Synthesis of thienoimidazo[4,5-b]pyridines and thenylidenoimidazolinones

Article abstract of DOI:10.3987/COM-05-10486

The two isomers 2-amino-1-methylimidazo[4,5-b]thieno[3,2-e]pyridine (3) and 2-amino-1-methylimidazo[4,5-b]thieno[2,3-e]pyridine (4) were synthesized by the Friedlaender reaction starting from creatinine and the appropriate aminothiophenecarbaldehydes (11 and 13). Creatinine was also condensed with 2-nitro-3-thiophenecarbaldehyde (10) in ethylene glycol to yield the 2-amino-1-methyl-5-[2-(2-nitro-3-thenylidene)]-2-imidazolin-4-one (7a), with 3-amino-2-thiophenecarbaldehyde (13) under Perkin conditions to yield 2-acetamido-5-[2-(3-acetamido-2-thenylidene)]-1-methyl-2-imidazolin-4-on e (8), and with 4-azido-3-thiophenecarbaldehyde (17) in acetic acid to yield 2-amino-5-[2-(4-azido-3-thenylidene)]-1-methyl-2-imidazolin-4-one (9). The thenylidenoimidazolinone (8) was converted into compound (4).{A figure is presented}.

Full text of DOI:10.3987/COM-05-10486

HETEROCYCLES, Vol. 65, No. 10, 2005
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HETEROCYCLES, Vol. 65, No. 10, 2005, pp. 2369 - 2380
Received, 21st June, 2005, Accepted, 8th August, 2005, Published online, 9th August, 2005
SYNTHESIS
OF
THIENOIMIDAZO[4,5-b]PYRIDINES
AND
THENYLIDENOIMIDAZOLINONES
Malin Björk and Spiros Grivas*
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and
Södertörn University College, Novum Research Park, SE-141 57 Huddinge,
Sweden
E-mail: spiros.grivas@biosci.ki.se
Abstract – The two isomers 2-amino-1-methylimidazo[4,5-b]thieno[3,2-
e]pyridine (3) and 2-amino-1-methylimidazo[4,5-b]thieno[2,3-e]pyridine (4) were
synthesized by the Friedländer reaction starting from creatinine and the
appropriate aminothiophenecarbaldehydes (11 and 13). Creatinine was also
condensed with 2-nitro-3-thiophenecarbaldehyde (10) in ethylene glycol to yield
the 2-amino-1-methyl-5-[2-(2-nitro-3-thenylidene)]-2-imidazolin-4-one (7a), with
3-amino-2-thiophenecarbaldehyde (13) under Perkin conditions to yield 2-
acetamido-5-[2-(3-acetamido-2-thenylidene)]-1-methyl-2-imidazolin-4-one (8),
and with 4-azido-3-thiophenecarbaldehyde (17) in acetic acid to yield 2-amino-5-
[2-(4-azido-3-thenylidene)]-1-methyl-2-imidazolin-4-one
(9).
The
thenylidenoimidazolinone (8) was converted into compound (4).
INTRODUCTION
There has been evidence that some mutagenic heterocyclic amines are formed during cooking of foods by
reaction between creatine, amino acids and sugars.1 One of these heterocyclic amines is 2-amino-1-
methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, Figure 1), and apart from its mutagenic/carcinogenic
properties it has also similarities to the linear imidazo[4,5-b]pyridines (1 and 2). Compounds (1 and 2) are
part of our synthetic programme towards structure-activity relationships2 and are also the parent
compounds to 3–5. Several imidazo[4,5-b]pyridines, -quinolines, -quinoxalines and -naphthyridines have
been synthesized by our group3-7 and others.8 The substitution of –CH= for –N= (benzene-pyridine) or –
CH=CH– for –S– (benzene-thiophene) in aromatic rings is an application of classical bioisosterism.9 In
this paper we present the synthesis towards analogues (3) and (4), which are related to 1 using
bioisosterism.

