Synthesis of dihydrothienopyridine derivatives fused with triazole rings

Article abstract of DOI:10.1002/hc.21087

New dihydro[3,2-c][1,2,4]triazolo[4,3-a]pyridines were synthesized by the reaction of 4-(methylsulfanyl)-6,7-dihydrothieno[3,2-c]pyridine with acid hydrazides. One bis(dihydrothienotriazolo-pyridine) was also prepared. In a few cases, the corresponding intermediate could be detected by LC-MS. The bromophenyl derivative was involved in Suzuki and Sonogashira cross-coupling reactions.

Full text of DOI:10.1002/hc.21087

Heteroatom Chemistry
Volume 24, Number 3, 2013
Synthesis of Dihydrothienopyridine
Derivatives Fused with Triazole Rings
1
1,2
Pe´ter Abra´nyi-Balogh, Ma´tya´s Milen, Andra´s Dancso´,2
´
Da´vid Frigyes,2 La´szlo´ Pongo´,2 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2EGIS Pharmaceuticals PLC., Division for Chemical Research, 1475 Budapest, Hungary
Received 22 January 2013; revised 27 February 2013
and the synthesis of this agent has been extensively
ABSTRACT: New dihydro[3,2-c][1,2,4]triazolo[4,3-
investigated [8,9].
a]pyridines were synthesized by the reaction of
In our previous study, the [3+2] and [2+2]
4-(methylsulfanyl)-6,7-dihydrothieno[3,2-c]pyridine
cycloadditions [10], as well as cyclocondensa-
with acid hydrazides. One bis(dihydrothienotriazolo-
tion reactions [11], were investigated to syn-
pyridine) was also prepared. In a few cases, the
thesize novel fused conformationally constrained
corresponding intermediate could be detected by
thienopyridines.
LC-MS. The bromophenyl derivative was involved
The 1,2,4-triazole derivatives form an important
in Suzuki and Sonogashira cross-coupling reac-
class within heterocyclic compounds, and, there-
ꢀC
tions.
2013 Wiley Periodicals, Inc. Heteroatom
fore, many analogues were synthesized and reported
[12–14]. A number of representatives are used in
agriculture as insecticides with low mammalian toxi-
city [15]. Other compounds containing 1,2,4-triazole
core exhibit various medicinal and pharmaceutical
properties [16–24]. Moreover, 1,2,4-triazole deriva-
tives play an important role in synthetic organic
chemistry. N-Heterocyclic carbenes, which can be
prepared from 1,2,4-triazolium salts, have been used
as ligands in several catalytic reactions [25]. A
few alkyl- or aryl-1,2,4-triazolium salts form a new
generation of ionic liquids with a high degree of
flexibility [26,27].
As a continuation of our work, we now describe
new, fused tricyclic heterocycles containing two
biologically significant cores, such as the thienopyri-
dine and the triazole units. To the best of our knowl-
edge, only one compound containing a dihydro[3,2-
c][1,2,4]triazolo[4,3-a]pyridine ring was described
in the literature, but there are no data on the
synthesis of this species represented by formula 4
(Fig. 2) [28].
Chem. 24:226–233, 2013; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.21087
INTRODUCTION
The thienopyridine ring system can be found in bio-
logically and pharmacologically active compounds,
such as ticlopidine (1), (S)-clopidogrel (2), and pra-
sugrel (3) (Fig. 1). These thienopyridine deriva-
tives block the P2Y12 component of the adenosine
diphosphate receptor and thus inhibit platelet ac-
tivation and aggregation [1–4]. Antiplatelet agents
are used for treatment of ischemic strokes, heart
attacks, artherosclerosis, and prevention of throm-
bosis [5–7]. (S)-Clopidogrel (trade name Plavix) (2)
was the world’s second top-selling drug in 2005,
Correspondence to: G. Keglevich; e-mail: gkeglevich@
mail.bme.hu.
2013 Wiley Periodicals, Inc.
ꢀC
226

Synthesis of Dihydrothienopyridine Derivatives Fused with Triazole Rings 227
FIGURE 1 Ticlopidine (1), (S)-clopidogrel (2) and prasugrel (3).
The methylation was carried out in acetoni-
trile/dichloromethane at 26◦C in the presence of
Cs2CO3.
