Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів
Practical, multi-gram routes to three med-chem-relevant partially saturated furo[3,2-c]- and furo[2,3-c]annulated N-heterocycles are described. The key β‑(furyl)ethylamine intermediates were accessed via DPPA-mediated Curtius rearrangement, replacing the traditional Henry/LAH sequence and eliminatin...
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874455191270457344 |
|---|---|
| author | Kishko, Ihor S. Vaskevych, Alla I. |
| author_facet | Kishko, Ihor S. Vaskevych, Alla I. |
| author_institution_txt_mv | [
{
"author": "Ihor S. Kishko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd.",
"orcid": ""
},
{
"author": "Alla I. Vaskevych",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_sort | Kishko, Ihor S. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 60 |
| container_issue | 1 |
| container_start_page | 53 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 24 |
| datestamp_date | 2026-08-24T19:33:19Z |
| description | Practical, multi-gram routes to three med-chem-relevant partially saturated furo[3,2-c]- and furo[2,3-c]annulated N-heterocycles are described. The key β‑(furyl)ethylamine intermediates were accessed via DPPA-mediated Curtius rearrangement, replacing the traditional Henry/LAH sequence and eliminating stoichiometric metal-hydride reductions. The tetrahydrofuropyridine cores were then assembled through Pictet-Spengler cyclization, while a previously unavailable dihydrofuropyridinone was obtained via Dieckmann/Feist-Benary annulation. All sequences proceed in ≤6 steps from commercial starting materials. |
| doi_str_mv | 10.24959/ophcj.26.357365 |
| first_indexed | 2026-05-02T01:00:11Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 53
Original Research
http://ophcj.nuph.edu.ua
UDC 547.721+547.8
I. S. Kishko1,2, A. I. Vaskevych1
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
Preparation of Partially Saturated Furo[3,2-c]-
and Furo[2,3-c]annulated N-Heterocycles
Abstract
Practical multi-gram routes for obtaining three med-chem-relevant partially saturated furo[3,2-c]- and furo[2,3-c]annulated
N-heterocycles that are significant for medical chemistry have been proposed. The key β‑(furyl)ethylamine intermediates
were accessed via the DPPA-mediated Curtius rearrangement, replacing the traditional Henry/LAH sequence and eliminat-
ing stoichiometric metal-hydride reductions. The tetrahydrofuropyridine cores were then assembled through the Pictet-
Spengler cyclization, while the dihydrofuropyridinone previously unavailable was obtained via the Dieckmann/Feist-Benary
annulation. All sequences proceed in ≤6 steps from commercial starting materials.
Keywords: furopyridine; Pictet-Spengler reaction; Curtius rearrangement; Feist-Benary reaction; tetrahydropyridine; heterocyclic
building blocks
І. С. Кішко1,2, А. І. Васькевич1
1 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
2 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів
Анотація
Запропоновано практичні мультиграмові методи одержання трьох значущих для медичної хімії частково насичених
N-гетероциклів, анельованих за типом фуро[3,2-c]- та фуро[2,3-c]. Ключові проміжні β-(фурил)етиламіни було отри-
мано за допомогою перегрупування Курціуса, під дією дифенілфосфорилазиду (DPPA), що дозволило замінити тради-
ційну послідовність «реакція Анрі/відновлення алюмогідридом літію (LiAlH4)» та уникнути використання стехіометрич-
них кількостей металогідридних відновників. Основні тетрагідрофуропіридинові похідні було синтезовано шляхом
циклізації Пікте-Шпенглера, тоді як раніше недоступний дигідрофуропіридинон було одержано за допомогою анелю-
вання Дікмана/Фейста-Бенарі. Усі синтетичні послідовності реалізуються щонайбільше в шість стадій з використан-
ням комерційно доступних реагентів.
Ключові слова: фуропіридин; реакція Пікте-Шпенглера; перегрупування Курціуса; реакція Файста-Бенарі; тетрагідропіридин;
гетероциклічні будівельні блоки
Citation: Kishko, I. S.; Vaskevych, A. I. Preparation of Partially Saturated Furo[3,2-c]- and Furo[2,3-c]annulated N-Heterocycles.
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1), 53 – 60.
https://doi.org/10.24959/ophcj.26.357365
Received: 4 December 2026; Revised: 28 March 2026; Accepted: 10 April 2026
Copyright© 2026, I. S. Kishko, A. I. Vaskevych. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Supporting information: Copies of 1H and 13C NMR spectra of the compounds synthesized.
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) 54
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
■ Introduction
Partially saturated furo[3,2-c]- and furo[2,3-c]-
pyridines are involved in various medicinal che-
mistry programs. The 4,5,6,7-tetrahydrofuro-
[3,2-c]pyridine core has been a key component
in potent Janus kinase (JAK) inhibitors with
the proven in vivo anti-inflammatory activity [1]
and in agents that promote the cholesterol efflux
via the reverse cholesterol transport [2]. Struc-
turally related partially saturated [c]-fused bicy-
clics, including a tetrahydrofuropyridine-based
Factor Xa inhibitor showing the submicromolar
anti-fXa activity, have been investigated as bind-
ing components in this context [3], whereas the
furo[2,3-c]pyridine motif and its variants appear
in recent patent claims aimed at the NLRP3 in-
flammasome inhibition [4] (Figure 1). The fully
aromatic counterparts of these ring systems have
also been proven to be effective as pharmacoph-
ores for the PDE4 inhibition [5] and modulation
of the α7 nicotinic acetylcholine receptor [6].
