Synthesis of Aminonaphthoquinones
J . Org. Chem., Vol. 62, No. 1, 1997
9
19b as a dark red powder: mp 168-170 °C (lit.21a mp 170-
171 °C); IR ν 3435, 3323, 3288, 1685 cm-1; 1H NMR δ 8.14 (m,
2H), 7.72 (m, 2H), 7.23 (s, 5H), 6.01 (s, 2H); MS m/ z 281 (M+,
61), 264 (5), 248 (16), 165 (5), 121 (100), 104 (15), 89 (16).
Sch em e 5
2-Am in o-3-m eth yl-1,4-n a p h th oqu in on e (19c). Follow-
ing the general procedure, 280 mg (1.63 mmol) of 2-methyl-
1,4-naphthoquinone (16c) afforded, after chromatographic
purification using 30% EtOAc/hexane as eluent, 180 mg (59%)
of 19c as a red powder: mp 158-159 °C (lit.21a mp 157-158
°C); IR ν 3450, 3338, 1667, 1615 cm-1; 1H NMR δ 8.20 (m, 2H),
7.78 (m, 2H), 5.15 (s, 2H), 2.19 (s, 3H); MS m/ z 187 (M+, 100),
160 (44), 130 (72), 104 (35), 76 (72), 54 (53).
2-Am in o-5,8-d ih yd r oxy-1,4-n a p h th oqu in on e (19d ). To
a stirred solution of 5,8-dihydroxy-1,4-naphthoquinone (16d )
(80 mg, 0.42 mmol) in 80 mL of methanol under argon was
added a solution of sodium azide (220 mg, 3.37 mmol) in 5
mL of water, acidified to pH 4 (with 1 N HCl). The reaction
mixture was stirred at 50 °C for 20 h. Then the mixture was
extracted with EtOAc, and the organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was crystallized from ether-hexane to afford 65 mg
(75%) of 19d as a dark red powder: mp 254-255 °C (lit.21a
kinase inhibitor24 (Scheme 5). Thus, starting from ben-
zoquinone 23a , compound 27 was readily prepared and
then converted efficiently to amine 28 upon treatment
with NaBH4/NiCl2 with 62% total yield for three steps
vs 12% of the recently reported procedure.25
1
mp >250 °C); IR ν 3410, 3140, 1655, 1575 cm-1; H NMR δ
In conclusion, we can state that the azide anion
addition to naphthoquinones and benzoquinones is an
interesting reaction that provides direct access to ami-
nonaphthoquinones and azidobenzohydroquinones, re-
spectively. In this report, the mechanism and various
aspects of this reaction are investigated, and a method
of general applicability for their high-yield synthesis
under mild experimental conditions is provided.
11.90 (s, 1H), 10.95 (s, 1H), 7.25 (d, J ) 10.9 Hz, 1H), 7.12 (d,
J ) 10.9 Hz, 1H), 5.90 (s, 1H), 5.30 (br, 2H); MS m/ z 205 (M+,
100), 178 (15), 136(9), 123 (17), 108 (8), 53 (10).
3-Am in o-5-h yd r oxy-1,4-n a p h th oqu in on e (19e). Follow-
ing the general procedure, 280 mg (1.61 mmol) of 5-hydroxy-
1,4-naphthoquinone (16e) afforded 295 mg (97%) of 19e as a
red powder: mp 253-254 °C (lit.21a mp >250 °C); IR ν 3398,
1
1600, 1580 cm-1; H NMR δ 11.57 (s, 1H), 7.64 (m, 2H), 7.18
(d, J ) 7.2 Hz, 1H), 5.98 (s, 1H), 5.18 (s, 2H); MS m/ z 189
(M+, 100), 162 (52), 132 (20), 121 (29), 92 (31), 63 (21).
Exp er im en ta l Section
2-Am in o-5-m eth oxy-1,4-n a p h th oqu in on e (19f). Follow-
ing the general procedure, 280 mg (1.49 mmol) of 5-methoxy-
1,4-naphthoquinone (16f) afforded, after chromatographic
purification using 50% EtOAc/hexane as eluent, 175 mg (58%)
of 19e as a yellow powder: mp 156-158 °C (lit.21a 157-158
°C); IR ν 3420, 3315, 1610, 1560 cm-1; 1H NMR δ 7.80 (d, J )
7.3 Hz, 1H), 7.72 (tr, J ) 8 Hz, 1H), 7.22 (d, J ) 7.3 Hz, 1H),
5.95 (s, 1H), 5.29 (br, 2H), 4.05 (s, 3H); MS m/ z 203 (M+, 25),
189 (8), 149 (23), 84 (55), 69 (77), 55 (73), 43 (100).
2-Azid o-1,4-n a p h th oqu in on e (20).10a To an ice-cold (0 °C)
solution of naphthoquinone (40 mg, 0.25 mmol) in 2.5 mL of
methanol was added a solution of sodium azide (98 mg, 1.5
mmol) in 1 mL of water, acidified (with 1 N HCl) to pH 4. The
reaction mixture was stirred at 0 °C for 1 h and then extracted
with EtOAc, washed with water and brine, dried over Na2-
SO4, and concentrated. The residue was chromatographed
using 5% Et2O/hexane, yielding 27 mg (45%) of 20 as an
amorphous solid: IR ν 2100, 1674, 1645, 1592, 1570 cm-1; 1H
NMR δ 8.08 (m, 2H), 7.75 (m, 2H), 6.45 (s, 1H).
