Synthesis of methyl 3-azidothieno[2,3-b]pyridine-2-carboxylates and application of the huisgen reaction

Article abstract of DOI:10.5560/ZNB.2014-3320

The preparation of new substituted methyl 3-azidothieno[2,3-b]pyridine carboxylates by azotization of methyl 3-aminothieno[2,3-b]pyridine and subsequent treatment with sodium azide is described. Via Huisgen's 1,3-dipolar cycloaddition between substituted alkynes and the prepared azides, methyl 1,2,3-triazolo-thieno[2,3-b]pyridine carboxylates have been obtained.

Full text of DOI:10.5560/ZNB.2014-3320

Synthesis of Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates and
Application of the Huisgen Reaction
Wafaâ Chaounia,b, Mina Aadilb, Ahmed Djellala,c, and Gilbert Kirscha
a
SRMSC (LIMBP), UMR 7565 Institut Jean Barriol, Université de Lorraine, 1 Boulevard
Arago, 57070 Metz, France
Laboratoire de Chimie Bioorganique et Analytique (LCBA), FST-Mohammedia, BP 146,
b
20800 Mohammedia, Maroc
Actual address: Institut de Chimie, Faculté des Sciences, Université d’Annaba, 23000 Annaba,
c
Algérie
Reprint requests to Prof Gilbert Kirsch. Fax: +33 387315801.
E-mail: gilbert.kirsch@univ-lorraine.fr
Z. Naturforsch. 2014, 69b, 509 – 518 / DOI: 10.5560/ZNB.2014-3320
Received December 4, 2013
Dedicated to Professor Willi Kantlehner on the occasion of his 70thbirthday for his longtime
involvement and promotion of the chemistry of iminium salts
The preparation of new substituted methyl 3-azidothieno[2,3-b]pyridine carboxylates by azoti-
zation of methyl 3-aminothieno[2,3-b]pyridine and subsequent treatment with sodium azide is de-
scribed. Via Huisgen’s 1,3-dipolar cycloaddition between substituted alkynes and the prepared azides,
methyl 1,2,3-triazolo-thieno[2,3-b]pyridine carboxylates have been obtained.
Key words: Vilsmeier-Haack-Arnold Reaction, 2-Chloro-3-cyano-pyridines, Thienopyridines,
1,2,3-Triazole
Introduction
Thieno[2,3-b]pyridines have received considerable
Results and Discussion
In the present work, we describe the synthesis
attention, since they show a wide variety of bioac- of methyl azidothieno[2,3-b]pyridine carboxylates 6
tivities, for example antiviral, antidiabetic, antimicro- and methyl triazolothieno[2,3-b]pyridine carboxylates
bial, antitumor, antiparasitic, and neurotopic activi- 8 from methyl 3-aminothieno[2,3-b]pyridine carboxy-
ties [1 – 9].
lates 5. The α-methylene ketones 1 were used as
In continuation of synthetic work with aminothieno- starting materials for the synthesis of thieno[2,3-
[2,3-b]pyridines previously developed in our labora- b]pyridines 5.
tory [10], we propose here a new route to methyl 1,2,3-
The alkylidene malononitriles 2, prepared by Knoe-
triazolo-thieno[2,3-b]pyridine carboxylates. The well- venagel condensation [13 – 16] from α-methylene ke-
established method for their synthesis is via Huisgen’s tones, served as intermediates for the synthesis of the
1,3-dipolar cycloaddition between an alkyne and an or- 2-chloro-3-cyanopyridines 4 (Scheme 1, Table 1).
ganic azide [11, 12].
Treatment of the alkylidene malononitriles with the
Heterocyclic aromatic azides with electron-deficient Vilsmeier-Haack reagent at 70 – 80 ◦C led to the for-
aromatic rings have been most widely studied. Such mation of 2-chloro-3-cyanopyridines 4 (Scheme 2, Ta-
azides are synthesized through nucleophilic substitu- ble 2). The cyclization occurred regioselectively at the
tion of halogen or a similar group by the azide ion. most active methylene group in γ position of the alkyli-
An electron-rich aromatic ring is not suitable for such dene malononitrile 2, leading to an intermediate I.
a reaction. Hence, diazotization of amino derivatives This intermediate cyclized “in situ” to yield 2-chloro-
and their conversion into azides by the reaction with 3-cyanopyridines 4. However, this reaction was ac-
sodium azide is the main method for the synthesis of complished in general with low yields (10 – 15%). We
such heteroazides.
could increase the yield by adding some natural phos-
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W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
1
1
R
Table 1. Synthesis of alkylidene malononitriles 2.
R
O
i
Ketone 1
Alkylidene
Yield (%)
R2
malononitrile 2
R2
CN
NC
CN
NC
2a–g
1
O
Scheme 1. Synthesis of compounds 2. Reagents and condi-
tions: (i) CH2(CN)2, CH3COONH4, CH3COOH, toluene,
reflux, 24 h.
1a
2a
83
90
74
45
51
NC
CN
O
phate (NP) [17] or some phosphate modified by potas-
sium fluoride (KF/NP) to the reaction mixture.
