Synthesis, and structure verification of an analogue of kuanoniamine A

Article abstract of DOI:10.1039/a809203f

Synthesis of 9-phenyl-7H-benzothiazolo[4,5,6-y][2,7]naphthyridin-7-one 11, an analogue of kuanoniamine A 8, is described. The synthesis involves a hetero Diels-Alder reaction of crotonaldehyde dimethylhydrazone with 4,7-dioxo-2-phenylbenzothiazole 18a or with 6-bromo-4,7-dioxo-2-phenylbenzothiazole 18b followed by annelation of the appropriate adduct. Reaction with 18a produced two sets of regioisomers-the thiazoloquinolinediones 19a,b, and the dimethylamino dioxobenzothiazoles 23a,b. The structure of 23b was determined by single-crystal X-ray structure analysis. Verification of the other structures, and methods used to improve the Diels-Alder reaction are described.

Full text of DOI:10.1039/a809203f

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Synthesis and structure verification of an analogue of
kuanoniamine A
Michael A. Lyon,a Simon Lawrence,b David J. Williamsb and Yvette A. Jackson*a
a Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica,
West Indies
b Department of Chemistry, Imperial College of Science, Technology and Medicine,
South Kensington, London, UK SW7 2AY
Received (in Cambridge) 25th November 1998, Accepted 21st December 1998
Synthesis of 9-phenyl-7H-benzothiazolo[4,5,6-ij][2,7]naphthyridin-7-one 11, an analogue of kuanoniamine A 8,
is described. The synthesis involves a hetero Diels–Alder reaction of crotonaldehyde dimethylhydrazone with
4,7-dioxo-2-phenylbenzothiazole 18a or with 6-bromo-4,7-dioxo-2-phenylbenzothiazole 18b followed by annelation
of the appropriate adduct. Reaction with 18a produced two sets of regioisomers—the thiazoloquinolinediones 19a,b,
and the dimethylamino dioxobenzothiazoles 23a,b. The structure of 23b was determined by single-crystal X-ray
structure analysis. Verification of the other structures, and methods used to improve the Diels–Alder reaction are
described.
Introduction
N
N
E
2
There has been extensive development in the study of marine
natural products over the last twenty five years. Among the
marine organisms, the invertebrates, e.g. sponges, soft corals,
molluscs and tunicates, have made a large contribution and a
vast array of metabolites has been isolated, characterised and
assessed for their pharmaco-biological activity.
N
A
C
D
S
B
N
H
N
H
1
Polycyclic aromatic alkaloids with the pyrido[2,3,4-mn]-
acridine skeleton 1 are perhaps the fastest growing and most
widely studied class of tunicate metabolites, and show several
specific biological properties. These include inhibition of topo-
isomerase II,1,2 anti-HIV activity,3 calcium release activity,4
metal chelating properties and intercalation of DNA,5 general
antiviral and antimicrobial activity and cytotoxicity to L1210
murine leukaemia cells.6
The subclass, the pyrido[2,3,4-mn]thiazolo[4,5-b]acridines 2,
includes dercitin alkaloids 3–75,7–8 and kuanoniamines A, B
and D 8–10.9 These pyrido[2,3,4-mn]thiazolo[4,5-b]acridines
show many of the biological properties of the class, and
demonstrate significant cytotoxicity, with kuanoniamine A 8—
the simplest member of the group—reportedly inhibiting the
proliferation of KB (human pharyngeal cancer) cell lines in
vitro at an IC50 of 1–2 mg mLϪ1.9
We set out to prepare substituted non-linear tetracyclic
analogues of kuanoniamine A, with a view to investigating
whether this was a structural feature responsible for cytotoxic
activity. Our analogue 11, is structurally similar to the sam-
pangines 12–16,10–12—metabolites obtained from terrestrial
plants—but have a thiazole moiety in place of the benzenoid
moiety. The sampangines show significant antifungal activity,
with 13 being very active in vitro against several AIDS-related
opportunistic pathogens such as Candida albicans, Crypto-
coccus neoformans, Aspergillus fumigatus and Mycobacterium
cellulare.11,13
CH3
N
N
N
S
N
S
N
N
H
R
N(CH3)2
4
5
6
R = NHCH3
R = N(CH3)2
R = NHCOC2H5
3
2
CH3
N1
3
N
12
4
N
S
N
5
11
+
6
9
S
N
N
10
7
8
Cl–
O
7
8
N
N
S
N
H
NHR
9
R = COCH2CH(CH3)2
10 R = COCH3
We recognized the pathway shown in Scheme 1 as the most
direct route for our synthesis.
