Fluoroalkyl-Containing 1,2-Disubstituted Cyclobutanes: Advanced Building Blocks for Medicinal Chemistry

Article abstract of DOI:10.1002/ejoc.202001345

Synthesis of previously unavailable 1,2-disubstituted cyclobutane building blocks bearing mono-, di- and trifluoromethyl groups are disclosed. The key steps included deoxofluorination or TMAF-mediated nucleophilic substitution in the appropriate bifunctional cyclobutanes; for the CF₃-substituted derivatives, alternative methods based on cyano- or azidotrifluoromethylation of cyclobutene using the Togni reagent II were also proposed. All methods provided trans diastereomers of the target primary amines and carboxylic acids (6 representatives) and were suitable for their multigram preparation. Furthermore, dissociation constants (pK_a) and lipophilicity (logP) values were measured to evaluate the effect of the fluoroalkyl substituents on acidity/basicity and lipophilicity of the building blocks obtained.

Full text of DOI:10.1002/ejoc.202001345

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Fluoroalkyl-containing 1,2-disubstituted cyclobutanes: advanced
building blocks for medicinal chemistry
Authors: Oleksandr P. Demchuk, Oleksandr V. Hryshchuk, Bohdan V.
Vashchenko, Serhii A. Trofymchuk, Kostiantyn P. Melnykov,
Artem Skreminskiy, Dmitriy M. Volochnyuk, and Oleksandr O
Grygorenko
This manuscript has been accepted after peer review and appears as an
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to ensure accuracy of information. The authors are responsible for the
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001345
Link to VoR: https://doi.org/10.1002/ejoc.202001345
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
Fluoroalkyl-containing 1,2-disubstituted cyclobutanes: advanced
building blocks for medicinal chemistry
[
a,b]
[a,c]
[a,c]
Oleksandr P. Demchuk,
Oleksandr V. Hryshchuk, Bohdan V. Vashchenko,
[
a]
[a,c]
[a]
Serhii A. Trofymchuk, Dr. Kostiantyn P. Melnykov, Artem Skreminskiy,
[a,b,c]
[a,c]
Prof. Dr. Dmitriy M. Volochnyuk,
Dr. Oleksandr O. Grygorenko*
[
a]
O. P. Demchuk, O. V. Hryshchuk, B. V. Vashchenko, S. A. Trofymchuk, Dr. K. P. Melnykov, A. Skreminskiy, Prof. Dr. D. M. Volochnyuk
Dr. O. O. Grygorenko
Enamine Ltd. (www.enamine.net),
Chervonotkatska Street 78, Kyiv 02094, Ukraine
[
b]
c]
O. P. Demchuk, Prof. Dr. D. M. Volochnyuk,
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
B. V. Vashchenko, Dr. K. P. Melnykov, Prof. Dr. D. M. Volochnyuk, Dr. O. O. Grygorenko
Taras Shevchenko National University of Kyiv
[
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua (O. O. G)
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Synthesis of previously unavailable 1,2-disubstituted
cyclobutane building blocks bearing mono-, di- and trifluoromethyl
groups are disclosed. The key steps included deoxofluorination or
TMAF-mediated nucleophilic substitution in the appropriate
2
of the CHF substituent in the cyclobutane moiety of compound
5 was found to be advantageous as compared to the non-
fluorinated analogues in a series of compounds active against
hepatitis C virus.[29]
3
bifunctional cyclobutanes; for the CF -substituted derivatives,
alternative methods based on cyano- or azidotrifluoromethylation of
cyclobutene using the Togni reagent II were also proposed. All
methods provided trans diastereomers of the target primary amines
and carboxylic acids (6 representatives) and were suitable for their
a
multigram preparation. Furthermore, dissociation constants (pK )
and lipophilicity (logP) values were measured to evaluate the effect
of the fluoroalkyl substituents on acidity/basicity and lipophilicity of
the building blocks obtained.
Introduction
Fluorinated conformationally restricted motifs are widely
recognized as promising chemotypes for modern drug
discovery.[1–3] Introducing the fluorinated substituents into
saturated ring systems has a complex impact on the physico-
chemical properties, which is important to ADMET parameters of
the corresponding derivatives including, for example, hERG
inhibition or P-glycoprotein efflux.[4–6] A number of recent papers
discussed the effect of mono-, di- and poly-fluorinated alkyl
groups on total molecular polarity regarding the relative spatial
arrangement of the fluorine atoms.[7–13]
Figure 1. Some useful fluoroalkyl-substituted cyclobutanes
All the compounds shown in Figure 1 demonstrate the 1,3-
substitution pattern of the fluorinated cyclobutane fragment; this
is partially related to their more or less satisfactory synthetic
accessibility. The known approaches to install the fluoroalkyl
group onto the cyclobutane ring relied on deoxofluorination
or decarboxylative trifluoromethylation[34] of carboxylic acids, the
[30–33]
addition of the Ruppert–Prakash reagent or its CHF
analogue to C=O and C=N bonds,[35,36] fluoride-mediated
2
-substituted
Among the known fluorinated ring systems, cyclobutane
derivatives are of special interest for modern synthetic and
medicinal chemistry, partially due to the unique conformational
[37]
3
[38]
nucleophilic substitution,
metal-catalyzed C(sp )–Br
and
3
[39]
3
C(sp )–H
trifluoromethylation, direct side-chain C(sp )−H
fluorination, rearrangement of fluoroalkyl-substituted cyclopro-
panes,[41–43] difluoromethylation of cyclobutene with CHF
properties of the cyclobutane ring.[14–20] In turn, several CF
CHF and CH F-containing cyclobutanes have found their
-,
[40]
3
-
2
I,[44]
2
2
application to date, including diagnostic agents for PET imaging,
i.e. Fluciclovine (FACBC)[21] or its homolog FMACBC (1),[22,23]
conformationally constrained fluorinated analogs of γ-aminobuty-
ric acid (GABA) (2[22]) or serine/threonine (3[24,25]), the tools for
solid-state 19F NMR peptide studies, as well as reagents for the
and other methods. Meanwhile, the corresponding 1,2-
disubstituted fluorinated counterparts have been largely
underrepresented in the literature to date.[39,41,44] Taking into
account this fact, in this work, we have aimed at the preparation
of simplest 1,2-disubstituted cyclobutane-derived building blocks
synthesis of peptidomimetics (Figure 1). CF
3
-substitued
6–11 bearing mono-, di- and trifluoromethyl groups (Figure 2).
cyclobutane derivatives were also studied as potent rat
Moreover, an effect of the fluoroalkyl substituents on the
physico-chemical properties (i.e. acidity/basicity and lipophilicity)
of the corresponding derivatives was also studied.
[26]
cannabinoid-1 receptor inhibitors, as well as fungicides (e.g. 4,
a potent inhibitor of scytalone dehydratase).[27,28] The presence
1
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
Figure 2. The target compounds of this work
Scheme 2. Synthesis of CF
3
-substituted building blocks 6 and 9 (relative
configurations are shown)
Results and Discussion
It was envisaged that target molecules 6–11 could be obtained
from trans-cyclobutane-1,2-dicarboxylate 12, with deoxofluorina-
tion or fluoride-mediated nucleophilic substitution as the key
Since chemoselective reduction of monoester 13 appeared to be
unfruitful, it was transformed into tert-butyl counterpart 15 by the
DMAP-mediated reaction with Boc
selective alkaline hydrolysis of orthogonally protected derivative
16 with NaOH in THF – H (97% yield) (Scheme 3).
