Structure elucidation of configurational isomers of nitrile-substituted spirocyclopropyloxindoles by NMR spectroscopy, molecular modeling, and X-ray crystallography

Full text of DOI:10.1002/mrc.4293

Letter ‐ spectral assignments
Received: 27 February 2015
Revised: 11 June 2015
Accepted: 15 June 2015
Published online in Wiley Online Library: 25 August 2015
(wileyonlinelibrary.com) DOI 10.1002/mrc.4293
Structure elucidation of configurational isomers
of nitrile-substituted spirocyclopropyloxindoles
by NMR spectroscopy, molecular modeling, and
X-ray crystallography
a,b
a
J. Benjamín García-Vázquez, Daphne E. González-Juárez,
a,b
c
Martha S. Morales-Ríos, * Oscar R. Suárez-Castillo
a
and Yolanda Mora-Pérez
pairs of novel synthesized diastereomeric anti- and syn-
spirocyclopropyloxindole derivatives (1a–f) characterized in pure
form. Their relative configuration has been independently
confirmed by determining its structure from X-ray diffraction data.
Molecular modeling calculations were in good agreement with
experimental values. For long-range protons (more than three
bonds removed), the substituent effects of the cyclopropane ring
were analyzed in terms of the cyclopropane magnetic anisotropy.
Introduction
Nitrile-substituted cyclopropanes are an important class of com-
pounds 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 comes probably from the significant
conformational restrictions that the cyclopropane ring imposes on
the molecule in which it is incorporated. As synthetic tools,
nitrile-substituted cyclopropanes are versatile templates for the
rapid formation of biologically active and synthetically useful func-
tionalized cyclopropane derivatives. Additionally, the release of
strain arising from cleavage of cyclopropanes has been frequently
utilized in organic synthesis and represents a useful method for
the construction of a wide variety of carbon skeletons. We have re-
ported the synthesis of nitrile-substituted spirocyclopropyloxindoles
[
1]
Results and discussion
[
2]
1
The H chemical shifts for compounds anti and syn 1a–f are given in
13
Tables 1 and 3. The C chemical shifts are presented in Tables 2
[
3]
1
13
and 4. Some of the experimental 1D H and C spectra can be
found in the Supporting Information as Figs S1–S16.
[
4]
[
5]
that offers a route to 2-oxohomotryptamines. In our ongoing study
on synthesizing fluorinated pharmaceuticals, we have prepared
three pairs of diastereomeric anti and syn spirocyclopropyloxindoles
substituted on the aromatic ring by a fluorine atom 1a–c, along with
two methoxylated 1d and 1e, and one methylated 1f compounds
Configurational assignment of the spirocyclopropyloxindole
1a–f isomers was established taking into account the NOESY
correlations. The concerted application of splitting patterns,
chemical shifts, and 2D NMR data from gHSQC and gHMBC
were used for the unambiguous assignment of the proton and
carbon resonances in the studied compounds. For the anti and
(Scheme 1). NMR data are described using the formula numbering
1
13
given in the succeeding text. Abbreviations a and s denote anti
and syn to the carbonyl group at C-2, respectively.
In these molecules where the indole moiety and cyclopropane
syn spirocyclopropyloxindoles 1a–f, typical H- and C-NMR
resonances can be observed for the indole and cyclopropane
rings. The discussion is performed in detail for the anti 5-fluoro de-
rivative 1a and then, a comparison to syn 1a is presented, pointing
[6]
ring are orthogonal, the anisotropy of the cyclopropane ring
results in an additional shielding of the H-4 hydrogen atom. In the
1
H-NMR spectra of syn isomers, this is manifested in the low-
1
2
frequency shift of the H-4 signal of the indole ring (R = H, R = Me:
Δδ ~0.28 ppm) compared with the H chemical shift of the
corresponding spirocyclopentyl- and spirocyclohexiloxindoles.
*
Correspondence to: Martha S. Morales-Ríos, Departamento de Química and
Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios
Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México, D. F.,
1
[
4,7]
0
7000, Mexico. E-mail: smorales@cinvestav.mx
In addition, a change in the spatial orientation of the nitrile group
in spirocyclopropyloxindoles leads to a considerable shift to higher
frequencies of the H-4 signal. This diminished shielding of the H-4
proton should be attributed to the influence of the anisotropy of
the cyano group located in the anti position with respect to the
carbonyl group at C-2. Particularly, the cyclopropane-carbon
a Departamento de Química, Centro de Investigación y de Estudios Avanzados del
Instituto Politécnico Nacional, Apartado 14-740, México, D. F. 07000, Mexico
[8]
b Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios
Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México, D. F.
0
7000, Mexico
resonances of the spirocyclopropyloxindoles experience
a
[4]
low-frequency shift relative to the higher homologues. This paper -
c Área Académica de Química, Universidad Autónoma del Estado de Hidalgo,
Mineral de la Reforma, Hidalgo, 42184, Mexico
1
13
reports the H- and C-NMR unambiguous assignments of six
Magn. Reson. Chem. 2015, 53, 1061–1070
Copyright © 2015 John Wiley & Sons, Ltd.

J. B. García-Vázquez et al.
Scheme 1. Scheme for the preparation of spirocyclopropyloxindoles (1a–f). (i) NaH, alkyl halide, CH
HCl, AcOH, rt; and (iii) NaH, CH Br , dimethylformamide, rt.
