Synthesis of 5-thioxo-hexahydrobenzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5- c]pyrimidines and related compounds based on cyclocondensations of 2-isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

Article abstract of DOI:10.1080/10426500802243216

5-Thioxo-4,6,8,9,10,11-hexahydro-benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1, 5-c]pyrimidines and related compounds were prepared based on cyclizations of 2-isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with aminoketones and carboxylic hydrazid

Full text of DOI:10.1080/10426500802243216

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Phosphorus, Sulfur, and Silicon
and the Related Elements
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Synthesis of 5-Thioxo-
hexahydrobenzo[b]thiopheno[2,3-
d]-1,2,4-triazolo[1,5-
c]pyrimidines and Related
Compounds Based on
Cyclocondensations
of 2-Isothiocyanato-3-
cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene
Wolf-Diethard Pfeiffer a , Horst Dollinger b & Peter
Langer c d
a Institut für Biochemie, Universität Greifswald,
Greifswald, Germany
b Boehringer Ingelheim Pharma GmbH & Co. KG,
Biberach, Riss, Germany
c Institut für Chemie, Universität Rostock, Rostock,
Germany
d Leibniz-Institut für Katalyse e.V. an der Universität
Rostock, Rostock, Germany
Version of record first published: 19 Feb 2009.
To cite this article: Wolf-Diethard Pfeiffer , Horst Dollinger & Peter Langer (2009):
Synthesis of 5-Thioxo-hexahydrobenzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-
c]pyrimidines and Related Compounds Based on Cyclocondensations of 2-
Isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene, Phosphorus, Sulfur, and
Silicon and the Related Elements, 184:3, 626-637

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Phosphorus, Sulfur, and Silicon, 184:626–637, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802243216
Synthesis of 5-Thioxo-hexahydrobenzo[b]thiopheno[2,3-
d]-1,2,4-triazolo[1,5-c]pyrimidines and Related
Compounds Based on Cyclocondensations of
2-Isothiocyanato-3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene
Wolf-Diethard Pfeiffer,1 Horst Dollinger,2 and Peter
Langer3,4
1Institut fu¨r Biochemie, Universita¨t Greifswald, Greifswald, Germany
2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach / Riss,
Germany
3Institut fu¨r Chemie, Universita¨t Rostock, Rostock, Germany
4Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Rostock,
Germany
5-Thioxo-4,6,8,9,10,11-hexahydro-benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]py-
rimidines and related compounds were prepared based on cyclizations of
2-isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with aminoketones
and carboxylic hydrazides.
Keywords Cyclizations; heterocycles; isothiocyanates; nitriles
INTRODUCTION
2-Isothiocyanatobenzonitrile represents a preparatively useful difunc-
tional benzene derivative that combines a nitrile and an isothiocya-
nate functionality. The reaction of this compound with O- and N-
nucleophiles, such as butan-1-ol,1 anilines,2 and acetamidines,3 was
reported. Radical-type cyclizations have also been studied.4 The cycliza-
tion of 2-isothiocyanatobenzonitrile with amines5a and hydrazine6 gave
4-imino-1,2,3,4-tetrahydroquinazoline-2-thiones. We reported cycliza-
tion reactions of 2-isothiocyanatobenzonitrile with arylacetonitriles,7
carboxylic hydrazides,8α-aminoesters,9 and α-aminoketones.10 Herein,
Received 26 March 2008; accepted 21 May 2008.
Financial support from Boehringer Ingelheim Pharma GmbH & Co. KG, from the
DFG, and from the state of Mecklenburg-Vorpommern is gratefully acknowledged.
Address correspondence to Peter Langer, Institut fu¨r Chemie, Universita¨t Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany. E-mail: peter.langer@uni-rostock.de
626

Benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines
627
we report what is, to the best of our knowledge, the first applica-
tion of this chemistry to a heterocyclic substrate. 2-Isothiocyanato-
3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene, a heterocyclic analog of
2-isothiocyanatobenzonitrile,5b was prepared by an improved proce-
dure and used for novel cyclization reactions. These reactions al-
low the synthesis of 5-thioxohexahydro-benzo[b]thiopheno[2,3-d]-1,2,4-
triazolo[1,5-c]pyrimidines and related compounds. It is also worth
noting that related 1,2,4-triazolo[1,5-c]quinazolines are of consider-
able pharmacological relevance (antihypertonic, antirheumatic, an-
tianaphylactic, antiasthmatic, tranquilizing, neurostimulating, and
benzodiazepine binding activity)11–13 and benzimidazo[2,1-b]quinazo-
line-12(5H)-ones are potent immunosuppressors.14
RESULTS AND DISCUSSION
The reaction of 2-amino-4,5,6,7-tetrahydrobenzo-[b]thiophene-3-
carbonitrile (1), available by a known procedure (Gewald synthesis),15
with formamide afforded 4-amino-tetrahydrobenzo[b]thiopheno-2,3-
d]pyrimidine (2) in 86% yield (Scheme 1).
SCHEME 1 Synthesis of 2. Conditions: i: reflux, neat.
2-Isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]-thiophene (3),
obtained by a modified protocol,16 was prepared by calcium carbonate
mediated reaction of 1 with thiophosgene (Scheme 2). During the op-
timization of this reaction, the use of ultrasound irradiation proved
to be important. In addition, the temperature and the purification

628
W.-D. Pfeiffer et al.
SCHEME 2 Synthesis of 3. Conditions: i: CSCl2, CaCO3, CH2Cl2, 20◦C, 4 h,
ultrasound.
(extraction with hot petroleum ether) were important parameters. Sev-
eral byproducts were formed (by reaction of 3 with unreacted 1) when
the temperature was allowed to rise above 20◦C.
The reaction of 3 with formic hydrazide (4a) and acetic hydrazide
(4b) afforded the 5-thioxo-4,6,8,9,10,11-hexahydro-benzo[b]thio-
pheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines 5a and 5b, respectively
(Scheme 3, Table I). The formation of 5a,b proceeds by attack of the
amino group onto the isothiocyanate, cyclization by attack of the
nitrogen atom onto the nitrile and subsequent attack of the imino
group onto the amide. The cyclization of 3 with phenacyl bromide (4c)
and 4-bromophenacyl bromide (4d) afforded the 5-thioxo-4,6,8,9,10,11-
hexahydro-benzo[b]thiopheno[2,3-d]-imidazo[1,2-c]pyrimidines 5c and
5d, respectively.
The reaction of 5a–d with methyl iodide and benzyl bromide af-
forded the sulfides 6a–e (Scheme 4, Table II). The reaction of 6a,
6b, and 6d with piperidine gave the 5-piperidino-hexahydro-benzo[b]-
thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines 7a and 7b and
the 5-piperidino-hexahydro-benzo[b]thiopheno[2,3-d]-imidazolo[1,2-c]-
pyrimidine 7c, respectively.
In conclusion, we have reported the synthesis of 5-thioxo-
4, 6, 8, 9, 10, 11-hexahydro-benzo[b] thiopheno [2,3-d]-1,2,4-triazolo[1,5-
c]pyrimidines and related compounds based on cyclocondensations
of 2-isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with
aminoketones and carboxylic hydrazides.
EXPERIMENTAL
General Comments
All solvents were dried by standard methods, and all reactions were car-
ried out under an inert atmosphere. For 1H and 13C NMR spectra, the
deuterated solvents indicated were used. Mass spectrometric data (MS)
were obtained by electron ionization (EI, 70 eV), chemical ionization

Benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines
629
SCHEME 3 Synthesis of 5a–d: i, method A (5a): EtOH, reflux, 12 h; method
B (5b): N(nPr)3, EtOH, reflux, 14 h; method C (5c,d): 1) Na2CO3, H2O, 20◦C,
20 min; 2) CH2Cl2, reflux, 15 min; 3) EtOH, reflux, 24 h.
TABLE I Synthesis of 5a–d
5
X
R
% (5)a
a
b
c
N
N
CH
CH
H
Me
Ph
76
78
81
84
d
4-BrC6H4
aIsolated yields.
(CI, H2O), or electrospray ionization (ESI). For preparative scale chro-
matography, silica gel (60–200 mesh) was used. Melting points are
uncorrected.
5,6,7,8-Tetrahydrobenzo[b]thiopheno[2,3-d]pyrimidine-4-yl-
amine (2)
A
mixture
of
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carbonitrile (1) (1.78 g, 10.0 mmol) and formamide (3.60 g, 80.0 mmol)

