Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу
Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suitable for the creation of focused combinatorial libraries of compounds.Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide unde...
Gespeichert in:
| Veröffentlicht in: | Журнал органічної та фармацевтичної хімії |
|---|---|
| Datum: | 2023 |
| Jahrgang: | 21 |
| Heft: | 2 |
| Сторінки: | 41-52 |
| ISSN: | 2518-1548 |
| Автори та афіліації: |
|
| Hauptverfasser: | , |
| Format: | Artikel |
| Sprache: | Englisch |
| Veröffentlicht: |
National University of Pharmacy
2023
|
| Schlagworte: | |
| Online Zugang: | https://ophcj.nuph.edu.ua/article/view/283988 |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Назва журналу: | Journal of Organic and Pharmaceutical Chemistry |
| Завантажити файл: |
|
Institution
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364456888172544 |
|---|---|
| author | Fedyk, Andrii V. Chalyk, Bohdan A. |
| author_facet | Fedyk, Andrii V. Chalyk, Bohdan A. |
| author_institution_txt_mv | [
{
"author": "Andrii V. Fedyk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Bohdan A. Chalyk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_sort | Fedyk, Andrii V. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 52 |
| container_issue | 2 |
| container_start_page | 41 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 21 |
| datestamp_date | 2026-08-23T19:38:20Z |
| description | Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suitable for the creation of focused combinatorial libraries of compounds.Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide under mild conditions allowed us to obtain 11 isoxazoline–dimethylphosphine oxide hybrids in moderate yields. The reaction was found to be regio- though non-stereoselective. Furoxans were identified as possible side products of the reaction.Experimental part. The one-pot interaction with dimethyl(vinyl)phosphine oxide was used for the synthesis of the target compounds. Nitrile oxides were obtained in situ from the corresponding halogenoximes by base-promoted generation. The ADME parameters for a synthesized 5-P(O)Me2-isoxazoline compared to its isosters with the same core structure were predicted using a SwissADME Web Tool. The compounds obtained were characterized by 1H, 13C, 19F, 31P NMR spectroscopy and HPLC-MS spectrometry methods, as well as the elemental analysis.Conclusions. A practical approach to the isoxazoline platform decorated with a 5-P(O)Me2 “magic” group and containing 3-substituent with an easy-to-modify functionality has been developed. On example of the piperidine derivative, the effect of the dimethylphosphinoyl group on physicochemical properties and ADME parameters compared to its isosters has been determined. |
| doi_str_mv | 10.24959/ophcj.23.283988 |
| first_indexed | 2025-07-23T04:43:19Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 41
Original Research
http://ophcj.nuph.edu.ua
UDC 54.057/.058:542.06:547.786.5
A. V. Fedyk, B. A. Chalyk
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., Kyiv 02660, Ukraine
The synthesis of functionalized 4,5-dihydroisoxazoles
decorated with the dimethylphosphinoyl group
Abstract
Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suit-
able for the creation of focused combinatorial libraries of compounds.
Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide under mild
conditions allowed us to obtain 11 isoxazoline–dimethylphosphine oxide hybrids in moderate yields. The reaction was found
to be regio- though non-stereoselective. Furoxans were identified as possible side products of the reaction.
Experimental part. The one-pot interaction with dimethyl(vinyl)phosphine oxide was used for the synthesis of the target com-
pounds. Nitrile oxides were obtained in situ from the corresponding halogenoximes by base-promoted generation. The ADME
parameters for a synthesized 5-P(O)Me2-isoxazoline compared to its isosters with the same core structure were predicted
using a SwissADME Web Tool. The compounds obtained were characterized by 1H, 13C, 19F, 31P NMR spectroscopy and HPLC-MS
spectrometry methods, as well as the elemental analysis.
Conclusions. A practical approach to the isoxazoline platform decorated with a 5-P(O)Me2 “magic” group and containing
3-substituent with an easy-to-modify functionality has been developed. On example of the piperidine derivative, the effect
of the dimethylphosphinoyl group on physicochemical properties and ADME parameters compared to its isosters has been
determined.
Keywords: dimethylphosphine oxide; isoxazoline; dipolar cycloaddition; nitrile oxide; halogenoximes; selectivity; ADME
profile
А. В. Федик, Б. А. Чалик
Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02660, Україна
Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу
Анотація
Мета. Синтезувати гібридну молекулярну платформу, яка містить диметилфосфіноїльну групу та фрагмент 4,5-дигі-
дроізоксазолу і в подальшому може бути використана для створення фокусованих комбінаторних бібліотек сполук.
Результати та їх обговорення. Взаємодія галогеноксимів із диметил(вініл)фосфіноксидом у присутності основи у м’яких
умовах дозволила одержати із помірними виходами 11 гібридних сполук, які містять фрагменти ізоксазоліну та ди-
метилфосфіноксиду. Виявлено, що реакція є регіо-, хоча й нестереоселективною. Фуроксани було ідентифіковано як
можливі побічні продукти реакції.
Експериментальна частина. Для синтезу цільових сполук було використано взаємодію нітрилоксидів з диметил(вініл)фосфінок-
сидом. Нітрилоксиди було одержано in situ з відповідних галогеноксимів дією основи. Для одного з представників
цільових 5-P(O)Me2-ізоксазолінів було спрогнозовано ADME-профіль та порівняно одержані значення з аналогічними
характеристиками для його ізостерів з базовою структурою ізоксазоліну. Розрахунки було здійснено за допомогою
вебресурсу SwissADME. Одержані сполуки схарактеризовано методами 1H, 13C, 19F, 31P ЯМР-спектроскопії та ВЕРХ-мас-
спектрометрії, а також елементного аналізу.
Висновки. Розроблено практичний підхід до одержання ізоксазолінової платформи, що містить «магічну» 5-P(O)Me2
групу та функціоналізований замісник у положенні 3. На прикладі похідної піперидину окреслено вплив диметилфос-
фіноїльної групи на фізико-хімічні властивості та ADME-параметри порівняно з її ізостерами.
Ключові слова: диметилфосфін оксид; ізоксазолін; диполярне циклоприєднання; нітрилоксид; галогеноксими; селек-
тивність; ADME-профіль
ISSN 2308-8303 (Print) / 2518-1548 (Online) 42
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
Citation: Fedyk, A. V.; Chalyk, B. A. The synthesis of functionalized 4,5-dihydroisoxazoles decorated with the dimethylphosphinoyl group.
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2), 41 – 52.
https://doi.org/10.24959/ophcj.23.283988
Supporting information: Copies of 1H, 13C, 19F, 31P NMR spectra of the synthesized compounds.
Received: 28 April 2023; Revised: 1 June 2023; Accepted: 10 June 2023
Copyright© 2023, A. V. Fedyk, B. A. Chalyk. 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.
■ Introduction
Phosphorus along with carbon, oxygen, and
nitrogen is an essential element undoubtedly re-
quired for the growth and development of all
known forms of life. Either in the form of inor-
ganic phosphates or being incorporated in the bio-
molecules (nucleotides, DNA, RNA, phospholipids,
phosphorylated proteins, etc.) phosphorus is in-
volved in multiple vital biochemical processes,
like storing and transferring genetic information,
transporting cellular energy, functioning the cell
membrane, including several transport mecha-
nisms and protection of the interior of all cells.
Hence, no wonder that this element gained much
attention from agriculture [1], biochemistry [2],
and medicinal chemistry [3] researchers. Thus,
organophosphates make up much part of insec-
ticides and have been investigated for applica-
tion in the veterinary field [4, 5]. The medical
application of phosphorus-containing organic sub-
stances started with the release of menadiol so-
dium diphosphate by Roche in 1941 [6]. Further
research has led to expansion of the nomencla-
ture of “P”-containing functional groups embed-
ded in drug molecules, and now it is possible to
find pharmaceutical agents belonging to phospho-
ric amides [7], phosphonates [8], phosphinates [9],
bisphosphonates [10], phosphoric anhydrides [11],
etc., which have achieved commercial success [12].
Recently, excellent reviews highlighting and sum-
marizing the phosphorus-containing drugs cur-
rently available at the market, their structural
features, biological mechanism, as well as his-
torical aspects of their development, have been
published [13, 14].
Broadly, a phosphorus-containing functiona-
lity is added to the molecule to create selectivity-
and bioavailability-enhanced pro-drugs and does
not constitute a pharmacophoric part of the mole-
cule [15]. This strategy is also frequently used to
improve the aqueous solubility of sparingly so-
luble molecules and achieve a suitable pharma-
cokinetics profile by introducing a charged phos-
phate and related units [16]. A major obstacle
associated with the latter approach is a low cell
permeability and poor oral bioavailability of the
charged molecules [17]. In view of this, it is sur-
prising that their uncharged counterparts, name-
ly phosphine oxides, have been largely neglect-
ed in drug discovery. It is quite strange as the
phosphine oxide residue is usually easily formed
and becomes (bio)chemically inert after its in-
corporation into the molecular structure. It also
does not display much redox properties com-
pared to carbonyl and alcohol functional groups.
