Оптимізація та масштабування методу синтезу похідних азаіндолу
In this study, an optimized method for the synthesis of azaindoles was developed and successfully scaled up to a 100 g batch. Improved yields were observed when using electron-deficient azaheterocycles and substrates bearing electron-withdrawing substituents. 6-Chloro-1H-pyrrolo[3,2-c]pyridine was s...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
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| Дата: | 2025 |
| Том: | 23 |
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| ISSN: | 2518-1548 |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874273843442352128 |
|---|---|
| author | Kordubailo, Mykyta V. Tolmachev, Andrey A. |
| author_facet | Kordubailo, Mykyta V. Tolmachev, Andrey A. |
| author_institution_txt_mv | [
{
"author": "Mykyta V. Kordubailo",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd",
"orcid": ""
},
{
"author": "Andrey A. Tolmachev",
"institution": "Taras Shevchenko National University of Kyiv",
"orcid": "0009-0001-4351-2829"
}
] |
| author_orcid_str_mv | 0009-0001-4351-2829 |
| author_sort | Kordubailo, Mykyta V. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 10 |
| container_issue | 3 |
| container_start_page | 4 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 23 |
| datestamp_date | 2026-08-22T19:32:42Z |
| description | In this study, an optimized method for the synthesis of azaindoles was developed and successfully scaled up to a 100 g batch. Improved yields were observed when using electron-deficient azaheterocycles and substrates bearing electron-withdrawing substituents. 6-Chloro-1H-pyrrolo[3,2-c]pyridine was selected for further functionalization using a carbonylation protocol involving carbon monoxide. As a result, novel and promising building blocks for medicinal chemistry were obtained. |
| doi_str_mv | 10.24959/ophcj.25.323307 |
| first_indexed | 2025-11-16T02:25:27Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Original Research
http://ophcj.nuph.edu.ua
UDC (542.06+542.9):547.752
M. V. Kordubailo1,2, A. A. Tolmachev3
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Akademik Kuhar str., 02094 Kyiv, Ukraine
2 Enamine Ltd, 78 Winston Churchill str., 02094 Kyiv, Ukraine
3 Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine
Optimization and Scaling up of the Azaindole Derivatives
Synthesis
Abstract
In this study, an optimized method for the synthesis of azaindoles was developed and successfully scaled up to a 100 g batch.
Improved yields were observed when using electron-deficient azaheterocycles and substrates bearing electron-withdrawing
substituents. 6-Chloro-1H-pyrrolo[3,2-c]pyridine was selected for further functionalization using a carbonylation protocol
involving carbon monoxide. As a result, novel and promising building blocks for medicinal chemistry were obtained.
Keywords: azaindoles; Sonogashira coupling; Larock synthesis; carbonylation
М. В. Кордубайло1,2, А. О. Толмачов3
1 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02094, Україна
2 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
3 Київський національний університет імені Тараса Шевченка,
вул. Володимирська, 60, м. Київ, 01033, Україна
Оптимізація та масштабування методу синтезу похідних азаіндолу
Анотація
У цьому дослідженні було розроблено оптимізований метод синтезу азаіндолів, який успішно масштабовано для одер-
жання до 100 г цільової сполуки. Кращі виходи спостерігали в разі використання електронодефіцитних азагетероциклів
та замісників з електронно-акцепторними властивостями. Для подальшої функціоналізації було обрано 6-хлоро-1H-
піроло[3,2-c]піридин шляхом його карбонілювання дією карбон(ІІ) оксиду. Внаслідок цього було одержано нові пер-
спективні будівельні блоки для потреб медичної хімії.
Ключові слова: азаіндоли; реакція Соногашіри; синтез Ларока; карбонілювання
Citation: Kordubailo, M. V.; Tolmachev, A. A. Optimization and Scaling up of the Azaindole Derivatives Synthesis.
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (3), 3 – 10.
https://doi.org/10.24959/ophcj.25.323307
Supporting information: Copies of 1H, 13C, and 19F NMR spectra of the synthesized compounds.
Received: 16 June 2025; Revised: 12 September 2025; Accepted: 19 September 2025
Copyright© 2025, M. V. Kordubailo, A. A. Tolmachev. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The author received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
Azaindoles are compounds composed of fused
azaheterocyclic and pyrrole rings, forming aro-
matic frameworks that serve as bioisosteres of in-
doles and are structurally similar to purine bases.
This structural similarity contributes to their
broad spectrum of biological activities, making
them valuable in pharmaceuticals, industrial ap-
plications, and natural product chemistry [1 – 4].
