Oxidative cyclization of N-methyl- and N-benzoylpyridylthioureas. Preparation of new thiazolo[4,5-b] and [5,4-b]pyridine derivatives

Article abstract of DOI:10.1002/jhet.5570400210

Cyclization of N-methyl- and N-benzoylpyridylthioureas, prepared from the corresponding aminopyridines, has been realized using various conditions. With bromine in acetic acid or potassium ferricyanide, the cyclization occurred on the nitrogen of the pyridine ring and pyridinium salts or 1,2,4-thiadiazolo[2,3-a]pyridylidene systems were obtained. On the other hand, treatment of the thioureas with sodium methoxide in N-methylpyrrolidinone (NMP) led to formation of thiazolo[4,5-b] and [5,4-b]pyridines, which are interesting targets for biological evaluation.

Full text of DOI:10.1002/jhet.5570400210

Mar-Apr 2003
Oxidative Cyclization of N-Methyl- and N-Benzoylpyridylthioureas.
Preparation of New Thiazolo[4,5-b] and [5,4-b]pyridine Derivatives.
Karine Jouve and Jan Bergman*
261
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and Södertörn University
College, Novum Research Park, SE-14157 Huddinge, Sweden
Received August 15, 2002
Cyclization of N-methyl- and N-benzoylpyridylthioureas, prepared from the corresponding aminopy-
ridines, has been realized using various conditions. With bromine in acetic acid or potassium ferricyanide,
the cyclization occurred on the nitrogen of the pyridine ring and pyridinium salts or 1,2,4-thiadiazolo[2,3-
a]pyridylidene systems were obtained. On the other hand, treatment of the thioureas with sodium methoxide
in N-methylpyrrolidinone (NMP) led to formation of thiazolo[4,5-b] and [5,4-b]pyridines, which are inter-
esting targets for biological evaluation.
J. Heterocyclic Chem., 40, 261 (2003).
Introduction.
to depend upon the activation of the pyridine ring [7]. On
the other hand, a two-step procedure was also described: a
thiourea derivative was obtained from the reaction
between an aminopyridine and an appropriate isothio-
cyanate which was subsequently cyclized by bromine in
acetic acid or chloroform [9] (Scheme 1, Method B). If a
halogen atom is present at the α position to the amino
group, the cyclization occurs spontaneously [10,11].
Synthetic and naturally occurring heterocyclic com-
pounds often possess various biological activities, and
more particularly those containing thiazole or benzothia-
zole rings. For instance, compounds such as 1 have been
found to be antitumoral [1] whereas 2 is known for its anti-
convulsant action [2]. On the other hand, heterocyclic
amines also present some biological properties [3] and
specifically the bicyclic amine 2-amino-1-methyl-6-
phenylimidazolo[4,5-b]pyridine (PhIP) (3) has mutagenic
activity [4]. Therefore it is of interest to prepare thiazole-
containing analogues of PhIP and to study their biological
properties. In view of these considerations, syntheses of
molecules such as 4 and 5 were scheduled (Figure 1).
This last method was chosen in order to get the required
heterocyclic amines 4 and 5.
Results and Discussion.
In order to study the influence of the substrate on the
cyclization step, various 5-substituted pyridylthioureas
were prepared. Thus, 2-amino-5-phenylpyridine (6b) was
first obtained by Suzuki cross-coupling of 2-amino-5-bro-
mopyridine (6a) with benzeneboronic acid [12]. Both of
these aminopyridines, 6a and 6b, were then used to get the
corresponding pyridylthioureas (Scheme 2). Treatment of
6a and 6b with methyl isothiocyanate in toluene led to the
formation of the N-methylpyridylthioureas 7a and 7b with
yields of 70 % and 56 %, respectively. In the same way, the
Literature studies revealed that two principal routes have
been used for the synthesis of such bicyclic systems. Thus,
various thiazolo[4,5-b]pyridines can be formed by a one-
step procedure starting from the appropriate aminopy-
ridines. Reacting them with a thiocyanate salt in acetic
acid with bromine led to the formation of the correspond-
ing thiocyanated intermediates, which then spontaneously
cyclized under the reaction conditions [5-8] (Scheme 1,
Method A). The success of the reaction has been reported

262
K. Jouve and J. Bergman
Vol. 40
N-benzoylpyridylthioureas 8a and 8b were obtained by
reaction of 6a and 6b with benzoyl isothiocyanate in aque-
ous ethanol, with yields of 80 % and 56 %.
Despite the results reported by Sarkis and Faisal [9],
where the same method was used to prepare various thia-
zolopyridines, the formation of the pyridinium salts under
the conditions used here was not surprising. A survey of
the literature showed that similar pyridinium salts have
been prepared by oxidative cyclization of unsubstituted
pyridylthioureas with bromine in acetic acid, chloroform
or methanol or with sulfuryl chloride in toluene [14,15].
Nevertheless, we decided to use another well-known
reaction for such a cyclization, the Jacobson reaction, with
potassium ferricyanide as oxidative agent [16]. When the
pyridylthiourea 7a was stirred at room temperature under
the Jacobson conditions, the starting material was recov-
ered unchanged after 5 hours. If the reaction medium was
submitted to prolonged stirring or refluxing, compound 11
was isolated with 30 % yield in both cases, with some
recovered starting material. The formation of 11 corre-
sponds to the hydrolysis of the thiocarbonyl group of 7a by
the hydroxide used during the reaction (Scheme 4).
