Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks

Article abstract of DOI:10.1021/acs.joc.9b00719

An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmeth

Full text of DOI:10.1021/acs.joc.9b00719

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Article
The Last of the gem-Difluorocycloalkanes: Synthesis and
Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks
Anton V. Chernykh, Kostiantyn P. Melnykov, Nataliya A. Tolmacheva, Ivan S.
Kondratov, Dmytro S. Radchenko, Constantin G. Daniliuc, Dmitriy M. Volochnyuk,
Sergey V. Ryabukhin, Yuliya O. Kuchkovska, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00719 • Publication Date (Web): 16 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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The Last of the gem-Difluorocycloalkanes:
Synthesis and Characterization of 2,2-
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Difluorocyclobutyl-Substituted Building Blocks
Anton V. Chernykh,a Kostiantyn P. Melnykov, a,b Nataliya A. Tolmacheva,a Ivan S. Kondratov,a,e
Dmytro S. Radchenko,a,b Constantin G. Daniliuc,c Dmitriy M. Volochnyuk,a,d Sergey V.
Ryabukhin,a,b Yuliya O. Kuchkovska a,b and Oleksandr O. Grygorenkoa,b*
a Enamine Ltd. (www.enamine.net) Chervonotkatska Street 78, Kyiv 02094, Ukraine
b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
c Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40,
48149 Münster, Germany
d Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street
5, Kyiv 02660, Ukraine
e Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Murmanska Street 1,
Kyiv 02660, Ukraine
*E-mail: gregor@univ.kiev.ua
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KEYWORDS: Fluorine, cyclobutanes, deoxofluorination, cycloalkanes, exit vector plots
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ABSTRACT. An efficient approach to synthesis of previously unavailable 2-substituted
difluorocyclobutane building blocks was developed and applied on a multigram scale. The key
step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)-
cyclobutanone. Dissociation constants (pKa) and LogP values for 2,2-difluorocyclobutaneamine
and 2,2-difluorocyclobutanecarboxylic acid or their derivatives were measured and compared
with the values obtained for the corresponding 3,3-difluorocyclobutane derivatives and non-
fluorinated counterparts. Three-dimensional structures of 2,2- and 3,3-difluorocyclobutanamines
were compared using exit vector plot (EVP) analysis of X-ray crystallographic data.
INTRODUCTION
Over the past decades, fluorine has become the most influential halogen in drug discovery,
resulting in about one-third of currently marketed pharmaceuticals being represented by
fluorinated derivatives.1–5 The ability of fluorine to modulate physicochemical and
conformational properties is commonly used to adjust the lead potency, metabolic pathways,
membrane permeability etc.6–11 Apart from that, introduction of fluorine atom in proximity to
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basic amine center was found to be beneficial for reduction of hERG inhibition12,13 and reduction
of P-glycoprotein efflux.14
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Among the known variety of fluorinated organic motifs, gem-difluoromethylene unit is of
special interest for medicinal chemistry. From one perspective, the CF2-group can serve as an
oxygen atom bioisostere in alcohols, ethers, phosphates, and heterocycles, as well as replacement
for the carbonyl group.6 Another feature of gem-difluoromethylene moiety is ability to provide a
greater impact on the compound pharmacokinetic profile as compared to mono-fluorinated
analogs. For example, introduction of an additional fluorine atom to c-Met inhibitor GEN-890
resulted in reduction of its pKa by 1.48 units as compared to the parent compound, GEN-203,
leading to a 4-fold drop in volume of distribution and increased plasma clearance (Figure 1).
This minimal structural modification allowed to achieve decreased liver and bone marrow
toxicity in preclinical species.15
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N
H
F
N
N
R
F
O
O
N
O
F
NH
N
N
N
H
GEN-203
GEN-890
R
H
F
5.93
5.2
pKa
7.45
4.3
35
cLogP
c-Met potency, nM
Vd (mL/min/kg)
Clp (mL/min/kg)
15
3.64
4.3
0.99
5.2
Figure 1. ADME properties of c-Met inhibitors GEN-203 and GEN-890.
Although a so-called fluorine scan (i.e. obtaining a set of compounds fluorinated at various
positions16) is a common approach in drug discovery, the range of available compounds can
sometimes be limited by synthetic accessibility of the corresponding fluorinated building
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(A)
Reaxys database search:
4
5
6
F
F
F
F
F
F
F
F
7
8
R
R
R
4
R
1
2
3
9
(854/1325)
(142/791)
(69/815)
(1/29)
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F
F
F
F
F
F
F
F
R
5
R
6
R
7
R
8
(14/72)
(17/45)
(30/227)
(7/53)
R = any functional group
(B)
F
F
O
N
NC
N
N
O
N
NH
Cl
O
N
H
N
F
O
N
F
N
N
F
Maraviroc
Ivosidenib
Figure 2. (a) Mono-functionalized gem-difluorinated cycloalkanes (numbers in brackets
correspond to number of papers / patents referenced by Reaxys database) (b) Structures of
maraviroc and ivosidenib.
blocks.17,18 The resulting gaps in comprehensive enumeration of structurally related fragments
may lead to underexplored pharmaceutically relevant chemical space. This is the case with
mono-functionalized gem-difluorinated cycloalkane derivatives; indeed, the Reaxys database
search19 has revealed that general structures 4–8 were represented to a lesser extent as compared
to compounds 1–3 (Figure 2, A). Nevertheless, the building blocks of the type 5–8 were
frequently used to build SAR studies along with 1–3.20–23 In this series, gem-difluorinated
cyclobutane motif 4 was the most scarcely explored in either synthetic or biological studies.
Since the most studied gem-difluoro-substituted cycloalkane fragments 1 and 3 can be found in
the structures of maraviroc24 and ivosidenib25 (Figure 2, B), which were brought to the market
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recently (in 2007 and 2018, respectively), other gem-difluorinated cycloalkane derivatives
including 4 are worth more thorough investigation.
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To date, the only reported attempt to synthesize gem-difluorocyclobutane derivatives bearing a
functional group at the C-2 position was based on the deoxofluorination of ketone 9 (Scheme
1).26 However, this reaction led to a mixture of the target product 10 and a rearrangement by-
product 11 in low yields, even if up to 15-fold excess of Deoxo-Fluor was used. Although other
methods were reported for the preparation of poly-substituted gem-difluoro-27,28 and polyfluoro-
cyclobutanes,29–32 their utility for mono-substituted derivatives 4 is not clear.
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F
O
(CH3OCH2CH2)2NSF3
(Deoxo-Fluor)
(415 eq)
F
F
F
N
N
N
O
O
O
O
O
O
CH2Cl2
9
10
11
512% yield
739% yield
Scheme 1. Attempted synthesis of compound 10
F
F
F
F
F
F
F
F
NH3+Cl
12·
CO2H
13
Bpin
15
Br
14
HCl
F
F
F
F
F
F
OH
NH3+Cl
HCl
SO2Cl
16
17·
18
Figure 3. Structures of 2,2-difluorocyclobutyl-substituted building blocks obtained in this work.