1b
2b
NC
We also used 2-chloro-6-methyl-3-cyanopyridine
4f. This compound was synthesized from 6-methyl-3-
cyanopyridin-2-one [18 – 29] by treatment with phos-
phorus oxychloride at 60 ◦C for 24 h (Scheme 3).
The chlorocyanopyridines 4 were used as intermedi-
ates for the synthesis of 3-aminothieno[2,3-b]pyridines
5. Synthesis of the thiophene ring could be accom-
plished via two routes. In route A, condensation with
methyl thioglycolate in DMF afforded the SNAr prod-
uct which could be isolated and cyclized in a second
step to the 3-amino-2-carbomethoxythiophene 5. Sub-
stitution and cyclization was realized in a one-pot route
B by reaction of the 2-chloro-3-cyanopyridine with
sodium sulfide and methyl bromoacetate in DMF in the
presence of sodium methanolate (Scheme 4, Table 3).
Azidothieno[2,3-b]pyridines 6 were obtained by di-
azotation of the corresponding amino derivatives in
70% sulfuric acid solution upon addition of sodium
azide in water to the diazonium salt. The precipitated
CN
O
1c
1d
1e
2c
NC
CN
O
2d
NC
CN
O
2e
1,3-Dipolar cycloaddition reactions between 3-
azides were filtered off (Scheme 5, Table 4). These azido derivatives 6 and alkynes 7 were run in chloro-
azido derivatives are light-sensitive. They should be form in the presence of copper(I) chloride and base.
stored in a dark place or used directly for further re- Huisgen’s cycloaddition took at least 24 h and the
actions.
yields were fair to good. The use of copper iodide did
R1
R1
CN
N
CN
R2
CN
Cl
without or with
catalyst
R1
Cl
H
N+
CN
PO2Cl2
R2
H3C N+
N
H
R2
4a–e
Cl
3
2
CH3
I
Scheme 2. Synthesis of compounds 4. Reagents: (i) Vilsmeier-Haack reagent or Vilsmeier-Haack reagent + modified phos-
phate, 70–80 ◦C, 3 h.
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W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
511
R
R
i
N
Cl
N
H
O
4f
Scheme 4. Synthesis of compounds 5. Reagents and condi-
tions: A) HSCH2CO2CH3, DMF, K2CO3, r. t., 24 h, MeONa,
MeOH, r. t., 1 h; B) Na2S·9H2O, BrCH2CO2CH3, MeONa,
MeOH, 50 ◦C, 3 h.
Scheme 3. Synthesis of 4f. Reagents and conditions: i)
POCl3, 60 ◦C, 24 h.
Table 2. Synthesis of 2-chloro-3-cyanopyridines 4.
Table 3. Synthesis of methyl 3-aminothienopyridine-2-
carboxylates 5.
Alkylidene
Yield (%) Yield (%)
malononitrile 2
(KF/NP)
5
Yield (%)
Method
NC
CN
CN
Cl
NH2
N
CO2Me
60
35
A
B
4a
S
2a
N
a
10
15
8
54
56
30
NC
CN
NH2
CN
Cl
CO2Me
61
38
A
B
N
S
N
b
c
2b
4b
Ph
NH2
NC
CN
Ph
CN
Cl
CO2Me
S
N
N
53
85
A
A
4c
2c
NC
CN
NH2
CN
CO2Me
S
N
d
N
Cl
2d
4d
15
62
NH2
NC
CN
CN
Cl
CO2Me
S
N
e
f
98
98
A
A
N
NH2
2e
4e
10
–
CO2Me
S
N
not lead to the formation of the triazole (Scheme 6, Ta-
ble 5).
Experimental Section
Conclusion
All melting points were measured in open capillary tubes
in a Stuart SMP 3 apparatus. NMR spectra were recorded
on a Bruker AC 250 (250 MHz) spectrometer in CDCl3,
[D6]acetone or [D6]DMSO. Chemical shifts (δ) are reported
in ppm and coupling constants (J) in Hz.
Starting from simple compounds we prepared
functionalized pyridines using a modified Vilsmeier-
Haack-Arnold reaction useful for constructing poly-
cyclic heterocyclic compounds.
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512
W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
Table 5. Synthesis of methyl 1,2,3-triazolylthienopyridine-2-
carboxylates 8.
8
a
b
c
d
e
f
Yield (%)
N
N
Scheme 5. Synthesis of compounds 6. Reagents and condi-
N
N
N
N
tions: i) 1. NaNO2, H2SO4; 2. NaN3.
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Table 4. Synthesis of methyl 3-azidothienopyridine-2-
carboxylates 6.
S
N
23
40
46
52
75
30
6
Yield (%)
N
N
N3
CO2Me
S
N
S
a
53
N
N3
N
N
CO2Me
Ph
N
S
N
b
c
67
47
Ph
N3
S
CO2Me
N
N
S
N
N3
S
N
N
N
CO2Me
S
N
N
N
d
58
N
N3
S
CO2Me
S
N
e
f
37
63
N
N
N
N3
CO2Me
S
N
S
Scheme 6. Synthesis of
compounds 8. Reagents
and conditions: i) 2,4-
lutidine, CuCl, CHCl3, r. t.,
24 h.
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W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
513
Table 5. (Continued.)
