Stereochemistry modulates the catalytic hydrogenolysis of nitrile-substituted cyclopropanes

Article abstract of DOI:10.1016/j.tet.2012.06.025

The study of Raney-Ni catalyzed chemo- and regioselective hydrogenolysis of diastereomeric nitrile-substituted spirocyclopropyloxindoles is presented. The chemoselectivity outcome of the reaction is remarkably influenced by the relative stereochemistry of

Full text of DOI:10.1016/j.tet.2012.06.025

Tetrahedron 68 (2012) 7187e7195
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereochemistry modulates the catalytic hydrogenolysis of nitrile-substituted
cyclopropanes
a
,
b
a
,
b
a,b
ꢀ
ꢀ
ꢀ
ꢀ~
Daphne E. Gonzalez-Juarez , J. Benjamín García-Vazquez , Violeta Zuniga-García
,
Joel J. Trujillo-Serrato , Oscar R. Suarez-Castillo , Pedro Joseph-Nathan b, Martha S. Morales-Ríos a
Departamento de Química, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado 14-740, Mexico 07000, D.F., Mexico
a
c
a
,
,b,
*
ꢀ
a
ꢀ
ꢀ
ꢀ
b
c
ꢀ
ꢀ
ꢀ
Programa de Posgrado en Farmacología, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado 14-740, Mexico 07000, D.F., Mexico
ꢀ
ꢀ
ꢀ
Area Academica de Química, Universidad Autonoma del Estado de Hidalgo, Mineral de la Reforma, Hidalgo, 42184, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
The study of Raney-Ni catalyzed chemo- and regioselective hydrogenolysis of diastereomeric nitrile-
substituted spirocyclopropyloxindoles is presented. The chemoselectivity outcome of the reaction is
remarkably influenced by the relative stereochemistry of the nitrile-substituted spirocyclopropylox-
indoles. Chemo- and high regioselective cyclopropane ring-opening occurs from the syn diastereomers to
give the corresponding 3-propylacetamide derivatives. X-ray crystallographic studies together with DFT
model chemistry calculations indicate that chemo- and regioselectivity are directly dependent on the
bond length asymmetry of the cyclopropane ring.
Received 2 March 2012
Received in revised form 5 June 2012
Accepted 6 June 2012
Available online 15 June 2012
Keywords:
Cyclopropane
Stereochemistry
Hydrogenolysis
Regioselectivity
Chemoselectivity
DFT study
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
involves transfer of electron density from the Walsh cyclopropane
orbitals to the substituent orbitals. For almost three decades the
Nitrile-substituted cyclopropanes are an important class of
compounds due to their role as structural components of a growing
number of more complex synthetic products presenting interesting
biological and pharmacological properties. Particular attention to
this type of compounds becomes probably from the significant
conformational restrictions that the cyclopropane ring imposes on
the molecule in which it is incorporated.1 As synthetic tools, nitrile-
substituted cyclopropanes are versatile templates for the rapid
formation of biologically active and synthetically useful function-
alized cyclopropane derivatives.2 Additionally, the release of strain
arising from cleavage of cyclopropanes has been frequently utilized
in organic synthesis and represents an useful method for the con-
struction of a wide variety of carbon skeletons.3
opening of cyclopropanes by lengthening of a ring bond has been
associated with variation on charge density.9 Moreover, X-ray
studies of cyclopropane derivatives recognize that substituent-
induced bond length asymmetries are consistently observed in
the geometries of derivatives involving
p-acceptor sub-
stituents.10,11 In these cases, the substituents on the cyclopropyl
group might be critical factors in controlling regioselectivity.
Considering the hydrogenolysis of the acceptor-substituted cy-
clopropanes, a literature survey revealed that opening of the
three-membered ring can be tuned by the substituents. However,
background information concerning this type of approach remains
scarce.12e15
In this paper, we wish to report that chemo- and regioselective
reactions occur in the catalytic hydrogenolysis of diastereomeric
(3R*,9R*)- and (3R*,9S*)-nitrile-substituted spiro[cyclopropyl-1,3-
oxindoles] 1ae1c by the use of Raney-Ni catalyst. In order to ra-
tionalize these results, X-ray studies together with DFT calculations
on the bond lengthening, the strain, and the charge distribution
induced in the cyclopropyl ring by the geometrical changes in di-
astereomeric spirocyclopropyloxindoles 1ae1c have also been
carried out.
In regard to reactivity, the chemical properties of cyclopro-
panes are unusual among cycloalkanes in that they conjugate with
p
-acceptor substituents, as is shown by experimental and ab initio
calculations.4e8 Molecular orbital theory suggests that conjugation
* Corresponding author. Tel.: þ52 55 57477112; fax: þ52 55 57477113; e-mail
address: smorales@cinvestav.mx (M.S. Morales-Ríos).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.025

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D.E. Gonzalez-Juarez et al. / Tetrahedron 68 (2012) 7187e7195
7188
2. Results and discussion
Fig. 2, the 5-methoxyl group in the anti-1b isomer crystallized in
the s-trans conformation with respect to H-4, while in the syn
isomer it was found to possess the s-cis conformation in the solid
state. Since the cyano group is linear, and internal rotation of the
carbonyl lactam group against the cyclopropane ring is restricted,
no additional conformational preferences are possible.
2.1. Preparation and structural analysis of diastereomeric
nitrile-substituted spirocyclopropyloxindoles, 1ae1c
Some years ago we reported a method leading, after one-pot
base-mediated
double-alkylation
process
of
3-
The crystal structures of anti- and syn-1b showed systematic
geometrical changes for the endocyclic cyclopropane CeC bonds
lengths. Although the average bond length (C3eC8/C3eC9/C8eC9)
cyanomethyloxindoles, to three-, five- and six-membered spiro
[cycloalkyl-1,30-oxindoles].16 Following our previously reported
procedure (NaH, CH2Br2, DMF, rt), nitrile-substituted cyclopropane
derivatives 1ae1c bearing two contiguous stereocenters were
prepared from the corresponding oxindoles 2ae2c as chromato-
graphically separable diastereomeric mixtures. In all cases, the
major isomer 3R*,9R*, with the cyano group anti with respect to the
carbonyl group at C-2, was the less polar compound (higher Rf
value) and was obtained in diastereomeric ratio (dr) of 2:1 to 3:1
(Table 1). The anti stereochemistry of these compounds is ther-
modynamically preferred.16
ꢁ
in anti- and syn-1b is only 0.001 A greater than the CeC bond
17
ꢁ
length in unsubstituted cyclopropane (1.503 A), the C3eC9 bond
of the three-membered ring in these compounds is significantly
ꢁ
lengthened by 0.020e0.025 A, while the C3eC8 and C8eC9 bonds
ꢁ
are shortened by 0.005e0.015 A. These results are construed to be
an indication that the cyclopropyl ring is conjugated with the cyano
and carbonyl lactam acceptor groups.10,18 Furthermore, the finding
ꢁ
that the C3eC9 bond in syn-1b is more lengthened by 0.005 A than
in the anti isomer (entries 5 and 6, Table 2), concomitant with
a decrease in the angle (a) at the spirocyclic carbon atom
(C8eC3eC9) from 59.05ꢀ in the anti isomer to 58.88ꢀ in the syn
compound evidenced an increased ring strain imposed by geo-
metrical factors in syn-1b. In view of these results, our next target
was to investigate the structural properties and quantify the sta-
bility differences of nitrile-substituted spirocyclopropyloxindoles
anti- and syn-1ae1c.
