Characterization of novel isobenzofuranones by DFT calculations and 2D NMR analysis

Article abstract of DOI:10.1002/mrc.4411

Phthalides are frequently found in naturally occurring substances and exhibit a broad spectrum of biological activities. In the search for compounds with insecticidal activity, phthalides have been used as versatile building blocks for the syntheses of novel potential agrochemicals. In our work, the Diels–Alder reaction between furan-2(5H)-one and cyclopentadiene was used successfully to obtain (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (2) and (3aS,4S,7R,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3). The endo adduct (2) was brominated to afford (3aR,4R,5R,7R,7aS,8R)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4S,5S,7S,7aR,8S)-5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (4) and (3aS,4R,5R,6S,7S,7aR)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4S,5S,6R,7R,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (5). Following the initial analysis of the NMR spectra and the proposed two novel unforeseen products, we have decided to fully analyze the classical and non-classical assay structures with the aid of computational calculations. Computation to predict the ¹³C and ¹H chemical shifts for mean absolute error analyses have been carried out by gauge-including atomic orbital method at M06-2X/6-31+G(d,p) and B3LYP/6-311+G(2d,p) levels of theory for all viable conformers. Characterization of the novel unforeseen compounds (4) and (5) were not possible by employing only the experimental NMR data; however, a more conclusive structural identification was performed by comparing the experimental and theoretical ¹H and ¹³C chemical shifts by mean absolute error and DP4 probability analyses. Copyright

Full text of DOI:10.1002/mrc.4411

Research article
Received: 27 July 2015
Revised: 23 December 2015
Accepted: 29 December 2015
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/mrc.4411
Characterization of novel isobenzofuranones by
DFT calculations and 2D NMR analysis
Milena G. Teixeira and Elson S. Alvarenga*
Phthalides are frequently found in naturally occurring substances and exhibit a broad spectrum of biological activities. In the search
for compounds with insecticidal activity, phthalides have been used as versatile building blocks for the syntheses of novel potential
agrochemicals. In our work, the Diels–Alder reaction between furan-2(5H)-one and cyclopentadiene was used successfully to obtain
(
3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoi-
sobenzofuran-1(3H)-one (2) and (3aS,4S,7R,7aR)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4R,7S,7aS)-
a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3). The endo adduct (2) was brominated to afford (3aR,4R,5R,7R,7aS,8R)
5,8-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aS,4S,5S,7S,7aR,8S)-5,8-dibromohexahydro-4,7-methanoisobe-
3
-
nzofuran-1(3H)-one (4) and (3aS,4R,5R,6S,7S,7aR)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4S,5S,6R,7-
R,7aS)-5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one (5). Following the initial analysis of the NMR spectra and the
proposed two novel unforeseen products, we have decided to fully analyze the classical and non-classical assay structures with the
13
1
aid of computational calculations. Computation to predict the C and H chemical shifts for mean absolute error analyses have been
carried out by gauge-including atomic orbital method at M06-2X/6-31+G(d,p) and B3LYP/6-311+G(2d,p) levels of theory for all viable
conformers. Characterization of the novel unforeseen compounds (4) and (5) were not possible by employing only the experimental
1
NMR data; however, a more conclusive structural identification was performed by comparing the experimental and theoretical H and
13
C chemical shifts by mean absolute error and DP4 probability analyses. Copyright © 2016 John Wiley & Sons, Ltd.
Keywords: GIAO; DP4; γ-lactones; Diels–Alder; phthalides; MAE
structures with the experimental values constitutes an excellent
tool to support structural analysis in organic chemistry.
Introduction
[
35]
Phthalides or isobenzofuranones are well known for their broad
range of natural products that display a considerable number of ef-
The gauge-including atomic orbitals method is the most widely
used method for achieving the theoretical calculations of NMR
chemical shifts; it can provide a better agreement with experimen-
tal results when compared with other methods using the same ba-
[
1,2]
[3]
[4]
fects such as insecticidal,
nematicidal, acaricidal, vaso-
[5]
[6]
[7,8]
dilatation, analgesic, anti-inflammatory,
against neuronal impairment induced by deprival of oxygen and
protection effect
[36,37]
sis set.
[9]
glucose, and other biological activities. One method that can be
used for the synthesis of isobenzofuran-1(3H)-ones derivatives is
the Diels–Alder (DA) reaction involving a α,β-unsaturated γ-lactone
dienophile.
NMR shift calculation has been used to determine or confirm the
stereochemistry and/or structure of products obtained in synthetic
[
38]
chemistry and natural products such as bicyclic peroxides, epox-
[
39]
[40]
ides of careen,
isohasubanan alkaloids,
rufoolivacins A and
[
41]
[42]
[43]
The DA reaction represents an important and useful strategy in
B, gloriosaols A and B, and obtusallenes V, VI, and VII.
Analyses of the discrepancy between calculated and experimen-
tal C and H NMR chemical shifts, mean absolute error (MAE), root
mean square, and linear regression methods are frequently de-
[
10–14]
modern organic chemistry.
This reaction usually requires
13
1
electron-withdrawing groups in the dienophile and electron-rich di-
enes, or vice versa, to afford acceptable reaction rates. The use of
butenolides in DA reactions has been investigated over the last
[
31,44,45]
scribed in the literature.
[15–18]
decades.
The CP3 is a parameter used to assign the data of two spectra to
two possible structures. This method compares the differences in
calculated shifts between two candidate structures with the corre-
sponding differences in experimental shifts. The advantage is that
in this method the systematic errors cancel out. A limitation is that
it requires two sets of experimental data from both isomers. If only
one set of experimental data is available, it can be compared with
the calculated data of all candidate structures by using the DP4
The high applicability of the DA cycloaddition in organic synthe-
sis is due, among other reasons, to build complex molecules where
two simple bonds can be formed in a region and stereocontrolled
manner, yielding six-membered rings and up to four stereogenic
[
19,20]
centers in a single step.
In general, NMR spectroscopy is one of the most useful tools for
[
21–23]
the structural determination of new compounds.
However,
even with the aid of 2D NMR, it is not uncommon that molecular
[
24]
elucidation conclusions are erroneous or incomplete. Therefore,
13
1
many researchers simulate C and H NMR chemical shifts for
[
25–27]
* Correspondence to: Elson S. Alvarenga, Departamento de Química, Universidade
Federal de Viçosa, Viçosa, MG 36571-900, Brazil. E-mail: elson@ufv.br
many compounds by using quantum chemistry calculations.
