M. M. Hossemi, C. Bub, Liebigs Ann. Chem. 1992,
51–158.
15] M. J. Kornet, A. P. Tnio, J. Med. Chem. 1976, 19, 892–898.
28
H
6
: C 62.24, H 2.61, N 2.59; found: C 62.31, H 2.57, N 2.66.
1
5
1
ACHTUNGTR[NENUNG 2,3-b]furan-3’,3’’-indoline)-
[
1
3
[16] a) M. A. Ali, R. Ismail, T. S. Choon, Y. K. Yoon, A. C. Wei, S. Pan-
dian, R. S. Kumar, H. Osman, E. Manogaran, Bioorg. Med. Chem.
Lett. 2010, 20, 7064–7066; b) A. S. Girgis, Eur. J. Med. Chem. 2009,
44, 91–100.
17] a) T. Eicher, S. Hauptmann; The Chemistry of Heterocycles: Struc-
ture, Reactions, Syntheses, and Applications; Wiley-VCH, Weinheim,
Germany, 2003; b) B. H. Lipshutz, Chem. Rev. 1986, 86, 795–819.
18] a) B. Yin, L. Huang, X. Wang, J. Liu, H. Jiang, Adv. Synth. Catal.
H NMR (300 MHz, [D
6
]DMSO): d=6.90 (d, J
J ACHTUNGTRENNUNG( H,H)=7.73 Hz, 1H; H-Ar), 7.84–7.90 (m, 4H; H-Ar),
ACHTUNGTRENNUNG( H,H)=8.282 Hz, 1H; H-
3
Ar), 7.74 (d,
8
1
.01 (brs, 2H; H-Ar), 8.13–8.19 (m, 2H; H-Ar), 8.45 (s, 1H; H-Ar),
1.47 ppm (s, 1H; NH); IR (KBr): n˜ =1728, 1685, 1631 cm ; elemental
[
analysis calcd (%) for C27
5.77, H 2.40, N 5.60.
12 2 8
H N O : C 65.86, H 2.46, N 5.69; found: C
6
[
2
013, 355, 370–376; b) Zh. Lian, M. Shi, Org. Biomol. Chem. 2012,
1
0, 8048–8050; c) V. Nair, C. Rajesh, R. Dhanya, N. P. Rath, Tetra-
hedron Lett. 2002, 43, 5349–5351.
[19] S. E. Kiruthika, R. Amritha, P. T. Perumal, Tetrahedron Lett. 2012,
3, 3268–3273.
Acknowledgements
5
We gratefully acknowledge financial support from the Research Council
of Shahid Beheshti University.
[20] R. Horcajada, B. Batanero, F. Barba, A. Martꢅn, Tetrahedron Lett.
2007, 48, 6437–6441.
[
21] a) E. Bꢀnary, Ber. Dtsch. Chem. Ges. 1911, 44, 489–492; b) F. Feist,
Ber. Dtsch. Chem. Ges. 1902, 35, 1537–1544.
[
22] a) M. Adamo, S. Suresh, L. Piras, Tetrahedron 2009, 65, 5402–5408;
b) C. P. Chuang, A. I. Tsai, Tetrahedron 2008, 64, 7511–7516; c) S.
Kitagaki, D. Shibata, C. Mukai, Tetrahedron Lett. 2007, 48, 1735–
[
1] a) G. M. Nicholas, L. L. Eckman, G. L. Newton, Bioorg. Med. Chem.
2
2
003, 11, 601–608; b) K. Suenaga, K. Araki, T. Sengoku, Org. Lett.
001, 3, 527–529; c) W. G. Beyersbergen van Henegouwen, R. M. Fi-
1
9
738; d) E. Tang, X. Huang, W. M. Xu, Tetrahedron 2004, 60, 9963–
969.
eseler, F. P. J. T. Rutjes, H. Hiemstra, J. Org. Chem. 2000, 65, 8317–
325; d) P. Ciminiello, C. DellꢄAversano, E. Fattorusso, S. Magno,
8
[
23] a) M. A. Calter, R. M. Phillips, C. Flaschenriem, J. Am. Chem. Soc.
2005, 127, 14566–14567; b) V. Calꢆ, F. Scordari, A. Nacci, E. Schin-
garo, L. D’Accolti, A. Monopoli, J. Org. Chem. 2003, 68, 4406–
4409; c) M. A. Calter, C. Zhu, Org. Lett. 2002, 4, 205–208; d) M. A.
Calter, C. Zhu, R. J. Lachicotte, Org. Lett. 2002, 4, 209–212.
M. Pansini, J. Nat. Prod. 1999, 62, 590–593; e) K. A. Metwally, M.
Dukat, J. Med. Chem. 1998, 41, 5084–5093; f) B. C. M. Potts, D. J.
Faulkner, J. A. Chan, G. C. Simolike, P. Offen, M. E. Hemling, T. A.
Francis, J. Am. Chem. Soc. 1991, 113, 6321–6322.
[
[
2] R. Rios, Chem. Soc. Rev. 2012, 41, 1060–1074.
3] N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol. Chem.
[24] a) S. Arai, K. Nakayama, Y. Suzuki, K. Hatano, T. Shioiri, Tetrahe-
dron Lett. 1998, 39, 9739–9742; b) H. Hagiwara, K. Sato, T. Suzuki,
M. Ando, Tetrahedron Lett. 1997, 38, 2103–2106; c) A. A. Jaxa-Cha-
miec, P. G. Sammes, P. D. Kennewell, J. Chem. Soc. Perkin Trans. 1
1980, 170–175.