2 2
Cl , room temperature (rt); (ii) dimethyl sulfoxide, 37% aq
2
2
1
Table 1. H-NMR chemical shifts (δ in ppm) and coupling constants (J in hertz) of anti-1a–f in CDCl
3
a
Proton
1a
1b
1c
1d
1e
1f
4
6
7
6.97 (dd, 7.8, 2.5)
7.00–6.92 (m)
7.00–6.92 (m)
6.77 (dd, 9.3, 4.2)
1.93 (dd, 7.1, 5.1)
2.23 (dd, 9.5, 5.1)
2.56 (dd, 9.5, 7.1)
5.00, 4.94 (AB, 15.7)
7.38–7.25 (m)
7.38–7.25 (m)
7.38–7.25 (m)
—
7.01–6.94 (m)
7.01–6.94 (m)
6.80 (dm, 9.1)
1.92 (dd, 7.1, 5.1)
2.21 (dd, 9.6, 5.1)
2.54 (dd, 9.6, 7.1)
4.93, 4.87 (AB, 16.2)
7.26–7.20 (m)
6.89–6.83 (m)
—
6.81 (dd, 2.3, 0.7)
6.78–6.73 (m)
6.78–6.73 (m)
1.91 (dd, 7.0, 4.9)
2.19 (dd, 9.5, 4.9)
2.52 (dd, 9.5, 7.0)
4.98, 4.92 (AB, 16.0)
7.37–7.25 (m)
7.37–7.25 (m)
7.37–7.25 (m)
3.77 (s)
6.81–6.74 (m)
6.81–6.74 (m)
6.81–6.74 (m)
1.88 (dd, 6.9, 5.0)
2.17 (dd, 9.5, 5.0)
2.50 (dd, 9.5, 6.9)
4.90, 4.85 (AB, 16.2)
7.26–7.20 (m)
6.88–6.82 (m)
—
7.01 (d, 1.8)
7.18 (dm, 7.9)
6.85 (d, 8.2)
1.86 (dd, 7.0, 5.0)
2.11 (dd, 9.4, 5.0)
2.43 (dd, 9.4, 7.0)
—
7.10 (ddd, 8.7, 8.7, 2.7)
6.89 (dd, 8.6, 4.1)
8
8
9
1
3
4
5
a
s
s
′
1.89 (dd, 7.1, 4.9)
2.16 (dd, 9.4, 4.9)
2.49 (dd, 9.4, 7.1)
—
—
—
—
′
—
′
—
′
—
Me/OMe 3.30 (s)
3.78 (s)
3.76 (s), 3.77 (s)
2.37 (s), 3.27 (s)
s, singlet; d, doublet; m, multiplet.
a
The diastereotopic methylene protons are designated as anti (a) or syn (s) with respect to the carbonyl group at C-2.
1
3
13 19
Table 2. C-NMR chemical shifts (δ in ppm) and C– F coupling constants (J in hertz) of anti-1a–f in CDCl
3
a
Carbon
1a
1b
1c
1d
1e
172.7
1f
2
3
172.6
172.8
172.7
172.8
31.9
172.8
31.6
124.0
121.6
132.5
129.0
108.3
141.7
21.2
14.6
—
31.9 (d, 2.3)
31.8 (d, 2.0)
125.8 (d, 8.9)
109.4 (d, 26.2)
159.1 (d, 242.1)
115.1 (d, 23.6)
110.3 (d, 8.4)
139.1 (d, 2.3)
21.9
31.8 (d, 2.3)
125.8 (d, 8.9)
109.4 (d, 26.2)
159.1 (d, 241.8)
115.1 (d, 23.6)
110.3 (d, 8.1)
139.2 (d, 2.0)
21.9
31.9
125.3
108.1
156.0
113.5
110.1
136.6
21.6
3
4
5
6
7
7
8
9
1
2
3
4
5
a
125.7 (d, 8.9)
125.3
108.1
156.1
113.5
110.2
136.5
21.6
109.4 (d, 25.9)
159.2 (d, 241.8)
115.1 (d, 23.6)
109.2 (d, 7.5)
a
140.0 (d, 2.0)
21.6
15.0
—
15.2
15.2
15.0
14.9
′
′
′
′
′
44.6
44.1
44.5
44.0
—
135.0
127.0
135.4
127.3
128.8
127.8
116.8
55.8
127.4
128.7
114.2
159.1
116.8
55.8, 55.2
—
—
127.3
128.7
—
—
128.9
114.2
—
—
128.0
159.2
—
CN
116.5
27.0
116.5
116.5
116.9
26.8, 21.1
Me/OMe
—
55.2
d, doublet.
a13
C Shifts assignments are in agreement with the gHSQC and gHMBC spectra.
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Magn. Reson. Chem. 2015, 53, 1061–1070

Anisotropic effects in configurational isomers of spirooxindoles
out salient proton and carbon resonances that have changed. The
D structure of compounds anti-1d, anti-1e, and syn-1f were
3
obtained by single-crystal X-ray analysis.
The indole ring
1
In the H-NMR spectrum of anti-1a (Table 1), the H-4 and H-7
benzene proton resonances both appear as doublets of doublets
at δ 6.97 and δ 6.89 because they experience a meta and ortho
H H
couplings constants of 2.5 and 8.6 Hz, respectively, which are
further split into doublets because of H–F ortho (J = 7.8 Hz) and
[
9]
meta (J = 4.1 Hz) couplings, respectively. The H-6 resonance at
7.10 occurs as a triplet-like signal because the H–F ortho coupling
δ
H
constant is similar to the H–H ortho coupling constant of 8.7 Hz in
addition to the H–H meta coupling constant of 2.7Hz.
In the anti-1a–f epimers, the H-4 chemical shift may be tuned by
the anisotropy of both the nitrile group and the cyclopropane ring,
and thus, the H-4 chemical shift would be significantly different
between diastereomers. In fact, the syn spatial orientation of the ni-
trile group in the syn-1a–f epimers causes the low-frequency shift
of remote H-4 by 0.38 ± 0.2 ppm (Table 3). The remaining H-6 and
H-7 resonances were not appreciably affected by change in the
1
stereochemistry. In addition, inspection of the H-NMR spectrum
of syn compounds 1a–f shows that the H-4 proton, localized in
the shielding region of the cyclopropane ring, resonated at lower
frequency (0.66± 0.02 ppm) than in oxindoles 4a–f (see Section
on Experimental, Table 8) This suggests that the observed shielding
of the H-4 proton in syn compounds 1a–f is induced by the diamag-
[
6]
netic anisotropy of the cyclopropane ring. Consequently, in the
case of anti compounds 1a–f, the chemical shift of H-4 is influenced
by the relation between the shielding effect of the cyclopropane
ring current and the deshielding effect of the anisotropy of the
nitrile group, operating in opposite directions. These findings
match with the lesser chemical shift difference (Δδ) between H-4
and H-6 in the anti isomers, which overlap in 1b, 1c, and 1e,
compared with the syn isomers (Tables 1 and 3).
13
In the C-NMR spectrum of anti-1a (Table 2), the correspond-
109.4
F–C = 25.9Hz, C-4), 115.1 ( JF–C = 23.6 Hz, C-6), and 109.2
F–C = 7.5Hz, C-7) and were attributed on the basis of direct
ing methine carbon resonances were present at δ
C
2
3
2
(
J
(
J
H/C correlation in the gHSQC spectrum (Fig. 1). The quaternary
carbon signals were assigned using gHMBC experiments. Most
essential correlations were as follows. The C-3a and C-7a signals
3
of the ring junction carbons occur at δ
1
C
125.7 ( JF–C = 8.9 Hz) and
4
40.0 ( JF–C = 2.0Hz), respectively, and were assigned because of
the three-bond correlation with H-7 and H-6 signals, respectively,
13
in the gHMBC spectra. In the C-NMR spectrum, C-5 occurs as a
1
doublet because of C–F coupling with J= 241.8Hz at δC 159.2
and shows a cross-peak in the gHMBC spectrum with H-7 signal.
