Synthesis of novel 2-(fluoroanilino)-3-(2,4-dinitroanilino) derivatives of 1,4-naphthoquinone

Article abstract of DOI:10.1016/j.tetlet.2015.07.046

Several novel 2-(fluoroanilino)-3-(2,4-dinitroanilino) derivatives of 1,4-naphthoquinone have been synthesized in good to excellent yields. First, 2-chloro-3-(2,4-dinitroanilino)-1,4-naphthoquinone was prepared in two steps beginning with the reaction of

Full text of DOI:10.1016/j.tetlet.2015.07.046

Accepted Manuscript
Synthesis of novel 2-(fluoroanilino)-3-(2,4-dinitroanilino) derivatives of 1,4-
naphthoquinone
Elisa Leyva, Kim M. Baines, Claudia G. Espinosa-González, Lluvia I. López,
Diego A. Magaldi-Lara, Socorro Leyva
PII:
S0040-4039(15)01199-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.046
TETL 46535
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
30 June 2015
15 July 2015
Please cite this article as: Leyva, E., Baines, K.M., Espinosa-González, C.G., López, L.I., Magaldi-Lara, D.A.,
Leyva, S., Synthesis of novel 2-(fluoroanilino)-3-(2,4-dinitroanilino) derivatives of 1,4-naphthoquinone,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.046
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Synthesis of novel 2-(fluoroanilino)-3-(2,4-dinitroanilino) derivatives
of 1,4-naphthoquinone
Elisa Leyva,1* Kim M. Baines,2 Claudia G. Espinosa-González1, Lluvia I. López,3
Diego A. Magaldi-Lara,1 Socorro Leyva1
1Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí,
Manuel Nava No.6, 78210, San Luis Potosí, S.L.P., México.
2Department of Chemistry, University of Western Ontario,
London, N6A 5B7, Ontario, Canada.
3Facultad de Ciencias Quimicas, Universidad Autónoma de Coahuila. Blvd. V. Carranza
E Ing. José Cardenas s/n Col República, CP 25250, Saltillo, Coahuila, México
Abstract
Several novel 2-(fluoroanilino)-3-(2,4-dinitroanilino)
derivatives of 1,4-
naphthoquinone have been synthesized in good to excellent yields. First, 2-chloro-3-(2,4-
dinitroanilino)-1,4-naphthoquinone was prepared in two steps beginning with the reaction of
2,3-dichloro-1,4-naphthoquinone with aniline in the presence of a Lewis acid (CeCl3.7H2O).
The resulting 2-(anilino)-1,4-naphthoquinone was then nitrated. The strong electron
withdrawing effect of the 2,4-dinitroanilino substituent on the naphthoquinone framework
facilitated the displacement of the second chlorine atom by a variety of weakly nucleophilic
fluoro-substituted anilines under reflux conditions.
Keywords: 2-(2,4-dinitroanilino)-1,4-naphthoquinone, Lewis acid catalyst, CeCl3.7H2O.
* Corresponding author. Tel.: 52 444 8262440 Ex 508; Fax: 52 444 8262371
E-mail address: elisa@uaslp.mx (E. Leyva).

