Synthesis of novel 2-aminoimidazo[4,5-b]pyridines, including the thieno analogue of the cooked-food mutagen IFP

Article abstract of DOI:10.1002/jhet.5570430116

Eight new compounds, including three new ring systems obtained via the Friedlunder condensation of ortto-aminothiophenecarbaldehydes 11, 21 and 24 with creatinine (8), are reported. The condensation afforded 1, which is the thieno analogue of the cooked-food mutagen IFP (2-amino-1,6-dimethylfuro[2,3-e] imidazo[4,5-b]pyridine), and the benzothieno[2,3-e]- and benzothieno[3,2-e] imidazo[4,5-b]pyridines 2 and 3. Attempts to condense 11 with isocreatinine (12) were unsuccesful. Desulfurization of 3 gave the known cooked-food carcinogen PhIP, The 2-nitro (4) and 2-hydroxy (5) derivatives of 3 are reported. The related 2-amino-1-methyl-imidazo[4,5-b]benzothiophene (25) was synthesized by a different route. Fully assigned ¹H and ¹³C nmr data of all new compounds are reported.

Full text of DOI:10.1002/jhet.5570430116

Synthesis of Novel 2-Aminoimidazo[4,5-b]pyridines, Including the
Thieno Analogue of the Cooked-food Mutagen IFP
Malin Björk and Spiros Grivas*
Jan-Feb 2006
101
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
Received June 10, 2005
Eight new compounds, including three new ring systems obtained via the Friedländer condensation of
ortho-aminothiophenecarbaldehydes 11, 21 and 24 with creatinine (8), are reported. The condensation
afforded 1, which is the thieno analogue of the cooked-food mutagen IFP (2-amino-1,6-dimethylfuro[2,3-
e]imidazo[4,5-b]pyridine), and the benzothieno[2,3-e]- and benzothieno[3,2-e]imidazo[4,5-b]pyridines 2
and 3. Attempts to condense 11 with isocreatinine (12) were unsuccesful. Desulfurization of 3 gave the
known cooked-food carcinogen PhIP. The 2-nitro (4) and 2-hydroxy (5) derivatives of 3 are reported. The
related 2-amino-1-methyl-imidazo[4,5-b]benzothiophene (25) was synthesized by a different route. Fully
1
13
assigned H and C nmr data of all new compounds are reported.
J. Heterocyclic Chem., 43, 101 (2006).
Introduction.
The imidazo[4,5-b]pyridine scaffold, which is a
bioisosteric analogue of purine, appears to be important
in molecules with pharmacological activities such as
angiotensin II receptor antagonist [1], thromboxane
A /prostaglandin H receptor antagonist [2], tuberculo-
2
2
static [3], inhibitors of leukotriene A hydrolase [4] and
4
anti HIV-1 [5]. The 2-aminoimidazole moiety is found in
molecules isolated from natural products such as marine
sponges and exhibit, for example, histamine receptor
antagonist activity [6], antimicrobial [7] and anticancer
activities [8]. Interestingly, several 2-aminoimidazo[4,5-
b]pyridines have been shown to be highly mutagenic and
carcinogenic and some of these are formed together with
other heterocyclic amines during the cooking of foods
[9]. In connection with our previous studies [10,11], and
for the ongoing studies on the quantitative structure
activity relationships (QSAR) additional compounds
containing the imidazopyridine core were needed. Based
on our model reaction systems where creatinine, reducing
sugars and amino acids were heated together in order to
form such 2-aminoimidazoheterocycles [12], IFP
(Figure 1) was recently isolated by heating such a reac-
tion system [13]. The mutagenic IFP was first isolated in
cooked meats [14].
Figure 1
Several other 2-aminoimidazo-heterocyclic amines
related to the cooked-food mutagens have been described
by our group [15–18] and others [19–21]. These hetero-
cyclic amines are promutagenic and the species responsi-
ble for their mutagenicity is believed to be the nitrenium
ion due to its high reactivity [22].
In the present article we report the sulfur analogue of
IFP, 2-amino-1,6-dimethylthieno[2,3-e]imidazo[4,5-b]-
pyridine (1, Figure 1) and the related substances 2-5. We

102
M. Björk and S. Grivas
Vol. 43
Scheme 1
envisioned that, in addition to the direct interest for com-
pound 3, it could also serve as precursor of PhIP after
removal of the sulfur atom and thus provide a new straight-
forward synthesis to PhIP.
Results and Discussion.
The Friedländer reaction [23], studies on the mechanism of
which were recently reported [24], have previously been used
by our group to obtain the related imidazo-quinoline [18] 6
(Figure 2) and -naphthyridines such as 7a-c [17,25] that are
analogous to the IFP sulfur analogue 1, by simply heating
creatinine (8, Scheme 2) or isocreatinine (12, Scheme 2) with
an appropriate ortho-aminocarbaldehyde in ethylene glycol
instead of using typical Friedländer conditions.
Reagents and Conditions: i. n-BuLi, THF, –78 ºC ii. DMF iii. NaN ,
3
DMPU, 35 ºC, overnight iv. 40% NH SH, MeOH, r.t., 10 min.
