Quantum reality in the selective reduction of a benzofuran system

Article abstract of DOI:10.3390/molecules24112061

Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA), were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore, theoretical calculations of global and local reactivity were performed based on Pearson's hard and soft acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for explaining the selectivity of the polar reactions. This local parameter was defined with the condensed Fukui function and redefined with the electrophilic (Pk⁺) Parr function. The similar patterns of both resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance hybrids showed the moieties in each compound that are most susceptible to reduction.

Full text of DOI:10.3390/molecules24112061

molecules
Article
Quantum Reality in the Selective Reduction of a
Benzofuran System
Arturo Coaviche-Yoval 1, Erik Andrade-Jorge 2,3 , Cuauhtémoc Pérez-González 4, Héctor Luna 4,
Ricardo Tovar-Miranda 5,* and José G. Trujillo-Ferrara 2,
*
1
Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Unidad Xochimilco,
Mexico City 04960, Mexico; a.cy2@hotmail.com
2
3
4
Departamento de Bioquímica, Sección de Estudios de Posgrado e Investigación, Escuela Superior de
Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico; andrade136@hotmail.com
Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional
Autónoma de México. Av. de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Estado de México, Mexico
Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana-Unidad Xochimilco,
Mexico City 04960, Mexico; cperezg@correo.xoc.uam.mx (C.P.-G.); lchm1964@correo.xoc.uam.mx (H.L.)
Instituto de Ciencias Básicas, Universidad Veracruzana, Xalapa 91190, Veracruz, Mexico
Correspondence: rtovar@uv.mx (R.T.-M.); jtrujillo@ipn.mx (J.G.T.-F.);
5
*
Tel.: +52-22-8841-8900 (ext. 13930) (R.T.-M.); +52-55-5729-6000 (ext. 62747) (J.G.T.-F.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 15 May 2019; Accepted: 27 May 2019; Published: 30 May 2019
Abstract: Two 2,3-disubstituted benzofurans (1 and 2), analogs of gamma-aminobutyric acid (GABA),
were synthesized to obtain their 2,3-dihydro derivatives from the Pd/C-driven catalytic reduction of
the double bond in the furanoid ring. The synthesis produced surprising by-products. Therefore,
theoretical calculations of global and local reactivity were performed based on Pearson’s hard and soft
acids and bases (HSAB) principle to understand the regioselectivity that occurred in the reduction of
the olefinic carbons of the compounds. Local electrophilicity (ωk) was the most useful parameter for
explaining the selectivity of the polar reactions. This local parameter was defined with the condensed
Fukui function and redefined with the electrophilic (Pk+) Parr function. The similar patterns of both
resulting sets of values helped to demonstrate the electrophilic behavior (soft acid) of the olefinic
carbons in these compounds. The theoretical calculations, nuclear magnetic resonance, and resonance
hybrids showed the moieties in each compound that are most susceptible to reduction.
Keywords: catalytic reduction; olefinic carbons; selectivity; global reactivity; local reactivity; electrophilic
1. Introduction
Compounds of the benzofuran series and the corresponding 2,3-dihydroderivatives are receiving
considerable attention due to their biological activity and chemical properties. They are used to treat
traumatic and ischemic central nervous system (CNS) lesions, arteriosclerosis, liver diseases, and
cerebrovascular diseases [1–3]. They serve as the starting material for synthesising new compounds [4],
such as the frequently-reported synthesis of 2,3-dihydrobenzofurans. One might think that the
hydrogenation of the corresponding 2,3-disubstituted benzofuran would be the most direct route for its
synthesis, since the reaction of hydrogen with the benzofuran is a simple addition to the double bond
of the furanoid ring to produce 2,3-dihydrobenzofurans. However, hydrogenation is more difficult
with oxygen-heterocycles than nitrogen-heterocycles and many other aromatic compounds. In the
former case, the catalysts based on group VIII metals and their oxides promote hydrogenation of the
heterocyclic ring, and can also stimulate the reaction to proceed with future saturation of the benzene
ring, producing the octahydrobenzofuran derivatives. After hydrogenolytic cleavage of the furanoid
Molecules 2019, 24, 2061; doi:10.3390/molecules24112061
www.mdpi.com/journal/molecules

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ring to produce phenols and alcohols, future reactions may lead to the elimination of oxygen with the
formation of alkyl-benzenes and cyclohexanes.
Raney nickel is the most active catalyst in the hydrogenation of benzofuran to
2,3-dihydrobenzofuran. With platinum oxide, the hydrogenation of the benzene ring occurs at
a considerably lower rate compared to that of the double bond of the heterocyclic ring. In the presence
of Pd/C, the rate of hydrogen absorption at 25 ◦C is considerably lower for benzofuran than indene
or furan. In the hydrogenation of 2-acetylbenzofuran, platinum oxide displays high selectivity, only
reducing the acetyl group, whereas Raney nickel also hydrogenates the C=C double bond of the
heterocycle (Scheme 1) [4–7].
Scheme 1. Catalytic reduction with platinum oxide and Raney nickel.
Given advances in computational chemistry, enormous progress has been made in the
characterization of different structural and electronic properties of atoms and molecules. Consequently,
it is now possible to predict reactivity and reaction mechanisms, design better synthesis strategies, and
explain unexpected results in organic synthesis [8,9] using density functional theory (DFT), which is
an important theoretical tool in chemistry and physics [10,11].
To more reliably predict reaction outcomes in organic synthesis, many parameters have been
described in computational chemistry, such as global and local reactivity based on Pearson’s acid-base
principle. This hard-soft concept has been used extensively to interpret reactivity and selectivity.
The global parameters encompass global hardness (
the electrophilicity ( ) and nucleophilicity (
) indices, as well as electron-donating power (ω−
and electron-accepting power (ω+). The local parameters include the Fukui functions
), the Parr
k) indices, and the local reactivity
as an electrophile that is susceptible
as a nucleophile and able to perform an
η), global softness (S), chemical potential (µ),
ω
N
)
f(k
functions
difference index (
P(r), the local electrophilicity (ωk) and nucleophilicity (N
R
k). The two Fukui functions ar−e fk+ (for atom
k
to receiving an attack from a nucleophile) and fk (for atom
attack against an electrophile). The two Parr functions are Pk (the local Parr function for nucleophilic
attacks) and Pk (the local Parr function for electrophilic susceptibility) [12–19].
k
+
−
The present study describes the synthesis of two isomers of 2,3-disubstituted benzofurans
(
1
and
their cis-2,3-dihydroderivatives. The application of 10% Pd/C for the selective reduction of the
-unsaturated C=C double bond in the furanoid ring generated surprising hydrogenated products
(Scheme 2).
Our aim was to seek the theoretical-experimental coherence that could account for the outcome
of the catalytic reduction (with 10% Pd/C) of the C=C double bond of the furanoid ring in ethyl
3- (acetamidomethyl)benzofuran-2-carboxylate ( ) and methyl 2-(acetamidomethyl)benzofuran-3-
carboxylate ( ) (Scheme 2). For this purpose, descriptors of global and local reactivity were calculated,
based on the DFT framework.
2), analogs of GABA, and the subsequent catalytic hydrogenation with Pd/C to obtain
α,β
1
2

