One-pot synthesis of conformationally restricted spirooxindoles

Article abstract of DOI:10.1016/j.tet.2007.05.009

Diastereomeric three-, five- and six-membered spirocycloalkyloxindoles were successfully synthesized in a rapid and convenient manner from readily accessible starting materials in moderate to high yields using 1-methyl-3-acetonitriloxindole after a one-pot base-mediated double-alkylation strategy. It was found that the diastereoselection is dependent on the reaction conditions and the spirocycloalkyl ring size, with the 3R^*,8R^* diastereomers being thermodynamically favored under the basic reaction conditions for three- and five-membered rings, and the 3R^*,8S^* diastereomer in the case of six-membered rings, as predicted by DFT calculations. The relative stereochemistry was supported by 2D NMR spectra and X-ray crystal structural analysis. The conformational rigidity of the spirocycloalkyloxindoles in solution was established based on NMR experimental and theoretical DFT approaches.

Full text of DOI:10.1016/j.tet.2007.05.009

Tetrahedron 63 (2007) 7702–7707
One-pot synthesis of conformationally restricted spirooxindoles
a,
Martha S. Morales-Rıos, Daphne E. Gonzalez-Juarez, Ernesto Rivera-Becerril,
a
a
*
ꢀ
ꢀ
Oscar R. Suarez-Castillo and Pedro Joseph-Nathan
ꢀ
b
a
ꢀ
aDepartamento de Quꢀımica y Seccioꢀn Externa de Farmacologꢀıa, Centro de Investigacioꢀn y de Estudios Avanzados del Instituto
´
Politecnico Nacional, Apartado 14-740, Mexico, D. F., 07000 Mexico
bCentro de Investigaciones Quꢀımicas, Universidad Autoꢀnoma del Estado de Hidalgo, Apartado 1-328, Pachuca,
42001 Hidalgo, Mexico
Received 30 March 2007; revised 1 May 2007; accepted 1 May 2007
Available online 6 May 2007
Abstract—Diastereomeric three-, five- and six-membered spirocycloalkyloxindoles were successfully synthesized in a rapid and convenient
manner from readily accessible starting materials in moderate to high yields using 1-methyl-3-acetonitriloxindole after a one-pot base-
mediated double-alkylation strategy. It was found that the diastereoselection is dependent on the reaction conditions and the spirocycloalkyl
ring size, with the 3R*,8R* diastereomers being thermodynamically favored under the basic reaction conditions for three- and five-membered
rings, and the 3R*,8S* diastereomer in the case of six-membered rings, as predicted by DFT calculations. The relative stereochemistry was
supported by 2D NMR spectra and X-ray crystal structural analysis. The conformational rigidity of the spirocycloalkyloxindoles in solution
was established based on NMR experimental and theoretical DFT approaches.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
species of 3-acetonitriloxindole with alkyl dibromides to
provide a new convenient approach to a homologated series
of conformationally restricted spirocycloalkyloxindoles.
Functionalized spirocycloalkyloxindoles are found in a
variety of natural products and bioactive molecules.1 Conse-
quently, many synthetic methodologies have been developed
for constructing these spirocycles, most of which were based
on cycloaddition or condensation reactions.2 Among them,
cyclization reactions of dianions3 with dielectrophiles
constitute a useful strategy for the synthesis of carbo- and
heterocyclic systems owing to their simplicity and synthetic
usefulness.4 However, cyclization reactions of dianions
often suffer from side reactions, such as polymerization,
decomposition, or formation of open-chain products. In
order to prevent some side reactions, or tedious protection–
deprotection sequences, selective sequential metalations and
electrophilic condensations constitute a valuable alterna-
tive.5 In particular, it has been known for many years that
enolate alkylation of oxindoles with dibromides6 results in
the formation of spirooxindoles. Recently, this methodology
has been proven powerful in the synthesis of the spirocyclo-
hexenyloxindole SR 121463 A, a potent and selective vaso-
pressin V2 receptor antagonist.7 As part of our continuing
indole chemistry studies, we have profited from the acidic
nature of oxindoles to introduce a variety of alkyl groups
at C3 and applied them as intermediates in natural product
synthesis.8 In this paper we report, to the best of our knowl-
edge, the first domino cyclization of sequential anionic
2. Results and discussion
2.1. Preparation and conformational analysis of
spirocyclopropyloxindoles, 4 and 5
The work began by establishing a general and practical
method for the spirocyclization of oxindole 1 through
coupling to alkyl dibromides (CH2)nBr2 (n¼1–4). The target
molecules are anticipated to be derived from intermediates
2a–d, which by bromide substitution reactions could gener-
ate a single C–C bond (path A), leading to the desired pairs
of diastereomeric spirooxindoles 4/5, 6/7, 8/9, and 10/11, or
alternatively to a C]C bond (path B) to give terminal
alkenes 3b–d (Scheme 1). Initial attempts to effect the
coupling reaction of 1 and dibromomethane using 1.5 equiv
of K2CO3 in DMSO at room temperature gave rise to a
complex mixture in which the spirocyclopropyloxindoles 4
and 5 were evidenced in a diastereomeric ratio (dr) of 7:2
1
as determined by H NMR analysis of unpurified reaction
products, along with a substantial amount of intermediate
2a and a significant formation of undesired oxidized side
product (3-hydroxy-1-methyl-2-oxo-2,3-dihydroindole-3-yl)-
acetonitrile9 (entry 1, Table 1). Substitution of the base for
NaOH (15% aqueous NaOH in THF, rt) also proved to be
unfruitful (entry 2). However, vastly improved yields of de-
sired spirocyclopropyloxindoles 4 and 5 in a 3:1 dr (65.4%
Keywords: Spirooxindoles; Sequential metalations; Diastereoselectivity;
DFT calculations.