The reaction of 4-(methylsulfanyl)-6,7-dihydro-
thieno[3,2-c]pyridine (6) with various acid hy-
drazides (7a–m) in the presence of catalytic amount
of concentrated HCl in boiling butanol took place
smoothly and resulted in the formation of dihydro-
triazolopyridine derivatives (10a–m) in moderate to
good yields (32%–94%) (Scheme 1; Table 1).
FIGURE 2 The only dihydrotriazolopyridine analogue de-
scribed [28].
RESULTS AND DISCUSSION
Synthesis of 5,6-Dihydrothieno[3,2-c][1,2,4]-
triazolo[4,3-a]pyridine Derivatives (10 a–m) by
the Cyclocondensation Reaction
TABLE 1 Details for the Synthesis of Dihydrotriazolopy-
ridines 10a–m
The starting material (5) was prepared by a
simple procedure based on a microwave-assisted
thionation reaction from commercially avail-
able 4,5,6,7-tetrahydrothieno[3,2-c]pyridine [29].
The 6,7-dihydrothieno[3,2-c]pyridine-4(5H)-thione
(5) seemed to be a useful intermediate for the
preparation of new 1,2,4-triazole derivatives [30–32].
However, no reaction was observed between com-
Entry
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
1
1
1
2
1
2
5
0.5
1
1
74
61
32
54
79
82
55
69
94
88
68
72
65
10g
10h
10i
pound
5 and acetic hydrazide (7b) in boil-
9
ing butanol. Therefore to convert the thione (5)
to a more reactive species, it was S-alkylated
with methyl iodide to form 4-(methylsulfanyl)-6,7-
dihydrothieno[3,2-c]pyridine (6) [11] (Scheme 1).
10
11
12
13
10j
10k
10l
1
1
1
10m
SCHEME 1
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´
228 Abra´nyi-Balogh et al.
We observed that the size and the electronic ef-
fect of the R group have an equal influence on the
reaction. As compared to H, the yields decreased in
the case of methyl and adamantyl substituents in
the order of 74%, 61%, and 32%, respectively. In
these cases, the reaction time was 1 h (Table 1, en-
tries 1–3). The ring closure of intermediates 8c/9c
was influenced by the steric hindrance due to the
adamantyl group. In the instance, when R = Ph, the
reaction took place in 2 h and the yield was 54%
(Table 1, entry 4). However, the 4-chlorophenyl sub-
stituent enhanced the ring closure reaction due to
the electron-withdrawing effect of the chlorine sub-
stituent. In this case, the reaction time was 1 h and
the product was obtained in 79% yield (Table 1, en-
try 5). In the case of the 4-bromobenzoic hydrazide,
the reaction time was 2 h and the yield of product
10f remained the same (Table 1, entry 6). This could
be explained by the lower extent of the electron-
withdrawing effect of the bromine atom. A bromine
substituent in the ortho position caused a prolonged
reaction time as a consequence of the steric hin-
drance (Table 1, entry 7). The 2-nitrophenyl group
with a strong electron withdrawing effect resulted
in a short reaction time of 30 min. Product 10h was
obtained in a yield of 69% (Table 1, entry 8). The
best results were obtained with nicotinic and iso-
nicotinic hydrazides, when the yields were 94% and
88%, respectively (Table 1, entries 9 and 10). With
other heterocyclic hydrazides, the products were ob-
tained in yields of 65%–72% (Table 1, entries 11–13).
All reactions were monitored by LC-MS and con-
tinued until the starting material disappeared. It is
worth mentioning that we were able to detect in-
termediate 8/9 by LC-MS in three instances. Thus,
8f/9f ([M + H]+ = 351), 8g/9g ([M + H]+ = 351),
and 8h/9h ([M + H]+ = 317) could be detected.
In the reaction of adipic acid dihydrazide (7n)
with two molecules of dihydrothienopyridine (6) un-
der the same conditions, the corresponding bis prod-
uct (11) was formed in a yield of 50%. Compound
11 contains two dihydrotriazolopyridine scaffolds
connected with a chain of four methylene groups
(Scheme 2). In many cases, dimeric molecules show
an increased biological activity, as compared to their
monomers [33].