Table 1
Synthesis of spiro[cyclopropyl-1,3-oxindoles] 1ae1ca
NC
R2
R2
CN
CH2Br2
DMF
*
N
2.2. Computational studies
O
O
N
R1
NaH 2.5 eq
rt
R1
anti/syn 1a-1c
In an attempt to study the conformational and structural
properties of anti and syn cyclopropane derivatives 1ae1c we cal-
culated their structures and relative stabilities by density functional
theory (DFT) computed at the B3LYP/6-31G(d,p) level. Geometry
optimization in gas phase for anti and syn diastereomers 1ae1c
resulted in one stable conformation for diastereomers 1a, two for
those of 1b (labeled C1 and C2), and four for those of 1c. The
structural parameters associated with the cyclopropane ring of
1ae1c are given in Table 2, for anti- and syn-1b and -1c, only data
for the most stable conformer (C1) are shown. As was observed, the
optimized parameters show relevant variations when going from
the anti to the syn diastereomer. As expected, the optimized
structures of anti- and syn-1ae1c reveal that the donoreacceptor
2
Entry
Oxindole 2
drb anti/syn 1
Yield 1c (%)
1
2
3
a
b
c
2:1
3:1
3:1
91
84
84
a
For R1 and R2 see Fig. 1.
b
Determined by GCeMS and/or 1H NMR after equilibration under the reaction
conditions.
c
Isolated combined yield.
NC
CN
O
interaction between the cyclopropyl group and the substituent
p-
R2
9
R2
ꢁ
4
system significantly lengthen the C3eC9 bond by 0.04e0.05 A, but
imparts much less changes in length of the other two C3eC8 and
8
5
3a
3
6
ꢁ
C8eC9 bonds, which vary from 0.002 to 0.006 A with respect to the
O
7a
2
7
N
value in unsubstituted cyclopropane (Table 2). In agreement with
N
X-ray crystallographic analysis, the largest effect on the C3eC9
R1
R1
(3R*,9R*)-anti
ꢁ
bond lengthening is found in the syn isomers by 0.001e0.002 A as
compared with the C3eC9 bond length in the anti isomers (Table 2).
In all cases the optimized structures of the anti-1ae1c isomers
appear to be more stable than their syn isomers, with an energy
difference of 2.45e3.51 kcal/mol between them (Table 2). There-
fore, from the thermodynamic view anti-1ae1c isomers are more
stable than their syn counterparts, in agreement with the experi-
mental data (Table 1). The relatively small energy difference be-
tween the two conformations C1 and C2 of anti- and syn-1b (Fig. 3)
is attributed to a rotation around the OeCH3 single bond of the
methoxy group, with C4eC5eO5eC12 dihedral angles close to
0ꢀ for C1 and 180ꢀ for C2. In addition, the anti isomers correspond to
C2eC3eC9eC10 dihedral angles of the order of ꢁ140ꢀ, whereas the
syn diastereomers have C2eC3eC9eC10 dihedral angles of about
ꢁ3ꢀ, consistent with crystallography results.
(3R*,9S*)-syn
1a: R1 = Me, R2 = H
1b: R1 = Me, R2 = OMe
1c: R1 = p-MeOBn, R2 = H
Fig. 1. Structures of diastereomers 1ae1c.
The relative stereochemistry attribution of the anti and syn di-
astereomers 1ae1c was based on anisotropic effects of the nitrile
and carbonyl groups on the chemical shifts of H-4 and H-9, re-
spectively, together with the spatial proximity determination of
characteristic protons by using a NOESY sequence. In addition, the
relative stereochemistry of anti- and syn-1b and anti-1c isomers
was confirmed by X-ray crystallographic analysis. As shown in
DFT calculations also suggest that the synperiplanar orientation
between the nitrile and carbonyl groups can result in a sensitive
increase in the corresponding spirocyclopropyloxindoles dipole
moment (m, Table 2). The Mulliken charge (q) distribution by DFT

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D.E. Gonzalez-Juarez et al. / Tetrahedron 68 (2012) 7187e7195
7189
Fig. 2. X-ray molecular structures of spiro[cyclopropyl-1,30-oxindoles] of anti- and syn-1b and anti-1c isomers. The methyl group C11 is disordered in anti-1b, but only one rep-
resentation is shown.19
Table 2
Relative energy (ER),a selected bond lengths,a,b dipole moment (
m
),a and Mulliken charges (q)a for anti- and syn-1ae1c
Bond lengthsc (A)
m
(D)
Charge (q)
d
ꢁ
Entry
ER
C3eC8
C3eC9
C8eC9
C9eC10
C-3
C-8
C-9
C-10
1a
2a
3a
4a
5b
6b
7a
8a
9b
anti-1a
syn-1a
C1-anti-1b
C1-syn-1b
anti-1b
0.0e
2.86
0.0f
3.51
d
1.509
1.508
1.509
1.507
1.498
1.498
1.509
1.507
1.507
1.542
1.543
1.541
1.543
1.523
1.528
1.543
1.544
1.529
1.507
1.505
1.507
1.506
1.489
1.488
1.507
1.505
1.493
1.440
1.443
1.440
1.443
d
4.19
6.55
3.17
6.58
d
þ0.235
þ0.622
þ0.531
þ0.955
d
ꢁ0.427
ꢁ0.509
ꢁ0.440
ꢁ0.523
d
þ0.071
þ0.038
þ0.064
þ0.025
d
þ0.088
þ0.007
þ0.082
þ0.004
d
syn-1b
d
d
d
d
d
d
d
C1-anti-1c
C1-syn-1c
anti-1c
0.0g,h
2.45g
d
1.440
1.442
d
3.01
5.13
d
þ0.441
þ0.674
d
ꢁ0.367
ꢁ0.455
d
þ0.266
þ0.078
d
0.000
ꢁ0.043
d
a
Computed data at the B3LYP/6-31G(d,p) level.
X-ray data.
b
c
See Fig. 2 for atom numbering.
Calculated relative energy (kcal/mol).
Ea¼ꢁ648.045735 au.
d
e
f
Ea¼ꢁ762.572717 au.
g
h
For the most stable conformer.
Ea¼ꢁ993.639213 au.
Fig. 3. Calculated molecular structures of spiro[cyclopropyl-1,30-oxindoles] anti- and syn-1c. ER: calculated relative energy (kcal/mol).
calculations reveals that while a negative charge accumulates on
the C-8 carbon, the spirocyclic carbon C-3 is predicted to have
a much more positive charge than the C-9 carbon in both anti and
syn isomers. In addition, the positive charge on C-3 increases
significantly on going from anti to syn isomers, whereas an inverse
trend is observed for the C-9 atom. Systematic changes are also
evidenced when comparing the increase of the C9eC10 bond
length with the decrease of the positive charge on C-10 on going

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D.E. Gonzalez-Juarez et al. / Tetrahedron 68 (2012) 7187e7195
7190
from anti to syn isomers (Table 2). In summary, all the above trends
predict that syn-1ae1c compounds should be more reactive than
anti isomers.