Furthermore, its capacity to act as an H-bond
acceptor makes the phosphine oxide group an ex-
cellent alternative to existing common H-bond
acceptors like carbonyls and sulfones [18].
A real breakthrough in understanding that a
phosphine oxide fragment can be a game chang-
er in creating innovative drugs have come with
the accelerated FDA granted approval of briga-
tinib (Alunbrig®) for the treatment of metasta-
tic non-small cell lung cancer [19]. A unique struc-
tural feature of brigatinib is the presence of the
dimethyl phosphine oxide (DMPO) moiety, which
solely causes the selectivity profile of brigatinib
over anaplastic lymphoma kinase. It is amazing
that such a simple group within a long thread-
like brigatinib structure 70 times increases its
potency compared to unsubstituted counterparts.
Moreover, DMPO provides brigatinib with re-
markable water solubility and reduced lipophi-
licity [20].
Later, after the release of brigatinib, a mag-
nificent work by Finkbeiner et al. comprehen-
sively showed that phosphine oxides (including
DMPO) were outstanding polar structural ele-
ments deserving to become a routine part of me-
dicinal chemistry toolkit [21]. In particular, the
authors thoroughly investigated in vitro proper-
ties of a series of phosphorus(V)-containing com-
pounds and came to conclusion that phosphine
oxides gave high solubility and metabolic stabil-
ity to organic substrates, but occasionally due to
the worsened cell membrane permeability. All of
the above has led to a revision of the generally
accepted paradigm of medical chemistry, accor-
ding to which phosphine oxides are considered
an undesirable group. This change of views has
ISSN 2308-8303 (Print) / 2518-1548 (Online) 43
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
given rise to several clinical candidates containing
the trialkylphosphine oxide group (Figure 1, A)
and, in particular, the DMPO moiety (Figure 1, B)
[13, 21]. Among them, Fosazepam deserves at-
tention; it is a water-soluble analog of Diazepam
and indicates the magic effect of the DMPO frag-
ment on the physicochemical properties of organ-
ic molecules.
Turning to the synthetic side of the issue it
should emphasized that the ability to readily in-
corporate new functional groups into molecular
frameworks is what determines how well these
groups are adopted by medicinal chemistry.
Taking into account the importance of the last
statement, as well as the lack of methods suita-
ble for introducing the DMPO fragment into low
molecular-weight saturated heterocyclic amines,
we have lately disclosed several scalable synthe-
tic approaches to DMPO-containing azetidine,
pyrrolidine, piperidine, and morpholine deriva-
tives [22]. This work significantly contributed
to medicinal chemistry and provided valuable
sp3-enriched building blocks for the use in early
drug discovery. Proceeding with the creation of
MedChem relevant DMPO containing functio-
nalized “bricks” with a high potential to gene-
rate lead-like compounds, in this report we de-
scribe an efficient strategy towards a hybrid mo-
lecular platform incorporating the Me2P(O) and
4,5-dihydroisoxazole moiety along with a ready-
to-modify functionality.
Interestingly, although the isoxazole ring is
among the top heterocycles used in medicinal che-
mistry [23], its 4,5-dihydro analog is overlooked
by major pharmaceutical players. The search over
different databases returned no marketed drugs
approved for the use in human medicine, and only
3 examples undergoing experimental clinical trials
with 2 of them approved for veterinary use (Figu-
re 2, A) [24 – 26]. On the other hand, naturally occur-
ring 4,5-dihydroisoxazoles are a well-known class
of heterocyclic compounds often with outstanding
pharmacological properties (Figure 2, B) [27 – 29].
One should note that our research group has
a profound experience in construction of polysub-
stituted isoxazoles and 4,5-dihydro analogs [30, 31].
We have devised new and optimized known me-
thods towards the heterocyclic platforms, which
rely on 1,3-dipolar addition of in situ generated
nitrile oxides from halogenoximes to diverse un-
saturated partners. It has been proven that the
use of a component containing an alkene fragment
is a simple and effective way to obtain isoxazo-
lines [32]. It is worth mentioning that we have
successfully exploited this way to reach diethyl
phosphonates (Scheme 1, A) [33]. In this way, it
becomes obvious that the target for working de-
rivatives can be achieved by replacing diethyl
P
Cl
N
H
O
Me
Me
O2
S CF3
Cl
CCR2 antagonist
OH
H
H
P
Me
Me
O
O
Me2N
N
NMeO
Me
O
PO
Me
Me
HN
NN
NH2Cl
NH2
O
CF3CO2
ENaC inhibitor
progesterone receptor antagonist
N
H
O
P
O
Me
Me NH2
S
HDAC1 inhibitor
N
P
O
Ph Ph
Cl
Cl
MetAP2 inhibitor
N
N
HN
Cl
H
N
N
OMe
N
N
MeP
Me
O
Me
N
N
N
H
F3C
HN
NC
P
NH
Me
Me
O
Me
Me
brigatinib
SY-5609
1 stage of clinical trials
(various cancer types)
O
Me
Me
Me
OMe
H
OP
Ph
O
Ph
MetAP2 inhibitor
N
Ph
O
P
Me
O
Me
Cl
Fosazepam
P
O
Ph
Ph H
N
O
NH2
Fosenazide
A B
Figure 1. Recent examples (or investigational and approved drugs) of the use of phosphine oxides in medicine
ISSN 2308-8303 (Print) / 2518-1548 (Online) 44
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
vinylphosphonate with dimethyl(vinyl)phosphi-
ne oxide in the last reaction. In turn, recently in
our work, the procedure for preparing the latter
on a scale of more than 100 g was disclosed [22].
Notably, the phosphine oxide was fruitfully ex-
amined in 1,3-dipolar addition with N-benzyl-1-
methoxy-N-((trimethylsilyl)methyl)methanami-
ne giving the corresponding pyrrolidine in a high
yield (Scheme 1, B).
Thus, herein we discuss the interaction of di-
methyl(vinyl)phosphine oxide with halogenoxi-
mes with an intention to assemble P(O)Me2 deco-
rated isoxazolines having an easy-to-modify ran-
domization point (Scheme 1, C).
■ Results and discussion
According to the planned research strategy,
we relied on the method for the synthesis of
3,5-disubstituted isoxazolines based on [3+2]-cy-
cloaddition of nitrile oxides and dimethyl(vinyl)
phosphine oxide (Scheme 2) [34]. The correspon-
ding nitrile oxides 12a – k could be produced in
situ from halogenoximes 4a – h, 6i, 8j and 11k,
which, in turn, were obtained from the correspon-
ding N-Boc-protected amino acids 1a – h (through
their sequential reduction to alcohols 2 and ge-
neration of aldehydes 3) (Scheme 2, A), glyoxa-
lic acid (5i) (Scheme 2, B) [35], hemiacetal 7j
N
N
Me
OH
O
SO2Me
Me
N
O
Topramezone
post-emergent herbicide
N
O
N
iPr
O
HN O
O
HO
F
Nivocasan
caspase 1 inhibitor vet approved insecticides and acaricides
Fluralaner
Afoxolaner
Cl
(F3C)Cl
N
O
F3C
O
NH
NH
O
CF3
Me(H)
A
verongidoic acid
Pseudovibrio denitrificans Ab134
O
N
Br
OMe
Br
CO2H
HO
B
phomopsisin A
Phomopsis sp. sh917
iPrHH
N
O
H
H
OH
N
O
HO
H O
H
H
CH3
H
N
O
Cl
H
H3N
CO2
U-42,126 (antitumor)
Streptomyces sviceus
Figure 2. Experimental (A) and natural (B) 4,5-dihydroisoxazoles
A
B
C
R
N
X
OH
R
N
O
PO(OEt)2
P
OEt
O OEt
R
N
O
base
Chalyk et al., 2018
This work
R
N
X
OH
P
Me
O
Me
+
Me
P
O
Me
N
O
R P(O)Me2 decorated
oxazolines
in situ
R is a FG bearing
fragment
Br P
Me
O
Me
MeO N TMS
BnH
P
Me
O
Me
N
Bn
P
Me
Me O
Fedyk et al., 2021
Scheme 1. Aim and background of this work
ISSN 2308-8303 (Print) / 2518-1548 (Online) 45
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
(Scheme 2, C) [36], or TIPS-protected acetyle-
ne 9k (Scheme 1, D) [37, 38] according to the
procedures previously published. The choice of
R-substituents in halogenoximes was justified
by the utility of the [3+2]-adducts derived from
them for subsequent synthetic transformations
(e.g., the presence of protected NH2 and alkyne
groups or bromine atom) and their attractive-
ness for medicinal chemistry in the case of the
CF3-substituent.