Synthesis of Additional 5,6-Dihydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine Derivatives
(12a,b,13) by Cross-Coupling Reactions
Finally, we studied the cross-coupling reactions,
such as the Suzuki and the Sonogashira reac-
tion of 3-(4-bromophenyl)-5,6-dihydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine (10f). The Suzuki
reaction was carried out with two arylboronic
acids in the presence of Pd(OAc)2 and triphe-
nylphosphine in PrOH–H2O at reflux [34]. The
corresponding products (12a and 12b) obtained
in the reaction with phenylboronic acid and
2,6-dimethoxyphenylboronic acid were isolated
in a yield of 99% (Scheme 3). The Sonogashira
coupling reaction of 3-(4-bromophenyl)-5,6-
dihydrothieno[3,2-c][1,2,4]triazolo[4,3-a]pyridine
(10f) with phenylacetylene in the presence of CuI,
PdCl2(PPh3)2, and piperidine [35] was unsuccessful.
However, product 13 was obtained, when Pd/C,
CuI, PPh3, diisopropylamine (DIPA) were used in
dimethylacetamide (DMA)–H2O solution (Scheme
3) [36]. The yield was 81%.
The structures of products 10a–m, 11, 12a, 12b,
and 13 were confirmed by 13C and 1H NMR, as well
as IR spectroscopy.
In summary, 17 new tricyclic 5,6-dihydrothie-
no[3,2-c][1,2,4]triazolo[4,3-a]pyridine derivatives
were synthesized, which are biologically and phar-
macologically interesting fused scaffolds. Among
them, 14 triheterocyclic compounds (10a–m) were
obtained by the reaction of 4-(methylsulfanyl)-
6,7-dihydrothieno[3,2-c]pyridine-4(5H)-thione (6)
with acid hydrazides (7a–m). In three cases,
the reaction intermediate (8/9) was observed by
LC-MS. A bis-product (11) was also made avail-
able. Three additional derivatives (12a, 12b, and
13) were prepared by the cross-coupling reac-
tion of 3-(4-bromophenyl)-5,6-dihydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine (10f).
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Dihydrothienopyridine Derivatives Fused with Triazole Rings 229
SCHEME 3
EXPERIMENTAL
General
1H and 13C NMR spectra were recorded with a Var-
ian Unity Inova 500 spectrometer (Agilent Technolo-
gies Inc., Santa Clara, CA) (500 and 125 MHz for 1H
and 13C NMR spectra, respectively) or with a Bruker
Avance III spectrometer (Bruker BioSpin GmbH,
hydrazide (7h), 0.72 g of nicotinic hydrazide (7i),
0.72 g of isonicotinic hydrazide (7j), 0.82 g of 5-
methylthiophene-2-carboxylic acid hydrazide (7k),
0.93 g of benzofuran-2-carboxylic acid hydrazide
(7l), and 0.99 g of quinoline-2-carbohydrazide (7m)]
were added to a stirred solution of 0.40 g (2.1
mmol) of 4-(methylsulfanyl)-6,7-dihydrothieno[3,2-
c]pyridine-4(5H)-thione (5) and 0.13 mL of cc. HCl
in 50 mL of butanol. The solution was stirred at
120◦C for 0.5–5 h until the starting material disap-
peared. The reaction mixture was concentrated in
vacuo. The crude product was partitioned between
100 mL of dichloromethane and 50 mL of 5% HCl
solution. The organic layer was washed with 25 mL
of water, dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash chromatography
on silica gel (PF254) using dichloromethane as the
eluent.
1
Rheinstetten, Germany) (400 and 100 MHz for H
and 13C NMR spectra, respectively). DMSO-d6 or
CDCl3 was used as the solvent, and tetramethylsi-
lane was used as the internal standard. The FT-IR
spectra of KBr pellets or neat samples were recorded
with a Bruker alpha spectrometer. All melting points
were measured with a Kofler–Boe¨tius microappara-
tus and were not corrected.
The reactions were monitored by analytical thin-
layer chromatography on silica gel 60 PF254 and
liquid chromatography–mass spectrometry chro-
matography. Analytical samples of new compounds
were obtained by crystallization.
Commercially available reagents were pur-
chased from Sigma–Aldrich and used without fur-
ther purification. Carboxylic acid hydrazides (7a–n)
are commercially available. They may be easily syn-
thesized from the appropriate esters by treatment
with hydrazine hydrate in ethanol according to the
analogous procedure described [37].