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HETEROCYCLES, Vol. 65, No. 10, 2005
Me
N
Me
N
Me
N
NH2
NH2
S
NH2
X
N
N
N
N
N
N
1 X=CH
2 X=N
PhIP
3-5
Figure 1
Heteroarylmethyleneimidazolinones have been described frequently in the last decades. Compound (6,10
Figure 2) has been isolated from natural sources, and shows specific cytotoxicity for cancer cells.11
Similar compounds have been used in medicinal chemistry; for example, arylideneimidazol-4-one amino
acids, which have been tested in structure-activity studies of glycine receptor ligands.12 Previously, the
benzene and furan analogues of these compounds have been described by our group7,13 and therefore it
was natural for us to choose these intermediate thenylideneimidazolinones (7a, 8 and 9) providing similar
features to natural products in the synthesis of our targets (3–5).
NH2
NH2
NHAc
O
N
N
Me
N
Me
N
Me
N
N
O
N
O
Me
O
S
NH2
N
S
NO2
N
S
Br
NHAc
N3
H
(E)-8
(E)-9
6
(E)-7a
Figure 2
RESULTS AND DISCUSSION
The title compounds (3–5) are imidazo[4,5-b]pyridines, and there is a possibility to synthesize them via
either of two condensation pathways; namely, the direct Friedländer condensation (Scheme 3) or the
stepwise condensation (Scheme 4 and 5) where the starting material has an amine equivalent rather than
the amine required for the direct condensation.
Traditionally, the Friedländer reaction14 has been used in quinoline synthesis, reacting an ortho-
aminocarbaldehyde with a carbonyl compound having an active methylene group. Recently some studies
on the mechanism of this reaction has been published.15 Often the Friedländer reaction is catalyzed with
an acid or base, but the neutral conditions are used since creatinine is sensitive to mineral acids.16 In the
stepwise condensation, compounds such as 7a were synthesized at first, and after reduction of the nitro
group, the compounds should be cyclizable to the desired compounds.

HETEROCYCLES, Vol. 65, No. 10, 2005
2371
The starting materials (10, 11 and 13, Scheme 1) and (17, Scheme 2) for these reactions were synthesized
according to the literature with a few modifications. Compound (10) was synthesized according to
Mąkosza.17 Vicarious nucleophilic substitution (VNS) on 2-nitrothiophene yielded 3-dichloromethyl-2-
nitrothiophene17-19 which was hydrolyzed in an aqueous solution of formic acid to afford the
carbaldehyde (10) in 80% yield.
CHO
CHO
i
70%
NO2
NH2
S
S
10
11
S
S
CHO
N3
ii
CHO
NH2
86%
13
12
Scheme 1. i. Fe/AcOH, 75 ºC, 30 min; ii. NH4SH, MeOH, rt, 10 min.
2-Amino-3-thiophenecarbaldehyde (11) has been described to be obtained via substitution of the nitro to
azide and then reduction to amino group in 20% yield from 10.20 However, the desired amine was
obtained in 70% yield by warming the nitro compound (10) with iron at 75 ˚C in acetic acid. Compound
(13) was prepared from 3-bromothiophene via 3-bromo-2-thiophenecarbaldehyde21,22 (organometallic
formylation) and 3-azido-2-thiophenecarbaldehyde (12).23,24 The azide was reduced with NH4SH in
methanol25 to provide the amine (13) in 86% yield.
O
O
CHO
Br
CHO
N3
O
O
i
ii-iv
v
S
S
S
S
68%
57%
72%
Br
N3
14
16
15
17
vi
vi, v
CHO
S
NH2
18
Scheme 2. i. Ethylene glycol, toluene, p-toluenesulfonic acid, Dean and Stark overnight; ii. n-BuLi, ether, –78 ˚C, 30
min.; iii, Tosyl azide, –78 ˚C, 5 h; iv. Na4P2O7/H2O, rt, overnight; v. 2M HCl, rt, overnight; vi. 40% NH4SH, MeOH, rt,
45 min.
