Synthesis and antimycobacterial activities of non-purine analogs of 6-aryl-9-benzylpurines: Imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles

Article abstract of DOI:10.1016/j.bmc.2011.04.023

6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Analogs modified in the six-membered ring (imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The 3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active than their 7-deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both 3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of non-replicating persistence.

Full text of DOI:10.1016/j.bmc.2011.04.023

Bioorganic & Medicinal Chemistry 19 (2011) 3483–3491
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antimycobacterial activities of non-purine analogs
of 6-aryl-9-benzylpurines: Imidazopyridines, pyrrolopyridines,
benzimidazoles, and indoles
Abhijit Datta Khoje a, Colin Charnock b, Baojie Wan c, Scott Franzblau c, Lise-Lotte Gundersen a,
⇑
a Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
b Faculty of Health Sciences, Oslo University College, PO Box 4, St. Olavs plass, N-0130 Oslo, Norway
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2011
Revised 6 April 2011
Accepted 11 April 2011
Available online 20 April 2011
6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium
tuberculosis (Mtb) in vitro. Analogs modified in the six-membered ring (imidazopyridines, pyrrolopyri-
dines, benzimidazoles, and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were
prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported
herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The
3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active
than their 7-deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further
enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both
3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of
non-replicating persistence.
Keywords:
Tuberculosis
Heterocycles
Deazapurines
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
were efficiently reduced to diamines 4 and the latter were reacted
with triethylorthoformate to give the targets 5.
Tuberculosis (TB) claims approximately 2 million deaths pr.
year worldwide and resistance to the drugs in use is a growing
problem. Also agents that reduce the duration and complexity of
the current therapy would have a major impact on the overall cure
rate.1 We have studied 6,9-disubstituted purines as potent inhibi-
tors of Mycobacterium tuberculosis (Mtb) in vitro, for instance com-
pounds 1a and 1b (Fig. 1).2 Lately we have examined several
classes of non-purine analogs, and identified the 7-deazapurines
1c and 1d as even more active antimycobacterials.3e These com-
pounds are highly selective towards Mtb compared to other micro-
organisms, active against several drug resistant strains of Mtb,
generally non-toxic towards mammalian cells, and able to affect
Mtb inside macrophages.2,3 We now report the synthesis and anti-
mycobacterial activities for purine- or 7-deazapurine analogs mod-
ified in the 6-membered ring (general structure, see Fig. 1).
The 3-deazapurine 7 was readily available by a Stille coupling to
introduce the furyl substituent on the previously known structure
65 as shown in Scheme 2.
For the chlorinated 3-deazapurine 12 the pyridine 86 was cho-
sen as the starting point (Scheme 3). The amine 8 was N-alkylated
with p-methoxybenzyl chloride, and the furyl group was intro-
duced by a highly regioselective Stille coupling, where only forma-
tion of a small amount of the difuryl analog was observed. The lasts
steps follows those used in the synthesis of the 1-deazapurines 5
(Scheme 1); reduction of the nitro group followed by reaction of
the diamine with triethylorthoformate to give the bicycle 12. The
regioselective outcome of the Stille coupling was determined by
NOE spectroscopy on the diamine 11 as shown in Scheme 3.
The bicyclic compounds 13 and 14 were attractive starting
materials for the synthesis of the 1,7-dideaza- 17 and 3,7-didea-
zapurines 18, since compounds 13a, 14a, and 14b were commer-
cially available (Scheme 4). Targets 17 and 18 were synthesized
by N-alkylation of the pyrrole nitrogen followed by Pd-catalyzed
cross coupling to introduce the furyl substituent. The 1,7-didea-
zapurine 15a was not reactive under conventional Stille coupling
conditions, but the target 17a was isolated in an excellent
yield when a Suzuki coupling employing the reactive catalyst
[(t-Bu)3P]2Pd was performed. The analog of compound 15b where
Y = Cl (structure not shown) was essentially unreactive under both
The synthesis of 1-deazapurines 5 is shown in Scheme 1.
2-Chloropyridines 24 were reacted with p-methoxybenzylamine
to give compounds 3 in high yields. The reaction on the 2,6-dichlo-
ropyridine 3b was highly regioselective and only minor amounts of
the other possible regioisomer were observed. The nitropyridines 3
⇑
Corresponding author. Tel.: +47 22857019; fax: +47 22855441.
E-mail address: l.l.gundersen@kjemi.uio.no (L.-L. Gundersen).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.04.023

3484
A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
Figure 1. Structures of some of the most active purines and deazapurines 1 as well the general structure of the target compounds described in this study.
Scheme 1. Reagents and conditions: (a) p-MeO–C6H4–CH2NH2, Et3N, n-BuOH (DMF as solvent for 3b); (b) Na2S2O4, K2CO3, MeOH, H2O, for 4a; (c) Raney Ni, NaBH4, MeOH for
4b; (d) CH(OEt3), Ac2O,
D
.
benzimidazoles in Pd-catalyzed cross couplings is reported before,9
and the final Stille coupling to give the target 22 required a reactive
catalyst; [(t-Bu)3P]2Pd.
Finally the indole 25, formally the 1,3,7-trideaza analog of the
purine 1a (Fig. 1) was synthesized by N-alkylation followed by
Stille coupling, from the bromoindole 23 (Scheme 6). Dialkylation
of indoles is not uncommon,10 and also compound 24b was formed
in the alkylation step. Due to the inactivity of the indole 25 as Mtb
inhibitor (see below), no attempt was done to improve the out-
come of the alkylation reaction.
Scheme 2. Reagents and conditions: (a) (2-furyl)SnBu3, Pd(dppf)Cl2, DMF, 90 °C.
2. Biological evaluation
Stille and Suzuki coupling conditions, but the bromide 15b, synthe-
sized by alkylation of 13b,7 could very easily be converted to the
furane 17 by a Stille coupling. The reaction was carried out at
ambient temperature to avoid exchange of both halides. The target
18b was synthesized from compound 16b by a Stille coupling. The
regioselectivity was complete, and proved by the selective NOE
shown in Scheme 4 as well as by HMBC NMR spectroscopy. The
conversion was moderate and 33% of the starting material 16b
was recovered.
The benzimidazole 22 was synthesized from the commercially
available nitrobenzene 19 (Scheme 5). The nitro group was conve-
niently reduced and the diamine 20 gave the benzimidazole 21
upon reaction with triethylorthoformate, but in contrast to similar
reactions on the diaminopyridines 4 (Scheme 1) and 11 (Scheme
3). When the ring forming reaction was performed with triethylor-
thoformate and acetic acid anhydride, the product 21 was contam-
inated with ca. 20% of the corresponding 3-metylbenzimidazole
(structure not shown). Instead the cyclization was carried out in
the presence of p-toluenesulfonic acid.8 Low reactivity of bromo-
The target compounds 5a, 5b, 7, 12, 17a, 17b, 18a, 18b, 22, and
24 were screened for activity against M. tuberculosis H37Rv in the
microplate alamar blue assay (MABA)11 and the MIC values are gi-
ven in Table 1. For compounds displaying substantial activity, cyto-
toxicity towards mammalian cells (VERO cells) was also examined.
The values for the previously synthesized purines and deazapu-
rines 1a–d as well as a general structure of the targets, are shown
in Figure 1. The 1-deazapurines 5a and 5b and the 1,7-dideazapu-
rines 17a and 17b possessed no significant inhibitory activity
against Mtb, indicating that a nitrogen in the purine 1-possition
may be important for binding to the (unknown) target. In contrast
to earlier findings studying purines,2 7-deazapurine3e or pyrimi-
dine3b,3d analogs as antimycobacterials, it is also interesting to note
that this is the first time we observe that a chlorine, in what may
be referred to as the 2-position in the parent purine, does not in-
crease the antimycobacterial activity. The 3-deazapurines 7 and
12, on the other hand, where slightly more active than the parent
purines (compounds 1a and 1b, respectively), indicating that the
Scheme 3. Reagents and conditions: (a) NaH, NaI, p-MeO–C6H4–CH2Cl, THF, 0 °C to rt; (b) (2-furyl)SnBu3, (Ph3P)2PdCl2, DMF; (c) Na2S2O4, K2CO3, MeOH, H2O; (d) CH(OEt)3,
Ac2O,
D
.

A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
3485
Scheme 4. Reagents and conditions: (a) NaH, p-MeO–C6H4–CH2Cl, DMF; (b) (2-furyl)B(OH)2, [(t-Bu)3P]2Pd, KF, dioxane,
17b (rt) and 18b (60 °C); (d) (2-Furyl)SnBu3, (t-Bu3P)2Pd, DMF, 85 °C, for 18a.