The dienophile 18 was obtained from readily available 2,5-
dimethoxyaniline according to Scheme 2. N-Benzoylation
of 2,5-dimethoxyaniline and subsequent thionation using
Lawesson’s reagent14 produced the thiobenzamide 21a. Treat-
ment with NaOH and potassium ferricyanide according to the
Results and discussion
Reaction of crotonaldehyde with 1.2 molar equivalents
of N,N-dimethylhydrazine produced the required azadiene 17.
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442
437

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N
O
N
N
S
Ph
N
N
O
11
12
R
N
O
R1
N
R2
Fig. 1 Molecular structure of 23b.
O
O
R
R1
R2
H
N
N
S
N
S
13
14
15
16
OMe
H
H
Ph
Ph
+
OMe
H
H
N
H
OMe
O
O
*
H
OMe OMe
+
18a
19a
19b
N
O
O
NMe2
O
O
O
O
Me2N
N
N
S
N
S
N
S
17
Ph
+
Ph
+
Ph
Ph
S
Me2N
N
N
NMe2
O
O
NMe2
23a
23b
17
18a
Scheme 3
mixture)—the fully aromatized Diels–Alder adducts (Scheme
3). We also obtained 23a and 23b (3:2)—products resulting
from addition of dimethylamine to the benzoquinone, in 29%
yield.
O
N
N
S
N
S
Ph
1. DMF–DMA
Ph
As expected, the NMR spectral data of these isomers were
very similar. The structure of 23b was unambiguously estab-
lished by a single crystal X-ray determination (see Fig. 1).
X-Ray analysis of 23b shows both the phenyl and dimethyl-
amino substituents to be twisted by only small amounts (by ca.
9 and 20Њ) out of their respective ring planes. Whilst the thiazole
ring is planar to within 0.007 Å, the quinone is more puckered,
with deviations of up to 0.06 Å from its mean plane. The carb-
onyl oxygen atom O(8) (numbering as in Fig. 1) lies essentially
in plane (∆ = 0.007 Å), but O(5) is folded by 0.32 Å (equivalent
to a 12Њ tilt) out of the plane of the ring—the amino nitrogen is
displaced by 0.12 Å in the opposite sense.
We have not been able to obtain suitable crystals of the
adducts 19a and 19b, and thus verification of these structures
had to be done by other means. One of the adducts showed two
carbonyl absorptions in the infrared spectrum, while the other
showed only one. IR studies on 1,8-diaza-9,10-anthraquinones
of type 24 and the isomeric 1,5-diaza-9,10-anthraquinones 25
2. NH4Cl, AcOH
N
N
O
O
19
11
Scheme 1
OCH3
OCH3
H
OCH3
OCH3
OCH3
H
N
Ph
NH2
N
Ph
Lawesson's
reagent
BnCl, py
S
O
R
R
OCH3
20a R = H
20b R = Br
21a R = H
21b R = Br
Br2, HOAc
O
OCH3
N
S
N
CAN
aq K3 [Fe(CN)6 ],
1.5 M NaOH
Ph
Ph
S
O
O
R
R
N
O
OCH3
18a R = H
18b R = Br
22a R = H
22b R = Br
N
N
N
O
O
Scheme 2
24
25
method of Jacobson15 afforded the benzothiazole 22a in 80%
yield, and oxidative demethylation with ceric ammonium
nitrate16 furnished the dienophile 18a.
We then heated the azadiene 17 with the thiazolobenzoquin-
one 18a in refluxing acetonitrile according to the method of
Ghosez.17 Unlike these workers, we did not obtain our adducts
in 94% yield. We obtained a 33% yield of 19a and 19b (3:2
O
O
N
S
N
26
438
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442

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Table 1 Hetero Diels–Alder reaction under microwave conditions
dienophile had required Lewis acid catalysis for reaction with
the very useful diene, anthracene. We thus proceeded with the
activated diene 17.
Solvent
t/min
19a:19b (%)
23a:23b (%)
p-Xylene
Toluene
Acetonitrile
Methanol
10
10
6
43
23
47
15
21
24
45
19
1
N
HN
showed that the former group exhibited two carbonyl stretching
frequencies while the latter showed only one.18 This is readily
explained by the symmetry of the molecule in the case of 25.
The compound 26 also showed only one carbonyl stretch-
ing frequency,19 leading us to suspect that the effect of the
sulfur is not dominant here, and further, that our adduct which
showed only one carbonyl stretching frequency was the com-
pound 19a. We sought to improve the Diels–Alder reaction and
to verify the structures of our adducts. These are dealt with in
turn.
Since the dienophile was being utilized in oxidation for re-
aromatization of the Diels–Alder adduct, we hoped that add-
ition of an external oxidant would be advantageous. Addition
of DDQ, however, had no effect on the yield, and neither did
addition of benzoquinone (which had been previously found to
be unreactive to diene 17).
