Double Sonogashira reactions on dihalogenated aminopyridines for the assembly of an array of 7-azaindoles bearing triazole and quinoxaline substituents at C-5: Inhibitory bioactivity against Giardia duodenalis trophozoites

Article abstract of DOI:10.1016/j.bmc.2015.05.024

The synthesis of 2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7-azaindoles from 3,5-dihalogenated 2-aminopyridines is outlined. Using a double Sonogashira coupling reaction on 2-amino-3,5-diiodopyridine followed by the Cacchi reaction the synthesis of 2,3,5-trisubstituted 7-azaindoles was accomplished. In addition, using two sequential Sonogashira coupling reactions on 2-amino-5-bromo-3-iodopyridine and a potassium t-butoxide mediated ring closure reaction resulted in the assembly of 2,5-disubstituted 7-azaindoles. The 5-alkynyl substituent of the azaindole was easily converted into both quinoxaline and triazole substituents, the latter utilizing an alkyne-azide cycloaddition reaction. Some of these azaindole derivatives showed very promising biological activity against the gastrointestinal protozoal parasite Giardia duodenalis.

Full text of DOI:10.1016/j.bmc.2015.05.024

Bioorganic & Medicinal Chemistry 23 (2015) 4943–4951
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Double Sonogashira reactions on dihalogenated aminopyridines
for the assembly of an array of 7-azaindoles bearing triazole and
quinoxaline substituents at C-5: Inhibitory bioactivity against Giardia
duodenalis trophozoites
Tlabo C. Leboho a, Somnath Giri a, Inessa Popova b, Ian Cock b, Joseph P. Michael a, Charles B. de Koning a,
⇑
a Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa
b Environmental Futures Research Institute and the School of Natural Sciences, Griffith University, Nathan Campus, 170 Kessels Road, Nathan, Queensland 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 March 2015
Revised 4 May 2015
Accepted 12 May 2015
Available online 20 May 2015
The synthesis of 2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7-azaindoles from 3,5-di-
halogenated 2-aminopyridines is outlined. Using a double Sonogashira coupling reaction on 2-amino-3,5-
diiodopyridine followed by the Cacchi reaction the synthesis of 2,3,5-trisubstituted 7-azaindoles was
accomplished. In addition, using two sequential Sonogashira coupling reactions on 2-amino-5-bromo-
3-iodopyridine and a potassium t-butoxide mediated ring closure reaction resulted in the assembly of
2,5-disubstituted 7-azaindoles. The 5-alkynyl substituent of the azaindole was easily converted into both
quinoxaline and triazole substituents, the latter utilizing an alkyne–azide cycloaddition reaction. Some of
these azaindole derivatives showed very promising biological activity against the gastrointestinal proto-
zoal parasite Giardia duodenalis.
Dedicated with respect and admiration to
Professor Cedric Holzapfel, University of
Johannesburg, on the occasion of his 80th
birthday.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
7-Azaindoles
Giardia duodenalis
Sonogashira reactions
1. Introduction
recently reprofiled and found to be effective against metronida-
zole-resistant giardiasis strains.6
Giardiasis, a disease caused by the gastrointestinal protozoal
parasite Giardia duodenalis, can cause debilitating diarrhea.1 It
was estimated in 2002 that 280 million people per year were diag-
nosed with giardiasis.2 The disease is often prevalent in poor coun-
tries and communities that have untreated water, inadequate
sanitation and poor dietary status. In South Africa a survey found
that the Giardia parasite was present in South African surface water
as well as treated effluent and drinking water in some rural areas.3
Worldwide, the drug of choice for the treatment of giardiasis is
metronidazole (1) (Fig. 1) owing to its efficacy, bioavailability, cost
and tolerance.4 However, a worrying factor is the emergence of
parasite drug resistance. In a 2014 review5 on giardiasis, the
authors state ‘Therefore, because of the prevalence of giardiasis
and limited treatment options, the development of new agents is
a high priority’. Hence, research for the development of novel,
alternative drugs for the treatment of giardiasis is highly desirable.
As a recent example, the antirheumatic drug auranofin (2) has been
2. Results and discussion
Recently, we reported the development of a new acid-catalyzed
method for the synthesis of 7-azaindoles from 3-alkynyl-2-
aminopyridines, and presented some results on their antimicrobial
activity.7 During the course of this work we were able to show that
through the use of the Sonogashira coupling reaction using dihalo-
genated aminopyridines we were able to introduce two acetylenes
onto a 2-aminopyridine nucleus (Fig. 2). In one example, it was
noted that if two different halogens were present on the aminopy-
ridine nucleus (e.g., 3) two different acetylenes could be intro-
duced sequentially to afford initially 4 and then aminopyridine 5.
The pyridine products containing the two acetylene moieties were
then transformed utilizing acidic conditions into the corresponding
7-azaindoles 6.
As the next phase of the project, we wished to take advantage of
our expertise in the synthesis of azaindoles to assemble a few small
libraries of substituted azaindoles. In addition, as we were able to
assemble azaindoles containing an acetylene at C-5, the
⇑
Corresponding author. Tel.: +27 11 7176724; fax: +27 11 7176749.
E-mail address: Charles.deKoning@wits.ac.za (C.B. de Koning).
http://dx.doi.org/10.1016/j.bmc.2015.05.024
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

4944
T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
TMS
(i)
TMS
(ii)
OAc
OH
P(Et)3
Au
N
I
I
O
NO2
AcO
AcO
N
S
OAc
2, Auranofin
N
NH2
N
NH2
1, Metronidazole
7
8
MeO
OMe
Figure 1. Structures of metronidazole (1) and auranofin (2).
(iii)
(iv)
N
NH2
R
N
NH2
(v)
9
10
Br
I
Br
A
A
MeO
OMe
N
NH2
N
NH2
3
4
R1
R
R1
B
N
NH
R
CF3
11
N
N
NH2
N
O
H
MeO
5
A = Sonogashira coupling
B = Acid catalyzed ring closure
6
Ar
Figure 2.
OMe
N
N
H
opportunity was available to expand the library by conducting
functional group manipulations on the acetylene. Finally, as we
were aware that azaindoles are a class of compounds known to
possess a range of interesting biological activities,8 we planned to
test them for their ability to inhibit Giardia duodenalis proliferation,
since a simple anti-giardial assay was available to us.
The first set of azaindoles we synthesized commenced with 3,5-
diiodoaminopyridine 7 (Scheme 1). A double Sonogashira coupling
reaction with trimethylsilylacetylene afforded 8. Removal of the
trimethylsilyl substituent with TBAF afforded 9 in good yield. A
13a, Ar = 3,5-diMeC6H4
13b, Ar = 2-MeOC6H5
13c, Ar = C6H54-CO2Me
Scheme 1. Reagents and conditions: (i) TMS-„-H, cat. Pd(PPh3)4, cat. CuI, Et3N,
THF, rt, 90%; (ii) TBAF, THF, 0 °C, 96%; (iii) 4-methoxyiodobenzene, cat. Pd(PPh3)4,
cat. CuI, Et3N, THF 93%; (iv) TFAA, THF, pyridine, 0 °C, 98%; (v) cat. Pd(PPh3)4, DMF,
aryl iodide (12a = 1-iodo-3,5-dimethylbenzene, 12b = 2-iodoanisole, 12c = ethyl 4-
iodobenzoate), Cs2CO3 or CsF, 80 °C, 83–90%.
further double Sonogashira coupling reaction on
9 with 4-
methoxyiodobenzene furnished 10. The process could be short-
ened by treating 7 with 1-ethynyl-4-methoxybenzene, but this
was the more expensive option.
apply another Sonogashira coupling reaction to the bromoazain-
doles 15a–e. Conducting the reaction on 15a–e at reflux led to
the formation of 16a–e, which was subjected to conditions
(TBAF) for the removal of the TMS substituent to furnish 17a–e
(Scheme 2).
As we had two sets of azaindoles 13a–c and 17a–e containing
an alkyne at C-5 in hand, this presented us with an ideal opportu-
nity for transformations into heterocyclic systems known to have
biological potential. We chose to explore conversions into two sys-
tems: quinoxalines,10 and also triazoles,11 with the latter accessible
by exploiting the well-known alkyne-azide cycloaddition, com-
monly known as the Click reaction.12 By using a range of azides
that were either commercially available or were easy to synthesize,
the azaindoles 17a–e were subjected to Click chemistry reaction
conditions, and eight triazoles 18a–h were assembled as shown
in Scheme 2.
Secondly, the other three acetylene-containing azaindoles 13a–
c were converted into their corresponding dicarbonyl-containing
compounds 19a–c by dissolving them in DMSO in the presence
of palladium dichloride,13 followed by irradiation with micro-
waves. These dicarbonyl-containing compounds 20a–c were con-
densed with 1,2-diamino-4,5-dimethylbenzene to afford three 7-
azaindoles 20a–c containing aryl substituents at C-2 and C-3 as
well as a quinoxaline moiety at C-5 (Scheme 3).