D
, for 17a; (c) (2-furyl)SnBu3, (Ph3P)2PdCl2, DMF, for
Scheme 5. Reagents and conditions: (a) Na2S2O4, K2CO3, MeOH, H2O; (b) CH(OEt)3, p-TSA,
D; (c) (2-furyl)SnBu3, [(t-Bu)3P]2Pd, DMF, 85 °C.
Scheme 6. Reagents and conditions: (a) K2CO3, p-MeO–C6H4–CH2Cl, DMF; (b) (2-furyl)SnBu3, (Ph3P)2PdCl2, DMF, 90 °C.
Table 1
Antibacterial activity against M. tuberculosis and cytotoxic activity against VERO cells for compounds 5a, 5b, 7, 12, 17a, 17b, 18a, 18b, 22 and 25
Compd No.
Xa
Aa
Ba
Ca
MIC (MABA) M. tuberculosis
37Rv ( M) [inhib. at 128 (
MIC (LORA) M. tuberculosis
37Rv pFPCA-luxABc
M)
IC50 VERO cells (
[inhib. at 128 (l
l
M)
SI (EC50:MIC)
H
l
l
M)]b
H
(l
M)]d
5a
5b
7
12
17a
17b
18a
18b
22
H
Cl
H
Cl
H
Cl
H
Cl
H
H
CH
CH
N
N
N
CH
CH
N
N
N
N
N
CH
CH
CH
CH
N
63
n.d.e
n.d.
80
48
n.d.
n.d.
28
>128 [53%]
n.d.
n.d.
n.d.
n.d.
>128 [0%]
>128 [30%]
n.d.
n.d.
12
58
n.d.
n.d.
n.d.
>150
>800
n.d.
n.d.
8.6
644
n.d.
n.d.
>128 [37%]
0.84
0.16
N
CH
CH
N
N
CH
CH
44
N
>128 [86%]
1.40
0.090
CH
CH
CH
CH
29
25
CH
>21 [0% at 21
lM]
n.d.
a
b
c
See Figure 1.
MIC rifampicin 0.09
MIC rifampicin 0.97
EC50 hyamine 0.01
Not determined.
l
l
M, MIC isoniazid 0.28
M, MIC isoniazid >128
M).
l
l
M, MIC PA-824 0.44
M, MIC PA-824 3.11
l
l
M.
M.
d
e
lg/mL (ca. 0.03
l
purine N-3 is not involved in binding to target. The toxicity
towards mammalian cells (EC50 VERO cells >128 M) was also
the N-7 nitrogen was removed. This is in accordance with what
we found when we were comparing purines 1a and 1b with the
deazapurines 1c and 1d.3e The benzimidazole 22 and the indole
25 did not exhibit significant antimycobacterial activity compared
with the most active compounds in this series. The results pre-
sented herein and in our recent paper on 7- and 9-deazapurines3e
indicate that the purine N-1 and N-9, but not N-3 and N-7, are
important for binding to the elusive target. However, it must be
l
low for these compounds. In compounds 18 both the purine N-3
and N-7 is changed with CH. These modifications did not result
in an additional improvement of the activity compared to the
corresponding 7-deaza- (1c and 1d), but the activity is slightly in-
creased compared to the 3-deazapurines 7 and 12. Furthermore,
the toxicity towards VERO cells was increased substantially when

3486
A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
stressed that the changes in antimycobacterial activities observed
may also be a result of different uptake or metabolism by the
Mtb cells.
heated at 100 °C for 18 h under N2 and evaporated in vacuo. The
residue was diluted with CH2Cl2 (ca. 10 mL) and evaporated with
small amount of silica gel. The product was purified by flash
chromatography on silica gel eluting with hexane followed by
EtOAc–hexane (1:5) and finally EtOAc–hexane (1:4); yield
435 mg (97%), mp 119–120 °C, yellow solid. 1H NMR (Me2CO-d6,
300 MHz) d 3.75 (s, 3H, CH3), 4.70 (d, J = 5.8 Hz, 2H, CH2), 6.73
(dd, J = 3.5 and 1.7 Hz, 1H, H-4 in furyl), 6.86 (d, J = 8.7 Hz, 2H,
Ar), 6.93–6.96 (m, 3H, NH, H-5 and H-3 in furyl), 7.32 (d,
J = 8.8 Hz, 2H, Ar), 7.73 (dd, J = 1.8 and 0.7 Hz, H-5 in furyl), 8.25
(d, J = 5.1 Hz, H-6); 13C NMR (Me2CO-d6, 75 MHz) d 44.9 (CH2),
55.4 (CH3), 110.8 (C-5), 112.8 (C-2 in furyl), 113.1 (C-4 in furyl),
114.5 (CH in Ar), 129.3 (C-3), 129.7 (CH in Ar), 132.5 (C-4/C-1 in
Ar), 132.8 (C-4/C-1 in Ar), 146.1 (C-5 in furyl), 148.6 (C-2 in furyl),
151.4 (C-2), 151.8 (C-6), 159.8 (C-4 in Ar); MS EI m/z (rel %) 325
(12, M+), 308 (95), 277 (100), 189 (30), 145 (24), 121 (70); HRMS
Found 325.1063, calcd for C17H15N3O4 325.1063.
A sub-population of the Mtb isolate in a state of non-replicating
persistence (NRP). NRP is considered to be an important factor con-
tributing to the long treatment duration (P6 months required).
Hence we investigated if the antimycobacterial purines and non-
purine analogs described herein also could affect Mtb in NRP. Com-
pounds 7, 12, and 18 were thus tested in the low-oxygen-recovery
assay (LORA)12 (Table 1). These substances (except 18b) were all
more active in the LORA assay than the purines and 7-deazapu-
rines (MIC LORA >128 l
M for all compounds 1a-d).3e Unfortu-
nately the activities found are still quite moderate. The most
potent compound in the LORA assay, the 3,7-dideazapurine 18a,
is unfortunately exhibiting the highest toxicity towards VERO cells
among the compounds tested for mammalian cytotoxicity.
Compounds 5a, 5b, 7, 12, 17a, 17b, 18a, 18b, 22, and 25 dis-
played no significant activities against Staphylococcus aureus and
Escherichia coli. The MICs for all compounds were >16
l
g/mL
3.2. 6-Chloro-4-(furan-2-yl)-N-(4-methoxybenzyl)-3-
against both bacteria. There was no visible difference in the growth
responses of the quality control (QC) strains across the range of
dilutions tested. The MICgentamicin value for the quality control
nitropyridin-2-amine (3b)
A mixture of compound 2b (300 mg, 1.16 mmol), 4-methoxy-
benzylamine (0.08 mL, 0.6 mmol) and triethylamine (0.08 mL,
0.6 mmol) in DMF (10 mL) was stirred under N2 at ambient tem-
perature for 24 h and poured in to water (100 mL). The resulting
mixture was extracted with EtOAc (2 Â 50 mL), the combined or-
ganic extracts were washed with brine (50 mL), dried (MgSO4)
and evaporated in vacuo. The residue was diluted with CH2Cl2
(ca. 20 mL) and evaporated with small amount of silica gel. The
product was purified by flash chromatography on silica gel eluting
with hexane followed by CH2Cl2–hexane (1:4) and finally CH2Cl2–
hexane (1:2); yield 183 mg (88%), yellow wax. 1H NMR (MeCN-d3,
300 MHz) d 3.75 (s, 1H, OCH3), 4.57 (d, J = 5.8 Hz, 2H, CH2), 6.59
(dd, J = 3.4 and 1.7 Hz, 1H, H-4 in furyl), 6.85–6.88 (m, 3H, H-5
and CH in Ar), 6.92 (br d, J = 3.5 Hz, 1H, H- 3 in furyl), 7.00 (br s,
1H, NH), 7.28 (d, J = 8.6 Hz, 2H, CH in Ar), 7.62 (br d, J = 0.9 Hz,
1H, H-5 in furyl); 13C NMR (MeCN-d3, 75 MHz) d 45.0 (CH2), 55.8
(OCH3), 110.6 (C-5), 113.3 (C-4 in furyl), 113.9 (C-3 in furyl),
114.7 (CH in Ar), 127.6 (C-3), 129.8 (CH in Ar), 131.7 (C-1 in Ar),
136.5 (C-6), 146.5 (C-5 in furyl), 147.9 (C-2 in furyl), 151.7 (C-2),
152.9 (C-6), 159.9 (C-4 in Ar), the signal from C-4 was hidden;
MS EI m/z (rel %) 359 (1, M+), 344 (18), 311 (44), 223 (15), 179
(19), 121 (100), 77 (12); HRMS Found 359.0663, calcd for
strains of S. aureus and E. coli was 0.5 lg/mL which is within the
acceptable specified range.13 This points towards a selective anti-
mycobacterial mechanism for the 3-deazapurines 7, 12 and 18 as
previously found also for purines2 and 7-deazapurines.3e
3. Experimental
The 1H NMR spectra were recorded at 600 MHz with a Bruker
AVII 600 instrument, at 300 MHz with a Bruker Avance DPX 300
instrument, or at 200 MHz with a Varian Gemini instrument. The
decoupled 13C NMR spectra were recorded at 150, 125, 75 or
50 MHz using instruments mentioned above. Mass spectra under
electron impact conditions were recorded with a VG Prospec
instrument at 70 eV ionizing voltage, and are presented as m/z (%
rel int.). Elemental analyses were performed at School of Chemis-
try, University of Birmingham, UK. Melting points were deter-
mined with a Büchi Melting Point B-545 apparatus and are
uncorrected. Triethylamine was distilled from CaH2 and stored
over molecular sieves (3 Å). Dioxane was distilled from Na/benzo-
phenone, n-butanol from BaO and acetic acid anhydride from
CaCl2. Dry THF and DMF were obtained from a solvent purification
system, MB SPS-800 from MBraun, Garching, Germany. Silica gel
for flash chromatography was purchased from Merck, Darmstadt,
Germany (Merck No. 09385). All other reagents were commercially
available and used as received. 4-Chloro-7-azaindole (13a) was
purchased from Carbocore Research Chemicals and Intermediates,
The Woodlands, USA; 4-chloro-1H-pyrrolo[3,2-c]pyridine (14a)
from CreaGen Biosciences Inc., Woburn, USA; 4,6-dichloro-1H-pyr-
rolo[3,2-c]pyridine (14b) from Activate Scientific GmbH, Prien,
Germany and 3-bromo-N-(4-methoxybenzyl)-2-nitroaniline (19)
from Combi-Blocks, LLC, San Diego, USA. Compounds synthesized
by literature procedures: 2a,4 2b,4 6,5 and 8.6 4-Bromo-6-chloro-
1H-pyrrolo[2,3-b]pyridine 13b was also synthesized according to
the literature7 and isolated as an inseparable mixture (77:23) of
13b and the 4,6-dichloro analog. Activities against Mtb H37Rv
(ATCC #27294) (MABA and LORA assay),3e,11,12 and VERO cells2
were determined as reported before.
