2-(Fluoro-) and 2-(methoxyanilino)-1,4-naphthoquinones. Synthesis and mechanism and effect of fluorine substitution on redox reactivity and NMR

Article abstract of DOI:10.1016/j.jfluchem.2015.08.016

The influence of catalysts on the addition of methoxy- and fluoroanilines with 1,4-naphthoquinone to give methoxy- and fluoro-substituted 2-(anilino)-1,4-naphthoquinones was investigated. In the absence of a catalyst, this reaction requires long times and

Full text of DOI:10.1016/j.jfluchem.2015.08.016

Journal of Fluorine Chemistry 180 (2015) 152–160
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
2-(Fluoro-) and 2-(methoxyanilino)-1,4-naphthoquinones. Synthesis
and mechanism and effect of fluorine substitution on redox reactivity
and NMR
b
a
a
Elisa Leyva a, , Kim M. Baines , Claudia G. Espinosa-Gonzalez , Diego A. Magaldi-Lara ,
*
´
a
a
c
´
´
Silvia E. Loredo-Carrillo , Telma A. De Luna-Mendez , Lluvia I. Lopez
a Facultad de Ciencias Quı´micas, Universidad Auto´noma de San Luis Potosı´, Manuel Nava No. 6, 78210 San Luis Potosı´, SLP, Mexico
b Department of Chemistry, University of Western Ontario, London, ON, Canada N6A 5B7
c
´
´
´
´
´
Facultad de Ciencias Quımicas, Universidad Autonoma de Coahuila, Blvd. V. Carranza e Ing. Jose Cardenas s/n Col. Republica, C.P. 25250 Saltillo, COAH,
Mexico
A R T I C L E I N F O
A B S T R A C T
Article history:
The influence of catalysts on the addition of methoxy- and fluoroanilines with 1,4-naphthoquinone to
give methoxy- and fluoro-substituted 2-(anilino)-1,4-naphthoquinones was investigated. In the absence
of a catalyst, this reaction requires long times and low yields of the anilino derivatives are obtained
accompanied with the formation of several secondary products. Excellent yields were obtained with a
catalytic amount of a Lewis acid with strong oxidation properties such as CeCl3 or FeCl3. Excellent yields
were also obtained when the reaction was performed with a Brønsted acid/oxidant mixture such as
AcOH/Cu(OAc)2. This addition reaction was also investigated using microwave irradiation. A discussion
on reaction conditions and mechanism is presented. The 1H and 13C NMR data of all the derivatives were
analyzed and assigned using two dimensional 1H–13C gHSQC and gHMBC NMR experiments. The effect
of fluorine substitution on redox and NMR properties was also investigated.
Received 27 June 2015
Received in revised form 18 August 2015
Accepted 19 August 2015
Available online 14 September 2015
Keywords:
2-(Fluoroanilino)-1,4-naphthoquinone
Redox potential
Lewis acid catalyst
Strong oxidizing agent
Microwave
ß 2015 Elsevier B.V. All rights reserved.
FeCl3
Cu(OAc)2/AcOH
Bifurcated hydrogen bond
1. Introduction
nitroanilines or fluoroanilines, do not readily react [13,14]. In some
cases, if the reaction is carried out without an adequate catalyst,
The preparation of substituted 2-anilino-1,4-naphthoquinone
derivatives is of great interest since these compounds have shown
biological activity and have been utilized as coloring agents
[1,2]. The arylamino 1,4-naphthoquinone moiety is a common
component of the molecular framework of many natural products
and has been used as a key intermediate in the synthesis of several
compounds with important biological applications [3,4].
The reaction of 1,4-naphthoquinone with anilines to give 2-
anilino-1,4-naphthoquinones has been known for several years [5–
9]. The accepted mechanism for this transformation involves a
Michael addition of an aniline to the reacting naphthoquinone
under an atmosphere of oxygen. Due to the high reactivity of the
quinone [10,11], several products [12] are usually obtained
(Scheme 1). In addition, weakly nucleophilic amines, such as
the formation of complex mixtures is observed or no reaction takes
place [12].
State-of-art research in organic chemistry requires the design of
highly selective transformations even when the structure of a
substrate presents several reaction pathways; the use of Lewis acids
often provides the desired selectivity [15]. There are some reports of
the use of Lewis acids to catalyze the coupling of anilines with 1,4-
naphthoquinone on the basis that they facilitate a Michael addition
to the quinone system [5–9]. During the course of our studies on the
synthesis and characterization of fluoroanilino naphthoquinone
derivatives, we noted that the use of CeCl3 as a catalyst greatly
improved the yields [7]. Furthermore, we have noted that the use of
FeCl3 can increase the yields of 2-(nitroanilino)-1,4-naphthoqui-
nones [14] and Garden and co-workers reported that the use of a
Brønsted acid/oxidant combination AcOH/Cu(OAc)2 improves the
yields of a variety of substituted aniline-1,4-naphthoquinone
derivatives [9]. In this study, we report on our attempts to improve
the yieldsof 2-(fluoroanilino)-1,4-naphthoquinonesusing the Lewis
*
Corresponding author. Tel.: +52 444 8262440x508; fax: +52 444 8262371.
E-mail address: elisa@uaslp.mx (E. Leyva).
http://dx.doi.org/10.1016/j.jfluchem.2015.08.016
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
153
Scheme 1. Reaction of 1,4-naphthoquinone 1 with aniline 2 without a catalyst.
acid/oxidant FeCl3 and the Brønsted acid/oxidant AcOH/Cu(OAc)2 as
catalysts under refluxing or microwave irradiation mw conditions
(Scheme 2). Furthermore, we have completely assigned the 1H and
13C NMR spectra of the 2-(anilino)-1,4-naphthoquinone derivatives
using two dimensional 1H–13C gHSQC and gHMBC NMR experi-
ments. This allowed us to investigate the electronic effects of the
anilino substituents by 1H and 13C chemical shift analysis and to
correlate the substituent effects with the electrochemical properties
of the naphthoquinones. The ability to assess the electronic
properties of the naphthoquinone derivatives using NMR spectros-
copy may be useful for the design of future anilino naphthoquinone
derivatives.
4-naphthoquinone 3. 1,4-Naphthoquinone is quite prone to
undergo disproportionation, and this can be avoided in an
oxidizing environment [7,16]. As a further complication, a 1,2-
Michael addition can take place resulting in the formation of an
amino alcohol 7 that very easily loses water to generate a
thermodynamically favored enamine 4.