4
For the reduction of the azide 10 to amine 11 we found
the use of commercial 40% ammonium sulfide (NH SH)
4
[36] advantageous compared to the highly poisonous
hydrogen sulfide (H S) gas [35] or the expensive
2
bis(trimethylsilyl)sulfide [37]. For compound 11 we report
the NMR-data obtained at 60 ºC in order to reduce the
effect of the strong intramolecular hydrogen bonding, due
to which both the formyl and the amino group gave two
very broad signals each. Similarly, strong hydrogen bond-
ing was also present in the benzothiophene analogue 24
(Scheme 4) described later. The amine 11 was treated with
creatinine (8, Scheme 2) in BSA to yield 1 in 45% yield.
Heating 11 with isocreatinine [38] (12, Scheme 2) did not
afford the expected 13 but a complex reaction mixture.
Several solvents (ethylene glycol, dimethylformamide,
Figure 2
Several other procedures have been described [23] for the
Friedländer reaction, including bismuth triflates catalysis
[26], solid state synthesis [27], tin chloride/zinc chloride con-
ditions on the ortho-nitrocarbaldehyde [28] and microwave
conditions [29]. In analogy with previous work [30], we
found that it was necessary to transform creatinine to its eno-
lic silyl ether with bis(trimethylsilyl)acetamide (BSA) for
our condensation with the thiophene ortho-aminocarbalde-
hyde 11 (Scheme 1) and the benzothiophene analogues 21
and 24 (Scheme 4) used in this work. The required 11, 21 and
24 for our Friedländer reactions were obtained according to
reported procedures with some modifications. The synthesis
of the novel compounds 3-azido-5-methyl-2-thiophenecar-
baldehyde (10) and 3-amino-5-methyl-2-thiophene-car-
baldehyde (11) from 2-bromo-5-methylthiophene is pre-
sented in Scheme 1. The first step, a halogen dance [31],
required pure and dry starting materials to give the product 9
[31–33] in good yields. The bromine of 9 was then substi-
Scheme 2
tuted for an azide by treatment with sodium azide (NaN ) to
3
give 10. Hexamethylphosphoramide (HMPA) [34] or
dimethylsulfoxide (DMSO) [35] have previously been used
for the formation of 3-azido-2-thiophenecarbaldehyde from
the corresponding 3-bromo compound. In our hands, treat-
ment of 9 with NaN in DMSO gave a complex mixture of
3
products. However, in 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) lower temperatures could be
employed and a single product was obtained.
Reagents and Conditions: i. CH C[=NSi(CH ) ]OSi(CH ) , 140 °C for 2
hours
3
3 3
3 3

Jan-Feb 2006
Synthesis of Novel 2-Aminoimidazo[4,5-b]pyridines
103
acetic acid, methanol, 1-butanol) and drying reagents
(molecular sieves, acetic anhydride, magnesium sulfate)
were used but the reaction tended to give a complex mix-
ture of products under all of these conditions.
follow a reasonable pattern. The pyridine derivative being
the least electron-rich condensed with isocreatinine giving
the expected imidazonaphthyridines [25] e.g., 7b and 7c
(Figure 2), the benzene analogue 17 formed alcohol 18
(Scheme 3) while the π-excessive thiophene derivative 11
(Scheme 2) gave a complex mixture of products.
Previously, we have treated ortho-aminopyridinecar-
baldehydes with creatinine and isocreatinine in the same
fashion to yield the expected imidazonaphthyridines
[17,25] (e.g. 7a-c, Figure 2). The condensation with
isocreatinine was less efficient compared to that with crea-
tinine. The analogous ortho-aminobenzaldehyde could
easily condense with creatinine to give the corresponding
imidazoquinoline 6 [18] (Figure 2). However, the isomer
16 (Scheme 3) was synthesized stepwise via the condensa-
tion of isocreatinine with ortho-nitrobenzaldehyde (14)
and subsequent reduction and cyclization of the formed
benzylidene-2-imidazolinone 15 by boiling in methanol
with molecular sieves [17, 25]. In the present work, ortho-
aminobenzaldehyde (17 [39]) was treated with isocreati-
nine (12) in ethylene glycol at 80 ºC to produce 16 but led
to an incomplete reaction with the major product formed
being the alcohol 18 (Scheme 3) as indicated by low reso-
lution ms where both the formula mass and the fragmenta-
tion fitted well, by hrms, by ir and by nmr experiments
[40]. Higher reaction temperatures gave complex mixtures
of products. Alcohol 18 could however dehydrate to 16
under the harsh conditions employed during its EI mass
spectrometric analysis. The results of the condensation
with isocreatinine in the ortho-aminocarbaldehyde series
of pyridine, benzene and thiophene obtained here seem to
3
The N-H HMBC experiment gave J correlations
between the N-4 and H-5 and between the N-1 and H-9.
1
The H-NMR spectra of the alcohol 18 and the expected
16 [25] showed mainly two differences. The shifting of the
methyl signal of 18 to higher fields by 1.1 ppm and of the
H-5 of 18 by 0.6 ppm. The C-9 of 18 at 135.2 ppm could
only be observed when the experiment was run at 50 ºC.