C17H14ClN3O4 359.0673.
3.3. 4-(Furan-2-yl)-N2-(4-methoxybenzyl)pyridine-2,3-diamine
(4a)
Na2S2O4 (125 mg, 0.740 mmol) was added to a well-stirred sus-
pension of compound 3a (60 mg, 0.18 mmol) and K2CO3 (124 mg,
0.900 mmol) in MeOH (3.00 mL) and water (0.50 mL) under N2
The resulting mixture was stirred at ambient temperature for
12 h and evaporated in vacuo. CH2Cl2 (10 mL) was added and the
resulting suspension was filtered through a cotton plug. The filtrate
was dried (MgSO4) and evaporated in vacuo. The product was puri-
fied by flash chromatography on silica gel eluting with hexane fol-
lowed by EtOAc–hexane (1:5); yield 50 mg (94%), pale yellow wax.
1H NMR (MeCN-d3, 300 MHz) d 3.75 (s, 3H, CH3), (br s, 2H, NH2),
4.55 (d, J = 5.7 Hz, 2H, CH2), (br s, 1H, NH), 6.58 (dd, J = 3.5 and
1.8 Hz, 1H, H-4 in furyl), 6.72–6.76 (m, 2H, H-5 and H-3 in furyl),
6.86 (d, J = 8.7 Hz, 2H, Ar), 7.30 (d, J = 8.8 Hz, 2H, Ar), 7.50 (d,
J = 5.4 Hz, H-6), 7.62 (dd, J = 1.8 and 0.6 Hz, H-5 in furyl); 13C
NMR (MeCN-d3, 75 MHz) d 45.4 (CH2), 55.7 (CH3), 109.2 (C-3 in fur-
yl), 111.2 (C-5), 112.4 (C-4 in furyl), 114.5 (CH in Ar), 120.1 (C-4),
126.3 (C-3), 129.7 (CH in Ar), 133.7 (C-1 in Ar), 137.0 (C-6), 143.4
(C-5 in furyl), 150.6 (C-2), 153.0 (C-2 in furyl), 159.5 (C-4 in Ar);
3.1. 4-(Furan-2-yl)-N-(4-methoxybenzyl)-3-nitropyridin-2-
amine (3a)
A
mixture of compound 2a (350 mg, ca. 88% pure, ca.
1.38 mmol), 4-methoxybenzylamine (0.400 mL, 3.12 mmol) and
triethylamine (0.430 mL, 3.12 mmol) in n-butanol (10 mL) was

A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
3487
MS EI m/z (rel %) 295 (57, M+), 136 (6), 121 (100), 78 (5), 77 (6);
HRMS Found 295.1320, calcd for C17H17N3O2 295.1321.
(CH2), 55.8 (OCH3), 112.2 (C-6), 113.7 (C-4 in furyl), 115.0 (CH in
Ar), 116.4 (C-3 in furyl), 129.3 (C-1 in Ar), 130.0 (C-7a), 130.1
(CH in Ar), 131.7 (C-7), 145.6 (C-2/C-5 in furyl), 145.7 (C-2/C-5 in
furyl), 146.5 (C-5), 147.9 (C-3a), 149.2 (C-2 in furyl), 160.4 (C-4
in Ar); MS EI m / z (rel %) 341/339 (17/40, M+), 122 (16), 121
(100), 78 (8), 77 (8); HRMS Found 339.0775, calcd for C18H14ClN3O2
339.0775. Anal. Found C, 63.58; H, 3.85; N, 12.37. C18H14ClN3O2 re-
quires C, 63.63; H, 4.15; N, 12.37.
3.4. 6-Chloro-4-(furan-2-yl)-N2-(4-methoxybenzyl)pyridine-2,3-
diamine (4b)
Raney Ni (ca. 100 mg, washed with methanol) was added to a
solution of compound 3b (165 mg, 0.46 mmol) in MeOH (10 mL)
at 0 °C, before NaBH4 (35 mg, 0.92 mmol) was added. The resulting
mixture was stirred at 0 °C for 10 min and at ambient temperature
for 10 min in an open flask. The reaction mixture was filtered
through a small Celite pad, and the filtrate was evaporated in va-
cuo. The residue was dissolved in EtOAc (20 mL), washed with
water (20 mL) and brine (10 mL), dried (MgSO4) and evaporated
in vacuo. The product was purified by flash chromatography on sil-
ica gel eluting with hexane followed by EtOAc–hexane (1:4) and fi-
nally EtOAc–hexane (2:3); yield 135 mg (89%), pale yellow wax. 1H
NMR (DMSO-d6, 300 MHz) d 3.71 (s, 1H, OCH3), 4.46 (d, J = 5.3 Hz,
2H, CH2), 5.16 (s, 2H, NH2), 6.64 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in
furyl), 6.70 (s, 1H, H-5), 6.76 (t, J = 5.4 Hz, 1H, NH), 6.88 (d,
J = 8.6 Hz, 2H, CH in Ar), 6.98 (d, J = 3.4 Hz, 1H, H-3 in furyl), 7.28
(d, J = 8.5 Hz, 2H, CH in Ar), 7.79 (br d, J = 1.3 Hz, 1H, H-5 in furyl);
13C NMR (DMSO-d6, 75 MHz) d 40.3 (CH2), 55.0 (OCH3), 106.8 (C-5),
109.2 (C-3 in furyl), 111.8 (C-4 in furyl), 113.6 (CH in Ar), 119.3 (C-
4), 124.2 (C-3), 128.9 (CH in Ar), 131.9 (C-1 in Ar), 135.0 (C-6),
142.8 (C-5 in furyl), 148.4 (C-2), 150.2 (C-2 in furyl), 158.2 (C-4
in Ar); MS EI m / z (rel %) 331/329 (8/23, M+), 208 (2), 122 (16),
121 (100), 77 (6); HRMS Found 329.0929, calcd for C17H16ClN3O2
329.0931.
