Direct nitration of 3-arylamino-2-chloro-1,4-naphthoquinones

Article abstract of DOI:10.1055/s-2005-865327

A convenient two-step synthesis of mononitro and dinitro derivatives of the title compounds is reported. The Michael type addition of aromatic amines to 2,3-dichloro-1,4-naphthoquinone, is followed by mixed acids nitration to yield nitro aromatic quinones

Full text of DOI:10.1055/s-2005-865327

PAPER
1631
Direct Nitration of 3-Arylamino-2-chloro-1,4-naphthoquinones
D
irec
t
N
itration
h
of
N
aphthoq
i
uinone
d
s
a Win,a,b Sarit Yerushalmi,b Shmuel Bittner*b
a
Department of Chemistry, University of Mandalay, Mandalay, Myanmar
Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva, 84105, Israel
E-mail: bittner@bgumail.bgu.ac.il
b
Received 15 December 2004; revised 8 February 2005
more severe conditions (concd acids) dinitration of the ar-
omatic ring took place. The 2,4-dinitro derivative 3g and
the 2,3-dinitro derivative 3h were obtained in very good
yields (80 and 68%, respectively). The mononitro deriva-
tives 3a–f and the dinitro derivatives 3g–h have not been
previously described in the literature.
Abstract: A convenient two-step synthesis of mononitro and dini-
tro derivatives of the title compounds is reported. The Michael type
addition of aromatic amines to 2,3-dichloro-1,4-naphthoquinone, is
followed by mixed acids nitration to yield nitro aromatic quinones
hard to get or unattainable before.
Key words: quinones, Michael additions, aromatic amines, nitra-
tions, nitroquinones
1,4-Napthoquinone derivatives in general, and those pos-
sessing an amino group in the 2-position in particular,
have been long the subject of intensive research. They are
of interest because many of them find use in a variety of
medical and biological applications. Thus, they can act as
antituberculars,1 antimalarials,2 antibacterials,3 antitumor
agents,4 larvicides,5 lamoluscicides,5 herbicides,6 and fun-
gicides.7 The synthesis of 2-aminoquinones, is usually ac-
complished via the Michael-type reaction of amines either
with 1,4-naphthoquinone itself or with 2,3-dichloro-1,4-
naphthoquionone. Primary and secondary aliphatic
amines, cyclic amines and anilines substituted with elec-
tron-donating groups, are quite reactive and afford high
yields of the corresponding aminoquinones.8,9 Only very
poor yields are obtained, or no reaction at all is observed
with aromatic amines, substituted with strong electron-
withdrawing groups. Thus, the Michael addition does not
allow the satisfactory preparation of nitro-substituted de-
rivatives (e.g. 3a–h). The reported yield of the reaction of
p-nitroaniline with 2,3-dichloro-1,4-naphthoquinone is
lower than 3%10 and with 1,4-naphthoquinone only traces
were obtained.11 Similarly, 2,4-dinitroaniline did not react
with these quinones.
In the course of our work on anticancer quinones,12,13 we
had to prepare and to test both the mononitro- and dinitro-
phenyl derivatives of naphthoquinone. As the classical
route to such compounds was unfeasible, we developed an
alternative two-step synthesis of such compounds. In the
first step, 2-anilino-3-chloro-1,4-naphthoquinones were
prepared by the classical Michael type addition-elimina-
tion reaction.8 In the second step, the phenyl group was ni-
trated via direct electrophilic aromatic substitution
(Scheme 1). Under quite mild conditions (5–40 °C, dilute
acids) we were able to obtain the mononitro derivatives
3a–f in moderate to good yield (35–65%). Under slightly
Scheme 1
All products were identified by IR, H NMR, 13C NMR,
1
MS, and UV/Vis spectral data. The infrared spectra of 3a–
h exhibit typical strong quinonic carbonyl absorption be-
tween 1635 and 1680 cm–1. The NH stretching vibration
appeared between 3237 and 3330 cm–1. In the H NMR
1
spectra (CDCl3) of 3, four naphthalenic protons with dif-
ferent chemical shifts were observed, as expected from
such non-symmetric systems.14,15 In the disubstituted
compounds 3b–f, the three benzenic hydrogens appeared
as doublet, double doublet, and doublet splittings. The po-
sition of the introduced nitro group was verified in the
case of 3f by an X-ray diffraction study (Figure 1)16 and in
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Advanced online publication: 19.04.2005
DOI: 10.1055/s-2005-865327; Art ID: T15504SS
© Georg Thieme Verlag Stuttgart · New York

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T. Win et al.