The competing addition reaction of dimethylamine to the
benzoquinone 18a needed to be suppressed, and/or the
Diels–Alder reaction accelerated. We explored, without effect,
bubbling the dimethylamine out of the reaction vessel as soon
as it was formed, and also quaternizing the dimethylamine in
the reaction medium.20 Running the reaction under microwave
conditions (17, 0.24 mmol and 18a, 0.2 mmol in 3.5 mL
acetonitrile at 600 W for up to 10 minutes) caused an increase in
the yield of adducts to 47%. The yield of aminoquinone side-
products, however, was also increased to 45%. Other solvents
were explored, and the results are shown in Table 1.
O
28
Regiospecificity in hetero Diels–Alder reactions of this type
has been achieved by using brominated quinones as dieno-
philes.25–28 All reports have shown that the position of the
bromine atom determines the regiochemistry of the reaction,
which is independent of any other electronic effect. The more
nucleophilic region (*) of the diene (Scheme 3) always adds at
the carbon adjacent to the one substituted by bromine. Hence,
reaction of azadiene 17 with 6-bromo-4,7-dioxo-2-phenylbenzo-
thiazole 18b, was expected to produce 19a. We also expected the
yield of 19a to be much improved over the reaction with the
non-halogenated quinone, since in reactions with halogenated
dienophiles, there have been no reports of products due to add-
ition of dimethylamine. It is possible that HBr, which is also
expelled in the reaction, traps the dimethylamine before it
attacks any unreacted quinone.
Direct bromination of 22a (1.1 mol equiv. of bromine in
HOAc or in CCl4–CHCl3, 1:1, as solvent) resulted in a mixture
of the 5- and 6-bromo analogues. Again we were unable to
quickly differentiate between these two regioisomers. We thus
attempted formation of a single regioisomer by introducing the
bromine at an earlier stage.
The literature29 shows that bromination of N-(2,5-dimethoxy-
phenyl)acetamide produces only the 4-bromo analogue—
position 4 is doubly activated to electrophilic attack, and is
not sterically hindered. We repeated this reaction, confirming
the sole monobromination product, and in similar fashion,
brominated N-(2,5-dimethoxyphenyl)benzamide to obtain only
the 4-bromo analogue 20b. Treatment with Lawesson’s reagent
and subsequent cyclization yielded 6-bromo-4,7-dimethoxy-2-
phenylbenzothiazole 22b which was then oxidized to the desired
18b (Scheme 2). We were then in a position to assign structures
to the monobromothiazoles obtained from direct bromination
(the major product is the 6-bromo isomer, 22b), and to proceed
with the improved hetero Diels–Alder reaction.
Catalysis of Diels–Alder reactions using Lewis acids is well
known.21–23 We explored this using our dienophile 18a and
anthracene as the diene (Scheme 4). When equimolar amounts
Ph
N
O
S
O
+
18a
27
Stirring a mixture of 18b and 17 in acetonitrile at ambient
temperature for 24 hours produced as we expected, only one
adduct, in 51% yield, which must be 19a. The structures of
our isomeric adducts were thus verified, and confirmed our
suspicions from the IR information.
One-pot annelation of 19a using N,N-dimethylformamide
dimethylacetal followed by ammonium chloride and acetic
acid30,31 afforded the desired analogue (Scheme 5) in 36% yield.
The H NMR spectrum of this product was in keeping with
that expected for 11, showing peaks for protons 2-H and 5-H at
δH 9.20 and 9.06 respectively, and was in good agreement with
the H NMR data for structurally similar sampangines. We
Scheme 4
of anthracene and 18a were stirred together in chloroform,
there was no reaction after four days. When an equimolar
amount of aluminium chloride was added to the reaction mix-
ture, there was the deposition of a bright orange crystalline
solid, the oxidized cycloadduct 27, within one hour. With the
azadiene 17, however, there was only very limited success. When
aluminium chloride was used as catalyst, there was no evidence
of aminoquinone formation, but there was no increase in
the yield of adducts 19a and 19b either. Addition of stannic
chloride or boron trifluoride–diethyl ether as catalysts pro-
duced intractable mixtures at room temperature.
1
1
have thus prepared 11, the novel analogue of kuanoniamine A,
from 2,5-dimethoxyaniline in seven easy steps.
α,β-Unsaturated acylhydrazones have been used as Diels–
Alder dienes.24 They are not as electron rich as their N,N-
dimethylamino analogues, but they have the advantage of
having a non-nucleophilic moiety expelled following adduct
formation. We used crotonaldehyde acylhydrazone 28 as the
diene, anticipating adduct formation without any amino-
quinones. We found, however, that adduct formation occurred
in only very low yield. This was not surprising, since our
Experimental
General
All mps 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. NMR spectra (Bruker 200 MHz
spectrometer) were determined in CDCl3 solution and the
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442
439

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NMe2
O
evaporated in vacuo and the thiobenzamides (yellow crystalline
solids) purified by column chromatography (CH2Cl2–hexane,
3:2, 21a; CHCl3–hexane, 3:2, 21b).