When the oxidative addition of anilines to 1,4-naphthoquinone
was carried out in the presence of CeCl3 under reflux, there was a
high conversion of the reactant species and the 2-(fluoroanilino)-
1,4-naphthoquinone derivatives 3b–3h were obtained in very
good yields (70–91%) (Table 1) [7]. Using FeCl3 as the catalyst also
under reflux either in ethanol or an aqueous ethanol solution, the
yields were still acceptable (60–80%). Notably, TLC analysis of
the reaction mixtures from either FeCl3 or CeCl3 indicated that
the reactions were much cleaner compared to the uncatalyzed
reactions.
2. Results and discussion
2.1. Synthesis and reaction pathway
Under an oxidative atmosphere, the oxidized species (Ce3+
/
Ce4+ = 1.7 V or Fe2+/Fe3+ = 1.3 V), predominates in solution
[17]. Therefore, in the reactions using these catalysts, the high
yields observed are most likely due to the presence of a strong
Lewis acid which is also a strong oxidizing agent. The general
mechanism for this transformation has been previous reported by
us (Scheme 4) for M(III). First, the catalyst generates a complex 8a
[14] that rearranges to isomer 8b and reacts in a regioselective
manner with the aniline 2 [7]. The final step is favored by the
presence of a small amount of oxidant that creates a strongly
oxidizing environment in solution resulting in a cleaner reaction.
The application of mw as an energy source for reactions has
become a very popular and useful technique in the synthesis of
organic compounds [18,19]. In general, the use of this type of
energy leads to enhanced conversion rates, higher yields, easier
work up and cleaner reactions demonstrating the distinct
advantages of this methodology. When the reaction of several
anilines (2a–j) with 1,4-naphthoquinone 1 was performed under
mw, contrasting results were obtained (Table 1). Very good yields
of adducts 3b–3j were obtained within few minutes (55–90%)
Without a catalyst, the reaction of 1,4-naphthoquinone 1 with
several weak amines such as fluoroanilines 2b–2h gives the
corresponding adducts 3b–3h in low to moderate yields (30–55%)
[7]. Under these conditions, the reaction requires several days to go
to completion (Table 1). Furthermore, TLC analysis of reaction
mixtures indicates the presence of several products. Particularly
low yields (30–45%) of adducts 3b, 3e, 3f, and 3h were observed
when the reaction was performed with ortho-substituted fluor-
oanilines indicating a steric effect on the Michael addition and
most likely it is influenced by intramolecular hydrogen bonding
(Fꢀ ꢀ ꢀH–N) present in this type of anilines [7]. A good yield (80%) is
obtained only when 4-methoxyaniline is utilized, where the amino
group is strongly activated by the electron-donating character of
the methoxy group.
The general mechanism for the reaction without a catalyst
involves 1,4-Michael addition of aniline 2 to 1,4-naphthoquinone 1
that, in the presence of ethanol, gives
a dihydroquinone
intermediate 6 (Scheme 3). Oxidation of 6 with oxygen or the
remaining 1,4-naphthoquinone 1 gives the resulting 2-anilino-1,
Scheme 2. Synthesis of 2-(fluoro-) and 2-(methoxyanilino)-1,4-naphthoquinones 3.

154
E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
tightly bond complex with Fe3+ (Scheme 4), quinone 1 is heated
rapidly and this leads to its decomposition. Microwave irradia-
tion is a very effective means of heating organic compounds in
polar solvents, and therefore, the reaction works better in a
water/ethanol mixture compared to ethanol alone. An aqueous
solvent dissipates the heat more effectively and homogenous
heating of the reaction mixture is achieved [18,19] resulting is
less decomposition.
The use of a catalytic amount of Cu(OAc)2 in AcOH gave
excellent yields of adducts 3b–3j after only two hours reflux (70–
90%) or after several minutes under mw (56–80%) (Table 1).
Cu(OAc)2 is not a good Lewis acid but it is a good oxidizing agent
[17]. Thus, under these conditions, a Brønsted acid (Scheme 5) is
required to enhance the electrophilicity of the quinone 1 by
generation of intermediate 10b which reacts with aniline 2 to give
a hydroquinone 6. This latter compound undergoes a subsequent
oxidation by Cu2+ (Cu1+/Cu2+ = 1.2 V) and eventual formation of the
anilino naphthoquinone 3.
Table 1
Effect of reaction conditions on the yields (Y) of substituted 2-(anilino)-1,4-
naphthoquinones.
Compound
Y (%)
a
b
c
d
e
f
g
h
i
PAN 3aj,k
60
30
50
55
40
35
30
45
60
80
85
91
72
85
70
70
74
74
70
85
57
55
60
83
55
73
90
55
55
75
78
72
74
80
80
60
65
65
75
82
60
20
40
65
30
31
52
45
50
65
75
60
72
85
75
60
62
65
60
85
58
58
56
84
75
60
60
61
56
65
80
85
75
90
70
75
73
70
85
85
60
56
65
80
56
65
70
65
70
80
2-FPAN 3b
3-FPAN 3c
4-FPAN 3d
2,4-FPAN 3e
2,5-FPAN 3f
3,4-FPAN 3g
2,4,5-FPAN 3h
2-MeOPAN 3ik
4-MeOPAN 3jk
a
Without catalyst in ethanol and 7 days reflux; for 3a–3h from Ref. [7]; for 3i–3j
from Ref. [14].
b
With CeCl3ꢀ7H2O in ethanol and 4 h reflux; for 3a–3h from Ref. [7]; for 3i–3j
from Ref. [14].
c
With CeCl3ꢀ7H2O in ethanol and 1–3 min microwave irradiation; for 3a–3h
from Ref. [7].
d
With FeCl3 in ethanol and 4 h reflux; for 3i–3j from Ref. [14].
2.2. Structure elucidation and analysis by NMR spectroscopy
e
f
With FeCl3 in ethanol and10 min microwave irradiation.
With FeCl3 in water/ethanol and 4 h reflux.
To completely assign the 1H and 13C NMR spectra of the
products 3b–j, several two-dimensional NMR experiments were
performed. In Scheme 6, the structure of 2-(2-methoxyanilino)-
1,4-naphthoquinone, 3i, is presented with the numbering system
used consistently for all the naphthoquinone derivatives. The
structure elucidation of 3i is representative and is discussed in
detail.
g
h
i
With FeCl3 in water/ethanol and 10 min microwave irradiation.
With Cu(OAc)2 in AcOH and 2 h reflux.
With Cu(OAc)2 in AcOH and 10 min microwave irradiation.
Anilino-1,4-naphthoquinone is known as 2-[(phenyl)amine]-1,4-naphthalene-
j
dione or PAN.
k
These compounds were prepared for comparison.
