Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків
Herein, we describe a concise and scalable strategy for the preparation of gem-difluorinated cyclobutanes and cyclopentanes from simple, commercially available precursors under mild deoxyfluorination conditions. Optimization of the fluorination step enabled direct access to key intermediates, such a...
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| Date: | 2025 |
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2025
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Ukrainica Bioorganica Acta| _version_ | 1869381607892189184 |
|---|---|
| author | Olifir, Oleksandr S. Liashuk, Oleksandr S. |
| author_facet | Olifir, Oleksandr S. Liashuk, Oleksandr S. |
| author_institution_txt_mv | [
{
"author": "Oleksandr S. Olifir",
"institution": "Enamine Ltd., Kyiv, Ukraine"
},
{
"author": "Oleksandr S. Liashuk",
"institution": "Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; Enamine Scientific Research Institute (SRI), Kyiv, Ukraine"
}
] |
| author_sort | Olifir, Oleksandr S. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-06-29T16:01:07Z |
| description | Herein, we describe a concise and scalable strategy for the preparation of gem-difluorinated cyclobutanes and cyclopentanes from simple, commercially available precursors under mild deoxyfluorination conditions. Optimization of the fluorination step enabled direct access to key intermediates, such as gem-difluorocyclobutyl bromides and boronates in two to three steps and on up to 77 g scale, avoiding the mercury-mediated or high-temperature processes typical of earlier methodologies. The developed protocol exhibits broad functional-group tolerance, allowing the preparation of amino-, hydroxy-, and sulfonyl-substituted derivatives, as (including deoxyfluorination of certainly functionalized cyclobutanones or by rearrangement of methylenecyclopropanes), remain hardly accessible due to lengthy synthetic procedures or limited scalability. Their higher homologues, gem-difluorinated cyclopentanes, are described significantly well as novel cis- and trans-difluorocyclopentane scaffolds including diols, diamines, and carboxylic acid analogues. The operational simplicity, scalability, and structural diversity of the resulting building blocks make this approach a valuable platform for the exploration of CF₂-containing fragments in medicinal and materials chemistry |
| doi_str_mv | 10.15407/bioorganica2025.02.024 |
| first_indexed | 2026-02-08T07:59:48Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
UDC 547.51/.513
DOI: https://doi.org/10.15407/bioorganica2025.02.024
24
Ukrainica Bioorganica Acta
www.bi oorgan ica . com.u a
RESEARCH ARTICLE
Synthesis of gem-difluorinated cyclobutane and cyclopentane
building blocks
Oleksandr S. Olifir1, Oleksandr S. Liashuk2,3*
1 Enamine Ltd. (www.enamine.net), Kyiv, Ukraine
2 Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
3 Enamine Scientific Research Institute (SRI), Kyiv, Ukraine
Abstract: Herein, we describe a concise and scalable strategy for the preparation of gem-difluorinated cyclobutanes and cyclopentanes
from simple, commercially available precursors under mild deoxyfluorination conditions. Optimization of the fluorination step enabled
direct access to key intermediates, such as gem-difluorocyclobutyl bromides and boronates in two to three steps and on up to 77 g scale,
avoiding the mercury-mediated or high-temperature processes typical of earlier methodologies. The developed protocol exhibits broad
functional-group tolerance, allowing the preparation of amino-, hydroxy-, and sulfonyl-substituted derivatives, as (including
deoxyfluorination of certainly functionalized cyclobutanones or by rearrangement of methylenecyclopropanes), remain hardly accessible
due to lengthy synthetic procedures or limited scalability. Their higher homologues, gem-difluorinated cyclopentanes, are described
significantly well as novel cis- and trans-difluorocyclopentane scaffolds including diols, diamines, and carboxylic acid analogues. The
operational simplicity, scalability, and structural diversity of the resulting building blocks make this approach a valuable platform for the
exploration of CF₂-containing fragments in medicinal and materials chemistry.
Keywords: fluorine; cyclobutane; cyclopentane; fluorinated building blocks.
Introduction
Fluorine-containing organic molecules occupy a
privileged position in contemporary chemical science [1-3].
The replacement of hydrogen by fluorine - or, more
strategically, by gem-difluoro units (CF₂) - has emerged as a
powerful design element for tuning the physicochemical
profile of small molecules [4-7]. Gem-difluorinated motifs
act as bioisosteres for oxygen or carbonyl functionalities,
introducing polarity and conformational control without
compromising hydrophobic character [8-11]. Their
incorporation into heterocycles, amino acids, or aliphatic
frameworks has yielded molecules with improved
pharmacokinetics and membrane permeability [12, 13]. In
medicinal chemistry, difluorocycloalkane motifs have
Received:
Revised:
Accepted:
Published online:
25.09.2025
30.10.2025
12.11.2025
30.12.2025
Corresponding author. Tel.: +380-66-728-1226;
e-mail: o.s.liashuk@gmail.com (O.S. Liashuk)
ORCID: 0000-0002-2677-435X
already demonstrated a significant impact (Figure 1, A). For
instance, in Maraviroc, a CCR5 receptor antagonist used in
HIV therapy, a difluorocyclohexane fragment was
employed to reduce the activity for the hERG channel [14].
Ivosidenib, a targeted inhibitor of mutant IDH1 in acute
myeloid leukemia, has a difluorocycloalkyl substituent,
utilized to improve metabolic stability [15]. Similarly,
NMS-P118, a potent PARP-1 inhibitor developed for
oncological indications, benefits from the presence of a
difluorocyclopentane ring, which contributes to
conformational preorganization and reduces off-target
oxidation [16].
Despite these advantages, scalable access to gem-
difluorinated building blocks remains challenging, often
limited by multistep protocols or harsh fluorination reagents
[12]. For example, 2-functionalized gem-difluorocyclo-
butanes, although being represented in literature and
accessed by a few different strategies better (more than
4500 compounds in the Reaxys database) [20]. However,
certain representatives (in particular, 3,4-disubstituted gem-
difluorocyclopentanes), although mentioned in patent
disclosures related to interleukin and orexin receptor
© Olifir O.S. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
https://orcid.org/0000-0002-2677-435X
O.S. Olifir, O.S. Liashuk
25
inhibitors, do not occur in articles at all.
To address these limitations, this work presents a
streamlined strategy for the synthesis of gem-difluoro-
cyclobutanes, which reduces the overall stage count to the
target building blocks while enabling preparative-scale
production up to 77 grams. The developed approach
combines operational simplicity, robust scalability, and high
commercial availability of the starting materials.
Furthermore, we propose novel routes toward
difluorocyclopentane derivatives with cis- and trans-isome-
ric heteroatom substituents, including access to correspond-
ding dialcohols, (monoprotected) diamines or
monofunctionalized compounds – epoxide, acid or ester.
Their synthesis expands the chemical space of saturated
fluorinated motifs, providing a foundation for exploring
their physicochemical properties and potential applications
in drug design.
F
F
O
H
N
N
N
N
N
Maraviroc
N
F
F
F
NH2
O
O
N
NMS-P118
N
O
N
O
N
F
N
N
O NH
F F
Cl
Ivosidenib
gem-CF2 in drugs
FG
F
F
Chernykh et al, 2019
FG = NH2, COOH,Br,
BPin, CH2OH, CH2NH2
and CH2SO2Cl
(B) Reported data on the synthesis of selected building blocks
Watanabe et al, 2016
Li et al, 2021
F F
R1 R2
- not reported
in articles
- part of
Interleukin-17A
and Orexin type 2
receptors inhibitor
R1,R2 - O- or N-derivatives
(C) This work
FG
F
F O
- 2 to 5 steps;
- up to 77 g scale;
+ new BBs: FG = I, C(O)H, SO2Cl, OH
commonly
accessible F F
R1 R2
- 3 to 8 steps;
- up to 35 g scale;
R1,R2 - OH, NH2, N3
**
- cis- and trans;
or monoprotected
diamine
9 steps
or via
rearrangements
(A) Fluorinated drugs
Figure 1. (A) Known drug substances with gem-difluorinated
cycloalkane unit; (B) Reported data on the synthesis of fluorinated
cyclobutane and cyclopentane building blocks; (C) Results
presented in this work.