Preliminary tests indicated that most of the new azaindoles
18a–h, 19a–c and 20a–c showed activity against Giardia duodenalis
trophozoites. Further investigations were then performed to deter-
mine their IC50 values. The in vitro studies as shown in Table 1
indicate that at least two of the azaindoles, namely 18a and 18g
At this point we decided that in order to diversify our set of
azaindoles it would be useful to use the Cacchi reaction9 in the
presence of a palladium catalyst to produce 2,3,5-trisubstituted
7-azaindoles directly from the alkynylated 2-aminopyridines.
Aminopyridine 10 first had to be converted into the corresponding
trifluoroacetamide 11 by treatment with trifluoroacetic anhydride.
Product 11, formed smoothly in 95% yield, was then subjected to
the Cacchi reaction. After trying the reaction under a variety of
reaction conditions we found that the best yields were obtained
with three different aromatic iodides 12a–c in the presence of cat-
alytic Pd(PPh3)4 and either cesium carbonate or cesium fluoride to
furnish three 2,3,5-trisubstituted azaindoles 13a–c containing an
acetylene substituent at C-5.
For the next set of azaindoles we wished to synthesize we
wanted to take advantage of the different reactivity of aromatic
halogens when subjected to Sonogashira coupling reaction condi-
tions. When 5-bromo-3-iodoaminopyridine 3 was exposed to a
range of acetylenes (both commercial and synthesized, see
Section 4) under Sonogashira coupling reaction conditions at room
temperature, reaction occurred exclusively at the iodine-substi-
tuted site to afford 14a–e in good yields.
The next step was to form the azaindole nucleus from acetyle-
nes 14a–e, which in this case would produce 2,5-disubstituted 7-
azaindoles. For this purpose we found that the use of potassium
t-butoxide in a mixture of DMF and THF was the best method to
afford the desired azaindoles 15a–e, rather than the acid-mediated
methodology we had developed.7 We were now in a position to

T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
MeO
4945
R
Br
Br
I
Br
(ii)
(i)
Ar
N
NH2
N
14a-e
NH2
(ii)
OMe
3
N
N
H
13a, Ar = 3,5-diMeC6H4
13b, Ar = 2-MeOC6H5
13c, Ar = C6H54-CO2Me
TMS
(iii)
R
R
O
Ar
N
H
N
H
N
16a-e
N
15a-e
O
(iii)
OMe
N
H
N
(iv)
(v)
e
19a, Ar = 3,5-diM C6H4
19b, Ar = 2-MeOC6H5
19c, Ar = C6H54-CO2Me
R
N
N
H
OMe
17a-e
N
N
N
Ar
R1
N
N
R
OMe
N
N
N
H
N
H
18a-h
20a, Ar = 3,5-diMeC6H4
20b, Ar = 2-MeOC6H5
20c, Ar = C6H54-CO2Me
18a R1 = Bn;
R=
18b R1= -CH2C6H4-4-OMe
18c R1 = Bn;
R= 2-MeOC6H4
OMe
R= Ph
N
N
Ph
Scheme 3. Reagents and conditions: (i) PdCl2, DMSO, microwave, 150 W and
150 °C, 65–73%; (ii) 4,5-dimethyl-1,2-diaminobenzene, DMSO, microwave, 150 W
and 150 °C, 65–73%.
18d R1= Bn;
R=
18e R1= -CH2C6H4-4-OMe
18f R1 = Bn
R= 2 -Me OC6H4
N
N
R=
N
O
Table 1
18g R1=-C6H3-2.4-(OMe)2
R=
18h R1
R= 2-MeOC6H4
=
C6H3-2.4-(OMe)2
Inhibitory bioactivity against Giardia duodenalis trophozoites (lg/mL)
Compound
IC50
Compound
IC50
N
O
18a
18b
18c
18d
18e
18f
14.3
80.6
18h
19a
19b
19c
20a
20b
20c
447
362.6
61.4
101.3
Scheme 2. Reagents and conditions: (i) alkyne, (For 14a = phenylacetylene, 14b = 2-
ethynylanisole, 14c = 3-methyl-1-(prop-2-ynyl)-1H-pyrazole, 14d = 4-(prop-2-
ynyl)morpholine, 14e = 1-phenyl-4-(prop-2-ynyl)piperazine) cat. Pd(PPh3)4, cat.
CuI, Et3N, THF rt, (ii) tBuOK, DMF/THF, 80 °C, 52–90%; (iii)–(v) (a) TMS-„-H, cat.
Pd(PPh3)4, cat. CuI, Et3N, THF, reflux, (b) TBAF, THF, (c) aryl or benzyl azide, THF, rt,
CuSO4, sodium ascorbate, 73–80%.
a
—
325.7
a
93.8
65.6
8.2
—
136.1
60.1
18g
Metronidazole
11.4
a
Not determined.
have IC50 values in the same range as that of the gold standard
metronidazole.4 Both of these were from the subset of triazole–
azaindole containing compounds. However, another four triazoles
spectrometer. All chemical shift values are reported in parts per
million referenced against TMS which is given an assignment of
zero parts per million. Coupling constants (J-values) are given in
Hertz (Hz). All mass spectroscopy data were collected on a
Waters Acquity UPLC system coupled to a Waters HDMS G1
QTOF mass spectrometer. UPLC settings: Analytical column: BEH
C18 150 Â 2.1 mm; Column temperature: 60 °C; Mobile phase:
90% water (0.1% formic acid): 5% acetonitrile; Flow rate:
0.4 mL/min. MS settings: Mode: VTOF; Ionisation: ESIPos and
ESINeg; Scan range: 100–1000 Da; Scan speed: 0.1 s; Run time:
10 min. Microwave reactions were conducted in a CEM Discover
microwave reactor. Infrared spectra were recorded on a Bruker
Tensor 27 standard system spectrometer with diamond ATR
attachment. Macherey-Nagel Kieselgel 60 (particle size 0.063–
0.200 mm) was used for conventional silica gel column chromatog-
raphy with various EtOAc and hexane mixtures as the mobile
phase. TLC was performed on aluminum-backed Macherey-Nagel
Alugram Sil G/UV254 plates pre-coated with 0.25 mm silica gel
60. The following acetylenes are commercially available: pheny-
lacetylene, trimethylsilylacetylene, 2-ethynylanisole, while the
remaining three acetylenes 3-methyl-1-(prop-2-ynyl)-1H-pyra-
zole, 1-phenyl-4-(prop-2-ynyl)piperazine and 4-(prop-2-ynyl)-
morpholine were prepared according to Refs. 14,15.
had IC50 values below 100 lg/mL of which two were from the same
class of compounds (18f and 18e). Two other compounds, the 1,2-
diketone 19b and the quinoxaline 20c, were also moderately
active.
3. Conclusions
We have developed new methodology for the synthesis of
2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7-
azaindoles. Some very promising biological activity against the
Giardia duodenalis trophozoites has been shown. The two tria-
zole-containing azaindoles compounds showing the best activity
(18a and18g) are currently being investigated to determine the
mode of action. We plan to synthesize other derivatives that we
hope may show even better activity against the Giardia duodenalis
trophozoites.
4. Experimental
1H NMR and 13C NMR spectra were recorded either on a Bruker
AVANCE 300 spectrometer or
a Bruker AVANCE III 500

4946
T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
4.1. 3,5-Bis[(trimethylsilyl)ethynyl]pyridin-2-amine (8)
To mixture of 2-amino-3,5-diiodopyridine (3.90 g,
0.20 mL, 3.56 mmol) and the reaction mixture was cooled to 0 °C
before trifluoroacetic anhydride (0.325 g, 0.22 mL, 1.55 mmol)
was added dropwise. After the addition, the reaction mixture
was stirred for a further 2 h at the same temperature and the reac-
tion was determined to be complete by thin layer chromatography.