* Corresponding author. E-mail: smorales@cinvestav.mx
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.009

M. S. Morales-Rꢀıos et al. / Tetrahedron 63 (2007) 7702–7707
7703
1
Table 2. Selected H NMR shifts (d), 3J(H,H) coupling constants (hertz),
and NOESY correlations of 4, 5, 8–11 in CDCl3
isolated combined yield) were obtained using 2.5 equiv of
NaH in DMF at room temperature for 1 h, without interfer-
ence of side reactions (entry 3). On the basis of experiments
monitored by GC/MS and 1H NMR, completion of the equil-
ibrated reaction was reached after 5 h leading to a 2:1 ratio in
favor of 4, evidencing that the kinetic product 4 epimerizes to
5 over time (entry 4). The same 2:1 dr was also reached by
subjecting samples of pure 4 or 5 to the same basic reaction
conditions (NaH in DMF). With the above evidence, it
follows that the base-promoted double alkylation proceeded
through initial C3 alkylation of the Na+ enolate derived
from oxindole 1, to give 2, which undergoes an intramolecular
nucleophilic attack of the nitrile-stabilized carbanion to yield
the desired spirooxindoles 4/5.
3
Compound dH4 dH8 J8,9c
a,b
b,c
3J8,9t
H4 NOESY correlations
4
5
8
9
10
11
7.20 2.44
6.86 2.36
7.34 3.30
7.14 3.04 11.0
7.61 3.08 11.3
7.16 2.86 12.6
6.9
7.4
9.3
9.4
9.4
8.5
7.7
4.1
3.6
H9c
H8, H9t
H9c, H10c, H11c
H8, H11t
H9c, H11c
H8, H12t
a
In anti relationship.
b
c
The diastereotopic methylene protons are designated as cis (c) or trans (t)
with respect to the cyano group.
In gauche relationship.
Spirocyclopropyloxindoles 4 and 5 were separated into indi-
vidual diastereomerically pure compounds by flash chroma-
tography on silica gel. The unambiguous attribution of their
relative configuration was based on the anisotropic effect of
the nitrile and carbonyl groups on 1H NMR chemical shifts
of H4 and H8, respectively (Table 2), together with the
spatial proximity determination of characteristic protons
by using a NOESY sequence. Notably, the spirocycles
3R*,8R*-4 and 3R*,8S*-5, have been previously prepared
on the basis of a reductive cyclization of isomerized bromo
derivative using the Baylis–Hillman approach.10 Consistent
with the experimental data, the conformational analysis car-
ried out using density functional theory (DFT) calculations
at the B3LYP/6-31G(d) level of theory,11 gave one opti-
mized conformer for each diastereomer, with 4 being lower
in energy by 2.7 kcal/mol,12 in agreement with experimental
data. The stereoelectronic repulsion between the C]O and
CN groups seems to be responsible for diastereomer 5 being
less stable than 4.
CN
O
N
Me
1
(CH2)nBr2
n = 1-4
Br
n
n
CN
CN
B
O
O
N
N
Me
Me
2a-d
3b-d
n = 0, 1, 2
A
2.2. Preparation and conformational analysis of
spirocyclopentyloxindoles, 8 and 9
H
NC
CN
H
8
4
5
n
n
3a
3
+
6
With an operative process identified, the scope of this syn-
thetic method was explored by envisaging the construction
of homologated spirocycloalkyloxindoles. As anticipated,
only traces of the homologated analogue 6/7 could be de-
tected after reaction of 1 with 1,2-dibromoethane (entry 5,
Table 1), affording the vinyloxindole 3b in 33% yield
(path B) together with unreacted starting material. This
result may be attributable to either the unfavorable cyclo-
butane ring strain or kinetic problems associated with its
O
N
O
7 a
2
7
N
Me
Me
(3R*,8R*)-4
(3R*,8R*)-6
(3R*,8R*)-8
n = 1
n = 2
n = 3
n = 4
(3R*,8S*)-5
(3R*,8S*)-7
(3R*,8S*)-9
(3R*,8R*)-10
(3R*,8S*)-11
Scheme 1.
Table 1. Reaction of 1 with alkyl dibromides
Entry
(CH2)nBr2/n
Base/equiv
Time/ha
Product (yield/%)
drb R*R*:R*S*
1
2
3
4
5
6
7
1
1
1
1
2
3
4
K2CO3/1.5
NaOH/8.0f
NaH/2.5
NaH/2.5
NaH/2.5
NaH/2.5
NaH/3.5
4c
20g
1
5
5
2a (51), 4/5 (23),d Side producte (18)
1 (17), 2a (Traces), 4/5 (24),d side producte (25)
1 (28), 4/5 (65.4)d
7:2
7:2
3:1
2:1
—
4/5 (91)d
1 (42), 3b (33), 6/7 (Traces)h
3c (10.5),h 8/9 (52.6)d
5
10
3:2
3:4
3d (2.3), 10/11 (52.2)d
a
Unless otherwise specified, reaction was carried out at rt in DMF.
