A convenient preparation of 7-bromo-2H-1,4-benzothiazine-3,5,8(4H)-trione and its application in the synthesis of the conaquinone B skeleton

Article abstract of DOI:10.1055/s-2007-990895

7-Bromo-2H-1,4-benzothiazine-3,5,8(4H)-trione was synthesized by reaction of 5-bromo-2-nitro-1,4-benzoquinone with methyl thioglycolate followed by reductive cyclization and oxidation. The Diels-Alder reaction of the product quinone with myrcene afforded

Full text of DOI:10.1055/s-2007-990895

SHORT PAPER
3773
A Convenient Preparation of 7-Bromo-2H-1,4-benzothiazine-3,5,8(4H)-trione
and Its Application in the Synthesis of the Conaquinone B Skeleton
A
Convenient
Sy
i
nthesis
cof the Conaquinone
B
r
Skeletondo A. Tapia,* Lorena Villalobos, Cristian Salas
Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 2609441, Chile
Fax +56(2)6864744; E-mail: rtapia@puc.cl.
Received 11 May 2007
account that a known method to obtain 2H-1,4-benzothi-
Abstract: 7-Bromo-2H-1,4-benzothiazine-3,5,8(4H)-trione was
synthesized by reaction of 5-bromo-2-nitro-1,4-benzoquinone with
methyl thioglycolate followed by reductive cyclization and oxida-
tion. The Diels–Alder reaction of the product quinone with myrcene
afforded the expected naphthothiazine.
azinones is by cyclization of (2-nitrophenylsulfanyl)ace-
tate esters,7 we decided to apply the reaction of methyl
thioglycolate with 2-nitro-1,4-benzoquinones8 to the
preparation of a suitable precursor of 4. Nitrobenzoqui-
nones could be useful substrates for the synthesis of het-
erocyclic quinones,9 but their use is limited by their low
stability at room temperature.10 The synthesis of the re-
quired nitrobenzoquinone 10 and of compound 6 is de-
scribed in Scheme 1.
Key words: natural products, quinines, Diels–Alder reactions, het-
erocycles, nitro compounds
Shermilamine A (1) and B (2)1 are members of the pyri-
doacridines alkaloids group2 of marine natural products
that incorporate a 1,4-thiazine ring fused to the pyri-
doacridine system. On the other hand, conaquinones A (3)
and B (4), a different type of marine natural product, have
a 1,1-dioxo-1,4-thiazine ring fused to a quinone moiety3
(Figure 1).
O
H
N
S
O
O
4
O
N
H
O
N
O
H
N
O
O
N
S
+
R
H
X
Y
S
Br
NHAc
1 = Br
2 = H
O
5
6
O
Figure 2 Retrosynthesis of conaquinone B
3 X = SO2, Y = NH
4 X = NH, Y = SO2
Our synthesis of quinone 10 began with commercially
available 1-bromo-2,5-dimethoxybenzene (7), which was
treated with nitric acid in acetic acid at room temperature
to give 1-bromo-2,5-dimethoxy-4-nitrobenzene (8) al-
most quantitatively. The 1H NMR spectrum of this com-
pound showed two singlets at d = 7.32 and 7.45
confirming that nitration occurs para to the bromine atom.
Then, demethylation of dimethyl ether 8 with hydrobro-
mic acid in acetic acid under reflux for four hours afforded
hydroquinone 9 in 89% yield. Next, oxidation of hydro-
quinone 9 was carried out with nitric acid impregnated
manganese(IV) oxide11 in dichloromethane at 0–5 °C for
45 minutes; however, the product, quinone 10, was unsta-
ble at room temperature and light-sensitive. Therefore, af-
ter oxidation of hydroquinone 9, the solids were removed
by filtration through a sintered-glass funnel under a nitro-
gen atmosphere and quinone 10 was trapped with methyl
thioglycolate to give hydroquinone 11 in 87% yield. The
optimal conditions for the reductive cyclization of methyl
(2-nitrophenylsulfanyl)acetate 11 were subsequently de-
termined. A number of methods have been used to reduce
Figure 1 Structures of shermilamine A (1) and B (2) and conaqui-
none A (3) and B (4)
The cytotoxic activity described for compounds 1–4 has
stimulate interest in their synthesis for the development of
new types of antitumor agents. The preparation of sherm-
ilamine B (2) by Ciufolini et al.4 via nitrene thermophoto-
lysis of an aryl azide is the only synthetic work available
for the total synthesis of compounds 1–4.