N
S
+
N-(2,5-Dimethoxyphenyl)thiobenzamide 21a. (956 mg, 90%),
mp 58–61 ЊC (MeOH) (Found: C, 65.77; H, 5.51; N, 5.07. Calc.
for C15H15NO2S: C, 65.91; H, 5.54; N, 5.13%); νmax/cmϪ1 3385,
1597, 1365; δH 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.74
(1H, dd, J 3 and 8, 3-H), 6.90 (1H, d, J 9, 4-H), 7.45 (3H, m,
3Ј,4Ј,5Ј-H), 7.83 (2H, d, J 8, 2Ј,6Ј-H), 9.1 (1H, s, 6-H), 9.74 (1H,
s, N-H); δC 55.76, 56.28, 106.82, 110.80, 111.16, 126.58, 128.54,
129.10, 130.91, 143.64, 145.0, 152.89, 195.62.
17
Ph
18b
19a
N
O
N
O
N
N-(4-Bromo-2,5-dimethoxyphenyl)thiobenzamide 21b. (890
mg, 85%), mp 154–156 ЊC (MeOH) (Found: C, 50.98; H, 4.01;
N, 3.95. Calc. for C15H14BrNO2S: C, 51.28; H, 4.02; N, 3.99%);
νmax/cmϪ1 3349, 1524, 1207; δH 3.85 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 7.10 (1H, s, 3-H), 7.48 (3H, m, 3Ј,4Ј,5Ј-H), 7.88 (2H, m,
2Ј,6Ј-H), 9.35 (1H, s, 6-H), 9.75 (1H, s, N-H); δC 56.57, 56.86,
105.27, 106.49, 115.01, 126.58, 128.48, 128.65, 131.11, 143.61,
149.34, 195.66.
Ph
S
N
11
Scheme 5
resonances 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.
Preparation of benzothiazoles
The thiobenzamide (2.0 g) was dissolved in 1.5 M sodium
hydroxide (150 mL) and the solution cooled in an ice–water
bath. To this was added freshly prepared (20%) aqueous potas-
sium ferricyanide (15 mL gϪ1 of thiobenzamide). The mixture
was stirred at room temperature for the appropriate time and
the benzothiazole was collected by filtration, washed with cold
water, dried and recrystallized to give white needles in each case.
N-(2,5-Dimethoxyphenyl)benzamide 20a
To a solution of 2,5-dimethoxyaniline (2.0 g, 13.2 mmol) in dry
toluene (12 mL) and pyridine (10 mL), benzoyl chloride (1.5
mL, 12.26 mmol) was added. The solution was heated on a
water bath at 60–70 ЊC for 1 hour. The mixture was cooled to
room temperature and poured into water (200 mL). The two
layers were separated and the aqueous layer extracted with
toluene (3 × 10 mL). The combined toluene solutions were
washed with 1 M HCl (3 × 10 mL) followed by brine (3 × 10
mL), dried (MgSO4) and the solvent removed in vacuo to yield
20a as a tan-coloured crystalline solid (3.02 g, 90%), mp 82–
84 ЊC (MeOH) (Found: C, 69.95; H, 5.92; N, 5.34. Calc. for
C15H15NO3: C, 70.01; H, 5.88; N, 5.45%); νmax/cmϪ1 3270, 1640;
δH 3.81 (3H, s, OCH3), 3.88 (3H, s, OCH3), 6.63 (1H, dd, J 3.5
and 6, 4-H), 6.84 (1H, d, J 8, 3-H), 7.50 (3H, m, 3Ј,4Ј,5Ј-H),
7.89 (2H, m, 2Ј,6Ј-H), 8.29 (1H, d, J 3.5, 6-H), 8.60 (1H, s,
N-H); δC 55.79, 56.29, 105.64, 108.87, 110.69, 126.98, 128.40,
128.75, 131.74, 135.15, 142.32, 153.92, 165.19.
4,7-Dimethoxy-2-phenylbenzothiazole 22a. Reaction time: 24
hours. (1.59 g, 80%), mp 122–124 ЊC (MeOH) (Found: C, 66.51;
H, 4.83; N, 5.12. Calc. for C15H13NO2S: C, 66.40; H, 4.83;
N, 5.16%); νmax/cmϪ1 1560, 1505, 1479, 1462; δH 3.98 (3H, s,
OCH3), 4.09 (3H, s, OCH3), 6.76 and 6.87 (each 1H, d, J 8, 5- or
6-H), 7.50 (3H, m, 3Ј,4Ј,5Ј-H), 8.16 (2H, m, 2Ј,6Ј-H); δC 56.02,
56.32, 105.30, 107.02, 127.63, 128.83, 130.79, 133.49, 148.0,
148.03, 167.62.