[
28,29]
The technique was pioneered by Bifulco
cessfully employed in numerous reports.
and has been suc-
Good matching be-
[
30–34]
Departamento de Química, Universidade Federal de Viçosa, Viçosa, MG, 36571-
900, Brazil
tween the calculated chemical shifts for one of the potential
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

M. G. Teixeira and E. S. Alvarenga
probability method. Therefore, the DP4 method is employed to de-
cide which set of calculated shifts provides the best fit to the data
from the experimental spectrum assigning a probability to each
candidate structure.
In this paper, we describe a detailed assignment of the NMR data
obtained for four phthalide derivatives, including the measurement
of most of the homonuclear hydrogen coupling constants. Their
stereostructures were thoroughly studied by NMR experiments,
1
13
such as H NMR, C NMR, COSY, HETCOR, HSQC, HMBC, NOESY,
and NOEDIFF. In some cases, it has not been possible to determine
the relative stereochemistry only from the NMR data; therefore, a
methodology for the assignment of the relative stereochemistry
using MAE analyses in conjunction with DP4 probability has been
employed.
Scheme 1. Synthesis of adducts 2 and 3 from Diels–Alder reaction.
13
The most characteristic signals for adduct 2 in the C NMR are
observed at δ 178.0, 134.3, and 136.7, which are assigned to the car-
bonyl and the double-bond carbons. The presence of the double
bond is confirmed by the multiplet at 6.25–6.33 ppm (H5 and H6)
1
in the H NMR spectrum. The correct assignment of C5 (134.3)
Results and discussion
and C6 (136.7) has been achieved by the long-range C-H correla-
tions observed in the HMBC as can be seen in Fig. 2. Correlations
In the search for compounds with insecticidal activity, furan-2(5H)-
one 1 has been used as starting material for the synthesis of
phthalides. DA [4+2] cycloaddition of 1 with cyclopentadiene
afforded adducts endo 2 and exo 3. These compounds have been
used as models for the following structural changes, aimed at in-
creasing the insecticidal activity. Given that halogenated com-
pounds have been the subject of research involving the
3
3
3
3
J
H7-C5, JH3a-C5, JH7a-C6, and JH4-C6, which can be seen in this figure,
13
have been used also for the complete assignment of the C NMR.
The COSY experiment has been obtained for compound 3 to as-
sign the protons H5 and H6. This was possible because they have
presented different chemical shifts and couplings to the neighbo-
ring protons. Not less important to say that H5 and H6 have shown
correlations with H4 and H7, respectively.
[
46]
development of new agrochemicals, we have decided to con-
duct the bromination and chlorination reactions of adducts ob-
tained from the DA reaction. Some of the halogenated
compounds obtained are represented in Fig. 1. These substances
have caused the mortality of 84.8 to 96.3% of Diaphania hyalinata,
Irradiation of H8 of adduct 2 in the NOEDIFF experiment has en-
hanced, besides H4 and H7, the spatially close H3a and H7a, which
have been essential to establish its relative stereochemistry (Fig. 3).
On the other hand for isomer 3, enhancement of H3′ has been ob-
served when H8 was irradiated in the NOEDIFF experiment. There-
fore, the complete assignments of all signals of compounds 2 and 3
have been accomplished using the aforementioned techniques.
Inspired by the insecticide activity of the halogenated products
of the exo adduct 3 (Fig. 1), we have decided to prepare analogues
using the endo adduct 2. Halogenation reactions are mostly
stereoselective leading to the trans-disubstituted double bond via
[47]
a key pest of Curcubitaceae, resulting in a patent application.
The pericyclic cycloaddition of a diene and a dienophile where
bonds are broken and formed consecutively in a six-membered
transition state has been successfully applied for the synthesis of
[
48]
a series of phthalides in our research group. The DA transforma-
tion is governed by the HOMOdiene–LUMOdienophile interaction ac-
cording to frontier molecular orbital (FMO) theory, but can be
alternatively seen as a nucleophilic attack of the diene to the
[14]
dienophile. The DA reaction of the diene and dienophile may in-
teract in two different orientations, leading to the formation of endo
and exo adducts. Frequently, the endo adduct is favored due to a
[
49,50]
higher orbital overlap in the transition state.
Consistent with
this observation, in our work, the endo adduct was the major pro-
duct obtained from the reaction of furan-2(5H)-one 1 with
cyclopentadiene. As presented in Scheme 1, the endo and exo (2
and 3) have been formed, and for simplicity, only one enantiomer
of each adduct is depicted.
Although these compounds have been previously described in
[
51–58]
the literature, their NMR spectra have not been fully assigned.
Therefore, the complete structural elucidations of 2 and 3 have
been carried out in the present work. The unequivocal definition
of the relative stereochemistry has been performed by the transfer
of nuclear spin polarization from one nuclear spin population to an-
other via cross-relaxation (nuclear Overhauser experiments).
1
13
Figure 1. Chemical structures of the halogenated compounds with
insecticidal activity.
Figure 2. The expanded region of the 2D H, C HMBC spectrum acquired
n
optimized for a JCH of 8.0 Hz of compound 2.
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Experimental and theoretical characterization of synthetic unforeseen isobenzofuranones
1
Figure 3. (a) normal H NMR spectra of adduct 2 as reference; (b) NOEDIFF experiment (presaturation time of 3.0 s and power of 86 Hz) of adduct 2,
1
irradiation of H8; (c) normal H NMR spectra of adduct 3 as reference; and (d) NOEDIFF experiment (presaturarion time of 3.0 s and power of 86 Hz) of
adduct 3, irradiation of H8 and H8′.
[
59–63]
a three-membered intermediate.
Bromination of the double
At this point, we have started to look at the major product 5
bond of bicyclic systems, dependent of the reaction conditions,
has provided a complex mixture of substituted and rearranged
products.
Bromination of the endo adduct 2, as shown in Scheme 2, has
provided two major products (4 and 5), which have been separated
and purified by flash column chromatography.
of the bromination reaction (Scheme 2). An important feature
observed in the H NMR is the broad signal integrated to two
1
[64–66]
hydrogens at δ 4.43, which was assigned to H5 and H6. These
protons are the most deshielded due to the withdrawing effect
of the bromines attached to C5 and C6. This is the first evidence
for the formation of an unexpected cis-5,6-disubstituted com-
pound. The chemical shifts of H5 and H6 should be different if
the product formed was the most commonly expected trans-
5,6-disubstituted compound because their chemical environment
would be different. Therefore, the trans product, after this prelim-
inary analysis, should be considered in a less probable scenario.
