Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione, the B,C,D ring core of the shermilamine alkaloids

Article abstract of DOI:10.1039/b307124c

The synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-trione(4), from N-(4-bromo-2,5-dimethoxyphenyl)acetamide was discussed. Oxidative cyclisation of 2,2′-disulfanediylbis[N-2,5-dimethoxyphenyl)acetamide] to 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H)-one(7b) was reported. It was found that the reaction proceeded through the disulfide and iodine acted as an oxidizing agent, enabling the cyclization.

Full text of DOI:10.1039/b307124c

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Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H)-
trione, the B,C,D ring core of the shermilamine alkaloids
Norman O. Townsend and Yvette A. Jackson*
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica,
West Indies
Received 25th June 2003, Accepted 27th August 2003
First published as an Advance Article on the web 24th September 2003
Synthesis of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-2,5,10(3H )-trione (4), from N-(4-bromo-2,5-
dimethoxyphenyl)acetamide (23) is described. Oxidative cyclisation of 2,2Ј-disulfanediylbis[N-(2,5-
dimethoxyphenyl)acetamide] (19) to 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H )-one (7b) is also reported.
i) hetero-Diels–Alder reaction on a thiazinoquinone or
ii) building the thiazinone ring onto a quinolinequinone.
We set out to explore these pathways.
Introduction
Pyridoacridine alkaloids of basic skeleton 1 are secondary
metabolites of marine invertebrates, which show a wide range
of biological activity.1 They vary in structure by having
different side chain appendages or different heterocyclic rings
fused to ring C. Shermilamine A and B (2 and 3) have a 2H-1,4-
thiazin-3(4H )-one ring fused to ring C.
Results and discussion
Formation of 4 by the hetero-Diels–Alder reaction would
require bromoquinone 6, the bromo substituent set to direct the
regiochemistry of the cycloaddition.2 7-Bromo-5,8-dimethoxy-
2H-1,4-benzothiazin-3(4H )-one (7a) was therefore the target
of this pathway, since it seemed that 6 could be obtained by
oxidative demethylation of 7a.
Popular methods for the synthesis of 2H-1,4-thiazin-3(4H )-
ones include condensation of 2-aminothiophenols with glycidyl
esters,3 2-haloacetic acids,4 or α,β-unsaturated acids,5 and
reductive cyclization of 2-nitrobenzenethioglycolic acids6 or
esters.7 More recently, other methods have been reported. These
include ring expansion of benzothiazoles,8 ring contraction
of 1,5-benzothiazepin-4-ones,9 reaction of bis(o-nitrophenyl)-
disulfides with samarium iodide followed by 2-haloacids or
esters,10 and treatment of N,N-diphenylacetamides with thionyl
chloride.11
We were drawn to a report which involved the synthesis of
2-carboxybenzothiophene by treatment of α-mercaptocinnamic
acid with iodine in nitrobenzene.12 Campaigne and Cline
established that the reaction proceeded via the disulfide, that the
reaction was acid-catalysed and that iodine proved very effect-
ive as it acted not only as a Lewis acid, but also as an oxidising
agent, thus enabling the cyclisation. These workers showed that
dihydronaphthothiophenes and -thiopyrans could also be
formed in this way (Fig. 1).13
Our interest in the synthesis of analogues of shermilamine B
led us to investigate the synthesis of 9-methyl-1H-[1,4]thiazino-
[3,2-g]quinoline-2,5,10(3H )-trione (4). Retrosynthetic analysis
(Scheme 1) pointed us to two likely pathways:
Scheme 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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Fig. 1
Kunzek and Barnikow later formed benzothiazoline 10 by
3B), thus improving the efficiency of the process. Both these
ideas were investigated.
treatment of thioenol
9
with bromine in formic acid
(Scheme 2).14
Reaction of 2,5-dimethoxyaniline with pyridine and
chloroacetyl chloride in THF gave the α-chloroacetanilide
14 in reasonable yield. This was brominated regioselectively
to produce 15. Treatment of compound 15 with thiol 16
(obtained from reaction of anisyl alcohol with Lawesson’s
reagent), formed the p-methoxybenzyl sulfide 17 (63%),
but this proved resistant to deprotection in refluxing TFA
(Scheme 4).