As part of our continuing interest in biologically active
heterocyclic quinones,5 we describe here an easy access to
1,4-benzothiazine-3,5,8(4H)-trione 6 and the synthesis of
the conicaquinone B (4) skeleton. Retrosynthetic analysis
(Figure 2) suggested that the carbon framework of 4
should be accessible by Diels–Alder reaction of myrcene
(5) with quinone 6. Recently, Townsend and Jackson
failed to obtain 6 from 2,5-dimethoxyaniline.6 Taking into
SYNTHESIS 2007, No. 24, pp 3773–3775
x
x.
x
x
.
2
0
0
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Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990895; Art ID: M03307SS
© Georg Thieme Verlag Stuttgart · New York

3774
R. A. Tapia et al.
SHORT PAPER
Melting points were determined with a Meltemp apparatus and are
not corrected. IR spectra were obtained in CDCl3 on a Bruker Model
Vector 22 spectrophotometer. H NMR spectra were recorded in
O
OR
OMe
NO2
NO2
1
a, b
c
CDCl3 with TMS as reference on Bruker ACP-200 and AM-400 in-
struments. 13C NMR spectra were recorded in CDCl3 at 50 and 100
MHz. Column chromatography was performed on silica gel Merck
60 (70–230 mesh). Elemental analyses were performed on a Fison
EA 1108 CHNS-O analyzer. Accurate MS measurements were de-
termined using a Thermo Finnigan MAT 95XP spectrometer at the
Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile.
Br
Br
Br
O
OR
OMe
8 R = Me
9 R = H
10
7
H
N
OH
OH
OH
NO2
1-Bromo-2,5-dimethoxy-4-nitrobenzene (8)
O
e
d
10
HNO3 (2 mL) was added to a stirred soln of 1-bromo-2,5-dimeth-
oxybenzene (7, 5.0 g, 23.04 mmol) in AcOH (10 mL) at r.t. After 15
min, H2O (40 mL) was added and the mixture was stirred for 10 min
at r.t. to give a yellow precipitate. The solid was filtered, washed
with H2O and dried at r.t. to give solely nitro isomer 8 (5.90 g, 98%);
mp 150–151 °C (EtOH).
IR (KBr): 1566, 1513, 1490, 1340, 1040 cm–1.
1H NMR: d = 3.90 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 7.32 (s, 1
H, H6), 7.45 (s, 1 H, H3).
SCH2CO2Me
S
Br
Br
OH
O
11
12
H
H
N
O
O
N
O
O
g
f
13C NMR: d = 57.0 (CH3), 57.3 (CH3), 108.6 (CH), 118.5 (C), 119.3
(CH), 136.0 (C), 147.5 (C), 149.5 (C).
S
S
Br
O
HRMS: m/z calcd for C8H8BrNO4: 260.96367; found: 260.96296.
6
13
Scheme 1 Reagents and conditions: (a) HNO3, AcOH, r.t., 98%; (b)
HBr, AcOH, reflux, 4 h, 89%; (c) HNO3/MnO2, CH2Cl2, 0–5 °C, 45
min; (d) HSCH2CO2Me, CH2Cl2, r.t., 2 h, 87% from 9; (e) Fe, EtOH,
5% HCl, reflux, 4 h; (f) Ag2O, CH2Cl2, r.t., 30 min, 64% from 11; (g)
(i) 5, toluene, reflux, 9 h, (ii) DBU, r.t., 4 h, 67%.