2.3. Preparation of 3-propionitrile oxindoles 3ae3c
It is noticeable that although reduction of nitrile-substituted
cyclopropanes to the corresponding aminomethyl compounds by
LiAlH4 has appeared in the literature,20 and the fact that a number of
3-acetonitriloxindoles are prone to undergo LiAlH4 reduction to
pyrrolidinoindolines,21 exploratory experiments on nitrile-
substituted spirocyclopropyloxindole anti-1a were unsuccessful. In
none of the test reactions could aminomethyl spirocyclopropylox-
indoles be detected, neither products derived from the carbonyl
amide group reduction, as determined by GCeMS analysis. In fact,
no recognizable products were isolated after treatment with aque-
ous base, even at only 50% conversion. In this case, a mixture of anti/
syn epimers of 1a was recovered. For the epimerization of anti-1a,
a plausible intermediacy of stabilized cyclopropyl anion through an
inductive effect of the cyano group is proposed.22
Hydrogenation using Raney-Ni as a catalyst was then exam-
ined.13 The initial screening results (Table 3) indicated that at
45 psi, at room temperature an 70% conversion of spiro[cyclo-
propyl-1,30-oxindole] anti-1a in THF was achieved after 5 h in the
absence or the presence of a base such as diethylamine allowing to
the regioselective formation of ring-opened 3-propionitrile oxin-
dole 3a, in a modest 31% yield after purification. It is worth noting
that the mass chromatogram of the crude reaction mixture showed
the presence of only four chromatographic peaks. The major com-
ponent of the chromatogram was 3a, as tested by the molecular ion
[M]þꢂ in the mass spectra, which was shifted by 2 Da with respect to
that of starting material (2:1 ratio), while the molecular ion [M]þꢂ of
the two lower components (ꢃ5%) were shifted by 32 and 46 Da
with respect to that of starting material (Fig. 4). Thus, we may as-
sume that the yield of 3a, obtained as single isomer, was lowered by
the formation of a large amount of unidentified byproducts, which
were retained in the precolumn of the ion-trap spectrometer. An
increased reaction time was found detrimental on the yield. A
slightly improved yield was achieved at lower pressure (35 psi) and
prolonged reaction time (24 h) producing 3a as single structural
isomer in some 40% yield and a trace amount of anti-1a. Catalytic
hydrogenation of spiro[cyclopropyl-1,30-oxindoles] anti-1b and
anti-1c at 45 psi, after 5 h caused cleavage of the C3eC9 bond to
give 3b and 3c in reliable 37e45% yields after purification (entries 3
Fig. 4. Mass chromatogram and mass spectra for the hydrogenation of anti-1a in the
presence of Ni-Raney/THF at 45 psi, 5 h, rt.
and 4, Table 3). These results suggest the lengthening and therefore
weakening of the C3eC9 cyclopropane ring bond is a dominant
factor in the regioselective opening of spiro[cyclopropyl-1,30-oxin-
doles] anti-1ae1c. The results are in accordance with our earlier
observations involving the regioselective opening of nitrile cyclo-
propanes with high level of substituent-induced endocyclic bond-
length asymmetry,23 together with X-ray analysis and DFT theo-
retical approach. Compounds 3ae3c were further subjected to
hydrogenation of the nitrile group with Raney-Ni in Ac2O to afford
3-propylacetamide oxindoles 4ae4c in 70e75% yield (Scheme 1).
Table 3
10
R2
R2
CN
Hydrogenolysis of spiro[cyclopropyl-1,30-oxindoles] anti-1ae1ca,b with Raney-Ni in
NHAc
8
8
THF
9
9
H2
NC
Raney-Ni
Ac2O
O
O
N
R1
N
R1
R2
R2
CN
*
H2
*
N
R1
3a-c
4a-c
Raney-Ni
THF
O
O
Scheme 1. Hydrogenolysis of 3-propionitrile oxindoles 3ae3c with Raney-Ni in Ac2O.
N
R1
3
anti 1a-c
2.4. Preparation of 3-propylacetamide oxindoles 4ae4c
Entry
Spirooxindole 1
Pressure (psi)
Yield 3 (%)
Conversionc (%)
We next examined the use of Ac2O as the solvent. Hydrogena-
tion of anti-1a in the presence of Raney-Ni at 45 psi gave mainly the
regioselectively cleaved cyclopropane ring product 4a accompa-
nied by the anti isomer of the ring-retained product 5a, which were
difficult to separate (entry 1, Table 4). The ratio of 4a to anti-5a was
3:1 as determined by GCeMS and 1H NMR of the chromatographed
mixture. Comparison of spectral data of 4a with those above de-
scribed confirmed the structural assignments. However, the minor
1
2
3
4
a
a
b
c
45
35d
45
31
40
37
45
70
>95
77
45
81
a
For R1 and R2 see Fig. 1.
Substrate (30 mg/mL) in THF, 5 h, rt.
Substrate.
24 h.
b
c
d

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D.E. Gonzalez-Juarez et al. / Tetrahedron 68 (2012) 7187e7195
7191
Table 4
Hydrogenolysis of spiro[cyclopropyl-1,30-oxindoles] anti-1ae1c and syn-1ae1c with Raney-Ni in Ac2Oa,b
10
NC
AcHN
R2
R2
R2
9
NHAc
8
H2
*
N
*
N
R1
+
Raney-Ni
Ac2O
O
O
O
N
R1
R1
anti/syn 1a-1c
4
5
Entry
Spirooxindole 1
4/5 Ratioc
Global yield (%)
1
2
3
4
5
6
anti-a
syn-a
anti-b
syn-b
anti-c
syn-c
3:1
6:1
3:1
6:1
3:1
6:1
75
78
87
84
85
90
a
For R1 and R2 see Fig. 1.
b
c
Substrate (30 mg/mL), catalyst 200% wt, 45 psi, 5 h.
Determined by GCeMS and/or 1H NMR of crude reaction mixture.
component anti-5a failed to separate completely by flash column
chromatography on silica gel and was spectroscopically character-
ized in the mixture. Conversion of starting nitrile anti-1a was
complete and the epimeric amide syn-5a was not formed to any
measurable extent, as determined by GCeMS and 1H NMR analysis
of unpurified reaction products. These observations evidence that
equilibration of the starting diastereomer anti-1a did not take place
appreciably, and diastereomer 5a is formed independently of their
relative thermodynamic stability.
sequence, with particular attention focused on the H-4, H-8, and H-
9 protons (Table 5).
Table 5
Selected 1H NMR shifts ( ), 2J(H,H) and 3J(H,H) coupling constants (Hz), and NOESY
d
correlations of spirocyclopropyl acetamides syn-5ae5c in CDCl3
a
syn 5
d
H-4
2J8a,8s
3J8a,9
3J8s,9
H-4 NOESY correlations
a
b
c
6.82
6.41
6.80
4.7
4.7
4.7
8.2
7.9
8.2
8.8
8.9
8.2
H-8a (
H-8a (
H-8a (
d
d
d
1.72), H-9 (
1.69), H-9 (
1.78), H-9 (
d
d
d
2.34)
2.31)
2.37)
To confirm the above result, we decided to examine the be-
havior of syn-1a toward the hydrogenation reaction. In fact, it is
very noticeable that a good chemoselectivity and high regiose-
lectivity were obtained when syn-1a was exposed to the same re-
action conditions (entry 2, Table 4). Analysis of the crude reaction
mixture by GCeMS and 1H NMR revealed formation of the 3-
propylacetamide oxindole 4a, together with a reduced yield of
the spiro[cyclopropyl-1,30-oxindole]-2-acetamide 5a, as single syn
diastereomer (6:1 ratio). After chromatography separation over
silica gel, products 4a and syn-5a were obtained in 67% and 11%
yield, respectively. An analogous result was obtained when syn-1b
or syn-1c was submitted to hydrogenolysis (entries 4 and 6, Table
4). Based on these results, together with modeling studies on
anti/syn-1aec discussed above, it seems reasonable to assume that
an enhanced strain in the syn isomers is responsible for the ob-
served diminished stability and increased chemoselectivity.