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Scheme 2. Products of the catalytic hydrogenation of benzofurans 1 and 2.
2. Results and Discussion
2.1. Chemistry
2.1.1. General Methodology for the Synthesis of 1
The synthesis of compound 1 was previously reported by our group [20].
A Williamson-type etherification between 2-acetylphenol
by an intramolecular aldol condensation to furnish the benzofuran
bromination was completed by free radicals and the bromine was replaced by the amino group through
an SN2 reaction with hexamethylenetetramine. The amino group was acetylated in to produce 1,
3
and ethyl bromoacetate
4
was followed
5
core. Subsequently, benzylic
7
which had a global yield of 23% (Scheme 3). The infrared (IR) spectrum shows a band of N–H at
3,291 cm−1, the C=O of the ester at 1,712 cm−1, and the carbonyl of the amide at 1,653 cm−1. In the
1H-nuclear magnetic resonance (NMR) spectrum (with CDCl3), there is a four-signal system from 7.88
to 7.30 ppm for aromatic protons, a broad signal at 6.36 for the NH proton, a double signal at 4.85
corresponding to the benzylic protons of methylene alpha of the amino group, an A2 × 3 system for
the ethyl fragment of the ester (q 4.48 ppm, t 1.45 ppm), and a singlet at 1.96 ppm characteristic of the
acetyl group. The peak in high-resolution mass spectrometry (HRMS) M+ + 1 (m/z) at 261.105 confirms
the structure of 1 (Supplementary Materials).
Scheme 3. General synthetic pathway to obtain compound 1. Reaction conditions: (a) Dimethylformamide
(DMF), K2CO3, 125 ◦C; (b) EtOH, H2SO4, 40 ◦C; (c) CCl4, N-bromosuccinimide (NBS), benzoyl peroxide,
reflux; (d) CHCl3, C6H12N4, reflux; (e) H2O, reflux; and (f) Dichloromethane (DCM), Et3N, Ac2O,
CH3COCl, room temperature (rt).
2.1.2. General Methodology for the Synthesis of 2
Etherification of the corresponding phenol
aldol condensation produced benzofuran 21]. The methyl group was functionalized by benzylic
bromination, followed by treatment of the brominated product with potassium acetate to produce 11
3 with chloroacetonitrile and subsequent intramolecular
9
[

Molecules 2019, 24, 2061
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and then hydrolysis of the acetate group to generate 12
[
22]. Afterward, the reduction of the nitrile
group furnished the amino-alcohol, which became acetylated to produce the diacetylated 13 [23–26].
The acetate group of 13 was selectively hydrolyzed with potassium carbonate to deprotect the hydroxyl
group and form the oxidized product (aldehyde) 14 [27,28]. The synthesis of 2 was completed by the
oxidation of 14 with manganese oxide in the presence of cyanide to form the methyl ester (5.4% overall
yield for the synthetic pathway, Scheme 4) [29–31].
Scheme 4. General synthetic pathway for preparing compound
K2CO3, 140 ◦C; (b) CCl4, NBS, benzoyl peroxide, reflux; (c) AcOH, AcOK, reflux; (d) MeOH, H2SO4, rt;
(e) MeOH, NaBH4-CoCl4 6H2O, rt; (f) DCM, Et3N, CH3COCl, rt; (g) MeOH, K2CO3, rt; (h) DCM, PCC,
2. Reaction conditions: (a) DMF,
·
AcONa, rt; and (i) MeOH, KCN, NaCN, AcOH, MnO2, rt.
The IR spectrum showed a stretch band of N–H at 3,289 cm−1, a band at 1,713 cm−1 indicating the
presence of the carbonyl carbon (C=O) of the ester, and a band at 1655 cm−1 confirming the existence of
the carbonyl carbon (C=O) of the amide. The proton NMR (1H-NMR) spectrum (CDCl3) presents four
aromatic protons between
δ 7.95 and 7.32 ppm, a wide signal at 6.44 ppm for the NH proton, a doublet
at 4.90 ppm that integrates the methylene CH2NHCO-, a singlet at 3.97 ppm for the methyl ester, and
finally a simple signal at 2.02 ppm that integrates for the amide acetyl NHCOCH3. The HRMS peak
M+ + 1 (m/z) at 248.08 confirms the structure of 2 (Supplementary Materials).
2.1.3. General Methodology for the Hydrogenation Reactions
All hydrogenation reactions proceeded in glass tubes sealed with rubber stoppers equipped
with needles [32–34]. The tubes were placed inside a flask, and the reaction was performed at
room temperature (rt) in a parr hydrogenation device at 60 psi H2 pressure and with a 10% Pd/C
catalyst. The reaction crudes corresponding to each hydrogenation experiment were analyzed by
1H-NMR and the relative proportions of each compound were calculated from the integral of the
signal corresponding to the methyls of the acetyl group (NHCOCH3). The reaction mixtures were
purified by flash silica column chromatography with hexane-ethyl acetate as the eluent. The isolated
products were characterised by their NMR spectroscopic data, identifying the chemical shifts (
of the typical signals of and its hydrogenated products (1a 1c), as well as of and its hydrogenated
derivative rac-2a (Table 1; Supplementary Materials).
δ, ppm)
1
–
2

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Table 1. Chemical shifts (
the methyls in compound
hydrogenated derivative 2a.
δ
, ppm) in the proton nuclear magnetic resonance (1H-NMR) spectra of
and its hydrogenated products (1a 1c), and in compound and its
1
–
2
Compound
Structure
δ NH-14
δ CH3-17
δ CH3-12
1.94 b
1.92 b
1.92 b
1.92 b
1.41 b
1.31 b
1.33 b
1.31 b
1
6.36 a
-
-
-
-
1.96 a
1.45 a
1a
1b
1c
5.73 a
6.61 a
6.27 a
1.87 a
1.94 a
1.96 a
1.34 a
1.38 a
1.34 a
δ NH-9
δ CH3-16
δ CH3-12
2
6.45 a
5.93 a
-
-
3.98 a
3.78 a
-
-
2.02 a
1.98 a
-
-
2a
Chemical shifts refer to internal Tetramethylsilane TMS at 600 MHz. (a CDCl3, b CD3OD.).
The relative magnitude of the coupling constants (J = Hz) in the series of 2,3-dihydrobenzofurans
is Jcis-2,3 > Jtras-2,3, in agreement with the Karplus equation. The NMR evidence showed that the
relative stereochemistry of 1a, 1c, and 2a is cis. The coupling constant for H2-H3 in the reduced
products (JH2-H3 = 9.1 Hz in 1a, JH2-H3 = 10.2 Hz and JH3a-H7a = 8.4 Hz in 1c, and JH2-H3 = 7.2 Hz in 2a
)
corresponds to the expected values for the cis isomers [32,35,36] (Supplementary Materials).
To optimize the reduction of the
compounds and , experiments were conducted with different concentrations of the catalysts and
distinct reaction times (Table 2). In the beginning, the attempts to perform the hydrogenation of
by applying minimum amounts of catalyst were unsuccessful (Table 2). The results demonstrate
the possibility of reducing the -unsaturated C=C double bond in the furanoid ring to furnish the
α,β-unsaturated C=C double bond of the furanoid ring in
1
2
1
α,β
target compound rac-1a. Curiously, the reaction generated a by-product of the partial reduction of the
benzene ring 1b. When the amount of catalyst increased, the reaction led to the total reduction of the
heterocycle to produce the octahydrobenzofuran derivative 1c (Figure 1).