Although the electrophilic addition of bromine on the double
bond has as main characteristic, the formation of trans-
dibrominated products, cis-dibrominated products have been de-
The absence of the signals of the vinyl hydrogens (H5 and H6) in
1
the H NMR for both products is a clear indication of the reaction
progress. The most deshielded proton of compound 4 has been
assigned to H5 (δ 4.74) because of the electrophilic character of
the bromine. This assignment has been confirmed after analysis
of the COSY and HSQC. This proton appears as a doublet of triplet
1
with coupling constants of 10.7 and 4.2 Hz in the H NMR. The for-
mation of the trans-disubstituted product may be doubted because
the trans-vicinal coupling constant is around 3 Hz. Careful inspec-
tion of the 2D NMR experiments have suggested C-6 bonded to
two hydrogens. Therefore, formation of the cis-disubstituted pro-
duct may be discredited also. Aligned with this observation (C6
with two hydrogens), we have proposed bromine addition to the
double bond followed by Wagner–Meerwein rearrangement to
[
67,68,70–72]
scribed for norbonenes.
Following the initial analysis of the NMR spectra and the proposal
of rearranged product 4 and cis-5,6-disubstituted product 5, we
have decided to fully characterize these compounds with the aid
1
3
of computational calculations. Computation to predict the
C
1
and H chemical shifts for the classical trans-brominated (5b and
5d), the cis-brominated (5a and 5c), and the rearranged structures
[
67–70]
give compound 4 as shown in Scheme 3.
(4a–h) have been carried out to find the correct products formed
in this reaction (Fig. 4).
At first, the DP4 method was applied without assignment of the
signals, which gave a probability that a set of experimental chemical
[73]
shifts matched the computed values of each proposed structure.
Furthermore, this methodology is convenient because it can be
used at the outset without full assignment of the experimental data.
Scheme 2. Bromination reaction of the substance 2.
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

M. G. Teixeira and E. S. Alvarenga
Scheme 3. Proposed mechanism for the formation of compound 4.
1
13
C
Table 1. DP4 analyses of the experimental and computed H and
NMR data for products 4 and 5 before assignment of the signals
a
Candidate
structures
DP4 probability (%)/NMR data
13
1
13
C
1
H
C and H
4
4
4
4
4
4
4
4
5
5
5
5
a
b
c
2.5
86.3
0.0
0.1
2.1
35.0
61.6
0.0
9.3
d
e
f
0.0
1.9
0.0
0.2
0.2
1.6
11.0
0.0
9.0
1.8
g
75.2
2.3
0.0
h
0.0
0.0
Figure 4. Candidate structures for compounds 4 and 5.
a
66.0
31.8
2.1
0.1
72.1
27.9
0.0
b
c
0.1
13
1
The first step is to calculate the C and H shifts for struc-
99.7
0.1
tures 4a–h and 5a–d as described in the Experimental section (cal-
culations) and tabulate the numbers (Calcd. δ and Calcd. δ in
H C
d
0.0
0.0
a
Calculations were carried using the B3LYP/6-31G(d,p)//molecular
mechanics level of theory.
Tables 2, 3 and 5). These numbers are now transferred into the
Web applet at http://www-jmg.ch.cam.ac.uk/tools/nmr/DP4/,
which will automatically calculate DP4 probability. In this stage,
the experimental shifts are assigned by matching up in order with
the calculated shifts. For example, H5 in 4a is calculated to have a
shift of 4.65 ppm, while H5 in 4b is calculated to have a shift of
The MAE is a quantity used to measure how close the calculated
chemical shifts are to the experimental chemical shifts. After
gaining substantial insight from the first computed data, such anal-
ysis should not influence the assignment process, and after all, it
turned out to be incorrect, as the correct compound is 4b, but 4a.
4.07 ppm; so when aligning the experimental data with those calcu-
lated for 4a and 4b, the 4.74 ppm experimental shift is assigned to
H5 in 4a and to H3′ in 4b. This is so because the chemical shift of H3′
in 4b is 4.48 ppm, which is closer to the experimental chemical shift
X ꢀ
ꢀ
ꢀ
ꢀ
(4.74ppm) than the chemical shift of H5 in 4b (4.07 ppm).
MAE ¼
δcalc ꢀ δexp
n
The candidate structure 4b has presented an 86.3% probability
1
of being the compound 4 by comparing the experimental H and
13
13
1
C NMR with the computed data without assignment of the signals
The first step is to calculate C and H shifts for structures 4a–h
and 5a–d as described in the Experimental (calculations). The next
step is to group the calculated C and H shifts for structures 4a–
4d in Table 2, for structures 4e–h in Table 3, and for struc-
tures 5a–d in Table 5.
All candidate structures were numbered in the same way
starting from the carbonyl carbon as shown for 4a and 4e in Fig. 5.
The structures 4a–d were grouped together in one table while
structures 4e–h and 5a–d were grouped in different tables. Struc-
tures 4a–d were grouped together in one table because they are
(Table 1).
1
3
1
In the case of the candidate structures 5, DP4 analyses without
assignment of the signals has returned a 66.0% probability of being
the compound 5a by comparing the experimental and computed
1
13
H and C NMR data (Table 1). Therefore, before making a final de-
cision, we have performed MAE analyses after assignment of the
signals by analyzing NMR spectra as presented in Tables 2, 3, and
5. All spectra can be found in the Supporting Information (Figs
S1–S13).
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Experimental and theoretical characterization of synthetic unforeseen isobenzofuranones
Table 2. The assigned and calculated NMR data for candidate structures 4a–d
Position
Expt.