Synthetic and natural 2-amino-1,4-naphthoquinone derivatives have been the subject of
intensive research. Many of them find use in a variety of medicinal and biological
applications,1,2 for example as antituberculars,3 antimalarials,4 antibacterials,5,6 antitumor
agents,7-11 larvicides, herbicides and fungicides.12-14
The synthesis of 2-amino-1,4-naphthoquinones (Method a, Scheme 1) is typically
performed via a Michael addition of an amine with 1,4-naphthoquinone15-20 or by nucleophilic
displacement of a halogenated 1,4-naphthoquinone (Method b, Scheme 1).21-28 However, both
methods are unpractical as they give low yields and many side products, especially with
primary amines. The mixture of compounds obtained in these reactions are a consequence of
the physicochemical properties of 1,4-naphthoquinone: the presence of several electrophilic
centers of comparable reactivity leads to the formation of 1,4- and 1,2-addition adducts and
the redox properties of the naphthoquinone favor the formation of an inert 1,4-naphthodiol.
Scheme 1
Anilines substituted with electron donating groups are quite reactive and afford high
yields of the corresponding anilinoquinones. However, using either method with anilines
substituted with electron withdrawing groups gives quite low yields (Scheme 1). As a
consequence, these methodologies cannot be used for the preparation of nitroanilino
derivatives.29 The preparation of 2-chloro-3-(2,4-dinitroanilino)-1,4-naphthoquinone was first
reported by Bittner and co-workers.30 In a subsequent study, they reported the preparation of
novel 2-amino-3-(2,4-dinitrophenylamino) derivatives of 1,4-naphthoquinone using 2-chloro-
3-(2,4-dinitroanilino)-1,4-naphthoquinone as a starting material.31 The electron-withdrawing
effects of the dinitroanilino ring facilitated the displacement reactions at the chlorine. The
reaction with primary, secondary, cyclic and electron-rich aromatic amines gave the di-
aminated naphthoquinones in good yields; however, it was noted that the reaction does not
proceed with amines of lower nucleophilicity such as p-toluidine and p-aminostilbene.
In the present communication, the preparation of novel 2-(fluoroanilino)-3-(2,4-
dinitroanilino) derivatives of 1,4-naphthoquinone (Scheme 2) by reaction of 2-chloro-3-(2,4-
dinitroanilino)-1,4-naphthoquinone with several weakly nucleophilic fluoroanilines by
modification of the Bittner methodology is presented.

Scheme 2
First, 2-anilino-3-chloro-1,4-naphthoquinone 3 (Scheme 3) was prepared in
quantitative yield by reacting aniline with 2,3-dichloro-1,4-naphthoquinone 2 in ethanol. This
reaction was performed in the presence of CeCl3.7H2O, a Lewis acid with strong oxidizing
properties. The proposed mechanism for this reaction is shown in Scheme 4. In an oxidative
atmosphere, the strong oxidant Ce4+ predominates in solution.32 It is envisioned that quinone 2
is activated by reaction with the Lewis acid to form an organic complex 2a with the carbonyl
group in the quinone ring becoming more electrophilic, and thus, facilitating a selective
nucleophilic attack by the aniline.33 The Lewis acidic and strong oxidizing properties of
cerium favor the exclusive formation of 2-anilino-1,4-naphthoquinone and avoid the formation
of the inert 1,4-naphthodiols and other secondary products associated with these reactions.33
The catalytic effect of Lewis acids in the reaction of anilines with 1,4-naphthoquinone has
been previously documented by us.34 We reported a bentonitic clay-assisted preparation of 2-
chloroanilino-1,4-naphthoquinones. The presence of a Lewis acid and oxidant species Fe+3 in
the clay was clearly important.34 In a subsequent study, we reported the preparation of novel
substituted 2-fluoroanilino-1,4-naphthoquinones in the presence of the Lewis acid
CeCl3.7H2O.33
Scheme 3
Scheme 4
Nucleophilic aryl amines react rather easily with 2,3-dichloro-1,4-naphthoquinone 2,
replacing one chlorine atom to give 2-anilino-3-chloro-1,4-naphthoquinone 3. However, the
electronically enriched quinone 3 is rendered less reactive to nucleophiles and further
substitution of second chlorine is inhibited. To prepare a 2,3-diamino-1,4-naphthoquinones, it
is necessary to make the molecule electron deficient by nitration of the aniline derivative 3 to
give 2-chloro-3-(2,4-dinitroanilino)-1,4-naphthoquinone 4. Indeed, it has been reported that a
strong electron withdrawing effect of a dinitroaniline group makes the quinone 4 sufficiently
electron deficient and the second chlorine is easily substituted by electron-rich aromatic
amines.31 To facilitate the same reaction with electron deficient anilines such as fluoroanilines
(6a-6d), a large excess of the corresponding aniline and vigorous refluxing of the reaction