General procedure for the synthesis of 2-chloro-
3-cyanopyridines 4
8
Yield (%)
To a flask containing 10 mmol of a gem-dicyanoalkene
1 and 20 mmol (3.0 g) of POCl3 in DMF (10 mL), 0.1 g of
phosphate catalyst (KF/NP) was added, and the mixture was
stirred at room temperature for 30 min. Then the bath temper-
ature was slowly raised to 70 – 80 ◦C. The reaction mixture
was heated for 3 h and after cooling poured into cold water.
The formed solid was filtered and recrystallized or purified
by column chromatography.
N
N
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
S
N
g
h
i
73
65
45
38
93
72
N
N
3-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-
4-carbonitrile (4a)
Brown solid, m. p. 105 ◦C (cyclohexane). – 1H NMR
(CDCl3, 250 MHz, 25 ◦C): δ = 2.19 – 2.31 (m, 2H, CH2),
2.98 – 3.04 (t, J = 7.5 Hz, 2H, CH2), 3.11 – 3.17 (t, J =
7.5 Hz, 2H, CH2), 8.38 (s, 1H, Har). – 13C NMR (CDCl3,
250 MHz): δ = 25.00, 25.38, 37.33, 81.62, 112.38, 140.74,
148.17, 162.63, 193.35.
S
N
N
N
Ph
N
3-Chloro-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (4b)
Brown solid, m. p. 126 ◦C (ethyl acetate-petroleum ether).
S
–
1H NMR (CDCl3, 250 MHz, 25 ◦C): δ = 1.83 – 1.94
(m, 4H, CH2CH2), 2.75 – 2.77 (t, J = 2.5 Hz, 2H, CH2),
2.93 – 2.98 (t, J = 6.25 Hz, 2H, CH2), 8.27 (s, 1H, Har). – 13
C
N
N
NMR (CDCl3, 250 MHz): δ = 21.37, 21.57, 25.70, 28.25,
110.38, 113.92, 139.62, 150.10, 152.43, 153.45.
2-Chloro-5-methyl-4-phenylnicotinonitrile (4c)
S
N
N
N
j
Orange solid, m. p. 125 – 127 ◦C (column chrom., 20%
ethyl acetate-cyclohexane). – 1H NMR (CDCl3, 250 MHz,
25 ◦C,): δ = 2.19 (s, 3H, CH3), 7.28 – 7.31 (m, 2H, Har),
7.52 – 7.57 (m, 3H, Har), 8.47 (s, 1H, Har). – 13C NMR
(CDCl3, 250 MHz): δ = 16.81, 110.65, 114.36, 128.03,
128.18, 129.78, 131.15, 134.48, 151.02, 152.98, 155.
N
N
N
S
k
2-Chloro-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile
(4d)
N
N
Yellow solid, m. p. 180 ◦C (column chrom., 20% ethyl
acetate-cyclohexane). – 1H NMR (CDCl3, 250 MHz, 25 ◦C):
δ = 2.16 – 2.28 (m, 2H, CH2), 3.00 – 3.06 (t, 2H, J = 7.5 Hz,
CH2), 3.38 – 3.44 (t, 2H, J = 7.5 Hz, CH2), 3.98 (s, 3H,
CH3), 8.56 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz):
δ = 24.14, 28.67, 96.40, 115.19, 117.49, 126.87, 127.18,
128.69, 129.08, 131.68, 140.93, 140.97, 151.37, 160.74.
N
S
l
General procedure for the synthesis of alkylidene
malononitriles
2-Chloro-6-methyl-5,6-dihydrobenzo[f]isoquinoline-
1-carbonitrile (4e)
These compounds were synthesized according to a known
procedure [10].
Yellow solid, m. p. 149 – 151 ◦C (column chrom., 20%
ethyl acetate-cyclohexane). – 1H NMR (CDCl3, 250 MHz,
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W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
25 ◦C): δ = 0.84 – 0.87 (m, 3H, CH3), 2.68 – 2.76 (m, 1H, Methyl 1-amino-6,7-dihydrobenzo[f]thieno[2,3-c]iso-
CH), 2.97 – 3.11 (m, 3H, CH3), 7.26 – 7.50 (m, 3H, Har), quinoline-2-carboxylate (5d)
8.44 (s, 2H, Har). – 13C NMR (CDCl3, 250 MHz): δ =
Yellow solid, m. p. 200 ◦C. – 1H NMR (CDCl3, 250 MHz,
18.58, 29.86, 36.26, 105.11, 116.10, 126.79, 127.76, 128.53,
129.60, 130.94, 136.65, 138.31, 147.40, 149.77, 153.23.
25 ◦C): δ = 2.79 (m, 4H, CH2CH2), 3.77 (s, 3H, CH3), 6.24
(s, 2H, NH2), 7.38 – 7.73 (m, 1H, Har), 8.55 (s, 1H, Har).
–
13C NMR (CDCl3, 250 MHz): δ = 25.83, 29.07, 51.65,
General procedure for the synthesis of methyl
97.38, 126.78, 127.11, 127.42, 128.33, 128.44, 129.20,
129.86, 130.19, 130.79, 131.17, 140.38, 147.50, 166.16.