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the other cases by analyzing chemical shifts and spin cou- erties and on the ease of substitution of the second
pling constants of the 1H and 13C NMR data. The double chlorine atom by nucleophiles is currently in progress.
nitration of 2 (R = H) yielded the expected meta-dinitro
compound 3g. However double nitration of the methoxy
IR spectra were recorded on a Nicolet 5ZDX FT-IR spectrometer.
1H and 13C NMR spectra were recorded on Bruker WP 200 SY and
Bruker DMX 500 instruments. Mass spectra (CI in CH4) were ob-
tained on a Finnigan 4020 quadropole spectrometer and LC-MS
(APCI, atmospheric pressure chemical ionization) was performed
using a Bruker esquire 3000plus (Bruker Daltonics, Germany). UV/
Vis spectra were measured using HP 8452A diode array spectro-
photometer. TLC was carried out on Merck 5554 pre coated silica
gel 60. Mps were measured using a Thomas-Hoover capillary appa-
ratus and are uncorrected. All chemicals, solvents and reagents were
of commercial quality. X-ray analysis was done on a Nonius Kappa
CCD diffractometer with MoKa radiation (l = 0.71073) with a
graphite monochrometer.
compound (2, R = OCH3) produced the unexpected deriv-
ative 3h in which the two nitro groups are ortho to each
other. The proton NMR spectrum of 3h showed two aro-
matic CH appearing as a double doublet at d = 7.72–7.78
(J = 9.1 Hz). The methoxy hydrogens appeared as a sin-
glet and the resonance of the naphthalene ring are highly
distorted due to second-order effects. We do not have an
explanation for this unusual orientation of the substitu-
tion.
The electronic absorption spectra showed the expected
benzene and naphthoquinone bands in the UV region
around 270–286 nm (l1, p→p* electron transition) and at
336–344 nm (l2). In addition, another lower energy band
appeared in the visible region centered between 430–490
nm (l3) which can be attributed to the n→p* transition.
Comparing compounds 3 with the non-nitrated analogs
showed that the values of l1 and l2 are not influenced by
the introduction of the nitro group. On the other hand, this
chromophore had a pronounced hypsochromic influence
on the l3 transition. Thus, in the case of mononitrated
compounds the shift is between 10 to 20 nm and in the
case of dinitrated compounds the shift is as large as 45 nm.
2-Arylamino-3-chloro-1,4-naphthoquinones 2; General Proce-
dure
Preparation of 2 was performed according to literature procedures.17
Thus, the aromatic amine (13.2 mmol) was mixed with a solution of
2,3-dichloro-1,4-naphthoquinone (1; 1.0 g, 4.4 mmol) in EtOH (300
mL). Stirring the mixture at r.t. overnight caused the precipitation
of the product. The precipitate was collected by filtration, washed
with EtOH and recrystallized from EtOH–CHCl3 (5:1) to afford the
pure 2-arylamino-3-chloro-1,4-naphthoquinones 2.
Nitration of 2a–f; General Procedure
The appropriate 1,4-naphthoquinone 2a–f (0.9 mmol) was added to
a stirred mixture of 70% HNO3 (7 mL), 95% concd H2SO4 (1.5 mL)
and H2O (3 mL) at 5 °C. The reaction mixture was allowed to warm
to r.t. for 2a,d and in all other cases was heated at 50 °C for 1 h. It
was diluted with H2O (100 mL) and the colored precipitate was col-
lected by suction filtration. The crude product was washed with aq
5% NaHCO3 solution, with H2O and cold EtOH.