The established route to 4,5,6,7-tetrahydro-
furopyridines depends on the Pictet-Spengler cyc-
lization of a β-(2-furyl)ethylamine with formal-
dehyde [2], a reaction which success depends on
easy access to the amine precursors. The main
approach, the Henry reaction of furfural with nit-
romethane followed by the lithium aluminum hyd-
ride reduction, has been used in the intramole-
cular Diels–Alder [7], N-acyliminium ion cycli-
zation [8], and alkaloid-targeted studies [8b], but
it only gives yields of 30 – 54 % [7, 8b] and re-
quires stoichiometric lithium aluminum hydri-
de (LAH), which limits scalability. For the [2,3-c]
isomeric series and the dihydrofuropyridinone
ring system, the situation is further complicated
by the near-absence of reported routes. As part
of a broader investigation into the fused-furan
heterocyclic chemistry, including our recently re-
ported tandem intramolecular Diels-Alder/retro-
Diels-Alder cascade approach to 5,5-fused dihy-
drofuran heterobicycles [9], we became interest-
ed in developing practical methods to access the
complementary 5,6-fused ring systems. Herein,
we present routes to 4,5,6,7-tetrahydrofuro[3,2-c]-
pyridine, 4,5,6,7-tetrahydrofuro[2,3-c]pyridine,
and the previously unavailable 6,7-dihydrofuro-
[2,3-c]pyridin-4(5H)-one that employs hydrocin-
namic acid (Meldrum’s acid pathway) and cinnama-
te (Wittig pathway). For 6,7-dihydrofuro[2,3-c]-
pyridin-4(5H)-one, a unique approach using a cus-
tom aminoketone precursor has been developed.
The resulting protocols produce the target com-
pounds in multi-gram quantities, making them
readily accessible as building blocks for further
N-functionalization and furan ring derivatization.
■ Results and discussion
The synthetic approach to 4,5,6,7-tetrahydro-
furo[3,2-c]pyridine (4) and 4,5,6,7-tetrahydrofu-
ro[2,3-c]pyridine (11) is built around the Pictet-
Spengler cyclization of an N-Boc-protected β-(2-fu-
ryl)ethylamine with paraformaldehyde, with the
amine precursor accessed in each case through
the modified Curtius rearrangement. For 6,7-di-
hydrofuro[2,3-c]pyridin-4(5H)-one (18), the order
of the ring assembly is reversed: the piperidine-
2,4-dione core is constructed first via the Dieck-
mann cyclization, and the furan ring is introduced
subsequently through the Feist–Benary conden-
sation.
The route to 4 begins with 3-(furan-2-yl)pro-
panoic acid (1), which is available from furfural
via the Meldrum’s acid condensation (Scheme 1).
The amine-forming step uses the Shioiri’s modi-
fication of the Curtius rearrangement: treating 1
with diphenylphosphoryl azide (DPPA) in tert-
butanol, with triethylamine, at 80 °C directly gives
N-Boc amine 2 in the yield of 47 %. This process
avoids the need for the separate acid chloride for-
mation, acyl azide isolation, or, most importantly,
the stoichiometric LAH reduction typical of the tra-
ditional Henry/nitroalkene pathway. The Pictet-
Spengler cyclization of 2 with paraformaldehyde
under catalytic p-TsOH in refluxing toluene (Dean-
Stark) provided N-Boc-tetrahydrofuropyridine 3
N
O S
O
O
HN
HN
O
R
S
O
O
N
N
O
ON
Cl
N
N
O
N
O
N
Me
HN N O
JAK inhibitor
Bioorg. Med. Chem. 272019, , 2592
R = H, (CH2)3OH; IC50 = 5 50 nM–
NLRP3 inhibitors
JAK2 IC50 = 0.5 nM
WO2024010772A1
IC50 = 0.5 µm
Factor Xa Inhibitor
J. Med. Chem. 47, , 51672004
Figure 1. Furo[3,2-c]- and furo[2,3-c]pyridines as pharmacophore fragments in bioactive molecules
ISSN 2308-8303 (Print) / 2518-1548 (Online) 55
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
in the yield of 41 %. The moderate yield can be
attributed to the well-documented sensitivity of
the furan ring to Bronsted acids, further com-
pounded by the vacant C-5 position of the furan
ring in 2, the most nucleophilic site of the het-
erocycle, which, under acidic conditions and in
the presence of excess formaldehyde, is expect-
ed to undergo a competing hydroxymethylation,
bis-aminomethylation, and acid-promoted oligo-
merization, accounting for the oligomeric/resinous
polar by-products observed in the crude mixture;
nonetheless, the reaction is operationally simple
and proceeds smoothly on a multi-gram scale.
The standard Boc cleavage (HCl/dioxane, rt) then
gave 4 in the near-quantitative yield (97 %).
Access to the isomeric [2,3-c] system required
the synthesis of 3-(furan-3-yl)propanoic acid (8),
which, unlike its furan-2-yl analog, is not easily
obtained through the Meldrum’s acid chemistry
due to the lower electrophilicity of furan-3-car-
baldehyde in Knoevenagel-type condensations.
