C-H functionalization of 1,4-naphthoquinone by oxidative coupling with anilines in the presence of a catalytic quantity of copper(II) acetate

Article abstract of DOI:10.1021/jo200354u

The oxidative addition of anilines (2) with 1,4-naphthoquinone (3) to give N-aryl-2-amino-1,4-naphthoquinones (1) was found to be catalyzed by copper(II) acetate. In the absence of the catalyst, the reactions are slower and give lower yields with the formation of many colateral products. In the presence of 10 mol % hydrated copper(II) acetate, the reactions are generally more efficient in that they are cleaner, higher yielding, and faster.

Full text of DOI:10.1021/jo200354u

ARTICLE
pubs.acs.org/joc
CꢀH Functionalization of 1,4-Naphthoquinone by Oxidative Coupling
with Anilines in the Presence of a Catalytic Quantity of Copper(II) Acetate
Cinthia da S. Lisboa,† Vanessa G. Santos,‡ Boniek G. Vaz,‡ Nanci C. de Lucas,† Marcos N. Eberlin,‡ and
Simon J. Garden*,†
†Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitꢀaria CT bloco A, Ilha do Fund~ao, RJ 21941-909, Brazil
‡Laboratꢀorio ThoMSon de Espectrometria de Massas, Instituto de Química, Universidade Estadual de Campinas ꢀ UNICAMP,
13084-971, Campinas SP, Brazil
S Supporting Information
b
ABSTRACT: The oxidative addition of anilines (2) with 1,4-
naphthoquinone (3) to give N-aryl-2-amino-1,4-naphthoqui-
nones (1) was found to be catalyzed by copper(II) acetate. In
the absence of the catalyst, the reactions are slower and give
lower yields with the formation of many colateral products. In
the presence of 10 mol % hydrated copper(II) acetate, the
reactions are generally more efficient in that they are cleaner, higher yielding, and faster.
’ INTRODUCTION
to enone systems. However, a recent study has revealed how
Ce(III) in the presence of oxygen results in the oxidation of 1,3-
dicarbonyl systems and this maybe of relevance to the oxidative
coupling of 2 and 3.23 The use of greater than stoichiometric
quantities of Cu(II) salts in MeOH has been reported although
long reaction times were required.24 Specifically, a molar equiva-
lent of hydrated copper acetate has been used for the oxidative
coupling of alkylamines, present in large excess, with 1,4-
naphthoquinone,25 naphthazarin,26 and juglone.27 Additionally,
nickel(II) salts were found to be beneficial in the oxidative
addition reactions of amines with (iso)quinolindiones.28
Recent studies on the oxidative coupling of 2 and 3 to give 1
reported that the use of warm water was beneficial, resulting in
excellent yields with only short reaction times.29 Additionally,
Tandon and Maurya reported the “on water” nucleophilic sub-
stitution and addition reactions with 1,4-quinones.30 The use of a
bentonitic clay was reported to give excellent yields (80ꢀ85%)
for the oxidative coupling but required long reaction times. In the
absence of the clay, yields were reduced to less than half.31 Finally,
the use of I2 and ultrasonic irradiation was reported to give
moderate to excellent yields of 1,32 while a gold(III) catalyzed
reaction gave moderate to good yields of 1 via oxidative coupling
of primary, or secondary, aliphatic and aromatic amines.33
The 2-amino-1,4-napthoquinone (1) moiety and the related
quinoline- and isoquinoline- 5,8-diones (azanaphthoquinones)
are found in a considerable number of natural product antibiotics
(Figure 1). The structures of these compounds are very diverse
possessing 2ꢀ5 fused rings, for example, cribrostatins;1 laven-
damycin2 and streptonigrin;3 renierones;4 mimosamycin;5 cau-
libugulones AꢀF;6 mansouramycins AꢀD, recently isolated
from the marine-derived Streptomyces sp. isolate Mei37;7 hygro-
cins A and B, isolated during the purification of the immuno-
suppressive agent rapamycin from Streptomyces hygroscopicus
ATC25293;8 benzo[b]phenanthridines, a subgroup of the angu-
cycline antibiotics,9 such as the jadomycins10 and phenanthro-
viridone;11 griffithazanone A and the azaanthracenetrione, iso-
lated from the ethanolic extract of the roots of G. griffithii;12 and
the more complex pentacyclic systems of jorunnamycin,13 re-
nieramycins14 and the saframycins.14a,15 Very significant cyto-
toxicity has been observed for the aforementioned natural products.
The reaction of amines and anilines (2) with 1,4-naphthoqui-
none (3) to give 2-amino- and 2-anilino-1,4-naphthoquinone (1)
has been known since the first reports by Schultz, Zincke and
Plimpton.16 Since then, two general methods for the synthesis of
derivatives of 1 have been developed: first, the oxidative coupling
of alkyl and aryl amines with naphthoquinone;17 and second, nu-
cleophilic substitution reactions of 2-halonaphthoquinones17c,18
or 2-methoxynaphthoquinone derivatives.19 The first method is
an example of a C(sp2)-H bond transformation whereby a new
C(sp2)-N bond is formed at the expense of 2 electrons and 2
protons via an addition-oxidation reaction sequence.20 It is
therefore, in principle, an atom economical method for the
construction of new bonds.21 To this end, Lewis acids such as
’ RESULTS AND DISCUSSION
With the objective of studying concise routes into natural
products, their analogues, and polyheteroaromatic systems with
the 2-amino-1,4-(aza)naphthoquinone moiety, we initially inves-
tigated a synthetic protocol based upon earlier work by Thomson
involving juglone derivatives and 2a in ethanol.17a,b Heating 2a
22
CeCl3 have been used to promote the oxidative coupling
Received: February 17, 2011
Published: May 23, 2011
reaction on the basis that they facilitate a Michael type addition
r
2011 American Chemical Society
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Figure 1. Some cytotoxic natural (aza)naphthoquinones.
and 3 in ethanol resulted in the precipitation of a dark-burgundy-
colored solid. The solid was isolated by filtration and recrys-
tallized from EtOAc to give 1a in a modest yield of 35%. Anal-
ysis of the reaction by TLC revealed the extensive formation
of colateral products. However, the yield could be improved
by precipitating all materials from the ethanolic reaction by
addition of water. The crude product obtained in this manner
was purified by column chromatography, as summarized in
Table 1/entry 1 (T1-E1), resulting in a moderate improve-
ment of the purified yield of 1a. Using a shorter heating period,
a smaller yield was obtained (T1-E2). A subsequent reaction
left for an additional period of time at room temperature gave
a substantially better yield of 1a (T1-E3). Changing the sol-
vent from ethanol to AcOH and using a shorter heating period
also gave a considerably better yield of 1a (T1-E4 compared
with E1). However, analysis of the AcOH reaction by TLC
also revealed the presence of colateral products.