In this work, we describe an efficient approach to the synthesis of various functionalized
building blocks 12–18 (Figure 3) and its application on a multigram scale. Additionally,
influence of introducing the gem-difluoro moiety into various positions of cyclobutane-derived
building blocks on their physicochemical properties was evaluated. Finally, three-dimensional
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structures of isomeric 2,2- and 3,3-difluorocycobutanamine hydrochlorides were obtained from
X-ray diffraction studies and analyzed using exit vector plot (EVP) tool.
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RESULTS AND DISCUSSION
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Synthesis. Taking into account our recent experience with the preparation of gem-difluorinated
+
cyclohexanes and cyclopentanes 5–8 (R = NH3 Cl–, COOH),33 as well as 3,3-difluoro-
+
cyclobutanes 3 (R = NH3 Cl–, COOH, and other functional groups),34 we have considered
adjustment of the deoxofluorination protocol for the synthesis of the compounds 12–18.
As it was mentioned previously, the reaction of phtalimide-protected 2-aminocyclobutanone 9
with Deoxo-Fluor did not enable to obtain the target product 10 in good yield (Scheme 1);
therefore, carbamate- and sulfonamide-based protecting groups were considered. However, all
attempts to perform deoxofluorination of N-Cbz- and N-tosyl-protected ketones 19a and 19b
with morpholinosulfur trifluoride (Morph-DAST) afforded only complex mixtures of
unidentified products (Scheme 2, Approach 1). Therefore, the corresponding carboxylic acid 13
was proposed as the synthetic target instead of amine 12; the latter could be subjected to the
Curtius rearrangement on the later steps. Because methyl ester of carboxylic acid 13 was
reported to be unstable,35 the deoxofluorination of 2-(het)arylcyclobutanones 20a–c, followed by
oxidative cleavage of the aromatic rings in the intermediates 21a–c was suggested (Approach 2).
Unfortunately, deoxofluorination of phenyl-, methoxyphenyl-, and furyl-substituted
cyclobutanones 20a–c with Morph-DAST also appeared to be unfruitful. Assuming that high
tendency of 19 and 20 towards enolization contributed to the observed reactivity, we have
switched to the less-enolizable ketone 22, which allowed us to obtain compound 13 via
sequential deoxofluorination, deprotection and oxidation as discussed below (Approach 3).
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O
O
F
F
F F
N
SF3
[H]
NH2
NHPG
NHPG
(Morph-
DAST)
12
19a
19b
, R = Cbz
, R = Ts
Curtius
rearrangement
9
O
F
F
F
F
Morph-
DAST
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[O]
CO2H
Ar
, R = Ph
, R = p-MeOPh
, R = 2-Furyl
Ar
13
21a
21b
21c
20a
20b
20c
, R = Ph
, R = p-MeOPh
, R = 2-Furyl
[O]
F
Morph-
DAST
O
F
F
F
OH
[H+]
OAc
OAc
16
32
22
Scheme 2. Retrosynthetic approaches to the compound 22 studied in this work
Initially, we attempted to adjust the procedure developed by Wasserman and colleagues for the
synthesis of the key intermediate 22 to the preparation of 23.36,37 The synthetic scheme
commenced with desilylation of (1-ethoxycyclopropoxy)trimethylsilane (24) in MeOH (91%
yield) (Scheme 3).38 The resulting 1-ethoxycyclopropanol (25) was further subjected to reaction
with vinylmagnesium bromide leading to the addition product 26 (68% yield). The subsequent
one-pot three-membered ring expansion upon action of meta-chloroperbenzoic acid, followed by
acylation with AcCl led to the target product 22 in 36% yield.
O
OTMS
O
MgBr
68%
MeOH
91%
OH
OH
24
25
26
O
O
O
Cl
OH
AcCl
36%
O
OAc
OH
23
22
Scheme 3. Synthesis of the intermediate 22 (an initial approach)
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Although the described method allowed for the preparation of 22 on up to 64 g scale, its
overall yield (22% over 3 steps) was unsatisfying; moreover, the use of an excess of
organometallic reagent at the second step was inconvenient upon the scale-up. Therefore, an
alternative synthetic approach based on [2+2] cycloaddition was proposed. In this case, the
reaction sequence commenced from 2-bromo-1,1-dimethoxyethane (27), which was dehydro-
brominated with KOt-Bu to generate ketene acetal 28. This product was not isolated but
subjected to reaction with methyl acrylate to give cyclobutane derivative 29 (50% yield for 2
steps) (Scheme 4). Reduction of ester moiety in 29 with LiAlH4 led to formation of alcohol 30
(93% yield), which was protected by acylation with AcCl (96% yield). The resulting ketal 31
was hydrolyzed to the target ketone 22 in 85% yield upon action of acid. It should be mentioned
that when this reaction was carried out for more than 45 min, partial hydrolysis at the acetyl
moiety was also observed.
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The latter approach resulted in 38% overall yield of 22; moreover, it commenced from
inexpensive and readily available starting materials. Hence, this method was chosen as more
convenient for scale-up, and it allowed for the preparation of up to 238 g of 22 in a single
synthetic run.
CO2Me
MeO
Br
KOt-Bu
OMe
LiAlH4
OMe
t-BuOH
OMe
THF
93%
50% for
2 steps
OMe
28
CO2Me
OMe
27
29
MeO
MeO
O
AcCl
TsOH
reflux
OMe
OH
OMe
Et3N,
CH2Cl2
96%
OAc
OAc 45 min
85%
30
31
22
Scheme 4. Synthesis of intermediate 22 (an alternative approach)
Further steps of the reaction sequence included deoxofluorination of the ketone 22 with
Morph-DAST to give 32 (70% yield), which was converted into alcohol 16 by alkaline
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hydrolysis (90% yield). Oxidation of alcohol 16 with NaIO4 – RuCl3 afforded the target
carboxylic acid 13 in 98% yield (Scheme 5). Further conversion of 13 into the corresponding
acyl chloride 33, generation of acyl azide (potentially explosive, should be handled with caution)
and the Curtius rearrangement led to compound 34 (55% overall yield). It should be noted that
when transformation of 13 into 34 was performed with the use of diphenylphospharyl azide
(DPPA), a complex mixture containing a minor amount of the target product was formed.
Finally, the subsequent deprotection of 34 with HCl gave 12 as a hydrochloride (96% yield).
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NaOH
H2O
Morph-
DAST
F
F
O
F
F
CH2Cl2
70%
90%
OAc
OH
OAc
OH
22
32
16
F
RuCl3
NaIO4
SOCl2
DMF (cat)
F
F
F
F
F
Cl
CH2Cl2
80%
98%
CO2H
O
16
13
33
F
1) NaN3
2) t-BuOH
F
HCl
MeOH
F
F
NH3+Cl
12·
96%
69%
NHBoc
34
HCl
Scheme 5. Synthesis of carboxylic acid 13 and amine 12
In addition to that, the carboxylic acid 13 was used to prepare bromide 14 by the
Hunsdiecker – Borodin reaction (HgO, Br2, CH2Cl2) (61% yield) (Scheme 6). Compound 14
reacted with bis(pinacolato)diboron in the presence of Cu(PPh3)I and LiOMe at 35 °C, giving
pinacolate 15 in 39% yield. It should be noted, that heating the reaction mixture at the
temperatures higher than 45 °C led to the elimination by-product.
