Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону
Practical, tens-of-grams-scale access to 2-oxaadamantan-1-amine and 2-oxaadamantan-1-ol – two overlooked heteroadamantane building blocks of interest for medicinal chemistry – has been achieved through optimization and scale-up of existing literature protocols. The key precursor, bicyclo[3.3.1]nonan...
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| author | Popov, Ioann O. Volochnyuk, Dmytro M. |
| author_facet | Popov, Ioann O. Volochnyuk, Dmytro M. |
| author_institution_txt_mv | [
{
"author": "Ioann O. Popov",
"institution": "Enamine Ltd; Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Dmytro M. Volochnyuk",
"institution": "Enamine Ltd.; Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Taras Shevchenko National University of Kyiv; Enamine Scientific Research Institute",
"orcid": ""
}
] |
| author_sort | Popov, Ioann O. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 52 |
| container_issue | 1 |
| container_start_page | 46 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 24 |
| datestamp_date | 2026-08-24T19:33:19Z |
| description | Practical, tens-of-grams-scale access to 2-oxaadamantan-1-amine and 2-oxaadamantan-1-ol – two overlooked heteroadamantane building blocks of interest for medicinal chemistry – has been achieved through optimization and scale-up of existing literature protocols. The key precursor, bicyclo[3.3.1]nonane-3,7-dione, and both target compounds are obtained in good overall yields using straightforward procedures and standard reagents. Notably, 2-oxaadamantan-1-amine is an exceptionally stable N,O-acetal, in stark contrast to the high hydrolytic lability usually seen in this compound class. |
| doi_str_mv | 10.24959/ophcj.26.357366 |
| first_indexed | 2026-05-02T01:00:11Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 46
Original Research
http://ophcj.nuph.edu.ua
UDC 547+547-316+547-31/-39
I. O. Popov 1,2, D. M. Volochnyuk1,2,3,4
1 Enamine Ltd, 78 Winston Churchill str., 02094 Kyiv, Ukraine
2 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02094 Kyiv, Ukraine
3 Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine
4 Enamine Scientific Research Institute, 67 Winston Churchill str., 02094 Kyiv, Ukraine
The Multigram-Scale Access to 2-Oxaadamantan-1-amine
and 2-Oxaadamantan-1-ol via the Optimized Synthesis
of Bicyclo[3.3.1]nonane-3,7-dione
Abstract
The practical tens-of-grams-scale access to 2-oxaadamantan-1-amine and 2-oxaadamantan-1-ol – two overlooked hetero-
adamantane building blocks of interest for medicinal chemistry – has been achieved through the optimization and scale-up of
existing literature protocols. The key precursor – bicyclo[3.3.1]nonane-3,7-dione– and both target compounds can be obtained
in good overall yields using straightforward procedures and standard reagents. It is noteworthy that 2-oxaadamantan-1-amine
is an exceptionally stable N,O-acetal, in stark contrast to the high hydrolytic lability usually seen in this compound class.
Keywords: oxaadamantane; bicyclo[3.3.1]nonane-3,7-dione; N,O-acetal; hemiaminal; cage compounds; scale-up synthesis;
heteroadamantane; building blocks
І. О. Попов1,2, Д. М. Волочнюк1,2,3,4
1 ТОВ НВП «Єнамін», вул. Вінстона Черчилля, 78, м. Київ, 02094, Україна
2 Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
3 Київський національний університет імені Тараса Шевченка,
вул. Володимирська, 60, м. Київ, 01033, Україна
4 Науково-дослідний інститут «Єнамін», вул. Вінстона Черчилля, 67, м. Київ, 02094, Україна
Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультиграмових кількостях
через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону
Анотація
Завдяки оптимізації та масштабуванню вже відомих методик вдалося розробити практичний спосіб синтезу 2-оксаадамантан-
1-аміну та 2-оксаадамантан-1-олу в кількостях, вимірюваних десятками грамів. Ці два структурні блоки, які раніше
лишалися поза увагою дослідників, становлять особливий інтерес для медичної хімії. Ключовий прекурсор – біцикло-
[3.3.1]нонан-3,7-діон – та обидві цільові сполуки можна отримати з високим загальним виходом, використовуючи не-
складні процедури й стандартні реагенти. Показово, що 2-оксаадамантан-1-амін виявляє виняткову стабільність як
N,O-ацеталь, що яскраво контрастує з високою гідролітичною лабільністю, зазвичай властивою сполукам цього класу.
