Generation and Trapping of 4-Methylene-5-(bromomethylene)-4,5-dihydrothiazole with Dienophiles

Article abstract of DOI:10.1021/jo961457n

4-(Bromomethyl)-5-(dibromomethyl)thiazole (1) was prepared in good yields by bromination of 4,5-dimethylthiazole with 3.3 equiv of NBS in the presence of AIBN. Treatment of 1 with sodium iodide led to a thiazole o-quinodimethane 2 which was trapped in sit

Full text of DOI:10.1021/jo961457n

J . Org. Chem. 1997, 62, 405-410
405
Gen er a tion a n d Tr a p p in g of
4-Meth ylen e-5-(br om om eth ylen e)-4,5-d ih yd r oth ia zole w ith
Dien op h iles
Mouaffak Al Hariri,† Karine J ouve,† Fe´lix Pautet,† Monique Domard,‡ Bernard Fenet,§ and
Houda Fillion*,†
Laboratoire de Chimie Organique and Laboratoire de Chimie Analytique II,
Institut des Sciences Pharmaceutiques et Biologiques, Universite´ Claude Bernard Lyon I,
8, Avenue Rockefeller F-69373 Lyon Cedex 08, France, and Centre de RMN,
Universite´ Claude Bernard Lyon I, F-69622 Villeurbanne Cedex, France
Received J uly 30, 1996X
4-(Bromomethyl)-5-(dibromomethyl)thiazole (1) was prepared in good yields by bromination of 4,5-
dimethylthiazole with 3.3 equiv of NBS in the presence of AIBN. Treatment of 1 with sodium
iodide led to a thiazole o-quinodimethane 2 which was trapped in situ with dienophiles such as
N-phenylmaleimide, DMAD, or acrylate derivatives. From the latter, 6-substituted-4,5-dihydroben-
zothiazoles 7 are selectively formed. Anthra[2,3-b]thiazole-4,5-diones 13-15 were obtained from
naphthoquinones. With 2- or 3-bromonaphthoquinones (11 or 12), the cycloadditions were found
1
highly regioselective. Structural assignment of the regioisomers was made by a 2D H-13C HMBC
technique performed on the aromatized cycloadduct 15b. Calculations of HOMO and LUMO frontier
orbital coefficients by the semiempirical PM3 method show that the regiochemistry observed in
the cycloadditions of 2 toward acrylate dienophiles or naphthoquinones 11 and 12 did not agree
with the corresponding values.
Sch em e 1
Because of the many proven applications of synthetic
heteroaromatic compounds, the Diels-Alder trapping of
heterocyclic analogues of o-quinodimethane (o-QDM) has
recently received attention.1 In this context, the prepa-
ration and cycloadditions of o-dimethylene thiazoles have
remained largely unexplored. The few known examples
of this type of reaction require very harsh conditions for
generation of the o-QDM. Thus, 4,5-dimethylene-4,5-
dihydrothiazole and its 2-phenyl derivative were obtained
by flash pyrolysis of the corresponding p-chlorobenzoate
esters2 (Scheme 1, eq 1). But only the latter was reported
to be trapped, although not with a dienophile. A heated
dichlorobenzene solution of R-(2-phenyl-4-methylthiazol-
5-yl)-R-phenylmethyl acetate gave, after acetic acid elimi-
nation, an o-QDM (eq 2).3 The latter was successfully
trapped with symmetrical dienophiles. On the other
hand, thiazole-fused 3-sulfolenes were described as high
temperature precursors of thiazole o-quinodimethanes
(eq 3).4
In order to get readily available precursors which
would give o-QDM under milder conditions, we turned
our attention to the preparation and use of the unknown
4-(bromomethyl)-5-(dibromomethyl)thiazole (1) since po-
lybrominated compounds of thiophene,5 pyrazole,6 and
furan7 give the corresponding o-QDM by treatment with
sodium iodide. This tribrominated thiazole derivative
was selected in order to obtain a well polarized “diene”,
expected to undergo highly regioselective Diels-Alder
reactions.
Treatment of the commercially available 4,5-dimeth-
ylthiazole with 3.3 equiv of N-bromosuccinimide (NBS)
and 10% of 2,2′-azobis(isobutyronitrile) (AIBN) in reflux-
ing carbon tetrachloride yielded compound 1 selectively
in 65% yield (Scheme 2). The structure of 1 was assigned
unambiguously by chemical correlation. Thus, 5-formyl-
4-methylthiazole (3)8 was reacted with bromine in the
presence of triphenyl phosphite9 to give the dibromo
derivative 4. Bromination of the latter with NBS (1.1
equiv) in the presence of AIBN (10%) led to the tribromo
derivative 1 identical with the compound prepared by the
above procedure.