B2pin2
F
F
CuI, PPh3,
LiOMe, DMF
35 °C
F
F
F
F
HgO, Br2
CH2Cl2
CO2H
13
Bpin
15
Br
39%
61%
14
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Scheme 6. Synthesis of bromide 14 and pinacolate 15
5
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8
9
Synthesis of the (2,2-difluorocyclobutyl)methyl-substituted derivatives 17 and 18 started with
mesylation of alcohol 16 (Scheme 7). The subsequent nucleophilic substitution in mesylate 35
with NaN3, followed by Staudinger reaction of azide 36 gave amine 17 (obtained as a
hydrochloride salt, 80% yield from 16). Alternatively, nucleophilic substitution of mesylate 35
with KSAc, followed by oxidative chlorination of thioacetate derivative 37 afforded sulfonyl
chloride 18 (72% yield from 16).
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PPh3
THF
F
F
F
36
F
F
NaN3
DMF
NH3+Cl
HCl
HCl
84%
N3
F
F
17·
KSAc
DMF
87%
OR
Cl2
CH2Cl2
H2O
F
F
F
35
, R = Ms
MsCl
CH2Cl2
96%
SAc
SO2Cl
87%
16
, R = H
37
18
Scheme 7. Synthesis of amine 17 and sulfonyl chloride 18
Physicochemical properties. The pKa values of 13 and 12·HCl were measured and compared
to those of 38, 39, 40·HCl and 41·HCl (Figure 4).39,40 It was found that gem-difluorination of the
parent cyclobutanecarboxylic acid at the γ-position (39) reduced the pKa value of 38 by 0.45,
whereas at the β-position (13) – by 0.84 units. Even more significant pKa modulation was
observed in the case of amines 40, 41 and 12. The pKa of conjugated acid of cyclobutaneamine
(40) was reduced by 1.42 units after gem-difluorination at the γ-position (derivative 41). The
most significant pKa reduction (2.59 units) was observed for 12. These results are in agreement
with the known ability of fluorine to reduce amine basicity by ca. 0.7 units (1.4 units for two
fluorine atoms) when introduced to the γ-position.7,8,41 However, for the compound 12 gem-
difluorinated at the β-position, a greater decrease of pKa (ca. 3.4 units, 1.7 units per one fluorine
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atom) was expected based to the literature data.41 The difference between expected and measured
pKa values for 12 can be attributed to antiparallel orientation of N–H+ bond and one of the C–F
dipoles observed in some of the conformations, which might cause partial stabilization of the
protonated amine form (an effect described by fluorinated piperidine derivatives8).
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F
F
F
F
CO2H
38
pKa = 4.49
CO2H
CO2H
13
39
pKa = 4.04
pKa = 3.65
F
F
F
F
NH3+Cl
NH3+Cl
NH3+Cl
40·
HCl
pKa = 9.79
41·
HCl
12·
HCl
pKa = 7.20
pKa = 8.37
Figure 4. Measured pKa values for 38, 39, 13, 40·HCl, 41·HCl, 12·HCl.
In addition to that, LogP and aqueous solubility (Sw) at 15 °C were measured for derivatives of
the aforementioned compounds. The studied carboxamides 42–44 were obtained from carboxylic
acids 38, 39, and 13 by activation of carboxylic group with CDI, followed by nucleophilic
substitution with aniline (Figure 5, A), whereas carboxamides 45–47 – by acylation of amines
40, 41, and 12 with BzCl in the presence of NEt3 (Figure 5, B). It was found that
gem-difluorination of cyclobutanecarboxamide 42 and N-cyclobutylbenzamide 45 at the γ-
position (derivatives 43 and 46, respectively) did not provide considerable changes to LogP
(Figure 5, C). In contrast to that, introduction of the gem-difluorine moiety at the β-position to
the carboxamide and benzamide groups in 44 and 47, respectively, decreased LogP of 42 and 45
by ca. 0.24 units in both cases.
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A
B
(
)
CDI
RCO2H
RCONHPh
42 44

PhNH2
38 39 13
,
,
(
)
BzCl
NEt3
RNH2
HCl
RNHCOPh
45 47

40 41 12
,
,
9
C
(
)
F
F
F
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F
NHPh
NHPh
NHPh
O
O
O
42
LogP = 2.26
Sw = 0.36 g/L
43
44
LogP = 2.27
Sw = 0.066 g/L
LogP = 2.03
Sw = 0.73 g/L
F
F
O
F
O
O
F
N
H
Ph
N
Ph
N
H
Ph
H
45
46
47
LogP = 1.95
Sw = 0.83 g/L
LogP = 1.94
Sw = 0.23 g/L
LogP = 1.70
Sw = 0.45 g/L
Figure 5. Measured LogP values and aqueous solubility (Sw) for 42–47.
EVP analysis. Molecular structure of gem-difluorinated cyclobutylamines 12 and 41 was
evaluated using an exit vector plot (EVP) tool.42,43 This approach represents the scaffold as a
simplified geometrical model based on two bound vectors n1 and n2 starting from two ring atoms
bearing the substituents (Figure 6). The size of the scaffold is measured by the distance r
between variation points X1 and X2 while the plane angles φ1 (between vectors n1 and X1X2), φ2
,
(between vectors n2 and X2X1), and the torsion angle θ (defined by vectors n1, X1X2, and n2)
describe its three-dimensionality. Although this method was previously utilized for analysis of
bifunctional scaffolds, it can be extended for characterization of monofunctional building blocks
containing polar C–X bonds, to which an electric dipole moment vector can be assigned.
X-ray single crystal diffraction experiments were carried out with racemic 12 and its structural
isomer 41 (Figure 7), and the collected data was used for calculation of the aforementioned
geometrical parameters (Table 1). The n1 and n2 vectors were defined using the C–N bond and
the bisector of the F–C–F angle, respectively.
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Figure 6. (a) Definition of exit vectors n1 and n2. (b) Definition of geometric parameters r, φ1, φ2
and θ.
Figure 7. ORTEP diagrams for compounds 12 and 41 (only (S)-12 isomer is depicted for 12;
only cations are shown). Thermal ellipsoids are shown at the 50% probability level
Variation in the r values observed for 12 and 41 (ca. 0.56 Å) is trivial; it is mainly defined by
the length of the chain separating the amino and CF2 groups. Considerable difference of the
three-dimensional characteristics of the discussed scaffolds is evident when planar angles φ1, φ2,
and dihedral angles θ are taken into account (Figure 8). The data points for the compound 41 are
found in the part of γ region which is common for trans-1,3-disubstituted cyclobutanes.41 On the
contrary, the geometrical parameters of 12 can be assigned to the part of α region characteristic
for cis-1,2-disubstituted cyclobutanes and cyclopentanes; they also reside on the borderline with
those of cis- and trans-1,2-disubstituted cyclohexanes, confirming potential utility of 2,2-di-
fluorocyclobutyl template for the replacement of vicinally substituted cycloalkane derivatives.
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Table 1. Geometric parameters r, φ1, φ2, and θ for 12 and 41.
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Compound
r (Å) φ1 (°) φ2 (°) |θ| (°)b
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12 (conformer A)a 1.528 62.4 46.9 38.6
12 (conformer B)a 1.531 62.9 46.7 32.8
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2.094 39.8 15.8 180
a Two very similar conformer types were observed in the unit cell for each enantiomer of 12.
b Since the signs of θ angle are opposite for different enantiomeric conformations, only absolute
values of θ are considered.