As can be seen from the crystal structure plot in Figure 1,
the phenyl ring and the naphthoquinone ring system of 3f
do not lie in the same molecular plane. The dihedral angle
between the two planes is 53.8°. This molecule is in-
volved in an intramolecular hydrogen bond between the
NH and one of the oxygens of the nitro group (N1–
H1···O4, 2.103 Å). In typical amino substituted naphtho-
quinones, an intramolecular hydrogen bond exists be-
tween the NH and one of the quinonic oxygens. In the
present case such an interaction is rather weak (2.173 Å)
because of the non-planarity of the system.
2-Chloro-3-[(4-nitrophenyl)amino]-1,4-naphthoquinone (3a)
Recrystallized from CH2Cl2 to afford orange crystals; yield: 64%;
mp 288–289 °C.
IR (KBr): 3237, 3067, 1675, 1348 cm–1.
1H NMR (200 MHz, DMSO-d6): d = 9.7 (br s, 1 H), 8.16 (d, J = 9.2
Hz, 2 H), 8.04–8.07 (m, 2 H), 7.82–7.90 (m, 2 H), 7.22 (d, J = 9.2
Hz, 2 H).
13C NMR (200 MHz, DMSO-d6): d = 177.6, 170.6, 147.1, 142.7,
141.9, 135.0, 133.8, 132.3, 126.8, 126.5, 124.7, 121.5, 104.9.
HRMS (CI in CH4): m/z calcd for C16H9ClN2O4: 328.025085;
found: 328.023509.
UV/Vis (CHCl3): lmax (log e) = 274 (4.18), 336 (4.18), 462 nm
(3.68).
2-Chloro-3-[(4-methyl-2-nitrophenyl)amino]-1,4-naphtho-
quinone (3b)
Recrystallized from n-hexane–CH2Cl2 (4:1) to afford orange crys-
tals; yield: 36%; mp 243–245 °C.
IR (KBr): 3245, 2931, 1683, 1346 cm–1.
Figure 1 Crystal structure of compound 3f
1H NMR (200 MHz, CDCl3): d = 9.32 (br s, 1 H), 8.18 (dd, J = 1.4,
7.7 Hz, 2 H), 7.95 (d, J = 2.6 Hz, 1 H), 7.77 (dt, J = 1.5, 7.4 Hz, 2
H), 7.39 (dd, J = 2.6, 8.9 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 2.17
(s, 3 H).
13C NMR (500 MHz, CDCl3): d = 179.4, 177.0, 140.2, 139.2, 134.6,
134.0, 133.6, 133.2, 131.6, 130.5, 130.1, 129.7, 126.9, 125.4, 124.1,
119.9, 30.5.
In conclusion, we have developed a route to the synthesis
of mononitro and dinitro derivatives of 2-arylamino-1,4-
naphthoquinones. Thus, we were able to prepare a variety
of nitro aromatic quinones difficult to get or unattainable
before. To the best of our knowledge, direct nitration of
such quinones, have not been reported before. The influ-
ence of the dinitro derivatives 3g–h on the quinonic prop-
ESI-MS: m/z = 342.0, 340.8 [C17H11ClN2O4 (M – H)–].
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Direct Nitration of Naphthoquinones
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UV/Vis (CHCl3): lmax (log e) = 276 (4.25), 344 (3.6), 466 nm
(3.66).
13C NMR (500 MHz, CDCl3): d = 179.0, 176.8, 163.8, 139.7, 137.3,
137.1, 134.8, 133.8, 133.7, 131.3, 129.8, 127.4, 127.1, 127.0, 124.8,
124.3, 122.3, 61.3, 13.9.
2-Chloro-3-[(4-tetradecyl-2-nitrophenyl)amino]-1,4-naphtho-
quinone (3c)
Recrystallized from CHCl3 to afford yellow crystals; yield: 57%;
ESI-MS: m/z = 400.0, 398.8 [C19H13ClN2O6, (M – H)–].
UV/Vis (CHCl3): lmax (log e) = 286 (4.47), 342 (3.8), 454 nm
(3.82).
mp 138–140 °C.