mixture was required (Table 1). In addition, the time of reaction was a strongly dependent on
the type of aniline. The strongly nucleophilic aniline, 2-methoxyaniline 6e, reacted in ten
hours whereas the weakly nucleophilic fluoroanilines (6a-6d) required longer reaction times.
Table 1
In summary, we have presented a facile preparation of novel 2-(fluoroanilino)-3-(2,4-
dinitroanilino)-1,4-naphthoquinones. These novel compounds were prepared from 2-chloro-3-
(2,4-dinitroanilino)-1,4-naphthoquinone. The strong electron withdrawing nature of 2,4-
dinitroaniline allowed the displacement of chlorine by weakly nucleophilic fluoroanilines
providing the reaction mixture was vigorously refluxed for extended periods of time in the
presence of excess fluoroaniline.
1
Spectral data: H and 13C signals were assigned using two dimensional NMR techniques
(COSY, gHSQC and gHMBC). The numbers in brackets refer to the numbering scheme
shown in Scheme 2.
Spectral data for 6a: 2-(2-fluorophenylamine)-3-(2,4-dinitrophenylamine)-1,4-
naphthoquinone, bright red powder, mp 204-206 °C; UV-Vis (CHCl3): λmax 477 nm (3.93 log
ξ), 325 nm (3.94 log ξ), 277 nm (4.80 log ξ); IR (ATR) 3231, 3039, 1673, 1589, 1558, 1489,
1443, 1286, 1240, 1139, 1016, 921, 756, 716 cm-1; 1H NMR (400 MHz, DMSO- d6): δ 6.70-
6.85 (m, 2H, 3´´ and 5´´), 6.92 (d, 1H, 6´, Jo = 9.4 Hz), 6.90-7.00 (m, 2H, 4´´, 6´´), 7.86 (td,
1H, 6, Jo=7.4 Hz, Jm=1.6 Hz), 7.91 (td, 1H, 7, Jo=7.4 Hz, Jm=1.6 Hz), 8.07 (dd, 1H, 8, Jo=7.4
Hz, Jm=1.6 Hz), 8.12-8.16 (m, 2H, 5, 5´), 8.55 (d, 1H, 3´, Jm=2.7 Hz), 9.19 (s, 1H, b), 9.33 (s,
1H, a); 13C{1H} NMR (100 MHz, DMSO-d6): δ 114.28 (2), 114.46 (d, 3´´, 2JC-F=19 Hz),
119.13 (6´), 122.32 (3´), 122.99 (d, 5´´, 4JC-F=3 Hz), 124.79 (d, 1´´, 2JC-F=11 Hz), 125.86 (8),
126.28 (5), 127.04 (d, 4´´, 3JC-F=7.7 Hz), 127.16 (6´´), 128.82 (5´), 130.63 (10), 130.72 (2´),
131.60 (9), 133.42 (6), 134.87 (7), 136.72 (4´), 137.21 (3), 143.18 (1´), 155.31 (d, 2´´, 1JC-
F=247 Hz), 179.30 (1), 180.95 (4); 19F{1H} NMR (376 MHz, DMSO-d6); δ -109.34; EI-MS
(m/z): 448 [M]+ (100%), 402 [M-NO2]+ (22%), 338 (17%), 310 (12%), 294 (22%), 254
(47%), 220 (7%), 158 (6%), 122 (28%), 104 (52%), 76 (15%); High-Resolution EI-MS for
C22H13FN4O6 m/z calcd: 448.0819, found: 448.0828; Elem. Anal. calcd for C22H13FN4O6: C,