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Table 2. Reaction conditions for the catalytic hydrogenation of compounds
room temperature (rt) and 65 psi of H2 pressure.
1
and 2 with 10% Pd/C, at
Yield (%)
1b
Substrate (S)
(mg/mmol)
Weight Ratio
(S/Catal)
Concentration Time
Entry a
[mmol]
(h)
1
rac-1a
1c
c
c
c
c
c
c
c
1
2
3
4
5
6
7
8
9
50/0.19
50/0.19
50/0.19
50/0.19
50/0.19
15/0.06
100/0.38
100/0.38
71/0.27
100/0.38
1/0.5
1/1
1/1.5
1/2
1/0.5
1/1
1/2
1/2.4
1/1
1/4
76
76
76
38
38
38
14
82
16
14
24
24
24
24
44
44
46
48
96
24
55
23
13
12
77
30
35
—
88
7
34
54
42
21
19
55
26
13
7
7
10
14
22
4
4
13
32
46
—
6
—
63
—
15
9
25
24
5
c, d
c
c, d
10
47
31
2
rac-2a
c
c
c
11
12
25/0.10
15/0.06
26/0.10
1/0.3
1/1
1/1
45
75
75
44
24
24
c
100
20
12
—
80
88
—
—
—
—
—
—
13 b
All reactions were performed with a EtOH or b MeOH as solvent. Ratios were determined by 1H-NMR of the
d
crude mixture. Yield of products isolated by chromatography.
The preparation of rac-1a was optimal when using an S:C ratio of 1:1 (Figure 1, graphs from entries
1–4; Table 2). A higher proportion of catalyst caused a significant decrease in the target compound
rac-1a and a significant increase in the proportion of the completely reduced compound 1c. Therefore,
1c appears to be mainly a by-product of rac-1a.
Unlike the case of
1, the hydrogenation of the α,β-unsaturated C=C double bond in the furanoid
ring of was fairly simple and selective, producing rac-2a as the main product. The relative proportions
2
of each product were calculated by analyzing the 1H-NMR spectral data of the reaction mixture from
each experiment, taking advantage of the difference in the chemical shifts of the methyl protons of the
acetyl group (CH3-17 and CH3-12) in the distinct compounds resulting from the reaction (Table 1, and
Figures 2 and 3).
Figure 1. Variation in the hydrogenated products obtained (%) from compound
effect of the S/C ratio (entries 1–4, Table 2).
1 at 24 h due to the

Molecules 2019, 24, 2061
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17
rac-1a
O
O
O
O
17
rac-1a
1
1b
1c
13
O
1
NH
17
NH
NH
NH
12
4
O
3
12
3a
7a
O
O
O
5
6
11
2
O
O
O
O
O
O
O
1b
1c
7
6%
30%
55%
9%
12
13
4,6
11
2
17
11
13
11
5,7
13
A-B
12
7
5
6
4
3
13
B 3
6,5
NH
7
4
NH
13
A
NH
NH
7,3a
2
7a
4
4,5
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
f1 (ppm)
Figure 2. 1H-NMR spectrum (CDCl3) of the crude reaction (entry 6, Table 2).
Figure 3. 1H-NMR spectrum (CDCl3) of the crude reaction (entry 12, Table 2).
2.2. Computational Studies (Theoretical Calculations)
2.2.1. Conformational and Optimization Geometry
The optimized geometries of the structures of
(Supplementary Materials).
1 and 2 are shown in Figures S3–S5
2.2.2. Indices of Global and of Local Reactivity
Theoretical calculations were used to explore possible reasons for the susceptibility to reduction
of the -unsaturated C=C double bond of the furanoid ring in and , and for the unexpectedly
α
,β
1
2
yielded reduction by-products. Hence, we determined the global and local reactivity [37] (Table 3),
which allowed for analysis of the selectivity of the reduction pathway (Table 4).
The potential ionization (
to donate and accept an electron, respectively. The chemical potentials of
and 4.0301 eV, respectively, suggesting that is more electron accepting and 2
donating. The most stable systems are those with the highest hardness values (those having the greatest
variation between the Highest Occupied Molecular Orbital and Lowest Unoccupied Molecular Orbital
(HOMO-LUMO). Since softness is the reciprocal of hardness, the most reactive systems possess greater
I
) and electron affinity (
A
) express the ability of a chemical species
and were 4.0833
is more electron
1
2
−
−
1

Molecules 2019, 24, 2061
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softness. The present global softness values were not capable of indicating the most reactive system,
evidenced by the lack of significant difference between and = 0.1267 and 0.1261 eV, respectively).
1
2 (S
Table 3. Global indices of reactivity: ionization potential (
global hardness ( ), global softness ( ), electrophilicity index (
donating power (ω−), and electron accepting power (ω+).
I
), electron affinity (
A
), chemical potential (
µ
),
η
S
ω
), nucleophilicity index (
N), electron
ω−(eV)
Comp.
I(eV)
A(eV)
µ(eV)
η(eV)
S(1/eV)
ω(eV)
N (eV)
ω+(eV)
1
2
8.031
7.993
0.136
0.067
−4.083
7.895
7.926
0.1267
0.1261
1.056
1.025
1.087
1.125
4.647
4.560
0.564
0.530
−4.030
The Highest Occupied Molecular Orbital (HOMO) energy of tetracyanoethylene (TCE) is −0.3351 au (27.21) = 9.118 eV
at the same level of theory.
The electrophilicity index
ω expresses the stabilization energy of an electrophile when it is
saturated by electrons from the external environment. It also serves to characterize nucleophilicity,
as a low electrophilicity value corresponds to elevated nucleophilicity. Based on the results, both
compounds can be classified as moderate electrophiles. Thus, the data point to a greater electrophilic
behavior for
by the nucleophilicity index
1.087, respectively). This nucleophilicity index refers to tetracyanoethylene (TCE,
The electron donating power (
−) and electron accepting power (ω+) have a behavior similar to
1
than
2
(
ω
= 1.056 versus 1.025 eV, respectively). This tentative conclusion was confirmed
, which showed a greater nucleophilicity for than = 1.125 versus
= 9.118 eV).
and
N
2
1 (N
I
ω
I
A
. The capacity of a chemical system to donate or accept a small fraction of charge is expressed as ω−
and ω+, where ω− refers to the propensity of the system to donate electron density and ω+ refers to
its propensity to accept electron density.
All the above information provides insights into global reactivity but not selectivity. The reactivity
of a particular site of a molecular species can be explained through the FF (border function f(r)), which
is a measure of the variation of the chemical potential in relation to the external potential at a particular
point (r) of the molecule. The FF varies in accordance with the variation in the electron density ρ(r)
from point to point in a molecule due to the extraction of electrons from HOMO or addition of these
to LUMO.
The electrophilic and nucleophilic local softness (sk+ and sk−) are given by FF multiplied by the
global softness
and nucleophilicity
the most electrophilic and nucleophilic centers in an organic molecule by revealing the distribution
of the indices of global electrophilicity and nucleophilicity at the atomic sites . In a detailed
S
. Similar to the
sk, other local descriptors are the indices of local electrophilicity ωk
+
N
k, where ωk
= ωfk and Nk =
Nfk−. They allow for the characterization of
ω
N
k
analysis of FF, however, Yang-Mortier (YM) presented some relevant errors. Even though the local
functions are normalized, the sum of the YM FF (fk+ or fk−) corresponding to heavy atoms (CH, CH2
+
and CH3) is below 1.0, a discrepancy with the sum of the Parr functions (Pk or Pk−), which is closer
to 1.0. Using the Parr functions, the local indices for electrophilicity ωk and nucleophilicity
Nk were
redefined. The relevant function for the reduction of olefinic carbons in and is local electrophilicity
1
2
ωk. A large value of this parameter at a particular site denotes greater reactivity toward a nucleophile.
To analyze the Fukui functions and compare them to the proposed Parr functions, the corresponding
local electrophilic values ωk are given in Table 4.
A preliminary examination of the data revealed similar patterns in both models for the local
reactivity of molecules
1 and 2. As shown, 1 contains three olefinic carbons, the most electrophilically
activated centers (C3, C4, and C6), indicating its susceptibility to nucleophilic attack and to the
consequent reduction by a polarized hydrogen induced by the catalyst. In
electrophilically activated center (C2) is susceptible to reduction (Figure 4).
2, conversely, only one