N-(6-Bromo-4,7-dimethoxy-2-phenyl)benzothiazole
22b.
Reaction time: 3 days. (1.1 g, 54%), mp 123–125 ЊC (CHCl3–
MeOH) (Found: C, 51.46; H, 3.43; N, 3.99. Calc. for C15H12-
BrNO2S: C, 51.58; H, 3.47; N, 4.01%); νmax/cmϪ1 1480, 1353;
δH 3.93 (3H, s, OCH3), 4.10 (3H, s, OCH3), 7.05 (1H, s, 5-H),
7.74 (3H, m, 3Ј,4Ј,5Ј-H), 8.10 (2H, m, 2Ј,6Ј-H); δC 56.43, 60.17,
127.47, 128.82, 130.30, 131.01, 132.53, 144.30, 149.96, 151.53,
151.57, 151.78, 167.41.
N-(4-Bromo-2,5-dimethoxyphenyl)benzamide 20b
To a solution of N-(2,5-dimethoxyphenyl)benzamide 20a (1.0 g,
3.9 mmol) in glacial acetic acid (10 mL) on an ice–water bath,
was added dropwise, a solution of bromine (771 mg, 0.25 mL,
4.29 mmol) in glacial acetic acid (5 mL). The mixture was
stirred at ambient temperature for 48 hours, then poured into a
1% sodium bicarbonate solution (100 mL) and extracted with
chloroform (2 × 150 mL). The organic solution was washed
with 1% aqueous sodium hydrogen sulfite then water, dried
(Na2SO4) and concentrated in vacuo to give a brick red solid.
The crude solid was purified by column chromatography
(chloroform–hexane, 3:2) and recrystallized (chloroform–
methanol) to yield 20b as light brown plates (828 mg, 60%),
mp 133–136 ЊC (Found: C, 53.47; H, 4.20; N, 4.13. Calc. for
C15H14BrNO3: C, 53.73; H, 4.21; N, 4.18%); δH 3.85 (3H, s,
OCH3), 3.90 (3H, s, OCH3), 7.1 (1H, s, 3-H), 7.50 (3H, m,
3Ј,4Ј,5Ј-H), 7.83 (2H, dd, J 2 and 6, 2Ј,6Ј-H), 8.40 (1H, s, 6-H),
8.55 (1H, s, N-H); δC 56.45, 56.74, 104.14, 104.53, 114.85, 126.9,
127.69, 128.8, 131.95, 142.29, 150.09, 165.17.
Preparation of 2-substituted-4,7-dioxobenzothiazoles
To a cold 2% suspension of the 4,7-dimethoxybenzothiazole
in acetonitrile was added over 5 minutes, with stirring, a 2%
aqueous solution of ceric ammoniun nitrate (CAN). The result-
ing mixture was stirred at ambient temperature for 1 hour, after
which the precipitate which formed was collected by filtration,
washed with cold water, and dried at the vacuum pump. The
product was purified by column chromatography (dichloro-
methane), yielding the corresponding 2-substituted-4,7-dioxo-
benzothiazoles as orange crystalline solids.
4,7-Dioxo-2-phenylbenzothiazole 18a. 2 Mol equiv. CAN
used. (160 mg, 90%), mp 195–198 ЊC (Found: C, 64.78; H, 2.99;
N, 5.74. Calc. for C13H7NO2S: C, 64.72; H, 2.93; N, 5.81%);
νmax/cmϪ1 1679, 1655; δH 6.90 (2H, s, 5,6-H), 7.50 (3H, m,
3Ј,4Ј,5Ј-H), 8.09 (2H, d, 2Ј,6Ј-H); δC 127.62, 129.22, 131.78,
132.34, 136.94, 137.41, 138.76, 179.52, 179.98.
Thionation of benzamides
To a solution of the benzamide (1.0 g) in dry toluene (40 mL)
was added Lawesson’s reagent (1.5 mol equiv.). The mixture was
heated under an atmosphere of nitrogen at 80 ЊC for 2 hours
after which time it was cooled and filtered. The solvent was
6-Bromo-4,7-dioxo-2-phenylbenzothiazole 18b. 3 Mol equiv.