The synthesis of the benzothiophene analogues, 2 and 3
(Figure 1) started in both cases with bromination of ben-
zothiophene. 2-Bromobenzothiophene [41–44] was syn-
thesized via organometallic bromination [44] and 3-bro-
mobenzothiophene by electrophilic substitution [45]. 2-
Bromobenzothiophene was treated according to the litera-
ture [46] to introduce the formyl group at C-3 yielding 2-
bromo-3-benzothiophenecarbaldehyde (19, Scheme 4)
[46–49] in 98% yield, in contrast to the reported [46] 34%
yield. Its 3-bromo isomer 22 [50] was obtained by lithia-
tion of 2,3-dibromobenzothiophene and subsequent treat-
ment of the lithio derivative with dimethylformamide in
situ [51]. The two isomeric bromoaldehydes 19 and 22
were then treated with NaN in DMSO [52] to give the
3
corresponding azides 20 [52,53] and 23 [52,53]. The
method has been published [52] for 23 where the substitu-
tion of a nitro group for the azide was compared to the sub-
stitution of the bromine for the azide. The substitution of
the bromine was more efficient and hence it was our
method of choice. By applying the same method on 19,
amine 21 [37,53] was obtained in 91% overall yield via
azide 20 [53].
Scheme 3
Scheme 4
Reagents and Conditions: i. AcOH, 100 ºC, 1 hour [25] ii. MeOH/EtOAc,
Raney nickel, H , ambient conditions, 15 min. iii. MeOH, molecular
2
sieves (3Å), reflux overnight iv. Water, FeSO , HCl, NH v. ethylene gly-
Reagents and Conditions: i. NaN , DMSO, r.t., 45 min. ii. 40% NH SH,
4
3
3
4
col, 80 ºC, 2 hours
MeOH, r.t. 10 min. 91% (two steps)

104
M. Björk and S. Grivas
Vol. 43
The azide 20 is isolable but light sensitive and thus
preferable to suspend it in methanol immediately and treat
The synthesis of the cooked-food carcinogen PhIP, its
precursors, labelled analogues and possible metabolites
has been, and still is, the object of extensive research for
analytical and biomedical studies carried out by our group
[16,30,54] and others [19,55–57]. A number of various
synthetic approaches towards PhIP have been reported
[21,58]. Some of these include Suzuki coupling of bro-
mopyridines with boronic acids [16,19], thermal electro-
cyclic ring closure of an isocyanate [56], a photochemical
transformation [59], and the Friedländer condensation
between 3-amino-2-phenylacrolein and the in situ formed
enolic silyl ether of creatinine [30]. In yet another way to
PhIP we envisioned the efficiently obtained 3 as a possible
starting material. Indeed, reductive desulfurization of 3 by
Raney nickel catalyst in refluxing ethanol-dioxane (1:1) or
Raney nickel alloy (50:50 Al-Ni)[60] in refluxing dioxane-
ethanol-0.2 M NaOH (1:1:0.5) afforded PhIP in the mod-
est yields of 25–35% (Scheme 6). Further, crucial for the
reproducibility of this desulfurization to PhIP was the use
of excess fresh Raney nickel. Removal of sulfur from 3 by
alternative reagents [61], will be the subject of a future
report.
it with 40% NH SH [36] to form amine 21 [37,53]. The
4
same procedure was used for the conversion of the 3-azido
isomer 23 [52,53] to amine 24 [37,53] which was obtained
in 92% overall yield from 22 [30]. The two ortho-
aminobenzothiophenecarbaldehydes 21 and 24 were
treated with creatinine in BSA [30] to give 2 and 3 in
almost quantitative yields (Scheme 5).
Scheme
5
The synthesis of the 2-nitro analogue NO -PhIP (Figure
2
1) from PhIP itself has been described previously [57,62]
and it has been found useful for metabolic and adduct for-
mation studies with biomolecules [62,63]. In connection to
that we treated compound 3 with sodium nitrite in acetic
acid-water according to the published procedure [64] to
yield the nitro derivative 4 in moderate yields (Scheme 6).
A short reaction time yielded 4 as the major product while
longer reaction times gave us 2-hydroxy-1-methylbenzoth-
ieno[3,2-e]imidazo[4,5-b]pyridine (5) which is an interest-
ing isoster of 3. Compound 5 could also be obtained by
heating 4 in dimethylformamide and water where 5 precip-
itated from the reaction mixture in 36% yield.
Reagents and Conditions: i. CH C[=NSi(CH ) ]OSi(CH ) , 140 °C for 2
hours
3
3 3
3 3
Scheme
6
Finally, in this series of the compounds reported here it
was also of interest to prepare 2-aminoimidazo-benzothio-
phene 25 (Scheme 7), which is related to 6 and 7 and to its
bioisoster 26 previously synthesized [65] and tested [11].
Nitration of 3-bromobenzothiophene [66], gave 3-bromo-
2-nitrobenzothiophene [45,67,68] (27, Scheme 7) which
when treated with methylamine [69] in ethanol, resulted in
the desired precursor 28 [69]. The choice of solvent in the
reduction towards the diamine 29 proved to be of impor-
tance. Pd/C and H in acetic acid [69] did not give us a
2
pure product, which in the next step gave low yields of the
target molecule 25. However, by using a 1:1 mixture of
ethanol and ethyl acetate instead of acetic acid the reduc-
tion to 29 was cleaner and subsequent treatment with
cyanogen bromide [70] gave 25 in moderate yields. Only a
few 2-substituted imidazo[4,5-b]benzothiophenes have
been previously reported, including 2-amino derivatives as
Reagents and Conditions: i. NaNO /AcOH/H O, r.t. ii. DMF/H O, 100
ºC, 10 min. iii. EtOH-dioxane, reflux, Raney Ni catalyst or Al-Ni alloy
with 0.2 M NaOH present
2
2
2
potential H -antihistaminic agents [71], but these do not
1
include compound 25.