1-Bromo-2,5-dihydroxy-4-nitrobenzene (9)
A soln of 8 (1.5 g, 5.72 mmol) in AcOH (25 mL) and 48% aq HBr
(100 mL) was heated to reflux for 4 h. After cooling, the mixture
was extracted with EtOAc (4 × 20 mL) and the combined extracts
were washed with H2O and dried (MgSO4). The solvent was evap-
orated under reduced pressure and the residue was purified by col-
umn chromatography (CH2Cl2) to give hydroquinone 9 (1.19 g,
89%) as an orange solid; mp 115–116 °C.
IR (KBr): 3448, 1572, 1519, 1300, 1177 cm–1.
1H NMR: d = 5.53 (s, 1 H, OH), 7.38 (s, 1 H, H6), 7.72 (s, 1 H, H3),
10.15 (s, 1 H, OH).
the aromatic nitro group, but many of them produce hy-
drogenolysis of carbon–halogen bonds.12 Initially, reduc-
tion of 11 was attempted with tin(II) chloride/
hydrochloric acid in refluxing ethanol because it was used
to obtain benzothiazinones from (2-nitrophenylsulfa-
nyl)acetate esters,7 but in our case the reduction of the ni-
tro group was not selective and hydrodehalogenation of
the C–Br bond was also observed. After exploring several
reaction conditions, we found that a highly selective re-
duction of 11 could be accomplished using iron in the
presence of hydrochloric acid in refluxing ethanol for four
hours. Under these conditions, the resulting hydroquinone
12 was immediately converted into 1,4-benzothiazine-
3,5,8(4H)-trione 6 using silver(I) oxide (64% yield over
two steps).
13C NMR: d = 109.9 (CH), 121.5 (C), 122.9 (CH), 133.0 (C), 145.7
(C), 146.7 (C).
HRMS: m/z calcd for C6H4BrNO4: 232.93237; found: 232.93150.
Methyl (3-Bromo-2,5-dihydroxy-6-nitrophenylsulfanyl)acetate
(11)
To a stirred soln of hydroquinone 9 (500 mg, 2.14 mmol) in CH2Cl2
(20 mL) cooled to 0 °C, HNO3-impregnated MnO2 (2.8 g) contain-
ing anhyd MgSO4 (1.0 g) was added. The mixture was stirred for 45
min at 0 °C under N2 and protected from light. The suspension was
filtered through a sintered-glass funnel under N2 and the filtrate was
added to a cooled soln (0 °C) of methyl thioglycolate (300 mg, 2.8
mmol) under N2. The solution was further stirred for 2 h and then
subsequent evaporation of the solvent gave 11 as an orange oil (630
mg, 87%).
IR (KBr): 3363, 1701, 1573, 1537, 1376, 1289 cm–1.
1H NMR: d = 3.79 (s, 3 H, CH3), 3.84 (s, 2 H, CH2), 7.50 (s, 1 H,
H4), 8.84 (s, 1 H, OH), 8.95 (s, 1 H, OH).
Finally, the Diels–Alder reaction of bromoquinone 6 with
myrcene (5) was studied. It has been shown that a bromo
atom on the quinone nucleus controls the regiochemistry
of the Diels–Alder reaction.13 Furthermore, high regiose-
lectivity was observed in the reaction of 2,5-dichloro-1,4-
benzoquinone with myrcene (5).14 Thus, cycloaddition of
bromoquinone 6 with myrcene (5) in toluene at reflux for
12 hours, and aromatization of the crude adduct with 1,8-
diazabicyclo[5.4.0]undec-7-ene gave heterocyclic qui-
none 13 in 67% yield.
13C NMR: d =39.1 (CH2), 53.5 (CH3), 95.4 (C), 120.3 (C), 126.1
(CH), 137.1 (C), 147.0 (C), 151.5 (C), 165.7 (C).
