Fluoroalkyl-substituted cyclopropane derivatives: Synthesis and physicochemical properties

Article abstract of DOI:10.1021/acs.joc.0c01848

A series of all 12 cis- and trans-cyclopropanecarboxylic acids and cyclopropylamines bearing CH2F, CHF2, and CF3 substituents were synthesized by different methods on a multigram scale. Dissociation constants (pKa) and log P values were measured for the o

Full text of DOI:10.1021/acs.joc.0c01848

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Article
Fluoroalkyl-Substituted Cyclopropane Derivatives:
Synthesis and Physicochemical Properties
Anton V. Chernykh, Oleksandr S. Olifir, Yuliya O. Kuchkovska, Dmitriy
M. Volochnyuk, Vladimir S. Yarmolchuk, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01848 • Publication Date (Web): 01 Sep 2020
Downloaded from pubs.acs.org on September 1, 2020
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Fluoroalkyl-Substituted Cyclopropane Derivatives:
Synthesis and Physicochemical Properties
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Anton V. Chernykh,a Oleksandr S. Olifir,a,b Yuliya O. Kuchkovska,a,b Dmitriy M. Volochnyuk,a,c
Vladimir S. Yarmolchuka 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 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street
5, Kyiv 02660, Ukraine
*E-mail: gregor@univ.kiev.ua
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ABSTRACT. A series of all twelve cis- and trans-cyclopropanecarboxylic acids and
cyclopropylamines bearing CH2F-, CHF2- and CF3-substituents was synthesized by different
methods on a multigram scale. Dissociation constants (pKa) and logP values were measured for
the obtained compounds or their derivatives in order to evaluate the influence of the type and
relative position of fluoroalkyl substituents on acidity and lipophilicity of monofunctionalized
cyclopropanes. Analysis of selected products by X-ray crystallography was carried out to obtain
a better insight into observed differences in physicochemical properties.
KEYWORDS: Fluorine, cyclopropane, deoxofluorination, lipophilicity, acidity/basicity
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INTRODUCTION
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Over the past decades, the introduction of fluorine atoms into the scaffolds of biologically
active molecules has become a universal tool for manipulation of a number of drug-related
properties.1–7 Meanwhile, a recent analysis of fluorinated groups commonly found in
pharmaceutically relevant molecules revealed that 95% of fluorine atom occurrences were found
in CF3 moieties, and 75% of these belonged to the aryl substituents, ArCF3 or ArOCF3.8 At the
same time, CF2- and aliphatic CF-containing derivatives were relatively scarce among the
compounds with abstracted pharmacological data.9
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One of the current challenges in modern medicinal chemistry is to find new relationships
between structure and physicochemical properties and to derive a set of rational rules for design
of fluorinated drugs.3,4,10 This problem was addressed extensively in several papers with regard
to mono-, di- and poly-fluorinated n-alkyl chains.11–17 A bond vector analysis was applied to
these groups in order to explain the changes in polarity of the molecule depending on the spatial
arrangement of the fluorine atoms. One more promising instance is utilization of pre-defined
orientation of the fluorine atoms in cyclic scaffolds which can be achieved due to decreased
conformational flexibility of cycloalkanes and their heterocyclic counterparts (Figure 1).18–20 For
example, a significant increase of piperidine basicity in 1 was observed when fluorine was
introduced into axial β position of 1b (pKa = 7.6) instead of equatorial β position of 1a
(pKa = 6.6). This effect can be explained by stabilization of the protonated form of 1b by
antiparallel H–N···C–F dipole–dipole interaction. Another noteworthy illustration is the ability of
fluorine atoms to modulate lipophilicity of cyclopropyl- and cyclohexyl-substituted benzenes 2a
and 3a, respectively, depending on their position.21,22 In particular, facially polarized derivatives
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2b and 3b were noted to be less hydrophobic as compared to their counterparts 2c and 3c
containing one F-atom in trans-configuration.
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Effect on pKa:
R
N
F
HO
N
O
N
1a
, equatorial position
F
N
6.6
=
pKa
R
N
N
N
F
F
F
1
1b
, axial position
Kinesin Spindle
Protein Inhibitor
7.6
pKa
=
Effect on LogP:
F
F
F
Ph
F
Ph
F
F
Ph
2a
2b
LogP =
2c
3.40
2.56
F
2.74
F
LogP =
LogP =
F
F
F
F
Ph
Ph
Ph
3a
3b
LogP =
3c
4.99
2.64
2.79
LogP =
LogP =
Figure 1. Previously studied effects of introducing fluorine atoms into specific positions of
cycloalkanes or their heterocyclic counterparts on pKa and LogP (selected examples)
Of the cyclic scaffolds, the cyclopropane ring is the smallest one and has multiple applications
in medicinal chemistry. Its ability to modulate a compounds physicochemical and
pharmacokinetic properties, potency and target specificity was extensively discussed in the
review by Talele.23 Due to the rigidity of the cyclopropane backbone, any contribution of
conformational transformations which can be found in other cyclic systems is excluded. Taking
into account the potential of fluoroalkyl and cyclopropyl fragments for drug discovery, intriguing
chemotypes can emerge from the combination thereof.24 One such structural pattern is already
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present in the hepatitis C virus NS3/4A protease inhibitors Glecaprevir25 and Voxilaprevir,26
both being components of combination drugs Mavyret and Vosevi, respectively (approved in
2017, Figure 2). The investigation of a co-crystal structure of their non-macrocyclic close
analogue 4a with the NS3/4A protease complex allowed an indication of a H-bond between the
CHF2 group and the backbone carbonyl of Leu135 of the enzyme.27 Importantly, the substitution
of the CHF2 group in 4a to either CH3 in 4b or CF3 in 4c led to 13- and 17-fold decrease in
potency, respectively.
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A
B
( )
(
)
R3
O
O
Cl
R1
O
O
R2
O
O
F
H
N
S
N
H
N
H
F
N
O
O
N
O
O
O
O
H
S
F
N
H
N
H
O
N
O
N
O
Glecaprevir
:
R4
F
O
O
R1 = H
O
N
R2 and R3
=
Inhibitor 4
N
R4
IC50, nM
Voxilaprevir
:
F
F
4a
4b
4c
CHF2
CH3
CF3
1
R1 = Et
N
N
13
17
R2 and R3
=
O
Figure 2. Inhibitors of hepatitis C virus NS3 protease
In this work, we describe straightforward synthetic protocols for the preparation of cis- and
trans- isomers of cyclopropanecarboxylic acids 5–7 and cyclopropylamine hydrochlorides 8–10
bearing CH2F, CHF2, and CF3 groups at the β-position (Figure 3). Moreover, an opportunity to
control the physicochemical properties of the resulting compounds is investigated by the
quantitative assessment of the influence of fluorinated moieties on acidity and lipophilicity. In
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addition, analysis of X-ray crystallographic data for selected representatives has been carried out
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in order to provide rationalization to the observed variations of the pKa and logP values.
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pK