Thiols are often obtained by acid hydrolysis of the corre-
sponding Bunte salt.15 Treatment of compound 14 with sodium
thiosulfate in ethanol produced the Bunte salt 18 in 87% yield,
verified by the known reaction with thiourea, to produce a
disulfide16—in this case, compound 19. All attempts at acid
hydrolysis of the salt 18, however, failed to give the α-mer-
captoacetanilide. Reaction of 2,5-dimethoxyaniline with thio-
glycolic acid in the presence of DCC–DMAP also gave the
disulfide 19 in 67% yield after 12 hours at room temperature
(Scheme 5).
With disulfide 19 in hand we explored ring closure to
thiazinone 7b using 1.1 molar equivalents of bromine in acetic
acid. After four hours at room temperature the 1H-NMR
spectrum of the major product showed two singlets in the
aromatic region resonating at 7.06 and 8.14 ppm and the
chemical shift of the methylene protons was not significantly
different from that in the starting material. This suggested
that the proton at position-4 had been substituted and that no
cyclisation had occurred. The major product of the reaction
was dibromodisulfide 20, obtained in 40% yield. Tribromide 21
was also obtained in 14% yield. Another product, which we
have identified from 1H-NMR as tetrabromide 22, was obtained
in 8% yield. This compound, however, was always obtained as a
mixture with the tribromide 21 (Scheme 6).
Scheme 2
We thought it possible that the desired 7-bromo-5,8-di-
methoxy-1,4-thiazin-3-one (7a) could be synthesised by similar
oxidative cyclization (Scheme 3A), and saw this as a more direct
route than via the highly substituted thiophenol required for
formation of the thiazinone by more customary pathways. This
route (Scheme 3A) would require α-mercapto-4-bromo-2,5-
dimethoxyacetanilide (11) or the corresponding disulfide 12.
With 2,5-dimethoxyaniline and chloroacetyl chloride in hand,
synthesis of 11 or 12 seemed to be straightforward.
It seemed also that Kunzek and Barnikow’s approach could
bring about bromination and cyclisation in one step (Scheme
Scheme 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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Scheme 4
Scheme 5
Scheme 6
Table 1 1H-NMR data of compound 19–22
The 1H-NMR data of compounds 19–22 are given in Table 1.
Note that bromination of the methylene group leads to a
methine proton resonating at about 5.5 ppm (the methylene
peak resonates at 3.6–3.7 ppm) and results in the peak corre-
sponding to the amido proton which is closer to the CHBr
group being shifted downfield by about 0.4 ppm. The 1H-NMR
spectrum of compound 21 is, as would be expected, a compos-
ite of the spectra of 20 and 22. Repeating the reaction in the
dark made no difference to the product composition. Bromin-
ation to form 21 and 22 may have occurred via a Pummerer-
type mechanism.17
Chemical shifts of protons (ppm)
Compound
CH2
CH–Br
H-3
H-4
H-6
NHa
NHb
19
3.69
3.63
3.70
—
—
—
5.53
5.56
6.78
6.96
6.97
6.97
6.58
—
—
8.07
8.09
8.06
8.07
8.57
8.42
8.29
—
—
20
21
8.73
8.76
22a
—
a Obtained as a mixture with 21.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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Scheme 7
Scheme 8
Table 2 Formation of thiazinone 7b from disulfide 19 using iodine in various solvents
Entry
I2 (mol. equiv.)
Solvent
Catalyst
T/ЊC
Time
Thiazinone 7b (%)
1
2
3
4
5
6
7
8
9
2
3
2
2
2
2
1
2
2
2
4
PhNO2
PhNO2
PhNO2
1,2-Ethanediol
1,2-Ethanediol
1,2-Ethanediol
EtOH
EtOH
EtOH
—
—
AlCl3
—
—
—
—
—
—
160
200
120
200
200
30
30
30
Reflux
Reflux
202
4 h
4 h
4 h
15
18
15
16
10
12
0
0
0
15
53
2 h
15 min
24 h
24 h
24 h
24 h
4 h
10
11
CCl4
PhNO2
AlCl3
—
5 min
Treatment of disulfide 19 with iodine–nitrobenzene did pro-
duce the thiazinone 7b in 53% yield after five minutes at 202 ЊC.