Instead, a four-step sequence was developed
(Scheme 2). The Horner-Wadsworth-Emmons
olefination of 3-furaldehyde (5) with methyl
2-(diethoxyphosphoryl)acetate provided (E)-cin-
namate ester 6 in the yield of 73 %. The subsequent
reduction of the double bond required a careful
reagent selection: the catalytic hydrogenation
was avoided owing to the risk of the furan ring
reduction, and instead the CuCl/NaBH4 system
in the aqueous methanol at 0 °C was employed,
delivering the saturated ester 7 in the yield of
87 % with complete chemoselectivity. The sapo-
nification (LiOH, THF/H2O) gave acid 8 in the
yield of 89 %, which was then subjected to the
same DPPA-mediated Curtius protocol to give 9
(58 %). The Pictet–Spengler cyclization of 9 to the
N-Boc-protected product 10 proceeded in the yield
of 30 % – appreciably lower than for the [3,2-c]
isomer (3, 41 %). This difference is consistent with
the reduced nucleophilic character of C-2 in the
furan-3-yl tether relative to C-3 in the furan-2-yl
series where the ring oxygen provides greater ac-
tivation of the carbon undergoing electrophilic
substitution [10]; additionally, the presence of
two vacant α-positions (C-2 and C-5) in the furan
ring of 9 – both available for competing the hy-
droxymethylation and oligomerization under the
Bronsted-acid conditions – diverts a larger frac-
tion of the substrate into higher-molecular-weight
decomposition products relative to the furan-2-yl
series. The Boc removal then gave 11 (96 %).
Notably, the HWE/CuCl-NaBH4/saponification/
Curtius sequence was equally applicable when
furan-2-carbaldehyde was used as the starting
material, providing an independent and fully
1 2, 47 % yield 3, 41 % yield 4, 97 % yield
O
H
N
Boc
O
N
Boc
O
NH
O
O
OH
(a) (b) (c)
Experimental conditions: (a) DPPA, Et3N, BuOH, 80 °C, 16 h; (CHt (b) 2O)n, TsOH·Hp 2
Dean–Stark, 16 h; 4N HCl/dioxane, rt, 12 h(c)
Scheme 1. The preparation of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine (4) via the Curtius/Pictet-Spengler route
5
O
N
H
Boc
O N
Boc O NH
O
O
O
O
O
6, 73 % yield
9, 58 % yield 10, 30 % yield 11, 96 % yield
(e)
(h) (i)
(d)
O
O
O
O
O
OH
(f) (g)
7, 87 % yield 8, 89 % yield
Scheme 2. The synthesis of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine (11) via the HWE/Curtius/Pictet-Spengler route
ISSN 2308-8303 (Print) / 2518-1548 (Online) 56
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
chromatography-stage-compatible route to 4 and
confirming the generality of this pathway across
both regioisomeric aldehyde series.
The construction of 6,7-dihydrofuro[2,3-c]py-
ridin-4(5H)-one (18) demanded a fundamentally
different approach (Scheme 3). The reaction se-
quence proceeds through the linear assembly of
an N-functionalized diester, its Dieckmann cyc-
lization to a 1,3-diketone, and the late-stage fu-
ran annulation. The N-alkylation of ethyl N-ben-
zylglycinate (12) with chloroacetone provided 13
in the yield of 84 %, installing the two-carbon ke-
tone appendage required for the eventual Dieck-
mann ring closure. The chemoselective N-deben-
zylation (Pd/C, H2, 1 atm) gave 14 (73 %), which
was protected as N-Boc derivative 15 (91 %).
The intramolecular Claisen condensation of 15
under the action of KOtBu at 5 °C gave piperi-
dine-2,4-dione 16 in the yield of 80 %, generating
the 1,3-dicarbonyl motif required for the subse-
quent furan ring formation. The exposure of 16
to chloroacetaldehyde under basic conditions
(KOH, MeOH, 0 °C → rt) affected the Feist-Benary
furan annulation, delivering N-Boc-furo[2,3-c]-
pyridinone 17 in the yield of 40 %. The modera-
te yield is typical of Feist–Benary annulations
involving chloroacetaldehyde, which is prone to
the base-mediated self-condensation under the
reaction conditions; nonetheless, the transforma-
tion proceeds cleanly on a preparative scale using
a simple, commercially available C2 electrophile.
The standard Boc removal then provided 18.
Across all three target compounds, the routes
described operate on a scale of tens to hundreds
of grams for the early-stage intermediates, de-
livering the final heterocycles in multi-gram
quantities. The use of the DPPA-mediated Cur-
tius rearrangement as the amine-forming step
throughout Schemes 1 and 2 eliminates the re-
liance on stoichiometric metal-hydride reductions
and gives the N-Boc amines in a single opera-
tion from the respective carboxylic acids. These
features combined with the modularity of the
Feist-Benary approach to the dihydropyridinone
ring system 18 provide a practical and operation-
ally straightforward entry to a set of partially
saturated furo-annulated N-heterocycles suitable
for further derivatization.
■ Conclusions
Three complementary partially saturated fu-
ropyridine scaffolds have been synthesized using
concise, straightforward methods suitable for the
multi-gram scale production. The main challenge
tackled in this work – obtaining β-(furyl)ethyl-
amine precursors reliably – was addressed through
the DPPA-mediated Curtius rearrangement pro-
ducing N-Boc-amines in a single step and over-
coming the poor atom economy and scalability is-
sues associated with the traditional Henry/LAH
pathway. The Feist-Benary annulation enabled
the synthesis of a dihydrofuropyridinone previ-
ously unreported, illustrating the orthogonal dis-
connection strategy that complements Pictet-Spen-
gler approaches. These protocols provide essen-
tial building blocks – pharmacophore property-
determining fragments of various bioactive hete-
rocycles – in forms ready for the direct N-functio-
nalization and the subsequent ring modifications.