Having intermediate halogenoximes, we star-
ted studying their interaction with dimethyl(vi-
nyl)phosphine oxide (13). For the reaction, we chose
conditions that previously proved themselves as
efficient and reliable ones for a wide range of sub-
strates [30]. Precisely, the reactions were carried
out using a 1-to-1 ratio of the starting materials
in the presence of a 1.3-fold excess of a weakly
basic sodium bicarbonate in the ethyl acetate me-
dium at room temperature. Such gentle condi-
tions allowed keeping intact all functional groups
besides the reaction centers. The progress of the
reaction was monitored by HPLC indicating
that the reaction usually completed within 60 h.
One should point out that application of insolu-
ble base in this setup made it possible gradual ge-
neration of nitrile oxides, thus mostly avoiding
dimerization of the latter with the formation of
the corresponding furoxans (Scheme 3). However,
during the HPLC-monitoring, we sometimes no-
ticed the formation of this by-product although
there were no obvious reasons for this fact. In this
case, an additional portion of nitrile oxide should
be added to the reaction mixture in order to use
up the remaining dipolarophile. As the result, the
target isoxazolines 14a – k were obtained in mo-
derate yields though all entries needed additional
chromatography purification step to isolate the
substance with 95 %+ purity. Importantly, all the
products were stable enough to store them at am-
bient conditions and did not show any notice-
able sign of decomposition within 2 years after
preparation.
Another issue to be addressed is the regiose-
lectivity of the reaction. 1,3-Dipolar cycloaddi-
tion is known to give several regioisomers when
non-symmetrical dipolarophiles are used [39].
Previously, we observed a lack of regioselectivi-
ty in the case of utilization of diethyl ethynyl-
phosphonate as the reaction partner with the
formation of a mixture of 4- and 5-isomers in
different ratios [33]. However, the switch to di-
ethyl vinylphosphonate restored the selectivity
providing 5-phosphonate solely. According to all
spectral data recorded, only one isomer was for-
med in the cycloaddition. Assignment of its struc-
ture to 5-dimethylphosphinoyl 14 was made ba-
sed on 13C NMR spectral data (Figure 3, A).
Thus, C-5 atom of the isoxazoline core was seen
as a doublet with the ipso-coupling constant of
~81 Hz; C-4, in turn, was found as a doublet
though with much lower J ~ 6 Hz. We did not
detect any traces of another feasible isomer 15
neither in NMR nor in HPLC spectra of the crude
products.
The regioselectivity of the process might be
governed by steric and/or electronic factors (Fi-
gure 3, B). In particular, the transition state TS1
leading to the formation of 3,4-disubstituted
isoxazolines 15 is unfavorable compared to TS1
(giving 3,5-disubstituted isomer) due to the ste-
ric repulsion between the R-group and the dime-
thylphosphinoyl fragment. In addition, informa-
tion complying with the above-stated one can be
derived from the analysis of the atomic charges
over alkene carbons in compound 13. The values
BF3* Et2O
NaBH4
THF
SO3*Py
TEA
DMSO
1) NH2OH
2) NCS, HCl
DMF
N
N
OH
Cl
NH
Boc Boc
4a h–1a h–
CO2H
NH
Boc
OH
3a h–
NH
Boc
O
O
OH
O
H
1. NH2OH HCl
Na2CO3, H2O
*
2. Br2, DCM
5i
Br
N
OH
Br
6i
TIPS
N
OH
Cl
11k9k
A
B
D
F3C OMe
OH
1. NH2OH HCl
NaOH, H2O/MeOH
*
2) NBS, DMF
F3C
N
OH
Br
8j7j
C
TIPS
1. BuLi, Etn 2O
then DMF, Et2O
2. NH2OH HCl
Na2CO3, MeOH
* TIPS
10k
N
OH tBuOCl, DCM
2 –a h
Scheme 2. Synthesis of the starting halogen oximes
ISSN 2308-8303 (Print) / 2518-1548 (Online) 46
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
retrieved from the Hückel molecular orbital
theory calculations (ChemBio3D Ultra, ver. 14.0,
https://www.cambridgesoft.com/Ensemble_for_
Chemistry/details/Default.aspx?fid=13&pid=668)
demonstrate a favored C•••C interaction (at-
traction of positive and negative charges) and
less pronounced C•••O repulsion than in TS1
compared to TS2. Thus, the charge distribution
also favors the product structures identical to
those found experimentally.
Unlike the regioselectivity, the reaction was
not stereoselective with reference to C-5 atom
of isoxazolidine. This was judged from the for-
mation of a diastereomeric pair in the cases of
chiral oximes 4b,d,f shown by NMR and HPLC
data (Figure 3, C).
Further, we studied suitable ways to remove
protecting Boc- (on the example of compound 14h)
and TIPS-groups. Previously, the Boc-protection
was washed out from similar isoxazoles with HCl
dissolved in MeOH [34]. Surprisingly, our attempt
to apply this method to 14h failed, and we ob-
tained inseparable mixture of products. Chang-
ing the reaction setup to TFA/DCM enabled the
Me
P
O
Me
N
O
Br
O
N
N
Boc
P
O
Me
Me
O
N
P
O
Me
Me
F F
F
O
N
TIPS
P
O
Me
Me
BocN
N
O P
O
Me
Me
Boc
N
O
N
O P
O
Me
Me
Me
HN
Boc
N
O P
O
Me
Me
Boc
HN
N
O P
O
Me
Me
Boc
N
H
N
O P
O
Me
Me
Boc
N
N
O P
O
Me
Me
MeHN
Boc
N
O P
O
Me
Me
Me
R
N
OH
X
4a h 6i– or or
8j 11kor
+
1.0 equiv
P
Me
O
Me
13
1.0 equiv
NaHCO3 (1.3 equiv)
EtOAc, rt, 60 h
N
O P
O
Me
MeX = Cl, Br
R
14a k–
N
O
P
O Me
Me
R
15
was not detected
14a, 52 % 14b, 58 % 14c, 67 % 14d, 55 %
14e, 50 % 14f, 61 % 14g, 69 % 14h, 45 %
14k, 43 %14i, 59 % 14j, 73 %
sole product
R
N
O
in situ
12a k–
NO
N
O
R
R
+
possible
by-product
Scheme 3. Synthetic approach to dimethyl phosphine oxide – isoxazoline hybrids
N
O
P
O
Me
Me
R
favorable TS1
no steric interactions
charge driven
( , , ) +4 6 8 9
N
O
P O
Me
Me
R
unfavorable TS2
steric hindrance
unwelcome charge
interactions
-0.18
-0.08-0.18
-0.08
N
O
P
O
Me
Me
CC - chiral center
formation of
diastereomeric pair
A B C
R
N
O P(O)Me2
~29 ppm
~75 ppm
2JCP ~ 6 Hz
1JCP ~ 81 Hz
CC
Figure 3. Regio- and stereoselective aspects of the reaction studied
ISSN 2308-8303 (Print) / 2518-1548 (Online) 47
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
isolation of the desired amine in the form of a
trifluoroacetate salt (Scheme 4). Unfortunately,
all our attempts to deprotect alkyne 14k under
standard conditions (TBAF, THF; HF, MeCN;
Et3N*3HF) did not result in a satisfactory result.
Currently, the above-mentioned unique pro-
perties of P(O)Me2 the substituent are widely used
by MedChem researchers, e.g. to dramatically in-
crease solubility and decrease lipophilicity of or-
ganic compounds. For instance, this tactic was
used to improve the solubility of the antihyper-
tensive drug prazosin without affecting its bio-
logical profile [40]. Broadly, available chemical
space of small molecular “bricks”, as well as po-
werful operational instruments allow altering the
ADME properties of potential drug candidates
to achieve necessary characteristics. This becomes
possible with a right choice of pieces within com-
plex thread-like molecules. Therefore, we decided
to trace how some properties of the target com-
pounds 14 changed with the replacement of the
DMPO group with its isosters. The analysis was
performed on the example of piperidine deriva-
tive 14c. As isosteric substituents, P-, C- and
S-centered functionalities were selected (Figure 4).