According to the SciFinder® database, azain-
doles have increasingly attracted research at-
tention since 2000 (Figure 1). Since 2004, due
to their recognized antiviral properties and in-
fluenced by global health crises, the number of
publications on azaindoles has nearly doubled.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 4
Журнал органічної та фармацевтичної хімії 2025, 23 (3)
Currently, over 100 articles related to azaindoles
are published annually [5].
Numerous synthetic approaches have been de-
veloped for azaindole formation, predominantly
involving the assembly of a pyrrole ring onto existing
azaheterocyclic frameworks. However, methods
assembling azaheterocycles onto a pyrrole core
have also been documented (Figure 2) [5, 6].
■ Results and discussions
Taking into account the significant range of
biological activities exhibited by azaindoles dis-
covered over the past two decades, optimizing
synthetic routes remains critically important.
This study aimed to validate and optimize syn-
thetic methods across various electron-deficient
azaheterocycles, such as pyridine, pyrazine, and
pyrimidine.
The Larock’s synthetic approach was select-
ed to achieve the research purposes due to its
versatility and potential for structural diversity.
This methodology involves a two-step process:
the Sonogashira coupling using TMS-acetylene,
followed by the heterocyclization mediated by
KOtBu [7 – 11]. Seven azaindole derivatives were
chosen for the synthesis, including compounds
(3a, 3c, 3g) previously described to establish a more
convenient and efficient method. For example, the
synthesis of 5H-pyrrolo[2,3-b]pyrazine deriva-
tive (3a) via N-mesyl amino pyrazine reported
earlier faced difficulties at the initial stage,
resulting in low overall yields [12]. Similarly,
the synthesis of 6-chloro-1H-pyrrolo[3,2-c]pyri-
dine (3c) involved a complicated multi-step cat-
alytic oxidation [13]. Additionally, the synthesis
of 7-methyl-1H-pyrrolo[3,2-b]pyridine (3g) was
previously achieved through the Bartoli method
with only 18 % yield [14] or a multistep Suzuki
coupling [15]. Derivatives 3b, 3d, 3e, and 3f have
not been previously reported.
Commercially available amines were utilized
for synthesizing 3a, 3c, 3f, and 3g derivatives,
namely 3-chloropyrazin-2-amine (1a), 5-bromo-
2-chloropyridin-4-amine (1c), 2-chloro-5-(trifluo-
romethyl)pyridin-3-amine (1f), and 2-bromo-4-me-
thylpyridin-3-amine (1g). 5-Bromo-2-methylpy-
rimidin-4-amine (1b) was obtained with a high
yield via the halogen reduction using Pd/C fol-
lowed by the bromination (Scheme 1) [16, 17].
3-Iodo-2-methoxypyridin-4-amine (1d) was pre-
pared by the iodination using NIS in acetonitri-
le at reflux conditions [18]. For 2-bromo-6-(trifluo-
romethyl)pyridin-3-amine (1e), the bromination
with NBS was conducted in acetonitrile instead
of CHCl3, significantly reducing the formation of
regioisomers [19].
The Sonogashira reaction was scaled up to
100 g for each amine, and intermediates 2a – g
were purified by flash chromatography, result-
ing in excellent yields (Scheme 2). The lowest
yield (64.3 %) was noted for alkyne 2c due to side
reactions employing chlorine atoms. The optimal
cyclization conditions involved the use of 1.2 equiv.
Figure 1. The published papers dedicated to azaindoles
H
N
R R
X
N
Me
R
NH2
Me
R R
NH2
X
R
NH2
N
H
R
NN NN N
Figure 2. Main strategies toward azaindoles
N
N NH2
1b
Me
Cl
N
N NH2Me
N
N NH2Me
Br
H2, Pd/C
NaHCO3, MeOH, rt, 16 h AcOH, NaHCO3, rt, 16 h
Br2
Scheme 1. The synthesis of starting pyrimidine 1b
ISSN 2308-8303 (Print) / 2518-1548 (Online) 5
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (3)
of KOtBu in THF. Compounds 2 with electron-
withdrawing substituents, such as CF3 (2e, 2f)
and chlorine (2c), along with a weakly electron-
donating methyl group (2g), secured higher yields
of the target azaindoles 3 of about 70 %. At the
same time, pyrazine and pyrimidine derivatives
(3a, 3b) were obtained with 55 – 57 % yields simi-
lar to the methoxy derivative 3d (56.1 %).
Derivative 3c, known for its biological activi-
ty [20, 21], offered the additional synthetic flex-
ibility due to its halogen substituent. The cata-
lytic carbonylation with CO in the methanol me-
dium provided the corresponding ester 4c with
a high yield, which after the acidic hydrolysis
yielded carboxylic acid 7c (Scheme 3). At the
same time, the reduction of the ester with LiAlH4
yielded alcohol 5c, which was likely to be a va-
luable intermediate for MedChem research.