■ Experimental part
General Information
The solvents were purified according to the
standard procedures. All starting materials were
N
O O
Boc
N
O
Boc
O
H
N
O O
N
Me
O
OEt
Ph
O
H
N
Me
O
OEt
O
N
Me
O
OEt
OBoc
H
N
OEt
Ph
O
14, 73 % yield 15, 91 % yield
16, 80 % yield 17, 40 % yield 18, 96 % yield
(j) (k) (l)
(n) (o)
(m)
12 13, 84 % yield
Experimental conditions j k
l m n
o
: ( ) ClCH COCH , NaHCO , THF/H O, 60 °C, 18 h; ( ) H (1 atm), 10 % Pd/C, MeOH, rt;
( ) Boc O, Et N, THF, rt, 14 h; ( ) KO Bu, THF, 5 °C → rt, 12 h; ( ) ClCH CHO (aq.), KOH, MeOH, 0 °C → rt;
( ) 4 M HCl/dioxane, rt, 12 h
2 3 3 2 2
2 3 2t
Scheme 3. The synthesis of 6,7-dihydrofuro[2,3-c]pyridin-4(5H)-one (18) via the Dieckmann/Feist-Benary route
ISSN 2308-8303 (Print) / 2518-1548 (Online) 57
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
obtained from Enamine Ltd. Melting points were
measured on an automated melting point system.
1H, and 13C NMR spectra were recorded on a Bru-
ker Avance 500 spectrometer (at 500 MHz for pro-
tons and 126 MHz for Carbon‑13) and a Varian
Unity Plus 400 spectrometer (at 400 MHz for
protons, 101 MHz for Carbon-13). Tetramethyl
silane (1H, 13C) was used as a standard. HPLC
analyses were done on an Agilent 1200 instru-
ment. Mass spectra were recorded on an Agilent
1100 LCMSD SL instrument (chemical ioniza-
tion (APCI)). The column chromatography was
performed using silica gel (200 – 300 mesh). High-
resolution mass spectrometric analyses (HRMS)
were conducted using an Agilent instrument, spe-
cifically a hybrid system comprising the 6200 Se-
ries Time-of-Flight (TOF) and the 6500 Series
Quadrupole Time-of-Flight (Q-TOF). This system
was operated with the software version B.08.00
(B8058.0). Elemental analyses were performed at
the Laboratory of Organic Analysis, Institute of
Organic Chemistry, National Academy of Sciences
of Ukraine, their results were found to be in good
agreement (±0.4 %) with the calculated values.
tert-Butyl (2-(furan-2-yl)ethyl)carbama-
te (2)
Diphenylphosphoryl azide (245.5 g, 0.89 mol)
was added to the solution of 3-(furan-2-yl)pro-
panoic acid (1) (125.0 g, 0.89 mol) and triethyl-
amine (108.3 g, 1.07 mol) in tert-butanol (2 L).
The mixture was stirred at 80 °C for 16 h, cooled
to room temperature, and concentrated under re-
duced pressure. The residue was purified by the
flash column chromatography (SiO2; hexane/EtOAc,
80:20 → 50:50) to give 2 as a colorless oil.
A yellow oil. Yield – 90 g (47 %). Anal. Calcd
for C11H17NO3, %: C 62.54, H 8.11, N 6.63. Found,
%: C 62.23, H 8.20, N 7.02. 1H NMR (400 MHz,
Chloroform-d), δ, ppm: 1.43 (9H, s), 2.82 (2H, t,
J = 6.63 Hz), 3.20 – 3.50 (2H, m), 4.67 (1H, br.
s), 6.06 (1H, d, J = 3.12 Hz), 6.19 – 6.39 (1H, m),
7.32 (1H, s). 13C NMR (151 MHz, Chloroform-d),
δ, ppm: 27.6, 28.5, 28.8, 39.3, 79.4, 85.3, 106.3,
110.4, 141.6, 146.9, 153.4, 155.9. LC-MS, m/z:
112 [M‑C4H8-CO2+H]+.
tert-Butyl 4,5,6,7-tetrahydrofuro[3,2-c]py-
ridine-5-carboxylate (3)
Paraformaldehyde (6.99 g, 0.233 mol) and
p-toluenesulfonic acid monohydrate (554 mg,
2.91 mmol) were added to the solution of 2 (24.6 g,
0.116 mol) in toluene (3500 mL). The reaction
mixture was heated to reflux for 16 h with azeo-
tropic removal of water (Dean-Stark trap). After
cooling to room temperature, the mixture was
diluted with EtOAc (1000 mL) and washed with
a saturated aqueous NaHCO3 (500 mL) and bri-
ne (500 mL). The organic layer was dried (Na2SO4),
filtered, and concentrated. The purification by the
flash column chromatography (hexane/EtOAc,
10:1) gave 3 as a yellow oil.
A yellow oil. Yield – 10.2 g (41 %). Anal. Calcd
for C12H17NO3, %: C 64.55, H 7.67, N 6.27. Found,
%: C 64.44, H 7.32, N 6.05. 1H NMR (400 MHz,
Chloroform-d), δ, ppm: 1.06 – 1.20 (1H, m), 1.33
(9H, s), 2.50 (2H, t, J = 6.90 Hz), 3.07 – 3.29 (2H,
m), 4.46 (1H, s), 6.17 (1H, s), 7.15 (1H, s). 13C NMR
(151 MHz, Chloroform-d), δ, ppm: 25.6, 28.6,
40.8, 111.0, 122.0, 139.7, 143.3, 156.0. LC-MS,
m/z: 265.2 [M+CH3CN+H]+.