* Address for correspondence to Prof. Houda Fillion Tel: +33 4 78
77 71 38; FAX: +33 4 78 77 71 58; E-mail: fillion@cismsun.univ-lyon1.
fr.
† Laboratoire de Chimie Organique.
‡ Laboratoire de Chimie Analytique II.
§ Centre de RMN.
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) Chou, T.-S. Rev. Heteroat. Chem. 1993, 8, 65-104 and references
cited therein.
(2) Chauhan, P. M. S.; Crew, A. P. A.; J enkins, G.; Storr, R. C.;
Walker, S. M.; Yelland, M. Tetrahedron Lett. 1990, 31, 1487-1490.
(3) Potter, A. J .; Storr, R. C. Tetrahedron Lett. 1994, 35, 5293-5296.
(4) Chou, T.-S.; Tsai, C.-Y. Tetrahedron Lett. 1992, 33, 4201-4204.
(5) Chadwick, D. J .; Plant, A. Tetrahedron Lett. 1987, 28, 6085-
6088.
(7) (a) Al Hariri, M.; Pautet, F.; Fillion, H. Synlett 1994, 459-460.
(b) Al Hariri, M.; Pautet, F.; Fillion, H.; Domard, M.; Fenet, B.
Tetrahedron 1995, 51, 9595-9602.
(8) White, R. L.; Spenser, I. D. J . Am. Chem. Soc. 1982, 104, 4934-
4943.
(6) Mitkidou, S.; Stephanidou-Stephanatou, J . Tetrahedron Lett.
1991, 32, 4603-4604.
(9) Hoffmann, R. W.; Bovicelli, P. Synthesis 1990, 657-659.
S0022-3263(96)01457-0 CCC: $14.00 © 1997 American Chemical Society

406 J . Org. Chem., Vol. 62, No. 2, 1997
Al Hariri et al.
Sch em e 2
exhibits pharmacological properties. A straightforward
access to thiazolo anthraquinone derivatives 13-15 of
biological interest makes use of condensations between
o-QDM 2 and naphthoquinones 9-12 (Scheme 4).
The results of these cycloadditions are summarized in
Table 1. First, 2 was generated under the sodium iodide
protocol (method A) and trapped with naphthoquinone
(9a ) and naphthazarine (9b) to give the corresponding
aromatized tetracyclic compounds 13a and 13b in good
yields. With 5-substituted naphthoquinones 10, the
condensations of 2 afford a mixture of the regioisomers
14+15. Opposite regioisomers were obtained from jug-
lone (10a ) and acetyljuglone (10b) (entries 3 and 5,
respectively).13 Using tetrabutylammonium iodide (meth-
od B) to prepare 2, a poorer regioselectivity was observed
(entries 4 and 6) than in method A (entries 3 and 5).
Highly regioselective Diels-Alder reactions were per-
formed by the use of 2- or 3-bromonaphthoquinones (11
or 12) (entries 7-10). The 1,6-regioisomers 14 obtained
as the major products from quinones 11 (entries 7 and
8) and the 1,9-regioisomers 15 formed in higher amounts
from 12 (entries 9 and 10) indicate that the regiochem-
istry is under control of the bromine atom position.
The 1,6- and 1,9-regioisomers are differentiated by the
1H-NMR chemical shifts of H-4 and H-11 (Table 2). In
compound 14a , the H-4 signal is shifted to lower field by
0.11 ppm relative to that of 14b while for 15a a similar
shift of 0.14 ppm was observed for H-11.
equiv
Sch em e 3
Further corroboration for the structure assignments
of regioisomers 14 and 15 was made by 2D 1H-13C NMR
HMBC correlations performed on 15b and then by
chemical transformations. The HMBC technique cor-
relates the protons with the carbon atoms through 1J ,
2J , and 3J couplings. For aromatic compounds, it is
3
known that long range J couplings are larger than 2J .
The spectral data of 15b are reported in Table 3. Thus,
C-3a and C-11a were first determined. Indeed, C-3a and
3
C-11a gave J couplings with the same proton H-2. But,
the former appeared as a doublet characteristic of a cross
peak through the nitrogen atom of a thiazole nucleus
(3J C3a-H2 ) 15.3 Hz) while the second one was an
unresolved singlet (indicating a coupling of <5 Hz for the
3J C11a-H2).15 Then, the three 3J couplings, C-11a with H-4,
C-5 with H-4, and C-5 with H-6, permit assignment of
the 1,9-regioisomeric structure to 15b. Only two 3J
couplings should be observed from the hypothetical
opposite 1,6-regioisomer since no proton would be avail-
able for coupling on C-6: C-11a with H-4 on one hand,
and C-5 with H-4 on the other hand (Table 3).