The reaction of 5c with SOCl2 produced chloro-
methyl derivative 8c, while the oxidation with
IBX in EtOAc yielded aldehyde 6c in a moderate
53 % yield. The corresponding amine 10c was also
synthesized via azide intermediate 9c, formed
using DPPA-DBU conditions, followed by the
Staudinger reduction, without the intermediate
purification.
■ Conclusion
In this study, an optimized method for the
azaindole synthesis was reviewed and success-
fully scaled up to a 100 g batch size. Higher yields
were achieved with electron-deficient azahetero-
cycles bearing electron-withdrawing substituents.
Additionally, 6-chloro-1H-pyrrolo[3,2-c]pyridine
was selected for further functionalization, leading
1a g–
N
N
H
N
N
H
N
N N
H
Me
N
N
H
F3C
N
N
N
H
OMe
Cl
3a, 55.2 %
N
N
H
F3C
N
N
H
Me
X
R
NH2
N
TEA, dioxane
TMS
+
CuI, Pd(dppf)Cl2
R
NH2
N
N
H
R N
3b, 56.8 % 3c, 73.7 % 3d, 56.1 % 3e, 78.2 % 3f, 74.9 % 3g, 67.0 %
N
N
NH2
TMS
N
N NH2
TMS
N
NH2
TMS
N
NH2
TMS
Me Cl
OMe
N
NH2
TMS
N
NH2
TMS
N
NH2
TMS
F3C
F3C
Me
2a
100.8 g ( )68.2 %
2b
81.2 g ( )74.4 %
2c
69.7 g ( )64.3 %
2d
67.6 g ( )76.7 %
2e
102.3 g ( )77.9 %
2f
91.2 g ( )70.2 %
2g
90.8 g ( )83.2 %
Sonogashira coupling products
Target azaindoles
64 83 %– (67 102 g)– 55 78 %– (67 102 g)–
scale: 17.2 g scale: 18.4 g scale: 45 g scale: 37.7 g scale: 30.5 g scale: 29.2 g scale: 21.7 g
2 –a g 3 –a g
Scheme 2. The synthesis of the target azaindoles: scales and yields
N
N
H
Cl
3c
N
N
H
MeO2C
N
N
H
HO
N
N
H
O
HN
N
H
Cl
N
N
H
N3
N
N
H
NH2
4c, 79 % 5c, 70 % 6c, 53 %
8c, 74 %
9c, 42.8 % 10c, 94.3 %
HN
N
H
HO2C
7c, 92 %
Cl Cl
TEA, Pd(dppf)Cl2
CO, MeOH
120
o
C;16 h
LiAlH4
THF
IBX
EtOAc
conc. HCl
80
o
C
SOCl2
CHCl3 DPPA, DBU PPh3, H2O
THFDCM
Scheme 3. The functionalization of product 3c
ISSN 2308-8303 (Print) / 2518-1548 (Online) 6
Журнал органічної та фармацевтичної хімії 2025, 23 (3)
to the preparation of novel and promising build-
ing blocks suitable for applications in medicinal
chemistry.
■ Experimental part
1H and 19F NMR spectra were recorded on
a Varian Unity Plus 400 instrument (400 and
376 MHz, respectively), 1H and 13C NMR spec-
tra were recorded on a Bruker 170 Avance 500
instrument (500 and 126 MHz, respectively),
13C NMR spectra were also recorded on an Agi-
lent ProPulse 600 (151 MHz) spectrometer.
The NMR chemical shifts were referenced using
the solvent signals at 7.26 and 77.1 ppm for 1H and
13C nuclei, respectively, in CDCl3 and 2.48 and
39.5 ppm for 1H and 13C nuclei, respectively, in
DMSO-d6; C6F6 was used as the internal stan-
dard for 19F NMR spectra. Mass spectra were ob-
tained on an Agilent LC/MSD SL 1100 instru-
ment (the atmospheric pressure electrospray ioni-
zation (ES-API)) or an Agilent 5890 Series II
5972 GCMS instrument (the electron impact (EI)
ionization (70eV)). HRMS experiments were per-
formed on an Agilent 6224 TOF LC/MS instru-
ment using the electrospray ionization. The com-
position of hydrochloride salts was determined
by the acid-base titration method. Melting points
were measured in open capillary tubes and were
given uncorrected. All starting compounds and
solvents were obtained from Enamine Ltd. and
used without additional purification.
