The Dimroth rearrangement: Synthesis and interconversion of isomeric triazolothienopyrimidines

Article abstract of DOI:10.3184/030823408X327875

Triazolo-thieno[3,2-e]pyrimidines obtained by cyclisation of 4-hydrazino-2-(methylthio)thieno[2,3-d]pyrimidine with formic acid, acetic acid, cyanogen bromide and carbon disulfide, and by oxidation of the derived aldehyde hydrazones, are found to be the triazolo[4,3-c] isomers. These [4,3-c] compounds resist isomerisation in acid, but they undergo Dimroth rearrangement to the [1,5-c] isomers under basic conditions. The crystal structure of one such rearranged product, 5-methoxy-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4] triazolo[1,5-c]pyrimidine (13b) was confirmed by X-ray analysis.

Full text of DOI:10.3184/030823408X327875

334 RESEARCH PAPER
JUNE, 334–339
JOURNAL OF CHEMICAL RESEARCH 2008
The Dimroth rearrangement: synthesis and interconversion of isomeric
triazolothienopyrimidines
Atef A. Hameda*, El-Sayed H. El-Ashryb, Ibrahim F. Zeida and Hesham F. Badra
aChemistry Department, Faculty of Science, Menoufia University, Egypt
bChemistry Department, Faculty of Science, Alexandria University, Egypt
Triazolo-thieno[3,2-e]pyrimidines obtained by cyclisation of 4-hydrazino-2-(methylthio)thieno[2,3-d]pyrimidine
with formic acid, acetic acid, cyanogen bromide and carbon disulfide, and by oxidation of the derived aldehyde
hydrazones, are found to be the triazolo[4,3-c] isomers. These [4,3-c] compounds resist isomerisation in acid, but
they undergo Dimroth rearrangement to the [1,5-c] isomers under basic conditions. The crystal structure of one
such rearranged product, 5-methoxy-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (13b)
was confirmed by X-ray analysis.
Keywords: dimroth rearrangement; hydrazines; fused pyrimidines, thiophenes, 1,2,4-triazoles; crystal structures
Fused pyrimidines attract considerable attention because of
their wide spectrum of biological activities. Thienopyrimidines
occupy a special position: some of them exhibit antiallergic,1,2
corresponding thienopyrimidines 2a,b. Subsequent reaction
with dimethyl sulfate, phosphorus oxychloride and then
hydrazine hydrate afforded the hydrazines 5a,b.24 (Scheme 1)
A series of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines
wassynthesisedbycondensationofthe4-hydrazino-2-(methyl-
thio)thienopyrimidines (5a,b) with various one-carbon donors.
For instance, with formic acid the thienotriazolopyrimidines
6a,b, were prepared, while with acetic acid the hydrazide 7b
was obtained, which underwent dehydrative cyclisation upon
heating in DMF to furnish the 3-methyl analogue 8b. The 3-
thioxo derivative 10b was obtained by the reaction of 5b with
carbon disulfide in pyridine. Reaction of 5a,b with cyanogen
bromide in presence of HCl resulted in the formation of
the 3-amino derivatives 9a,b. Condensation of 5a,b with
aromatic aldehydes gave the hydrazones 11a–e, and oxidative
cyclisation of these last compounds by ethanolic FeCl3 gave
the 3-aryl-5-(methylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]py
rimidine derivatives 12a–c (Scheme 2).
The structure proposals of these compounds were consistent
with their analytical and spectral data (1H and 13C NMR, IR,
mass spectra and elemental analyses). The 1H NMR spectrum
of 6a showed singlets at 2.45, 2.56 and 2.78 ppm for three
methyl groups. The triazole proton absorbed at d 9.35 ppm.
The methylene groups of 6b resonated at 1.88, 2.83 and
3.02 ppm, besides a singlet signal at 2.78 ppm due to the
methylthio group. The triazole proton gave a peak at 9.38 ppm.
When thienotriazolopyrimidines 6a,b were allowed to
react with NaOCH3, new compounds were obtained. The
products were 5-methoxythieno[3,2-e][1,2,4]triazolo[1,5-c]
antihistaminic,3,4
antihypertensive,5,6
antiinflamatory,7,8
antimicrobial,9,10 antiviral,11 antitumor12,13 activities.
Heterocycles containing the 1,2,4-triazole nucleus also show
biological activity; several have been used as bactericidal,14
insecticidal,15 antitumor,16 and antiinflammatory17 agents. The
introduction of a triazole ring into the thienopyrimidine system
is expected to influence the biological activities significantly.
In fact, some of them have been reported to display pronounced
antibacterial18 and anticonvulsant19 activities.
Rearrangements in heterocyclic chemistry are of potential
value for the synthesis of heterocyclic compounds which
may otherwise require more elaborate routes, particularly
in the pyrimidine series. One of the most interesting of
these is the Dimroth rearrangement.20 Isomerisation of
triazolothienopyrimidines has been reported by a number of
workers. Several factors may influence this rearrangement,
such as the reaction conditions and the type and position
of the substituents. In continuation of our interest in the
synthesis and structural elucidation of thienopyrimidines,21,22
we report herein the synthesis, structure and reactivity of
some compounds of this class which possess a methylthio or
methoxy group on the pyrimidine ring.
Results and discussion
The reaction of enamino esters 1a,b, prepared by Gewald's
method,23 with thiourea or potassium thiocyanate gave the
O
R1
R1
CO2Et
R1
O
CO2Et
NH
b
a
+
S
+
CN
R2
R2
R2
NH2
S
S
S
N
H
1a,b
2a,b
c
O
Cl
NHNH2
R1
R2
R1
R2
R1
R2
NH
d
e
N
N
SMe
S
N
S
N
SMe
S
N
SMe
5a,b
3a,b
4a,b
1-5: a, R1 = R2 = CH3, b, R1R2 = (CH2)4
Reagents and conditions: a, morpholine, EtOH; b, KSCN, dioxan/ EtOH; c, aq. NaOH, Me2SO4;
d, POCl3; e, N2H4.H2O / EtOH
Scheme 1 Formation of the hydrazines 5a,b.