The calculation was carried out with the aid of
a SwissADME web tool [41, 42] and concerned
two issues:
• prediction of the passive gastrointestinal
absorption (HIA) and penetration of the blood-
brain barrier (BBB) (BOILED-Egg method, Fi-
gure 4, A);
Boc
N
H
N
O P
O
Me
Me
H3N
N
O P
O
Me
Me
CF3CO2
TFA, DCM, rt
14h 1 h6 , 83 %
Scheme 4. Boc-deprotection of compound 14h
O
N
HN
P
O
Me
Me
O
N
HN
C
O
Me
O
N
HN
S
O
Me
O
N
HN
S
O
Me
O
O
N
HN
S
O
N
HO
MeO
N
HN
P
O
OMe
Me
O
N
HN
P
O
OMe
MeO
O
N
HN
C
O
OMe
1 2 3 4 5 6 7 8
phosphorus-centered carbon-centered sulfur-centered
Figure 4. (A) The BOILED-Egg model; WLOGP – lipophilicity; TPSA – the Topological Polar Surface Area; blue dots for P-gp substrates, red
dots for P-gp non-substrate. (B) The bioavailability radar: LIPO – lipophilicity from −0.7 to +5.0; SIZE – the molecular weight from 150 to
500 g mol–1; POLAR – the topological polar surface area from 20 to 130 Å2; INSOLU – the decimal logarithm of water solubility less than 6;
INSATU – the fraction of sp3 hybridized carbons not less than 0.25; FLEX – rotatable bonds not more than 9
ISSN 2308-8303 (Print) / 2518-1548 (Online) 48
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
• retrieval of the Bioavailability radar that
provides predicted information about 6 important
physicochemical characteristics – lipophilicity,
size, polarity, solubility, flexibility and saturation
of molecules. An optimal range for each value is
represented as a red area.
One can see that the DMPO derivative (1) falls
into the “yolk” area meaning its highly probable
BBB permeation; it is not also a subject to active
efflux by means of P-glycoprotein (a red dot).
The presence of other functional groups decreas-
es likelihood of this process, and the isosters are
predicted as well-absorbed in the gastrointesti-
nal tract, but not accessing the brain (a white
region). As for the Bioavailability radar, for all
isosters examined the plots perfectly fit the red
region leaving a wide gap to alter the character-
istics of molecules. All derivatives feature close
calculated characteristics with none of them fall-
ing out significantly.
■ Conclusions
A practical approach to the isoxazoline plat-
form decorated with a 5-P(O)Me2 substituent and
based on 1,3-dipolar addition between in situ ge-
nerated nitrile oxides and dimethyl(vinyl)phos-
phine oxide has been developed. The base-promoted
interaction of halogenoxides with dimethyl(vinyl)-
phosphine oxide under mild conditions has allowed
us to obtain 11 isoxazoline–dimethylphosphine
oxide hybrids in moderate yields. The reaction
has been found to be regio- though non-stereo-
selective. The approach to the Boc-deprotection
has been also described. On the example of the
piperidine derivative, the effect of the dimethyl-
phosphinoyl group on physicochemical properties
and ADME parameters compared to its isosters
has been determined.
■ Experimental part
All starting compounds and solvents were ob-
tained from commercial sources and used with-
out further purification. Melting points were meas-
ured in open capillary tubes and given uncorrected.
NMR experiments were performed on a Bruker
170 Avance 500 (at 500 MHz for 1H NMR, 470 MHz
for 19F NMR, 202 MHz for 31P NMR, and 126 MHz
for 13C NMR) or a Varian Unity Plus 400 (at 400 MHz
for 1H NMR and 101 MHz for 13C NMR) spectro-
meters in the DMSO‑d6 or CDCl3 solution. NMR
chemical shifts were reported in ppm units us-
ing the δ scale and referenced using the solvent
peaks at 7.26 and 77.1 ppm (CDCl3) for 1H and
13C nuclei, respectively, and 2.48 and 39.5 ppm
(DMSO-d6) for 1H and 13C nuclei, respectively.
For 19F NMR experiments hexafluorobenzene was
used as an internal standard. The chemical shifts
in 31P NMR studies were referenced to external
85 % H3PO4. HPLC experiments were carried
out on an Agilent LC/MSD SL 1100 instrument
(atmospheric pressure electrospray ionization
(ES-API)), GCMS spectra were taken on an Agi-
lent 5890 Series II 5972 GCMS instrument (elec-
tron impact ionization (EI)). According to chro-
matographic studies, all compounds had purity
of more than 95 %. Elemental analyses were per-
formed in the Analytical Laboratory of the Insti-
tute of Organic Chemistry of the National Aca-
demy of Sciences of Ukraine.
The general procedure for the synthesis
of 3-(5-dimethylphosphoryl)-4,5-dihydroiso-
xazoles 14
To the solution of the corresponding halogen-
oxime 4 or 6 or 8 or 11 (5 mmol, 1.0 equiv) and
dimethyl(vinyl)phosphine oxide (13, 0.52 g, 5 mmol,
1.0 equiv) in EtOAc (10 mL), NaHCO3 (0.57 g,
6.5 mmol, 1.3 equiv) was added. The mixture was
vigorously stirred at room temperature for 60 h.
Then the inorganic precipitate was filtered off,
the filtrate was dried over Na2SO4 and evapo-
rated under reduced pressure. The residue was
purified by the preparative high-performance li-
quid chromatography or flash column chroma-
tography (details are given for each compound
below) resulting in the target 4,5-dihydroisoxa-
zoles 14.
tert-Butyl 3-(5-(dimethylphosphoryl)-4,5-
dihydroisoxazol-3-yl)azetidine-1-carboxy-
late (14a)
A colorless oil, solidified upon standing. HPLC
purification: 9 % water-acetonitrile 0.5 – 6.5 min;
flow 30 mL min–1 (loading pump 4 mL min–1 aceto-
nitrile); column SunFireC18 100×19 mm 5um (R).
Yield – 0.78 g (52 %). Anal. Calcd for C13H23N2O4P, %:
C 51.65; H 7.67; N 9.27. Found, %: C 51.82; H 7.74;
N 9.11. 1H NMR (400 MHz, CDCl3), δ, ppm: 1.42
(9H, s, 3×CH3); 1.46 (3H, d, 2JHP = 12.7 Hz, CH3P);
1.61 (3H, d, 2JHP = 12.8 Hz, CH3P); 3.31 – 3.45 (2H,
m); 3.53 (1H, dq, J = 8.8, 4.4 Hz); 3.99 (2H, dd, J =
9.2, 4.9 Hz); 4.17 (2H, t, J = 8.7 Hz); 4.70 – 4.81
(1H, m). 13C NMR (126 MHz, CDCl3), δ, ppm: 11.40
(d, 1JCP = 68 Hz, CH3P); 14.79 (d, 1JCP = 68 Hz,
CH3P); 26.53; 28.24; 35.93; 52.09; 77.66; 79.95
(C(CH3)3); 155.91 (C=O); 158.30 (d, 3JCP = 3.7 Hz,
C-3 isoxazoline). 31P NMR (202 MHz, CDCl3), δ,
ppm: 43.38. LC-MS (ES-API), m/z: 325.2 [M+Na]+.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 49
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
tert-Butyl (2R)-2-(5-(dimethylphosphoryl)-
4,5-dihydroisoxazol-3-yl)pyrrolidine-1-car-
boxylate (14b)
A colorless oil. HPLC purification: 20 – 45 % wa-
ter-acetonitrile 2 – 7 min; flow 30 mL min–1 (load-
ing pump 4 mL min–1 acetonitrile); column Sun-
FireC18 100×19 mm 5um (R). Yield – 0.91 g (58 %).
Anal. Calcd for C14H25N2O4P, %: C 53.16; H 7.97;
N 8.86. Found, %: C 53.04; H 7.92; N 9.03. 1H NMR
(400 MHz, CDCl3), δ, ppm: 1.37 – 1.48 (12H, m,
3×CH3 + CH3P); 1.58 (3H, d, 2JHP = 12.9 Hz, CH3P);
1.82 – 2.29 (4H, m); 3.19 – 3.58 (4H, m); 4.55 – 4.80
(2H, m). 13C and 31P NMR spectra are not inform-
ative due to hindered rotation (see Supporting
information file). LC-MS (ES-API), m/z: 317.0
[M+H]+.
tert-Butyl 4-(5-(dimethylphosphoryl)-4,5-
dihydroisoxazol-3-yl)piperidine-1-carboxy-
late (14c)
A yellow oil. Flash column chromatography
(FCC) purification: CHCl3:MeOH (10:1), Rf = 0.27.