The general procedure for the Sonoga-
shira reaction (compounds 2a – g)
To the solution of 1a – g (100 g) in 1.0 L dioxa-
ne, TMS-acetylene (1.2 equiv.) and TEA (4.0 equiv.)
were was added. Then the mixture was degassed
under argon and stirred for 10 min, CuI (0.05 equiv.)
and Pd(dppf)Cl2 (0.03 equiv.) were added in one
portion under the argon atmosphere, the result-
ing mixture was stirred at 90 °C for 16 h. Upon
completion of the reaction, the mixture was fil-
tered through a celite pad and concentrated un-
der vacuum. The crude mixture was purified by
flash column chromatography in the correspond-
ing eluent described below to give pure 2a – g.
3-((Trimethylsilyl)ethynyl)pyrazin-2-amine (2a)
Flash chromatography purification using
CHCl3–MeCN mixture (9:1) as an eluent.
A yellow solid. Yield – 100.8 g (68.2 %). M. p.
115 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
0.24 (9H, s), 6.48 (2H, s), 7.72 (1H, d, J = 2.5Hz),
7.93 (1H, d, J = 2.2Hz). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: -0.4, 100.1, 100.8, 122.9,
132.5, 142.2, 156.3. LCMS (ES-API), m/z 192
[M+H]+. HRMS (APCI), m/z: calcd for C9H13N3Si
191.0879, found 191.0875.
2-Methyl-5-((trimethylsilyl)ethynyl)pyrimi-
din-4-amine (2b)
Flash chromatography purification using CHCl3
as an eluent.
A white solid. Yield – 81.2 g (74.4 %). M. p.
125 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
0.21 (9H, s), 2.31 (3H, s), 7.46 (2H, br. s), 8.12
(1H, s). 13C NMR (126 MHz, DMSO-d6), δ, ppm:
-0.2, 25.5, 97.5, 98.0, 102.2, 157.9, 162.9, 166.1.
LCMS (ES-API), m/z 206 [M+H]+. HRMS (APCI),
m/z: calcd for C10H15N3Si 205.1030, found 205.1035.
2-Chloro-5-((trimethylsilyl)ethynyl)pyridin-
4-amine (2c)
Flash chromatography purification using CHCl3
as an eluent.
A yellow solid. Yield – 69.7 g (64.3 %). M. p.
108 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
7.93 (1H, s), 6.63 (1H, s), 6.58 (2H, br. s), 0.22
(9H, s). 13C NMR (126 MHz, DMSO-d6), δ, ppm:
0.4, 98.5, 103.1, 103.5, 106.8, 150.6, 152.4, 157.0.
LCMS (ES-API), m/z: 225 [M+H]+.
2-Methoxy-3-((trimethylsilyl)ethynyl)pyridin-
4-amine (2d)
The reaction mixture was stirred at 60° C for
16 h. Flash chromatography purification using
CHCl3 as an eluent.
A yellow solid. Yield – 67.6g (76.7 %). M. p. 72 °C.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 0.20 (9H,
s), 3.77 (3H, s), 6.09 (2H, br. s), 6.32 (1H, d, J =
6.0 Hz), 7.60 (1H, d, J = 6.0 Hz). 13C NMR
(126 MHz, DMSO-d6), δ, ppm: 0.6, 53.6, 88.0, 98.1,
104.0, 104.5, 145.9, 157.8, 164.6. LCMS (ES-API),
m/z: 221 [M+H]+. HRMS (APCI), m/z: calcd for
C11H16N2OSi 220.1032, found 220.1026.
6-(Trifluoromethyl)-2-((trimethylsilyl)ethy-
nyl)pyridin-3-amine (2e)
Flash chromatography purification using CHCl3
as an eluent.
A white solid. Yield – 102.3 g (77.9 %). M. p.
110 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm: 0.25
(9H, s), 6.16 (2H, s), 7.21 (1H, d, J = 8.5Hz), 7.49
(1H, d, J = 8.5Hz). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: -0.3, 99.8, 100.6, 120.4, 121.4, 125.5, 133.7,
134.0, 148.5. 19F NMR (376 MHz, DMSO-d6), δ,
ppm: -65.35. LCMS (ES-API), m/z: 259 [M+H]+.
HRMS (APCI), m/z: calcd for C11H13F3N2Si 258.0798,
found 258.0800.
5-(Trifluoromethyl)-2-((trimethylsilyl)ethy-
nyl)pyridin-3-amine (2f)
Flash chromatography purification using CHCl3
as an eluent.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 7
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (3)
A white solid. Yield – 91.2 g (70.2 %). M. p.
132 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
0.26 (9H, s), 5.94 (2H, s), 7.37 (1H, s), 8.01 (1H,
s). 13C NMR (126 MHz, DMSO-d6), δ, ppm: -0.4,
100.2, 101.7, 116.6, 122.5, 124.7, 129.4, 132.9,
146.0. 19F NMR (376 MHz DMSO-d6), δ, ppm:
-61.99. LCMS (ES-API), m/z: 259 [M+H]+.