Ключові слова: оксаадамантан; біцикло[3.3.1]нонан-3,7-діон; N,O-ацеталь; геміаміналь; каркасні сполуки; масштабований
синтез; гетерадамантан; будівельні блоки
Citation: Popov, I. O.; Volochnyuk D. M. The Multigram-Scale Access to 2-Oxaadamantan-1-amine and 2-Oxaadamantan-1-ol via the
Optimized Synthesis of Bicyclo[3.3.1]nonane-3,7-dione. Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1), 46 – 52.
https://doi.org/10.24959/ophcj.26.357366
Received: 15 February 2026; Revised: 9 April 2026; Accepted: 13 April 2026
Copyright© 2026, I. O. Popov, D. M. Volochnyuk. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Supporting information: X-Ray Experimental Part, Copies of NMR Spectra for the Synthesized Compounds.
Funding: The work was funded by the internal Enamine grant and the National Research Foundation of Ukraine
(the grant number 0125U001943, the NRFU registration number 2023.03/0250).
Conflict of interests: The authors have no conflict of interests to declare.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 47
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
■ Introduction
The 2-oxaadamantane motif appears in se-
veral biologically important natural products.
Tetrodotoxin (TTX), a powerful neurotoxin from
pufferfish, has a densely functionalized dioxa-
adamantane core that enables its highly selecti-
ve blockage of voltage-gated Na+ ion channels [1].
Other naturally occurring (poly)oxaadamantanes,
including the trioxaadamantanes muamvatin and
caloundrin B, the sedative daigremontianin, and
bersaldegenin orthoacetate, further demonstrate
the recurrence of this cage scaffold in nature [1].
In synthetic chemistry, despite the difficulties
in constructing and functionalizing the hetero-
adamantane skeleton, several oxaadamantane-
containing compounds show a significant biolo-
gical activity across various targets, such as NMDA
receptor antagonists and trypanocidal agents [2],
heteroadamantyl cannabinoids with the nanomo-
lar CB1/CB2 affinity [3], σ-receptor ligands [4],
reversed-chloroquine antimalarial conjugates [5]
(Figure 1), rigid acetylcholine-like pharmacopho-
re models [6], and the highly efficient AZADO
family of nitroxyl-radical oxidation catalysts [7].
Additionally, the constrained geometry of (oxa)
adamantane systems has been used to explore
the fundamental chemical reactivity, including
the transition-state geometry in aldol condensa-
tions [8].
The simplest way to synthesize 1-heteroatom-
substituted 2-oxaadamantanes involves bicyclo-
[3.3.1]nonane-3,7-dione, which acts as a common
precursor for both the amine and the alcohol through
the transannular cyclization. Several synthetic ap-
proaches to this diketone have been reported: the
condensation of dicarboxylic acid derivatives [9],
the fragmentation–ozonolysis of 1,3-dibromoada-
mantane [10], the double-condensation of dime-
thyl 3-oxoglutarate with malondialdehyde [11],
routes via bicyclo[3.3.1]nonanone intermedi-
ates [12], and a three-step sequence from ada-
mantan-2-one through a lactone and diol [13].
Of these, the latter route is arguably the most
practical, employing inexpensive, commercially
available adamantan-2-one and involving the
Baeyer-Villiger oxidation, the LiAlH4 reduction,
and the chromium-based oxidation of the result-
ing diol – a versatile intermediate that has also
been used in related skeletal transformations [14].
However, all reported procedures for the dike-
tone have been developed and validated only on
a small scale (typically ≤ 10 g), and reliable up-
scale methods have not been documented. This li-
mitation has thus restricted practical access to
the downstream target compounds – 2-oxaada-
mantan-1-amine and 2-oxaadamantan-1-ol –
which remain underexplored as building blocks
despite their potential. The amine itself has been
prepared via reductive amination of the dike-
tone [2, 10], but the reported protocols operate
on a few-gram scale and require a high-pressure
hydrogenation for the final deprotection step.
Herein, we report modifications to existing pro-
tocols that enable a reliable, the tens-of-grams-
scale access to the diketone in three steps with
a good overall yield, thereby enabling the access
to both the amine and the alcohol in multigram
quantities – determining these compounds as
practical building blocks for further research.