CAN used. (350 mg, 85%), mp 186–188 ЊC (Found: C, 48.94;
440
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442

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H, 2.12; N, 4.22. Calc. for C13H6BrNO2S: C, 48.91; H, 1.90; N,
4.39%); νmax/cmϪ1 1668, 1647; δH 7.55 (4H, m, 5, 3Ј,4Ј,5Ј-H),
8.09 (2H, m, 2Ј,6Ј-H); δC 127.67, 129.32, 131.59, 132.57, 132.67,
137.19, 138.01, 139.40, 139.64, 177.23, 193.96.
scheme, see ‘Instructions for Authors’, J. Chem. Soc., Perkin
Trans. 1, available via the RSC web page (http://www.rsc.org/
authors). Any request to the CCDC for this material should
quote the full literature citation and the reference number 207/
294.
The hetero Diels–Alder reaction
(b) With 6-bromo-4,7-dioxo-2-phenylbenzothiazole (18b) as
dienophile. To a suspension of 6-bromo-4,7-dioxo-2-phenyl-
benzothiazole 18b (150 mg, 0.47 mmol) in dry acetonitrile
(30 mL) was added a solution of crotonaldehyde dimethyl-
hydrazone (63 mg, 0.56 mmol) in acetonitrile (5 mL). The
mixture which resulted was stirred for 24 hours at ambient tem-
perature. Acetonitrile was removed in vacuo and the residue
purified by column chromatography (dichloromethane–hexane,
2:1) to give 19a as a yellow crystalline solid (72.5 mg, 51%).
(a) With 2-phenyl-4,7-dioxobenzothiazole 18a as dienophile.
Compound 18a (2.0 g, 8.3 mmol) was stirred in acetonitrile
(150 mL), and to this suspension was added a solution of
crotonaldehyde dimethylhydrazone 17 (1.12 g, 9.96 mmol) in
acetonitrile (20 mL). The mixture was then stirred at room tem-
perature for 48 hours. The acetonitrile was removed in vacuo
and the residue purified by column chromatography (dichloro-
methane) to give cycloadducts 19a,b (836 mg, 33%), and
aminoquinones 23a,b (676.7 mg, 29%).
8-Methyl-2-phenylthiazolo[4,5-g]quinoline-4,9-dione
19a.
9-Phenyl-7H-benzothiazolo[4,5,6-ij][2,7]naphthyridin-7-one 11
Yellow crystalline solid (20%), mp 241–244 ЊC (chloroform–
hexane) (Found: C, 66.44; H, 3.26; N, 9.05. Calc. for
C17H10N2O2S: C, 66.66; H, 3.29; N, 9.15%); νmax/cmϪ1 1679,
1431, 1324; δH 2.93 (3H, s, CH3), 7.54 (4H, m, 7, 3Ј,4Ј,5Ј-H),
8.14 (dd, 2H, J 2 and 5, 2Ј,6Ј-H), 8.86 (d, 1H, J 5, 6-H);
δC 22.69, 126.99, 127.69, 127.92, 129.24, 131.33, 131.75, 132.52,
149.98, 152.06, 152.75, 175.70, 179.17.
8-Methyl-2-phenylthiazolo[4,5-g]quinoline-4,9-dione 19a (240
mg, 0.67 mmol) was stirred in dry DMF (3 mL) under
nitrogen for 30 minutes at 120 ЊC. To this solution was added
N,N-dimethylformamide dimethylacetal (199 mg, 1.67 mmol)
with stirring, and the heating continued at 120 ЊC for a further
hour. The mixture was cooled to 100 ЊC, ammonium chloride
(5 g) and acetic acid (15 mL) were added, and the resulting
mixture heated at 120 ЊC for 1 hour. The reaction mixture was
then cooled, poured into water (100 mL) and extracted with
chloroform (3 × 50 mL). The combined organic layer was
washed with saturated aqueous sodium bicarbonate (3 × 50
mL), followed by water (3 × 50 mL) and dried (MgSO4). The
solvent was removed in vacuo and the residue purified by
column chromatography (chloroform–ethyl acetate, 2:1) to
give 11 (89 mg, 36%), mp 264–266 ЊC (Found: C, 66.88; H,
2.91; N, 12.68. Calc. for C18H9N3OSؒ1/2H2O: C, 66.65; H, 3.11;
N, 12.95%); νmax/cmϪ1 1656, 1406, 1357; δH 7.55 (3H, m, 3Ј,4Ј,5Ј-
H), 7.85 (1H, d, J 8, 4-H), 8.02 (1H, d, J 7, 3-H), 8.28 (2H,
d, J 8, 2Ј,6Ј-H), 9.06 (1H, d, J 8, 5-H), 9.18 (1H, d, J 7, 2-H);
δC 119.80, 120.54, 124.13, 127.86, 129.19, 129.31, 132.25,
132.37, 138.56, 148.01, 148.32, 148.54, 157.50, 176.47.
8-Methyl-2-phenylthiazolo[5,4-g]quinoline-4,9-dione
19b.