* Correspondent. E-mail: atef2000_99@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2008 335
N
N
NH
N
R1
R2
NH2
S
N
N
S
N
SMe
S
N
SMe
9a,b
b
10b
a
NHNH2
N
NHNHCOCH3
N
NHN=CHAr
R1
R2
R1
N
f
c
R2
S
N
SMe
S
N
N
SMe
S
N
SMe
5a,b
e
7b
d
11a-e
g
N
N
N
N
N
R1
R2
R1
R2
CH3
Ar
N
N
N
S
N
6a,b
SMe
S
N
SMe
S
N
SMe
8b
12a-c
R1 R2
Ar
Compd
R1 R2
Compd
R1 R2
Ar
Compd
9a
CH3 CH3
11d
11e
(CH2)4
(CH2)4
4-BrC6H4
4-FC6H4
Ph
5a
5b
6a
6b
CH3 CH3
(CH2)4
CH3 CH3
(CH2)4
9b
(CH2)4
11a CH3 CH3
11b CH3 CH3 4-BrC6H4
11c CH3 CH3 4-FC6H4
Ph
12a CH3 CH3
12b CH3 CH3 4-FC6H4
12c
(CH2)4
4-BrC6H4
Reagents and conditions: a, CS2, pyridine; b, BrCN/HCl; c, CH3CO2H, heat; d, DMF, heat; e, HCO2H; f, ArCHO; g, FeCl3/EtOH
Scheme 2 Synthesis of the thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines 6, 8–10, 12.
pyrimidines (13a,b) as indicated by their physical and spectral
Table 1 Selected bond lengths(Å) and angles(°) of compound
13b
characteristics.
1
The H NMR spectrum of 13a showed bands at 2.41 and
Atoms
Distance
Atoms
Angle
2.49 ppm for two methyl groups beside resonance at 4.22 ppm
due to a methoxy group, with disappearance of the methylthio
group. The triazole proton of 13a and 13b appeared at
d 8.52 and 8.34 ppm respectively. The 13C NMR spectrum
of 13b displayed signals at 22.5, 23.4, 25.25 and 25.4 ppm
for the methylene carbons and a signal at 57.0 ppm from the
methoxy group. Additionally, seven sp2 carbon peaks are
found, attributed to the thiophene ring and C=N groups. The
1H NMR showed a marked contrast in the absorption of the
triazole protons. While compounds 6a,b showed the peak at
around 9.4 ppm, the triazole proton in 13a,b appeared more
shielded, showing as a singlet around 8.4 ppm. This is in
accordance with the observation of Shishoo et al.25-27 that the
triazole protons of triazolo[4,3-c] isomers are more deshielded
than those of [1,5-c] isomers. The structural proposal of
5-methoxy-8,9,10,11-tetramethylenethieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidine (13b) was further confirmed by
X-ray crystallographic analysis. (Fig. 1 and Table 1)
C11–C13
C11–C24
C24–C34
C34–C33
C33–C26
C26–C13
C13–C16
C16–C20
C20–S1
1.359(4)
1.513(4)
1.534(5)
1.490(5)
1.527(5)
1.501(4)
1.433(4)
1.374(4)
1.727(3)
1.736(3)
1.368(4)
1.287(4)
1.380(4)
1.386(4)
1.419(4)
1.372(3)
1.316(4)
1.367(4)
1.332(4)
1.323(4)
1.439(4)
C11–S1–C20
S1–C11–C24
C13–C11–C24
C22–N12–C28
C11–C13–C16
C11–C13–C26
C19–N4–C31
C16–C13–C26
C19–N5–C20
C13–C16–C20
C13–C16–C22
C20–C16–C22
O4–C19–N5
90.97(14)
121.4(2)
125.1(3)
102.5(3)
110.6(3)
123.0(3)
115.7(2)
126.4(3)
116.7(3)
114.0(3)
130.6(3)
115.4(3)
125.2(3)
113.2(3)
121.5(3)
122.1(2)
111.0(2)
126.9(3)
127.0(3)
109.9(2)
123.1(2)
134.6(3)
108.7(3)
111.0(3)
117.1(3)
114.0(3)
112.6(3)
S1–C11
C20–N5
N5–C19
C19–N8
N8–C22
C22–C16
N8–N10
N10–C28
C28–N12
N12–C22
C19–O4
O4–C31
O4–C19–N8
N5–C19–N8
S1–C20–N5
S1–C20–C16
N5–C20–C16
N10–N8–C19
N10–N8–C22
C19–N8–C22
N12–C22–C16
C11–C24–C34
C13–C26–C33
N10–C28–N12
C26–C33–C34
C24–C34–C33
Atoms
Angle
N8–C22–N12
N8–C22–C16
N8–N10–C28
S1–C11–C13
109.0(3)
116.4(2)
101.4(2)
113.4(2)
The reaction of 13a,b with hydrazine hydrate afforded
the hydrazino derivatives 14a,b. Furthermore, when the
triazolothienopyrimidines 6a,b reacted with hydrazine hydrate
they produced compounds identical with 14a,b in all respects
(NMR, IR, mass spectrum, elemental analysis and mixed
m.p). The 1H NMR spectrum (DMSO-d6) of 14a showed
two signals at 2.47 and 2.62 ppm for methyl groups and two
broad signals at 4.18 and 8.91 ppm for the NHNH2 group.
The triazole proton signal appeared at 8.29 ppm. Evidently
isomerisation has occurred during the course of nucleophilic
replacement of the methylthio group by hydrazine. A rare
Fig. 1 Crystal structure of compound 13b.