The currently considered mechanism for this coupling reac-
tion (Scheme 1) initially involves a Michael addition of 2a to 3 to
give a dihydroquinone intermediate (4), which tautomerizes to
the hydroquinone (5). Oxidation of 5 in the presence of molec-
ular oxygen, or as a consequence of excess 3, gives 1a.
We suspected that the oxidation reaction could be responsible
for the plethora of side products and therefore reasoned that the
inclusion of an efficient, chemoselective, oxidizing agent would
allow for a cleaner reaction with a better yield. A copper(II) salt,
such as Cu(OAc)2.H2O (6), seemed attractive as the Cu(I)
reduction product is readily oxidized by atmospheric oxygen
back to Cu(II). Indeed, when 10 mol % 6 was added to the
reaction mixture (T1-E6 and E7), an extremely rapid reaction
was observed to occur and 1a crystallized from the reaction
medium. TLC examination of the crude reaction revealed it to be
surprisingly clean. The colateral products that had been observed
in the previous oxidative coupling reactions were absent. The
product 1a was isolated by evaporation of the volatiles under
reduced pressure, the solid was solubilized in CH2Cl2, and the
solution was filtered through a short column of silica eluting with
CH2Cl2 to remove the copper salts. After prolonged evaporation
of the solvent under reduced pressure, 1a was obtained in a very
high yield of 97% (T1-E6 and E7). Notably, Inoue obtained a
53% yield of 1a after bubbling air through a refluxing methanolic
solution of 2a and 3 during three hours in the presence of a molar
equivalent of hydrated Cu(OAc)2.24a,b The use of an acetoni-
trile/AcOH solution in the presence of 6, followed by a similar
workup, gave an 81% yield of 1a (T1-E8) while the addition of
the copper catalyst to an ethanolic reaction resulted in a 68%
yield (T1-E5 compare with E2). A reduction of the quantity of
the copper salt to 5 mol % gave an almost equally good yield after
50 min (compare T1-E9 with E7) while further reduction to
about 2 mol % of copper salt gave a result similar to the absence of
the catalyst (compare T1-E10 with E4). The use of water as a me-
dium for agitating the reactants was briefly investigated (T1 entries
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Table 1. Oxidative Coupling of 1,4-Naphthoquinone (3) with Amines (2) in the Absence and in the Presence of Cu(OAc)2.
H2O (6)
entry
aminea R-(NH2)
Cu(OAc)2.H2O(mol %)
solventb
EtOH (5)
time (mins)
yield (%)
mp (°C)c
1
Ph
0
0
120
55
41
80
76
68
97
97
81
93
71
16
63
66
78
35
82
63
90
75
97
188ꢀ9
190ꢀ1
188ꢀ90
191
2
Ph
EtOH
35
3
Ph
0
EtOH (5)
AcOH
90 þ 23 h rt
4
Ph
0
80
35
30
25
40
50
65
60
60
60
60
120
20
60
30
60
40
5
Ph
10
9
EtOH
191ꢀ2
190
6
Ph
AcOH
7
Ph
10
11
5
AcOH
190
8
Ph
AcOH (1):ACN (4)
AcOH
188ꢀ90
189ꢀ90
191ꢀ2
184ꢀ6
185ꢀ6
191ꢀ2
191ꢀ2
199ꢀ200
197ꢀ200
171ꢀ3
173ꢀ4
147ꢀ8
147ꢀ8
9
Ph
10
11
12
13e
14e,f
15
16
17
18
19
20
Ph
2
AcOH
Ph
0
H2O (25)d
H2O (25)d
AcOH (20)
AcOH (20)
EtOH (3)
AcOH
Ph
14
10
10
0
Ph
Ph
4-MePh
4-MePh
3-CF3Ph
3-CF3Ph
2-MeOPh
2-MeOPh
9
0
AcOH
13
0
AcOH
AcOH
12
AcOH
a R-NH2: R = Ph, aniline; R = 4-MePh, p-toluidine; R = 3-CF3Ph, 3-trifluoromethylaniline; R = 2-MeOPh, 2-methoxyaniline. b 1,4-Naphthoquinone
(1 mmol) and amine (1 mmol), with or without Cu(OAc)2.H2O, were heated (65 °C) in 2 mL of solvent unless otherwise indicated by a value in
parentheses. c R = Ph: mp (lit.): 189ꢀ190 °C;31 R = 4-MePh: mp (lit.): 200ꢀ201 °C;32 and R = 3-CF3Ph mp (lit.): 174 °C;24c and R = 2-MeOPh: mp
(lit.): 146 °C.34 d A larger volume of water was used in relation to the other solvents due to the poor solubility of 3, but even under the conditions used 3
e
was incompletely soluble. A 10-fold increase in the scale of the reaction. The reactions are exothermic on addition of the aniline and the internal
temperature rose from 60 °C to about 75 °C. The crude products obtained, after evaporation of the volatiles, were solubilized in CH2Cl2 and filtered
through a short column of silica gel eluting with CH2Cl2 (respective mass balances for table entries 13 and 14 were 82% and 93%). The products were
then recrystallized from EtOH/H2O (aprox. 2:1 V/V). The yields given in the table are for the first crop of crystals. A further crop of crystals can be
obtained by concentration of the filtrates, filtration, and recrystallization of the solids from a respectively smaller volume of EtOH/H2O. f An atmosphere
of oxygen was used.
Scheme 1. Schematic Representation of the Mechanism for Oxidative Coupling of Aniline and 1,4-Naphthoquinone
11 and 12) and reactions were intentionally terminated after
60 min. Despite the inferior results, the use of the copper salt as
an additive was revealed to be a significant advantage. Further,
the reaction of 2a with 3 was conducted on a 10-fold larger scale.
In the first instance (T1-E13), the reaction was stirred open to
the atmosphere where it was noted that copper was deposited
onto the surface of the reaction vessel, and that the reaction
mixture did not crystallize, during the reaction. Repetition of the
10-fold larger scale reaction but using an atmosphere of oxygen
(T1-E14) resulted in the crystallization of the reaction product
within the first 30 min (as in T1-E6 and E7), and no evidence for
the deposition of copper metal was observed during the reaction.
The experiments clearly indicate how the mass transfer of oxygen
during the reaction influences the outcome of the reaction.
In a similar manner, the aniline derivatives 2bꢀd were sub-
jected to oxidative coupling with 3 in the presence and absence of
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Scheme 2. Schematic Representation of the Proposed Participation of Cu(II) in the Oxidative Coupling of Anilines and 1,4-
Naphthoquinone
10 mol % 6. The results reveal in all cases that the reactions
incorporating the copper salt, and using AcOH as the solvent,
give superior yields in shorter reaction times (T1-E15 to E20).