IR (KBr): 3295, 2921, 1679, 1348 cm–1.
Dinitro Derivatives 3g,h; General Procedure
1H NMR (200 MHz, CDCl3): d = 9.33 (br s, 1 H), 8.17 (dd, J = 1.4,
7.4 Hz, 2 H), 7.95 (d, 1 H, J = 1.8 Hz, 1 H), 7.77 (dt, J = 1.4, 7.4
Hz, 2 H), 7.38 (dd, J = 1.8, 8.1 Hz, 1 H), 6.83 (d, J = 8.5 Hz, 1 H),
2.65 (t, 2 H), 1.62–1.65 (m, 2 H), 1.24–1.35 (m, 22 H), 0.85 (t, 3 H).
13C NMR (500 MHz, CDCl3): d = 179.6, 177.2, 140.5, 139.5, 139.0,
134.8, 133.6, 133.4, 131.9, 130.9, 130.0, 127.0, 124.9, 124.3, 120.2,
34.7, 31.7, 30.7, 29.5, 29.0, 22.5, 13.9.
A mixture of 70% HNO3 (5.5 mL) and 95% concd H2SO4 (0.5 mL)
was added to 2 (0.5 mmol) at 5 °C. The reaction mixture was al-
lowed to stir at r.t. for 2 h, diluted with H2O (100 mL) and the pre-
cipitate was collected by filtration. The crude product was washed
with aq NaHCO3 solution, then with H2O and with cold EtOH to
give the desired compound.
2-Chloro-3-[(2,4-dinitrophenyl)amino]-1,4-naphthoquinone
(3g)
Recrystallized from CH2Cl2 to afford an orange solid; yield: 80%;
mp 240–242 °C.
IR (KBr): 3286, 3091, 1666, 1353 cm–1.
ESI-MS: m/z = 524.2, 522.7 [C30H37ClN2O4 (M – H)–], 525.3 (M +
H)+.
UV/Vis (CHCl3): lmax (log e) = 278 (4.42), 342 (3.73), 474 nm
(3.81).
1H NMR (200 MHz, DMSO-d6): d = 9.84 (br s, 1 H), 8.83 (d,
J = 2.7 Hz, 1 H), 8.43 (dd, J = 2.7, 9.1 Hz 1 H), 8.03–8.12 (m, 2 H),
7.83–7.96 (m, 2 H), 7.4 (d, J = 9.2 Hz, 1 H).
13C NMR (200 MHz, DMSO-d6): d = 179.0, 177.2, 141.6, 141.3,
140.1, 136.6, 135.1, 134.1, 131.5, 130.4, 128.2, 126.7, 126.5, 124.2,
121.9, 104.3.
2-Chloro-3-[(4-methoxy-2-nitrophenyl)amino]-1,4-naphtho-
quinone (3d)
Recrystallized from CH2Cl2 to afford orange crystals; yield: 37%;
mp 205–207 °C.
IR (KBr): 3245, 3077, 1677, 1351 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.07 (br s, 1 H), 8.18 (dd, J = 1.4,
7.4 Hz, 2 H), 7.77 (dt, J = 1.4, 7.4 Hz, 2 H), 7.62 (d, J = 2.9 Hz, 1
H,), 7.16 (dd, J = 2.9, 8.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 3.9 (s,
3 H).
13C NMR (500 MHz, CDCl3): d = 179.0, 177.3, 155.5, 141.5, 140.7,
135.3, 133.5, 132.2, 130.0, 127.9, 126.6, 121.2, 118.8, 108.9, 102.6,
56.1.
HRMS (CI in CH4): m/z calcd for C16H8ClN3O6: 373.010163;
found: 373.005714.
UV/Vis (CHCl3): lmax (log e) = 264 (4.09), 286 (3.98), 334 (4.03),
440 nm (3.73).
2-Chloro-3-[(4-methoxy-2,3-dinitrophenyl)amino]-1,4-naph-
thoquinone (3h)
Recrystallized from CH2Cl2 to give a yellow powder; yield: 68%;
ESI-MS: m/z = 358.0, 359.0 [C17H11ClN2O5 (M + H)+].
mp 248–250 °C.