Subsequent generation of 4-methylene-5-(bromometh-
ylene)-4,5-dihydrothiazole 2 was performed with sodium
iodide in DMF. The o-QDM 2 formed was trapped in situ
with a set of dienophiles (Scheme 3). The corresponding
aromatized cycloadducts 5 and 6 or the dihydro deriva-
tives 7 were obtained in good yields. The cycloadditions
of o-QDM 2 with unsymmetrical dienophiles are highly
1
Treatment of the acetate 15b with 10% KOH in ethanol
regioselective. The H-NMR spectra of the crude prod-
1
afforded the corresponding hydroxyl derivative. The H-
ucts indicate that the dihydro adducts 7 are the major
regioisomers (7a /7′a : 95/5, 7b/7′b: 87/13). Trapping 2
with methyl vinyl ketone yielded a mixture of 4,5-
dihydro-6-acetylbenzothiazole (7c) and the spontaneously
aromatized 5-acetyl derivative 8′c in a respective ratio
(7c/8′c: 81/19). The structure of 8′c was assigned by
comparison of its spectroscopic data with those of 8c. The
latter was obtained by treatment of 7c with Pd-C (10%)
in refluxing diphenyl ether.
NMR spectrum of this compound is identical with that
of 15a obtained by cycloaddition from 12a . Then, the 1,6-
structure was attributed to 14a and 14b.
The results given in Scheme 3 and Table 1 indicate
that the regiochemistry of the cycloadditions between 2
and 11 or 12 is governed both by the position of the
bromine atom on the dienophile and on the “diene”.
(12) Dzieduszycka, M.; Stefanska, B.; Tarasiuk, J .; Martinelli, S.;
Bontemps-Gracz, M.; Borowski, E. Eur. J . Med. Chem. 1994, 29, 561-
567.
(13) The regiochemistry observed agrees with the known directing
effect of the 5-peri OH group in juglone 5a and the opposite one in
acetyljuglone 5b.14
On the other hand, some naturally occurring alkaloids
like the cytotoxic derivative kuanoniamine A (I)10,11
contain a thiazole ring fused to a quinone-imine system
while the recently synthesized naphthothiazoledione II12
(14) Kelly, T. R.; Gillard, J . W.; Goerner, R. N., J r.; Lyding, J . M. J .
Am. Chem. Soc. 1977, 99, 5513-5514 and references cited therein.
(15) A similar cross peak through nitrogen was reported to appear
as a doublet in the HMBC spectrum of benzothiazole or kuanoniamine
A.10
(10) Carroll, A. R.; Scheuer, P. J . J . Org. Chem. 1990, 55, 4426-
4431.
(11) Molinski, T. F. Chem. Rev. 1993, 93, 1825-1838.

Diels-Alder of 4-Methylene-5-(bromomethylene)-4,5-dihydrothiazole
J . Org. Chem., Vol. 62, No. 2, 1997 407
Sch em e 4
Ta ble 1. F or m a tion a n d Tr a p p in g of o-QDM 2 w ith
Na p h th oqu in on es 9-12
Ta ble 3. 2D 1H-13C NMR HMBC Cor r ela tion s for
Com p ou n d 15b (DMSO-d 6, δ)
starting
entry quinone methoda compounds ratio of 14/15b yield [%]c
1
2
3
4
5
6
7
8
9
9a
9b
A
A
A
B
A
B
A
A
A
A
13a
13b
-
-
52
70
70
63
37
46
60
56
73
58
10a
10a
10b
10b
11a
11b
12a
12b
14a + 15a
14a + 15a
14b + 15b
14b + 15b
14a + 15a
14b + 15b
14a + 15a
14b + 15b
70/30
57/43
40/60
46/54
92/8
95/5
8/92
5/95
HMBC (J C-H)
position 1H (300 MHz) 13C (75 MHz)
1J
2J
3J
2
3a
4
4a
5
5a
6
7
8
9
9a
10
10a
11
11a
12
13
9.74
-
8.73
-
-
-
7.67
7.99
8.25
-
-
-
-
162.2
156.1
121.0
131.7
181.6
135.2
125.3
135.4
130.3
150.0
124.8
180.9
130.3
122.9
140.2
168.7
20.9
H-2
-
H-4
-
-
-
H-6
H-7
H-8
-
-
-
-
-
-
-
-
-
-
-
-
-
10
H-2, H-11
-
H-11
H-4, H-6
H-7
a
b
Method A: NaI/DMF; method B: Bu4N+I-/toluene. Deter-
mined by 1H-NMR at 300 MHz. c From isolated pure products.