A
contour plot of the 1H–1H COSY spectrum for 2-(2-
when CeCl3 is utilized as the catalyst [7]. Presumably, mw
accelerates both complex formation and the final oxidation
(Scheme 4). However, performing the same reaction using FeCl3
in ethanol under mw gave rather low yields (20–65%) of adducts
3b–3j after several minutes of irradiation; the reaction mixture
appeared to decompose resulting in the formation of a dark solid.
In contrast, using FeCl3 in aqueous ethanol under mw gave good
yields (56–84%) of adducts 3b–3j. In this particular case, having a
methoxyanilino)-1,4-naphthoquinone, 3i, is given in Fig. 1. Two
signals along the diagonal do not correlate with any other signal.
The broad signal at 8.66 ppm is assigned to HA of the amino group
on the basis of the characteristic appearance and chemical shift for
this type of hydrogen. The signal at 5.79 ppm is characteristic of the
vinylic hydrogen in a naphthoquinone and is assigned to H3. The
singlet at 3.86 ppm (not shown in Fig. 1) was assigned to the 2-
methoxy group (H70).
Scheme 3. Mechanism for the reaction of aniline 2 with naphthoquinone 1 without a catalyst.

E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
155
Scheme 4. Mechanism for the reaction of aniline 2 with naphthoquinone 1 in the presence of catalyst M(III).
An expansion of the 1H–13C gHSQC spectrum of 3i is shown in
Fig. 2. The chemical shift of the signal at 112.14 ppm in the 13C
dimension is characteristic of a carbon ortho to an electron-
donating methoxy group, and thus, can be assigned to C30 and, as a
consequence, the dd at 7.18 ppm in the 1H dimension can be
assigned to H30. The signal at 7.18 ppm in the 1H dimension (H30)
shows a strong correlation to the signal at 7.28 ppm (td) in the
1H–1H COSY spectrum of 3i (Fig. 1), and thus, can be assigned to
H40. The signal at 7.28 ppm also correlates to the signal at 7.05 ppm
(td), which can, thus, be assigned to H50. Finally, the signal at
7.05 ppm correlates to the signal at 7.38 ppm (dd) which can, thus,
be assigned to H60, allowing for complete assignment of the 1H
signals of the aniline ring of 3i. Expansions of the 1H–1H COSY
spectrum of 3i can be found in the Supplementary data (S2).
Assignment of signals in the region of 7.8–8.1 ppm in the 1H
NMR spectrum of 3i relies on the correlation observed between the
signal assigned to H3 at 5.79 ppm in the 1H dimension of the
1H–13C gHMBC spectrum of 3i and the signal(s) at 132.65 ppm in
the 13C dimension which is assigned to C10 (see Fig. S3 in the
Supplementary data). The signal at 132.65 ppm also shows a
correlation with the signals at 8.07 (dd) ppm and 7.87 (dt) ppm in
the 1H dimension of the 1H–13C gHMBC spectrum of 3i which is
shown in Fig. 3. Thus, the signals at 8.07 ppm and 7.87 ppm are
assigned to H8 and H6, respectively. The 1H signals of the
naphthoquinone ring can then be assigned using the 1H–1H COSY
spectrum of 3i: the signal at 8.07 ppm correlates to the signal at
7.80 (dt) ppm which can be assigned to H7 (see Fig. S4 in the
Supplementary data). As expected, the signal at 7.80 ppm (H7)
shows a correlation to the signal assigned to H6 (7.87 ppm) and the
signal at 7.87 ppm (H6) shows a correlation to the signal at 7.96
(dd) ppm which is assigned to H5 (see Fig. S5 in the Supplementary
data). Assignment of the signals in the aromatic region of the 13C
Scheme 5. Mechanism for the reaction of aniline 2 with naphthoquinone 1 in the presence of. Acetic acid and Cu(II).

156
E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
modified by the substituted aniline group. In addition, the redox
properties of naphthoquinones can also be modified by the
presence of intramolecular hydrogen bonds [7]. The influence of
the substituents in the 2-(substituted-anilino)-1,4-napthoquinone
derivatives 3b–3j on the 1H and 13C NMR chemical shifts of the NQ
framework was investigated to determine if the chemical shifts
correlated with the redox properties of the napthoquinones.
The 1H chemical shifts of 3b–3j are given in Table 2; the related
numbering scheme is shown in Scheme 6. The 1H chemical shifts of
the NQ hydrogens (H5, H6, H7, H8), distant from the substituted
anilino group, experience essentially no change with varying
substitution on the aniline ring. For example, H8 has a chemical
shift at 8.06 ꢁ 0.02 ppm for compounds 3b–3j. In contrast, the
analogous hydrogens (H5, H6, H7, H8) are deshielded when a nitro
group is present in the aniline ring (Table 2); for example, H8 has a
chemical shift of 8.21 or 8.33 ppm when there is a 2-NO2 or 4-NO2
substituent on the aniline ring, clearly demonstrating the strong
electronic influence of the nitro substituent.
The only hydrogen on the naphthoquinone ring which
experiences a significant change in chemical shift (Table 2) with
varying substitution on the aniline ring is H3 which is quite close to
the substituted anilino group. When there is a NO2 group in the
ortho or para position of the aniline ring, H3 is deshielded (6.26 and
6.53 ppm, respectively). When there is a OMe group in the same
positions, H3 is shielded (5.79 and 5.92 ppm, respectively). In the
case of fluorine, the effect of the substituent changes dramatically
with the position. A fluorine in meta or para position has a
deshielding effect on H3 relative to the effect of the para-methoxy
substituent. Interestingly, when fluorine is in the ortho position, it
actually exerts a shielding effect on the chemical shift of H3.
The experimental 1H chemical shifts of 3b–3h can be
understood in terms of the electronic properties of the sub-
stituents. Indeed, we and others have reported [7,10] that, in the
case of PAN derivatives, electron-donating groups such as
methoxy, result in an increase in electron density in the quinone
ring while unsaturated electron-accepting groups such as nitro,
withdraw electron density from the nitrogen toward the aromatic
Scheme 6. Numbering for 2-(2-methoxyanilino)-1,4-naphthoquinone 3i.