Molecules 2019, 24, 2061
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Table 4. The electrophilic (fk+) and nucleophilic (fk−) Fukui functions, as well as the electrophilic and
+
−
a
nucleophilic local softness sk and sk
, and the corresponding local electrophilicity index ωk at
different positions in the compound. Also presented are the electrophilic (Pk+) and nucleophilic (Pk
Parr functions, and the corresponding local electrophilicity index redefined as ωk
)
−
b
.
+
b
−
Comp.
Pk
s
Pk
ρ
rc(k)
s
ωk
+
+
a
−
−
sk
fk
sk
ωk eV
fk
k
ρ
ra(k)
eV
1
2
C2
0.0350
0.0646
0.0059
0.0451
0.0255
0.0462
0.0373
0.0068
0.05505
0.02911
0.01383
0.04218
0.03098
0.04162
0.04826
0.00060
0.0044
0.0082
0.0007
0.0057
0.0032
0.0059
0.0047
0.0009
0.0070
0.0037
0.0018
0.0053
0.0039
0.0053
0.0061
0.0001
0.03696
0.06822
0.00623
0.04763
0.02693
0.04879
0.03939
0.00718
0.1170
0.2372
−0.0763
0.173
−0.0768
0.1407
0.0237
0.0199
0.2227
0.1198
0.1236
0.2505
−0.0806
0.1827
−0.0811
0.1486
0.025
C3
C3a
C4
C5
C6
−0.0261
0.2393
−0.0856
0.1436
0.1308
−0.0388
0.1473
0.1408
0.0321
0.1899
−0.1063
0.2217
0.0442
0.0156
C7
C7a
0.021
C2
C3
C3a
C4
C5
C6
0.0935
0.0270
0.0033
0.0327
0.0302
0.0366
0.0405
−0.0107
0.03574
0.03411
0.01697
0.03945
0.02737
0.04421
0.04005
0.01281
0.0115
0.0033
0.0004
0.0040
0.0037
0.0045
0.0050
−0.0013
0.0044
0.0042
0.0021
0.0049
0.0034
0.0054
0.0049
0.0016
0.09584
0.02768
0.00338
0.03352
0.03096
0.03752
0.04151
−0.0109
0.5483
−0.0608
−0.0145
0.0749
0.562
−0.0623
−0.0149
0.0768
−0.0045
−0.0046
0.0140
0.0144
C7
C7a
0.0779
−0.0441
0.0798
−0.0452
The electron population for calculating the Fukui functions was based on the theory of atoms in molecules (AIM).
The Parr functions were obtained through the analysis of the Mulliken atomic spin density (ASD) of the radical anion
and the radical cation. ωk was calculated with the Fukui functions; b ωk was calculated with the Parr functions.
a
Figure 4. Indices of local electrophilicity ωk (Parr) in compounds 1 and 2.
α
,β-unsaturated carbonyl compounds present the most electrophilic center at the
β conjugated
position, and electrophilicity is expressed well by the Parr and the Fukui functions. This parameter is
in clear agreement with the regioselectivity experimentally observed in the catalytic reduction of
1 and
2, as well as with the zwitterionic species of the resonance structures (Scheme 5).

Molecules 2019, 24, 2061
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Scheme 5. Resonance structures for compounds 1 and 2.
The
system from the carbonyl carbon of the ester to the benzene ring, making it more aromatic and more
electrophilic than . The sites having greater electrophilicity, as observed in the resonance structures
(Scheme 4), coincide with the values of local softness sk+ and ωk. In addition, the chemical shifts of
the 13C-NMR spectra of the olefinic carbons are in agreement with the electron density
) of these
atoms, indicating their electrophilicity. The δ of the olefinic carbons centers that show relatively high
electrophilicity for δC) are 122 (C4), 127 (C3), and 128 (C6). The corresponding carbon center for
δC) is 162 (C2) (Supplementary Materials: Figures S2 and S20, respectively). Thus, these values
denote a greater susceptibility of to receiving a local nucleophilic attack. The experimental results of
α,β-unsaturated C=C double bond in 1 extends the conjugation of the entire heterocyclic
2
ρ(r
1
(
2
(
1
catalytic reduction are corroborated by the theoretical calculations of global and local reactivity.
3. Materials and Methods
3.1. General Information
Reagents and solvents were purchased from Sigma-Aldrich (Toluca, Edo. De Mexico, Mexico).
Thin layer chromatography (TLC) was conducted on Merck 60 F254 silica gel plates (Toluca, Edo. De
Mexico, Mexico) eluted with mixtures of hexane-AcOEt and read with ultraviolet (UV) light at 254 nm.
The products were purified on a chromatography column with Merck (Toluca, Edo. De Mexico, Mexico)
silica gel 60 (0.040–0.063 mm), and the corresponding structures were assigned by 1H and 13C-NMR on
an Agilent-600 apparatus (at 600 MHz and 150 MHz, respectively, Mexico City, Mexico) with CDCl3
and CD3OD as solvent and tetramethylsilane (TMS) as the internal reference. Chemical shifts (δ)
are reported in ppm and coupling constants (J) in hertz (Hz). Each signal is described as a singlet
(s), doublet (d), triplet (t), quadruplet (q), multiplet (m), or broad signal (bs). Melting points were
determined on a FisherScientific apparatus (Thermo Fisher Scientific, Waltham, MA, USA) and are
uncorrected. Fourier transform infrared (FT-IR) spectra were recorded on a Perkin-Elmer Spectrum
BX-II spectrophotometer (Mexico City, Mexico). The high performance liquid chromatography (HPLC)
analysis (Agilent 1260; Agilent Technologies, Mexico City, Mexico) was carried out on a Chiralcel OJ-H
column (4.6
×
250 mm; Chiral technologies Europe, bd girthier d’andernach, Illkirch, France), using a
hexane:i-PrOH (80:20) mixture as the mobile phase at a flow rate of 0.6 mL/min and at 25 ◦C, and with
a UV detector at a wavelength of 279 nm. Electrospray ionization high-resolution mass spectrometry
(ESI-HRMS) was performed on a Bruker micrOTOF-Q-II apparatus (0.4 bar at rt, setting the dry heater
at 180 ◦C, Mexico City, Mexico). The UHPLC 1290 Infinity II was coupled to electrospray ionization
Quadrupole Time-Of-Flight (QTOF) 6545 (Agilent Technologies, Mexico City, Mexico).
3.2. Chemistry
Ethyl 3-(acetamidomethyl)benzofuran-2-carboxylate (
0.36, Hex/AcOEt 4:6); m.p. 136–137 ◦C; IR (cm−1): 3291, 1712, 1653, 1598; 1H-NMR (600 MHz; CDCl3):
7.87 (1H, d, J = 8.4 Hz, CH-4), 7.52 (1H, d, J = 7.8 Hz, CH-7), 7.45 (1H, t, J = 8.4 Hz, CH-6), 7.32 (1H, t,
1) [20]. Yellow solid (23% yield): (Ratio of front (Rf) =
δ

