Palladium-catalyzed amination of 2,3-dichloro-1,4-naphthoquinone with nitroarylamines

Article abstract of DOI:10.1055/s-2006-939047

A convenient one-step synthesis of 2-[(nitroaryl)amino]-3-chloro-1,4- naphthoquinones is reported. The direct amination of 2,3-dichloro-1,4- naphthoquinone with nitro-substituted aryl amines is catalyzed by PdCl ₂(dppf)/dppf in the presence of

Full text of DOI:10.1055/s-2006-939047

942
LETTER
Palladium-Catalyzed Amination of 2,3-Dichloro-1,4-naphthoquinone with
Nitroarylamines
A
mination of 2,3-D
i
ichlor
a
o-1,4-napht
o
hoquinone
w
-
ith Nitro
L
arylamines ei Wang, Xiu-Fang Zheng, John Reiner*
College of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(022)27890968; E-mail: jreiner@tju.edu.cn
Received 11 January 2006
O
O
O
Abstract: A convenient one-step synthesis of 2-[(nitroaryl)amino]-
3-chloro-1,4-naphthoquinones is reported. The direct amination of
Cl
PdCl2(dppf), dppf
[Pd0(dppf)]
Cl
Cl
2,3-dichloro-1,4-naphthoquinone with nitro-substituted aryl amines
is catalyzed by PdCl2(dppf)/dppf1 in the presence of t-BuONa as
base to yield 2-[(nitroaryl)amino]-3-chloro-1,4-naphthoquinones,
several of which were previously unavailable. Traces of the 2,3-
di[(nitroaryl)amino]-1,4-naphthoquinones were detected as side
products.
NHAr
O
reductive
elimination
oxidative
addition
O
O
O
Cl
Cl
Ph2P
Ph2P
Key words: quinones, amines, catalysis, aminations, palladium
Fe
Pd
Fe
Pd
P
Cl
O
P
HN
Ar
Ph2
Ph2
The amino naphthoquinone structure is common to nu-
merous natural products (e.g., rifamycins,2 damavaricins,3
streptovaricins4) and has been used as a key synthetic in-
termediate for the construction of biologically important
compounds associated with antitrypanosomal,5 antimalar-
ial,6 antitumor7 and antineoplastic8 activities. In addition,
they have found widespread industrial applications in col-
or chemistry and hair dying,9 and as photo stabilizers.10
The classical routes to 2-amino-1,4-naphthoquinones are
achieved either by the 1,4-type addition of amines with
1,4-naphthoquinone followed by air oxidation11 or by
nucleophilic addition–elimination on 2-halo-1,4-naphtho-
quinones.12 High yields of the corresponding 2-amino-
naphthoquinones can be obtained when primary and
secondary aliphatic amines or anilines substituted with
electron-donating groups are used; however, anilines sub-
stituted with strongly electron-withdrawing groups afford
either poor yields of the corresponding aminonaphtho-
quinones or fail to react.13 Thus, an alternative to the
Michael addition protocols to prepare amino-substituted
naphthoquinones with less nucleophilic amines and
anilines would be useful to enhance the diversity of readi-
ly available amino-substituted naphthoquinones.
O
Cl
t-BuONa
–NaCl
Ph2P
t-BuOH
Fe
Pd
ArNH2
O
P
t-BuO
Ph2
transmetallation
Scheme 1
In all of the coupling reactions, only a trace of 2,3-di[(ni-
troaryl)amino]-1,4-naphthoquinones 3 resulting from
overamination of 2,3-dichloro-1,4-naphthoquinone can
be detected as side products. To the best of our
knowledge, these 2,3-dianilino-1,4-naphthoquinone de-
rivatives have not been previously synthesized. After
separation, compounds 3 were characterized by NMR
spectroscopy.16 As expected for such symmetrical com-
pounds, the 1H NMR spectra of 3 display four naphthalene
protons with only two different chemical shifts and one
set of aniline protons with double the integration. In the
13C NMR spectra of 3, fewer than ten aromatic carbon
peaks and one carbonyl carbon peak can be detected
further verifying the symmetrical structure of the 2,3-
di[(nitroaryl)amino]-1,4-naphthoquinones.