630
W.-D. Pfeiffer et al.
SCHEME 4 Synthesis of 6a–e and 7a–c. i: method A (6a,b,d,e): NaOH, H2O,
MeI, 60◦C; method B (6c): MeOH, NaOMe, BnBr, 2 h reflux; ii, neat, reflux,
16–18 h.
TABLE II Synthesis of 6a–e and 7a–c
5
6
7
X
R1
R2
% (6) a
% (7)a
a
b
b
c
a
b
c
d
e
a
b
N
N
N
CH
CH
H
Me
Me
Me
Me
Bn
Me
Me
71
73
86
82
87
89
81
—
b
c
Ph
81
b
D
4-BrC6H4
—
aIsolated yields; bexperiment not carried out.
was refluxed for 20 min. On cooling, a precipitate crystallized, which
was filtered off. Yield: 1.76 g (86%), orange prisms (EtOH), mp. 188◦C.
IR (KBr, cm−1): ν˜ = 580 (m), 688 (m), 1099 (m), 1168 (s), 1336 (m), 1446
(m), 1519 (m), 1599 (m), 2934 (m).1H NMR (300 MHz, CDCl3): δ =
1.74–1.76 (t, 4H, 2 × CH2), 2.59 (m, 4H, 2 × CH2), 8.36 (s, 1H, Hetar),
11.89 (s, 2H, NH2).13C NMR (50 MHz, DMSO-d6): δ = 21.6, 22.5, 23.3,
23.4, 113.8, 127.6, 130.6, 145.0, 158.9. MS (EI, 70 eV): m/z = 206 (M+,
47), 178 (48), 149 (100), 77 (3), 28 (3). Anal.: calcd. for C10H11N3S
(205.28): C, 58.51; H, 5.40; N, 20.47. Found: C, 58.62; H, 5.45; N,
20.51.

Benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines
631
2-Isothiocyanato-3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophene (3)
A suspension of 1 (36.7 g, 0.20 mol) in dichloromethane (300 mL) was
slowly (within 20 min) added to a dichloromethane suspension (850
mL) of finely pulverized calcium carbonate (50.0 g, 0.50 mol) and of
thiophosgene (28.7 g, 0.25 mol) at 20◦C with vigorous stirring. After
stirring for 4 h at 20◦C with ultrasound irradiation, the solid was fil-
tered off and washed with anhydrous dichloromethane (50 mL). The
solvent and unreacted thiophosgene were distilled off using a rotary
evaporator at 20◦C. The crude product was dissolved in hot petroleum
ether, and the red insoluble residue was filtered off. The solvent was
removed in vacuo. Yield: 40.1 g (91%), light-brown crystals (petroleum
ether), mp 68–70◦C. IR (KBr, cm−1): ν˜ = 1565 (s, C=C), 2225 (m, CN),
2000 (m, NCS), 2950 (s, CH), 2870 (s, CH). 1H NMR (300 MHz, CDCl3):
δ = 1.71–1.95 (m, 4H, CH2), 2.49–2.76 (m, 4H, CH2). Anal. calcd. for
C18H12N5Cl (220.32): C, 54.52; H, 3.66; N, 12.72. Found: C, 54.61; H,
3.72; N, 12.78.
5-Thioxo-4,6,8,9,10,11-hexahydro-benzo[b]thiopheno[2,3-
d]1,2,4-triazolo[1,5-c]pyrimidine (5a)
An ethanol solution (30 mL) of 4a (0.60 g, 10.0 mmol) was added to an
ethanol solution (20 mL) of 3 (2.20 g, 10.0 mmol), and the mixture was
refluxed for 12 h. The solvent was concentrated in vacuo to ca. 15 mL.
After cooling, a precipitate formed, which was filtered off. Yield: 1.99 g
(76%), yellow prisms (EtOH), mp. 246◦C. IR (KBr, cm−1): ν˜ = 869 (m),
1049 (m), 1172 (m), 1224 (m), 1310 (s), 1526 (s), 1607 (s), 2936 (m). 1H
NMR (300 MHz, DMSO-d6): δ = 1.78–1.85 (m, 4H, 2 × CH2), 2.77 (t, 2H,
CH2), 2.94 (t, 2H, CH2), 8.55 (s, 1H, Hetar). 13C NMR (50 MHz, DMSO-
d6): δ = 21.1, 21.2, 22.1, 23.7, 24.1, 24.2, 24.3, 108.0, 117.5, 124.8. MS
(EI, 70 eV): m/z = 262 (M+, 100), 234 (35), 110 (3.65), 91 (3), 58 (4), 44
(7), 28 (48). Anal.: calcd. for C11H10N4S2 (262.36): C, 50.36; H, 3.84; N,
21.36. Found: C, 50.41; H, 3.81; N, 21.41.
2-Methyl-5-thioxo-5,6,8,9,10,11-
hexahydrobenzo[b]thiopheno[2,3-d]1,2,4-triazolo[1,5-
c]pyrimidine (5b)
A mixture of 4b (0.64 g, 10.0 mmol), 3 (2.20 g, 10.0 mmol), and tri(n-
propyl)amine (0.5 mL) in ethanol (220 mL) was refluxed for 14 h. The
solvent (200 mL) was evaporated in vacuo. After cooling, AcOH (1.5
mL) and water (20 mL) were added to give a precipitate, which was