The results from the experiments as summarized in Table 1
reveal the value of adding a catalytic quantity of 6 to the reaction.
Scheme 2 depicts a proposal for the reaction mechanism with the
copper cation as the isotopologues 63Cu(I)(ACN)2þ (m/z 145)
and 65Cu(I)(ACN)2þ (m/z 147) in an approximately 2:1 ratio.
The observation of this ion is consistent with the facile reduction
of the initial Cu(II) salt under the reaction conditions. The
difficulty in detecting copper ion reaction intermediates by ESI-
MS in this case, is probably related to their very transient nature
and the facility with which they undergo decomposition.37 It is
notable that Cu(I) phenoxide species are oxygen (air) sensitive
compounds that have only been adequately characterized by the
inclusion of ligands or ligating groups in the Cu(I) coordination
sphere.38
A thorough literature search turned up a few more examples of
oxidative addition reactions of quinones, other than 3, that
envolved the participation of copper salts. Matsuoka and collea-
gues observed that a large excess of butylamine reacts with 5,8-
dihydroxy-1,4-naphthoquinone in the presence of 2 mol equiva-
lents of copper(II) salts to give a variety of products resulting
from both nucleophilic substitution of the hydroxyl groups and
oxidative coupling,39 whereas the analogous reaction with 1,4-
dihydroxyanthraquinone selectively gave 2-butylamino-1,4-dihydro-
xyanthraquinone.40 A similar reaction with ethylenediamine gave
a product resulting from oxidative addition and cyclization.41
Yoshida and co-workers found that N-alkylanilines regioselec-
tively react at the 6-position with quinolin-5,8-dione in the pre-
sence of a molar equivalent of copper(II) acetate to give mixtures
of products resulting from oxidative coupling to both the para
position and the nitrogen of the aniline derivative.28c Kitahara
participation of Cu2þ
.
In support of the proposed mechanism, copper(II) ions are
known to oxidize hydroquinones to the respective quinones.
Whereas in the present study the end oxidant is atmospheric
oxygen, catalytic studies of the oxidation of hydroquinone have
generally used hydrogen peroxide as the stoichiometric oxidant.35 In
Scheme 2, Michael addition of 2 to 3 could be facilitated by either
protonation of 3 or complexation of 6 to 3. The resulting copper
hydroquinone complex could interact directly with oxygen to
give the quinone product or could pass through sequential one
electron oxidation steps where the resulting Cu(I) species would
then be reoxidized to Cu(II) by oxygen. The oxygen should
eventually be reduced to water and this may occur through the
formation of reactive oxygen species (ROS). In the absence of
the copper salt, the ROS maybe responsible for the formation of
colateral products. Therefore, the presence of the copper salt
may also serve to eliminate the ROS.
ESI-MS monitoring of reactions has proven to be a versatile
method for the interception and characterization of actual reaction
intermediates.36 To this end, extensive experimentation was con-
ducted but the only copper species reliably observed was the
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Table 2. Oxidative Coupling of Amines (2aꢀz) with 1,4-Naphthoquinone (3) in the Presence of 10 mol % Cu(OAc)2.H2O in
AcOH (approx. 60 °C) in Air
R1ꢀ6a
time (mins)b
yield (%)
R1ꢀ6a
time (mins)b
yield (%)
a
b
c
d
e
f
R1ꢀ6 = H
R3 = Me
25
20
97
82
90
97
92
93
32
40
78
68
64
63
24
n
o
p
q
r
R2 = NO2
40
30
82
73
87
85
71
63
99
88
90
55
42
74
50
R3 = F
R2 = CF3
R1 = OMe
R3 = OMe
R2 = OMe
R3 = CN
30
R3 = Cl
30
40
R3 = Br
30
30
R1 = I
30
30
s
R2 = Cl, R3 = OMe
R1 = OMe, R4= Cl
R1 = OMe, R3 = NO2
R1 = Me, R3 = MeO
R1, R5 = Me
R1, R4 = OMe
R6 = Me
40
g
h
i
240
240
240
40
t
40
R2 = CN
u
v
w
x
y
z
240
30
R1 = CN
j
R3 = CO2H
R2 = CO2H
R1 = CO2H
R3 = NH2
180
25
k
l
25
40
70
m
65
Bn(c)c
80
a R1ꢀ6 = H unless otherwise indicated. b The reactions were followed by TLC until the apparent consumption of the limiting substrate. c Benzylamine
was used.
Scheme 3. N-Methylation of Derivatives of 1 to Give 7a
and co-workers as part of their synthetic studies on the prepara-
tion of isoquinolindiones reported the oxidative coupling of
amines with 5-isoquinolinol to give 8-dialkylamino-5,6-isoqui-
nolinediones and the 7-isoquinolinol to give 3,5-(dialkylamino)-
7,8-isoquinolinediones in the presence of 50 mol % copper(II)
acetate.42 However, more recently Park and co-workers reported
the use of copper nanoparticles entrapped in aluminum oxyhydr-
oxide for the oxidative coupling of amines with hydroquinones in
ethyl acetate.35e In building upon these precedents, the present
study has found that catalytic quantities (10 mol %) of 6 in AcOH
result in good to excellent yields for the regiospecific oxidative
coupling of anilines with 3 in very short reaction times.
a R1, R2 and R3 = H unless otherwise stated. 7g R3 = CN, 80%; 7k R2 =
CO2Me, 87%; 7o R3 = F, 90%; 7p R3 = Cl, 58%; 7q R3 = Br, 60%; 7s R2 =
Cl, R3 = MeO, 73%; 7u R1 = MeO, R3 = NO2, 68%.
some of the derivatives 1 were N-methylated by reaction with
MeI in the presence of K2CO3 in DMF to give 7 (Scheme 3) with
the intention of improving their solubility for analysis by 1H and
13C NMR. Kallmayer has reported an alternative methodology
for the N-alkylation of 1.43
The copper acetate/AcOH methodology was subsequently
applied to a variety of substituted anilines and benzylamine. The
results are detailed in Table 2. A few observations but no general
trends can be made with respect to the results: the cyano-anilines
(2g, 2h and 2i), and aniline 2u, all required a longer period of
heating but only 2i and 2u gave good yields of the respective
products 1i and 1u; the carboxylic acids (1j, 1k and 1l) were
isolated by precipitating with water and washed with ethanol, this
procedure may account for the lower yields; the product 1m from
aniline 2m was difficult to purify from the reaction mixture; the
hindered 2,6-dimethylaniline (2w) gave a reduced yield and
required a longer period of heating in comparison to other aniline
derivatives that did not have two ortho substituents; aniline 2x
gave a lower yield in comparison to the other disubstituted
methoxyaniline derivatives possibly due to it being easily oxi-
dized; and N-methyl aniline 2y required a slightly longer reaction
time, and gave a reduced yield of 1y in comparison to the for-
mation of 1a. The products were physically and spectroscopically
characterized. In a number of cases, the derivatives of 1 were
poorly soluble in commonly used NMR solvents. Therefore,
’ CONCLUSION
The inclusion of a catalytic quantity of Cu(OAc)2.H2O in the
oxidative coupling of anilines (2) with naphthoquinone (3),
resulting in the C(sp2)-H functionalization of 3, was found to
have a beneficial effect upon both the time required for reaction
to complete and in eliminating or reducing the formation of side
products. No systematic effect of the substituents on 2 was
observed, although steric hindrance due to two ortho-substitu-
ents may reduce the yield.