HRMS (APCI), m/z: calcd for C11H13F3N2Si
258.0804, found 258.0800.
4-Methyl-2-((trimethylsilyl)ethynyl)pyridin-
3-amine (2g)
The crude mixture was treated with MTBE.
A gray solid. Yield – 90.8 g (83.2 %). M. p. 121 °C.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 0.24 (9H,
s), 5.13 (2H, s), 6.97 (1H, d, J = 4.6 Hz), 7.66 (1H,
d, J = 4.3 Hz). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: -0.2, 17.0, 98.7, 102.0, 125.3, 125.7,
129.7, 138.0, 144.8. LCMS (ES-API), m/z: 205
[M+H]+. HRMS (APCI), m/z: calcd for C11H16N2Si
204.1083, found 204.1089.
The general procedure for heterocycli-
zation 3a – g
KOtBu (1.2 equiv.) was added in one por-
tion to a stirring solution of compound 2a – g
(1 equiv., 50 g) in 1.0 L THF at 0 °C. The tem-
perature was brought to reflux, and the result-
ing mixture was stirred for 15 h. After that, the
solvent was evaporated to dryness, the residue
was poured into the mixture of the concentrat-
ed HCl and water (100 mL–400 mL), the mix-
ture was stirred for 30 min and filtered through
celite; the mother liquid was neutralized with
ammonia to pH = 10, stirred for another 30 min.
Then the precipitate was collected via the vacu-
um filtration. In case if the precipitate was not
formed, the mixture was extracted with DCM
(3×200 mL), combined organic layers were dried
with the anhydrous Na2SO4 and concentrated.
Compounds 3a – g required no additional puri-
fication.
5H-Pyrrolo[2,3-b]pyrazine (3a)
A white solid. Yield – 17.2 g (55.2 %). M. p.
153 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm: 6.61
(1H, dd, J = 3.5, 1.7 Hz), 7.85 (1H, t, J = 3.2 Hz),
8.21 (1H, d, J = 2.6 Hz), 8.36 (1H, d, J = 2.3 Hz),
12.03 (1H, s). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: 100.8, 131.5, 137.1, 138.5, 139.6, 141.7.
LCMS (ES-API), m/z: 120 [M+H]+. HRMS
(APCI), m/z: calcd for C6H5N3Si 119.0492, found
119.0483.
2-Methyl-7H-pyrrolo[2,3-d]pyrimidine (3b)
A white solid. Yield – 18.4 g (56.8 %). M. p.
179 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
2.60 (3H, s), 6.49 (1H, d, J = 2.6Hz), 7.42 (1H, s),
8.85 (1H, s), 11.88 (1H, s). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 25.9, 99.6, 116.0, 126.8,
149.2, 152.4, 159.73. LCMS (ES-API), m/z: 134
[M+H]+. HRMS (APCI), m/z: calcd for C7H7N3
133.0644, found 133.0640.
6-Chloro-1H-pyrrolo[3,2-c]pyridine (3c)
A brown solid. Yield – 45 g (73.7 %). M. p. 189 °C.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 6.59 (1H,
m), 7.42 (1H, s), 7.48 (1H, m), 8.60 (1H, s), 11.62
(1H, s). 13C NMR (126 MHz, DMSO-d6), δ, ppm:
101.0, 106.4, 125.0, 128.7, 141.7, 141.8, 142.5.
LCMS (ES-API), m/z: 153 [M+H]+. HRMS (APCI),
m/z: calcd for C7H5ClN2 152.0139, found 152.0141.
4-Methoxy-1H-pyrrolo[3,2-c]pyridine (3d)
A brown solid. Yield – 37.7 g (56.1 %). M. p.
139 °C. 1H NMR (400 MHz, CDCl3), δ, ppm: 4.10
(3H, s), 6.66 (1H, d, J = 2.3Hz), 6.97 (1H, d, J =
5.7 Hz), 7.13 (1H, m), 7.84 (1H, d, J = 5.7 Hz),
8.59 (1H, s). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: 52.9, 99.5, 103.2, 112.1, 124.7, 137.4,
141.5, 157.7. LCMS (ES-API), m/z: 149 [M+H]+.
HRMS (APCI) m/z: calcd for C8H8N2O 148.0637,
found 148.0637.
5-(Trifluoromethyl)-1H-pyrrolo[3,2-b]pyridi-
ne (3e)
A white solid. Yield – 30.5 g (78.2 %). M. p.
213 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
6.7 (1H, s), 7.54 (1H d, J = 8.2 Hz), 7.88 (1H, s),
7.99 (1H, d, J = 8.5 Hz), 11.76 (1H, br). 13C NMR
(126 MHz, DMSO-d6), δ, ppm: 102.0, 112.5, 119.4,
121.7 – 123.8 (q, J = 265 Hz, CF3), 129.6, 132.3,
139.4, 145.7. 19F NMR (376 MHz, DMSO-d6)
δ -64.47 LCMS (ES-API), m/z: 187 [M+H]+.