To obtain 3-amino-4-thiophenecarbaldehyde (18, Scheme 2), the route we used was in analogy with that
of compound (13). The aldehyde (14) was obtained from 3,4-dibromothiophene via organometallic
formylation26 and protected as an acetal to give 15.27 The second organometallic reaction was performed

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HETEROCYCLES, Vol. 65, No. 10, 2005
1
by quenching with tosyl azide to give 16.28 The H-NMR showed, apart from the expected coupling
between H-2 and H-5, also a long range coupling between H-2 and H-2' explained by the favourable zig-
zag arrangement of these protons. Hydrolysis of 16 gave 1728 but the reduction of the azide (17) to the
amine (18) was unsuccessful. In addition, the reduction of the protected 16 gave the amine, 3-amino-4-
thiophenecarbaldehyde ethylene acetal, but the hydrolysis of the acetal failed to give the desired product
(18).
We have previously investigated the reaction of the four possible isomers of the vicinal
aminopyridinecarbaldehyde with creatinine (19, Figure 3) and its isomer, 2-amino-1-methyl-2-
imidazolin-5-one (isocreatinine, 20) in ethylene glycol4,7 and also 2-aminobenzaldehyde with creatinine
in ethylene glycol.5
Me
N
N
N
Me
20
N
N
NH2
NH2
NH2
N
N
H
O
O
OH
Me
19
21
Figure 3
By using the two compounds (19 and 20), the isomers with the N-methyl groups pointing in opposite
directions, could be obtained exclusively. The 2-aminobenzaldehyde afforded only the alcohol (21) when
treated with isocreatinine in the Friedländer reaction but the π-excessive thiophene compound gave a
complex mixture of products.
CHO
Me
NH2
S
11
N
BSA, 62%
NH2
S
S
N
N
Me
N
3
NH2
S
CHO
N
19
O
Me
N
NH2
BSA, 85%
13
NH2
N
N
4
Scheme 3. Heated at 140 ºC for 2 h.
Attempts to use ethylene glycol or DMF in the Friedländer reaction did not give the desired compounds
for either of the aminothiophenecarbaldehyde (11 or 13). However, by using bis(trimethylsilyl)acetamide
(BSA) as solvent, previously used in our group to synthesize PhIP,6 creatinine was forced into its enol

HETEROCYCLES, Vol. 65, No. 10, 2005
2373
form and the desired compounds (3) and (4) were obtained in 62 and 85% yields, respectively (Scheme 3).
The 2-nitro-3-thiophenecarbaldehyde (10)17-19 was treated with 19 in ethylene glycol and the
condensation reaction resulted in the (E) isomer (25% yield, Scheme 4). Other solvents such as methanol
or DMF did not improve the yield to any extent. When other conditions were applied to 10 (such as the
Perkin conditions,29 sodium acetate in a mixture of acetic anhydride and acetic acid) the acetylated (E)-
isomer [(E)-7b] was obtained in a somewhat higher yield (59%). When these conditions were used on 3-
amino-2-thiophenecarbaldehyde, the diacetylated product [(E)-8] was obtained. When stored in DMSO at
room temperature for one week, the acetylated products ((E)-7b and (E)-8) were isomerized to a ratio of
90/10 and 75/25 (E/Z) respectively. To condense the azide (17) with creatinine, acetic acid was used at a
lower temperature (65 ˚C due to the sensitivity of the azide) and the compound obtained was again the E-
isomer. To be able to diffrentiate between the (E)- and the (Z)-isomers NOE diff. nmr experiments were
performed and it was obvious from the NOE coupling between the N-methyl and the α-H that the isomer
obtained was the E-isomer.
NHR
CHO
RHN
Me
N
N
Me
N
O
N
NO2
O
S
a. R=H (25%)
b. R=Ac (59%)
+
10
i or ii
NO2
NO2
S
S
(E)-7
(Z)-7
AcHN
S
NHAc
2
CHO
N
N
Me
O
S
N
N
1
Me
N
Me
NH2
O
S
α
13
5'
+
NH2
4'
ii, 58%
N
O
NHAc
(E)-8
NHAc
19
(Z)-8
NH2
N
H2N
CHO
N
N
O
S
Me
N
Me
S
N3
O
S
17
iii, 40%
+
N3
N3
(E)-9
(Z)-9
Scheme 4. i. Ethylene glycol, 140 ºC for 1.5 h; ii. NaOAc, AcOH, Ac2O, 140 ºC for 20 min; iii. AcOH, 65 ºC,
overnight

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HETEROCYCLES, Vol. 65, No. 10, 2005
The reduction of the nitro group in 7a proceeded smoothly in ethanol with 10% Pd/C under H2 at 50 psi,
without reducing the double bond to give 2230 (Scheme 5), and the azide in 9 was reduced similarly at
ambient pressure to afford 24.31 The diacetyl compound (8) was deacetylated completely giving 2332 in
concentrated H2SO4 at 50 ˚C and attempts were made to cyclize these three compounds. Cyclisation in
methanol, ethylene glycol with molecular sieves, or in ortho-xylene with a Dean and Stark trap did not
give the desired cyclized product. Cyclisation of 23 to 4 was successful in refluxing acetic acid but
neither 3 nor 5 could be obtained from cyclisation of 22 and 24.