’ EXPERIMENTAL SECTION
General. The solvents and reagents used in the present study were
purchased from commercial suppliers and were used as received. Thin
layer chromatography was performed with fluorescent silica coated
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aluminum sheets. Silica gel (70ꢀ230 mesh) was used for column chro-
matography.
125.5; 126.1; 126.4; 126.6; 130.4; 132.4; 132.9; 134.8; 145.3; 152.2;
181.6; 182.7.
Reaction products were characterized by nuclear magnetic resonance
spectroscopy (1H - 200 MHz, 13C - 50 MHz). The 1H NMR spectra data
is expressed in the form: Chemical shift in units of ppm (normalized
integration, multiplicity, the value of J in Hz). The multiplicity of the
observed signals is expressed as: s (singlet), d (doublet), t (triplet), m
(multiplet) or a combination thereof, for example dd (doublet of
doublets). The Fourier transform infrared spectra were obtained as
KBr pellets. High resolution mass spectra (HRMS) were obtained by
dissolving compounds (1 mg) in methanol (1 mL, HPLC grade). For an
analysis in the positive ion mode, a total of 2 μL of a 1% aqueous solution
of formic acid was added into the same volume. Direct infusion automated
chip-based nano-ESI-MS was performed. Samples were loaded into 96-
well plates (total volume of 100 μL in each well) and analyzed using a
Fourier transform mass spectrometer. ESI general conditions were: gas
pressure of 0.3 psi and capillary voltage of 1.55 kV. Mass spectra were the
result of over 100 microscans, centered, and aligned using the supplied
software. Melting points were recorded in open capillaries and are
uncorrected.
1e 2-(4-Methoxyphenyl)amino-1,4-naphthoquinone. M.p.: 154ꢀ
5 °C; (lit.): 155ꢀ6 °C.29 IR (cmꢀ1): 3222; 1678; 1615; 1597; 1566;
1507; 1357; 1292; 1234; 1173; 1123; 1041; 991; 830; 778; 722. HRMS
(m/z): Obs. 280.0963; Calcd 280.0974 (C17H14NO3þ). 1H NMR
(DMSO-d6): 3.77 (3H, s); 5.92 (1H, s); 7.00 (2H, d, 8.0); 7.29 (2H,
d, 8.0); 7.9 (4H, m); 9.15 (1H, s). 13C NMR: 55.3; 101.0; 114.5; 125.2;
125.6; 126.0; 130.6; 132.4; 134.8; 138.7; 146.9; 156.9; 181.6; 182.2.
1f 2-(3-Methoxyphenyl)amino-1,4-naphthoquinone. The products
from the two reactions were purified by silica gel column chromatog-
raphy eluting with CH2Cl2. Bright red crystals. M.p.: 160ꢀ163 °C; (lit.):
172 °C.34 IR (cmꢀ1): 3327; 1676; 1606; 1594; 1568; 1530; 1500; 1351;
1298; 1265; 1242; 1215; 1160; 1120; 1002; 869; 775; 726. HRMS (m/z):
Obs. 280.0968; Calcd 280.0974 (C17H14NO3þ). 1H NMR (DMSO-d6):
3.77 (3H, s); 6.15 (1H, s); 6.79 (1H, d, 8.0); 6.95 (1H, s); 6.97 (1H, d,
8.0); 7.34 (1H, t, 8.0); 7.76 (1H, td, 2.0, 8.0); 7.85 (1H, td, 2.0, 8.0); 7.95
(1H dd, 2.0, 8.0); 8.04 (1H, dd, 2.0, 8.0); 9.17 (1H, s). 13C NMR: 55.2;
102.5; 109.4; 110.7; 115.5; 125.3; 126.1; 130.0; 130.4; 132.5; 132.6;
134.9; 139.3; 146.0; 159.9; 181.5; 182.6.
1g 2-(4-Cyanophenyl)amino-1,4-naphthoquinone. The products
from the two reactions were purified by silica gel column chromatog-
raphy eluting with CH2Cl2. Red crystals. M.p.: Exp. 1. 302ꢀ306 °C; Exp.
2. 302ꢀ304 °C. IR (cmꢀ1): 3204; 2222; 1676; 1638; 1598; 1571; 1530;
1502; 1415; 1356; 1298; 992; 835; 776; 724. HRMS (m/z): Obs.
275.0819; Calcd 275.0821 (C17H11N2O2þ).
General Experimental Procedure. 1,4-Naphthoquinone hy-
drate (3) (1 mmol) and hydrated Cu(OAc)2 (0.1 mmol) were solubi-
lized by gently warming in AcOH (2 mL). Amine (2) (1 mmol) was
added and the reaction was gently warmed (60ꢀ70 °C). After the
indicated reaction time, all the volatiles were removed under reduced
pressure irrespective of complete or incomplete consumption of the
reagents. The resulting crude product was taken up in a minimal volume
of CH2Cl2 and applied to a column of silica gel. The column was eluted
with CH2Cl2 and the product, generally a dark burgundy colored or a
dark red colored band, was readily separated from any impurities. Where
other solvents or mixtures were used, these are indicated with the
description of each product. The solvent was removed under reduced
pressure to give 2-amino-1,4-naphthoquinone derivatives (1aꢀz).
Physical and Spectroscopic Characterization Data for
Compounds 1aꢀz. 1a 2-(Phenyl)amino-1,4-naphthoquinone.
M.p.: 191ꢀ2 °C; (lit.): 189ꢀ190 °C.31 IR (cmꢀ1): 3318, 1668, 1639,
1609, 1596, 1572, 1528, 1354, 1304, 776, 752, 724, 709. HRMS
The product has very poor solubility in solvents commonly used for
NMR analysis.
1h 2-(3-Cyanophenyl)amino-1,4-naphthoquinone. Purified by sili-
ca gel column chromatography eluting with EtOAc. Red crystals. M.p.:
290ꢀ291 °C; (lit.): 296ꢀ298 °C.22b IR (cmꢀ1): 3183; 2227; 1677;
1622; 1574; 1524; 1357; 1301; 1125; 776; 723; 679. HRMS (m/z): Obs.