3.7. 4-(Furan-2-yl)-1-(4-methoxybenzyl)-1H-imidazo[4,5-
c]pyridine (7)
A mixture of compound 6 (100 mg, 0.370 mmol), Pd(dppf)Cl2
(15 mg, 0.019 mmol) and 2-furyl(tributyl)tin (0.14 mL, 0.44 mmol)
in DMF (4 mL) was stirred at 90 °C under N2 for 18 h, and evapo-
rated in vacuo. KF in MeOH (satd soln, 10 mL) was added to the res-
idue and the mixture stirred for 24 h. The solvent was evaporated
with small amount of silica. The product was purified by flash
chromatography on silica gel eluting with hexane followed by
EtOAc–hexane (1:2); yield 66 mg (60%), mp 126–128 °C, pale yel-
low solid. 1H NMR (CDCl3, 300 MHz) d 3.77 (s, 3H, OCH3), 5.28 (s,
2H, CH2), 6.60 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.85 (d,
J = 8.7 Hz, 2H, Ar), 7.10 (d, J = 8.3 Hz, 2H, Ar), 7.10 (d, J = 5.7 Hz,
1H, H-7), 7.66 (dd, 1H, J = 0.8 and 1.7 Hz, H-5 in furyl), 7.72 (dd,
1H, J = 0.7 and 3.4 Hz H-5 in furyl); 13C NMR (CDCl3, 75 MHz) d
48.7 (CH2), 55.3 (OCH3), 104.2 (C-7), 112.0 (C-4 in furyl), 113.7
(C-3 in furyl), 114.6 (CH in Ar), 126.4 (C-1 in Ar), 128.7 (CH in
Ar), 136.5 (C-3a), 139.5 (C-7a), 141.5 (C-4), 141.9 (C-6), 144.0 (C-
2 and C-5 in furyl), 151.1 (C-2 in furyl), 159.8 (C-4 in Ar); MS EI
m/z (rel %) 305 (43, M+), 122 (9), 121 (100), 77 (5); HRMS Found
305.1164, calcd for C18H15N3O2 305.1164. Anal. Found C, 70.89;
H, 4.86; N, 13.58. C18H15N3O2 requires C, 70.81; H, 4.95; N, 13.76.
3.5. 7-(Furan-2-yl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-
b]pyridine (5a)
A mixture of compound 4 (150 mg, 0.510 mmol) in triethylor-
thoformate (2.0 mL) and acetic anhydride (2.0 mL) was heated at
reflux under N2 for 1.5 h and evaporated in vacuo. The product
was purified by flash chromatography on silica gel eluting with
hexane followed by EtOAc–hexane (1:5) and finally EtOAc–hexane
(1:4); yield 140 mg (90%), mp 105–107 °C, colorless solid. 1H NMR
(CDCl3, 300 MHz) d 3.76 (s, 3H, CH3), 5.41 (s, 2H, CH2), 6.60 (dd,
J = 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.85 (d, J = 8.7 Hz, 2H, Ar),
7.25 (d, J = 8.7 Hz, 2H, Ar), 7.56–7.60 (m, 2H, H-6 and H-5 in furyl),
7.66 (d, J = 3.5 Hz, 1H, H-3 in furyl), 8.01 (s, 1H, H-2), 8.41 (d,
J = 5.1 Hz, H-5); 13C NMR (CDCl3, 75 MHz) d 46.8 (CH2), 55.3
(CH3), 112.4 (C-6/C-4 in furyl), 112.5 (C-6/C-4 in furyl), 114.2
(C-3 in furyl), 114.4 (CH in Ar), 127.7 (C-1 in Ar), 129.0 (C-7),
129.3 (CH in Ar), 129.7 (C-7a), 143.3 (C-2), 143.7 (C-5 in furyl),
144.7 (C-5), 147.5 (C-3a), 149.2 (C-2 in furyl), 159.6 (C-4 in Ar);
MS EI m/z (rel %) 305 (87, M+), 290 (15), 153 (6), 121 (100), 77
(7); HRMS Found 305.1164, calcd for C18H15N3O2 305.1164. Anal.
Found C, 71.00; H, 4.96; N, 13.72. C18H15N3O2 requires C, 70.81;
H, 4.95; N, 13.76.
3.8. 2,6-Dichloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine
(9)
NaH (69 mg, ca. 60%, ca. 1.73 mmol) was suspended in THF
(4 mL) at 0 °C and a solution of compound 8 (300 mg, 1.44 mmol)
in THF (4 mL) was added dropwise under N2 The resulting red mix-
ture was stirred at 0 °C for 1 h. In another flask containing NaI
(259 mg, 1.73 mmol) in THF (4 mL), was added 4-methoxybenzyl
chloride (0.23 mL, 1.7 mmol) and the resulting suspension was
stirred at ambient temperature under N2 for 1 h. The benzyl halide
suspension was slowly added to the compound 8 containing solu-
tion at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, the ice
bath was removed and the reaction was allowed to stir at ambient
temperature for 14 h before the reaction mixture was poured on to
ice-water (ca. 100 mL) and extracted with EtOAc (2 Â 70 mL). The
combined organic layers were washed with brine (50 mL), dried
(MgSO4) and evaporated in vacuo. The product was purified by
flash chromatography on silica gel eluting with hexane followed
by EtOAc–hexane (1:5); yield 330 mg (69%), yellow wax. 1H NMR
(DMSO-d6, 300 MHz) d 3.72 (s, 3H, CH3), 4.43 (d, J = 6.0 Hz, 2H,
CH2), 6.89–6.93 (m, 3H, H-5 and 2H in Ar), 7.25 (d, J = 8.7 Hz, 2H,
Ar), 8.29 (t, J = 6.0 Hz, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d
44.9 (CH2), 55.0 (CH3), 106.9 (C-5), 114.0 (CH in Ar), 128.3 (CH in
Ar), 128.8 (C-1 in Ar), 131.5 (C-3), 141.2 (C-2), 148.7 (C-4), 149.7
(C-6), 158.5 (C-4 in Ar); MS EI m / z (rel %) 329/327 (3/4, M+), 311
(11), 309 (17), 135 (38), 121 (100), 78 (9), 77 (8); HRMS Found
327.0178, calcd for C13H11Cl2N3O3 327.0177.
3.6. 5-Chloro-7-(furan-2-yl)-3-(4-methoxybenzyl)-3H-
imidazo[4,5-b]pyridine (5b)
A mixture of compound 4b (120 mg, 0.510 mmol) in triethylor-
thoformate (2.0 mL) and acetic anhydride (2.0 mL) was heated at
reflux under N2 for 1.5 h and evaporated in vacuo. The product
was purified by flash chromatography on silica gel eluting with
hexane followed by EtOAc–hexane (1:4) and finally EtOAc–hexane
(2:3); yield 102 mg (83%), mp 121–122 °C, colorless crystals. 1H
NMR (MeCN-d3, 300 MHz) d 3.74 (s, 1H, OCH3), 5.35 (s, 2H, CH2),
6.68 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.88 (d, J = 8.7 Hz,
2H, CH in Ar), 7.53 (s, 1H, H-6), 7.72–7.75 (m, 2H, H-5 and H-3 in
furyl), 8.21 (s, 1H, H-2); 13C NMR (MeCN-d3, 75 MHz) d 47.4
3.9. 6-Chloro-2-(furan-2-yl)-N-(4-methoxybenzyl)-3-
nitropyridin-4-amine (10)
A mixture of compound 9 (141 mg, 0.430 mmol), (PPh3)2PdCl2
(9 mg, 0.01 mmol) and 2-furyl(tributyl)tin (0.15 mL, 0.47 mmol)

3488
A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
in DMF (3 mL) was stirred at ambient temperature for 1 h under N2
and poured into water (25 mL). The resulting mixture was ex-
tracted with EtOAc (3 Â 20 mL), the combined organic extracts
were washed with water (40 mL) and brine (30 mL), dried (MgSO4)
and evaporated in vacuo. The residue dissolved in THF (8 mL) and
KF (500 mg) was added. The resulting suspension was stirred at
ambient temperature for 18 h, and evaporated with small amount
of silica gel. The product was purified by flash chromatography on
silica gel eluting with hexane followed by EtOAc–hexane (1:5);
yield 120 mg (78%), yellow wax. 1H NMR (DMSO-d6, 300 MHz) d
3.72 (s, 3H, OCH3), 4.41 (d, J = 5.9 Hz, 2H, CH2), 6.67 (dd, J = 3.5
and 1.8 Hz, 1H, H-4 in furyl), 6.73 (s, 1H, H-5), 6.91 (d, J = 8.7 Hz,
2H, CH in Ar), 7.07 (dd, J = 3.5 and 0.7 Hz, 1H, H-3 in furyl), 7.25
(d, J = 8.7 Hz, 2H, CH in Ar), 7.85–7.88 (m, 2H, NH and H-5 in furyl);
13C NMR (DMSO-d6, 75 MHz) 44.6 (CH2), 55.0 (OCH3), 105.1 (C-5),
112.4 (C-4 in furyl), 113.5 (C-3 in furyl), 114.0 (CH in Ar), 128.2 (CH
in Ar), 129.2 (C-1 in Ar), 130.6 (C-3), 139.9 (C-6), 145.9 (C-5 in
furyl), 148.3 (C-2 in furyl), 148.7 (C-2), 150.9 (C-4), 158.4 (C-4 in
Ar); MS EI m/z (rel %) 359 (3, M+), 330 (6), 135 (6), 122 (11), 121
(100), 77 (5); HRMS Found 359.0673, calcd for C17H14ClN3O4
359.0673.