Results and Discussion
As was mentioned in introduction, access to gem-
difluorocyclobutanes is scarcely reported in literature; the
most prominent is the approach reported by Chernykh and
co-authors (Scheme 1, A) [21]. Albeit giving access to
target building blocks, it requires a 5-step long synthesis of
the key building block – cyclobutanone 1 – and a few
additional steps for achieving the preparation of the gem-
difluorinated functionalized cyclobutanes (in particular,
bromoderivative 2 required four additional steps, including
Hg-mediated bromodecarboxylation). To overcome this, we
developed a new protocol, starting from 2-
bromocyclobutanone 3 (which could be easily prepared by
bromination of commercially available cyclobutanone 4)
[22]. Screening of the most utilizable deoxyfluorination
reagents (i.e., DAST, MorphDAST, Deoxofluor, and in situ
prepared XtalFluor-E) revealed that the latter reagent was
the only one capable of producing the target material; with
the developed protocol in hand, gem-difluorinated
cyclobutylbromide 2 was prepared in 61% yield on up to 77
g scale. Copper-mediated borylation of this bromide
afforded boronate ester 5, which upon treatment with KHF2
cleanly produced corresponding trifluoroborate salt 6 – a
potentially useful building block in the construction of
alkyl-(het)aryl frameworks [23]. Bromide 3 was also used
for the preparation of sulphonylchloride 7. We have found
that direct substitution of the bromide in bromide 5 with
KSAc (a key step in the preparation of sulfonyl moiety) was
unfruitful; to overcome this, bromide 3 was transformed
into the corresponding iodinated derivative 8 by classical
Finkelstein reaction. Further deoxyfluorination with DAST
(productive in this case) and treatment of the intermediate
iodide 9 with KSAc produced the corresponding thioacetate
derivative 10 in moderate yield. Finally, oxidative
chlorination of 10 afforded tarhet sulfonyl chloride 7 in
46% yield on an 11 g scale.
O
O
O Br
4 steps
including Hg-catalyzed
decarboxylation
O O
Br
overall yield
37% from 1
F
F
available
from 5 steps
protocol
2.3 g
scale
Br
F
F
3 2
77 g
scale
XtalFluor-E
CH2Cl2
NBS
CH2Cl2
TsOH
315 g
B2pin2
CuI, PPh3,
Br
F
F
BPin
F
F
BF3K
F
F
KHF2
MeOH
65
O
Br
acetone
NaI
O
I
CH2Cl2
DAST
I
F
F
30 g
scale
S
F
F
O
S
F
F
ClO
O
KSAc
NMP
Cl2
CH2Cl2
H2O 736%992%
11 g
scale
1 2
4
2
LiOMe, DMF
3
46%
1030%8
83% 61%
23% 90%
(A)
(B)
Figure 2. (A) Reported synthesis of the key building block
cyclobutylbromide 2; (B) Proposed approach to the bromide 2 and
further transformations thereof.
Furthermore, the N-Boc-protected methyleneamino
fragment in cyclobutanone 11 was compatible with
deoxyfluorination conditions, producing amine 12 upon
treatment with MorphDAST (52% yield on 115 g scale).
Acidic cleavage of the protecting group afforded amine 13
[21]. previously reported to be accessible in 5 steps and
significantly lower scale (up to 9 g in one run). Reduction
of the carbamate fragment in 12 with LiAlH4 cleanly
produced N-Me amine 14 in good yield on a 14 g scale.
Hydroxycyclobutane 15 was obtained in a 3-step procedure,
starting from the rearrangement of the commercially
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
26
available cyclobutene 16 to acetoxycyclobutanone 17 (77%
yield). Treatment of the latter material with XtalFluor-E
resulted in the O-protected gem-difluorocyclobutane 18,
albeit in relatively low yield (18%). Finally, deprotection of
the ester fragment was achieved through the reaction with
hydrazine hydrate; upon distillation, cyclobutanol 15 was
obtained in 12% overall yield on a 26 g scale. In addition,
oxidation of the alcohol 19 [21] using trichloroisocyanuric
acid and TEMPO afforded aldehyde 20 in 38% yield, and
reduction of the carbamate fragment in 21 gives N-Me
amine 22 in preparative yield.
OTMS
OTMS
O
O
O
O
O
F
F
OH
F
F
O
NHBoc
F
F
F
F
NHBoc N
H2
+
F
F
F
F
OH
O
NHBoc
F
F
NH3
+
F
F
Cl-
H2
+
N
F
F
Cl-
MorphDAST
12, 52%
115 g scale
dry HCl
MeOH
13, 90%
61 g scale
accessed
previously
in 5 steps and
9 g scale
LiAlH4
THF
then HCl
14, 88%
14 g scale
AcOH
17, 77%
257 g scale
18, 18%
43 g
XtalFluor-E
Et3N·3HF
CH2Cl2
Et2O
15, 86%
26 g
TCICA
TEMPO
NaOAc
Et2O 20 38%
13 g
LiAlH4
THF
then HCl
22, 67%
26 g
CH2Cl2
11
16
19 21
Cl-
N2H4·H2O
Figure 3. Synthesis of building blocks 12, 13, 15, 20 and 22.
Synthesis of gem-Difluorinated Cyclopentane Derivatives.
A set of gem-difluorinated, difunctionalized cyclopen-
tane derivatives was synthesized from a common precursor,
alkene 23. This highly volatile intermediate was obtained as
diluted solution in DCM upon treatment of the
cyclopentenone 24 (in turn, obtained by oxidation of
alcohol 25 with Dess-Martin periodinane) with
MorphDAST on more than 60 g scale.
The obtained solution of 23 in DCM (ca. 3% w/w) was
used to prepare the target mono- and bifunctionalized
fluorinated building blocks. In particular, treatment of the
latter alkene with N-methylmorpholine N-oxide (NMO) in
the presence of catalytic amounts of osmium tetroxide
afforded diol cis-26, albeit in relatively low yield (21% on
an 11 g scale). The isomeric compound trans-26 was
obtained by acid-catalyzed ring opening of oxirane 27 (96%
yield), which was prepared by epoxidation of alkene 23
with m-chloroperbenzoic acid (mCPBA). Cyclopropanation
of the latter compound with ethyldiazoacetate in the
presence of catalytic amounts of dirhodium tetraacetate
produced fluorinated bicyclic ester 28 as a single exo-
isomer exclusively, which could be easily transformed to
the corresponding acid 29 upon alkaline saponification [6].
Epoxide 27 also served as a versatile precursor for amino
derivatives of gem-difluorocyclobutanes. Oxirane ring
opening with NaN3 produced azidoalcohol 30 in 53%
isolated yield; the latter reaction occurred stereoselectively,
producing trans-isomer exclusively. Treatment of the
alcohol 30 with MsCl and subsequent reaction with NaN3
produced diazide 31, which was immediately subjected to
LiAlH4-mediated reduction of azidofragment, producing
cis-32 as HCl salt in 58% yield over two steps.
Alternatively, azidoalcohol 30 was hydrogenated over Pd/C,
giving aminoalcohol trans-33 in high isolated yield (93%
isolated yield on 20 g scale). Upon installation of the N-Boc
protection group, the hydroxyl fragment in trans-34 was
transformed into protected aminoazide cis-35 in a two-step
mesylation-azidation sequence; a complete inversion of
configuration was observed, producing cis-isomeric product
exclusively. Subsequent Staudinger reduction of cis-35
furnished the monoprotected diamine cis-36, a versatile
derivative of cis-32 suitable for selective functionalization.
OH O F F
MorphDAST
CH2Cl2
Dess-Martin
periodinane
tBuOMe
24, 83%
68 g scale
ca. 95 g
(3% w/w in CH2Cl2)
F FF F
HO OH
F F
O
F F
HO OH
mCPBA
CH2Cl2
27, 42%,
70% purity
60 g scale
OsO4
*NMO =
N-methyl-
morpholine
N-oxide
NMO
CH2Cl2
cis-26, 21%
11 g scale
CH2Cl2
TFA
H2O
trans-26, 96%
17 g scaleRh2(OAc)4
N2
OEt
O
F
F
O
OEt
F
F
O
OH
NaOH
MeOH
H2O 29, 93%
17 g scale
28, 23%
21 g scale
F F
O N3 OH
F F
H2N OH
F F
N3 N3
F F
H2N NH2
F F
BocHN OH
F F
BocHN N3
F F
BocHN NH2
F F
NaN3
NH4Cl
EtOH/H2O
30, 53%
35 g scale
NH3 in MeOH
trans-33, 93%
20 g scale
H2, Pd/C
1. MsCl
TEA
2. NaN3
DMF
LiAlH4
Et2O
cis-32, 58%
22 g scale
HCl
HCl
Boc2O
CH2Cl2
trans-34, 98%
17 g scale
1. MsCl
TEA
2. NaN3
DMF
cis-35, 45%
70% purity
PPh3
THF
cis-36, 42%
5 g scale
23
25
23
27 31
Figure 4. Synthesis of bifunctionalized gem-CF2-cyclopentane
building blocks 23, 26, 30, 32-36.