Attempts to reduce the spirocyclopropyl acetamide syn-5a under
similar reduction conditions were unsuccessful as this cyclopropane
was completely unreactive toward catalytic hydrogenation. These
results evidence that the lengthening and therefore weakening of
the C3eC9 cyclopropane ring bond is not only strongly dependent
on the electron-withdrawing character of the neighboring sub-
stituentsdnitrile and amidedin a vicinal relationship, but also on
the stereochemistry of the C-3 and C-9 stereogenic centers.
As in the case of the syn diastereomers 1b and 1c described
above, the influence of an electron-donating methoxy group on the
remote aromatic ring, or substitution by a benzyl group at the N1
position in the corresponding anti diastereomers (entries 3 and 5,
Table 4) did not make much a difference when such compounds
were submitted to hydrogenolysis, giving mixtures of the ring-
opening/cyclopropyl acetamide products 4b,c/5b,c (3:1 ratio) in
87% and 85% global yields, respectively.
a
The diastereotopic methylene protons are designated as anti (a) or syn (s) with
respect to the carbonyl group at C-2.
3. Conclusions
In summary, we have demonstrated that while Raney-Ni cata-
lyzed hydrogenolysis of nitrile-substituted cyclopropanes 1ae1c in
THF was quite challenging, a more chemoselective hydrogenolysis
reaction takes place using Ac2O as the solvent. Under these reaction
conditions, a competitive reduction of the nitrile group in parallel
with the ring-opening of cyclopropane occurs. It was found that
this competition is shifted by a factor of 2 in favor of ring-opening of
cyclopropane with the syn isomers. The hydrogenolysis proceed in
a highly regioselective manner at the C3eC9 bond of the cyclo-
propane ring to give 3-propylacetamide oxindoles. The lengthening
and therefore weakening of the cyclopropane C3eC9 bond is
influenced by the relative stereochemistry of the stereogenic cen-
ters. The predictions of DFT computations are completely in line
with the available experimental indications.
4. Experimental section
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 purification. Analytical
thin-layer chromatography (TLC) was performed on silica gel 60
F254 coated aluminum sheets (0.25 mm thickness) with a fluores-
cent indicator. Visualization was accomplished with UV light
(254 nm). Flash chromatography was performed using silica gel 60
(230e400 mesh). IR spectra were obtained in chloroform using
The unambiguous attribution of the relative configuration of
both anti and syn diastereomers 5 was based on the spatial prox-
imity determination of characteristic protons using a NOESY

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D.E. Gonzalez-Juarez et al. / Tetrahedron 68 (2012) 7187e7195
7192
a Buck Scientific 500 spectrophotometer. NMR spectra were
recorded in deuterochloroform on Varian Mercury spectrometers
working at 300 and 75.4 MHz for 1H and 13C, respectively. NMR
GCeMS (EI, 70 eV): m/z (%)¼228 (Mþ, 100), 213 (88), 185 (17);
HRESI/APCIMS: m/z calcd for C13H12N2O2þH: 229.0977; found:
229.0978.
data are reported in parts per million (d) downfield from tetrame-
thylsilane, using the formulas numbering given in Fig. 1 with the
normal abbreviations (s, singlet; d, doublet; t, triplet; br, broad; m,
multiplet) and a and s to denote anti and syn to the carbonyl group
at C-2, respectively. All structural assignments were supported by
gHMBC, gHSQC, and NOESY. GCeMS analyses were conducted on
a Varian CP 3800 GC spectrometer 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), pro-
grammed from 70 ꢀC to 250 ꢀC at a rate of 30 ꢀC/min, with the in-
jector 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 Spectrometry Facility, University of
California, Riverside, CA. Compounds 1a,16 2a,21a,24 2b,21a and 2c25
are known.
4.2.3. (1R*,2R*)-10-(4-Methoxybenzyl)-20-oxo-10,20-dihydrospiro[cy-
clopropane-1,30-indole]-2-carbonitrile (anti-1c) and (1R*,2S*)-10-(4-
methoxybenzyl)-20-oxo-10,20-dihydrospiro[cyclopropane-1,30-indole]-
2-carbonitrile (syn-1c). Application of the typical procedure using
oxindole 2c (200 mg, 0.68 mmol) gave a 3:1 mixture of anti/syn
isomers 1c that was separated by flash chromatography (hexane/
EtOAc 9:1) to afford successively anti-1c (131.2 mg, 63%) and syn-1c
(43.7 mg, 21%). For anti-1c: yellow crystals (acetone/hexane), mp
182e183 ꢀC. Rf : 0.57 (hexane/EtOAc 3:2); IR (CHCl3, cmꢁ1): 2251,
1715; dH: 7.28 (1H, td, J¼7.6, 1.3 Hz, H-5), 7.25 (2H, m, Ho), 7.20 (1H,
ddd, J¼7.6,1.3, 0.6 Hz, H-4), 7.10 (1H, td, J¼7.6,1.0 Hz, H-6), 6.90 (1H,
dd, J¼7.8, 1.0 Hz, H-7), 6.85 (2H, m, Hm), 4.94 and 4.88 (2H, AB,
J¼14.7 Hz, CH2), 3.77 (3H, s, OMe), 2.51 (1H, dd, J¼9.5, 7.0 Hz, H-9s),
2.18 (1H, dd, J¼9.5, 5.0 Hz, H-8s), 1.92 (1H, dd, J¼7.0, 5.0 Hz, H-8a);
dC: 173.0 (C-2), 159.2 (Cp), 143.3 (C-7a), 128.8 (2Co), 128.7 (C-5),
127.4 (Ci), 124.1 (C-3a), 122.8 (C-6), 120.9 (C-4), 116.8 (CN), 114.2
(2Cm), 109.6 (C-7), 55.2 (OMe), 43.9 (NCH2), 31.6 (C-3), 21.5 (C-8),
14.9 (C-9); MS (EI, 70 eV): m/z (%)¼304 (Mþ, 15), 265 (12), 121
(100); HRESI/APCIMS: m/z calcd for C19H16N2O2þH: 305.1285;
found: 305.1291. For syn-1c: pale yellow solid (acetone/hexane),
mp 132e133 ꢀC. Rf : 0.38 (hexane/EtOAc 3:2); IR (CHCl3, cmꢁ1):
2252,1717; dH: 7.29 (2H, m, Ho), 7.23 (1H, td, J¼7.7,1.2, Hz, H-5), 7.01
(1H, td, J¼7.7, 0.9 Hz, H-6), 6.87 (1H, br d, J¼7.7 Hz, H-7), 6.85 (2H,
m, Hm), 6.81 (1H, br d, J¼7.7 Hz, H-4), 4.98 and 4.90 (2H, AB,
J¼15.3 Hz, CH2), 3.76 (3H, s, OMe), 2.35 (1H, dd, J¼9.2, 7.4, H-9a),
4.2. Typical spirocyclization procedure: synthesis of anti/syn-
1a
To a solution of oxindole 2a (200 mg, 1.1 mmol) in DMF (4 mL)
was added NaH (64.5 mg, 2.68 mmol), and the suspension was
stirred at room temperature for 5 min before addition of CH2Br2
(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 (3ꢄ25 mL), washed with brine,
dried over Na2SO4, and concentrated in vacuo to give a mixture of
anti/syn isomers 1a that was separated by flash chromatography
(hexane/EtOAc 4:1) to afford successively anti-1a (130.0 mg, 61%)
and syn-1a (64.9 mg, 30%).
