The acid-catalysed synthesis of 7-azaindoles from 3-alkynyl-2- aminopyridines and their antimicrobial activity

Article abstract of DOI:10.1039/c3ob41798k

The synthesis of 7-azaindoles from 3-alkynyl-2-aminopyridines using acidic conditions, namely, a mixture of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA), is described. This methodology resulted in the synthesis of fifteen 7-azaindoles, with most containing substituents at the 2- and 5-positions. The majority of these were tested for antimicrobial activity against a range of bacteria and yeasts. The 7-azaindoles displayed the best activity against the yeasts, particularly against Cryptococcus neoformans, where activities as low as 3.9 μg ml^-1 were observed.

Full text of DOI:10.1039/c3ob41798k

Organic &
Biomolecular Chemistry
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The acid-catalysed synthesis of 7-azaindoles from
3-alkynyl-2-aminopyridines and their antimicrobial
activity†
Cite this: Org. Biomol. Chem., 2014,
12, 307
Tlabo C. Leboho,a Sandy F. van Vuuren,b Joseph P. Michaela and
Charles B. de Koning*a
The synthesis of 7-azaindoles from 3-alkynyl-2-aminopyridines using acidic conditions, namely, a mixture
of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA), is described. This methodology resulted
in the synthesis of fifteen 7-azaindoles, with most containing substituents at the 2- and 5-positions. The
majority of these were tested for antimicrobial activity against a range of bacteria and yeasts. The 7-aza-
indoles displayed the best activity against the yeasts, particularly against Cryptococcus neoformans,
where activities as low as 3.9 µg ml−1 were observed.
Received 3rd September 2013,
Accepted 7th November 2013
DOI: 10.1039/c3ob41798k
www.rsc.org/obc
Introduction
The azaindoles are a growing class of indole isosteres that
possess promising biological profiles. For example, the natural
product variolin B 1 (Fig. 1) isolated from an extremely rare
Antarctic sponge is a promising anti-cancer agent.1
Other examples include the synthetic azaindole derivative
of rebeccamycin, known as diazarebeccamycin 2, which has
also been shown to exhibit promising anticancer activity,2 and
6-azaindole 3 which has demonstrated activity as an inhibitor
of HIV-1 attachment to CD4+ T cells.3
The synthesis of 7-azaindoles is often accomplished by
initial Sonogashira coupling of a 3-halosubstituted-2-amino-
pyridine as shown in Scheme 1.4 The intermediate alkynylpyri-
dines are then exposed to a variety of different reaction
conditions and reagents to afford the desired azaindoles.
Many methods have been developed for this step and include
the use of cesium- or potassium-containing bases such as pot-
assium hydride, potassium t-butoxide or cesium t-butoxide5a–d
or even bases such as DBU5e and triethylamine.5f Metal-
containing catalysts have also been used for this purpose and
include amongst others, the use of copper,6a an indium salt6b
or even gold catalysts.6c The Cacchi reaction in the presence of
a palladium catalyst6d has also been successfully used to facili-
tate both the Sonogashira coupling reaction and the azaindole
Fig. 1 Examples of biologically active azaindoles.
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
PO Wits 2050, Johannesburg, South Africa. E-mail: Charles.deKoning@wits.ac.za;
Fax: +27 11 7176749; Tel: +27 11 7176724
bDepartment of Pharmacy and Pharmacology, Faculty of Health Sciences, University
of the Witwatersrand, Johannesburg, South Africa
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra are provided. See DOI: 10.1039/c3ob41798k
Scheme 1
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ring forming step to produce 2,3-disubstituted azaindoles
directly from the aminopyridines. Even the use of microwaves
in the presence of water with7a or without7b added salts has
been reported.
As a result of our interest in the synthesis of indole-contain-
ing compounds and their antibacterial and antifungal
activity,8 we initiated a programme directed towards the syn-
thesis of the related compounds, azaindoles. The specific goal
described in this publication was to attempt to develop versa-
tile and cheap conditions for the synthesis of 7-azaindoles
from the corresponding Sonogashira coupled 3-alkynyl-
2-aminopyridine precursors. Thereafter, as azaindoles have
interesting biological profiles, we wished to ascertain if the
7-azaindoles we had synthesized would display activity against
a range of bacterial and yeast cell lines.
Results and discussion
Initially the required halogenated substituted pyridines were
prepared or obtained from commercial sources. 5-Chloro-
2-aminopyridine 4, 2-aminopyridine 5, 3-bromo-2-amino-
pyridine 6 and 5-methyl-2-amino-3-bromopyridine 7 were
obtained from Sigma-Aldrich. 5-Chloro-2-aminopyridine 4 was
Scheme 3 Reagents and conditions: (i) RCuCH, Et3N, CuI, cat. Pd-
(PPh3)4, THF, 70 °C; (ii) RCuCH Et3N, CuI, cat. Pd(PPh3)4, THF, rt.
9
treated with I2 in the presence of Ag2SO4 in ethanol to afford
the 3-iodo substituted aminopyridine 8 in good yield.
Finally, 5-bromo-3-iodopyridin-2-amine 10 was prepared by
initially treating 2-aminopyridine 5 with NBS10 in MeCN to
afford 5-bromo-2-aminopyridine 9. Then 9 was subjected to
potassium iodate, I2 and a mixture of H2SO4, acetic acid and
water6a to provide 5-bromo-3-iodopyridin-2-amine 10 in good
yield (Scheme 2).
We were now in a position to attempt the Sonogashira coup-
ling reaction, for which we believed that coupling would take
place at the more reactive iodine substituent in substrates 8
and 10, or at the bromine in the case of aminopyridines 6 and
7. The 2-amino-3-halogen containing pyridines were treated
The stage was now set to attempt the formation of the
pyrrole ring in order to assemble the 7-azaindole nucleus. For
this step we wished to investigate if it was possible to use
acidic conditions to affect the ring closure. A variety of acids
(HCl, H2SO4, AcOH and trifluoroacetic acid (TFA)) were initially
used. The use of TFA seemed to be promising as a small
amount of azaindole was forming but the conversion rate was
estimated to be only 10%. Since there are examples in the
literature4 of the corresponding amide (rather than amine)
undergoing ring closure to afford azaindoles, we thought that
the addition of trifluoroacetic anhydride (TFAA) to the reaction
mixture containing TFA might improve the rate, conversion
and yield of the desired azaindoles. After much experimen-
tation we found that in the presence of 1 equivalents of TFA
and 1.3 equivalents of TFAA in MeCN as a solvent and heating
to reflux for 8 h, the substrate afforded the desired azaindoles
(15–18) in generally excellent yields (Scheme 4).
with
catalytic
tetrakis(triphenylphosphine)palladium(0),
copper(I) iodide, triethylamine as a base and a range of acety l-
enes to afford the desired compounds (11–14) in good to excel-
lent yield as shown in Scheme 3.