2
O (98% yield), followed by
3 2 2
steps for the CF -/CHF - and CH F-substituted derivatives,
respectively (Scheme 1). Intermediate 12 was prepared in eight
steps (albeit many of them were performed in a one-pot manner)
according to the literature protocols starting from adipic
acid.[45,46]
2
O
2-(Hydroxymethyl)cyclobutanecarboxylate 17 thus obtained was
oxidized into the corresponding aldehyde 18 using the Swern
reagent. Although the product 18 could be isolated and fully
characterized, it was advantageous to use derivative 18 directly
in the key deoxofluorination step without additional isolation and
purification due to its instability upon storage. The reaction with
morph-DAST proceeded smoothly in CH
2 2
Cl and resulted in the
formation of CHF -substituted cyclobutanecarboxylate 19 in 71%
2
yield (over two steps). The subsequent acid-mediated tert-butyl
group cleavage provided the target carboxylic acid 7 in 88%
yield. The modified Curtius rearrangement in the presence of
Et
was involved in mild protecting group cleavage (4 M HCl – 1,4-
dioxane in Et O) giving CHF -substituted cyclobutanamine
hydrochloride 10 (78% yield).
Next, hydroxyester 17 was used for the preparation of CH
3
N in t-BuOH gave N-Boc-protected amine 20 (91% yield), that
Scheme 1. Retrosynthetic analysis of building blocks 6–11
2
2
The reaction sequence proposed in this work commenced with
2
F-
the chemoselective hydrolysis of 12 into corresponding
substituted building blocks 8 and 11. Thus, derivative 17 was
transformed into corresponding mesylate 21 (94% yield), that
was then involved in the TMAF-mediated nucleophilic substitu-
tion giving 2-(fluoromethyl)cyclobutanecarboxylate 22 (69% yield,
Scheme 4). Ester 22 was smoothly transformed into the target
carboxylic acid 8 upon treatment with HCl – 1,4-dioxane (87%
yield).
monoester 13 (66% yield). The deoxofluorination of 13 with SF
4
in a Hastelloy autoclave, followed by alkaline hydrolysis of the
ester group provided the target product 6 in 67% yield (Scheme
2
). The DPPA-mediated Curtius rearrangement of 6 in the
presence of Et N in t-BuOH gave N-Boc-protected amine 14
88% yield), that was treated with 4 M HCl – 1,4-dioxane in Et
to obtain hydrochloride 9 (85% yield).
3
(
2
O
Scheme 3. Preparation of CHF
2
-substituted building blocks 7 and 10 (relative configurations are shown)
2
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
2
Scheme 4. Synthesis of CH F-substituted building blocks 8 and 11 (relative configurations are shown)
Further reactions included the modified Curtius rearrangement
of 8 (91% yield) and Boc group cleavage in derivative 23 thus
obtained, which gave hydrochloride 11 in 76% yield.
None of the steps in the aforementioned reaction sequences
was accompanied by epimerization of the chiral centers, so that
pure trans isomers of the target building blocks were obtained.
Furthermore, all the steps were efficient and scalable, which
allowed obtaining up to 65 g for carboxylic acids 6–8 and up to
carboxylic acid 6 – N-Boc-protected amine 14 was obtained in
only 8% overall yield.
Physicochemical Properties. In order to evaluate an impact of
the fluoroalkyl moiety on the carboxylate or amino groups at the
a
cyclobutane core, pK values were measured for carboxylic
acids 6–8 and amines 9–11 (Figure 3). It was found that the
values varied in an expected manner within the studied series.
Thus, introducing the fluoromethyl group into the cyclobutane-
carboxylic acid, as well as the subsequent addition of the
fluorine atoms increased acidity by 0.11 (8), 0.12 (7), and 0.39
30 g for the primary amines 9–11 in a single run. Nevertheless,
the overall reaction sequences were rather lengthy, the shortest
of them including 11 steps (in the case of 6). Therefore, we have
considered an alternative approach to the synthesis of 6 based
on the cyanotrifluoromethylation of cyclobutene (24, obtained
from bromocyclobutane). In particular, treatment of 24 with the
(6) pK
a
units, respectively. For the corresponding amines, a
units was observed for 9 and 10,
maximum difference of 1.03 pK
a
and the observed values followed a general rule-of-thumb:
introducing the fluorine atoms into the γ-position of aliphatic
Togni reagent II in the presence of TMSCN and Cu(OTf)
DMSO provided trans-CF -substituted cyclobutanecarbonitrile
5 as a single diastereomer in 61% yield after distillation in
2
in
amine leads to the decrease of pK
a
by ca. 0.7 units per each
γ-F.[4,13]
3
2
vacuo (Scheme 5). Subsequent alkaline hydrolysis of nitrile 25
finished the synthesis of target building block 6 (75% yield).
a
Figure 3. Measured pK values (23 ºC) for building blocks 6–11, as well as the
parent cyclobutane derivatives (R = H[47])
Scheme 5. Alternative synthesis of compound 6 (relative configurations are
shown)
To evaluate the effect of the fluoroalkyl substituents on the
lipophilicity, compounds 6–8 and 9–11 were transformed into the
corresponding amides 27–29 and 30–32, respectively (Scheme
Analogously, to shorten the synthetic scheme for the preparation
of 9, the direct azidotrifluoromethylation of in-situ-generated
7). In the series of compounds 27–29, the measured LogP
cyclobutene with the Togni reagent II and TMSN
3
in the
values followed the trend reported in the literature for the acyclic
fluorinated derivatives bearing the F-atoms at the C-3 position:
presence of Cu(MeCN) PF was performed. This reaction
4
6
provided azidocyclobutane 26, which was immediately involved
in the Staudinger reaction followed by N-protection reaction with
Boc O (Scheme 6). However, this approach was much efficient
2
[13]
CH
.66 for 28 and 29 (Figure 4). Interestingly, introducing either
CH F or CHF group instead of the hydrogen atom slightly
2
F ≤ CHF
2
<< CF
3
,
with ∆logP of 0.11 for 27 and 28, and
0
2
2
as less efficient as compared to the Curtius rearrangement of
diminished the lipophilicity of the compounds in these series,
even despite the increased carbon atom count. The isomeric
cyclobutanamide-derived amides 30–32 demonstrated similar
behavior, with slightly lower logP values as compared to 27–29.
w
Finally, aqueous solubility (S ) of compounds 27–32 varied
symbatically with their lipophilicity, with the CF
derivatives being the least soluble.
3
-substituted
Scheme 6. An alternative approach to 14 via azidotrifluoromethylation (relative
configurations are shown)
3
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
provided trans-1,2-disubstituted cyclobutane carboxylic acids
(
on up to 65 g scale in a single run) and the corresponding
primary amines (up to 30 g);[50] therefore, these advanced
fluorinated building blocks are now readily available for drug
discovery programs.
a
The pK values of the target compounds, as well as the parent
cyclobutanamine and cyclobutanecarboxylic acid followed the
theoretically predicted trend and correlated with the literature
data for acyclic analogues, which indicated that acidity/bacisity
within the series was affected mainly by the extent of through-
bond polarization caused by the fluorine atoms. The lipophilicity
varied according to the following pattern: H > CH
CF , which is also in accordance with the literature data for the
acyclic counterparts. It is interesting to note that introducing
CH F or even CHF substituent into the cyclobutane ring instead
2 2
F ≤ CHF <<
3
2
2
of the hydrogen atom either did not change or increased
hydrophilicity of the compounds, even despite higher carbon
atom count.