Ta ble 2. Ch em ica l Sh ifts (300 MHz, DMSO-d 6, δ) of H-4
a n d H-11 for Com p ou n d s 14 a n d 15
H-8
-
regioisomer (1,6-) H-11 H-4 regioisomer (1,9-) H-11 H-4
H-7 H-6
H-8 H-7
14a
14b
9.12 8.80
9.10 8.69
15a
15b
9.19 8.76
9.05 8.73
-
-
-
-
-
H-6, H-8
H-11
H-4
Thus, the unsubstituted carbon atom of bromonaphtho-
quinones is attacked by the unbrominated methylene end
of o-QDM 2. These observations are in contradiction with
some [4 + 2] cycloadditions in which juglone 10a and its
3-bromo derivative 12a gave the same orientation while
an opposite one was observed between 10a and 2-bro-
mojuglone 11a .16 An analogous kind of orientational
control occurred in the Diels-Alder trapping of the
brominated o-xylylene 16 with 2-bromobenzoquinones 17
or 1817 (Scheme 5).
9.05
-
H-11
-
-
H-2, H-4
2.45
LUMO for the most stable (Z) configuration. Comparison
of these values (HOMO ) -9.051 and LUMO ) 0.983)
with those of buta-1,3-diene (HOMO ) -9.502 and
LUMO ) 0.282) and 1-methoxybuta-1,3-diene (HOMO
) -8.854 and LUMO ) 0.351) suggests that the reactiv-
ity of 2 is intermediate between that of a neutral and an
electron rich diene. Then, calculations of HOMO orbital
coefficients at the ends of (Z)- or (E)-2 and 16 indicate
that their Diels-Alder reactions with unsymmetrical and
In search for a better understanding of o-QDM 2
behavior in cycloaddition reactions, we calculated, by the
semiempirical PM3 method,18 the energies of HOMO and

408 J . Org. Chem., Vol. 62, No. 2, 1997
Al Hariri et al.
Sch em e 5
Ta ble 4. Or bita l Coefficien ts of HOMO for o-QDMs a n d
LUMO for Acr yla te Dien op h iles a n d Un sym m etr ica l
Qu in on es
larger values are situated at C-2. Concerning 5-acetoxy-
naphthoquinones, the larger values of LUMO orbital
coefficients are at C-3 for 10b and 11b, but they are
similar for 12b. For 2-bromobenzoquinones 17 and 18,
the larger coefficients are situated at the unbrominated
carbon C-3. So, calculations of frontier orbital coefficients
agree with the regiochemistry observed in the cycload-
ditions between 2 and quinones 10a (syn), 10b, and
bromoquinone 11a , but they remain unsufficient to
explain it in the cases of bromoquinones 11b, 12a , 12b,
17, 18, and acrylate dienophiles as well.
This work describes the ability of 4-(bromomethyl)-5-
(dibromomethyl)-4,5-dihydrothiazole (1) to afford an o-
quinodimethane analogue 2 under mild conditions. Trap-
ping of 2 with N-phenylmaleimide, DMAD, or acrylate
derivatives provides an efficient route to 5,6-disubstituted
or 4,5-dihydro-6-substituted benzothiazoles, the latter not
readily available by other methods. Anthrathiazole-5,
10-dione derivatives 14 or 15 were regioselectively ob-
tained from 2- and 3-bromo-5-substituted naphthoquino-
nes. Indeed, strategic placement of bromine atoms on
the o-QDM and naphthoquinones provides highly regio-
controlled cycloadditions to give the 1,6- (or 1,9-) regio-
isomers. The regiochemistry observed on one hand with
acrylate dienophiles and on the other hand with bromo-
quinones 11b, 12a , and 12b is opposite to that predicted
by calculations of the frontier orbital coefficients by the
semiempirical PM3 method. In the case of quinones, the
blocking effect of bromine seems a more significant factor
for the regiochemical control. Further investigations will
be developed to generate other brominated thiazole
o-quinodimethanes by this method in order to elucidate
the regiocontrol of their Diels-Alder trapping.
Exp er im en ta l Section
Melting points were measured in a capillary tube. Column
chromatography was carried out with silica gel (60 Å, 35-70
µm). 1H- and 13C-NMR spectra were recorded with tetra-
methylsilane as an internal standard. For recording out 2D
1H-13C HMBC spectra, 5 mg of compound 15b were dissolved
at room temperature in 0.5 mL of DMSO-d6. The HMBC
technique was performed with gradients selection19 which gave
a very clean 2D matrix with very small T1 noise. The J filter
and transfer time for long range coupling were fixed, respec-
tively, to 3.22 and 80 ms. The acquisition parameters were
AQ ) 0.18 ms, SW2 ) 2793 Hz, SW1 ) 3586 Hz, NE ) 512,
NS ) 48, and relaxation delay D1 ) 1.5 s. Prior to the FFT,
the signal was weighted by a nonshifted sine bell in the two
dimensions. The size of the final matrix was 1K × 1K.