A saturated aqueous ammonium chloride solution (25 mL) was
added and the reaction mixture was then extracted with EtOAc
(2 Â 20 mL). The combined organic fractions were dried over
MgSO4, the excess solvent was removed on a rotary evaporator
and the residue was purified by silica flash chromatography (10%
EtOAc/hexane) to give the product 11 (0.522 g, 98%). Mp: 229–
231 °C; 1H NMR (500 MHz, CDCl3) d 8.91 (s, 1H), 8.56 (s, 1H),
7.95 (s, 1H), 7.48 (d, J = 8.8, 4H), 6.92 (d, J = 8.2, 4H), 3.85 (s, 6H);
13C NMR (125 MHz, CDCl3) d 160.85, 160.27, 149.78, 147.30,
141.88, 133.31, 133.29, 118.52, 116.73, 114.47, 114.43, 114.20,
113.08, 111.26, 100.10, 93.70, 83.44, 80.17, 55.42, 55.37; IR
(cmÀ1) 3343 (NH str.), 3006 (CH str.), 2214 (alkyne), 1721 (C@O),
1606 (C@N), 1444 (C@C), 1188 (CAO); HRMS (ES+) Calculated for
C25H18N2O3F3 [M+H]+: 451.1270, found 451.1253.
a
7
11.3 mmol), copper(I) iodide (86.0 mg, 0.451 mmol), trimethylsily-
lacetylene (2.77 g, 3.96 mL, 0.028 mol) and triethylamine (5.71 g,
7.86 mL, 0.057 mol) in tetrahydrofuran (60 mL), Pd(PPh3)4
(522 mg, 0.451 mmol) was added in one portion. The resulting
mixture was stirred at rt for 8 h after which it was quenched with
a saturated aqueous ammonium chloride solution (60 mL). The
organic material was extracted with CH2Cl2 (3 Â 50 mL), separated,
dried over MgSO4 and filtered. The excess solvent was removed
under reduced pressure and the product was purified by silica col-
umn chromatography (30% EtOAc/hexane) to give 3,5-
bis[(trimethylsilyl)ethynyl]pyridin-2-amine (8) as a cream white
solid (2.90 g, 90%). Mp: 141–143 °C; 1H NMR (300 MHz, CDCl3) d
7.90 (d, J = 1.8, 1H), 7.41 (d, J = 1.9, 1H), 5.02 (s, 2H), 0.03 (s,
18H); 13C NMR (75 MHz, CDCl3) d 158.17, 151.46, 143.10, 109.66,
102.75, 101.90, 101.88, 99.25, 94.99, 0.06; HRMS (ES+) Calculated
for C15H23N2Si2 [M+H]+: 287.1400, found 287.1398.
4.2. 3,5-Diethynylpyridin-2-amine (9)
4.5. General procedure for Cacchi reaction
To a solution of 3,5-bis[(trimethylsilyl)ethynyl]pyridin-2-amine
8 (0.786 g, 2.74 mmol) in THF (20 mL) was added TBAF (3.56 mL,
3.56 mmol) dropwise at 0 °C. The resulting mixture was then stir-
red at 0 °C for 1 h. After this time, the reaction mixture was
quenched with a saturated aqueous ammonium chloride solution
(40 mL) and was extracted with EtOAc (2 Â 50 mL). The combined
organic extracts were dried over MgSO4 and were concentrated
under reduced pressure to give a brownish solid which was puri-
fied by silica column chromatography (30% EtOAc/hexane) to give
3,5-diethynylpyridin-4-amine (9) (0.374 g, 96%) as a cream white
solid. Mp: 134–137 °C; 1H NMR (300 MHz, CDCl3) d 8.18 (d,
J = 1.8, 1H), 7.66 (d, J = 1.9, 1H), 5.37 (s, 2H), 3.42 (s, 1H), 3.06 (s,
1H); 13C NMR (75 MHz, CDCl3) d 158.68, 152.02, 143.46, 108.34,
101.45, 83.98, 80.39, 78.23, 77.95; HRMS (ES+) Calculated for
C9H7N2 [M+H]+: 143.0609, found 143.0618.
To a mixture of amide 11, cesium carbonate or cesium fluoride,
and aryl iodide 12 in DMF under nitrogen atmosphere Pd(PPh3)4
was added in one portion. The reaction mixture was heated at
80 °C for 8 h followed by cooling to rt. Water was added and either
the product precipitated from the solution or was extracted with
EtOAc (3 Â 50 mL). It was either filtered or the combined organic
extracts were dried over MgSO4, were filtered and the excess sol-
vent was removed on a rotary evaporator. The resulting residue
was purified by flash chromatography (10–50% EtOAc/hexane).
4.5.1. 3-(3,5-Dimethylphenyl)-2-(4-methoxyphenyl)-5-[(4-meth-
oxyphenyl)ethynyl]-1H-pyrrolo[2,3-b]pyridine (13a)
The product 13a was produced from 11 (0.932 g, 2.07 mmol)
and 12a (0.722 g, 3.11 mmol) as a as a cream white solid (1.02 g,
83%). Mp: 249–252 °C; 1H NMR (500 MHz, CDCl3) d 12.02 (s, 1H),
8.40 (s, 1H), 8.12 (s, 1H), 7.58 (d, J = 8.1, 2H), 7.51 (d, J = 8.0, 2H),
7.09 (s, 2H), 6.99 (d, J = 7.5, 3H), 6.92 (d, J = 8.1, 2H), 3.89 (t,
J = 13.7, 6H), 2.36 (s, 6H); 13C NMR (125 MHz, CDCl3) d 159.71,
159.57, 147.69, 145.27, 138.18, 135.84, 134.07, 132.95, 130.48,
129.78, 128.36, 127.71, 124.61, 121.76, 115.55, 114.23, 114.06,
112.56, 112.16, 89.57, 86.74, 55.34, 55.33, 21.42; IR (cmÀ1) 3250
(NH str.), 3000 (CH str.), 2240 (alkyne), 1603 (C@N), 1509 (C@C),
1169 (CAO); HRMS (ES+) Calculated for C31H26N2O2 [M+H]+:
591.2756, found 591.2755.
4.3. 3,5-Bis[(4-methoxyphenyl)ethynyl]pyridin-2-amine (10)
To a mixture of 2-amino-3,5-bisethynylpyridine 9 (0.500 g,
3.52 mmol), copper (I) iodide (13.4 mg, 0.070 mmol), 4-
methoxyiodobenzene (2.06 g, 8.80 mol) and triethylamine (1.78 g,
2.45 mL, 0.018 mol) in THF (20 mL) was added a catalytic amount
of Pd(PPh3)4 (81.4 mg, 0.070 mmol). The resulting reaction mixture
was stirred at rt for 8 h after which it was quenched with a satu-
rated aqueous solution of ammonium chloride (20 mL) before being
extracted with CH2Cl2 (2 Â 20 mL). The organic layer was dried over
MgSO4, filtered and the excess solvent was removed under reduced
pressure. The resulting residue was purified by silica column chro-
matography (30% EtOAc/hexane) to give 3,5-bis[4-methoxypheny-
l)ethynyl]pyridin-2-amine (10) as a cream white solid (1.16 g, 93%).
Mp: 152–155 °C; 1H NMR (500 MHz, CDCl3) d 8.22 (d, J = 2.1, 1H),
7.73 (d, J = 2.2, 1H), 7.50–7.44 (m, 4H), 6.94–6.87 (m, 4H), 5.26 (s,
2H), 3.85 (s, 6H); 13C NMR (125 MHz, CDCl3) d 160.09, 159.58,
157.53, 150.50, 141.80, 133.09, 132.89, 115.37, 114.52, 114.19,
114.05, 110.18, 103.31, 95.91, 89.88, 84.92, 82.35, 55.37, 55.32; IR
(cmÀ1) 3387 (NH str.), 3100 (CH str.), 2250 (alkyne), 1601 (C@N),
1461 (C@C), 1108 (CAO); HRMS (ES+) Calculated for C23H19N2O2
[M+H]+: 355.1447, found 355.1439.
4.5.2. 3-(2-Methoxyphenyl)-2-(4-methoxyphenyl)-5-[(4-meth-
oxyphenyl)ethynyl]-1H-pyrrolo[2,3-b]pyridine (13b)
The product 13b was furnished from 11 (1.13 g, 2.50 mmol) and
12b (0.878 g, 3.75 mmol) as a cream white solid (1.02 g, 89%). Mp:
247–250 °C; 1H NMR (500 MHz, CDCl3) d 11.88 (s, 1H), 8.30 (s, 1H),
7.83 (s, 1H), 7.41 (d, J = 7.9, 4H), 7.28 (d, J = 7.8, 1H), 7.24 (d, J = 7.5,
1H), 6.96–6.91 (m, 2H), 6.85 (d, J = 8.0, 2H), 6.80 (d, J = 7.9, 2H),
3.76 (s, 6H), 3.56 (s, 3H); 13C NMR (125 MHz, CDCl3) d 159.55,
159.50, 157.55, 147.78, 145.11, 136.77, 132.92, 132.52, 130.91,
129.06, 128.56, 125.32, 123.15, 122.11, 120.90, 115.64, 114.12,
114.03, 112.41, 111.50, 108.18, 89.34, 86.89, 55.32; IR (cmÀ1
)
3300 (NH str.), 3001 (CH str.), 2230 (alkyne), 1605 (C@N), 1509
(C@C), 1177 (CAO); HRMS (ES+) Calculated for C30H25N2O3
[M+H]+: 461.1865, found 461.1864.