3.12. 4-Chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine
(15a)
Compound 13a (153 mg, 1.00 mmol) was dissolved in DMF
(4.0 mL) and cooled to 0 °C. NaH (ca. 60%, 44 mg, ca. 1.1 mmol)
was added and reaction mixture was stirred under N2 for 1 h before
4-methoxybenzyl chloride (0.14 mL, 1.0 mmol) was added. The
resulting mixture was stirred for 19 h and evaporated in vacuo.
Water (40 mL) was added to the residue, which was extracted with
EtOAc (2 Â 40 mL). The combined organic layers were washed with
brine (40 mL), dried (MgSO4) and evaporated in vacuo. The product
was purified by flash chromatography on silica gel eluting with
CH2Cl2 followed by MeOH–CH2Cl2 (1:19); yield 235 mg (86%), pale
yellow wax. 1H NMR (CDCl3, 300 MHz) d 3.77 (s, 3H, OCH3), 5.41
(s, 2H, CH2), 6.55 (d, J = 3.5 Hz, 1H, H-3), 6.82 (d, J = 8.7 Hz, 2H, Ar),
7.09 (d, J = 5.2 Hz, 1H, H-5), 7.16 (d, J = 8.7 Hz, 2H, Ar), 7.18 (d,
J = 3.5 Hz, 1H, H-2), 8.22 (d, J = 5.2 Hz, 1H, H-6); 13C NMR (CDCl3,
75 MHz) d 48.3 (CH2), 55.7 (OCH3), 99.1 (C-3), 114.6 (CH in Ar),
116.4 (C-5), 120.4 (C-3a), 128.8 (C-1 in Ar), 129.6 (CH in Ar), 129.8
(C-2), 136.7 (C-4), 143.3 (C-6), 159.7 (C-4 in Ar); MS EI m / z (rel %)
274/272 (14/43 M+), 122 (10), 121 (100), 78 (5); HRMS Found
272.0717, calcd for C15H13ClN2O 272.0716.
3.10. 6-Chloro-2-(furan-2-yl)-N4-(4-methoxybenzyl)pyridine-
3,4-diamine (11)
3.13. 4-Bromo-6-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridine (15b)
A suspension of compound 10 (95 mg, 0.29 mmol), K2CO3
(240 mg, 1.74 mmol) and Na2S2O4 (252 mg, 1.45 mmol) in MeOH
(4.0 mL) and water (0.20 mL) was stirred under N2 at ambient tem-
perature for 12 h before the MeOH was removed in vacuo. The res-
idue dissolved in EtOAc (30 mL), washed with water (20 mL), dried
(MgSO4) and evaporated in vacuo. The product was purified by
flash chromatography on silica gel eluting with hexane followed
by EtOAc–hexane (1:4); yield 80 mg (93%), pale yellow wax. 1H
NMR (DMSO-d6, 300 MHz) d 3.73 (s, 3H, CH3), 4.33 (d, J = 5.5 Hz,
2H, CH2), 5.21 (br s, 2H, NH2), 6.23 (s, 1H, H-5), 6.59–6.61 (m,
2H, H-4 in furyl and NH), 6.81 (dd, J = 3.4 and 0.7 Hz, 1H, H-3 in fur-
yl), 6.90 (d, J = 8.7 Hz, 2H, Ar), 7.28 (d, J = 8.6 Hz, 2H, Ar), 7.76 (dd,
J = 1.7 and 0.8 Hz, 1H, H-5 in furyl); 13C NMR (DMSO-d6, 75 MHz) d
45.4 (CH2), 55.0 (CH3), 101.7 (C-5), 108.6 (C-3 in furyl), 111.5 (C-4
in furyl), 113.8 (CH in Ar), 126.7 (C-6), 128.5 (CH in Ar), 129.2 (C-2),
130.2 (C-1 in Ar), 139.1 (C-3), 142.2 (C-5 in furyl), 145.1 (C-4),
153.3 (C-2 in furyl), 158.4 (C-4 in Ar); MS EI m/z (rel %) 329 (11,
M+), 330 (6), 180 (2), 122 (10), 121 (100), 77 (5); HRMS Found
329.0932, calcd for C17H16ClN3O2 329.0931.
Compound 13b (80 mg, ca. 0.35 mmol, cont. ca. 0.10 mmol of 6-
chloro-1H-pyrrolo[2,3-b]pyridine) was dissolved in DMF (3.0 mL)
and cooled to 0 °C. NaH (ca. 60%, 22 mg, ca. 0.54 mmol) was added
and reaction mixture was stirred under N2 for 1 h before 4-methoxy-
benzyl chloride (0.07 mL, 0.5 mmol) was added. The reaction mix-
ture was stirred for 1.5 h while reaching ambient temperature and
quenched by adding few drops of water. The mixture was poured
into water (25 mL) and extracted with EtOAc (2 Â 30 mL). The com-
bined organic layers were dried (MgSO4) and evaporated in vacuo.
The product was purified by flash chromatography on silica gel elut-
ing with hexane followed by EtOAc–hexane (1:5); yield 101 mg (ca.
82% 15b and 6% 15a), pale yellow wax. 1H NMR (CDCl3, 300 MHz) d
3.76 (s, 3H, OCH3), 5.33 (s, 2H, CH2), 6.45 (d, J = 3.5 Hz, 1H, H-3), 6.83
(d, J = 8.6 Hz, 2H, CH in Ar), 7.11–7.15 (m, 3H, H-2 and CH in Ar), 7.28
(s, 1H, H-5); 13C NMR (CDCl3, 75 MHz) d 47.9 (CH2), 55.3 (CH3), 100.5
(C-3), 114.2 (CH in Ar), 118.6 (C-5), 120.6 (C-3a), 126.3 (C-4), 128.4
(C-2), 128.7 (C-1 in Ar), 129.2 (CH in Ar), 144.3 (C-6), 146.0 (C-7a),
159.4 (C-4 in Ar); HRMS Found 349.9827, calcd for C15H12BrClN2O
349.9822.
3.11. 6-Chloro-4-(furan-2-yl)-1-(4-methoxybenzyl)-1H-
imidazo[4,5-c]pyridine (12)
3.14. 4-Chloro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-c]pyridine
(16a)
A solution of compound 11 (70 mg, 0.24 mmol) in triethylortho-
formate (2 mL) and Ac2O (2 mL) was heated at reflux for 2 h under
N2 and evaporated in vacuo. The product was purified by flash
chromatography on silica gel eluting with hexane followed by
EtOAc–hexane (3:7); yield 65 mg (79%), mp 155–157 °C, pale yel-
low solid. 1H NMR (Me2CO-d6, 300 MHz) d 3.77 (s, 3H, CH3), 5.53
(s, 2H, CH2), 6.68 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.93
(d, J = 8.7 Hz, 2H, Ar), 7.36 (d, J = 8.7 Hz, 2H, Ar), 7.48 (s, 1H, H-7),
7.77 (dd, J = 1.7 and 0.8 Hz, 1H, H-5 in furyl), 7.84 (dd, J = 3.4 and
0.7 Hz, 1H, H-3 in furyl), 8.43 (s, 1H, H-2); 13C NMR (Me2CO-d6,
75 MHz) 48.9 (CH2), 55.5 (CH3), 105.2 (C-7), 112.9 (C-4 in furyl),
115.1 (CH in Ar), 115.7 (C-3 in furyl), 128.6 (C-1 in Ar), 130.0 (CH
in Ar), 137.0 (C-3a), 140.8 (C-4), 142.6 (C-7a), 143.3 (C-6), 145.2
(C-5 in furyl), 147.2 (C-2), 151.1 (C-2 in furyl), 160.7 (C-4 in Ar);
MS EI m / z (rel %) 341/339 (17/47, M+), 122 (13), 121 (100), 78
Compound 14a (125 mg, 0.82 mmol) was dissolved in DMF
(3.0 mL) and cooled to 0 °C. NaH (ca. 60%, 43 mg, ca. 1.07 mmol)
was added and reaction mixture was stirred under N2 for 1 h be-
fore 4-methoxybenzyl chloride (0.13 mL, 0.98 mmol) was added.