336 JOURNAL OF CHEMICAL RESEARCH 2008
N
N
N
N
R1
R2
R1
R2
N
N
N
Me
Me
N
N
N
N
a
SMe
OMe
S
N
S
S
N
S
N
N
18
N
6a,b
13a,b
+
b
N
N
N
N
Me
Me
R1
R2
N
N
Me
Me
N
c
N
e
(14a)
(14a)
S
N
N
N
N3
S
N
N
NHNH2
14a,b
17
15
12a-c
d
(14a)
N
Ph
(12a)
b
Ar
a
N
N
N
Me
Me
N
N
R1
R2
N
Me
Me
N
N
b
S
N
N
N
(19a)
S
N
NHNH2
OMe
S
N
20
H2N
16
19a-c
Compd
R1 R2
Compd R1
R2
Ar
19a CH3 CH3
Ph
13a, 14a
13b, 14b
CH3 CH3
(CH2)4
19b CH3 CH3 4-FC6H4
19c
(CH2)4
4-BrC6H4
Reagents and conditions: a, NaOMe / MeOH; b, N2H4.H2O; c, HCO2H, heat; d, BrCN / HCl; e, NaNO2 / HCl
Scheme 3 Synthesis of the thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines 13–20.
example of the Dimroth rearrangement catalysed by hydrazine
Isomerisation of the fused triazole system can be assumed to
proceed through a sequence of ring opening and ring closure
reactions of the pyrimidine ring as shown in Scheme 4.
hydrate has been reported before.28
Boiling 14a under reflux in formic acid resulted in the
formation of the corresponding bis-triazolothienopyrimidine
Apparently, a methylthio or methoxy group at the 5-
position in the triazolo[4,3-c]thienopyrimidines renders them
resistant towards acid-catalysed isomerisation. This failure
to isomerise under acidic conditions could be due to the
stabilisation through delocalisation of the positive charge on
the pyrimidine ring (21), thereby rendering the nucleophilic
ring opening of the pyrimidine system more difficult. It has
been observed that 5-unsubstituted, 5-alkyl- and 5-aralkyl-
1
15. Its H NMR spectrum showed two signals at d 2.50 and
2.56 ppm for the two methyl groups and two triazole protons
at 8.68 and 9.65 ppm. The reaction of 14a with cyanogen
bromide in presence of HCl afforded the 7-amino–bis-
1
triazolothienopyrimidine derivative 16. Its H NMR spectrum
showed two methyl signals at 2.38 and 2.45 ppm and a broad
peak at d 3.44 due to NH2 group. The triazole proton appeared
at d 8 49 ppm.
thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines
undergo
The reaction of 14a with nitrous acid at 0°C led to the
formation of the tetracyclic compound 18, as a minor
product which was found in equilibrium in DMSO with the
isomerisation to [1,5-c] isomers under both acidic and basic
conditions, whereas the systems with 5-phenyl and 5-styryl
substituents resist isomerisation under acidic conditions.25,27
1
5-azido derivative 17. The H NMR spectrum of 17 and 18
(in DMSO-d6) showed signals at 2.43, 2.44 (major), 2.55,
2.56 (minor) corresponding to the four methyl groups of the
two tautomers, beside two peaks at 8.57 (major) and 8.86 ppm
(minor), characteristic for the triazole protons. The relatively
downfield region of the methyl groups as well as the triazole
proton of 18 is probably attributable to the deshielding effect
of the tetrazole ring. Its 13C NMR exhibit resonances at
13.14, 13.88 (major) and 13.29, 13.78 (minor) for the methyl
groups. Thiophene carbons appeared at d 118.9, 127.0, 133.8
and 140.8 ppm, in addition to four signals characteristic of
C=N groups. The IR spectrum (KBr) of 17 showed a strong
absorption band at 2162 cm-1 due to the azido group.
Treatment of 3-arylthieno[3,2-e][1,2,4]triazolo[4,3-c]
pyrimidines (12a–c) with NaOCH3 furnished the isomeric
products 2-arylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines
(19a–c). Compound 19a underwent hydrazinolysis to afford
the hydrazine derivative 20 (Scheme 3). Reaction of 12a
with hydrazine hydrate gave a product identical with 20 in all
respects (1H NMR, IR, mixed m.p.).
N
N
R3
R1
R2
N
21
XCH3
S
N
H
Experimental
IR spectra were recorded with Perkin–Elmer model 1720 FT IR
spectrometer. 1H and 13C NMR spectra were determined with Varian
EM390 and Bruker AC–250 spectrometers. The chemical shifts in
ppm are expressed in the d scale using TMS as internal standard.
Coupling constants are given in Hz. Mass spectra were recorded on
an AEI MS 30 spectrometer. TLC was performed on Merck silica
gel 60-F254 precoated plastic plates. Microanalyses were performed
in the microanalysis units of the Universities of Cairo (Egypt) and
Odense (Denmark).
4-Hydrazino-5,6-dimethyl-2-(methylthio)thieno[2,3-d]pyrimidine
(5a): The chloro-compound 4a24 (0.24 g, 1 mmol) and N2H4.H2O
(5 ml) were boiled under reflux in ethanol (10 ml) for 1 h. The
colourless product that separated on cooling was filtered off and

JOURNAL OF CHEMICAL RESEARCH 2008 337
N
N
N
N
N
N
R3
:B
R1
R2
R3
R1
R2
R3
R1
R2
N
N
N
B
B
R4
S
N
R4
S
S
N
S
N
R4
R3
R3
N
R3
N
N
N
N
B
R1
R2
N
R1
R2
R1
R2
N
N
N
B
R4
S
N
S
N
N
R4
R4
Scheme 4 The Dimroth rearrangement of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines.
recrystallised from ethanol as colourless crystals (0.18 g, 75%), m.p.