275.0811; Calcd 275.0821 (C17H11N2O2þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1i 2-(2-Cyanophenyl)amino-1,4-naphthoquinone. Purified by silica
gel column chromatography eluting with CH2Cl2. Orange crystals. M.p.:
225ꢀ227 °C. IR (cmꢀ1): 3326; 2222; 1674; 1645; 1620; 1576; 1530;
1453; 1346; 1295; 1271; 991; 757; 718. HRMS (m/z): Obs. 275.0817;
Calcd 275.0821 (C17H11N2O2þ). 1H NMR (DMSO-d6): 5.70 (1H, s);
7.50 (1H, t, 8.0); 7.60 (1H, d, 8.0); 7.82 (3H, m); 7.96 (2H, m); 8.08
(1H, dd, 2.0, 8.0); 9.43 (1H, s). 13C NMR: 103.6; 109.4; 116.5; 125.4;
126.2; 127.0; 127.1; 130.2; 132.3; 132.9; 133.9; 134.5; 135.0; 140.6;
146.7; 181.0; 182.6.
1j 4-(2-Amino-1,4-naphthoquinone) benzoic acid. The crude pro-
ducts from the three experiments were suspended in EtOH and filtered.
The residues, red crystals, were washed with EtOH. M.p.: Exp. 1.
319ꢀ321 °C; Exp. 2. 317ꢀ320 °C; (lit.): 319 °C.44 IR (cmꢀ1): 3469;
3369; 3187; 3077; 1682; 1639; 1599; 1573; 1526; 1421; 1307; 1292;
1
(m/z): Obs. 250.0863; Calcd 250.0868 (C16H12NO2þ). H NMR
(pyridine-d5 þ DMSO-d6): 6.40 (1H, s); 7.30 (1H, m); 7.52 (4H, m);
7.76 (1H, m); 7.86 (1H, m); 8.17 (2H, m); 9.59 (1H, s). 13C NMR:
102.6; 124.1; 125.7; 125.8; 126.5; 129.7; 131.0; 132.8; 133.3; 135.0;
138.7; 146.7; 182.1; 183.3.
1b 2-(4-Methylphenyl)amino-1,4-naphthoquinone. M.p.: 199ꢀ
200 °C; (lit.): 200ꢀ201 °C.32 IR (cmꢀ1): 3325; 1668; 1636; 1603;
1571; 1526; 1349; 1304; 1290; 774; 724. HRMS (m/z): Obs. 264.1019;
1
Calcd 264.1025 (C17H14NO2þ). H NMR (pyridine-d5/DMSO-d6):
2.26 (3H, s); 6.52 (1H, s); 7.20 (2H, d, 8.0); 7.37 (2H, d, 8.0); 7.65 (2H,
m); 8.17 (2H, d, 8.0); 8.31 (2H, d, 8.0); 9.80 (1H, s). 13C NMR: 20.4;
101.7; 123.7; 125.3; 126.0; 129.7; 130.5; 132.3; 132.7; 134.6; 134.7;
135.5; 146.4; 181.7; 182.5.
1274; 1249; 1183; 992; 845; 776; 721. HRMS (m/z): Obs. 294.0763;
þ
1c 2-(3-Trifluoromethylphenyl)amino-1,4-naphthoquinone. M.p.:
173ꢀ4 °C; (lit.): 174 °C.24c IR (cmꢀ1): 3235; 1677; 1623; 1574; 1528;
1334; 1245; 1121; 1074; 994; 779; 722; 698. HRMS (m/z): Obs.
Calcd 294.07663 (C17H12NO4
)
The product has very poor solubility in solvents commonly used for
NMR analysis.
1
318.0737; Calcd 318.0742 (C17H11F3NO2þ). H NMR (DMSO-d6):
1k 3-(2-Amino-1,4-naphthoquinone) benzoic acid. The crude
product was suspended in EtOH and filtered. The residue, orange crystals,
was washed with EtOH. M.p.: 264ꢀ265 °C; (lit.): 254 °C.44 IR (cmꢀ1):
3551; 3479; 3414; 3295; 3222; 3069; 1699; 1679; 1605; 1574; 1533;
1418; 1355; 1299; 775; 754; 720; 679. HRMS (m/z): Obs. 294.0756;
Calcd 294.0766 (C17H12NO4þ).
6.15 (1H, s); 7.52 (1H, d, 8.0); 7.82 (6H, m); 8.04 (1H, dd, 2.0, 8.0);
9.39 (1H, s). 13C NMR: 103.1; 119.9; 121.2; 125.3; 126.1; 126.9; 130.4;
130.5; 132.4; 132.8; 134.2; 134.9; 138.7; 139.2; 145.7; 181.3; 182.8.
1d 2-(2-Methoxyphenyl)amino-1,4-naphthoquinone. M.p.: 147ꢀ8 °C;
(lit.): 146 °C.34 IR (cmꢀ1): 3307; 1672; 1617; 1575; 1533; 1487; 1463;
1292; 1248; 1190; 1110; 1028; 988; 752; 727; 542. HRMS (m/z):
The product has very poor solubility in solvents commonly used for
NMR analysis.
Obs. 280.0964; Calcd 280.0974 (C17H14NO3þ). H NMR (pyridine-
1
d5þDMSO-d6): 3.76 (3H, s); 6.02 (1H, s); 7.00 (1H, t, 8.0); 7.06 (1H, d,
8.0); 7.20 (1H, t, 8.0); 7.39 (1H, d, 8.0); 7.67 (1H, t, 8.0); 7.77 (1H, t, 8.0);
8.03 (2H, d, 8.0); 8.77 (1H, s). 13C NMR: 55.6; 102.8; 112.0; 120.8; 123.6;
1l 2-(2-Amino-1,4-naphthoquinone) benzoic acid. The crude pro-
duct was suspended in EtOH and filtered. The residue, red crystals, was
washed with EtOH. M.p.: 237ꢀ40 °C decomp. with gas evolution; (lit.):
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ARTICLE
265 °C.44 IR (cmꢀ1): 3456; 3276; 1686; 1608; 1567; 1534; 1358; 1296;
1210; 1152; 1083; 777; 752; 721. HRMS (m/z): Obs. 294.0757; Calcd
294.0766 (C17H12NO4þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
by a CH2Cl2/EtOAc gradient up to 20% EtOAc. Burgundy crystals. M.p.:
160ꢀ163 °C. IR (cmꢀ1): 3201; 1680; 1622; 1606; 1570; 1520; 1493;
1406; 1358; 1300; 1288; 1238; 1124; 1095; 824; 825; 775; 723. HRMS
1
(m/z): Obs. 314.0573; Calcd 314.0584 (C17H13ClNO3þ). H NMR
(DMSO-d6): 3.84 (3H, s); 5.72 (1H, s); 7.17 (1H, d, 8.0); 7.32 (1H, dd,
8.0, 2.0); 7.37 (1H, d, 2.0); 7.78 (1H, t, 8.0); 7.84 (1H, d, 8.0); 7.93(1H,
t, 8.0); 8.04 (1H, d, 8.0); 8.69 (1H, s). 13C NMR: 56.1; 103.6; 113.7;
123.9; 124.2; 125.4; 126.1; 126.4; 127.5; 130.2; 132.5; 132.8; 135.0;
145.2; 151.4; 181.3; 182.5.