Yield – 1.1 g (67 %). Anal. Calcd for C15H27N2O4P, %:
C 54.54; H 8.24; N 8.48. Found, %: C 54.73; H
8.11; N 8.54. 1H NMR (400 MHz, CDCl3), δ, ppm:
1.38 – 1.47 (12H, m); 1.49 – 1.65 (5H, m); 1.83 (2H,
d, J = 13.0 Hz); 2.56 (1H, tt, J = 11.1, 3.2 Hz);
2.79 (2H, t, J = 12.3 Hz); 3.24 – 3.37 (2H, m); 4.11
(2H, d, J = 13.5 Hz); 4.63 – 4.73 (1H, m). 13C NMR
(126 MHz, CDCl3), δ, ppm: 10.60 (d, 1JCP = 68 Hz,
CH3P); 13.24 (d, 1JCP = 68 Hz, CH3P); 27.90; 28.75
(d, 2JCP = 6.3 Hz, C-4 isoxazoline); 34.88; 35.87;
42.80; 75.91 (d, 1JCP = 81 Hz, C-5 isoxazoline);
79.25 (C(CH3)3); 154.09 (C=O); 160.77 (d, 3JCP =
3.8 Hz, C-3 isoxazoline). 31P NMR (202 MHz, CDCl3),
δ, ppm: 44.13. LC-MS (ES-API), m/z: 331.1 [M+H]+.
tert-Butyl (4S)-4-(5-(dimethylphosphoryl)-
4,5-dihydroisoxazol-3-yl)-2,2-dimethyloxa-
zolidine-3-carboxylate (14d)
A white amorphous solid. HPLC purification:
20 – 45 % water-acetonitrile 2 – 7 min; flow 30 mL min–1
(loading pump 4 mL min–1 acetonitrile); SunFireC18
100×19 mm 5um (R). Yield – 0.95 g (55 %). Anal.
Calcd for C15H27N2O5P, %: C 52.02; H 7.86; N 8.09.
Found, %: C 52.10; H 7.97; N 8.01. 1H NMR
(400 MHz, CDCl3), δ, ppm: 1.40 – 1.73 (21H, m);
3.31 – 3.53 (2H, m); 3.93 – 4.11 (1H, m); 4.13 – 4.30
(1H, m); 4.67 – 4.99 (2H, m). 13C and 31P NMR spec-
tra are not informative due to hindered rotation
and diastereomeric (see Supporting information
file). LC-MS (ES-API), m/z: 347.2 [M+H]+.
tert-Butyl ((5-(dimethylphosphoryl)-4,5-
dihydroisoxazol-3-yl)methyl)carbamate (14e)
A colorless oil. HPLC purification: 0 – 15 % wa-
ter-acetonitrile 0.5 – 6.5 min; flow 30 mL min–1
(loading pump 4 mL min–1 acetonitrile); column
SunFireC18 100×19 mm 5um (R). Yield – 0.69 g
(50 %). Anal. Calcd for C11H21N2O4P, %: C 47.82;
H 7.66; N 10.14. Found, %: C 47.98; H 7.57;
N 10.04. 1H NMR (400 MHz, DMSO-d6), δ, ppm:
1.31 – 1.47 (16H, m); 3.09 – 3.33 (2H, m); 3.78 – 3.93
(2H, m); 4.70 (1H, ddd, J = 12.0, 9.5, 6.5 Hz).
13C NMR (126 MHz, DMSO-d6), δ, ppm: 11.62 (d,
1JCP = 68 Hz); 13.76 (d, 1JCP = 68 Hz); 28.09; 36.22;
36.63; 76.83 (d, 1JCP = 81 Hz, C-5 isoxazoline);
78.24 (C(CH3)3); 155.58 (C=O); 157.55 (d, 3JCP =
3.8 Hz, C-3 isoxazoline). 31P NMR (162 MHz,
DMSO-d6), δ, ppm: 41.17. LC-MS (ES-API), m/z:
355.2 [M+DMSO+H]+.
tert-Butyl ((1R)-1-(5-(dimethylphosphoryl)-
4,5-dihydroisoxazol-3-yl)ethyl)carbamate
(14f)
A white amorphous solid. HPLC purification:
9 % water-acetonitrile 0.5 – 6.5 min; flow 30 mL min–1
(loading pump 4 mL min–1 acetonitrile); column
SunFireC18 100×19 mm 5um (R). Yield – 0.88 g
(61 %). Anal. Calcd for C12H23N2O4P, %: C 49.65;
H 7.99; N 9.65. Found, %: C 49.58; H 7.95; N 9.78.
1H NMR (400 MHz, CDCl3), δ, ppm: 1.41 – 1.54
(15H, m); 1.60 – 1.69 (3H, m, CH3P); 3.41 (2H, dd,
J = 20.2, 11.7 Hz); 4.58 (1H, s); 4.71 – 4.91 (2H, m).
13C NMR (126 MHz, CDCl3), δ, ppm: 10.41 (d, 1JCP
= 68 Hz, CH3P); 10.70 (d, 1JCP = 68 Hz, CH3P);
13.98 (d, 1JCP = 68 Hz, CH3P); 14.05 (d, 1JCP =
68 Hz, CH3P); 18.09; 18.21; 27.78; 35.19; 35.80;
43.78; 43.98; 76.35 (d, 1JCP = 81 Hz, C-5 isoxa-
zoline); 76.48 (d, 1JCP = 81 Hz, C-5 isoxazoline);
79.18 (C(CH3)3); 154.50; 154.63; 160.26; 160.57.
31P NMR (202 MHz, CDCl3), δ, ppm: 43.71, 44.19.
LC-MS (ES-API), m/z: 291.4 [M+H]+.
tert-Butyl (2-(5-(dimethylphosphoryl)-4,5-
dihydroisoxazol-3-yl)propan-2-yl)carba-
mate (14g)
A white amorphous solid. HPLC purification:
10 – 35 % water-acetonitrile 2 – 7 min; flow 30 mL min–1
(loading pump 4 mL min–1 acetonitrile); column
sunfire SunFireC18 100×19 mm 5um (R). Yield –
1.05 g (69 %). Anal. Calcd for C13H25N2O4P, %: C
51.31; H 8.28; N 9.21. Found, %: C 51.25; H 8.34;
N 9.29. 1H NMR (400 MHz, CDCl3), δ, ppm: 1.40
(9H, s, 3×CH3); 1.44 – 1.51 (6H, m, CH3P + CH3CNH);
1.53 (3H, s, CH3CNH); 1.60 (3H, d, 2JHP = 12.8 Hz,
CH3P); 3.37 (2H, dd, J = 20.5, 10.7 Hz, CH2CH
oxazoline); 4.74 (1H, t, J = 10.2 Hz, CH oxazoline);
4.85 (1H, s, NH). 13C NMR (101 MHz, CDCl3), δ,
ppm: 10.67 (d, 1JCP = 68 Hz, CH3P); 14.67 (d, 1JCP
= 68 Hz, CH3P); 26.11; 26.79; 28.26; 35.80; 51.79;
76.98 (d, 1JCP = 82 Hz, C-5 isoxazoline); 79.71
(C(CH3)3); 154.38 (C=O); 164.18 (d, 3JCP = 4 Hz,
ISSN 2308-8303 (Print) / 2518-1548 (Online) 50
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
C-3 isoxazoline). 31P NMR (202 MHz, CDCl3),
δ, ppm: 44.93. LC-MS (ES-API), m/z: 327.2
[M+Na]+.
tert-Butyl (1-(5-(dimethylphosphoryl)-4,5-
dihydroisoxazol-3-yl)cyclobutyl)carbama-
te (14h)
A white amorphous solid. HPLC purification:
12 % water-acetonitrile 0.5 – 6.5 min; flow 30 mL min–1
(loading pump 4 mL min–1 acetonitrile); column
SunFireC18 100×19 mm 5um (R). Yield – 0.71 g
(45 %). Anal. Calcd for C14H25N2O4P, %: C 53.16;
H 7.97; N 8.86. Found, %: C 53.25; H 7.93; N 8.92.
1H NMR (400 MHz, CDCl3), δ, ppm: 1.45 (9H, s,
3×CH3); 1.54 (3H, d, 2JHP = 12.6 Hz, CH3P); 1.68
(3H, d, 2JHP = 12.9 Hz, CH3P); 1.96 – 2.12 (2H, m);
2.21 – 2.34 (2H, m); 2.50 (1H, s); 2.69 (1H, s);
3.33 – 3.54 (2H, m); 4.86 (1H, t, J = 8.6 Hz, CH
oxazoline); 5.05 (1H, s, NH). 13C NMR (126 MHz,
CDCl3), δ, ppm: 14.74; 28.30; 28.38; 32.71; 32.97;
35.51; 54.39; 80.16; 154.38; 162.10. 31P NMR
(202 MHz, CDCl3), δ, ppm: 45.55. LC-MS (ES-API),
m/z: 317.2 [M+H]+.
(3-Bromo-4,5-dihydroisoxazol-5-yl)dime-
thylphosphine oxide (14i)
A white amorphous solid. HPLC purification:
0 – 20 % water-acetonitrile 0.5 – 6.5 min; flow
30 mL min–1 (loading pump 4 mL min–1 aceto-
nitrile); column SunFireC18 100×19 mm 5um (R).