Other reaction conditions tried are reported in Table 2. With
solvents such as ethylene glycol and carbon tetrachloride
(entries 4–6 and 10), yields were very low and under the con-
ditions used there was much charring of the material. When the
reaction was carried out in ethanol (entries 7–9), only starting
material was obtained (Table 2).
Reaction of 23 with azadiene 520 gave the adduct 24 as the sole
product in 50% yield. When quinone 24 was treated with
equimolar amounts of methyl thioglycolate in refluxing ethanol,
dihydroxyquinoline 25 and the corresponding quinone 26 were
obtained in 49 and 15% yield, respectively (Scheme 7).
We found that when the Diels–Alder adduct was not isolated,
i.e. when bromoquinone 23 was treated with crotonaldehyde
dimethylhydrazone 5 in acetonitrile at room temperature for
24 hours, and then the solvent removed, methyl thioglycolate
added in ethanol and this mixture heated at reflux for one hour,
compounds 25 and 26 were obtained in 28% and 4% yield,
respectively, and benzoxazole 27 was also formed in 10% yield.
Both compounds 25 and 27, when heated in 6 M HCl, produce
the amino acid 28, which cyclizes on treatment with DCC–
DMAP to give the target thiazinone 4 (56%) (Scheme 8). Amino
acid 28 is also gradually converted to the thiazinone 4 on
standing in air. Compound 26 on the other hand, produces the
desired thiazinone 4 directly, and in 70% yield, on treatment
with 6 M HCl.
Treatment of the dibromodisulfide 20 under conditions
which brought about thiazinone formation in 19 failed to give
the desired 7a. Oxidative demethylation was therefore attempted
on thiazinone 7b using CAN. This yielded a product which was
1
insoluble in most organic solvents and in water. H-NMR of
the crude material suggested that no demethylation had
occurred and that the thiazinone ring had been oxidised (S to
SO) since the peak corresponding to the methylene protons
resonated at about 5.2 ppm, and the methoxy peaks were still
quite prominent.
Route ii) as shown in Scheme 1 was thus investigated.
2-Acetamido-5-bromo-1,4-benzoquinone (23) was easily pre-
pared from the corresponding 4-bromo-N-(2,5-dimethoxy-
phenyl)acetamide18 by oxidative demethylation using CAN.19
We have thus prepared the BCD ring core of the shermil-
amine alkaloids in four steps and 18% overall yield from the
known N-(4-bromo-2,5-dimethoxyphenyl)acetamide.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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mL) then sodium thiosulfate pentahydrate (250 mg, 1.00 mmol)
Experimental
was added to the solution which was then heated at reflux for
3 h under nitrogen. The reaction mixture was cooled to room
temperature, diluted with water (5 mL) and filtered to remove
any organic impurities. The filtrate was evaporated to dryness
in vacuo and the residue extracted exhaustively with boiling
ethanol. The salt (18) crystallized out on cooling. A second
crop was obtained by concentrating the mother liquor. Com-
bined yield—308 mg (97%).
Without further purification the thiosulfate (308 mg, 0.93
mmol) was added to 1 M HCl (20 mL). Thiourea (73 mg, 0.96
mmol) was added to the mixture which was heated at 100 ЊC for
3 h. The mixture was cooled to room temperature and then
extracted with dichloromethane (3 × 15 mL). The combined
extract was washed with water (3 × 10 mL), dried (Na2SO4) and
concentrated in vacuo. The product was purified by column
chromatography (CH2Cl2 : EtOAc 1 : 10) to give 19 as a white
solid (76 mg, 35% overall yield from 14).
General
All melting points are uncorrected. IR spectra were obtained on
a Perkin Elmer 735B model or a Perkin Elmer 1600 FT-IR
spectrometer and are for KBr discs. Unless otherwise stated,
NMR spectra were run on a Bruker 200 MHz or 500 MHz
spectrometer and were determined in CDCl3 solution. Reson-
ances are reported in δ units downfield from TMS; J values are
given in Hz. Elemental analyses were carried out by MEDAC
Ltd., Egham, Surrey, UK.