The lactam carbonyl resonance (C-2) at δC 172.6 shows gHMBC
correlation to the N-methyl signal. Further, the C-3 signal of
4
the spiranic carbon at δC 31.9 ( J = 2.1Hz) was distinguished
F–C
by the presence of cross-peaks in the gHMBC spectrum with
Figure 1. Key gHMBC correlations of compound anti-1a.
Magn. Reson. Chem. 2015, 53, 1061–1070
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J. B. García-Vázquez et al.
the H-4 signal. The indole-carbon chemical shifts in compounds
syn-1a–f (Table 4) were only slightly affected or not affected
by changes in the compounds stereochemistry. The C-2 and
C-4 signals were more shielded with resonance differences of
À1.5 ± 0.1 and À1.8±0.3 ppm, respectively, whereas the C-3a
were less shielded by 1.9± 0.1ppm between anti and syn
isomers.
in the NOESY spectrum. A NOESY correlation between H-8 and
a
H-9 further confirms the assignment of these resonances.
a
The cyclopropane coupling constants in compounds anti- and
syn-1a–f are summarized in Table 5. The value of the trans coupling
is unusually large as compared with the characteristic value in
[
10]
cyclopropanes of 4 to 6 Hz. The increase of the trans couplings
in both anti and syn series may be produced by an increase in the
C3–C9 bond length (Table S1 in the Supporting Information) due
to the conjugative interaction of the π-acceptor nitrile and the
The cyclopropane ring
[
11]
amide carbonyl substituents with the three-membered ring.
The relative configuration at C-9 for the anti and syn
spirocyclopropyloxindoles (1a–f) was deduced taking into account
the NOESY correlations. The H-NMR spectrum of anti-1a (Table 1)
The coupling constants for the CH/CH groups in the structure of
2
the cyclopropane ring were only slightly affected or not affected
by changes in the stereochemistry.
1
13
shows three cyclopropyl proton resonances (H-8
each a doublet of doublets, at, respectively, δ
.9 Hz), 2.16 (J = 9.4 and 4.9Hz), and 2.49 (J= 9.4 and 7.1 Hz). The
a
, H-8
s
, and H-9
s
),
In the C-NMR spectrum of anti-1a, the remaining CH and CH
cyclopropane-carbon resonances (Table 2) were present at δ 21.6
2
H
1.89 (J = 7.1 and
C
4
(C-8) and 15.0 (C-9) and were attributed on the basis of direct H/C
anti position of the nitrile group in anti-1a and hence the relative
R configuration at the stereogenic center C-9 were supported by
a two-dimensional NOESY experiment. The NOESY data demon-
correlation in the gHSQC spectrum. The anomalous low-frequency
13
chemical shift of the C nucleus in cyclopropane-carbon resonances
[4]
(Tables 2 and 4) relative to the higher homologues could be attrib-
uted to a strong localized diamagnetic vortex about each carbon
strated that H-8
a
at δ 1.89 is in the anti-orientation as it was corre-
proton at
[6b]
lated to H-4 at δ 6.97. In addition, the syn oriented H-8
s
atom, which is winding up and down along the C–H bonds.
δ 2.16 was correlated to H-9 at δ 2.49, indicating that H-9 was in
the same face as syn H-8 . In the case of syn-1a the syn position of
s
Molecular modeling
the nitrile group and hence the relative S configuration of C-9 were
unequivocally established because of the steric proximities be-
tween H-8 (δ = 1.99) and H-9 (δ = 2.33) with H-4 (δ = 6.60) detected
To observe a more detailed information about the stereochemistry
of the studied molecules, we carried out quantum chemical
a
a
1
3
13 19
Table 4. C-NMR chemical shifts (δ in ppm) and C– F coupling constants (J in hertz) of syn-1a–f in CDCl
3
a
Carbon
1a
1b
1c
1d
1e
171.2
1f
2
3
171.2
171.3
171.2
171.2
32.0
171.4
31.8
126.0
119.6
132.2
129.0
108.4
141.7
21.0
14.9
—
32.1 (d, 1.9)
32.0 (d, 2.0)
127.6 (d, 8.6)
107.3 (d, 25.6)
159.1 (d, 241.8)
115.0 (d, 24.9)
110.4 (d, 8.1)
139.0 (d, 2.0)
21.5
32.0 (d, 2.2)
127.6 (d, 8.3)
107.3 (d, 25.4)
159.0 (d, 242.1)
115.0 (d, 23.8)
110.4 (d, 8.3)
139.1 (d, 2.2)
21.5
32.0
127.2
106.6
155.8
112.6
110.0
136.3
21.2
3
4
5
6
7
7
8
9
1
2
3
4
5
a
127.6 (d, 8.7)
127.1
106.6
155.8
112.6
109.9
136.2
21.2
107.3 (d, 26.7)
159.1 (d, 241.8)
115.1 (d, 23.5)
109.3 (d, 8.5)
a
140.0 (d, 2.0)
21.3
15.4
—
15.6
15.6
15.1
15.2
′
′
′
′
′
44.6
44.1
44.2
43.8
—
135.2
127.2
135.4
127.3
128.6
127.5
115.9
55.6
127.5
128.8
114.0
159.0
115.9
55.7, 55.1
—
—
127.5
128.9
—
—
128.9
114.2
—
—
127.9
159.2
—
CN
115.5
27.0
115.5
115.5
116.0
26.8, 21.0
Me/OMe
—
55.2
d, Doublet.
a13
C Shifts assignments are in agreement with the gHSQC and gHMBC spectra.
a
Table 5. Experimental cyclopropane coupling constants (Hz) for anti/syn-1a–f and corresponding calculated bond angles (deg) and dihedral angles
deg) for anti/syn-1a
(
2
a
3
a
3
a
Series
gem ( JH–H
)
Bond angle
trans ( JH–H
)
Dihedral angle
cis ( JH–H
)
Dihedral angle
anti
syn
À5.0 ± 0.1
À5.1 ± 0.2
116.47
116.45
7.0 ± 0.1
7.4 ± 0.1
À149.29
9.5 ± 0.1
9.1 ± 0.2
À3.70
151.43
5.61
a
Computed data at the B3LYP/6-31G(d) level.