With these N-methyl- and N-benzoylpyridylthioureas in
hand, we then continued the sequence with the cyclization
step. The first method chosen for this purpose was the
Hugershoff reaction, which has been widely used to obtain
benzothiazoles [13]. Thus, when compound 7a was
reacted with bromine in acetic acid at room temperature a
beige solid was obtained with 70 % yield after
Scheme 4
work-up. Examination of the NMR data led to the con-
clusion that a cyclization had occurred but on the nitrogen
atom of the pyridine ring and thus the pyridinium salt 9a
was formed rather than the expected thiazolopyridine.
Indeed, in compound 9a, the H-6 proton of the pyridine
ring is strongly deshielded from 8.30 ppm to 9.42 ppm.
Similar results were obtained with the N-methylpyridylth-
iourea 7b on one hand and the N-benzoylpyridylthioureas
8a and 8b on the other hand. For these latter compounds,
1
the absence of a labile proton in the H NMR spectra led us
to assume the thiadiazolopyridylidene structures shown in
Scheme 3 for 10a and 10b.
In the same way, no reaction was observed when 7b was
stirred at room temperature with potassium ferricyanide
during 5 hours. On the contrary, when the N-ben-
zoylpyridylthiourea 8a was reacted under the same condi-
tions, the cyclization occurred once again on the nitrogen
of the pyridine ring, and the corresponding product 10a
was obtained quantitatively (Scheme 4).
It consequently appeared that the targeted thiazolopyri-
dine structures could not be prepared by either Hugershoff
or Jacobson reactions, whatever the subtitution of the pyri-
dine ring or of the thiourea was. An explanation for the
favoured formation of pyridinium salts can be furnished
by consideration of the reaction mechanisms [17]
(Scheme 5).

Mar-Apr 2003
Oxidative Cyclization of N-Methyl- and N-Benzoylpyridylthioureas
263
In the Hugershoff reaction, the oxidation of the initial
thiourea with bromine led to the formation of structure A,
in which the sulfur atom is electrophilic. In the same way,
good yield (67 %). Palladium cross-coupling reaction with
benzeneboronic acid produced then compound 15 (32 %)
which, after hydrolysis, led to the target structure 4.
in the Jacobson conditions, thioenolization and attack of
the ferricyanide anion resulted in the transient species A’
with an electrophilic sulfur. The subsequent cyclization is
then performed on the more nucleophilic nitrogen atom of
the pyridine ring rather than the C-3 carbon. It would be
better therefore to get an intermediate with a nucleophilic
sulfur that can then react on the pyridine ring. This was
realised when the reaction was carried out under basic
conditions, by abstraction of one of the labile hydrogen of
the thiourea and formation of a thiolate anion.
Nevertheless, treatment of 8a with sodium methoxide in
N-methylpyrrolidinone (NMP) at 120° during 4 hours did
not give the expected thiazolopyridine structure but only
recovered starting material. In order to enhance the reac-
tivity of this compound, it was then decided to introduce a
halogen atom on the pyridine ring [11]. Thus the
pyridylthiourea 13 was prepared from 2-amino-5-bromo-
3-chloropyridine (12) [18] in 86 % yield as shown in
Scheme 6. Treatment of 13 under basic conditions led, in
this case, to the formation of the thiazolopyridine 14 in
The yield of the palladium cross-coupling step is unusu-
ally low for this type of reaction and optimization were
undertaken. Thus the reaction was carried out in various
solvents such as benzene, toluene-methanol or
dimethoxyethane or with sodium carbonate as base.
Various amounts of benzeneboronic acid were also used
but none of these modifications improved the yield of this
reaction. It appeared that a large excess of base and ben-
zeneboronic acid is necessary to get a reasonable yield of
the coupled product. A similar sequence was then used to
prepare the regioisomeric thiazolopyridine 5 (Scheme 7).
First, compound 16 was prepared by a substitutive
deamination process [19] starting from the commercially
available 2-amino-5-bromo-3-nitropyridine, tert-butylni-
trite and anhydrous copper (II) chloride. It was then
reduced to 3-amino-5-bromo-2-chloropyridine (17) with
tin (II) chloride dihydrate. The corresponding thiourea was
then formed by the same method as previously described
and 18 was obtained in 75 % yield. Subsequent cyclization
was realized under basic conditions, followed by the

264
K. Jouve and J. Bergman
Vol. 40
1
palladium cross-coupling reaction that led to the formation
of 20, once again with a low yield (46 %). Finally 20 was
hydrolyzed to 5 in 61 % yield.
ir (potassium bromide): 3465, 3273, 3140, 1622, 1467, 888, 745; H
nmr (dimethyl sulfoxide-d6): δ 8.02 (d, J = 2.1 Hz, 1H, H-6), 7.84
(d, J = 2.2 Hz, 1H, H-4), 6.53 (b, 2H, NH ); C nmr (dimethyl sul-
13
2
foxide-d6): δ 154.7(s), 146.6(d), 138.1(d), 113.9(s), 104.1(s).
Conclusion.
5-Bromo-2-chloro-3-nitropyridine (16).