220–221°C (lit.24 m.p. 222°C). NMR (DMSO-d6): dH 2.33 (s, 3H,
Me), 2.36(s, 3H, Me), 2.50 (s, 3H, SMe), 4.66 (bs, 2H, NH) 8.09,
(bs, 1H, NH); dC 13.42 (SMe), 14.08 (Me), 14.35 (Me), 113.34 (C5),
125.02 (C4a), 126.61 (C6),158.18 (C7a), 164.53 (C2), 165.00 (C4).
4-Hydrazino-2-(methylthio)-5,6,7,8-tetrahydro[1]benzothieno
[2,3-d]pyrimidine (5b): Compound 5b was prepared from 4b24 by
the procedure described above for 5a, as colourless crystals (0.19 g,
71%), m.p. 180–182°C. NMR (DMSO-d6): dH 1.77 (bm, 4H, 2CH2),
2.50 (s, 3H, Me), 2.71 (bm, 2H, CH2), 2.86 (bm, 2H, CH2), 4.63
(bs, 2H, NH), 7.93 (bs, 1H, NH); dC 14.49 (SMe), 22.95 (CH2),
23.14 (CH2), 25.68 (CH2), 26.26 (CH2), 112.59 (C5), 127.57 (C4a),
130.16 (C6), 158.52 (C7a), 165.55 (C2), 165.60 (C4). Anal. calcd for
C11H14N4S2 (266.36): C, 49.60; H, 5.29; N, 21.03. Found: C, 49.83;
H, 5.54; N, 21.23%.
C, 45.26; H, 4.17; N, 26.39. Found: C, 45.52; H, 4.33; N, 26.27%.
3-Amino-5-(methylthio)-8,9,10,11-tetrahydro[1]benzothieno[3,2-e]
[1,2,4]triazolo[4,3-c]pyrimidine (9b): From 5b and cyanogen
bromide as described for 9a: yellow crystals (1.9 g, 65%), m.p. 188–
191°C (lit.29 m.p. 252°C). MS: m/z 291(M+).
5-(Methylthio)-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine-3(2H)-thione (10b): The hydrazine 5b
(2.66 g, 10 mmol) and CS2 (5 ml) in pyridine (15 ml) were slowly
brought to the boil, heated under reflux for 8 h, and then allowed to
cool. The solid product was collected and recrystallised from ethanol
to give a yellow powder (2.06 g, 67%), m.p. 268–270°C. NMR
(DMSO-d6): dH 1.83 (bm, 4H, 2CH2), 2.50 (s, 3H, SMe), 2.80 (bm,
2H, CH2), 3.19 (bm, 2H, CH2), 14.33 (bs, 1H, NH). Anal. calcd for
C12H12N4S3 (308.44): C, 46.73; H, 3.91; N, 18.16. Found: C, 46.80;
H, 3.83; N, 18.28%.
8,9-Dimethyl-5-(methylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]
pyrimidine (6a)
The hydrazones 11a–e: general procedure
The hydrazines 5a,b (10 mmol) and the appropriate aromatic aldehyde
(10 mmol) in ethanol (30 ml) containing a few drops of glacial acetic
acid, were boiled under reflux for 2 h. The product that separated on
cooling was filtered off, dried, and crystallised from ethanol.
Benzaldehyde [5,6-dimethyl-2-(methylthio)thieno[2,3d]pyrimidin-
4-yl]hydrazone (11a): From 5a and benzaldehyde (1.06 g, 10 mmol);
colourless crystals (2.46 g, 75%), m.p. 208–211°C (lit.24 m.p. 182°C).
NMR (DMSO-d6): dH 2.39 (s, 3H, Me), 2.49 (s, 3H, Me), 2.56 (s, 3H,
SMe), 7.44 – 7.73 (m, 5H, Ph), 8.39 (s, 1H, N=CH), 10.21 (s, 1H,
NH); dC 14.1 (Me), 14.45 (Me), 15.3 (Me), 114.5 (C5), 125.4 (C4a),
127.7 (C6), 128.5, 129.75, 130.5, 135.5 (Ph), 146.9 (C7a), 154.9
(C2), 165.4 (C4), 167.7 (N=CH).
4-bromobenzaldehyde [5,6-dimethyl-2-(methylthio)thieno[2,3-d]
pyrimidin-4-yl]hydrazone (11b): From 5a and 4-bromobenzalde-
hyde(1.85 g, 10 mmol); yellow crystals (2.80, 69%), m.p. 200–203°C.
NMR (DMSO-d6): dH 2.40 (s, 3H, Me), 2.48 (s, 3H, Me), 2.55 (s, 3H,
SMe), 7.66 (s, 4H, ArH), 8.35 (s, 1H, N=CH), 10.30 (s, 1H, NH); dC
13.77 (Me), 14.1 (Me), 14.9 (Me), 114.05 (C5), 123.3 (C4a), 128.2
(C-6), 124.95, 130.1, 132.4, 134.3 (Ar), 145.2 (C7a), 154.25 (C2),
165.0 (C4), 167.2 (N=CH). Anal. calcd for C16H15BrN4S2 (407.30):
C, 47.18; H, 3.70; N, 13.75. Found: C, 47.43; H, 3.95; N, 13.59%.
4-Fluorobenzaldehyde [5,6-dimethyl-2-(methylthio)thieno[2,3-d]
pyrimidin-4-yl]hydrazone (11c): From 5a (1.24 g, 10 mmol) and
4-fluorobenzaldehyde; colourless crystals (2.46 g, 71%), m.p.188–
190°C. NMR (DMSO-d6): dH 2.40 (s, 3H, Me), 2.49 (s, 3H, Me),
2.55 (s, 3H, SMe), 7.28-7.34 (m, 2H, Ar), 7.75–7.80 (m, 2H, ArH),
8.38 (s, 1H, N=CH), 10.24 (s, 1H, NH); dC 13.8 (Me), 14.1 (Me), 14.9
(SMe), 114.0 (C5), 125,0 (C4a), 128.1 (C6), 116.6, 129.35, 129.5,
131.5, 131.7, 161.7 (Ar), 145.4 (C7a), 154.35 (C2), 165.0 (C4), 167.1
(N=CH). Anal. calcd for C16H15FN4S2 (346.40): C, 55.49; H, 4.37;
N, 16.20. Found: C, 55.88; H, 4.29; N, 16.46%.