2.22 (1H, dd, J¼7.4, 5.0 Hz, H-8s), 2.01 (1H, J¼9.2, 5.0 Hz, H-8a); dC
:
171.5 (C-2), 159.1 (Cp), 143.0 (C-7a), 128.9 (2C, Co), 128.6 (C-5), 127.5
(Ci), 125.9 (C-3a), 122.4 (C-6), 118.9 (C-4), 115.9 (CN), 114.1 (2C, Cm),
109.6 (C-7), 55.2 (OMe) 43.8 (NCH2), 31.8 (C-3), 21.2 (C-8), 15.2 (C-
9); GCeMS (EI, 70 eV): m/z (%)¼304 (Mþ, 14), 265 (11), 121 (100);
HRESI/APCIMS: m/z calcd for C19H16N2O2þNa: 327.1104; found:
327.1111.
4.2.1. (1R*,2R*)-10-Methyl-20-oxo-10,20-dihydrospiro[cyclopropane-
1,30-indole]-2-carbonitrile (anti-1a) and (1R*,2S*)-10-methyl-20-oxo-
10,20-dihydrospiro[cyclopropane-1,30-indole]-2-carbonitrile
(syn-
4.3. Typical catalytic hydrogenolysis procedure in THF:
1a). The spectral data of anti-1a and syn-1a were identical with
catalytic hydrogenolysis of anti-1a
those reported.16
A
solution of the nitrile-substituted cyclopropane anti-1a
4.2.2. (1R*,2R*)-50-Methoxy-10-methyl-20-oxo-10,20-dihydrospiro[cy-
clopropane-1,30-indole]-2-carbonitrile (anti-1b) and (1R*,2S*)-50-
methoxy-10-methyl-20-oxo-10,20-dihydrospiro[cyclopropane-1,30-in-
dole]-2-carbonitrile (syn-1b). Application of the typical procedure
using oxindole 2b (200 mg, 0.93 mmol) gave a 3:1 mixture of anti/
syn isomers 1b that was separated by flash chromatography (hex-
ane/EtOAc 4:1) to afford successively anti-1b (133.7 mg, 63%) and
syn-1b (44.5 mg, 21%). For anti-1b: colorless crystals (acetone/
hexane), mp 164e165 ꢀC. Rf : 0.31 (hexane/EtOAc 3:2); IR (CHCl3,
cmꢁ1): 2248, 1712; dH: 6.90 (1H, dd, J¼8.5, 2.2 Hz, H-6), 6.86 (1H, br
d, J¼8.5 Hz, H-7), 6.82 (1H, br d, J¼2.2 Hz, H-4), 3.78 (3H, s, OMe),
3.25 (3H, s, NMe), 2.43 (1H, dd, J¼9.3, 7.1 Hz, H-9s), 2.11 (1H, dd,
J¼9.3, 4.9 Hz, H-8s), 1.86 (1H, dd, J¼7.1, 4.9 Hz, H-8a); dC: 172.5 (C-
2), 156.0 (C-5), 137.4 (C-7a), 125.2 (C-3a), 116.7 (CN), 113.4 (C-6),
109.0 (C-7), 108.1 (C-4), 55.7 (OMe), 31.9 (C-3), 26.8 (NMe), 21.3 (C-
8), 14.6 (C-9); MS (EI, 70 eV): m/z (%)¼228 (Mþ, 100), 213 (89), 185
(2); HRESI/APCIMS: m/z calcd for C13H12N2O2þH: 229.0977; found:
229.0976. For syn-1b: colorless crystals (acetone/hexane), mp
208e210 ꢀC. Rf : 0.23 (hexane/EtOAc 3:2); IR (CHCl3, cmꢁ1): 2248,
1716; dH: 6.86 (H, dd, J¼8.4, 2.0 Hz, H-6), 6.84 (1H, dd, J¼8.4, 1.1 Hz,
H-7) 6.44 (1H, dd, J¼2.0, 1.1 Hz, H-4), 3.78 (3H, s, OMe), 3.30 (3H, s,
NMe), 2.30 (1H, dd, J¼9.2, 7.5 Hz, H-9a), 2.18 (1H, dd, J¼7.5, 5.1 Hz,
H-8s), 1.96 (1H, dd, J¼9.2, 5.1 Hz, H-8a); dC: 171.1 (C-2), 156.0 (C-5),
137.5 (C-7a), 127.3 (C-3a), 115.9 (CN), 112.8 (C-6), 109.0 (C-7), 106.7
(C-4), 55.9 (OMe), 32.1 (C-3), 26.9 (NMe), 21.2 (C-8), 15.1 (C-9);
(200 mg, 1.0 mmol) was hydrogenated in a Parr bomb over W-526
Raney-Ni catalyst (550 mg) in dry THF (8 mL) at room temperature
under 45 psi H2 for 5 h. The mixture was filtered through Celite and
concentrated in vacuo to dryness. The residue was dissolved in
CH2Cl2 (50 mL) and washed with water and brine. The organic layer
was dried over Na2SO4, filtered, and concentrated, and the residue
was purified by flash chromatography on silica (hexane/EtOAc 9:1)
afforded3-propionitrile oxindole 3a as paleyellow oil (62.7 mg, 31%).
4.3.1. 3-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)propanenitrile
(3a). Rf: 0.37 (hexane/EtOAc 1:1); IR (CHCl3, cmꢁ1): 2256, 1707; dH
:
7.33 (1H, tm, J¼7.7 Hz, H-6), 7.25 (1H, dm, J¼7.7 Hz, H-4), 7.09 (1H,
td, J¼7.7, 1.0 Hz, H-5), 6.86 (1H, br d, J¼7.7 Hz, H-7), 3.54 (1H, dd,
J¼8.1, 5.1 Hz, H-3), 3.21 (3H, s, NMe), 2.58 (2H, m, H-9), 2.37 and
2.17 (2H, m, H-8); dC: 176.3 (C-2), 144.2 (C-7a), 126.8 (C-3a), 128.7
(C-6), 123.7 (C-4), 122.7 (C-5), 119.0 (CN), 108.4 (C-7), 43.6 (C-3),
26.5 (C-8), 26.2 (NMe), 14.0 (C-9); GCeMS (EI, 70 eV): m/z (%)¼200
(Mþ, 100), 160 (95), 146 (64); HRESI/APCIMS: m/z calcd for
C12H12N2OþHþ: 201.1022; found: 201.1023.