NH2
N
NH2
N
N
N
Me
N
Me
Me
iv
i
O
O
NH2
60%
S
S
N
N
3
NO2
NH2
S
S
22
7a
NH2
Me
NHAc
Me
N
N
Me
O
O
N
N
N
iv
38%
ii
NH2
S
S
15%
N
N
4
NH2
NHAc
23
8
NH2
N
NH2
N
N
N
Me
Me
Me
O
S
O
S
N
iv
iii
63%
S
NH2
N
N
NH2
N3
5
24
9
Scheme 5. i. EtOH, Pd/C (10%), H2, 3.4 atm, overnight; ii. conc. H2SO4, 50 ºC, 30 min.; iii. EtOH, Pd/C (10%), H2, 1
atm, rt, overnight; iv. AcOH, mol. sieves, reflux overnight
In conclusion, three new thenylideneimidazolinone (7–9) were synthesized and attempts were made to
cyclize these to the corresponding imidazo[4,5-b]pyridines (3–5), but only 4 was obtained. Compounds (3
and 4) are new compounds and 3 has a new ring system. These (3 and 4) were obtained in good yields by
treating the ortho-aminocarbaldehydes (11 and 13) with the enolic silyl ether of creatinine.
EXPERIMENTAL
All chemicals and solvents were of analytical grade and used as purchased. Evaporations were performed
at reduced pressure below 40 °C. The reactions and purifications were monitored by TLC (UV detection)

HETEROCYCLES, Vol. 65, No. 10, 2005
2375
on aluminium sheets coated with silica gel 60 F254 (Merck). Flash chromatography (FC) was performed
on silica gel (63–200 µ, J.T. Baker). Melting points were taken using a Büchi Melting Point B-545
instrument and are uncorrected. IR spectra (neat) were recorded on an Avatar 330 FT-IR Termo Nicolet.
13
NMR spectra were recorded on a Bruker DPX 300 spectrometer (1H: 300 MHz, C: 75 MHz) at 25 °C,
unless otherwise stated, and referenced to the solvent [DMSO-d6 2.50, 39.5 and CDCl3 7.26, 77.0]. The
coupling constants are reported in Hz. HMBC, HMQC, NOE diff. and decoupled 13C-NMR spectra were
used for the assignments. In assigning 7a, 7b, 8, 9 the numbering in Scheme 4 is used. MS spectra were
obtained on a Micromass Platform instrument using EI ionization (direct insertion at 70 eV). For
81
compounds containing bromine the Br peak is reported. 3-Bromothiophene and 3,4-dibromothiophene
were commercially available. 2-Nitro-3-thiophenecarbaldehyde (10)17-19,33 was prepared from 3-
dichloromethyl-2-nitrothiophene (4.0 g, 18.9 mmol) as described18 in 80% yield. 3-Bromo-2-
thiophenecarbaldehyde21,22 was prepared from 3-bromothiophene (6.0 g, 36.8 mmol) as described21 in
70% yield.
The condensation reaction in bis(trimethylsilyl)acetamide - general procedure
Creatinine (1.3 g, 12.0 mmol) and the appropriate aminocarbaldehyde (4.0 mmol) were heated in
bis(trimethylsilyl)acetamide (BSA) (3.0 mL, 12 mmol) at 140 °C for 2 h. After cooling, 1M HCl (20 mL)
was added. The mixture was stirred for 30 min and then the pH was adjusted to 11 with 2M NaOH. The
reaction mixture was poured into water and the precipitate was filtered off.