2-Chloro-N-(2,5-dimethoxyphenyl)acetamide 14
Dimethoxyaniline (2.01 g, 13.1 mmol) was dissolved in a
solution of THF (20 mL) and pyridine (1 mL) and the resulting
solution cooled in an ice–water bath. Chloroacetyl chloride
(3 mL, 4.25 g, 37.6 mmol) was added dropwise to the cold
solution with vigorous stirring. After the addition was complete
the reaction was allowed to come to room temperature and was
then stirred for 2 h. The solvent was removed in vacuo and the
crude product recrystallized from ethanol to give 14 as a grey
crystalline solid (2.50 g, 83%): mp 76–78 ЊC (ethanol) (Found C,
52.51; H, 5.30; N, 6.08. Calc. for C10H12NO3Cl: C, 52.30; H,
Bromination of disulfide 19
A solution of bromine (0.51 mL, 1.58 g, 9.88 mmol) in glacial
acetic acid (5 mL) was added dropwise to a cold suspension of
2,2Ј-disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] (19)
(1.51 g, 3.34 mmol) in acetic acid (50 mL). When the addition
of bromine was complete, the mixture was stirred at room
temperature for 4 h then poured into water (200 mL) and the
resultant precipitate was collected by filtration, washed with
water (5 × 25 mL) and then air-dried. The crude product was
purified by column chromatography (dichloromethane) to give
three products.
5.27; N, 6.10%); IR νmax/cmϪ1 3396, 1682, 1491; H-NMR δH
1
3.81 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.20 (s, 2H, CH2Cl),
6.63 (dd, 1H, J 3.4 and J 8, 4-H), 6.85 (d, 1H, J 8, 3-H), 8.08 (d,
1H, J 3.4, 6-H), 8.97 (br s, 1H, NH); 13C-NMR δC 43.1, 55.8,
56.4, 106.0, 109.3, 110.9, 127.3, 142.5, 153.8, 165.6.
N-(4-Bromo-2,5-dimethoxyphenyl)-2-chloroacetamide 15
2-Chloro-N-(2,5-dimethoxyphenyl)acetamide (14) (5.20 g, 22.6
mmol) was dissolved in glacial acetic acid (26 mL) and the
resulting solution cooled in an ice–water bath. A solution of
bromine (1.5 mL, 4.65 g, 29.1 mmol) in glacial acetic acid
(10 mL) was then added dropwise and the temperature of this
mixture allowed to rise to room temperature. Stirring was con-
tinued at room temperature for 5 h after which the reaction
mixture was poured into water (150 mL) containing sodium
bisulfite (10% aqueous, 5 mL). The precipitate formed was
collected by filtration, washed with water (3 × 50 mL) and then
air dried. The crude product was recrystallized from methanol
to give 15 as a grey crystalline solid (5.51 g, 79%): mp 117–120
ЊC (methanol) (Found C, 39.33; H, 3.67; N, 4.44. Calc. for
C10H11NO3BrCl: C, 38.93; H, 3.59; N, 4.54%) IR νmax/cmϪ1
3392, 1678, 1588; 1H-NMR δH 3.87 (s, 6H, 2 × OCH3), 4.19 (s,
2H, CH2Cl), 7.07 (s, 1H, 3-H), 8.18 (s, 1H, 6-H), 8.90 (br s, 1H,
NH); 13C-NMR δC 43.1, 56.6, 56.8, 104.4, 105.2, 110.9, 126.5,
142.5, 150.1, 163.7.
i)
2,2Ј-Disulfanediylbis[N-(4-bromo-2,5-dimethoxyphenyl)-
acetamide] (20). Off-white solid (804 mg, 40%): mp 170–171 ЊC
(ethanol) (Found: C, 39.62; H, 3.74; N, 4.46. Calc. for
C20H22N2O6S2Br2: C, 39.36; H, 3.63; N, 4.59%); IR νmax/cmϪ1
1
3422, 3336, 2935, 2837, 1690; H-NMR δH 3.63 (s, 4H, 2 ×
SCH2), 3.75 (s, 6H, 2 × OCH3), 3.78 (s, 6H, 2 × OCH3), 6.96 (s,
2H, 2 × 3-H), 8.09 (s, 2H, 2 × 6-H), 8.42 (br s, 2H, 2 × NH);
13C-NMR δC 44.7, 56.9, 57.2, 105.1, 105.2, 115.6, 127.4, 142.7,
150.5, 166.3.