Although some 2-[(nitroaryl)amino]-3-chloro-1,4-naph-
thoquinones have recently been synthesized via a direct
mixed acids nitration of 2-arylamino-3-chloro-1,4-naph-
thoquinones,14 the yields and generality of the method are
limited. In this letter we present an alternative strategy for
the synthesis of 2-(nitroanilino)-3-chloro-1,4-naphtho-
quinones by the coupling of nitro-substituted aryl amines
with 2,3-dichloro-1,4-naphthoquinone catalyzed by
PdCl2(dppf) in the presence of t-BuONa.15 The results are
summarized in Table 1.
As outlined in Scheme 1, we believe the catalytic cycle
for this process is similar to that postulated for many
palladium-catalyzed C–N bond forming reactions which
involve an oxidative addition of the aryl halide, followed
by transmetalation and reductive elimination.17
In conclusion, PdCl2(dppf) has been found to catalyze
the coupling of nitro-substituted arylamines with 2,3-
dichloro-1,4-naphthoquinone. A variety of 2-[(nitro-
aryl)amino]-3-chloronaphthoquinones, some unattainable
by any other procedure, are now available by a simple and
mild method. An extension of this coupling methodology
to synthesize nonsymmetrical diaminonaphthoquinones is
currently in progress.
SYNLETT 2006, No. 6, pp 0942–0944
0
4.
0
4.
2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939047; Art ID: W00906ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Amination of 2,3-Dichloro-1,4-naphthoquinone with Nitroarylamines
943
Table 1 Palladium-Catalyzed Amination of 2,3-Dichloro-1,4-naphthoquinone with Nitroanilines
NH2
R3
R4
R1
R2
R4
R1
R4
R2
O
O
O
O
O
H
N
R3
NH R1
NH R1
Cl
Cl
R3
+
R2
t-BuONa
PdCl2(dppf)/dppf
toluene, 80 °C
Cl
4
O
R
R2
R3
1
2a–i
3a–i
2, 3
a
R1
H
R2
R3
R4
Yield (%)a
H
NO2
NO2
NO2
H
H
H
Cl
H
H
H
H
H
H
90
55
45
63
85
64
40
42
64
b
c
CF3
Cl
H
H
d
e
H
NO2
NO2
NO2
NO2
H
H
CH3
OCH3
Cl
f
H
g
H
h
i
NO2
NO2
H
H
NO2
a Isolated yield of compound 2 (average of two runs).
(10) (a) Escolastico, C.; Santa Maria, M. D.; Claramunt, R. M.;
Jimeno, M. L.; Alkorta, I.; Foces-Foces, C.; Cano, F. H.;
Elguero, J. Tetrahedron 1994, 50, 12489. (b) Catalan, J.;
Febero, F.; Guijarro, M. S.; Claramunt, R. M.; Santa Maria,
M. D.; Foces-Foces, M.; Cano, F. H.; Elguero, J.; Sastre, R.
J. Am. Chem. Soc. 1990, 112, 747.
Acknowledgment
We acknowledge the Tianjin Municipal Science and Technology
Commission (043186011), the Basic Research Project
(#2003AA223151) of the MOST for financial support.
(11) (a) Kutyrev, A. Tetrahedron 1991, 47, 8043. (b) Aguilar-
Martinez, M.; Cuevas, G.; Jimenez-Estrada, M.; Gonzalez,
I.; Lotina-Hennsen, B.; Macias-Ruvalcaba, N. J. Org. Chem.
1999, 64, 3684.
(12) (a) Matsuoka, M.; Hamano, K.; Kitao, T. Synthesis 1984,
953. (b) Nakazumi, H.; Kondo, K.; Kitao, T. Synthesis 1982,
878.
(13) Vladimirtsev, I. F.; Stromberg, A. G. Zh. Obshch. Khim.
1957, 27, 1029; Chem. Abstr. 1958, 52, 3753.
(14) Thida, W.; Sarit, Y.; Shmuel, B. Synthesis 2005, 10, 1631.