The thiazolopyridine derivatives described herein repre-
sent interesting targets for biological evaluation, if we con-
sider the parent benzothiazole compounds or the hetero-
cyclic amine PhIP (3). Moreover, the methodology
described here can be used to prepare various analogues
substituted for structure-activity relationship studies.
Compound 16 was prepared by a procedure similar to that
described in [19]. A solution of 2.5 g (24 mmol; 1.5 eq.) of tert-
butylnitrite, 2.6 g (19.2 mmol; 1.2 eq.) of anhydrous copper (II)
chloride and anhydrous acetonitrile (70 mL) was warmed to 70
°C under stirring. 2-Amino-5-bromo-3-nitropyridine (16 mmol)
was then added portionwise over a period of 5 minutes to the
green reaction solution. During this addition the solution turned
black and nitrogen gas evolved. The mixture was heated during 2
hours and then allowed to reach room temperature. After which
the reaction mixture was poured in to 100 mL of 20 % HCl, fol-
lowed by extraction with ether. The organic layer was washed
EXPERIMENTAL
General.
Melting points were measured using the capillary method in a
Büchi apparatus B-545 and are uncorrected. Infrared spectra
were obtained from a Perkin-Elmer 1600 series FTIR. Nmr
with 20 % HCl and dried over anhydrous Na SO . After concen-
2
4
tration under reduced pressure, the residue was purified on a sil-
ica gel column using CH Cl as eluent. Compound 16 was then
2
2
1
13
spectra were recorded at 300 MHz for H and 75 MHz for
C
obtained (1.35 g; 36 %) as a white solid, that could be recrystal-
lized from hexane; mp = 67 °C (lit [21] mp = 68 °C ); ir (potas-
13
on a Bruker AM 300 apparatus. C at 125 MHz were recorded
on a JEOL Eclipse + 500 apparatus, using Delta program.
Chemical shifts (δ) are reported in ppm and are referenced to the
solvent (δ = 2.51 and 7.26 ppm). Mass spectra (ESI) were per-
formed on a Perkin-Elmer API 150 EX spectrometer. Elemental
analyses were performed by H. Kolbe Mikroanalytisches
Laboratorium, Mülheim am Ruhr, Germany. All reagents were
of commercial quality and were used as received. All solvents
were purified by distillation or were of HPLC grade. Reactions
were monitored by thin layer chromatography using Macherey-
1
sium bromide): 3025, 1566, 1543, 1519, 1337, 1055, 755; H
nmr (deuteriochloroform): δ 8.69 (d, J = 2.2 Hz, 1H, H-4), 8.37
13
(d, J = 2.2 Hz, 1H, H-6); C nmr (dimethylsulfoxide-d6): δ
153.8(d), 144.5(s), 140.3(s), 137.3(d), 119.1(s).
3-Amino-5-bromo-2-chloropyridine (17).
A solution of 200 mg (0.84 mmol) of 5-bromo-2-chloro-3-
nitropyridine (16) and 950 mg (4.2 mmol; 5 eq.) of SnCl •2H O
2
2
in ethyl acetate(2 mL) was refluxed under nitrogen during 3
hours. After cooling to room temperature, the reaction mixture
Nagel Alugram SIL G/UV
aluminium plates. Separations
254
by column chromatography were performed using 60A (40-
63µm) silica. tert-Butylnitrite was prepared according to a liter-
ature procedure [20]. Copper (II) chloride was dried in an oven
at 110 °C before use.
was poured into water. The resulting solid (residue from SnCl )
2
was filtered off and washed with ethyl acetate, and the aqueous
filtrate extracted by the same solvent. The combined organic lay-
ers were washed with brine and dried over anhydrous Na SO .
2
4
After filtration, the filtrate was concentrated under reduced pres-
sure and purified by silica gel column (ether/hexane 5/5). The
white solid thus obtained (152 mg; 87 %) was recrystallized from
water. Mp = 130 °C (lit [21°] mp = 131 °C); ir (potassium
Aminopyridine Compounds.
2-Amino-5-bromo-3-chloropyridine (12).
This compound was prepared according to the procedure
described in [18]. Mp (aq. CH OH) = 97 °C (lit [18] mp = 95 °C);
1
bromide): 3453, 1623, 1435, 1111, 859, 708; H nmr (dimethyl
3

Mar-Apr 2003
Oxidative Cyclization of N-Methyl- and N-Benzoylpyridylthioureas
265
sulfoxide-d6): δ 7.66 (d, J = 2.2 Hz, 1H, H-6), 7.30 (d, J = 2.2 Hz,
mp = 164 °C (lit [23] mp = 164-168 °C); ir (potassium bromide):
3378, 2990, 1666, 1525, 703; H nmr (dimethyl sulfoxide-d6): δ
1
13
1H, H-4), 5.89 (b, 2H NH ); C nmr (dimethyl sulfoxide-d6): δ
2
13.23 (boad s, 1H, NH), 11.95 (b, 1H, NH), 8.66 (broad s, 1H, H-
3), 8.59 (d, J = 2.2 Hz, 1H, H-6), 8.16 (dd, J = 8.8, 2.3 Hz, 1H, H-
4), 7.98 (d, J = 7.6 Hz, 2H, Ph), 7.54-7.71 (m, 3H, Ph); C nmr
142.8(s), 135.6(d), 133.7(s), 123.1(d), 119.1(d).