632
W.-D. Pfeiffer et al.
filtered off. Yield: 2.15 g (78%), yellow needles (EtOH), mp. 276◦C. IR
(KBr, cm−1): ν˜ = 872 (m), 1222 (s), 1308 (s), 1380 (m), 1440 (m), 1539
1
(s), 1610 (s), 2934 (s). H NMR (300 MHz, CDCl3): δ = 1.59–1.63 (m,
4H, 2 × CH2), 2.66 (s, 3H, Me), 2.79–2.82 (t, 2H, CH2), 3.06–3.09 (t, 2H,
CH2). 13C NMR (75 MHz, DMSO-d6): δ = 14.2, 21.5, 22.9, 24.1, 24.6,
128.5, 147.3. MS (EI, 70 eV): m/z = 276 (M+, 100), 248 (26), 141 (21),
91 (12), 70 (10), 32 (12), 28 (57). Anal.: calcd. for C12H12N4S2 (276.38):
C, 52.15; H, 4.38 N, 20.27. Found: C, 52.20; H, 4.41; N 20.35.
2-Phenyl-5-thioxo-5,6,8,9,10,11-
hexahydrobenzo[b]thiopheno[2,3-d]imidazo[1,2-
c]pyrimidine (5c)
To a CH2Cl2 solution (50 mL) of 3 (2.20 g, 10.0 mmol) was added an
aqueous solution (50 mL) of 2-amino-1-phenylethan-1-one hydrochlo-
ride (1.72 g, 10.0 mmol) and an aqueous solution (15 mL) of sodium
carbonate (2.00 g) with stirring. The solution was stirred for 15 min
at room temperature. The mixture was extracted with CH2Cl2 (2 ×
100 mL), and the CH2Cl2 solution was refluxed for 15 min. The mix-
ture was concentrated at reduced pressure. A precipitate formed, which
was filtered off. The product was suspended in EtOH (250 mL), and the
mixture was refluxed for 24 h. The product, which crystallized upon
cooling, was filtered off. The filtrate was concentrated at reduced pres-
sure to give an additional amount of product. Yield: 2.73 g (81%), yellow
needles (EtOH), mp. 281◦C. IR (KBr, cm−1): ν˜ =729 (m), 862 (m), 1199
(m), 1262 (s), 1313 (s), 1531 (s), 1612 (s), 2936 (m). 1H NMR (300 MHz,
CDCl3): δ = 1.87–2.88 (m, 8H, 4 × CH2), 7,33–8.13 (m, 5H, ArH), 8.53
(s, 1H, Hetar). 13C NMR (50 MHz, DMSO-d6): δ = 21.2, 22.2, 23.7, 24.5,
110.4, 125.3, 127.5. 128.0, 128.7, 130.0, 132.4. MS (EI, 70 eV): m/z =
337 (M+, 100), 277 (10), 168 (7), 117 (29), 115 (15), 101 (17), 91 (21), 45
(42), 32 (16). Anal.: calcd. for C18H15N3S (337.07): C, 64.06; H, 4.48; N,
12.45. Found: C, 64.12; H 51; N, 12.45.
2-(Bromophenyl)-5-thioxo-4,5,8,9,10,11-
hexahydrobenzo[b]thiopheno-[2,3-d]imidazo[1,2-
c]pyrimidine (5d)
The reaction was carried out following the procedure as given
for 5c. Starting with 3 (2.20 g, 10.0 mmol) and 2-amino-1-(4-
bromophenyl)ethan-1-one hydrochloride (2.51 g, 10.0 mmol), 5d was
isolated (3.50 g, 84%) as yellow prisms (EtOH), mp. 295◦C. IR (KBr,
cm−1): ν˜ = 862 (m), 1009 (m), 1197 (s), 1316 (s), 1400 (m), 1477 (m),
1534 (s), 1578 (s), 2933 (m).1H NMR (300 MHz, CDCl3) δ = 1.95 (m,

Benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines
633
6H, 2 × CH2), 2.80–2.85 (t, 2H, CH2), 3.25 (t, 2H, CH2), 7.25–8.09 (m,
5H, ArH, Hetar). MS (EI, 70 eV): m/z = 416 (M+, 33), 335 (2), 154 (5), 43
(5), 40 (13), 32 (80), 28 (100). Anal.: calcd. for C18H14N3S2Br (416.36).
C, 51.02; H, 3.34; N, 10.09. Found: C, 51.05; H, 3.41; N, 10.21.
5-Methylsulfanyl-8,9,10,11-tetrahydrobenzo[b]thiopheno[2,3-
d]1,2,4-triazolo[1,5-c]pyrimidine (6a)
Compound 5a (2.62 g, 10.0 mmol) was dissolved in an aqueous solution
of sodium hydroxide (0.02 M, 120 mL). The mixture was heated to 60◦C,
and methyl iodide (1.99 g, 14.0 mmol) was added dropwise over a period
of 5 min. The precipitate formed on cooling was filtered off and washed
with water. Yield: 1.96 g (71%), yellow prisms (EtOH), 258oC. IR (KBr,
cm−1): ν˜ = 1177 (m), 1263 (m), 1351 (m), 1458 (m), 1532 (m), 1609 (s),
1625 (m), 2935 (m). 1H NMR (300 MHz, CDCl3): δ = 1.96–1.22 (m, 4H,
2 × CH2), 1.60–1.65 (t, 2H, CH2), 1.95–1.98 (t, 2H, CH2), 2.79 (s, 3H,
Me), 8.37 (s, 1H, 2-H, Hetar). 13C NMR (50 MHz, DMSO-d6): δ = 13.0,
14.0, 21.5, 22.4, 24.5, 65.5, 116.2, 127.9, 127.9, 132.9, 135.2, 153.9. MS
(EI, 70 eV): m/z = 276 (M+, 100), 246 (64), 218 (36), 77 (4), 32 (12), 28
(50). Anal.: calcd. for C12H12N4S2 (276.38). C, 52.25; H, 4.38; N, 20.27.
Found: C, 52.25; H, 4.41; N, 20.35.
2-Methyl-5-methylsulfanyl-8,9,10,11-
tetrahydrobenzo[b]thiopheno-[2,3-d]1,2,4-triazolo[1,5-
c]pyrimidine (6b)
From5b (2.76 g, 10.0 mmol), an aqueous solution of sodium hydroxide
(0.02 M, 120 mL) and methyl iodide (1.99 g, 14.0 mmol), 6b was isolated
(2.12 g, 73%) as yellow needles (EtOH), mp. 184–185oC. IR (KBr, cm−1):
1
ν˜ = 856 (m), 1305 (s), 1450 (s), 1495 (m), 1511 (s), 2931 (m). H NMR
(300 MHz, CDCl3): δ = 1.93–2.01 (m, 4H, 2 × CH2), 2.67 (s, 3H, Me),
2.77 (s, 3H, Me), 2.87–2.89 (t, 2H, CH2), 3.12–3.14 (t, 2H, CH2). 13C
NMR (75 MHz, CDCl3): δ = 13.7, 15.0, 22.4, 23.3, 25.5, 116.7, 128.8,
135.5, 147.4, 149.9, 154.9, 164.4. MS (EI, 70 eV): m/z = 290 (M+, 100),
230 (36), 189 (16), 70 (4), 28 (27). Anal.: calcd. for C13H14N4S2 (290.41):
C, 53.77; H, 4.86; N, 19.29. Found: C, 53.81; H, 4.92; N, 19.25.
2-Methyl-5-benzylsulfanyl-8,9,10,11-
tetrahydrobenzo[b]thiopheno-[2,3-d]-1,2,4-triazolo[1,5-
c]quinazoline (6c)
Compound 5b (2.76 g, 10.0 mmol) and NaOMe (0.54 g, 10.0 mmol) were
dissolved in absolute methanol (200 mL), and the mixture was heated