4,5,6,7-Tetrahydrofuro[3,2-c]pyridine hyd-
rochloride (4·HCl)
The solution of 3 (10.2 g, 45.6 mmol) in 4 M
HCl in dioxane (100 mL) was stirred at room
temperature for 12 h (LC-MS control). The sol-
vent was removed under reduced pressure, and
the residue was dried under high vacuum to give
4·HCl as a beige solid.
A beige powder. M. p. 192 – 196 ºC. Yield – 6.8 g
(97 %). Anal. Calcd for C7H10ClNO, %: C 52.68,
H 6.32, N 8.78, Cl 22.21. Found, %: C 52.77,
H 6.03, N 8.61, Cl 22.27. 1H NMR (500 MHz,
DMSO-d6), δ, ppm: 2.90 (3H, t, J = 6.12 Hz),
4.02 (3H, br. s), 6.44 (1H, d, J = 2.09 Hz), 7.61
(1H, d, J = 2.02 Hz), 9.60 (2H, br. s). 13C NMR
(126 MHz, DMSO-d6), δ, ppm: 20.2, 40.5, 108.8,
111.3, 142.4, 146.2. LC-MS, m/z: 124.4 [M+H]+
(compound as a hydrochloride salt).
Methyl (E)-3-(furan-3-yl)acrylate (6)
Methyl 2-(diethoxyphosphoryl)acetate (243 g,
1.16 mol) was added to the suspension of NaH
(60 % dispersion in mineral oil, 48.6 g, 1.16 mol)
in THF (2500 mL) at 0 °C under the nitrogen at-
mosphere. After stirring for 1 h, 3-furaldehyde
(5) (101 g, 1.05 mol) was added in one portion.
The mixture was stirred at room temperature
for 16 h, then poured into the saturated aqueous
NH4Cl (2 L). The organic layer was separated,
washed with water (1 L), dried (Na2SO4), filtered,
and concentrated under reduced pressure to
give 6 as a yellow solid.
Yellow crystals. Yield –116 g (73 %). M. p.
35 – 37 ºC. Anal. Calcd for C8H8O3, %: C 63.15,
H 5.30. Found, %: C 62.85, H 5.21.1H NMR
(400 MHz, DMSO-d6), δ, ppm: 3.69 (3H, s), 6.36
(1H, d, J = 15.82 Hz), 6.96 (1H, d, J = 1.76 Hz),
7.58 (1H, d, J = 15.85 Hz), 7.74 (1H, s), 8.10 (1H, s).
13C NMR spectrum is identical to that reported
in literature [11].
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Methyl 3-(furan-3-yl)propanoate (7)
Sodium borohydride (28.7 g, 0.759 mol) was
added portionwise to the solution of 6 (116 g,
0.759 mol) and cuprous chloride (75.1 g, 0.759 mol)
in methanol (1.6 L) and water (400 mL) at 0 °C.
The reaction mixture was allowed to warm to room
temperature and stirred for 16 h. The mixture
was concentrated in vacuo, the residue was dilut-
ed with the saturated aqueous K2CO3 (500 mL),
and extracted with EtOAc (2 L). The organic
layer was washed with brine (500 mL), dried
(Na2SO4), and concentrated in vacuo to give 7 as
a yellow oil.
A yellow oil. Yield – 102 g (87 %). Anal. Calcd
for C8H10O3, %: C 62.33, H 6.54. Found, %: C
61.93, H 6.81. 1H NMR (400 MHz, DMSO-d6),
δ, ppm: 2.54 – 2.60 (2H, m), 2.61 – 2.72 (2H, m),
3.59 (3H, s), 6.39 (1H, s), 7.44 (1H, s), 7.48 – 7.61
(1H, m). 13C NMR spectrum is identical to that
reported in literature [12].
3-(Furan-3-yl)propanoic acid (8)
The solution of 7 (102.0 g, 0.66 mol) and lithi-
um hydroxide (55.7 g, 1.33 mol) in THF (1 L)
and water (500 mL) was stirred at room tem-
perature for 16 h (LC-MS control). The mixture
was concentrated in vacuo. The residue was dis-
solved in water (400 mL), acidified to pH 2 with
the 1 M aqueous HCl, and extracted with EtOAc
(3 × 500 mL). The combined organic layers were
washed with brine (500 mL), dried (Na2SO4), fil-
tered, and concentrated under reduced pressure
to give 8 as a brown solid.
A brown crystalline powder. Yield – 83 g (89 %).
M. p. 67 ºC. Anal. Calcd for C7H8O3, %: C 60.00,
H 5.75. Found, %: C 59.87, H 5.81. 1H NMR
(400 MHz, Chloroform-d), δ, ppm: 2.63 (2H, t,
J = 7.41 Hz), 2.78 (2H, t, J = 7.40 Hz), 6.29 (1H,
s), 7.26 (1H, d, J = 1.89 Hz), 7.36 (1H, s), 10.0
(1H, br. s, H-bond). 13C NMR (126 MHz, Chloro-
form-d), δ, ppm: 20.0, 34.5, 110.7, 123.2, 139.1,
143.0, 179.0. LC-MS, m/z: 139.0 [M-H]-.
tert-Butyl (2-(furan-3-yl)ethyl)carbama-
te (9)
Diphenylphosphoryl azide (162.8 g, 0.59 mol)
was added to the solution of 8 (83 g, 0.59 mol)
and triethylamine (71.8 g, 0.71 mol) in tert-bu-
tanol (1 L). The mixture was stirred at 80 °C for
16 h, cooled to room temperature, and concen-
trated under reduced pressure. The residue was
purified by the flash column chromatography
(SiO2; hexane/EtOAc, 80:20 → 50:50) to give 9.