?
a
RF
FG
RF
FG
LogP

?
trans
cis
F
F
F
COOH
COOH
COOH
F
F
F
5
6
7
cis- and trans-
cis- and trans-
cis- and trans-
F
F
F
NH3+Cl
NH3+Cl
NH3+Cl
F
F
F
8
9
10
cis- and trans-
cis- and trans-
cis- and trans-
Figure 3. Fluoroalkyl-substituted cyclopropane building blocks 5–10 studied in this work
RESULTS AND DISCUSSION
Synthesis. A literature survey on the synthesis of close derivatives of monofluorinated 2-
methylcyclopropanecarboxylic acid 5 has revealed that preparation of its methyl ester 11 was
previously reported by de Meijere and co-workers (Scheme 1).28 The reaction sequence included
reduction of the carboxylic acid moiety in 12 with borane – dimethylsulfide complex and then
deoxofluorination of 13. After reproducing these transformations in our laboratory, we subjected
intermediate 11 to hydrolysis with NaOH which gave the target carboxylic acid trans-5 in 75%
yield.
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de Meijere et al.:[28]
4
5
6
7
Deoxo-
Fluor
Me2S·BH3
THF
O
O
O
O
0 °C to rt
OMe 95% OH
PhMe,
CH2Cl2
47%
OH
O
F
O
12
13
11
8
9
NaOH
THFH2O
Deoxo-Fluor :
O
10
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O
N
O
F
OH
75%
5
SF3
trans-
Scheme 1. Preparation of carboxylic acid trans-5
Taking into account the efficiency of the described approach to the preparation of trans-5, a
similar reaction sequence was examined for the synthesis of cis-5. In contrast to the case of
trans-isomer, the usage of more sterically hindered isopropyl ester 14 instead of methyl ester was
envisaged in order to avoid intramolecular lactonization of the alcohol 15 (Scheme 2, A). The
synthesis of 14 and reduction of its carboxylic acid group with Me2S·BH3 was previously
described by Polonski and colleagues.29,30 Although product 15 was observed to undergo partial
cyclization to 16 upon concentration, it can be stored as an EtOAc solution, and carefully
concentrated and redissolved in CH2Cl2 directly before the next step. The same undesired
cyclization into 16 appeared to be an obstacle for deoxofluorination of 15 with Morph-DAST
(conditions A). An alternative approach based on the conversion of 15 to the triflate and further
substitution with TBAF was also unsuccessful – only trace amounts of the compound 17 were
identified by 1H NMR of a crude mixture, whereas 16 was present as a major product (conditions
B). The satisfactory yield of the fluoromethyl substituted derivative 17 was only achieved when
XtalFluor-M31,32 was used (45% yield from 14, conditions C). The next alkaline hydrolysis of 17
afforded carboxylic acid cis-5 in 55% yield. Noteworthy, the hydrolysis should be carried out for
no more than 15 min, otherwise lactone 16 and the product of its hydrolysis were formed as
major products, and cis-5 was obtained only in trace quantities. The isolated pure carboxylic acid
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cis-5 also tends to gradually undergo intramolecular cyclization with the formation of 16 upon
standing at rt. Nevertheless it was possible to store this compound at –10 °C for about 3 weeks
without significant change in purity.
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A
(
)
Morph-DAST:
F
XtalFluor-M :
F
O
O
BF4
O
N
S
F
O
N
S
OH
Oi-Pr
14
F
F
Me2S·BH3
THF
0 °C to rt
A
:
conditions
Morph-DAST
CH2Cl2
O
O
O
B
:
conditions
OH
Oi-Pr
16
1) (CF3SO2)2O
2) TBAF
15