Figure 8. Geometric parameters of 12 (conformers A and B) and 41 shown in the (a) r–θ plot
(polar coordinates), and (b) θ–φ1/φ2 plot.
CONCLUSIONS
A series of building blocks bearing gem-difluorinated cycloalkyl groups was completed with
2,2-difluorocyclobutyl-substituted derivatives. Among possible 2-substituted cyclobutanones, (2-
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acetoxymethyl)cyclobutanone was found to be the most convenient substrate for the deoxo-
fluorination. This compound was obtained from readily available starting materials on a 200 g
scale via a four-step reaction sequence in 38% overall yield. Reaction of the aforementioned
cyclobutanone derivative with Morph-DAST, followed by subsequent functional group transfor-
mations was used for efficient preparation of seven novel 2,2-difluorocyclobutyl-substituted
building blocks, which were synthesized in 2–8 steps in overall 14–63% yields on a multigram
scale. Analysis of pKa and LogP values in a series of non-fluorinated and isomeric gem-
difluorinated cyclobutanecarboxylic acid and cyclobutaneamines or their derivatives revealed
that introduction of the CF2-moiety at the β position to the corresponding functional groups had
the most pronounced effect on these physicochemical properties. In particular, the pKa values
were affected in an expected manner due to strong electron-withdrawing effect of the fluorine
atoms. Moreover, gem-difluorination of the cyclobutyl substituent at the C-3 atom did not
change the lipophilicity of the compounds, whereas for the 2-substituted isomers, the LogP
values decreased by 0.24 units. Finally, exit vector plot (EVP) analysis of 2,2-difluorocyclo-
butanamine molecular geometry showed that such building blocks can be used for replacements
of other vicinally disubstituted cycloalkane derivatives.
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EXPERIMENTAL SECTION
General Methods. The solvents were purified according to the standard procedures.43 All
starting materials were purchased from commercial sources. Melting points were measured on
automated melting point system. Column chromatography was performed using Kieselgel Merck
1
60 (230–400 mesh) as the stationary phase. H, 19F and 13C NMR spectra were recorded at
500 MHz or 400 MHz, 470 or 376 MHz, and 126 MHz or 101 MHz, respectively. Chemical
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shifts are reported in ppm downfield from TMS as an internal standard. Elemental analyses were
performed at the Laboratory of Organic Analysis, Department of Chemistry, Taras Shevchenko
National University of Kyiv. HRMS were obtained on Bruker Daltonics MicroTof. Mass spectra
were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI),
electrospray ionization (ESI)) and Agilent 5890 Series II 5972 GCMS instrument (electron
impact ionization (EI)). pKa values were measured by acid-base titration using a pH-meter. The
LogP values were obtained from three independent experiments according to a literature
procedure,45 and the mean value was reported. The aqueous solubility of the compounds was
determined by analogy with lyophilized solubility assay (LYSA) using pure compounds instead
of lyophilized stock solutions.46 The X-ray diffraction data sets were collected with a CMOS
diffractometer for compound 12HCl, and with CCD diffractometer for compound 41HCl.
Programs used: data collection, APEX3 V2016.1-0;47 cell refinement and data reduction, SAINT
V8.37A;48, absorption correction, SADABS V2014/7;49 structure solution; structure refinement,
SHELXL-2015.50 R-values are given for observed reflections, and wR2 values are given for all
reflections. CCDC-1901193 (12·HCl), -1902436 (41·HCl) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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1-Ethoxycyclopropanol (25).38 A solution of (1-ethoxycyclopropoxy)trimethylsilane (24) (278
g, 1.60 mol) in MeOH (2 L) was stirred overnight at rt. The obtained solution was concentrated
under reduced pressure and distilled in vacuo. Colorless liquid, yield 91% (148 g). Bp = 65 °C /
10 mmHg. For other physical and spectral data, see refs.38,51,52
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1-Vinylcyclopropanol (26). The compound was obtained by a method of Wasserman and
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colleagues36,37 in 68% yield. For spectral and physical data, see refs.36,37
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(2-Oxocyclobutyl)methyl acetate (22).36 To a pre-cooled to 10 °C solution of 1-
vinylcyclopropan-1-ol (26) (83.0 g, 0.987 mol) in CH2Cl2 (1.5 L), meta-chloroperoxybenzoic
acid (256.0 g (85%), 1.26 mol) was added portionwise. The reaction mixture was stirred at rt for
1 h. The precipitate was filtered off and washed with CH2Cl2 (150 mL). The filtrate was cooled
to 5 °C, and Et3N (550 mL, 3.95 mol) was added dropwise. Then acetyl chloride (200 mL, 2.81
mol) was added dropwise at the same temperature, the reaction mixture was stirred for additional
10 min, warmed to rt and poured into H2O (1 L). The organic layer was separated and washed
with 10% aq. Na2SO3 (800 mL) and saturated aq NaHCO3 (800 mL), dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The crude product was purified by column
1
chromatography (hexane–EtOAc = 5:1, Rf = 0.29). Colorless oil; 36% yield (64.5 g). H NMR
(500 MHz, CDCl3): δ 4.14 (qd, J = 11.6, 5.2 Hz, 2H), 3.59–3.46 (m, 1H), 3.06–2.94 (m, 1H),
2.93–2.83 (m, 1H), 2.19–2.08 (m, 1H), 1.96 (s, 3H), 1.90–1.77 (m, 1H) ppm. 13C{1H} NMR
(126 MHz, CDCl3): δ 208.1, 170.9, 61.5, 58.8, 45.5, 20.6, 14.1 ppm. GCMS (m/z): 100 (M+ –
+
C2H2O). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C7H10NaO3 165.0522; Found: 165.0525.
Methyl 2,2-dimethoxycyclobutanecarboxylate (29).53 To a vigorously stirred 2-bromo-1,1-
dimethoxyethane (27) (1000 g, 5.92 mol), t-BuOK (680 g, 6.06 mol) was added portionwise,
exothermic reaction was observed, and the temperature of the mixture was maintained below 70
°C. The reaction mixture was stirred for 1 h, and then distilled at 80–100 °C under atmospheric
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pressure. The obtained mixture of t-BuOH and 1,1-dimethoxyethene (28) (782 g) was dissolved
in a mixture of t-BuOH (800 mL) and methyl acrylate (390 g, 4.53 mol). The reaction mixture
was refluxed under argon atmosphere for 12 d, evaporated under reduced pressure and distilled
in vacuo. Colorless oil; yield 50% (395 g). Bp = 56 °C / 1 mmHg. 1H NMR (500 MHz, CDCl3):
δ 3.70 (s, 3H), 3.31–3.24 (m, 4H), 3.13 (s, 3H), 2.30 (ddd, J = 11.0, 8.3, 5.1 Hz, 1H), 2.19–2.08
(m, 1H), 2.06–1.98 (m, 1H), 1.90–1.79 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
171.5, 103.0, 51.9, 49.3, 48.7, 48.6, 29.9, 14.2 ppm. GCMS (m/z): 174 (M+), 143 (M+ – OCH3).
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+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C8H14NaO4 197.0784; Found: 197.0785.