The energies and coefficients of the molecular frontier
orbitals were calculated from MOPAC of SYBYL program.
2-Bromo-5-hydroxynaphthoquinone (11a ) and 2-bromo-5-
acetoxynaphthoquinone (11b) were prepared according to
Grunwell et al.16 3-Bromo-5-hydroxynaphthoquinone (12a )
was obtained by treating juglone with bromine in glacial acetic
acid.20 By this method 13% of the 2-bromo derivative 11a was
polarized dienophiles should be highly regioselective. On
the other hand, the larger coefficients are located at the
brominated carbon atom (Table 4). The LUMO orbital
coefficients for the unsymmetrical acrylate dienophiles
and naphthoquinones 10a , 11a , and 12a show that the
(16) It was demonstrated that the electron rich end of carbodienes16a
or azadienes16b,c attacks exclusively the unbrominated carbon of
naphthoquinones 6 and 7. (a) Grunwell, J . R.; Karipides, A.; Wigal, C.
T.; Heinzman, S. W.; Parlow, J .; Surso, J . A.; Clayton, L.; Fleitz, F. J .;
Daffner, M.; Stevens, J . E. J . Org. Chem. 1991, 56, 91-95. (b)
Bouammali, B. Pautet, F.; Fillion, H. Tetrahedron 1993, 49, 3125-
3130. (c) Chaker, L.; Pautet, F.; Fillion, H. Heterocycles 1995, 41, 1169-
1179.
(18) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-221.
(19) Hurd, R. E.; J ohn, B. K. J . Magn. Reson. 1991, 91, 648-653.
(20) Thomson, R. H. J . Org. Chem. 1948, 13, 377-383.
(17) Wiseman, J . R.; Pendery, J . J .; Otto, C. A.; Chiong, K. G. J .
Org. Chem. 1980, 45, 516-519.

Diels-Alder of 4-Methylene-5-(bromomethylene)-4,5-dihydrothiazole
J . Org. Chem., Vol. 62, No. 2, 1997 409
also formed which was removed by recrystallization from
acetone. Acetylation of 12a was performed as described for
10b.21 The melting points of 11 and 12 are identical with the
values reported in the literature.22,23
chromatography on silica gel using EtOAc/petroleum ether (8:
2) as the eluent.
6-Cya n o-4,5-d ih yd r oben zoth ia zole (7a ). Starting with
cyanoethylene as the dienophile, the cycloaddition gave a
mixture of regioisomers 7a +7′a (7a /7′a : 95/5) from which
compound 7a was isolated as a white solid in 55% yield after
recrystallization from hexane. Mp 99 °C. IR (KBr): ν 3060,
4-(Br om om eth yl)-5-(d ibr om om eth yl)th ia zole (1). To a
stirred solution of 4,5-dimethylthiazole (0.560 g, 5 mmol) in
CCl4 (100 mL) were added NBS (2.94 g, 16.5 mmol) and AIBN
(0.1 g, 10%). Then, the reaction mixture was heated to reflux
for 1 h. After cooling, the succinimide was removed by
filtration. The filtrate was concentrated under vacuum and
purified by column chromatography on silica gel using a
mixture of ether/CH2Cl2/petroleum ether 3/3/4 as the eluent.
The corresponding tribromo derivative 1 was obtained in 65%
yield. It was not stable at room temperature but may be stored
at -18 °C for several days. 1H-NMR (CDCl3, 300 MHz) δ 8.80
(s, 1H, H-2), 7.0 (s, 1H, 5-CHBr2), 4.60 (s, 2H, 4-CH2Br). 13C-
NMR (CDCl3, 75 MHz) δ 153.3 (C-2), 147.0 (C-5), 140.2 (C-4),
26.3 (5-CHBr2), 23.4 (4-CH2Br). MS: m/ z (%): 349.6 (M+, 0.6),
269.8 (100), 190.9 (42), 188.9 (41). HRMS cannot be measured
due to the very low percentage of the molecular peak.
5-F or m yl-4-m eth ylth ia zole (3). Aldehyde 3 was prepared
according to the procedure described in reference.8 Mp 74 °C
2900, 2200, 1590, 1500, 1440 cm-1
.
1H-NMR (CDCl3, 200
MHz) δ 8.78 (s, 1H, H-2), 7.25 (t, 1H, J ) 1.6 Hz with allylic
coupling, H-7), 3.14 (m, 2H, H-4), 2.76 (m, 2H, H-5). Anal.
Calcd for C8H6N2S: C, 59.24; H, 3.73; N, 17.27; S, 19.76.