As one final example we wished to take advantage of the
different reactivity of the halogens on substrate 10 to establish
if it was possible to introduce two different alkyne substituents
using different temperatures. Hence as shown in Scheme 5, 10
was treated under Sonogashira reaction conditions with
phenylacetylene initially at room temperature. After TLC
showed that the starting material had all been consumed, the
solvent was evaporated under reduced pressure and the crude
material was then subjected to the same palladium catalyst
using trimethylsilylacetylene as the alkyne coupling partner.
After the reaction was deemed to be complete by TLC, work-up
of the reaction and analysis of the product by NMR spectroscopy
showed that two different alkyne substituents were present on
Scheme 2 Reagents and conditions: (i) I2, Ag2SO4, EtOH, rt, 86%; (ii)
NBS, MeCN, rt, 98%; (iii) I2, KIO3, H2SO4, AcOH, H2O, 80 °C, 90%.
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(Table 1). While compound 16b showed promising antibacte-
rial activity (7.8 µg ml−1) against Pseudomonas aeruginosa, many
of the azaindoles showed very good and selective anti-yeast
activity, particularly against Cryptococcus neoformans, where all
compounds showed noteworthy inhibitory values of between
3.9–15.6 µg ml−1. Previous studies on the antimicrobial effects
of other azaindole derivatives include the quantitative study by
Kumaran et al.,11 and the promising antifungal effects found
by Lebouvier.12 Previous antimicrobial studies on azaindoles
for activity against Cryptococcus neoformans is, however,
lacking and the promising activity noted here warrants further
examination, particularly, given that increased reports of infec-
tions from Cryptococcus neoformans show that this represents a
major health threat for HIV infected patients.13,14 Newer anti-
fungals to combat this opportunistic pathogen will certainly be
beneficial in future treatments, particularly with emerging
trends of resistance evident.
In summary, to the best of our knowledge this is the first
report outlining the synthesis of azaindoles from 3-alkynyl-
2-aminopyridines under acidic conditions. The azaindoles syn-
thesized display significant anti-yeast activity.
Experimental
1H NMR and 13C NMR spectra were recorded either on a
Bruker AVANCE 300 spectrometer or a Bruker AVANCE III 500
spectrometer. All chemical shift values are reported in parts
per million referenced against TMS which is given an assign-
ment of zero parts per million. Coupling constants (J-values)
are given in hertz (Hz). All mass spectroscopy data were col-
lected on a Waters Acquity UPLC system coupled to a Waters
HDMS G1 QTOF mass spectrometer. UPLC settings: analytical
column: BEH C18 150 × 2.1 mm; column temperature: 60 °C;
mobile phase: 90% water (0.1% formic acid): 5% acetonitrile;
flow rate: 0.4 ml min−1. MS settings: mode: VTOF; ionisation:
ESIPos and ESINeg; scan range: 100–1000 Da; scan speed: 0.1
second; run time: 10 min. 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
chromatography 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 com-
mercially available: phenylacetylene, trimethylsilylacetylene,
Scheme 4 Reagents and conditions: (i) TFA, TFAA, MeCN, 100 °C.
Scheme 5 Reagents and conditions: (i) Ph-CuCH, Et3N, CuI, Pd-
(PPh3)4, THF, rt; (ii) TMS-CuCH, Et3N, CuI, Pd(PPh3)4, THF, 70 °C. 85%
over two steps; (iii) TFA, TFAA, MeCN, 100 °C, 91%.
2-ethynylanisole,
4-ethynylanisole,
1-ethynyl-4-methoxy-2-
methylbenzene, 1-ethynyl-3,5-bis(trifluoromethyl)benzene and
propargylbenzoate. The remaining two acetylenes 1-(prop-2-
ynyl)piperidine and 4-(prop-2-ynyl)morpholine were prepared
according to ref. 15 and 16.
the 3,5-substituted aminopyridine 19. Presumably, this is due to
the different reactivities of the iodine and bromine substituents
in the two Sonogashira reactions. Exposure of 19 to our acid
mediated reaction conditions for azaindole formation resulted
in the formation of the desired azaindole 20 in excellent yield.
As we now had a series of substituted azaindoles on hand
they were quantitatively evaluated for antimicrobial activity
5-Chloro-3-iodo-2-aminopyridine 8
To
a solution of 2-amino-5-chloropyridine 4 (0.700 g,
5.45 mmol) in ethanol was added silver sulfate (1.699 g,
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Table 1 Antimicrobial and antifungal activity of selected azaindoles (µg ml−1
)
Pseudomonas
aeruginosa
Escherichia
coli
Klebsiella
pneumoniae
Staphylococcus
aureus
Enterococcus
faecalis
Cryptococcus
neoformans
Candida
tropicalis
ATCC
Candida
albicans
ATCC
Compound NCTC 9027
ATCC 8739
ATCC 8739
ATCC25923
ATCC 29212
ATCC 90112
201380
10231
15a
15b
15c
16a
16b
16c
17a
17b
18a
18b
18c
18d
18e
20
31.3
31.3
31.3
31.3
7.8
31.3
31.3
31.3
31.3
31.3
31.3
62.5
62.5
46.9
62.5
62.5
31.3
31.3
62.5
46.9
62.5
31.3
31.3
31.3
31.3
31.3
31.3
250.0
31.3
31.3
23.5
31.3
31.3
31.3
31.3
31.3
46.9
31.3
31.3
62.5
31.3
31.3
31.3
31.3
31.3
62.5
31.3
31.3
62.5
250.0
31.3
62.5
62.5
31.3
62.5
250.0
93.8
125.0
62.5
250.0
125.0
62.5
125.0
125.0
250.0
62.5
4.0
7.8
15.6
7.8
3.9
7.8
15.6
15.6
7.8
5.9
31.3
31.3
31.3
31.3
15.6
15.6
15.6
15.6
31.3
31.3
31.3
31.3
31.3
7.8
15.6
31.3
15.6
31.3
31.3
31.3
250.0
23.5
31.3
31.3
15.6
15.6
31.3
8.0
62.5
15.6
15.6
15.6
3.9
250.0
250.0
125.0
Controla
0.3
0.6
0.6
0.6
0.3
0.8
2.5
2.5
a Control for bacteria, ciprofloxacin; for the yeasts, amphotericin.