Determined by GC/MS and/or 1H NMR of crude reaction mixture.
At rt in DMSO.
b
c
d
e
f
Overall isolated yield.
(3-Hydroxy-1-methyl-2-oxo-2,3-dihydroindole-3-yl)acetonitrile.9
In the presence of (t-Bu)4NHSO4.
At rt in THF.
g
h
Determined by 1H NMR integration after silica gel column chromatography.

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M. S. Morales-Rꢀıos et al. / Tetrahedron 63 (2007) 7702–7707
formation. Conversely, the reaction involving 1 and 1,3-
dibromopropane gives rise to a mixture of three isomeric
products having an m/z of 226 in a 3:2:1 ratio, as shown
1
by GC/MS. Analysis of the isomers by H NMR showed
them to be the expected spirocyclopentyloxindoles 8 and
9, in addition to terminal alkene 3c, respectively. Product
purification was extremely difficult owing to very similar
chromatographic mobilities of side product 3c and diastereo-
mers 8/9. Complete separation of 8 and 9 from undesired 3c
was achieved by slow fractional crystallization. It was also
observed that stirring samples of pure 8 or 9 at room temper-
ature in methanolic K2CO3 solution sufficed to induce slight
epimerization.
Detailed conformational analysis of cyclopentane rings13 of-
ten is precluded for pseudorotating ring molecules in which
all geometrical parameters change significantly making it
difficult to obtain sufficient information for setting up a
Karplus relationship. Microwave14 and electron diffraction15
studies on cyanocyclopentane agreed that the cyano group
prefers the equatorial position at the flap of an envelope con-
formation. Here we extended these studies to investigate the
conformer preferences in solution of spirocyclopentanes 8
and 9. As in the case of 4 and 5, the key features which allow
us to assign the relative stereochemistry of diastereomers 8
and 9 were based on the anisotropic effect of the nitrile
and carbonyl groups on 1H chemical shifts of H4 and H8, re-
spectively (Table 2), together with diagnostic sets of cross-
peaks observed in the NOESY spectra between aromatic
H4 (d¼7.34) and the diastereotopic methylene protons cis
to the cyano group (Table 2). In addition, the vicinal cou-
Figure 1. Crystal structure of 8. The methyl group is disordered.19
29.8% yields (entry 7, Table 1). Equilibration was also
equally observed in 10/11, for example, when minor iso-
mer 10 was treated with NaH in DMF at room temperature,
isomerization to 10/11 in a 3:4 ratio takes place proving the
higher thermodynamic stability of 11 under these condi-
tions. Despite the expected disfavored entropic factor in-
volving the larger bromoalkylated chain of intermediate
2d, which could favor increased amounts of debromohy-
drated product 3d, the chemoselectivity is similar to that
of 2c.
3
pling constants for the H8 signal at d 3.30 (dd, J¼9.3,
8.5 Hz) suggest that the molecule exists in a preferred confor-
mation.16 Similarly, 9 appears to exist in solution as a pre-
ferred envelope conformer with the opposite orientation of
the nitrile group as evidenced by the strong NOESY interac-
tion between H4 (d¼7.14) and H8 (d¼3.04), as well as the
magnitude of the observed vicinal coupling constants for
The attribution of the relative configuration of 10 and 11 was
based on 1H NMR analysis (Table 2) in combination with di-
agnostic sets of cross-peaks observed in the NOESY spectra.
Thus, for 10 the proton signal pattern17 for H8 at d 3.08 (dd,
3J¼11.3, 4.1 Hz) indicated their axial position at the spiro-
cyclohexane ring based upon their axial and equatorial inter-
actions with H9c and H9t, respectively (Table 2). Similarly,
for 11 the proton signal pattern for H8 at d 2.86 (dd, 3J¼12.6,
3.6 Hz) and its NOESY interaction with H4 (d 7.16) evi-
dence equally the axial orientation for this hydrogen and
confirms the equatorial disposition of the cyano group in so-
lution. Therefore, the relative configurations of these diaste-
reomers were 3R*,8R* for 10 and 3R*,8S* for major product
11 (Scheme 1). These data are predictive for a prioritary
chair conformation for both 10 and 11 in solution. Single
crystals of 10 and 11 could be obtained and the molecular
structures shown in Figure 2 clearly reveal the chair confor-
mation of the spirocyclohexane ring, with the cyano group in
an equatorial position in accordance with NMR data, and
further supported the relative stereochemistry of both diaste-
reomers. The high stability of 11, as determined using the
B3LYP/6-31+G(d,p) basis set18 with Gaussian 03W, may
be rationalized in terms of minor 1,3-diaxial and electro-
static interactions and explains the observed conformational
rigidity of diastereomer 11 in solution, as well as its higher
product ratio.