– HRMS (APCI): m/z = 310.0806 (calcd. 310.0800 for
[C17H14N2O2S1+H]+).
aminothienopyridine-2-carboxylates 5
Chlorocyanopyridine (0.005 mol), methyl thioglycolate
(0.01 mol) and potassium carbonate (0.0075 mol) were
mixed in 100 mL of DMF. The mixture was stirred for 24 h
at room temperature and then poured into ice-water. The pre-
cipitated product was filtered off and dried. It was then cy-
clized by adding it to 0.005 moles of sodium methanolate in
25 mL of methanol. The mixture was stirred for one hour at
room temperature and then poured into ice-water. The pre-
cipitated product was filtered off, dried and purified by re-
crystallization from methanol.
Methyl 1-amino-6,7-dihydro-7-methylbenzo[f]thieno-
[2,3-c]isoquinoline-2-carboxylate (5e)
Yellow solid, m. p. 162 – 164 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 1.47 (m, 3H, CH3), 2.72 – 2.78 (m,
1H, CH), 3.02 – 3.08 (m, 2H, CH2), 3.91 (s, 3H, CH3), 6.23
(s, 2H, NH2), 7.37 – 7.42 (m, 3H, Har), 7.68 – 7.72 (m, 1H,
Har), 8.57 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz): δ =
18.40, 30.53, 36.61, 51.63, 97.36, 119.57, 126.79, 129.17,
129.57, 129.88, 134.77, 138.65, 139.81, 147.65, 148.64,
148.75, 161.17, 166.17. – HRMS (APCI): m/z = 324.0932
(calcd. 324.0900 for [C18H16N2O2S1+H]+).
Methyl 1-amino-7, 8-dihydro-6H-cyclopenta[d]thieno-
[2,3-b]pyridine-2-carboxylate (5a)
Yellow solid, yield 60%, m. p. 215 ◦C. – 1H NMR
(CDCl3, 250 MHz): δ = 2.25 – 2.34 (m, 2H, CH2),
2.99 – 3.05 (t, 2H, J = 7.5 Hz, CH2), 3.33 – 3.39 (t, 2H, J =
7.5 Hz, CH2), 6.01 (s, 2H, NH2), 8.52 (s, 1H, Har). – 13C
NMR (CDCl3, 250 MHz): δ = 24.83, 29.50, 31.60, 51.59,
97.97, 123.27, 136.24, 146.65, 147.52, 148.74, 158.70,
165.95. – HRMS (APCI): m/z = 248.0587 (calcd. 248.0600
for [C12H12N2O2S1+H]+).
Methyl 3-amino-6-methylthieno[2,3-b]pyridine-
2-carboxylate (5f)
Yellow solid, m. p. 182 – 185 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 2.68 (s, 3H, CH3), 3.89 (s, 3H, CH3),
5.90 (s, 2H, NH2), 7.15 – 7.18 (d, 1H, J = 7.5 Hz, Har),
7.79 – 7.83 (d, 1H, J = 10 Hz, Har). – 13C NMR (CDCl3,
250 MHz): δ = 24.81, 51.61, 97.56, 119.21, 122.93, 129.22,
146.36, 160.34, 160.80, 165.89. – HRMS (APCI): m/z =
222.0463 (calcd. 222.0500 for [C10H10N2O2S1+H]+).
Methyl 1-amino-6,7,8,9-tetrahydrothieno[2,3-c]iso-
quinoline-2-carboxylate (5b)
Yellow solid, m. p. 218 ◦C. – 1H NMR (CDCl3, 250 MHz,
25 ◦C): δ = 1.81 – 1.95 (m, 4H, CH2CH2), 2.81 – 2.86 (t,
2H, J = 6.25 Hz, CH2), 3.25 – 3.30 (t, 2H, J = 6.25 Hz,
CH2), 6.23 (s, 2H, NH2), 8.32 (s, 1H, Har). – 13C NMR
(CDCl3, 250 MHz): δ = 26.4, 26.85, 30.94, 31.25, 129.12,
133.51, 136.51, 149.03, 154.69, 156.76, 162.73, 171.82.
– HRMS (APCI): m/z = 262.0776 (calcd. 262.0800 for
[C13H14N4O2S1+H]+).
General procedure for the synthesis of methyl azido-thieno-
pyridine-2-carboxylates 6
3-Aminothieno[2,3-b]pyridine (1.79 mmol) was dis-
solved in concentrated sulfuric acid (70%, 10 mL)
containing ice. When the mixture reached 0 ◦C, a saturated
aqueous solution of sodium nitrite (3 equiv.) was added
keeping the temperature below 5 ◦C. After 10 min, sodium
azide (3 equiv.) in 5 mL of water was added dropwise. The
solution was left for 30 min at room temperature, and the
azide was precipitated in water. The solid was filtered off
and washed with water and acetone.