IR (KBr): 3332, 3092, 1675, 1382 cm–1.
UV/Vis (CHCl3): lmax (log e)= 278 (4.29), 342 (3.54), 486 nm
(3.69).
1H NMR (500 MHz, DMSO-d6): d = 9.27 (br s, 1 H), 8.01 (t, J = 7.7
Hz, 2 H), 7.88–7.80 (m, 2 H), 7.78–7.72 (dd, J = 9.1 Hz, 2 H), 4.00
(s, 3 H).
13C NMR (200 MHz, DMSO-d6): d = 179.7, 177.2, 149.5, 144.1,
138.1, 135.3, 134.0, 133.4, 132.1, 130.5, 127.1, 127.0, 126.6, 118.6,
115.9, 104.9, 58.4.
2-Chloro-3-[(4-fluoro-2-nitrophenyl)amino]-1,4-naphtho-
quinone (3e)
Recrystallized from EtOH to afford pure solid; yield: 39%; mp 240–
242 °C.
IR (KBr): 3309, 3095, 1673, 1365 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.24 (br s, 1 H), 8.18 (dd, J = 1.1,
7.4 Hz, 2 H), 7.9 (dd, J = 2.6, 7.7 Hz, 1 H), 7.8 (dt, J = 1.1, 7.4 Hz,
2 H), 7.35 (dt, J = 2.6, 7.4, 9.2 Hz, 1 H), 6.9 (dd, J = 4.8, 9.2 Hz, 1
H).
13C NMR (200 MHz, CDCl3): d = 179.8, 177.0, 155.6, 143.3, 135.3,
133.9, 130.9, 130.4, 130.2, 126.9, 126.6, 121.5, 121.1, 117.0, 116.5,
112.1, 104.8.
LCMS: m/z = 403.9 [C17H10ClN3O7, (M + H)+], 403.01, 401.8
[(M – H)–].
UV/Vis (CHCl3): lmax (log e) = 246 (4.15), 272 (4.15), 340 (3.69),
458 nm (3.72).
X-ray Crystal Data
Single crystal 3f was obtained by slow evaporation from CHCl3,
yellowish crystal, C19H13ClN2O6 (400.76); triclinic, P1 with
a = 4.4690(9) Å, b = 6.7590(14) Å, c = 14.267(3) Å, a = 92.38(3)°,
b = 84.132(4)°, g = 91.47(3)°, V = 430.28(15) Å3, Z = 1,
ESI-MS: m/z = 346.0, 344.8 [C16H8ClFN2O4, (M – H)–].
UV/Vis (CHCl3): lmax (log e) = 272 (4.38), 340 (3.68), 460 nm
(3.79).
r
calcd = 1.547 Mg/m3, absorption coefficient 0.129 mm–1 was per-
formed at 120 K using graphite monochromated MoKa radiation
(l = 0.71073 Å), limiting indices –5 h £ 5, –8 £ k £ 8, 0 £ l £ 17,
q-range for data collection 2.86 to 26.37°, reflections measured
1727, unique reflections 1727 (Rint = 0.0000). Completeness to
q = 26.37° 98%, data/restraints/parameters 1727/3/258. The struc-
ture was solved by direct methods and refined by full-matrix least-
squares on F2 using SHELXL-9718 program system. All non-hydro-
gen atoms were refined anisotropically and the position of the hy-
drogen atoms was calculated as a riding model. Goodness-of-fit on
2-Chloro-3-[(4-ethoxycarbonyl-2-nitrophenyl)amino]-1,4-
naphthoquinone (3f)
Recrystallized from CHCl3 to afford yellow needles; yield: 45%;
mp 193–195 °C.