3
the H8 signal (dd, J¼11.0, 7.7 Hz). These data allowed to
define the relative stereochemistry as 3R*,8R* for major
product 8 and 3R*,8S* for 9 (Scheme 1). The structure and
relative stereochemistry of major diastereomer 8 was con-
firmed by X-ray crystallography (Fig. 1). These data are in
good agreement with the computational search, which gave
single low-energy envelope conformation for 8 and 9, with
the cyano group disposed equatorial and 8 being lower in
energy by 0.35 kcal/mol.12
2.3. Preparation and conformational analysis of
spirocyclohexyloxindoles, 10 and 11
When 1,4-dibromobutane was used as dielectrophile, the
reaction with 1, using 2.5 equiv of NaH in DMF at room
temperature for 5 h, gave rise to only one product having
m/z 320/322, which was identified as brominated interme-
diate 2d. Optimization of this reaction was achieved with
2.5 equiv of NaH for 3 h at room temperature and adding
another 1.0 equiv with additional stirring for 7 h, thus af-
fording diastereomers 10 and 11 together with terminal
alkene 3d in a 3:4:1 ratio, respectively, as determined by
GC/MS of the crude reaction mixture. Both diastereomers
were separated by careful column chromatography and
crystallization procedures yielding 10 in 22.4% and 11 in

M. S. Morales-Rꢀıos et al. / Tetrahedron 63 (2007) 7702–7707
7705
spirocyclohexyloxindole 11 the conformational ring inter-
conversion is frozen in a chair conformation with the cyano
group in an equatorial position, whereas for 10 inverted chair
conformations could exist in solution, with one of them
being highly populated. It is clear that in these compounds
the general conformation of the backbone revealed by NMR
studies in solution is retained in the solid. X-ray diffraction
studies finally served as an ultimate proof of relative con-
figuration assignments.
4. Experimental
4.1. General
DMF was dried by standard method from MgSO4 and
NaOH, successively, and stored over molecular sieves. All
commercial grade reagents were used without further purifi-
cation. Analytical thin-layer chromatography (TLC) was
performed on silica gel 60 F254 coated aluminum sheets
(0.25 mm thickness) with a fluorescent indicator. Visualiza-
tion was accomplished with UV light (254 nm). Flash chro-
matography was performed using silica gel 60 (230–400
mesh). IR spectra were obtained using a Perkin–Elmer 16
FPC FT spectrophotometer. NMR spectra were recorded
on Varian Mercury spectrometers working at 300 and
10
1
75.4 MHz for H and 13C, respectively. NMR data are re-
ported in parts per million (d) downfield from tetramethyl-
silane, using the formulae numbering given in Scheme 1
with the normal abbreviations (s, singlet; d, doublet; t, trip-
let; br, broad; m, multiplet) and c and t to denote cis and trans
to CN, respectively. All structural assignments were sup-
ported by gHMBC, gHSQC, and NOESY. GC/MS analyses
were conducted on a Varian CP 3800 GC equipped with a
selective mass Varian Saturn 2000 detector and a 30 m,
0.25 mm i.d., 0.25 mm CP-SIL capillary column, using
helium as carrier gas (1 mL/min), programmed from
70 ꢀC, to 250 ꢀC at a rate of 30 ꢀC/min, with the injector
temperature at 200 ꢀC. Relative percentage amounts were
calculated from total ion chromatograms by the computer.
MS analyses were obtained in the electron impact (EI)
mode at an ionizing voltage of 70 eV. High-resolution
(HR) mass spectra were measured at the UCR Mass Spec-
trometry Facility, University of California, Riverside, CA.
11
Figure 2. Crystal structures of 10 and 11. The methyl group is disordered.19
4.1.1. General procedure for spirocyclization of oxindole
1. To a solution of oxindole 1 (200 mg, 1.07 mmol) in DMF
(4 mL) was added NaH (64.5 mg, 2.68 mmol), and the sus-
pension was stirred at room temperature for 5 min before ad-
dition of the corresponding alkyl dibromide (1.3 mmol). The
resulting mixture was stirred for 5 h at the same temperature,
quenched with water (5 mL) and 5% aqueous HCl (1.5 mL),
extracted with EtOAc (3ꢁ25 mL), washed with brine, dried
over Na2SO4, and concentrated in vacuo to give a mixture
containing mainly isomers 4/5, 8/9 or 10/11.
3. Conclusions
A series of spirooxindoles were prepared by cyclization re-
action of sequential anionic species derived from oxindole
1 with dielectrophiles in a one-pot procedure to obtain equil-
ibrated mixtures of diastereomers through a nitrile-stabilized
carbanion, with the 3R*,8R* diastereomers being the ther-
modynamic products for three- and five-membered rings,
and the 3R*,8S* diastereomer in the case of six-membered
rings, as predicted by DFT calculations. The diastereo-
selectivity of the reactions was dependent on ring size, and
systematically diminished with ring size increase. In spiro-
cyclopentyloxindoles 8 and 9 pseudorotation is largely
hindered by high barriers. In these compounds, envelope
conformations with the cyano group disposed equatorial
and the spiranic carbon atom at the flap in 8, and C9 at the
flap in 9, were identified by NMR measurements, DFT
calculations, and by single-crystal X-ray analysis of 8. In
4.1.1.1. (1R*,2R*)- and (1S*,2R*)-10-Methyl-20-oxo-
10,20-dihydrospiro[cyclopropane-1,30-indole]-2-carbonitrile
4 and 5.10 Following the general procedure, 1 was reacted
with dibromomethane (226.0 mg, 1.3 mmol) to give a 2:1
mixture of 4 and 5 that was separated by flash chromato-
graphy (acetone/hexane 1:19) to afford successively 4
(130.0 mg, 60.7%) and 5 (64.9 mg, 30.3%). The spectral
and analytical data were consistent with those reported.10

7706
M. S. Morales-Rꢀıos et al. / Tetrahedron 63 (2007) 7702–7707
4.1.1.2. (10-Methyl-20-oxo-3-vinyl-2,3-dihydro-3-indo-
mixture was stirred for 3 h at the same temperature and
then an additional portion of NaH (25.8 mg, 1.07 mmol)
was added. After 7 h at room temperature, the reaction
was quenched with water (5 mL) and 5% aqueous HCl
(1.5 mL), extracted with EtOAc (3ꢁ25 mL), washed with
brine, dried over Na2SO4, and concentrated in vacuo to
give a mixture of diastereomers 10 and 11 together with al-
kene 3d in a 3:4:1 ratio, respectively. The mixture was puri-
fied by flash chromatography (EtOAc/hexane 1:19) to afford
successively 11, 10, and 3d. The GC retention times (min)
for the three compounds are: 3d, 5.57; 10, 6.21; 11, 6.04.