Methyl 3-amino-5-methyl-4-phenylthieno[2,3-b]pyridine-
2-carboxylate (5c)
Green solid, m. p. 214 – 216 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 2.31 (s, 3H, CH3), 3.80 (s, 3H, CH3),
5.43 (s, 2H, NH2), 7.30 – 7.33 (m, 2H, Har), 7.54 – 7.56 (m,
3H, Har), 8.50 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz):
δ = 16.33, 51.51, 96.80, 117.38, 127.22, 129.02, 129.17,
Methyl 1-azido-7,8-dihydro-6H-cyclopenta[d]thieno-
[2,3-b]pyridine-2-carboxylate (6a)
Colorless solid, m. p. 137 – 140 ◦C. – 1H NMR (CDCl3,
135.49, 145.73, 147.85, 151.70, 159.35, 161.09, 165.92. 250 MHz, 25 ◦C): δ = 2.16 – 2.28 (m, 2H, CH2), 3.00 – 3.06
– HRMS (APCI): m/z = 298.0796 (calcd. 298.0800 for (t, 2H, J = 7.5 Hz, CH2), 3.38 – 3.44 (t, 2H, J = 7.5 Hz,
[C16H14N2O2S1+H]+).
CH2), 3.98 (s, 3H, CH3), 8.56 (s, 1H, Har). – 13C NMR
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515
(CDCl3, 250 MHz): δ = 24.89, 29.92, 32.32, 52.54, 117.10, Methyl 3-azido-6-methylthieno[2,3-b]pyridine-
125.59, 135.88, 137.58, 147.19, 150.67, 157.00, 162.31. 2-carboxylate (6f)
– HRMS (APCI): m/z = 275.0629 (calcd. 275.0597 for
[C12H10N4O2S1+H]+).
Yellow solid, m. p. 112 – 113 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 2.703 (s, 3H, CH3), 3.97 (s, 3H,
CH3), 7.21 – 7.25 (d, 1H, J = 10 Hz, Har), 8.02 – 8.05 (d,
1H, J = 7.5 Hz, Har). – 13C NMR (CDCl3, 250 MHz):
δ = 24.88, 52.55, 116.03, 120.59, 125.89, 131.15, 135.18,
158.88, 160.81, 162.30. – HRMS (APCI): m/z = 249.0433
(calcd. 249.0441 for [C10H8N4O2S1+H]+).
Methyl 1-azido-6,7,8,9-tetrahydrothieno[2,3-c]iso-
quinoline-2-carboxylate (6b)
Colorless solid, m. p. 133 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 1.81 – 1.90 (m, 4H, CH2CH2),
2.83 – 2.87 (t, 2H, J = 5 Hz, CH2), 3.34 – 3.36 (t, 2H,
J = 2.5 Hz, CH2), 3.90 (s, 3H, CH3), 8.5 (s, 1H, Har). –
13C NMR (CDCl3, 250 MHz): δ = 21.83, 22.18, 26.67,
26.87, 30.91, 52.54, 117.13, 129.93, 136.79, 144.76, 152.15,
156.94, 162.17. – HRMS (APCI): m/z = 289.0751 (calcd.
289.0754 for [C13H12N4O2S1+H]+).
General procedure for the synthesis of methyl
1,2,3-triazolylthienopyridine-2-carboxylates 8
The azide (1.04 mmol) was dissolved in 30 mL of chloro-
form. The mixture was cooled to 0 ◦C, and the alkyne (1.2
equiv.) was added. Then, copper(I) chloride (0.05 g) and one
drop of 2,4-lutidine were added. The mixture was stirred at
room temperature and the reaction monitored by TLC until
the disappearance of the starting material. The organic phase
was then washed with water, dried and concentrated. The
residue was purified by column chromatography (30% ethyl
acetate-cyclohexane).
Methyl 3-azido-5-methyl-4-phenylthieno[2,3-b]pyridine-
2-carboxylate (6c)
Yellow solid, m. p. 139 – 143 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 2.17 (s, 3H, CH3), 3.95 (s, 3H,
CH3), 7.18 – 7.21 (d, 2H,J= 7.5 Hz, Har), 7.40 – 7.50 (m,
3H, Har), 8.26 (s, 1H, Har).13C NMR (CDCl3, 250 MHz):
δ = 16.78, 30.90, 52.61, 118.90, 128.15, 128.17, 129.14,
135.77, 135.94, 146.94, 151.87, 157.28, 161.93, 208.11.
– HRMS (APCI): m/z = 325.0749 (calcd. 325.0750 for
[C16H12N4O2S1+H]+).
Methyl 1-(4-propyl-1H-1,2,3-triazol-1-yl)-7,8-dihydro-
6H-cyclopenta[d]thieno[2,3-b]pyridine-2-carboxylate (8a)
Colorless solid, m. p. 126 – 128 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 1.01 (t, 3H, J = 7.5 Hz, CH3),
1.75 – 1.87 (m, 2H, CH2), 2.00 – 2.12 (m, 2H, CH2),
2.39 – 2.45 (t, 2H, J = 7.5 Hz, CH2), 2.83 – 2.89 (t, 2H,
J = 7.5 Hz, CH 2), 2.98 – 3.04 (t, 2H, J = 7.5 Hz, CH2),
3.81 (s, 3H, CH3), 7.63 (s, 1H, Har), 8.7 (s, 1H,
H). – 13C NMR (CDCl3, 250 MHz): δ = 13.62, 21.38,
22.72, 27.52, 30.02, 30.43, 52.91, 124.37, 127.18, 128.40,
130.66, 138.79, 147.26, 147.78, 149.65, 156.80, 160.63.
