Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації
The synthetic accessibility of fused pyridoazepane frameworks was investigated through a series of strategies designed to construct differently fused azepane systems. Several precursor designs enabling alternative ring-closure topologies were explored. A “lactam” pathway proved synthetically inacces...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
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| Дата: | 2026 |
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| ISSN: | 2518-1548 |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874455190435790848 |
|---|---|
| author | Solod, Bohdan Yu. Vovk, Mykhailo V. |
| author_facet | Solod, Bohdan Yu. Vovk, Mykhailo V. |
| author_institution_txt_mv | [
{
"author": "Bohdan Yu. Solod",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd",
"orcid": ""
},
{
"author": "Mykhailo V. Vovk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_sort | Solod, Bohdan Yu. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 37 |
| container_issue | 1 |
| container_start_page | 29 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 24 |
| datestamp_date | 2026-08-24T19:33:19Z |
| description | The synthetic accessibility of fused pyridoazepane frameworks was investigated through a series of strategies designed to construct differently fused azepane systems. Several precursor designs enabling alternative ring-closure topologies were explored. A “lactam” pathway proved synthetically inaccessible under various conditions due to chemoselectivity issues and competing intermolecular processes. In contrast, an efficient route to the 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine framework was achieved via an intramolecular cyclization strategy, in which the amine functionality was introduced prior to ring assembly. The developed route proceeds under practical laboratory conditions using inexpensive reagents and was demonstrated on a gram scale. These findings provide insight into the structural factors governing ring-closure efficiency in pyridoazepine systems and establish a practical entry to a previously underexplored fused heterocyclic scaffold. |
| doi_str_mv | 10.24959/ophcj.26.354129 |
| first_indexed | 2026-05-02T01:00:11Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 29
Original Research
http://ophcj.nuph.edu.ua
UDC 542.06:547.83:547.891.2
B. Yu. Solod1,2, M. V. Vovk1
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02094 Kyiv, Ukraine
2 Enamine Ltd, 78 Winston Churchill str., 02094 Kyiv, Ukraine
The Synthetic Access to Fused 6,7,8,9-Tetrahydro-
5H-pyridoazepines: Evaluation of Ring-Closure Strategies
Abstract
The synthetic accessibility of fused pyridoazepine frameworks was investigated by evaluating a series of strategies designed
to construct differently fused azepine systems. Several precursor designs enabling alternative ring-closure topologies were
considered. The “lactam” pathway proved to be synthetically inaccessible under various conditions due to chemoselectivity
issues and competing intermolecular processes. In contrast, an efficient route to the 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine
framework was achieved via the intramolecular cyclization strategy, in which the amine functionality was introduced prior
to the ring assembly. The route developed proceeded under practical laboratory conditions using inexpensive reagents and
was demonstrated on a gram scale. The results obtained provide insight into the structural factors governing the ring-closure
efficiency in pyridoazepine systems and open up a practical access to a fused heterocyclic scaffold previously underexplored.
Keywords: pyridoazepine; fused heterocycles; ring-closure reactions; synthetic accessibility; organic synthesis
Б. Ю. Солод1,2, М. В. Вовк1
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
Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання
стратегій циклізації
Анотація
Синтетичну доступність конденсованих каркасів піридоазепіну було досліджено шляхом оцінювання серії стратегій,
спрямованих на конструювання різних топологій конденсованих азепінових систем. Було розглянуто декілька варіан-
тів синтетичних попередників, що дозволяють реалізувати альтернативні шляхи стадії циклізації. «Лактамний» шлях
виявився синтетично непридатним за різних умов через проблеми хемоселективності та конкурентні міжмолекулярні
процеси. Натомість ефективний шлях до каркаса 6,7,8,9-тетрагідро-5H-піридо[3,2-c]азепіну було реалізовано за до-
помогою стратегії внутрішньомолекулярної циклізації, коли аміногрупу вводили до стадії формування азепанового
циклу. Розроблений синтетичний маршрут перебігає в практичних лабораторних умовах із використанням доступних
недорогих реагентів. Його було продемонстровано у грамовому масштабі. Отримані результати дають уявлення про
структурні чинники, що визначають ефективність замикання циклу в системах піридоазепіну, та відкривають практич-
ний підхід до малодослідженого класу конденсованих гетероциклічних каркасів.
Ключові слова: піридоазепан; конденсовані гетероцикли; реакції циклізації; синтетична доступність; органічний синтез
Citation: Solod, B. Y.; Vovk, M. V. The Synthetic Access to Fused 6,7,8,9-Tetrahydro-5H-pyridoazepines: Evaluation of Ring-Closure
Strategies. Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1), 29 – 37.
https://doi.org/10.24959/ophcj.26.354129
Received: 14 October 2025; Revised: 4 January 2026; Accepted: 12 December 2026
Copyright© 2026, B. Y. Solod, M. V. Vovk. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The authors received no specific funding for this work
Conflict of interests: The authors have no conflict of interests to declare.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 30
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
■ Introduction
Nitrogen-containing heterocyclic compounds
constitute a fundamental structural motif in or-
ganic chemistry and play a central role in natu-
ral products, pharmaceuticals, agrochemicals, and
functional materials. Consequently, the develop-
ment of efficient synthetic methodologies for the
preparation of nitrogen heterocycles remains a ma-
jor focus of modern synthetic chemistry [1].