Gen er a l P r oced u r e for th e Syn th esis of Azid o-1,4-
ben zoh yd r oqu in on es. To a dry ice-acetone (-78 °C) stirred
solution of benzoquinone (2.6 mmol) in 10 mL of methanol
under argon atmosphere was added a solution of sodium azide
(9.4 mmol) in 10 mL of methanol/water (2:3 vol/vol), acidified
(with 1 N HCl) to pH 4. The mixture was stirred at -78 °C
for 1 h, concentrated, and partitioned between CH2Cl2 and
water. The organic layer was evaporated under reduced
pressure and chromatographed using 25% EtOAc/hexane,
yielding the azido-1,4-benzohydroquinone product.
Gen er a l P r oced u r es. Reaction progress was monitored
with analytical TLC on 0.25 mm silica gel precoated glass
plates with fluorescent indicator UV254 (Merck). Flash chro-
matography was conducted with Merck silica gel 32-63 mm
packing. Melting points were determined in open capillary
tubes and are uncorrected. IR spectra were obtained in
accordance with the KBr disk technique. 1H NMR spectra
were recorded at 200 MHz in CDCl3 using TMS as internal
standard. Mass spectra were acquired by electron impact at
70 eV. Solvents and commercial reagents were purchased as
analytical reagent grade and used without any further puri-
fication. Starting quinones were purified by crystallization or
sublimation, since the reaction yields depend strongly on their
purity.
Gen er a l P r oced u r e for th e Syn th esis of 2-Am in o-1,4-
n a p h th oqu in on es. To a stirred solution of naphthoquinone
(1.8 mmol) in 15 mL of methanol under argon was added a
solution of sodium azide (10.6 mmol) in 5 mL of water, acidified
to pH 4 (with 1 N HCl). The reaction was stirred at rt (or 50
°C) and monitored by TLC (the exact times and temperatures
are depicted in Table 1), and then the mixture was extracted
twice with EtOAc and the combined organic layers were
washed with water and brine, dried over Na2SO4, and con-
centrated. The residue was crystallized from an ether-hexane
mixture.
2-Am in o-1,4-n a p h th oqu in on e (19a ). Following the gen-
eral procedure, 280 mg (1.79 mmol) of naphthoquinone (16a )
afforded 297 mg (97%) of 19a as an orange powder: mp 202-
2-Azid o-1,4-ben zoh yd r oqu in on e (24a ). Following the
general procedure, 280 mg (2.59 mmol) of benzoquinone (23a )
afforded 344 mg (88%) of 24a as a pink powder: mp 97-99
204 °C (lit.21a 204-205 °C); IR ν 3392, 1685, 1618 cm-1 1H
;
NMR δ 8.07 (m, 2H), 7.68 (m, 2H), 6.01 (s, 1H), 5.14 (s, 2H);
MS m/ z 173 (M+, 89), 146 (52), 145 (25), 117 (15), 105 (74),
104 (40), 76 (100), 50 (42).
°C; IR ν 3320, 2105 cm-1 1H NMR δ 6.79 (d, J ) 10.7 Hz,
;
1H), 6.72 (s, 1H), 6.57 (m, 1H), 4.95 (s, 1H), 4.68 (s, 1H); MS
m/ z 151 (M+, 29), 123 (19), 110 (100), 109 (29), 95 (52), 82
(29), 68 (39), 53 (39). Anal. Calcd for C6H5O2N3: C, 47.69; H,
3.33; N, 27.80. Found C, 47.55; H, 3.12; N, 28.01.
2-Am in o-3-(ph en ylth io)-1,4-n aph th oqu in on e (19b). Fol-
lowing the general procedure, 280 mg (1.05 mmol) of 2-(phe-
nylthio)-1,4-naphthoquinone (16b) afforded 242 mg (82%) of
2-Az i d o -5-(p h e n y lt h i o )-1,4-b e n z o h y d r o q u i n o n e -
(24b).14 Following the general procedure, 280 mg (1.30 mmol)
of 2-(phenylthio)benzoquinone (23b) afforded 265 mg (79%) of
(24) (a) Imoto, M.; Kakeya, H.; Sawa, T.; Hayashi, C.; Hamada, M.;
Takeuchi, T.; Umezawa, K. J . Antibiot. 1993, 46, 1342. (b) Kakeya,
H.; Imoto, M.; Takahashi, Y.; Naganawa, H.; Takeuchi, T.; Umezawa,
K. J . Antibiot. 1993, 46, 1716.
24b as an ivory powder: mp 99-101 °C; IR ν 3350, 2075 cm-1
;
(25) Hamel, P.; Girard, Y. Tetrahedron Lett. 1994, 35, 8101.
1H NMR δ 7.22 (m, 6H), 6.85 (s, 1H), 6.25 (s, 1H), 4.95 (s, 1H);