A colorless oil. Yield – 72.5 g (58 %). Anal.
Calcd for C11H17NO3, %: C 62.54, H 8.11, N 6.63.
Found, %: C 62.77, H 8.24, N 6.62. 1H NMR
(400 MHz, Chloroform-d), δ, ppm: 7.38 (1H, t,
J = 1.7 Hz), 7.27 (1H, s), 6.30 (1H, s), 4.58 (1H,
s), 3.32 (, J = 6.7 Hz), 2.62 (2H, t, J = 6.9 Hz),
1.45 (9H, s). 13C NMR (151 MHz, Chloroform-d),
δ, ppm: 155.8, 143.1, 139.5, 121.8, 110.8, 79.3,
40.6, 28.4, 25.4. LCMS, m/z: 157.2 [M-tBu+H]+.
tert-Butyl 4,7-dihydrofuro[2,3-c]pyridine-
6(5H)-carboxylate (10)
Paraformaldehyde (6.99 g, 0.233 mol) and
p-toluenesulfonic acid monohydrate (554 mg,
2.91 mmol) were added to the solution of 9 (24.6 g,
0.116 mol) in toluene (3500 mL). The reaction
mixture was heated to reflux for 16 h with the
azeotropic removal of water (Dean-Stark trap).
After cooling to room temperature, the mixture
was diluted with EtOAc and washed with the
saturated aqueous NaHCO3 and brine. The or-
ganic layer was dried (Na2SO4), filtered, and con-
centrated. The purification by the flash column
chromatography (hexane/EtOAc, 10:1) gave 10
as light brown powder.
A light brown powder. M. p. 60 – 70 ºC. Yield –
7.7 g (30 %). Anal. Calcd for C12H17NO3, %: C
64.55, H 7.67, N 6.27. Found, %: C 64.39, H 7.98,
N 6.41. 1H NMR (500 MHz, Chloroform-d),
δ, ppm: 1.41 (9H, s), 2.62 (2H, s), 3.65 (2H,
br.s), 4.27 (2H, s), 6.16 (1H, s), 7.21 (1H, d, J =
13.50 Hz). 13C NMR (126 MHz, Chloroform-d), δ,
ppm: 24.0, 27.6, 28.6, 80.1, 108.5, 141.5. LC-MS,
m/z: 124.2 [M-C4H8-CO2+H]+.
4,5,6,7-Tetrahydrofuro[2,3-c]pyridine hyd-
rochloride (11·HCl)
The solution of 10 (7.7 g, 34.4 mmol) in 4 M
HCl in dioxane (70 mL) was stirred at room tem-
perature for 12 h (LC-MS control). The solvent
was removed under reduced pressure, and the
residue was dried under high vacuum to give
11·HCl as a beige solid.
A light beige powder. M. p. 193 – 196 ºC.
Yield – 5.2 g (96 %). Anal. Calcd for C7H10ClNO, %:
C 52.68, H 6.32, N 8.78, Cl 22.21. Found, %: C
52.89, H 6.72, N 9.12, Cl 22.05. 1H NMR (500 MHz,
DMSO-d6), δ, ppm: 2.70 (2H, t, J = 6.05 Hz), 3.29
(2H, t, J = 5.96 Hz), 4.18 (2H, s), 6.46 (1H, s), 7.65
(1H, s), 9.74 (2H, s). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: 19.3, 41.5, 110.8, 115.4, 142.6, 143.4
(one signal is obscured by the solvent signals).
LC-MS, m/z: 124.0 [M+H]+ (compound as a hy-
drochloride salt).
Ethyl N-benzyl-N-(2-oxopropyl)glycina-
te (13)
The solution of chloroacetone (251.3 g, 2.71 mol)
in THF (500 mL) was added slowly to the mixture
of ethyl N‑benzylglycinate (12) (500 g, 2.59 mol)
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Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
and sodium bicarbonate (260.8 g, 3.10 mol) in
THF (4 L) and water (500 mL) at 60 °C. The reac-
tion mixture was stirred at 60 °C for 18 h, cooled
to room temperature, diluted with water (2 L),
and extracted with EtOAc. The combined or-
ganic extracts were washed with brine, dried
(Na2SO4), and concentrated on a rotary evapora-
tor to give 13 as a yellow oil.
A yellow oil. Yield – 550 g (84 %). B. p.
193 – 198 ºC. Anal. Calcd for C14H19NO3, %: C 67.45,
H 7.68, N 5.62. Found, %: C 67.06, H 7.55, N
5.77. 1H NMR (500 MHz, Chloroform-d), δ, ppm:
1.14 – 1.39 (3H, m), 2.12 (3H, s), 3.45 (2H, s),
3.51 (2H, s), 3.84 (2H, s), 4.05 – 4.26 (2H, m),
7.12 – 7.44 (5H, m). 13C NMR (126 MHz, Chloro-
form-d), δ, ppm: 14.2, 27.5, 54.5, 58.5, 60.4, 63.2,
127.5, 128.4, 129.0, 138.2, 171.1, 207.9. LCMS,
m/z: 250.2 [M+H]+.
Ethyl N-(2-Oxopropyl)glycinate hydro-
chloride (14·HCl)
A 10 % Pd/C (5 g) was added to the solution
of 13·HCl (630 g, 2.20 mol) in methanol (4 L).
The mixture was hydrogenated under the atmo-
sphere of hydrogen (1 atm) at room temperature
until the reaction was complete (LC-MS control).