Conclusions
In summary, we have developed a concise and scalable
strategy for the synthesis of gem-difluorinated cyclobutanes
and cyclopentanes that addresses key limitations of
previously reported methods. The new protocol relies on
readily available starting materials and mild fluorination
O.S. Olifir, O.S. Liashuk
27
conditions, providing straightforward access to structurally
diverse CF₂-containing building blocks on multigram to
decagram scales. Compared to previously reported
approaches, which required five or more steps to generate
the core difluorocyclobutane and employed mercury-
mediated transformations, the proposed methods reduce the
overall step count to two or three operations while
maintaining operational simplicity and reproducibility. In
addition, the successful preparation of cis- and trans-
difluorocyclopentane derivatives – including diols,
diamines, and carboxylic acid analogues - expands the
available library of conformationally defined fluorinated
scaffolds. These compounds are expected to serve as
valuable fragments for the design of next-generation
bioactive molecules, particularly where precise control of
polarity, rigidity, and lipophilicity is desired.
Experimental section
The solvents were purified according to the standard
procedures [24]. All reagents and starting compounds (4,
16, 25) were obtained from Enamine Ltd stock.
Difluorocyclobutanes 19 and 21 were synthesized according
to a previously reported protocol [21]. Melting points were
measured on MPA100 OptiMelt automated melting point
system. Analytical TLC was performed using Polychrom SI
F254 plates. Column chromatography was performed using
Kieselgel Merck 60 (230-400 mesh) as the stationary phase.
1H, 13C{1H} and 19F{1H} NMR spectra were recorded on an
Agilent ProPulse 600 spectrometer (at 151 MHz for
13C{1H} NMR), a Bruker 170 Avance 500 spectrometer (at
500 MHz for 1H, 126 MHz for 13C{1H} NMR and 470 MHz
for 19F{1H} NMR), or a Varian Unity Plus 400 spectrometer
(at 400 MHz for 1H, 101 MHz for 13C{1H} and 376 MHz
for 19F{1H} NMR). NMR chemical shifts are reported in
ppm (δ scale) downfield from TMS as an internal standard
and are referenced using residual NMR solvent peaks at
7.26 and 77.16 ppm for 1H and 13C in CDCl3, 2.50 and
39.52 ppm for 1H and 13C in DMSO-d6, at 4.80 ppm for 1H
in D2O. Spectra are reported as follows: chemical shift (δ,
ppm), multiplicity, integration, coupling constants (J).
Coupling constants (J) are given in Hz. Elemental analyses
were performed at the Laboratory of Organic Analysis,
Department of Chemistry, Taras Shevchenko National
University of Kyiv. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument (chemical ionization
(CI)) and Agilent 5890 Series II 5972 MS instrument
(electron impact ionization (EI)). High-resolution mass
spectra (HRMS) were obtained on an Agilent 1260 Infinity
UHPLC instrument coupled with an Agilent 6224 Accurate
Mass TOF mass spectrometer.
Synthesis
2-Bromo-1,1-difluorocyclobutane (2).
To a pre-cooled to 0 °C solution of DAST (300.0 g,
1.86 mol) in DCM (1.5 L) neat BF3⸱Et2O (264.0 g,
1.86 mol) was added in a dropwise manner, maintaining the
reaction temperature below 10 °C. After further stirring at
0 °C for 15 min, neat NEt3⸱3HF (180 g, 1.12 mol) and then
3 (110.0 g, 0.743 mol) were sequentially added to the in situ
formed solution of XtalFluor-E. The resulting mixture was
stirred at room temperature for 24 h and then poured into
ice-cold water (ca. 2 L). The organic layer was separated,
washed with sat. aq NaHCO3 (1.5 L), dried over anhydrous
Na2SO4, and concentrated by distillation under atmospheric
pressure at 50-60 °C. The crude product was purified by
vacuum distillation. Yield: 77.0 g, 0.450 mol, 61%.
Colourless liquid; bp = 59 °C/110 mmHg. 1H NMR
(500 MHz, CDCl3) δ 4.57-4.45 (m, 1H), 2.78-2.64 (m, 1H),
2.59-2.48 (m, 1H), 2.49-2.40 (m, 1H), 2.11-1.98 (m, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 118.2 (dd, JC-F = 289.9,
277.0 Hz), 44.0 (dd, JC-F = 27.2, 22.3 Hz), 32.6 (dd, JC-F
= 23.7, 23.5 Hz), 22.8 (d, J JC-F = 14.7 Hz). 19F{1H} NMR
(376 MHz, CDCl3) δ -86.3 (d, J = 189.6 Hz), -106.7 (d,
J = 190.1 Hz). MS (EI) m/z = 170 ([M]+). Anal. calcd. for
C4H5BrF2: C, 28.10; H, 2.95; Br, 46.73. Found: C, 28.50; H,
2.67; Br, 46.39. The spectral data are consistent with those
previously reported [21].
2-Bromocyclobutan-1-one (3).
The compound was prepared according to the published
procedure [22]. Yield: 315.0 g, 2.13 mol, 83% (from
180.0 g, 2.57 mol of cyclobutanone 4). Yellowish oil;
purified by column chromatography (hexane/EtOAc 10:1,
v/v). Rf 0.55; 1H NMR (400 MHz, CDCl3) δ 5.02-4.93 (m,
1H), 3.27-3.04 (m, 2H), 2.79-2.65 (m, 1H), 2.29-2.15 (m,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 200.4, 49.5, 45.0,
23.1. MS (EI) m/z = 148/150 ([M]+). Anal. calcd. for
C4H5BrO: C 32.25; H 3.38; Br 53.63. Found : C 32.52; H
3.52; Br 53.89.
2-(2,2-Difluorocyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (5).
The compound was prepared according to the published
procedure [21]. Yield: 17.5 g, 80.3 mmol, 23% (from
60.0 g, 0.351 mol of 2). Colorless liquid; purified by
distillation, bp = 25-27 °C/1 mmHg. 1H NMR (500 MHz,
CDCl3) δ 2.66-2.54 (m, 2H), 2.54-2.42 (m, 1H), 1.87-1.77
(m, 2H), 1.27 (s, 12H). 13C{1H} NMR (126 MHz, CDCl3) δ
122.7 (dd, JC-F = 284.1, 279.1 Hz), 84.0, 35.5 (t, JC-F = 22.8
Hz), 24.8 (d, JC-F = 9.4 Hz), 11.2 (t, JC-F = 9.0 Hz). 19F{1H}
NMR (376 MHz, CDCl3) δ -83.1 (d, J = 186.8 Hz), -87.5
(d, J = 186.6 Hz). MS (EI) m/z = 218 ([M]+). Anal. calcd.
for C10H17BF2O2: C 55.08; H 7.86. Found : C 54.69; H 7.96.
Potassium (2,2-difluorocyclobutyl)trifluoroboranuide (6).
A solution of 5 (36.0 g, 0.165 mol) in MeOH (360 ml)
and a solution of KHF2 (64.3 g, 0.825 mol) in H2O (180 ml)
were mixed. The resulting solution was stirred at room
temperature for 16 h and then concentrated under reduced
pressure. The remaining solid was dried under high vacuum
(1 mmHg), suspended in acetone (300 ml), and heated to
gentle reflux. The heterogeneous mixture was filtered, and
the filter cake was washed with hot acetone (2×150 ml).
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
28
The combined filtrate and washings were concentrated
under reduced pressure. Yield: 29.5 g, 0.149 mol, 90 %.
Colourless powder, mp ˃ 230 °C. 1H NMR (500 MHz,
DMSO-d6) δ 2.41-2.25 (m, 1H), 2.24-2.10 (m, 1H), 1.58 (br
s, 1H), 1.47-1.36 (m, 2H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 34.6 (t, JC-F = 22.7 Hz), 12.2 (d, JC-F = 14.5
Hz). 19F{1H} NMR (376 MHz, DMSO-d6) δ -82.7-(-84.5)
(m), -142.4 (dd, J = 108.1, 51.1 Hz). MS (APCI) m/z = 159
([M]-). Anal. calcd. for C4H5BF5K: C, 24.27; H, 2.55.
Found: C, 24.09; H, 2.79.
2,2-Difluorocyclobutane-1-sulfonyl chloride (7).
To a solution of 9 (80.0 g, 0.367 mol) in 1-methyl-2-
pyrrolidinone (800 ml) a pre-dried potassium thioacetate
(84.5 g, 0.740 mol) was added in one portion. The resulting
mixture was heated at 100 °C with stirring for 48 h, then
diluted with H2O (1.5 L) and extracted with 1.5 L of
t-BuOMe (3×800 ml). The organic layer was separated,
washed with water (3×1.5 L), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residual
crude product was purified by vacuum distillation
(1 mmHg) to give 10, that was used in the next step as
obtained.
Yield 22.1 g, 0.133 mol, 36 %. Yellow oil; bp = 32-
34 °C/1 mmHg. NOTE: It is important to avoid any traces
of water during the reaction, as its presence leads to
significant formation of thiol by-products.