Jan-Feb 2006
Synthesis of Novel 2-Aminoimidazo[4,5-b]pyridines
105
Scheme 7
General Procedure for the Friedländer Reaction [30] of ortho-
Aminocarbaldehydes 11, 21 and 24 with Creatinine (8).
Creatinine (1.3 g, 11.5 mmol) and the appropriate ortho-
aminocarbaldehyde (4 mmol) were heated in BSA (2.4 g, 12
mmol) at 140 °C for 2 h. After cooling 1 M HCl (20 mL) was
added. The mixture was stirred for 30 minutes and the pH was
adjusted to ~11 with 2 M NaOH. The reaction mixture was
poured in water and the precipitate was collected by filtration to
give 1, 2 and 3 in 45, 98 and 98% yield respectively.
2-Amino-1,6-dimethylimidazo[4,5-b]thieno[2,3-e]pyridine (1).
This compound was obtained as beige needles (ethanol/water),
mp 324–326 ºC; ir: 3279, 3053, 1663, 2911, 2848, 1579, 1556,
–1
1
1527, 1473, 1409, 1314, 1239, 1090, 818 cm
; H nmr
((CD ) SO): δ 7.91 (1H, s, H-8), 7.1 (2H, br s, NH ), 7.05 (1H, s,
3 2
2
13
H-5), 3.52 (3H, s, 1-Me), 2.55 (3H, s, 6-Me); C nmr
((CD ) SO): δ 158.3 (C-2), 155.8 (C-3a), 149.9 (C-4a), 139.4 (C-
3 2
7a), 126.0 (C-8a), 123.6 (C-6), 122.1 (C-5), 107.1 (C-8), 28.5 (1-
Me), 16.3 (6-Me); ms: m/z 218 (M, 100%), 217 (70), 203 (7), 190
(10), 176 (5), 161 (6), 109 (12).
Anal. Calcd. for C H N S: C, 55.0; H, 4.6; N, 25.7. Found:
10 10
4
C, 54.9; H, 4.6; N, 25.6.
2-Amino-1-methylbenzothieno[2,3-e]imidazo[4,5-b]pyridine
(2).
Reagents and Conditions: i. MeNH , EtOH, reflux, 2 h ii. Pd/C, H ,
EtOH/EtOAc 1:1, 200 psi, r.t., 2 h iii. BrCN, MeOH, r.t., overnight, 33%
(two steps)
2
2
This compound was obtained as beige prisms (sublimation),
mp 348–350 ºC; ir: 3462, 3306, 3056, 1653, 1534, 1469, 1416,
–1
1
1303, 757, 726 cm ; H nmr ((CD ) SO): δ 8.29 (1H, m, H-5),
3 2
8.09 (1H, s, H-10), 7.96 (1H, m, H-8), 7.48 (2H, m, H-6, H-7),
13
7.2 (2H, br s, NH ), 3.59 (3H, s, Me); C nmr ((CD ) SO): δ
Concluding Remarks.
2
3 2
158.7 (C-2), 156.0 (C-3a), 143.9 (C-4a), 137.7 (C-8a), 135.2 (C-
4b), 128.2 (C-10a), 126.3 (C-7), 124.4 (C-6), 123.5 (C-9a), 123.1
(C-8), 121.4 (C-5), 107.7 (C-10), 28.6 (Me); ms: m/z 254 (M,
100%), 239 (5), 212 (7), 197 (4), 185 (4), 170 (5).
The three ortho-aminocarbaldehydes 11, 21 and 24 were
treated with the enolic silyl ether of creatinine to give 1,
and two additional new ring systems, 2 and 3. Compound 3
was desulfurized to PhIP and also diazotized and con-
verted into the nitro derivative 4, which in turn could be
transformed to the isosteric 2-hydroxy derivative of 3.
Selective reduction of the nitro group in 28 made it possi-
ble to obtain the novel imidazobenzothiophene 25.
Anal. Calcd. for C H N S: C, 61.4; H, 4.0; N, 22.0. Found:
13 10
4
C, 61.3; H, 3.9; N, 21.9.
2-Amino-1-methylbenzothieno[3,2-e]imidazo[4,5-b]pyridine
(3).
This compound was obtained as beige prisms (sublimation),
mp 346–348 ºC; ir: 3297, 3045, 1650, 1624, 1530, 1470, 1433,
–1
1
1406, 1316, 1112, 940, 776, 720 cm ; H nmr ((CD ) SO): δ
3 2
EXPERIMENTAL
8.37 (1H, s, H-10), 8.22 (1H, d, H-9, 7.1), 7.92 (1H, d, H-6, 7.4),
7.46–7.36 (2H, m, H-7 and H-8), 7.2 (2H, br s, NH ), 3.63 (3H, s,
2
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) on aluminium sheets coated with silica gel 60
F254 (Merck). Flash chromatography (FC) was performed on sil-
ica 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. Nmr spectra were recorded on a Bruker DPX 300 spec-
13
Me); C nmr ((CD ) SO): δ 158.9 (C-2), 157.6 (C-3a or C-4a),
3 2
153.0 (C-4a or C-3a), 135.2 (C-5a), 134.3 (C-9a), 126.9 (C-10a),
125.2 (C-7), 124.5 (C-8), 122.9 (C-6), 120.7 (C-9), 119.9 (C-9b),
107.1 (C-10), 28.7 (Me); ms: m/z 254 (M, 100%), 253 (48), 239
(7), 226 (12), 212 (6), 197 (6), 185 (3).