■ Results and discussion
Our approach follows the general strategy out-
lined by Zalikowski et al. [13], with modifications
at each step to ensure reproducibility and enhanced
yields during scale-up (Scheme 1). The Baeyer-
Villiger oxidation of adamantan-2-one (1) with
mCPBA in CH2Cl2 proceeded smoothly, deliver-
ing lactone 2 quantitatively on a 77 g scale –
O
Me
N
Me
Me
NMDAR antagonist
Synthetic bioactive oxaadamantanes
O
Me
N
O
N
H
Me
O
Me
N
Me
Me
anti-T. bruceiAnti-T. Brucei
NMDAR blocker
O
Me
Me
OH
OH
O
O O
O
O
Me
Me
O
HO
O
O
O
O
O
OH
O�
OH
HO
Tetrodotoxin (TTX)
HO
N
H
H
N
NH2
+
H Bersaldegenin-1,3,5-orthoacetate
Caloundrin B
Naturaly occuring bioactive oxaadamantane derivatives
CB1/2 Modulator
O O
O
Me
OH
Me
O O
O
HO
Et
Me
Me Me Me
Me
Me
O
O
O
Me
HO
Me
CHO
O
O
Figure 1. Selected natural products and synthetic bioactive compounds incorporating oxaadamantane and related (poly)oxaadamantane
scaffolds
ISSN 2308-8303 (Print) / 2518-1548 (Online) 48
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
approximately fifteen-fold larger than the batch
size reported in the previous work [13]. The sin-
gle aqueous NaOH wash of the original proto-
col was replaced by sequential Na2CO3/Na2S2O3
washes followed by the MTBE trituration; both
were necessary to achieve complete removal of
mCPBA and residual CH2Cl2 at this scale, which
otherwise interfered with the subsequent reduc-
tion with LiAlH4 in THF – substituted for the
less practical diethyl ether used in the original
protocol [13] – gave diol 3 in 96 % yield (73.5 g).
As previously noted [13], diol 3 is poorly solu-
ble in common organic solvents; therefore, the
inorganic residue from the LiAlH4 quench must
be washed repeatedly with a hot THF to ensure
complete recovery of the product. The oxidation
of diol 3 to diketone 4 was the main bottleneck
in the sequence. While the literature protocol
uses pyridinium dichromate (PDC) and reports
a 75 % yield on about 5 g [13], we could not rep-
licate this result on larger scales. Testing alter-
natives, including PDC at higher temperatures
and Dess-Martin periodinane, produced inferior
or inconsistent results. Ultimately, 7 equiv. of py-
ridinium chlorochromate (PCC), on silica in CH2Cl2
at room temperature over three days delivered
diketone 4 reproducibly in the yield of 59 % (35 g
from 66 g of 3) – modestly below the 75 % report-
ed previously [13] on a ~5 g batch, but, crucially,
reliably reproducible at the tens-of-grams scale,
with lactone 2 (from over-oxidation) as the main
by-product. The overall three-step yield of di-
ketone from adamantan-2-one is 57 %, and the
entire sequence requires no chromatography,
which is a key advantage for the routine prepa-
ration.
With a sustainable supply of diketone 4, the
target oxaadamantanes were synthesized via two
different routes. 2-Oxaadamantan-1-ol (5) was ob-
tained simply through the NaBH4 reduction of 4
in methanol (95 % yield, 11.2 g). The amine was
synthesized through the two-step process adap-
ted from Duque et al. [2] work: the one-pot con-
densation of 4 with benzylamine followed by
the in situ LiAlH4 reduction produced N-benzyl-
2-oxaadamantan-1-amine (6) as its hydrochlori-
de salt (54 %, 21.6 g), and the subsequent hydro-
genolysis over Pd/C at atmospheric pressure in
methanol yielded the primary 2-oxaadamantan-
1-amine as its hydrochloride 7 (90 %, 12.6 g).
Both the yield and operational simplicity of this
debenzylation significantly improve upon the li-
terature methods, which involve the high-pres-
sure hydrogenation (40 atm, 100 °C), followed
by the base extraction and sublimation, yielding
only 70 % on an around 1 g scale [2].
Compound 7 is a bridgehead hemiaminal:
the amine nitrogen is directly attached to the car-
bon that also forms part of the oxaadamantane
ether linkage, making it a cyclic N,O-acetal.