(15) General Experimental Procedure.
References and Notes
(1) dppf = 1,1¢-bis(diphenylphosphino)ferrocene.
(2) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873; and
references cited therein.
(3) Roush, W. R.; Coffey, D. S. J. Org. Chem. 1995, 60, 4412.
(4) (a) Rinehart, K. L.; Knoll, W. M. J.; Kakinuma, K.; Antosz,
F. J.; Paul, I. C.; Wang, A. H. J.; Reusser, F.; Li, L. H.;
Krueger, W. C. J. Am. Chem. Soc. 1975, 97, 196. (b)Wang,
A. H. J.; Paul, I. C. J. Am. Chem. Soc. 1976, 98, 4612.
(5) Salmon-Chemin, L.; Buisine, E.; Yardley, V.; Kohler, S.;
Debreu, M. A.; Landry, V.; Sergheraert, C.; Croft, S. L.;
Krauth-Siegel, R. L.; David-Charvet, E. J. Med. Chem.
2001, 44, 548.
(6) (a) Prescott, B. J. Med. Chem. 1969, 12, 181. (b) Lin, T. S.;
Zhu, L. Y.; Xu, S. P.; Divo, A. A.; Sartorelli, A. C. J. Med.
Chem. 1991, 34, 1634.
(7) Hodnett, E. M.; Wongwiechintana, C.; Dunn, W. J.; Marrs,
P. J. Med. Chem. 1983, 26, 570.
(8) (a) Giorgi-Renault, S.; Renault, J.; Gebel-Servolles, P.;
Baron, M.; Paolett, C.; Cros, S.; Bissery, M. C.; Lavelle, F.;
Atassi, G. J. Med. Chem. 1991, 34, 38. (b) Lin, T. S.; Xu, S.
P.; Zhu, L. Y.; Cosby, L. A.; Sartorelli, A. C. J. Med. Chem.
1989, 32, 1467.
(9) (a) Takagi, K.; Matsuoka, M.; Hamano, K.; Kitao, T. Dyes
Pigm. 1984, 5, 241. (b) Matsuoka, M.; Takagi, K.;
Obayashi, H.; Wakasugi, K.; Kitao, T. J. Soc. Dyers Colour
1983, 99, 257. (c) Kikuchi, M.; Komatsu, K.; Nakano, M.
Dyes Pigm. 1990, 12, 107.
A mixture of 2,3-dichloro-1,4-naphthoquinone (200 mg,
0.88 mmol), nitroarylamine (0.97 mmol), t-BuONa (1.01
mmol), PdCl2(dppf) (0.04 mmol), and dppf (0.04 mmol) in
5 mL toluene were stirred under a nitrogen atmosphere at
80 °C for 12 h, and then the reaction was concentrated and
the products were purified by column chromatography
(40–80% CH2Cl2–PE).
(16) 1H NMR and 13C NMR spectra were recorded on a Varian
Inova 500 MHz instrument.
Compound 2a:14 1H NMR (CDCl3): d = 8.22–8.25 (m, 3 H),
8.16 (dd, J = 7.5, 1.0 Hz, 1 H), 7.82 (dt, J = 7.5, 1.5 Hz, 1 H),
7.76 (dt, J = 7.5, 1.5 Hz, 1 H), 7.71 (s, 1 H), 7.08 (dd, J = 7.0,
2.0 Hz, 2 H).
Compound 3a: 1H NMR (DMSO-d6): d = 8.06 (dd, J = 5.5,
3.5 Hz, 2 H), 7.84 (dd, J = 5.5, 3.0 Hz, 2 H), 7.74 (dd,
J = 7.5, 2.0 Hz, 4 H), 6.56 (t, 4 H). 13C NMR (DMSO-d6):
d = 181.61, 145.08, 140.32, 134.75, 131.83, 126.67, 126.30,
124.02, 119.06.
Synlett 2006, No. 6, 942–944 © Thieme Stuttgart · New York

944
X.-L. Wang et al.