4.3.2. 3-(5-Methoxy-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)
propanenitrile (3b). Application of the typical procedure using
nitrile-substituted cyclopropane anti-1b (200 mg, 0.88 mmol)
gave 3-propylacetamide oxindole 3b as pale yellow crystals
(75 mg, 37%), mp 91e93 ꢀC (acetone/hexane). Rf: 0.28 (hexane/

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7193
EtOAc 1:1); IR (CHCl3, cmꢁ1): 2256, 1699; dH: 6.86 (1H, m, H-4),
6.83 (1H, dd, J¼8.4, 2.5 Hz, H-6), 6.76 (1H, br d, J¼8.4 Hz, H-7),
3.80 (3H, s, OMe), 3.51 (1H, dd, J¼8.1, 5.1 Hz, H-3), 3.18 (3H, s,
NMe), 2.57 (2H, m, H-9), 2.36 and 2.15 (2H, m, H-8); dC: 175.7 (C-
2), 155.9 (C-5), 137.5 (C-7a), 128.0 (C-3a), 118.9 (CN), 112.5 (C-6),
111.2 (C-4), 108.5 (C-7), 55.6 (NMe), 43.8 (C-3), 26.4 (C-8), 26.1
(OMe), 13.8 (C-9); GCeMS (EI, 70 eV): m/z (%)¼230 (Mþ, 100), 216
(84), 177 (30); HRESI/APCIMS: m/z calcd for C13H14N2O2þHþ:
231.1133; found: 231.1129.
HRESI/APCIMS: m/z calcd for C15H20N2O3þH: 277.1547; found:
277.1551.
4.4.3. N-{3-[1-(4-Methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]
propyl}acetamide (4c). Application of the typical procedure using
3-propionitrile oxindole 3c (200 mg, 0.65 mmol) gave 3-
propylacetamide oxindole 4c as pale yellow oil (172 mg, 75%). Rf:
0.41 (CH2Cl2/MeOH 9:1); IR (CHCl3, cmꢁ1): 3451, 3366, 1700, 1669;
dH: 7.25e7.19 (3H, m, Ho and H-4), 7.17 (1H, tdd, J¼8.1, 1.3, 0.7 Hz, H-
6), 7.02 (1H, td, J¼7.9, 1.0 Hz, H-5), 6.83 (2H, m, Hm), 6.76 (1H, br d,
J¼7.8 Hz, H-7), 5.96 (1H, br s, NH), 4.86 and 4.79 (2H, AB, J¼15.2 Hz,
CH2), 3.76 (3H, s, OMe), 3.54 (1H, t, J¼5.4 Hz, H-3), 3.21 (2H, m, H-
10), 2.01 (2H, m, H-8),1.95 (3H, s, COMe),1.58 (2H, m, H-9); dC: 177.9
(C-2), 170.2 (COMe), 159.0 (Cp), 143.2 (C-7a), 128.6 (2C, Co), 128.6 (C-
3a), 127.9 (C-6), 127.8 (Ci), 123.8 (C-4), 122.5 (C-5), 114.1 (2C, Cm),
109.0 (C-7), 55.2 (OMe), 44.9 (C-3), 43.1 (NCH2), 39.1 (C-10), 27.7 (C-
8), 25.6 (C-9), 23.2 (COMe). GCeMS (EI, 70 eV): m/z (%)¼352 (Mþ,
7), 121 (100); HRESI/APCIMS: m/z calcd for C21H24N2O3þHþ:
353.1865; found: 353.1859.
4.3.3. 3-[1-(4-Methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]
propanenitrile (3c). Application of the typical procedure using
nitrile-substituted cyclopropane anti-1c (200 mg, 0.66 mmol)
gave 3-propylacetamide oxindole 3c as colorless needles (90 mg,
45%), mp 109e110 ꢀC (acetone/hexane). Rf: 0.54 (hexane/EtOAc
1:1); IR (CHCl3, cmꢁ1): 2253, 1704; dH: 7.23 (2H, m, Ho), 7.23 (1H,
partially overlapped, H-4), 7.21 (1H, partially overlapped, H-6),
7.04 (1H, td, J¼7.6, 0.9 Hz, H-5), 6.84 (2H, m, Hm), 6.79 (1H, br d,
J¼6.8 Hz, H-7), 4.83 (2H, s, NCH2), 3.76 (3H, s, OMe), 3.60 (1H, m,
H-3), 2.63 (2H, m, H-9), 2.43 and 2.21 (2H, m, H-8); dC: 176.3 (C-
2), 159.0 (Cp), 143.2 (C-7a), 128.6 (2C, Co), 128.5 (C-6), 127.6 (Ci),
126.8 (C-3a), 123.7 (C-4), 122.6 (C-5), 119.0 (CN), 114.1 (2C, Cm),
109.3 (C-7), 55.1 (OMe), 43.5 (C-3), 43.1 (NCH2), 26.6 (C-8), 13.9
(C-9); GCeMS (EI, 70 eV): m/z (%)¼306 (Mþ, 20), 121 (100);
HRESI/APCIMS: m/z calcd for C19H18N2O2: 329.1260þNa; found:
329.1261.
4.4.4. N-[3-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)propyl]acet-
amide (4a) and N-{[(1R*,2R*)-10-methyl-20-oxo-10,20-dihydrospiro
[cyclopropane-1,30-indol]-2-yl]methyl}acetamide
(anti-
5a). Application of the typical procedure using spirooxindole anti-
1a (200 mg, 1.0 mmol) gave a pale yellow oil containing an in-
separable mixture of 4a and anti-5a in a 3:1 ratio (187 mg total,
75%). For 4a: NMR data were consistent with those described above
for the same compound prepared from 3a. For anti-5a: Rf: 0.47
(CH2Cl2/MeOH 9:1); dH: 7.31 (1H, partially overlapped, H-6), 7.06
(1H, dd, J¼7.1, 1.0 Hz, H-4), 7.05 (1H, td, J¼7.1, 1.0 Hz, H-5), 6.93 (1H,
br d, J¼7.8 Hz, H-7), 5.84 (1H, br s, NH), 3.97 (1H, m, H-10), 3.27 (3H,
s, NMe), 2.13 (1H, m, H-9), 1.90 (3H, s, COMe) 1.90 and 1.52 (2H,
partially overlapped, H-8); dC: 176.2 (C-2), 170.1 (COMe), 144.0 (C-
7a), 127.2 (C-3a), 127.1 (C-6), 122.0 (C-5), 120.7 (C-4), 108.2 (C-7),
38.1 (C-10), 31.2 (C-3), 31.2 (C-9), 22.8 (C-8), 26.6 (NMe), 23.1
(COMe); GCeMS (EI, 70 eV): m/z (%)¼244 (Mþ, 70), 159 (100).
4.4. Typical catalytic hydrogenolysis procedure in Ac2O:
catalytic hydrogenolysis of 3a
A solution of 3-propionitrile oxindole 3a (200 mg, 1.0 mmol)
was hydrogenated in a Parr bomb over W-5 Raney-Ni catalyst
(550 mg) in dry Ac2O (8 mL) at room temperature under 45 psi H2
for 5 h. The mixture was filtered through Celite and concentrated in
vacuo to dryness. The residue was dissolved in CH2Cl2 (50 mL) and
washed with water and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated, and the residue was purified by
flash chromatography on silica (CH2Cl2/MeOH 99:1) to give 3-
propylacetamide oxindole 4a as pale yellow oil (172 mg, 70%).