The importance of nitrogen heterocycles is
particularly evident in medicinal chemistry.
The analysis of FDA-approved small-molecule
drugs showed that approximately 60 % of them
contained at least one nitrogen heterocycle as of
2014 [2a]. A subsequent analysis of ring systems
presented in drug molecules conducted by Taylor
and co-workers revealed that 63 of the Top 100
most frequently used ring systems found in drugs
listed in the FDA Orange Book (as of January
2020) are nitrogen-containing heterocycles [3].
Notably, this represents a slight increase compa-
red with their earlier 2014 study, where 61 ni-
trogen-containing heterocycles were identified
among the top 100 ring systems [4]. A stronger
trend is observed among clinical candidates.
Among the Top 100 most frequently used ring
systems in U.S. clinical trials (as of January
2020), 83 contain a nitrogen heterocycle [2a].
Recent analyses of the structural diversity of he-
terocycles in pharmaceuticals approved by the
European Medicines Agency between 2014 and
2023 have confirmed the continuing dominance
of N-heterocycles, both monocyclic and polycyclic,
in the design of small-molecule drugs [2b].
One effective strategy for expanding the he-
terocyclic chemical space involves combining well-
established ring fragments to form new bicyclic or
polycyclic fused systems [5, 6]. In this context, and
in line with the research direction of our group,
we became interested in frameworks combining
pyridine and azepane motifs [7 – 9]. This choice was
motivated by two key considerations. First, py-
ridine is among the most frequently encountered
heterocycles in pharmaceutical compounds and
is widely recognized as a privileged scaffold in me-
dicinal chemistry [10]. Second, azepane repre-
sents a member of the medium-sized ring fa-
mily, which has attracted increasing attention in
drug discovery [11]. Azepane, as a member of the
saturated medium-sized rings family, provides
a unique balance between conformational rigi-
dity and three-dimensional spatial characteris-
tics compared with small rings and macrocycles.
These structural features can confer favorable
physicochemical and biological properties, mak-
ing medium-sized rings attractive motifs in me-
dicinal chemistry. However, despite these advan-
tages, medium-sized rings remain significantly
underrepresented in screening libraries and mar-
keted drugs, largely due to the intrinsic syn-
thetic challenges associated with their prepara-
tion [12].
In the present study, we focused on fused py-
ridoazepane frameworks A – D differing in the
relative position of the pyridine nitrogen atom
with respect to the azepane ring (Figure 1a).
From a medicinal chemistry perspective, such po-
sitional isomers are particularly attractive since
they enable implementation of the nitrogen walk
concept [13], allowing systematic tuning of elec-
tronic properties and interaction patterns while
preserving the overall molecular framework.
A survey of the literature revealed that these
frameworks remain largely unexplored. The un-
substituted topologies A and D have each been
mentioned only once in the patent literature. In the
case of compound A, the reported synthesis in-
volved five steps and yielded only 5 % [14], where-
as for compound D [15], no synthetic route has
been described. The topologies B and C have re-
ceived somewhat greater attention. For example,
6,7,8,9-tetrahydro-5H-pyrido[3,4-c]azepine (B) has
been investigated as a ligand for nicotinic ace-
tylcholine receptors (nAChRs) [16]. Its synthe-
sis relied on a Beckmann rearrangement of
5,6,7,8-tetrahydroisoquinolin-8-one followed by
the reduction of the resulting lactam with lithi-
um aluminum hydride. Meanwhile, 6,7,8,9-tetra-
hydro-5H-pyrido[4,3-c]azepine (C) has been stud-
ied in the development of matrix metalloprote-
inase-9 inhibitors [17] (Figure 1b). In that stu-
dy, a substituted derivative of this scaffold dis-
played the highest inhibitory activity toward the
target protease. However, the synthesis of the
unsubstituted core was not described, and the
reported substituted derivative required a nine-
step sequence employing ring-closing metathesis
as the key transformation.
Therefore, in contrast to benzannulated ana-
logs, which synthesis has been extensively stud-
ied (19 documents in the Reaxys® database for
2,3,4,5-tetrahydro-1H-benzo[c]azepine) [18], the
preparation of pyridoazepane scaffolds remains
poorly developed, with only a few isolated exam-
ples. As a result, their easy implementation in
drug-discovery programs is complicated. Taking
into account the potential of structures, such as
ISSN 2308-8303 (Print) / 2518-1548 (Online) 31
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
three-dimensional nitrogen-rich scaffolds for me-
dicinal chemistry, creating reliable routes to these
systems represents an important synthetic chal-
lenge (Figure 1c).
In this work, we present an evaluation of ring-
closure strategies toward fused pyridoazepane
frameworks A – D (Figure 1d). By exploring the
alternative cyclization approaches and compar-
ing their efficiency and synthetic practicality,
we aim to identify viable routes to these under-
explored heterocyclic scaffolds and thereby ex-
pand the accessible chemical space of condensed
medium-sized nitrogen heterocycles relevant to
medicinal chemistry.