N-Methylpyridylthioureas.
13
N-(5-Bromo-2-pyridyl),N’-methylthiourea (7a).
(dimethyl sulfoxide-d6): δ 178.0(s), 150.2(s), 148.9(d), 140.6(d),
133.2(d), 132.1(s), 128.6(d), 128.5(d), 117.0(d), 115.5(s). The
broad signal from the H-3 atom sharpened upon heating. The des-
bromo analog of 8a displayed a similar phenomenon.
Compound 7a was prepared as follows: a solution of 500 mg
(2.9 mmol) of 2-amino-5-bromopyridine 6a and 630 mg (8.7
mmol; 3 eq.) of methyl isothiocyanate in 15 mL of toluene was
refluxed during 48 hours. The solution was then allowed to cool to
room temperature and by this time a precipitate appeared slowly in
the reaction solution that was collected by filtration and washed
with ether. More substance was obtained from the filtrate by keep-
ing it at –18 °C. Compound 7a (496 mg; 70 %) was recrystallized
from aq. ethanol; mp = 206 °C (lit [22] mp = 224 °C); ir (potassium
N-Benzoyl-N’-(5-phenyl-2-pyridyl)thiourea (8b).
Compound 8b (222 mg; 56 %) was prepared using Method 1,
with 200 mg (1.18 mmol) of 6b and benzoyl isothiocyanate (0.16
mL; 1 eq.). White crystals were obtained from aq. ethanol, mp =
1
155 °C; ir (potassium bromide): 3283, 3025,1666, 1531; H nmr
(dimethyl sulfoxide-d6): δ 13.38 (1b, 1H, NH), 11.79 (b, 1H, NH),
8.58 (m, 2H, H-3 and H-6), 8.24 (dd, J = 8.6, 2.4 Hz, 1H, H-4),
8.01 (d, J = 7.4 Hz, 2H, COPh), 7.77 (d, J = 7.4 Hz, 2H, Ph), 7.43-
1
bromide): 3214, 3151, 3088, 1596; H nmr (dimethyl sulfoxide-
d6): δ 11.05 (s, 1H, NHMe), 10.69 (s, 1H, NH), 8.30 (d, J = 2.2 Hz,
1H, H-6), 7.95 (dd, J = 8.9, 2.2 Hz, 1H, H-4), 7.10 (d, J = 8.9 Hz,
+
7.70 (m, 6H, Ph and COPh); m/z (ESI) ([M+H] , 100 %) = 334.3.
13
1H, H-3), 3.05 (s, 3H, Me); C nmr (dimethyl sulfoxide-d6): δ
Anal. Calcd. for C H N OS (333.41): C, 68.45; H, 4.53; N,
19 15
3
180.1(s), 152.3(s), 146.0(d), 141.3(d), 114.3(d), 111.7(s), 31.6(q).
12.60. Found: C, 68.33; H, 4.59; N, 12.52.
N-Methyl,N’-(5-phenyl-2-pyridyl)thiourea (7b).
N-Benzoyl-N’-(5-bromo-3-chloro-2-pyridyl)thiourea (13).
The same procedure as above was used with the following
amounts: 2-amino-5-phenylpyridine (6b): 560 mg (3 mmol);
methyl isothiocyanate: 650 mg (9 mmol; 3 eq.). 7b was obtained
with 56 % yield (410 mg) as a white solid; it was recrystallized
from aq. ethanol; mp = 211 °C; ir (potassium bromide): 3203,
According to Method 2, the following quantities were used: 1
g (4.8 mmol) of 2-amino-5-bromo-3-chloropyridine (12) in 1.5
mL of acetone; 400 mg (5 mmol; 1.04 eq.) of ammonium thio-
cyanate and 0.6 mL (5mmol; 1.04 eq.) of benzoyl chloride in 1.5
mL of acetone. Compound 13 (1.55 g; 86 %) was recrystallized
from ethanol; mp = 156 °C; ir (potassium bromide): 3155, 3026,
1
3144, 3026, 1591, 1573; H nmr (dimethyl sulfoxide-d6): δ 11.49
(b, 1H, NHMe), 10.69 (s, 1H, NH), 8.51 (d, J = 2.2 Hz, 1H, H-6),
8.09 (dd, J = 8.7, 2.4 Hz, 1H, H-4), 7.31-7.71 (m, 5H, Ph), 7.24
1
1666, 1502, 1155, 71; H nmr (dimethyl sulfoxide-d6): δ 12.38
(b, 1H, NH), 11.89 (b, 1H, NH), 8.66 (d, J = 2.1 Hz, 1H, H-6),
8.59 (d, J = 2.2 Hz, 1H, H-4), 7.80 (d, J = 7.3 Hz, 2H, Ph), 7.52-
13
(d, J = 8.7 Hz, 1H, H-3), 3.11 (s, 3H, Me); C nmr (dimethyl sul-
foxide-d6): δ 180.2(s), 152.8(s), 143.3(d), 137.0(d), 136.5(s),
13
7.71 (m, 3H, Ph); C nmr (dimethyl sulfoxide-d6): δ 180.7(s),
129.5(d), 129.0(d), 127.6(d), 126.2(d), 112.5(d), 31.4(q); m/z
168.1(s), 147.9(d), 147.8(s), 140.6(d), 133.3(d), 131.9(s),
129.3(s), 128.7(d), 128.5(d), 118.6(s).