Data for 10: (57.7 mg, 22.4%) as colorless crystals (ace-
tone/hexane), mp 154–156 ꢀC. Rf 0.41 (EtOAc/hexane
lyl)acetonitrile (3b). Following the general procedure, 1
was reacted with 1,2-dibromoethane (244.2 mg, 1.3 mmol)
to give alkene 3b (74.3 mg, 33%) as colorless oil, after flash
chromatography (EtOAc/hexane 1:19). Rf 0.42 (EtOAc/hex-
1
ane 2:3). IR (CHCl3, cmꢂ1): 3012, 2254, 1716, 1614. H
NMR (CDCl3): d 7.50 (1H, ddd, J¼7.4, 1.1, 0.5 Hz, H4),
7.40 (1H, td, J¼7.7, 1.2 Hz, H6), 7.17 (1H, td, J¼7.6,
1.2 Hz, H5), 6.93 (1H, br d, J¼8.0 Hz, H7), 6.00 (1H, dd,
J¼17.3, 10.4 Hz, H9), 5.35 (1H, d, J¼10.4 Hz, H10), 5.23
(1H, d, J¼17.3 Hz, H100), 3.23 (3H, s, Me), 3.02 (1H, d,
J¼16.5 Hz, H8), 2.71 (1H, d, J¼16.5 Hz, H80). 13C NMR
(CDCl3): d 174.9 (C2), 143.1 (C7a), 134.0 (C9), 129.6
(C6), 127.7 (C3a), 124.7 (C4), 123.2 (C5), 118.9 (C10),
116.3 (CN), 108.9 (C7), 51.6 (C3), 26.6 (Me), 25.4 (C8).
EIMS m/z (relative intensity) 212 (M+, 38.7), 172 (100),
144 (52.2). HRMS calcd for C13H12N2O [M+H]+
213.1028, found 213.1028.
1
3:7). IR (CHCl3, cmꢂ1): 3014, 2244, 1712, 1614, 1472. H
NMR (CDCl3): d 7.61 (1H, br d, J¼7.4 Hz, H4), 7.38 (1H,
td, J¼7.7, 1.1 Hz, H6), 7.12 (1H, td, J¼7.7, 1.1 Hz, H5),
6.94 (1H, br d, J¼7.7 Hz, H7), 3.26 (3H, s, Me), 3.08 (1H,
dd, J¼11.3, 4.1 Hz, H8), 2.28 (1H, m, H9t), 2.06 (1H, m,
H9c), 2.00 (1H, m, H10c), 1.86 (1H, m, H11t), 1.86 (1H,
m, H11c), 1.83 (1H, m, 12t), 1.72 (1H, m, 12c), 1.60 (1H,
m, H10t). 13C NMR (CDCl3): d 177.4 (C2), 143.4 (C7a),
130.0 (C3a), 129.0 (C6), 125.0 (C4), 122.6 (C5), 119.1
(CN), 108.7 (C7), 49.0 (C3), 34.2 (C8), 32.1 (C12), 26.5
(Me), 25.3 (C9), 23.4 (C10), 20.0 (C11). EIMS m/z (relative
intensity) 240 (M+, 100), 186 (46), 160 (85). HRMS calcd
for C15H16N2O [M+H]+ 241.1341, found 241.1343. Data
for 11: (76.9 mg, 29.8%) as colorless crystals (acetone/
hexane), mp 149–151 ꢀC. Rf 0.44 (EtOAc/hexane 3:7). IR
4.1.1.3. (1R*,2R*)- and (1S*,2R*)-10-Methyl-20-oxo-
10,20-dihydrospiro[cyclopentane-1,30-indole]-2-carbonitrile
8 and 9. Following the general procedure, 1 was reacted with
1,3-dibromopropane (262.5 mg, 1.3 mmol) to give a mixture
of 3c, 8, and 9 in a 1:3:2 ratio, respectively. The GC retention
times (min) for the three compounds are: 3c, 5.26; 8, 5.84; 9,
5.86. Pure 8 and 9 were obtained by fractional crystallization
(acetone/hexane) after flash chromatography (EtOAc/
hexane 1:4) of the crude mixture. Data for 8: (76.7 mg,
31.6%) as colorless crystals (acetone/hexane), mp 135–
137 ꢀC. Rf 0.26 (EtOAc/hexane 3:7). IR (CHCl3, cmꢂ1):
1
(CHCl3, cmꢂ1): 3014, 2244, 1706, 1614, 1472. H NMR
(CDCl3): d 7.32 (1H, dd, J¼7.7, 1.5 Hz, H6), 7.16 (1H,
ddd, J¼7.4, 1.6, 0.6 Hz, H4), 7.10 (1H, dd, J¼7.4, 1.0 Hz,
H5), 6.88 (1H, br d, J¼7.7 Hz, H7), 3.24 (3H, s, Me), 2.86
(1H, dd, J¼12.6, 3.6 Hz, H8), 2.62 (1H, m, H9c), 2.24
(1H, m, H11c), 2.00 (1H, m, H10c), 2.01 (1H, m, H9t),
1.85 (1H, m, 12c), 1.70 (1H, m, 12t), 1.63 (1H, m, H11t),
1.41 (1H, m, H10t). 13C NMR (CDCl3): d 176.4 (C2),
143.1 (C7a), 131.5 (C3a), 129.0 (C6), 122.8 (C5), 121.8
(C4), 119.2 (CN), 108.4 (C7), 47.7 (C3), 35.9 (C8), 33.5
(C12), 26.1 (Me), 24.8 (C9), 24.3 (C10), 19.4 (C11).