5.45 mmol) in one portion followed by the addition of iodine chromatography to give 2-amino-5-bromo-3-iodopyridine 106a
(1.383 g, 5.45 mmol) portionwise. The heterogeneous mixture as a white solid (70.11 g, 90%). 1H NMR (300 MHz, CDCl3)
was stirred at rt until determined complete by TLC. After the δ 8.05 (s, 1H), 7.95 (s, 1H), 5.03 (s, 2H); 13C NMR (75 MHz,
reaction was complete, the mixture was filtered through celite CDCl3) δ 156.75, 148.72, 148.57, 107.58, 77.93.
or silica gel and the ethanol removed under reduced pressure.
General procedure for the Sonogashira reaction to synthesize
11a–c and 12a–d
The resulting crude material was re-dissolved in dichloro-
methane and washed with a saturated solution of aqueous
sodium thiosulfate. The separated dichloromethane layer was
removed under reduced pressure and the resulting solid was
purified by silica gel chromatography to give 2-amino-5-chloro-
3-iodopyridine 89 (1.189 g 86%). 1H NMR (300 MHz, CDCl3)
δ 7.98 (d, J = 2.2, 1H), 7.84 (d, J = 2.2, 1H), 5.06 (s, 2H).
To a flame-dried round-bottom flask under a nitrogen or argon
atmosphere containing 2-amino-3-bromopyridine derivative (6
and 7) was added CuI (2 mol%) and Pd(PPh3)4 (2 mol%) in
one portion followed by the addition of the degassed alkyne
solution in THF (20 ml). Triethylamine (5 ml) was then added
and the reaction mixture was stirred at 70 °C until no starting
material was present as monitored by thin layer chromato-
graphy (TLC). After this time, the reaction was quenched with
a saturated aqueous ammonium chloride and was then
extracted with either dichloromethane or ethyl acetate. The
combined organic extracts were dried over magnesium sulfate,
filtered through either silica or celite and the excess solvent
was removed on a rotary evaporator, followed by purification
using flash chromatography (30% EtOAc–hexane) to yield the
desired products 11a–c and 12a–d.
5-Bromo-2-aminopyridine 9
2-Aminopyridine 5 (2.600 g, 0.0276 mol) was dissolved in dry
MeCN (100 ml), treated with N-bromosuccinimide (5.219 g,
0.0293 mol) and stirred for 2 h at rt. The solvent was removed
and the resulting cream white solid purified by flash chromato-
graphy to give 2-amino-5-bromopyridine 910 as a white solid
1
(4.692 g, 98%). H NMR (300 MHz, CDCl3) δ 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) δ 157.36, 148.88, 140.49, 110.42, 108.56.
3-[(2-Methoxyphenyl)ethynyl]pyridin-2-amine
2-amino-3-bromopyridine (0.450 g, 2.60 mmol), 1-ethynyl-
11a. Using
5-Bromo-3-iodo-2-aminopyridine 10
A mixture of 2-amino-5-bromopyridine 9 (45.00 g, 0.260 mol), 2-methoxybenzene (0.343 g, 2.60 mmol), CuI (9.91 mg,
iodic acid (11.86 g, 0.0676 mol), iodine (26.40 g, 0.104 mol), 0.0520 mmol) and Pd(PPh3)4 (0.0612 g, 0.0520 mmol) the
sulfuric acid (4.50 ml), acetic acid (150 ml) and water (30 ml) product 11a was obtained as a cream white solid (0.351 g,
1
was heated to 80 °C for 8 h. After this time, the reaction 75%). Mp: 118–120 °C; H NMR (500 MHz, CDCl3) δ 8.03 (d,
mixture was concentrated under vacuum and then made basic J = 5.0, 1.6, 1H), 7.57 (dt, J = 13.5, 6.7, 1H), 7.46 (dd, J = 7.6,
with an aqueous 12 M sodium hydroxide solution. The basic 1.6, 1H), 7.32 (td, J = 8.4, 1.7, 1H), 6.98–6.89 (m, 2H), 6.62 (dd,
solution was extracted with dichloromethane, washed with a J = 7.5, 5.0, 1H), 5.34 (s, 2H), 3.92 (s, 3H); 13C NMR (126 MHz,
saturated solution of sodium thiosulfate and then brine, dried CDCl3) δ 159.92, 159.17, 147.83, 138.83, 132.44, 129.95, 120.65,
over MgSO4 and then the organic solvent was removed under 113.27, 112.09, 110.53, 103.46, 92.26, 89.30, 55.82. IR (cm−1
)
vaccum. The resulting cream white solid was purified by flash 3298 (NH str.), 2997 (CH str.), 2312 (alkyne), 1619 (CvN), 1580
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(CvC), 1181 (C–O). HRMS (ES+) Calculated for C14H13N2O 1-ethynyl-4-methoxybenzene (0.3177 g, 2.41 mmol), CuI
[M + H]+: 225.1028, found 225.1032.
(9.18 mg, 0.0482 mmol) and Pd(PPh3)4 (0.0557 g,
3-[(4-Methoxyphenyl)ethynyl]pyridin-2-amine
11b. Using 0.0482 mmol), the desired product 12c (0.472 g, 82%) was
2-amino-3-bromopyridine (0.450 g, 2.60 mmol), 1-ethynyl- obtained as a cream white solid. Mp: 94–96 °C; 1H NMR
4-methoxybenzene (0.350 g, 2.60 mmol), CuI (9.91 mg, (500 MHz, CDCl3) δ 7.86 (d, J = 1.6, 1H), 7.46–7.43 (m, 2H),
0.0520 mmol) and Pd(PPh3)4 (0.0612 g, 0.0520 mmol) the 7.42 (d, J = 1.9, 1H), 6.91–6.85 (m, 2H), 4.92 (s, 2H), 3.82 (s,
product 3-[(4-methoxyphenyl)ethynyl]pyridin-2-amine 11b 3H), 2.18 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.87, 156.86,
(0.389 g, 80%) was obtained as a cream white solid. Mp: 147.56, 140.38, 132.97, 122.51, 114.90, 114.12, 103.24, 95.30,
1
159–161 °C; H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 4.9, 1.5, 83.30, 55.33, 17.26; IR (cm−1) 3276 (NH str.), 2987 (CH str.),
1H), 7.57 (dd, J = 7.5, 1.7, 1H), 7.50–7.41 (m, 2H), 6.93–6.83 2238 (alkyne), 1618 (CvN), 1564 (CvC), 1170 (C–O); HRMS
(m, 2H), 6.63 (dd, J = 7.5, 5.0, 1H), 5.05 (s, 2H), 3.83 (s, 3H); (ES+) Calculated for C15H15N2O [M + H]+: 239.1184, found
13C NMR (126 MHz, CDCl3) δ 159.93, 158.75, 147.69, 139.71, 239.1185.