Found: C, 58.99; H, 3.78; N, 17.39; S, 19.24.
4,5-Dih yd r o-6-(et h oxyca r b on yl)b en zot h ia zole (7b ).
Starting with ethyl acrylate as the dienophile, the cycloaddi-
tion gave a mixture of regioisomers 7b+7′b (7b/7′b: 87/13)
from which compound 7b was isolated as an oil by column
chromatography on silica gel using EtOAc/hexane 30/70 as the
eluent. Yield: 67%. IR (KBr): ν 3080, 2900, 1700, 1600 cm-1
.
1H-NMR (CDCl3, 200 MHz) δ 8.61 (s, 1H, H-2), 7.50 (s, 1H,
H-7), 4.24 (q, 2H, CH2CH3), 3.05 (t, 2H, H-4), 2.71 (t, 2H, H-5),
1.22 (t, 3H, CH2CH3). Anal. Calcd for C10H11NO2S, 0.2 H2O:
C, 56.42; H, 5.39; N, 6.58; S, 15.06. Found: C, 56.59; H, 5.42;
N, 6.44; S, 15.09.
(lit.8 66-70 °C). IR (KBr): ν 2890, 1660 cm-1
.
1H-NMR
6-Acetyl-4,5-d ih yd r oben zoth ia zole (7c) a n d 5-Acetyl-
ben zoth ia zole (8′c). Starting with methyl vinyl ketone as
the dienophile, the dihydro derivative 7c was obtained as a
white solid admixed with the aromatized 8′c (12%). These
compounds were separated by column chromatography as
described in the general procedure. 7c: Yield 52%. Mp 106
(CDCl3, 200 MHz) δ 10.12 (s, 1H, CHO), 8.96 (s, 1H, H-2), 2.77
(s, 3H, 4-CH3). 13C-NMR (CDCl3, 50 MHz) δ 182.3 (5-CHO),
161.7 (C-5), 158.7 (C-2), 132.8 (C-4), 16.1 (4-CH3).
4-Meth yl-5-(d ibr om om eth yl)th ia zole (4). The procedure
used to obtain the dibromo derivative 4 from aldehyde 3 was
that described in reference 9. Compound 4 is unstable.
Yield: 40%. It may be stored in CH2Cl2 at -18 °C for few
days. 1H-NMR (CDCl3, 200 MHz) δ 8.77 (s, 1H, H-2), 6.91 (s,
1H, 5-CHBr2), 2.46 (s, 3H, 4-CH3). 13C-NMR (CDCl3, 50 MHz)
δ 151.6 (C-2), 147.6 (C-5), 135.0 (C-4), 27.2 (5-CHBr2), 14.4
(4-CH3).
°C (hexane). IR (KBr): ν 2900, 1640, 1590 cm-1
.
1H-NMR
(CDCl3, 200 MHz) δ 8.75 (s, 1H, H-2), 7.45 (s, 1H, H-7), 3.02
(t, 2H, H-4), 2.79 (t, 2H, H-5), 2.39 (s, 3H, COCH3). Anal. Calcd
for C9H9NOS: C, 60.31; H, 5.06; N, 7.81; S, 17.89. Found: C,
60.45; H, 5.13; N, 7.77; S, 17.96. 8′c : Yield 12%. Mp 102 °C
(hexane). IR (KBr): ν 3080, 1680, 1360, 1300 cm-1 1H-NMR
.
6-P h en ylth ia zolo[2,3-f]isoin d ol-5,7(6H)-d ion e (5).
A
(CDCl3, 200 MHz) δ 9.10 (s, 1H, H-2), 8.71 (s, 1H, H-4), 8.08
(m, 2H, H-6 and H-7), 2.72 (s, 3H, COCH3). Anal. Calcd for
C9H7NOS, 0.2 H2O: C, 59.78; H, 4.12; N, 7.74. Found: C,
59.63; H, 4.04; N, 7.43.
solution of the tribromo derivative 1 (0.21 g, 0.6 mmol) in DMF
(2 mL) was added over 10 min to a stirred, heated (70 °C)
mixture of NaI (0.36 g, 2.4 mmol) and N-phenylmaleimide
(0.519 g, 3 mmol) in DMF (4 mL). The reaction mixture was
heated at 70 °C for 20 min. After cooling, the brown solution
was poured into 50 mL of water and treated with a 10%
aqueous solution of NaHSO3 until its decoloration. The
solution was extracted with EtOAc (2 × 30 mL) and the organic
phase dried over anhydrous MgSO4. After elimination of the
solvent, the residue was purified by column chromatography
on silica gel using EtOAc/hexane (5:5) as the eluent. Com-
pound 5 was obtained as a white solid in 88% yield. Mp 246
6-Acetylben zoth ia zole (8c). A stirred suspension of
compound 7c (0.13 g, 0.73 mmol) and Pd-C 10% (0.077 g, 0.1
equiv) in diphenyl ether (2mL) was heated at 220 °C for 27 h.