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Anisotropic effects in configurational isomers of spirooxindoles
calculations using the Density Functional Theory (DFT) method
provided by the Gaussian 03 W suite of programs. The density
functional employed is the hybrid functional B3LYP, adopting
configuration of the analyzed models can be quantified by compar-
[
12]
ing the dihedral angles along the C8–C9 bond between the H-8 or
a
H-8
H-8
s
and H-9 protons (Table 5). The close approach of the H-4 to
6-31G(d) basis set, which includes polarization functions for first-
a
in conformer anti-1a evidenced by the estimated distance value
[14]
and second-row elements. For the sake of simplicity, and low-cost
performance for geometry optimization, the diastereomeric pairs
anti/syn of N-methyl substituted cyclopropyloxindoles 1a and 1f
were used as models. Conformational searching was performed
using the Monte Carlo search protocol. The calculations show
one conformer for each structure (100% of the Boltzmann popu-
lation). The calculated structures of anti/syn 1a and 1f showed
systematic geometrical changes for the endocyclic cyclopropane
C–C bonds lengths as compared with the length in unsubstituted
of 2.85 Å is within the limit required for the occurrence of NOEs
and in excellent agreement with experimentally established stereo-
chemistry based on correlations in the NOESY spectrum. The same
is true for syn-1a, with an estimated distance H-4 to H-8
a
of 2.83 Å,
and H-4 to H-9 of 2.71 Å.
a
X-Ray diffraction
[
13]
cyclopropane (1.503Å).
Thus, while the C3–C9 bond in these
Compounds anti-1d, anti-1e, and syn-1f, which provided suitable
crystals, were subjected to single-crystal X-ray analysis. In the com-
pounds, all hydrogen atoms were located from difference Fourier
syntheses but were included in the final calculations at the posi-
tions calculated from geometries of the molecules. The cyclopro-
pane dihedral angles and the endocyclic cyclopropane C–C bonds
lengths were extracted and compared with that derived from the
molecular calculations. The data in Fig. 3 show that the calculated
dihedral angles in the models (Table 5) are in good agreement with
the crystal structures of anti-1d, anti-1e and syn-1f, and also with
compounds is significantly lengthened by 0.038–0.040Å, the
C3–C8 and C8–C9 bonds are shortened by 0.001–0.006 Å (Table S1
in the Supporting Information). The syn epimers 1a and 1f are
higher in energy by 2.89 ± 0.11 kcal/mol than their anti
counterparts. Some structural parameters associated with the
cyclopropane ring are included in Table 5.
From molecular models of anti- and syn-1a (Fig. 2), it appeared
that the perpendicular arrangement of the cyclopropane ring
to the indole main plane set the H-4 proton on the anisotropy
region of the cyclopropane ring. The differences in molecular
[
5]
the expected average values for related compounds. In particular,
Figure 2. Optimized structures of anti/syn-1a at the B3LYP/6-31G(d) level. Energies in kilocalorie per mole relative to anti-1a are given in parentheses.
Figure 3. X-ray molecular structures of anti-1d, anti-1e, and syn-1f. Selected dihedral angles (deg), bond angles (deg), and atom distances (Å) are shown.
Magn. Reson. Chem. 2015, 53, 1061–1070
Copyright © 2015 John Wiley & Sons, Ltd.
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J. B. García-Vázquez et al.
the lengthened influence of the π-acceptor nitrile and amide
carbonyl substituents on the C3–C9 cyclopropane bond is
evidenced in Table S1 in the Supporting Information.
Conclusions
In summary, we have prepared several diastereomeric pairs of
spirocyclopropyloxindole derivatives and characterized them using
1
13
H- and C-NMR spectroscopy together with DFT calculations and
X-ray crystallography. In these conformational fixed molecules
where the indole moiety and the cyclopropane ring are orthogonal,
the mutual influence of the anisotropic effects of the nitrile group
and the cyclopropane ring on the H-4 proton shielding was reliably
13
1
determined. The vicinal C– H coupling constants indicate that the
dihedral angle between the H-8 and H-9 (trans coupling) signifi-
cantly increases as compared with the characteristic value in cyclo-
propanes. The cause of this is attributed to an increase in the C3–C9
bond length due to the conjugative interaction of the π-acceptor
nitrile and the amide carbonyl substituents with the three-
membered ring.
Experimental
Synthesis
The synthesis of the spirocyclopropyloxindoles 1a–f was carried out
after one-pot base-mediated double-alkylation process of
3
-cyanomethyloxindoles 4a–f using procedures described from this
[4]
laboratory (Scheme 1). Essentially, the 3-acetonitrilindoles 2a–c
were N-alkylated with MeI, benzyl chloride, or p-methoxybenzyl chlo-
ride using NaH in dimethylformamide anhydrous at room tempera-
ture (rt) for 3–5 h producing the intermediates 3a–f, which were
then converted to the 3-cyanomethyloxindole intermediates 4a–f with
dimethyl sulfoxide and 37% aq HCl/AcOH 1 : 1 by being stirred at rt
from 4 h until 3 days. Final conversion to the spirocyclopropyloxindoles
1
a–f was carried out using NaH and CH
2 2
Br in dimethylformamide
[15]
anh. at rt for 4–5 h. Compounds 2a–c, 3d, and 4d are known.
The spiroannulation of 4a–f gave the target nitrile-substituted
spirocyclopropyloxindoles 1a–f in good yield (80–90%) as a ther-
modynamic mixture of two epimeric isomers at the nitrile-bearing
carbon. In all cases, the isomer 3R*, and 9R*, with the cyano group
anti with respect to the carbonyl group at C-2, was the major
1
product, as shown by H-NMR analysis. The anti and syn
spirocyclopropyloxindoles 1b–f could be separated by flash
column chromatography on silica gel and characterized in pure
form. In the case of the anti/syn-1a mixture, pure samples were ob-
tained by partially resolved chromatography fractions. In each of
the anti/syn mixtures 1a–f, the more quickly eluted isomer was
the anti-diastereomer accounting for 4 : 3 to 5 : 1 of the diastereo-
meric ratio (dr), as determined by Gas Chromatography-Mass Spec-
1
trometry (GC-MS) and H-NMR analyses of unpurified reaction
1
products. The H chemical shifts for compounds 3a–f and 4a–f
13
are given in Tables 6 and 8. The C chemical shifts are presented
in Tables 7 and 9. The 3D structure of compounds 3a–c, 3e, and
4a obtained by single-crystal X-ray analysis can be found in the
Supporting Information as Figs S17 and S18. Cambridge Crystallo-
graphic Data Center (CCDC) number contains crystallographic data
for compounds anti-1d, anti-1e, syn-1f, 3a, 3b, 3c, 3e, and 4a. These
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Center via www.ccdc.cam.a-c.uk/data_request/cif.