5,6-Dihydrothieno[3,2-c][1,2,4]triazolo[4,3-a]-
pyridine (10a). Yield 0.28 g (74%); white crystals;
mp 201–204◦C (EtOH); 1H NMR (500 MHz, DMSO):
δ = 9.45 (s, 1H), 7.72 (d, J = 5.3 Hz, 1H), 7.69 (d, J
= 5.3 Hz, 1H), 4.53 (t, J = 7.3 Hz, 2H), 3.43 (t, J =
7.2 Hz, 2H); 13C NMR (125 MHz, DMSO): δ = 146.3
(C N), 143.6 (C ), 142.7 (HC N), 127.4 (HC ),
123.2 (HC ), 120.9 (C ), 43.1 (CH2), 23.0 (CH2); IR
(KBr): ν = 2489, 1785, 1622, 1566, 1229, 936 cm−1
;
HRMS calcd. for C8H8N3S [M + H]+ 178.0433;
General Procedure for the Preparation of the
5,6-Dihydrothieno[3,2-c][1,2,4]triazolo-
[4,3-a]pyridine Derivatives
found 178.0434.
3-Methyl-5,6-dihydrothieno[3,2-c][1,2,4]-
5.3 Mmol of the appropriate acylhydrazide [0.32
g of formic hydrazide (7a), 0.39 g of acetic hy-
drazide (7b), 1.0 g of adamantine-1-carbohydrazide
(7c), 0.72 g of benzoic hydrazide (7d), 0.90 g
of 4-chlorobenzoic hydrazide (7e), 1.14 g of 4-
bromobenzoic hydrazide (7f), 1.14 g of 2-bromo-
benzoic hydrazide (7g), 0.96 g of 2-nitrobenzoic
triazolo[4,3-a]pyridine (10b). Yield 0.25 g (61%);
white crystals; mp 196–198◦C (MeOH); 1H NMR
(400 MHz, CDCl3): δ = 7.53 (d, J = 5.2 Hz, 1H),
7.25 (d, J = 5.2 Hz, 1H), 4.12 (t, J = 7.1 Hz, 2H),
3.27 (t, J = 7.1 Hz, 2H), 2.45 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 149.6 (C N), 148.6 (C N), 135.6
(C ), 126.3 (C ), 124.9 (HC ), 123.3 (HC ), 40.9
Heteroatom Chemistry DOI 10.1002/hc

´
230 Abra´nyi-Balogh et al.
(KBr): ν = 3382, 2375, 1605, 1011, 859, 728 cm−1
;
(CH2), 23.9 (CH2), 10.4 (CH3); IR (KBr): ν = 3052,
1482, 1430, 944, 763, 725 cm−1; HRMS calcd. for
C9H10N3S [M + H]+ 192.0590; found 192.0591.
HRMS calcd. for C14H11BrN3S [M + H]+ 331.9852;
found 331.9846.
3-Tricyclo[3.3.1.13,7]dec-1-yl-5,6-dihydrothieno-
3-(2-Bromophenyl)-5,6-dihydrothieno[3,2-c]-
[3,2-c][1,2,4]triazolo[4,3-a]pyridine
(10c). Yield
[1,2,4]triazolo[4,3-a]pyridine (10g). Yield 0.39 g
0.21 g (32%); white crystals; mp 273–275◦C (de-
comp.) (MeCN); 1H NMR (500 MHz, CDCl3): δ =
7.57 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H),
4.40 (t, J = 6.8 Hz, 2H), 3.23 (t, J = 6.9 Hz, 2H),
2.20–2.16 (m, 6H), 2.16–2.10 (m, 3H), 1.86–1.78
(m, 6H); 13C NMR (125 MHz, CDCl3): δ = 158.8
(C N), 149.8 (C N), 135.3 (C ), 126.9 (C ), 124.6
(HC ), 123.9 (HC ), 44.1 (CH2), 39.8 (CH2), 36.6
(CH2), 34.6 (C), 28.1 (CH), 24.5 (CH2); IR (KBr): ν =
2899, 1589, 1478, 944, 701 cm−1; HRMS calcd. for
C18H22N3S [M + H]+ 312.1529; found 312.1524.