Yield – 0.66 g (59 %). Anal. Calcd for C5H9BrNO2P,
%: C 26.57; H 4.01; N 6.20. Found, %: C 26.43; H
4.04; N 6.25. 1H NMR (400 MHz, CDCl3), δ, ppm:
1.40 (3H, d, 2JHP = 12.8 Hz, CH3P); 1.51 (3H, d,
2JHP = 13.1 Hz, CH3P); 3.48 (2H, dd, J = 19.4,
11.0 Hz, CH2CH oxazoline); 4.73 (1H, td, J =
11.0, 4.4 Hz, CH oxazoline). 13C NMR (101 MHz,
CDCl3), δ, ppm: 11.30 (d, 1JCP = 69 Hz, CH3P);
14.65 (d, 1JCP = 68 Hz, CH3P); 42.27 (C-4 isoxa-
zoline); 78.07 (d, 1JCP = 79 Hz, C-5 isoxazoline);
137.59 (d, 3JCP = 5 Hz, C-3 isoxazoline); 137.61.
31P NMR (202 MHz, CDCl3), δ, ppm: 42.66. LC-
MS (ES-API), m/z: 226.0 [M+H]+.
Dimethyl(3-(trifluoromethyl)-4,5-dihydro-
isoxazol-5-yl)phosphine oxide (14j)
A white amorphous solid. FCC purification:
CHCl3:MeOH (10:1), Rf = 0.35. Yield – 0.78 g (73 %).
Anal. Calcd for C6H9F3NO2P, %: C 33.50; H 4.22;
N 6.51. Found, %: C 33.55; H 4.32; N 6.43. 1H NMR
(400 MHz, CDCl3), δ, ppm: 1.49 (3H, d, 2JHP = 12.6 Hz,
CH3P); 1.65 (3H, d, 2JHP = 12.9 Hz, CH3P); 3.48 – 3.64
(2H, m, CH2CH oxazoline); 4.98 (1H, ddt, J = 11.6,
9.5, 2.8 Hz, CH oxazoline). 13C NMR (101 MHz,
CDCl3), δ, ppm: 11.53 (d, 1JCP = 69 Hz, CH3P); 14.58
(d, 1JCP = 69 Hz, CH3P); 33.27; 79.99 (d, 1JCP = 78 Hz,
C-5 isoxazoline); 119.30 (q, 1JCF = 272 Hz, CF3);
149.45 (qd, 2JCF = 38 Hz, 3JCP = 5 Hz, C-3 isoxazo-
line). 19F NMR (470 MHz, CDCl3), δ, ppm: -66.15.
31P NMR (202 MHz, CDCl3), δ, ppm: 41.84. GC-MS
(EI), m/z: 215.0 [M]•+; 78.0 [HP(O)Me2]•+ (100 %).
Dimethyl(3-((triisopropylsilyl)ethynyl)-
4,5-dihydroisoxazol-5-yl)phosphine oxide (14k)
A white amorphous solid. FCC purification:
CHCl3:MeOH (10:1), Rf = 0.32. Yield – 0.70 g (43 %).
Anal. Calcd for C16H30NO2PSi, %: C 58.68; H 9.23;
N 4.28. Found, %: C 58.77; H 9.27; N 4.11. 1H NMR
(500 MHz, CDCl3), δ, ppm: 1.03 – 1.19 (21H, m,
3×iPr); 1.49 (3H, d, 2JHP = 12.6 Hz, CH3P); 1.64
(3H, d, 2JHP = 12.8 Hz, CH3P); 3.46 (2H, dd, J =
19.9, 11.0 Hz, CH2CH oxazoline); 4.83 (1H, td,
J = 11.2, 3.9 Hz, CH oxazoline). 13C NMR (126 MHz,
CDCl3), δ, ppm: 10.51; 10.77 (d, 1JCP = 69 Hz, CH3P);
14.34 (d, 1JCP = 69 Hz, CH3P); 17.97; 38.67; 77.76
(d, 1JCP = 81 Hz, C-5 isoxazoline); 92.76; 103.29;
142.70 (d, 3JCP = 3.8 Hz, C-3 isoxazoline). 31P NMR
(202 MHz, CDCl3), δ, ppm: 43.34. LC-MS (ES-API),
m/z: 328.0 [M+H]+.
The synthesis of 1-(5-(dimethylphospho-
ryl)-4,5-dihydroisoxazol-3-yl)cyclobutan-
1-aminium 2,2,2-trifluoroacetate (16h)
tert-Butyl (1-(5-(dimethylphosphoryl)-4,5-di-
hydroisoxazol-3-yl)cyclobutyl)carbamate (14h)
(0.316 g, 1.0 mmol) was dissolved in DCM (20 mL),
the solution was cooled to 0 oC. Then 10 equiv
of TFA was added dropwise to the solution, and
the mixture was allowed to stir overnight at room
temperature. All volatile components were evapo-
rated under reduced pressure resulting in the
title compound.
A white amorphous solid. Yield – 0.27 g (83 %).
Anal. Calcd for C11H18F3N2O4P, %: C 40.01; H 5.49;
N 8.48. Found, %: C 40.32; H 5.69; N 8.21. 1H NMR
(400 MHz, DMSO-d6), δ, ppm: 1.40 – 1.70 (6H, m),
1.83 – 2.14 (3H, m), 2.32 – 2.47 (3H, m), 3.37 – 3.73
(2H, m), 4.85 – 4.98 (1H, m), 8.72 (3H, s). 19F NMR
(470 MHz, CDCl3), δ, ppm: -75.21. 31P NMR (202 MHz,
DMSO-d6), δ, ppm: 40.63. LC-MS (ES-API), m/z:
217.1 [M-C2F3O2]+.
■ References
1. Bhattu, M.; Verma, M.; Kathuria, D., Recent advancements in the detection of organophosphate pesticides: a review. Analytical Methods
2021, 13 (38), 4390 – 4428. https://doi.org/10.1039/D1AY01186C.
2. Thakur, M.; Medintz, I. L.; Walper, S. A., Enzymatic Bioremediation of Organophosphate Compounds — Progress and Remaining Chal-
lenges. Frontiers in Bioengineering and Biotechnology 2019, 7. https://doi.org/10.3389/fbioe.2019.00289.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 51
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
3. Iaroshenko, V. Phosphorus in Chemical Biology and Medicinal Chemistry. In Organophosphorus Chemistry, V. Iaroshenko (Ed.). 2019;
pp 499 – 544. https://doi.org/10.1002/9783527672240.ch10.
4. Denoix, J. M.; Thibaud, D.; Riccio, B., Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind
placebo-controlled clinical trial. Equine Veterinary Journal 2003, 35 (4), 407 – 413. https://doi.org/10.2746/042516403776014226.
5. Akre, C. The Use of Pyrethroids, Carbamates, Organophosphates, and Other Pesticides in Veterinary Medicine. In Chemical Analysis of
Non‐antimicrobial Veterinary Drug Residues in Food, 2016; pp 383 – 426. https://doi.org/10.1002/9781118696781.ch7.
6. Pharmaceutical Manufacturing Encyclopedia. 3rd Ed. William Andrew Publishing, Norwish NY: Elsevier; 2007; pp. 56m – 57m.
https://doi.org/10.1016/B978-0-8155-1526-5.50017-9.
7. Garnock-Jones, K. P., Fosaprepitant Dimeglumine: A Review in the Prevention of Nausea and Vomiting Associated with Chemotherapy.
Drugs 2016, 76 (14), 1365 – 1372. https://doi.org/10.1007/s40265-016-0627-7.
8. Nordgren, I.; Bengtsson, E.; Holmstedt, B.; Pettersson, B.-M., Levels of Metrifonate and Dichlorvos in Plasma and Erythrocytes during Treatment of Schis-
tosomiasis with Bilarcil®. Acta Pharmacologica et Toxicologica 1981, 49 (s5), 79 – 86. https://doi.org/10.1111/j.1600-0773.1981.tb03256.x.
9. Duchin, K. L.; Waclawski, A. P.; Tu, J. I.; Manning, J.; Frantz, M.; Willard, D. A., Pharmacokinetics, Safety, and Pharmacologic Effects of
Fosinopril Sodium, an Angiotensin-Converting Enzyme Inhibitor in Healthy Subjects. The Journal of Clinical Pharmacology 1991, 31 (1),
58 – 64. https://doi.org/10.1002/j.1552-4604.1991.tb01887.x.
10. Ala-Houhala, I.; Saha, H.; Liukko-Sipi, S.; Ylitalo, P.; Pasternack, A., Pharmacokinetics of clodronate in haemodialysis patients. Nephrology
Dialysis Transplantation 1999, 14 (3), 699 – 705. https://doi.org/10.1093/ndt/14.3.699.