ii)
2-Bromo-N-(4-bromo-2,5-dimethoxyphenyl)-2-({2-[(4-
bromo-2,5-dimethoxyphenyl)amino]-2-oxoethyl}disulfanyl)-
acetamide 21. Light brown solid (320 mg, 14%): mp 168–170 ЊC
(ethanol) (Found: C, 35.29; H, 3.07; N, 3.98. Calc. for
C20H21N2O6S2Br3: C, 34.85; H, 3.07; N, 4.06%); IR νmax/cmϪ1
3287, 2942, 2833, 1656; 1H-NMR δH 3.70 (s, 2H, SCH2), 3.76 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 5.53 (s, 1H, SCHBr), 6.97 (s,
2H, 2 × 3-H), 8.06 (s, 2H, 2 × 6-H), 8.29 (br s, 1H, NH), 8.73 (br
s, 1H, NH); 13C-NMR δC 44.6, 54.1, 56.9, 57.0, 57.2, 104.9,
105.2, 106.1, 115.6, 115.7, 126.8, 143.0, 150.5, 163.2, 165.8.
2,2Ј-Disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] 19
Method 1. Thioglycolic acid (1.6 g, 17.4 mmol) and di-
methoxyaniline (2.63 g, 17.2 mmol) were stirred together in dry
dichloromethane (30 mL). DCC (3.64 g, 17.6 mmol) and
DMAP (100 mg, 0.8 mmol) were then added to the solution
and the resulting mixture stirred at room temperature for 18 h.
After evaporation of the solvent, the crude product was puri-
fied by column chromatography, eluting first with dichloro-
methane to remove impurities higher in Rf than the product.
Subsequent elution with ethanol then yielded 19 as a white solid
(2.60 g, 67%): mp 129–131 ЊC (ethanol); IR νmax/cmϪ1 3370,
iii) 2,2Ј-Disulfanediylbis[N-(4-bromo-2,5-dimethoxyphenyl)-2-
bromoacetamide] 22. (8%), obtained as a mixture with 21.
N-(4-Bromo-2,5-dimethoxyphenyl)-2-(4Ј-methoxybenzyl-
sulfanyl)acetamide 17
4-Methoxybenzyl alcohol (2.0 mL, 2.34 g, 16.9 mmol) and
Lawesson’s reagent (4.80 g, 11.9 mmol) were added to dry
toluene (30 mL) and the mixture heated at reflux under nitrogen
for 3 h. The reaction was cooled to 0 ЊC and filtered. The filtrate
was evaporated in vacuo and the crude product added to
ethanol (35 mL). Potassium carbonate (1.01 g, 7.31 mmol) and
1
3306, 2938, 2837, 1656 cmϪ1; H-NMR δH 3.69 (s, 4H, 2 ×
SCH2), 3.78 (s, 6H, 2 × OCH3), 3.82 (s, 6H, 2 × OCH3), 6.58
(dd, 2H, J 3.4 and J 8, 2 × 4-H), 6.84 (d, 2H, J 8, 2 × 3-H), 8.07
(d, 2H, J 3.4, 2 × 6-H), 8.57 (br s, 2H, 2 × NH); 13C-NMR δC
44.1, 55.8, 56.3, 106.2, 108.9, 110.9, 127.8, 142.3, 153.7, 165.9;
HRMS calcd. for C20H24N2O6S2: 452.1076; found: 452.1085.