Yellow crystalline solid (13%), mp 277 ЊC (decomp.) (Found: C,
66.23; H, 3.30; N, 9.12. Calc. for C17H10N2O2S: C, 66.66; H,
3.29; N, 9.15%); νmax/cmϪ1 1694, 1653, 1457, 1433; δH 2.95 (3H,
s, CH3), 7.59 (4H, m, 3Ј,4Ј,5Ј, 7-H), 8.24 (2H, d, J 8, 2Ј,6Ј-H),
8.95 (1H, d, J 6, 6-H); δC 22.54, 127.81, 129.25, 130.99, 131.83,
132.52, 149.81, 151.25, 153.19, 153.98, 157.23, 175.23, 180.0.
6-Dimethylamino-2-phenyl-4,7-dioxobenzothiazole
23a.
Purple crystalline solid (12%), mp 191–193 ЊC (Found: C,
62.94; H, 4.10; N, 9.61. Calc. for C15H12N2O2S: C, 63.37; H,
4.26; N, 9.86%); νmax/cmϪ1 1664, 1616, 1560, 1427; δH 3.25 (6H,
s, N(CH3)2), 5.68 (1H, s, 5-H), 7.52 (3H, m, 3Ј,4Ј,5Ј-H), 8.13
(2H, m, 2Ј,6Ј-H); δC 43.06, 127.50, 127.59, 127.70, 129.27,
131.98, 132.20, 132.52, 151.60, 152.77, 155.23, 177.85, 178.34.
5-Dimethylamino-2-phenyl-4,7-dioxobenzothiazole
23b.
Purple crystalline solid (17%), mp 188–191 ЊC (Found: C,
63.09; H, 4.15; N, 9.64. Calc. for C15H12N2O2S: C, 63.37; H,
4.26; N, 9.86%); νmax/cmϪ1 1678, 1606, 1564, 1436; δH 3.28 (6H,
s, N(CH3)2), 5.68 (1H, s, 6-H), 7.46 (3H, m, 3Ј,4Ј,5Ј-H), 8.05
(2H, dd, J 2 and 6, 2Ј and 6Ј-H); δC 43.23, 127.25, 127.28,
127.60, 127.74, 128.95, 129.07, 129.26, 131.60, 151.76, 177.01,
177.33.
The anthracene cycloadduct 27
Aluminium chloride (183 mg, 1.03 mmol) was added to
chloroform (5 mL) and to this was added 2-phenyl-4,7-
dioxobenzothiazole 18a (250 mg, 1.03 mmol). The mixture was
stirred for 30 minutes at room temperature. Anthracene (184
mg, 1.03 mmol) was then added, and the mixture stirred at
ambient temperature for 1 hour. The orange solid which
formed was collected by filtration, purified by column chrom-
atography (dichloromethane–hexane, 3:1) and recrystallized
from dichloromethane–ethanol to give 27 (154 mg, 35%), mp
300 ЊC (decomp.) (Found: C, 77.92; H, 3.36; N, 3.27. Calc. for
C27H15NO2S: C, 77.68; H, 3.59; N, 3.36%); νmax/cmϪ1 1669,
1648; δH 5.90 (1H, s), 6.03 (1H, s), 7.06 (4H, m), 7.50 (7H, m),
8.05 (2H, dd, J 3.5 and 7); δC 47.57, 47.7, 124.43, 124.54, 125.67,
125.71, 127.55, 129.18, 132.08, 138.17, 143.44, 143.6, 153.11,
153.19, 153.66, 174.34, 176.29, 176.43.
Crystal data for 23b. C15H12N2O2S, M = 284.3. Monoclinic
a = 27.252(2), b = 6.619(3), c = 16.385(7) Å, β = 115.23(1)Њ, U =
2673.2(2) Å3, space group C2/c, Z = 8, Dc = 1.41 g cmϪ3,
µ = 21.8 cmϪ1. For a crystal of dimensions 0.03 × 0.07 × 0.20
mm, 2164 independent reflections (θ > 63Њ) were measured on a
Siemens P4/RA diffractometer with Cu-Kα radiation (graphite
monochromator) using ω-scans. Of these, 1677 had [Fo] >
4σ([Fo]) and were considered to be observed. The data were
corrected for Lorentz and polarization effects and an empirical
absorption correction based on ψ-scans was applied (maximum
and minimum transmission factors 0.934, 0.789). The structure
was solved by direct methods and the non-hydrogen atoms were
refined anisotropically. The positions of the hydrogen atoms
were determined from a ∆F map, idealized C–H = 0.96 Å,
assigned isotropic thermal parameters U(H) = 1.2Ueqv(C),
[1.5Ueqv(CMe)], and allowed to ride on their parent carbon
atoms. Refinement was by full-matrix least-squares based on F 2
and converged to give R1 = 0.048 and wR2 = 0.122. The maxi-
mum and minimum residual electron densities in the final
∆F map were 0.19 and Ϫ0.28 e ÅϪ3. Computations were carried
out using the SHELXTL program package version 5.03. The
crystallographic data (excluding structure factors) for com-
pound 23b, have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC). For details of the deposition
References
1 F. J. Schmitz, F. S. deGuzman, M. B. Hossain and D. Vanderhelm,
J. Org. Chem., 1991, 56, 804.
2 J. Minford, Y. Pommier, J. Filipski, K. W. Kohn, D. Kerrigan,
M. Mattern, S. Michaels, R. Schwartz and L. A. Zwelling,
Biochemistry, 1986, 25, 9.