wileyonlinelibrary.com/journal/mrc
Copyright © 2015 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2015, 53, 1061–1070

Anisotropic effects in configurational isomers of spirooxindoles
1
3
13 19
Table 7. C-NMR chemical shifts (δ in ppm) and C– F coupling constants (J in hertz) of 3a–f in CDCl
3
a
b
Carbon
3a
3b
3c
3d
3e
126.9
3f
2
3
128.9
128.3
128.1
127.2
103.0
127.0
99.9
127.3
102.2
126.6
117.7
129.0
124.0
109.3
135.5
14.2
c
102.7 (d, 5.2)
103.5 (d )
126.87 (d, 9.8)
103.3 (d, 23.9)
157.9 (d, 236.1)
111.04 (d, 26.2)
110.97 (d, 9.8)
133.2
103.4 (d, 4.9)
126.9 (d, 9.8)
103.3 (d, 23.6)
157.9 (d, 236.4)
111.01 (d, 26.2)
110.99 (d, 9.5)
133.2
102.8
127.0
99.8
3
4
5
6
7
7
8
1
2
3
4
5
a
126.51 (d, 10.1)
103.1 (d, 23.9)
157.8 (d, 235.8)
154.4
112.9
111.0
131.9
14.4
154.3
112.7
110.9
131.7
14.3
110.7 (d, 26.5)
110.4 (d, 9.9)
a
133.6
14.0
—
14.2
14.3
′
′
′
′
′
50.4
49.9
50.3
49.7
—
—
136.6
128.5
137.0
126.8
128.8
127.8
118.2
55.8
128.8
128.2
114.1
159.1
118.1
55.8, 55.2
—
—
126.7
128.3
—
—
128.8
114.2
—
—
127.9
159.3
—
CN
118.0
32.9
117.9
117.9
118.3
32.8, 21.4
Me/OMe
—
55.3
d, doublet.
a13
C Shifts assignments are in agreement with the gHSQC and gHMBC spectra.
Data taken from Ref. [15b].
b
c
Partial overlap.
(5-Fluoro-1-methyl-1H-indol-3-yl)acetonitrile (3a)
(1-Benzyl-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (4b)
Starting from 2a (200 mg, 1.15 mmol). Yield: 192 mg (89%). Color-
less crystals, mp 95–96°C. R : 0.4 (hexane/EtOAc 7 : 3); IR (CHCl
Starting from 3b (200mg, 0.76mmol). Yield: 117 mg (55%). Orange
À1
f
3
,
solid, mp 94–95 °C. R
f
: 0.58 (hexane/EtOAc 1 : 1); IR (CHCl
3
, cm
)
À1
+
+
cm ) νmax = 2253; GC-MS (EI, 70 eV): m/z (%) = 188 (M , 100), 162
36). HRESI/Atmospheric Pressure Chemical Ionisation Mass
ν
max = 2257, 1716; GC-MS (EI, 70 eV): m/z (%) = 280 (M , 99), 91 (100).
(
[
5-Fluoro-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile (4c)
9 2
Spectrometry (APCIMS): m/z calcd for C11H FN + H: 189.0828;
found: 189.0828. CCDC-1063672.
Starting from 3c (200 mg, 0.68 mmol). Yield: 112 mg (53%). Orange
À1
solid, mp 147–150 °C. R
f
: 0.52 (hexane/EtOAc 1 : 1); IR (CHCl
3
, cm
)
(1-Benzyl-5-fluoro-1H-indol-3-yl)acetonitrile (3b)
+
ν
max = 2255, 1709; GC-MS (EI, 70 eV): m/z (%) = 310 (M , 5), 283 (8),
Starting from 2a (200 mg, 1.15 mmol). Yield: 279 mg (92%). Orange
121 (100).
À1
solid, mp 134–135 °C. R : 0.7 (hexane/EtOAc 7 : 3); IR (CHCl , cm
νmax = 2253; GC-MS (EI, 70 eV): m/z (%) = 264 (M , 100), 238 (29),
1 (33). CCDC-1062964.
)
f
3
+
[5-Methoxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile
4e)
(
9
Starting from 3e (200 mg, 0.65 mmol). Yield: 147 mg (70%). Orange
[
5-Fluoro-1-(4-methoxybenzyl)-1H-indol-3-yl]acetonitrile (3c)
À1
solid, mp 147–150 °C. R
νmax = 2266, 1720; GC-MS (EI, 70 eV): m/z (%) = 322 (M , 12), 121
(100). HRESI/APCIMS: m/z calcd for C H N O + H: 323.1390;
f
: 0.38 (hexane/EtOAc 1 : 1); IR (CHCl
3
, cm
)
+
Starting from 2a (200 mg, 1.15 mmol). Yield: 304 mg (90%). Color-
less crystals, mp 134–136 °C. R
cm ) νmax =2253; GC-MS (EI, 70 eV): m/z (%) = 294 (M , 17), 121
f
: 0.6 (hexane/EtOAc 7 : 3); IR (CHCl
3
,
19 18 2 3
À1
+
found: 323.1388.
(100). CCDC-1063697.
(
1,5-Dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (4f)
[5-Methoxy-1-(4-methoxybenzyl)-1H-indol-3-yl]acetonitrile (3e)
Starting from 3f (200 mg, 1.09 mmol). Yield: 195mg (90%). Orange
Starting from 2b (200mg, 1.08 mmol). Yield: 296mg (90%). Color-
less crystals, mp 88–89°C. R : 0.4 (hexane/EtOAc 7 : 3); IR (CHCl ,
solid, mp 136–137 °C. R
cm ) νmax = 2255, 1712; GC-MS (EI, 70 eV): m/z (%) = 200 (M , 48),
183 (29), 160 (100).
f
: 0.43 (hexane/EtOAc 1 : 1); IR (CHCl
3
,
À1
+
f
3
À1
+
cm ) νmax =2255; GC-MS (EI, 70 eV): m/z (%) = 306 (M , 26), 121
100). CCDC-1062749.
(
(1R*,2R*)-5′-Fluoro-1′-methyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-
(1,5-Dimethyl-1H-indol-3-yl)acetonitrile (3f)
2
-carbonitrile (anti-1a) and (1R*,2S*)-5′-fluoro-1′-methyl-2′-oxo-1′,2′-
dihydrospiro[cyclopropane-1,3′-indole]-2-carbonitrile (syn-1a)
Starting from 2c (200mg, 1.18 mmol). Yield: 193mg (89%). Orange
À1
oil. R
f
: 0.5 (hexane/EtOAc 7 : 3); IR (CHCl
3
, cm ) νmax = 2255; GC-MS
Starting from 4a (200mg, 0.98 mmol) gave an anti/syn-1a mixture
(4: 1 dr) in an isolated combined yield of 89%. Pure samples were
obtained by partially resolved chromatography fractions (CH Cl ).