(2,2-Dimethoxycyclobutyl)methanol (30). A solution of methyl 2,2-dimethoxycyclobutane-1-
carboxylate (29) (395 g, 2.27 mol) in THF (400 mL) was added to a stirred suspension of LiAlH4
(120 g, 3.16 mol) in THF (4 L). The reaction mixture was stirred at rt overnight and quenched
carefully by sequential addition of H2O (120 mL), NaOH (120 g, 3.00 mol) in H2O (120 mL),
and H2O (360 mL). The mixture was stirred for 1 h, filtered and the residue was washed with
THF (2×500 mL). The combined organic phase was evaporated under reduced pressure,
dissolved in CH2Cl2 (2 L), dried over anhydrous Na2SO4, concentrated under vacuum and
distilled in vacuo. Colorless oil; yield 93% (308 g). Bp = 37 °C / 1 mmHg. 1H NMR (400 MHz,
CDCl3): δ 3.63–3.49 (m, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 2.71 (t, J = 6.3 Hz, 1H), 2.59–2.46 (m,
1H), 2.08 (td, J = 11.3, 6.8 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.73–1.59 (m, 1H), 1.34 (tt, J = 11.6,
13
6.1 Hz, 1H) ppm. C{1H} NMR (126 MHz, CDCl3): δ 103.9, 62.5, 48.4, 48.0, 44.8, 29.3, 13.7
+
ppm. GCMS (m/z): 129 (M+ – OH). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C7H14NaO3
169.0835; Found: 169.0828.
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(2,2-Dimethoxycyclobutyl)methyl acetate (31). AcCl (161 mL, 2.25 mol) was added to a
solution of (2,2-dimethoxycyclobutyl)methanol (30) (300 g, 2.05 mol) and Et3N (430 mL, 312 g,
3.08 mol) in CH2Cl2 (4 L) at –30 °C under argon atmosphere. The reaction mixture was warmed
to rt, washed with H2O (1.3 L), aq. NaHCO3 (1 L), dried over anhydrous Na2SO4, concentrated
under reduced pressure and distilled in vacuo. Colorless oil; yield 96% (372 g). Bp = 51 °C / 1
mmHg. 1H NMR (500 MHz, DMSO-d6): δ 4.01 (dd, J = 10.8, 8.3 Hz, 1H), 3.86 (t, J = 10.8, 7.0
Hz, 1H), 2.96 (s, 3H), 2.95 (s, 3H), 2.49 (quint, J = 8.1, 7.5 Hz, 1H), 2.03 – 1.95 (m, 1H), 1.83
(s, 3H), 1.81 – 1.73 (m, 1H), 1.71 – 1.60 (m, 1H), 1.27 – 1.15 (m, 1H) ppm. 13C{1H} NMR (126
MHz, DMSO-d6): δ 170.2, 102.3, 63.2, 48.3, 47.8, 42.8, 28.5, 20.4, 15.1 ppm. GCMS (m/z): 145
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+
(M+ – C2H2O). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C9H16NaO4 211.0941; Found:
211.0942.
(2-Oxocyclobutyl)methyl acetate (22).36
To a solution of (2,2-dimethoxycyclobutyl)methyl acetate (31) (370 g, 1.97 mol) in acetone (2.8
L), H2O (900 mL) and TsOH·H2O (78.0 g, 0.41 mol) were added. The reaction mixture was
heated to reflux for 45 min, cooled to rt, and acetone was evaporated under reduced pressure.
NaHCO3 was added carefully to the mixture to neutralize the acid. The resulting mixture was
extracted with EtOAc (2×700 mL). The combined organic phases were dried over anhydrous
Na2SO4 and concentrated under vacuum. The crude product was purified by column
chromatography (hexane–EtOAc = 5:1, Rf = 0.29). Colorless oil; yield 85% (238.5 g). The
spectral and physical data was in accordance with those, described above.
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(2,2-Difluorocyclobutyl)methyl acetate (32). Morpholinosulfur trifluoride (700 g, 4.00 mol)
was added to an ice-cold solution of (2-oxocyclobutyl)methyl acetate (22) (235 g, 1.65 mol) in
anhydrous CH2Cl2 (2 L). The reaction mixture was stirred at rt for 2 d and poured carefully into
aq Na2CO3 (2 L). The mixture was extracted with CH2Cl2 (2×700 mL). The combined organic
phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude
product was distilled in vacuo. Colorless oil; yield 70% (189 g). Bp = 50 °C / 5 mmHg. 1H NMR
(500 MHz, CDCl3): δ 4.14 (d, J = 7.2 Hz, 2H), 3.11–2.95 (m, 1H), 2.52–2.34 (m, 2H), 2.02 (s,
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3H), 1.94–1.79 (m, 1H), 1.58–1.40 (m, 1H) ppm. C{1H} NMR (126 MHz, CDCl3): δ 171.1,
121.2 (dd, J = 286.6, 278.7 Hz), 61.4 (d, J = 6.3 Hz), 45.3 (t, J = 21.9 Hz), 32.9 (t, J = 22.6 Hz),
19
20.9, 13.6 (dd, J = 13.7, 4.6 Hz) ppm. F NMR (376 MHz, CDCl3): –85.0 (dd, J = 195.1, 10.6
Hz), –110.2 (dq, J = 195.1, 15.4 Hz) ppm. GCMS (m/z): 149 (M+ – CH3), 122 (M+ – C2H2O).
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C7H10F2NaO2 187.0541; Found: 187.0538.
(2,2-Difluorocyclobutyl)methanol (16). (2,2-Difluorocyclobutyl)methyl acetate (32) (120 g,
0.73 mol) was added in one portion to a solution of NaOH (150 g, 3.75 mol) in H2O (450 mL).
The reaction mixture was heated to reflux for 30 min, cooled to rt and extracted with CH2Cl2
(2×300 mL). The combined organic phases were dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude product was distilled in vacuo. Colorless oil; yield 90% (80.1
g). Bp = 44 °C / 5 mmHg. 1H NMR (500 MHz, CDCl3): δ 3.82–3.73 (m, 1H), 3.68 (dd, J = 11.7,
5.7 Hz, 1H), 3.04–2.83 (m, 1H), 2.57–2.36 (m, 3H), 1.92– 1.77 (m, 1H), 1.58–1.42 (m, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 122.3 (dd, J = 285.9, 279.1 Hz), 60.3 (d, J = 6.0 Hz), 48.4
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(t, J = 21.0 Hz), 32.8 (t, J = 22.4 Hz), 12.9 (dd, J = 13.0, 6.1 Hz) ppm. F NMR (376 MHz,
CDCl3): δ –85.0 (dq, J = 195.6, 12.8 Hz), –108.4 (dq, J = 195.6, 14.1 Hz) ppm. GCMS (m/z):
104 (M+ – H2O). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C5H8F2NaO+ 145.0435; Found:
145.0429.