The reaction mixture was stirred for 1.5 h while reaching ambient
temperature and quenched by adding few drops of water. The mix-
ture was poured into water (25 mL) and extracted with EtOAc
(2 Â 30 mL). The combined organic layers were dried (MgSO4)
and evaporated in vacuo. The product was purified by flash chro-
matography on silica gel eluting with hexane followed by
CH2Cl2–hexane (1:1); and finally CH2Cl2; yield 165 mg (82%), col-
orless wax. 1H NMR (CDCl3, 300 MHz) d 3.76 (s, 3H, OCH3), 5.22
(s, 2H, CH2), 6.65 (d, J = 3.2 Hz, 1H, H-3), 6.83 (d, J = 8.6 Hz, 2H,
Ar), 7.03 (d, J = 8.5 Hz, 2H, Ar), 7.12–7.24 (m, 2H, H-2 and H-7),
8.02 (d, J = 5.8 Hz, 1H, H-6); 13C NMR (CDCl3, 75 MHz) d 50.2
(CH2), 55.3 (OCH3), 101.6 (C-3), 104.9 (C-7), 114.4 (CH in Ar),
123.8 (C-3a), 127.8 (C-1 in Ar), 128.3 (CH in Ar), 129.5 (C-2),
(8), 77 (7); HRMS Found 339.0775, calcd for
C18H14ClN3O2
339.0775. Anal. Found C, 63.77; H, 4.31; N, 12.31. C18H14ClN3O2
requires C, 63.63; H, 4.15; N, 12.37.

A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
3489
139.7 (C-6), 141.0 (C-4), 144.0 (C-7a), 159.5 (C-4 in Ar); MS EI m / z
(rel %) 274/272 (7/22 M+), 122 (10), 121 (100), 78 (6); HRMS Found
272.0716, calcd for C15H13ClN2O 272.0716.
was stirred at ambient temperature for 18 h, and evaporated with
small amount of silica gel. The product was purified by flash chroma-
tography on silica gel eluting with hexane followed by EtOAc–hex-
ane (1:9) and finally EtOAc–hexane (1:4); yield 85 mg (60%),
yellow wax. 1H NMR (MeCN-d3, 300 MHz) d 3.73 (s, 3H, OCH3),
5.34 (s, 2H, CH2), 6.63 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 in furyl), 6.85
(d, J = 8.8 Hz, 2H, CH in Ar), 7.16–7.20 (m, 3H, CH in Ar and H-3 in fur-
yl), 7.40–7.41 (m, 2H, H-2 and H-5 in furyl), 7.73 (dd, J = 1.7 and
0.5 Hz, H-5 in furyl); 13C NMR (MeCN-d3, 75 MHz) d 48.2 (CH2),
55.8 (OCH3), 101.2 (C-3), 110.9 (C-5), 112.2 (C-3 in furyl), 113.3 (C-
4 in furyl), 114.6 (C-3a), 114.9 (CH in Ar), 129.7 (CH in Ar), 130.3
(C-2), 130.8 (C-1 in Ar), 133.1 (C-4), 145.3 (C-6), 145.4 (C-5 in furyl),
148.4 (C-7a), 151.9 (C-2 in furyl), 160.2 (C-4 in Ar); MS EI m / z (rel %)
340/338 (18/51, M+), 122 (11), 121 (100), 91 (3), 77 (4); HRMS Found
338.0822, calcd for C19H15ClN2O2 338.0822. Anal. Found C, 67.66; H,
4.55; N, 8.20. C19H15ClN2O2 requires C, 67.36; H, 4.46; N, 8.27.
3.15. 4,6-Dichloro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-
c]pyridine (16b)
Compound 14b (200 mg, 1.07 mmol) was dissolved in DMF
(4.0 mL) and cooled to 0 °C. NaH (ca. 60%, 56 mg, ca. 1.39 mmol)
was added and reaction mixture was stirred under N2 for 1 h be-
fore 4-methoxybenzyl chloride (0.16 mL, 1.18 mmol) was added.
The reaction mixture was stirred for 1.5 h while reaching ambient
temperature and quenched by adding few drops of water. The mix-
ture was poured into water (25 mL) and extracted with EtOAc
(2 Â 30 mL). The combined organic layers were dried (MgSO4)
and evaporated in vacuo. The product was purified by flash chro-
matography on silica gel eluting with hexane followed by
CH2Cl2–hexane (1:1); and finally CH2Cl2; yield 250 mg (75%), col-
orless wax. 1H NMR (CDCl3, 300 MHz) d 3.78 (s, 3H, CH3), 5.40 (s,
2H, CH2), 6.62 (d, J = 3.3 Hz, 1H, H-3), 6.86 (d, J = 8.6 Hz, 2H, CH
in Ar), 7.03 (d, J = 8.6 Hz, 2H, CH in Ar), 7.12 (d, J = 3.3 Hz, 1H, H-
2), 7.16 (br s, 1H, H-7); 13C NMR (CDCl3, 75 MHz) d 50.2 (CH2),
55.3 (CH3), 101.7 (C-3), 104.3 (C-7), 114.5 (CH in Ar), 123.4 (C-
3a), 127.3 (C-1 in Ar), 128.4 (CH in Ar), 130.5 (C-2), 141.0 (C-6),
142.3 (C-7a/C-4), 142.4 (C-7a/C-4), 159.6 (C-4 in Ar); MS EI m / z
(rel %) 308/306 (8/12, M+), 122 (10), 121 (100), 78 (5); HRMS Found
306.0327, calcd for C15H12Cl2N2O 306.0327.
3.18. 4-(Furan-2-yl)-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-
c]pyridine (18a)
A mixture of compound 16a (100 mg, 0.37 mmol) and Pd(Pt-Bu)2
(6.0 mg, 0.011 mmol) in DMF (3 mL) was stirred at ambient temper-
ature under N2 for 5 min before 2-furyl(tributyl)tin (0.16 mL,
0.52 mmol) was added. The resulting mixture was stirred at 85 °C
for 20 h. DMF was removed in vacuo, the residue was dissolved in
THF (4 mL) and KF (ca. 0.2 g) was added. The resulting suspension
was stirred at ambient temperature for 24 h and evaporated with
small amount of silica gel. The product was purified by flash chroma-
tography on silica gel eluting with hexane, followed by EtOAc–hex-
ane (1:4) and finally EtOAc–hexane (1:1); yield 82 mg, (73%), pale
yellow wax. 1H NMR (MeCN-d6, 300 MHz) d 3.73 (s, 3H, OCH3),
5.31 (s, 2H, CH2), 6.62 (dd, J = 3.3 and 1.8 Hz, 1H, H-4 in furyl), 6.85
(d, J = 8.7 Hz, 2H, CH in Ar), 7.11–7.16 (m, 4H, H-3, CH in Ar and
H-3 in furyl), 7.28 (d, J = 5.7 Hz, 1H, H-7), 7.40 (d, J = 3.3 Hz, 1H,
H-2), 7.70 (br s, 1H, H-5 in furyl), 8.20 (d, J = 5.7 Hz, 1H, H-6), 13C
NMR (MeCN-d6, 75 MHz) d 50.0 (CH2), 55.8 (OCH3), 102.7 (C-3),
105.3 (C-7), 110.1 (C-3 in furyl), 112.7 (C-4 in furyl), 115.0 (CH in
Ar), 121.5 (C-3a), 129.5 (CH in Ar), 130.3 (C-1 in Ar), 131.1 (C-2),
141.1 (C-6), 141.8 (C-7a), 143.0 (C-4), 144.4 (C-5 in furyl), 156.2
(C-2 in furyl), 160.2 (C-4 in Ar); MS EI m/z (rel %) 304 (56, M+), 122
(10), 121 (100), 78 (5); HRMS Found 304.1212, calcd for
3.16. 4-(Furan-2-yl)-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-
b]pyridine (17a)
To a mixture of KF (59 mg, 1.0 mmol) and bis(tri-tert-butyl-
phosphine)palladium(0) (4.8 mg, 5.0 lmol) was added a solution
of compound 15a (85 mg, 0.31 mmol) in dioxane (3 mL) and the
mixture was stirred at ambient temperature under N2 for 15 min,
before furan-2-boronic acid (69 mg, 0.62 mmol) was added. The
resulting mixture was stirred at reflux under N2 for 2 h before
the solvent was evaporated in vacuo. The product was purified
by flash chromatography on silica gel eluting with hexane followed
by EtOAc–hexane (2:3); yield 86 mg (90%), pale yellow wax. 1H
NMR (CDCl3, 300 MHz) d 3.76 (s, 3H, OCH3), 5.48 (s, 2H, CH2),
(dd, J = 3.4 and 1.8 Hz 1H, H-4 in furyl), 6.82 (d, J = 8.7 Hz, 2H,
Ar), 6.90 (d, J = 3.5 Hz, 1H, H-3), 7.01 (d, J = 3.4, 1H, H-3 in furyl),
7.19 (d, J = 7.6 Hz, 2H, Ar), 7.21 (d, J = 3.5 Hz, 1H, H-3), 7.38 (d,
J = 5.2 Hz, 1H, H-5), 7.62 (br d, J = 1.3 Hz, 1H, H-5 in furyl), 8.34
(d, J = 5.2 Hz, 1H, H-6); 13C NMR (CDCl3, 75 MHz) d 47.8 (CH2),
55.25 (OCH3), 100.7 (C-3), 110.4 (C-5), 110.8 (C-3 in furyl), 112.1
(C-4 in furyl), 114.1 (CH in Ar), 115.7 (C-3a), 128.5 (C-2), 129.1
(CH in Ar), 129.2 (C-1 in Ar), 141.9 (C-6), 143.7 (C-5 in furyl),
152.2 (C-2 in furyl), 159.2 (C-4 in Ar), C-4 and C-7a were hidden;
MS EI m/z (rel %) 304 (100, M+), 303 (38), 289 (13), 197 (10), 121
(99); HRMS Found 304.1209, calcd for C19H15ClN2O2 304.1212.