NMR spectrum of 3i can be completed using the observed
correlations in both the 1H–13C gHSQC and gHMBC spectra of
3i. The remaining signals in the 13C NMR spectrum of 3i at
181.49 and 182.29 ppm can be assigned to the carbonyl carbons on
the basis of the chemical shifts and can be distinguished on the
basis of correlations observed in the 1H–13C gHMBC spectrum of
3i. A correlation was observed between the signals at 5.79 ppm and
8.07 ppm in the 1H dimension and assigned to H3 and H8,
respectively, and the signal at 181.49 ppm in the 13C dimension
allowing the signal to be assigned to C1. A correlation was also
observed between the signal at 7.96 ppm in the 1H dimension and
assigned to H5 and the signal at 182.29 ppm in the 13C dimension
allowing the carbon signal to be assigned to C4 (see Fig. S3 in the
Supplementary data). Similarly, all the signals in the 1H and 13C
spectra of 3b–3h and 3j could be completely assigned.
2.3. Analysis of substituent effects by NMR spectroscopy
Organic compounds containing a naphthoquinone (NQ) struc-
ture have been associated with many biological activities primarily
related to their capacity to accept one or two electrons to give
radical anions or radical dianions, since these latter intermediate
species interact with crucial cellular molecules like DNA and
proteins [14]. The ability of NQs to accept electrons may be
Fig. 1. 1H–1H COSY spectrum of 3i.

E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
157
Fig. 2. 1H–13C gHSQC spectrum of 3i from 6.9 to 8.3 ppm in the 1H dimension and from 111 to 137 ppm in the 13C dimension.
ring. However, fluorine is both electron-attracting (
s
acceptor) and
H3 even more due to the strong inductive effect of the halogen in
this position [7]. Therefore, aniline-substituted naphthoquinone
derivatives with a fluorine in the meta or para position of the
aniline ring are expected to be easier to reduce than the p-methoxy
derivative. On the other hand, according to the 1H chemical shifts
for H3 when fluorine is in the ortho position on the anilino ring (i.e.
electron-donating donor) and the effect of the fluorine
(
p
substituent depends on its position on the aniline ring. On the
basis of the 1H chemical shifts for the various fluorine-substituted
derivatives, we observe that a fluoro substituent in the meta or para
position exerts a
s acceptor effect and, as a consequence, deshields
H3 (Table 2, compounds 3c, 3d and 3g). A meta-fluorine deshields
derivatives 3b, 3e and 3h), the fluorine actually acts as a
p donor
Fig. 3. 1H–13C gHMBC spectrum of 3i from 7.0 to 8.3 ppm in the 1H dimension and from 120 to 135 ppm in the 13C dimension. The correlation between the signal assigned to
H3 (5.76 ppm) and the signal assigned to C10 (132.65 ppm) is not shown; the correlation between the signal at 132.65 ppm (C10) and 7.87 (H6) and 8.07 (H8) are circled in
blue as are the correlations between the signal assigned to C10 and H30/H50.

158
E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
Table 2
Chemical shift (
d
, ppm) of the different hydrogens in the derivatives 2-(R-anilino)-1,4-naphthoquinone.
H
2-F
3-F
4-F
2,4-F
2,5-F
3,4-F
2,4,5-F
2-MeO
4-MeO
2-NO2
4-NO2
3
5.56
7.95
7.86
7.80
8.07
–
6.22
7.97
7.88
7.81
8.08
6.00
5.50
7.94
7.86
7.79
8.06
–
5.56
7.96
7.88
7.81
8.06
–
6.12
5.62
7.95
7.87
7.80
8.07
–
5.79
7.95
7.86
7.79
8.06
–
5.92
7.94
7.85
7.77
8.05
7.29
7.01
–
6.26
8.10
7.99
7.91
8.21
–
6.53
8.17
7.89
7.83
8.33
7.46
7.22
–
5
7.95
7.86
7.78
8.07
7.96
6
7.87
7
7.80
8
8.07
20
30
40
50
60
70
A
7.25–7.30
–
7.38–7.45
7.28
–
7.45–7.55
–
7.35–7.42
7.45
7.38–7.55
–
7.45
7.19–7.27
–
7.76
–
7.17
7.27
7.04
7.37
3.85
8.65
7.84
7.83
7.45
7.81
–
7.04
–
7.27–7.34
7.35–7.42
–
7.48
7.25–7.30
–
7.28
7.38–7.45
–
7.2
7.45–7.55
7.22–7.29
–
–
7.01
7.29
3.78
9.15
7.22
7.46
–
7.4–7.55
–
7.35
–
7.62
–
9.13
9.31
9.24
9.10
9.16
9.29
9.12
9.74
9.56
Table 4
Chemical shift (
naphthoquinone.
and shields H3. Furthermore, the presence of a bifurcated (three-
center) intramolecular hydrogen bond enhances electron density
on the naphthoquinone ring (Scheme 7) and thus modulates
electron acceptor–donor properties of Fluorine. Theoretical and
experimental evidence for this bifurcated bond was recently
reported by us [8].
Substituted-anilino-1,4-naphthoquinone derivatives can easily
undergo reduction to generate a radical anion (Qꢂ, Eq. (1)) and a
second reduction to generate a dianion (Q2ꢂ, Eq. (2)). Only the
second reduction [10] is associated with the carbonyl adjacent to
H3, and therefore, a change in electron density near this carbonyl
(as indicated by the 1H chemical shift of H3) will modulate its
reduction potential.
d
, ppm) for the different carbons in derivatives 2-(R-anilino)-1,4-
C
2-F
3-F
4-F
2,4-F
2,5-F
3,4-F
2,4,5-F 2-MeO 4-MeO
1
2
3
4
5
6
7
8
9
181.15 181.38 181.48 181.10 181.00 181.33 180.97 181.49 181.63
146.79 146.59 146.56 147.18 146.19 146.97 146.92 145.49 146.88
102.92 103.20 101.74 102.81 103.90 102.83 103.68 102.52 101.30
182.39 182.80 182.49 182.37 182.58 182.75 182.55 182.29 182.19
125.35 125.28 125.25 125.36 125.39 125.29 125.04 125.33 125.22
134.91 134.90 134.88 134.92 134.96 134.92 134.97 134.97 134.84
132.74 132.77 132.61 132.75 132.88 132.76 132.87 132.62 132.44
126.11 126.15 126.09 126.09 126.15 126.14 126.12 126.11 126.02
130.33 130.38 130.4 130.32 130.27 130.35 130.27 130.24 130.41
10 132.46 132.39 132.54 132.44 132.33 132.41 132.34 132.65 132.73
10 125.23 140.09 134.33 121.85 126.60 135.21 122.06 126.09 130.56
20 152.12 110.27 126.00 156.48 152.38 113.05 151.92 152.31 125.57
30 116.56 162.35 116.05 105.16 105.16 146.96 106.95 122.14 114.50
40 128.31 111.70 159.36 160.46 114.38 146.56 145.92 126.89 156.91
50 125.18 130.89 116.05 112.22 157.94 117.92 147.64 120.83 114.50
60 127.78 125.25 126.00 129.35 117.76 120.37 116.19 124.22 125.57
Q þ eꢂ ¼ Qꢂ
E1=2
(1)
(2)
I
II
Q
ꢂ þ eꢂ ¼ Q2ꢂ
E1=2
70
55.75 55.30
Accordingly, certain correlation between the reduction poten-
tials for the second reduction wave (E1/2II) of several 2-fluoro-
substituted-anilino-1,4-naphthoquinones(3b, 3c, 3d, 3e, 3g and 3h)
and their H3 chemical shift was observed (Table 3). Indeed, fluoro
derivativeswithmetaandparasubstituentsareeasiertoreducethan
the corresponding methoxy derivatives. If there was a strong
electron-attracting (s acceptor) effect, one would expect the
derivatives with ortho fluorine substituents to show by far less
negative values in their reduction potentials (E1/2II). However, they
only show a slight change in these potentials relative to the values
obtainedformetaandparafluorosubstitutedderivatives.Inaddition
to this, the 1H NMR chemical shifts for H3 in 3b, 3e, 3f and 3h
revealed that the ortho-fluoro substituent actually has a shielding
effect on H3.