LETTER
2 H), 2.25 (s, 3 H). 13C NMR (DMSO-d6): d = 181.52,
148.03, 136.95, 134.43, 131.88, 131.35, 126.42, 125.08,
124.78, 124.50, 115.79, 19.42.
Compound 2b: 1H NMR (CDCl3): d = 8.57 (d, J = 2.5 Hz, 1
H), 8.39 (dd, J = 9.0, 2.5 Hz, 1 H), 8.23 (dd, J = 7.5, 1.0 Hz,
1 H), 8.17 (dd, J = 7.5, 1.0 Hz, 1 H), 7.87 (s, 1 H), 7.84 (td,
J = 7.5, 1.5 Hz, 1 H), 7.78 (td, J = 7.5, 1.5 Hz, 1 H), 7.04 (d,
J = 8.5 Hz, 1 H). 13C NMR (CDCl3): d = 179.56, 177.18,
143.22, 141.38, 140.24, 135.44, 133.98, 131.95, 129.79,
127.59, 127.39, 126.89, 124.95, 123.85, 122.82, 122.78,
122.73, 122.69, 122.53, 122.28, 121.68, 121.52.
Compound 2f:14 1H NMR (DMSO-d6): d = 8.04 (dd, J = 8.0,
1.0 Hz, 2 H), 7.88 (td, J = 7.5, 1.5 Hz, 1 H), 7.82 (td, J = 7.5,
1.5 Hz, 1 H), 7.68 (d, J = 3.0 Hz, 1 H), 7.46 (dd, J = 9.0, 3.0
Hz, 1 H), 7.32 (d, J = 9.0 Hz, 1 H), 3.93 (s, 1 H). 13C NMR
(DMSO-d6): d = 180.51, 177.53, 149.63, 143.83, 138.82,
135.53, 134.02, 132.50, 132.29, 130.90, 130.71, 127.24,
126.79, 120.91, 115.19, 114.44, 57.50.
Compound 3b: 1H NMR (CDCl3): d = 8.40 (s, 2 H), 8.24 (m,
4 H), 8.13 (dd, J = 9.0, 2.0 Hz, 2 H), 7.85 (dd, J = 6.0, 3.5
Hz, 2 H), 6.56 (d, J = 9.0 Hz, 2 H). 13C NMR (CDCl3): d =
180.55, 141.30, 139.97, 135.07, 130.50, 127.87, 127.37,
123.87, 122.76, 122.72, 122.67, 122.63, 121.68, 119.49,
118.47, 118.21.
Compound 3f: 1H NMR (DMSO-d6): d = 8.03 (dd, J = 5.5,
3.5 Hz, 2 H), 7.81 (dd, J = 5.5, 3.5 Hz, 2 H), 6.90 (d, J = 9.0
Hz, 2 H), 6.74 (d, J = 2.0 Hz, 2 H), 6.63 (dd, J = 9.0, 2.0 Hz,
2 H), 3.77 (s, 6 H). 13C NMR (DMSO-d6): d = 181.40,
147.50, 138.47, 134.34, 131.90, 131.19, 126.35, 126.17,
124.13, 116.39, 113.60, 57.51.
Compound 2c: 1H NMR (CDCl3): d = 8.26 (s, 2 H), 8.18 (m,
1 H), 8.12 (m, 1 H), 7.80 (td, J = 7.5, 1.5 Hz, 1 H), 7.74 (td,
J = 7.5, 1.0 Hz, 1 H), 7.28 (s, 1 H). 13C NMR (CDCl3): d =
178.88, 177.00, 145.36, 140.96, 140.00, 135.20, 133.57,
132.84, 131.99, 129.75, 127.31, 127.19, 123.44, 118.34.
Compound 2d: 1H NMR (DMSO-d6): d = 8.02–8.04 (m, 2
H), 7.90–7.92 (m, 2 H), 7.86 (td, J = 7.5, 1.0 Hz, 1 H), 7.81
(td, J = 7.5, 1.0 Hz, 1 H), 7.56 (t, J = 8.0, 1 H), 7.50 (dt,
J = 8.0, 1.0 Hz, 1 H). 13C NMR (DMSO-d6): d = 180.47,
177.77, 148.16, 143.42, 140.98, 135.48, 134.24, 132.39,
131.09, 129.91, 129.79, 127.28, 126.90, 118.91, 117.98,
117.79.