Calcd. δ
H
Calcd. δ
C
Η
|Δδ |
C
|Δδ |
δ
Η
δ
C
4a
4b 4c
4d
4a
4b 4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
1
177.4
176.7 177.4 176.3 176.9
0.7
0
1.1
0.5
3
′
4.05
4.59
3.44
2.57
4.74
2.82
1.61
2.82
2.82
4.01
3.87 4.48 3.84 4.46
0.18 0.43 0.21 0.41
3
3
4
5
6
6
7
7
8
71.5 4.37 4.44 4.28 4.37
36.2 3.35 3.39 2.49 2.50
54.3 2.31 2.47 2.43 2.47
47.4 4.65 4.07 3.77 3.77
70.1
37.5
56.7
58.7
69.0
37.8
54.9
57.6
69.7
43.6
58.2
57.9
68.8 0.22 0.15 0.31 0.22
43.0 0.09 0.05 0.95 0.94
57.4 0.26 0.10 0.14 0.10
1.4
1.3
2.4
2.5
1.6
0.6
1.8
7.4
3.9
2.7
6.8
3.1
a
′
59.4 0.09 0.67 0.97 0.97 11.3 10.2 10.5 12
0.00 0.42 0.21 0.82
2.82 2.4
2.61 2.00
37.3 1.48 1.37 2.25 2.07
46.5 2.53 2.74 2.63 2.83
45.7 2.72 2.69 2.56 2.55
50.2 4.13 3.85 4.05 4.46
38.2
49.3
47.2
63.4
40.5
49.5
48.5
62.0
40.6
50.7
46.2
60.4
42.5 0.13 0.24 0.64 0.46
49.1 0.29 0.08 0.19 0.01
48.1 0.10 0.13 0.26 0.27
0.9
2.8
1.5
3.2
3
3.3
4.2
0.5
5.2
2.6
2.4
a
2.8
62.4 0.12 0.16 0.04 0.45 13.2 11.8 10.2 12.2
a,b
MAE
0.15 0.24 0.39 0.47
3.9
4.0
4.8
5.3
a
MAE, mean absolute error.
b
Calculations were carried out using the B3LYP/6-311+G(2d,p)//M06-2X/6-31+G(d,p) level of theory.
Table 3. The assigned and calculated NMR data for candidate structures 4e–h
Position
Expt.
Calcd. δ
H
Calcd. δ
C
Η
|Δδ |
C
|Δδ |
δ
Η
δ
C
4e
4f 4 g
4 h
4e
4f 4 g
4 h
4e
4f
4 g
4 h
4e
4f
4 g
4 h
1
177.4
177.3 178.0 175.1 176.0
0.1
0.6
2.3
1.4
3
′
4.05
4.59
3.44
2.82
2.82
1.61
4.74
2.57
2.82
4.01
3.88 4.43 3.88 4.47
0.17 0.38 0.17 0.42
3
3
4
5
5
6
7
7
8
71.5 4.34 4.41 4.28 4.34
36.3 2.63 2.65 2.44 2.46
46.5 2.18 2.33 2.28 2.41
2.77 2.33 2.54 1.92
70.8
42.4
52.0
69.6
43.5
49.5
70.7
41.2
53.2
69.3 0.25 0.18 0.31 0.25
43.7 0.81 0.79 1.00 0.98
48.8 0.64 0.49 0.54 0.41
0.05 0.49 0.28 0.90
0.7
6.2
5.5
1.9
7.2
2.9
0.8
5.0
6.6
2.2
7.4
2.3
a
′
37.3 1.39 1.34 2.15 2.01
47.4 4.67 4.10 3.85 3.81
54.3 2.71 2.92 2.79 2.87
45.7 3.44 3.44 2.60 2.61
50.2 4.12 3.83 4.01 4.42
38.3
58.6
54.7
43.4
63.5
41.4
57.0
55.5
44.0
61.9
40.4
58.4
55.4
48.0
60.8
43.3 0.22 0.27 0.54 0.40
1.0
4.1
3.1
6.0
59.2 0.07 0.64 0.89 0.93 11.2
9.6 11.0 11.8
57.5 0.14 0.35 0.22 0.30
47.4 0.62 0.62 0.22 0.21
0.4
2.3
1.1
1.7
1.0
2.3
3.1
1.7
a
62.0 0.11 0.18 0.00 0.41 13.3 11.7 10.6 11.8
0.31 0.44 0.42 0.52 4.5 4.5 4.8 5.3
a,b
MAE
a
MAE, mean absolute error.
b
Calculations were carried out using the B3LYP/6-311+G(2d,p)//M06-2X/6-31+G(d,p) level of theory.
stereoisomers. Structures 4e–h and 5a–d were not grouped in the
same table of 4a–d because these structures are not stereoiso-
mers between themselves. Therefore, the nuclei with the same
numbering (for the constitutional isomers) present distinct chem-
ical shifts. For example, H5 in 4a is calculated to have a shift of
observed for hydrogen chemical shift are inherently smaller than
carbon and are generally considered to provide better distinction
between isomers. After this first MAE analysis, we can exclude
tentative structures 4e–h, because their MAE values have been su-
perseded by 4a–b.
[
74]
4
.65 ppm (Table 2), while H5 in 4e is calculated to have a shift
Following MAE output for compound 4, we have excluded tenta-
tive structures 4e–h for DP4 analyses. Therefore, only the candidate
structures 4a–d have been considered in the following DP4 analy-
ses at this time after assignment of the signals (Table 4). The DP4
analysis showed that the calculated data of 4a were closely
matched to the experimental data with a probability of 99.3%, con-
of 1.39ppm (Table 3). H5 in 4a is much more deshielded than
H5 in 4e because of the electron-withdrawing effect of the bro-
mine directly attached to C5 in 4a.
The candidate structures 4a (0.15) and 4b (0.24) presented better
MAE values matching than 4e–h (from 0.31 to 0.52) by comparing
1
1
13
the experimental and calculated H NMR values. The MAEs
sidering H and C chemical shifts. The conclusion taken from DP4
about the candidate structure was in line with the MAE output
(Table 2).
Following MAE and DP4 analyses to characterize compound 4,
we have gone back to the desk for a deeper evaluation of the
NMR spectra. The assignment of H6 was carried out by detecting
the long-range ‘W’ coupling with H8 in the COSY. By using this
NMR experiment, we have been able to assign H6′ also. By using
5
Figure 5. Candidate structures 4a and 4e.
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

M. G. Teixeira and E. S. Alvarenga
1
13
1
13
Table 4. DP4 analysis of H and C NMR data for products 4a–d
Table 6. DP4 analysis of H and C NMR data for products 5a and 5c
a
a
Candidate
structures
DP4 probability (%)
Candidate
structures
DP4 probability (%)
13
1
13
C
1
H
13
1
13
C
1
H
C and H
C and H
4
4
4
4
a
b
c
99.3
0.7
1.4
28.1
57.3
13.2
100.0
0.0
5a
5b
5c
5d
100
–
96.5
–
100
–
0.0
0.0
0.0
–
3.5
–
0.0
d
0.0
0.0
–
a
a
Calculations were carried using the B3LYP/6-31G(d,p)//molecular
mechanics level of theory.