– HRMS (APCI): m/z = 343.1210 (calcd. 343.1223 for
[C17H8N4O2S1+H]+).
Methyl 1-azido-6,7-dihydrobenzo[f]thieno[2,3-c]iso-
quinoline-2-carboxylate (6d)
Yellow solid, m. p. 120 – 123 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 2.88 (s, 4H, CH2CH2), 4.00 (s,
3H, CH3), 7.38 – 7.41 (m, 3H, Har), 7.67 – 7.68 (d, 1H,
J = 2.5 Hz, Har), 8.59 (s, 1H, Har). – 13C NMR (CDCl3,
250 MHz): δ = 26.03, 28.82, 52.71, 118.54, 125.83, 127.36,
129.72, 130.20, 131.20, 131.58, 135.75, 139.34, 141.06,
147.75, 149.62, 159.38, 161.99. – HRMS (APCI): m/z =
337.0756 (calcd. 337.0754 for [C17H12N4O2S1+H]+).
Methyl 1-(4-propyl-1H-1,2,3-triazol-1-yl)-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate (8b)
Methyl 1-azido-6,7-dihydro-7-methylbenzo[f]thieno-
[2,3-c]isoquinoline-2-carboxylate (6e)
Yellow solid, m. p. 145 – 146 ◦C. – 1H NMR (CDCl3,
Yellow solid, m. p. 134 – 135 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 1.14 – 1.17 (d, 3H, J = 7.5 Hz, CH3), 250 MHz, 25 ◦C): δ = 0.98 – 1.03 (t, 3H, J = 6.3 Hz, CH3),
2.71 – 2.79 (m, 1H, CH), 3.02 – 3.15 (m, 2H, CH2), 4.00 (s, 1.58 – 2.15 (m, 8H, -CH2-CH2-), 2.79 – 2.88 (m, 4H, -CH2-
3H, CH3), 7.35 – 7.39 (m, 3H, Har), 7.65 – 7.67 (d, 1H, J = CH2-), 3.74 (s, 3H, CH3), 7.58 (s, 1H, Har), 8.44 (s, 1H, Har).
5 Hz, Har), 8.62 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz):
–
13C NMR (CDCl3, 250 MHz): δ = 13.15, 21.60, 21.70,
δ = 18.39, 30.65, 36.33, 52.70, 118.56, 125.85, 128.32, 22.73, 23.09, 26.82, 27.50, 52.88, 77.22, 124.59, 129.13,
129.58, 129.74, 131.47, 135.74, 135.90, 137.51, 140.31, 130.90, 131.21, 143.42, 148.01, 152.20, 156.67, 160.57.
149.16, 154.26, 159.24, 161.98. – HRMS (APCI): m/z = – HRMS (APCI): m/z = 357.1363 (calcd. 357.1380 for
351.0905 (calcd. 351.0910 for [C18H14N4O2S1+H]+).
[C18H20N4O2S1+H]+).
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W. Chaouni et al. · Methyl 3-Azidothieno[2,3-b]pyridine-2-carboxylates
Methyl 5-methyl-4-phenyl-3-(4-propyl-1H-1,2,3-triazol-
1-yl)thieno[2,3-b]pyridine-2-carboxylate (8c)
(t, 2H, J = 7.5 Hz, CH2), 3.88 (s, 3H, CH3), 7.28 – 7.31
(d, 1H, J = 7.5 Hz, Har), 7.83 (s, 1H, Har), 7.98 – 8.02 (d,
1H, J = 7.5 Hz, Har). – 13C NMR (CDCl3, 250 MHz): δ =
13.76, 22.59, 24.87, 26.90, 27.55, 52.94, 121.69, 123.19,
124.31, 126.75, 131.20, 132.69, 147.28, 158.74, 160.89.
– HRMS (APCI): m/z = 317.1068 (calcd. 317.1067 for
[C15H16N4O2S1+H]+).
Colorless solid, m. p. 158 – 160 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 0.91 – 0.97 (t, 3H, J = 7.5 Hz, CH3),
1.49 – 1.59 (m, 2H, CH2), 2.12 (m, 3H, CH3), 2.38 – 2.44 (t,
2H, J = 7.5 Hz, CH2), 3.73 (s, 3H, CH 3), 6.80 (s, 1H, Har),
6.88 – 6.91 (m, 2H, Har), 7.19 – 7.22 (m, 2H, Har), 8.86 (s,
1H, Har). – 13C NMR (CDCl3, 250 MHz): δ = 13.86, 16.86,
22.08, 27.14, 52.96, 123.25, 126.82, 127.53, 127.65, 128.14,
130.14, 130.50, 130.79, 133.86, 146.07, 146.82, 152.00,
157.04, 160.41. – HRMS (APCI): m/z = 393.1381 (calcd.
393.1380 for [C21H20N4O2S1+H]+).
Methyl 1-(4-phenyl-1H-1, 2,3-triazol-1-yl)-7,8-dihydro-
6H-cyclopenta[d]thieno[2,3-b]pyridine-2-carboxylate (8g)
Colorless solid, m. p. 206 – 209 ◦C.