The hydrazine 5a (2.40 g, 10 mmol) was boiled under reflux in formic
acid (10 ml) for 8 h. The reaction mixture was allowed to cool and
poured onto ice-cold water (100 ml). The product that separated was
filtered off, washed with water, dried and crystallised from ethanol as
colourless crystals (1.75 g, 70%), m.p. 238-240°C (lit.24 m.p. 242°C).
NMR (DMSO-d6): dH 2.45 (s, 3H, Me), 2.56 (s, 3H, Me), 2.77 (s, 3H,
SMe), 9.35 (s, 1H, N=CH). MS: m/z 250 (M+).
5-(Methylthio)-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine (6b): From 5b (2.66 g, 10 mmol) and
formic acid as described above, the product was obtained as colourless
crystals (2.04 g, 74%), m.p. 208–210°C. NMR (DMSO-d6): dH 1.88
(bs, 4H, 2CH2), 2.78 (s, 3H, SMe), 2.83 (bm, 2H, CH2), 3.02 (bm,
2H, CH2), 9.38 (s, 1H, N=CH). Anal. calcd for C12H12N4S2 (276.34):
C, 52.15; H, 4.37; N, 20.27. Found: C, 52.3; H, 4.46; N, 20.17%.
4-(2-Acetylhydrazino)-2-(methylthio)-5,6,7,8-tetrahydro[1]benzo-
thieno[2,3-d]pyrimidine (7b): The hydrazine 5b (2.66 g, 10 mmol)
was boiled under reflux in glacial acetic acid for 6 h. The reaction
mixture was allowed to cool and poured into water (100 ml). The
solid that separated was filtered off, dried and crystallised from
ethanol as a yellow powder (2.18 g, 71%), m.p. 258-260°C. IR
(KBr): νmax 1622 (C=N and C=C), 1674 cm-1 (C=O). NMR (CDCl3):
dH 1.93 (bm, 4H, 2CH2), 2.73 (s, 3H, Me), 2.85 (bm, 2H, CH2), 3.11
(s, 3H, Me), 3.15 (bm, 2H, CH2), 4.81 (s, 1H, NH). Anal. calcd for
C13H16N4OS2 (308.40): C, 50.62; H, 5.22; N, 18.16. Found: C, 50.93;
H, 5.16; N, 18.43%.
3-Methyl-5-(methylthio)-8,9,10,11-tetrahydro[1]benzo-
thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (8b): The acetyl-
hydrazine 7b (3.08 g, 10 mmol) was boiled under reflux in DMF
(15 ml) for 4 h and then allow to cool. The solid product was collected
and recrystallised from DMF as yellow crystals (1.65 g, 57%),
m.p.255–258°C. Anal. calcd for C13H14N4S2 (290.24): C, 53.79; H,
4.86; N, 19.30. Found: C, 53.52; H, 4.92; N, 19.51
4-Bromobenzaldehyde
[2-(methylthio)-5,6,7,8-tetrahydro[1]
benzothieno[2,3-d]pyrimidin-4-yl]hydrazone (11d): From 5b (2.66 g,
10 mmol) and 4-bromobenzaldehyde (1.85 g, 10 mmol); pale yellow
crystals (2.68, 62%), m.p. 141–143°C. NMR (DMSO-d6): dH 1.82
(bs, 4H, 2CH2), 2.55 (s, 3H, SMe), 2.78 (bm, 2H, CH2), 3.00 (bm,
2H, CH2), 7.66 (s, 4H, ArH), 8.34 (s, 1H, N=CH), 10.17 (s, 1H, NH);
dC 14.47 (Me), 23.0, 23.1, 25.9, 26.9 (4CH2), 113.6 (C5), 123.65
(C4a), 127.5 (C6), 129.5, 131.1, 131.7, 132.8, 132.9, 134.7 (Ar),
145.6 (C7a), 154.6 (C2), 165.5 (C4), 168.3 (N=CH). Anal. calcd for
C18H17BrN4S2 (433.34): C, 49.88; H, 3.95; N, 12.92. Found: C, 49.56
H, 3.68; N, 12.77%.
3-Amino-8,9-dimethyl-5-(methylthio)thieno[3,2-e][1,2,4]triazolo-
[4,3-c]pyrimidine (9a): The hydrazine 5a (2.4 g, 10 mmol) and
cyanogen bromide (1.06 g, 10 mmol) were stirred in 2N hydrochloric
acid (30 ml) at room temperature for 24 h. The solid that separated was
filtered off, washed with water, and dried in vacuo. Recrystallisation
from ethanol afforded yellow crystals (1.4 g, 52%), m.p. 178–180°C.