After cooling, the reaction mixture was filtered through Celite
and the latter washed with CH2Cl2. The filtrate and dichlo-
romethane fractions were combined, concentrated under
vacuum, and chromatographed on silica gel using EtOAc/
petroleum ether 40/60 as the eluent. Compound 8c was
obtained as a white solid in 44% yield. Mp 94 °C (hexane). IR
°C (methanol). IR (KBr): ν 1715, 1610, 1500, 1460 cm-1 1H-
.
(KBr): ν 3100, 1675, 1435, 1300, 1280, 1260 cm-1 1H-NMR
.
NMR (DMSO-d6, 200 MHz) δ 9.73 (s, 1H, H-2), 8.91 (s, 1H,
H-8), 8.57 (s, 1H, H-4), 7.51 (m, 5H, C6H5). Anal. Calcd for
C15H8NO2S, 0.66 H2O: C, 61.66; H, 2.85; N, 9.44; S, 10.64.
Found: C, 61.59; H, 3.21; N, 9.58; S, 10.97.
(CDCl3, 200 MHz) δ 9.17 (s, 1H, H-2), 8.62 (s, 1H, H-7), 8.18
(m, 2H, H-4 and H-5), 2.72 (s 3 H, COCH3). Anal. Calcd for
C9H7NOS: C, 60.99; H, 3.98; N, 7.90; S, 18.09. Found: C,
61.06; H, 3.84; N, 7.65; S, 17.77.
5,6-Bis(m eth oxyca r bon yl)ben zoth ia zole (6). Compound
6 was prepared from the tribromo derivative 1 and DMAD
(0.43 g, 3 mmol) as above. Stirring and heating were main-
tained for 2.5 h. After the same workup and purification
described above, the white solid was recrystallized from EtOAc/
hexane, affording 6 in 56% yield. Mp 120 °C. IR (KBr): ν
Gen er a l P r oced u r es for th e Syn th esis of An th r a [2,3-
b]th ia zole-5,10-d ion es (13, 14, a n d 15). Method A:
A
solution of the tribromo derivative 1 (0.316 g, 0.6 mmol) in
DMF (2 mL) was slowly added to a stirred hot (60 °C) solution
of the corresponding quinone (0.5 mmol) and NaI (5 equiv) in
3 mL of DMF. Stirring and heating were maintained for 1 h,
and then the reaction mixture was cooled to room temperature.
The precipitated product was filtered off and washed with
water and then with EtOAc. Evaporation of the filtrate gave
an additional fraction of the corresponding tetracyclic quino-
nes. The anthra[2,3-b]thiazole-5,10-diones were purified by
column chromatography using a mixture of EtOAc/hexane 40/
60 or 70/30 as the eluent. In each case, the major regioisomer
was isolated from the mixture by recristallization from an
appropriate solvent.
Method B: A solution of the tribromo derivative 1 (0.316 g,
0.6 mmol) in toluene (3 mL) was added in 10 min to a stirred
hot (80 °C) mixture of quinone 10a or 10b (0.5 mmol) and
Bu4N+I- (0.93 g, 3 mmol) in 15 mL of toluene. Stirring and
heating were maintained for 15 min. By cooling the reaction
mixture, a precipitate of the corresponding tetracyclic quinones
was formed. It was collected by filtration and washed with
EtOAc. An additionnal fraction of the aromatized cycloadducts
3120, 2960, 1740, 1715, 1600, 1445, 1435 cm-1
.
1H-NMR
(CDCl3, 300 MHz) δ 9.19 (s, 1H, H-2), 8.48 (s, 1H, H-7), 8.38
(s, 1H, H-4), 3.97 (s, 3H, COOCH3), 3.95 (s, 3H, COOCH3).
Anal. Calcd for C11H9NO4S: C, 52.58; H, 3.61; N, 5.57; S,
12.76. Found: C, 52.49; H, 3.60; N, 5.57; S, 12.60.
Gen er a l P r oced u r e for th e Syn th esis of 4,5-Dih yd r o-
6-su bstitu ted Ben zoth ia zole (7). A mixture of the tribromo
derivative 1 (0.35 g, 1 mmol) and the corresponding dienophile
(20 mmol) in DMF (3 mL) was added over 10 min to a stirred
solution of NaI (0.6 g, 4 mmol) heated at 70 °C and highly
activated molecular sieves (4 Å, 1 g) in DMF (3 mL). Stirring
and heating were maintained for 30 min. After the same
workup described as above, the residue was purified by column
(21) Bernthsen, A.; Semper, A. Chem. Ber. 1885, 18, 203-213.