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2,2-Difluorocyclobutanecarboxylic acid (13). To
a
solution of (2,2-difluoro-
cyclobutyl)methanol (16) (50.0 g, 0.41 mol) and NaIO4 (350 g, 1.64 mol) in CCl4 (500 mL),
CH3CN (500 mL) and H2O (750 mL), RuCl3 hydrate (4.25 g, 20.5 mmol) was added and the
mixture was stirred at rt for 2 h. Aq NaHCO3 (300 mL) was added to the mixture to neutralize
the acid. The solid phase was filtered and washed with H2O (200 mL). The filtrate was extracted
with CHCl3, the organic layer was separated and acidified with 10% aq. NaHSO4. The aqueous
phase was extracted with EtOAc (2×400 mL). The combined organic phases were dried over
anhydrous Na2SO4, and concentrated under reduced pressure. White solid, mp 66–68 °C; yield
1
98% (54.7 g). H NMR (500 MHz, CDCl3): δ 11.35 (br s, 1H), 3.68 (quint, J = 10.5 Hz, 1H),
2.67–2.45 (m, 2H), 2.18 (quint, J = 9.7 Hz, 1H), 2.08–1.90 (m, 1H) ppm. C{1H} NMR (126
13
MHz, CDCl3): δ 174.4, 119.4 (dd, J = 290.7, 281.5 Hz), 50.6 (t, J = 22.8 Hz), 33.4 (t, J = 22.0
Hz), 12.9 (dd, J = 11.4, 3.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ –84.2 (d, J = 192.3 Hz), –
102.5 (dq, J = 192.3, 14.5 Hz) ppm. GCMS (m/z): 119 (M+ – OH), 91 (M+ – COOH). HRMS
–
(ESI-TOF) m/z: [M – H]– Calcd. for C5H5F2O2 135.0263; Found: 135.0273.
2,2-Difluorocyclobutanecarbonyl chloride (33). To a solution of 2,2-difluorocyclobutane-1-
carboxylic acid (13) (50.0 g, 0.37 mol) and DMF (2 mL) in CH2Cl2 (500 mL), SOCl2 (75.0 mL,
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1.03 mol) was added dropwise. The reaction mixture was heated to reflux for 1.5 h, cooled to rt
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and evaporated under reduced pressure. The crude product was distilled in vacuo. Colorless oil;
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yield 80% (45.6 g). Bp = 55 °C / 21 mmHg. H NMR (400 MHz, CDCl3): δ 4.08 (dq, J = 12.6,
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9.6 Hz, 1H), 2.65 – 2.48 (m, 2H), 2.28 (quint, J = 9.6 Hz, 2H), 2.15 – 2.02 (m, 1H) ppm.
13C{1H} NMR (126 MHz, CDCl3): δ 168.9, 119.3 (dd, J = 294.4, 279.7 Hz), 60.3 (dd, J = 24.0,
21.6 Hz), 32.9 (t, J = 21.9 Hz), 14.7 (d, J = 12.0 Hz) ppm. 19F NMR (470 MHz, CDCl3): δ –82.4
(d, J = 193.7 Hz), –104.8 (dtd, J = 193.7, 16.7, 12.5 Hz) ppm. GCMS (m/z): 119 (M+ – Cl). Anal.
Calcd. for C5H5ClF2O: C, 38.86; H, 3.26; Cl, 22.94. Found: C, 38.52; H, 3.40; Cl, 22.56.
tert-Butyl (2,2-difluorocyclobutyl)carbamate (34). 2,2-Difluorocyclobutanecarbonyl chloride
(33) (45.0 g, 0.29 mol) was dissolved in acetone (150 mL) and added dropwise to a pre-cooled (0
°C) solution of NaN3 (63.1 g, 0.97 mol) in H2O (225 mL). The mixture was stirred at the same
temperature for 1 h, diluted with ice-cold H2O (350 mL) and extracted with EtOAc (2×400 mL).
The combined organic phase was dried over anhydrous Na2SO4 and concentrated to a volume of
ca. 100 mL on a rotary evaporator at a water bath temperature of 40 °C. CAUTION! The acyl
azide is potentially explosive. The solution should not be evaporated to dryness. The residue was
dissolved in toluene (375 mL) and t-BuOH (135 mL, 1.42 mol) was added. The reaction mixture
was slowly heated under argon atmosphere and refluxed overnight. The mixture was cooled to rt
and concentrated under reduced pressure. The crude product was purified by column
chromatography (hexane–EtOAc = 8:1, Rf = 0.30). White solid, mp 97–99 °C; yield 69% (41.7
1
g). H NMR (500 MHz, CDCl3): δ 5.00 (s, 1H), 4.53 (s, 1H), 2.38 – 2.13 (m, 3H), 1.60 – 1.48
13
(m, 1H), 1.43 (s, 9H) ppm. C{1H} NMR (126 MHz, CDCl3): δ 154.6, 121.9 (dd, J = 298.6,
270.0 Hz), 80.3, 53.6 (t, J = 21.2 Hz), 29.8 (t, J = 21.5 Hz), 28.4, 20.8 (d, J = 19.6 Hz) ppm.
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19F{1H} NMR (376 MHz, CDCl3) δ –86.7 (d, J = 194.2 Hz), –121.6 (d, J = 194.2 Hz). LCMS
(m/z): 108 (M+ – CO2 – (CH3)2CCH2 + H). Anal. Calcd. for C9H15F2NO2: C, 52.17; H, 7.30; N,
6.76. Found: C, 51.99; H, 6.97; N, 6.95.
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2,2-Difluorocyclobutanaminium
chloride
(12·HCl).
tert-Butyl
(2,2-
difluorocyclobutyl)carbamate (34) (41.0 g, 0.20 mol) was dissolved in 2 M methanolic HCl (300
mL). After 15 min the reaction mixture was concentrated under reduced pressure, and the crude
1
product was recrystallized from CH3CN. White solid, mp 155–157 °C; yield 96% (27.5 g). H
NMR (500 MHz, D2O): δ 4.29 (quint, J = 8.3 Hz, 1H), 2.75–2.51 (m, 2H), 2.41–2.25 (m, 1H),
1.96 (quint, J = 10.7 Hz, 1H) ppm. C{1H} NMR (126 MHz, D2O): δ 118.9 (dd, J = 293.4,
13
19
272.6 Hz), 51.8 (dd, J = 27.3, 19.5 Hz), 30.0 (t, J = 21.4 Hz), 16.0 (d, J = 15.3 Hz) ppm. F
NMR (376 MHz, D2O): δ –86.2 (d, J = 199.3 Hz), –117.3 (dtd, J = 199.3, 20.3, 11.5 Hz) ppm.
LCMS (m/z) 108 (M + H+ – HCl). HRMS (ESI-TOF) m/z: [M – Cl]+ Calcd. for C4H8F2N+
108.0619; Found: 108.0612.
2-Bromo-1,1-difluorocyclobutane (14). A mixture of HgO (4.77 g, 0.022 mol) and 2,2-
difluorocyclobutanecarboxylic acid (13) (3.00 g, 0.022 mol) in CH2Cl2 (120 mL) was refluxed
under an argon atmosphere for 20 min. Note: the reaction flask was covered with aluminum foil
to prevent access of light. Bromine (4.37 g, 1.40 mL, 0.0273 mol) in CH2Cl2 (15 mL) was slowly
added dropwise to the resulting mixture at reflux upon stirring over 20 min. Then, the reaction
mixture was refluxed for additional 45 min. The solution was cooled in a cold water bath, and
the insoluble precipitate was filtered off. The filtrates were washed with sat. aq NaHCO3 (2×25
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mL) and brine (50 mL) and dried over Na2SO4. The solution was subjected to fractional
distillation at atmospheric pressure until most of CH2Cl2 was distilled. The residue was distilled
at atmospheric pressure to give the title product. Colorless oil, yield 61% (2.30 g). Bp = 112–114
°C / 1 atm. 1H NMR (400 MHz, CDCl3) δ 4.49 (quint, J = 8.7 Hz, 1H), 2.77 – 2.65 (m, 1H), 2.57
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– 2.40 (m, 2H), 2.04 (quint, J = 10.1 Hz, 1H) ppm. C{1H} NMR (126 MHz, CDCl3): δ 118.3
(dd, J = 289.8, 277.3 Hz), 44.2 (dd, J = 27.3, 22.2 Hz), 32.8 (dd, J = 23.8, 21.1 Hz), 23.0 (d, J =
19
14.7 Hz) ppm. F NMR (470 MHz, CDCl3): δ –86.8 (d, J = 188.8 Hz), –107.6 (dq, J = 188.8,
15.7 Hz) ppm. GCMS (m/z): 170/172 (M+), 151/153 (M+ – F), 106/108 (CH2CHBr+). Anal.
Calcd. for C4H5BrF2: C, 28.10; H, 2.95; Br, 46.73. Found: C, 27.91; H, 3.25; Br, 47.06.
2-(2,2-Difluorocyclobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(15).
2-Bromo-1,1-
difluorocyclobutane (14) (300 mg, 1.75 mmol) was added dropwise through a syringe to a
mixture of CuI (33 mg, 0.175 mmol), PPh3 (60 mg, 0.229 mmol), LiOMe (0.141 g, 3.71 mmol),
bis(pinacolato)diboron (0.680 g, 2.68 mmol), and DMF (3.5 mL) under argon atmosphere. The
resulting mixture was stirred vigorously at 35 °C for 24 h, then diluted with EtOAc (10 mL) and
washed with H2O (3×5 mL). The organic layer was dried over Na2SO4 and evaporated under
vacuum. The residue was purified by column chromatography (hexanes – EtOAc, 24:1).
1
Colorless oil, yield 39% (149 mg). H NMR (500 MHz, CDCl3): δ 2.64 – 2.52 (m, 2H), 2.51 –
2.41 (m, 1H), 1.86 – 1.76 (m, 2H), 1.26 (s, 12H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ
122.7 (dd, J = 284.1, 279.1 Hz), 84.0, 35.5 (t, J = 22.8 Hz), 32.9, 24.8 (d, J = 9.3 Hz), 11.2 (t, J =
9.2 Hz) ppm. F{1H} NMR (376 MHz, CDCl3): δ –83.1 (d, J = 187.3 Hz), –87.4 (d, J = 187.3
19
Hz) ppm. GCMS (m/z): 218 (M+). Anal. Calcd. for C10H17BF2O2: C, 55.08; H, 7.86. Found: C,
55.20; H, 7.74.
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(2,2-Difluorocyclobutyl)methyl methanesulfonate (35). Methanesulfonyl chloride (29.5 mL,
0.38 mol) was added dropwise to a cooled solution of (2,2-difluorocyclobutyl)methanol (35.8 g,
0.29 mol) (16) and Et3N (61.2 mL, 0.45 mol) in CH2Cl2 (700 mL) at –30 °C under argon
atmosphere. The reaction mixture was allowed to warm to rt, washed with H2O (300 mL), aq.
NaHCO3 (300 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure.
Colorless oil, yield 96% (56.6 g). 1H NMR (500 MHz, CDCl3): δ 4.36 (dd, J = 10.6, 8.2 Hz, 1H),
4.28 (dd, J = 10.6, 6.0 Hz, 1H), 3.24 – 3.10 (m, 1H), 3.02 (s, 3H), 2.60 – 2.43 (m, 2H), 2.06 –
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1.91 (m, 1H), 1.67 – 1.54 (m, 1H) ppm. C NMR (126 MHz, CDCl3): δ 120.7 (dd, J = 288.3,
277.9 Hz), 66.2 (d, J = 6.7 Hz), 45.3 (dd, J = 23.4, 20.7 Hz), 37.5, 32.8 (t, J = 22.5 Hz), 13.3 (dd,
J = 13.5, 4.2 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –84.6 (d, J = 196.4 Hz), –110.1 (d, J
= 196.4 Hz) ppm. GCMS (m/z): 200 (M+). Anal. Calcd. for C6H10F2O3S: C, 36.00; H, 5.03; S,
16.01. Found: C, 36.08; H, 5.09; S, 15.67.
(2,2-Difluorocyclobutyl)methanaminium chloride (17·HCl). NaN3 (13.7 g, 0.21 mol) was
added to a solution of (2,2-difluorocyclobutyl)methyl methanesulfonate (35) (14.0 g, 69.9 mmol)
in DMF (100 mL). The reaction mixture was heated to 65 °C in an oil bath overnight, then
cooled to rt, poured into H2O (300 mL) and extracted with EtOAc (300mL). The organic phase
was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude
product which was used in the next step without further purification.
The crude 2-(azidomethyl)-1,1-difluorocyclobutane (36) was dissolved in dry THF (150 mL) and
the mixture was cooled to 0 °C. PPh3 (18.3 g, 69.9 mmol) was added portionwise to the solution.
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The resulting mixture was warmed to rt and stirred overnight. H2O (10 mL) was added and the
mixture was heated to reflux for 2 h, cooled to rt and evaporated under reduced pressure. The
residue was treated with 2M aq solution of HCl (100 mL) and extracted with CH2Cl2 (2×100
mL). The aqueous phase was concentrated under vacuum and the crude product was
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recrystallized from CH3CN. White solid, mp 211–213 °C; yield 84% (9.23 g). H NMR (400
MHz, D2O): δ 3.38 – 3.25 (m, 1H), 3.24 – 3.08 (m, 2H), 2.70 – 2.37 (m, 2H), 2.14 – 1.98 (m,
1H), 1.60 (quint, J = 9.4 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, D2O): δ 121.4 (dd, J = 288.9,
275.5 Hz), 43.2 (dd, J = 23.0, 20.9 Hz), 37.2 (d, J = 7.3 Hz), 31.8 (t, J = 21.9 Hz), 13.9 (dd, J =
14.7, 3.4 Hz) ppm. 19F NMR (470 MHz, D2O): δ –83.4 (d, J = 193.6 Hz), –110.8 (dq, J = 193.6,
16.7 Hz) ppm. LCMS (m/z): 122 (M+ – Cl). Anal. Calcd. for C5H10ClF2N: C, 38.11; H, 6.40; N,
8.89; Cl, 22.50. Found: C, 38.01; H, 6.62; N, 9.25; Cl, 22.40.