NMR (DMSO-d6): dH 2.40 (s, 3H, Me), 2.44 (s, 3H, Me), 2.68 (s, 3H,
Me), 4.12 (bs, 2H, NH); dC 12.67 (Me), 12.75 (Me), 14.13 (SMe),
115.31 (C9), 126.59 (C9a), 132.17 (C8), 142.51 (C6a), 146.89 (C10),
147.03 (C3) and 148.30 (C5). Anal. calcd for C10H11N5S2 (265.33):

338 JOURNAL OF CHEMICAL RESEARCH 2008
4-Fluorobenzaldehyde[2-(methylthio)-5,6,7,8-tetrahydro[1]benzo-
thieno[2,3-d]pyrimidin-4-yl]hydrazone (11e): From 5b (2.66 g,
10 mmol) and 4-fluorobenzaldehyde (1.24 g, 10 mmol); orange
crystals (2.65 g, 71%), m.p. 200–201°C. NMR (DMSO-d6): dH 1.82
(bm, 4H, 2CH2), 2.55 (s, 3H, SMe), 2.76 (bm, 2H, CH2), 3.00 (bm,
2H, CH2), 7.27–7.33 (m, 2H, ArH), 7.74–7.78 (m, 2H, ArH), 8.37 (s,
1H, N=CH), 10.08 (s, 1H, NH); dC 14.50 (Me), 23.0, 23.1, 25.9, 26.9
(4CH2), 113.2 (C-5), 124.9 (C4a), 127.5 (C6), 116.7, 129.7, 131.6,
132.0, 132.1, 162.1 (Ar), 145.75 (C7a), 165.4 (C2), 165.5 (C4), 168.2
(N=CH). Anal. calcd for C18H17FN4S2 (372.34): C, 58.05; H, 4.59;
N, 15.04. Found: C, 58.29; H, 4.89; N, 15.32%.
62%), m.p. 244–247°C. NMR (DMSO-d6): dH 1.86 (bm, 4H, 2CH2),
2.77 (bm, 2H, CH2), 2.96 (bm, 2H, CH2), 4.62 (s, 2H, NH2), 8.49 (s,
1H, N=CH), 9.12 (s, 1H, NH). Anal. Calcd for C11H12N6S (260.28):
C, 50.75; H, 4.64; N, 32.28; Found: C, 50.90; H, 4.37; N, 32.51%.
10,11-Dimethylthieno[3,2-e]bis[1,2,4]triazolo[4,3-a:1',5'-c]
pyrimidine (15): Compound 14a (0.23 g, 1 mmol) was heated in
formic acid or triethyl orthoformate (10 ml)under reflux for 4 h.
After cooling, the reaction mixture was poured into ice-water. The
solid product that separated was collected and isolated by column
chromatography, using 10% CH2Cl2/MeOH) as eluent to give
colourless crystals (0.14 g, 57%), m.p. 297–300°C. NMR (DMSO-d6):
dH 2.50 (s, 3H, Me),2.56 (s, 3H, Me), 8.68 (s, 1H, N=CH), 9.64 (s,
1H, N=CH); dC 13.5 (Me), 13.6 (Me), 116.5 (C11), 128.8 (C11a),
130.8 (C10), 137.6 (C8a), 143.7 (C4a), 148.1 (C12), 154.9 (C2 + C7).
MS: m/z 244 (M+). Anal. Calcd for C10H8N6S (244.25): C, 49.17; H,
3.30; N, 34.40; Found: C, 49.43; H, 3.64; N, 34.16%.
7-Amino-10,11-dimethylthieno[3,2-e]bis[1,2,4]triazolo[4,3-a:1',
5'-c]pyrimidine (16): The hydrazine 14a (2.3 g, 10 mmol) and
cyanogen bromide (1.06 g, 10 mmol) in 2N HCl (30 ml) were stirred
at room temperature for 24 h. The solid product that separated was
filtered off, washed with water, dried and crystallised from ethanol
to furnish fine yellow crystals (1.97 g, 76%), m.p. 220–222°C. NMR
(DMSO-d6): dH 2.39 (s, 3H, Me), 2.49 (s, 3H, Me), 3.28 (bs, 2H,
NH2), 8.49 (s, 1H, N=CH). Anal. Calcd for C10H9N7S (259.26): C,
46.32; H, 3.49; N, 37.81; Found: C, 46.11; H, 3.13; N, 37.67%.
5-Azido-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidine (17) and 8,9-dimethyltetrazolo[1,5-a]thieno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidine (18): NaNO2 (0.52 g) in water
(3 ml) was added dropwise with stirring to an ice-cold solution
of 14a (1.15 g. 5 mmol) in conc. HCl (35%, 10 ml). Stirring was
continued for 48 h at room temperature and then the mixture was
poured into cold water. The solid formed was collected by filtration,
dried and crystallised from ethanol as yellow fine crystals (0.16 g,
65%), m.p. 150–153°C. IR (KBr): νmax 2162 (N3), 1615 cm-1 (C=N
and C=C). (17): NMR (DMSO-d6): dH 2.43 (s, 3H, Me), 2.44 (s, 3H,
Me), 8.57(s, 1H, N=CH); dC 13.1 (Me), 13.9 (Me), 118.9 (C9), 127.0
(C9a), 133.8 (C8), 140.8 (C6a), 150.2 (C5), 151.0 (C10), 155.1 (C2).
(18): NMR (DMSO-d6): dH 2.55 (s, 3H, Me), 2.56 (s, 3H, Me), 8.86
(s, 1H, N=CH); dC 13.3 (Me), 13.8 (Me), 118.9 (C11), 127.0 (C11a),
133.8 (C10), 140.8 (C8a), 150.2 (C4a), 151.0 (C12), 156.1 (C-). MS:
m/z 245 (M+). Anal. Calcd for C9H7N7S (245.24): C, 44.07; H, 2.87;
N, 39.98; Found: C, 44.42; H, 2.57; N, 39.67%.
5-Methoxy-8,9-dimethyl-2-phenylthieno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidine (19a): This was prepared from 12a (0.34 g, 1 mmol) as
described in the formation of 13a; colourless crystals (0.22 g, 71%),
m.p. 200–202°C. NMR (DMSO-d6): dH 2.42 (s, 3H, Me), 2.57 (s, 3H,
Me), 4.22 (s, 3H, OMe),7.55 (m, 3H, Ph), 8.22 (m, 2H, Ph). Anal.