HRMS (APCI), m/z: calcd for C8H5F3N2
186.0402, found 186.0405.
6-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine (3f)
A white solid. Yield – 29.2 g (74.9 %). M. p.
190 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
6.71 (1H, s), 7.95 (1H, s), 8.16 (1H, s), 8.65 (1H,
s), 11.85 (1H, br). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: 101.9, 117.3, 117.4, 124.5 – 126.3 (q, J =
227 Hz, CF3), 128.1, 134.7, 138.4, 147.8. 19F NMR
(376 MHz, DMSO-d6) δ -58.81. LCMS (ES-API),
m/z: 187 [M+H]+. HRMS (APCI), m/z: calcd for
C8H5F3N2 186.0406, found 186.0405.
Methyl-1H-pyrrolo[3,2-b]pyridine (3g)
A brown solid. Yield – 21.7 g (67.0 %) M. p.
189 °C. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
2.48 (3H, s), 6.51 (1H, s), 6.89 (1H, s), 7.57 (1H,
s), 8.17 (1H, s), 11.35 (1H, s). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 16.2, 101.8, 117.4, 128.3,
128.9, 142.3, 145.2, 145.6. LCMS (ES-API)
m/z: 133 [M+H]+. HRMS (APCI), m/z: calcd for
C8H8N2 132.0685, found 132.0687.
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Журнал органічної та фармацевтичної хімії 2025, 23 (3)
The procedure for the preparation of me-
thyl 1H-pyrrolo[3,2-c]pyridine-6-carboxyla-
te (4c)
To the solution of compound 3c (30 g, 0,196 mol)
and TEA (32.9 mL, 0.234 mol) in 400 mL MeOH in
500 mL autoclave, Pd(dppf)Cl2 (4.75 g, 0.006 mol)
was added. The reaction vessel was flushed three
times with CO gas and stirred under 20 atm at
120 °C for 16 h. Upon completion, the reaction
mixture was cooled to room temperature, and the
precipitate was collected via the vacuum filtra-
tion, washed with water and MTBE, then dried
in air to obtain a pure product 4c (27.3 g, 78.9 %).
A yellow solid. Yield – 27.3 g (78.9 %). M. p.
183 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
3.85 (3H, s), 6.70 (1H, d, J = 3.2 Hz), 7.62 – 7.73
(1H, m), 8.15 (1H, s), 8.89 (1H, s), 11.94 (1H, s).
13C NMR (151 MHz, DMSO-d6), δ, ppm: 52.4,
101.5, 110.0, 127.3, 130.4, 138.6, 139.2, 143.0,
166.8. LCMS (ES), m/z: 177 [M+H]+. HRMS
(APCI), m/z: calcd for C9H8N2O2 176.0586,
found 176.0581.
The procedure for the preparation of me-
thyl 1H-pyrrolo[3,2-c]pyridine-6-carboxyla-
te (5c)
To a cooled solution of LiAlH4 (14.25 g, 1.25 equiv.)
in THF (1 L) at 0 °C, 4c (53.0 g, 0.30 mol) was
added portionwise, keeping temperature bellow
0 °C. Then mixture was stirred at room tempe-
rature for 15 h. Upon completion, the reaction
mixture was cooled to 0 oC and carefully neutra-
lized with the water-NaOH solution and water.
The mixture was stirred for 1 h at room temper-
ature, and the precipitate was filtered through
celite, washed with MTBE, then the mother liquid
was evaporated in vacuo to give a pure product 5c
(31.3 g, 70.2 %)
A yellow solid. Yield 31.3 g (70.2 %). M. p. 132 °C.
1H NMR (500 MHz, DMSO-d6), δ, ppm: 4.26 (s,
2H), 5.27 (1H, br. s), 6.51 (1H, s), 7.37 (1H, s),
7.42 (1H, s), 8.69 (1H, s), 11.44 (1H, s). 13C NMR
(151 MHz, DMSO-d6), δ, ppm: 65.0, 100.6, 103.1,
123.9, 126.7, 140.7, 142.2, 153.1; LCMS (ES),
m/z: 149 [M+H]+. HRMS (APCI), m/z: calcd for
C8H8N2O 148.0637, found 148.0635.
The procedure for the preparation of 1H-
pyrrolo[3,2-c]pyridin-6-yl)methanol (6c)
To the mixture of 5c (20.0 g, 0.135 mol) in
400 mL of EtOAc, IBX (1.5 equiv.) was added
in one portion. Then the mixture was stirred at
reflux for 15 h. Upon completion, the reaction
mixture was filtered hot through celite, washed
with EtOAc, then the mother liquid was washed
with the K2CO3 water solution (20 g in 500 mL of
water), the organic phase was dried and evapo-
rated in vacuo to give a pure product 6c (10.4 g,
52.7 %).