Calculations were carried using the B3LYP/6-31G(d,p)//molecular
mechanics level of theory. 5b and 5d were not included in the
DP4 analysis. The chemical shifts of carbons C5 and C6 were not
included in the analysis.
the NOESY experiment (Fig. 6), we have been able to confirm the
identities of H6 and H6′ because the correlation contour between
H5/H6′ is stronger than for H5/H6. This is due to the proximity of
H5 and H6′. The deeper NMR analyses corroborate with the calcula-
tions using both MAE and DP4 methods confirming the candidate
structure 4a for compound 4.
The analyses of MAE carried out for compound 4 have been
done for compound 5 considering the tentative structures 5a–d
(
Table 5). Considering all possible candidate structures, 5a has pre-
1
sented the best-matching in the MAE method (0.16 for H NMR and
4
1
3
.1 for C NMR). The MAE result is in line with previous NMR anal-
yses where the 5,6-trans-disubstituted candidate structures 5b and
5d have been discarded.
The protons H5 and H6 have been spotted by the correlation
contours with H8 observed in the COSY experiment. These cou-
plings are due to the long-range ‘W’ coupling, which are possible
only if H5 and H6 are at the endo position. Therefore, the DP4 meth-
odology has been employed for compound 5 considering potential
structures 5a and 5c after assignment of the signals (Table 6).
There is a significant difference between the experimental and
computed shifts for the carbon atoms attached to bromine. This
[
75]
general trend has been noted by Bagno and Saielli who found
that the omission of spin-orbit contributions can lead to errors of
more than 10 ppm for carbon atoms attached to bromine, but this
difference is not a factor for the other assignments. Therefore, the
chemical shifts of carbons C5 and C6, which are bonded to bro-
mine, were disregarded in the DP4 analysis for compound 5.
1
1
Figure 6. 2D H, H NOESY spectrum acquired for optimized mixing time of
700 ms of compound 4.
Table 5. The assigned and calculated NMR data for 5a–d
Position
Expt.
Calcd. δ
H
Calcd. δ
C
Η
|Δδ |
C
|Δδ |
δ
Η
δ
C
5a
5b 5c
5d
5a
5b 5c
5d
5a
5b
5c
5d
5a
5b
5c
5d
1
176.0
176.1 175.8 176.4 176.0
0.1
0.2
0.4
0.0
3
′
4.34
4.34
2.97
2.80
4.43
4.43
3.07
3.15
2.54
1.71
4.13 4.17 4.04 4.07
0.21 0.17 0.30 0.27
3
3
4
5
6
7
7
8
8
67.5 4.12 4.22 5.50 5.17
41.6 2.78 2.96 2.94 2.84
52.3 2.44 2.45 2.58 2.48
49.9 4.36 4.02 4.72 4.32
53.2 4.39 4.18 4.54 3.96
51.1 2.79 2.84 2.95 2.72
46.0 3.03 2.85 2.97 3.23
2.50 2.15 1.67 2.21
66.4
43.9
54.2
62.8
66.6
53.2
47.4
65.2
44.2
52.5
65.6
70.3
51.1
43.9
64.9
44.2
47.6
64.7
62.9
50.0
45.2
65.6 0.22 0.12 1.16 0.83
43.6 0.19 0.01 0.03 0.13
48.6 0.36 0.35 0.22 0.32
1.1
2.3
1.9
2.3
2.6
0.2
2.6
2.6
4.7
1.9
2.0
3.7
a
70.0 0.07 0.41 0.29 0.11 12.9 15.7 14.8 20.1
67.5 0.04 0.25 0.11 0.47 13.4 17.1 9.7 14.3
51.1 0.28 0.23 0.12 0.35
48.3 0.12 0.30 0.18 0.08
0.04 0.39 0.87 0.33
2.1
1.4
0.0
2.1
1.1
0.8
0.0
2.3
a
′
37.6 1.60 1.71 1.73 1.71
36.0
39.6
42.5
39.8 0.11 0.00 0.02 0.00
0.16 0.22 0.33 0.29
1.6
4.1
2.0
4.7
4.9
4.6
2.2
5.2
a,b
MAE
a
MAE, mean absolute error.
b
Calculations were carried out using the B3LYP/6-311+G(2d,p)//M06-2X/6-31+G(d,p) level of theory.
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Experimental and theoretical characterization of synthetic unforeseen isobenzofuranones
1
13
Figure 7. 2D H, C HETCOR spectrum of compound 5.
The H8 and H8′ at the methylene bridge (δΗ8 1.71 and δΗ8′ 2.54)
have been easily identified by analysis of the HETCOR (Fig. 7), be-
cause they are more shielded than the protons attached to C3
(300MHz), using deuterated chloroform as solvent. The proton
chemical shifts are reported relative to the signal of the residual
13
chloroform in δ = 7.27 ppm. The C chemical shifts are reported
using the signal in δ = 77 ppm from CDCl as reference.
(which is a methylene at the lactone ring).
3
After the MAE and DP4 analyses we have been able to focus on
one of the candidates and characterize compound 5 as molecule
a.
Synthesis
3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-
5
(
1(3H)-one and (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-4,7-metha-
noisobenzofuran-1(3H)-one (2) and (3aS,4S,7R,7aR)-3a,4,7,7a-
tetrahydro-4,7-methanoisobenzofuran-1(3H)-one and (3aR,4R,7-
S,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1(3H)-one (3)
Furan-2(5H)-one 1 (1.0012 g, 11.9mmol) and cyclopentadiene
Conclusion
The structures and relative stereochemistry of two DA adducts (2
and 3) have been established with the aid of 1D/2D NMR spectros-
copy. However, the structures of the bromination products (4 and
(8.1g, 0.12 mol) have been added to sealed tube. The resulting re-
action mixture has been magnetically stirred and heated at 100 °C
for 72 hours. The excess of cyclopentadiene has been evaporated,
and the crude product was purified by column chromatography (el-
uent: hexane:ethyl acetate 2:1v/v) to give 1.139 g (66% yield) of 2
and 0.363 g (18% yield) of 3.
5
) of the endo adduct (2) were determined only by combining
NMR spectroscopy data with theoretical calculations.