This functional motif – a cyclic α-amino ether –
belongs to a notoriously unstable compound class:
most known representatives decompose upon the
attempted isolation, and even the comparative-
ly stabilized 1-aminoisochroman can only be
handled in situ in solution and must be reacted
immediately to avoid decomposition [15]. In con-
trast, 7 remains stable after the prolonged ex-
posure to both acidic and basic aqueous condi-
tions at high temperatures. This notable stabi-
lity results from the geometric constraints of the
Bredt’s rule, which prevents the formation of
O O
O
O
OH
H
H
O
O
O
O
OH
N
H
Bn
NH2
( )a
( )b
( )d
HO
yield: 100 %
scale: 85 g
yield: 95 %
scale: 11.2 g1
5
2
yield: 59 %
scale: 35 g
4
yield: 54 %
scale: 21.6 g
6
yield: 90 %
scale: 12.6 g
7
yield: 96 %
scale: 73.5 g
3
3 XRD
7 (HCl) XRD
( )c ( )e ( )f
Scheme 1. The synthesis of 2-oxaadamantan-1-ol (5) and 2-oxaadamantan-1-amine (7) from adamantan-2-one (1). Thermal ellipsoid
plots from the single-crystal X-ray diffraction of 7·(HCl) and 5 are given with the 50 % probability (see SI File)
ISSN 2308-8303 (Print) / 2518-1548 (Online) 49
Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
the bridgehead iminium ion needed for the hy-
drolytic cleavage – a stabilization first noted by
Stetter for the related 1-hydroxy-2-oxaadaman-
tane [9]. The structures of 5 and 7 (hydrochlo-
ride) were confirmed by the single-crystal X-ray
diffraction (Scheme 1).
Since 2-oxaadamantane-derived 1-amines have
already withstood the conditions of biological
assays without the apparent breakdown of the
N,O-acetal linkage (see Introduction), the ques-
tion is whether this robustness extends to both
amine 7 and alcohol 5 derivatives in more chal-
lenging environments, such as extended meta-
bolic exposure and in vivo testing. With multi-
gram quantities now available, we plan to un-
dertake a systematic ADMET profiling as the
next logical step.
■ Conclusions
We have shown that two previously overlooked
heteroadamantane building blocks – 2-oxaada-
mantan-1-amine and 2-oxaadamantan-1-ol – can
be reliably prepared on the tens-of-grams scale
from commercially available adamantan-2-one by
optimizing existing literature protocols. All steps
use standard reagents, do not require chromato-
graphic purification, and yield good overall re-
sults. The exceptional hydrolytic stability of
2-oxaadamantan-1-amine – a rare trait for an
N,O-acetal – is a unique feature that, along with
the increased practical accessibility of both com-
pounds, may promote their wider study as rigid,
heteroatom-containing scaffolds in medicinal che-
mistry and drug discovery.
■ Experimental part
General Information
The solvents were purified according to the
standard procedures. All starting materials were
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 1H,
101 MHz for 13C). Tetramethyl silane (1H, 13C)
was used as a standard. HPLC analyses were
done on an Agilent 1200 instrument. Mass spec-
tra were recorded on an Agilent 1100 LCMSD SL
instrument (chemical ionization (APCI)). The co-
lumn chromatography was performed using si-
lica gel (200 – 300 mesh). The high-resolution mass
spectrometric analyses (HRMS) were conducted
using an Agilent instrument, specifically a hybrid
system comprising the 6200 Series 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). Elemen-
tal analyses were performed at the Laboratory
of Organic Analysis, Institute of Organic Che-
mistry, National Academy of Sciences of Ukraine.
All crystallographic measurements for this
publication were performed at 173K on a Bruker
Smart Apex II diffractometer operating in the
φ and w scans mode. The intensity data were col-
lected using the Mo-Ka radiation (l = 0.71078 Å).
The crystals were mounted on a glass fiber and
mounted on the diffractometer. The structures
were solved by direct methods and refined by the
full-matrix least-squares technique using the Bru-
ker SHELXTL program package [16].
Non-hydrogen atoms were refined anisotro-
pically. All CH hydrogen atoms were placed at cal-
culated positions and refined as ‘riding’ model,
with Uiso(H)=1.2Ueq(CH2) and Uiso(H)=1.5Ueq(CH3).