Molecules 2019, 24, 2061
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J = 7.2 Hz, CH-5), 6.36 (1H, bs, NH), 4.86 (2H, d, J = 6.2 Hz, CH2-13), 4.47 (2H, q, J = 7.2 Hz, CH2-11),
1.96 (3H, s, CH3-17), 1.45 (3H, t, J = 7.2 Hz, CH3-12); 13C-NMR (150 MHz; CDCl3):
169.6 (C-15),
δ
160.2 (C-8), 154.3 (C-7a), 141.8 (C-2), 128.3 (CH-6), 127.1 (C-3a), 126.9 (C-3), 123.8 (CH-5), 122.0 (CH-4),
112.1 (CH-7), 61.7 (CH2-11), 32.4 (CH2-13), 23.2 (CH3-17), 14.3 (CH3-12); HRMS (ESI+): calculated for
C14H15NO4Na [M + Na]+, 284.090; found 284.087; HPLC on a Chiralcel OJ-H column (4.6
Chiral technologies Europe, bd girthier d’andernach, Illkirch, France), with the mobile phase of an
80:20 Hex:i-PrOH system at a flow rate of 0.6 mL/min and at 25 ◦C, and with the UV light detector at
λ = 279 nm. Retention time (Rt) = 11.12 min.
×
250 mm;
Ethyl (
Hex/AcOEt 4:6); m.p. 117–118 ◦C; IR (cm−1): 3311, 2936, 1750, 1638, 1597; 1H-NMR (600 MHz; CDCl3):
7.22–7.17 (2H, m, CH-4, CH-6), 6.95-6.88 (2H, m, CH-5, CH-7), 5.70 (1H, bs, NH), 5.21 (1H, d,
±
)-3-(acetamidomethyl)-2,3-dihydrobenzofuran-2-carboxylate (rac-1a) [20]. White crystals: (Rf = 0.18,
δ
J = 9.1 Hz, CH-2), 4.30 (2H, qq, J = 10.8, 7.2 Hz, CH2-11); 3.96–3.90 (1H, m, CH-3), 3.60 (1H, ddd,
J = 14.1, 6.5, 4.9 Hz, CH2-13A), 3.43 (1H, ddd, J = 14.1, 6.3, 5.6 Hz, CH2-13B), 1.87 (3H, s, CH3-17), 1.34
(3H, t, J = 7.2 Hz, CH3-12); 13C-NMR (150 MHz; CDCl3):
δ 172.8 (C-8), 172.5 (C-15), 161.5 (C-7a), 132.1
(CH-6), 128.8 (C-3a), 127.3 (CH-4), 124.4 (CH-5), 112.9 (CH-7), 84.8 (CH-2), 64.7 (CH2-11), 47.3 (CH-3),
42.6 (CH2-13), 25.9 (CH3-17), 16.9 (CH3-12); HRMS (ESI+): calculated for C14H17NO4Na [M + Na]+,
20
286.110; found 286.105; [
OJ-H column (4.6
α
]
= –0.002; The racemic mixture was examined by HPLC on a Chiralcel
D
×
250 mm; Chiral technologies Europe, bd girthier d’andernach, Illkirch, France),
with the mobile phase of an 80:20 Hex:i-PrOH system at a flow rate of 0.6 mL/min and at 25 ◦C, and
with the UV light detector at λ = 279 nm. Rt1 = 13.10, Rt2 = 18.83 min.
Ethyl 3-(acetamidomethyl)-4,5,6,7-tetrahydrobenzofuran-2-carboxylate (1b) [20]. Beige crystals: (Rf = 0.29,
Hex/AcOEt 4:6); m.p. 115–116 ◦C; IR (cm−1): 3282, 2937, 1698, 1657; 1H-NMR (600 MHz; CDCl3):
δ 6.61
(1H, bs, NH), 4.41 (2H, d, J = 6.1 Hz, CH2-13), 4.36 (2H, q, J = 7.2 Hz, CH2-11), 2.60 (2H, ddd, J = 6.3,
3.9, 1.5 Hz, CH2-7), 2.47 (2H, tt, J = 6.0, 1.5 Hz, CH2-4), 1.94 (3H, s, CH3-17), 1.81 (2H, m, CH2-6), 1.72
(2H, m, CH2-5), 1.38 (3H, t, J = 7.2 Hz, CH3-12); 13C-NMR (150 MHz; CDCl3):
δ 172.3 (C-15), 162.5
(C-8), 158.0 (C-7a), 141.6 (C-2), 135.1 (C-3), 123.1 (C-3a), 63.6 (CH2-11), 35.5 (CH2-13), 26.2 (CH2-7),
25.9 (CH3-17), 25.1 (CH2-6), 25.0 (CH2-5), 22.9 (CH2-4), 17.1 (CH3-12); HRMS (ESI+): calculated for
C14H19NO4Na [M + Na]+, 288.120; found 288.117; HPLC on a Chiracel OJ-H column (4.6
Chiral technologies Europe, bd girthier d’andernach, Illkirch, France), with the mobile phase of an
80:20 Hex:i-PrOH system at a flow rate of 0.6 mL/min and at 25 ◦C, and with the UV light detector at
λ = 279 nm. Rt = 8.83 min.
×
250 mm;
Ethyl 3-(acetamidomethyl)octahydrobenzofuran-2-carboxylate (1c). White oil: (Rf = 0.12 Hex/AcOEt 3:7);
IR (cm−1): 3299, 2935, 1745, 1651, 1188; 1H-NMR (600 MHz; CDCl3):
δ 6.28 (1H, bs, NH), 4.55 (1H,
d, J = 10.0 Hz, CH-2), 4.36–4.18 (2H, m, CH2-11), 4.00 (1H, q, J = 8.4, 6, 3.1 Hz, CH-7a), 3.77 (1H, m,
CH2-13A), 2.93 (1H, m, CH2-13B), 2.87 (1H, m, CH-3), 2.11 (1H, m, CH2-7), 2.02 (1H, m, CH-3a), 1.98
(3H, s, CH3-16), 1.74–1.68 (1H, m, CH2-5), 1.62–1.52 (2H, m, CH2-6, CH2-7), 1.52–1.47 (1H, m, CH2-6),
1.44–1.38 (1H, m, CH2-4), 1.34 (3H, t, CH3-12), 1.27–1.19 (1H, m, CH2-4), 1.16–1.10 (1H, m, CH2-5);
13C-NMR (150 MHz; CDCl3):
δ 172.9 (C-8), 170.0 (C-15), 78.4 (CH-7a), 77.1 (CH-2), 61.2 (CH2-11),
48.1 (CH-3), 39.5 (CH-3a), 36.7 (CH2-13), 28.1 (CH2-7), 24.3 (CH2-5), 23.4 (CH3-17), 22.2 (CH2-4), 20.0
(CH2-6), 14.1 (CH3-12); HRMS (ESI+): calculated for C14H23NO4, 269.16; found 270.1721 (M + 1).
3-methylbenzofuran-2-carbonitrile (
and K2CO3 (48.37 g, 350 mmol) in 65 mL of DMF without drying, chloroacetonitrile (
9
) [21]. To a mixture of 20-hydroxyacetophenone (
3
) (6.80 g, 50 mmol)
) (6.96 mL,
8
110 mmol) was added. The solution was stirred at rt under nitrogen atmosphere for 18 h. It was
subsequently heated at 140 ◦C for 3 h. After cooling to rt, 150 mL of water was added and extracted with
Et2O (3
The organic phase was dried with Na2SO4 and evaporated to produce a dark brown solid, which was
purified on a SiO2 column (hexane/AcOEt, 95:5) to deliver as beige crystals (5.98 g, 76%): (Rf = 0.7
hexane/AcOEt, 85:15); m.p. 105 ◦C; IR (cm−1): 2926, 2220, 1445, 1247, 1102; 1H-NMR (600 MHz; CDCl3):
×
200 mL), and the ether mixture was washed with water (3
× 250 mL) and brine (1 × 250 mL).
9
,