S-((2,2-Difluorocyclobutyl)methyl) ethanethioate (37). KSAc (34.5 g, 0.30 mol) was added to
solution of (2,2-difluorocyclobutyl)methyl methanesulfonate (35) (55.0 g, 0.27 mol) in DMF
(400 mL). The reaction mixture was stirred overnight, then poured into H2O (1 L) and extracted
with EtOAc (600 mL). The organic phase was washed with H2O (400 mL), dried over anhydrous
Na2SO4, and evaporated under reduced pressure. The crude product was purified by column
1
chromatography (hexane–EtOAc = 20:1, Rf = 0.70). Colorless oil; yield 87% (42.3 g). H NMR
(400 MHz, CDCl3): δ 3.11 – 2.83 (m, 3H), 2.48 – 2.36 (m, 2H), 2.32 (s, 3H), 2.02 – 1.88 (m,
1H), 1.45 (quint, J = 9.6 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 195.4, 121.5 (dd, J
= 289.5, 277.2 Hz), 46.1 (t, J = 21.5 Hz), 32.3 (t, J = 22.5 Hz), 30.6, 26.8 (d, J = 5.9 Hz), 16.7
(dd, J = 15.5, 3.2 Hz) ppm. 19F NMR (470 MHz, CDCl3): δ –83.7 (d, J = 193.1 Hz), –111.3 (dtd,
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J = 193.1, 17.0, 11.9 Hz) ppm. GCMS (m/z): 180 (M+). Anal. Calcd. for C7H10F2OS: C, 46.66;
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H, 5.59; S, 17.79. Found: C, 46.90; H, 5.39; S, 17.48.
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(2,2-Difluorocyclobutyl)methanesulfonyl chloride (18). S-((2,2-Difluorocyclobutyl)methyl)
ethanethioate (37) (42.0 g, 0.23 mol) was dissolved in CH2Cl2 (600 mL) and H2O (300 mL) was
added. The mixture was cooled to 0 °C and Cl2 was bubbled through at 0–10 °C with stirring for
1–2 h (reaction was monitored by TLC). The organic phase was separated, washed with H2O
(200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography (hexane–EtOAc = 20:1, Rf = 0.36). Colorless
oil; yield 87% (41.7 g). 1H NMR (500 MHz, CDCl3): δ 4.03 (dd, J = 14.4, 5.1 Hz, 1H), 3.80 (dd,
J = 14.4, 9.2 Hz, 1H), 3.52 – 3.38 (m, 1H), 2.66 – 2.51 (m, 2H), 2.33 – 2.20 (m, 1H), 1.81 (quint,
J = 9.3 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 120.2 (dd, J = 294.7, 274.2 Hz), 63.4
(d, J = 6.1 Hz), 41.5 (dd, J = 23.9, 21.0 Hz), 33.2 (t, J = 22.1 Hz), 17.0 (d, J = 15.6 Hz) ppm. 19F
NMR (470 MHz, CDCl3): δ –81.2 (d, J = 193.5 Hz), –112.1 (dddd, J = 193.5, 20.8, 16.9, 13.1
Hz) ppm. GCMS (m/z): 169 (M+ – Cl). Anal. Calcd. for C5H7ClF2O2S: C, 29.35; H, 3.45; S,
15.67; Cl, 17.32. Found: C, 29.02; H, 3.06; S, 15.49; Cl, 17.08.
General procedure for preparation of 42–44. Carbonyldiimidazole (1.94 g, 0.012 mol) was
added to a solution of the corresponding acid (0.010 mol) in THF (15 mL), and the solution was
stirred at 40 °C for 2 h. The reaction mixture was cooled to rt, aniline (1.02 g, 0.011 mol) was
added and the reaction mixture was stirred at 40 °C overnight. The obtained mixture was
concentrated under vacuum, the residue was dissolved in CH2Cl2 (20 mL), washed with 5% aq
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HCl (10 mL), NaHCO3 (10 mL), and brine (10 mL). The combined organic layers were dried
over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was purified by
flash column chromatography (CHCl3–MeOH = 70:1 as eluent).
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N-Phenylcyclobutanecarboxamide (42). Beige solid, mp = 113–115 °C; yield 77% (0.674 g)
from 0.50 g (5.00 mmol) of 38. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.36 (br
s, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 3.16 (quint, J = 8.5 Hz, 1H), 2.45 – 2.32
13
(m, 2H), 2.25 – 2.15 (m, 2H), 2.04 – 1.84 (m, 2H) ppm. C{1H} NMR (126 MHz, CDCl3): δ
173.4, 138.2, 129.0, 124.2, 119.9, 41.0, 25.4, 18.2 ppm. LCMS (m/z): 176 (M + H+). Anal. Calcd.
for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.65; H, 7.70; N, 8.36.
3,3-Difluoro-N-phenylcyclobutanecarboxamide (43). Beige solid, mp = 174–176 °C; yield
69% (0.535 g) from 0.50 g (3.68 mmol) of 39. 1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H),
7.60 (d, J = 8.0 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 3.10 (quintd, J = 8.3,
13
3.4 Hz, 1H), 2.89 – 2.69 (m, 4H) ppm. C{1H} NMR (126 MHz, DMSO-d6): δ 170.5, 138.9,
128.7, 123.4, 119.7 (dd, J = 284.7, 269.5 Hz), 119.2, 38.0 (t, J = 23.5 Hz), 27.5 (dd, J = 14.2, 5.0
19
Hz) ppm. F{1H} NMR (376 MHz, DMSO-d6): δ –81.0 (d, J = 189.4 Hz), –96.0 (d, J = 189.4
Hz) ppm. LCMS (m/z): 212 (M + H+). Anal. Calcd. for C11H11F2NO: C, 62.55; H, 5.25; N, 6.63.
Found: C 62.83; H 4.96; N 6.53.
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(0.481 g) from 0.50 g (3.68 mmol) of 13. H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.0 Hz,
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2H), 7.41 – 7.26 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 3.64 (quint, J = 10.6 Hz, 1H), 2.73 – 2.48 (m,
2H), 2.41 – 2.25 (m, 1H), 2.10 – 1.92 (m, 1H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 165.1,
137.5, 129.2, 124.9, 120.3, 120.2 (dd, J = 296.1, 283.5 Hz), 52.5 (t, J = 22.3 Hz), 33.3 (t, J =
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21.8 Hz), 13.0 (dd, J = 11.6, 4.6 Hz) ppm. F{1H} NMR (376 MHz, CDCl3): δ –84.2 (d, J =
191.1 Hz), –101.5 (d, J = 191.1 Hz) ppm. LCMS (m/z): 212 (M + H+). Anal. Calcd. for
C11H11F2NO: C, 62.55; H, 5.25; N, 6.63. Found: C 62.39; H 4.95; N 6.82.
General procedure for preparation of 45–47. To a solution of the corresponding amine (0.010
mol) in CH2Cl2 (10 mL) was added NEt3 (3.49 mL, 0.025 mol), and the solution was cooled to
0–5 °C in an ice bath. A solution of benzoyl chloride (1.10 mL, 0.0095 mol) in CH2Cl2 (11 mL)
was added dropwise, and the reaction mixture was stirred at rt overnight. The resulting mixture
was quenched with 10% aq citric acid (25 mL), the organic layer was separated, washed with aq
NaHCO3 (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced
pressure.
N-Cyclobutylbenzamide (45). White solid, mp = 119–121 °C; yield 92% (0.748 g) from 0.50 g
(4.65 mmol) of 40·HCl. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.4 Hz, 2H), 7.46 (t, J = 7.4
Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 6.49 (s, 1H), 4.58 (sext, J = 8.1 Hz, 1H), 2.44 – 2.35 (m, 2H),
2.03 – 1.90 (m, 2H), 1.80 – 1.67 (m, 2H) ppm. 13C{1H} NMR (126 MHz, CDCl3): δ 166.7,
ACS Paragon Plus Environment
29