2-Amino-1-methylimidazo[4,5-b]thieno[3,2-e] pyridine (3)
This compound was obtained from 2-amino-3-thiophenecarbaldehyde (11), using the above method to
yield 3 (0.5 g, 62%). mp 299–302 ºC (MeCN); IR ν 3271, 3091, 1670, 1653, 1578, 1540, 1465, 1445,
1420, 1399, 1249, 1111 cm–1; 1H-NMR (DMSO-d6) δ 7.83 (1H, s, H-8), 7.42 (1H, d, 6.0, H-6), 7.31 (1H,
d, 6.0, H-7), 7.1 (2H, br s, NH2), 3.55 (3H, s, 1-Me); 13C-NMR (DMSO-d6) δ 158.8 (C-2), 156.3 (C-3a),
153.9 (C-4a), 127.0 (C-8a), 124.5 (C-7a), 122.0 (C-7), 121.1 (C-6), 107.9 (C-8), 28.5 (1-Me); MS m/z
204 (M, 100%), 203 (53), 188 (7), 176 (20); Anal. Calcd for C9H8N4S: C, 52.92; H, 3.95; N, 27.43.
Found: C, 53.10; H, 3.86; N, 27.33.
2-Amino-1-methylimidazo[4,5-b]thieno[2,3-e] pyridine (4)
Method 1: This compound was obtained from 3-amino-2-thiophenecarbaldehyde (13), using the above
method to yield 4 (0.7 g, 85%).
Method 2: Compound (4) was also obtained by refluxing 23 (20 mg, 0.09 mmol) in AcOH (3 mL)
overnight in the presence of molecular sieves (7 mg, 38%).
1
mp 298–301 ºC (MeCN); IR ν 3270, 3087, 3069, 1668, 1580, 1538, 1465, 1420, 1407, 1255 cm–1; H-
NMR (DMSO-d6) δ 8.01 (1H, s, H-8), 7.71 (1H, d, 5.5, H-5), 7.35 (1H, d, 5.5, H-6), 7.1 (2H, br s, NH2),

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HETEROCYCLES, Vol. 65, No. 10, 2005
3.55 (3H, s, 1-Me); 13C-NMR (DMSO-d6) δ 158.8 (C-2), 156.4 (C-3a), 149.6 (C-4a), 126.8 (C-8a), 126.0
(C-5), 124.1 (C-6), 123.8 (C-7a), 107.1 (C-8), 28.5 (1-Me); MS m/z 204 (M, 100%), 203 (58), 188 (6),
176 (17); Anal. Calcd for C9H8N4S: C, 52.92; H, 3.95; N, 27.43. Found: C, 53.06; H, 4.05; N, 27.28.
2-Amino-1-methyl-5-[2-(2-nitro-3-thenylidene)]-2-imidazolin-4-one (E-7a)
Compound (10) (330 mg, 2.1 mmol) and 19 (0.3 g, 2.6 mmol) were heated in ethylene glycol (2 mL) at
140 °C for 1.5 h. The reaction mixture was poured on ice water and the precipitate was filtered off and
recrystallized from DMA/2-PrOH to yield E-7a (132 mg, 25%); mp 232–235 ºC (decomp); IR ν 3015,
1
1664, 1634, 1565, 1476, 1350, 1311, 1211, 1067 cm–1; H-NMR (DMSO-d6) δ 8.6 (2H, br s, NH2), 8.10
(1H, d, 5.6, H-4'), 7.86 (1H, d, 5.6, H-5'), 6.76 (1H, s, α-H), 3.21 (3H, s, 1-Me); 13C-NMR (DMSO-d6) δ
173.9 (C-4), 167.2 (C-2), 146.1 (C-2'), 139.0 (C-5), 136.8 (C-3'), 131.5 (C-4'), 130.8 (C-5'), 101.6 (C-α),
28.0 (1-Me); MS, m/z 252 (M, 28%), 206 (52), 109 (100); Anal. Calcd for C9H8N4O3S: C, 42.85; H, 3.20;
N, 22.21. Found: C, 42.77; H, 3.28; N, 22.11.