+
(EI, 70 eV): m/z (%) = 184 (M , 100), 170 (21), 159 (30).
2
2
(5-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (4a)
For anti-1a: white solid (acetone), sublimation point 220–222 °C. R
f
À1
Starting from 3a (200 mg, 1.06 mmol). Yield: 189 mg (87%). Orange
crystals, mp 136–137 °C. R : 0.39 (hexane/EtOAc 1 : 1); IR (CHCl ,
0.55 (hexane/EtOAc 1 : 1); IR (CHCl , cm ) νmax = 2250, 1711; GC-
3
+
MS (EI, 70 eV): m/z (%) = 216 (M , 100), 189 (25), 161 (10).
f
3
À1
+
cm ) νmax = 2259, 1715; GC-MS (EI, 70 eV): m/z (%) = 204 (M ,
00), 164 (93). CCDC-1063671.
HRESI/APCIMS: m/z calcd for C H FN O + H: 217.0772; found:
12
9
2
1
217.0777. For syn-1a: colorless crystals, mp 239–240 °C. R 0.54
f
Magn. Reson. Chem. 2015, 53, 1061–1070
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

J. B. García-Vázquez et al.
À1
(
hexane/EtOAc 1 : 1); IR (CHCl , cm ) νmax = 2250, 1711; GC-MS (EI,
3
70eV) promotes isomerization to give a mixture of anti/syn-1a
showing different retention times but identical MS patterns.
(
2
1R*,2R*)-1′-Benzyl-5′-fluoro-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-
-carbonitrile (anti-1b) and (1R*,2S*)-1′-benzyl-5′-fluoro-2′-oxo-1′,2′-
dihydrospiro[cyclopropane-1,3′-indole]-2-carbonitrile (syn-1b)
Starting from 4b (200 mg, 0.71 mmol) gave an anti/syn-1b mixture
(3: 1 dr) that was separated by flash chromatography (hexane/
EtOAc 4 : 1) to afford successively anti-1b (119 mg, 57%) and
syn-1b (50 mg, 24%). For anti-1b: slightly yellow crystals (CH Cl /
2
2
hexane), mp 147–148 °C. R 0.43 (hexane/EtOAc 7 : 3); IR (CHCl ,
f
3
À1
+
cm ) νmax = 2250, 1713; GC-MS (EI, 70 eV): m/z (%)= 292 (M , 57),
2
7
=
52 (26), 91 (100). For syn-1b: pale yellow oil. R 0.35 (hexane/EtOAc
f
À1
: 3); IR (CHCl
3
, cm ) νmax = 2252, 1720; GC-MS (EI, 70 eV): m/z (%)
+
292 (M , 52), 252 (29), 91 (100).
(1R*,2R*)-5′-Fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[cyclopropane-
1
2
,3′-indole]-2-carbonitrile (anti-1c) and (1R*,2S*)-5′-fluoro-1′-(4-methoxybenzyl)-
′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2-carbonitrile (syn-1c)
Starting from 4c (200mg, 0.65 mmol) gave an anti/syn-1c mixture
5: 1 dr) that was separated by flash chromatography (hexane/
(
EtOAc 4 : 1) to afford successively anti-1c (148 mg, 71%) and
syn-1c (29 mg, 14%). For anti-1c: colorless crystals, mp 133–135 °C.
À1
R
f
0.40 (hexane/EtOAc 7 : 3); IR (CHCl
3
, cm ) νmax = 2250, 1713;
+
GC-MS (EI, 70eV): m/z (%) = 322 (M , 9), 121 (100), 77 (10). For
syn-1c: pale yellow oil. R
cm ) νmax = 2248, 1716; GC-MS (EI, 70 eV): m/z (%)= 322 (M , 10),
f
0.30 (hexane/EtOAc 7 : 3); IR (CHCl
3
,
À1
+
1
21 (100), 77 (10).
(
1R*,2R*)-1′-Benzyl-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-
indole]-2-carbonitrile (anti-1d) and (1R*,2S*)-1′-benzyl-5′-methoxy-2′-oxo-
′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2-carbonitrile (syn-1d)
1
Starting from 4d (200 mg, 0.69 mmol) gave an anti/syn-1d mixture
3: 1 dr) that was separated by flash chromatography (hexane/
(
EtOAc 9 : 1) to afford successively anti-1d (131 mg, 63%) and
syn-1d (46 mg, 22%). For anti-1d: colorless crystals (acetone/hex-
À1
ane), mp 161–162 °C. R
2
f
0.51 (hexane/EtOAc 3 : 2); IR (CHCl
3
, cm ):
+
250, 1711; GC-MS (EI, 70 eV): m/z (%) = 304 (M , 90), 91 (100).
HRESI/APCIMS: m/z calcd for C19 + H: 305.1290; found:
05.1291. CCDC-1063932. For syn-1d: pale orange oil. R 0.31
, cm ) νmax = 2251, 1716; GC-MS
EI, 70eV): m/z (%) = 304 (M , 84), 91 (100); HRESI/APCIMS: m/z calcd
+ H: 305.1290; found: 305.1289.
H N O
16 2 2
3
f
À1
(
(
hexane/EtOAc 3 : 2); IR (CHCl
3
+
16 2 2
for C19H N O
(1R*,2R*)-5′-Methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[cyclopropane-
1,3′-indole]-2-carbonitrile (anti-1e) and (1R*,2S*)-5′-methoxy-1′-(4-methoxybenzyl)-
2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2-carbonitrile (syn-1e).
Starting from 4e (200mg, 0.62 mmol) gave an anti/syn-1e mixture
(4: 3 dr) that was separated by flash chromatography (hexane/
EtOAc 4 : 1) to afford successively anti-1e: (103 mg, 50%) and
syn-1e (69 mg, 33%). For anti-1e: colorless crystals (acetone/hex-
À1
ane), mp 154–155 °C. R 0.46 (hexane/EtOAc 3 : 2); IR (CHCl , cm
)
f
3
+
νmax = 2251, 1715; GC-MS (EI, 70 eV): m/z (%) = 334 (M , 19), 121
100). HRESI/APCIMS: m/z calcd for C H N O + H: 335.1395;
(
20 18 2 3
found: 335.1400. CCDC-1062748. For syn-1e: yellowish oil. R 0.26
f
À1
(
(
hexane/EtOAc 3 : 2); IR (CHCl , cm ) νmax = 2251, 1715; GC-MS
EI, 70 eV): m/z (%) = 334 (M , 21), 121 (100). HRESI/APCIMS: m/z
3
+
calcd for C H N O + H: 335.1395; found: 335.1402.