N-(4-bromo-2,5-dimethoxyphenyl)-2-chloroacetamide
(15)
(1.52 g, 4.92 mmol) were added to the solution and the resulting
mixture heated at reflux for 6 h. The reaction mixture was
cooled to room temperature, filtered to remove the K2CO3 and
the ethanol evaporated in vacuo. The product was purified by
column chromatography (dichloromethane : hexane 2 : 1) to
Method 2. 2-Chloro-N-(2,5-dimethoxyphenyl)acetamide (14)
(220 mg, 0.96 mmol) was dissolved in 20% aqueous ethanol (13
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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give a brownish grey solid (1.32 g, 63%): mp 87–89 ЊC (ethanol);
IR νmax/cmϪ1 3298, 2998, 2935, 2833, 1667; 1H-NMR δH 3.29 (s,
2H, SCH2), 3.75 (s, 3H, OCH3), 3.77 (s, 2H, SCH2), 3.89 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 6.81 (d, 2H, J 9, 3Ј-, 5-H), 7.08 (s,
1H, 3-H), 7.22 (d, 2H, J 9, 2Ј-, 6Ј-H), 8.19 (s, 1H, 6-H), 9.12 (br
s, 1H, NH); 13C-NMR δC 36.9, 37.0, 55.6, 56.9, 57.3, 104.8,
104.9, 114.5, 115.4, 127.7, 128.9, 130.6, 142.9, 150.5, 159.4,
167.1 (HRMS calcd. for C18H20NO4SBr: 425.0296; found:
425.0289.
ii) Methyl {[6-(acetylamino)-4-methyl-5,8-dioxo-5,8-di-
hydroxyquinolin-7-yl]sulfanyl}acetate 26. Obtained as a deep
yellow solid (0.280, 15%): mp 160–163 ЊC (MeOH) (Found: C,
54.01; H, 4.27; N, 8.07. Calcd. for C15H14N2O5S: C, 53.89; H,
4.22; N, 8.38%); IR νmax/cmϪ1 3331, 3211, 1734, 1681, 1658;
1H-NMR δH 2.29 (s, 3H, CH3), 2.76 (s, 3H, CH3), 3.59 (s, 3H,
CH3), 3.87 (s, 2H, SCH2), 7.42 (d, 1H, J 5, 3-H), 8.19 (s, 1H,
NH), 8.77 (d, 1H, J 5, 2-H); 13C-NMR δC 22.3, 24.3,35.4, 52.9,
126.7, 131.1, 134.9, 141.3, 150.0, 151.2, 153.7, 168.3, 170.5,
179.8, 180.6.
5,8-Dimethoxy-2H-1,4-benzothiazin-3(4H)-one 7b
One-pot Diels–Alder sulfenylation reaction
2,2Ј-Disulfanediylbis[N-(2,5-dimethoxyphenyl)acetamide] (19)
(1.02 g, 2.21 mmol) was dissolved in nitrobenzene (30 mL).
Iodine (2.25 g, 8.86 mmol) was added to the solution and the
mixture stirred vigorously to dissolve the iodine. The resulting
solution was heated at 202 ЊC for 5–10 min. The reaction mix-
ture was cooled rapidly under tap water then adsorbed on to a
column of silica (40 : 1, SiO2 : compound) and eluted with
hexane to remove the nitrobenzene. The product was obtained
by eluting with dichloromethane. Recrystallization from
methanol yielded 5,8-dimethoxy-2H-1,4-benzothiazin-3(4H )-
one (7b) as a light brown crystalline solid (525 mg, 53%): mp
148–150 ЊC (methanol) (Found: C, 53.11; H, 4.94; N, 6.12. Calc.
for C10H11NO3S: C, 53.32; H, 4.92; N, 6.22%); IR νmax/cmϪ1
3220, 2998, 2935, 2841, 1671; 1H-NMR δH 3.32 (s, 2H, SCH2),
3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.43 (d, 1H, J 9, 7-H),
6.60 (d, 1H, J 9, 6-H), 7.95 (br s, 1H, NH); 13C-NMR δC 29.4,
56.6, 56.7, 104.8, 108.4, 109.7, 126.9, 141.7, 50.5, 164.6.