4.4. N-{3,5-Bis[(4-methoxyphenyl)ethynyl]pyridin-2-yl}-2,2,2-
trifluoroacetamide (11)
4.5.3. Ethyl 4-{2-(4-methoxyphenyl)-5-[(4-methoxyphenyl)-
ethynyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzoate (13c)
The product 13c was yielded from 11 (1.18 g, 2.62 mmol) and 12c
(1.09 g, 3.93 mmol) as a cream white solid (1.18 g, 90%). Mp: 182–
To a solution of 3,5-bis(4-methoxybenzene)pyridin-2-amine 10
(0.420 g, 1.19 mmol) in THF (25 mL) was added pyridine (0.285 g,

T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
4947
185 °C; 1H NMR (500 MHz, CDCl3) d 12.25 (s, 1H), 8.32 (s, 1H), 8.12 (s,
1H), 8.07 (d, J = 8.2, 2H), 7.49 (m, 6H), 6.90 (d, J = = 8.5, 4H), 4.41 (q,
J = 7.1, 2H), 3.82 (s, 6H), 1.42 (t, J = 7.1, 3H); 13C NMR (125 MHz,
CDCl3) d 166.63, 160.06, 159.64, 147.63, 145.37, 139.36, 137.10,
132.96, 130.21, 130.04, 130.01, 129.60, 128.33, 123.93, 121.11,
115.36, 114.45, 114.07, 113.09, 110.86, 89.99, 86.37, 60.93, 55.33,
14.40; IR (cmÀ1) 3385 (NH str.), 2900 (CH str.), 2230 (alkyne), 1709
(C@O), 1604 (C@N), 1509 (C@C), 1172 (CAO); HRMS (ES+)
Calculated for C32H26N2O4 [M+H]+: 503.1893, found 503.1891.
Mp: 126–128 °C. 1H NMR (300 MHz, CDCl3) d 8.06 (d, J = 2.3, 1H),
7.67 (d, J = 2.3, 1H), 7.46 (dd, J = 7.5, 1.5, 1H), 7.40–7.29 (m, 1H),
7.00–6.91 (m, 2H), 5.51 (s, 2H), 3.92 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 160.00, 157.82, 148.21, 140.39, 132.47, 130.34, 120.70,
111.56, 110.55, 106.69, 105.26, 93.51, 88.04, 55.81; IR (cmÀ1
)
3310 (NH str.), 3002 (CH str.), 2358 (alkyne), 1627 (C@N), 1571
(C@C), 1181 (CAO); HRMS (ES+) Calculated for C14H12N2BrO
[M+H]+: 303.0133, found 303.0147.
4.6.3. 5-Bromo-3-[3-(3-methyl-1H-pyrazol-1-yl)-1-propynyl]-
pyridin-2-amine (14c)
4.5.4. 5-Bromopyridin-2-amine
2-Aminopyridine (2.60 g, 0.028 mol) was dissolved in dry ace-
tonitrile (100 mL), treated with N-bromosuccinimide (5.22 g,
0.029 mol) and stirred for 2 h at rt. The solvent was removed and
the resulting cream white solid purified by flash chromatography
to give commercially available 2-amino-5-bromopyridine as a
white solid (98%). 1H NMR (300 MHz, CDCl3) d 8.08 (s, 1H), 7.48
(dd, J = 8.7, 2.4, 1H), 6.41 (d, J = 8.7, 1H), 4.44 (s, 2H); 13C NMR
(75 MHz, CDCl3) d 157.36, 148.88, 140.49, 110.42, 108.56.
A cream white solid 14c (2.13 g, 89%) was furnished from 3
(2.46 g, 8.23 mmol) and 3-methyl-1-(prop-2-ynyl)-1H-pyrazole,
(1.29 g, 10.7 mmol). Mp: 113–116 °C; 1H NMR (300 MHz, CDCl3)
d 8.02 (d, J = 2.4, 2H), 8.01 (d, J = 2.4, 1H), 7.57 (d, J = 2.4, 2H),
7.54 (d, J = 2.4, 1H), 7.44 (d, J = 2.2, 2H), 7.41 (d, J = 1.5, 1H), 6.07
(d, J = 2.2, 2H), 6.05 (s, 1H), 5.24 (s, 4H), 5.09 (s, 4H), 5.08 (s, 2H),
2.36 (s, 4H), 2.27 (s, 6H); 13C NMR (75 MHz, CDCl3) d 158.28,
149.79, 149.37, 149.27, 142.09, 141.95, 139.42, 138.44, 132.44,
129.91, 106.88, 106.81, 106.49, 106.32, 103.89, 103.84, 90.34,
90.26, 80.53, 79.98, 42.25, 39.98, 13.86, 11.39; IR (cmÀ1) 3303
(NH str.), 2991 (CH str.), 2319 (alkyne), 1640 (C@N), 1572 (C@C);
HRMS (ES+) Calculated for C12H12N4Br [M+H]+: 291.0245, found
291.0261.
4.5.5. 5-Bromo-3-iodopyridin-2-amine (3)
A mixture of 2-amino-5-bromopyridine (45.0 g, 0.260 mol),
iodic acid (11.86 g, 0.068 mol), iodine (26.40 g, 0.104 mol), sulfuric
acid (4.50 mL), acetic acid (150 mL) and water (30 mL) was heated
to 80 °C for 8 h. After this time, the reaction mixture was concen-
trated under vacuum and then made basic with an aqueous 12 M
sodium hydroxide solution. The resulting basic solution was
extracted with dichloromethane (3 Â 200 mL), washed with an
aqueous saturated solution of sodium thiosulfate and then brine,
dried over magnesium sulfate and the excess organic solvent was
removed. The resulting cream white solid was purified by flash sil-
ica chromatography to give 2-amino-5-bromo-3-iodopyridine 316
as a white solid (69.94 g, 90%). 1H NMR (300 MHz, CDCl3) d 8.05
(s, 1H), 7.95 (s, 1H), 5.03 (s, 2H); 13C NMR (75 MHz, CDCl3) d
156.75, 148.72, 148.57, 107.58, 77.93.
4.6.4. 5-Bromo-3-[3-(4-morpholinyl)-1-propynyl]pyridin-2-
amine (14d)
A brown solid 14d (2.12 g, 86%) was formed from 3 (2.49 g,
8.32 mmol) and 4-(prop-2-ynyl)morpholine, (1.35 g, 10.8 mmol).
Mp: 115–118 °C; 1H NMR (300 MHz, CDCl3) d 8.01 (d, J = 2.4, 1H),
7.57 (d, J = 2.4, 1H), 5.14 (s, 2H), 3.80–3.66 (m, 4H), 3.53 (s, 2H),
2.66–2.50 (m, 4H); 13C NMR (75 MHz, CDCl3) d 157.94, 148.74,
142.22, 107.06, 104.78, 91.93, 80.05, 67.05, 52.68, 48.38; IR
(cmÀ1) 3310 (NH str.), 2959 (CH str.), 2291 (alkyne), 1630 (C@N),
1572 (C@C), 1132 (CAO); HRMS (ES+) Calculated for C12H15N3BrO
[M+H]+: 296.0398, found 296.0420.
4.6. General procedure for Sonogashira coupling reactions
4.6.5. 5-Bromo-3-[3-(4-phenylpiperazin-1-yl)-1-propynyl]-
pyridin-2-amine (14e)
To a flame-dried round-bottom flask under nitrogen or argon
atmosphere containing 2-amino-5-bromo-3-iodopyridine 3 was
added CuI (2 mol %) and Pd(PPh3)4 (2 mol %) in one portion fol-
lowed by the addition of the degassed alkyne solution in either
THF or DMF. Triethylamine was then added and the reaction mix-
ture was stirred at rt until no starting material was present as
monitored by thin layer chromatography. After this time, the reac-
tion was quenched with a saturated aqueous ammonium chloride
solution and was extracted with either CH2Cl2 or EtOAc
(3 Â 50 mL). The combined organic extracts were dried over
MgSO4, was filtered through either silica or celite and the excess
solvent was removed on a rotary evaporator, followed by purifica-
tion using silica flash chromatography (30% EtOAc/hexane) to
afford the products 14a–e.
A brown solid 14e (2.16 g, 91%) was formed from 3 (1.91 g,
6.38 mmol) and 1-phenyl-4-(prop-2-ynyl)piperazine, (1.66 g,
8.29 mmol). Mp: 94–95 °C; 1H NMR (300 MHz, CDCl3) d 8.03 (d,
J = 2.4, 1H), 7.61 (d, J = 2.4, 1H), 7.32–7.21 (m, 2H), 6.94 (dd,
J = 8.7, 0.9, 2H), 6.87 (t, J = 7.3, 1H), 5.14 (s, 2H), 3.63 (s, 2H),
3.31–3.19 (m, 4H), 2.84–2.72 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 157.94, 151.36, 148.72, 142.22, 129.42, 120.21, 116.46, 107.09,
104.85, 92.11, 80.04, 52.37, 49.37, 48.10; IR (cmÀ1) 3298 (NH
str.), 2931 (CH str.), 2298 (alkyne), 1629 (C@N), 1553 (C@C);
HRMS (ES+) Calculated for C18H20N4Br [M+H]+: 371.0871, found
371.0873.