A solution of intermediate product 10 (22.0 g,
0.133 mol) in DCM (200 ml) was mixed with H2O (200 ml)
and cooled to 0 °C, using a crushed ice/water bath. A
stream of chlorine gas was passed through the reaction
mixture, maintaining the temperature below 10 °C. Chlorine
addition was discontinued when the temperature remains
constant for 3 min and the solution turned a yellowish-green
color. The mixture was stirred for an additional 15 min and
then poured into ice-cold water (200 mL). The organic
phase was separated, washed with ice-cold water (200 mL),
dried over anhydrous Na₂SO₄, and concentrated under
reduced pressure. The crude product was purified by
column chromatography. Yield: 11.5 g, 60.7 mmol, 46 %.
Colourless oil; CC (hexane/EtOAc 5:1, v/v) Rf 0.30; 1H
NMR (500 MHz, CDCl3) δ 4.74 (p, J = 8.8 Hz, 1H), 2.96-
2.81 (m, 1H), 2.78-2.62 (m, 1H), 2.64-2.53 (m, 1H), 2.53-
2.44 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 117.1
(dd, JC-F = 289.3, 288.9 Hz), 74.6 (dd, JC-F = 28.2, 21.2 Hz),
33.3 (t, JC-F = 22.1 Hz), 16.1 (dd, JC-F = 8.5, 4.4 Hz).
19F{1H} NMR (376 MHz, CDCl3) δ -83.9 (d, J = 203.5 Hz),
-101.4 (d, J = 203.4 Hz). MS (EI) m/z = 91 ([M-SO2Cl]-).
Anal. calcd. for C4H5ClF2O2S: C, 25.21; H, 2.64; S, 16.82;
Cl, 18.60. Found: C, 25.41; H, 2.63; S, 16.49; Cl, 18.23.
2-Iodocyclobutan-1-one (8).
To a solution of 3 (250.0 g, 1.69 mol) in acetone (4 L)
solid NaI (1.02 kg, 6.80 mol) was added in a single run. The
resulting mixture was stirred at reflux for 16 h. Upon
cooling to room temperature, the suspension was filtered,
and the filtrate was concentrated under reduced pressure.
The residual viscous oil was extracted with t-BuOMe (2 L).
The inhomogeneous mixture was filtered, and the filtrate
was concentrated under reduced pressure and dried under
high vacuum (1 mmHg) to give the title product. Yield:
304.9 g, 1.56 mol, 92%. Brown oil; 1H NMR (500 MHz,
CDCl3) δ 5.31-5.23 (m, 1H), 3.35-3.24 (m, 1H), 3.15-3.04
(m, 1H), 2.80-2.69 (m, 1H), 2.33-2.22 (m, 1H). Compound
demonstrated limited stability and was used immediately
without full characterization.
1,1-Difluoro-2-iodocyclobutane (9).
To a pre-cooled solution of 8 (304.9 g, 1.56 mol) in
DCM (3 L) at 0 °C, neat DAST (806.0 g, 5.00 mol) was
added in a dropwise manner, maintaining the reaction
temperature below 5 °C. The resulting mixture was stirred
at room temperature for 36 h and then poured into ice-cold
water (3 L). The organic layer was separated and
sequentially washed with 0.4 M aq Na2SO3 (2 L), sat. aq
NaHCO3 (2 L), then dried over anhydrous Na2SO4, and
concentrated by distillation under atmospheric pressure.
The residual crude product was purified by vacuum
distillation (30 mmHg). Yield: 100.9 g, 0.463 mol, 30 %.
Pale-pink liquid; bp = 40 °C/30 mmHg. 1H NMR
(500 MHz, CDCl3) δ 4.67-4.55 (m, 1H), 4.61 (dq, J = 13.3,
9.4 Hz, 1H), 2.75-2.57 (m, 2H), 2.53-2.41 (m, 1H), 2.07 (p,
J = 9.5 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 118.1
(dd, JC-F = 289.7, 276.4 Hz), 34.1 (dd, JC-F = 24.6, 20.8 Hz),
23.2 (d, JC-F = 14.3 Hz), 17.6 (t, JC-F = 24.5 Hz).
19F{1H} NMR (376 MHz, CDCl3) δ -84.7 (d, J = 185.8 Hz),
-96.6 (d, J = 186.0 Hz). MS (EI) m/z = 218 ([M]+). Anal.
calcd. for C4H5F2I: C, 22.04; H, 2.31. Found : C, 21.72; H,
2.45.
tert-Butyl N-[(2-oxocyclobutyl)methyl]carbamate (11).
The compound was prepared according to the published
procedure [25]. Yield: 200.0 g, 30% overall. Colourless
powder; mp = 78-79 °C; 1H NMR (400 MHz, CDCl3) δ
4.84 (br s, 1H), 3.52-3.36 (m, 2H), 3.27 (dt, J = 13.4, 6.3
Hz, 1H), 3.13-2.99 (m, 1H), 2.98-2.84 (m, 1H), 2.23-2.09
(m, 1H), 1.84-1.70 (m, 1H), 1.41 (s, 9H). 13C{1H} NMR
(151 MHz, CDCl3) δ 210.4, 156.1, 79.6, 77.4, 77.2, 77.0,
60.3, 45.3, 39.6, 28.5, 14.5. HRMS (ESI/QTOF) m/z Сalcd.
for C10H17NO3Na (M+Na)+ 222.1101. Found 222.1098.
1-(2,2-Difluorocyclobutyl)methanamine hydrochloride (13).
To a pre-cold to 0-5 °C solution of ketone 11 (200.0 g,
1.00 mol) in anhydrous DCM (2 L) neat morpholinosulfur
trifluoride (MorphDAST, 404.4 g, 2.31 mol) was added.
The reaction mixture was stirred at room temperature for 2
days (the conversion was monitored by 1H NMR spectrum
of small aliquots of the reaction mixture) and quenched by
careful transfer to the beaker with crushed ice (2 kg). The
layers were separated, and the aqueous phase was re-
extracted with EtOAc (2×1.5 L). The combined organic
layers were washed with 1.1 M aq Na2CO3 (3 L), dried over
O.S. Olifir, O.S. Liashuk
29
anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column
chromatography (hexanes/EtOAc 6:1 to 3:1, v/v) to give
difluorocyclobutane 12 as white solid; mp 77-78 °C. Yield
115.5 g, 0.522 mol, 52%.
Compound 12 (95.0 g, 0.430 mol) was dissolved in
anhydrous HCl (2 M in MeOH, 1 L) and stirred at room
temperature for 15 min. The reaction mixture was
concentrated under reduced pressure, and the residual crude
product was purified by crystallization from CH3CN. Yield:
61.0 g, 0.387 mol, 90%. White solid, mp 211-213 °C
(CH3CN); 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 2H),
3.12 (dt, J = 9.9, 8.5 Hz, 1H), 3.07-3.00 (m, 1H), 2.94-2.86
(m, 1H), 2.00-1.88 (m, 1H), 1.62 (p, J = 8.7 Hz, 1H). 1H
NMR (400 MHz, DMSO-d6) δ 8.33 (s, 3H), 3.21-3.07 (m,
1H), 3.09-2.96 (m, 1H), 2.96-2.83 (m, 1H), 2.49-2.42 (m,
2H, overlapped with solvent residual peak), 2.01-1.86 (m,
1H), 1.62 (p, J = 8.7 Hz, 1H). 13C{1H} NMR (151 MHz,
DMSO-d6) δ 121.4 (dd, JC-F = 287.9, 277.5 Hz), 43.4 (dd,
JC-F = 22.7, 20.4 Hz), 36.7 (d, JC-F = 7.3 Hz), 31.9 (t, JC-
F = 21.7 Hz), 14.7 (dd, JC-F = 14.0, 4.2 Hz). 19F{1H} NMR
(376 MHz, DMSO-d6) δ -84.0 (d, J = 196.4 Hz), -115.2 (d,
J = 196.5 Hz). HRMS (ESI/QTOF) m/z Calcd. for
C5H10F2N+ (M+H)+ 122.0776. Found: 122.0777. All the
spectral data are consistent with those previously reported
[21].
[(2,2-Difluorocyclobutyl)methyl](methyl)amine hydrochlo-
ride (14).
In a three-necked reactor equipped with a mechanical
stirrer, an Ar inlet, and a reflux condenser, a suspension of
LiAlH4 (6.87 g, 0.181 mol) in THF (300 ml) was prepared
and heated to gentle reflux. To this suspension a solution of
gem-difluorocyclobutane 12 (20.0 g, 90.4 mmol) in THF
(100 ml) was then added at the same temperature with
mechanical stirring under an Ar atmosphere. The resulting
mixture was left with stirring at reflux overnight, then
cooled to 10 °C using ice-cold water bath and quenched by
sequential addition of H2O (7 mL), 10M aq solution of
NaOH (92.5 mmol), and H2O (21 ml) at 10 °C (NOTE:
careful addition with periodic cooling is recommended to
ensure that the internal temperature remains below 20 °C).