Experimental Section
The solvents were purified according to the standard procedures.[48] All
starting materials were available from Enamine Ltd. or purchased from
other commercial sources. Melting points were measured on MPA100
OptiMelt automated melting point system. Column chromatography was
performed using Kieselgel Merck 60 (230–400 mesh) as the stationary
Scheme 7. Synthesis and measured aqueous solubilities (S
derivatives 27–32 (relative configurations are shown)
w
, 23 ºC) of
phase. 1H, 13C{ H} and F NMR spectra were recorded on a Bruker 170
1
19
Avance 500 spectrometer (at 500 MHz for 1H NMR, 126 MHz for 13C{ H}
1
NMR and 470 MHz for 19F NMR) and Varian Unity Plus 400 spectrometer
1
(
at 400 MHz for 1H NMR, 101 MHz for 13C{ H} NMR and 376 MHz for 19F
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{ H} in CDCl3, 2.50
and 39.52 ppm for 1H and 13C{ H} in DMSO-d6. Coupling constants (J)
are given in Hz. Spectra are reported as follows: chemical shift (δ, ppm),
multiplicity, integration, coupling constants (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 GCMS instrument
1
1
(
electron impact ionization (EI)).
Figure 4. Measured LogP values (23 ºC) for derivatives 27–32, as well as the
(
1R*,2R*)-2-(Methoxycarbonyl)cyclobutanecarboxylic acid (13).[49]
parent cyclobutanes (R = H[47]
)
Dimethyl ester 12 (290 g, 1.68 mol) was dissolved in MeOH (2.5 L), and
the solution was warmed up to reflux. Then, KOH (99.2 g, 1.77 mol) in
MeOH (500 mL) was added dropwise for 90 min. The resulting mixture
was refluxed for 30 min, then cooled to rt, and evaporated in vacuo. The
residue was partitioned between H2O (2.0 L) and CH2Cl2 (1.0 L). The
aqueous layer was separated, acidified with 6 M aq HCl to pH = 1 and
extracted with CH2Cl2 (3×500 mL). Combined layers were washed with
brine (500 mL), dried over Na2SO4, filtered, and evaporated in vacuo.
Yield 176 g (66%). Yellowish liquid. Starting material 16 (80.1 g) was also
recovered by evaporation of CH2Cl2 solution obtained upon partitioning.
Conclusions
Despite growing interest in fluoroalkyl-substituted cycloalkanes,
the simplest 1,2-disubstituted cyclobutane derivatives were
virtually omitted in the literature previously. In this work, we
disclosed several efficient approaches to diastereomerically pure
mono-, di- and trifluoromethyl-substituted cyclobutane building
blocks, i.e. carboxylic acids and primary amines. A general but
multistep approach to the target compounds relied on the
deoxofluorination or fluoride-mediated nucleophilic substitution
in the appropriate 1,2-difunctionalized cyclobutanes, in turn
obtained from dimethyl trans-cyclobutane-1,2-dicarboxylate. For
Yellowish liquid. 1H NMR (500 MHz, CDCl3) δ 11.19 (s, 1H), 3.65 (s, 3H),
1
3
.48 – 3.33 (m, 2H), 2.22 – 2.05 (m, 4H). 13C{ H} NMR (126 MHz, CDCl3)
δ 179.2, 173.9, 52.0, 40.1, 39.9, 21.9, 21.8. GC/MS (EI): m/z = 127 [M–
+
+
OMe] , 140 [M–H2O] . Anal. Calcd. for C7H10O4: C 53.16; H 6.37. Found:
C 53.49; H 6.71.
(1R*,2R*)-2-(Trifluoromethyl)cyclobutanecarboxylic acid (6). Method
the CF
3
-substituted cyclobutanes, a shorter reaction sequence
A (from 13): Monoester 13 (4.59 g, 29.0 mmol) was placed into a 60-mL
Hastelloy autoclave, which was then cooled to –196 °C and evacuated.
Next, SF4 (9.40 g, 87.0 mmol) was condensed into the autoclave, and the
was also proposed that involved cyanotrifluoromethylation of
cyclobutene as the key step. The proposed methods and
4
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
+
reaction mixture was kept at 75 °C. The completion of the reaction was
monitored by 19F NMR spectra (ca. 72 h). Then, the gaseous products
were released carefully, and the reaction mixture was poured into a
solution of KOH (6.51 g, 116 mmol) in H2O – MeOH (2:1, v/v, 45 mL).
The resulting mixture was refluxed for 1 h, then cooled to rt, and
evaporated in vacuo. The residue was acidified with 12 M aq HCl (15 mL)
and extracted with Et2O (2×30 mL). The combined organic layers were
dried over Na2SO4, filtered and evaporated in vacuo. The crude product
was purified by distillation in vacuo. Yield 3.27 g (67%). Method B (from
MS (ESI): m/z = 140 [M+H] . Anal. Calcd. for C5H9ClF3N: C 34.20; H
5.17; N 7.98; Cl 20.19. Found: C 34.08; H 4.78; N 7.60; Cl 19.91.
(
1R*,2R*)-1-tert-Butyl 2-methyl cyclobutane-1,2-dicarboxylate (15).
Boc2O (254 g, 1.16 mol) was added dropwise to a solution of 13 (176 g,
.11 mol) and DMAP (4.07 g, 33.3 mmol) in CH2Cl2 (1.5 L). When the
gas evolution ceased, the resulting mixture was washed with 1 M aq HCl
500 mL), brine (500 mL), dried over Na2SO4, filtered, and evaporated in
vacuo. Yield 233 g (98%). Yellowish liquid. 1H NMR (500 MHz, CDCl3) δ
1
(
2
5): Compound 25 (74.1 g, 0.497 mol) was added to a solution of KOH
3
.66 (s, 3H), 3.39 – 3.18 (m, 2H), 2.14 – 2.07 (m, 4H), 1.41 (s, 9H).
(111 g, 1.99 mol) in H2O (1 L), and the resulting mixture was refluxed
13
1
C{ H} NMR (151 MHz, CDCl3) δ 174.2, 172.8, 80.5, 51.7, 41.5, 40.1,
overnight. Then, it was washed with CH2Cl2 (2×500 mL), acidified to
pH = 1 with 6 M HCl, and extracted with CH2Cl2 (2×500 mL). The
combined organic layers were washed with brine (500 mL), dried over
Na2SO4, filtered, and evaporated. The residue was purified by distillation
+
28.0, 21.9, 21.5. MS (ESI): m/z = 237 [M+Na] . GC/MS (EI): m/z = 141
+
+
[
M–Ot-Bu] , 183 [M–OMe] . Anal. Calcd. for C11H18O4: C 61.66; H 8.47.
Found: C 61.86; H 8.57.
in vacuo (59–60 °C, 2 mbar). Yield 62.6 g (75%). Colorless liquid. 1
H
(1R*,2R*)-2-(tert-Butoxycarbonyl)cyclobutanecarboxylic acid (16).