1
(55%); brown oil; H NMR (500 MHz, CDCl3): δ =
7.73–7.70 (m, 1H), 7.66 (d, J = 5.1 Hz, 1H), 7.58–7.55
(m, 1H), 7.49–7.45 (m, 1H), 7.43–7.39 (m, 1H), 7.30
(d, J = 5.3 Hz, 1H), 4.11 (t, J = 7.0 Hz, 2H), 3.26 (t,
J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ =
152.1 (C N), 149.2 (C N), 136.6 (C ), 133.0 (HC ),
132.9 (HC ), 131.9 (HC ), 128.8 (C ), 127.8 (HC )
126.2 (C ), 125.1 (HC ), 123.6 (two signals: 123.62,
123.59) (HC , BrC ), 42.4 (CH2), 24.1 (CH2); IR
(film): ν = 3384, 3074, 1476, 1438, 765 cm−1; HRMS
calcd. for C14H11BrN3S [M + H]+ 331.9852; found
331.9845.
3-Phenyl-5,6-dihydrothieno[3,2-c][1,2,4]triazolo-
[4,3-a]pyridine (10d). Yield 0.29 g (54%); white
crystals; mp 177–180◦C (MeCN); 1H NMR (500
MHz, CDCl3): δ = 7.70–7.67 (m, 2H), 7.63 (d, J =
5.1 Hz, 1H), 7.53–7.49 (m, 3H), 7.29–7.28 (m, 1H),
4.33 (t, J = 7.0 Hz, 2H), 3.26 (t, J = 7.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ = 152.8 (C N), 149.4
(C N), 136.1 (C ), 130.0 (HC ), 128.9 (HC ), 128.5
(HC ), 127.1 (C ), 126.5 (C ), 125.0 (HC ), 123.6
(HC ), 42.4 (CH2), 24.3 (CH2); IR (KBr): ν = 1588,
1508, 1478, 709, 700, 687 cm−1; HRMS calcd. for
C14H12N3S [M + H]+ 254.0746; found 254.0744.
3-(2-Nitrophenyl)-5,6-dihydrothieno[3,2-c]-
[1,2,4]triazolo[4,3-a]pyridine (10h). Yield 0.43 g
(69%); yellow crystals; mp 208–211◦C (MeCN); H
1
NMR (500 MHz, DMSO): δ = 8.39–8.36 (m, 1H),
8.12–8.10 (m, 1H), 7.92–7.89 (m, 1H), 7.88 (d, J =
4.8 Hz, 1H), 7.84–7.80 (m, 1H), 7.71 (d, J = 5.3 Hz,
1H), 3.76–3.71 (m, 2H), 3.26–3.22 (m, 2H); 13C NMR
(125 MHz, DMSO): δ = 165.1 (C N), 154.5 (C ),
150.6 (O2NC ), 147.6 (C N), 133.4 (HC ), 132.3
(HC ), 131.0 (HC ), 128.5 (C ), 126.7 (HC ), 124.2
(HC ), 124.1 (HC ), 121.8 (C ), 40.2 (CH2), 22.8
(CH2); IR (KBr): ν = 3075, 2879, 1705, 1635, 1528,
1344 cm−1; HRMS calcd. for C14H13N4O3S [M +
H]+ 317.0703; found 317.0702.
3-(4-Chlorophenyl)-5,6-dihydrothieno[3,2-c]-
[1,2,4]triazolo[4,3-a]pyridine (10e). Yield 0.48 g
(79%); pale yellow crystals; mp 208–210◦C (EtOH);
1H NMR (500 MHz, DMSO): δ = 7.82–7.79 (m, 2H),
7.66–7.63 (m, 2H), 7.60 (d, J = 5.1 Hz, 1H), 7.49 (d,
J = 5.1 Hz, 1H), 4.39 (t, J = 7.1 Hz, 2H), 3.30 (t, J =
7.1 Hz, 2H); 13C NMR (125 MHz, DMSO): δ = 151.5
(C N), 149.2 (C N), 137.7 (C ), 134.8 (ClC ), 130.2
(HC ), 129.1 (HC ), 126.2 (two signals: 126.21,
126.15) (C , HC ), 125.7 (C ), 122.8 (HC ), 42.3
(CH2), 23.6 (CH2); IR (KBr): ν = 1589, 1475, 1463,
1096, 840, 701 cm−1; HRMS calcd. for C14H11ClN3S
[M+H]+ 288.0357; found 288.0361.