Experimental
(
3aR,4R,5R,7R,7aS,8R)-5,8-dibromohexahydro-4,7-methanoisoben-
zofuran-1(3H)-one and (3aS,4S,5S,7S,7aR,8S)-5,8-dibromohexahydro-
,7-methanoisobenzofuran-1(3H)-one (4) and (3aS,4R,5R,6S,7S,7aR)-
5,6-dibromohexahydro-4,7-methanoisobenzofuran-1(3H)-one and
3aR,4S,5S,6R,7R,7aS)-5,6-dibromohexahydro-4,7-
General experimental procedures
4
Reagents and solvents have been purified according to the proce-
dures described by Perrin and Armarego.
followed by visualizing the thin-layer chromatography plates
[
76]
The reactions were
(
[
77]
methanoisobenzofuran-1(3H)-one (5)
coated with silica gel in an ultraviolet chamber at 254nm. The
Phthalide 2 (0.5054 g, 3.37 mmol) has been dissolved in dichloro-
methane (10 ml) and transferred to a septum sealed round-bottom
flask containing a magnetic bar. Then a solution of bromine in di-
chloromethane has been added dropwise using a syringe. The reac-
tion progress has been followed by thin-layer chromatography and
gas chromatography and the substrate was totally consumed after
furan-2(5H)-one 1 have been obtained as previously described by
[78]
Näsman. The cyclopentadiene has been obtained by distillation
of dicyclopentadiene, commercially available (Sigma-Aldrich) be-
fore use in the DA reaction. Infrared spectra were recorded on a
Varian 660-IR, equipped with GladiATR scanning from 4000 to
ꢀ
1
5
00 cm . Mass spectra were recorded on a Shimadzu GCMS-
1
h. The solvent was evaporated under reduced pressure and the
QP5050A instrument using electron impact (70 eV) for ionization.
Melting points are uncorrected and were obtained in MQAPF-301
melting point apparatus (Microquimica, Brazil). Column chromatog-
raphy was performed over silica gel (60–230 mesh).
residue was flashed in a silica gel column chromatography using
hexane:ethyl acetate 3:1 as eluent to afford 0.1180 g (11% yield)
of 4 and 0.5021 g (48% yield) of 5.
Calculations
NMR spectral methods
1
13
The H and C NMR, COSY, HSQC, HETCOR, HMBC, NOEDIFF, and
NOESY spectra were recorded on a Varian Mercury instrument
Geometry optimizations and conformational searches were per-
[79]
formed with molecular mechanics in MacroModel.
The input
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

M. G. Teixeira and E. S. Alvarenga
[
[
13] P. Merino, E. Marqués-López, T. Tejero, R. P. Herrera. Synthesis 2010, 1,
geometry was submitted to a molecular mechanics current-energy
calculation to determine the force field best parameterized for the
conformer. Each of these conformers was then submitted to geom-
etry optimization and frequency calculation using DFT at M06-2X/6-
1–26. doi:10.1055/s-0029-1217130.
14] A. M. Sarotti. Org. Biomol. Chem. 2014, 12, 187–199. doi:10.1039/
c3ob41628c.
[15] M. Watanabe, M. Tsukazaki, Y. Hamada, M. Iwao, S. Furukana. Chem.
Pharm. Bull. 1989, 37, 2948–2951. doi:10.1248/cpb.37.2948.
[
80]
31+G(d,p) level of theory.
Chemical shifts were obtained from
[
16] V. Branchadell, J. Font, A. Oliva, J. Ortí, R. M. Ortuo. Tetrahedron 1991,
47, 8775–8786. doi:10.1016/S0040-4020(01)96199-X.
the NMR shielding tensor values, which were computed for each
[
81]
conformer at B3LYP/6-311+G(2d,p) level in Gaussian 09.
The
[
17] Z. Chen, R. M. Ortuno. Tetrahedron Asymm. 1994, 5, 371–376.
doi:10.1016/S0957-4166(00)86208-4.
conformers were subjected to Boltzmann weighting and then con-
verted to empirically scaled chemical shift values for each nucleus
of the candidate structure. Regression analysis parameters by
[18] A. Benmeddah, S. M. Mekelleche, W. Benchouk, B. Mostefa-Kara,
D. Villemin. J. Mol. Struc.- THEOCHEM 2007, 821, 42–46. DOI: 10.1016/j.
theochem.2007.06.018
[
82]
1
13
Lodewyk were used to scale and reference H and C chemical
shifts. These operations were repeated for each of all diastereoiso-
mers. The NMR and free-energy data were assembled by using
[
19] F. Fringuelli, A. Taticchi, The Diels-Alder Reaction: Selected Practical
Methods, John Wiley & Sons, New York, 2002.
20] I. Fleming, Pericyclic Reactions, Oxford University Press Inc., New York,
1999.
[
[
83]
the python script created by Willoughby. The experimental data
set were compared with the calculated data and mean absolute er-
ror values were determined.
[21] A. E. Taggi, J. Meinwald, F. C. Schroeder. J. Am. Chem. Soc. 2004, 126,
0364–10369. doi:10.1021/ja047416n.
1
[
22] J. K. Nicholson, J. Connelly, J. C. Lindon, E. Holmes. Nat. Rev. Drug
Discovery 2002, 1, 153–161. doi:10.1038/nrd728.
23] E. M. Lenz, I. D. Wilson. J. Proteome Res. 2007, 6, 443–458. doi:10.1021/
pr0605217.
A goodness-of-fit probability was determined using the DP4
[
84]
method described by Goodman. Specifically, a conformational
search was performed using the Monte Carlo Multiple Minimum
method and the Merck Molecular Force Field. The searches were
done in the gas phase with the number of steps large enough to
find all low-energy conformers at least ten times. The resulting con-
formers were subjected to DFT calculations of single-point energy
and gauge-including atomic orbitals shielding tensors at the
B3LYP/6-31G(d,p) level in the gas phase. The shielding tensors were
converted into referenced chemical shifts by subtracting the com-
[
[24] K. C. Nicolaou, S. A. Snyder. Angew. Chem. Int. Ed. 2005, 44, 1012–1044.
doi:10.1002/anie.200460864.
25] T. Helgaker, M. Jaszunski, K. Ruud. Chem. Rev. 1999, 99, 293–352.
doi:10.1021/cr960017t.
26] G. Bifulco, P. Dambruoso, L. Gomez-Paloma, R. Riccio. Chem. Rev. 2007,
107, 3744–3779. doi:10.1021/cr030733c.
[
[
[27] P. Tahtinen, A. Bagno, K. D. Klika, K. Pihlaja. J. Am. Chem. Soc. 2003, 125,
609–4618. doi:10.1021/ja021237t.
[28] G. Barone, L. Gomez-Paloma, D. Duca, A. Silvestri, R. Riccio, G. Bifulco.
4
[
84]
puted shielding tensors of tetramethylsilane.