11. Roberti, G.; Tanga, L.; Michelessi, M.; Quaranta, L.; Parisi, V.; Manni, G.; Oddone, F. Cytidine 5′-Diphosphocholine (Citicoline) in Glaucoma: Ra-
tionale of Its Use, Current Evidence and Future Perspectives. Int. J. Mol. Sci. 2015, 16, 28401 – 28417. https://doi.org/10.3390/ijms161226099.
12. Smith, B. R.; Eastman, C. M.; Njardarson, J. T., Beyond C, H, O, and N! Analysis of the Elemental Composition of U.S. FDA Approved Drug
Architectures. J. Med. Chem. 2014, 57 (23), 9764 – 9773. https://doi.org/10.1021/jm501105n.
13. Yu, H.; Yang, H.; Shi, E.; Tang, W. Development and Clinical Application of Phosphorus-Containing Drugs. Medicine in Drug Discovery
2020, 8, 100063. https://doi.org/10.1016/j.medidd.2020.100063.
14. Rodriguez, J. B.; Gallo-Rodriguez, C. The Role of the Phosphorus Atom in Drug Design. ChemMedChem 2019, 14 (2), 190 – 216.
https://doi.org/10.1002/cmdc.201800693.
15. Buckner, F. S.; Urbina, J. A. Recent developments in sterol 14-demethylase inhibitors for Chagas disease. International Journal for Para-
sitology: Drugs and Drug Resistance 2012, 2, 236 – 242. https://doi.org/10.1016/j.ijpddr.2011.12.002.
16. Rodriguez, J. B.; Falcone, B. N.; Szajnman, S. H. Detection and treatment of Trypanosoma cruzi: a patent review (2011-2015). Expert
Opinion on Therapeutic Patents 2016, 26 (9), 993 – 1015. https://doi.org/10.1080/13543776.2016.1209487.
17. Wiemer, A. J.; Wiemer, D. F. Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier. In Phosphorus Chemistry I:
Asymmetric Synthesis and Bioactive Compounds, Montchamp, J.-L., Ed. Springer International Publishing: Cham, 2015; pp 115 – 160.
https://doi.org/10.1007/128_2014_561.
18. Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J.-Y.; Renault, E. The pKBHX Database: Toward a Better Understanding of Hydrogen-
Bond Basicity for Medicinal Chemists. J. Med. Chem. 2009, 52 (14), 4073 – 4086. https://doi.org/10.1021/jm801331y.
19. National Cancer Institute. FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer.
https://www.cancer.gov/news-events/cancer-currents-blog/2017/brigatinib-fda-lung-cancer (accessed Apr 15, 2023).
20. Bedi, S.; Khan, S. A.; AbuKhader, M. M.; Alam, P.; Siddiqui, N. A.; Husain, A. A comprehensive review on Brigatinib – A wonder drug for targeted
cancer therapy in non-small cell lung cancer. Saudi Pharmaceutical Journal 2018, 26 (6), 755 – 763. https://doi.org/10.1016/j.jsps.2018.04.010.
21. Finkbeiner, P.; Hehn, J. P.; Gnamm, C. Phosphine Oxides from a Medicinal Chemist’s Perspective: Physicochemical and in Vitro Param-
eters Relevant for Drug Discovery. J. Med. Chem. 2020, 63 (13), 7081 – 7107. https://doi.org/10.1021/acs.jmedchem.0c00407.
22. Fedyk, A.; Slobodyanyuk, E. Y.; Stotska, O.; Vashchenko, B. V.; Volochnyuk, D. M.; Sibgatulin, D. A.; Tolmachev, A. A.; Grygorenko, O. O.
Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico-chemical Properties. Eur. J. Org. Chem. 2021, 2021
(47), 6591 – 6603. https://doi.org/10.1002/ejoc.202100581.
23. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Hetero-
cycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57 (24), 10257 – 10274. https://doi.org/10.1021/jm501100b.
24. Nath, C. P.; Kumar, N.; Hazra, K. K.; Praharaj, C. S.; Singh, S. S.; Dubey, R. P.; Sharma, A. R. Topramezone: A selective post-emer-
gence herbicide in chickpea for higher weed control efficiency and crop productivity. Crop Protection 2021, 150, 105814.
https://doi.org/10.1016/j.cropro.2021.105814.
25. Arends, J. E.; Hoepelman, A. I. M.; Nanlohy, N. M.; Höppener, F. J. P.; Hirsch, K. R.; Park, J. G.; van Baarle, D. Low doses of the novel
caspase-inhibitor GS-9450 leads to lower caspase-3 and -8 expression on peripheral CD4+ and CD8+ T-cells. Apoptosis 2011, 16 (9),
959 – 966. https://doi.org/10.1007/s10495-011-0620-2.
26. Walther, F. M.; Allan, M. J.; Roepke, R. K. A.; Nuernberger, M. C. The effect of food on the pharmacokinetics of oral fluralaner in dogs.
Parasites & Vectors 2014, 7 (1), 84. https://doi.org/10.1186/1756-3305-7-84.
27. Martin, D. G.; Chidester, C. G.; Mizsak, S. A.; Duchamp, D. J.; Baczysnkyj, L. The isolation, structure, and absolute configuration of
U-43,795, a new antitumor agent. J. Antibiot. (Tokyo) 1975, 28 (1), 91 – 93. https://doi.org/10.7164/antibiotics.28.91.
28. Nicacio, K. J.; Ióca, L. P.; Fróes, A. M.; Leomil, L.; Appolinario, L. R.; Thompson, C. C.; Thompson, F. L.; Ferreira, A. G.; Williams, D. E.;
Andersen, R. J.; Eustaquio, A. S.; Berlinck, R. G. S. Cultures of the Marine Bacterium Pseudovibrio denitrificans Ab134 Pro-
duce Bromotyrosine-Derived Alkaloids Previously Only Isolated from Marine Sponges. J. Nat. Prod. 2017, 80 (2), 235 – 240.
https://doi.org/10.1021/acs.jnatprod.6b00838.
29. Tang, J.-w.; Hu, K.; Su, X.-z.; Li, X.-n.; Yan, B.-c.; Sun, H.-d.; Puno, P.-t. Phomopsisins A–C: Three new cytochalasans from the plant endo-
phytic fungus Phomopsis sp. sh917. Tetrahedron 2020, 76 (39), 131475. https://doi.org/10.1016/j.tet.2020.131475.
30. Chalyk, B. A.; Hrebeniuk, K. V.; Gavrilenko, K. S.; Shablykin, O. V.; Yanshyna, O. O.; Bash, D.; Mykhailiuk, P. K.; Liashuk, O. S.; Grygorenko, O. O.
Synthesis of Bi- and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles. Eur. J. Org. Chem.
2018, 2018 (22), 2753 – 2761. https://doi.org/10.1002/ejoc.201800311.
31. Chalyk, B. A.; Hrebeniuk, K. V.; Gavrilenko, K. S.; Kulik, I. B.; Rozhenko, A. B.; Volochnyuk, D. M.; Liashuk, O. S.; Grygorenko, O. O. Syn-
thesis of 4-Hetarylisoxazoles from Amino Acid-Derived Halogenoximes and Push-Pull Enamines. Eur. J. Org. Chem. 2018, 2018 (40),
5585 – 5595. https://doi.org/10.1002/ejoc.201800753.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 52
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
32. Chalyk, B. A.; Khutorianskyi, A. V.; Vashchenko, B. V.; Danyleiko, K.; Grynyova, A.; Osipova, A. O.; Kozytskiy, A.; Syniuchenko, D.; Tsym-
baliuk, A.; Gavrilenko, K. S.; Biitseva, A. V.; Volochnyuk, D. M.; Komarov, I. V.; Grygorenko, O. O. Reductive Recyclization of sp3-Enriched
Functionalized Isoxazolines into α-Hydroxy Lactams. J. Org. Chem. 2022, 87 (2), 1001 – 1018. https://doi.org/10.1021/acs.joc.1c02301.
33. Chalyk, B. A.; Sosedko, A. S.; Volochnyuk, D. M.; Tolmachev, A. A.; Gavrilenko, K. S.; Liashuk, O. S.; Grygorenko, O. O. Regioselective syn-
thesis of isoxazole and 1,2,4-oxadiazole-derived phosphonates via [3 + 2] cycloaddition. Org. Biomol. Chem. 2018, 16 (47), 9152 – 9164.
https://doi.org/10.1039/C8OB02257G.
34. Chalyk, B. A.; Kandaurova, I. Y.; Hrebeniuk, K. V.; Manoilenko, O. V.; Kulik, I. B.; Iminov, R. T.; Kubyshkin, V.; Tverdokhlebov, A. V.; Abliali-
mov, O. K.; Mykhailiuk, P. K. A base promoted multigram synthesis of aminoisoxazoles: valuable building blocks for drug discovery and
peptidomimetics. RSC Adv. 2016, 6 (31), 25713 – 25723. https://doi.org/10.1039/C6RA02365G.