4.7. General method for the formation of 7-azaindoles
4.6.1. 5-Bromo-3-(phenylethynyl)pyridin-2-amine (14a)
To a solution of starting material 14a–e in a mixture of DMF and
THF (1:6) was added potassium tert-butoxide (2 equiv) portion-
wise. The resulting mixture was heated at 80 °C for 8 h under a
nitrogen or argon gas atmosphere. After this time, THF was
removed and water was added. The precipitate was then collected,
washed with water and dried by storing in a desiccator in the pres-
ence of KOH. After drying, the solid products 15a–e were washed
with hexane to give the resulting products as cream white to white
solids.
The product 14a7 (2.13 g, 95%) was formed as a cream white solid
from
3
(2.45 g, 8.19 mmol) and phenylacetylene (1.09 g,
10.7 mmol). 1H NMR (300 MHz, CDCl3) d 8.06 (d, J = 2.4, 1H), 7.68
(d, J = 2.4, 1H), 7.57–7.45 (m, 2H), 7.42–7.31 (m, 3H), 5.22 (s, 2H);
13C NMR (75 MHz, CDCl3) d 157.76, 148.75, 141.89, 131.86, 129.29,
128.82, 122.46, 107.26, 105.22, 96.85, 83.47; IR (cmÀ1) 3298 (NH
str.), 3001 (CH str.), 2169 (alkyne), 1631 (C@N), 1581 (C@C).
4.6.2. 5-Bromo-3-[(2-methoxyphenyl)ethynyl]pyridin-2-amine
(14b)
A cream white solid 14b (2.01 g, 73%) was produced from 3
(2.72 g, 9.10 mmol) and 2-ethynylanisole, (1.56 g, 11.8 mmol).
4.7.1. 5-Bromo-2-phenyl-1H-pyrrolo[2,3-b]pyridine (15a)
A cream white solid7 of 15a (2.32 g, 75%) was yielded from 14a
(3.09 g, 11.3 mmol) and tBuOK (2.54 g, 22.2 mmol). 1H NMR

4948
T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
(500 MHz, DMSO) d 12.38 (s, 1H), 8.26 (d, J = 1.6, 1H), 8.16 (s, 1H),
7.94 (d, J = 7.7, 2H), 7.48 (t, J = 7.6, 2H), 7.38 (t, J = 7.3, 1H), 6.91 (s,
1H); 13C NMR (125 MHz, DMSO) d 148.00, 142.65, 140.06, 131.01,
solution in THF. Triethylamine was then added and the reaction
mixture stirred at reflux for 24 h. After this time, the reaction
was quenched with a saturated aqueous ammonium chloride solu-
tion and was extracted with either CH2Cl2 or EtOAc (3 Â 20 mL).
The combined organic extracts were dried over magnesium sulfate,
were filtered using either silica or celite and the excess solvent was
removed on a rotary evaporator. The crude material of 16a–e was
taken up in THF (15–40 mL) and was treated with TBAF (1 equiv) to
remove the silyl protecting group. This was followed by quenching
the reaction with a saturated aqueous ammonium chloride solu-
tion, extraction with either CH2Cl2 or EtOAc, filtration through a
pad of silica and then the solvent removed utilizing a rotary evap-
orator which gave the crude terminal alkynes 17a–e which was
employed in the next reaction without further purification. The
alkynes 17a–e were then treated with the appropriate azide
(2 equiv) in THF (10–15 mL) at rt for 48 h in the presence of copper
sulfate (30%), sodium ascorbate (80%) and water (5 mL). Following
extraction with CH2Cl2 (3 Â 30 mL) and drying with magnesium
sulfate, the combined organic fractions were filtered through celite
and then the organic solvent was removed on a rotary evaporator
and the resulting crude material was purified by flash silica chro-
matography using 5% MeOH/CH2Cl2 as an eluting solvent to give
the corresponding triazole derivative 18a–h.
129.64, 128.97, 128.47, 125.52, 122.78, 111.15, 96.72; IR (cmÀ1
)
3236 (NH str.), 3006 (CH str.), 2259 (alkyne), 1642 (C@N), 1573
(C@C).
4.7.2. 5-Bromo-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine
(15b)
A cream white solid 15b (1.01 g, 75%) was formed from 14b
(1.35 g, 4.45 mmol) and tBuOK (0.999 g, 8.90 mmol). Mp: 196–
197 °C; 1H NMR (300 MHz, CDCl3) d 10.38 (s, 1H), 8.30 (d, J = 1.7,
1H), 8.02 (d, J = 1.6, 1H), 7.84 (dd, J = 7.8, 1.6, 1H), 7.43–7.32 (m,
1H), 7.17–7.02 (m, 2H), 6.78 (d, J = 2.1, 1H), 4.02 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 156.08, 146.82, 143.27, 137.88, 129.87,
129.80, 128.24, 122.21, 121.55, 119.34, 111.96, 97.29, 55.81; IR
(cmÀ1) 3229 (NH str.), 2955 (CH str.), 1624 (C@N), 1576 (C@C),
1160 (CAO); HRMS (ES+) Calculated for C14H12N2BrO [M+H]+:
303.0133, found 303.0146.
4.7.3. 5-Bromo-2-[(3-methyl-1H-pyrazol-1-yl)methyl]-1H-pyr-
rolo[2,3-b]pyridine (15c)
A white solid of 15c (2.01 g, 90%) was furnished from 14c
(2.24 g, 7.68 mmol) and tBuOK (1.72 g, 15.4 mmol). Mp: 200–
203 °C; 1H NMR (500 MHz, CDCl3) d 10.97 (s, 1H), 10.58 (s, 1H),
8.35 (d, J = 13.1, 2H), 7.97 (dd, J = 12.3, 1.7, 2H), 7.46 (s, 1H), 7.31
(d, J = 1.9, 1H), 6.37 (s, 1H), 6.30 (s, 1H), 6.05 (s, 2H), 5.41 (s, 2H),
5.40 (s, 2H), 2.31 (s, 3H), 2.29 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 149.97, 147.74, 147.68, 144.09, 144.07, 139.67, 138.90, 136.25,
136.09, 131.17, 131.00, 130.46, 122.50, 122.42, 112.20, 112.14,
4.8.1. 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-[(4-phenylpiperazin-
1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (18a)
Starting material 17a (154 mg, 0.488 mmol), benzyl azide
(2 equiv, 0.98 mmol, 130 mg), CuSO4Á2H2O (0.3 equiv, 0.146 mmol,
36.6 mg), sodium ascorbate (0.8 equiv, 0.391 mmol, 77.3 mg). A
cream white solid 18a was obtained (190 mg, 87%). Mp: 228–
230 °C; 1H NMR (500 MHz, CDCl3) d 9.97 (s, 1H), 8.71 (s, 1H),
8.30 (s, 1H), 7.67 (s, 1H), 7.43–7.36 (m, 3H), 7.35–7.31 (m, 2H),
7.25 (d, J = 1.3, 1H), 7.24 (s, 1H), 6.91 (d, J = 7.9, 2H), 6.85 (t,
J = 7.3, 1H), 6.37 (s, 1H), 5.56 (s, 2H), 3.77 (s, 2H), 3.27–3.07 (m,
4H), 2.76–2.59 (m, 4H); 13C NMR (125 MHz, CDCl3) d 151.19,
148.62, 147.00, 140.64, 137.71, 134.67, 129.17, 129.11, 128.80,
128.11, 125.36, 119.77, 118.88, 116.10, 99.92, 55.91, 54.26, 53.27,
49.16; IR (cmÀ1) 3321 (NH str.), 2913 (CH str.), 1613 (C@N),
1568 (C@C); HRMS (ES+) Calculated for C27H28N7 [M+H]+:
450.2634, found 450.2403.
106.57, 106.45, 99.49, 99.03, 49.39, 46.88, 13.93, 11.40; IR (cmÀ1
)
3214 (NH str.), 2989 (CH str.), 1645 (C@N), 1576 (C@C); HRMS
(ES+) Calculated for C12H12N4Br [M+H]+: 291.0245, found 291.0265.