Calcd for C16H14N4OS (310.33): C, 61.92; H, 4.54; N, 18.05; Found:
C, 61.67; H, 4.84; N, 18.29%.
2-(4-Fluorophenyl)-5-methoxy-8,9-dimethylthieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidine (19b): From 12b (0.32 g, 1 mmol) as
described for 13a: colourless crystals (0.24 g, 73%), m.p. 190–192°C.
NMR (DMSO-d6): dH 2.42 (s, 3H, Me), 2.56 (s, 3H, Me), 4.22 (s,
3H, OMe), 7.35 (m, 2H, ArH), 8.23 (m, 2H, ArH). Anal. Calcd for
C16H13FN4OS (328.22): C, 58.54; H, 3.98; N, 17.06; Found: C,
58.79; H, 3.70; N, 17.32%.
2-(4-Bromophenyl)-5-methoxy-8,9,10,11-tetrahydro[1]benzothieno
[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (19c): From 12c (0.43 g,
1 mmol) as described for 19a.; colourless crystals (0.29 g, 70%),
m.p. 212–215°C. NMR (DMSO-d6): dH 1.97 (bm, 4H, 2CH2), 2.87
(bm, 2H, CH2), 3.19 (bm, 2H, CH2), 4.35 (s, 3H, OMe), 7.62 (bd, 2H,
ArH), 8.25 (bd, 2H, Ar-H). Anal. calcd for C18H15BrN4OS (415.26):
C, 52.05; H, 3.63; N, 13.49; Found: C, 52.42; H, 3.37; N, 13.68%.
5-Hydrazino-8,9-dimethyl-2-phenylthieno[3,2-e][1,2,4]triazolo
[1,5-c]pyrimidine (20): Compound 12a (0.32 g, 1 mmol) or 19a
(0.33 g, 1 mmol) was heated under reflux in ethanol (15 ml)
containing hydrazine hydrate (2 ml) for 4 h. The solid product that
separated on cooling was collected and recrystallised from ethanol
as white leaflets (0.16 g, 52%), m.p. 245–248°C. NMR (DMSO-d6):
dH 2.41 (s, 3H, Me), 2.55 (s, 3H, Me), 4.65 (bs, 2H, NH2), 7.57
(m, 3H, Ph), 8.28 (m, 2H, Ph), 9.09 (s, 1H, NH). Anal. Calcd for
C15H14N6S (310.33): C, 58.05; H, 4.54; N, 27.07; Found: C, 57.85;
H, 4.24; N, 27.42%.
Synthesis of 3-aryl compounds 12a–c: general procedure
Ferric chloride (0.4 g) in ethanol (5 ml) was added dropwise into a
boiling solution of the aldehyde hydrazone 11 (2 mmol) in ethanol
(50 ml). Heating was continued for 30 min and the mixture was then
kept overnight at room temperature. Evaporation of the solvent under
reduced pressure, washing the residue rapidly with water, and drying,
afforded a solid product which could be recrystallised from ethanol.
8,9-Dimethyl-5-(methylthio)-3-phenylthieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine (12a): From 11a (0.65 g, 2 mmol);
colourless crystals (0.40 g, 62%), m.p. 215–217°C. NMR (DMSO-d6):
dH 2.48 (s, 3H, Me), 2.51 (s, 3H, Me), 2.61 (s, 3H, SMe), 7.53-7.71
(m, 5H, Ph); dC 12.9 (Me), 12.95 (SMe), 14.8 (Me), 116.3 (C9),
126.8 (C9a), 127.3 (C8), 127.6, 130.7, 131.5, 132.1 (Ph), 145.75
(C6a), 146.2 (C5), 146.7 (C10), 148.65 (C3). MS: m/z 326 (M+).
Anal. Calcd for C16H14N4S2 (326.40): C, 58.87; H, 4.32; N, 17.16;
Found: C, 58.57; H, 4.65; N, 17.44%.
8,9-Dimethyl-3-(4-fluorophenyl)-5-(methylthio)thieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine (12b): From 11c (0.67 g, 2 mmol); pale
yellow crystals (0.42 g, 63%), m.p. 259–260°C. NMR (DMSO-d6):
dH 2.51 (s, 3H, Me), 2.64 (s, 3H, Me), 2.65 (s, 3H, SMe), 7.39 (m,
2H, ArH), 7.74 (m, 2H, ArH). Anal. Calcd for C16H13FN4S2 (344.28):
C, 55.81; H, 3.81; N, 16.29; Found: C, 55.50; H, 4.11; N, 16.54%.
3-(4-Bromophenyl)-5-(methylthio)-8,9,10,11-tetrahydro[1]benzo-
thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (12c): From 11d
(0.87 g, 2 mmol); pale yellow crystals (0.48 g, 55%), m.p. 187–190°C.
NMR (DMSO-d6): dH 1.91 (bm, 4H, 2CH2), 2.55 (s, 3H, SMe), 2.86
(bm, 2H, CH2), 3.05 (bs, 2H, CH2), 7.67 (d, 2H, ArH), 7.77 (d, 2H,
ArH); dC 15.6 (Me), 22.4, 23.2, 25.3, 25.7 (4CH2), 115.5 (C9), 125.2
(C9a), 127.2 (C8), 129.4, 131.3, 134.1, 135.5 (Ar), 145.3 (C6a), 146.7
(C5), 147.2 (C10), 150.2 (C3). Anal. Calcd for C18H15BrN4S2 (431.38):
C, 50.12; H, 3.51; N, 13.01; Found: C, 50.43; H, 3.77; N, 13.29%.