20 18 2 3
wileyonlinelibrary.com/journal/mrc
Copyright © 2015 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2015, 53, 1061–1070

Anisotropic effects in configurational isomers of spirooxindoles
1
3
13 19
Table 9. C-NMR chemical shifts (δ in ppm) and C– F coupling constants (J in hertz) of 4a–f in CDCl
3
a
b
Carbon
4a
4b
4c
4d
4e
173.9
4f
2
3
173.7
174.0
173.9
174.0
41.8
174.1
41.3
125.6
124.9
132.7
129.5
108.3
141.6
18.9
—
41.5 (d, 2.0)
126.9 (d, 8.6)
115.6 (d, 23.3)
159.2 (d, 241.8)
112.4 (d, 25.3)
109.1 (d, 8.1)
140.1 (d, 2.0)
18.7
41.7 (d, 2.2)
126.9 (d, 8.9)
115.7 (d, 23.7)
159.3 (d, 242.7)
112.5 (d, 25.5)
110.3 (d, 8.3)
139.2 (d, 1.6)
19.0
41.6 (d, 1.7)
127.0 (d, 9.8)
115.6 (d, 23.6)
159.2 (d, 242.4)
112.5 (d, 25.0)
110.3 (d, 8.1)
139.2 (d, 2.0)
18.9
41.7
126.8
111.4
156.2
113.6
110.1
136.5
19.0
3
4
5
6
7
7
8
1
2
3
4
5
a
126.8
111.5
156.3
113.7
110.1
136.5
19.2
a
′
′
′
′
′
—
44.2
43.7
44.1
43.5
—
134.8
126.8
135.2
127.2
128.8
127.8
117.1
55.8
127.2
128.6
114.1
159.1
117.0
55.1, 55.7
—
—
127.2
128.6
—
—
128.9
114.3
—
—
128.0
159.3
—
CN
116.8
116.7
116.7
117.3
21.0, 18.9
Me/OMe
26.5
—
55.2
d, doublet.
a13
C Shifts assignments are in agreement with the gHSQC and gHMBC spectra.
Data taken from Ref. [15b].
b
(
1R*,2R*)-1′,5′-Dimethyl-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2-
CPSIL capillary column, using helium as carrier gas (1 ml/min),
programmed from 70 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.
Low-resolution mass spectra were obtained in the electron impact
carbonitrile (anti-1f) and (1R*,2S*)-1′,5′-dimethyl-2′-oxo-1′,2′-dihydrospiro[cy-
clopropane-1,3′-indole]-2-carbonitrile (syn-1f)
Starting from 4f (200 mg, 1.0mmol) gave an anti/syn-1f mixture
(
EtOAc 4 : 1) to afford successively anti-1f (127 mg, 60%) and
2: 1 dr) that was separated by flash chromatography (hexane/
(EI) mode at an ionizing voltage of 70 eV. High-resolution mass
spectra were recorded in the electrospray ionization or in the chem-
ical ionization mode on an Agilent Liquid Chromatography Time Of
Flight (LCTOF) spectrometer at the UCR Mass Spectrometry Facility,
University of California, Riverside, CA. Analytical thin-layer chroma-
tography was performed on silica gel 60 F254 coated aluminum
sheets (0.25 mm thickness) with a fluorescent indicator. Visualization
was accomplished with UV light (254 nm). Flash chromatography
was performed using silica gel 60 (230–400 mesh).
syn-1b (64 mg, 30%). For anti-1f: colorless crystals, mp 183–185 °C.
À1
R
f
0.25 (hexane/EtOAc 7 : 3); IR (CHCl
3
, cm ) νmax = 2249, 1717;
+
GC-MS (EI, 70 eV): m/z (%) = 212 (M , 100), 198 (22), 186 (23). For
syn-1f: colorless crystals, mp 222°C. R 0.15 (hexane/EtOAc 7 : 3); IR
, cm ) νmax = 2250, 1715; GC-MS (EI, 70 eV): m/z (%) = 212
M , 100), 198 (23), 186 (23). CCDC-1063930.
f
À1
(
(
CHCl
3
+
NMR spectra
1
13
Acknowledgements
The H- and C-NMR spectra were recorded at 298 (±1) K with
5
–10mg samples dissolved in 0.5ml of CDCl
3
in 5-mm NMR tubes
The present work is partially supported by CONACYT (grant 179187)
and Programa de Fortalecimiento Académico del Posgrado de Alta
Calidad from CONACYT.
1
using Varian Mercury spectrometers (300.1MHz for H and
1
3
75.4 MHz for C). Chemical shifts (δ) are reported in ppm with the
normal spin multiplicity abbreviations (Tables 1–9). Coupling con-
1
13
stants are given in hertz. The H- and C-NMR chemical shifts of
the deuterated solvent (CDCl ) were δ 7.24 and 77.0 referenced to
the internal standard, TMS, respectively. For the H-NMR analyses,
6 transients were acquired with a 1-s relaxation delay using 32-K
data points. The 90° pulse duration was 10.0 μs, and the spectral
width was 4800 Hz. The C-NMR spectra were obtained with a
spectral width of 18867 Hz using 64-K data points. The 90° pulse
duration was 17.0 μs. For the two-dimensional (2D) experiments
including NOESY, gHSQC, and gHMBC, all data were acquired with
3
References
1
1
[1] (a) D. Guay, C. Beaulieu, R. T. Jagadeeswar, R. Zamboni, N. Methot,
J. Rubin, D. Ethier, M. D. Percival. Bioorg. Med. Chem. Lett. 2009, 19,
5392–5396. doi:10.1016/j.bmcl.2009.07.114; (b) C. Cativiela,
M. D. Díaz-de-Villegas, Tetrahedron: Asymm. 2000, 11, 645–732. DOI:
13
1
0.1016/S0957-4166(99)00565-0.
[2] (a) S. Jaegli, J.-P. Vors, L. Neuville, J. Zhu. Tetrahedron 2010, 66,
911–8921. doi:10.1016/j.tet.2010.09.056; (b) R. P. Wurz, W. Lin,
8
A. B. Charette. Tetrahedron Lett. 2003, 44, 8845–8848. doi:10.1016/j.
tetlet.2003.09.197; (c) F. Brackmann, A. de Meijere. Chem. Rev. 2007,
4
-K × 128 data points (t × t ). The mixing time for the NOESY exper-
2 1
iment was 0.8s, and the long-range coupling time for HMBC was
0 ms. All data were analyzed with Dell Precision T3500 using the
107, 4538–4583. doi:10.1021/cr0784083; (d) E. W. Yankee, B. Spencer,
1
N. E. Howe, D. J. Cram. J. Am. Chem. Soc. 1973, 95, 4220–4230.
doi:10.1021/ja00794a017; (e) F. Gnad, O. Reiser. Chem. Rev. 2003, 103,
Red Hat Enterprise Linux 5 platform and VNMRJ 2.2D software.