+
(ESI) ([M+H] ), 100 %) = 244.3.
Anal. Calcd. for C H N S (243.33): C, 64.17; H, 5.38; N,
13 13
3
Anal. Calcd. for C H N OSBrCl (370.66): C, 42.13; H, 2.45;
13
9 3
17.26. Found: C, 64.11; H, 5.27; N, 17.24.
N-Benzoylpyridylthioureas.
Method 1.
N, 11.34; S, 8.65. Found C, 42.10; H, 2.36; N, 11.22; S, 8.54.
N-Benzoyl-N’-(5-bromo-2-chloro-3-pyridyl)thiourea (18).
Compound 18 was obtained according to Method 2 by using
500 mg (2.4 mmol) of 17 in 1.5 mL of acetone; 190 mg (2.5
mmol; 1.04 eq.) of ammonium thiocyanate and 0.3 mL (2.5
mmol; 1.04 eq.) of benzoyl chloride in acetone (1 mL).
Compound 18 was prepared with 75 % yield (666 mg) and was
recrystallized from ethanol; mp = 177 °C; ir (potassium bro-
Benzoyl isothiocyanate was added dropwise to a stirred solu-
tion of 6a or 6b in aq. ethanol at room temperature. The resulting
mixture was stirred for 15 minutes more and the precipitate was
collected by filtration, washed with ethanol and dried under
reduced pressure.
1
mide): 3459, 3295, 1672, 1513, 679; H nmr (dimethyl sulfoxide-
Method 2.
d6): δ 12.77 (b, 1H, NH), 12.04 (b, 1H, NH), 8.81 (d, J = 2.3 Hz,
Benzoyl isothiocyanate was prepared in situ. A mixture of
ammonium thiocyanate and acetone was warmed until a clear
solution was obtained. Benzoyl chloride was then slowly dropped
in and the resulting suspension refluxed 5 minutes. The aminopy-
ridine dissolved in acetone was thus added and the reaction mix-
ture was refluxed for 1 hour. After cooling to room temperature,
the solution was poured into water and the resulting solid was
collected by filtration, washed with water and ether and dried
under reduced pressure.
1H, H-6), 8.53 (d, J = 2.3 Hz, 1H, H-4), 8.01 (d, J = 7.4 Hz, 2H,
Ph), 7.54-7.72 (m, 3H, Ph); C nmr (dimethyl sulfoxide-d6): δ
180.6(s), 168.5(s), 147.5(d), 144.7(s), 138.5(d), 133.9(s),
133.4(d), 131.7(s), 128.8(d), 128.5(d), 117.8(s).
13
Anal. Calcd. for C H N OSBrCl (370.66): C, 42.13; H, 2.45;
13
9 3
N, 11.34; S, 8.65. Found: C, 42.24; H, 2.34; N, 11.30, S, 8.71.
Hugershoff Reaction Compounds.
General procedure: a mixture of thiourea in acetic acid was
warmed until a clear solution was obtained. Bromine was then
added dropwise and the resulting mixture was stirred 1 hour at
room temperature. The orange solid was collected by filtration,
washed with acetic acid, water and acetonitrile and dried under
reduced pressure.
N-Benzoyl-N’-(5-bromo-2-pyridyl)thiourea (8a).
Compound 8a (312 mg; 80 %) was obtained according to
Method 1 by using 200 mg (1.16 mmol) of 6a and benzoyl isoth-
iocyanate (0.16 mL; 1 eq.). It was recrystallized from benzene;

266
K. Jouve and J. Bergman
Vol. 40
6-Bromo-2-methylamino-1,2,4-thiadiazolo[2,3-a]pyridinium
Bromide (9a).
Jacobson Reaction Compounds.
General Procedure.
Compound 9a was obtained according to the general proce-
dure from 150 mg (0.6 mmol) of 7a in acetic acid (4 mL) and 0.2
mL (4 mmol; 6.5 eq.) of bromine. Compound 9a (137 mg; 70 %)
was recrystallized from water; mp = 229 °C; ir (potassium bro-
mide): 3447, 1590, 1455, 1387, 822; H nmr (dimethyl sulfoxide-
d6): δ 9.42 (d, J = 1.8 Hz, 1H, H-6), 9.30 (b, 1H, NH), 8.27 (dd, J
Potassium ferricyanide and potassium hydroxide were added to
a suspension of thiourea in water at room temperature. The reac-
tion mixture was then stirred or refluxed during the time required
and the solid was collected by filtration, washed with water and
dried under reduced pressure after appropriate work-up.
1
1-(5-Bromo-pyridin-2-yl)-3-methyl-urea (11).
= 9.3, 2 Hz, 1H, H-4), 7.74 (d, J = 9.2 Hz, 1H, H-3), 3.17 (d, J =
13
4.9 Hz, 3H, Me); C nmr (dimethyl sulfoxide-d6): δ 171.2(s),
This compound (178 mg; 31 %) was prepared according to the
general procedure by using 615 mg (2.5 mmol) of 7a, 1.9 g (5.75
156.3(s), 143.8(d), 135.8(d), 118.1(d), 109.6(s), 31.3(q).