35. Leng, L.; Zhou, X.; Liao, Q.; Wang, F.; Song, H.; Zhang, D.; Liu, X.-Y.; Qin, Y. Asymmetric Total Syntheses of Kopsia Indole Alkaloids. Angew.
Chem. Int. Ed. 2017, 56 (13), 3703 – 3707. https://doi.org/10.1002/anie.201700831.
36. Poh, J.-S.; García-Ruiz, C.; Zúñiga, A.; Meroni, F.; Blakemore, D. C.; Browne, D. L.; Ley, S. V., Synthesis of trifluoromethylated isox-
azoles and their elaboration through inter- and intra-molecular C–H arylation. Org. Biomol. Chem. 2016, 14 (25), 5983 – 5991.
https://doi.org/10.1039/C6OB00970K.
37. Kusakabe, K.-I.; Yoshida, S.; Nakahara, K.; Hasegawa, T.; Tadano, G.; Fuchino, K. Dihydrooxazine or oxazepine derivatives having bace1
inhibitory activity. WO2014065434A1, May 5, 2014.
38. Minter, A. R.; Fuller, A. A.; Mapp, A. K. A Concise Approach to Structurally Diverse β-Amino Acids. J. Am. Chem. Soc. 2003, 125 (23),
6846 – 6847. https://doi.org/10.1021/ja0298747.
39. Breugst, M.; Reissig, H.-U., The Huisgen Reaction: Milestones of the 1,3-Dipolar Cycloaddition. Angew. Chem. Int. Ed. 2020, 59 (30),
12293 – 12307. https://doi.org/10.1002/anie.202003115.
40. Stambirskyi, M. V.; Kostiuk, T.; Sirobaba, S. I.; Rudnichenko, A.; Titikaiev, D. L.; Dmytriv, Y. V.; Kuznietsova, H.; Pishel, I.; Borysko, P.;
Mykhailiuk, P. K. Phosphine Oxides (−POMe2) for Medicinal Chemistry: Synthesis, Properties, and Applications. J. Org. Chem. 2021, 86
(18), 12783 – 12801. https://doi.org/10.1021/acs.joc.1c01413.
41. Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry
friendliness of small molecules. Scientific reports 2017, 7 (1), 42717. https://doi.org/10.1038/srep42717.
42. SwissADME. http://www.swissadme.ch/index.php (accessed Mar 13, 2023).
Information about the authors:
Andrii V. Fedyk (corresponding author), Ph.D. Student of the Biologically Active Compounds Department, Institute of Organic Chemistry
of the National Academy of Sciences of Ukraine; e-mail for correspondence: andrefedyk@ukr.net.
Bohdan A. Chalyk, Ph.D. Student of the Biologically Active Compounds Department, Institute of Organic Chemistry of the National
Academy of Sciences of Ukraine.
|
| id | oai:ojs.journals.uran.ua:article-283988 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-24T01:00:42Z |
| publishDate | 2023 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/61/2790984b0fa28db5923e0a2727fcdd61.pdf |
| spelling | oai:ojs.journals.uran.ua:article-2839882026-08-23T19:38:20Z Synthesis of Functionalized 4,5-Dihydroisoxazoles Decorated with the Dimethylphosphinoyl Group Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу Fedyk, Andrii V. Chalyk, Bohdan A. диметилфосфін оксид ізоксазолін диполярне циклоприєднання нітрилоксид галогеноксими селективність ADME-профіль dimethylphosphine oxide isoxazoline dipolar cycloaddition nitrile oxide halogenoximes selectivity ADME profile Aim. To synthesize a hybrid molecular platform incorporating dimethylphosphinoyl and 4,5-dihydroisoxazole moieties suitable for the creation of focused combinatorial libraries of compounds.Results and discussion. The base-promoted interaction of halogenoxides with dimethyl(vinyl)phosphine oxide under mild conditions allowed us to obtain 11 isoxazoline–dimethylphosphine oxide hybrids in moderate yields. The reaction was found to be regio- though non-stereoselective. Furoxans were identified as possible side products of the reaction.Experimental part. The one-pot interaction with dimethyl(vinyl)phosphine oxide was used for the synthesis of the target compounds. Nitrile oxides were obtained in situ from the corresponding halogenoximes by base-promoted generation. The ADME parameters for a synthesized 5-P(O)Me2-isoxazoline compared to its isosters with the same core structure were predicted using a SwissADME Web Tool. The compounds obtained were characterized by 1H, 13C, 19F, 31P NMR spectroscopy and HPLC-MS spectrometry methods, as well as the elemental analysis.Conclusions. A practical approach to the isoxazoline platform decorated with a 5-P(O)Me2 “magic” group and containing 3-substituent with an easy-to-modify functionality has been developed. On example of the piperidine derivative, the effect of the dimethylphosphinoyl group on physicochemical properties and ADME parameters compared to its isosters has been determined. Мета. Синтезувати гібридну молекулярну платформу, яка містить диметилфосфіноїльну групу та фрагмент 4,5-дигідроізоксазолу і в подальшому може бути використана для створення фокусованих комбінаторних бібліотек сполук.Результати та їх обговорення. Взаємодія галогеноксимів із диметил(вініл)фосфіноксидом у присутності основи у м’яких умовах дозволила одержати із помірними виходами 11 гібридних сполук, які містять фрагменти ізоксазоліну та диметилфосфіноксиду. Виявлено, що реакція є регіо-, хоча й нестереоселективною. Фуроксани було ідентифіковано як можливі побічні продукти реакції.Експериментальна частина. Для синтезу цільових сполук було використано взаємодію нітрилоксидів з диметил(вініл)фосфіноксидом. Нітрилоксиди було одержано in situ з відповідних галогеноксимів дією основи. Для одного з представників цільових 5-P(O)Me2-ізоксазолінів було спрогнозовано ADME-профіль та порівняно одержані значення з аналогічними характеристиками для його ізостерів з базовою структурою ізоксазоліну. Розрахунки було здійснено за допомогою вебресурсу SwissADME. Одержані сполуки схарактеризовано методами 1H, 13C, 19F, 31P ЯМР-спектроскопії та ВЕРХ-мас-спектрометрії, а також елементного аналізу.Висновки. Розроблено практичний підхід до одержання ізоксазолінової платформи, що містить «магічну» 5-P(O)Me2 групу та функціоналізований замісник у положенні 3. На прикладі похідної піперидину окреслено вплив диметилфосфіноїльної групи на фізико-хімічні властивості та ADME параметри порівняно з її ізостерами. National University of Pharmacy 2023-08-30 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/283988 10.24959/ophcj.23.283988 Journal of Organic and Pharmaceutical Chemistry; Vol. 21 No. 2 (2023); 41-52 Журнал органической и фармацевтической химии; Том 21 № 2 (2023); 41-52 Журнал органічної та фармацевтичної хімії; Том 21 № 2 (2023); 41-52 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/283988/279922 Copyright (c) 2023 Andrii V. Fedyk, Bohdan A. Chalyk http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | диметилфосфін оксид ізоксазолін диполярне циклоприєднання нітрилоксид галогеноксими селективність ADME-профіль Fedyk, Andrii V. Chalyk, Bohdan A. Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title | Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title_alt | Synthesis of Functionalized 4,5-Dihydroisoxazoles Decorated with the Dimethylphosphinoyl Group |
| title_full | Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title_fullStr | Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title_full_unstemmed | Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title_short | Синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| title_sort | синтез функціоналізованих 4,5-дигідроізоксазолів, які містять диметилфосфіноїльну групу |
| topic | диметилфосфін оксид ізоксазолін диполярне циклоприєднання нітрилоксид галогеноксими селективність ADME-профіль |
| topic_facet | диметилфосфін оксид ізоксазолін диполярне циклоприєднання нітрилоксид галогеноксими селективність ADME-профіль dimethylphosphine oxide isoxazoline dipolar cycloaddition nitrile oxide halogenoximes selectivity ADME profile |
| url | https://ophcj.nuph.edu.ua/article/view/283988 |
| work_keys_str_mv | AT fedykandriiv synthesisoffunctionalized45dihydroisoxazolesdecoratedwiththedimethylphosphinoylgroup AT chalykbohdana synthesisoffunctionalized45dihydroisoxazolesdecoratedwiththedimethylphosphinoylgroup AT fedykandriiv sintezfunkcíonalízovanih45digídroízoksazolívâkímístâtʹdimetilfosfínoílʹnugrupu AT chalykbohdana sintezfunkcíonalízovanih45digídroízoksazolívâkímístâtʹdimetilfosfínoílʹnugrupu |