■ Results and discussion
The development of a practical synthetic route
to the pyridoazepane frameworks required the
evaluation of several strategic disconnections
(Schemes 1 – 3). Particular attention was paid
to the efficiency of the key ring-closure step and
the chemoselectivity of the subsequent functio-
nal group interconversions within the electroni-
cally coupled pyridine-azepine system.
The first approach toward the target bicyclic
compound A (Scheme 1) relied on the intramole-
cular cyclization of a suitably functionalized pre-
cursor 3 to furnish the fused seven-membered
lactam 4. Ester 3 was prepared in a high yield on
a gram scale from commercially available alde-
hyde 1 via the Horner-Wadsworth-Emmons reac-
tion (compound 2), followed by the chemoselec-
tive catalytic hydrogenation of the alkene moiety.
The cyclization 3→4 proceeded cleanly and re-
producibly, delivering the desired bicyclic aze-
panone 4 core in a satisfactory yield. Structur-
ally, this lactam intermediate appeared to be
a promising platform for further transformation
into the corresponding amine via well-established
approaches for the lactam reduction. However,
attempts to reduce the lactam carbonyl to the
target amine revealed significant chemoselec-
tivity challenges (Scheme 1). The mild sodium
>80 FDA
approved
drugs
8 FDA
approved
drugs
a
[MEDCHEM SIGNIFICANCE OF PYRIDOAZEPANES]b
N NHN NH
N
NH
N
NH
N
NH
N
NH
project on metabotropic
glutamate receptor modulators
(WO2012052451A1) N NH
potassium channel
modulators
(US12157726B2) N
NH
nicotinic receptor
ligand (Ki = 1100 nM)
( )Glennon et al.
A B C D
N
H
OH
N
O
N
H2N
F
matrix metalloproteinase-9
inhibitor ( )Asami et al.
[ELEMENTS OF SAR ANALYSIS]
IC50 = 44 nM
N
N
N
N N
H
N
O
>50000 nMIC50 >50000 nM 81 nM
c
N
NH
D
NO SYNTHETIC
PROTOCOLS REPORTED
A
N NH
N CO2Me
Br
NHBoc+
5 steps
OY ~ 5 %
Scale 100 mg
reported in 1 patent
(US12157726B2)
N
NH
2 steps
OY ~ 48 %
Scale ~ 200 mg
N
O
2 steps
N NH2
CO2H
OY ? %
Scale ~ 200 mg
Glennon et al., 1996 Glennon et al., 1999
N
CO2Me
Br 9 steps
OY ~ 23 %
Scale 350 mg
Asami et al.
N
NH
[THIS REPORT]d
N
CO2Me
O
OR N
Br
O
evaluation of ring-closure strategies toward
fused pyridoazepane frameworks
gram scale synthesis
limitations & optimization
Figure 1. The status quo of the topic and the current work
ISSN 2308-8303 (Print) / 2518-1548 (Online) 32
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
borohydride proved to be excessively reactive
under the conditions studied. Instead of the se-
lective reduction of the lactam carbonyl group,
a rapid non-selective hydride transfer occurred,
leading to complex product mixtures. The high
intrinsic hydride reactivity likely promotes re-
duction at multiple electrophilic sites within the
fused heterocyclic framework. Borane-based re-
ducing systems commonly employed for the lac-
tam reduction also failed to achieve the desired
chemoselectivity. Although the partial conversion
of the lactam functionality was observed, the si-
multaneous hydrogenation of the pyridine ring
consistently occurred, producing mixtures of par-
tially reduced intermediates. The lack of selecti-
vity observed under borane conditions can be ra-
tionalized by competing coordination pathways.
In addition to the activation of the lactam car-
bonyl group, borane can coordinate to the pyri-
dine nitrogen atom. Such coordination increases
the susceptibility of the heteroaromatic ring to-
ward the hydride attack, thereby facilitating an
undesired reduction of the pyridine fragment.
Furthermore, the rigid fused architecture of the
system likely enhances the electronic communica-
tion between the two heterocyclic subunits, altering
the reduction behavior compared with simple mo-
nocyclic lactams. Consequently, in contrast to iso-
lated lactams that are typically reduced smoothly
under borane conditions, the presence of a fused
electron-deficient pyridine ring significantly per-
turbs the reduction profile. Since competing reduc-
tion pathways could not be effectively suppressed,
this synthetic direction was ultimately abandoned.
Faced with significant difficulties in reduc-
ing lactam 4 to obtain pyridoazepane A, we then
attempted to apply an appropriate strategy to
synthesize the alternative target framework D,
using the isomeric aldehydoester 5 as the key
precursor (Scheme 2). The starting nitrile 7 de-
signed for the subsequent cyclization to the bi-
cyclic lactam was obtained in two steps from the
readily available precursor 5 in a high overall
yield. However, the standard conditions for the
nitrile reduction that proved to be effective in
the previous system failed to deliver the expect-
ed transformation to intermediate 8. Unexpect-
edly, instead of the anticipated intramolecular
cyclization, the reaction predominantly proceed-
ed through intermolecular pathways, leading to
the formation of the insoluble polymeric mate-
rial. No detectable formation of the desired bi-
cyclic product was observed. This behavior sug-
gests that, under the applied conditions, the un-
controlled intermolecular reactivity outcom-
peted the intended intramolecular ring closure.