EIMS m/z (relative intensity) 240 (M+, 100), 186 (35), 160
(70). HRMS calcd for C15H16N2O [M+H]+ 241.1341, found
241.1342. Data for 3d: (6.0 mg, 2.3%) as colorless oil Rf
0.40 (EtOAc/hexane 3:7). IR (CHCl3, cmꢂ1): 3014, 2252,
1
3016, 2244, 1710, 1614. H NMR (CDCl3): d 7.34 (1H, br
d, J¼7.4 Hz, H4), 7.33 (1H, td, J¼7.7, 1.4 Hz, H6), 7.11
(1H, td, J¼7.7, 1.1 Hz, H5), 6.84 (1H, br d, J¼7.7 Hz,
H7), 3.30 (1H, dd, J¼9.3, 8.5 Hz, H8), 3.25 (3H, s, Me),
2.58 (1H, m, H9t), 2.30 (1H, m, H9c), 2.25 (1H, m, H11t),
2.15 (1H, m, H10t), 2.15 (1H, m, H10c), 1.98 (1H, m,
H11c). 13C NMR (CDCl3): d 178.1 (C2), 143.0 (C7a),
130.7 (C3a), 129.0 (C6), 123.8 (C4), 123.1 (C5), 119.1
(CN), 108.5 (C7), 56.0 (C3), 38.3 (C8), 37.4 (C11), 31.7
(C9), 26.6 (Me), 24.6 (C10). EIMS m/z (relative intensity)
226 (M+, 100), 185 (75), 160 (70). HRMS calcd for
C14H14N2O [M+H]+ 227.1184, found 227.1184. Data for
9: (51.2 mg, 21.0%) as white solid (acetone/hexane), mp
123–126 ꢀC. Rf 0.28 (EtOAc/hexane 3:7). IR (CHCl3,
1
1712, 1640, 1470. H NMR (CDCl3): d 7.44 (1H, br d,
1
cmꢂ1): 3014, 2244, 1712, 1614. H NMR (CDCl3): d 7.29
J¼7.4 Hz, H4), 7.37 (1H, td, J¼7.7, 1.1 Hz, H6), 7.16
(1H, td, J¼7.7, 1.1 Hz, H5), 6.90 (1H, br d, J¼7.7 Hz,
H7), 5.62 (1H, ddt, J¼12.1, 5.2, 6.6 Hz, CH]), 4.87 (1H,
dq, J¼5.2, 1.6 Hz, CH2]), 4.83 (1H, dq, J¼12.3, 1.6 Hz,
CH2]), 3.23 (3H, s, Me), 2.86 and 2.58 (2H, d, J¼
16.7 Hz, H8,80), 2.10 (2H, t, J¼8 Hz, CH2-9), 1.69 (2H, m,
CH2-10). 13C NMR (CDCl3): d 176.7 (C2), 143.5 (C7a),
136.6 (CH]), 129.3 (C6), 128.8 (C3a), 123.3 (C4, C5),
116.5 (CN), 115.4 (CH2]), 108.6 (C7), 48.7 (C3), 35.2
(C9), 28.5 (C10), 26.4 (Me), 26.1 (C8). EIMS m/z (relative
intensity) 240 (M+, 6), 186 (65), 159 (100). HRMS calcd
for C15H16N2O [M+H]+ 241.1341, found 241.1338.
