N. S. Polonik, S. G. Polonik / Tetrahedron Letters 57 (2016) 3303–3306
3305
Table 1
Transformation of 3-amino-2-hydroxynaphthazarins to 2,3-dihydroxynaphthazarins
OH
O
OH
OH
O
O
R2
R1
R2
R1
OH
OH
OH
Method A: DMSO-HCOOH-H2O
Method B: DMSO-HCOOH-H2SO4-H2O
NH2
OH
O
Entrya
Aminoquinoneb
R1
Hydroxyquinone
Yield (%)
R2
Method Ad
Method Be
1
2
3
4
5
6
7
8
7ac
7b
7c
H
Me
Et
t-Bu
Me
Cl
Cl
Me
Et
OMe
OMe
OMe
OEt
OEt
OH
OH
H
H
H
H
1
2
3
80
60
68
76
80
68
34
74
63
50
57
60
80
44
63
75
89
88
80
80
88
76
87
86
82
85
82
84
82
86
80
81
7d
7ec
7f
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8lf
4f
Me
H
Cl
Cl
Cl
H
Me
Et
Me
Et
Me
Et
7gc
7h
7i
9
10
11
12
13
14
15
16
7j
7k
7l
7m
7n
7oc
7pc
a
b
c
d
e
f
Reactions were performed on a 0.2-mmol scale.
Mixtures of regioisomers unless otherwise indicated.
Single isomer of the starting aminoquinone.
Reaction conditions: DMSO (2 mL), HCOOH (2 mL, 85%), reflux (4.5 h).
Reaction conditions: DMSO (200
Reflux (10 min).
lL, 0.35 mmol), HCOOH (4 mL, 85%), H2SO4 (1 mL, 25%), reflux (30 min).
The reaction was extended to different 3-amino-2-hydrox-
and could decompose or undergo transformation to tetraone C by
the elimination of two water molecules. In fact an equilibrium
between tetraone C and its hydrated form D has been reported.27
We believe that another mechanism for the acid-catalyzed
transformation was present using Method B (Scheme 1, path B).
In this case sulfuric acid protonates the carbonyl group to give acti-
vated quinone F. The addition of formic acid to the activated dou-
ble bond of quinone F leads to the unstable intermediate G, which
is converted to spinazarins 2, 3 with the elimination of dimethyl-
sulfide and carbon dioxide. Evidently, this step proceeds as a con-
certed process in contrast with path A. The proposed mechanism
explains the critical role of sulfuric acid for the protonation of
aminoquinones, as well as quinone intermediates, and shows that
formic acid is involved in the reaction as a reducing agent (steps
F?G?2, 3).
With the improved method in hand we synthesized a series of
2,3-dihydroxynaphthazarins 1–4, 8a–l (Table 1, entries 1–16,
method B). 3-Amino-2-hydroxynaphthazarins 7a–n reacted
smoothly with DMSO–HCOOH–H2SO4–H2O in 30 min to give 2,3-
dihydroxynaphthazarins 1–3, 8a–k in good to excellent yields.
Aminoquinones 7o, p were converted to dihydroxyquinones 8l, 4
in only 10 min in 80% and 81% yield, respectively. Notably, we
did not detect tetraone hydrate D in these experiments and pure
samples of hydroxynaphthazarins were obtained using this
method.
yquinones (Table 1, entries 1–16, method A). We found that
aminonaphthazarins 7a–f, 7h–p were converted into 2,3-dihy-
droxynaphthazarins by heating at reflux in DMSO–HCOOH–H2O
in moderate to good yields. However, aminoquinone 7g, bearing
two chlorine atoms on the benzene ring, was converted to 8d in
only 34% yield (entry 7). Aminoquinones 7o, p reacted with
DMSO–HCOOH–H2O in only 10 min to give pure hydroxyquinones
8l and 4 in 63% and 75% yields, respectively (entries 15 and 16).
We continued our investigation to develop an effective method
of acid-catalyzed transformation. To simplify product isolation, a
smaller amount of DMSO (200 lL per 0.2 mmol of aminoquinone)
was used in subsequent experiments. It was also established that
the addition of sulfuric acid to the DMSO–HCOOH–H2O system
dramatically accelerated the rate of reaction and gave better yields
of spinazarins. Thus, heating aminoquinones 7b, 7c at reflux for
30 min led to spinazarins 2, 3 in 88% and 80% yields, respectively
(Table 1, method B, entries 2 and 3). Gratifyingly, even traces of tet-
raone hydrate D were not detected and only pure 2,3-dihydroxy-
naphthazarins were isolated. Nevertheless, the formation of
dimethylsulfide was also observed under these conditions.
Reaction mechanisms were proposed for each set of conditions
(Scheme 1, path A and B). The conversion of the aminoquinone to
the hydroxyquinone involves several stages. In the first step in
both pathways, dimethylsulfoxide is added to the C@CAC@O qui-
nonoid core of the protonated aminoquinone followed by elimina-
tion of ammonia and the formation of DMSO–quinone conjugates B
and F. Intermediate B is easily converted to tetraone C with the
elimination of dimethylsulfide. For tetraone C two feasible trans-
formations are possible. In the first transformation, it can be
reduced by HCOOH to give spinazarins 2 or 3. In the second trans-
formation, hydration of tetraone C occurs and tetraone dihydrate D
is formed. Dihydrate D is unstable under the reaction conditions
Conclusion
In conclusion, a operationally simple, versatile, and effective
route for the synthesis of natural and related 6,7-substituted 2,3-
dihydroxynaphthazarins has been developed. The method uses
inexpensive and readily available reagents and allows obtaining
chloro- and alkoxy- derivatives of various natural 2,3-dihydroxy-