The formation of a polymeric material likely ref-
lects the insufficient conformational preorgani-
zation of the substrate and/or the excessive
intrinsic reactivity of the functional groups in-
volved, both of which favor the chain propaga-
tion. As a result, the pathway discussed proved
to be synthetically impractical, and further op-
timization of this approach was considered un-
justified, as well as its implementation for the
synthesis of isomeric compounds B and C.
These observations prompted us to recon-
sider the disconnection strategy and explore an
N CO2Me
N
N CO2Me
O
1 2, 91.7 % 3, 95 %
H2, 10 % Pd/C H2, Ni-Ra
P CN
EtO
O
EtO
tBuOK, THF MeOH N CO2Me
N
MeOH N NH
O
[H]
conditions
[H]
4, 82 %
A
NaBH4 complex mixture, amine was not detectedA
BH3 (DMS complex)
BH3 (generated )in situ mixture of partially reduced species
BH3
[CONDITIONS FOR THE REDUCTION OF LACTAM 4]
N NH
Reducing agent Conditions Result
MeOH, RT, 2 hours
Scheme 1. The initial strategy toward A and lactam reduction studies
N
CO2Me
N
N
CO2Me
O
5 6, 84.3 % 7, 94 %
H2, 10 % Pd/C H2, Ni-Ra
P CN
EtO
O
EtO
tBuOK, THF MeOH
N
CO2Me
N
MeOH
N
NH
O 8
Scheme 2. Attempts to synthesize pyridoazepane D
ISSN 2308-8303 (Print) / 2518-1548 (Online) 33
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
alternative approach to constructing the pyri-
doazepane core.
To circumvent the chemoselectivity issues as-
sociated with the post-cyclization lactam reduc-
tion and the intermolecular side reactions ob-
served in the previous approaches, a redesigned
synthetic strategy was implemented (Scheme 3).
In this route, the amine functionality was intro-
duced prior to the final ring-closure step, there-
by eliminating the need for the fused lactam re-
ductive transformation.
The optimized route proved to be operation-
ally straightforward and relied on inexpensive,
commercially available reagents. The synthesis
commenced with bromoaldehyde 9, which scala-
ble preparation had previously been reported by
our group [9]. The Sonogashira coupling of 9 with
N-Boc-propargylamine enabled the installation
of all carbon atoms required for the construction
of the target pyridoazepane framework, giving
aldehyde 10. The subsequent catalytic hydrogena-
tion reduced both the alkyne and aldehyde func-
tionalities, delivering the corresponding amino
alcohol 11. The conversion of the hydroxyl group
into the corresponding chloride, followed by the
intramolecular nucleophilic substitution, provid-
ed the bicyclic intermediate 13. Notably, in this
case, the cyclization proceeded smoothly and in
a practical yield on a gram scale without detect-
able intermolecular side reactions. The target
building block D was obtained after removal of
the Boc protecting group with the total yield of
37 %. All transformations were carried out un-
der practical laboratory conditions without the
need for rigorously anhydrous techniques or spe-
cialized equipment. Intermediates were purified
by the standard column chromatography or simple
recrystallization. The scalability of the sequence
further highlights its preparative robustness and
synthetic utility.
The findings highlight the critical role of the pre-
cursor design in enabling the efficient formation
of medium-ring systems within pyridine-contain-
ing fused systems. With an efficient route to py-
ridoazepane D in hand, future studies will focus
on extending this strategy toward the scalable
synthesis of the remaining isomeric pyridoaze-
pane frameworks.
■ Conclusions
Thus, we evaluated several synthetic strate-
gies for the construction of fused pyridoazepane
frameworks. Initial approaches based on the post-
cyclization reduction of fused lactam intermedi-
ates or nitrile-derived precursors proved to be
synthetically impractical due to chemoselectivity
issues and competing intermolecular processes.
These observations highlight the challenges as-
sociated with the formation and functionalization
of medium-sized nitrogen heterocycles embedded
within electronically coupled pyridine systems.
The redesigned strategy, in which the amine
functionality was introduced prior to the ring clo-
sure, made it possible to effectively construct the
pyrido[3,2-c]azepine framework. The route deve-
loped proceeds under practical laboratory condi-
tions, employs inexpensive and readily available
reagents, and has proven its reliability on a gram
scale. With an efficient entry to pyridoazepane D
established (5-step synthetic sequence, 37 % to-
tal yield), ongoing studies are directed toward ex-
tending this strategy to the scalable synthesis of
the remaining positional isomers. The access to
these frameworks will expand the available chemi-
cal space of pyridine-containing medium-sized he-
terocycles and facilitate their further study as nit-
rogen-rich building blocks for medicinal chemistry.