The condensation reaction under Perkin conditions – General procedure
Creatinine (95 mg, 0.84 mmol) and the appropriate thiophenecarbaldehyde (0.79 mmol) were heated
together with NaOAc (0.31 g, 3.7 mmol) in AcOH (1.0 mL) and Ac2O (0.3 mL) for 20 min to precipitate
an orange solid. After pouring the reaction mixture into water, the orange solid was filtered off.
2-Acetamido-1-methyl-5-[2-(2-nitro-3-thenylidene)]-2-imidazolin-4-one (7b)
This compound was obtained from 2-nitro-3-thiophenecarbaldehyde (10) using the above method to yield
(E)-7b (137 mg, 59%). mp 267–268 ºC (MeCN); IR ν 3283, 3151, 3112, 3074, 1739, 1630, 1568, 1353,
1309, 1261, 1123, 1070, 999 cm–1; 1H-NMR (DMSO-d6 at 80 ºC) δ 11.3 (1H, br s, NH), 7.88 (1H, d, 5.5,
H-5'), 7.75 (1H, d, 5.5, H-4'), 6.94 (1H, s, α-H), 3.26 (3H, s, 1-Me), 2.15 (3H, s, 2-Me); 13C-NMR
(DMSO-d6 at 80 ºC) δ 181.4 (2-CO), 162.3 (C-4), 150.5 (C-2), 147.4 (C-2'), 134.8 (C-3'), 132.5 (C-5),
130.7 (C-4' or C-5'), 130.6 (C-5' or C-4'), 105.4 (C-α), 27.2 (1-Me), 27.1 (2-Me); MS m/z 294 (M, 15%),
279 (4), 248 (45), 235 (61), 206 (89), 153 (41), 109 (100); When stored in DMSO for one week the
product isomerised to a ratio of 90/10 (E/Z). (Z)-7b 1H-NMR (DMSO-d6 at 80 ºC) δ 11.3 (1H, br s, NH),
8.03 (1H, d, 5.5), 7.32 (1H, d, 5.6), 6.85 (1H, s, α-H), 2.97 (3H, s, 1-Me), 2.14 (3H, s, 2-Me); Anal. Calcd
for C11H10N4O4S: C, 44.90; H, 3.43; N, 19.04. Found: C, 44.73; H, 3.35; N, 19.10.
2-Acetamido-5-[2-(3-acetamido-2-thenylidene)]-1-methyl-2-imidazolin-4-one (8)
This compound was obtained from 3-amino-2-thiophenecarbaldehyde (13), using the above method to
yield (E)-8 (140 mg, 58%); mp 291–292 ºC (decomp) (MeCN); IR ν 3160, 3084, 1731, 1650, 1623, 1577,
1
1353, 1331, 1275, 1234, 1113, 1071, 1016, 983 cm–1; H-NMR (DMSO-d6) δ 11.4 (1H, br s, NH), 10.0
(1H, s, NH'), 7.63 (1H, d, 5.5, H-5'), 7.42 (1H, d, 5.5, H-4'), 6.79 (1H, s, α-H), 3.30 (3H, s, 1-Me), 2.11
13
(3H, s, 3'-Me), 2.10 (3H, s, 2-Me); C-NMR (DMSO-d6) δ 181.1 (2-CO), 168.2 (3'-CO), 161.9 (C-4),

HETEROCYCLES, Vol. 65, No. 10, 2005
2377
151.2 (C-2), 140.0 (C-3'), 128.6 (C-5'), 124.0 (C-5), 123.9 (C-4'), 120.7 (C-2'), 109.0 (C-α), 27.7 (2- or 1-
Me), 27.4 (1- or 2-Me), 23.4 (3'-Me); MS m/z 306 (M, 100%), 291 (4), 264 (42), 247 (86), 205 (82);
1
When stored in DMSO for one week the product isomerised to a ratio of 75/25 (E/Z). (Z)-8 H-NMR
(DMSO-d6) δ 11.4 (1H, br s, NH), 9.8 (1H, s, NH'), 7.67 (1H, d, 5.4), 7.49 (1H, d, 5.4), 6.75 (1H, s, α-H),
3.15 (3H, s, 1-Me), 2.10 (3H, s, Ac), 2.05 (3H, s, Ac); Anal. Calcd for C13H14N4O3S: C, 50.97; H, 4.61; N,