Anal. Found C, 74.60; H, 5.35; N, 9.01. C19H15ClN2O2 requires C,
74.98; H, 5.30; N, 9.20.
C19H16N2O2 304.1212. Anal. Found C, 74.75; H, 5.16; N, 9.21.
C19H16N2O2 requires C, 74.98; H, 5.30; N, 9.20.
3.19. 6-Chloro-4-(furan-2-yl)-1-(4-methoxybenzyl)-1H-
pyrrolo[3,2-c]pyridine (18b)
A mixture of compound 16b (150 mg, 0.49 mmol), (PPh3)2PdCl2
(18 mg,
0.025 mmol)
and
2-furyl(tributyl)tin
(0.170 mL,
0.54 mmol) in DMF (3 mL) was stirred under N2 at 60 °C for 18 h
and poured into water (20 mL). The resulting mixture was ex-
tracted with EtOAc (3 Â 30 mL) and the combined organic extracts
were washed with water (40 mL) and brine (30 mL), dried (MgSO4)
and evaporated in vacuo. The residue was dissolved in THF (8 mL)
and KF (ca. 200 mg) was added. The resulting suspension was stir-
red at ambient temperature for 18 h, and evaporated with small
amount of silica gel. The product was purified by flash chromatog-
raphy on silica gel eluting with hexane followed by CH2Cl2–hexane
(3:7); yield 70 mg (43%), yellow wax. 1H NMR (Me2CO-d6,
600 MHz) d 3.74 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.65 (dd, J = 3.4
and 1.8 Hz, 1H, H-4 in furyl), 6.78 (d, J = 8.7 Hz, 2H, Ar), 7.14 (dd,
J = 3.2 and 0.7 Hz, 1H, H-3), 7.21–7.23 (m, 3H, CH in Ar and H-3
in furyl), 7.41 (d, J = 0.7 Hz, 1H, H-7), 7.53 (d, J = 3.2 Hz, 1H, H-2),
7.80–7.81 (m, 1H, H-5 in furyl); 13C NMR (Me2CO-d6, 150 MHz) d
50.0 (CH2), 55.5 (CH3), 103.0 (C-3), 104.3 (C-7), 111.3 (C-3 in furyl),
112.6 (C-4 in furyl), 114.9 (CH in Ar), 120.9 (C-3a), 129.5 (CH in Ar),
3.17. 6-Chloro-4-(furan-2-yl)-1-(4-methoxybenzyl)-1H-
pyrrolo[2,3-b]pyridine (17b)
A mixture of compound 15b (175 mg, ca. 0.410 mmol, purity see
above), (PPh3)2PdCl2 (15 mg, 0.021 mmol) and 2-furyl(tributyl)tin
(0.13 mL, 0.41 mmol) in DMF (3 mL) was stirred under N2 at ambient
temperature for 40 min and poured into water (20 mL). The result-
ing mixture was extractedwith EtOAc (3 Â 20 mL), the combinedor-
ganic extracts were washed with water (40 mL) and brine (30 mL),
dried (MgSO4) and evaporated in vacuo. The residue was dissolved
in THF (8 mL) and KF (500 mg) was added. The resulting suspension

3490
A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
129.8 (C-1 in Ar), 132.4 (C-2), 142.1 (C-4), 142.9 (C-6), 144.0 (C-7a),
145.0 (C-5 in furyl), 155.1 (C-2 in furyl), 160.3 (C-4 in Ar); MS EI m
/ z (rel %) 340/338 (10/33, M+), 122 (7), 121 (100), 78 (3); HRMS
Found 338.0822, calcd for C19H15ClN2O2 338.0822. Anal. Found C,
67.35; H, 4.67; N, 8.56. C19H15ClN2O2 requires C, 67.36; H, 4.46;
N, 8.27.
OCH3), 5.29 (s, 2H, CH2), 6.56 (dd, J = 3.3 and 1.8 Hz, 1H, H-4 in furyl),
6.84 (d, J = 8.7 Hz, 2H, Ar), 7.11 (d, J = 8.8 Hz, 2H, Ar), 7.18 (dd, J = 8.0
and 1.1 Hz, 1H, H-6), 7.24–7.28 (m, 1H, H-7), 7.50–7.52 (m, 2H, H-3
and H-5 in furyl), 7.69 (dd, J = 7.4 and 1.1 Hz, 1H, H-5), 7.97 (s, 1H, H-
2); 13C NMR (CDCl3, 75 MHz) d 48.5 (CH2), 55.3 (OCH3), 109.0 (C-6),
110.1 (C-3 in furyl), 111.9 (C-4 in furyl), 114.4 (CH in Ar), 117.7 (C-5),
122.6 (C-6/C-7), 123.1 (C-6/C-7), 127.4 (C-1 in Ar), 128.5 (CH in Ar),
134.5 (C-7a), 139.5 (C-3a), 141.8 (C-5 in furyl), 142.9 (C-2), 151.4 (C-
2 in furyl), 159.5 (C-4 in Ar); MS EI m/z (rel %) 304 (67, M+), 122 (12),
121 (100), 78 (5), 77 (6); HRMS Found 304.1202, calcd for
3.20. 3-Bromo-N1-(4-methoxybenzyl)benzene-1,2-diamine (20)
Compound 19 (338 mg, 1.00 mmol) was suspended in MeOH
(10 mL) and K2CO3 (829 mg, 6.00 mmol) were added followed by
Na2S2O4 (871 mg, 5.00 mmol) and water (0.3 mL). The resulting
suspension was stirred under N2 for 36 h, additional Na2S2O4
(871 mg, 5.00 mmol) was added and the reaction mixture was stir-
red for further 12 h. The mixture was evaporated in vacuo and the
residue was partitioned between water (40 mL) and EtOAc (40 mL).
The phases were separated and the aq phase was re-extracted with
EtOAc (40 mL). The combined organic layers were washed with
brine (40 mL), dried (MgSO4) and evaporated in vacuo. The product
was purified by flash chromatography on silica gel eluting with
hexane, followed by EtOAc–hexane (1:9); yield 230 mg (75%), pale
yellow oil. 1H NMR (DMSO-d6, 300 MHz) d 3.71 (s, 3H, CH3), 4.21
(d, J = 5.7 Hz, 2H, CH2), 4.73 (s, 2H, NH2), 7.73 (t, J = 5.6 Hz, 1H,
NH), 6.33–6.36 (m, 2H, H-5 and H-6), 6.66 (dd, J = 6.7 and 2.6 Hz,
1H, H-4), 6.86 (d, J = 8.7 Hz, 2H, CH in Ar), 7.26 (d, J = 8.7 Hz, 2H,
CH in Ar); 13C NMR (DMSO-d6, 75 MHz) d 46.4 (CH2), 55.0 (CH3),
108.1 (C-3), 109.2 (C-6), 113.66 (CH in Ar), 118.2 (C-5), 119.7 (C-
4), 128.4 (CH in Ar), 131.6 (C-1 in Ar), 132.3 (C-2), 136.6 (C-1),
158.1 (C-4 in Ar); MS EI m / z (rel %) 308/306 (15/16, M+), 122
(17), 121 (100), 91 (5), 78 (9), 77 (7); HRMS Found 306.0358, calcd
for C14H15BrN2O 306.0368.
C
C
19H16N2O2 304.1212. Anal. Found C, 74.99; H, 5.47; N, 9.27.
19H16N2O2 requires C, 74.98; H, 5.30; N, 9.20.
3.23. 4-Bromo-1-(4-methoxybenzyl)-1H-indole (24a) and 4-
bromo-1,3-di(4-methoxybenzyl)-1H-indole (24b)
4-Bromoindole (23) (0.38 mL, 3.0 mmol) was added drop wise to
a stirring mixture of K2CO3 (1.24 g, 9.00 mmol) in DMF (12 mL) un-
der N2 at ambient temperature. The resulting mixture was stirred for
1 h, before 4-methoxybenzyl chloride (0.81 mL, 6.0 mmol) was
added drop wise. The reaction mixture was stirred for 18 h, filtered
and evaporated in vacuo. The products were separated by flash chro-
matography on silica gel eluting with EtOAc–hexane (1:20) followed
by EtOAc–hexane (1:10).