Anal. Calcd. for C H N S: C, 61.4; H, 4.0; N, 22.0. Found:
13 10
4
C, 61.5; H, 3.8; N, 22.2.
1-Methyl-2-nitrobenzothieno[3,2-e]imidazo[4,5-b]pyridine (4).
1
13
trometer ( H: 300 MHz, C: 75MHz) at 25 °C unless otherwise
stated and referenced to the solvent [(CD ) SO 2.50, 39.5, CDCl
Compound 3 (0.19 g, 0.75 mmol) was treated with sodium
nitrite in aqueous acetic acid as reported for analogous 2-
aminoimidazoquinoxalines [64] to afford 4, which was crystal-
lized from dimethylacetamide/2-propanol to yield 0.13 g (57%),
mp 254–255 ºC; ir: 3037, 2948, 1693, 1546, 1503, 1483, 1447,
3 2
3
7.26, 77.0 and CD OD 3.31, 49.0]. The coupling constants are
3
15
reported in Hz. HMBC, HMQC and N-HMBC experiments
were used for the assignments. Mass spectra were obtained on a
Micromass Platform instrument using electron inpact ionisation
(direct insertion at 70 eV, unless otherwise stated). For com-
–1
1
1404, 1324, 1290, 1243, 881, 779, 768 cm
; H nmr
((CD ) SO): δ 9.40 (1H, s, H-10), 8.49 (1H, m, H-9), 8.09 (1H,
3 2
81
13
pounds containing bromine the Br is reported.
m, H-6), 7.63 (2H, m, H-7 and H-8), 4.28 (3H, s, Me); C nmr

106
M. Björk and S. Grivas
Vol. 43
13
((CD ) SO): δ 159.7 (C-3a or C-4a), 149.9 (C-2), 149.1 (C-4a or
Me, J 0.6); C nmr ((CD ) SO, 60 ºC): δ 179.0 (CHO), 156.0
3 2
3 2
C-3a), 136.8 (C-5a), 132.3 (C-9a), 128.5 (C-7), 128.4 (C-9b),
127.6 (C-10a), 125.5 (C-8), 123.4 (C-6), 122.8 (C-9), 115.0 (C-
10), 34.1 (Me); ms: m/z 284 (M, 70%), 269 (51), 268 (5), 255
(C-3), 150.7 (C-5), 119.2 (C-4), 110.3 (C-2), 15.9 (Me); ms: m/z
141 (M, 100%), 140 (21), 124 (7), 113 (17), 112 (40).
Anal. Calcd. for C H NOS: C, 51.0; H, 5.0; N, 9.9. Found: C,
6
7
(100), 254 (26), 238 (12), 226 (39); hrms: calcd. for
51.1; H, 4.9; N, 9.9.
+
C H N O S (M+H) 285.0447, found 285.0454.
13
9 4 2
2-Bromobenzothiophene [41-43].
2-Hydroxy-1-methylbenzothieno[3,2-e]imidazo[4,5-b]pyridine (5).
2-Bromobenzothiophene was synthesized from benzothio-
phene as published [44] mp 38–40 ºC (distillation) (lit. [42]
41–42 ºC, lit. [43] 46–47 ºC); ir: 3082, 3056, 1502, 1455, 1422,
1174, 1152, 944, 829, 819, 747, 724, 706 cm ; ms: m/z 214 (M,
39%), 133 (30), 106 (13), 93 (23), 89 (100). The H- and C-
nmr data were in good agreement with those reported [41].
Compound 4 (150 mg, 0.5 mmol) was boiled in dimethylfor-
mamide (3 mL) and water (0.5 mL) for 10 min. The crystals
formed after cooling to room temperature were pure 5, 48 mg
(37%), mp >410 ºC; ir: 3024, 2937, 2741, 1692, 1626, 1586,
1464, 1438, 1418, 1224, 1170, 1112, 1057, 719, 703, 691, 609
–1
1
13
–1 1
cm ; H nmr ((CD ) SO): δ 11.8 (1H, br s, OH), 8.37 (1H, s, H-
3 2
2-Bromo-3-benzothiophenecarbaldehyde [46–49] (19).
10), 8.29 (1H, d, H-9, J 7.4), 7.97 (1H, d, H-6, J 7.6), 7.53–7.43
(2H, m, H-8 and H-7), 3.40 (3H, s, Me); C nmr ((CD ) SO): δ
13
This compound was synthesized from 2-bromobenzothio-
phene as described [46] and crystallisation from hexane yielded
19, mp 73–74 ºC (lit. [46] 70 ºC; lit. [47] 73 ºC; lit. [49] 74–76
ºC); ir: 3083, 2835, 2736, 1667, 1495, 1460, 1421, 1379, 1345,
1104, 1044, 749, 729 cm ; C nmr (CDCl ): δ 185.9 (CHO),
138.7 (C-7a), 135.5 (C-3a), 133.4 (C-2), 131.3 (C-3), 126.4 (C-5
3 2
154. 0 (C-2), 151.3 (C-4a), 144.1 (C-3a), 135.4 (C-5a), 133.6 (C-
9a), 126.0 (C-7), 124.8 (C-8), 124.0 (C-10a), 123.0 (C-6), 122.6
(C-9b), 121.4 (C-9), 107.7 (C-10), 26.6 (Me); ms: m/z 256 (48),
255 (M, 100%), 240 (21), 226 (33), 213 (29).