5-Methoxy-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidine (13a): Sodium metal (0.04 g, 1 mg-atom) was dissolved
in absolute methanol (10 ml). The methylthio compound 6a (0.25 g,
1 mmol) was added and the solution heated under reflux for 1 h and
then allowed to stand 12 h at room temperature. The solid product
obtained was filtered off, dried, and crystallised from ethanol as
colourless crystals (0.16 g, 68%), m.p. 190–192°C. NMR (DMSO-d6):
d
H 2.41 (s, 3H, Me), 2.50 (s, 3H, Me) 4.22, (s, 3H, OMe), 8.52 (s, 1H,
N=CH). Anal. Calcd for C10H10N4OS (234.24): C, 51.27; H, 4.29; N,
23.92; Found: C, 51.49; H, 4.63; N, 23.81%.
5-Methoxy-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidine (13b): Prepared from 6b (0.28 g, 1 mmol)
as described for 13a; colourless crystals (0.18 g, 69%), m.p. 188–
190°C. NMR (DMSO-d6): dH 1.96 (bm, 4H, 2CH2), 2.87 (bm, 2H,
CH2), 3.13 (bm, 2H, CH2), 4.34 (s, 3H, OMe), 8.34 (s, 1H, N=CH); dC
22.5, 23.4, 25.3, 25.4 (4CH2), 57.1 (OMe), 116.0 (C9), 128.8 (C9a),
134.0 (C8), 147.3 (C6a), 150.7 (C5), 153.1 (C10), 154.65 (C2). MS:
m/z 260 (M+). Anal. calcd for C12H12N4OS (260.27): C, 55.37; H,
4.64; N, 21.52; Found: C, 55.56; H, 4.79; N, 21.77%.
5-Hydrazino-8,9-dimethylthieno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidine (14a): Method A: A mixture of 6a (0.25 g, 1 mmol) and
hydrazine hydrate (10 ml) was heated under reflux for 4 hours. The
solid product that separated after cooling was filtered, dried and
crystallised from ethanol to furnish colourless crystals (0.16 g, 68%),
m.p. 258–260°C. NMR (DMSO-d6): dH 2.48 (s, 3H, Me), 2.59 (s,
3H, Me), 4.67 (s, 2H, NH2), 8.27 (s, 1H, N=CH), 8.88 (s, 1H, NH);
d
C 12.4 (Me), 12.5 (Me), 112.0 (C9), 125.4 (C9a), 126.2 (C8), 145.4
(C6a), 148.8 (C5), 153.2 (C10), 154.6 (C2). MS: m/z 234 (M+). Anal.
Calcd for C9H10N6S (234.26): C, 46.14; H, 4.30; N, 35.87; Found: C,
46.43; H, 4.49; N, 36.11%.
Crystal structure determination
Method B: From the methoxy compound 13a (0.23 g, 1 mmol) and
hydrazine hydrate as described above: yield (0.17 g, 72%).
5-Hydrazino-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo
[1,5-c]pyrimidine (14b): From 6b (0.28 g, 1 mmol) and hydrazine
hydrate as described for 14a; the product formed white leaflets (0.16 g,
Compound 13b, C12H12N4OS¸ formed triclinic crystals which were
examined at the X-ray Crystallography Unit of the N.R.C., Cairo. The
data were handled, and all diagrams and calculations were performed,
using maXus (Bruker Nonius, Delt & MacScience, Japan). One

JOURNAL OF CHEMICAL RESEARCH 2008 339
M. Fujino, J. Med. Chem., 2003, 46, 113.
13 V.D. Patil, D.S. Vise, L.L. Worting, R.C. Bloomer and L.B. Townsend,
J. Med. Chem., 1985, 28, 423.
14 V.J. Ram, H.K. Pandey and A.J. Vietinek, J. Heterocycl. Chem., 1981, 18,
1277.
molecule of the unit cell is shown in Fig. 1, and the bond lengths and
angles are listed in Table 1. Fuller details can be obtained from the
corresponding author.
The Danish International Development Agency (DANIDA) is
gratefully acknowledged for financial support.
15 R.P. Dickinson, A.W. Bell, C.A. Hitchcock, S. Narayana-Swami, S.J. Ray,
K. Richardson and P.F. Troke, Bioorg. Med. Chem. Lett., 1996, 6, 2031.
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17 E. Palaska, G. Sahin, P. Kelicen, N.T. Durlu and G. Altinok, Farmaco,
2002, 57,101.
18 M.A. El-Sherbeny, M.B. El-Ashmawy, H.I. El-Subbagh, A.A. El-Emam
and F.A. Badria, Eur. J. Med. Chem., 1995, 30, 445.
19 M. Santagati, M. Modica, A. Santagati, F. Russo and S. Spampinato,
Pharmazie, 1996, 51, 7.
20 D.J. Brown and J.S. Harper, J. Chem. Soc., 1963, 1276.
21 A.A. Hamed, H.F. Badr and E.H. El-Ashry, Z. Naturforsch., 2001, 56B,
826.
22 A.A. Hamed, I.F. Zeid, H.H. El-Ganzory and M.T. Abdel Aal, Monatsh.
Chem., 2008, in press.
23 K. Gewald, E. Schinke and H. Bottcher, Chem. Ber., 1966, 99, 94.
24 A.M. Abdel-Fatah, A.S. Aly, F.A. Gad, N.A. Hassan and A.B.A.
El-Gazzar, Phosphorus, Sulfur, Silicon, 1991, 60, 223.
25 C.J. Shishoo, M.B. Devani, G.V. Ullas, S. Ananthar,and V.S. Bhadti,
J. Heterocycl. Chem., 1985, 22, 83
26 C.J. Shishoo, M.B. Devani, G.V. Ullas, S. Ananthar and V.S. Bhadti,
J. Heterocycl. Chem., 1981, 18, 43.
27 C.J. Shishoo, M.B. Devani, G.V. Ullas, S. Ananthar and V.S. Bhadti,
J. Heterocycl. Chem., 1985, 22, 825.
Received 16 February 2008; accepted 16 May 2008
Paper 08/5099 doi:10.3184/030823408X327875
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