3-Pyridin-3-yl-5,6-dihydrothieno[3,2-c][1,2,4]-
triazolo[4,3-a]pyridine (10i). Yield 0.50 g (94%);
white crystals; mp 162–164◦C (EtOH); 1H NMR (500
MHz, CDCl3): δ = 8.94–8.90 (m, 1H), 8.77–8.74 (m,
1H), 8.11–8.07 (m, 1H), 7.63 (d, J = 5.2 Hz, 1H),
7.50–7.46 (m, 1H), 7.32 (d, J = 5.2 Hz, 1H), 4.38 (t,
J = 7.0 Hz, 2H), 3.32 (t, J = 7.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): δ = 151.0 (HC N), 150.2 (C N),
149.8 (C N), 148.7 (HC ), 136.3 (C ), 136.1 (HC ),
126.2 (C ), 125.2 (HC ), 123.8 (HC ), 123.6 (HC ),
123.5 (C ), 42.5 (CH2), 24.2 (CH2); IR (KBr): ν
= 1583, 1572, 1475, 722 cm−1; HRMS calcd. for
C13H11N4S [M + H]+ 255.0699; found 255.0700.
3-(4-Bromophenyl)-5,6-dihydrothieno[3,2-c]-
[1,2,4]triazolo[4,3-a]pyridine (10f). Yield 0.57 g
(82%); white crystals; mp 216–219◦C (BuOH); 1H
NMR (500 MHz, DMSO): δ = 7.89–7.86 (m, 2H),
7.80–7.78 (m, 2H), 7.71 (d, J = 5.1 Hz, 1H), 7.67 (d,
J = 5.3 Hz, 1H), 4.49 (t, J = 7.2 Hz, 2H), 3.41 (t, J =
7.2 Hz, 2H); 13C NMR (125 MHz, DMSO): δ = 151.3
(C N), 147.7 (C N), 141.9 (C ), 132.4 (HC ), 131.0
(HC ), 127.3 (HC ), 125.3 (C ), 123.6 (BrC ),
123.1 (HC ), 122.4 (C ), 43.0 (CH2), 23.3 (CH2); IR
3-Pyridin-4-yl-5,6-dihydrothieno[3,2-c][1,2,4]-
triazolo[4,3-a]pyridine (10j). Yield 0.47 g (88%);
white crystals; mp 214–216◦C (MeCN); 1H NMR
(400 MHz, CDCl3): δ = 8.80–8.77 (m, 2H), 7.65–7.63
(m, 2H), 7.61 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 5.2 Hz,
1H), 4.42 (t, J = 7.1 Hz, 2H), 3.33 (t, J = 7.0 Hz, 2H);
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Dihydrothienopyridine Derivatives Fused with Triazole Rings 231
13C NMR (100 MHz, CDCl3): δ = 150.5 (two signals:
3,3’-Butane-1,4-diylbis(5,6-dihydrothieno[3,2-c]-
[1,2,4]triazolo[4,3-a]pyridine) (11). Compound 11
was prepared in a similar manner as described in
the preparation of 10a–m. In this reaction, 1.25
equiv (0.46 g, 2.64 mmol) of adipic acid dihydrazide
(7n) was used. Yield 0.22 g (50%); white crystals;
150.52, 150.47) (C N, HC N), 150.1 (C N), 136.4
(C ), 134.6 (C ), 126.0 (C ), 125.3 (HC ), 123.6
(HC ), 122.2 (HC = ), 42.6 (CH2), 24.2 (CH2); IR
(KBr): ν = 3067, 1603, 1585, 1473, 1460, 708 cm−1
;
HRMS calcd. for C13H11N4S [M+H]+ 255.0699;
1
mp >335◦C (DMF); H NMR (400 MHz, DMSO): δ
found 255.0703.
= 7.54 (d, J = 5.2 Hz, 2H), 7.39 (d, J = 5.2 Hz, 2H),
4.19 (t, J = 7.1 Hz, 4 H), 3.26 (t, J = 6.9 Hz, 4H),
2.83–2.78 (m, 4H), 1.83–1.78 (m, 4H); 13C NMR (100
MHz, DMSO): δ = 152.8 (C N), 148.0 (C N), 141.5
(C ), 137.0 (C ), 125.9 (HC ), 122.6 (HC ), 40.6
(CH2), 26.0 (CH2), 23.7 (CH2), 23.4 (CH2); IR (KBr):
ν = 2323, 1610, 1566, 1426, 855, 726 cm−1; HRMS
calcd. for C20H21N6S2 [M + H]+ 409.1264; found
409.1265.