The catalyst was removed by the filtration and
washed with methanol. The combined filtrate was
concentrated under reduced pressure to give
14·HCl (314.6 g, 73 %).
White crystals. M. p. 93 ºC. Yield – 314.6 g
(73 %). Anal. Calcd for C7H14ClNO3, %: C 42.98,
H 7.21, N 7.16, Cl 18.12. Found, %: C 42.66,
H 7.48, N 6.93, Cl 18.50. 1H NMR (500 MHz,
DMSO-d6), δ, ppm: 1.23 (3H, t, J = 6.89 Hz), 2.19
(3H, s), 3.90 (2H, s), 4.13 (2H, s), 4.20 (2H, q, J =
6.79 Hz), 9.76 (2H, s). The 13C NMR spectrum is
identical to that reported in the literature [13].
tert-Butyl N-(1-(ethoxycarbonyl)methyl)-
N-(2-oxopropyl)carbamate (15)
Di-tert-butyl dicarbonate (351 g, 1.61 mol) was
added dropwise to a stirred solution of 14·HCl
(314.6 g, 1.60 mol) and triethylamine (211.5 g,
2.09 mol) in THF (3 L) at room temperature.
The mixture was stirred for 14 h (LC-MS con-
trol), then diluted with CH2Cl2 (2 L) and washed
with the saturated aqueous citric acid (1 L) and
water (2 L). The organic layer was dried (Na2SO4),
filtered, and concentrated under reduced pres-
sure to give 15.
A yellow oil. Yield – 417 g (91 %). Anal. Calcd
for C12H21NO5, %: C 55.58, H 8.16, N 5.40. Found,
%: C 55.32, H 8.11, N 5.35. 1H NMR (400 MHz,
Chloroform-d), δ, ppm: 1.26 (3H, q, J = 6.96 Hz),
1.42 (9H, d, J = 1.80 Hz), 3.93 (1H, s), 2.14
(3H, s), 4.03 (2H, d, J = 16.11 Hz), 4.13 (1H, s),
4.13 – 4.23 (2H, m). 13C NMR spectrum is identi-
cal to that reported in literature [13].
tert-Butyl 3,5-dioxopiperidine-1-carboxy-
late (16)
The solution of 15 (380 g, 1.46 mol) in THF (4 L)
was added over 3 h to a cooled (5 °C) suspen-
sion of potassium tert-butoxide (214 g, 1.46 mol)
in THF. The resulting mixture was allowed to
warm to room temperature, stirred for 12 h, and
then concentrated in vacuo. The residue was
dissolved in water (3 L) and acidified to pH 4
with the 1 M aqueous HCl. The precipitate was
collected by the filtration, washed with water
(2 × 1 L), and air-dried to give 16.
A beige powder. M. p. 149 ºC. Yield – 250 g
(80 %). Anal. Calcd for C10H15NO4, %: C 56.33, H
7.09, N 6.57. Found, %: C 56.11, H 7.42, N 6.83.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.41 (9H,
s), 3.97 (6H, s). 13C NMR (126 MHz, DMSO-d6),
δ, ppm: 27.9, 80.0, 101.9, 153.4. LC-MS, m/z:
212.0 [M-H]-.
tert-Butyl 4-oxo-4,7-dihydrofuro[2,3-c]-
pyridine-6(5H)-carboxylate (17)
Under the argon atmosphere, 16 (50 g,
0.235 mol) was dissolved in methanol (700 mL)
and cooled to 0 °C. Potassium hydroxide (13.2 g,
0.235 mol) was added, and the mixture was
stirred at 0 °C for 30 min. A 50 % aqueous solution
of chloroacetaldehyde (66.2 mL, 0.29 mol) was
then added. The reaction mixture was allowed
to warm to room temperature and stirred over-
night. The mixture was acidified with the 1 M
aqueous HCl, extracted with EtOAc, and the or-
ganic layer was washed with water and brine,
dried (MgSO4), and concentrated to dryness to
give a crude intermediate (41.4 g of a crude mix-
ture). The purification by the flash column chro-
matography (MeCN/CHCl3) gave 17.
A yellow crystalline powder. M. p. 72 ºC.
Yield – 22 g (40 %). Anal. Calcd for C12H15NO4, %:
C 60.75, H 6.37, N 5.90. Found: C 60.68, H 6.52,
N 5.58. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
1.42 (9H, s), 4.12 (2H, s), 4.75 (2H, s), 6.80 (1H, d,
J = 2.04 Hz), 7.86 (1H, d, J = 2.01 Hz). 13C NMR
(126 MHz, DMSO-d6), δ, ppm: 27.8, 79.1, 80.5,
105.9, 119.0, 144.8, 153.6, 188.5. LC-MS, m/z:
260.0 [M+Na]+.
6,7-Dihydrofuro[2,3-c]pyridin-4(5H)-one
hydrochloride (18·HCl)
The solution of 17 (22 g, 93 mmol) in 4 M
HCl in dioxane (200 mL) was stirred at room
temperature for 12 h (LC-MS control). The sol-
vent was removed under reduced pressure, and
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the residue was dried under high vacuum to
give 18·HCl (12.2 g, 96 %).
A light brown crystalline powder. M. p.