The mixture was stirred at room temperature for 1 h, the
fine suspension was filtered, and the filter cake was washed
with THF (3×100 ml). The combined filtrate and washings
were acidified with anhydrous HCl (ca. 2 M in diethyl
ether, 100 ml) while cooling to 10-20 °C and then
concentrated under reduced pressure and the residue was
treated with CH3CN/Et2O mixture (30 ml, 1:1 v/v). The
precipitate was filtered, washed with Et2O (2×20 ml) and
dried under reduced pressure (1 mmHg) to give amine 14.
Yield: 13.7 g, 79.8 mmol, 88%. Colourless powder,
mp = 153-155 °C; 1H NMR (500 MHz, D2O) δ 3.41-3.32
(m, 1H), 3.25-3.16 (m, 2H), 2.74 (d, J = 1.7 Hz, 3H), 2.68-
2.48 (m, 2H), 2.13-2.01 (m, 1H), 1.60 (q, J = 9.7 Hz, 1H).
13C{1H} NMR (151 MHz, D2O) δ 121.3 (dd, JC-F = 289.4,
274.8 Hz), 46.4 (d, JC-F = 7.1 Hz), 42.2 (dd, JC-F = 23.1,
20.8 Hz), 33.0, 31.8 (t, JC-F = 21.8 Hz), 14.1 (dd, JC-
F = 15.2, 3.0 Hz). 19F{1H} NMR (376 MHz, DMSO-d6) δ
-82.2 (d, J = 190.9 Hz), -109.1 (d, J = 190.9 Hz). MS
(APCI) m/z = 136 ([M-HCl+H]+). Anal. calcd. for
C6H12ClF2N: C, 41.99; H, 7.05; N, 8.16; Cl,, 20.66. Found:
C, 41.95; H, 6.92; N, 8.26; Cl, 20.99.
2,2-Difluorocyclobutan-1-ol (15).
To a pre-cooled to 0 °C solution of DAST (630.0 g,
3.91 mol) in DCM (3 L) neat BF3⸱Et2O (556.0 g, 3.92 mol)
was added, maintaining the temperature below 10 °C. After
further stirring at 0 °C for 15 min, neat NEt3⸱3HF (378.5 g,
2.35 mol) and then acetate 17 (200.2 g, 1.56 mol) were
sequentially added to the in situ formed solution of
XtalFluor-E. The reaction mixture was stirred at room
temperature for 24 h and then poured into a crushed
ice/water mixture (ca. 3 L). The organic layer was
separated, washed with sat. aq NaHCO3 (1.5 L), dried over
anhydrous Na2SO4, and concentrated by distillation under
atmospheric pressure. The residual crude oil contained two
fluorinated compounds in ca. 1:1 ratio as determined by the
analysis of 1H and 19F NMR spectra (target gem-
difluorinated cyclobutyl acetate 18, along with a side
product, probably arised from a cationic rearrangement).
The crude mixture was dissolved in Et2O (2 L), cooled to
0 °C using ice/water bath, and a stream of NH3 gas was
passed through the solution for 1 h, maintaining the
temperature below 10 °C. The obtained solution was stirred
at room temperature for 24 h. Upon completion of the
reaction (concluded by 1H NMR of the small aliquots of the
reaction mixture) it was concentrated under reduced
pressure. The residue was distilled in vacuo (27 mmHg,
52 °C), the main fraction contains 2,2-difluorocyclobutyl
acetate 18 as colorless liquid that was used in the next step
as obtained. Yield: 42.2 g, 0.281 mol, 18%.
To a solution of 18 (42.0 g, 0.280 mol) in Et2O (400 ml),
hydrazine hydrate (21.0 g, 0.420 mol) was added, and the
resulting mixture was stirred at room temperature for 24 h.
Anhydrous HCl (150 ml, 2 M solution in Et2O) and then
anhydrous MgSO4 (100.0 g) were added to the mixture, the
resulting suspension was stirred at room temperature for
20 min, and then filtered. The filtrate was dried over fresh
portion of anhydrous MgSO4 and concentrated by distilla-
tion under atmospheric pressure. The crude product was
purified by vacuum distillation (20 mmHg). Yield: 26.0 g,
0.241 mol, 86%. Colorless liquid that solidifies on storage;
bp = 46-48 °C/20 mmHg; 1H NMR (500 MHz, CDCl3) δ
4.39 (p, J = 8.4 Hz, 1H), 2.43-2.30 (m, 1H), 2.28-2.17 (m,
1H), 2.11 (td, J = 21.9, 9.1 Hz, 1H), 1.63 (p, J = 9.3 Hz,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 121.8 (dd,
J = 296.5, 271.8 Hz), 72.5 (dd, J = 25.3, 20.2 Hz), 28.0 (t,
J = 21.7 Hz), 22.8 (d, J = 20.3 Hz). 19F{1H} NMR
(376 MHz, CDCl3) δ -90.8 (dd, J = 196.1, 2.1 Hz), -125.6
(d, J = 196.1 Hz). MS (EI) m/z = 88/106 ([M-H]-). Anal.
calcd. for C4H6F2O: C 44.45; H 5.60. Found : C 44.81; H
5.58.
2-Oxocyclobutyl acetate (17).
The compound was prepared according to the published
procedure [26]. Yield: 257 g, 2.01 mol, 77% (from 600.0 g,
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
30
2.60 mol of 16. Colorless oil; bp = 39-40 °C/1 mmHg; 1H
NMR (500 MHz, CDCl3) δ 5.63 (t, J = 8.6 Hz, 1H), 2.92 (t,
J = 9.1 Hz, 2H), 2.54-2.43 (m, 1H), 2.15-2.05 (m, 1H), 2.10
(s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 202.8, 169.5,
80.5, 40.5, 20.5, 19.7. MS (EI) m/z = 85 ([M-C2H3O]-).
Anal. calcd. for C6H8O3: C 56.25; H 6.29. Found : C 56.64;
H 6.23.
2,2-Difluorocyclobutane-1-carbaldehyde (20).
An alcohol 19 (35.0 g, 0.287 mol, prepared as descry-
bed previously [21]), 2,2,6,6-tetramethylpiperidine-N-oxyl
(2.33 g, 14.9 mmol) and NaOAc (33.0 g, 0.402 mol) were
mixed in Et2O (350 ml), and the obtained mixture was
cooled to 0-5 °C using ice/water bath. Trichloroisocyanuric
acid (23.3 g, 0.100 mol) was subsequently added in small
portions. The reaction mixture was kept with intensive
stirring at 5 °C for 1 h and then solid K2CO3 (150.0 g,
1.09 mol) was added. After further stirring at 10 °C for 1 h,
the heterogeneous mixture was filtered and the filter cake
was washed with Et2O (2×100 ml). The filtrate was
evaporated to ca. 70 ml under reduced pressure (75 mmHg)
at 25 °C, and the residual liquid was purified by vacuum
distillation (75 mmHg). Yield: 13.2 g, 0.110 mol, 38%.
Yellow liquid, bp = 50 °C/75 mmHg; 1H NMR (400 MHz,
CDCl3) δ 9.82 (s, 1H), 3.79-3.62 (m, 1H), 2.69-2.40 (m,
2H), 2.34-2.18 (m, 1H), 2.00-1.85 (m, 1H). 13C{1H} NMR
(126 MHz, CDCl3) δ 196.4 (br), 120.4 (dd, JC-F = 289.9,
279.9 Hz), 57.1 (t, JC-F = 21.4 Hz), 33.7 (t, JC-F = 22.0 Hz),
10.7 (dd, JC-F = 10.8, 5.3 Hz). 19F{1H} NMR (376 MHz,
CDCl3) δ -83.5 (d, J = 196.5 Hz), -101.0 (d, J = 196.4 Hz).
Anal. calcd. for C5H6F2O: C, 50.00; H, 5.04. Found: C,
50.37; H, 5.04.
2,2-Difluoro-N-methylcyclobutan-1-amine hydrochloride
(22).
In a three-necked reactor equipped with a mechanical
stirrer, an Ar inlet, and a reflux condenser a suspension of
LiAlH4 (27.5 g, 0.725 mol) in THF (1 L) was prepared and
heated to gentle reflux. To this suspension the solution of
compound 21 (50.0 g, 0.241 mol) in THF (300 ml) was
added in a dropwise manner at the same temperature. The
resulting mixture was left with stirring at the same
temperature overnight, then cooled to 10 °C and quenched
by sequential addition of H2O (28 ml), 10 M aq NaOH
(0.35 mol) and again H2O (84 ml) at 10 °C (NOTE: careful
addition with periodic cooling is recommended to ensure
that the internal temperature remains below 20 °C). The
obtained mixture was stirred at room temperature for 1 h,
filtered, and the filter cake was washed with THF
(3×200 ml). The combined filtrate and washings were
acidified with anhydrous HCl (ca. 2 M in Et2O, 200 ml) to
pH = 2-3 with occasional cooling in a water bath (NOTE:
the temperature range should be kept between 10-20 °C).
The resulting solution was concentrated under reduced
pressure and the residue was treated with CH3CN/Et2O
mixture (60 ml, 1:1 v/v). The precipitate was filtered and
washed with Et2O (3×30 ml) to give the title compound.
Yield: 25.6 g, 0.162 mol, 67%. Colourless crystals,
mp = 137-140 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.94
(br s, 2H), 4.28-4.16 (m, 1H), 2.60-2.48 (m, 4H), 2.20-2.08
(m, 1H), 1.89 (p, J = 9.7 Hz, 1H). 13C{1H} NMR
(126 MHz, D2O) δ 119.2 (dd, JC-F = 294.0, 271.6 Hz), 59.2
(dd, JC-F = 26.9, 19.0 Hz), 31.1, 29.7 (t, JC-F = 21.2 Hz),
15.4 (d, JC-F = 15.2 Hz). 19F{1H} NMR (376 MHz, DMSO-
d6) δ -84.0 (d, J = 196.4 Hz), -115.2 (d, J = 196.5 Hz). MS
(APCI) m/z = 122.2 ([M-HCl+H]+). Anal. calcd. for
C5H10ClF2N: C, 38.11; H, 6.40; N, 8.89; Cl, 22.50. Found:
C, 38.24; H, 6.33; N, 8.97; Cl, 22.90.
Cyclopent-3-en-1-one (24).
To a stirred solution of 3-cyclopenten-1-ol 25 (84.0 g,
1.00 mol) in t-BuOMe (4 L), Dess-Martin periodinane
(550.6 g, 1.30 mol) was added in equal portions with
occasional cooling in a water bath. The resulting mixture
was stirred at room temperature for 2 h, the precipitated
solid was filtered, and the filtrate was quenched by gradual
addition of Na2CO3 (413.0 g, 3.90 mol). The inhomogene-
ous mixture was filtered, and the filtrate was concentrated
under reduced pressure to give the title compound. Yield:
68.0 g, 0.828 mol, 83%. Colourless volatile liquid; 1H NMR
(500 MHz, CDCl3) δ 6.08 (s, 2H), 2.87 (s, 4H). 13C{1H}
NMR (126 MHz, CDCl3) δ 217.2, 128.8, 42.7. MS (EI)
m/z = 82.1 ([M]+). The spectral data are consistent with
those previously reported [27].
(4,4-Difluorocyclopent-1-ene) (23).
To a pre-cooled to 0 °C solution of compound 24 (68.0 g,
0.828 mol) in DCM (1.5 L) neat MorphDAST (363.7 g,
2.07 mol) was added in a dropwise manner while stirring
and the resulting mixture was left with stirring at room
temperature for 36 h. The obtained solution was quenched
with 1 M aq. solution of Na2CO3 to pH = 8-10, the layers
were separated, and the aqueous phase was re-extracted
with DCM (500 ml). The combined organic phases were
washed with H2O (2×300 ml) and brine (300 ml), dried
over Na2SO4, and collected by filtration to give the title
compound as a ca. 3.5 % w/w solution in DCM. The
product was used in the next step as obtained without
characterization.
(1R*,2S*)-4,4-Difluorocyclopentane-1,2-diol (cis-26).
To a pre-cooled to 0 °C in ice/water bath mixture of
compound 23 (1.13 kg, 3.5 %, w/w solution in DCM,
0.380 mol) and H2O (50 ml), OsO4 (3.22 g, 12.7 mmol) neat
N-methylmorpholine N-oxide (201.5 g, 1.72 mol) were
sequentially added keeping the internal temperature below
5 °C. The cooling bath was removed, and the reaction
mixture was lefy with stirring for 16 h. After completion of
the reaction (concluded by 1H NMR spectra of the small
aliquots of the reaction mixture) the mixture was quenched
with H2O (0.5 L), the layers were separated, the organic
phase was washed with H2O (2×200 ml) and sat aq Na2S2O3
(100 ml), then dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography to give the title compound. Yield: 11.2 g,
81.1 mmol, 21%. Brown crystals, mp = 50-53 °C; FCC
(hexanes/EtOAc/i-PrOH 10:1:0.13) Rf 0.18; 1H NMR
O.S. Olifir, O.S. Liashuk
31
(400 MHz, DMSO-d6) δ 4.87 (d, J = 4.2 Hz, 2H), 3.97 (q,
J = 4.5 Hz, 2H), 2.31-2.03 (m, 4H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 130.3 (dd, J = 251.4, 245.0 Hz),
70.7, 41.9 (t, J = 23.6 Hz). 19F{1H} NMR (376 MHz,
CDCl3) δ -84.4 (d, J = 233.6 Hz), -86.1 (d, J = 233.6 Hz).
MS (EI) m/z = 138.1 ([M]+). Anal. calcd. for C5H8F2O2: C,
43.48; H, 5.84. Found: C, 43.78; H, 6.19.
(1R*,2R*)-4,4-Difluorocyclopentane-1,2-diol (trans-26).
Compound 27 (15.0 g, 0.125 mol) was dissolved in
DCM (90 ml), then H2O (30 ml) and TFA (15 ml) were
sequentially added. The reaction mixture was stirred at
room temperature for 16 h. The solvents were evaporated
under reduced pressure to give the title product. Yield:
16.5 g, 0.119 mol, 96%. Yellow oil; 1H NMR (500 MHz,
D2O) δ 4.19-4.13 (m, 2H), 2.62 (qd, J = 15.3, 6.2 Hz, 2H),
2.21-2.07 (m, 2H); 13C{1H} NMR (101 MHz, D2O) δ
127.6 (t, J = 248.2 Hz), 72.8 (t, J = 4.6 Hz), 39.3 (t,
J = 24.2 Hz); 19F{1H} NMR (376 MHz, D2O) δ -87.0. MS
(EI) m/z = 99 ([M-F2+H]+). Anal. calcd. for C5H8F2O2: C
43.48; H 5.84. Found: C 43.20; H 6.21.
(1R*,5S*)-3,3-Difluoro-6-oxabicyclo[3.1.0]hexane (27).
A solution of compound 23 (1.86 kg, 3.5 %, w/w
solution in DCM, 0.624 mol) was cooled to 0 °C using an
ice-cold water bath. Then solid mCPBA (150.8 g,
0.874 mol) was added and the resulting mixture was stirred
at room temperature for 16 h. After completion of the
reaction (concluded by 1H NMR spectra of the small
aliquots of the reaction mixture), the mixture was
quenched with 0.9 M aq Na2CO3 (1.1 L) and extracted
with DCM (2×500 ml). The combined organic layers were
washed with H2O (2×200 ml) and sat aq Na2S2O3 (100 ml).
The organic layer was separated, dried over Na2SO4, and
concentrated under reduced pressure to give the title
compound. Yield: 60.0 g, 0.500 mol, 42%, ca. 70% purity.
Colourless oil. 1H NMR (500 MHz, CDCl3) δ 3.59 (t,
J = 4.2 Hz, 2H), 2.52 (t, J = 16.0 Hz, 2H), 2.33 (q, J = 16.1
Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 129.5 (dd,
J = 251.9, 249.8 Hz), 54.5 (d, J = 10.3 Hz), 39.0 (t,
J = 25.1 Hz), the signals corresponding to residual
mCPBA were excluded at δ 130.9 (d, J = 216.1 Hz) and
127.7 (d, J = 218.4 Hz); 19F{1H} NMR (470 MHz, CDCl3)
δ -77.2 (dp, J = 235.4, 17.3 Hz), -87.9 (dt, J = 235.8, 15.9
Hz).
(1R*,5S*,6S*)-3,3-Difluorobicyclo[3.1.0]hexane-6-carbo-
xylic acid (29).
To a solution of compound 23 (1.43 kg, 3.5 %. w/w
solution in DCM, 0.481 mol) rhodium(II) acetate dimer
(4.25 g, 9.61 mmol) was added. Ethyl diazoacetate (82.2 g,
0.720 mol) was subsequently added in a dropwise manner
under an argon atmosphere at room temperature over 2 h
and the resulting mixture was stirred at the same
temperature overnight. The mixture was concentrated
under reduced pressure, and the residue was purified by
flash column chromatography (hexanes/EtOAc 10:1;
Rf 0.24) to give intermediate carboxylate 28 as orange oil
that was used in the next step as obtained. Yield: 21.1 g,
0.111 mol, 23%.
To the solution of compound 28 (21.1 g, 0.111 mol) in
MeOH/H2O mixture (210 ml, 1:6 v/v) solid NaOH (13.3 g,
0.333 mol) was added in one portion. The reaction mixture
was stirred at room temperature for 16 h, and then diluted
with t-BuOMe (50 ml). The layers were separated, and the
aqueous phase was acidified with NaHSO4 to pH = 2-3 and
then re-extracted with EtOAc (2×110 mL). The combined
organic layers were separated, dried over Na2SO4, and
concentrated under reduced pressure to give the title
compound. Yield: 16.6 g, 0.102 mol, 93 %. Yellowish
powder; mp = 101-104 °C; 1H NMR (500 MHz, CDCl3) δ
2.55-2.37 (m, 2H), 2.30 (dd, J = 19.1, 15.0 Hz, 2H), 2.08-
1.99 (m, 2H), 1.69-1.63 (m, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 178.8, 131.00 (dd, J = 253.9, 245.3 Hz), 38.1 (t,
J = 25.9 Hz), 25.1 (d, J = 10.5 Hz), 24.6 (d, J = 3.6 Hz).
19F{1H} NMR (376 MHz, CDCl3) δ -79.0 (d, J = 240.0 Hz),
-92.3 (d, J = 240.0 Hz). MS (APCI) m/z = 163.2 ([M+H]+).
Anal. calcd. for C7H8F2O2: C, 51.86; H, 4.97. Found: C,
52.07; H, 4.687.
(1R*,2R*)-2-Azido-4,4-difluorocyclopentan-1-ol (trans-30).
To a stirred solution of compound 27 (49.0 g, 0.408 mol)
in EtOH/H2O mixture (625 ml, 4:1 v/v) solid NaN3 (40.0 g,
0.615 mol) and then NH4Cl (65.5 g, 1.22 mol) were added,
and the resulting mixture was stirred at reflux overnight.
Upon cooling to room temperature, the mixture was
concentrated under reduced pressure and the residue was
extracted with EtOAc (3×350 ml). The combined organic
layers were dried over Na2SO4 and concentrated under
reduced pressure. The oily residue was purified by flash
column chromatography to yield the title compound. Yield:
35.0 g, 0.215 mol, 53%. Yellow liquid. Rf 0.32,
hexanes/tBuOMe/MeOH 10:1:0.1. 1H NMR (500 MHz,
CDCl3) δ 4.21 (q, J = 6.6 Hz, 1H), 3.90 (q, J = 7.1 Hz, 1H),
2.71-2.52 (m, 2H), 2.24-2.06 (m, 2H); 13C{1H} NMR
(126 MHz, CDCl3) δ 127.7 (t, J = 250.1 Hz), 74.7 (t, J = 4.5
Hz), 65.6 (t, J = 4.1 Hz), 42.9 (t, J = 24.6 Hz), 39.9 (t,
J = 25.9 Hz); 19F{1H} NMR (376 MHz, CDCl3) δ -85.0 (d,
J = 233.8 Hz), -86.1 (d, J = 233.9 Hz). MS (EI) m/z = 135
([M-N2]-). Anal. calcd. for C5H7F2N3O: C, 36.81; H, 4.33;
N, 25.76. Found: C, 36.92; H, 4.63; N, 25.63.
(1R*,2S*)-4,4-Difluorocyclopentane-1,2-diamine dihyd-
rochloride (cis-32).
To a pre-cooled to 0 °C solution of compound 30
(30.0 g, 0.184 mol) and Et3N (38.5 ml, 27.9 g, 0.276 mol) in
THF (400 ml) neat MsCl (27.4 g, 0.239 mol) was added in a
dropwise manner. The resulting mixture was stirred at 0 °C
for 30 min, then quenched with H2O (200 ml) and extracted
with EtOAc (2×400 ml). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure
to give intermediate mesylate derivative, which was used
immediately in the next step.
The residue was dissolved in DMF (300 ml), neat NaN3
(35.9 g, 0.552 mol) was added, and the reaction mixture
was stirred at 50 °C overnight. Upon cooling to room
ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
32
temperature, the mixture was diluted with H2O (300 ml) and
extracted with Et2O (2×600 ml). The combined organic
layers were separated, washed with H2O (3×300 ml) and
brine (3×300 ml), dried over Na2SO4, and concentrated to
ca. half of the initial volume under reduced pressure.
Crude compound 31 from previous step (0.184 mol,
solution in Et2O) was added dropwise to the suspension
LiAlH4 (14.0 g, 0.369 mol) in Et2O (600 ml) at 20 °C under
argon atmosphere and the resulting mixture was further
stirred at room temperature for 5 h. Upon completion, the
mixture was quenched by sequential addition of H2O
(14 ml), 10 M aq NaOH (0.188 mol) and again H2O
(42 ml), followed by stirring at room temperature for an
additional 1 h. The precipitate was filtered, the filtrate was
dried over MgSO4 and acidified with anhydrous HCl (2 M
in Et2O, 100 ml) to pH = 2-3. The resulting precipitate was
filtered, washed with Et2O (2×50 ml) and dried under
vacuum (0.75 mmHg) to give the title compound as
dihydrochloride salt. Yield: 22.3 g, 0.107 mol, 58%. Beige
powder; mp = 171-172 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.90 (s, 4H), 3.97 (p, J = 5.9 Hz, 2H), 2.79-2.59 (m, 4H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 128.1 (dd,
J = 250.9, 245.6 Hz), 48.9 (d, J = 6.4 Hz), 38.2 (t, J = 26.2
Hz); 19F{1H} NMR (376 MHz, DMSO-d6) δ -86.5 (dd,
J = 233.4, 12.3 Hz), -91.5 (dd, J = 232.9, 13.1 Hz). MS
(APCI) m/z = 137 ([M+H]+). HRMS (ESI/QTOF) m/z
Calcd. for C5H11F2N2
+[M + H]+ 137.0885. Found:
137.0885.
(1R*,2R*)-2-Amino-4,4-difluorocyclopentan-1-ol (trans-
33).
To a solution of compound trans-30 (25.0 g, 0.153 mol)
in methanolic NH3 (7 M, 700 ml) solid Pd/C (10 % w/w,
5.0 g) was added in one portion. The reaction vessel was
evacuated and refilled with H2 from a baloon (repeated 2
times), and the resulting suspension was intensively stirred
under continuous flow of H2 that was bubbled through the
solution at 25 °C for 2 h. Once the reduction was complete
(as determined by the ¹H NMR spectrum of a small aliquot
of the reaction mixture), the catalyst was filtered, and the
filter cake was washed with fresh portions of MeOH
(2×100 ml). The organic solutions were combined and
concentrated under reduced pressure to give the title
compound. Yield: 19.5 g, 0.142 mol, 93%. Brown crystals,
mp = 67-69 °C; 1H NMR (400 MHz, CDCl3) δ 3.91 (q,
J = 7.4 Hz, 1H), 3.24 (q, J = 7.7 Hz, 1H), 2.68-2.47 (m,
2H), 2.18-2.00 (m, 1H), 1.95-1.77 (m, 2H, overlapped with
NH2 peak); 13C{1H} NMR (151 MHz, CDCl3) δ 127.9 (t,
J = 249.7 Hz), 76.7, 57.8 (t, J = 3.8 Hz), 43.6 (t, J = 23.9
Hz), 43.2 (t, J = 24.2 Hz); 19F{1H} NMR (376 MHz,
CDCl3) δ -84.5 (d, J = 231.8 Hz), -85.3 (d, J = 231.7 Hz).
HRMS (ESI/QTOF) m/z Calcd. for C5H10F2NO+ [M+H]+
138.0725. Found: 138.0729.
tert-Butyl N-[(1S*,2R*)-2-amino-4,4-difluorocyclopentyl]-
carbamate (cis-36).
To the solution of compound trans-33 (10.0 g,
72.9 mmol) in DCM (100 ml) neat Boc2O (16.0 g,
73.3 mmol) was added in a dropwise manner. The reaction
mixture was stirred at room temperature for 16 h and then
concentrated under reduced pressure to yield the compound
trans-34 as a white solid, which was used in the next step
without spectral characterization. Yield: 17.0 g, 98%.