Molecules 2019, 24, 2061
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δ
7.61 (1H, dt, J = 7.8, 1.2 Hz, CH-4), 7.50 (1H, d, J = 0.9 Hz, CH-7), 7.49 (1H, t, J = 1.2 Hz, CH-6),
7.38–7.32 (1H, m, CH-5), 2.46 (3H, s, CH3-10); 13C-NMR (150 MHz; CDCl3):
δ: 155.4 (C-7a), 129.7
(C-3), 128.4 (CH-6), 126.9 (C-3a), 124.9 (C-2), 123.9 (CH-5), 120.9 (CH-4), 112.1 (CH-7), 111.8 (C-8),
8.7 (CH3-10).
(2-cyanobenzofuran-3-yl)methyl acetate (11) [20–22]. To benzofuran 9 (1 g, 6.37 mmol) in 18 mL of CCl4
we added N-bromosuccinimide (2.267 g, 12.74 mmol) and benzoyl peroxide (20 mg, 0.08 mmol).
The reaction mixture was heated (under constant stirring) to reflux for 8 h under nitrogen atmosphere.
After cooling to rt, it was filtered and the filtrate was evaporated to produce 10 as an amber solid
(
Rf = 0.65, hexane/AcOEt 85:15). Following dissolution of the reaction crude (without purification) in
30 mL AcOH, AcOK (3.12 g, 31.85 mmol) was added and heated to reflux for 1 h. Once the mixture
was cooled, 20 mL of water was added and extracted with DCM (2 50 mL), and then the organic
phase was washed with a saturated solution of NaHCO3 (2 80 mL), water (1 80 mL), and brine
(1 80 mL). The mixture was dried with Na2SO4, filtered, and evaporated, resulting in a brown oily
×
×
×
×
substance that was purified on a column of flash silica gel with hexane/AcOEt 90:10 to produce 930 mg
(68%) of 11 as beige crystals: (Rf = 0.45, hexane/AcOEt 85:15); m.p. 38–39 ◦C; IR (cm−1): 2926, 2231,
1746, 1600, 1447, 1368, 1187, 1028; 1H-NMR (600 MHz; CDCl3):
δ
7.68 (1H, dt, J = 7.8, 1.2 Hz, CH-4),
7.52 (1H, d, J = 1.2 Hz, CH-7), 7.51 (1H, t, J = 1.2 Hz, CH-6), 7.37 (1H, ddd, J = 8.4, 4.5, 3.6 Hz, CH-5),
5.38 (2H, s, CH2-10), 2.15 (3H, s, CH3-13); 13C-NMR (150 MHz; CDCl3):
170.4 (C-12), 155.5 (C-7a),
δ
128.8 (CH-6), 127.9 (C-3a), 125.9 (C-3), 124.8 (C-2), 124.6 (CH-5), 121.3 (CH-4), 112.2 (CH-7), 111.0 (C-8),
55.8 (CH2-10), 20.5 (CH3-13).
3-(hidroxymethyl)benzofuran-2-carbonitrile (12). A solution of 11 (500 mg, 2.33 mmol) in 10 mL of absolute
MeOH and 0.5 mL of concentrated H2SO4 was heated at reflux for 4 h. After cooling, 20 mL of water
was added and extracted with DCM (2
(2 40 mL) and brine (1 40 mL). The organic extract was treated with Na2SO4 before being filtered
and evaporated to dryness to complete the synthesis of 12, yielding 400 mg (99%) as beige crystals:
Rf = 0.43, hexane/AcOEt 75:25); m.p. 85–87 ◦C; IR (cm–1): 3409, 2925, 2230, 1447, 1186, 1016; 1H-NMR
(600 MHz; CDCl3): 7.77 (1H, dt, J = 7.8, 1.2 Hz, CH-4), 7.52–7.49 (2H, m, CH-7, CH-6), 7.36 (1H,
ddd, J = 8.0, 5.2, 2.9 Hz, CH-5), 4.99 (2H, s, CH2-10); 13C-NMR (150 MHz; CDCl3):
155.7 (C-7a),
×
25 mL), and then the organic phase was washed with water
×
×
(
δ
δ
132.4 (C-3a), 128.7 (CH-6), 125.1 (C-3), 124.6 (C-2), 124.4 (CH-5), 121.7 (CH-4), 112.2 (CH-7), 111.4 (C-8),
55.5 (CH2-10).
(2-(acetamidomethyl)benzofuran-3-yl)methyl acetate (13) [23–26]. To a mixture of 12 (400 mg, 2.31 mmol)
and cobalt chloride (550 mg, 2.31 mmol) in 10 mL of MeOH (HPLC grade) at rt, sodium borohydride
was carefully added in small portions (193 mg, 5.10 mmol). The solution was stirred under nitrogen
atmosphere for 30 min, and then the reaction was completed by carefully adding 10 mL of water
and 1 mL of 5N HCl. Subsequently, the mixture was made alkaline (pH
NH4OH, filtered under vacuum through celite, and rinsed with 10 mL water. The filtrate was treated
with DCM (3 20 mL), the organic phase was washed with brine (1 40 mL) and dried with Na2SO4,
≈
9) by adding concentrated
×
×
and the solvent was evaporated to produce 240 mg of the residue. Without purification, the amino
alcohol crude was dissolved with 15 mL of DCM before adding 0.56 mL (4.06 mmol) of triethylamine
and stirring under nitrogen atmosphere. Little by little, 0.3 mL (4.06 mmol) of acetyl chloride was
added and the mixture was left at rt for 12 h (under constant stirring). To the reaction crude, 20 mL of
DCM was added and the mixture was washed with water (2
dried with Na2SO4, filtered, and concentrated to dryness. The crude was purified on a rotor with
×
25 mL) and brine (1
×
25 mL), then
hexane/AcOEt (40:60), producing 200 mg (33%) of 13 as white crystals: (Rf = 0.15, hexane/AcOEt 40:60);
IR (cm−1): 3284, 2930, 1737, 1655, 1454, 1369, 1226, 1177, 1022, 746; 1H-NMR (600 MHz; CDCl3):
δ 7.60
(1H, d, J = 7.6 Hz, CH-4), 7.43 (1H, d, J = 8.2 Hz, CH-7), 7.31–7.23 (2H, m, CH-6, CH-5), 6.34 (1H, bs,
NH), 5.28 (2H, s, CH2-12), 4.67 (2H, d, J = 5.7 Hz, CH2-8), 2.04 (3H, s, CH3-15), 2.01 (3H, s, CH3-11);
13C-NMR (150 MHz; CDCl3):
δ 171.4 (C-10), 169.9 (C-14), 154.1 (C-7a), 152.6 (C-2), 127.7 (C-3a), 124.8