The NH hydrogen atoms in structures 5 and 7
(HCl) were found in difference Fourier synthe-
ses and refined isotropically. The absolute con-
figuration of 8 is not determined because no heavy
atoms are present in the molecule. The X-ray
crystallographic data for all compounds are list-
ed in the SI File.
Crystallographic data for the structures in
this paper were deposited at the Cambridge Cry-
stallographic Data Centre as supplementary pub-
lication numbers CCDC 2543739 (compound 3)
and 2543738 (compound 7). Copies of the data
can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB21EZ,
UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
4-Oxatricyclo[4.3.1.13,8]undecan-5-one (2)
The solution of adamantan-2-one (1; 77.2 g,
0.514 mol, 1.0 equiv.) in CH2Cl2 (2400 mL) was
stirred at room temperature (25 °C) with a mag-
netic stirrer (400 rpm). mCPBA (177.4 g, 90 % pu-
rity, 1.028 mol, 2.0 equiv.) was added portionwise
over 5 min. The reaction mixture was stirred at
room temperature for 24 h, then washed with
a 10 % aqueous Na2CO3 (2 × 1400 mL) and
a 10 % aqueous Na2S2O3 (2 × 1400 mL), dried over
Na2SO4, and filtered. The filtrate was concentrat-
ed under reduced pressure, MTBE (600 mL) was
added, and the mixture was evaporated again
to remove residual CH2Cl2. The product was ob-
tained as white crystals.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 50
Журнал органічної та фармацевтичної хімії 2026, 24 (1)
Yield – 85 g (100 %). M. p. 238 – 248 ºC (dec.).
Anal. Calcd for C10H14O2, %: C 72.26, H 8.49.
Found, %: C 72.38, H 8.28. 1H NMR (500 MHz,
Chloroform-d), δ, ppm: 1.73 (1H, s), 1.79 – 1.88
(2H, m), 1.89 – 1.98 (2H, m), 1.98 – 2.07 (3H, m),
2.10 (1H, br.s), 2.98 – 3.13 (4H, m), 4.47 (1H, s).
13C NMR (126 MHz, Chloroform-d), δ, ppm: 26.0,
31.1, 33.9, 35.9, 41.4, 73.3, 179.0. 13C NMR_APT
(126 MHz, Chloroform-d), δ, ppm: 25.7, 30.9,
33.7, 35.7, 41.1, 73.0. GC-MS, m/z (EI): 166 [M]+.
7-(Hydroxymethyl)bicyclo[3.3.1]nonan-
3-ol (3)
To an ice-cooled dry THF (1100 mL), LiAlH4
(20.55 g, 0.542 mol, 1.2 equiv.) was added por-
tionwise. The suspension was stirred at 0 °C for
10 min, then lactone 2 (75.0 g, 0.451 mol, 1.0 equiv.)
was added portionwise over 5 min at 0 °C. The re-
action mixture was allowed to warm to room tem-
perature and stirred overnight. The reaction
was quenched by the dropwise addition of water
(75 mL) at 0 °C, followed by stirring at 0 °C for
15 min. Na2SO4 (150 g) was added, and the inor-
ganic solids were collected by the filtration and
washed thoroughly with a hot THF. The com-
bined filtrates were concentrated under reduced
pressure, and the residue was triturated with
CH2Cl2 (300 mL).
Note: The product is insoluble in CHCl3;
NMR spectra were recorded in DMSO-d6.
A white-yellow solid. Yield – 73.5 g (96 %).
M. p. 175 ºC. Anal. Calcd for C10H18O2, %: C 70.55,
H 10.66. Found, %: C 70.67, H 10.54. 1H NMR
(400 MHz, DMSO-d6), δ, ppm: 1.04 (1H, d, J =
12.39 Hz), 1.48 – 1.84 (8H, m), 1.97 (2H, s), 2.54
(1H, s), 3.14 (2H, t, J = 5.51 Hz), 3.32 (2H, br.s), 3.93
(1H, s), 4.09 – 4.24 (1H, m). 13C NMR (126 MHz,
DMSO-d6), δ, ppm: 23.7, 28.2, 29.6, 32.9, 65.3,
67.4. 13C NMR_APT (126 MHz, DMSO-d6), δ, ppm:
23.6, 28.1, 29.5, 32.7, 65.1, 67.2, 108.8, 109.2,
159.2. GC-MS, m/z (EI): 152 [M-H2O]+.
Bicyclo[3.3.1]nonane-3,7-dione (4)
To the solution of diol 3 (66.0 g, 0.388 mol,
1.0 equiv.) in CH2Cl2 (3000 mL), SiO2 (600 g) and
PCC (585 g, 2.71 mol, 7.0 equiv.) were added.