The resulting
Chem. Eur. J. 2002, 8, 3233–3239. DOI: 0947-6539/02/0814-3233
chemical shift values have been Boltzmann averaged using the
single-point energy obtained from the calculation. The temperature
used was 298 K. DP4 analysis was accomplished by inputting com-
puted and experimental chemical shifts into the DP4 analysis tool
[
[
[
[
[
[
[
[
[
[
[
29] G. Barone, D. Duca, A. Silvestri, L. Gomez-Paloma, R. Riccio, G. Bifulco.
Chem. Eur. J. 2002, 8, 3240–3245. DOI: 0947-6539/02/0814-3240
30] B. Wang, A. T. Dossey, S. S. Walse, A. S. Edison, K. M. J. Merz. J. Nat. Prod.
2
009, 72, 709–713. doi:10.1021/np8005056.
31] C. K. Tai, P. L. Yeh, Y. S. Wu, T. L. Shih, B. C. Wang. J. Mol. Struc. 2014,
068, 84–93. doi:10.1016/j.molstruc.2014.03.070.
(located at: http://www-jmg.ch.cam.ac.uk/tools/nmr/DP4/).
1
32] Z. Li, J. Zhang, Y. Li, H. Gao. J. Mol. Struc. 2013, 1035, 69–75. doi:10.1016/
j.molstruc.2012.09.030.
33] L. Zhang, S. Q. Wang, X. J. Li, A. L. Zhang, Q. Zhang, J. M. Gao. J. Mol.
Struc. 2012, 1016, 72–75. doi:10.1016/j.molstruc.2012.02.041.
34] S. G. Smith, J. M. Goodman. J. Org. Chem. 2009, 74, 4597–4607.
doi:10.1021/jo900408d.
35] A. M. Sarotti, S. C. Pellegrinet. J. Org. Chem. 2009, 74, 7254–7260.
doi:10.1021/jo901234h.
36] K. Wolinski, J. F. Hinton, P. Pulay. J. Am. Chem. Soc. 1990, 112,
Acknowledgements
We are grateful to FAPEMIG, CNPq, and CAPES for financial support.
We would like to thank Professor JB from Université Laval for the
helpful suggestions. We are grateful to Flavio and Vinicius from
DTI for technical assistance.
8
251–8260. doi:10.1021/ja00179a005.
37] J. R. Cheeseman, G. W. Trucks, T. A. Keith, M. J. Frisch. J. Chem. Phys.
996, 104, 5497–5509. doi:10.1063/1.471789.
38] A. G. Griesbeck, D. Blunk, T. T. El-Idreesy, A. Raabe. Angew. Chem. Int. Ed.
007, 46, 8883–8886. doi:10.1002/anie.200701397.
39] S. M. Koskowich, W. C. Johnson, R. S. Paley, P. R. Rablen. J. Org. Chem.
008, 73, 3492–3496. doi:10.1021/jo702722g.
References
1
[
[
[
[
[
[
[
1] M. Miyazawa, T. Tsukamoto, J. Anzai, Y. Ishikawa. J. Agric. Food Chem.
004, 52, 4401–4405. doi:10.1021/jf0497049.
2] T. Tsukamoto, Y. Ishikawa, M. Miyazawa. J. Agric. Food Chem. 2005, 53,
549–5553. doi:10.1021/jf050110v.
3] R. A. Momin, M. G. J. Nair. J. Agric. Food Chem. 2001, 49, 142–145.
doi:10.1021/jf001052a.
4] J. H. Kwon, Y. J. Ahn. Pest Manag. Sci. 2003, 59, 119–123. doi:10.1002/
ps.607.
5] S. S. K. Chan, T. Y. Cheng, G. Lin. J. Ethnopharmacol. 2007, 111, 677–680.
doi:10.1016/j.jep.2006.12.018.
2
2
5
2
[
[
40] D. K. Nielsen, L. L. Nielsen, S. B. Jones, L. Toll, M. C. Asplund, S. L. Castle.
J. Org. Chem. 2009, 74, 1187–1199. doi:10.1021/jo802370v.
41] J. M. Gao, J. C. Qin, G. Pescitelli, S. D. Pietro, Y. T. Ma, A. L. Zhang. Org.
Biomol. Chem. 2010, 8, 3543–3551. doi:10.1039/c002773a.
[
42] D. C. Braddock, H. S. Rzepa. J. Nat. Prod. 2008, 71, 728–730. doi:10.1021/
np0705918.
6] J. Du, Y. Yu, Y. Ke, C. Wang, L. Zhu, Z. M. Qian. J. Ethnopharmacol. 2007,
[
43] C. Bassarello, G. Bifulco, P. Montoro, A. Skhirtladze, E. Kemertelidze,
C. Pizza, S. Piacente. Tetrahedron 2007, 63, 148–154. doi:10.1016/j.
tet.2006.10.034.
112, 211–214. doi:10.1016/j.jep.2007.02.007.
7] M. Shao, K. Qu, K. Liu, Y. Zhang, L. Zhang, Z. Lian, T. Chen, J. Liu, A. Wu,
Y. Tang, H. Zhu. Planta Med. 2011, 77, 809–816. doi:10.1055/s-0030-
[
44] W. Migda, B. Rys. Magn. Reson. Chem. 2004, 42, 459–466. doi:10.1002/
mrc.1366.
1
250573.
8] J. Huang, X. Q. Lu, C. Zhang, J. Lu, G. Y. Li, R. C. Lin, J. H. Wang. Fitoterapia
013, 91, 21–27. doi:10.1016/j.fitote.2013.08.013.
9] Q. Wei, J. Yang, J. Ren, A. Wang, T. Ji, Y. Su. Fitoterapia 2014, 93,
26–232. doi:10.1016/j.fitote.2014.01.010.
[
[
[
45] G. Saielli, K. C. Nicolaou, A. Ortiz, H. Zhang, A. Bagno. J. Am. Chem. Soc.
2
2
011, 133, 6072–6977. doi:10.1021/ja201108a.
[
[
46] P. Jeschke. Pest Manag. Sci. 2010, 66, 10–27. doi:10.1002/ps.1829.
47] E. S. Alvarenga, M. G. Teixeira, M. F. Pimentel, M. C. Picanço. BR Patent
2
[
[
[
10] K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogiannakis. Angew.
Chem. Int. Ed. 2002, 41, 1668–1698. DOI: 1433-7851/02/4110-1669
11] E. J. Corey. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. DOI: 1433-7851/
2
014, 10 2014, 031753.
[
48] F. Fringuelli, A. Taticchi, The Diels-Alder Reaction: Selected Practical
Methods, Wiley, Chichester, 2002.