133.01, 114.79, 114.13, 113.57, 103.54, 95.49, 83.14, 55.34; IR
3-[(3-Chlorophenyl)ethynyl]-5-methylpyridin-2-amine
12d.
(cm−1) 3245 (NH str.), 2986 (CH str.), 2359 (alkyne), 1619 Using 2-amino-3-bromo-5-methylpyridine (0.450 g, 2.41 mmol),
(CvN), 1558 (CvC), 1144 (C–O). HRMS (ES+) Calculated for 1-ethynyl-3-chlorobenzene (0.328 g, 2.41 mmol), CuI (9.18 mg,
C14H13N2O [M + H]+: 225.1028, found 225.1039.
0.0482 mmol) and Pd(PPh3)4 (0.0557 g, 0.0482 mmol), the
3-[(3-Chlorophenyl)ethynyl]pyridin-2-amine
11c. Using product 12d (0.482 g, 83%) was obtained as a cream white
2-amino-3-bromopyridine (0.450 g, 2.60 mmol), 1-ethynyl- solid. Mp: 104–106 °C; 1H NMR (500 MHz, CDCl3) δ 7.89 (s,
3-chlorobenzene (0.354 g, 2.60 mmol), CuI (9.91 mg, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.39 (d, J = 7.3, 1H), 7.31 (dt, J =
0.0520 mmol) and Pd(PPh3)4 (0.0612 g, 0.0520 mmol) the 13.3, 6.8, 2H), 4.93 (s, 2H), 2.20 (s, 3H); 13C NMR (126 MHz,
product 11c (0.373 g, 86%) was obtained as a cream white CDCl3) δ 156.84, 148.16, 140.86, 134.35, 131.31, 129.70, 129.58,
solid. Mp: 117–120 °C; 1H NMR (500 MHz, CDCl3) δ 8.06 (s, 128.84, 124.49, 122.68, 102.36, 93.87, 85.78, 17.25; IR (cm−1
)
1H), 7.60 (d, J = 7.3, 1H), 7.51 (s, 1H), 7.40 (d, J = 7.2, 1H), 3347 (NH str.), 3005 (CH str.), 2259 (alkyne), 1624 (CvN), 1590
7.37–7.27 (m, 2H), 6.67 (s, 1H), 5.10 (s, 2H); 13C NMR (CvC), 1176 (C–O); HRMS (ES+) Calculated for C14H12N2Cl
(126 MHz, CDCl3) δ 158.72, 148.28, 140.23, 134.37, 131.34, [M + H]+: 243.0689, found 243.0705.
129.72, 129.61, 128.91, 124.40, 113.66, 102.65, 94.04, 85.60; IR
General procedure for the Sonogashira reaction to synthesize
13a–b and 14a–e
(cm−1) 3326 (NH str.), 3003 (CH str.), 2219 (alkyne), 1627
(CvN), 1565 (CvC), 1198 (C–O); HRMS (ES+) Calculated for
C13H10N2Cl [M + H]+: 229.0533, found 229.0542.
To a flame-dried round-bottom flask under a nitrogen or argon
5-Methyl-3-(phenylethynyl)pyridin-2-amine
12a. Starting atmosphere containing 2-amino-3-iodopyridine derivative 9
with 2-amino-3-bromo-5-methylpyridine (0.450 g, 2.41 mmol), and 10 was added CuI (2 mol%) and Pd(PPh3)4 (2 mol%) in
phenylacetylene (0.2455 g, 2.41 mmol), CuI (9.18 mg, one portion followed by the addition of the degassed alkyne
0.0482 mmol) and Pd(PPh3)4 (0.0557 g, 0.0482 mmol) the solution in THF (20 ml). Triethylamine (5 ml) was then added
product 12a5c (0.450 g, 90%) was obtained as a cream white and the reaction mixture was stirred at rt, until no starting
solid. 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 1.6, 1H), material was present as monitored by thin layer chromato-
7.57–7.49 (m, 2H), 7.47 (d, J = 1.9, 1H), 7.38 (dd, J = 6.5, 2.7, graphy (TLC). After this time, the reaction was quenched with
3H), 4.97 (s, 2H), 2.21 (s, 3H); 13C NMR (75 MHz, CDCl3) a saturated aqueous ammonium chloride and was extracted
δ 156.86, 147.82, 140.62, 131.47, 128.57, 128.45, 122.77, with either dichloromethane or ethyl acetate. The combined
122.55, 102.87, 95.30, 84.58, 17.27.
organic extracts were dried over magnesium sulfate, filtered
3-[(2-Methoxyphenyl)ethynyl]-5-methylpyridin-2-amine 12b. through either silica or celite and the excess solvent was
Using
2.41
2-amino-3-bromo-5-methylpyridine
mmol), 1-ethynyl-2-methoxybenzene
(0.450
(0.3177
g, removed on a rotary evaporator, followed by purification using
g, flash chromatography (30% EtOAc–hexane) to yield the desired
2.41 mmol), CuI (9.18 mg, 0.0482 mmol) and Pd(PPh3)4 products 12a–b and 14a–e.
(0.0557 g, 0.0482 mmol), the product 3-((2-methoxyphenyl)- 5-Chloro-3-[(trimethylsilyl)ethynyl]pyridin-2-amine
13a.
ethynyl)-5-methylpyridin-2-amine 12b (0.404 g, 70%) was Using 2-amino-3-iodo-5-chloropyridine (4.475 g, 17.6 mmol),
obtained as a cream white solid. Mp: 120–123 °C; 1H NMR trimethylsilylacetylene (8.626 g, 88.1 mmol), CuI (0.06704 g,
(500 MHz, CDCl3) δ 7.86 (s, 1H), 7.49–7.39 (m, 2H), 7.31 (d, J = 0.352 mmol) and Pd(PPh3)4 (0.4068 g, 0.352 mmol) 13a
1.7, 1H), 6.94 (ddd, J = 22.1, 11.0, 4.6, 2H), 5.16 (s, 2H), 3.92 (s, (3.626 g, 92%) was obtained as a cream white solid17 (0.2153 g,
1
3H), 2.18 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.90, 157.30, 92%). H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 2.4, 1H), 7.51
147.73, 139.55, 132.45, 129.87, 122.17, 120.62, 112.19, 110.53, (d, J = 2.5, 1H), 5.06 (s, 2H), 0.27 (s, 9H).