1u 2-(2-Methoxy-4-nitrophenyl)amino-1,4-naphthoquinone. Puri-
fied by silica gel column chromatography eluting with CH2Cl2. Orange
crystals. M.p.: 236ꢀ238 °C. IR (cmꢀ1): 3276; 1673; 1638; 1626; 1589;
1578; 1546; 1518; 1489; 1339; 1291; 1272; 1247; 1095; 1024; 741.
HRMS (m/z): Obs. 325.0824; Calcd 325.0825 (C17H13N2O5þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1v 2-(2-Methyl-4-methoxyphenyl)amino-1,4-naphthoquinone. Puri-
fied by silica gel column chromatography eluting with CH2Cl2. Bright red
crystals. M.p.: 121ꢀ124 °C. IR (cmꢀ1): 3361; 2943; 1672; 1638; 1575;
1530; 1493; 1349; 1331; 1304; 1256; 1116; 1022; 829; 810; 775; 719; 666;
592. HRMS (m/z): Obs. 294.1120; Calcd 294.1130 (C18H16NO3þ). 1H
NMR (pyridine-d5 þ DMSO-d6): 2.20 (3H, s); 3.74 (3H, s); 6.08 (1H, s);
6.98 (2H, m); 7.20 (1H, s); 7.68 (1H, t, 7.0); 7.78 (1H, t, 7.0); 8.06 (2H, d,
7.0); 8.79 (1H, s, NH). 13C NMR: 20.0; 55.5; 102.7; 111.7; 124.0; 125.3;
125.97; 126.03; 126.8; 129.8; 130.3; 132.3; 132.8; 134.6; 145.2; 150.0;
181.6; 182.5.
1w 2-(2,6-Dimethylphenyl)amino-1,4-naphthoquinone. Purified
by silica gel column chromatography eluting with CH2Cl2. Orange
crystals. M.p.: 186ꢀ190 °C. IR (cmꢀ1): 3288; 1678; 1625; 1605; 1590;
1572; 1492; 1352; 1300; 1247; 1121; 987; 842; 777; 727; 523. HRMS
(m/z): Obs. 278.1176; Calcd 278.1181 (C18H16NO2þ). 1H NMR
(DMSO-d6): 2.14 (6H, s); 4.93 (1H, s); 7.20 (3H, s); 7.80 (3H, m);
8.06 (1H, d, 8.0); 9.06 (1H, s, NH). 13C NMR: 17.5; 100.6; 125.3;
126.0; 127.6; 128.4; 130.6; 132.4; 133.0; 134.6; 134.8; 135.5; 147.7;
181.3; 181.9.
1m 2-(4-Aminophenyl)amino-1,4-naphthoquinone. Purified by
silica gel column chromatography eluting with EtOAc. Burgundy crystals.
M.p.: 205ꢀ210 °C; (lit.): 214 °C.45 IR (cmꢀ1): 3415; 3315; 1671; 1630;
1600; 1570; 1513; 1354; 1297; 1268; 1248; 992; 817; 773; 725; 496.
HRMS (m/z): Obs. 265.0967; Calcd 265.0977 (C16H13N2O2þ). H
1
NMR (pyridine-d5 þ DMSO-d6): 6.22 (1H, s); 6.97 (2H, d, 8.0); 7.27
(2H, d, 8.0); 7.90 (4H, m); 9.41 (1H, s); 4-NH2 group not observed due
to the presence of water in the deuterated solvents. 13C NMR: 100.7;
114.4; 125.3; 125.4; 125.9; 126.3; 130.6; 131.9; 133.2; 134.5; 147.2;
147.2; 182.0; 182.1.
1n 2-(3-Nitrophenyl)amino-1,4-naphthoquinone. Recrystallized
from EtOAc after hot filtration. Orange crystals. M.p.: 258ꢀ262 °C;
(lit.): 252ꢀ255 °C;19c 258ꢀ260 °C.22b IR (cmꢀ1): 3293; 3219; 1676;
1626; 1606; 1576; 1527; 1354; 1300; 1273; 719. HRMS (m/z): Obs.
295.0718; Calcd 295.0719 (C16H11N2O4þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1o 2-(4-Fluorophenyl)amino-1,4-naphthoquinone. Purified by sili-
ca gel column chromatography eluting with CH2Cl2. Bright red crystals.
M.p.: 246ꢀ248 °C; (lit.): 227 °C;24c 248ꢀ9 °C.46 IR (cmꢀ1): 3319;
1667; 1640; 1611; 1574; 1508; 1352; 1301; 1231; 827; 776; 725. HRMS
(m/z): Obs. 268.0770; Calcd 268.0774 (C16H11FNO2þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1p 2-(4-Chlorophenyl)amino-1,4-naphthoquinone. A mixture of
30% EtOAc in hexane was added to the reaction mixture and the sus-
pension was filtered then washed with the same solvent mixture. Bright red
crystals. M.p.: 250ꢀ253 °C; (lit.): 248ꢀ249 °C;31 264 °C.24a IR (cmꢀ1):
3201; 1679; 1621; 1607; 1571; 1519; 1492; 1357; 1300; 1288; 825; 775;
723. HRMS (m/z): Obs. 284.0476; Calcd 284.0478 (C16H11ClNO2þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1q 2-(4-Bromophenyl)amino-1,4-naphthoquinone. The product
was purified by silica gel column chromatography eluting with CH2Cl2
followed by a CH2Cl2/EtOAc gradient with up to 20% EtOAc. Bright
red crystals. M.p.: 258ꢀ262 °C (recryst. EtOAc). IR (cmꢀ1): 3209;
1679; 1634; 1605; 1568; 1514; 1488; 1402; 1358; 1299; 1287; 823; 777;
723. HRMS (m/z): Obs. 327.9972; Calcd 327.9973 (C16H11BrNO2þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1x 2-(2,5-Dimethoxyphenyl)amino-1,4-naphthoquinone. Purified
by silica gel column chromatography eluting with CH2Cl2. Burgundy
crystals. M.p.: 99ꢀ101 °C. IR (cmꢀ1): 3350; 2945; 1674; 1638; 1601;
1575; 1534; 1493; 1348; 1331; 1306; 1250; 1217; 1116; 1047; 1022;
777; 721. HRMS (m/z): Obs. 310.1069; Calcd 310.1079 (C18H16NO4þ).