–
1H NMR
([D6]acetone, 250 MHz, 25 ◦C): δ = 2.02 – 2.11 (m,
2H, CH2), 2.48 – 2.54 (t, 2H, J = 7.5 Hz, CH2), 2.99 – 3.05
(t, 2H, J = 7.5 Hz, CH2), 3.82 (s, 3H, CH3), 7.36 – 7.52
(m, 3H, Har), 7.95 – 7.99 (dd, 2H, J = 5 Hz, 2H, Har),
8.13 (s, 1H, Har), 8.70 (s, 1H, Har). – 13C NMR ([D6]
acetone, 250 MHz): δ = 24.67, 30.03, 30.63, 53.04,
123.10, 125.90, 128.54, 128.61, 128.96, 130.04, 130.20,
139.81, 146.90, 147.38, 149.71, 156.76, 158.45, 160.59.
– HRMS (APCI): m/z = 377.1056 (calcd. 377.1067 for
[C20H16N4O2S1+H]+).
Methyl 1-(4-propyl-1H-1,2,3-triazol-1-yl)-6,7-dihydro-
benzo[f]thieno[2,3-c]isoquinoline-2-carboxylate (8d)
Yellow solid, m. p. 162 – 164 ◦C.
–
1H NMR
([D6]acetone, 250 MHz, 25 ◦C): δ = 0.88 – 0.94 (t,
3H, J = 7.5 Hz, CH3), 1.52 – 1.61 (m, 2H, CH2), 2.53 – 2.59
(t, 2H, J = 7.5 Hz, CH2), 2.86 (s, 4H, CH2CH2), 3.84 (s,
3H, CH 3), 6.61 – 6.64 (d, 1H, J = 7.5 Hz, Har), 6.74 – 6.77
(t, 1H, J = 3.75 Hz, Har), 7.14 – 7.21 (t, 1H, J = 8.8 Hz,
Har), 7.27 – 7.31 (d, 1H, J = 10 Hz, Har), 7.79 (s, 1H,
Har), 8.73 (s, 1H, CH). – 13C NMR (CDCl3, 250 MHz):
δ = 8.32, 14.06, 23.40, 26.42, 27.52, 28.03, 53.27, 126.28,
126.82, 127.65, 127.99, 128.10, 128.42, 129.79, 129.82,
130.96, 132.23, 139.79, 141.73, 150.53, 159.84, 161.47.
– HRMS (APCI): m/z = 405.1377 (calcd. 405.1380 for
[C22H20N4O2S1+H]+).
Methyl 1-(4-phenyl-1H-1, 2, 3-triazol-1-yl)-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate (8h)
Colorless solid, m. p. 229 – 230 ◦C. – 1H NMR ([D6]
acetone, 250 MHz, 25 ◦C) δ = 1.62 – 2.85 (m, 8H,
CH2CH2CH2CH2), 3.79 (s, 3H, CH3), 7.36 – 7.52 (m, 3H,
Har), 7.92 – 7.99 (dd, 2H, J = 8.75 Hz, 2H, Har), 8.099 (s, 1H,
Har), 8.47 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz) δ =
21.56, 21.72, 23.41, 26.84, 52.98, 123.30, 125.89, 127.33,
128.53, 128.95, 129.32, 130.05, 130.77, 131.10, 143.55,
147.58, 152.24, 156.57, 160.48. – HRMS (APCI): m/z =
391.1232 (calcd. 391.1223 for [C21H18N4O2S1+H]+).
Methyl 7-methyl-1-(4-propyl-1H-1,2,3-triazol-1-yl)-6,7-di-
hydrobenzo[f]thieno[2,3-c]isoquinoline-2-carboxylate (8e)
Colorless solid, m. p. 154 – 155 ◦C.
–
1H NMR
([D6]acetone, 250 MHz, 25 ◦C): δ = 0.75 – 0.80 (t,
3H, J = 6.3 Hz, CH3), 0.97 – 0.99 (d, 3H, J = 5 Hz, CH3),
1.39 – 1.48 (m, 2H, CH2), 2.39 – 2.45 (t, 2H, J = 7.5 Hz,
CH2), 2.58 – 2.66 (dd, 1H, J = 10.0 Hz, CH), 2.86 – 3.10
(m, 2H, CH2), 3.67 (s, 3H, CH3), 6.49 – 6.52 (d, 1H,
J = 7.5 Hz, Har), 6.62 – 6.65 (t, 1H, J = 3.8 Hz, Har),
7.02 – 7.16 (m, 2H, Har), 7.67 (s, 1H, Har), 8.64 (s, 1H,
Har). – 13C NMR ([D6]acetone, 250 MHz): δ = 14.06,
18.50, 23.41, 28.04, 31.31, 36.56, 53.24, 124.48, 125.47,
126.87, 127.95, 128.40, 129.12, 129.82, 130.62, 132.40,
137.73, 137.79, 141.03, 147.62, 150.14, 159.79, 161.48.
– HRMS (APCI): m/z = 419.1531 (calcd. 419.1536 for
[C23H23N4O2S1+H]+).