103.13, 92.05, 89.43, 55.80, 17.29; IR (cm−1) 3301 (NH str.),
5-Chloro-3-[(4-methoxy-2-methylphenyl)ethynyl]pyridin-2-amine
3001 (CH str.), 2212 (alkyne), 1639 (CvN), 1594 (CvC), 1179 13b. Using 2-amino-3-iodo-5-chloropyridine (0.300 g,
(C–O); HRMS (ES+) Calculated for C15H15N2O [M + H]+: 1.19 mmol), 1-ethynyl-4-methoxy-2-methylbenzene (0.1740 g,
239.1184, found 239.1198. 1.19 mmol), CuI (4.517 mg, 0.0237 mmol) and Pd(PPh3)4
3-[(4-Methoxyphenyl)ethynyl]-5-methylpyridin-2-amine 12c. (0.4068 g, 0.0237 mmol) the product 13b was produced
Using 2-amino-3-bromo-5-methylpyridine (0.450 g, 2.41 mmol), (0.2834 g, 87%) as a cream white solid. Mp: 127–130 °C;
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1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.55 (s, 1H), 7.41 (d, CDCl3) δ 157.71, 150.16, 142.56, 132.76, 132.49, 131.74, 131.72,
J = 8.4, 1H), 6.79 (s, 1H), 6.74 (d, J = 8.4, 1H), 5.04 (s, 2H), 3.83 124.92, 124.25, 122.64, 122.08, 107.59, 103.59, 93.49, 86.93; IR
(s, 3H), 2.48 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.17, (cm−1) 3309 (NH str.), 2995 (CH str.), 2319 (alkyne), 1629
156.92, 145.88, 141.88, 138.66, 133.38, 120.18, 115.32, 114.26, (CvN), 1571 (CvC); HRMS (ES+) Calculated for C15H8N2BrF6
111.56, 105.04, 95.67, 85.77, 55.31, 21.18; IR (cm−1) 3368 (NH [M + H]+: 408.9775, found 408.9778.
str.), 2989 (CH str.), 2287 (alkyne), 1605 (CvN), 1558 (CvC),
1164 (C–O); HRMS (ES+) Calculated for C15H14N2ClO [M + H]+: Using 2-amino-3-iodo-5-bromopyridine (2.500 g, 8.36 mmol),
273.0795, found 273.0801. 1-ethynyl-2-methoxybenzene (1.105 g, 8.36 mmol), CuI
5-Bromo-3-[(2-methoxyphenyl)ethynyl]pyridin-2-amine 14e.
3-(2-Amino-5-bromopyridin-3-yl)prop-2-yn-1-yl benzoate 14a. (31.84 mg, 0.167 mmol), Pd(PPh3)4 (0.1932 g, 0.167 mmol)
Using 2-amino-3-iodo-5-bromopyridine (2.600 g, 8.70 mmol), furnished the product 14e as a cream white solid (2.013 g,
1
prop-2-yn-1-yl benzoate (1.672 g, 16.4 mmol), CuI (33.14 mg, 83%). Mp: 126–128 °C; H NMR (300 MHz, CDCl3) δ 8.06 (d,
0.174 mmol) and Pd(PPh3)4 (0.2011 g, 0.174 mmol) 14a J = 2.3, 1H), 7.67 (d, J = 2.3, 1H), 7.46 (dd, J = 7.5, 1.5, 1H),
(2.546 g, 88%) was obtained as a brown solid. Mp: 126–128 °C; 7.40–7.29 (m, 1H), 7.00–6.91 (m, 2H), 5.51 (s, 2H), 3.92 (s, 3H);
1H NMR (300 MHz, CDCl3) δ 8.11–8.02 (m, 3H), 7.63–7.53 (m, 13C NMR (75 MHz, CDCl3) δ 160.00, 157.82, 148.21, 140.39,
2H), 7.45 (t, J = 7.6, 2H), 5.23 (s, 2H), 5.14 (s, 2H); 13C NMR 132.47, 130.34, 120.70, 111.56, 110.55, 106.69, 105.26, 93.51,
(75 MHz, CDCl3) 13C NMR (75 MHz, CDCl3) δ 166.30, 158.39, 88.04, 55.81; IR (cm−1) 3310 (NH str.), 3002 (CH str.), 2358
149.54, 142.34, 133.77, 130.12, 129.63, 128.80, 106.91, 103.77, (alkyne), 1627 (CvN), 1571 (CvC), 1181 (C–O); HRMS (ES+) Cal-
90.95, 81.23, 53.41; IR (cm−1) 3249 (NH str.), 2989 (CH str.), culated for C14H12N2BrO [M + H]+: 303.0133, found 303.0147.
2312 (alkyne), 1629 (CvN), 1548 (CvC), 1173 (C–O); HRMS
General method for the synthesis of azaindoles 15a–c, 16a–d,
17a–b and 18a–e
(ES+) Calculated for C15H12N2O2Br [M + H]+: 331.0082, found
331.0080.
5-Bromo-3-(3-morpholinoprop-1-yn-1-yl)pyridin-2-amine 14b. The corresponding 2-amino-3-ethynylpyridine derivatives
Starting with 2-amino-3-iodo-5-bromopyridine (3.000 g, (40–200 mg) 11a–c, 12a–d, 13a–b and 14a–e were dissolved in
10.0
mmol),
4-(prop-2-yn-1-yl)morpholine
(1.253
g, MeCN. To the resulting solution was added trifluoroacetic acid
10.0 mmol), CuI (38.23 mg, 0.201 mmol) and Pd(PPh3)4 (1 eq.) in one portion followed by the addition of trifluoro-
(0.2320 g, 0.201 mmol), the product 5-bromo-3-(3-morpholino- acetic anhydride (1.3 eq.) dropwise. The resulting mixture was
prop-1-yn-1-yl)pyridin-2-amine 14b (2.541 g, 86%) was then heated to reflux for 8 h and was allowed to cool to rt. The
obtained as a brown solid. Mp: 115–118 °C; 1H NMR solvent was then removed on a rotary evaporator and the
(300 MHz, CDCl3) δ 8.01 (d, J = 2.4, 1H), 7.57 (d, J = 2.4, 1H), resulting crude material was re-dissolved in dichloromethane
5.14 (s, 2H), 3.80–3.66 (m, 4H), 3.53 (s, 2H), 2.66–2.50 (m, 4H); and washed with aqueous sodium carbonate (10%). The sepa-
13C NMR (75 MHz, CDCl3) δ 157.94, 148.74, 142.22, 107.06, rated and dried (MgSO4) organic phase was purified by flash
104.78, 91.93, 80.05, 67.05, 52.68, 48.38; IR (cm−1) 3310 (NH silica chromatography using ethyl acetate–hexane mixture
str.), 2959 (CH str.), 2291 (alkyne), 1630 (CvN), 1572 (CvC), (10–50%) gave desired azaindoles 15a–c, 16a–d, 17a–d and
1132 (C–O); HRMS (ES+) Calculated for C12H15N3BrO [M + H]+: 18a–e in good yields.