2-Acetamido-5-bromo-1,4-benzoquinone (23) (4.20 g, 17.2
mmol) was stirred in acetonitrile (250 mL) and crotonaldehyde
N,N-dimethylhydrazone (20) (2.50 g, 22.1 mmol) in acetonitrile
(20 mL) was added dropwise to the suspension. The mixture
was stirred at room temperature for 36 h then the acetonitrile
evaporated in vacuo to give an amorphous solid. Ethanol (100
mL) was added to the crude product followed by the careful
addition of methyl thioglycolate (2.2 mL, 2.55 g, 24.1 mmol).
The resulting mixture was heated at reflux for 1 hour after
which it was cooled to room temperature and stirred at that
temperature for a further 12 h. The solvent was removed
in vacuo and the crude product purified by column chromato-
graphy (EtOAc : CH2Cl2 5 : 1) to give compound 25 (1.59 g,
27.5%), compound 26 (218 mg, 4%) and methyl [(5-hydroxy-
2,9-dimethyl[1,3]oxazolo[5,4-f ]quinolin-4-yl)sulfanyl]acetate
(27) (520 mg, 9.5%) as a white crystalline solid (122 mg, 17.5%):
mp 180 ЊC (Found: C, 56.53; H, 4.43; N, 8.71. Calcd. for
C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80%); IR νmax/cmϪ1 3332,
N-(4-Methyl-5,8-dioxo-5,8-dihydroquinolin-6-yl)acetamide 24
1
3021, 2953, 1742; H-NMR δH 2.74 (s, 3H, CH3), 2.91 (s, 3H,
2-Acetamido-5-bromo-1,4-benzoquinone (23) (0.761 g, 3.12
mmol) was stirred in acetonitrile (50 mL), and to this suspen-
sion was added crotonaldehyde N,N-dimethylhydrazone (450
mg, 3.98 mmol) in acetonitrile (10 mL). The reaction was
stirred at room temperature for 48 h. The acetonitrile was then
removed in vacuo and the crude product purified by column
chromatography (dichloromethane) to give 24 as a green solid
(346 mg, 48%): mp 232–234 ЊC (methanol) (Found: C, 62.49; H,
4.38; N, 12.11. Anal. Calcd. for C12H10N2O3: C, 62.61; H, 4.38;
N, 12.17%); IR νmax/cmϪ1 3223, 1670, 1504; 1H-NMR δH 2.30 (s,
3H, CH3), 2.81 (s, 3H, CH3), 7.44 (d, 2H, J 5, 3-H), 7.98 (s, 1H,
7-H), 8.34 (br s, 1H, NH), 8.86 (d, 2H, J 5, 2-H); 13C-NMR δC
22.4, 25.1, 116.5, 125.7, 130.5, 140.2, 148.8, 151.0, 153.4, 169.3,
182.3, 183.7.
CH3), 3.63 (s, 3H, CH3), 3.94 (s, 2H, SCH2), 7.35 (d, 1H, J 5,
3-H), 8.62 (d, 1H, J 5, 2-H); 13C-NMR δC 14.8, 21.0, 35.3, 52.4,
106.4, 116.0, 123.7, 135.5, 138.8, 139.8, 142.9, 146.4, 150.6,
164.0, 170.2.
Preparation of 9-methyl-1H-[1,4]thiazino[3,2-g]quinoline-
2,5,10(3H)-trione 4
From compound 25. Methyl {[6-(acetylamino)-5,8-dihydroxy-
4-methylquinolin-7-yl]sulfanyl}acetate (25) (2.40 g, 7.23 mmol)
was dissolved in 6 M HCl (20 mL) and the solution heated at
reflux for 3 h. The heat was removed and the mixture allowed
to cool to room temperature. Upon standing for 2 h at room
temperature a solid precipitated out of solution. This was
collected by filtration, washed with small amounts of cold
water, followed by ethanol (3 × 5 mL) and then air dried to
give compound 28 as the hydrochloride salt—confirmed by
13C-NMR data (1.93 g, 84%): mp >250 ЊC; 1H-NMR
δH (CD3OD) 3.10 (s, 3H, CH3), 3.50 (s, 2H, SCH2), 7.57 (d, 1H,
J 5, 3-H), 8.54 (d, 1H, J 5, 2-H); 13C-NMR δC 25.8, 30.4, 120.8,
123.5, 124.4, 130.2, 136.2, 139.2, 142.1, 161.5, 168.1.