Methyl 5-methyl-4-phenyl-3-(4-phenyl-1H-1,2,3-triazol-
1-yl)thieno[2,3-b]pyridine-2-carboxylate (8i)
Colorless solid, m. p. 264 ◦C. – 1H NMR ([D6] DMSO,
250 MHz, 25 ◦C): δ = 2.37 (s, 3H, CH3), 3.69 (s, 3H,
CH3), 7.01 – 704 (m, 5H, Har), 7.39 – 7.56 (m, 5H, Har),
8.20 (s, 1H, Har), 8.89 (s, 1H, Har). – 13C NMR (CDCl3,
250 MHz) δ = 16.31, 53.08, 120.35, 124.03, 125.25, 126.06,
127.41, 127.57, 127.65, 128.63, 128.89, 129.98, 130.30,
131.06, 132.36, 133.07, 145.48, 145.73, 152.56, 159.83.
– HRMS (APCI): m/z = 427.1234 (calcd. 427.1223 for
[C24H18N4O2S1+H]+).
Methyl 1-(4-phenyl-1H-1,2,3-triazol-1-yl)-6,7-dihydro-
Methyl 6-methyl-3-(4-propyl-1H-1,2,3-triazol-1-yl)thieno-
benzo[f]thieno[2,3-c]isoquinoline-2-carboxylate (8j)
[2,3-b]pyridine-2-carboxylate (8f)
Colorless solid, m. p. 259 – 262 ◦C.
–
1H NMR
Colorless solid, m. p. 116 – 118 ◦C. – 1H NMR (CDCl3, ([D6]acetone, 250 MHz, 25 ◦C) δ = 2.88 (s, 4H, CH2CH2),
250 MHz, 25 ◦C): δ = 1.02 – 1.08 (t, 3H, J = 7.5 Hz, CH3), 3.86 (s, 3H, CH3), 6.62 – 6.75 (m, 2H, Har), 7.03 – 7.09
1.75 – 1.87 (m, 2H, CH2), 2.74 (s, 3H, CH3), 2.82 – 2.88 (t, 1H, J = 7.5 Hz, Har), 7.21 – 7.24 (d, 2H, J = 7.5 Hz,
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517
Har), 7.34 – 7.41 (m, 2H, Har), 7.44 – 7.66 (m, Hz, 2H, 30.71, 36.17, 53.16, 123.08, 124.18, 126.05, 126.27, 126.96,
Har), 7.78 (s, 1H, Har), 8.73 (s, 1H, Har). – 13C NMR 128.24, 128.43, 128.59, 128.72, 129.20, 129.69, 130.08,
(CDCl3, 250 MHz) δ = 26.13, 28.71, 53.08, 124.70, 130.55, 136.93, 141.54, 147.30, 147.64, 158.04, 160.63,
125.47, 126.05, 126.21, 126.88, 127.49, 128.21, 128.34, 174.69. – HRMS (APCI): m/z = 453.1382 (calcd. 453.1380
128.44, 128.71, 129.27, 130.05, 130.16, 131.16, 131.20, for [C26H20N4O2S1+H]+).
132.23, 133.94, 138.53, 141.01, 147.00, 160.82.
–
Methyl 6-methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)thieno-
[2,3-b]pyridine-2-carboxylate (8l)
HRMS (APCI): m/z = 439.1223 (calcd. 439.1223 for
[C25H18N4O2S1+H]+).
Yellow solid, m. p. 188.6 – 189.9 ◦C. – 1H NMR ([D6]
DMSO, 250 MHz, 25 ◦C): δ = 2.70 (s, 3H, CH3), 3.80 (s,
3H, CH3), 7.31 – 7.50 (m, 5H, Har), 7.94 – 8.04 (m, 2H,
Har), 9.15 (s, 1H, Har). – 13C NMR (CDCl3, 250 MHz):
δ = 24.35, 53.09, 122.32, 123.67, 124.57, 125.34, 126.05,
128.28, 129.04, 130.03, 130.40, 132.20, 145.97, 157.41,
160.13, 161.22. – HRMS (APCI): m/z = 351.0909 (calcd.
351.0910 for [C18H14N4O2S1+H]+).
Methyl 7-methyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)-6,7-di-
hydrobenzo[f]thieno[2,3-c]isoquinoline-2-carboxylate (8k)
Colorless solid, m. p. 235 – 237 ◦C. – 1H NMR (CDCl3,
250 MHz, 25 ◦C): δ = 1.43 (d, 3H, J = 7.5 Hz, CH3),
2.71 – 2.80 (m, 1H, CH), 3.02 – 3.21 (m, 2H, CH2), 3.85 (s,
3H, CH3), 6.62 – 6.65 (d, 1H, J = 7.5 Hz, Har), 6.70 – 6.76
(t, 1H, J = 7.5 Hz, Har), 7.07 – 7.12 (t, 1H, J = 6.3 Hz, Har),
7.21 – 7.23 (d, 1H, J = 5.0 Hz, Har), 7.34 – 7.43 (m, 3H, Har),
7.66 – 7.68 (d, 2H, J = 5.0 Hz, Har), 7.86 (s, 1H, Har), 8.72
Acknowledgement
The authors are thankful to Prof. Gerhard Maas for helpful
(s, 1H, Har). – 13C NMR (CDCl3, 250 MHz): δ = 18.20, discussion and advice.
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