18.29. Found: C, 51.12; H, 4.81; N, 18.07.
2-Amino-5-[2-(4-azido-3-thenylidene)]-1-methyl-2-imidazolin-4-one (E-9)
Compound (17) (100 mg, 0.65 mmol) and 19 (220 mg, 2.0 mmol) were dissolved in AcOH (3 mL) and
the solution was heated at 65 ºC and left overnight. Evaporation in vacuo and FC (CHCl3 to CHCl3-
MeOH 4:1) yielded a yellow solid (64 mg, 40 %); mp 178 ºC (decomp) (CHCl3/MeOH); IR ν 3315, 3106,
1
2969, 2116, 2093, 1693, 1668, 1631, 1548, 1501, 1355, 1258, 1233 cm–1; H-NMR (DMSO-d6) δ 9.14
(1H, d, 3.2, H-2'), 7.9 (2H, br s, NH2), 7.40 (1H, d, 3.2, H-5'), 5.86 (1H, s, α-H), 3.15 (3H, s, 1-Me); 13C-
NMR (DMSO-d6) δ 174.9 (C-4), 166.2 (C-2), 136.2 (C-3'), 135.5 (C-5), 127.0 (C-2'), 126.5 (C-4'), 110.1
(C-5'), 101.2 (C-α), 21.1 (1-Me); MS (ES+) m/z 249 (M+H, 97), 221 (100), 206 (51). Anal. Calcd for
C9H8N6OS: C, 43.54; H, 3.25; N, 33.85. Found: C, 43.37; H, 3.18; N, 33.95.
2-Amino-3-thiophenecarbaldehyde (11)20
A mixture of 10 (1.1 g, 7.0 mmol) and 1.4 g of iron powder in AcOH (700 mL ) was heated at 75 ºC for
30 min. After cooling, the solvent was evaporated and the residue partitioned between EtOAc and sat.
NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in
vacuo. The residue was filtered through a plug of silica and gave a dark red oil (620 mg, 70%). 1H-NMR
13
(DMSO-d6) δ 9.58 (1H, CHO), 8.0 (2H, br s, NH2), 6.89 (1H, d, 5.8, H-4), 6.28 (1H, d, 5.8, H-5); C-
NMR (DMSO-d6) δ 183.5 (CHO), 165.6 (C-2), 125.7 (C-4), 116.1 (C-3), 107.5 (C-5).
3-Azido-2-thiophenecarbaldehyde (12)23,24,28,34
3-Bromo-2-thiophenecarbaldehyde (4.0 g, 21.0 mmol) was dissolved in DMPU (50 mL), and NaN3 (5.5 g,
84.0 mmol) was added portionwise under argon at ambient temperature. The reaction was warmed at 35
°C for 24 h, poured onto ice water and extracted with ether. The organic layer was washed with brine and
dried (MgSO4). Evaporation in vacuo and FC (CHCl3) of the residue gave 12 (2.6 g, 81%); mp 56–58 ºC
(MeOH) (lit.,23 56.6–57.2 ºC (MeOH), lit.,24 57–58 ºC, lit.,28 57–58 ºC, lit.,34 55 ºC) IR ν 3275, 3103,
1
3075, 2110, 1640, 1525, 1428, 1388, 1356, 1279, 1226 cm–1; H-NMR was in agreement with published
data.23 13C-NMR (CDCl3) δ 180.2 (CHO), 144.9 (C-3), 135.2 (C-5), 127.6 (C-2), 120.6 (C-4); MS m/z
153 (M, 12%), 125 (58), 97 (87), 70 (100).