Without further purification the salt (1.93 g, 6.09 mmol) was
added to chloroform (40 mL). DCC (1.50 g, 7.27 mmol) and
DMAP (1.0 g, 8.18 mmol) were then added to the suspension
and the reaction mixture stirred at room temperature for 10 h.
The chloroform was removed and the crude product purified by
column chromatography (dichloromethane) to give 4 as a red
solid (1.37 g, 86%): mp 252 ЊC (decomp.) (Found: C, 55.51; H,
3.31; N, 10.76. Calcd. for C12H8N2O3S: C, 55.38; H, 3.10; N,
10.76%); IR νmax/cmϪ1 3220, 2998, 1693, 1656; 1H-NMR δH 2.75
(s, 3H, CH3), 3.50 (s, 2H, SCH2), 7.38 (d, 1H, J 5, 3-H), 8.37 (s,
1H, NH), 8.76 (d, 1H, J 5, 2-H); 13C-NMR δC 22.6, 28.8, 123.2,
126.3, 131.3, 136.2, 149.2, 151.7, 153.8, 161.4, 177.3, 178.8.
(Using the above procedure, compound 27 produced
thiazinone 4 in similar yield.)
Reaction of methyl thioglycolate with N-(4-methyl-5,8-dioxo-
5,8-dihydroquinolin-6-yl)acetamide 24
Method 1. N-(4-Methyl-5,8-dioxo-5,8-dihydroquinolin-6-yl)-
acetamide (24) (1.25 g, 5.43 mmol) was stirred in ethanol
(20 mL) at 60 ЊC in a round bottom flask fitted with a con-
denser. Methyl thioglycolate (0.49 mL, 573 mg, 5.39 mmol) was
then carefully added to the warm suspension. The resulting
mixture was heated at reflux for 1 h after which the heat source
was removed and the reaction stirred for a further 3 h. The
solvent was evaporated in vacuo with special care being taken to
keep the temperature below 80 ЊC. The crude product was then
purified by column chromatography (CH2Cl2 : EtOAc 10 : 1) to
give two products.
i) Methyl {[6-(acetylamino)-5,8-dihydroxy-4-methylquinolin-
7-yl]sulfanyl}acetate 25. Obtained as an off-white crystalline
solid (0.894, 49%): mp 155–157 ЊC (Found: C, 53.57; H, 4.82; N,
8.27. Calcd. for C15H16N2O5S: C, 53.56; H, 4.79; N, 8.33%); IR
1
νmax/cmϪ1 3340, 2991, 2927, 1735, 1637; H-NMR δH 2.42 (s,
3H, CH3), 2.95 (s, 3H, CH3), 3.64 (s, 3H, CH3), 3.78 (s, 2H,
SCH2), 7.16 (d, 1H, J 5, 3-H), 8.77 (d, 1H, J 5, 2-H), 9.92 (s, 1H,
NH); 13C-NMR δC 23.5, 24.1, 37.0, 53.0, 107.6, 122.9, 123.1,
125.1, 136.9, 139.7, 147.3, 148.2, 148.9, 170.8, 172.2.
From compound 26. Quinolinedione 26 (71 mg, 0.23 mmol)
was dissolved in 6 M HCl (2 mL) and the solution was heated at
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
3562

View Online
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100 ЊC for 1 h. The mixture was cooled to room temperature,
neutralized with solid sodium bicarbonate, then extracted with
dichloromethane (3 × 5 mL). The combined organic layer was
washed with water (2 × 5 mL), dried (Na2SO4), then evaporated
in vacuo. Recrystallization from ethanol gave thiazinone 4
(42 mg, 70%).
12 E. Campaigne and R. E. Cline, J. Org. Chem., 1956, 21, 39.
13 E. Campaigne and B. G. Heaton, J. Org. Chem., 1964, 29, 2372.
14 H. Kunzek and G. Barnikow, Chem. Ber., 1969, 102, 351.
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18 T. R. Kelly, E. Echavarren and M. Behforouz, J. Org. Chem., 1983,
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 5 7 – 3 5 6 3
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