(1H, td, J¼7.7, 1.4 Hz, H6), 7.14 (1H, dd, J¼7.4, 1.1 Hz,
H4), 7.06 (1H, td, J¼7.4, 1.1 Hz, H5), 6.84 (1H, br d,
J¼7.7 Hz, H7), 3.24 (3H, s, Me), 3.04 (1H, dd, J¼11.0,
7.7 Hz, H8), 2.56 (1H, m, H9t), 2.35 (1H, m, H9c), 2.31
(1H, m, H10c), 2.25 (1H, m, H11c), 2.00 (1H, m, H11t),
1.98 (1H, m, H10t). 13C NMR (CDCl3): d 177.2 (C2),
143.5 (C7a), 130.3 (C3a), 128.8 (C6), 122.8 (C5), 121.7
(C4), 118.7 (CN), 108.3 (C7), 56.4 (C3), 39.7 (C8), 36.5
(C11), 30.7 (C9), 26.5 (Me), 24.7 (C10). EIMS m/z (relative
intensity) 226 (M+, 63), 185 (100), 160 (70). HRMS calcd
for C14H14N2O [M+H]+ 227.1184, found 227.1183.
4.1.1.4. (1R*,2R*)- and (1S*,2R*)-10-Methyl-20-oxo-
10,20-dihydrospiro[cyclohexane-1,30-indole]-2-carbonitrile
10 and 11. To a solution of oxindole 1 (200 mg, 1.07 mmol)
in DMF (4 mL) was added NaH (64.5 mg, 2.68 mmol), and
the mixture was stirred at room temperature for 5 min before
addition of 1,4-dibromobutane (280.7 mg, 1.3 mmol). The
4.2. X-ray diffraction analysis of 8, 10, and 11
Single crystals of 8, 10, and 11 were grown by slow crystal-
lization from acetone/hexane. The X-ray data of 8 were
measured on a Bruker Smart 6000 CCD diffractometer using
˚
Mo Ka radiation (l¼0.71073 A). A total of 1321 frames

M. S. Morales-Rꢀıos et al. / Tetrahedron 63 (2007) 7702–7707
7707
were collected with a scan width of 0.3ꢀ and exposure time
of 10 s/frame. The frames were processed with the SAINT
software package, provided by the diffractometer manu-
facturer. The X-ray data of 10 and 11 were collected on a
Bruker-Nonius CAD4 diffractometer using Cu Ka radiation
12, 3487–3490; (l) Mekhael, M. K. G.; Bienz, S.; Linden, A.;
Heimgartner, H. Helv. Chim. Acta 2004, 87, 2385–2404.
3. For reviews of dianions, see: (a) Kaiser, E. M.; Petty, J. D.;
Knutson, P. L. A. Synthesis 1977, 509–550; (b) Thompson,
C. M.; Green, D. Tetrahedron 1991, 47, 4223–4285.
4. (a) For a review of cyclization reactions of dianions, see:
Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125–4150;
(b) Dang, T. T.; Albrecht, U.; Gerwien, K.; Siebert, M.;
Langer, P. J. Org. Chem. 2006, 71, 2293–2301.
5. (a) Gros, P.; Viney, C.; Fort, Y. Synlett 2002, 628–630; (b)
Marzi, E.; Mongin, F.; Spitaleri, A.; Schlosser, M. Eur. J. Org.
Chem. 2001, 2911–2915; (c) Hassan, A. E. A.; Parker, W. B.;
Allan, P. W.; Montgomery, J. A.; Secrist, J. A. Nucleosides
Nucleotides 2003, 22, 747–749; (d) Apen, P. G.; Rasmussen,
P. G. J. Am. Chem. Soc. 1991, 113, 6178–6187; (e) Marino,
J. P.; Browne, L. J. Tetrahedron Lett. 1976, 3241–3244.
6. (a) Wenkert, E.; Blossey, E. C. J. Org. Chem. 1962, 27, 4656–
4659; (b) Somei, M.; Yamada, F.; Kurauchi, T.; Nagahama, Y.;
Hasegawa, M.; Yamada, K.; Teranishi, S.; Sato, H.; Kaneko, C.
Chem. Pharm. Bull. 2001, 49, 87–96; (c) Fischer, C.; Meyers,
C.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175–1181.
7. Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta,
D. C. J. Org. Chem. 2001, 66, 3653–3661.
˚
(l¼1.54184 A). The data were collected in the uꢂ2q scan
mode. Unit cell refinements were done using the CAD4
Express v 2.0 software. All structures were solved by direct
methods using the SHELXS-97 program included in the
WinGX v 1.64.05 crystallographic software package. For
the structural refinement, the non-hydrogen atoms were
treated anisotropically, and the hydrogen atoms, included
in the structure factor calculation, were refined isotropically.
The idealized disordered N-methyl groups in 8, 10, and 11
were assumed with two positions rotated by 60ꢀ and with
a half occupancy for hydrogen atoms.19 Compound 8
crystallized as colorless blocks in the monoclinic space
˚
group P21/n with cell dimensions a¼7.4840(3) A, b¼
ꢀ
˚
˚
16.8650(7) A, c¼9.5910(4) A, b¼102.75(2) and was
refined to final R indices (all data) R (%)¼5.5, Rw (%)¼
12.3. Compound 10 crystallized as colorless blocks in the tri-
˚
ꢀ
clinic space group P-1 with cell dimensions a¼7.995(1) A,
ꢀ
˚
˚
b¼8.911(1) A, c¼10.321(2) A, a¼65.67(1) , b¼80.04(1) ,
g¼89.59(1)ꢀ and was refined to final R indices (all data) R
(%)¼4.4, Rw (%)¼11.8. Compound 11 crystallized as
colorless blocks in the orthorhombic space group Pcab
ꢀ
8. (a) Morales-Rıos, M. S.; Rivera-Becerril, E.; Joseph-Nathan, P.