1H NMR (pyridine-d5 þ DMSO-d6): 3.70 (3H, s); 3.73 (3H, s); 6.07
(1H, s); 6.81 (1H, dd, 2.0, 8.0); 7.02 (1H, d, 8.0); 7.03 (1H, d, 2.0); 7.68
(1H, t, 8.0); 7.78 (1H, t, 8.0); 8.05 (2H, d, 8.0); 8.80 (1H, s). 13C NMR:
55.4; 55.9; 103.2; 110.0; 110.7; 112.8; 125.4; 126.0; 127.1; 130.4; 132.4;
132.8; 134.7; 145.1; 146.4; 153.4; 181.5; 182.6.
1r 2-(2-Iodophenyl)amino-1,4-naphthoquinone. Purified by silica
gel column chromatography eluting with CH2Cl2. Orange crystals. M.p.:
156ꢀ158 °C. IR (cmꢀ1): 3301; 1680; 1614; 1603; 1564; 1487; 1478;
1469; 1349; 1331; 1307; 1253; 1119; 1018; 989; 842; 780; 727; 721;
553. HRMS (m/z): Obs. 375.9823; Calcd 375.9835 (C16H11INO2þ).
1H NMR (pyridine-d5 þ DMSO-d6): 5.69 (1H, s); 7.05 (1H, m); 7.44
(1H, m); 7.73 (3H, m); 8.03 (3H, m); 9.32 (1H, s). 13C NMR: 97.7;
102.9; 125.5; 126.0; 127.1; 128.5; 129.5; 130.4; 132.4; 132.8; 134.7;
139.7; 139.7; 146.7; 181.3; 182.6.
1s 2-(3-Chloro-4-methoxyphenyl)amino-1,4-naphthoquinone.
Purified by silica gel column chromatography eluting with CH2Cl2
followed by a CH2Cl2/EtOAc gradient up to 20% EtOAc. Burgundy
crystals. M.p.: 235ꢀ237 °C. IR (cmꢀ1): 3212; 1678; 1630; 1618;
1596; 1577; 1500; 1359; 1259; 1120; 1063; 1026; 996; 779; 722. HRMS
(m/z): Obs. 314.0582; Calcd 314.0584 (C17H13ClNO3þ).
The product has very poor solubility in solvents commonly used for
NMR analysis.
1y N-Methyl-2-(phenyl)amino-1,4-naphthoquinone. Purified by
silica gel column chromatography eluting with CH2Cl2. Bright red
crystals. M.p.: 189ꢀ191 °C; (lit.): 186ꢀ188 °C.47 IR (cmꢀ1): 3064;
2924; 1674; 1626; 1589; 1560; 1492; 1371; 1346; 1288; 1263; 1135;
949; 782; 769; 727; 698. HRMS (m/z): Obs. 264.1014; Calcd 264.1025
(C17H14NO2þ). H NMR (CDCl3): 3.31 (3H, s); 6.03 (1H, s); 7.02
1
(1H, d, 8); 7.03 (1H, d, 8); 7.17 (1H, t, 8); 7.30 (2H, m); 7.50 (1H, td, 2,
8); 7.60 (1H, td, 2, 8); 7.79 (1H, dd, 2, 8); 7.97 (1H, dd, 2, 8). 1H NMR
(DMSO-d6): δ 7.94 (1H, m), 7.77 (3H, m), 7.36 (2H, m), 7.21 (3H, m),
6.15 (1H, s), 3.34 (N-Meþwater from solvent). 13C NMR (DMSO-d6):
42.9; 111.7; 124.9; 125.0; 125.5; 126.2; 129.2; 132.0; 132.1; 132.8;
134.1; 148.0; 151.9; 181.6; 182.4.
1z 2-N-Benzylamino-1,4-naphthoquinone. Purified by silica gel
column chromatography eluting with CH2Cl2. Red crystals. M.p.:
155 °C; (lit.): 158ꢀ9 °C;32 160ꢀ1 °C.48 IR (cmꢀ1): 3333; 1681;
1606; 1595; 1562; 1504; 1362; 1338; 1259; 1124; 729. 1H NMR
(DMSO-d6): 4.44 (2H, d, 6.0); 5.53 (1H, s); 7.32 (5H, s); 7.85 (4H,
m); 8.13 (1H, bs). 13C NMR: 45.4; 100.6; 125.5; 126.1; 127.3; 127.4;
128.7; 130.5; 132.5; 133.2; 135.1; 137.5; 148.7; 181.7; 181.8.
1t 2-(2-Methoxy-5-chlorophenyl)amino-1,4-naphthoquinone. Pur-
ified by silica gel column chromatography eluting with CH2Cl2 followed
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The Journal of Organic Chemistry
ARTICLE
N-Methylation of 2-(R-Phenyl)amino-1,4-naphthoquinone Deriva-
tives (1). Because of the poor solubility of a number of the derivatives 1,
some of these compounds were N-methylated with the intention of
improving their solubility so as to be able to characterize the N-methylated
derivative by 1H and 13C NMR.
General Experimental Protocol. To a round bottomed flask
were added: K2CO3 (3 mmol), the 2-phenylamino-1,4-naphthoquinone
derivative 1 (1 mmol), methyl iodide (1ꢀ2 mL), and DMF (1ꢀ2 mL).
The reaction flask was closed with a septum but allowed to pressure
equalize with the atmosphere via an open syringe needle. The reaction
mixture was stirred at room temperature and periodically monitored by
TLC. After the indicated reaction time (not optimized), all volatiles were
removed under reduced pressure to give a crude product that was taken
up in CH2Cl2 and applied to a column of silica gel. Eluting the column
with CH2Cl2 readily separated the N-methylated products 7.
Physical and Spectroscopic Characterization of 7. 7g
N-Methyl-2-(4-cyanophenyl)amino-1,4-naphthoquinone. Reaction
time 114 h, Red crystals, 80% yield. M.p.: 173ꢀ6 °C; IR (cmꢀ1):
3091; 3055; 2225; 1674; 1630; 1591; 1381; 1327; 1296; 1267; 1138;
789; 723; 577. 1H NMR (CDCl3): 8.07 (1H, dd, 8, 2), 7.89 (1H, dd, 8,
2), 7.73 (2H, m), 7.63 (2H, d, 8), 7.14 (2H, d, 8), 6.36 (1H, s), 3.39 (3H, s).
13C NMR (CDCl3): 183.9; 181.5; 151.9; 151.3; 134.4; 133.5; 133.2;
132.4; 132.2; 127.0; 126.0; 124.7; 118.6; 116.5; 108.6; 42.4.