A yellow solid. Yield – 10.4 g (52.7 %). M. p.
162 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
6.73 (1H, d, J = 2.5 Hz), 7.75 (1H, d, J = 3Hz), 8.01
(1H, s), 9.01 (1H, s), 10.05 (1H, s), 12.08 (1H, s).
13C NMR (151 MHz, DMSO-d6), δ, ppm: 101.3,
106.6, 127.9, 131.0, 138.6, 143.2, 144.8, 193.6.
GCMS, m/z: 146 [M]+; HRMS (APCI), m/z: calcd
for C8H6N2O 146.0476, found 146.0480.
The procedure for the preparation of 1H-
pyrrolo[3,2-c]pyridine-6-carboxylic acid hyd-
rochloride (7c)
To the solution of compound 4c (1.0 g, 0.0057 mol),
the conc. HCl (10 mL) was added. The resulting
mixture was stirred at 80 °C for 15 h. Upon com-
pletion, the reaction mixture was evaporated to
dryness to obtain a yellow solid product 7c in the
form of HCl salt (1.04 g, 92.0 %).
A yellow solid. Yield – 1.04 g (92 %). M. p.
280 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
7.15 (1H, s), 8.12 (1H, s), 8.49 (1H, s), 9.29 (1H, s),
13.81 (1H, s), 14.80 (1H, br). 13C NMR (151 MHz,
DMSO-d6), δ, ppm: 105.9, 111.3, 126.0, 130.9,
135.2, 137.8, 141.6, 162.3. LCMS (ES), m/z: 163
[M+H]+. HRMS (APCI) m/z: calcd for C8H6N2O2
162.0428, found 162.0429.
The procedure for the preparation of
6-(chloromethyl)-1H-pyrrolo[3,2-c]pyridine
hydrochloride (8c)
To the solution of SOCl2 (1.5 equiv.) in 400 mL
of CHCl3, alcohol 5c (30 g, 0.20 mol) was added
dropwise at 0 °C. Then the mixture was stirred
at room temperature for 16 h. Upon completion,
the precipitate was collected via vacuum filtra-
tion, washed with CHCl3, then dried to obtain pure
product 8c (30.5 g, 74.2 %, hydrochloride salt).
A yellow solid. Yield – 30.5 g (74.2 %). M. p.
209 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
5.20 (2H, s), 7.01 (1H, d, J = 0.5 Hz), 7.96 (1H,
d, J = 2.2Hz), 8.12 (1H, s), 9.27 (1H, s), 13.37
(1H, s), 15.86 (1H, br. s). 13C NMR (151 MHz,
DMSO-d6), δ, ppm: 41.5, 104.8, 110.1, 124.1,
133.6, 136.8, 139.7, 142.4. LCMS (ES), m/z: 167
[M+H]+. HRMS (APCI) m/z: calcd for C8H7ClN2
166.0297, found 166.0298.
The procedure for the preparation of
6-(azidomethyl)-1H-pyrrolo[3,2-c]pyridine
(9c)
To a cooled to 0 °C solution of DBU (1.2 equiv.)
and 5c (5.0 g, 0.03 mol) in 200 mL of THF, DPPA
(1.2 equiv.) was added portionwise keeping tem-
perature bellow 0 °C. Then the mixture was
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (3)
stirred at room temperature for 15 h. Upon com-
pletion, the reaction mixture was evaporated to
dryness. The crude mixture was purified by co-
lumn chromatography using the CHCl3-MeCN
system as an eluent to give 9c (2.5 g, 42.8 %) as
a yellow solid with 80 % purity. The product was
used in the next step without any purification
due to stability issues.
Yield – 2.5 g (42.8 %). Purity 80 %. 1H NMR
(500 MHz, DMSO-d6), δ, ppm: 4.50 (2H, s), 6.58
(1H, d, J = 2.8 Hz), 7.41 – 7.52 (2H, m), 8.82 (1H,
s), 11.66 (1H, s).
The procedure for the preparation of
(1H-pyrrolo[3,2-c]pyridin-6-yl)methanami-
ne (10c)
To the solution of crude 9c (2.5 g, 0.01 mol)
in 50 mL of THF, PPh3 (1.2 equiv.) was added
in one portion and H2O (1.5 equiv.) in 30 min.