4.7.4. 5-Bromo-2-(4-morpholinylmethyl)-1H-pyrrolo[2,3-b]-
pyridine (15d)
A cream white solid 15d (2.13 g, 52%) was furnished after chro-
matography from 14d (4.09 g, 13.8 mmol) and tBuOK (3.10 g,
27.6 mmol). Mp: 189–192 °C; 1H NMR (300 MHz, CDCl3) d 11.21
(s, 1H), 8.37 (d, J = 2.1, 1H), 7.97 (d, J = 2.0, 1H), 6.28 (s, 1H),
3.78–3.70 (m, 6H), 2.59–2.44 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 147.70, 142.96, 138.67, 130.56, 123.04, 111.75, 99.65, 67.19,
56.72, 54.07; IR (cmÀ1) 3223 (NH str.), 2969 (CH str.), 1640
(C@N), 1573 (C@C), 1140 (CAO); HRMS (ES+) Calculated for
4.8.2. 5-[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]-2-phenyl-
1H-pyrrolo[2,3-b]pyridine (18b)
Starting material 17b (101 mg, 0.465 mmol), 4-methoxybenzyl
azide (1.5 equiv, 0.698 mmol, 113 mg), CuSO4Á2H2O (0.3 equiv,
0.140 mmol, 34.9 mg), sodium ascorbate (0.8 equiv, 0.373 mmol,
73.8 mg). A yellow solid was 18b obtained (130 mg, 73%). Mp:
286–288 °C; 1H NMR (500 MHz, DMSO) d 12.25 (s, 1H), 8.71 (d,
J = 1.8, 1H), 8.63 (s, 1H), 8.36 (d, J = 1.7, 1H), 7.96 (d, J = 7.7, 2H),
7.49 (t, J = 7.7, 2H), 7.40–7.33 (m, 3H), 6.99 (d, J = 1.9, 1H), 6.97
(d, J = 8.7, 2H), 5.58 (s, 2H), 3.75 (s, 3H); 13C NMR (125 MHz,
DMSO) d 159.15, 149.39, 145.57, 140.65, 139.13, 131.38, 129.61,
128.93, 128.15, 127.90, 125.35, 124.14, 120.79, 120.54, 119.45,
114.15, 97.37, 66.99, 55.13; IR (cmÀ1) 3214 (NH str.), 2959 (CH
str.), 1610 (C@N), 1586 (C@C), 1179 (CAO); HRMS (ES+)
Calculated for C23H20N5O [M+H]+: 382.1644, found 382.1665.
C
12H15N3BrO [M+H]+: 296.0398, found 296.0401.
4.7.5. 5-Bromo-2-[(4-phenylpiperazin-1-yl)methyl]-1H-pyrrolo-
[2,3-b]pyridine (15e)
A cream white solid 15e (1.81 g, 72%) was formed from 14e
(2.52 g, 6.78 mmol) and tBuOK (1.52 g, 13.6 mmol). Mp: 239–
241 °C; 1H NMR (500 MHz, CDCl3) d 9.70 (s, 1H), 8.32 (d, J = 2.1,
1H), 7.96 (d, J = 2.0, 1H), 7.37–7.11 (m, 3H), 7.02–6.71 (m, 3H),
6.29 (d, J = 1.6, 1H), 3.75 (s, 2H), 3.30–3.09 (m, 4H), 2.74–2.57 (m,
4H); 13C NMR (125 MHz, CDCl3) d 151.51, 147.42, 143.38, 130.47,
129.50, 122.94, 120.26, 116.53, 112.08, 99.52, 56.17, 53.67,
49.56; IR (cmÀ1) 3201 (NH str.), 2975 (CH str.), 1635 (C@N), 1575
(C@C); HRMS (ES+) Calculated for C18H20N4Br [M+H]+: 371.0871,
found 371.0885.
4.8.3. 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-(2-methoxyphenyl)-
1H-pyrrolo[2,3-b]pyridine (18c)
4.8. General procedure for the synthesis of 1,2,3-triazoles 18a–h
by the Click reaction
Starting material 17c (141 mg, 0.572 mmol), benzyl azide
(2 equiv, 1.14 mmol, 152 mg), CuSO4Á2H2O (0.3 equiv, 0.172 mmol,
43 mg), sodium ascorbate (0.8 equiv, 0.457 mmol, 0.091 mg). A
cream white solid 18c was obtained (144 mg, 79%). Mp: 223–
226 °C; 1H NMR (500 MHz, CDCl3) d 10.44 (s, 1H), 8.46 (s, 1H),
7.86 (d, J = 7.2, 1H), 7.72 (s, 1H), 7.40–7.28 (m, 7H), 7.12–7.00 (m,
3H), 5.60 (s, 2H), 4.00 (s, 3H); 13C NMR (125 MHz, CDCl3) d
To a flame-dried round-bottom flask under nitrogen or argon
containing the 5-bromo-2-substituted 7-azaindoles 15a–e was
added CuI (2 mol %) and Pd(PPh3)4 (2 mol %) in one portion fol-
lowed by the addition of the degassed trimethylsilylacetylene

T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
4949
156.02, 137.28, 134.70, 132.14, 129.54, 129.19, 128.81, 128.23,
128.13, 124.55, 121.50, 119.56, 119.03, 111.91, 98.50, 98.47,
55.80, 54.29; IR (cmÀ1) 3433 (NH str.), 2919 (CH str.), 1605
(C@N), 1569 (C@C), 1184 (CAO); HRMS (ES+) Calculated for
1639 (C@N), 1573 (C@C), 1160 (CAO); HRMS (ES+) Calculated for
C22H25N6O3 [M+H]+: 421.1988, found 421.1971.
4.8.8. 5-[1-(2,4-Dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2-
methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (18h)
C
23H20N5O [M+H]+: 382.1668, found 382.1665.
Starting material 17h (120 mg, 0.486 mmol), 1-azido-2,4-
dimethoxybenzene (2 equiv, 0.972 mmol, 174 mg), CuSO4Á2H2O
(0.3 equiv, 0.146 mmol, 36.4 mg), sodium ascorbate (0.8 equiv,
0.389 mmol, 0.077 mg). A cream white solid 18h was obtained
(165 mg, 80%). Mp: 243–246 °C; 1H NMR (500 MHz, CDCl3) d
10.18 (s, 1H), 8.79 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 7.88 (d,
J = 6.6, 1H), 7.71 (d, J = 9.2, 1H), 7.34 (t, J = 7.2, 1H), 7.08 (dd,
J = 18.6, 7.9, 2H), 6.90 (s, 1H), 6.67–6.59 (m, 2H), 4.03 (s, 3H),
3.90 (2Â s, 6H); 13C NMR (125 MHz, CDCl3) d 161.28, 156.02,
152.70, 148.39, 145.98, 141.43, 129.50, 128.21, 126.59, 125.23,
121.59, 121.30, 120.15, 119.71, 111.99, 104.85, 101.60, 99.69,
98.11, 56.06, 55.85, 55.73; IR (cmÀ1) 3421 (NH str.), 2989 (CH
str.), 1603 (C@N), 1515 (C@C), 1163 (CAO); HRMS (ES+)
Calculated for C24H22N5O3 [M+H]+: 428.1723, found 428.1719.
4.8.4. 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-(4-morpholinylme-
thyl)-1H-pyrrolo[2,3-b]pyridine (18d)
Starting material 17d (99.1 mg, 0.411 mmol), benzyl azide
(2 equiv,
0.822 mmol,
109 mg),
CuSO4Á2H2O
(0.3 equiv,
0.123 mmol, 27 mg), sodium ascorbate (0.8 equiv, 0.290 mmol,
65 mg). A cream white solid 18d was obtained (121 mg, 79%).
Mp: 227–229 °C; 1H NMR (500 MHz, CDCl3) d 10.38 (s, 1H), 8.73
(s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.43–7.38 (m, 3H), 7.37–7.32
(m, 2H), 6.35 (s, 1H), 5.60 (s, 2H), 3.72 (d, J = 5.8, 4H), 2.52 (s,
4H); 13C NMR (125 MHz, CDCl3) d 148.76, 147.05, 140.58, 137.48,
134.65, 129.20, 128.84, 128.16, 125.40, 120.93, 119.40, 118.84,
100.03, 66.95, 56.35, 54.30, 53.70; IR (cmÀ1) 3273 (NH str.), 2969
(CH str.), 1632 (C@N), 1573 (C@C), 1158 (CAO); HRMS (ES+)
Calculated for C21H23N6O [M+H]+: 375.1933, found 375.1919.
4.9. General procedure for microwave assisted synthesis of
diketone derivatives 19a–c
4.8.5. 5-[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]-2-(2-meth-
oxyphenyl)-1H-pyrrolo[2,3-b]pyridine (18e)
Starting material 17e (136 mg, 0.551 mmol), 4-methoxybenzyl
azide (2 equiv, 1.10 mmol, 180 mg), CuSO4Á2H2O (0.3 equiv,
0.165 mmol, 41.3 mg), sodium ascorbate (0.8 equiv, 0.441 mmol,
87.2 mg). A cream white solid 18e was obtained (176 mg, 77%).
Mp: 183–185 °C; 1H NMR (500 MHz, CDCl3) d 10.32 (s, 1H), 8.68
(s, 1H), 8.37 (s, 1H), 7.85 (d, J = 6.8, 1H), 7.67 (s, 1H), 7.36–7.32
(m, 1H), 7.30 (d, J = 8.6, 2H), 7.10–7.02 (m, 2H), 6.95–6.91 (m,
2H), 6.88 (s, 1H), 5.50 (s, 2H), 4.00 (s, 3H), 3.81 (s, 3H); 13C NMR
A mixture of 2,3,5-trisubstituted 7-azaindoles 13a–c (1 equiv),
palladium chloride (0.1 equiv) and DMSO (2.50 mL) in a 10 mL
microwave tube was irradiated at 150 W and 150 °C for 25 min.