296.0398, found 296.0420.
2-(2-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine
15a. The
5-Bromo-3-[3-(piperidin-1-yl)prop-1-yn-1-yl]pyridin-2-amine product 15a was produced as a cream white solid (0.1236 g,
1
14c. Using
2-amino-3-iodo-5-bromopyridine
(3.000
g, 92%). Mp: 125–128 °C; H NMR (500 MHz, CDCl3) δ 10.47 (s,
10.0 mmol), 1-(prop-2-yn-1-yl)piperidine (1.235 g, 10.0 mmol), 1H), 8.30–8.20 (m, 1H), 7.93–7.87 (m, 1H), 7.84 (dd, J = 7.7,
CuI (38.23 mg, 0.201 mmol) and Pd(PPh3)4 (0.2320 g, 1.5, 1H), 7.36–7.27 (m, 1H), 7.12–6.98 (m, 3H), 6.84 (d, J = 1.6,
0.201 mmol) the product 14c (2.451 g, 83%) was obtained as 1H), 3.98 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 156.08, 148.60,
1
brown solid. Mp: 79–81 °C; H NMR (300 MHz, CDCl3) δ 7.99 142.91, 136.27, 129.31, 128.23, 128.04, 121.46, 120.66, 120.05,
(d, J = 2.4, 1H), 7.57 (d, J = 2.4, 1H), 5.15 (s, 2H), 3.50 (s, 2H), 116.14, 111.91, 98.09, 55.76; IR (cm−1) 3234 (NH str.), 2933
2.52 (m, 4H), 1.61 (dt, J = 11.0, 5.6, 4H), 1.42 (d, J = 5.1, 2H); (CH str.), 1626 (CvN), 1578 (CvC), 1179 (C–O); HRMS (ES+)
13C NMR (75 MHz, CDCl3) δ 157.99, 148.50, 142.11, 107.04, Calculated for C14H13N2O [M + H]+: 225.1028, found 225.1042.
105.15, 92.92, 79.53, 53.75, 48.81, 26.16, 24.09; IR (cm−1) 3262
2-(4-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine
15b. The
(NH str.), 2988 (CH str.), 2259 (alkyne), 1639 (CvN), 1558 product 15b was furnished as a cream white solid (0.1542 g,
1
(CvC); HRMS (ES+) Calculated for C13H17N3Br [M + H]+: 88%). Mp: 182–184 °C; H NMR (500 MHz, CDCl3) δ 12.35 (s,
294.0606, found 294.0613.
1H), 8.25 (d, J = 3.3, 1H), 7.92 (d, J = 7.7, 1H), 7.82 (d, J = 8.8,
3-[(3,5-Bis(trifluoromethyl)phenyl)ethynyl]-5-bromopyridin- 2H), 7.15–6.97 (m, 3H), 6.67 (s, 1H), 3.90 (s, 3H); 13C NMR
2-amine 14d. Using 2-amino-3-iodo-5-bromopyridine (1.500 g, (126 MHz, CDCl3) δ 159.83, 149.92, 141.64, 139.57, 128.25,
5.02 mmol), 1-ethynyl-3,5(trifluoromethyl)benzene (1.235 g, 127.21, 125.15, 122.56, 116.06, 114.52, 96.24, 55.44; IR (cm−1
)
10.0 mmol), CuI (19.12 mg, 0.100 mmol) and Pd(PPh3)4 3281 (NH str.), 2986 (CH str.), 1671 (CvN), 1594 (CvC), 1176
(0.1160 g, 0.100 mmol) the product 14d (1.436 g, 70%) was (C–O); HRMS (ES+) Calculated for C14H13N2O [M + H]+:
obtained as white crystals. Mp: 194–196 °C; 1H NMR 225.1028, found 225.1035.
(500 MHz, CDCl3) δ 8.14 (d, J = 2.4, 1H), 7.94 (s, 2H), 7.86 (s,
2-(3-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridine 15c. The aza-
1H), 7.74 (d, J = 2.4, 1H), 5.10 (s, 2H); 13C NMR (126 MHz, indole 15c was produced as a cream white solid (0.08213 g,
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1
81%). Mp: 205–207 °C; H NMR (500 MHz, CDCl3) δ 11.82 (s, CDCl3) δ 10.13 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.47 (d, J = 8.2,
1H), 8.37 (s, 1H), 7.98 (d, J = 7.9, 1H), 7.86 (s, 1H), 7.72 (d, J = 1H), 6.89 (s, 2H), 6.44 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H); 13C
7.5, 1H), 7.44 (t, J = 7.9, 1H), 7.37 (d, J = 7.8, 1H), 7.14 (s, 1H), NMR (126 MHz, CDCl3) δ 159.87, 147.00, 140.74, 140.15,
6.82 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 149.76, 143.05, 137.90, 130.45, 127.34, 124.29, 123.95, 122.37, 116.68, 111.72,
137.60, 135.14, 134.05, 130.36, 129.12, 128.18, 125.73, 123.79, 99.84, 55.36, 21.28; IR (cm−1) 3210 (NH str.), 2989 (CH str.),
122.03, 116.56, 98.53; IR (cm−1) 3255 (NH str.), 2987 (CH str.), 1637 (CvN), 1571 (CvC), 1182 (C–O). HRMS (ES+) Calculated
1631 (CvN), 1588 (CvC); HRMS (ES+) Calculated for for C15H14N2ClO [M + H]+: 273.0795, found 273.0803.
C13H10N2Cl [M + H]+: 229.0533, found 229.0536.
(5-Bromo-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl benzoate 18a.