IR (KBr): 3215, 2981, 1710, 1677, 1367 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.82 (br s, 1 H), 8.86 (d, J = 2.0
Hz, 1 H), 8.16–8.23 (m, 3 H), 7.77–7.84 (m, 2 H), 6.86 (d, J = 8.6
Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
Synthesis 2005, No. 10, 1631–1634 © Thieme Stuttgart · New York

1634
T. Win et al.
PAPER
F2 1.036; final R indices [I > 2s (I)], R1 = 0.0442, wR2 = 0.1124; R
indices (all data) R1 = 0.0519, wR2 = 0.1182.
(5) Lopes, J. N. C.; Johnson, A. W.; Grove, J. F.; Bulhoes, M. S.
Cienc. Cult. (Sao Paulo) 1977, 29, 1145.
(6) (a) U.S. Rubber Co., British Patent GB 862489, 1961; Chem.
Abstr. 1961, 55, 120651. (b) Sekioks, H.; Hirota, Y.; Sakata,
M.; Kawaguchi, Y.; Takamura, S.; Hibi, T. Ube Industries
Ltd., Japanese Patent JP 54126725, 1979; Chem. Abstr.
1980, 92, 141803. (c) Entwistle, I. D.; Devlin, B. J. Shell
International Research Maatschappij N.V, British Patent GB
7010904, 1973; Chem. Abstr. 1973, 79, 53095.
(7) Clark, N. G. Pestic. Sci. 1985, 16, 23.
(8) Finley, K. T. The Chemistry of Quinonoid Compounds, Part
II; Patai, S., Ed.; Wiley: London, 1974, 877–1144.
(9) Aguilar-Martinez, M.; Cuevas, G.; Jimenez-Estrada, M.;
Gonzalez, I.; Lotina-Hennsen, B.; Macias-Ruvalcaba, N. J.
Org. Chem. 1999, 64, 3684.
Selected bond distances (Å) and bond angles (°): Cl(1)–C(10)
1.718(4); C(1)–N(1) 1.383(6); C(1)–C(2) 1.508(6); C(2)–O(1)
1.209(6); C(2)–C(3) 1.489(6); C(3)–C(8) 1.403(6); C(3)–C(4)
1.408(6); C(4)–C(5) 1.375(7); C(4)–H(4) 0.9300; C(9)–O(2)
1.221(6); N(1)–C(11) 1.390(6); C(11)–C(12) 1.406(6); C(12)–
C(13) 1.370(6); C(16)–N(2) 1.461(5); C(10)–C(1)–N(1) 127.2(4);
N(1)–C(1)–C(2) 111.8(4); O(1)–C(2)–C(3) 123.1(4); O(1)–C(2)–
C(1) 119.0(4); C(1)–C(10)–Cl(1) 122.5(3); C(1)–N(1)–H(1)
109(3); C(11)–N(1)–H(1) 121(4); C(1)–N(1)–C(11) 127.4(4);
N(1)–C(11)–C(16) 120.7(4); C(11)–C(16)–N(2) 122.2(4); O(4)–
N(2)–C(16) 118.7(4); N(1)–C(11)–C(12) 122.5(4); C(11)–C(12)–
H(12) 119.1; C(15)–C(14)–H(17) 117.5(4).
(10) Agarwal, N. L.; Schafer, W. J. Am. Chem. Soc. 1980, 102,
5139.
Acknowledgment
(11) Vladimirtsev, I. F.; Stromberg, A. G. Zh. Obshch. Khim.
1957, 27, 1029; Chem. Abstr. 1958, 52, 3753.
(12) Rahimipour, S.; Weiner, L.; Fridkin, M.; Dawadi, P. B. S.;
Bittner, S. Lett. Pept. Sci. 1996, 3, 263.
(13) Gorohovsky, S.; Bittner, S. Amino Acids 2001, 20, 135.
(14) Sutovsky, Y.; Likhtenshtein, G. I.; Bittner, S. Tetrahedron
2003, 59, 2939.
Thida Win wishes to thank UNESCO for a post-doctoral research
fellowship. We wish to thank Mrs. Ethel Solomon and Mrs. Aliza
Levkowitz for skillful technical help and Dr. T. Win and Dr. W.
Walther for MS analyses.
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Synthesis 2005, No. 10, 1631–1634 © Thieme Stuttgart · New York