(22) Garden, J . F.; Thomson, R. H. J . Chem. Soc. 1957, 2483-2489.
(23) Hannan, R. L.; Barber, R. A.; Rapoport, H. J . Org. Chem. 1979,
44, 2153-2158.

410 J . Org. Chem., Vol. 62, No. 2, 1997
Al Hariri et al.
was isolated after evaporation of the filtrate and then, a
column chromatography of the residue was performed as
above.
δ 12.54 (s, 1H, OH); 9.76 (s, 1H, H-2), 9.19 (s, 1H, H-11); 8.76
(s, 1H, H-4), 7.84 (m, 2H, H-8 and H-9); 7.43 (d, 1H, J ) 12
Hz, H-7). 14a +15a : Anal. Calcd for C15H7NO3S: C, 64.05;
H, 2.50; N, 4.98; S, 11.39. Found: C, 64.03; H, 2.46; N, 5.03;
S, 11.58.
An th r a [2,3-b]th ia zole-5,10-d ion e (13a ). Mp 294 °C dec.
IR (KBr) ν 1675 (CO) cm-1 1H-NMR (300 MHz, DMSO-d6) δ
.
9.76 (s, 1H, H-2), 9.14 (s, 1H, H-11), 8.78 (s, 1H, H-4), 8.29
(m, 2H, H-7 and H-8), 7.98 (m, 2H, H-6 and H-9). Anal. Calcd
for C15H7NO2S: C, 67.91; H, 2.66; N, 5.28; S, 12.08. Found:
C, 67.79; H, 2.92; N, 5.30; S, 11.90.
6 (an d 9)-Acetoxyan th r a[2,3-b]th iazole-5,10-dion es (14b
a n d 15b). 14b (1,6-regioisomer): Mp 257 °C (DME). IR (KBr)
ν 1770, 1670 (CO) cm-1 1H-NMR (300 MHz, DMSO-d6) δ 9.74
.
(s, 1H, H-2), 9.10 (s, 1H, H-11), 8.69 (s, 1H, H-4), 8.24 (d, 1H,
J ) 8 Hz, H-7); 7.99 (t, 1H, J ) 8 Hz, H-8), 7.67 (d, 1H, J ) 8
Hz, H-9), 2.44 (s, 3H, OCOCH3). 15b (1,9-regioisomer): Mp
6,9-Dih yd r oxya n th r a [2,3-b]th ia zole-5,10-d ion e (13b).
Mp > 300 °C. IR (KBr) ν 1640 (CO) cm-1 1H-NMR (300 MHz,
.
253 °C (acetone). IR (KBr) ν 1770, 1670 (CO) cm-1 1H-NMR
.
DMSO-d6) δ 12.81 (s, 2H, OH), 9.80 (s, 1H, H-2), 9.24 (s, 1H,
H-11), 8.85 (s, 1H, H-4), 7.49 (s, 2H, H-7 and H-8). Anal.
Calcd for C15H7NO4S: C, 60.59; H, 2.37; N, 4.71; S, 10.78.
Found: C, 60.48; H, 2.49; N, 4.45; S, 10.69.
(300 MHz, DMSO-d6) δ 9.74 (s, 1H, H-2), 9.05 (s, 1H, H-11),
8.73 (s, 1H, H-4), 8.25 (d, 1H, J ) 8 Hz, H-8), 7.99 (t, 1H, J )
8 Hz, H-7); 7.67 (d, 1H, J ) 8 Hz, H-6), 2.45 (s, 3H, OCOCH3).
14b+15b: Anal. Calcd for C17H9NO4S: C, 62.80; H, 2.85; N,
4.31; S, 9.86. Found: C, 62.53; H, 2.80; N, 4.55; S, 9.90.
6 (an d 9)-Hydr oxyan th r a[2,3-b]th iazole-5,10-dion es (14a
a n d 15a ). 14a (1,6-regioisomer): Mp > 300 °C (DMF). IR
(KBr) ν 1670, 1640 (CO) cm-1
.
1H-NMR (300 MHz, DMSO-
d6) δ 12.54 (s, 1H, OH); 9.76 (s, 1H, H-2), 9.12 (s, 1H, H-11);
8.80 (s, 1H, H-4), 7.84 (m, 2H, H-8 and H-9); 7.43 (d, 1H, J )
12 Hz, H-7). 15a (1,9-regioisomer): Mp > 300 °C (DMF); IR
(KBr) ν 1670, 1640 (CO) cm-1; 1H-NMR (300 MHz, DMSO-d6)
Ack n ow led gm en t . We thank Dr. J . L. Luche for
useful discussions.
J O961457N