The resulting mixture was stirred at room tem-
perature for 15 h. Upon completion, a diluted HCl
(2 equiv.) was added, the water solution was ex-
tracted twice with CHCl3 (for PPh3 and Ph3PO
separation), and then the water solution was
neutralized with K2CO3. The precipitate was
collected via the vacuum filtration, washed with
THF, then dried to obtain a pure product 10c
(2.0 g, 94.3 %).
A white solid. Yield – 2.0 g (94.3 %). M. p.
190 °C. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
1.96 – 2.40 (1H, br. s), 3.85 (2H, s), 6.52 (1H, d,
J = 2.3 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.39 (1H, s),
8.72 (1H, s), 11.45 (1H, br. s). 13C NMR (151 MHz,
DMSO-d6), δ, ppm: 48.0, 100.5, 103.6, 123.8,
126.6, 140.7, 142.3, 154.0. LCMS (ES), m/z: 148
[M+H]+. HRMS (APCI), m/z: calcd for C8H9N3
147.0794, found 147.0796.
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Information about the authors:
Mykyta V. Kordubailo (corresponding author), Ph.D. student, Medicinal Chemistry Department, Institute of Organic Chemistry of the
National Academy of Sciences of Ukraine; https://orcid.org/0000-0002-8567-9838; e-mail for correspondence: nikita141193@gmail.com.
Andrey A. Tolmachev, D.Sci. in Chemistry, Professor, Director of ChemBioCenter of Taras Shevchenko National University of Kyiv;
https://orcid.org/0009-0001-4351-2829.
|
| id | oai:ojs.journals.uran.ua:article-323307 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-23T01:00:26Z |
| publishDate | 2025 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/10/a31dace92809fbb771ed6c6427e21310.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3233072026-08-22T19:32:42Z Optimization and Scaling up of the Azaindole Derivatives Synthesis Оптимізація та масштабування методу синтезу похідних азаіндолу Kordubailo, Mykyta V. Tolmachev, Andrey A. азаіндоли реакція Соногашіри синтез Ларока карбонілювання azaindoles Sonogashira coupling Larock synthesis carbonylation In this study, an optimized method for the synthesis of azaindoles was developed and successfully scaled up to a 100 g batch. Improved yields were observed when using electron-deficient azaheterocycles and substrates bearing electron-withdrawing substituents. 6-Chloro-1H-pyrrolo[3,2-c]pyridine was selected for further functionalization using a carbonylation protocol involving carbon monoxide. As a result, novel and promising building blocks for medicinal chemistry were obtained. У цьому дослідженні було розроблено оптимізований метод синтезу азаіндолів, який успішно масштабовано для одержання до 100 г цільової сполуки. Кращі виходи спостерігались у разі використання електронодефіцитних азагетероциклів та замісників з електронно-акцепторними властивостями. Для подальшої функціоналізації було обрано 6-хлоро-1H-піроло[3,2-c]піридин шляхом його карбонілювання дією карбон(ІІ) оксиду. Як результат було одержано нові перспективні будівельні блоки для потреб медичної хімії. National University of Pharmacy 2025-11-21 Article Article application/pdf application/pdf https://ophcj.nuph.edu.ua/article/view/323307 10.24959/ophcj.25.323307 Journal of Organic and Pharmaceutical Chemistry; Vol. 23 No. 3 (2025); 4-10 Журнал органической и фармацевтической химии; Том 23 № 3 (2025); 4-10 Журнал органічної та фармацевтичної хімії; Том 23 № 3 (2025); 4-10 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/323307/331397 https://ophcj.nuph.edu.ua/article/view/323307/331451 Copyright (c) 2025 Mykyta V. Kordubailo, Andrey A. Tolmachev http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | азаіндоли реакція Соногашіри синтез Ларока карбонілювання Kordubailo, Mykyta V. Tolmachev, Andrey A. Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title | Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title_alt | Optimization and Scaling up of the Azaindole Derivatives Synthesis |
| title_full | Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title_fullStr | Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title_full_unstemmed | Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title_short | Оптимізація та масштабування методу синтезу похідних азаіндолу |
| title_sort | оптимізація та масштабування методу синтезу похідних азаіндолу |
| topic | азаіндоли реакція Соногашіри синтез Ларока карбонілювання |
| topic_facet | азаіндоли реакція Соногашіри синтез Ларока карбонілювання azaindoles Sonogashira coupling Larock synthesis carbonylation |
| url | https://ophcj.nuph.edu.ua/article/view/323307 |
| work_keys_str_mv | AT kordubailomykytav optimizationandscalingupoftheazaindolederivativessynthesis AT tolmachevandreya optimizationandscalingupoftheazaindolederivativessynthesis AT kordubailomykytav optimízacíâtamasštabuvannâmetodusintezupohídnihazaíndolu AT tolmachevandreya optimízacíâtamasštabuvannâmetodusintezupohídnihazaíndolu |