■ Experimental part
All solvents were purified according to the
standard procedures. The starting materials were
obtained from Enamine Ltd. NMR spectra were
N Br
O
9
NHBoc
Et3
Pd(PPh3)2Cl2
N
O
10, 63.2 %
NHBoc
H2, 10 % Pd/C
MeOH
N
OH
NHBoc MeSO2Cl
Et3N, DCM
11, 91.1 %
N
Cl
NHBoc
12, 96.8 %
NaH
THF
N
NBoc
13, 69.2 %
HCl / dioxane
MeOH
D, 96.7 %
N
NH
Scheme 3. The development of an optimized route toward isomer D
ISSN 2308-8303 (Print) / 2518-1548 (Online) 34
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
recorded on a Bruker Avance 500 spectrometer
(at 500 MHz for 1H and 126 MHz for 13C) and
a Varian Unity Plus 400 spectrometer (at 400 MHz
for 1H, 101 MHz for 13C). Tetramethylsilane (1H, 13C)
was used as an internal standard. The column
chromatography was performed with silica gel
(200 – 300 mesh). The elemental analysis was
performed at the Analytical Laboratory of the
Institute of Organic Chemistry, NAS of Ukraine.
Methyl-3-(2-cyanovinyl)picolinate (2)
Potassium tert-butoxide (8.5 g, 75.8 mmol)
was added to the solution of diethyl (cyanome-
thyl)phosphonate (15.0 g, 84.8 mmol) in the
anhydrous THF (150 mL) at 0 °C. The mixture
was stirred for 30 min at room temperature, af-
ter which methyl 3-formylpicolinate (1) (10.0 g,
60.6 mmol) was added. The reaction mixture
was stirred overnight at room temperature, di-
luted with water, and extracted with ethyl ace-
tate (3 × 100 mL). The organic layer was washed
with water (1 × 100 mL), dried over Na2SO4, and
concentrated under reduced pressure to give
compound 2, which was used in the next step
without further purification.
A pale yellow amorphous solid. Yield – 11.0 g
(91.7 %). Anal. Calcd. for C10H8N2O2, %: C 63.83;
H 4.29; N 14.89. Found, %: C 64.09; H 4.10;
N 14.59. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
3.87 (3H, s), 6.10 (1H, d, J = 11.8 Hz), 7.77 (1H,
dd, J = 7.8, 4.8 Hz), 7.83 (1H, d, J = 11.8 Hz),
8.21 (1H, d, J = 8.0 Hz), 8.73 (1H, d, J = 4.4 Hz).
13C NMR (126 MHz, DMSO-d6), δ, ppm: 52.40,
101.97, 117.50, 124.32, 130.11, 136.08, 144.90,
145.45, 146.56, 166.78. LC–MS, m/z (ES–API):
189.1 [M+H]+.
Methyl-3-(2-cyanoethyl)picolinate (3)
To the solution of compound 2 (11.0 g,
58.5 mmol) in MeOH (150 mL), Pd/C (10 %) (1 g)
was added. The mixture was hydrogenated at
1 atm and room temperature until the LC–MS
analysis indicated the complete consumption of
the starting material. The catalyst was removed
by filtration, and the filtrate was evaporated un-
der reduced pressure to give compound 3.
A colorless oil. Yield – 11.0 g (95 %). Anal.
Calcd. for C10H10N2O2, %: C 63.15; H 5.30; N 14.73.
Found, %: C 63.53; H 4.81; N 14.83. 1H NMR
(500 MHz, DMSO-d6), δ, ppm: 2.84 (2H, t, J =
7.3 Hz), 3.11 (2H, t, J = 7.1 Hz), 3.86 (3H, s),
7.58 (1H, dd, J = 8.0, 4.7 Hz), 7.90 (1H, d, J =
7.7 Hz), 8.53 – 8.56 (1H, m). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 16.68, 28.08, 52.40, 119.11,
125.18, 134.46, 136.22, 146.67, 148.27, 165.99.
LC–MS, m/z (ES–API): 191.1 [M+H]+.
5,6,7,8-Tetrahydro-9H-pyrido[2,3-c]azepin-
9-one (4)
To the solution of compound 3 (11.0 g,
57.9 mmol) in MeOH (200 mL), Raney nickel was
added. The mixture was hydrogenated at 70 atm
and 70 °C in a 500 mL autoclave until the LC–MS
analysis indicated the reaction was complete
(typically within 16 h). The catalyst was filtered
off, and the solvent was removed under reduced
pressure to give compound 4.
An off-white solid. Yield – 9.3 g (82 %). Anal.
Calcd. for C9H10N2O, %: C 66.65; H 6.21; N 17.27.
Found: C 66.83; H 6.49; N 17.62. 1H NMR
(400 MHz, DMSO-d6), δ, ppm: 1.87 (2H, t, J =
6.8 Hz), 2.73 (2H, t, J = 7.1 Hz), 2.89 (2H, q, J =
6.3 Hz), 7.41 (1H, dd, J = 7.6, 4.6 Hz), 7.71 (1H,
d, J = 7.8 Hz), 8.23 (1H, s), 8.48 – 8.58 (1H, m).