Anal. Calcd. for C H N SBr (325.03): C, 25.87; H, 2.17; N,
7
7
3
2
mmol; 2.3 eq.) of KOH in 60 mL of H O. It was stirred 2.5 days
2
12.93. Found: C, 25.9; H, 2.12; N, 12.84.
at room temperature. The solid collected after filtration was puri-
fied by column of silica gel (ethyl acetate/petroleum ether 8/2)
and 11 was obtained altogether with the starting material 7a (225
mg; 37 %). The same compound 11 was also prepared by reflux-
ing the reaction mixture 5 hours instead with a similar yield of 30
%. It was recrystallized from water; mp = 201 °C; ir (potassium
2-Methylamino-6-phenyl-1,2,4-thiadiazolo[2,3-a]pyridinium
Bromide (9b).
Compound 9b (178 mg; 89 %) was prepared from 150 mg (0.6
mmol) of 7b in 4 mL of acetic acid and 0.2 mL (4 mmol; 6.5 eq.)
of bromine. It was recrystallized from water; mp = 222 °C; ir
1
bromide): 3260, 3037, 1690, 1584, 822, 626; H nmr (dimethyl
1
(potassium bromide): 3458, 2989, 1594, 1467, 1398, 757; H
sulfoxide-d6): δ 9.32 (s, 1H, NH), 8.26 (d, J = 2.3 Hz, 1H, H-6),
nmr (dimethyl sulfoxide-d6): δ 9.53 (d, J = 1.6 Hz, 1H, H-6);
9.39 (d, J = 4.6 Hz, 1H, NH), 8.46 (dd, J = 9.1, 1.9 Hz, 1H, H-4),
7.86 (d, J = 9.1 Hz, 1H, H-3), 7.45-7.78 (m, 5H, Ph), 3.20 (d, J =
7.88 (dd, J = 8.9, 2.5 Hz, 1H, H-4), 7.51 (s, 1H, NH), 7.46 (d, J =
8.9 Hz, 1H, H-3), 2.70 (s, 3H, Me); C nmr (dimethyl sulfoxide-
d6): δ 154.9(s), 152.3(s), 147.2(d), 140.4(d), 113.2(d), 110.6(s),
25.9(q).
13
13
4.9 Hz, 3H, Me); C nmr (dimethyl sulfoxide-d6): δ 170.6(s),
155.7(s), 139.8(d), 134.1(s), 133.1(d), 117.0(d), 129.5(s),
129.4(d), 128.8(d), 126.5(d), 126.4(d), 31.2(q).
Anal. Calcd. for C H N OBr (230.06): C, 36.54; H, 3.50; N,
18.26. Found: C, 36.66; H, 3.42; N, 18.14.
7
8 3
Anal. Calcd. for C H N SBr (322.23): C, 48.4; H, 3.7; N,
13.04; S, 9.95. Found: C, 48.45; H, 3.74; N, 12.87; S, 9.77.
13 12
3
N-[6-Bromo-[1,2,4]thiadiazolo[2,3-a]pyridylidene]benzamide
(10a).
N-[6-Bromo-[1,2,4]thiadiazolo[2,3-a]pyridylidene]benzamide
(10a).
Compound 10a described above, was prepared from 200 mg
(0.6 mmol) of 8a, 454 mg (1.38 mmol; 2.3 eq.) of potassium fer-
ricyanide and 155 mg (2.76 mmol; 4.6 eq.) of KOH in 15 mL of
Compound 10a was formed by reaction between 200 mg (0.6
mmol) of 8a and 0.2 mL (4 mmol; 6.5 eq.) of bromine in 4 mL of
acetic acid; 10a was obtained with 98 % yield (193 mg) and was
H O. 10a was produced in quantitative yield (208 mg).
2
Thiazolopyridine Compounds.
recrystallized from a mixture of DMF and H O; mp = 246 °C; ir
2
1
N-(6-Bromo-thiazolo[4,5-b]pyridin-2-yl)-benzamide (14).
(potassium bromide): 3442, 3054, 1581, 1517, 1358, 721; H
nmr (dimethyl sulfoxide-d6): δ 9.45 (d, J = 1.7 Hz, 1H, H-7),
A mixture of 1.5 g (4 mmol) of 13, 432 mg (8 mmol; 2 eq.) of
sodium methoxide and 10 mL of NMP was heated to 120 °C
during 4 hours. It was then allowed to reach room temperature
and was poured into water. The resulting pale brown solid was
collected by filtration, washed with water and ether and dried
under reduced pressure. More substance was obtained by
extracting the previous filtrate with chloroform and evaporating
to dryness the organic layer after usual work-up. 14 (893 mg)
was obtained in 67 % yield. It can be recrystallized from a mix-
8.24-8.28 (m, 3H, H-5 and Ph), 7.83 (d, J = 9.2 Hz, 1H, H-4),
13
7.56-7.69 (m, 3H, Ph) C nmr (dimethyl sulfoxide-d6): δ
177.0(s), 176.2(s), 154.6(s), 142.00(d), 135.0(d), 132.8(d),
132.7(s), 128.7(d), 119.8(d), 109.9(s).
Anal. Calcd. for C H N OSBr (334.20): C, 46.72; H, 2.41; N,
13
8 3
12.57; S, 9.59; Br, 23.91. Found: C, 46.67; H, 2.33; N, 12.63; S,
9.46; Br, 23.85.