634
W.-D. Pfeiffer et al.
under reflux for 1 h. Benzylbromide (2.05 g, 12.0 mmol) was added to
the solution and the solution was heated under reflux for further 2 h.
On cooling, a crystalline precipitate separated, which was filtered off
and washed with water. Yield: 3.15 g (86%), yellow needles (EtOH), mp.
141◦C. IR (KBr, cm−1): ν˜ = 699 (m), 855 (m), 1043 (m), 1304 (s), 1457 (s),
1
1498 (s), 1611 (s), 2931 (s). H NMR (300 MHz, CDCl3): δ = 1.92–1.96
(m, 4H, 2 × CH2), 2.64 (s, 3H, Me), 2.87–2.89 (t, 2H, CH2), 3.09–3.11
(t, 2H, CH2), 4.62 (s, 2H, CH2, Bn), 7.24–7.49 (m, 5H, ArH). 13C NMR
(50 MHz, DMSO-d6): δ = 14.1, 21.6, 22.4, 24.6, 24.7, 33.9, 116.0, 127.4,
128.0, 128.4, 129.0, 135.2, 136.4, 146.1, 148.1, 153.1, 163.5. MS (EI, 70
eV): m/z = 366 (M+, 70), 334 (100), 162 (6), 91 (60). Anal.: calcd. for
C19H18N4S2 (366.51): C, 62.26; H, 4.95; N, 15.29. Found: C, 62.37; H,
4.81; N, 15.35.
2-Phenyl-5-methylsulfanyl-8,9,10,11-
tetrahydrobenzo[b]thiopheno-[2,3-d]imidazo[1,2-
c]pyrimidine (6d)
Starting with 5c (3.37 g, 10.0 mmol) and methyl iodide (1.99 g, 14.0
mmol, 6d was isolated (2.88 g, 82%) as colorless prisms (EtOH), mp.
196oC. IR (KBr, cm−1): ν˜ = 711 (s), 1162 (m), 1220 (m), 1368 (m), 1471
(s), 1607 (m), 2932 (m). 1H NMR (300 MHz, CDCl3): δ = 1.95–1.97 (m,
4H, 2 × CH2), 2.74 (s, 3H, Me), 2,84–2.86 (t, 2H, CH2), 3.26–3.27 (t, 2H,
CH2), 7.31–8.04 (m, 6H, ArH, 1 Hetar). 13C NMR (50 MHz, DMSO-d6):
δ = 13.0, 21.4, 22.2, 24.2, 24.7, 105.0, 125.6, 127.5, 128.0, 128.3, 132.6,
133.4, 144.1. MS (EI, 70 eV): m/z = 351 (M+, 15), 346 (15), 198 (100),
145 (15), 129 (11), 102 (12), 90 (28), 64 (10). Anal.: calcd. for C19H17N3S
(351.19): C, 64.92; H, 4.87; N, 11.95. Found: C, 64.93; H, 4.91; N, 11.97.
2-(4-Bromophenyl)-5-methylsulfanyl-8,9,10,11-
tetrahydrobenzo-[b]thiopheno[2,3-d]imidazo[1,2-
c]pyrimidine (6e)
Starting with 5d (4.16 g, 10.0 mmol) and methyl iodide (1.99 g, 14.0
mmol), 6e was isolated (3.76 g, 87%) as yellow prisms (EtOH), mp.
209◦C. IR (KBr, cm−1): ν˜ = 732 (s), 1162 (m), 1220 (m), 1368 (m), 1472
(s), 1604 (s), 2932 (m). 1H NMR (300 MHz, CDCl3): δ = 1.96 (m, 4H, 2 ×
CH2), 2.81 (s, 3H, Me), 2.85–2.87 (t, 2H, CH2), 3.26–3.27 (t, 2H, CH2),
7.55–7.91 (m, 5H, ArH, Hetar). MS (EI, 70 eV): m/z = 430 (M+, 20), 415
(3), 194 (2), 117 (3), 32 (23), 28 (100). Anal.: calcd. for C19H16Br N3S2
(430.39): C, 53.02; H, 3.75; N, 9.76. Found: C, 53.01; H, 3.76; N, 9.81.

Benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines
635
5-Piperidino-8,9,10,11-tetrahydrobenzo[b]thiopheno][2,3-
d]1,2,4-triazolo[1,5-c]pyrimidine (7a)
A mixture of 6a (2.76 g, 10.0 mmol) was dissolved in piperidine (10 mL),
and the mixture was heated under reflux for 18 h. After cooling to room
temperature, the precipitate was filtered and washed with methanol.
Yield: 2.79 g (89%), colorless rods (EtOH), mp. 163◦C. IR (KBr, cm−1):
ν˜ = 963 (m), 1173 (s), 1443 (s), 1528 (s), 1617 (s), 2932 (m). 1H NMR (300
MHz, CDCl3) δ = 1.70–1.95 (m, 10H, 5 × CH2), 2.80–2.83 (t, 2H, CH2),
3.09–3.10 (t, 2H, CH2), 3.86–3.89 (m, 4H, 2 × CH2), 8.26 (s, 1H, Hetar).
MS (EI, 70 eV): m/z = 313 (M+, 100), 285 (16), 202 (10), 128 (6), 84 (19),
55 (11), 41 (18), 28 (74). Anal calcd. for C16H19N5S (313.42): C, 61.31;
H, 6.11; N, 22.34. Found: C, 61.42; H, 6.23; N, 22.41.
2-Methyl-5-piperidino-8,9,10,11-
tetrahydrobenzo[b]thiopheno[2,3-d]1,2,4-triazolo[1,5-
c]pyrimidine (7b)
A mixture of 6b (2.90 g, 10.0 mmol) was dissolved in piperidine (10 mL),
and the mixture was heated under reflux for 16 h. After cooling to room
temperature, the precipitate was filtered and washed with methanol.
Yield: 1.65 g (81%), colorless prisms (EtOH), mp. 134–135◦C. IR (KBr,
cm−1): ν˜ = 1190 (m), 1243 (m), 1304 (s), 1380 (s), 1443 (s), 1517 (s), 1619
(s), 2852 (m), 2935 (s). 1H NMR (300 MHz, CDCl3) δ = 1.63–1.94 (m,
10H, 5 × CH2), 2.62 (s, 3H, Me), 2.81–2.83 (t, 2H, CH2), 3.08–3.09 (t,
2H, CH2), 3.82–3.85 (t, 4H, 2 × CH2). 13C NMR (300 MHz, CDCl3): δ =
14.8, 22.3, 23.3, 24.6, 25.2, 25.5, 25.6, 49.1, 114.3, 128.4, 132.0, 145.4,
151.5, 155.4, 162.6. MS (EI, 70 eV): m/z = 327 (M+, 100), 285 (7), 155
(8), 84 (8), 32 (12), 28 (54). Anal calcd. for C17H21N5S (327.45): C, 62.36;
H, 6.46; N, 21.39. Found: C, 62.41; H, 6.51; N, 21.43
2-Phenyl-5-piperidino-8,9,10,11-
tetrahydrobenzo[b]thiopheno[2,3-d]imidazo[1,2-
c]pyrimidine (7c)
A mixture of 6d (3.51 g, 10.0 mmol) was dissolved in piperidine (10
mL), and the mixture was heated under reflux for 18 h. After cooling
to room temperature, the precipitate was filtered off and washed with
methanol. Yield: 3.14 g (81%), mp. 168–170◦C, colorless rods (EtOH).
IR (KBr, cm−1): ν˜ = 710 (m), 850 (m), 1027 (m), 1162 (s), 1218 (s), 1368
1
(s), 1471 (s), 1510 (m), 1611 (s), 2932 (s). H NMR (300 MHz, CDCl3):
δ = 1.96–1.98 (m, 8H, 5 × CH2), 2.82–2.88 (m, 6H, 2 × CH2), 3.27–
3.28 (m, 4H, 2 × NCH2), 7.33–8.04 (m, 6H, ArH, Hetar). 13C NMR

636
W.-D. Pfeiffer et al.
(50 MHz, DMSO-d6): δ = 14.2, 22.7, 23.5, 24.7, 25.6, 25.9, 26.0, 45.3,
50.1, 104.8, 117.9, 126.4, 128.2, 128.9, 129.6, 133.7, 134.2, 144.7, 145.0,
145.1, 146.9, 150.5. MS (EI, 70 eV): m/z = 388 (M+, 57), 351 (100), 335
(28), 318 (11), 303 (10), 277 (11), 118 (6), 91 (3), 28 (3). Anal calcd. for
C23H24N4S (388.53): C, 71.10; H, 6.23; N, 14.42. Found: C, 71.12; H,
6.12; N, 14.41.
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