After this time, the reaction mixture was allowed to cool to rt
and water (10 mL) was added. The resulting mixture was extracted
with EtOAc (3 Â 20 mL) and was washed with a saturated aqueous
ammonium chloride solution. The combined organic fractions
were dried over MgSO4, were filtered through celite and the excess
solvent was removed on a rotary evaporator. The resulting crude
material was purified by flash chromatography (10–50%
EtOAc/hexane) to give the resulting diketones 19a–c.
(125 MHz, CDCl3)
137.20, 129.74, 129.51, 128.20, 126.63, 125.02, 121.52, 119.62,
118.71, 114.54, 111.92, 98.17, 55.79, 55.35, 53.84; IR (cmÀ1
d 159.98, 155.99, 148.33, 148.32, 147.02,
)
3449 (NH str.), 2986 (CH str.), 1620 (C@N), 1576 (C@C), 1179
(CAO); HRMS (ES+) Calculated for C24H22N5O2 [M+H]+: 412.1774,
found 412.1769.
4.9.1. 1-[3-(3,5-Dimethylphenyl)-2-(4-methoxyphenyl)-1H-pyr-
rolo[2,3-b]pyridin-5-yl]-2-(4-methoxyphenyl)ethane-1,2-dione
(19a)
4.8.6. 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-[(3-methyl-1H-pyr-
azol-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (18f)
The product 19a (53.4 mg, 70%). was formed as a yellow solid
from 13a (71.5 mg, 0.156 mmol). Mp: 245–247 °C; 1H NMR
(500 MHz, CDCl3) d 13.34 (s, 1H), 8.77 (d, J = 1.9, 1H), 8.66 (d,
J = 1.8, 1H), 8.02–7.95 (m, 2H), 7.58–7.52 (m, 2H), 7.05 (s, 2H),
7.02–6.89 (m, 5H), 3.92 (s, 3H), 3.88 (s, 3H), 2.32 (d, J = 7.9, 6H);
13C NMR (125 MHz, CDCl3) d 193.77, 192.86, 164.98, 160.12,
151.15, 145.72, 138.40, 137.50, 133.26, 132.47, 129.76, 129.35,
128.83, 127.67, 126.25, 123.86, 122.82, 122.73, 114.41, 114.37,
113.59, 55.64, 55.41, 21.40; IR (cmÀ1) 3325 (NH str.), 3000 (CH
str.), 1730 (C@O), 1609 (C@N), 1508 (C@C), 1187 (CAO); HRMS
(ES+) Calculated for C31H27N2O4 [M+H]+: 491.1971, found
491.1982.
Starting material 17f (118 mg, 0.502 mmol), benzyl azide
(2 equiv, 1.00 mmol, 134 mg), CuSO4Á2H2O (0.3 equiv, 0.151 mmol,
38 mg), sodium ascorbate (0.8 equiv, 0.402 mmol, 79.5 mg). A
white solid 18f was obtained (1340 mg, 75%). Mp: 245–246 °C;
1H NMR (300 MHz, CDCl3) d 10.05 (s, 1H), 8.66 (s, 1H), 8.38 (s,
1H), 7.72 (d, J = 2.7, 1H), 7.48–7.33 (m, 6H), 6.44–6.20 (m, 1H),
6.05 (d, J = 4.9, 1H), 5.62 (s, 2H), 5.42 (s, 2H), 2.45 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 153.04, 149.73, 148.76, 146.80, 141.46,
139.38, 135.14, 134.62, 130.23, 129.19, 128.84, 128.13, 125.93,
118.90, 105.93, 99.75, 54.31, 49.04, 13.60; IR (cmÀ1) 3348 (NH
str.), 2961 (CH str.), 1633 (C@N), 1577 (C@C); HRMS (ES+)
Calculated for C21H20N7 [M+H]+: 370.2008, found 370.1777.
4.9.2. 1-(4-Methoxyphenyl)-2-[3-(2-methoxyphenyl)-2-(4-meth-
oxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]ethane-1,2-dione
(19b)
The product 19b (71.1 mg, 73%) was produced as a yellow solid
from 13b (95.0 mg, 0.206 mmol). Mp: >300 °C; 1H NMR (500 MHz,
CDCl3) d 13.35 (s, 1H), 8.82 (d, J = 1.9, 1H), 8.44 (d, J = 1.9, 1H), 7.97
(d, J = 8.9, 2H), 7.51 (d, J = 8.9, 2H), 7.37 (ddd, J = 8.3, 7.4, 1.8, 1H),
7.30–7.23 (m, 1H), 7.03–6.98 (m, 2H), 6.98–6.95 (m, 2H), 6.93–
6.89 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.62 (s, 3H); 13C NMR
4.8.7. 5-[1-(2,4-Dimethoxyphenyl)-1H-1,2,3-triazol-4-yl]-2-(4-
morpholinylmethyl)-1H-pyrrolo[2,3-b]pyridine (18g)
Starting material 17g (87 mg, 0.363 mmol), 1-azido-2,4-
dimethoxybenzene (2 equiv, 0.725 mmol, 124 mg), CuSO4Á2H2O
(0.3 equiv, 0.109 mmol, 31 mg), sodium ascorbate (0.8 equiv,
0.329 mmol, 57 mg). A cream white solid 18g was obtained
(114 mg, 74%). Mp: 218–220 °C; 1H NMR (500 MHz, CDCl3) d 9.71
(s, 1H), 8.77 (s, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.70 (d, J = 9.2, 1H),
6.64 (d, J = 7.5, 2H), 6.40 (s, 1H), 3.89 (2Â s, 6H), 3.77 (s, 4H),
2.58 (s, 4H); 13C NMR (125 MHz, CDCl3) d 161.29, 152.66, 145.81,
126.56, 125.56, 121.27, 120.80, 120.09, 104.86, 99.69, 66.77,
56.06, 55.73, 53.55; IR (cmÀ1) 3291 (NH str.), 2956 (CH str.),
(125 MHz, CDCl3)
d 194.01, 192.99, 164.93, 159.98, 157.42,
151.28, 145.30, 138.44, 132.43, 130.18, 129.22, 128.93, 126.27,
124.48, 122.86, 122.50, 122.24, 120.99, 114.35, 114.29, 111.48,
109.69, 55.63, 55.37, 55.23; IR (cmÀ1) 3315 (NH str.), 2998 (CH
str.), 1770 (C@O), 1617 (C@N), 1526 (C@C), 1187 (CAO); HRMS

4950
T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
(ES+) Calculated for C30H24N2O5 [M+H]+: 493.1728, found
493.1763.
129.79, 128.88, 128.23, 128.15, 128.12, 127.75, 125.79, 123.35,
121.98, 120.74, 114.02, 113.95, 111.42, 108.27, 55.31, 55.27,
55.25, 20.40, 20.34; IR (cmÀ1) 3301 (NH str.), 3005 (CH str.),
1606 (C@N), 1509 (C@C), 1173 (CAO); HRMS (ES+) Calculated for
4.9.3. Ethyl 4-{2-(4-methoxyphenyl)-5-[2-(4-methoxyphenyl)-
2-oxoacetyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzoate (20c)
The product 19c (60.1 mg, 65%) was formed as a yellow solid
from 13c (87.0 mg, 0.173 mmol). Mp: >300 °C; 1H NMR
(500 MHz, CDCl3) d 13.45 (s, 1H), 8.78 (d, J = 2.0, 1H), 8.66 (d,
J = 1.9, 1H), 8.09 (d, J = 8.4, 2H), 7.99 (d, J = 9.0, 2H), 7.51 (dd,
J = 10.1, 8.5, 4H), 6.98 (d, J = 9.0, 2H), 6.94 (d, J = 8.8, 2H), 4.42 (q,
J = 7.1, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 1.43 (t, J = 7.1, 3H); 13C
NMR (125 MHz, CDCl3) d 193.32, 192.46, 166.50, 165.06, 160.48,
151.11, 145.72, 138.66, 138.43, 132.53, 130.18, 130.00, 129.65,
129.21, 128.87, 126.09, 123.21, 123.01, 122.09, 114.65, 114.41,
112.30, 61.02, 55.66, 55.42, 14.39; IR (cmÀ1) 3305 (NH str.), 2995
(CH str.), 1750 (C@O), 1619 (C@N), 1529 (C@C), 1197 (CAO);
HRMS (ES+) Calculated for C32H26N2O6 [M+H]+: 535.1869, found
535.1849.
C
38H33N4O3 [M+H]+: 593.2553, found 593.2560.