The 13C chemical shifts of 3b–3j are given in Table 4. 13C NMR
chemical shifts are quite sensitive to substituent effects and we
expected to observe some correlations with the nature of the
substituents. However, we only observed a very minor change, if
any, in the chemical shift of C3. For example, the 13C chemical shift
of C3 for 3j (4-OMe) is 101.01 ppm, while the 13C chemical shift of
C3 for 3h (2,4,5-F) is 103.68 ppm.
Scheme 7. Structure of 2-(2-fluoroanilino)-1,4-naphthoquinone 3b showing the
effect of fluorine through a bifurcated hydrogen bond that increases electron
density on the anilino nitrogen.
Table 3
Correlation of electrochemical parameters of 2-(fluoro-) and 2-(methoxyanilino)-
1,4-naphthoquinones with 1H NMR Chemical Shifts
d
for H3.
Compound
Substituent
d
for H3 (ppm)
dEII
1/2
3h
3b
3e
3f
2,4,5-F
2-F
5.62
5.56
5.50
5.56
6.22
6.12
6.00
5.92
ꢂ1611a
ꢂ1636a
ꢂ1636a
Ndc
ꢂ1639a
ꢂ1658a
ꢂ1698a
ꢂ1809b
3. Conclusions
2,4-F
2,5-F
3-F
3c
3g
3d
3j
The addition of a catalytic quantity of a Lewis acid and a good
oxidant such as CeCl3 or FeCl3 in the coupling of a weak amine like a
fluoroaniline and 1,4-naphthoquinone resulted in moderate to
high yields of adducts and minimal formation of secondary
products. Under microwave irradiation, only two Lewis acid
catalytic systems gave good yields of pure crystalline compounds
in short times (CeCl3/ethanol and FeCl3/water/ethanol). The use
of FeCl3/ethanol as a catalyst/solvent system under the same
3,4-F
4-F
4-MeO
a
Determined by cyclic voltammetry at 100 mV/s. Ref. [7].
Determined by cyclic voltammetry at 100 mV/s. Ref. [10].
b
c
Since the signals were not well-defined, this value could not be accurately
determined.
d
EII is the second wave reduction potential.
1/2

E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
159
conditions gave low yields of adducts because of decomposition of
the starting 1,4-naphthoquinone.
4.2.3. Preparation of substituted 2-(anilino)-1,4-naphthoquinones
using Cu(OAc)2/AcOH
The reaction of a variety of substituted anilines with naphtho-
quinoneusingCu(OAc)2 inAcOHunderrefluxingconditionsgavethe
best yields of adducts 3b–3j. Under microwave irradiation good
yields were obtained and the time utilized was much less than
conventional heating.
A different mechanism takes place when the reaction is
performed without a catalyst, with a Lewis acid/oxidant catalyst
and with a Brønsted acid/oxidant.
A correlation was observed between the 1H chemical shifts of
H3 (next to C455O) on the napthoquinone ring and the second wave
reduction potential of some of the naphthoquinone derivatives. A
methoxy substituent in ortho or para position shielded H3 while
an unsaturated nitro group deshielded it. A fluorine in meta or para
position deshields H3 (relative to MeO substituent in para) and
makes second wave reduction an easier process. A fluorine in ortho
position actually shields H3, its electron acceptor–donor charac-
ter is modulated by a bifurcated (three center) intramolecular
hydrogen bond.
The substituted naphthoquinones were prepared by the
method reported in the literature with several modifications [9].
1,4-Naphthoquinone (1 mmol), a substituted aniline (1 mmol) and
an amount (0.1 mmol) of Cu(AcO)2 were solubilized by gently
warming in AcOH (2 mL) for 30 min. The reaction mixture was
gently warmed in a water bath for two hours at 70 8C. The solid that
precipitated was separated by filtration and washed with an
aqueous solution of NaHCO3 (10%) to neutralize the remaining
acid. The reaction mixture was dissolved in a small amount of
CH2Cl2 and was passed through a small silica gel column to remove
the remaining copper salts.
4.2.4. Preparation of substituted 2-(anilino)-1,4-naphthoquinones
using mw irradiation
A reaction mixture was prepared as previously described and
placed in a microwave reactor and irradiated (20–50 W) for
several minutes under the ambient atmosphere. The temperature
was set to 65 8C. After this time, the reaction mixture was
submitted to the previously described separation and/or purifi-
cation procedures.
4. Experimental
4.3. Characterization of 2-(2-fluoroanilino)-1,4-naphthoquinone (3b)
4.1. General methods
1H (400 MHz, DMSO-d6):
d5.56 (d, 1H, 3, J = 3.1 Hz), 7.27–7.34 (m,
The solvents, reagents and FeCl3, CeCl3ꢀ7H2O, Cu(OAc)2ꢀH2O used
in the present study were purchased from Aldrich and were used as
received. Melting points were measured with a Fisher Johns
apparatus. NMR spectra were obtained on a Mercury 400 MHz
spectrometer and mass spectra were obtained on a MAT 8400 mass
spectrometer. Reactions under microwave irradiation (mw) were
performed in a CEM microwave reactor, Discover System No.