The resulting mixture was stirred at room tem-
perature for 3 days. EtOAc (600 mL) was added,
and the mixture was filtered through a silica pad,
which was washed with EtOAc (2000 mL), and
the combined filtrates were concentrated under
reduced pressure. The residue was dissolved in
MTBE (2000 mL) and heated to reflux; the mix-
ture was filtered while hot, and the filtrate was
partially concentrated to approximately one-
quarter of its original volume, cooled with ice,
and the precipitate was collected by the filtra-
tion and air-dried for 1 h.
A white-yellow solid. Yield – 35.0 g (59 %).
M. p. 214 – 223 ºC. Anal. Calcd for C9H12O2, %:
C 71.03, H 7.95. Found, %: C 70.89, H 8.05.
1H NMR (500 MHz, Chloroform-d), δ, ppm: 2.20
(2H, s), 2.41 (4H, d, J = 15.42 Hz), 2.58 (4H, dd,
J = 15.46, 5.41 Hz), 2.86 (2H, br.s). 13C NMR
(126 MHz, Chloroform-d), δ, ppm: 31.7, 32.8,
48.0, 208.4. 13C NMR_APT (126 MHz, Chloro-
form-d), δ, ppm: 31.7, 32.8, 48.0. GC-MS, m/z (EI):
152 [M]+.
2-Oxaadamantan-1-ol (5)
To an ice-cooled solution of diketone 4 (11.69 g,
76.8 mmol, 1.0 equiv.) in a dry MeOH (210 mL),
NaBH4 (3.49 g, 92.2 mmol, 1.2 equiv.) was added
portionwise. The reaction mixture was stirred at
room temperature for 24 h, then concentrated
under reduced pressure. The residue was quenched
with a saturated aqueous Na2CO3 (350 mL) and
stirred for 10 min. The aqueous layer was ex-
tracted with CHCl3/MeOH (6:1, 3 × 400 mL).
The combined organic layers were dried over
Na2SO4, filtered, and concentrated under redu-
ced pressure.
A white solid. Yield – 11.2 g (95 %). M. p.
195 – 238 (dec.). Anal. Calcd for C9H14O2, %: C 70.10,
H 9.15. Found, %: C 70.26, H 9.03. 1H NMR
(500 MHz, Chloroform-d), δ, ppm: 1.55 (2H,
d, J = 12.35 Hz), 1.72 (1H, d, J = 11.90 Hz),
1.76 – 1.87 (5H, m), 1.92 (2H, d, J = 11.59 Hz),
2.30 (2H, s), 2.96 (1H, br. s, H-bond), 4.28 (1H, s).
13C NMR (101 MHz, Chloroform-d), δ, ppm: 29.3,
34.7, 42.0, 72.2, 93.8. 13C NMR_APT (101 MHz,
Chloroform-d), δ, ppm: 29.3, 34.7 42.0, 72.2, 93.8.
EIMS, m/z (EI): 154 [M]+.
N-Benzyl-2-oxaadamantan-1-amine hydro-
chloride (6)
To the solution of diketone 4 (22.0 g, 0.144 mol,
1.0 equiv.) in a dry THF (800 mL), benzylamine
(17.6 mL, 0.159 mol, 1.1 equiv.) was added. The mix-
ture was stirred at 65 °C for 30 min, then cool-
ed to room temperature to form the solution of the
corresponding imine. Separately, to an ice-cooled
dry THF (280 mL), LiAlH4 (10.8 g, 0.289 mol,
2.0 equiv.) was added portionwise and stirred at
0 °C for 10 min. The solution of the imine was
then added dropwise to the LiAlH4 suspension at
0 °C. The reaction mixture was allowed to warm to
room temperature and stirred overnight. The re-
action was quenched by the dropwise addition of
the solution of NaOH (5.6 g, 0.144 mol, 1.0 equiv.)
in H2O (40 mL) at 0 °C, stirred for 15 min, and
Na2SO4 (400 g) was added. The inorganic solids
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Journal of Organic and Pharmaceutical Chemistry 2026, 24 (1)
were removed by the filtration and washed with
EtOAc. The combined filtrates were concen-
trated under reduced pressure. The residue was
taken up in methyl acetate (440 mL), treated
with 10 M HCl (22 mL), and stirred at 0 °C for
10 min. The precipitate was collected by the fil-
tration and air-dried.