4.10.3. Ethyl 4-{2-(4-methoxyphenyl)-5-[3-(4-methoxyphenyl)-
6,7-dimethylquinoxalin-2-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-
benzoate (20c)
A brownish solid 20c (120 mg, 65%) was formed from 13c
(156 mg, 0.292 mmol). Mp: 288–291 °C; 1H NMR (500 MHz,
CDCl3) d 13.07 (s, 1H), 8.62 (d, J = 2.0, 1H), 8.02 (d, J = 1.9, 1H),
7.97 (d, J = 8.4, 2H), 7.90 (t, J = 4.0, 2H), 7.55–7.48 (m, 2H), 7.47
(t, J = 6.2, 2H), 7.27 (d, J = 8.5, 2H), 6.95 (d, J = 8.2, 4H), 4.41 (q,
J = 7.1, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.53 (d, J = 1.1, 3H), 2.52 (s,
3H), 1.43 (t, J = 7.1, 3H); 13C NMR (125 MHz, CDCl3) d 160.16,
159.94, 152.34, 150.48, 148.70, 144.22, 140.36, 140.30, 140.28,
140.08, 139.45, 137.09, 132.08, 131.28, 130.06, 129.85, 129.65,
129.47, 128.20, 128.10, 128.07, 127.87, 124.23, 120.54, 118.59,
114.49, 114.07, 111.16, 60.88, 55.40, 55.31, 20.44, 20.37, 14.42;
IR (cmÀ1) 3320 (NH str.), 2933 (CH str.), 1711 (C@O), 1606
(C@N), 1512 (C@C), 1175 (CAO); HRMS (ES+) Calculated for
C40H34N4O4 [M+H]+: 635.2650, found 635.2647.
4.10. General procedure for microwave assisted synthesis of
quinoxaline derivatives 20a–c
A mixture of 2,3,5-trisubstituted 7-azaindoles 13a–c (1 equiv),
palladium chloride (0.1 equiv) and DMSO (2.50 mL) in a 10 mL
microwave tube was irradiated at 150 W and 150 °C for 25 min.
After this time, the reaction mixture was allowed to cool to rt,
and this time the intermediate diketones 19a–c were not charac-
terized but were treated with 4,5-dimethyl-1,2-diaminobenzene
and stirred at rt for about 5 mins before being irradiated under
the same conditions (150 W, 150 °C) for 25 min. The reaction mix-
ture was cooled to rt and water was added. The resulting mixture
was extracted with EtOAc (3 Â 20 mL) and washed with a satu-
rated aqueous ammonium chloride solution. The combined organic
fractions were dried over magnesium sulfate, were filtered through
celite and the excess solvent was removed on a rotary evaporator.
The resulting crude material was purified by flash chromatography
(20–50% EtOAc/hexane) to give the title compounds 20a–c.
4.11. Inhibitory bioactivity against Giardia duodenalis
trophozoites
4.11.1. Parasite culture
The Giardia duodenalis S-2 (sheep strain 2) trophozoite strain
used in this study was supplied by Assoc Prof Ann McDonnell,
Griffith University, Australia. G. duodenalis tropozoites were main-
tained and subcultured anaerobically at 37 °C in TYI-S-33 growth
media supplemented with 1% bovine bile (Sigma), 10% Serum
Supreme
(Cambrex
Bioproducts)
and
200 IU/mL
penicillin/200
lg/mL streptomycin (Invitrogen, USA). Confluent
mid log phase cultures were passaged every 2 days by chilling
the cultures on ice for a minimum of 10 min, followed by vortexing
to dislodge the adherent trophozoites from the walls of the culture
vessel. Fresh culture media (5 mL) was seeded with approximately
1 Â 105 trophozoites for each passage.
4.10.1. 2-[3-(3,5-Dimethylphenyl)-2-(4-methoxyphenyl)-1H-
pyrrolo[2,3-b]pyridin-5-yl]-3-(4-methoxyphenyl)-6,7-dime-
thylquinoxaline (20a)
The product 20a (55.1 mg, 73%) was formed as a yellow solid
from 13a (64.0 mg, 0.128 mmol). Mp: 195–198 °C; 1H NMR
(500 MHz, DMSO) d 12.15 (s, 1H), 8.45 (d, J = 2.1, 1H), 7.92 (s,
1H), 7.88 (s, 1H), 7.79 (d, J = 2.0, 1H), 7.49 (d, J = 8.8, 2H), 7.43 (d,
J = 8.8, 2H), 6.98 (d, J = 8.8, 2H), 6.94 (d, J = 8.9, 2H), 6.90 (s, 1H),
6.72 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 2.49 (s, 3H), 2.48 (s, 3H),
4.11.2. Evaluation of anti-Giardial activity
To test for anti-Giardial activity, confluent cultures were chilled
on ice for a minimum of 10 min, followed by vortexing to dislodge
the adherent trophozoites. Aliquots of the trophozoite suspension
(70
l
L) containing approximately 1 Â 105 trophozoites were added
to the wells of a 96 well plate. A volume of 30 lL of the azaindoles
2.20 (s, 6H); 13C NMR (125 MHz, DMSO)
d
159.59, 159.11,
in water containing 1% DMSO or the vehicle solvent or culture
media (for the negative controls) was added to individual wells
and the plates were incubated anaerobically at 37 °C for 12 h in a
151.81, 150.66, 148.09, 144.31, 140.30, 140.27, 139.41, 139.33,
137.58, 135.17, 133.97, 131.41, 131.26, 129.63, 127.98, 127.81,
127.60, 127.55, 127.34, 127.09, 123.72, 119.55, 113.95, 113.68,
111.38, 55.17, 20.86, 19.86, 19.84; IR (cmÀ1) 3225 (NH str.), 2900
(CH str.), 1605 (C@N), 1510 (C@C), 1174 (CAO); HRMS (ES+)
Calculated for C39H34N4O2 [M+H]+: 591.2682, found 591.2678.
humidified anaerobic atmosphere. A volume of 20 lL of CellTiter
96Ò AQueous One Solution Cell Proliferation Assay Reagent
(Promega) was subsequently added to each well and the plates
were incubated for a further 3 h. Absorbances were recorded at
490 nm using a Molecular Devices, Spectra Max M3 plate reader.
All tests were performed in at least triplicate and triplicate controls
were included on each plate. The anti-proliferative activity of each
test was calculated as a percentage of the negative control using
the following formula:
4.10.2. 2-(4-Methoxyphenyl)-3-[3-(2-methoxyphenyl)-2-(4-meth-
oxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dimethylquinox-
aline (20b)
A brownish solid 20b was formed (120 mg, 66%) from 13b
(152 mg, 0.308 mmol). Mp: 285–287 °C; 1H NMR (500 MHz,
CDCl3) d 12.76 (s, 1H), 8.50 (d, J = 1.8, 1H), 7.95 (d, J = 1.6, 1H),
7.90 (d, J = 10.5, 2H), 7.49 (d, J = 7.5, 4H), 7.33–7.27 (m, 1H),
7.15–7.11 (m, 1H), 6.98–6.90 (m, 2H), 6.87 (t, J = 8.1, 4H), 3.83 (s,
3H), 3.79 (s, 3H), 3.50 (s, 3H), 2.51 (s, 6H); 13C NMR (125 MHz,
CDCl3) d 160.04, 159.35, 157.29, 152.37, 151.21, 148.72, 143.69,
140.29, 140.13, 140.09, 140.07, 136.88, 132.40, 131.99, 131.24,
Giardial growth (% untreated control) = (Act/Acc) Â 100. Act is the
corrected absorbance for the test extract (calculated by subtracting
the absorbance of the test extract in media without cells from the
extract/cell/test combination) and Acc is the corrected untreated
control (calculated by subtracting the absorbance of the untreated
control in media without cells from the untreated cell media com-
bination). All compounds were 1 in 2 serially diluted from the

T. C. Leboho et al. / Bioorg. Med. Chem. 23 (2015) 4943–4951
2. Lane, S.; Lloyd, D. Crit. Rev. Microbiol. 2002, 28, 123.
4951
initial concentration and were tested across 6 dilutions and dose
response curves (% untreated Giardia vs dose) was plotted for each.
IC50 values (with 95% confidence limits) were calculated for each
compound using Probit analysis using the software package
XLSTAT (Addinsoft, USA).
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Acknowledgments
This work was supported by the National Research Foundation
(NRF, GUN 2053652 and IRDP of the NRF (South Africa) for finan-
cial support provided by the Research Niche Areas Programme),
Pretoria, and the University of the Witwatersrand (Science
Faculty Research Committee). The anti-Giardial studies were
funded by the Environmental Futures Research Institute, Griffith
University, Australia. We also gratefully acknowledge the NRF
scarce skills programme and the CSIR scholarship scheme for gen-
erous funding to T.C.L. The University of the Witwatersrand is
thanked for a SPARC postdoctoral fellowship award to S.G. Dr R.
Mampa (University of the Witwatersrand) and Dr P. Steenkamp
(CSIR, Pretoria) are thanked for providing the NMR and HRMS MS
spectroscopy services, respectively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2015.05.024.
15. Acquaah-Harrison, G.; Zhou, S.; Hines, J. V.; Bergmeier, S. C. J. Comb. Chem.
2010, 12, 491.
16. Barl, N. M.; Sansiaume-Dagousset, E.; Karaghiosoff, K.; Knochel, P. Angew.
Chem., Int. Ed. 2013, 52, 10093.
References and notes
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