DU8756. The 1H NMR data of 3b–3j were previously reported,
however, were not assigned [7]. In some cases, the high resolution
data of the derivatives were repeated in an effort to obtain more
precise data compared to the previously reported data [7].
1H, 50), 7.35–7.42 (m, 2H, 30 and 60), 7.45 (td, 1H, 40, Jo = 7.4 Hz,
Jm = 1.2 Hz), 7.80 (td, 1H, 7, Jo = 7.4 Hz, Jm = 1.6 Hz), 7.87 (td, 1H, 6,
Jo = 7.4 Hz, Jm = 1.2 Hz), 7.95 (dd, 1H, 5, Jo = 7.8 Hz, Jm = 1.2 Hz), 8.07
(dd, 1H, 8, Jo = 7.4 Hz, Jm = 1.2 Hz), 9.13 (s, 1H, A); 13C{1H} (100 MHz,
2
DMSO-d6):
d
102.92 (3), 116.56 (d, 30, JC–F = 19 Hz), 125.18 (50),
125.23 (d, 10, 2JC–F = 15 Hz), 125.35 (5), 126.11 (8), 127.78 (d, 40, 3JC–
3
F = 1.5 Hz), 128.31 (d, 60, JC–F = 7.7 Hz), 130.33 (9), 132.46 (10),
132.74 (7), 134.91 (6), 146.79 (2),156.12 (d, 20, 1JC–F = 249 Hz), 181.15
(1), 182.39 (4).
4.4. Characterization of 2-(3-fluoroanilino)-1,4-naphthoquinone (3c)
4.2. Synthetic procedures
1H (400 MHz, DMSO-d6):
d 6.22 (d, 1H, 3, J = 1.2 Hz), 7.04 (tm,
1H, 40, Jo = 8.6 Hz), 7.23–7.30 (m, 2H, 20 and 60), 7.48 (qm, 1H, 50,
Jo = 8.2 Hz, Jo = 8.09 Hz), 7.81 (tm, 1H, 7, Jo = 7.4 Hz), 7.88 (tm, 1H, 6,
Jo = 7.4 Hz), 7.97 (dm, 1H, 5, Jo = 7.8 Hz), 8.08 (d, 1H, 8, Jo = 7.4 Hz),
4.2.1. Preparation of substituted 2-(anilino)-1,4-naphthoquinones
using FeCl3 in ethanol
The substituted naphthoquinones were prepared by the
method reported in the literature [14] with several modifications.
1,4-Naphthoquinone (1 mmol) was dissolved in ethanol (10 mL)
and an amount (0.1 mmol) of FeCl3 was added. The reaction
mixture was stirred for 15 min to allow the reaction between
the Lewis base (1,4-naphthoquinone) and catalyst. A solution of
the substituted aniline (1 mmol) in ethanol (10 mL) was slowly
added and the mixture was refluxed for four hours. TLC analysis
indicated only one product was formed. The resulting solid
was filtered, washed with cold ethanol and recrystallized from
ethanol.
9.31 (s, 1H, A). 13C{1H} (100 MHz, DMSO-d6):
d 103.20 (3), 110.27
(d, 20, 2JC–F = 24 Hz), 111.60 (d, 40, 2JC–F = 20 Hz), 119.11 (d, 60, 4JC–
3
F = 3.1 Hz), 125.28 (5), 126.15 (8), 130.38 (9), 130.89 (d, 50, JC–
3
F = 10 Hz), 132.39 (10), 132.77 (7), 134.90 (6), 140.09 (d, 10, JC–
1
F = 11 Hz), 145.59 (2), 162.35 (d, 30, JC–F = 243.92 Hz), 181.38 (1),
182.80 (4).
4.5. Characterization of 2-(4-fluoroaniline)-1,4-naphthoquinone (3d)
1H (400 MHz, DMSO-d6):
d
6.00 (s, 1H, 3), 7.24–7.33 (m, 2H, 30
and 50), 7.37–7.45 (m, 2H, 20 and 60), 7.78 (t, 1H, 7, Jo = 7.2 Hz), 7.86
(t, 1H, 6, Jo = 7.4 Hz), 7.95 (d, 1H, 5, Jo = 8.2 Hz), 8.06 (d, 1H, 8,
4.2.2. Preparation of substituted 2-(anilino)-1,4-naphthoquinones
using FeCl3 in aqueous ethanol
Jo = 7.8 Hz), 9.24 (s, 1H, A). 13C{1H} (100 MHz, DMSO-d6):
d 101.74
(3), 116.06 (d, 30 and 50, 2JC–F = 23 Hz), 125.25 (5) 126.00 (d, 20 and
3
1,4-Naphthoquinone (1 mmol) was dissolved in
a
water/
60, JC–F = 8.4 Hz), 126.09 (8), 130.40 (9), 132.56 (10), 132.61 (7),
4
ethanol mixture (10/2.5 mL) and an amount (0.1 mmol) of the
Lewis acid catalyst (FeCl3) was added. The reaction mixture was
stirred for 15 min to allow the reaction between the Lewis base
(1,4-naphthoquinone) and catalyst. A solution of a substituted
aniline (1 mmol) in a water/ethanol mixture (10/2.5 mL) was
slowly added and the mixture was refluxed for four hours at 65 8C.
TLC analysis of the reaction mixture indicated only one product
was formed. The resulting solid was filtered, washed with cold
ethanol and recrystallized from ethanol.
134.33 (d, 10, JC–F = 3.1 Hz), 134.88 (6), 146.56 (2), 159.36 (d, 40,
1JC–F = 242.38 Hz), 181.48 (1), 182.49 (4).
4.6. Characterization of 2-(2,4-difluoroanilino)-1,4-naphthoquinone
(3e)
1H (400 MHz, DMSO-d6):
1H, 50, Jo = 8.6 Hz, Jm = 1.6 Hz), 7.40–7.55 (m, 2H, 30 and 60), 7.79 (td,
1H, 7, Jo = 7.4 Hz, Jm = 1.2 Hz), 7.86 (td, 1H, 6, Jo = 7.4 Hz,
d 5.50 (d, 1H, 3, J = 2.7 Hz), 7.20 (dd,

160
E. Leyva et al. / Journal of Fluorine Chemistry 180 (2015) 152–160
Jm = 1.2 Hz), 7.94 (dd, 1H, 5, Jo = 7.4 Hz, Jm = 0.78 Hz), 8.07 (dd, 1H,
8, Jo = 7.4 Hz, Jm = 0.79 Hz), 9.10 (s, 1H, A); 13C{1H} (100 MHz,
Jm = 1.2 Hz), 8.07 (dd, 1H, 8, Jo = 7.6 Hz, Jm = 1.4 Hz), 8.66 (s, 1H, A);
13C{1H} (100 MHz, DMSO-d6): 55.75 (70), 102.52 (3), 112.14 (30),
d
DMSO-d6):
d
102.81 (3), 105.16 (dd, 30, 2JC–F = 26 Hz, 2JC–F = 26 Hz),
120.83 (50), 124.22 (60), 125.33 (5), 126.09 (10), 126.11 (8), 126.89
(40), 130.24 (9), 132.62 (7), 132.65 (10), 134.97 (6), 145.49 (2),
152.31 (20), 181.49 (1), 182.29 (4); Low Resolution EI-MS m/z (%):
279 [M]+ (100%), 264 [M ꢂ Me]+ (37%), 248 (14%), 236 (16%), 208
(8%), 180 (8%), 146 (9%), 105 (13%), 77 (13%); High-Resolution EI-
MS for C17H13NO3 m/z calcd: 279.0895, found: 279.0898.