A white-yellow solid (HCl salt). Yield – 21.6 g
(54 %). M. p. 218 – 227 °C (dec.). Anal. Calcd for
C16H21NO, %: C 78.97, H 8.70, N 5.76. Found, %:
C 78.81, H 8.55, N 5.66. 1H NMR (500 MHz,
Chloroform-d), δ, ppm: 1.55 (2H, d, J = 12.84 Hz),
1.74 (3H, s), 1.83 – 2.04 (5H, m,), 2.11 – 2.24 (2H,
m), 4.06 (1H, t, J = 5.44 Hz), 4.19 – 4.37 (1H, m),
7.20 – 7.34 (3H, m), 7.61 (2H, d, J = 7.47 Hz), 9.83
(2H, s). 13C NMR (126 MHz, Chloroform-d), δ, ppm:
28.0, 34.0, 34.4, 37.0, 44.1, 72.0, 85.7, 128.8,
131.5. 13C NMR_APT (126 MHz, Chloroform-d),
δ, ppm: 27.7, 33.9, 36.7, 43.9, 71.7, 85.5, 128.5,
131.3, 159.8. LC-MS, m/z (CI): 244.2 [M+H]+.
2-Oxaadamantan-1-amine Hydrochlori-
de (7)
To the solution of 6 (21.0 g, 74.9 mmol, 1.0 equiv.)
in MeOH (630 mL), 10 % Pd/C (7.0 g) was added.
The flask was evacuated and backfilled with
hydrogen five times, then stirred under the
hydrogen atmosphere (1 atm, balloon) at room
temperature for 24 h. The reaction mixture was
filtered through a thin pad of SiO2, and the fil-
trate was concentrated under reduced pressure.
The residue was triturated with a dry MeCN
(350 mL) and concentrated under reduced pres-
sure.
A beige powder (HCl salt). Yield – 12.6 g
(90 %). M. p. >200 °C (gradual dec.). Anal. Calcd
for C9H15NO, %: C 70.55, H 9.87, N 9.14. Found, %:
C 70.39, H 9.97, N 9.25. 1H NMR (500 MHz,
DMSO-d6), δ, ppm: 1.63 (2H, d, J = 12.47 Hz),
1.71 (1H, d, J = 12.42 Hz), 1.75 – 1.99 (8H, m), 2.24
(2H, s), 4.21 (1H, s), 8.60 (2H, s). 13C NMR_APT
(126 MHz, DMSO-d6), δ, ppm: 27.1, 33.5, 38.3,
39.9, 70.3, 80.6. GC-MS, m/z (EI): 153 [M]+.
■ Acknowledgments
The authors express their gratitude to Dr. Svit-
lana V. Shishkina for performing the X-ray dif-
fraction analysis.
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Information about the authors:
Ioann O. Popov, Ph.D. Student of Chemistry of the Department of Medicinal Chemistry, Institute of Organic Chemistry of the National
Academy of Sciences of Ukraine; Senior Chemist at Enamine Ltd. https://orcid.org/0009-0007-5366-802X.
Dmytro M. Volochnyuk (corresponding author), Dr.Sci. in Chemistry, Head of the Biologically Active Compounds Department,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Professor at the Educational Scientific Institute
of High Technologies, Taras Shevchenko National University of Kyiv; Senior Scientific Advisor, Enamine Ltd.;
https://orcid.org/0000-0001-6519-1467; e-mail for correspondence: d.volochnyuk@gmail.com.