02/4110-1651
12] K. Takao, R. Munakata, K. Tadano. Chem. Rev. 2005, 105, 4779–4807.
[49] A. Arrieta, F. P. Cossío. J. Org. Chem. 2001, 66, 6178–6180. doi:10.1021/
doi:10.1021/cr040632u.
jo0158478.
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Experimental and theoretical characterization of synthetic unforeseen isobenzofuranones
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
50] S. Lahiri, S. Yadav, S. Banerjee, M. P. Patil, R. B. Sunoj. J. Org. Chem. 2008,
3, 435–444. doi:10.1021/jo701884d.
51] K. P. Lok, I. J. Jakovac, J. B. Jones. J. Am. Chem. Soc. 1985, 107,
521–2526. doi:10.1021/ja00294a052.
52] P. Metz. Tetrahedron 1989, 45, 7311–7316. doi:10.1016/S0040-4020(01)
9192-4.
53] A. J. M. Janssen, A. J. H. Klunder, B. Zwanenburg. Tetrahedron Lett. 1990,
1, 7219–7222. doi:10.1016/S0040-4039(00)97284-8.
54] A. J. M. Janssen, A. J. H. Klunder, B. Zwanenburg. Tetrahedron 1991, 47,
513–5538. doi:10.1016/S0040-4020(01)80984-4.
55] K. Suzuki, K. Inomata. Synthesis 2002, 1819–1822. doi:10.1055/s-2002-
3911.
[73] S. G. Smith, J. M. Goodman. J. Am. Chem. Soc. 2010, 132, 12946–12959.
doi:10.1021/ja105035r.
[74] S. G. Brown, M. J. Jansma, T. R. Hoye. J. Nat. Prod. 2012, 75, 1326–1331.
doi:10.1021/np300248w.
[75] A. Bagno, G. Saielli. WIREs Comput Mol Sci 2015, 5, 228–240.
doi:10.1002/wcms.1214.
[76] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals,
Pergamon Press, Great Britain, 1988.
[77] E. S. Alvarenga, W. A. Saliba, B. G. Milagres. Quím. Nova 2005, 28, 927.
[78] J. H. Näsman. Organic Synth. 1990, 68, 162–167. DOI: 10.15227/
orgsyn.068.0162
[79] Schrödinger Release 2015-1: MacroModel, version 10.7, Schrödinger,
LLC, New York, NY, 2015.
7
2
8
3
5
3
56] H. Fujioka, T. Fujita, N. Kotoku, Y. Ohba, Y. Nagatomi, A. Hiramatsu, Y. Kita.
Chem. Eur. J. 2004, 10, 5386–5397. doi:10.1002/chem.200400444.
57] C. A. Citron, S. M. Wickel, B. Schulz, S. Draeger, J. Dickschat. Eur. J. Org.
Chem. 2012, 6636–6646. doi:10.1002/ejoc201200991.
[80] G. C. Resende, E. S. Alvarenga, P. H. Willoughby. J. Mol. Struc. 2015, 1101,
212–218. doi:10.1016/j.molstruc.2015.08.028.
[81] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino,
G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery, J. E. Peralta, F. Ogliaro, M. Bearpark,
J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
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, R. L. Martin, K. Morokuma, V. G. Zakrzewski,
G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian
’09, Revision A.1, Gaussian, Inc., Wallingford CT, 2009.
58] H. Yanai, A. Takahashi, T. Taguchi. Tetrahedron Lett. 2007, 48,
2
293–2297. doi:10.1016/j.tetlet.2007.02.131.
59] D. D. Gultekin, Y. T. Taskesenligil, A. Dasxtan, M. Balci. Tetrahedron 2008,
4, 4377–4383. doi:10.1016/j.tet.2008.02.067.
6
60] R. Rathore, S. V. Lindeman, C. J. Zhu, T. Mori, P. V. R. Schleyer, J. K. Kochi.
J. Org. Chem. 2002, 67, 5106–5116. doi:10.1021/jo0200724.
61] D. Lenoir, C. Chiappe. Chem. Eur. J. 2003, 9, 1037–1044. DOI: 0947-6539/
0
3/0905-1037
62] H. Slebocka-Tilk, R. G. Ball, R. S. Brown. J. Am. Chem. Soc. 1985, 107,
504–4508. doi:10.1021/ja00301a021.
4
63] M. F. Ruasse. Adv. Phys. Org. Chem. 1993, 28, 207–291. doi:10.1016/
S0065-3160(08)60183-5.
64] A. Dastan, M. Balci, T. Hokelek, D. Ulku, O. Buyukgungor. Tetrahedron
1
994, 50, 10555–10578. doi:10.1016/S0040-4020(01)89596-X.
65] M. E. Sengul, D. D. Gultekin, S. Essiz, A. Dastan. Turk J Chem 2009, 33,
9–86. doi:10.3906/kim-0805-37.
[82] M. W. Lodewyk, M. R. Siebert, D. J. Tantillo. Chem. Rev. 2011, 112,
1839–1862. doi:10.1021/cr200106v.
[83] P. H. Willoughby, M. J. Jansma, T. R. Hoye. Nat. Protoc. 2014, 9, 643–660.
doi:10.1038/nprot.2014.042.
[84] S. G. Smith, J. A. Channon, I. Paterson, J. M. Goodman. Tetrahedron
2010, 66, 6437–6444. doi:10.1016/j.tet.2010.06.022.
7
66] A. Dastan, U. Demir, M. Balci. J. Org. Chem. 1994, 59, 6534–6538.
doi:10.1021/jo00101a011.
67] S. J. Cristol, G. W. Nachtigall. J. Org. Chem. 1967, 32, 3727–3737.
doi:10.1021/jo01287a001.
68] J. M. Coxon, P. J. Steel, A. Burritt, B. I. Whittington. Tetrahedron 1995, 51,
8057–8072. doi:10.1016/0040-4020(95)00420-D.
69] W. B. Smith, C. Saint, L. Johnson. J. Org. Chem. 1984, 49, 3771–3774.
doi:10.1021/jo00194a018.
Supporting information
[70] A. Dastan. Turk J. Chem. 2002, 26, 535–546. doi:10.3906/kim-0107-11.
[71] M. Balci, A. Dastan. Jordan J. Chem. 2006, 1, 25–38.
[72] D. R. Marshall, P. ReynoldS-Warnhoff, E. W. Warnhoff, J. R. Robinson.
Can. J. Chem. 1971, 49, 885–903. doi:10.1139/v71-148.
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site.
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc