Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків
Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to determine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.Results and discussion. Synthetic approaches to 1-(fluoromethyl...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
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| Дата: | 2023 |
| Том: | 21 |
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| ISSN: | 2518-1548 |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874364440338497536 |
|---|---|
| author | Demchuk, Oleksandr P. Grygorenko, Oleksandr O. |
| author_facet | Demchuk, Oleksandr P. Grygorenko, Oleksandr O. |
| author_institution_txt_mv | [
{
"author": "Oleksandr P. Demchuk",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Oleksandr O. Grygorenko",
"institution": "Taras Shevchenko National University of Kyiv",
"orcid": ""
}
] |
| author_sort | Demchuk, Oleksandr P. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 9 |
| container_issue | 2 |
| container_start_page | 3 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 21 |
| datestamp_date | 2026-08-23T19:38:20Z |
| description | Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to determine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the pKa (pKa(H)) values measured for the title compounds, as well as for their non-substituted and CF3-substituted analogues, are consistent with the electron-withdrawing effect of the corresponding fluoroalkyl substituents.Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutanecarboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The pKa value was determined from the pre-equivalence point part of the titration curve using the standard acid-base titration.Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and CF3-substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s). |
| doi_str_mv | 10.24959/ophcj.23.274017 |
| first_indexed | 2025-07-23T04:43:14Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Original Research
http://ophcj.nuph.edu.ua
UDC 547.513+546.16
O. P. Demchuk1,2, O. O. Grygorenko2,3
1 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academician Kukhar str., 02660 Kyiv, Ukraine
2 Enamine Ltd., 78 Winston Churchill str., 02094 Kyiv, Ukraine
3 Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., 01033 Kyiv, Ukraine
The Synthesis and Acid-base Properties
of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted
Cyclobutane Building Blocks
Abstract
Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to deter-
mine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.
Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluorome-
thyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the pKa (pKa(H)) values
measured for the title compounds, as well as for their non-substituted and CF3-substituted analogues, are consistent with
the electron-withdrawing effect of the corresponding fluoroalkyl substituents.
Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutane-
carboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester
hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The pKa value was determined from the
pre-equivalence point part of the titration curve using the standard acid-base titration.
Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluo-
romethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities
(up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and
CF3-substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine
atom(s).
Keywords: cyclobutane; fluorine; acidity/basicity; amine; carboxylic acid
О. П. Демчук1,2, О. О. Григоренко2,3
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
3 Київський національний університет імені Тараса Шевченка,
вул. Володимирська, 60, м. Київ, 01033, Україна
Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених
циклобутанових будівельних блоків
Анотація
Мета. Синтезувати аміни та карбонові кислоти на основі циклобутану із групами CH2F або CHF2 в α-положенні; визна-
чити закономірності впливу флуороалкільних замісників на кислотно-основні властивості цільових сполук.
Результати та їх обговорення. Було розроблено синтетичні підходи до 1-(флуорометил)- та 1-(дифлуорометил)ци-
клобутанамінів, 1-(флуорометил)- та 1-(дифлуорометил)циклобутанкарбонових кислот. Було визначено, що виміряні
показники pKa (pKa(H)) одержаних сполук, а також їх незаміщених та CF3-заміщених аналогів узгоджуються з електро-
ноакцепторним ефектом відповідних фтороалкільних замісників.
Експериментальна частина. Синтез цільових сполук виходив з відомого етил-1-(гідроксиметил)циклобутанкарбокси-
лату або продукту його окиснення за Сверном (відповідного альдегіду) та передбачав флуорування, лужний гідроліз
естеру (для карбонових кислот) та модифіковане перегрупування Курціуса (для амінів). Показники pKa було визначено із
частини кривої титрування до точки еквівалентності шляхом стандартного кислотно-основного титрування.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 4
Журнал органічної та фармацевтичної хімії 2023, 21 (2)
Висновки. Новий розроблений синтетичний підхід до 1-(флуорометил)- та 1-(дифлуорометил)циклобутанамінів,
1-(флуорометил)- та 1-(дифлуорометил)циклобутанкарбонових кислот дозволяє одержувати цільові сполуки в бага-
тограмових кількостях (аж до 97 г). За єдиним винятком – кислотно-основні властивості цих продуктів, а також відпо-
відних родоначальних незаміщених та CF3-заміщених аналогів змінюються монотонним чином згідно з індуктивним
електронним ефектом атому(ів) фтору.
Ключові слова: циклобутан; флуор; кислотність/основність; амін; карбонова кислота
Citation: Demchuk, O. P.; Grygorenko, O. O. The synthesis and acid-base properties of α-(fluoromethyl)- and α-(difluoromethyl)-
substituted cyclobutane building blocks. Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2), 3 – 9.
https://doi.org/10.24959/ophcj.23.274017
Received: 16 February 2023; Revised: 18 April 2023; Accepted: 21 April 2023
Copyright© 2023, O. P. Demchuk, O. O Grygorenko. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The work was supported by Enamine Ltd., Ministry of Education and Science of Ukraine (grants No. 0121U100387 (21BF037-01M)
and 0122U001962 (22BF037-02)), and National Academy of Sciences of Ukraine (grant No. 0119U102718).
Conflict of interests: The authors are employees or consulting scientists at Enamine Ltd. that offers the title compounds
from the company’s catalog.
■ Introduction
Introducing fluorinated substituents into the
molecules of interest is a well-recognized design
approach in modern drug discovery, and it is sup-
ported by numerous recent success stories [1 – 5].
Fluorine atoms or fluoroalkyl groups can improve
the compound potency, physicochemical proper-
ties relevant to medicinal chemistry, or the met-
abolic stability. On the other hand, cyclobutane
derivatives have become increasingly popular in
drug discovery [6, 7] as small sp3-rich three-
dimensional structural motifs fully compliant with
recent trends in this area [8]. Therefore, it is
not surprising that functionalized cyclobutanes
containing fluoroalkyl substituents have become
very promising building blocks that have already
confirmed their value for medicinal chemistry.
For example, they were used in the discovery of
cannabinoid receptor type 2 (CB2) antagonists [9],
FMS-like tyrosine kinase 3 (FLT3) inhibitors [10],
or interleukin-1 receptor-associated kinase 4
(IRAK-4) inhibitors [11] (Figure 1).
Meanwhile, the simplest fluoroalkyl-substi-
tuted cyclobutane-derived amines and carboxylic
acids have been insufficiently represented in the
literature until recently. The corresponding a-,
β-, and γ-CF3-substituted building blocks have
been studied most thoroughly (Figure 2) [12 – 17].
Among the CH2F- and CHF2-substituted analogues,
N
N
O
O
NH
F
FF
N
N
CB2 agonist
EC50 = 0.04 nM
O
N
H
ON
FF
F
N
H2N
FLT3 inhibitor
EC50 = 0.48 nM
N
N
O
N
H O
N
F
F
O
FF
IRAK-4 inhibitor
EC50 = 0.5 nM
Figure 1. Representatives of MedChem relevant molecules with the a-fluoroalkyl-substituted cyclobutane moiety
F3C CO2H
Dolbier et al., 1990
Song et al., 2021
F3C NH2
McMillan et al., 2020
R
F
CO2H
R
F
NH2
Grygorenko et al., 2021
R
F
= CH2F, CHF2, CF3
CF3
5, Dmowski
et al., 2000
CO2H
CF3
NH2
6, Semple
et al., 2017
CH2F
1
CO2H
CH2F
NH2
2
CHF2
3
CO2H
CHF2
NH2
4
Figure 2. Status quo for fluoroalkylcyclobutanes
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Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
β-substituted derivatives were described by our
group recently [16]. On the contrary, cyclobutane-
derived amines and carboxylic acids bearing CH2F
or CHF2 groups in the a position (compounds 1 – 4)
are unknown in the literature to date.
In this work, we were focused on the deve-
lopment of an efficient approach to the synthesis
of compounds 1 – 4 allowing for their preparation
on a multigram scale. In addition to that, acid-
base properties of the products synthesized, as
well as their CF3-substituted analogues 5 and 6
were evaluated and compared to the parent non-
substituted compounds to determine the effects
of CH2F, CHF2, and CF3 groups in the series
studied.
■ Results and discussion
The synthetic part of our work commenced
from hydroxy ester 7 that was prepared on a
100-g scale starting from ethyl cyclobutane-
carboxylate using the method reported [18].
To obtain the CH2F-substituted series, com-
pound 7 was mesylated and then subjected to the
reaction with tetramethylammonium fluoride
(TMAF) in refluxing toluene to give an fluoroor-
ganic intermediate 8 (Scheme 1). Compound 8
was not isolated in a pure form, but subjected to
the next step, namely the alkaline hydrolysis, to
provide target carboxylic acid 1 (38 % yield from 7).
The reaction of compound 1 with diphenyl phos-
phoroyl azide (DPPA) in the presence of triethyl-
amine and then with tert-butanol (the modified
Curtius reaction protocol) gave carbamate 9 that
was immediately subjected to acid-promoted de-
protection resulting in amine 2 in the form of
hydrochloride (55 % yield from 1).
The synthesis of CHF2-substituted analogues
included a similar reaction sequence commenc-
ing from aldehyde 10 – a product of the Swern
oxidation of compound 7 according to the reported
procedure [18]. In particular, deoxoflurionation
of compound 10 with morph-DAST in CH2Cl2 gave
intermediate ester 11 that was subjected to alka-
line hydrolysis providing carboxylic acid 3 (58 %
yield from 10) (Scheme 2). Surprisingly, the mo-
dified Curtius rearrangement protocol described
above did not work well with compound 3 when
O
OEt
HO
1. MsCl, Et3N
CH2Cl2, -10 °C
2. TMAF, toluene
reflux
O
OEt
F7 8
KOH, H2O, MeOH
0 °C to rt
O
OH
F 1
2. BuOHt
reflux
NH3
F 2
.
HCl
NHBoc
F
9
Cl
HCl, 1,4-dioxane
tBuOMe, 0 °C to rt
1. DPPA, Et3N
toluene, 70 °C
38 % (from )7
55 % (from )1
Scheme 1. Synthetic approach to a-(fluoromethyl)cyclobutanecarboxylic acid and a-(fluoromethyl)cyclobutaneamine
O
OEt
O
morph-DAST
CH2Cl2, 5 °C to rt
O
OEt
F10 11
NaOH, H2O, MeOH
0 °C to rt
O
OH
F 3
2. Me3Si(CH2)2OH,
reflux
NH3
F 4
.
HCl
NHTeoc
F
12
Cl
6 M aq HCl
reflux
F F
FF
1. DPPA, Et3N
toluene, 100 °C
Me3Si
O
O
Teoc
58 % (from )10
64 % (from )3
Scheme 2. S ynthetic approach to a-(difluoromethyl)cyclobutanecarboxylic acid and a-(difluoromethyl)cyclobutaneamine
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Журнал органічної та фармацевтичної хімії 2023, 21 (2)
tert-butanol was used as the reagent for the in-
termediate isocyanate quenching, possibly due
to the steric effects. Meanwhile, Teoc-protected
derivative 12 (Teoc – 2-(trimethylsilyl)ethoxy-
carbonyl) was formed efficiently when tert-buta-
nol was replaced with 2-(trimethylsilyl)ethanol.
After acid-promoted deprotection, amine 4 was
obtained as hydrochloride in 64 % yield (from 3).
The pKa values of carboxylic acids 1, 3, and 5,
as well as the pKa(H) values of amines 2, 4, and
6 were determined by the acid-base titration ac-
cording to the previously reported protocol [19].
It was found that, generally, the pKa values fol-
lowed rules-of-thumb reported previously for the
analogous acyclic series (DpKa ≈ 1.7 and 0.7 per
each fluorine atom in the positions β and γ to the
(de)protonation site, respectively) [20] (Table 1).
These results confirm that the inductive effect of
the fluorine atoms is the main factor governing
acidic/basic properties within the series studied.
The only exception was compound 5 that was
somewhat less acidic than might be expected
(Figure 3); perhaps, some intramolecular inter-
actions (e.g., H∙∙∙F or F∙∙∙C=O) might be respon-
sible for this behavior.
■ Conclusions
A newly developed synthetic approach to
1-(fluoromethyl)- and 1-(difluoromethyl)cyclobu-
tanamines, 1-(fluoromethyl)- and 1-(difluorome-
thyl)cyclobutanecarboxylic acids allows to obtain
the title compounds in multigram quantities (up
to 97 g). The acid-base properties of these pro-
ducts, as well as their parent non-substituted
and CF3-substituted analogues, change in a mo-
notonous manner in accordance with inductive
electronic effect of the fluorine atom(s). In parti-
cular, the DpKa values were ca. 0.7 and 1.7 units
per single fluorine atom for carboxylic acids and
amines, respectively. The only exception was 1-(tri-
fluoromethyl)cyclobutanecarboxylic acid that was
somewhat less acidic than might be expected;
perhaps, some intramolecular interactions
might be responsible for this behavior.
■ Experimental part
The solvents were purified according to the
standard procedures [21]. All starting materials
were available from Enamine Ltd. or purchased
from other commercial sources. Melting points
were measured on a MPA100 OptiMelt automated
melting point system. 1H, 13C{H} and 19F{H} NMR
spectra were recorded on a Bruker 170 Avance
500 spectrometer (at 500 MHz for 1H NMR, and
126 MHz for 13C{H} NMR) and a Varian Unity
Plus 400 spectrometer (at 400 MHz for 1H NMR,
101 MHz for 13C{H} NMR, and 376 MHz for
19F{H} NMR). NMR chemical shifts were reported
in ppm (δ scale) upfield from TMS as an inter-
nal standard and were referenced using residual
NMR solvent peaks at 7.26 and 77.16 ppm for 1H
and 13C{1H} in CDCl3, 2.50 and 39.52 ppm for
1H and 13C{1H} in DMSO-d6, 4.79 for 1H in D2O.
Coupling constants (J) were given in Hz. Spectra
were reported as follows: chemical shift (δ, ppm),
integration, multiplicity, and coupling constants (Hz).
Table 1. The pKa (pKa(H)) values of compounds 1 – 6 (21 °C)
Compound RF pKa (pKa(H)) ΔpKa
[a]
1 CH2F 3.66 0.84
3 CHF2 3.08 1.42 / 0.71
5 CF3 2.90 1.60 / 0.53
c-C4H7COOH H 4.50 [19] –
2×HCl CH2F 8.10 1.76
4×HCl CHF2 6.62 3.24 / 1.62
6×HCl CF3 5.00 4.86 / 1.62
c-C4H7NH2 H 9.86 [19] –
Note: [a] Compared to the parent non-fluorinated compound; the second number is per one fluorine atom
Figure 3. Change in the pKa (pKa(H)) values of compounds 1 – 6
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Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
High-resolution mass spectra were obtained on
an Agilent 1260 Infinity UHPLC instrument cou-
pled with an Agilent 6224 Accurate Mass TOF
mass spectrometer.
For compounds 1 – 4 synthesized, the yields,
melting points, data of high-resolution mass
spectra (HRMS) (Table 2), 1H NMR spectra (Ta-
ble 3), 13C NMR spectra (Table 4), and 19F NMR
spectra (Table 5) were given in a tabular format.
1-(Fluoromethyl)cyclobutanecarboxylic
acid (1)
To a pre-cooled (–15 °C) solution of com-
pound 7 [18] (120 g, 0.76 mol) and Et3N (125 mL,
0.90 mol) in CH2Cl2 (1000 mL), MsCl (65.8 mL,
0.85 mol) was added in a dropwise manner while
keeping the internal temperature below –10 °C.
After additional stirring for 30 min, the thick sus-
pension obtained was washed with ice-cold wa-
ter (3×150 mL), the organic layer was dried over
Na2SO4 and evaporated under reduced pressure
to give a crude mesylate (ca. 185 g), which was
immediately used in the next step without pu-
rification.
The amount of the mesylate obtained and
freshly dried TMAF (119 g, 1.28 mol) were mixed
in toluene (900 mL), and the resulting mixture
was stirred at reflux overnight. The progress of
the reaction was monitored by 1H NMR; in case
of incomplete conversion an additional portion
of TMAF was added. After the reaction comple-
tion, the resulting mixture was cooled to room
temperature, diluted with hexanes (700 mL),
washed with ice-cold water (3×200 mL), dried over
Na2SO4 and evaporated under reduced pressure
to give a crude compound 8 (ca. 110 g).
The amount of compound 8 obtained was dis-
solved in MeOH (800 mL), and the solution was
cooled to 0 °C on an ice-water bath. An aqueous
solution of KOH (47.6 mL, 0.50 M, 0.85 mol) was
added while keeping the internal temperature
below 5 °C. The resulting turbid solution was
stirred for 2 h, and most of the organic solvent was
evaporated under reduced pressure. The residue
was washed with CH2Cl2 (2×100 mL), tBuOMe
(2×100 mL), diluted with a fresh portion of CH2Cl2
(300 mL), and acidified with 10 % aq NaHSO4
(1100 mL). The aqueous layer was additionally
Table 2. Yields, melting points, HRMS data for compounds 1 – 4 synthesized
Compound Yield, % M. p., °С HRMS
1 38 (from 7) liquid Calculated for [C6H9FO2–H]– 131.0508. Found 131.0509
2×HCl 58 (from 1) 178 – 181 (dec.) Calculated for [C5H10FN+H]+ 104.0876. Found 104.0871
3 58 (from 10) liquid Calculated for [C6H8F2O2–H]– 149.0414. Found 149.0412
4×HCl 64 (from 3) 188 – 192 (dec.) Calculated for [C5H9F2N+H]+ 122.0781. Found 122.0776
Table 3. 1H NMR spectra data for compounds 1 – 4 synthesized
Compound Solvent 1H NMR (400 MHz), δ, ppm
1 CDCl3 1.95 – 2.22 (4H, m); 2.52 (2H, dd, J = 8.8, 7.8 Hz); 4.66 (2H, d, J = 47.2 Hz); 11.04 (1H, s)
2×HCl[a] DMSO-d6
1.78 – 1.94 (2H, m); 1.94 – 2.09 (2H, m); 2.27 – 2.36 (2H, m);
4.66 (2H, d, J = 47.2 Hz); 8.81 (3H, s)
3 CDCl3 1.96 – 2.21 (2H, m); 2.36 – 2.65 (4H, m); 6.11 (1H, t, J = 56.5 Hz); 10.66 (1H, br. s)
4×HCl DMSO-d6
1.76 – 1.93 (1H, m); 1.91 – 2.07 (1H, m); 2.19 – 2.32 (2H, m); 2.32 – 2.46 (2H, m);
6.43 (1H, t, J = 54.6 Hz); 9.15 (3H, s)
Note: [a] At 500 MHz
Table 4. 13C NMR spectra data for compounds 1 – 4 synthesized
Compound Solvent 13С{1H} NMR (126 MHz), δ, ppm
1[a] CDCl3 15.6; 26.0 (d, J = 6.4 Hz); 47.2 (d, J = 19.6 Hz); 85.3 (d, J = 173 Hz); 180.9 (d, J = 4.1 Hz)
2×HCl DMSO-d6 14.0; 27.5 (d, J = 6.3 Hz); 55.4 (d, J = 18.3 Hz); 84.8 (d, J = 171 Hz)
3 CDCl3 15.2; 23.4 (t, J = 4.5 Hz); 49.3 (t, J = 23.4 Hz); 115.0 (t, J = 242 Hz); 178.2
4×HCl DMSO-d6 13.8; 25.8 (t, J = 3.8 Hz); 56.0 (t, J = 22.8 Hz); 115.2 (t, J = 244 Hz)
Note: [a] At 151 MHz
Table 5. 19F NMR spectra data for compounds 1 – 4 synthesized
Compound Solvent
19F{1H} NMR (376
MHz), δ, ppm
1 CDCl3 –223.5
2×HCl DMSO-d6 –226.9
3 CDCl3 –129.5
4×HCl DMSO-d6 –133.0
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Журнал органічної та фармацевтичної хімії 2023, 21 (2)
washed with CH2Cl2 (2×300 mL) and discarded.
The combined organic layers were washed with
brine (2×100 mL), dried over Na2SO4, and evapora-
ted under reduced pressure to give compound 1
as a beige solid (38.2 g, 0.29 mol, 38 % yield over
three steps).
1-(Fluoromethyl)cyclobutanamine hydro-
chloride (2×HCl)
To a solution of compound 1 (38.2 g, 0.29 mol)
in toluene (500 mL), Et3N (61.4 mL, 0.44 mol)
was added in one portion. The resulting solu-
tion was cooled to 0 °C on an ice-water bath, and
DPPA (87.8 g, 0.32 mol) was added portionwise
while keeping the internal temperature below
5 °C. After the addition, the reaction mixture was
slowly heated to 70 °C and then stirred at the
same temperature for 3 h. After the gas evolu-
tion ceased, the mixture was heated to intensive
reflux, and tert-butanol (83 mL, 0.87 mol) was
added in a dropwise manner, following by addi-
tional stirring at reflux overnight. The resulting
solution was cooled to room temperature, dilut-
ed with t-BuOMe (300 mL), washed successively
with 10 % aq KHSO4 (2×100 mL), saturated aq
NaHCO3 (2×100 mL), and brine (50 mL). The or-
ganic phase was dried over Na2SO4 and evapo-
rated under reduced pressure to give a crude com-
pound 9 (ca. 43.3 g).
To a solution of the amount of 9 obtained in
tBuOMe (250 mL), 10 M HCl in 1,4-dioxane (35
mL) was added in one portion at 0 °C, and the
resulting mixture was stirred overnight. The re-
sulting suspension was filtered, the precipitate
was washed with tBuOMe (3×75 mL) and dried
in vacuo (0.1 mbar) to give target product 2×HCl
as a colorless solid (22.7 g, 0.16 mol, 55 % yield
over two steps).
1-(Difluoromethyl)cyclobutanecarboxy-
lic acid (3)
To an ice-cold solution of aldehyde 10 [18]
(174 g, 1.11 mol) in CH2Cl2 (2 L), a solution of
morph-DAST (291 g, 1.67 mol) in CH2Cl2 (300 mL)
was added dropwise while maintaining the tem-
perature below 5 °C. When the addition was
complete, the resulting mixture was left to stir
at room temperature overnight. The reaction
mixture was slowly poured into saturated aq
NaHCO3, the aqueous phase was separated and
extracted with CH2Cl2 (500 mL). The combined or-
ganic extracts were washed with brine (200 mL),
dried over Na2SO4, and evaporated in vacuo.
The residue was purified by distillation (b. p. 51 °C /
5 mbar) to give crude ester 11 (ca. 125 g) as a color-
less liquid.
To a solution of the amount of compound 11
obtained in MeOH (1 L), NaOH (84.3 g, 2.11 mol)
was added portionwise (an exotherm was ob-
served during the addition). After 2 h of stirring,
the reaction mixture was evaporated in vacuo
and partitioned between water (1 L) and CH2Cl2
(1 L). The organic phase was discarded, and the
aqueous phase was acidified with 6 M aq HCl
to to pH ca. 3, extracted with CH2Cl2 (2×1 L).
The combined organic phases were washed with
brine (300 mL), dried over Na2SO4, and evapo-
rated to give carboxylic acid 3 (97.0 g, 58 % from
10) as a colorless oil.
1-(Difluoromethyl)cyclobutanamine hy-
drochloride (4×HCl)
To a solution of carboxylic acid 3 (97.0 g,
0.646 mol) in toluene (1 L), Et3N (99.0 g, 0.711 mol)
was added, and the resulting mixture was heated
to 100 °C. DPPA (179 g, 0.65 mol) was added drop-
wise at such a rate to maintain a gentle reflux.
When the gas evolution ceased, 2-(trimethylsi-
lyl)ethanol (84.1 g, 0.711 mol) was added in one
portion, and the heating was continued for 18 h.
The reaction mixture was allowed to cool to room
temperature, washed with saturated aq K2CO3
(300 mL), brine (300 mL), dried over Na2SO4,
and evaporated in vacuo to give carbamate 12
(ca. 141 g) as a brown solid used in the next step
without further purification.
The amount of compound 12 obtained was sus-
pended in 6 M aq HCl and refluxed until all so-
lids dissolved. The resulting mixture was eva-
porated to dryness and triturated with tBuOMe
(1 L). The precipitate was filtered, washed with
tBuOMe (2×400 mL), and dried in vacuo to give
4×HCl (84.1 g, 64 % yield) as a colorless solid.
■ Acknowledgments
The authors thank Dr. O. V. Hryshchuk,
O. S. Liashuk, and Y. Y. Yurov for their help
with the synthesis, O. Kovalenko and M. Bolgo-
va – with pKa determinations, Prof. Dr. D. M. Vo-
lochnyuk and B. V. Vashchenko for insightful
discussions, Prof. Dr. A. O. Tolmachov for his
encouragement and support, and all the brave
defenders of Ukraine for making this publica-
tion possible.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 9
Journal of Organic and Pharmaceutical Chemistry 2023, 21 (2)
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Information about the authors:
Oleksandr P. Demchuk, Ph.D. Student of the Medicinal Chemistry Department, Institute of Organic Chemistry
of the National Academy of Sciences of Ukraine; Chemist at Enamine Ltd.; https://orcid.org/0009-0007-4002-4823.
Oleksandr O. Grygorenko (corresponding author), Dr.Sci. in Chemistry, Head of the Organic Chemistry Department,
Taras Shevchenko National University of Kyiv; Consulting Scientist, Enamine Ltd.; https://orcid.org/0000-0002-6036-5859;
e-mail for correspondence: gregor@univ.kiev.ua.
|
| id | oai:ojs.journals.uran.ua:article-274017 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-24T01:00:26Z |
| publishDate | 2023 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/7c/5bfc83f3296dbbbfafa16abafc1d8d7c.pdf |
| spelling | oai:ojs.journals.uran.ua:article-2740172026-08-23T19:38:20Z The Synthesis and Acid-base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted Cyclobutane Building Blocks Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків Demchuk, Oleksandr P. Grygorenko, Oleksandr O. циклобутан флуор кислотність/основність амін карбонова кислота cyclobutane fluorine acidity/basicity amine carboxylic acid Aim. To synthesize cyclobutane-derived amines and carboxylic acids bearing CH2F or CHF2 groups in the α position; to determine the regularities of the effect of fluoroalkyl substituents on the acid-base properties of the title compounds.Results and discussion. Synthetic approaches to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids have been developed. It has been found that the pKa (pKa(H)) values measured for the title compounds, as well as for their non-substituted and CF3-substituted analogues, are consistent with the electron-withdrawing effect of the corresponding fluoroalkyl substituents.Experimental part. The synthesis of the title compounds commenced from the known ethyl 1-(hydroxymethyl)cyclobutanecarboxylate or the product of its Swern oxidation (the corresponding aldehyde) and included fluorination, alkaline ester hydrolysis (for carboxylic acids), and modified Curtius rearrangement (for amines). The pKa value was determined from the pre-equivalence point part of the titration curve using the standard acid-base titration.Conclusions. A newly developed synthetic approach to 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanamines, 1-(fluoromethyl)- and 1-(difluoromethyl)cyclobutanecarboxylic acids allows to obtain the title compounds in multigram quantities (up to 97 g). With a single exception, the acid-base properties of these products, as well as their parent non-substituted and CF3-substituted analogues, change in a monotonous manner in accordance with inductive electronic effect of the fluorine atom(s). Мета. Синтезувати аміни та карбонові кислоти на основі циклобутану із групами CH2F або CHF2 в α-положенні; визначити закономірності впливу флуороалкільних замісників на кислотно-основні властивості цільових сполук.Результати та їх обговорення. Було розроблено синтетичні підходи до 1-(флуорометил)- та 1-(дифлуорометил)циклобутанамінів, 1-(флуорометил)- та 1-(дифлуорометил)циклобутанкарбонових кислот. Було визначено, що виміряні показники pKa (pKa(H)) одержаних сполук, а також їх незаміщених та CF3-заміщених аналогів узгоджуються з електроноакцепторним ефектом відповідних фтороалкільних замісників.Експериментальна частина. Синтез цільових сполук виходив з відомого етил-1-(гідроксиметил)циклобутанкарбоксилату або продукту його окиснення за Сверном (відповідного альдегіду) та передбачав флуорування, лужний гідроліз естеру (для карбонових кислот) та модифіковане перегрупування Курціуса (для амінів). Показники pKa було визначено із частини кривої титрування до точки еквівалентності шляхом стандартного кислотно-основного титрування.Висновки. Новий розроблений синтетичний підхід до 1-(флуорометил)- та 1-(дифлуорометил)циклобутанамінів, 1-(флуорометил)- та 1-(дифлуорометил)циклобутанкарбонових кислот дозволяє одержувати цільові сполуки в багатограмових кількостях (аж до 97 г). За єдиним винятком – кислотно-основні властивості цих продуктів, а також відповідних родоначальних незаміщених та CF3-заміщених аналогів змінюються монотонним чином згідно з індуктивним електронним ефектом атому(ів) фтору. National University of Pharmacy 2023-08-30 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/274017 10.24959/ophcj.23.274017 Journal of Organic and Pharmaceutical Chemistry; Vol. 21 No. 2 (2023); 3-9 Журнал органической и фармацевтической химии; Том 21 № 2 (2023); 3-9 Журнал органічної та фармацевтичної хімії; Том 21 № 2 (2023); 3-9 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/274017/274352 Copyright (c) 2023 Oleksandr P. Demchuk, Oleksandr O. Grygorenko http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | циклобутан флуор кислотність/основність амін карбонова кислота Demchuk, Oleksandr P. Grygorenko, Oleksandr O. Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title | Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title_alt | The Synthesis and Acid-base Properties of α-(Fluoromethyl)- and α-(Difluoromethyl)-substituted Cyclobutane Building Blocks |
| title_full | Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title_fullStr | Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title_full_unstemmed | Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title_short | Синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| title_sort | синтез та кислотно-основні властивості α-(флуорометил)- та α-(дифлуорометил)заміщених циклобутанових будівельних блоків |
| topic | циклобутан флуор кислотність/основність амін карбонова кислота |
| topic_facet | циклобутан флуор кислотність/основність амін карбонова кислота cyclobutane fluorine acidity/basicity amine carboxylic acid |
| url | https://ophcj.nuph.edu.ua/article/view/274017 |
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