2
012, 10, 5165–5181.
[
[
4] G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104–6155.
5] J. J. Badillo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug Discovery
Dev. 2010, 13, 758–776.
[
6] A. Fensome, W. R. Adams, A. L. Adams, T. J. Berrodin, J. Cohen, C.
Huselton, A. Illenberger, J. C. Karen, M. A. Hudak, A. G. Marella,
E. G. Melenski, C. C. McComas, C. A. Mugford, O. D. Slayeden, M.
Yudt, J. Zhang, P. Zhang, Y. Zhu, R. C. Winneker, J. E. Wrobel, J.
Med. Chem. 2008, 51, 1861–1873.
[25] Q.-F. Wang, H. Hou, L. Hui, C.-G. Yan, J. Org. Chem. 2009, 74,
7403–7406.
[26] Y. Li, X. M. Hong, D. M. Collard, M. A. El-Sayed, Org. Lett. 2000,
11, 2385–2388.
[27] S. Ahadi, M. Abaszadeh, A. Bazgir, Mol. Diversity 2012, 16, 299–
306.
[28] S. Ahadi, R. Ghahremanzadeh, P. Mirzaei, A. Bazgir, Tetrahedron
2009, 65, 9316–9321.
[
[
7] G. Kumari, M. Modi, S. K. Gupta, R. K. Singh, Eur. J. Med. Chem.
2
011, 46, 1181–1188.
8] a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, S. Qiu, Y. Ding, W. Gao,
J. Stuckey, K. Krajewski, P. P. Roller, Y. Tomita, D. A. Parrish, J. R.
Deschamps, S. Wang, J. Am. Chem. Soc. 2005, 127, 10130–10131;
[29] R. Ghahremanzadeh, M. Sayyafi, S. Ahadi, A. Bazgir, J. Comb.
Chem. 2009, 11, 393–396.
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

A. Bazgir et al.
[
[
30] R. Ghahremanzadeh, S. Ahadi, G. I. Shakibaei, A. Bazgir, Tetrahe-
dron Lett. 2010, 51, 499–502.
31] a) I. Yavari, M. Sabbaghan, Z. Hossaini, M. Ghazanfarpour-Darjani,
Helv. Chim. Acta 2008, 91, 1144–1147; b) I. Yavari, A. Mokhtarpor-
yani-Sanandaj, L. Moradi, A. Mirzaei, Tetrahedron 2008, 64, 5221–
14, 5175–5178; h) S.-T. Huang, H.-S. Kuo, C.-L. Hsiao, Y.-L. Lin,
Bioorg. Med. Chem. 2002, 10, 1947–1952; i) A. J. M. Da Silva, C. D.
Buarque, F. V. Brito, L. Aurelian, L. F. Macedo, L. H. Malkas, R. J.
Hickey, D. V. S. Lopes, F. Noel, Y. L. B. Murakami, N. M. V. Silva,
P. A. Melo, R. R. B. Caruso, N. G. Castro, P. R. R. Costa, Bioorg.
Med. Chem. 2002, 10, 2731–2738.
5
225; c) F. Schevenels, B. Tinant, J. P. Declercq, I. Mark, Chem. Eur.
J. 2013, 19, 4335–4343.
32] a) J. Koyama, Recent Pat. Anti-Cancer Drug Discovery 2006, 1, 113–
[33] S. A. Kotharkar, D. B. Shinde, Bioorg. Med. Chem. Lett. 2006, 16,
6181–6184.
[
1
25; b) C. K. Ryu, J. Y. Han, O. J. Jung, S. K. Lee, J. Y. Lee, S. H.
[34] M. Kirihara, S. Ogawa, T. Noguchi, K. Okubo, Y. Monma, I. Shimi-
zu, R. Shimosaki, A. Hatano, Y. Hirai, Synlett 2006, 2287–2289.
[35] Stoe & Cie, X-AREA, Version 1.30, Program for the acquisition and
analysis of data, Stoe & Cie GmbH, Darmstadt, Germany, 2005.
[36] Stoe & Cie, X-STEP32, Version 1.07b, Crystallographic package,
Stoe & Cie GmbH, Darmstadt, Germany, 2000.
Jeong, Bioorg. Med. Chem. Lett. 2005, 15, 679–682; c) V. K. Tandon,
D. B. Yadav, R. V. Singh, A. K. Chaturvedi, P. K. Shukla, Bioorg.
Med. Chem. Lett. 2005, 15, 5324–5328; d) C.-K. Ryu, M. J. Chae,
Arch. Pharmacal Res. 2005, 28, 750–755; e) T. Tran, E. Saheba,
A. V. Arcerio, V. Chavez, Q.-Y. Li, L. E. Martinez, T. P. Primm,
Bioorg. Med. Chem. 2004, 12, 4809–4813; f) V. K. Tandon, R. B.
Chhor, R. V. Singh, S. Rai, D. B. Yadav, Bioorg. Med. Chem. Lett.
2
004, 14, 1079–1083; g) E. J. Lee, H. J. Lee, H. J. Park, H. Y. Min,
Received: March 27, 2013
M. E. Suh, H. J. Chung, S. K. Lee, Bioorg. Med. Chem. Lett. 2004,
Published online: && &&, 0000
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8
&
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!