N-[6-Phenyl-[1,2,4]thiadiazolo[2,3-a]pyridylidene]benzamide
(10b).
ture of DMF and H O; mp = 328 °C; ir (potassium bromide):
2
1
3421, 3049, 2939, 1665, 1575, 1519, 1283, 695; H nmr
Compound 10b was obtained according to the general proce-
dure with 150 mg (0.45 mmol) of 8b and 0.15 mL of bromine in
quantitative yield. White crystals were obtained from aq. ethanol;
mp = 256 °C; ir (potassium bromide): 3413, 3049, 1525, 1373,
(dimethyl sulfoxide-d6): δ 13.25 (b, 1H, NH), 8.79 (d, J = 2.2
Hz, 1H, H-5), 8.66 (d, J = 2.2 Hz, 1H, H-7), 8.16 (d, J = 7.3 Hz,
13
2H, Ph), 7.56-7.70 (m, 3H, Ph); C nmr (dimethyl sulfoxide-
d6): δ 166.6(s), 162.9(s), 159.1(s), 148.1(d), 132.2(d), 131.4(s),
128.7(d), 128.4(d), 127.0(s), 113.6(s).
1
720, 691; H nmr (dimethyl sulfoxide-d6): δ 9.54 (d, J = 1.4 Hz,
1H, H-7), 8.53 (dd, J = 9, 1.7 Hz, 1H, H-5), 8.27 (d, J = 7.2 Hz,
2H, COPh), 8.01 (d, J = 9 Hz, 1H, H-4), 7.84 (d, J = 7.5 Hz, 2H,
Anal. Calcd. for C H N OSBr (334.20): C, 46.72; H, 2.41; N,
13
8 3
12.57; S, 9.59. Found: C, 46.67; H, 2.28; N, 12.39; S, 9.71.
13
Ph), 7.49-7.69 (m, 6H, COPh and Ph); C nmr (dimethyl sulfox-
N-(6-Bromo-thiazolo[5,4-b]pyridin-2-yl)-benzamide (19).
ide-d6): 176.8(s), 154.6(s), 138.2(d), 134.8(s), 133.1(s), 132.6(d),
131.9(d), 129.6(s), 129.2(d), 128.7(d), 128.6(d), 126.7(d),
118.5(d).
Compound 19 was obtained according to a procedure similar
to the one described above. 18 (600 mg; 1.6 mmol) was heated
with 173 mg (3.2 mmol; 2 eq.) of sodium methoxide in 8 mL of
NMP. 19 was recrystallized from acetonitrile; mp = 250 °C; ir
Anal. Calcd. for C H N OS (331.40): C, 68.86; H, 3.95; N,
19 13
3
12.68; S, 9.67. Found: C, 68.73; H, 3.90; N, 12.75; S, 9.70.

Mar-Apr 2003
Oxidative Cyclization of N-Methyl- and N-Benzoylpyridylthioureas
267
(potassium bromide): 3467, 3143, 2941, 1677, 1587, 1531, 1296,
933, 704; H nmr (dimethyl sulfoxide-d6): δ 13.18 (b, 1H, NH),
Anal. Calcd. for C H N S (227.29): C, 63.41; H, 3.99; N,
12 9 3
18.49. Found: C, 63.70; H, 4.12; N, 18.18.
1
8.63 (d, J = 2 Hz, 1H, H-5), 8.48 (d, J = 2 Hz, 1H, H-7), 8.16 (d,
J = 7.4 Hz, 2H, Ph), 7.57-7.73 (m, 3H, Ph); C nmr (dimethyl
6-Phenylthiazolo[5,4-b]pyridin-2-ylamine (5).
13
sulfoxide-d6): δ 166.3(s), 159.9(s), 153.6(s), 145.8(d), 143.1(s),
133.3(d), 131.4(s), 129.6(d), 128.7(d), 128.5(d), 117.6(s).
Anal. Calcd. for C H N OSBr (334.20): C, 46.72; H, 2.41; N,
Compound 5 (48 mg; 61 %) was prepared according to a pro-
cedure similar to the one described for 4, starting from 115 mg
(0.35 mmol) of compound 20. It was recrystallized from a mix-
ture of ethyl acetate and hexane; mp = 207 °C; ir (potassium bro-
mide): 3455, 3287, 3084, 1641, 1523, 1362, 754; H nmr
(dimethyl sulfoxide-d6): 8.41 (d, J = 2.1 Hz, 1H, H-5), 7.87 (m,
13
8 3
12.57; S, 9.59. Found: C, 46.57; H, 2.29; N, 12.39; S, 9.71.
1
N-(6-Phenyl-thiazolo[4,5-b]pyridin-2-yl)-benzamide (15).
A solution of Pd(PPh ) (111 mg; 0.1 eq.), triethylamine (1.1
3H, H-7 and NH ), 7.73 (d, J = 7.1 Hz, 2H, Ph), 7.41-7.52 (m,
3 4
2
mL; 7.7 mmol; 8 eq.), benzeneboronic acid (703 mg; 5.8 mmol;
6 eq.) in 2 mL of DMF was deoxygenated during 30 minutes by
3H, Ph).