Tetrahedron: Asymmetry 2005, 16, 2493–2499; (b) Morales-
ꢀ
Rıos, M. S.; Santos-Sanchez, N. F.; Mora-Perez, Y.; Joseph-
Nathan, P. Heterocycles 2004, 63, 1131–1142.
ꢀ
ꢀ
˚
˚
with cell dimensions a¼10.925(3) A, b¼11.069(1) A, c¼
˚
21.435(3) A and was refined to final R indices (all data)
ꢀ
ꢀ
ꢀ
9. Suarez-Castillo, O. R.; Sanchez-Zavala, M.; Melendez-
ꢀ
ꢀ
ꢀ
Rodrıguez, M.; Castelan-Duarte, L. E.; Morales-Rıos, M. S.;
Joseph-Nathan, P. Tetrahedron 2006, 62, 3040–3051.
10. Shanmugam, P.; Vaithiyanathan, V.; Viswambharan, B. Tetra-
hedron 2006, 62, 4342–4348.
R (%)¼3.8, Rw (%)¼10.9. Data collection and refinement
parameters, atom coordinates, bond lengths and bond angles
have been deposited with the Cambridge Crystallographic
Data Centre. The CCDC deposition number for 8 is
645052, that for 10 is 645053, and that for 11 is 645054.
11. (a) Perdew, J. P. Phys. Rev. B 1986, 33, 8822–8824; (b) Becke,
A. D. Phys. Rev. A 1988, 38, 3098–3100.
12. The DFT/B3LYP/6-31G(d) optimized energies (E, kcal/
mol) for 4, 5, 8, and 9 are ꢂ406,631.75, ꢂ406,629.00,
ꢂ455,986.47 and ꢂ455,986.12, respectively.
Acknowledgements
The authors are grateful to CONACYT for partial financial
support.
ꢀ
ꢀ
ꢀ
13. (a) Morales-Rıos, M. S.; Santos-Sanchez, N. F.; Suarez-
Castillo, O. R.; Joseph-Nathan, P. Magn. Reson. Chem. 2002,
References and notes
ꢀ
40, 677–682; (b) Morales-Rıos, M. S.; Santos-Sanchez, N. F.;
Perez-Rojas, N. A.; Joseph-Nathan, P. Magn. Reson. Chem.
ꢀ
ꢀ
2004, 42, 973–976.
14. Hilderbrandt, R. L.; Leavitt, H.; Shen, Q. J. Mol. Struct. 1984,
116, 29–37.
1. For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem.
Res. 2003, 36, 127–139; (b) Da Silva, J. F. M.; Garden, S. J.;
Pinto, A. C. J. Braz. Chem. Soc. 2001, 273–324.
15. Choe, J.-I.; Harmony, M. D. J. Mol. Spectrosc. 1980, 81, 480–493.
16. (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, NY, 1994; Chapter 11; (b)
Abraham, R. J.; Koniotou, R. Magn. Reson. Chem. 2003,
41, 1000–1008; (c) Abraham, R. J.; Koniotou, R.; Sancassan, F.
J. Chem. Soc., Perkin Trans. 2 2002, 2025–2030; (d) Altona,
C.; Geise, H. J.; Romers, C. Tetrahedron 1968, 24, 13–32; (e)
Abraham, R. J.; Parry, K.; Thomas, W. A. J. Chem. Soc. B
1971, 446–453.
17. The signals corresponding to H8 and the diastereotopic methyl-
ene protons at C9, lacking overlap between them, were parti-
cularly useful to obtain accurate values of the gauche and
anti coupling constants in both six- and five-membered rings.
18. Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer,
P. v. R. J. Comput. Chem. 1983, 4, 294–301. The DFT/
B3LYP/6-31+G(d,p) optimized energies (E, kcal/mol) for 10
and 11 are ꢂ480689.185 and ꢂ480689.345, respectively.
19. Stomberg, R.; Langer, V.; Hauteville, M. Acta Crystallogr.
2002, E58, o1116–o1118.
2. For some recent synthetic studies, see: (a) Yong, S. R.; Ung, A. T.;
Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 2007, 63,
1191–1199; (b) Marti, C.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 11505–11515; (c) Jiang, T.; Kuhen, K. L.; Wolff,
K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu,
T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2105–
2108; (d) Robertson, D. W.; Krushinski, J. H.; Pollock, G. D.;
Wilson, H.; Kauffman, R. F.; Hayes, J. S. J. Med. Chem. 1987,
30, 824–829; (e) Yong, S. R.; Williams, M. C.; Pyne, S. G.;
Ung, A. T.; Skelton, B. W.; White, A. H.; Turner, P. Tetrahedron
2005, 61, 8120–8129; (f) Feldman, K. S.; Vidulova, D. B.;
Karatjas, A. G. J. Org. Chem. 2005, 70, 6429–6440; (g) Osman,
F. H.; El-Samahy, F. A. Tetrahedron 2000, 56, 1863–1871; (h)
Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425–2428; (i)
Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137–4140;
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Fensome, A.; Bender, R.; Cohen, J.; Collins, M. A.; Mackner,
V. A.; Miller, L. L.; Ullrich, J. W.; Winneker, R.; Wrobel, J.;
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