44.90; H, 2.22; N, 33.33; O, 16.32; F, 3.23. Found: C, 44.88; H, 2.23; N, 33.33; O, 16.32; F,
3.24.
Spectral data for 6b: 2-(3-fluorophenylamine)-3-(2,4-dinitrophenylamine)-1,4-
naphthoquinone, dark red solid powder, mp 232-234 °C; UV-Vis (CHCl3): λmax 504 nm (3.69
log ξ), 361 nm (4.24 log ξ), 286 nm (4.50 log ξ); IR (ATR) 3312, 3093, 1662, 1586, 1574,
1499, 1428, 1323, 1269, 1134, 986, 918, 786, 721, 691 cm-1; 1H NMR (400 MHz, DMSO-d6)
δ 6.55 (d, 1H, 6´´, Jo=8.6 Hz), 6.57-6.65 (m, 2H, 2´´ and 4´´ ), 6.87 (d, 1H, 6´, Jo = 9.4 Hz),
6.85-6.93 (m, 1H, 5´´), 7.86 (td, 1H, 6, Jo=7.4 Hz, Jm=1.6 Hz), 7.91 (td, 1H, 7, Jo=7.4 Hz,
Jm=1.6 Hz), 8.07-8.14 (m, 3H, 8, 5, 5´), 8.53 (d, 1H, 3´, Jm=2.7 Hz), 9.53 (s, 1H, b), 9.54 (s,
1H, a); 13C{1H} NMR (100 MHz, DMSO-d6): δ 109.86 (d, 2´´, 2JC-F=25 Hz), 110.31(d, 4´´,
2JC-F=19 Hz), 116.17 (2), 119.30 (6´´), 120.29 (6´), 121.97 (3´), 125.83 (8), 126.21 (5), 128.24
(d, 5´´, 3JC-F=8.4 Hz), 128.50 (5´), 130.85 (10), 131.61 (9), 131.82 (2´), 133.48 (6), 134.33
(3), 134.65 (7), 137.10 (4´), 138.44 (d, 1´´, 3JC-F=10 Hz), 141.38 (1´), 161.55 (d, 3´´, 1JC-F=237
Hz), 179.58 (1), 181.26 (4); 19F{1H} NMR (376 MHz, DMSO-d6): δ -111.49; EI-MS (m/z):
448 [M]+ (100%), 402 [M-NO2]+ (30%), 355 (13%), 310 (12%), 294 (22%), 254 (47%), 220
(7%), 122 (28%), 104 (42%), 76 (15%); High-Resolution EI-MS for C22H13FN4O6 m/z calcd:
448.0819, found: 448.0828; Elem. Anal. calcd for C22H13FN4O6: C, 44.90; H, 2.22; N, 33.33;
O, 16.32; F, 3.23. Found: C, 44.88; H, 2.23; N, 33.34; O, 16.32; F, 3.24.
Spectral data for 6c: 2-(4-flourophenylamine)-3-(2,4-dinitrophenylamine)-1,4-
naphthoquinone, dark red solid powder, mp 230-232 °C; UV-Vis (CHCl3): λmax 504 nm (3.70
log ξ), 361 nm (4.27 log ξ), 284 nm (4.50 log ξ); IR (ATR) 3344, 3101, 1664, 1649, 1584,
1573, 1507, 1494, 1414, 1325, 1285, 1260, 1212, 1149, 1134, 973, 913, 837, 806, 791, 743,
3
726, 717 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 6 .71 (dd, 2H, 5´´, 3´´, JH-H=9 Hz, 3JH-F=9
3
Hz), 6.78 (dd, 2H, 6´´, 2 ´´, JH-H=9 Hz, 4JH-F=5 Hz), 6.84 (d, 1H, 6´, Jo=9.4 Hz), 7.84 (td, 1H,
6, Jo=7.4 Hz, Jm=1.2 Hz), 7.89 (td, 1H, 7, Jo=7.4 Hz, Jm=1.6 Hz), 8.05-8.14 (m, 3H, 8, 5´, 5),
8.53 (d, 1H, 3´, Jm=2.7 Hz), 9.42 (s, 1H, a), 9.44 (s, 1H, b); 13C{1H} NMR (100 MHz, DMSO-
d6): δ 113.52 (d, 3´´, 5´´, 2JC-F=22 Hz), 114.30 (2), 119.88 (6´), 120.08 (3´), 125.73 (d, 2´´ , 6´´,
3JC-F=9.2 Hz), 125.77 (8), 126.20 (5), 128.63 (5´), 130.77 (10), 131.37 (2´), 131.75 (9), 132.66
(d, 1´´, 4JC-F=2.3 Hz), 133.28 (6), 134.72 (7), 135.85 (3), 136.90 (4´), 142.01 (1´), 158.67 (d,
4´´, 1JC-F =241 Hz), 179.28 (1), 181.34 (4); 19F{1H} NMR (376 MHz, DMSO-d6): δ -114.79;
EI-MS (m/z): 448 [M]+ (100%), 402 [M-NO2]+ (20%), 294 (16%), 254 (47%), 220 (9%), 122