Molecules 2019, 24, 2061
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(CH-6), 123.1 (CH-5), 119.7 (CH-4), 112.4 (C-3), 111.3 (CH-7), 56.4 (CH2-12), 35.0 (CH2-8), 23.1 (CH3-11);
21.0 (CH3-15).
N-((3-formylbenzofuran-2-yl)methyl)acetamide (14) [27
8 mL of MeOH, 530 mg (3.83 mmol) of K2CO3 was added and stirred at rt for 30 min. Then, 10 mL
of water was added to dissolve the excess carbonate before extraction with DCM (3 20 mL). The
,28]. To a solution of 13 (200 mg, 0.766 mmol) in
×
organic phase was treated with Na2SO4 and filtered, and the solvent was evaporated to generate
N-((3-(hydroxymethyl)benzofuran-2-yl) methyl) acetamide (160 mg, 95%), which was used in the
1
ensuing oxidation reaction. H-NMR (600 MHz; CDCl3):
δ 7.60 (1H, d, J = 7.1 Hz, CH-4), 7.40 (1H,
d, J = 7.1 Hz, CH-7), 7.31–7.23 (2H, m, CH-6, CH-5), 6.23 (1H, bs, NH), 4.87 (2H, s, CH2-12), 4.57
(2H, d, J = 6.1 Hz, CH2-8), 3.94 (1H, bs, OH) and 1.98 (3H, s, CH3-11). In 20 mL of DCM, 150 mg
(0.685 mmol) of the above product was dissolved, followed by the addition of 295 mg (1.37 mmol) of
pyridinium chlorochromate (PCC) and 147 mg of AcONa (1.8 mmol). The mixture was stirred at rt
under nitrogen atmosphere and the progress of the reaction was monitored by TLC. Subsequently,
the crude reaction mixture was filtered through neutral Al2O3 by rinsing with 30 mL acetone, and
the filtrate was concentrated and subjected to column chromatography on silica gel (hexane/AcOEt,
50:50 to 30:70), resulting in 70 mg (47%) of 14 as a yellow solid: (Rf = 0.24, hexane/AcOEt 40:60); m.p.
153–155 ◦C; 1H-NMR (600 MHz, CDCl3):
(1H, d, J = 6.6 Hz, CH-7), 7.40–7.35 (2H, m, CH-6, CH-5), 6.26 (1H, bs, NH), 4.87 (2H, d, J = 6 Hz,
CH2-8), 2.05 (3H, s, CH3-11); 13C-NMR (150 MHz, CDCl3):
185.3 (C-12), 169.9 (C-10), 162.9 (C-2),
δ 10.38 (1H, s, CHO-13), 8.12 (1H, d, J = 6.5 Hz, CH-4), 7.49
δ
154.1 (C-7a), 126.0 (CH-6), 124.9 (CH-5), 124.5 (C-3a), 121.8 (CH-4), 118.2 (C-3), 111.3 (CH-7), 35.4
(CH2-8); 23.1 (CH3-11).
Methyl 2-(acetamidomethyl)benzofuran-3-carboxylate (
5 mL MeOH, we added 105 mg KCN (1.6 mmol) and 0.036 mL glacial acetic acid (0.64 mmol), and
the mixture was stirred at rt for 1 h. After adding 78 mg NaCN (1.6 mmol) and 36 L glacial acetic
2) [29–31]. To 70 mg aldehyde 14 (0.32 mmol) in
µ
acid (0.64 mmol) and stirring continuously for 30 min, 560 mg MnO2 (6.4 mmol) was added and the
mixture was stirred for another 2 h at rt before being filtered through celite and concentrated under
vacuum. The residue was diluted with water and extracted with DCM (3
phase was washed with water (1 30 mL) and brine (1 x 30 mL), then dried with anhydrous Na2SO4
and concentrated under vacuum. The crude mixture was subjected to column chromatography on
silica gel (hexane/AcOEt, 35:65) to produce methyl ester as beige crystals: (Rf = 0.4, hexane/AcOEt
30:70); m.p. 128–130 ◦C; IR (cm−1): 3290, 3070, 1714, 1655, 1595, 1544, 1452, 1238, 1175, 1107, 1073, 752;
1H-NMR (600 MHz; CDCl3):
7.94 (1H, m, CH-4), 7.48 (1H, m, CH-7), 7.34–7.30 (2H, m, CH-6, CH-5),
6.44 (1H, bs, NH), 4.91 (2H, d, J = 6.1 Hz, CH2-8), 3.97 (3H, s, CH3-16), 2.02 (3H, s, CH3-12); 13C-NMR
(150 MHz, CDCl3): 169.8 (C-10), 164.8 (C-13), 161.7 (C-2), 153.7 (C-7a), 125.3 (C-3a), 125.3 (CH-6),
×
15 mL), and the organic
×
2
δ
δ
124.2 (CH-5), 122.0 (CH-4), 111.5 (CH-7), 110.2 (C-3), 51.8 (CH3-16), 36.4 (CH2-8), 23.2 (CH3-12); HRMS
(ESI+): calcd for C13H13NO4Na [M + Na]+, 270.0692; found, 270.0692.
Methyl 2-(acetamidomethyl)-2,3-dihydrobenzofuran-3-carboxylate (rac-2a). Yellow Oil: (Rf = 0.09 Hex/AcOEt
1:1); 1H-NMR (600 MHz, CDCl3):
δ 7.36 (1H, d, J = 7.5 Hz, CH-4), 7.20 (1H, t, J = 7.5 Hz, CH-6), 6.91
(1H, t, J = 7.5 Hz, CH-5), 6.80 (1H, d, J = 7.8 Hz, CH-7); 5.91 (1H, bs, NH), 5.17 (1H, td, J = 6.5, 4.1 Hz,
CH-2), 4.09 (1H, d, J = 7.2 Hz, CH-3), 3.79 (3H, s, CH3-16), 3.72 (1H, m, CH2-8A), 3.59 (1H, m, CH2-8B),
1.98 (3H, s, CH3-12); 13C-NMR (150 MHz; CDCl3):
δ 170.9 (C-13), 170.5 (C-10), 153.7 (C-7a), 129.6
(CH-6), 125.6 (CH-4), 123.9 (C-3a), 121.1 (CH-5), 109.8 (CH-7), 83.2 (CH-2), 52.7 (CH3-16), 49.9 (CH-3),
42.5 (CH2-8), 23.2 (CH3-12); The racemic mixture was examined by HPLC on a Chiralcel OJ-H column
(4.6
phase of an 80:20 Hex:i-PrOH system at a flow rate of 0.6 mL/min and at 25 ◦C, and with the UV light
detector at
= 279 nm. Rt1 = 13.31, Rt2 = 16.86 min; HRMS (ESI+): calculated for C13H15NO4, 249.10;
found 250.1082 (M+1).
×
250 mm; Chiral technologies Europe, bd girthier d’andernach, Illkirch, France), with the mobile
λ