13C NMR (101 MHz, DMSO-d6), δ, ppm: 29.52, 31.17,
41.74, 125.01, 138.26, 139.69, 148.10, 153.80,
166.68. LC–MS, m/z (ES–API): 163.1 [M+H]+.
Methyl-2-(2-cyanovinyl)nicotinate (11)
Potassium tert-butoxide (8.5 g, 75.8 mmol)
was added to the solution of diethyl (cyanome-
thyl)phosphonate (15 g, 84.8 mmol) in the anhy-
drous THF (150 mL) at 0 °C. The mixture was
stirred for 30 min at room temperature, and me-
thyl 2-formylnicotinate (10) (10 g, 60.6 mmol) was
added. The reaction mixture was stirred overnight
at room temperature, diluted with water, and ex-
tracted with ethyl acetate (3 × 100 mL). The or-
ganic layer was washed with water (1 × 100 mL),
dried over Na2SO4, and concentrated under re-
duced pressure to give compound 11.
A pale yellow amorphous solid. Yield – 10.1 g
(84.3 %). Anal. Calcd. for C10H8N2O2, %: C 63.83;
H 4.29; N 14.89. Found, %: C 63.61; H 3.93;
N 15.09. 1H NMR (500 MHz, DMSO-d6), δ, ppm:
3.89 (3H, s), 6.12 (1H, d, J = 11.8 Hz), 7.56 – 7.66
(1H, m), 7.98 (1H, d, J = 11.8 Hz), 8.27 – 8.36
(1H, m), 8.73 – 8.90 (1H, m). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 52.32, 104.51, 117.83, 121.06,
122.04, 137.02, 138.28, 148.91, 152.75, 167.48.
LC–MS, m/z (ES–API): 189.1 [M+H]+.
Methyl-2-(2-cyanoethyl)nicotinate (12)
To the solution of compound 11 (10.1 g,
53.7 mmol) in MeOH (150 mL), Pd/C (10 %) (1 g)
was added. The mixture was hydrogenated at
ambient pressure and room temperature until
the LC–MS analysis indicated the reaction was
complete. The catalyst was filtered off, and the
filtrate was evaporated under reduced pressure
to give compound 12.
A colorless oil. Yield – 10.0 g (94 %). Anal.
Calcd. for C10H10N2O2, %: C, 63.15; H, 5.30; N, 14.73.
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Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
Found, %: C, 63.31; H, 5.49; N, 14.26. 1H NMR
(500 MHz, DMSO-d6), δ, ppm: 2.91 (2H, t, J =
7.2 Hz), 3.41 (2H, t, J = 7.2 Hz), 3.86 (3H, s),
7.45 (1H, dd, J = 7.6, 4.9 Hz), 8.23 (1H, d, J =
7.9 Hz), 8.68 – 8.76 (1H, m). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 15.39, 31.49, 52.31, 119.22,
121.50, 126.27, 137.81, 151.67, 159.73, 167.92.
LC–MS, m/z (ES–API): 191.1 [M+H]+.
tert-Butyl (3-(3-formylpyridin-2-yl)prop-
2-yn-1-yl)carbamate (15)
A mixture of 2-bromonicotinaldehyde (14)
(10.0 g, 54.0 mmol), tert-butyl prop-2-yn-1-yl-
carbamate (10.0 g, 64.8 mmol), CuI (0.6 g,
3.2 mmol), Pd(PPh3)2Cl2·DCM (1.3 g, 1.6 mmol)
and Et3N (16.4 g, 162.2 mmol) in a dry THF
(120 mL) was stirred under argon at 60 °C for 16 h.
After the completion (TLC monitoring), the mix-
ture was cooled, diluted with ethyl acetate (150 mL)
and washed with water (100 mL) and brine.
The organic layer was dried over Na2SO4 and con-
centrated under reduced pressure. The purifica-
tion by column chromatography (hexane/ethyl
acetate) gave compound 15.
A pale yellow amorphous solid. Yield – 8.9 g
(63.2 %). Anal. Calcd. for C14H16N2O3, %: C, 64.60;
H, 6.20; N, 10.76. Found, %: C, 64.75; H, 5.94;
N, 10.70. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
1.40 (9H, s), 4.08 (2H, d, J = 5.5 Hz), 7.57 (1H,
dd, J = 7.7, 4.9 Hz), 8.14 (1H, dd, J = 7.9, 1.4 Hz),
8.74 – 8.85 (1H, m), 10.41 (1H, s). 13C NMR
(101 MHz, DMSO-d6), δ, ppm: 28.31, 32.02, 79.69,
79.73, 82.57, 123.55, 131.62, 134.00, 146.19,
151.09, 155.30, 189.99. LC–MS, m/z (ES–API):
261.1 [M+H]+.
tert-Butyl (3-(3-(hydroxymethyl)pyri-
din-2-yl)propyl)carbamate (16)
Compound 15 (8.9 g, 34.2 mmol) was dis-
solved in MeOH and hydrogenated over Pd/C
(10 %) (1 g) at ambient pressure and room tem-
perature until the LC–MS analysis indicated
the completion of the reaction. The catalyst
was removed by filtration, and the filtrate was
evaporated under reduced pressure to give com-
pound 16.
A colorless oil. Yield – 8.3 g (91.1 %). Anal.