–1 13
3
Anal. Calcd. for C H N OS: C, 61.2; H, 3.5; N, 16.5. Found:
13
9 3
1
C, 61.2; H, 3.5; N, 16.4.
or C-6), 126.1 (C-6 or C-5), 123.8 (C-4), 121.2 (C-7). The H
nmr [47] and ms [48] data were in agreement with those pub-
lished.
3-Bromo-5-methyl-2-thiophenecarbaldehyde [31-33] (9).
This compound was prepared from 2-bromo-5-methylthiophene
[72] (1.0 g, 5.6 mmol) as described [31]. FC (hexane to
hexane/ethyl acetate, 8:1) of the crude product yielded 9, which was
recrystallized from hexane to yield 0.9 g (78%), mp 50–51 ºC (lit.
[31] 45–47 ºC, lit. [32] 30–32 ºC); ir: 3080, 2845, 1650, 1512, 1445,
2-Azido-3-benzothiophenecarbaldehyde [52,53] (20).
A solution of 19 (2.1 g, 8.7 mmol) in dimethylsulfoxide (20 mL)
was treated with sodium azide (2.3 g, 35.4 mmol) under argon at
room temperature. Tlc (chloroform-methanol, 8:1) showed com-
pletion of the reaction after 2 h. The reaction mixture was poured
in water, the precipitate was filtered, and washed with a small
aliquot of cold methanol to give 20, 1.7 g (97%), mp 95–96 ºC
(dec.) (lit. [52] 90–93 ºC, lit. [53] 91–94 ºC (dec.)); ir: 2833, 2748,
2350, 2122, 1800, 1657, 1507, 1461, 1428, 1389, 1364, 1296,
–1
1364, 1325, 1221, 1178, 855, 839, 698, 688 cm ; ms: m/z 206 (65),
1
13
205 (M, 100%), 177 (11), 167 (5), 96 (25). The H- and C-NMR
data were in good agreement with those published [31,32].
3-Azido-5-methyl-2-thiophenecarbaldehyde (10).
–1
1
Compound 9 (1.65 g, 8.0 mmol) was dissolved in DMPU (20
mL), sodium azide (2.1 g, 32.3 mmol) was added in portions
under argon at ambient temperature. The reaction was warmed to
35 °C for 24 hours, poured onto ice-water and extracted with
diethyl ether. The organic layer was washed with brine and dried
(magnesium sulfate). Evaporation in vacuo and FC (chloroform)
of the residue gave 10, which was recrystallized from hexane to
yield 530 mg (39%), mp 70–72 ºC; ir: 3054, 2857, 2110, 1649,
1138, 1046, 751 cm ; H nmr (CDCl ): δ 10.17 (1H, s, CHO),
3
8.55 (1H, d, H-4, J 7.8), 7.69 (1H, d, H-7, J 8.0), 7.49 (1H, t, H-5,
J 7.2), 7.38 (1H, t, H-6, J 7.7); C nmr (CDCl ): δ 182.6 (CHO),
13
3
156.4 (C-2), 135.4 (C-3a), 132.6 (C-7a), 126.7 (C-5 or C-6), 125.7
(C-6 or C-5), 124.5 (C-4), 121.8 (C-3), 121.7 (C-7); ms (20 eV):
m/z 203 (M, 7%), 177 (36), 175 (45) 147 (76), 120 (100).
2-Amino-3-benzothiophenecarbaldehyde [37, 53] (21).
–1
1
1539, 1462, 1379, 1367, 1260, 1236, 814, 695 cm ; H nmr
Compound 20 (1.7 g, 8.5 mmol) was suspended in methanol
(100 mL) and 40% ammonium sulfide (2.2 mL, 17.6 mmol) was
added dropwise. Tlc (chloroform-methanol, 8:1) showed com-
pletion of the reaction after 15 min at room temperature while the
gas evolution had ceased. The reaction mixture was evaporated
in vacuo and FC (chloroform) of the residue gave 21, which after
sublimation yielded 1.4 g (94%), mp 142–144 ºC (lit. [53] 73–77
ºC); ir: 3337, 3230, 3117, 2807, 1610, 1574, 1474, 1459, 1432,
(CDCl ): δ 9.82 (1H, s, CHO), 6.75 (1H, d, H-4, J 0.7) and 2.53
3
13
(3H, d, Me, J 0.7); C nmr (CDCl ): δ 179.7 (CHO), 151.5 (C-
5), 144.9 (C-3), 126.0 (C-2), 119.1(C-4) and 16.8 (Me); ms: m/z
167 (M, 31%), 139 (100), 111 (69), 110 (49), 84 (94).
3
Anal. Calcd. for C H N OS: C, 43.1; H, 3.0; N, 25.1. Found:
6
5 3
C, 43.1; H, 3.0; N, 25.1.
3-Amino-5-methyl-2-thiophenecarbaldehyde (11).