5-Methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine
16a. The The azaindole 18a was formed as a cream white solid
product 16a was formed as a cream white solid15 (86%). 1H (0.4211 g, 83%). Mp: 181–184 °C; H NMR (500 MHz, MeOD)
NMR (500 MHz, DMSO) δ 11.98 (s, 1H), 8.07 (d, J = 1.3, 1H), δ 8.33 (s, 1H), 8.27 (d, J = 2.2, 1H), 8.15 (d, J = 2.2, 1H),
7.93 (d, J = 7.5, 2H), 7.72 (s, 1H), 7.46 (t, J = 7.7, 2H), 7.34 (t, J = 8.10–8.07 (m, 2H), 7.64 (t, J = 7.5, 1H), 7.50 (t, J = 7.8, 2H), 6.60
7.4, 1H), 6.84 (d, J = 1.8, 1H), 2.37 (s, 3H); 13C NMR (126 MHz, (s, 1H), 5.52 (s, 2H); 13C NMR (126 MHz, MeOD) δ 167.67,
DMSO) δ 148.33, 143.62, 138.25, 131.71, 128.84, 127.83, 148.54, 144.41, 137.76, 134.49, 132.25, 131.11, 130.77, 130.71,
1
127.56, 125.19, 124.37, 120.73, 96.49, 18.09.
129.68, 123.83, 112.41, 101.66, 60.78; IR (cm−1) 3368 (NH str.),
2-(2-Methoxyphenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine 16b. 3000 (CH str.), 1605 (CvN), 1559 (CvC), 1164 (C–O); HRMS
The desired azaindole 16b was furnished as a cream white (ES+) Calculated for C15H12N2BrO2 [M + H]+: 331.0082, found
solid (0.1001 g, 94%). Mp: 169–171 °C; 1H NMR (500 MHz, 331.0100.
CDCl3) δ 10.21 (s, 1H), 8.10 (s, 1H), 7.83 (dd, J = 7.8, 1.6, 1H),
4-[(5-Bromo-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]morpholine
7.69 (s, 1H), 7.33–7.26 (m, 1H), 7.05 (ddd, J = 13.7, 10.3, 4.6, 18b. The product 18b formed as a cream white solid (0.159 g,
1
2H), 6.75 (d, J = 2.0, 1H), 3.98 (s, 3H), 2.42 (s, 3H); 13C NMR 79%). Mp: 189–192 °C; H NMR (300 MHz, CDCl3) δ 11.21 (s,
(126 MHz, CDCl3) δ 155.99, 147.26, 143.95, 136.31, 129.14, 1H), 8.37 (d, J = 2.1, 1H), 7.97 (d, J = 2.0, 1H), 6.28 (s, 1H),
128.10, 127.97, 125.04, 121.45, 120.41, 120.14, 111.91, 97.37, 3.78–3.70 (m, 6H), 2.59–2.44 (m, 4H); 13C NMR (75 MHz,
55.75, 18.60; IR (cm−1) 3240 (NH str.), 2981 (CH str.), 1624 CDCl3) δ 147.70, 142.96, 138.67, 130.56, 123.04, 111.75, 99.65,
(CvN), 1579 (CvC), 1178 (C–O); HRMS (ES+) Calculated for 67.19, 56.72, 54.07; IR (cm−1) 3223 (NH str.), 2969 (CH str.),
C15H15N2O [M + H]+: 239.1184, found 269.1190.
2-(4-Methoxyphenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine 16c. for C12H15N3BrO [M + H]+: 296.0398, found 296.0401.
The product 16c was produced as a cream white solid 5-Bromo-2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-b]pyridine
1640 (CvN), 1573 (CvC), 1140 (C–O); HRMS (ES+) Calculated
1
(0.1011 g, 85%). Mp: 245–247 °C; H NMR (500 MHz, MeOD) 18c. The azaindole 18c was furnished as a cream white solid
1
δ 7.99 (s, 1H), 7.78 (d, J = 8.8, 2H), 7.75 (s, 1H), 7.04 (d, J = 8.8, (0.1131 g, 83%). Mp: 194–195 °C; H NMR (300 MHz, CDCl3)
2H), 6.64 (s, 1H), 3.87 (s, 3H), 2.43 (s, 3H); 13C NMR (126 MHz, δ 10.55 (s, 1H), 8.35 (d, J = 2.1, 1H), 7.94 (d, J = 2.0, 1H), 6.23
MeOD) δ 161.32, 149.06, 143.26, 140.97, 129.54, 129.51, (s, 1H), 3.65 (s, 2H), 2.43–2.38 (m, 4H), 1.66–1.53 (m, 4H), 1.46
127.96, 126.28, 126.05, 115.41, 96.61, 55.83, 18.50; IR (cm−1
)
(d, J = 4.9, 2H); 13C NMR (75 MHz, CDCl3) δ 147.50, 142.89,
3298 (NH str.), 2972 (CH str.), 1635 (CvN), 1575 (CvC), 1168 139.93, 130.25, 123.12, 111.74, 98.93, 57.02, 55.11, 26.28,
(C–O); HRMS (ES+) Calculated for C15H15N2O [M + H]+: 24.55; IR (cm−1) 3217 (NH str.), 2989 (CH str.), 1631 (CvN),
239.1184, found 239.1190.
2-(3-Chlorophenyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine 16d. 294.0606, found 294.0621.
1572 (CvC); HRMS (ES+) Calculated for C13H13N3Br [M + H]+:
The product 16d was formed as a cream white solid (0.1012 g,
82%). Mp: 239–242 °C; H NMR (500 MHz, DMSO) δ 12.07 (s, pyridine 18d. The azaindole 18d was produced as a white
2-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-1H-pyrrolo[2,3-b]-
1
1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 7.7, 1H), 7.75 (s, 1H), solid (0.1009 g, 78%). Mp: 251–253 °C; 1H NMR (500 MHz,
7.48 (t, J = 7.6, 1H), 7.39 (d, J = 7.8, 1H), 6.97 (s, 1H), 2.38 (s, acetone) δ 11.69 (s, 1H), 8.60 (s, 2H), 8.33 (d, J = 2.2, 1H), 8.21
3H); 13C NMR (126 MHz, DMSO) δ 148.34, 144.28, 136.55, (d, J = 2.2, 1H), 8.03 (s, 1H), 7.30 (s, 1H), 6.43 (s, 1H); 13C NMR
133.85, 133.80, 130.69, 127.90, 127.46, 124.75, 124.63, 123.76, (126 MHz, acetone) δ 149.39, 145.63, 137.75, 134.97, 132.78,
120.52, 97.78, 18.07; IR (cm−1) 3347 (NH str.), 2947 (CH str.), 131.55, 126.75, 126.72, 125.47, 123.56, 123.30, 122.19, 112.87,
1630 (CvN), 1587 (CvC); HRMS (ES+) Calculated for 100.82; IR (cm−1) 3293 (NH str.), 2952 (CH str.), 1641 (CvN),
C14H12N2Cl [M + H]+: 243.0689, found 243.0697.