112.22(dd,50,2JC–F = 22 Hz, 4JC–F = 3.8 Hz), 121.85 (d, 10, 2JC–F = 12 Hz,
4JC–F = 3.8 Hz), 125.36 (5), 126.09 (8), 129.35 (d, 60, 3JC–F = 2.5 Hz, 3JC–
F = 10 Hz), 130.32 (9), 132.44 (10), 132.75(7), 134.92 (6), 147.18 (2),
3
1
156.48 (dd, 20,1JC–F = 251 Hz, JC–F = 13 Hz), 160.46 (dd, 40, JC–
F = 246 Hz, 3JC–F = 12 Hz), 181.10 (1), 182.37 (4). High-Resolution EI-
MS for C16H9F2NO2 m/z calcd: 285.0601, found: 285.0598.
4.11. Characterization of 2-(4-methoxyanilino)-1,4-naphthoquinone
4.7. Characterization of 2-(2,5-difluoroanilino)-1,4-naphthoquinone
(3j)
(3f)
1H (400 MHz, DMSO-d6):
d
3.78 (s, 3H, 70), 5.92 (s, 1H, 3), 6.99–
1H (400 MHz, DMSO-d6):
d
5.65 (d, 1H, 3, J = 3.1 Hz), 7.19–7.27
7.04 (AA0XX0, 2H, 30 and 50), 7.27–7.33 (AA0XX0, 2H, 20 and 60) 7.77 (td,
1H, 7, Jo = 7.4 Hz, Jm = 1.2 Hz), 7.85 (td, 1H, 6, Jo = 7.5 Hz, Jm = 1.4 Hz),
7.94 (dd, 1H, 5, Jo = 7.6 Hz, Jm = 0.97 Hz), 8.05 (dd, 1H, 8, Jo = 7.6 Hz,
(m, 1H, 40), 7.35 (ddd, 1H, 60, JoHF = 9.2 Hz, JmHF = 5.9 Hz,
JmHH = 3.2 Hz), 7.45 (ddd, 1H, 30, JoHH = 10 Hz, JoHF = 9.4 Hz,
JmHF = 5.1 Hz), 7.81 (td, 1H, 7, Jo = 7.5 Hz, Jm = 1.6 Hz), 7.88 (td,
1H, 6, Jo = 7.5 Hz, Jm = 1.2 Hz), 7.96 (dd, 1H, 5, Jo = 7.2 Hz,
Jm = 0.97 Hz), 9.15 (s, 1H, A);. 13C{1H} (100 MHz, DMSO-d6):
d 55.30
(70), 101.01 (3), 114.50 (30 and 50), 125.22 (5), 125.57 (20 and 60),
126.02(8), 130.41(9), 130.56(10), 132.44(7), 132.73(10), 134.84(6),
146.88 (2), 156.91 (40), 181.63 (1), 182.19 (4); Low Resolution EI-MS
m/z (%): 279 [M]+ (100%), 264 [M ꢂ Me]+ (41%), 248 (12%), 236 (15%),
208 (9%), 146 (4%), 105 (14%), 76 (11%); High-Resolution EI-MS for
Jm = 1.4 Hz), 8.08 (dd, 1H, 8, Jo = 7.6 Hz, Jm = 0.97 Hz), 9.16 (s, 1H,
A); 13C{1H} (100 MHz, DMSO-d6):
F = 26 Hz), 114.38 (dd, 40, JC–F = 24 Hz, JC–F = 8.4 Hz), 117.76 (dd,
30, 2JC–F = 22 Hz, 3JC–F = 10 Hz), 125.39 (5), 126.15 (8), 126.6 (m, 10),
130.27 (9), 132.33 (10), 132.88 (7), 134.96 (6), 146.19 (2), 152.38
(d, 20, JC–F = 245 Hz), 157.94 (d, 50, JC–F = 241 Hz) 181.00 (1),
182.58 (4); High-Resolution EI-MS for C16H9F2NO2 m/z calcd:
285.0601, found: 285.0602.
2
d
103.90 (3), 114.09 (d, 60, JC–
2
3
C
17H13NO3 m/z calcd: 279.0895, found: 279.0901.
1
1
Acknowledgements
This work was supported by CONACyT (Grant 155678) and the
NSERC (Canada). C.G.E.G. acknowledges financial support by
CONACyT (Scholarship 219859-290917). D.A.M.L acknowledges
financial support by CONACyT (National Scholarship 268070 and
International Scholarships 290749).
4.8. Characterization of 2-(3,4-difluoroanilino)-1,4-naphthoquinone
(3g)
1H (400 MHz, DMSO-d6): 6.12 (s, 1H, 3), 7.22–7.29 (m, 1H, 60),
d
7.45–7.55 (m, 2H, 20 and 50), 7.80 (td, 1H, 7, Jo = 7.4 Hz, Jm = 1.6 Hz),
7.87 (td, 1H, 6, Jo = 7.5 Hz, Jm = 1.4 Hz), 7.96 (dd, 1H, 5, Jo = 7.8 Hz,
Appendix A. Supplementary data
Jm = 1.2 Hz), 8.07 (dd, 1H, 8, Jo = 7.6 Hz, Jm = 0.97 Hz), 9.29 (s, 1H, A);
2
13C{1H} (100 MHz, DMSO-d6):
d
102.83 (3), 113.05 (d, 50, JC–
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.08.
016.