Molecules 2019, 24, 2061
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3.3. Theoretical Calculations
Structures
1 and 2 were optimized using the B3LYP level of theory with the 6-31G basis on
Gaussian 09 software (Gaussian Inc., Quinnipiac St Bldg 40 Wallingford, CT 06492 USA). Single-point
energies for the ionic structures (anion and cation) were calculated at the same level of theory with
UB3LYP/6-31G [37].
Indices of Global and Local Reactivity
All above calculations were performed on Gaussian 09 software (Gaussian Inc., Quinnipiac St
Bldg 40 Wallingford, CT 06492 USA), which allows for the calculation of the first ionization potential (
and the electron affinity ( ) to obtain the global parameters. The chemical potential ( ) was calculated
as = –( )/2, global hardness ( ) as ) as = 1/
2/2 −) as ω− = (3
index ( , the electron donating power (
accepting power (ω+) as ω+ = (
HOMO (Nu) (eV)
fk+) = [qk (N + 1)
1)] for reaction
I)
A
µ
µ
I
+
A
ω
η
η
= (I − A), global softness (
S
S
η, the electrophilicity
ω
) as
=
µ
η
ω
I
+
A
)2/16 (I − A), the electron
I
+ 3
A
)2/16 (I − A), and the nucleophilicity index (
N) as N(Nu) =
E
(
−
EHOMO (TCE) (eV). The condensed FFs were evaluated by the following equations:
−
qk (N)] for reaction with nucleophiles, and (fk−) = [qk (N)
−
qk (N
−
with electrophiles. Another local descriptor is local softness, which is the product of the condensed FF
(fk+/−) multiplied by the global softness (S).
+
+
For each atom in the
k
position of −a molecule, sk
= fk S expresses the susceptibility to receiving
−
a local nucleophilic attack, whereas sk
The local electrophilicity (ωk) is calculated as ωk
=
fk
S
indicates the tendency to make a nucleophilic attack.
+
= ωfk and the local nucleophilicity (Nk) as Nfk.
The electron population for calculating the FFs was based on the formulation of the quantum theory
of atoms in molecules (QTAIM). The wave function was calculated for each of the neutral and ionic
systems, using the geometry optimized for the neutral molecule. By using the wave function value, the
electron population was determined on AIM 2000 software (Version 2.37, Chemical advice by R.F.W.
Bader, McMaster University, Hamilton, Canada). The electrophilic (Pk+) and nucleophilic (Pk−) Parr
functions were defined through the analysis of the Mulliken atomic spin density (ASD) of the radical
anion and the radical cation by single-point energy calculations over the optimized neutral geometries,
employing the unrestricted UB3LYP formalism for radical species.
4. Conclusions
Compounds ethyl 3-(acetamidomethyl)benzofuran-2-carboxylate and methyl 2-(acetamidomethyl)
benzofuran-3-carboxylate (
respectively. They were characterised by their FT-IR, NMR, and HRMS spectral data. Since obtaining
the 2,3-dihydroderivatives was more difficult for than , the catalytic reduction conditions were
optimized with Pd/C at 10% for the former. The reduction of produced the hydrogenated derivatives
rac-1a and 1b as the main products. When the concentration of the catalyst increased, the reaction
1 and 2, respectively) were synthesized with overall yields of 23 and 5.4%,
1
2
1
produced the octahydroderivative 1c. Conversely, the hydrogenation of
2 only led to rac-2a as the
main product. 1H-NMR was crucial for evaluating the relative proportions of each product in the
reduction experiments. These results were corroborated by theoretical calculations of global and local
reactivity, which indicated the electrophilic behavior of
susceptible to reduction (C3, C4, and C6), this susceptibility only exists with one olefinic carbon (C2) in
. The theoretical calculations, NMR spectra, and the resonance structures clearly revealed the most
1. Whereas three olefinic carbons in 1 are
2
susceptible moieties for a nucleophilic attack, thus explaining the selectivity in reduction.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/11/2061/s1,
Figures S1–S22 describe NMR data for all compounds. Figures S23–S28 provide HRMS spectra for
1
,
rac-1a
, 1b,
1c, 2, and rac-2a. Figures S29–S33 describe HPLC data for 1, rac-1a, 1b, 2 and rac-2a. Figures S34 and S35 depict
optimized geometries of 1 and 2. Tables S1–S8 describe computational data.
Author Contributions: The chemical synthesis and spectroscopic analysis were completed by A.C.-Y., R.T.-M.,
and C.P.-Z.; the NMR experiments were analysed by A.C.-Y., R.T.-M., H.L., and J.G.T.-F.; the interpretation of data
and theoretical calculations were conducted by Erik Andrade-Jorge, A.C.-Y., and J.G.T.-F. The paper was drafted

Molecules 2019, 24, 2061
15 of 17
by A.C.-Y. and E.A.-J. All authors participated in discussing the different versions of the manuscript and gave
their approval for the final version.
Funding: This work was supported by project funds from the Consejo Nacional de Ciencia y Tecnolog
ía in Mexico
(CB166271) and by SIP (m1930 and 20194934) from the Instituto Politécnico Nacional.
Acknowledgments: The authors are grateful to the Consejo Nacional de Ciencia y Tecnolog
scholarship to A.C.-Y. and for financial support of this project (CB166271). We also thank the en Ciencias
Biol gicas y de la Salud of the Universidad Aut noma Metropolitana-Unidad Xochimilco. The authors gratefully
recognize the experimental support received from the NMR lab of the UAM-Xochimilco and from the Centro de
Nanociencias y Micro Nanotecnolog a of the Instituto Polit cnico Nacional. We are indebted to the Laboratory
cnico
ía-México for the
ó
ó
í
é
of Molecular Modeling, Drug Design and Bioinformatic, Escuela Superior de Medicina, Instituto Polit
é
Nacional, Mexico. We also thank Bruce Allan Larsen for reviewing the English in the manuscript. In memory of J.
Samuel Cruz-Sánchez †.
Conflicts of Interest: All the authors declare that there is no conflict of interest related to the design of the study,
the collection or analyses of data, the writing of the manuscript, or the decision to publish the results.
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Sample Availability: Samples of the compounds are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).