1576 (CvC); HRMS (ES+) Calculated for C15H8N2BrF6 [M + H]+:
5-Chloro-1H-pyrrolo[2,3-b]pyridine 17a. The azaindole 17a 408.9775, found 408.9764.
1
was yielded as a cream white solid16 (0.1032 g, 84%). H NMR
5-Bromo-2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 18e.
(300 MHz, CDCl3) δ 10.89 (s, 1H), 8.29 (d, J = 2.0, 1H), 7.94 (d, The desired product 18e was produced as a cream white solid
J = 2.0, 1H), 7.46–7.35 (m, 1H), 6.62–6.24 (m, 1H); 13C NMR (0.1069, 80%). Mp: 196–197 °C; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3) δ 146.94, 141.20, 128.27, 126.86, 123.80, δ 10.38 (s, 1H), 8.30 (d, J = 1.7, 1H), 8.02 (d, J = 1.6, 1H), 7.84
121.28, 100.59; IR (cm−1) 3288 (NH str.), 2969 (CH str.), 1629 (dd, J = 7.8, 1.6, 1H), 7.43–7.32 (m, 1H), 7.17–7.02 (m, 2H),
(CvN), 1553 (CvC).
6.78 (d, J = 2.1, 1H), 4.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
5-Chloro-2-(4-methoxy-2-methylphenyl)-1H-pyrrolo[2,3-b]pyri- δ 156.08, 146.82, 143.27, 137.88, 129.87, 129.80, 128.24,
dine 17b. The desired product 17b was produced as a yellow 122.21, 121.55, 119.34, 111.96, 97.29, 55.81; IR (cm−1) 3229
solid (0.08109 g, 80%). Mp: 209–211 °C; 1H NMR (500 MHz, (NH str.), 2955 (CH str.), 1624 (CvN), 1576 (CvC), 1160
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(C–O); HRMS (ES+) Calculated for C14H12N2BrO [M + H]+: number of reference test organisms including Gram-positive
303.0133, found 303.0146. (Enterococcus faecalis ATCC 29212 and Staphylococcus aureus
3-(Phenylethynyl)-5-[(trimethylsilyl)ethynyl]pyridin-2-amine ATCC 25923), Gram-negative (Pseudomonas aeruginosa NCTC
19. To a flame-dried round-bottom flask under an argon 9027, Escherichia coli ATCC 8739 and Klebsiella pneumoniae
atmosphere containing 2-amino-3-iodopyridine derivative 10 ATCC 13883) and yeasts (Candida tropicalis ATCC 201380,
(1.379 g, 4.61 mmol) was added CuI (0.01756 g, 2 mol%) and Candida albicans ATCC 10231 and Cryptococcus neoformans
Pd(PPh3)4 (0.1066 g, 2 mol%) in one portion followed by the ATCC 90112). The positive control used for the bacteria was
addition of a degassed phenylacetylene solution in THF ciprofloxacin, while that used for the yeasts was amphotericin.
(0.4702 g, 4.61 mmol). Triethylamine (5 ml) was then added The solvent (acetone) was included in the assay as a negative
and the reaction mixture was stirred at rt, until no starting control. All antimicrobial assays were undertaken at least in
material was present as monitored by thin layer chromato- duplicate or triplicate where necessary.
graphy (TLC). After this time, the reaction was quenched with
a saturated aqueous ammonium chloride and was extracted
with dichloromethane. The combined organic extracts were
Acknowledgements
dried over magnesium sulfate, filtered through either silica or
This work was supported by the National Research Foundation
celite and the excess solvent was removed on a rotary
(NRF, GUN 2053652 and IRDP of the NRF (South Africa) for
evaporator. The resulting crude material was taken up in dry
financial support provided by the Research Niche Areas pro-
THF (20 ml) and treated with trimethylsilylacetylene (5 ml),
gramme), Pretoria, and the University of the Witwatersrand
Et3N (5 ml), CuI (17.56 mg), Pd(PPh3)4 (0.1066 g) and the reac-
(Science Faculty Research Council). We also gratefully acknowl-
tion mixture was heated to 70 °C. After 8 h the reaction mixture
edge the NRF scarce skills programme and the CSIR scholar-
was worked up as described previously, followed by purification
ship scheme for generous funding to TCL. Dr R Mampa
using flash chromatography (30% EthOAc–hexane) to afford 19
(University of the Witwatersrand) and Dr P Steenkamp (CSIR,
1
as a yellowish solid (1.139 g, 85%). Mp: 155–158 °C; H NMR
Pretoria) are thanked for providing the NMR and HRMS MS
(300 MHz, CDCl3) δ 8.18 (d, J = 1.9, 1H), 7.71 (d, J = 2.1, 1H),
spectroscopy services, respectively.
7.57–7.46 (m, 2H), 7.37 (dd, J = 9.6, 6.1, 3H), 5.34 (d, J = 23.2,
2H), 0.26 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.79, 151.11,
142.72, 131.56, 128.89, 128.53, 122.35, 109.63, 102.85, 101.84,
Notes and references
95.90, 94.99, 83.38, 0.01; IR (cm−1) 3283 (NH str.), 2956
(CH str.), 2144 (alkyne), 1625 (CvN), 1583 (CvC); HRMS (ES+)
Calculated for C18H18N2Si [M + H]+: 291.2238, found 291.2237.
2-Phenyl-5-[(trimethylsilyl)ethynyl]-1H-pyrrolo[2,3-b]pyridine
20. The forgoing 2-amino-3-ethynylpyridine derivative 19
(0.5513 g, 1.90 mmol) was dissolved in MeCN. To the resulting
solution was added trifluoroacetic acid (0.2164 g, 0.15 ml,
1.90 mmol) in one portion followed by the addition of trifluoro-
acetic anhydride (0.5187 g, 0.35 ml, 2.47 mmol) dropwise.
The resulting mixture was then heated to reflux for 8 h and
then allowed to cool to rt. The solvent was then removed on a
rotary evaporator and the resulting crude material was re-
dissolved in dichloromethane and washed with aqueous
sodium carbonate (10%). Purification by flash silica using
ethyl acetate–hexane mixture (10–50%) gave 2-phenyl-5-[(tri-
methylsilyl)ethynyl]-1H-pyrrolo[2,3-b]pyridine 20 (0.4236 g,
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91%). Mp: 255–258 °C; H NMR (500 MHz, CDCl3) δ 11.56 (s,
1H), 8.40 (d, J = 1.7, 1H), 8.05 (d, J = 1.6, 1H), 7.85–7.76 (m,
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