Compound 24a: Yield 242 mg (26%), colorless oil. 1H NMR
(CDCl3, 200 MHz) d 3.75 (s, 3H, OCH3), 5.21 (s, 2H, CH2), 6.57 (d,
J = 3.0 Hz, 1H, H-3), 6.81 (d, J = 8.6 Hz, 2H, Ar), 6.96–7.05 (m, 3H,
Ar and indole), 7.14 (d, J = 3.0 Hz, H-2), 7.20–2.28 (m, 2H, indole);
13C NMR (CDCl3, 50 MHz) d 49.7 (CH2), 55.3 (CH3), 101.9 (C-3),
108.9 (C-7), 114.1 (CH in Ar), 114.8 (C-4), 122.3 (C-5/C-6), 122.4
(C-5/C-6), 128.1 (CH in Ar), 128.6 (C-2), 128.8 (C-1 in Ar), 129.3
(C-3a), 136.4 (C-7a), 159.1 (C-4 in Ar); MS EI m / z (rel %) 317/315
(26/27, M+), 228 (7), 197 (7), 122 (13), 121 (100), 115 (19); HRMS
Found 315.0268, calcd for C16H14BrNO 3150259.
3.21. 4-Bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazole
(21)
Compound 24b: Yield 344 mg (26%), colorless oil. 1H NMR
(CDCl3, 200 MHz) d 3.77 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.40 (s,
2H, CH2), 5.13 (s, 2H, CH2), 6.72 (s, 1H, H-2), 6.80–6.93 (m, 4H),
6.98–7.03 (m, 3H), 7.17–2.28 (m, 4H); 13C NMR (CDCl3, 50 MHz)
d 31.5 (CH2), 49.5 (CH2), 55.2 (2 Â CH3), 109.0 (C-7), 113.6 (CH in
Ar), 114.0 (CH in Ar), 114.5 (C-3/C-4), 116.1 (C-3/C-4), 122.4
(C-5/C-6), 123.5 (C-5/C-6), 126.0 (C-3a), 127.8 (CH in Ar), 128.5
(C-2), 129.0 (C-1 in Ar), 129.7 (CH in Ar), 133.6 (C-1 in Ar), 137.8
(C-7a), 157.6 (C-4 in Ar), 159.0 (C-4 in Ar); MS EI m / z (rel %)
437/435 (15/15, M+), 355 (1), 316 (2), 315 (1), 235 (3), 234 (2),
192 (2), 191 (4), 190 2) 122 (9), 121 (100); HRMS Found
435.0813, calcd for C24H22BrNO2 435.0834.
p-Toluenesulfonic acid monohydrate (11 mg, 0.059 mmol) was
added to a solution of 20 (120 mg, 0.390 mmol) in triethylorthofor-
mate (4.5 mL) and the resulting mixture was heated at reflux under
N2 for 2 h and excess of triethylorthoformate was removed in va-
cuo. The product was purified by flash chromatography on silica
gel eluting with hexane followed by EtOAc–hexane (3:1); yield
110 mg (90%), colorless wax. 1H NMR (CDCl3, 300 MHz) d 3.76 (s,
3H, OCH3), 5.26 (s, 2H, CH2), 6.84 (d, J = 8.7 Hz, 2H, CH in Ar),
7.05–7.11 (m, 3H, H-6 and CH in Ar), 7.20–7.24 (m, 1H, H-7),
7.44 (dd, J = 7.7 and 0.9 Hz, 1H, H-5), 7.96 (s, 1H, H-2); 13C NMR
(CDCl3, 75 MHz) d 48.8 (CH2), 55.3 (OCH3), 109.5 (C-7), 113.9 (C-
4), 114.5 (CH in Ar), 124.0 (C-6), 125.3 (C-5), 126.8 (C-1 in Ar),
128.6 (CH in Ar), 134.4 (C-7a), 142.7 (C-3a), 143.4 (C-2), 159.7
(C-4 in Ar); MS EI m / z (rel %) 318/316 (12/13, M+), 122 (9), 121
(100), 78 (6), 77 (5); HRMS Found 316.0203, calcd for C15H13BrN2O
316.0211.
3.24. 4-(Furan-2-yl)-1-(4-methoxybenzyl)-1H-indole (25)
A mixture of 24a (190 mg, 0.600 mmol), 2-furyl(tributyl)tin
(0.28 mL, 0.90 mmol) and (Ph3P)2PdCl2 (22 mg. 0.030 mmol) in
DMF (5 mL) was stirred at 90 °C under N2 for 17 h, and evaporated
in vacuo. KF in MeOH (satd soln, 10 mL) was added to the residue
and the resulting mixture was stirred for 18 h. The product was
purified by flash chromatography on silica gel eluting with
EtOAc–hexane (1:10); yield 138 mg (76%), pale yellow oil. 1H
NMR (CDCl3, 200 MHz) d 3.76 (s, 3H, OCH3), 5.27 (s, 2H, CH2),
6.53 (m, 1H, furyl), 6.79–6-84 (m, 3H, H-3 and Ar), 6.98 (d,
J = 3.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H, Ar), 7.17–7.21 (m, 3H), 7.48
(m, 1H), 7.54 (br s, 1H); 13C NMR (CDCl3, 50 MHz) d 49.6 (CH2),
55.1 (CH3), 101.5 (C-3), 106.3 (C-7/CH in furyl), 109.1 (C-7/CH in
furyl), 111.4 (C-7/CH in furyl), 116.2 (C-5/C-6), 121.6 (C-5/C-6),
123.1 (C-3a/C-4), 124.2 (C-3a/C-4), 128.0 (CH in Ar), 128.6 (C-2),
129.2 (C-1 in Ar), 136.8 (C-7a), 141.5 (CH in furyl), 154.4 (C in fur-
yl), 158.9 (C-4 in Ar); MS EI m/z (rel %) 303 (100, M+), 183 (6), 182
(6), 155 (4), 154 (5), 153 (3), 127 (6), 126 (3), 122 (10), 121 (100),
3.22. 4-(Furan-2-yl)-1-(4-methoxybenzyl)-1H-
benzo[d]imidazole (22)
A mixture of compound 21, (90 mg, 0.25 mmol) and Pd(Pt-Bu)2
(7.0 mg, 0.013 mmol) in DMF (3 mL) was stirred ambient tempera-
ture under N2 for 5 min before 2-furyl(tributyl)tin (0.1 mL,
0.3 mmol) was added. The resulting mixture was stirred at 85 °C
for 2 h. DMF was removed in vacuo, the residue was dissolved in
THF (4 mL) and KF (ca. 0.2 g) was added. The resulting suspension
was stirred at ambient temperature for 24 h and evaporated with
small amount of silica gel. The product was purified by flash chroma-
tography on silica gel eluting with hexane, followed by EtOAc–hex-
ane (1:4) and finally EtOAc–hexane (2:3); yield 58 mg (76%), mp 99–
100 °C, pale yellow crystals. 1H NMR (CDCl3, 300 MHz) d 3.76 (s, 3H,

A. D. Khoje et al. / Bioorg. Med. Chem. 19 (2011) 3483–3491
3491
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78 (6), 77 (6); HRMS Found 303.1252, calcd for C20H17NO2
303.1259.
3.25. Determination of activity against S. aureus and E. coli
The antimicrobial susceptibilities of the quality control (QC)
strains S. aureus (ATCC 29213) and E. coli (ATCC 25922) to test anti-
microbials were determined by the broth microdilution method
using cation-adjusted Mueller-Hinton broth (Oxoid, UK) essen-
tially as previously described.14 In brief, serial twofold dilutions
(16–0.125 lg/mL) of all samples were prepared in triplicate in
microtiter plates and inoculated with a suitably prepared cell sus-
pension to achieve the required start concentration. DMSO was
used as solvent and diluent for the test substances, whereas the
gentamicin control (used to control the accuracy of testing) was
prepared using water as solvent and broth as diluent. Dilution
schemes, preparation of the inoculum and incubation conditions
were as described in the standard method and in the performance
standards supplement.13,14 For both test substances and gentami-
cin the lowest concentration that completely inhibited microbial
growth as detected by the unaided eyes was taken as the substance
MIC value
Acknowledgments
The Norwegian Research Council is gratefully acknowledged for
a grant to A.D.K. (KOSK II, project number 177368) as well as for
partial financing of the Bruker Avance instruments used in this
study.
13. Clinical and Laboratory Standards Institute (CLSI): Performance standards for
antimicrobial susceptibility testing; twentieth informational supplement. CLSI
document M100-S20, Wayne, PA, USA 2010.
14. Clinical and Laboratory Standards Institute (CLSI): Method for dilution
antimicrobial susceptibility tests for bacterial that grow aerobically;
approved standard—8th ed. CLSI document M07-A8, Wayne, PA, USA 2009.
References and notes
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Besra, G. S. Prog. Med. Chem. 2007, 45, 169.