3-(5-Methylthiophen-2-yl)-5,6-dihydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine (10k). Yield 0.39 g
(68%); white crystals; mp 164–166◦C (EtOH); 1H
NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 4.6 Hz,
1H), 7.26 (d, J = 4.0 Hz, 1H), 7.26–7.22 (m, 1H),
6.84–7.79 (m, 1H), 4.39 (t, J = 6.6 Hz, 2H), 3.29
(t, J = 6.6 Hz, 2H), 2.54 (s, 3H); 13C NMR (125
MHz, CDCl3): δ = 149.1 (C N), 148.1 (C N), 143.2
(C ), 135.8 (C ), 127.8 (HC ), 126.3 (C ), 126.0
(HC ), 125.6 (C ), 124.9 (HC ), 123.7 (HC ), 42.0
(CH2), 24.1 (CH2), 15.2 (CH3); IR (KBr): ν = 1588,
1571, 1508, 930, 791, 700 cm−1; HRMS calcd. for
C13H12N3S2 [M + H]+ 274.0467; found 274.0467.
General Procedure for the Suzuki Reaction
The solution of 0.10 g (0.30 mmol) of 10f and
0.33 mmol of the appropriate boronic acid (40
mg of phenylboronic acid and 60 mg of 2,6-
dimethoxyphenylboronic acid) in 20 mL of propane-
1-ol was purged with argon for 15 min. 1 mg of
Pd(OAc)2 (1.5%), 3.5 mg of PPh3 (4.5%), 38 mg (0.36
mmol) of Na2CO3, and 3 mL of water were added,
and the solution was stirred at 110◦C for 2 h until the
starting material disappeared. The reaction mixture
was concentrated in vacuo. The crude product was
partitioned between 20 mL of dichloromethane and
15 mL of water. The organic layer was washed with
10 mL of brine, dried (MgSO4), and concentrated in
vacuo.
3-(1-Benzofuran-2-yl)-5,6-dihydrothieno[3,2-c]-
[1,2,4]triazolo[4,3-a]pyridine (10l). Yield 0.45 g
(72%); white crystals; mp 240–242◦C (MeCN); 1H
NMR (400 MHz, CDCl3): δ = 7.69–7.66 (m, 1H), 7.63
(d, J = 5.2 Hz, 1H), 7.58–7.50 (m, 1H), 7.48 (d, J =
0.8 Hz, 1H), 7.40–7.36 (m, 1H), 7.33–7.30 (m, 1H),
7.28 (d, J = 5.2 Hz, 1H), 4.73 (t, J = 7.0 Hz, 2H),
3.37 (t, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ = 155.0 (HC ), 149.5 (C N), 145.3 (C ), 144.2
(C ), 136.6 (C ), 127.6 (HC ), 125.8 (C ), 125.7
(HC ), 125.0 (HC ), 123.8 (HC ), 123.7 (HC ),
121.9 (HC ), 111.4 (C ), 107.7 (C ), 42.9 (CH2),
3-Biphenyl-4-yl-5,6-dihydrothieno[3,2-c][1,2,4]-
triazolo[4,3-a]pyridine (12a). Yield 98 mg (99%);
white crystals; mp 259–261◦C (MeCN); 1H NMR
(500 MHz, CDCl3): δ = 7.77–7.75 (m, 2H), 7.74–7.72
(m, 2H), 7.64 (d, J = 5.3 Hz, 1H), 7.64–7.61 (m,
2H), 7.49–7.45 (m, 2H), 7.41–7.37 (m, 1H), 7.28
(d, J = 5.1 Hz, 1H), 4.38 (t, J = 7.1 Hz, 2H), 3.28
(t, J = 7.1 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ = 152.6 (C N), 149.5 (C N), 142.8 (C ), 140.0
(C ), 136.1 (C ), 128.9 (two signals: 128.91, 128.87)
(2×HC ), 127.9 (HC ), 127.5 (HC ), 127.1 (HC ),
126.5 (C ), 125.9 (C ), 125.0 (HC ), 123.7 (HC ),
42.4 (CH2), 24.3 (CH2); IR (KBr): ν = 1467, 843,
768, 700, 695 cm−1; HRMS calcd. for C20H16N3S
[M+H]+ 330.1059; found 330.1054.
24.1 (CH2); IR (KBr): ν = 1420, 1252, 931, 691 cm−1
;
HRMS calcd. for C16H12N3OS [M+H]+ 294.0696;
found 294.0700.