All reagent-grade chemicals were obtained from commercial sup-
pliers and were used as received. IR spectra were obtained in chloro-
form. GC-MS analyses were conducted on a spectrometer equipped
with a selective mass detector and a 30 m, 0.25 mm i.d., 0.25 mm
1
603–1624. doi:10.1021/cr010015v.
3] For reviews see:(a) L. K. Sydnes, Chem. Rev. 2003, 103, 1133–1150. DOI:
0.1021/cr010025w; (b) H.-U. Reissing, R. Zimmer. Chem. Rev. 2003,
03, 1151–1196. doi:10.1021/cr010016n; (c) A. Reichelt, S. F. Martin.
Acc. Chem. Res. 2006, 39, 433–442. doi:10.1021/ar030255s.
[
1
1
Magn. Reson. Chem. 2015, 53, 1061–1070
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

J. B. García-Vázquez et al.
[
4] (a) M. S. Morales-Ríos, D. E. González-Juárez, E. Rivera-Becerril,
Chim. Pays-Bas. 1992, 111, 407–410. doi:10.1002/recl.19921110905;
(c) E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic
Compounds. Wiley & Sons: New York, NY, 1994, Chapters 2-4.
[12] Gaussian 03, Revision C.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas,
D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz,
Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith,
M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and
J. A. Pople, Gaussian, Inc., Wallingford CT, 2004.
O. R. Suárez-Castillo, P. Joseph-Nathan. Tetrahedron 2007, 63,
7
702–7707. doi:10.1016/j.tet.2007.05.009; (b) M. S. Morales-Ríos,
N. F. Santos-Sánchez, Y. Mora-Pérez, P. Joseph-Nathan. Heterocyc.
004, 63, 1131–1142. doi:10.3987/COM-04-10041.
2
[
5] D.E.González-Juárez,J. B.García-Vázquez,V.Zúñiga-García, J. J.Trujillo-Serrato,
O. R. Suárez-Castillo, P. Joseph-Nathan, M. S. Morales-Ríos. Tetrahedron 2012,
6
8, 7187–7195. doi:10.1016/j.tet.2012.06.025.
6] (a) S. Pelloni, P. Lazzeretti, R. Zanasi. J. Phys. Chem. A. 2007, 111,
163–8169. doi:10.1021/jp0710638; (b) R. Carion, B. Champagne,
G. Monaco, R. Zanasi, S. Pelloni, P. Lazzeretti, J. Chem. Theory Comput.
010, 6, 2002–2018. doi:10.1021/ct100175j; (c) R. J. Abraham,
[
8
2
P. Leonard, C. F. Tormena. Magn. Reson. Chem. 2012, 50, 305–313.
doi:10.1002/mrc.3808.
[
[
7] P. Shanmugam, V. Vaithiyanathan, B. Viswambharan. Tetrahedron
2
006, 62, 4342–4348. doi:10.1016/j.tet.2006.02.072.
8] (a) R. J. Abraham, M. Reid. Magn. Reson. Chem. 2000, 38, 570–579.
doi:10.1002/1097-458X(200007)38:7<570::AID-MRC687>3.0.CO;2-O;
(
b) M. Rouillard, S. Geribaldi, J. Khazarian, M. Azzaro. Org. Magn. Reson.
980, 13, 323–327. doi:10.1002/mrc.1270130504.
9] (a) Y. G. Gakh, A. A. Gakh, A. M. Gronenborn. Magn. Reson. Chem.
000, 38, 551–558. doi:10.1002/1097-458X(200007)38:7<551::AID-
MRC686>3.0.CO;2-Q; (b) D. J. Sardella, E. Boger. Magn. Reson. Chem.
989, 27, 13–20. doi:10.1002/mrc.1260270104; (c) J. W. Lyga,
1
[
[13] (a) J. Gauss, D. Cremer, J. F. Stanton. J. Phys. Chem. A 2000, 104,
1319–1324. doi:10.1021/jp993189d; (b) S. Yamamoto, M. Nakata,
T. Fukayama, K. Kuchitsu. J. Phys. Chem. 1985, 89, 3298–3302.
doi:10.1021/j100261a027.
2
1
R. N. Henrie II, G. A. Meier, R. W. Creekmore, R. M. Patera. Magn.
Reson. Chem. 1993, 31, 323–328. doi:10.1002/mrc.1260310402; (d)
S. Suntioinen, R. Laatikainen, V. Král. Magn. Reson. Chem. 1994, 32,
[14] D. Neuhaus, M. P. Williamson, The Nuclear Overhauser Effect in Structural
and Conformational Analysis, 2nd Edition. WILEY-VCH: New York, 2000.
[15] (a) V. Pérez-Alvarez, M. S. Morales-Ríos, E. Hong, P. Joseph-Nathan.
J. Pharm. Pharmacol. 1997, 49, 246–252. doi:10.1111/j.2042-
7158.1997.tb06789.x; (b) E. Rivera-Becerril, P. Joseph-Nathan,
V. M. Pérez-Álvarez, M. S. Morales-Ríos. J. Med. Chem. 2008, 51,
5271–5284. doi:10.1021/jm800277g.
5
1–54. doi:10.1002/mrc.1260320111; (e) L. Ernst, K. Ibrom. Magn.
Reson. Chem. 1997, 35, 868–876. doi:10.1002/(SICI)1097-458X(199712)
5:12<868::AID-OMR195>3.0.CO;2-6.
3
[
10] (a) K. B. Wiberg, B. J. Nist. J. Am. Chem. Soc. 1963, 85, 2788–2790.
doi:10.1021/ja00901a026; (b) D. J. Patel, M. E. H. Howden,
J. D. Roberts. J. Am. Chem. Soc. 1963, 85, 3218–3223. doi:10.1021/
1
ja00903a036; (c) R. J. Abraham, M. Mobli, Modelling H NMR Spectra of
Organic Compound: Theory, Applications and NMR Prediction Software,
J. Wiley & Sons, Chichester, UK, 2008.
Supporting information
Additional supporting information may found in the online version
of this article at publisher’s web site.
[
11] (a) F. H. Allen, O. Kennard, R. Taylor. Acc. Chem. Res. 1983, 16, 146–153.
doi:10.1021/ar00089a001; (b) J. S. A. M. de Boer, C. H. Stam. Recl. Trav.
wileyonlinelibrary.com/journal/mrc
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