The solution of carbamate trans-34 (17.0 g, 71.7 mmol)
and Et3N (15.0 ml, 107.5 mmol, 10.9 g) in THF (200 ml)
was cooled to 0 °C using an ice-water bath, and then neat
methansulfonylchloride (7.2 ml, 93.2 mmol, 10.7 g) was
added in a dropwise manner at the same temperature and
the mixture was stirred for another 30 min at 0 °C. The
cooling bath was removed, the reaction mixture was
quenched with H2O (100 ml) and extracted with EtOAc
(300 ml). The organic layer was separated, dried over
Na2SO4, filtered and evaporated under reduced pressure.
The residue was dissolved in DMF (200 ml) and NaN3
(14.0 g, 0.215 mol) was added in one portion and the
reaction mixture was stirred at 50 °C overnight. Upon
cooling to room temperature the mixture was quenched with
H2O (200 ml) and extracted with Et2O (2×400 ml). The
organic layer was separated, dried over Na2SO4 and
concentrated under reduced pressure to give product trans-
35 as brown liquid, which was used in the next step without
further purification. Yield: 12.1 g, 46.0 mmol, 64% (70%
purity).
To the solution of trans-35 (12.0 g, 45.8 mmol, 70%
purity) in THF (150 ml) PPh3 (18.0 g, 68.7 mmol) was
added and the reaction mixture was stirred at room
temperature for 16 h. Then H2O (20 mL) was added, and the
resulting mixture was stirred at reflux for 5 h. Upon cooling
to room temperature, the mixture was quenched with 0.3 M
aq NaHSO4 (210 ml) and extracted with DCM (2×100 ml).
The layers were separated, the aqueous phase was basified
with solid Na2CO3 (9.70 g, 91.5 mmol) to pH = 9, and
extracted with DCM (2×200 ml). The combined organic
layers were dried over Na2SO4 and concentrated under
reduced pressure to give the title compound. Yield: 4.50 g,
19.0 mmol, 42 %. Beige powder, mp = 122-124 °C; 1H
NMR (500 MHz, CDCl3) δ 5.12 (s, 1H), 4.07 (s, 1H), 3.57
(q, J = 6.3 Hz, 1H), 2.53-2.42 (m, 1H), 2.42-2.31 (m, 1H),
2.27-2.13 (m, 1H), 2.08-1.96 (m, 1H), 1.45 (s, 9H), 1.23-
1.19 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 155.6,
129.8 (t, J = 248.6 Hz), 79.8, 52.4 and 51.7, 43.7 (t, J = 24.2
Hz) and 40.8 (t, J = 26.5 Hz), 28.4; 19F{1H} NMR
(376 MHz, CDCl3) δ -83.6 (d, J = 233.4 Hz), -87.2 (d,
J = 233.9 Hz). MS (APCI) m/z = 181.2 ([M-C4H9+H]+).
HRMS (ESI/QTOF) m/z Calcd. for C10H19F2N2O2
+ [M+H]+
237.1409. Found: 237.1409.
Notes
Acknowledgments and finances. O.S.L. received
additional funding from the Ministry of Education and
Science of Ukraine, grant No. 25BF037-01 (0125U002249).
The authors thank Dr. Anastasiia Hurieva for help with
manuscript preparation. We also thank Prof. Andriy A.
Tolmachov for his encouragement and support, and all the
people of Ukraine for making this manuscript possible.
O.S. Olifir, O.S. Liashuk
33
Data availability statement. The raw NMR data
is freely available in public repository (DOI:
https://doi.org/10.5281/zenodo.17822399).
The authors declare no conflict of interest. The
authors are / have been employees, trainees, or consulting
scientists of Enamine Ltd. that offers all the building blocks
described in this paper in the company’s catalog.
Supporting information
Copies of the NMR spectra of the compounds, prepared
in this work could be found in the Supporting Information.
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ISSN 1814-9758. Ukr. Bioorg. Acta, 2025, Vol. 20, N 2
34
Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних
блоків
O.С. Оліфір1, О.C. Ляшук2,3*
1 ТОВ НВП «Єнамін» (www.enamine.net), Київ, Україна
2 Київський національний університет імені Тараса Шевченка, Київ, Україна
3 Науково-дослідний інститут (НДІ) «Єнамін», Київ, Україна
Резюме: У цій статті представлено стислу та масштабовану стратегію отримання гем-дифлуорованих циклобутанів та циклопентанів з простих,
комерційно доступних прекурсорів. Оптимізація етапу деоксофлуорування дозволила отримати прямий доступ до ряду функціоналізованих
циклобутанів в масштабі до 77 г. Розроблений підхід демонструє широку толерантність до функціональних груп, що дозволяє отримувати аміно-,
гідрокси- та сульфонілзаміщені похідні, а також нові цис- та транс-дифлуороциклопентанові каркаси, включаючи діоли, діаміни та аналоги
карбонових кислот. Простота синтезу, масштабованість та структурна різноманітність отриманих будівельних блоків роблять цей підхід цінною
платформою для дослідження гем-дифлуорованих фрагментів у медичній хімії та хімії матеріалів.
Ключові слова: флуор; циклобутан; циклопентан; флуоровані будівельні блоки.
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| id | oai:ojs2.bioorganica.com.ua:article-105 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-06-30T01:00:26Z |
| publishDate | 2025 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/89/a0061dcde25e4063f1e2139bebf3c589.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-1052026-06-29T16:01:07Z Synthesis of gem-difluorinated cyclobutane and cyclopentane building blocks Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків Olifir, Oleksandr S. Liashuk, Oleksandr S. fluorine cyclobutane cyclopentane fluorinated building blocks флуор циклобутан циклопентан флуоровані будівельні блоки Herein, we describe a concise and scalable strategy for the preparation of gem-difluorinated cyclobutanes and cyclopentanes from simple, commercially available precursors under mild deoxyfluorination conditions. Optimization of the fluorination step enabled direct access to key intermediates, such as gem-difluorocyclobutyl bromides and boronates in two to three steps and on up to 77 g scale, avoiding the mercury-mediated or high-temperature processes typical of earlier methodologies. The developed protocol exhibits broad functional-group tolerance, allowing the preparation of amino-, hydroxy-, and sulfonyl-substituted derivatives, as (including deoxyfluorination of certainly functionalized cyclobutanones or by rearrangement of methylenecyclopropanes), remain hardly accessible due to lengthy synthetic procedures or limited scalability. Their higher homologues, gem-difluorinated cyclopentanes, are described significantly well as novel cis- and trans-difluorocyclopentane scaffolds including diols, diamines, and carboxylic acid analogues. The operational simplicity, scalability, and structural diversity of the resulting building blocks make this approach a valuable platform for the exploration of CF₂-containing fragments in medicinal and materials chemistry У цій статті представлено стислу та масштабовану стратегію отримання гем-дифлуорованих циклобутанів та циклопентанів з простих, комерційно доступних прекурсорів. Оптимізація етапу деоксофлуорування дозволила отримати прямий доступ до ряду функціоналізованих циклобутанів в масштабі до 77 г. Розроблений підхід демонструє широку толерантність до функціональних груп, що дозволяє отримувати аміно-, гідрокси- та сульфонілзаміщені похідні, а також нові цис- та транс-дифлуороциклопентанові каркаси, включаючи діоли, діаміни та аналоги карбонових кислот. Простота синтезу, масштабованість та структурна різноманітність отриманих будівельних блоків роблять цей підхід цінною платформою для дослідження гем-дифлуорованих фрагментів у медичній хімії та хімії матеріалів V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2025-12-31 Article Article application/pdf application/pdf https://bioorganica.com.ua/index.php/journal/article/view/105 10.15407/bioorganica2025.02.024 Ukrainica Bioorganica Acta; Vol. 20 No. 2 (2025): Ukrainica Bioorganica Acta; 24-34 Ukrainica Bioorganica Acta; Том 20 № 2 (2025): Ukrainica Bioorganica Acta; 24-34 1814-9766 1814-9758 10.15407/bioorganica2025.02 en https://bioorganica.com.ua/index.php/journal/article/view/105/102 https://bioorganica.com.ua/index.php/journal/article/view/105/103 Copyright (c) 2025 Oleksandr S. Olifir, Oleksandr S. Liashuk https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | флуор циклобутан циклопентан флуоровані будівельні блоки Olifir, Oleksandr S. Liashuk, Oleksandr S. Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title | Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title_alt | Synthesis of gem-difluorinated cyclobutane and cyclopentane building blocks |
| title_full | Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title_fullStr | Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title_full_unstemmed | Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title_short | Синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| title_sort | синтез гем-дифлуорованих циклобутанових та циклопентанових будівельних блоків |
| topic | флуор циклобутан циклопентан флуоровані будівельні блоки |
| topic_facet | fluorine cyclobutane cyclopentane fluorinated building blocks флуор циклобутан циклопентан флуоровані будівельні блоки |
| url | https://bioorganica.com.ua/index.php/journal/article/view/105 |
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