F = 20 Hz) [20], 117.92 (d, 20, 2JC–F = 17 Hz) [20], 120.39 (dd, 60, 3JC–
F = 6.5 Hz, 4JC–F = 3.5 Hz), 125.29 (5), 126.14 (8), 130.35 (9), 132.41
3
4
(10), 132.76 (7), 134.92 (6), 135.21 (dd, 10, JC–F = 8.44 Hz, JC–
F = 3.07 Hz), 146.97 (2), 146.56 (d, 40, 1JC–F = 243.92 Hz) [21], 146.69
(d,30, 1JC–F = 244 Hz)[21], 181.33(1), 182.75(4);High-ResolutionEI-
MS for C16H9F2NO2 m/z calcd: 285.0601, found: 285.0602.
References
[1] R.A. Morton, Biochemistry of Quinones, Academic Press, New York, NY, 1965.
´
´
[2] Ll.I. Lopez, E. Leyva, R.F. Garcıa de la Cruz, Rev. Mex. Cienc. Farm. 42 (2011) 6–17.
[3] A. Marcos, C. Pedregal, C. Avendan˜o, Tetrahedron 51 (1995) 6565–6572.
[4] P.A. Aristoff, P.D. Johnson, J. Org. Chem. 57 (1992) 6234–6239.
[5] Y.T. Pratt, J. Org. Chem. 27 (1962) 3905–3910.
4.9. Characterization of 2-(2,4,5-trifluoroaniline)-1,4-
naphthoquinone (3h)
[6] E. Leyva, Ll.I. Lo´pez, E. Moctezuma, H. De Lasa, Top. Catal. 49 (2008) 281–287.
´
´
[7] E. Leyva, Ll.I. Lopez, S.E. Loredo-Carrillo, M. Rodrıguez-Kessler, A. Montes-
1H (400 MHz, DMSO-d6):
d 5.62 (d, 1H, 3, J = 3.1 Hz), 7.63 (dt,
Rojas, J. Fluorine Chem. 132 (2011) 94–101.
1H, 60, JoHF = 10.8 Hz, JmHF = 7.9 Hz), 7.76 (td, 2H, 30, JoHF = 10 Hz,
JmHF = 7.4 Hz), 7.80 (td, 1H, 7, Jo = 7.5 Hz, Jm = 1.4 Hz), 7.87 (td, 1H,
6, Jo = 7.5 Hz, Jm = 1.3 Hz), 7.95 (dd, 1H, 5, Jo = 7.6 Hz, Jm = 0.98 Hz),
8.07 (dd, 1H, 8, Jo = 7.61 Hz, Jm = 0.97 Hz), 9.12 (s, 1H, A); 13C{1H}
[8] S. Vega-Rodrı´guez, R. Jime´nez-Catan˜o, E. Leyva, S.E. Loredo-Carrillo, J. Fluorine
Chem. 145 (2013) 58–62.
[9] C. da, S. Lisboa, V.G. Santos, B.G. Vaz, N.C. de Lucas, M.N. Eberlin, S.J. Garden, J.
Org. Chem. 76 (2011) 5264–5273.
[10] M. Aguilar-Martı´nez, G. Cuevas, M. Jime´nez-Estrada, I. Gonza´lez, B. Lotina
(100 MHz, DMSO-d6):
d
103.68 (3), 106.95 (dd, 30, 2JC–F = 26 Hz, 2JC–
´
Hennsen, N. Macıas-Ruvalcaba, J. Org. Chem. 64 (1999) 3684–3694.
[11] N. Macı´as-Ruvalcaba, G. Cuevas, I. Gonza´lez, M. Aguilar-Martı´nez, J. Org. Chem.
67 (2002) 3673–3681.
2
F = 22 Hz), 116.19 (d, 60, JC–F = 20 Hz), 122.06 (m, 10), 125.40 (5),
126.12 (8), 130.27 (9), 132.34 (10), 132.87 (7), 134.97 (6), 145.92
[12] E.A. Couladouros, Z.P. Plyta, V. Papageorgiou, J. Org. Chem. 61 (1996) 3013–3033.
[13] A.I. Francisco, M.D. Vargas, J.W. de, M. Carneiro, M. Lanznaster, J.C. Torres, C.A.
Camara, A.C. Pinto, J. Mol. Struct. 891 (2008) 228–232.
[14] E. Leyva, S.J. Schmidke-Sobeck, S.E. Loredo-Carrillo, D.A. Magaldi-Lara, J. Mol.
Struct. 1068 (2014) 1–7.
[15] Y. Yamamoto, J. Org. Chem. 72 (2007) 7817–7831.
[16] A.E. Alegrı´a, M. Lo´pez, N. Guevara, J. Chem. Soc. Faraday Trans. 92 (1996)
4965–4968.
1
1
(dm, 40, JC–F = 240 Hz) [22], 146.69 (2), 147.64 (dm, 50, JC–
1
3
F = 235 Hz) [22], 151.92 (dd, 20, JC–F = 247 Hz, JC–F = 11 Hz),
180.97 (1), 182.55 (4); High-Resolution EI-MS C16H8F3NO2 m/z
calcd: 303.0507, found: 303.0507.
4.10. Characterization of 2-(2-methoxyanilino)-1,4-naphthoquinone
[17] W.M. Haynes, T.J. Bruno, D.R. Lide, CRC Handbook of Chemistry and Physics,
International Edition, 94th ed., CRC Press, Taylor & Francis, Boca Raton, FL,
2014, pp. 5.81–5.89.
(3i)
[18] B.L. Hayes, Microwave Synthesis: Chemistry at the Speed of Light, CEM
Publishing, USA, 2002.
[19] J.P. Tierney, P. Lidstro¨m, Microwave Assisted Organic Synthesis, Blackwell
Publishing, Oxford, UK, 2005.
[20] The assignment of C20 and C50 may be reversed.
[21] The assignment of C40 and C30 may be reversed.
[22] The assignment of C40 and C50 may be reversed.
1H (400 MHz, DMSO-d6):
d
3.86 (s, 3H, 70), 5.79 (s, 1H, 3), 7.05
(td, 1H, 50, Jo = 7.6 Hz, Jm = 1.24 Hz), 7.18 (dd, 1H, 30, Jo = 8.2 Hz,
Jm = 1.2 Hz), 7.28 (td, 1H, 40, Jo = 8.0 Hz, Jm = 1.4 Hz), 7.38 (dd, 1H, 60,
Jo = 7.8 Hz, Jm = 1.2 Hz), 7.80 (td, 1H, 7, Jo = 7.5 Hz, Jm = 1.4 Hz), 7.87
(td, 1H, 6, Jo = 7.4 Hz, Jm = 1.6 Hz), 7.96 (dd, 1H, 5, Jo = 7.4 Hz,