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| id | oai:ojs.journals.uran.ua:article-357366 |
| 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/e8/79beedd3bca32454b59b909f97dbeee8.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3573662026-08-24T19:33:19Z Multigram-Scale Access to 2-Oxaadamantan-1-amine and 2-Oxaadamantan-1-ol via Optimized Synthesis of Bicyclo[3.3.1]nonane-3,7-dione Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону Popov, Ioann O. Volochnyuk, Dmytro M. oxaadamantane bicyclo[3.3.1]nonane-3,7-dione N,O-acetal hemiaminal cage compounds scale-up synthesis heteroadamantane building blocks оксаадамантан біцикло[3.3.1]нонан-3,7-діон N,O-ацеталь геміаміналь каркасні сполуки масштабований синтез гетерадамантан будівельні блоки Practical, tens-of-grams-scale access to 2-oxaadamantan-1-amine and 2-oxaadamantan-1-ol – two overlooked heteroadamantane building blocks of interest for medicinal chemistry – has been achieved through optimization and scale-up of existing literature protocols. The key precursor, bicyclo[3.3.1]nonane-3,7-dione, and both target compounds are obtained in good overall yields using straightforward procedures and standard reagents. Notably, 2-oxaadamantan-1-amine is an exceptionally stable N,O-acetal, in stark contrast to the high hydrolytic lability usually seen in this compound class. Завдяки оптимізації та масштабуванню вже відомих методик вдалося розробити практичний спосіб синтезу 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в кількостях, що вимірюються десятками грамів. Ці два структурні блоки, які раніше лишалися поза увагою дослідників, становлять особливий інтерес для медичної хімії. Ключовий прекурсор – біцикло[3.3.1]нонан-3,7-діон – та обидві цільові сполуки можна отримати з високим загальним виходом, використовуючи нескладні процедури та стандартні реагенти. Примітно, що 2-оксаадамантан-1-амін виявляє виняткову стабільність як N,O-ацеталь, що яскраво контрастує з високою гідролітичною лабільністю, зазвичай властивою сполукам цього класу. National University of Pharmacy 2026-05-04 Article Article application/pdf application/pdf https://ophcj.nuph.edu.ua/article/view/357366 10.24959/ophcj.26.357366 Journal of Organic and Pharmaceutical Chemistry; Vol. 24 No. 1 (2026); 46-52 Журнал органической и фармацевтической химии; Том 24 № 1 (2026); 46-52 Журнал органічної та фармацевтичної хімії; Том 24 № 1 (2026); 46-52 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/357366/345443 https://ophcj.nuph.edu.ua/article/view/357366/345242 Copyright (c) 2026 Ioann O. Popov, Dmytro M. Volochnyuk http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | оксаадамантан біцикло[3.3.1]нонан-3,7-діон N,O-ацеталь геміаміналь каркасні сполуки масштабований синтез гетерадамантан будівельні блоки Popov, Ioann O. Volochnyuk, Dmytro M. Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title | Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title_alt | Multigram-Scale Access to 2-Oxaadamantan-1-amine and 2-Oxaadamantan-1-ol via Optimized Synthesis of Bicyclo[3.3.1]nonane-3,7-dione |
| title_full | Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title_fullStr | Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title_full_unstemmed | Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title_short | Отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| title_sort | отримання 2-оксаадамантан-1-аміну та 2-оксаадамантан-1-олу в мультіграмових кількостях через оптимізований синтез біцикло[3.3.1]нонан-3,7-діону |
| topic | оксаадамантан біцикло[3.3.1]нонан-3,7-діон N,O-ацеталь геміаміналь каркасні сполуки масштабований синтез гетерадамантан будівельні блоки |
| topic_facet | oxaadamantane bicyclo[3.3.1]nonane-3,7-dione N,O-acetal hemiaminal cage compounds scale-up synthesis heteroadamantane building blocks оксаадамантан біцикло[3.3.1]нонан-3,7-діон N,O-ацеталь геміаміналь каркасні сполуки масштабований синтез гетерадамантан будівельні блоки |
| url | https://ophcj.nuph.edu.ua/article/view/357366 |
| work_keys_str_mv | AT popovioanno multigramscaleaccessto2oxaadamantan1amineand2oxaadamantan1olviaoptimizedsynthesisofbicyclo331nonane37dione AT volochnyukdmytrom multigramscaleaccessto2oxaadamantan1amineand2oxaadamantan1olviaoptimizedsynthesisofbicyclo331nonane37dione AT popovioanno otrimannâ2oksaadamantan1amínuta2oksaadamantan1oluvmulʹtígramovihkílʹkostâhčerezoptimízovanijsintezbíciklo331nonan37díonu AT volochnyukdmytrom otrimannâ2oksaadamantan1amínuta2oksaadamantan1oluvmulʹtígramovihkílʹkostâhčerezoptimízovanijsintezbíciklo331nonan37díonu |