NMR (400 MHz, CDCl3) δ 11.57 (s, 1H), 3.41 – 3.09 (m, 2H), 2.29 – 2.08
Compound 15 (233 g, 1.09 mol) was dissolved in THF – H2O (2.4 L, 2:1,
v/v), and the solution was cooled to 0 °C. Then, 4 M aq NaOH (545 mL,
m, 4H). 13C{ H} NMR (151 MHz, CDCl3) δ 179.2, 125.9 (q, J = 276 Hz),
1
(
3
9.0 (q, J = 31.5 Hz), 37.4 (q, J = 3.5 Hz), 21.5, 17.8 (q, J = 3.3 Hz).
2.18 mol) was added dropwise at 0 °C (NOTE: the temperature should
1
9
1
+
F{ H} NMR (376 MHz, CDCl3) δ –74.5. GC/MS (EI): m/z = 99 [M–CF3] ,
not exceed 5 °C). The resulting mixture was stirred at 0 °C for 2 h, then
diluted with H2O (1 L), and washed with CH2Cl2 (1 L). The aqueous layer
was acidified to pH = 2 with 2 M HCl and extracted with CH2Cl2 (3×1 L).
The combined organic layers were dried over Na2SO4, filtered, and
evaporated in vacuo. Yield 212 g (97%). Colorless crystals; mp 49–52 °C.
+
+
124 [M–CO2] , 168 [M] . Anal. Calcd. for C6H7F3O2: C 42.87; H 4.20.
Found: C 42.73; H 4.07.
tert-Butyl ((1R*,2R*)-2-(trifluoromethyl)cyclobutyl)carbamate (14).
Method A (from 6): Et3N (16.6 g, 0.164 mol) was added to a solution of
1
H NMR (400 MHz, CDCl3) δ 11.30 (s, 1H), 3.57 – 3.01 (m, 2H), 2.18 –
6
(25.0 g, 0.149 mol) in t-BuOH (250 mL), and the resulting mixture was
warmed up to 75 °C. DPPA (41.0 g, 0.149 mol) was added dropwise at
5 °C, the resulting mixture was stirred at 80 °C overnight, then
.06 (m, 4H), 1.40 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.6,
2
1
72.8, 80.8, 41.3, 40.2, 28.0, 21.8, 21.5. MS (ESI): m/z = 157 [M–
7
+
+
CO2+H] , 199 [M–H] . Anal. Calcd. for C10H16O4: C 59.98; H 8.05. Found:
evaporated in vacuo to dryness. The residue was partitioned between
saturated aq K2CO3 (250 mL) and CH2Cl2 (400 mL), the organic layer
was separated, the aqueous phase was back-extracted with CH2Cl2 (250
mL). Combined organic layers were washed with brine (250 mL), dried
over Na2SO4, filtered, and evaporated in vacuo. Yield 31.3 g (88%).
Method B (from cyclobutene): Togni reagent II (78.2 g, 0.248 mol) and
Cu(MeCN)4PF6 (1.85 g, 4.96 mmol) were dissolved in MeCN (1 L). Then,
cyclobutene[51] (16.1 g, 0.298 mol; see preparation of 25) and TMSN3
C 60.18; H 8.18.
(1R*,2R*)-tert-Butyl 2-(hydroxymethyl)cyclobutanecarboxylate (17).
A solution of 16 (212 g, 1.06 mol) in THF (2 L) was cooled to 0 °C, and
.
1
0 M BH3 SMe2 (159 mL, 1.59 mol) was added at 0 °C under argon
atmosphere (NOTE: the temperature should not exceed 5 °C). Then, the
reaction mixture was warmed up to rt, then carefully poured into pre-
coooled MeOH (1 L), and the resulting mixture was evaporated in vacuo.
The residue was diluted with MeOH (1 L) and evaporated in vacuo. Yield
(42.9 g, 372 mmol) were added under argon atmosphere, the mixture
was stirred at rt for 12 h, and PPh3 (102 g, 0.391 mol) was added in
portions. When the gas evolution ceased, 4 M aq HCl (200 mL) was
added at rt, the resulting mixture was stirred at rt overnight, then
evaporated. The residue was partitioned between H2O (250 mL) and
CHCl3 (250 mL), the organic phase was separated, the aqueous phase
was washed with CHCl3 (250 mL). Organic layers were combined, and
saturated aq NaHCO3 was added to pH = 9. The resulting mixture was
diluted with MeOH (250 mL), and Boc2O (81.1 g, 0.372 mol) was added
dropwise at rt. The reaction mixture was stirred at rt overnight, then most
of MeOH was evaporated in vacuo. The aqueous residue was extracted
with CH2Cl2 (2×200 mL), the combined organic layers were washed with
brine (200 mL), dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by column chromatography using gradient
hexanes – t-BuOMe as eluent. Yield 4.73 g (8%). Colorless solid; mp
1
1
2
1
9
2
59 g (81%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.63 (dd, J =
0.8, 5.2 Hz, 1H), 3.57 (dd, J = 10.8, 7.6 Hz, 1H), 2.85 – 2.76 (m, 1H),
.63 (dtd, J = 17.0, 8.5, 5.1 Hz, 1H), 2.15 – 2.08 (m, 2H), 1.99 (tdd, J =
1.4, 8.3, 2.4 Hz, 1H), 1.89 – 1.81 (m, 1H), 1.70 – 1.61 (m, 1H), 1.43 (s,
H). 13C{ H} NMR (126 MHz, CDCl3) δ 174.3, 80.5, 66.1, 42.5, 41.5, 28.0,
1
+
1.1, 20.3. MS (ESI): m/z = 209 [M+Na] . GC/MS (EI): m/z = 113 [M–Ot-
+
+
Bu] , 131 [M–H2C=C(CH3)2] . Anal. Calcd. for C10H18O3: C 64.49; H 9.74.
Found: C 64.34; H 9.84.
(1R*,2R*)-tert-Butyl 2-formylcyclobutanecarboxylate (18). A solution
of DMSO (43.3 g, 0.554 mol) in CH2Cl2 (50 mL) was added dropwise to a
solution of (COCl)2 (64.9 g, 0.511 mol) in CH2Cl2 (1 L) at –78 °C under
argon atmosphere. After stirring at –78 °C for 5 min, a solution of 17
(79.3 g, 0.426 mol) in CH2Cl2 (50 mL) was added dropwise maintaining
1
02–103 °C. 1H NMR (500 MHz, CDCl3) δ 4.79 (s, 1H), 4.18 (s, 1H), 3.05
the temperature below –65 °C. The resulting mixture was stirred for 5 min,
and Et3N (108 g, 1.07 mol) was added dropwise at –70 °C. The reaction
mixture was warmed up to 0 °C and quenched with H2O (500 mL). The
organic layer was separated, washed with 1 M aq HCl (500 mL), brine
–
2.62 (m, 1H), 2.27 (q, J = 8.9 Hz, 1H), 2.02 – 1.86 (m, 2H), 1.80 – 1.74
1
(
m, 1H), 1.44 (s, 9H). 13C{ H} NMR (151 MHz, CDCl3) δ 154.5, 125.7 (q,
J = 277 Hz), 79.8, 45.5, 28.2, 26.6, 14.8 (q, J = 2.8 Hz). 19F NMR (376
+
MHz, CDCl3) δ –72.7. MS (ESI): m/z = 262 [M+Na] . Anal. Calcd. for
(500 mL), and dried over Na2SO4. The compound was used in the next
C10H16F3NO2: C 50.21; H 6.74; N 5.85. Found: C 49.96; H 6.34; N 5.57.
step as a solution in CH2Cl2 (1 L), while a small aliquot was evaporated in
vacuo to dryness to obtain the spectral data. Yellowish oil. 1H NMR (400
MHz, CDCl3) δ 9.66 (s, 1H), 3.46 – 3.31 (m, 1H), 3.31 – 3.04 (m, 1H),
(1R*,2R*)-2-(Trifluoromethyl)cyclobutanaminium chloride (9). 4 M
HCl – 1,4-dioxane (70 mL) was added to a solution of 14 (31.3 g, 0.131
mol) in Et2O (300 mL), and the resulting mixture was stirred at rt
overnight. The precipitate formed was filtered, washed with Et2O (300
mL), and dried in vacuo (0.5 mbar). Yield 19.5 g (85%). Colorless solid;
mp 194–197 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 3H), 3.84 –
.22 – 2.04 (m, 4H), 1.39 (s, 9H). 13C{ H} NMR (126 MHz, CDCl3) δ
00.4, 172.8, 80.7, 47.8, 38.8, 28.0, 21.6, 18.8.