4.4.5. N-[3-(5-Methoxy-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)
propyl]acetamide (4b) and N-{[(1R*,2R*)-50-methoxy-10-methyl-20-
oxo-10,20-dihydrospiro[cyclopropane-1,30-indol]-2-yl]methyl}acet-
amide (anti-5b). Application of the typical procedure using spi-
rooxindole anti-1b (200 g, 0.88 mmol) gave a pale yellow oil
containing an inseparable mixture of 4b and anti-5b in a 3:1 ratio
(211 mg total, 87%). For 4b: NMR data were consistent with those
described above for the same compound prepared from 3b. For
anti-5b: Rf: 0.46 (CH2Cl2/MeOH 9:1); dH: 5.93 (1H, br s, NH), 3.97
(1H, m, H-8), 3.26 (3H, s, NMe), 2.14 (1H, m, H-9), 1.93 (3H, s, COMe)
(other signals indistinguishable); dC: 176.0 (C-2), 170.2 (COMe),
155.6 (C-5), 137.6 (C-7a), 128.7 (C-3a), 111.3 (C-4), 108.4 (C-7), 55.8
(OMe), 37.8 (C-10), 31.6 (C-3), 31.1 (C-9), 26.6 (NMe), 23.0 (COMe),
22.8 (C-8); GCeMS (EI, 70 eV): m/z (%)¼274 (Mþ, 100), 216 (26), 202
(42), 174 (47).
4.4.1. N-[3-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)propyl]acet-
amide (4a). Rf: 0.44 (CH2Cl2/MeOH 9:1); IR (CHCl3, cmꢁ1): 3453,
3350, 1697, 1669; dH: 7.28 (1H, td, J¼8.0, 1.3 Hz, H-6), 7.25 (1H, br d,
J¼7.7 Hz, H-4), 7.07 (1H, td, J¼7.5, 1.0 Hz, H-5), 6.84 (1H, br d,
J¼7.5 Hz, H-7), 6.02 (1H, br s, NH), 3.46 (1H, t, J¼6.0 Hz, H-3), 3.25
(2H, m, H-10), 3.20 (3H, s, NMe), 2.00 (2H, m, H-8), 1.95 (3H, s,
COMe),1.54 (2H, m, H-9); dC: 177.8 (C-2),170.2 (COMe),144.1 (C-7a),
128.6 (C-3a), 128.0 (C-6), 123.7 (C-4), 122.5 (C-5), 108.0 (C-7), 44.9
(C-3), 39.1 (C-10), 27.6 (C-8), 26.1 (NMe), 25.6 (C-9), 23.2 (COMe).
GCeMS (EI, 70 eV): m/z (%)¼246 (Mþ, 87), 188 (100), 161 (64);
HRESI/APCIMS: m/z calcd for C14H18N2O2þHþ: 247.1446; found:
247.1448.
4.4.2. N-[3-(5-Methoxy-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)
propyl]acetamide (4b). Application of the typical procedure using
3-propionitrile oxindole 3b (200 mg, 0.87 mmol) gave 3-
propylacetamide oxindole 4b as pale yellow crystals (180 mg,
75%), mp 122e125 ꢀC. Rf: 0.43 (CH2Cl2/MeOH 9:1); IR (CHCl3,
cmꢁ1): 3450, 1692; dH: 6.87 (1H, dd, J¼2.5, 0.4 Hz, H-4), 6.81 (1H,
dd, J¼8.6, 2.5 Hz, H-6), 6.73 (1H, br d, J¼8.6 Hz, H-7), 5.92 (1H, br s,
NH), 3.78 (3H, s, OMe), 3.43 (1H, t, J¼6.0 Hz, H-3), 3.24 (2H, m, H-
10), 3.16 (3H, s, NMe), 1.99 (2H, m, H-8),1.94 (3H, s, COMe), 1.54 (2H,
m, H-9); dC: 177.4 (C-2); 170.1 (COMe); 156.0 (C-5), 137.7 (C-7a),
129.9 (C-3a), 112.0 (C-6), 111.4 (C-4), 108.2 (C-7), 55.8 (OMe), 45.3
(C-3), 39.1 (C-10), 27.6 (C-8), 26.2 (NMe), 25.6 (C-9), 23.2 (COMe);
GCeMS (EI, 70 eV): m/z (%)¼276 (Mþ, 100), 217 (83), 189 (54);
4.4.6. N-{3-[1-(4-Methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]
propyl}acetamide (4c) and N-{[(1R*,2R*)-10-(4-methoxybenzyl)-20-
oxo-10,20-dihydrospiro[cyclopropane-1,30-indol]-2-yl]methyl}acet-
amide (anti-5c). Application of the typical procedure using spi-
rooxindole anti-1c (200 mg, 0.66 mmol) gave a pale yellow oil
containing an inseparable mixture of 4c and anti-5c in a 3:1 ratio
(195 mg total, 85%). For 4c: NMR data were consistent with those
described above for the same compound prepared from 3c. For
anti-5c: Rf: 0.43 (CH2Cl2/MeOH 9:1); dH: 7.08 (1H, br d, J¼8.0 Hz, H-
4), 7.01 (1H, br t, J¼8.1 Hz, H-5), 6.04 (1H, br s, NH), 4.94 and 4.84
(2H, AB, J¼15.9 Hz, NCH2), 3.92 and 3.24 (2H, m, H-10), 2.18 (1H, m,
H-9) (other signals indistinguishable); dC: 176.3 (C-2),170.1 (COMe),
143.0 (C-7a), 128.0 (Ci), 127.2 (C-3a), 126.9 (C-6), 121.9 (C-5), 120.8

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(C-4), 109.2 (C-7), 43.5 (NCH2), 37.9 (C-10), 31.1 (C-3), 30.3 (C-9),
23.1 (COMe), 23.0 (C-8) (other signals indistinguishable); GCeMS
(EI, 70 eV): m/z (%)¼350 (Mþ, 19), 121 (100).
HRESI/APCIMS: m/z calcd for C21H22N2O3þHþ: 351.1703; found:
351.1709.
4.5. X-ray diffraction analysis of anti-1b, syn-1b, and anti-1c
4.4.7. N-[3-(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)propyl]acet-
amide (4a) and N-{[(1R*,2S*)-10-methyl-20-oxo-10,20-dihydrospiro
The studies were done on a Bruker-Nonius CAD4 diffractometer
[cyclopropane-1,30-indol]-2-yl]methyl}acetamide
(syn-
ꢁ
using Cu K
ꢁ2
a
radiation (
l
¼1.54184 A). The data were collected in the
5a). Application of the typical procedure using spirooxindole syn-
1a (200 mg, 1.0 mmol) gave a pale yellow oil, which was purified
by flash chromatography on silica (CH2Cl2/MeOH 99:1) to give 4a
and syn-5a in a 6:1 ratio (194 mg total, 78% or 27.5 mg spi-
roacetamide syn-5a, 11%). For 4a: NMR data were identical to
those described above for the same compound prepared from 3a.
For syn-5a: Rf: 0.48 (CH2Cl2/MeOH 9:1); IR (CHCl3, cmꢁ1): 3449,
3350, 1696, 1669; dH: 7.28 (1H, td, J¼7.6, 1.2 Hz, H-6), 7.06 (1H, br t,
J¼7.6 Hz, H-5), 6.91 (1H, br d, J¼7.6 Hz, H-7), 6.82 (1H, br d,
J¼7.6 Hz, H-4), 6.22 (1H, br s, NH), 3.81 (2H, m, H-10), 3.31 (3H, s,
NMe), 2.34 (1H, m, H-9a), 1.95 (3H, s, COMe), 1.77 (1H, dd, J¼8.8,
4.7 Hz, H-8s), 1.72 (1H, dd, J¼8.2, 4.7 Hz, H-8a); dC: 176.2 (C-2),
170.2 (COMe), 142.7 (C-7a), 130.7 (C-3a), 126.8 (C-6), 122.3 (C-5),
118.2 (C-4), 108.0 (C-7), 36.5 (C-10), 32.6 (C-9), 30.6 (C-3), 26.6
(NMe), 23.9 (C-8), 23.3 (COMe); GCeMS (EI, 70 eV): m/z (%)¼244
(Mþ, 40), 159 (100); HRESI/APCIMS: m/z calcd for C14H16N2O2þHþ:
245.1290; found: 245.1283.
u
q scan mode. Unit cell refinements were done using CAD4
Express v 2.0 software and structures were solved by direct
methods using the SHELXS-97 program included in the WINGX v
1.64.05 package. The non-hydrogen atoms were treated aniso-
tropically, and the hydrogen atoms, included in the structure factor
calculation, were refined isotropically. The X-ray data collection
and processing parameters are presented in Table 6. Complete X-
ray data are in deposit at the Cambridge Crystallographic Data
Center. The CCDC deposition number for anti-1b is 883298, for syn-
1b is 883299, and for anti-1c is 883300.