(20%), 104 (39%), 76 (9%); High-Resolution EI-MS for C22H13FN4O6 m/z calcd: 448.0819,
found: 448.0828; Elem. Anal. calcd for C22H13FN4O6: C, 44.90; H, 2.22; N, 33.33; O, 16.32;
F, 3.23. Found: C, 44.88; H, 2.23; N, 33.33; O, 16.32; F, 3.24.
Spectral data for 6d: 2-(3,4-difluorophenylamine)-3-(dinitrophenylamine)-1,4-napthoquinone,
dark red solid powder, mp 226-228 °C; IR (ATR): 3320, 1662, 1605, 1588, 1517, 1498, 1436,
1327, 1265, 1133, 984, 905, 797, 721 cm-1; UV-Vis (CHCl3): λmax 494 nm (3.69 log ξ), 356
1
nm (4.29 log ξ), 282 nm (4.47 log ξ), 232 nm (4.19 log ξ); H NMR (400 MHz, DMSO-d6) δ
6.52-6.56 (m, 1H, 6´´), 6.83-6.88 (m, 1H, 2´´), 6.88 (d, 1H, 6´, Jo = 9.8 Hz), 6.94 (q, 1H, 5´´,
J=9.8 Hz) 7.86 (td, 1H, 6, Jo=7.4 Hz, Jm=1.6 Hz), 7.91 (td, 1H, 7, Jo=7.4 Hz, Jm=1.6 Hz), 8.09
(dd, 1H, 8, Jo=7.4 Hz, Jm=1.6 Hz), 8.11-8.16 (m, 2H, 5, 5´), 8.56 (d, 1H, 3´, Jm=2.73 Hz), 9.46
13
2
(s, 1H, a), 9.48 (s, 1H, b); C{1H} NMR (100 MHz, DMSO-d6): δ 112.32 (d, 2´´, JC-F=19
2
Hz), 115.35 (d, 5´´, JC-F=17 Hz), 115.82 (2), 120.17 (m, 6´´), 120.27 (6´), 121.93 (3´), 125.82
(8), 126.20 (5), 128.63 (5´), 130.80 (10), 131.61 (9), 131.97 (2´), 133.45 (6), 133.64 (d, 1´´,
1
3JC-F=3.1 Hz) 133.68 (7), 134.73 (3), 137.21 (4´), 141.37 (1´), 145.51 (dd, 4´´, JC-F=244 Hz,
1
2
2JC-F=12 Hz), 147.95 (dd, 3´´, JC-F=244 Hz, JC-F=12 Hz), 179.56 (1), 181.22 (4); 19F{1H}
NMR (376 MHz, DMSO-d6): δ -139.34, -135.08; EI-MS (m/z): 466 [M]+ (100%), 420 [M-
NO2]+ (25%), 310 (11%), 294 (22%), 272 (43%), 260 (20%), 248 (12%), 220 (11%), 140
(24%), 104 (36%), 76 (13%); High-Resolution EI-MS for C22H12F2N4O6 m/z calcd: 466.0725,
found: 466.0713.
Spectral data for 6e: 2-(2-methoxyaniline)-3-(2,4-dinitrophenylamine)-1,4-naphthoquinone,
dark red solid powder, mp 235-237 °C; UV-Vis (CHCl3): λmax 526 nm (3.48 log ξ), 380 nm
(4.06 log ξ), 291 nm (4.29 log ξ), 231 nm (4.02 log ξ); IR (ATR) 3368, 3318, 3108, 1653,
1583, 1497, 1465, 1429, 1325, 1259, 1231, 1134, 1096, 1029, 974, 918, 762, 720 cm-1; 1H
NMR (400 MHz, DMSO-d6): δ 3.55 (s, 3H, 7´´), 6.52 (t, 1H, 5´´, Jo=7.8 Hz), 6.59 (d, 1H, 3´´,
Jo=8.2 Hz), 6.79 (d, 2H, 6´, 6´´ Jo=8.6 Hz) 6.88 (t, 1H, 4´´, Jo=7.4 Hz), 7.85 (t, 1H, 6, Jo=7.4
Hz), 7.91 (t, 1H, 7, Jo=7.4 Hz), 8.05-8.14 (m, 3H, 5, 8, 5´), 8.51 (dd, 1H, 3´, JO=2.7 Hz, Jm=1.2
Hz), 8.59 (s, 1H, b), 9.36 (s, 1H, a); 13C{1H} NMR (100 MHz, DMSO-d6): δ 55.13 (7´´),
109.81 (3´´), 113.46 (2), 118.94 (5´´), 119.29 (6´), 122.22 (3´), 124.47 (1´´), 125.12 (6´´),
125.86 (8), 126.25 (5), 126.58 (4´´), 128.39 (5´), 130.54 (2´), 130.61 (10), 131.81 (9), 133.30
(6), 134.92 (7), 136.12 (3), 136.40 (4´), 142.73 (1´), 151.78 (2´´), 179.03 (1), 181.20 (4); EI-
MS (m/z): 460 [M]+ (100%), 414 [M-NO2]+ (12%), 383 [M-NO2-OCH3]+ (11%), 294 (22%),