3-(Quinolin-2-yl)-5,6-dihydrothieno[3,2-c][1,2,4]-
triazolo[4,3-a]pyridine
(10m). Yield
0.42
g
(65%); white crystals; mp 231–232◦C (MeCN);
1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.6 Hz,
1H), 8.26 (d, J = 8.7 Hz, 1H), 8.13–8.09 (m, 1H),
7.88–7.84 (m, 1H), 7.77–7.72 (m, 1H), 7.67 (d, J =
5.2 Hz, 1H), 7.61–7.56 (m, 1H), 7.30 (d, J = 5.2 Hz,
1H), 5.23 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ = 150.8 (C N),
150.7 (C N), 148.1 (C N), 147.2 (C ), 137.4 (C ),
136.8 (HC ), 129.9 (HC ), 129.4 (HC ), 127.8
(HC ), 127.2 (C ), 126.1 (C ), 124.8 (HC ), 123.8
(HC ), 120.7 (HC ), 44.0 (CH2), 24.3 (CH2); IR
(KBr): ν = 1599, 1582, 1421, 841, 761 cm−1; HRMS
calcd. for C17H13N4S [M + H]+ 305.0855; found
305.0854.
3-(2’,6’-Dimethoxybiphenyl-4-yl)-5,6-dihydrothi-
eno[3,2-c][1,2,4]triazolo[4,3-a]pyridine
(12b).
Yield 116 mg (99%); white crystals; mp 241–243◦C
(MeCN); 1H NMR (400 MHz, CDCl3): δ = 7.74–
7.71 (m, 2H), 7.66 (d, J = 5.2 Hz, 1H), 7.53–7.49
Heteroatom Chemistry DOI 10.1002/hc

´
232 Abra´nyi-Balogh et al.
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(m, 2H), 7.31 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 4.7 Hz,
1H), 6.67 (d, J = 8.4 Hz, 2H), 4.43 (t, J = 7.0 Hz,
2H), 3.75 (s, 6H), 3.27 (t, J = 7.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ = 157.5 (HC ), 153.0
(C N), 149.3 (C N), 136.2 (C ), 136.1 (C ), 131.6
(HC ), 129.2 (C ), 127.7 (HC ), 126.6 (C ), 125.1
(HC ), 125.0 (C ), 123.7 (HC ), 118.4 (C ), 104.2
(HC ), 55.9 (CH3), 42.4 (CH2), 24.4 (CH2); IR
(KBr): ν = 1584, 1242, 1104, 845, 732 cm−1; HRMS
calcd. for C22H20N3O2S [M + H]+ 390.1271; found
390.1265.
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3-[4-(Phenylethynyl)phenyl]-5,6-dihydrothieno-
[3,2-c][1,2,4]triazolo[4,3-a]pyridine (13). To the
mixture of 15 mg of Pd/C (5%), 6 mg of CuI
(10%), 8 mg of PPh3 (10%) in 5 mL of N,N-
dimethylacetamide, 0.25 mL of water, 0.1 g (0.3
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trated in vacuo. The crude product was purified by
flash chromatography on silica gel (PF254) using
dichloromethane–hexane as the eluent.
Yield 86 mg (81%); white crystals; mp 248–250◦C
1
(MeCN); H NMR (500 MHz, CDCl3): δ = 7.71–7.68
(m, 2H), 7.68–7.65 (m, 2H), 7.64 (d, J = 5.1 Hz, 1H),
7.57–7.54 (m, 2H), 7.38–7.35 (m, 3H), 7.29 (d, J = 5.3
Hz, 1H), 4.36 (t, J = 7.1 Hz, 2H), 3.28 (t, J = 7.0 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ = 152.3 (C N),
149.6 (C N), 136.2 (C ), 132.0 (HC ), 131.7 (HC ),
128.6 (HC ), 128.4 (two signals: 128.40, 128.36)
(2×HC ), 126.6 (C ), 126.4 (C ), 125.1 (two sig-
nals: 125.13, 125.09) (C , HC ), 123.7 (HC ), 122.8
(C ), 91.5 (C ), 88.6 (C ), 42.5 (CH2), 24.3 (CH2);
IR (KBr): ν = 3077, 2887, 1571, 1463, 944, 835, 755,
689, 520 cm−1; HRMS calcd. for C22H16N3S [M +
H]+ 354.1059; found 354.1057.
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