3 I. B. Taraporewala, J. W. Cessac, T. C. Chanh, A. V. Delgado and
R. F. Schinazi, J. Med. Chem., 1992, 35, 2744.
4 J. Kobayashi, J. Cheng, M. R. Walchli, H. Nakamura, H.
Yoshimasa, S. Takuma and Y. Ohizumi, J. Org. Chem., 1988, 53,
1800.
5 G. P. Gunawardana, F. E. Koehn, A. Y. Lee, J. Clardy, H. He and
D. J. Faulkner, J. Org. Chem., 1992, 57, 1523.
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442
441

View Article Online
6 M. Alvarez and J. A. Joule, Heterocycles, 1992, 34, 2385.
7 G. P. Gunawardana, S. Kohmoto, S. P. Gunasekera, O. J. McConnell
and F. E. Koehn, J. Am. Chem. Soc., 1988, 110, 4356.
8 G. P. Gunawardana, S. Kohmoto and N. S. Burres, Tetrahedron
Lett., 1989, 30, 359.
9 A. R. Carroll and P. J. Scheuer, J. Org. Chem., 1990, 55, 4426.
10 J. K. Zjawiony, A. R. Srivastava, D. Hufford and A. M. Clark,
Heterocycles, 1994, 39, 779.
19 Y. Kitahara, S. Nakahara, T. Yonezawa, M. Nagatsu, Y. Shibano
and A. Kubo, Tetrahedron, 1997, 53, 17029.
20 H. Z. Sommer, H. I. Lipp and L. L. Jackson, J. Org. Chem., 1971,
36, 1824.
21 P. Yates and P. Eaton, J. Am. Chem. Soc., 1960, 82, 4436.
22 W. E. Bachmann and L. B. Scott, J. Am. Chem. Soc., 1948, 70, 1458.
23 E. Ohgaki, J. Motoyoshiya, S. Narita, T. Kakurai, S. Hayashi and
K. Hirakawa, J. Chem. Soc., Perkin Trans. 1, 1990, 3109.
24 J. M. Pérez, C. Avendaño and J. C. Menendez, Tetrahedron, 1995, 51,
6573.
11 S. Liu, B. Oguntimein, C. D. Hufford and A. M. Clark, Antimicrob.
Agents Chemother., 1990, 34, 529.
12 A. R. Caroll and W. C. Taylor, Aust. J. Chem., 1991, 44, 1615.
13 J. R. Peterson, J. K. Zjawiony, S. Liu, C. D. Hufford, A. M. Clark
and R. D. Rogers, J. Med. Chem., 1992, 35, 4069.
14 (a) I. Thomsen, K. Clausen, S. Scheibye and S. O. Lawesson,
Org. Synth., 1984, 62, 158; (b) M. P. Cava and M. I. Levinson,
Tetrahedron, 1985, 41, 5061.
15 P. Jacobson, Chem. Ber., 1886, 19, 1067.
16 N. Castagnoli, Jr., P. Jacob, III, P. S. Callery and A. T. Shulgin,
J. Org. Chem., 1976, 41, 3627.
25 L. Chaker, F. Pautet and H. Fillion, Heterocycles, 1995, 41, 1169.
26 S. Lévesque and P. Brassard, Heterocycles, 1994, 38, 2205.
27 O. Cherkaoni, P. Nebois and H. Fillion, Tetrahedron, 1996, 52, 9499.
28 J. M. Pérez, C. Avendaño and J. C. Menendez, Tetrahedron Lett.,
1997, 38, 4717.
29 T. R. Kelly, A. Echavarren and M. Behforouz, J. Org. Chem., 1983,
48, 3849.
30 F. Bracher, Heterocycles, 1989, 29, 2093.
31 F. Bracher, Liebigs Ann. Chem., 1989, 87.
17 B. Serckx-Poncin, A. Hesbain-Frisque and L. Ghosez, Tetrahedron
Lett., 1989, 23, 3261.
18 A. J. Birch, D. N. Butler and J. B. Siddal, J. Chem. Soc., 1964, 2941.
Paper 8/09203F
442
J. Chem. Soc., Perkin Trans. 1, 1999, 437–442