182.8. 1H NMR (CDCl3): 8.06 (1H, d, 6), 7.87 (1H, d, 8), 7.70 (1H, t, 6),
7.60 (1H, t, 8), 7.48 (2H, d, 8), 6.98 (2H, d, 8), 6.16 (1H, s), 3.35 (3H, s).
13C NMR (CDCl3): 183.8; 182.0; 151.7; 147.2; 134.2; 132.8; 132.8; 132.6;
132.4; 126.9; 125.8; 119.7; 112.9; 43.1.
7s N-Methyl-2-(3-chloro-4-methoxyphenyl)amino-1,4-naphtho-
quinone. Reaction time 79 h, Burgundy crystals, 73% yield. M.p.:
143ꢀ144 °C; IR (cmꢀ1): 3053; 2964; 1674; 1626; 1595; 1560; 1504;
1294; 1253; 1139; 1062; 1022; 962; 783; 725; 613. HRMS (m/z): Obs.
328.0730; Calcd 328.0741 (C18H15ClNO3þ). H NMR (DMSO-d6):
1
3.29 (3H, s); 3.87 (3H, s); 6.11 (1H, s); 7.09 (1H, d, 8); 7.17 (1H, dd, 8,
2); 7.39 (1H, d, 2.0); 7.76 (3H, m); 7.93 (1H, m). 13C NMR: 43.1; 56.2;
111.1; 112.9; 121.1; 124.9; 125.1; 126.2; 126.7; 132.0; 132.7; 134.1;
141.3; 151.5; 152.5; 181.5; 182.4.
7u N-Methyl-2-(2-methoxy-4-nitrophenyl)amino-1,4-naphthoqui-
none. Reaction time 20 h, Bright red crystals, 68% yield. M.p.: 128ꢀ
130 °C; IR (cmꢀ1): 3078; 1678; 1628; 1594; 1557; 1517; 1500; 1340;
1
1293; 1267; 1256; 1126; 1088; 1028; 870; 806; 775; 723. H NMR
(DMSO-d6): 3.30 (3H, s); 3.71 (3H, s); 6.20 (1H, s); 7.51 (1H, d, 8.0);
7.83 (6H, m). 13C NMR (DMSO-d6): 41.7; 56.6; 107.3; 109.8; 117.1;
125.3; 126.3; 126.3; 131.7; 132.1; 133.2; 134.5; 143.2; 145.3; 151.9;
153.0; 180.8; 183.0. 1H NMR (CDCl3): 8.08 (1H, d, 8), 7.90 (1H, dd, 8,
2), 7.84 (1H, d, 8), 7.77 (1H, d, 2), 7.71 (1H, t, 8), 7.61 (1H, t, 8), 7.24
(1H, d, 8), 6.16 (1H, s), 3.80 (3H, s). 13C NMR (CDCl3): 184.0; 181.3;
153.9; 151.7; 146.3; 143.2; 134.2; 132.8; 132.7; 132.0; 126.6; 126.2;
125.9; 117.3; 110.8; 107.4; 56.4; 41.9.
7k Methyl N-Methyl-(2-N-1,4-naphthoquinone)-3-amino-benzo-
ate. Reaction time 20 h, Bright red crystals, 87% yield. M.p.: 148ꢀ
150 °C; IR (cmꢀ1): 3068; 2951; 1716; 1676; 1634; 1588; 1557; 1441;
1297; 1259; 1215; 1148; 1089; 984; 785; 756; 697. 1H NMR (DMSO-
d6): 3.33 (3H, s); 3.81 (3H, s); 6.21 (1H, s); 7.48 (2H, m); 7.74 (5H,
m); 7.93 (1H, d, 6.0). 13C NMR (DMSO-d6): 43.0; 52.5; 112.6; 125.3;
125.5; 126.4; 126.5; 130.0; 130.1; 131.0; 132.1; 133.2; 134.5; 148.5;
’ ASSOCIATED CONTENT
S
Supporting Information. Complete nongeneralized ex-
b
perimental parameters and copies of the spectra from which the
reported spectroscopic data were obtained. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
151.6; 166.1; 181.6; 183.0. H NMR (CDCl3): 8.07 (1H, d, 8), 7.93
(1H, d, 8), 7.85 (1H, d, 8), 7.77 (1H, s), 7.70 (1H, t, 8), 7.60 (1H, t, 8),
7.45 (1H, t, 8), 7.30 (1H, d, 8), 6.18 (1H, s), 3.90 (3H, s), 3.39 (3H, s).
13C NMR (CDCl3): 183.8; 181.9; 166.4; 151.7; 148.3; 134.1; 132.7;
132.6; 132.4; 131.9; 129.8; 129.7; 127.4; 126.9; 126.3; 125.8; 112.9;
52.4; 43.2.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: garden@iq.ufrj.br. Tel: 55-21-2562-7135. Fax: 55-21-
2562-7256.
7o N-Methyl-2-(4-fluorophenyl)amino-1,4-naphthoquinone. Reac-
tion time 82 h, Brown red crystals, 90% yield. M.p.: 310ꢀ311 °C; IR
(cmꢀ1): 3051; 1674; 1629; 1591; 1556; 1506; 1290; 1265; 1213; 1133;
835; 779; 731; 717; 563; 534. HRMS (m/z): Obs. 282.0920; Calcd
282.0930 (C17H13FNO2þ). 1H NMR (DMSO-d6): 3.29 (3H, s); 6.11
(1H, s); 7.21 (4H, m); 7.76 (3H, m); 7.93 (1H, d, 6.0). 13C NMR
(DMSO-d6): 43.4; 111.4; 116.2 (d, 2JCF 22.5); 125.2; 126.5; 127.3 (d,
3JCF 8.5); 132.2; 132.3; 133.2; 134.5; 144.5 (4JCF 1.5); 152.0; 181.8;
182.9; δ CꢀF not observed. 1H NMR (CDCl3): 8.05 (1H, d, 8), 7.87
(1H, d, 8), 7.69 (1H, t, 8), 7.59 (1H, t, 8), 7.07 (4H, m), 6.09 (1H, s),
’ ACKNOWLEDGMENT
We thank CNPq, CAPES, and FAPERJ for financial support.
’ REFERENCES
1
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7p N-Methyl-2-(4-chlorophenyl)amino-1,4-naphthoquinone43. Re-
action time 24 h, Brown red crystals, 58% yield. M.p.: 142ꢀ144 °C. IR
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7q N-Methyl-2-(4-bromophenyl)amino-1,4-naphthoquinone43.
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NMR (DMSO-d6): 3.29 (3H, s); 6.21 (1H, s); 7.15 (2H, d, 8.0); 7.50 (2H,
d, 10.0); 7.76 (3H, m); 7.93 (1H, d; 6.0). 13C NMR: 42.8; 112.7; 117.9;
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5271
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