Calcd. for C14H22N2O3, %: C, 63.13; H, 8.33;
N, 10.52. Found, %: C, 63.38; H, 8.18; N, 10.12.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.41 (9H,
s), 1.81 – 1.90 (2H, m), 2.98 (2H, t, J = 6.4 Hz),
3.22 (2H, td, J = 6.3, 4.4 Hz), 4.62 (1H, dd, J
= 7.8, 5.9 Hz), 4.65 – 4.74 (2H, m), 6.68 (1H, t,
J = 4.4 Hz), 7.33 (1H, dd, J = 7.7, 3.5 Hz), 7.71
(1H, dd, J = 7.9, 2.2 Hz), 8.42 – 8.57 (1H, m).
13C NMR (101 MHz, DMSO-d6), δ, ppm: 26.89,
28.32, 32.64, 39.54, 61.28, 79.56, 121.64, 133.83,
134.05, 147.39, 156.55, 157.25. LC–MS, m/z
(ES–API): 267.2 [M+H]+.
tert-Butyl (3-(3-(chloromethyl)pyridin-
2-yl)propyl)carbamate (17)
Methanesulfonyl chloride (4.2 g, 37.4 mmol)
was added to a stirred solution of alcohol 16
(8.3 g, 31.1 mmol) and triethylamine (9.4 g,
93.5 mmol) in a dry dichloromethane at 0 °C.
The reaction mixture was stirred for 3 h while
warming to room temperature. The mixture was
quenched with water and extracted with dichlo-
romethane (3 × 80 mL). The organic layer was
washed with brine (50 mL), dried over Na2SO4
and concentrated under reduced pressure to give
compound 17, which was used in the next step
without further purification.
A light-yellow oil. Yield – 8.6 g (96.8 %). Anal.
Calcd. for C14H21ClN2O2, %: C, 59.05; H, 7.43;
N, 9.84. Found, %: C, 59.07; H, 7.07; N, 9.88.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.40 (9H,
s), 1.83 – 1.91 (2H, m), 2.98 (2H, t, J = 6.4 Hz),
3.17 – 3.26 (2H, m), 4.78 (2H, s), 6.57 (1H, t, J =
4.4 Hz), 7.24 (1H, dd, J = 7.8, 3.5 Hz), 7.46
(1H, dd, J = 7.8, 2.2 Hz), 8.40 – 8.48 (1H, m).
13C NMR (101 MHz, DMSO-d6), δ, ppm: 26.91,
28.32, 32.69, 39.27, 41.93, 79.50, 122.15, 129.00,
135.56, 147.52, 155.71, 156.55. LC–MS, m/z
(ES–API): 285.1 [M+H]+.
tert-Butyl 5,7,8,9-tetrahydro-6H-pyrido-
[3,2-c]azepine-6-carboxylate (18)
Compound 17 (8.6 g, 30.2 mmol) was dis-
solved in a dry THF and cooled to 0 °C. Sodium
hydride (60 % dispersion in mineral oil, 1.4 g,
36.3 mmol) was added portionwise under argon.
The mixture was stirred for 1 h at 0 °C and then
for 16 h at room temperature. The reaction was
quenched with water and extracted with ethyl
acetate (3 × 100 mL). The combined organic lay-
ers were dried over Na2SO4 and concentrated
under reduced pressure. The purification by col-
umn chromatography gave compound 18.
A white amorphous solid. Yield – 5.2 g (69.2 %).
Anal. Calcd. for C14H20N2O2, %: C, 67.72; H, 8.12;
N, 11.28. Found, %: C, 67.49; H, 7.68; N, 10.98.
1H NMR (500 MHz, DMSO-d6), δ, ppm: 1.44
(9H, s), 1.98 – 2.05 (2H, m), 2.94 – 3.01 (2H, m),
3.35 – 3.43 (1H, m), 3.44 – 3.53 (1H, m), 4.25 – 4.33
(1H, m), 4.46 (1H, d, J = 13.5 Hz), 7.16 (1H, dd, J =
7.8, 3.5 Hz), 7.54 (1H, dd, J = 7.9, 2.2 Hz), 8.39
(1H, dd, J = 3.5, 2.2 Hz). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 25.91, 28.35, 32.73, 47.97, 50.19,
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Журнал органічної та фармацевтичної хімії 2026, 24 (1)
79.50, 121.50, 130.75, 135.21, 147.48, 154.78,
158.37. LC–MS, m/z (ES–API): 249.2 [M+H]+.
6,7,8,9-Tetrahydro-5H-pyrido[3,2-c]azepi-
ne (19)
Compound 18 (5.2 g, 20.9 mmol) was dis-
solved in methanol (100 mL) and treated with
hydrochloric acid (100 mL) (4 M in dioxane).
The reaction mixture was stirred for 2 h at room
temperature. The solvent was removed under re-
duced pressure, and the residue was neutralized
with a saturated NaHCO3 solution. The extrac-
tion with dichloromethane (3 × 80 mL) followed
by drying (Na2SO4) and the concentration gave
compound 19.
A colorless oil. Yield – 3.0 g (96.7 %). Anal.
Calcd. for C9H12N2, %: C, 72.94; H, 8.16; N, 18.90.