1
2
2
(1R*,2R*)-tert-Butyl 2-(difluoromethyl)cyclobutanecarboxylate (19).
A solution of 18 in CH2Cl2 (1 L) was cooled to 0 °C, and a solution of
morph-DAST (112 g, 0.639 mol) in CH2Cl2 (150 mL) was added dropwise
at 0 °C (NOTE: the temperature should not exceed 5 °C). Then, the
reaction mixture was warmed up to rt, stirred for 1 h, then carefully
poured into saturated aq NaHCO3 (2 L), and the resulting mixture was
3
.74 (m, 1H), 3.56 – 3.46 (m, 1H), 2.22 – 2.03 (m, 3H), 1.89 – 1.79 (m,
H). 1 C{ H} NMR (126 MHz, DMSO-d6) δ 125.5 (q, J = 276.5 Hz), 43.5
3
1
1
(
q, J = 3.8 Hz), 40.9 (q, J = 30.6 Hz), 22.8, 15.20 (q, J = 3.5 Hz). 19
NMR (470 MHz, DMSO-d6) δ –70.6. GC/MS (EI): m/z = 120 [M–HCl–F]+.
F
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
stirred until the gas evolution ceased. The organic layer was separated,
and the aqueous phase was extracted with CH2Cl2 (500 mL). THE
combined organic layers were washed with brine (250 mL), dried over
Na2SO4, filtered, and evaporated in vacuo. The crude product was
added dropwise under argon atmosphere while maintained at –30°C
(NOTE: the temperature should not exceed –20°C). The resulting mixture
was warmed up to rt, washed with water (500 mL), brine (500 mL), dried
over Na2SO4, filtered, and evaporated in vacuo. The compound was used
in the next step without additional purification. Yield 107 g (94%).
Yellowish solid; mp 58–61 °C (the compound decomposed upon heating).
1H NMR (500 MHz, CDCl3) δ 4.18 (d, J = 4.9 Hz, 2H), 3.01 – 2.99 (m,
3H), 2.98 – 2.76 (m, 2H), 2.16 – 2.03 (m, 2H), 2.00 – 1.92 (m, 1H), 1.84 –
1.77 (m, 1H), 1.42 (s, 9H). 13C{ H} NMR (126 MHz, CDCl3) δ 173.1, 80.5,
71.6, 41.1, 37.5, 37.3, 28.0, 21.4, 20.5. MS (ESI): m/z = 287 [M+Na]+.
purified by distillation in vacuo (bp 33–34 °C / 0.5 mbar). Yield 62.3 g
1
(
71% from 17). Colorless liquid . H NMR (500 MHz, CDCl3) δ 5.81 (td, J
=
(
56.9, 1.8 Hz, 1H), 3.22 – 3.05 (m, 1H), 3.05 – 2.90 (m, 1H), 2.27 – 2.13
m, 2H), 2.10 – 1.95 (m, 2H), 1.49 (s, 9H). 13C{ H} NMR (126 MHz,
1
1
CDCl3) δ 177.2, 120.4 (t, J = 240 Hz), 85.0, 44.5 (t, J = 22.6 Hz), 42.6 (t,
J = 5.8 Hz), 32.4, 25.9, 21.2 (t, J = 5.8 Hz). 19F NMR (470 MHz, CDCl3) δ
–
124.1 (ddd, J = 283, 56.9, 14.0 Hz), –125.3 (ddd, J = 283, 56.9, 17.1
+
+
Hz). GC/MS (EI): m/z = 151 [M–H2C=C(CH3)2] , 191 [M–Me] . Anal.
(
1R*,2R*)-tert-Butyl 2-(fluoromethyl)cyclobutanecarboxylate (22).
Calcd. for C10H16F2O2: C 58.24; H 7.82. Found: C 58.38; H 7.81.
TMAF (48.9g, 0.525 mol) was added to a solution of 21 (107 g, 0.404
mol) in tBuOH (1 L, pre-distilled over CaH2). The resulting mixture was
refluxed for 18 h and then evaporated in vacuo to dryness. The residue
was dissolved in CH2Cl2 (1 L), washed with H2O (2×500 mL), brine (500
mL), dried over Na2SO4, filtered, and evaporated in vacuo. The residue
was purified by distillation in vacuo (bp 36–37 °C / 0.5 mbar). Yield 52.4 g
(69%). Colorless liquid. 1H NMR (500 MHz, CDCl3) δ 4.33 (dt, J = 47.9,
4.0 Hz, 2H), 3.02 – 2.85 (m, 1H), 2.83 – 2.66 (m, 1H), 2.12 – 1.97 (m,
2H), 1.91 – 1.81 (m, 2H), 1.40 (s, 9H). 13C{ H} NMR (126 MHz, CDCl3) δ
173.6, 84.6 (d, J = 167 Hz), 80.0, 40.1 (d, J = 5.7 Hz), 39.0 (d, J = 20.4
Hz), 28.0, 21.2, 19.5 (d, J = 5.6 Hz). 19F NMR (470 MHz, CDCl3) δ
(
1R*,2R*)-2-(Difluoromethyl)cyclobutanecarboxylic acid (7). tert-Butyl
ester 19 (62.3 g, 0.302 mol) was dissolved in 1,4-dioxane (500 mL) and
M HCl – 1,4-dioxane (100 mL) was added. The resulting solution was
4
stirred at rt for 48 h and evaporated in vacuo. The residue was purified by
distillation in vacuo (66–68 °C, 0.5 mbar) followed by dissolving in CH2Cl2
(500 mL) and extraction with saturated aq. NaHCO3 (2×500 mL). The
1
combined aqueous phases were washed with CH2Cl2 (500 mL), acidified
with 6 M aq HCl to pH = 1, extracted with CH2Cl2 (2×500 mL), dried over
Na2SO4, filtered, and evaporated in vacuo. Yield 39.9 g (88%). Colorless
liquid. 1H NMR (500 MHz, CDCl3) δ 9.91 (s, 1H), 5.79 (td, J = 56.8, 3.1
+
–226.4 (td, J = 47.9, 26.7 Hz). GC/MS (EI): m/z = 133 [M–H2C=C(CH3)2] ,
173 [M–Me] . Anal. Calcd. for C10H17FO2: C 63.81; H 9.10. Found: C
63.43; H 8.81.
+
Hz, 1H), 3.34 – 3.14 (m, 1H), 3.14 – 2.93 (m, 1H), 2.37 – 2.13 (m, 2H),
1
2
.13 – 1.90 (m, 2H). 13C{ H} NMR (126 MHz, CDCl3) δ 179.8, 115.6 (t, J
=
240 Hz), 39.8 (t, J = 22.8 Hz), 36.8 (t, J = 6.0 Hz), 21.7, 17.0 (t, J = 5.6
Hz). 19F NMR (470 MHz, CDCl3) δ –125.00 (ddd, J = 265, 56.8, 15.5 Hz),
(
1R*,2R*)-2-(Fluoromethyl)cyclobutanecarboxylic acid (8). tert-Butyl
ester 21 (52.4 g, 0.279 mol) was dissolved in 1,4-dioxane (500 mL), and
M HCl – 1,4-dioxane (100 mL) was added. The resulting solution was
–
–125.41 (ddd, J = 265, 56.8, 16.1 Hz). MS (ESI): m/z = 149 [M–H] . Anal.
Calcd. for C6H8F2O2: C 48; H 5.37. Found: C 48.07; H 5.22.
4
stirred at rt for 48 h and evaporated in vacuo. The residue was purified by
distillation in vacuo (73–75 °C, 0.5 mbar). Yield 32.0 g (87%). Colorless
liquid. 1H NMR (500 MHz, CDCl3) δ 11.70 (s, 1H), 4.38 (dddd, J = 47.6,
22.2, 9.7, 4.3 Hz, 2H), 3.19 – 3.00 (m, 1H), 2.86 (dqt, J = 26.3, 8.6, 4.2
Hz, 1H), 2.23 – 2.09 (m, 2H), 1.95 (dd, J = 11.0, 7.4 Hz, 2H). 13C{ H}
NMR (126 MHz, CDCl3) δ 180.8, 84.3 (d, J = 167 Hz), 39.0 (d, J = 1.3
Hz), 38.9 (d, J = 13.5 Hz), 21.2, 19.5 (d, J = 5.7 Hz). 19F NMR (470 MHz,
tert-Butyl ((1R*,2R*)-2-(Difluoromethyl)cyclobutyl)carbamate (20).
Et3N (29.6 g, 0.293 mol) was added to a solution of 7 (39.9 g, 0.266 mol)
in t-BuOH (400 mL), and the resulting mixture was warmed up to 75 °C.
DPPA (73.2 g, 0.266 mol) was added dropwise at 75 °C, the reaction
mixture was stirred at 80 °C overnight and then evaporated in vacuo to
dryness. The residue was partitioned between saturated aq K2CO3 (500
mL) and CH2Cl2 (500 mL), the organic phase was separated, the
aqueous phase was extracted with CH2Cl2 (250 mL). The combined
organic layers were washed with brine (200 mL), dried over Na2SO4,
1
+
CDCl3) δ –226.8 (td, J = 47.6, 26.8 Hz). GC/MS (EI): m/z = 113 [M–F] ,
+
132 [M] . Anal. Calcd. for C6H9FO2: C 54.54; H 6.87. Found: C 54.61; H
6.91.
filtered, and evaporated in vacuo. Yield 53.6 g (91%). Beige solid; mp
1
5
1
1
1
0–52 °C. H NMR (500 MHz, CDCl3) δ 5.88 (t, J = 56.8 Hz, 1H), 4.71 (s,
H), 4.13 – 3.96 (m, 1H), 2.65 – 2.44 (m, 1H), 2.25 (dt, J = 8.7, 4.4 Hz,
H), 1.86 – 1.75 (m, 3H), 1.43 (s, 9H). 13C{ H} NMR (151 MHz, CDCl3) δ
54.8, 115.9 (t, J = 240 Hz), 79.7, 46.9, 45.3, 28.3, 26.7, 13.8 (t, J = 5.4
tert-Butyl ((1R*,2R*)-2-(fluoromethyl)cyclobutyl)carbamate (23). Et3N
(26.9 g, 0.266 mol) was added to a solution of 8 (32.0 g, 0.242 mol) in t-
1
BuOH (350 mL), and the resulting mixture was warmed up to 75 °C.
DPPA (66.6 g, 0.242 mol) was added dropwise at 75 °C, the resulting
mixture was stirred at 80 °C overnight and then evaporated in vacuo to
dryness. The residue was partitioned between saturated aq K2CO3 (500
mL) and CH2Cl2 (500 mL), the organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (250 mL). The combined
organic layers were washed with brine (200 mL), dried over Na2SO4,
filtered, and evaporated in vacuo. Yield 44.8 g (91%). Colorless solid; mp
56–58 °C. 1H NMR (500 MHz, CDCl3) δ 4.73 (s, 1H), 4.42 (dd, J = 47.6,
4.8 Hz, 2H), 4.01 – 3.87 (m, 1H), 2.54 – 2.37 (m, 1H), 2.27 – 2.19 (m,
1H), 1.86 – 1.70 (m, 2H), 1.62 – 1.54 (m, 1H), 1.42 (s, 9H). 13C{ H} NMR
(126 MHz, CDCl3) δ 154.9, 84.2 (d, J = 166 Hz), 79.3, 47.0, 45.1 (d, J =
Hz). 19F NMR (470 MHz, CDCl3) δ –126.5 (dd, J = 285, 56.8 Hz), –129.4
ddd, J = 285, 56.8, 19.2 Hz). MS (ESI): m/z = 244 [M+Na] . Anal. Calcd.
for C10H17F2NO2: C 54.29; H 7.75; N 6.33. Found: C 54.42; H 7.59; N
.56.
+
(
6
(
1R*,2R*)-2-(Difluoromethyl)cyclobutan-1-aminium chloride (10). 4 M
HCl – 1,4-dioxane (100 mL) was added to a solution of 20 (53.6 g, 0.242
mol) in Et2O (500 mL), and the resulting mixture was stirred at rt
overnight. The precipitate formed was filtered, washed with Et2O (500
mL), and dried in vacuo (0.5 mbar). Yield 29.8 g (78%). Greyish powder;
mp 221–223 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 3H), 6.20 (td, J
1
19
1
19.7 Hz), 28.3, 27.2, 16.9. F{ H} NMR (376 MHz, CDCl3) δ –224.7. MS
+
=
(
56.8, 3.3 Hz, 1H), 3.71 – 3.51 (m, 1H), 3.14 – 2.87 (m, 1H), 2.17 – 1.99
m, 2H), 1.95 – 1.84 (m, 1H), 1.84 – 1.72 (m, 1H). 13C{ H} NMR (126
(ESI): m/z = 226 [M+Na] . Anal. Calcd. for C10H18FNO2: C 59.09; H 8.93;
1
N 6.89. Found: C 58.70; H 8.55; N 6.94.
MHz, DMSO-d6) δ 115.5 (t, J = 238 Hz), 43.6 (dd, J = 9.6, 5.4 Hz), 41.7 (t,
J = 22.9 Hz), 23.2, 14.0 (t, J = 5.4 Hz). 19F NMR (376 MHz, DMSO-d6) δ
(1R*,2R*)-2-(Fluoromethyl)cyclobutanaminium chloride (11). 4 M
–
122.9 (d, J = 284 Hz), –125.8 (d, J = 284 Hz). MS (ESI): m/z = 122 [M–
HCl – 1,4-dioxane (100 mL) was added to a solution of 23 (44.8 g, 0.221
mol) in Et2O (500 mL), and the resulting mixture was stirred at rt
overnight. The precipitate formed was filtered, washed with Et2O (500
mL), and dried in vacuo (0.5 mbar). Yield 23.4 g (76%). Colorless solid;
mp 186–189 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 3H), 4.56 –
4.35 (m, 2H), 3.50 – 3.43 (m, 1H), 2.86 – 2.67 (m, 1H), 2.09 – 1.96 (m,
2H), 1.91 – 1.82 (m, 1H), 1.69 – 1.58 (m, 1H). 13C{ H} NMR (126 MHz,
DMSO-d6) δ 83.6 (d, J = 163 Hz), 45.4 (d, J = 7.5 Hz), 40.7 (d, J = 20.4
+
HCl+H] . Anal. Calcd. for C5H10ClF2N: C 38.11; H 6.40; N 8.89; Cl 22.50.
Found: C 38.41; H 6.28; N 9; Cl 22.28.
(
1R*,2R*)-tert-Butyl
carboxylate (21). Et3N (47.9 g, 0.473 mol) was added to a solution of 17
80.0 g, 0.430 mol) in CH2Cl2 (1 L), and the resulting mixture was cooled
to –30°C. A solution of MsCl (51.7 g, 0.452 mol) in CH2Cl2 (100 mL) was
2-(((methylsulfonyl)oxy)methyl)cyclobutane-
1
(
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
Hz), 23.8, 17.5 (d, J = 5.2 Hz). 19F NMR (470 MHz, DMSO-d6) δ –225.7
was washed with 1 M aq HCl (10 mL), brine (10 mL), dried over Na2SO4,
and evaporated in vacuo. Yield 1.35 g (86%). Colorless solid; mp 108–
109 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.61 (d, J = 8.0 Hz,
2H), 7.28 (t, J = 7.7 Hz, 2H), 7.02 (t, J = 7.5 Hz, 1H), 4.42 (dd, J = 47.8,
+
(td, J = 47.6, 26.2 Hz). MS (ESI): m/z = 104 [M–HCl+H] . Anal. Calcd. for
C5H11ClFN: C 43.02; H 7.94; N 10.03; Cl 25.39. Found: C 43.28; H 8.13;
N 10.34; Cl 24.99.
4
2
.8 Hz, 2H), 3.14 – 3.03 (m, 1H), 2.86 (dtd, J = 27.6, 8.6, 3.9 Hz, 1H),
.17 – 1.98 (m, 2H), 1.97 – 1.74 (m, 2H). 13C{ H} NMR (126 MHz,
1
(
1R*,2R*)-2-(Trifluoromethyl)cyclobutanecarbonitrile (25). A solution
DMSO-d6) δ 172.2, 139.7, 129.0, 123.5, 119.6, 85.5 (d, J = 164.3 Hz),
of bromocyclobutane (300 g, 2.22 mol) in DMSO (100 mL) was added
dropwise at 75 °C for 40 min under argon atmosphere to a vigorously
stirred suspension of t-BuOK (660 g, 2.66 mol) in DMSO (2.5 L) placed in
the 5 L reaction vessel with a water-cooled condenser attached to a
transfer manifold. Then, the reaction mixture was stirred at 70 °C for 2 h,
the manifold system was closed off from the reaction vessel, and the
material collected in the first trap was slowly warmed. Cyclobutene was
distilled at 2–3 °C into the second cooled trap.[51] A solution of TMSCN
4
1.7 (d, J = 5.7 Hz), 37.9 (d, J = 19.6 Hz), 21.7, 19.7 (d, J = 6.7 Hz).
1
9
1
F{ H} NMR (376 MHz, DMSO-d6) δ –223.0. MS (ESI): m/z = 208
+
[
M+H] . Anal. Calcd. for C12H14FNO: C 69.55; H 6.81; N 6.76. Found: C
69.38; H 6.47; N 6.74.
N-((1R*,2R*)-2-(Trifluoromethyl)cyclobutyl)benzamide (30). Et3N (633
mg, 6.27 mmol) was added to a suspension of 9 (1.00 g, 5.70 mmol) in
CH2Cl2 (15 mL) at rt. Then, BzCl (841 mg, 5.99 mmol) was added
dropwise at rt (NOTE: the temperature should not exceed 25 °C). The
resulting mixture was stirred at rt for 2 h, then washed with 1 M aq HCl
(10 mL), brine (10 mL), dried over Na2SO4, and evaporated in vacuo.
Yield 1.32 g (95%). Colorless solid; mp 148–149 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.83 (d, J = 8.4 Hz, 1H), 7.89 – 7.78 (m, 2H), 7.60 – 7.51 (m,
1H), 7.48 (t, J = 7.3 Hz, 2H), 4.70 – 4.53 (m, 1H), 3.33 – 3.21 (m, 1H),
2.32 – 2.15 (m, 1H), 2.15 – 2.03 (m, 1H), 2.03 – 1.89 (m, 1H), 1.87 –
1.61 (m, 1H). 13C{ H} NMR (126 MHz, DMSO-d6) δ 165.8, 134.4, 131.8,
128.7, 127.6, 126.7 (q, J = 276 Hz), 44.30 (q, J = 29.0 Hz), 44.0 (q, J =
(74.0 g, 0.746 mol) and cyclobutene (32.3 g, 0.596 mol) in DMSO (100
mL) was added dropwise to a solution of Togni II reagent (157 g, 0.497
mol) and Cu(OTf)2 (8.99 g, 24.9 mmol) in DMSO (1 L) under argon
atmosphere maintaining the temperature below 60 °C (CAUTION: highly
exothermic reaction occured upon addition of the solution of TMSCN and
cyclobutene). The reaction mixture was stirred at 60 °C for 2 h, then
extracted with Et2O (3×400 mL). Combined organic layers were washed
with H2O (500 mL), brine, dried and evaporated in vacuo. Yield 74.1 g
1
(61%). The compound was obtained with satisfactory purity after
distillation in vacuo and used in the next step without additional
purification. Brownish liquid. 1H NMR (400 MHz, CDCl3) δ 3.35 – 3.17 (m,
2
19
1
3.9 Hz), 26.3, 14.9 (q, J = 2.9 Hz). F{ H} NMR (376 MHz, DMSO-d6) δ –
H), 2.44 – 2.30 (m, 2H), 2.20 (td, J = 8.6, 6.1 Hz, 2H). 13C{ H} NMR
1
71.2. MS (ESI): m/z = 244 [M+H] . Anal. Calcd. for C12H12F3NO: C 59.26;
+
(
2
126 MHz, CDCl3) δ 124.9 (q, J = 276 Hz), 119.2, 41.4 (q, J = 32.2 Hz),
H 4.97; N 5.76. Found: C 59.58; H 4.80; N 5.49.
2.6, 21.9 (q, J = 4.1 Hz), 19.3 (q, J = 3.0 Hz). 1 F{ H} NMR (376 MHz,
9
1
+
+
CDCl3) δ –74.8. GC/MS (EI): m/z = 122 [M–HCN] , 149 [M] .
N-((1R*,2R*)-2-(Difluoromethyl)cyclobutyl)benzamide (31). Et3N (641
mg, 6.99 mmol) was added to a suspension of 10 (1.00 g, 6.35 mmol) in
CH2Cl2 (15 mL) at rt. Then, BzCl (937 mg, 6.67 mmol) was added
dropwise at rt (NOTE: the temperature should not exceed 25 °C). The
resulting mixture was stirred at rt for 2 h, then washed with 1 M aq HCl
(10 mL), brine (10 mL), dried over Na2SO4, and evaporated in vacuo.