3-Amino-2-thiophenecarbaldehyde (13)23,35

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HETEROCYCLES, Vol. 65, No. 10, 2005
Compound (12) (3.25 g, 21.0 mmol) was dissolved in MeOH (150 mL) and 40% NH4SH (3.3 mL, 26.0
mmol) was added dropwise. TLC (CHCl3/MeOH, 8:1) showed completion of the reaction after 10 min at
rt while the gas evolution had ceased. The reaction mixture was evaporated in vacuo and FC (CHCl3) of
the residue provided 13 (2.3 g, 86%). mp 66–68 ºC (EtOH/H2O), (lit.,23 68–70 ºC (EtOH/H2O), lit.,35 67
ºC (petroleum ether)) IR ν 3398, 3252, 3171, 2835, 1606, 1499, 1455, 1420, 1385, 1298, 1238, 1081 cm–
1
1; H-NMR (CDCl3) δ 9.53 (1H, d, 0.6, CHO), 7.44 (1H, d, 5.3, H-5), 6.51 (1H, dd, 5.3, 0.6, H-4), 6.1
13
(2H, br s, NH2); C-NMR (CDCl3) δ 182.4 (CHO), 154.3 (C-3), 136.2 (C-5), 119.6 (C-4), 113.2 (C-2);
MS m/z 127 (M, 100%), 126 (21), 99 (39), 98 (21), 72 (28).
3-Bromo-4-thiophenecarbaldehyde (14)26,36
This compound was prepared from 3,4-dibromothiophene (4.0 g, 16.5 mmol) as described26 to yield 14
(1.85 g, 59%). IR ν 3103, 2853, 2792, 1681, 1490, 1408, 1154, 1002, 803, 746 cm–1; 1H-NMR (CDCl3) δ
13
9.94 (1H, s, CHO), 8.15 (1H, d, 3.5, H-2), 7.36 (1H, d, 3.5, H-5); C-NMR (CDCl3) δ 184.6 (CHO),
137.5 (C-3), 134.6 (C-2), 125.0 (C-5), 111.3 (C-4); MS, m/z 192 (M, 88%), 191 (100), 163 (7).
3-Bromo-4-thiophenecarbaldehyde ethylene acetal (15)27
This compound was prepared from 14 (1.55 g, 8.1 mmol) as described27 to yield 15 (1.3 g, 68%). IR ν
3108, 2953, 2885, 1528, 1326, 1094, 1000, 962, 937, 804 cm–1; 1H-NMR (CDCl3) δ 7.47 (1H, d, 3.5, H-
2), 7.28 (1H, d, 3.5, H-5), 5.90 (1H, s, H-2'), 3.94 (4H, m, H-4' and H-5'); 13C-NMR (CDCl3) δ 137.8 (C-
3), 124.9 (C-2), 124.2 (C-5), 109.6 (C-4), 99.8 (C-2'), 65.2 (C-4' and C-5'); MS, m/z 236 (M, 93%), 235
(100).
3-Azido-4-thiophenecarbaldehyde ethylene acetal (16)28
This compound was prepared from 15 (1.0 g, 4.3 mmol) as described28 to yield 16 (480 mg, 57%); IR ν
3096, 2946, 2886, 2112, 1687, 1519, 1435, 1365, 1257, 1108 cm–1; 1H-NMR (CDCl3) δ 7.42 (1H, dd, 3.4,
0.6, H-2), 6.86 (1H, d, 3.4, H-5) 5.78 (1H, d, 0.6, H-2') 4.05 (4H, m, H-4' and H-5'); 13C-NMR (CDCl3) δ
136.0 (C-4), 132.1 (C-3), 125.1 (C-2), 110.8 (C-5), 98.5 (C-2'), 65.1 (C-4' and C-5').
3-Azido-4-thiophenecarbaldehyde (17)28
This compound was prepared from 16 (480 mg, 2.4 mmol) as described28 to yield 17 (264 mg, 72%); mp:
45–47 ºC (MeOH) (lit.,28 50–52 ºC); IR ν 3085, 2120, 1674, 1508, 1431, 1422, 1370, 1260, 1163, 825,
1
13
709 cm–1; H-NMR (CDCl3) δ 9.82 (1H, s, CHO), 8.09 (1H, d, 3.4, H-2), 6.93 (1H, d, 3.4, H-5); C-
NMR (CDCl3) δ 183.3 (CHO), 138.2 (C-4), 135.5 (C-2), 133.3 (C-3), 111.6 (C-5).
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