154 – 170 ºC. Yield – 12.2 g (96 %). Anal. Calcd
for C7H8ClNO2, %: C 48.43, H 4.65, N 8.07, Cl
20.42. Found: C 48.15, H 4.45, N 8.01, Cl 20.63.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 3.91
(2H, s), 4.61 (2H, s), 6.88 (1H, d, J = 2.08 Hz),
7.97 (1H, d, J = 2.18 Hz), 10.73 (2H, s). 13C NMR
(126 MHz, DMSO-d6), δ, ppm: 49.1, 66.3, 106.0,
119.6, 145.8, 159.5, 184.3. LC-MS, m/z: 138.2
[M+H]+ (compound as a hydrochloride salt).
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Information about the authors:
Ihor S. Kishko, Ph.D. Student of the Department of Chemistry of Functional Heterocyclic Systems, Institute of Organic Chemistry
of the National Academy of Sciences of Ukraine; Senior Chemist at Enamine Ltd.; https://orcid.org/0009-0000-4322-0431.
Alla I. Vaskevych (corresponding author), Ph.D. in Chemistry, Senior Researcher of the Department of Chemistry of Functional
Heterocyclic Systems, Institute of Organic Chemistry, National Academy of Sciences of Ukraine. https://orcid.org/0000-0003-0370-6626;
e-mail: a.yu.vaskevich@gmail.com.
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| id | oai:ojs.journals.uran.ua:article-357365 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-25T01:02:53Z |
| publishDate | 2026 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/b9/3a5b1a2f2b5c84eb0a2a9d3357de03b9.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3573652026-08-24T19:33:19Z Preparation of Partially Saturated Furo[3,2-c]- and Furo[2,3-c]annulated N-Heterocycles Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів Kishko, Ihor S. Vaskevych, Alla I. фуропіридин реакція Піктета-Шпенглера перегрупування Курціуса реакція Файста-Бенарі тетрагідропіридин гетероциклічні будівельні блоки furopyridine Pictet-Spengler reaction Curtius rearrangement Feist-Benary reaction tetrahydropyridine heterocyclic building blocks Practical, multi-gram routes to three med-chem-relevant partially saturated furo[3,2-c]- and furo[2,3-c]annulated N-heterocycles are described. The key β‑(furyl)ethylamine intermediates were accessed via DPPA-mediated Curtius rearrangement, replacing the traditional Henry/LAH sequence and eliminating stoichiometric metal-hydride reductions. The tetrahydrofuropyridine cores were then assembled through Pictet-Spengler cyclization, while a previously unavailable dihydrofuropyridinone was obtained via Dieckmann/Feist-Benary annulation. All sequences proceed in ≤6 steps from commercial starting materials. Запропоновано практичні мультиграмові методи одержання трьох значущих для медичної хімії частково насичених N-гетероциклів, анельованих за типом фуро[3,2-c]- та фуро[2,3-c]. Ключові проміжні β-(фурил)етиламіни були отримані за допомогою перегрупування Курціуса, під дією дифенілфосфорилазиду (DPPA), що дозволило замінити традиційну послідовність «реакція Анрі/відновлення алюмогідридом літію (LiAlH4)» та уникнути використання стехіометричних кількостей металогідридних відновників. Основні тетрагідрофуропіридинові похідні було синтезовано шляхом циклізації Пікте-Шпенглера, тоді як раніше недоступний дигідрофуропіридинон було одержано за допомогою анелювання Дікмана/Фейста-Бенарі. Усі синтетичні послідовності реалізуються щонайбільше у шість стадій, виходячи з комерційно доступних реагентів. National University of Pharmacy 2026-05-04 Article Article application/pdf application/pdf https://ophcj.nuph.edu.ua/article/view/357365 10.24959/ophcj.26.357365 Journal of Organic and Pharmaceutical Chemistry; Vol. 24 No. 1 (2026); 53-60 Журнал органической и фармацевтической химии; Том 24 № 1 (2026); 53-60 Журнал органічної та фармацевтичної хімії; Том 24 № 1 (2026); 53-60 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/357365/345455 https://ophcj.nuph.edu.ua/article/view/357365/345241 Copyright (c) 2026 Ihor S. Kishko, Alla I. Vaskevych http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | фуропіридин реакція Піктета-Шпенглера перегрупування Курціуса реакція Файста-Бенарі тетрагідропіридин гетероциклічні будівельні блоки Kishko, Ihor S. Vaskevych, Alla I. Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title | Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title_alt | Preparation of Partially Saturated Furo[3,2-c]- and Furo[2,3-c]annulated N-Heterocycles |
| title_full | Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title_fullStr | Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title_full_unstemmed | Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title_short | Отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих N-гетероциклів |
| title_sort | отримання частково насичених фуро[3,2-c]- та фуро[2,3-c]анельованих n-гетероциклів |
| topic | фуропіридин реакція Піктета-Шпенглера перегрупування Курціуса реакція Файста-Бенарі тетрагідропіридин гетероциклічні будівельні блоки |
| topic_facet | фуропіридин реакція Піктета-Шпенглера перегрупування Курціуса реакція Файста-Бенарі тетрагідропіридин гетероциклічні будівельні блоки furopyridine Pictet-Spengler reaction Curtius rearrangement Feist-Benary reaction tetrahydropyridine heterocyclic building blocks |
| url | https://ophcj.nuph.edu.ua/article/view/357365 |
| work_keys_str_mv | AT kishkoihors preparationofpartiallysaturatedfuro32candfuro23cannulatednheterocycles AT vaskevychallai preparationofpartiallysaturatedfuro32candfuro23cannulatednheterocycles AT kishkoihors otrimannâčastkovonasičenihfuro32ctafuro23canelʹovanihngeterociklív AT vaskevychallai otrimannâčastkovonasičenihfuro32ctafuro23canelʹovanihngeterociklív |