Table 6
X-ray data collection and processing parameters for nitrile-substituted spi-
rocyclopropyloxindoles anti-1b, syn-1b, and anti-1c
Compound
anti-1b
13H12N2O2
293(2)
syn-1b
anti-1c
Formula
T (K)
C
C13H12N2O2
293(2)
C19H16N2O2
293(2)
Size (mm)
Crystal system
Space group
0.40ꢄ0.32ꢄ0.32
Monoclinic
C2/c
16.833(3)
15.946(3)
9.020(2)
112.21(3)
2241.5(8)
1.353
0.40ꢄ0.22ꢄ0.20
Monoclinic
P21/n
8.464(1)
10.243(1)
13.209(2)
91.84(1)
1144.7(2)
1.324
0.36ꢄ0.32ꢄ0.30
Monoclinic
P21/c
9.0587(8)
11.086(3)
15.132(3)
92.546(3)
1518.1(5)
1.332
4.4.8. N-[3-(5-Methoxy-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)
propyl]acetamide (4b) and N-{[(1R*,2S*)-50-methoxy-10-methyl-20-
oxo-10,20-dihydrospiro[cyclopropane-1,30-indol]-2-yl]methyl}acet-
amide (syn-5b). Application of the typical procedure using spi-
rooxindole syn-1b (200 mg, 0.88 mmol) gave a pale yellow oil,
which was purified by flash chromatography on silica (CH2Cl2/
MeOH 99:1) to give 4b and syn-5b in a 6:1 ratio (203 mg total, 84%
or 29 mg spiroacetamide syn-5b, 12%). For 4b: NMR data were
identical to those described above for the same compound pre-
pared from 3b. For syn-5b: Rf: 0.47 (CH2Cl2/MeOH 9:1); IR (CHCl3,
cmꢁ1): 3452, 1682; dH: 6.80 (1H, br d, J¼8.1, 1.0 Hz, H-7), 6.79 (1H,
dd, J¼8.1,1.9 Hz, H-6), 6.41 (1H, dd, J¼1.9,1.0 Hz, H-4), 6.28 (1H, br s,
NH), 3.81 (2H, m, H-10), 3.78 (3H, s, OMe), 3.28 (3H, s, NMe), 2.31
(1H, m, H-9a), 1.95 (3H, s, COMe), 1.78 (1H, dd, J¼8.9, 4.7 Hz, H-8s),
1.69 (1H, dd, J¼7.9, 4.7 Hz, H-8a); dC: 176.0 (C-2), 170.3 (COMe),
156.1 (C-5), 136.3 (C-7a), 132.1 (C-3a), 111.3 (C-6), 108.3 (C-7), 105.6
(C-4), 55.8 (OMe), 36.6 (C-10), 32.8 (C-9), 30.9 (C-3), 26.6 (NMe),
24.0 (C-8), 23.3 (COMe); GCeMS (EI, 70 eV): m/z (%)¼274 (Mþ, 100),
215 (35), 202 (75), 174 (92); HRESI/APCIMS: m/z calcd for
C15H18N2O3þHþ: 275.1395; found: 275.1397.
ꢁ
a (A)
ꢁ
b (A)
ꢁ
c (A)
b
(ꢀ)
3
ꢁ
V (A )
Dcalcd (g cmꢁ3
)
Z
m
8
4
4
(mmꢁ1
)
0.760
3.97e59.92
3715
0.745
5.47e59.95
1908
0.704
4.89e60.07
2588
qrange (ꢀ)
Refl total
Refl. unique
Rint (%)
Refl. observ.
1594
0.0001
1497
1694
0.0001
1499
1780
0.0001
1780
Param. refined
159
158
213
R (%), Rw (%)
5.4, 15.5
0.261
4.9, 14.1
0.300
4.6, 12.8
0.219
ꢁꢁ3
emax (e A
)
4.6. Computational methods
For all calculations, we used the density functional program
packages provided by the Gaussian 03W suite of programs. The
densityfunctionalemployedisthe hybridfunctionalB3LYP/6-31g(d),
which includes polarization functions for first- and second-row el-
ements. Frequency calculations after each geometry optimization
ensured that the calculated structure is a real minimum.
4.4.9. N-{3-[1-(4-Methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]
propyl}acetamide (4c) and N-{[(1R*,2S*)-10-(4-methoxybenzyl)-20-
oxo-10,20-dihydrospiro[cyclopropane-1,30-indol]-2-yl]methyl}acet-
amide (syn-5c). Application of the typical procedure using spi-
rooxindole syn-1c (200 mg, 0.66 mmol) gave a pale yellow oil,
which was purified by flash chromatography on silica (CH2Cl2/
MeOH 99:1) to give 4c and syn-5c in a 6:1 ratio (207 mg total, 90%
or 29 mg spiroacetamide syn-5c, 13%). For 4c: NMR data were
identical to those described above for the same compound pre-
pared from 3c. For syn-5c: Rf: 0.45 (CH2Cl2/MeOH 9:1); IR (CHCl3,
cmꢁ1): 3452, 3350, 1696, 1670; dH: 7.24 (2H, m, Ho), 7.16 (1H, td,
J¼7.6, 1.2 Hz, H-6), 7.00 (1H, td, J¼7.6, 1.0 Hz, H-5), 6.87e6.82 (3H,
m, Hm, H-7), 6.80 (1H, ddd, J¼7.5, 1.2, 0.6 Hz, H-4), 6.12 (1H, br s,
NH), 4.98 and 4.90 (2H, AB, J¼15.5 Hz, NCH2), 3.86 and 3.76 (2H, m,
H-10), 2.37 (1H, m, H-9a), 1.91 (3H, s, COMe), 1.85 (1H, dd, J¼8.2,
4.7 Hz, H-8s),1.78 (1H, dd, J¼8.2, 4.7 Hz, H-8a); dC: 176.3 (C-2),170.2
(COMe), 159.1 (Cp), 141.9 (C-7a), 130.7 (Ci), 128.5 (2C, Co), 128.1 (C-
3a), 126.7 (C-6), 122.3 (C-5), 118.2 (C-4), 114.2 (2C, Cm), 108.9 (C-7),
55.3 (OMe), 43.5 (NCH2), 36.8 (C-10), 33.1 (C-9), 30.6 (C-3), 24.2 (C-
8), 23.3 (COMe); GCeMS (EI, 70 eV): m/z (%)¼350 (Mþ, 8),121 (100);
Acknowledgements
Financial support by CONACYT grants 81810 and 139736 is
gratefully acknowledged.
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