266 (45%), 220 (12%), 104 (40%), 76 (15%); High-Resolution EI-MS for C23H16N4O7 m/z
calcd: 460.1019, found: 460.1011.
Acknowledgements
This work was supported by CONACyT (Grant 155678). C.G.E.G. acknowledges
financial support by CONACyT (Scholarship 165111). D.A.M.L acknowledges financial
support by CONACyT (National Scholarship 268070 and International Scholarships 290749).
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35. General procedure. 2,3-Dichloro-1,4-naphthoquinone 2 (3.6 mmol) and CeCl3.7H2O (0.36
mmol) were placed in a flask containing 50 mL of ethanol. The mixture was stirred for ten
minutes and then aniline (5.4 mmol) was added. The reaction mixture was refluxed for two
hours. After cooling, cold water (10 mL) was added and the mixture was placed in an ice-
bath for several hours to complete precipitation. The solid product was separated by
filtration and washed with cold ethanol. 2-Anilino-3-chloro-1,4-naphthoquinone, 3, was
obtained as an orange product. An amount of 3 (1 mmol) was added to a solution of
concentrated acids (8 mL of conc. HNO3 and 2 mL of conc. H2SO4) and the resulting
mixture was stirred for three hours. Cold water (10 mL) was added and the mixture was
placed in an ice-bath for several hours. 2-Chloro-3-(2,4-dinitroanilino)-1,4-
naphthoquinone 4 was obtained as a red solid which was separated by filtration and
washed with an aqueous solution (5%) Na2CO3. 4 (0.13 mmol), 7 mL of ethanol and a
large amount of the substituted aniline (5a-5e) were placed in a flask. The exact molar
ratio is given in Table 1. The reaction mixture was allowed to reflux vigorously for several
hours (Table 1). After cooling, cold distilled water was added to the reaction mixture
which was then placed in an ice-bath for several hours. The corresponding product (6a-6e)
was separated by filtration and purified by column chromatography (silica gel/CHCl3).

Table 1. Reaction conditions in the preparation of
2-(fluoroanilino)-3-(2,4-dinitroanilino)-1,4-naphthoquinones
Aniline Substituent Ratio
Time
Yield
[4:aniline] (Hours) (%)
2-FPh
1:30
1:40
1:10
1:40
1:15
35
12
15
22
10
68
70
90
60
90
5a
5b
5c
5d
5e
3-FPh
4-FPh
3,4-FPh
2-MeOPh

Highlights
A facile preparation of novel 2-(fluoroanilino-)-3-(2,4-dinitroanilino)-1,4-
naphthoquinone derivatives is presented.
2-anilino-3-chloro-1,4-naphthoquinone was prepared in quantitative yields utilizing a
Lewis acid with good oxidation properties like CeCl3.7H2O. This compound was nitated.
2-chloro-3-(2,4-dinitroanilino)-1,4-naphthoquinone reacted with weakly nucleophilic
fluoro anilines.
1
The H and 13C NMR signals were assigned using two dimensional NMR techniques
(COSY, gHSQC and gHMBC).