Anal. Calcd. for C H N S (227.29): C, 63.41; H, 3.99; N,
18.49; S, 14.11. Found: C, 63.42; H, 4.12; N, 18.36; S, 14.06.
12
9 3
bubbling N in it. It was then added to a deoxygenated solution
2
of 14 (320 mg; 0.96 mmol) and 2 mL of DMF and the resulting
Acknowledgements.
mixture was heated to slight reflux during 24 hours, under N
2
atmosphere. After allowing it to reach room temperature, the
reaction suspension was poured into water and extracted with
chloroform. The organic layer was washed with water and dried
13
Thanks are due to Dr Ivar Romero for the recording of the
spectrum at 125 MHz (compound 15).
C
over anhydrous Na SO . After filtration, it was concentrated
2
4
under reduced pressure and purified by silica gel column with
ethyl acetate and hexane (5/5) as eluent. Compound 15 was thus
obtained in 32 % yield (100 mg) as a white solid. Mp = 301 °C
(ethyl acetate); ir (potassium bromide): 3463, 3053, 1665, 1528,
REFERENCES AND NOTES
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Lelieveld, I. Fichtner and M. F. G. Stevens, J. Med. Chem., 39, 3375
(1996).
1
1283, 701; H nmr (dimethyl sulfoxide-d6): δ 13.25 (b, 1H,
NH), 8.89 (s, 1H, H-5), 8.81 (s, 1H, H-7), 8.18 (d, J = 7.6 Hz,
2H, COPh), 7.69 (d, J = 7.8 Hz, 2H, Ph), 7.44-7.63 (m, 6H,
[2] P. Jimonet, F. Audiau, M. Barreau, J.-C. Blanchard, A.
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[3] For a review on the properties and synthesis of hetero-
cyclic amines, see: Food Borne Carcinogens, Heterocyclic Amines,
ed by M. Nagao, T. Sugimura, John Wiley, 2000.
13
COPh and Ph); C nmr (dimethyl sulfoxide-d6, 125 MHz): δ
167.0(s), 162.8(s), 160.3(s), 146.8(d), 137.8(s), 133.7(d),
132.1(s), 131.6(s), 129.7(d), 129.4(d), 129.3(d), 129.00(d),
128.4(d), 127.6(d), 126.0(s).
Anal. Calcd. for C H N OS (331.40): C, 68.86; H, 3.95; N,
19 13
3
12.68; S, 9.68. Found: C, 68.95; H, 3.78; N, 12.49; S, 9.82.
N-(6-Phenyl-thiazolo[5,4-b]pyridin-2-yl)-benzamide (20).
This compound was prepared according to the procedure
described for 15, starting from the same amounts of chemicals
(compound 19 was used instead). In this case, the reaction mix-
ture was refluxed 2 hours. 20 (145 mg; 46 %) was then recrystal-
lized from ethyl acetate; mp = 257 °C; ir (potassium bromide):
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(1999); [b] A. M. Lynch, N. J. Gooderham, D. S. Davies and A. R.
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Japan, 64, 26 (1944); Chem. Abstr., 46, 111c (1952).
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725 (1985).
[10] V. P. Arya, K. G. Dave, S. J. Shenoy, V. G. Khadse and R.
H. Nayak, Indian J. Chem., 11, 744 (1973).
1
3447, 3053, 1669, 1545, 1297, 710; H nmr (dimethyl sulfoxide-
d6): δ 13.10 (b, 1H, NH), 8.84 (d, J = 1.9 Hz, 1H, H-5), 8.39 (d,
J = 1.7 Hz, H-7), 8.17 (d, J = 7.4 Hz, 2H, COPh), 7.84 (d, J = 7.3
Hz, 2H, Ph), 7.44-7.73 (m, 6H, COPh and Ph).
Anal. Calcd. for C H N OS (331.40): C, 68.86; H, 3.95; N,
19 13
3
12.68; S, 9.68. Found: C, 68.75; H, 3.93; N, 12.61; S, 9.55.
6-Phenylthiazolo[4,5-b]pyridin-2-ylamine (4).
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Compound 15 (140 mg; 0.4 mmol) was heated to slight reflux
in 2 mL of 70 % H SO during 20 minutes. During this time, the
2
4
[12] J. Stavenuiter, M. Hamzink, R. van der Hulst, G. Zomer,
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initial white suspension turned to a brown solution. After cooling
to room temperature, it was poured into water and basified by 30
% NaOH. The resulting precipitate was collected by filtration,
washed with H O and ether and dried under reduced pressure.
2
Compound 4 (38 mg) was produced in 40 % yield as a beige
solid. It can be recrystallized from a mixture of ethyl acetate and
DMF; mp = 257 °C; ir (potassium bromide): 3455, 3270, 3050,
1
1635, 1436, 1374, 764; H nmr (dimethyl sulfoxide-d6): δ 8.54
(d, J = 2.2 Hz, 1H, H-5), 8.39 (d, J = 2.2 Hz, 1H, H-7), 8.01 (b,
2H, NH ), 7.69 (d, J = 7.4 Hz, Ph), 7.35-7.51 (m, 3H, Ph); m/z
2
+
(ESI) ([M+H] ), 100 %) = 228.4.
[18] M. Gacek, S. Gronowitz and C. Hedbom, Acta Pharm.

268
K. Jouve and J. Bergman
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