Yield 1.31 g (92%). Beige solid; mp 100–102 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.74 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.53 (t, J =
7.2 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 6.13 (td, J = 57.0, 3.7 Hz, 1H), 4.50
– 4.36 (m, 1H), 2.87 (tdd, J = 21.1, 8.8, 4.0 Hz, 1H), 2.30 – 2.11 (m, 1H),
2.11 – 1.90 (m, 1H), 1.91 – 1.75 (m, 1H), 1.76 – 1.48 (m, 1H). 13C{ H}
NMR (126 MHz, DMSO-d6) δ 165.9, 134.6, 131.7, 128.7, 127.7, 117.2 (t,
J = 238 Hz), 45.4 (t, J = 21.2 Hz), 44.2, 26.4, 14.3 (t, J = 5.7 Hz). 19F{ H}
NMR (376 MHz, DMSO-d6) δ –121.6 (d, J = 282 Hz), –123.6 (d, J = 282
(
1R*,2R*)-N-Phenyl-2-(trifluoromethyl)cyclobutanecarboxamide (27).
CDI (1.16 g, 7.14 mmol) was added in portions to a solution of 6 (1.00 g,
.95 mmol) in CH2Cl2 (15 mL) at rt. When the gas evolution ceased,
5
PhNH2 (720 mg, 7.74 mmol) was added in one portion at rt, and the
resulting mixture was stirred at rt overnight. Then, the reaction mixture
was washed with 1 M aq HCl (10 mL), brine (10 mL), dried over Na2SO4,
and evaporated in vacuo. Yield 1.23 g (85%). Colorless solid; mp 95–
9
7
–
8 °C. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 2H), 7.47 (s, 1H),
.29 (t, J = 7.9 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 3.42 – 3.30 (m, 1H), 3.29
3.16 (m, 1H), 2.40 – 2.25 (m, 1H), 2.21 – 2.03 (m, 3H). 13C{ H} NMR
1
1
1
(126 MHz, CDCl3) δ 170.3, 137.5, 129.0, 126.3 (q, J = 276 Hz), 124.6,
1
20.2, 40.1 (q, J = 3.0 Hz), 39.2 (q, J = 30.8 Hz), 21.0, 17.7 (q, J = 3.4
Hz). 1 F{ H} NMR (376 MHz, CDCl3) δ –73.6. MS (ESI): m/z = 244
9
1
Hz). MS (ESI): m/z = 226 [M+H] . Anal. Calcd. for C12H13F2NO: C 63.99;
H 5.82; N 6.22. Found: C 64.11; H 5.47; N 6.30.
+
+
[
M+H] . Anal. Calcd. for C12H12F3NO: C 59.26; H 4.97; N 5.76. Found: C
58.98; H 5.12; N 5.95.
N-((1R*,2R*)-2-(Fluoromethyl)cyclobutyl)benzamide (32). Et3N (795
mg, 7.88 mmol) was added to a suspension of 11 (1.00 g, 7.16 mmol) in
CH2Cl2 (15 mL) at rt. Then, BzCl (1.06 g, 7.52 mmol) was added
dropwise at rt (NOTE: the temperature should not exceed 25 °C). The
resulting mixture was stirred at rt for 2 h, then washed with 1 M aq HCl
(10 mL), brine (10 mL), dried over Na2SO4, and evaporated in vacuo.
Yield 1.34 g (90%). Colorless solid; mp 114–116 °C. 1H NMR (400 MHz,
CDCl3) δ 7.76 – 7.71 (m, 2H), 7.47 (td, J = 7.2, 1.5 Hz, 1H), 7.43 – 7.37
(m, 2H), 6.33 (s, 1H), 4.59 – 4.52 (m, 1H), 4.47 – 4.36 (m, 2H), 2.64 –
2.52 (m, 1H), 2.39 – 2.31 (m, 1H), 1.96 – 1.88 (m, 2H), 1.74 – 1.65 (m,
1H). 13C{ H} NMR (126 MHz, CDCl3) δ 166.4, 133.8, 131.0, 128.0, 126.4,
84.1 (d, J = 166 Hz), 46.1 (d, J = 7.9 Hz), 44.4 (d, J = 19.6 Hz), 26.6,
16.9 (d, J = 5.9 Hz). 19F NMR (470 MHz CDCl3) δ –223.8 (td, J = 47.5,
(
1R*,2R*)-2-(Difluoromethyl)-N-phenylcyclobutanecarboxamide (28).
CDI (1.30 g, 7.99 mmol) was added in portions to a solution of 7 (1.00 g,
.66 mmol) in CH2Cl2 (15 mL) at rt. Since the gas evolution ceased,
6
PhNH2 (806 mg, 8.66 mmol) was added in one portion at rt, and the
resulting mixture was stirred at rt overnight. Then, the reaction mixture
was washed with 1 M aq HCl (10 mL), brine (10 mL), dried over Na2SO4,
and evaporated in vacuo. Yield 1.22 g (81%). Colorless solid; mp 102–
1
2
1
2
1
05 °C. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 7.52 (d, J = 8.1 Hz,
H), 7.30 (t, J = 7.5 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 5.83 (t, J = 56.9 Hz,
H), 3.29 – 3.19 (m, 1H), 3.19 – 3.01 (m, 1H), 2.41 – 2.30 (m, 1H), 2.17 –
.08 (m, 1H), 2.03 – 1.96 (m, 2H). 13C{ H} NMR (151 MHz, CDCl3) δ
1
1
71.2, 137.8, 129.0, 124.4, 119.9, 116.4 (t, J = 239 Hz), 40.1 (t, J = 21.8
Hz), 39.1 (t, J = 5.2 Hz), 21.0, 17.1 (dd, J = 7.1, 4.8 Hz). 19F{ H} NMR
1
22.3 Hz). MS (ESI): m/z = 208 [M+H] . Anal. Calcd. for C12H14FNO: C
+
(
376 MHz, CDCl3) δ –122.3 (d, J = 283 Hz), –125.1 (d, J = 283 Hz). MS
69.55; H 6.81; N 6.76. Found: C 69.15; H 6.92; N 6.48.
+
(ESI): m/z = 226 [M+H] . Anal. Calcd. for C12H13F2NO: C 63.99; H 5.82;
N 6.22. Found: C 63.68; H 5.61; N 5.85.
Acknowledgements
(
1R*,2R*)-2-(Fluoromethyl)-N-phenylcyclobutanecarboxamide (29).
CDI (1.47 g, 9.08 mmol) was added in portions to a solution of 8 (1.00 g,
.57 mmol) in CH2Cl2 (15 mL) at rt. Since the gas evolution ceased,
The work was funded by Enamine Ltd. O.O.G. was also funded
by Ministry of Education and Science of Ukraine (Grant
No.19BF037-03). The authors thank Prof. Andrey A. Tolmachev
7
PhNH2 (916 mg, 9.84 mmol) was added in one portion at rt, and the
resulting mixture was stirred at rt overnight. Then, the reaction mixture
7
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.202001345
FULL PAPER
Fluorinated cyclobutanes
Scalable and efficient approaches towards the synthesis of 1,2-disubstituted mono-, di- and trifluoromethylcyclobutane building
blocks are reported. Physico-chemical properties of the title building blocks or derivative thereof (i.e. pK and LogP) are measured
a
and compared with those for the non-fluorinated counterparts.
Institute and/or researcher Twitter usernames: @EnamineLtd @KyivUniversity @DrGregor2
1
0
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