–1
1
1359, 1203, 1066, 742, 720 cm ; H nmr ((CD ) SO): δ 10.02
3 2
Compound 10 (530 mg, 3.2 mmol) was dissolved in methanol
(25 mL) and 40% ammonium sulfide (0.5 mL, 4.0 mmol) was
added dropwise. Tlc (chloroform-methanol, 8:1) showed com-
pletion of the reaction after 10 min at room temperature while the
gas evolution had ceased. The reaction mixture was evaporated
in vacuo and FC (chloroform) of the residue gave 11, which was
recrystallized from hexane-diethyl ether to yield 400 mg (89%),
mp 65–66 ºC; ir: 3416, 3281, 3165, 2794, 2744, 1620, 1586,
(1H, s, CHO), 8.6 (2H, br s, NH ), 7.92 (1H, d, H-4, J 7.7), 7.63
2
(1H, d, H-7, J 7.9), 7.25 (1H, dt, H-5, J 7.4, 0.9), 7.10 (1H, dt, H-
13
6, J 7.6, 0.9); C nmr ((CD ) SO): δ 182.0 (CHO), 167.5 (C-2),
3 2
137.4 (C-3a), 128.4 (C-7a), 125.4 (C-5), 122.3 (C-7 or C-6),
121.9 (C-6 or C-7), 117.7 (C-4), 107.8 (C-3); ms: m/z 177 (M,
71%), 160 (21), 149 (28), 148 (10), 121 (100).
3-Bromo-2-benzothiophenecarbaldehyde [50] (22).
–1
1
1467, 1384, 828, 696 cm ; H nmr ((CD ) SO, 60 ºC): δ 9.53
A 1.6 M solution of buthyl lithium (8.0 mL, 12.8 mmol) in
hexane was added dropwise at –78 ºC to a solution of 2,3-dibro-
3 2
(1H, s, CHO), 6.9 (2H, br s, NH ), 6.37 (1H, s, H-4), 2.37 (3H, d,
2

Jan-Feb 2006
Synthesis of Novel 2-Aminoimidazo[4,5-b]pyridines
107
mobenzothiophene [73] (3.3 g, 11.3 mmol) in diethylether (35
mL). The mixture was stirred for 1 h before dimethylformamide
(0.9 mL, 11.5 mmol) was added, keeping the temperature below
–65 ºC. When the reaction had reached ambient temperature sat-
urated ammonium chloride (20 mL) was added and the mixture
was extracted with diethylether (3 x 20 mL), washed with brine,
dried (sodium sulfate) and evaporated in vacuo. FC (hexane to
hexane-ethyl acetate, 4:1) of the residue yielded 22, which was
recrystallized from acetone to yield 2.5 g (92%), mp 118–119 ºC
(lit. [50] 118–118.5 ºC); ir: 3260, 2825, 1661, 1500, 1304, 1248,
7.54 (1H, d, J 7.7), 7.39 (1H, d, J 7.7), 7.19 (1H, t, J 7.4), 6.98
13
(1H, t, J 7.3), 5.2 (2H, br s), 2.67 (3H, s); C nmr ((CD ) SO): δ
3 2
139.5 (C), 136.9 (C), 128.9 (C), 124.0 (CH), 121.9 (CH), 120.4
(CH), 118.3 (C), 117.7 (CH), 34.9 (CH )] and the mixture was
3
left over night under argon at ambient temperature. The pH of the
mixture was adjusted to ~10 with 28% ammonia solution and was
evaporated in vacuo. FC (chloroform to chloroform-methanol,
8:1) of the residue gave 25, which was recrystallized from
ethanol-water to yield 1.0 g (43 %), mp 267–271 ºC; ir: 3430,
3291, 3113, 3043, 1638, 1539, 1512, 1452, 1421, 1282, 745, 717
–1
1
–1 1
cm ; H nmr ((CD ) SO): δ 7.79 (2H, m, H-5, H-8), 7.31 (1H,
1195, 1158, 919, 808, 760 cm ; H nmr (CDCl ): δ 10.29 (1H, s,
3 2
3
app t, H-7, J 7.6), 7.10 (1H, app t, H-6, J 7.6), 6.2 (2H, br s,
CHO), 8.02 (1H, dd, H-4, J 7.2, 1.9), 7.88 (1H, dd, H-7, J 6.9,
13
13
NH ), 3.75 (3H, s, Me); C nmr ((CD ) SO): δ 155.2 (C-2),
1.3), 7.55 (2H, m, H-5 and H-6); H nmr (CDCl ): δ 184.7
2
3 2
3
139.6 (C-3a), 136.4 (C-4a), 126.1 (C-8a), 124.5 (C-8b), 124.3 (C-
5), 124.2 (C-7), 120.6 (C-6), 116.2 (C-8) and 30.7 (Me); ms: m/z
203 (M, 100%), 188 (13), 175 (9), 161 (33), 148 (12), 134 (32).
Anal. Calcd. for C H N S: C, 59.1; H, 4.5; N, 20.7. Found: C,
(CHO), 140.5 (C-7a), 138.0 (C-3a), 136.5 (C-2), 129.3 (C-7),
126.0 (C-4), 125.0 (C-5 or C-6), 123.4 (C-6 or C-5), 118.8 (C-3);
ms: m/z 242 (M, 5%), 214 (4), 213 (4), 133 (20), 132 (51), 93
(70), 89 (100).
10
9 3
59.1; H, 4.8; N, 20.7.
3-Azido-2-benzothiophenecarbaldehyde [52, 53] (23).
3-Bromo-2-nitrobenzothiophene [45,66–68] (27).