HRMS: m/z calcd for C9H8BrNO6S: 336.92556; found: 336.92471.
7-Bromo-2H-1,4-benzothiazine-3,5,8(4H)-trione (6)
In summary, we have reported a convenient synthesis of
the conaquinone B skeleton. The synthesis of shermil-
amine B analogues from 7-bromo-2H-1,4-benzothiazine-
3,5,8(4H)-trione (6) is in progress.
To a soln of hydroquinone 11 (500 mg, 1.49 mmol) in EtOH (15
mL) and 20% aq AcOH (6 mL) was added iron powder (10 mm. Al-
drich, 363 mg, 6.5 mmol) followed by 5% aq HCl (0.5 mL). The
mixture was vigorously stirred at reflux for 4 h, then cooled to r.t.,
Synthesis 2007, No. 24, 3773–3775 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient Synthesis of the Conaquinone B Skeleton
3775
diluted with EtOAc (80 mL), and filtered through a Celite pad. The
filtrate was washed with 5% aq NaHCO3 (40 mL) and H2O (2 × 50
mL). The organic phase was dried (Na2SO4), filtered, concentrated
in vacuo, and the residue was dissolved in CH2Cl2 (15 mL). Ag2O
(626 mg, 2.7 mmol) was added and the suspension was stirred at r.t.
for 30 min and filtered. After evaporation of the solvent the residue
was purified by flash chromatography to afford quinone 6 (260 mg,
64%) as an orange solid, mp 170–171 °C.
IR (KBr): 3199, 1652, 1459, 1033 cm–1.
1H NMR: d = 3.54 (s, 2 H, CH2), 7.31 (s, 1 H, H6), 8.10 (s, 1 H, NH).
13C NMR: d = 28.5 (CH2), 119.5 (C), 134.2 (C), 135.4 (CH), 138.5
(C), 160.6 (C), 174.7 (C), 175.6 (C).
References
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HRMS: m/z calcd for C8H4BrNO3S: 272.90952; found: 272.90866.
7-(4-Methylpent-3-enyl)-2H-naphtho[2,3-b][1,4]thiazine-
3,5,10(4H)-trione (13)
To a soln of quinone 6 (150 mg, 0.55 mmol) in toluene (10 mL) was
added myrcene (5, 75 mg, 0.55 mmol) and the mixture was heated
to reflux for 9 h. After evaporation of the solvent the residue was
dissolved in CH2Cl2 (10 mL), DBU (84 mg, 0.55 mmol) was added,
and the mixture was stirred at r.t. for 4 h. The solvent was evaporat-
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1H NMR: d =1.52 (s, 3 H, CH3), 1.67 (s, 3 H, CH3), 2.30–2.40 (m,
2 H, CH2), 2.7–2.8 (m, 2 H, CH2), 3.53 (s, 2 H, CH2), 5.1–5.2 (m, 1
H, CH), 7.55 (dd, J = 7.9, 1.7 Hz, 1 H, H8), 7.9 (d, J = 1.7 Hz, 1 H,
H6), 7.99 (d, J = 7.9 Hz, 1 H, H9), 8.55 (s, 1 H, NH).
13C NMR: d = 17.7 (CH3), 25.6 (CH3), 28.3 (CH2), 29.2 (CH2), 36.2
(CH2), 122.4 (CH), 123.5 (C), 127.0 (CH), 127.2 (CH), 129.8 (C),
130.2 (C), 133.4 (C), 134.8 (CH), 135.5 (C), 149.7 (C), 161.1 (C),
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HRMS: m/z calcd for C18H17NO3S: 327.09292; found: 327.09275.
Acknowledgment
We are grateful to FONDECYT (Research Grant 1060592) for fi-
nancial support.
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Synthesis 2007, No. 24, 3773–3775 © Thieme Stuttgart · New York