Found, %: C, 72.97; H, 8.33; N, 18.43. 1H NMR
(500 MHz, CDCl3), δ, ppm: 1.73 – 1.82 (2H, m),
3.15 – 3.21 (2H, m), 3.21 – 3.27 (2H, m), 3.93 (2H,
s), 7.04 (1H, dd, J = 7.3, 4.9 Hz), 7.38 (1H, dd,
J = 7.5, 1.4 Hz), 8.33 (1H, dd, J = 4.9, 1.5 Hz).
13C NMR (126 MHz, CDCl3), δ, ppm: 28.55, 35.10,
50.17, 53.78, 121.42, 134.57, 135.86, 147.42,
161.35. LC–MS, m/z (ES–API): 149.1 [M+H]+.
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Information about the authors:
Bohdan Yu. Solod, Ph.D. Student of the Department of Chemistry of Functional Heterocyclic Systems, Institute of Organic Chemistry
of the National Academy of Sciences of Ukraine.
Mykhailo V. Vovk (corresponding author), Dr. Sci. in Chemistry, Professor, Corresponding Member of the National Academy
of Sciences of Ukraine, Director of the Institute of Organic Chemistry of the National Academy of Sciences of Ukraine;
https://orcid.org/0000-0003-3101-9911; e-mail for correspondence: mvovk@ioch.kiev.ua.
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| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
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| language | English |
| last_indexed | 2026-08-25T01:02:52Z |
| publishDate | 2026 |
| publisher | National University of Pharmacy |
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| resource_txt_mv | ophcjnupheduua/91/803feb9f50e3be74e790e48902d72e91.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3541292026-08-24T19:33:19Z The Synthetic Access to Fused 6,7,8,9-Tetrahydro- 5H-pyridoazepines: Evaluation of Ring-Closure Strategies Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації Solod, Bohdan Yu. Vovk, Mykhailo V. pyridoazepane fused heterocycles ring-closure reactions synthetic accessibility organic synthesis піридоазепан конденсовані гетероцикли реакції циклізації синтетична доступність органічний синтез The synthetic accessibility of fused pyridoazepane frameworks was investigated through a series of strategies designed to construct differently fused azepane systems. Several precursor designs enabling alternative ring-closure topologies were explored. A “lactam” pathway proved synthetically inaccessible under various conditions due to chemoselectivity issues and competing intermolecular processes. In contrast, an efficient route to the 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine framework was achieved via an intramolecular cyclization strategy, in which the amine functionality was introduced prior to ring assembly. The developed route proceeds under practical laboratory conditions using inexpensive reagents and was demonstrated on a gram scale. These findings provide insight into the structural factors governing ring-closure efficiency in pyridoazepine systems and establish a practical entry to a previously underexplored fused heterocyclic scaffold. Синтетичну доступність конденсованих каркасів піридоазепану було досліджено шляхом оцінки серії стратегій, спрямованих на конструювання різних топологій конденсованих азепанових систем. Було розглянуто декілька варіантів синтетичних попередників, що дозволяють реалізувати альтернативні шляхи стадії циклізації. «Лактамний» шлях виявився синтетично непридатним за різних умов через проблеми хемоселективності та конкуруючі міжмолекулярні процеси. Натомість ефективний шлях до каркасу 6,7,8,9-тетрагідро-5H-піридо[3,2-c]азепіну було реалізовано за допомогою стратегії внутрішньомолекулярної циклізації, у якій аміногрупа вводилася до стадії формування азепанового циклу. Розроблений синтетичний маршрут перебігає за практичних лабораторних умов із використанням доступних недорогих реагентів, і його було продемонстровано у грамовому масштабі. Отримані результати дають уявлення про структурні чинники, що визначають ефективність замикання циклу в системах піридоазепіну, та відкривають практичний підхід до малодослідженого класу конденсованих гетероциклічних каркасів. National University of Pharmacy 2026-05-04 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/354129 10.24959/ophcj.26.354129 Journal of Organic and Pharmaceutical Chemistry; Vol. 24 No. 1 (2026); 29-37 Журнал органической и фармацевтической химии; Том 24 № 1 (2026); 29-37 Журнал органічної та фармацевтичної хімії; Том 24 № 1 (2026); 29-37 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/354129/345445 Copyright (c) 2026 Bohdan Yu. Solod, Mykhailo V. Vovk http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | піридоазепан конденсовані гетероцикли реакції циклізації синтетична доступність органічний синтез Solod, Bohdan Yu. Vovk, Mykhailo V. Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title | Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title_alt | The Synthetic Access to Fused 6,7,8,9-Tetrahydro- 5H-pyridoazepines: Evaluation of Ring-Closure Strategies |
| title_full | Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title_fullStr | Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title_full_unstemmed | Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title_short | Синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5Н-піридоазепінів: оцінювання стратегій циклізації |
| title_sort | синтетичний доступ до конденсованих 6,7,8,9-тетрагідро-5н-піридоазепінів: оцінювання стратегій циклізації |
| topic | піридоазепан конденсовані гетероцикли реакції циклізації синтетична доступність органічний синтез |
| topic_facet | pyridoazepane fused heterocycles ring-closure reactions synthetic accessibility organic synthesis піридоазепан конденсовані гетероцикли реакції циклізації синтетична доступність органічний синтез |
| url | https://ophcj.nuph.edu.ua/article/view/354129 |
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