Compound 2g: 1H NMR (DMSO-d6): d = 8.04–8.07 (m, 2
H), 7.89 (td, J = 7.5, 1.5 Hz, 1 H), 7.84 (td, J = 7.5, 1.0 Hz,
1 H), 7.77 (d, J = 2.5 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.42
(dd, J = 9.0, 2.5 Hz, 1 H). 13C NMR (DMSO-d6): d = 180.38,
177.77, 147.65, 143.20, 140.04, 135.47, 134.31, 132.30,
131.60, 131.10, 128.07, 127.29, 126.91, 119.50, 119.28,
119.18.
Compound 2h: 1H NMR (CDCl3): d = 9.49 (s, 1 H), 8.22 (dd,
J = 6.5, 1.0 Hz, 1 H), 8.16–8.21 (m, 2 H), 7.81 (td, J = 8.0,
1.5 Hz, 1 H), 7.76 (td, J = 7.5, 1.0 Hz, 1 H), 7.58 (td, J = 8.0,
1.5 Hz, 1 H), 7.20 (td, J = 6.0, 1.0 Hz, 1 H), 6.90 (m, 1 H).
13C NMR (CDCl3): d = 179.71, 177.41, 140.54, 139.46,
135.06, 133.77, 133.62, 133.61, 131.99, 130.19, 127.39,
127.31, 125.95, 124.08, 123.26, 121.88.
Compound 3d: 1H NMR (DMSO-d6): d = 8.05 (dd, J = 6.0,
3.0 Hz, 2 H), 7.82 (J = 6.0, 3.0 Hz, 2 H), 7.42 (dd, J = 8.5,
1.5 Hz, 2 H), 7.06–7.11 (m, 4 H), 6.72 (dd, J = 8.5, 2.0 Hz,
2 H). 13C NMR (DMSO-d6): d = 181.58, 147.45, 139.23,
134.55, 131.89, 128.61, 126.53, 126.07, 124.88, 115.47,
114.24.
Compound 3h: 1H NMR (DMSO-d6): d = 8.10 (dd, J = 5.5,
3.0 Hz, 2 H), 7.86 (dd, J = 5.5, 2.5 Hz, 2 H), 7.68 (dd,
J = 8.5, 1.5 Hz, 2 H), 7.27 (m, 2 H), 6.78 (m, 4 H). 13C NMR
(DMSO-d6): d = 181.34, 137.02, 135.04, 134.42, 133.45,
131.66, 126.89, 125.66, 124.54, 122.33, 122.23.
Compound 2e:14 1H NMR (CDCl3): d = 8.20 (dd, J = 7.5, 1.0
Hz, 1 H), 8.14 (dd, J = 7.5, 1.0 Hz, 1 H), 7.80 (td, J = 7.5, 1.5
Hz, 1 H), 7.70–7.74 (m, 2 H), 7.63 (s, 1 H), 7.32 (d, J = 8.5
Hz, 1 H), 7.19 (dd, J = 8.0, 2.0 Hz, 1 H), 2.61 (s, 3 H).
Compound 3e: 1H NMR (DMSO-d6): d = 8.01 (dd, J = 5.5,
3.5 Hz, 2 H), 7.79 (dd, J = 5.5, 3.5 Hz, 2 H), 6.93 (d, J = 8.5
Hz, 2 H), 6.78 (d, J = 2.0 Hz, 2 H), 6.50 (dd, J = 8.0, 2.0 Hz,
Compound 2i:14 1H NMR (DMSO-d6): d = 8.86 (s, 1 H), 8.42
(d, J = 6.0 Hz, 1 H), 8.06–8.12 (m, 2 H), 7.90–7.95 (m, 2 H),
7.40 (d, J = 9.0 Hz, 1 H).
(17) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 204.
Synlett 2006, No. 6, 942–944 © Thieme Stuttgart · New York