A solution of 22 (2.1 g, 8.7 mmol) in dimethylsulfoxide (20
mL) was treated with sodium azide (2.3 g, 35.4 mmol) under
argon at room temperature. Tlc (chloroform-methanol, 8:1)
showed that the reaction was complete after 45 min. The reaction
mixture was poured in water and the precipitate was filtered and
washed with a small aliquot of cold methanol to yield 23, 1.6 g
(93%), mp 87–88 ºC (lit. [52] 84–86 ºC, lit. [53] 88–90 ºC
(dec.)); ir: 2848, 2243, 2105, 1649, 1595, 1513, 1382, 1358,
Compound 27 was prepared from 3-bromobenzothiophene as
described [66]. Recrystallisation from ethanol yielded 27, mp
160–162 ºC (lit. [45] 160–161 ºC, lit. [66] 164–165 ºC, lit. [67]
162–162.8 ºC); ir: 1590, 1551, 1515, 1482, 1419, 1301, 1331,
–1
1241, 1114, 916, 868, 759, 726 cm ; ms: m/z 259 (M, 36%), 229
1
13
(5), 213 (11), 201 (36), 132 (100), 93 (39). The H- and C-nmr
data were in agreement with those published [68].
–1
1
1235, 1207, 748, 725 cm ; H nmr ((CD ) SO): δ 10.18 (1H, s,
3 2
3-Methylamino-2-nitrobenzothiophene [69] (28).
CHO), 8.07 (1H, d, H-7, J 8.2), 8.01 (1H, d, H-4, J 8.2), 7.64 (1H,
13
Compound 27 (3.4 g, 13.2 mmol) was suspended in ethanol
(65 mL) and heated to reflux with 40% aqueous methylamine
(4.5 mL, 58.0 mmol) being added in portions under the surface of
the reaction mixture. After heating for a total of 2.5 h the mixture
was concentrated to ~35 mL and was allowed to cool. The pre-
cipitate was filtered and washed with cold ethanol to afford 28,
which after recrystallisation from ethanol yielded 2.5 g (91%),
mp 205–206 ºC (lit. [69] 200–202 ºC); ir: 3247, 1607, 1587,
1554, 1503, 1442, 1393, 1339, 1285, 1252, 1174, 1129, 998, 726
t, H-6, J 7.2), 7.54 (1H, t, H-5, J 8.1); C nmr ((CD ) SO): δ
3 2
182.4 (CHO), 139.5 (C-7a), 137.3 (C-3), 133.2 (C-3a), 129.3 (C-
6), 127.8 (C-2), 125.7 (C-5), 124.2 (C-7), 123.0 (C-4); ms: m/z
203 (M, 3%), 175 (47), 146 (100), 103 (68).
3-Amino-2-benzothiophenecarbaldehyde [37,53] (24).
Compound 23 (1.6 g, 8.0 mmol) was suspended in methanol
(100 mL) and 40% ammonium sulfide (2.2 mL, 17.6 mmol) was
added dropwise. Tlc (chloroform-methanol, 8:1) showed comple-
tion of the reaction after 45 min at room temperature while the
gas evolution had ceased. The reaction mixture was evaporated in
vacuo and FC (chloroform) of the residue gave 24, which after
sublimation yielded 1.3 g (91%), mp 127–130 ºC (lit. [53]
118–120 ºC); ir: 3368, 3339, 3205, 1655, 1578, 1554, 1516,
–1
1
cm ; H nmr ((CD ) SO): δ 9.6 (1H, br s, NH), 8.45 (1H, d, H-
3 2
4, J 8.4), 7.92 (1H, d, H-7, J 8.1), 7.68 (1H, dt, H-6, J 8.1, 0.9),
13
7.46 (1H, dt, H-5, J 8.3, 0.9), 3.57 (3H, d, Me, J 5.5); C nmr
((CD ) SO): δ 149.0 (C-3), 138.3 (C-7a), 131.4 (C-6), 128.9 (C-
3 2
3a), 128.2 (C-4), 125.0 (C-5), 123.8 (C-7), 118.7 (C-2), 33.1
–1
1
(Me); ms: m/z 208 (M, 46%), 193 (1), 191 (1), 179 (6), 134 (100).
1472, 1432, 1371, 1317, 1238, 765, 724 cm
; H nmr
((CD ) SO): δ 10.03 (1H, s, CHO), 8.16 (1H, d, J 8.1), 7.83 (1H,
3 2
1
d, J 8.1), 7.7 (2H, br s), 7.53 (1H, t, J 7.2), 7.39 (1H, t, J 7.2); H
REFERENCES AND NOTES
nmr (CD OD): δ 9.7 (1H, br s, CHO), 8.02 (1H, d, H-4, J 8.2),
3
7.75 (1H, d, H-7, J 8.2), 7.53 (1H, dt, H-6, J 7.7, 1.0), 7.39 (1H,
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13
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H
N O (M+H) 217.1090, found
11 13
4
–1
217.1092; ν /cm 3155, 2967, 1642, 1612, 1574, 1527, 1430, 1357,
max
1
1295, 1238; H nmr (CD OD): δ 7.96 (1H, s, H-9), 7.69 (1H, dd, H-8, J
3
7.95, 1.25), 7.55 (1H, ddd, H-6, J 7.93, 7.30, 1.25), 7.38 (1H, d, H-5, J
13
8.55), 7.28 (1H, app. t, H-7, J 7.33), 2.93 (3H, s, Me); C nmr (CD OD):
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