major product
C
conditions
XtalFluor-M
Et3N·3HF, CH2Cl2
:
14
45% from
NaOH
MeOHH2O
O
O
55%
F
F
Oi-Pr
OH
17
5
cis-
O
B
(
)
Cl
Cl
O
N
N
O
N
Morph-DAST
Cl
O
15
TEMPO, AcONa
CH2Cl2, 0 °C
78% from
CH2Cl2, 0 °C
38%
O
Oi-Pr
18
(in solution)
14
NaOH
F
O
THFH2O
F
O
F
Oi-Pr
95%
F
OH
6
cis-
19
Scheme 2. Preparation of the compounds cis-5 (A) and cis-6 (B).
cis-Difluoromethyl-substituted cyclopropanecarboxylic acid (cis-6) was accessed via a three-
step reaction sequence starting from intermediate alcohol 15 (Scheme 2, B). Oxidation of 15 with
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trichloroisocyanuric acid in the presence of TEMPO as a catalyst (78% from 14) was followed
by deoxofluorination of 18 with Morph-DAST (38% yield) to give 19. Finally, hydrolysis of 19
with NaOH solution afforded target product cis-6 in 95% yield.
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A
(
)
1) aq NaOH, 50 °C
F
F
2) (t-BuOCO)2O
DMAP, THF
66% for 2 steps
F
CO2Et
F
CO2t-Bu
22
20
F
O
S
I
CF3CO2H
CH2Cl2
NaH, DMSO
45%
F
O
O
92%
F
F
Ot-Bu
OH
21
6
trans-
NaBH4
B
LDA
EtOAc
(
)
O
O
O
PhMe or PhH
OEt
rt, 80%
F2HC
O
F2HC
OEt
70 °C, 80%
P2O5
OH
O
O
, 75%
F2HC
F2HC
OE
22
Scheme 3. Synthesis of trans-6 (A); previously reported synthesis of starting material 22 (B).
Although the preparation of the methyl ester of trans-6 by a reaction sequence similar to that
described in Scheme 2 (B) was reported previously,28 a different method was examined here for
the synthesis of this carboxylic acid (Scheme 3, A). The key step of the selected synthetic
approach involved a Corey-Chaykovsky cyclopropanation and was carried out with difluorinated
crotonic acid ester 20 (45% yield). This step was followed by deprotection of the tert-butyl ester
moiety in 21 with CF3CO2H, which afforded trans-6 in 92% yield. Importantly, neither ethyl
ester 22 nor its benzyl counterpart were appropriate substrates for the cyclopropanation step –
they both led to complex mixtures of products. Therefore, the use of 20, which can be accessed
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from 22 by basic hydrolysis and tert-butyl ester formation (66% yield over 2 steps), was crucial.
The starting material 20 can in turn be obtained by a procedure which was previously reported by
Zanda and colleagues (Scheme 3, B).33
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O
A
( )
S
I
F3C
CO2R
F3C
CO2R
NaH, DMSO
23a
23b
24a,b
unsuccessful
, R = Et
, R = t-Bu
AlCl3, LiAlH4
Et2O
with
23a
ZnEt2, CH2I2
CH2Cl2
OH
F3C
OH
F3C
26
25
unsuccessful
B
( )
NC
CO2Et
F3C
K2CO3, KF
CO2Et
CN
CO2H
CO2H
KOH
H2O
F3C
F
F
Br
27
F
DMF, 28%
reflux, 79%
28
29
1) 
distillation
29
F
F
O
F
and
O
2) separation
by column
chromatography
F
F
OH
F
OH
7
cis- , 30%
7
trans- , 41%
Scheme 4. Synthesis of cis-7 and trans-7.
Among the two stereoisomeric trifluoromethyl-substituted cyclopropanecarboxylic acids, only
trans-7 was previously obtained and characterized.28,34,35 Importantly, it was mentioned in one of
the reports that the preparation of esters of trans-7 could not be achieved by deoxofluorination of
carboxylic acid 12 with Deoxo–Fluor.28 Similarly, all our attempts to carry out deoxofluorination
of the corresponding cis-disubstituted cyclopropane carboxylic acids were also unsuccessful.
Therefore, Corey-Chaykovsky cyclopropanation of 2336 was next examined (Scheme 4, A).
Unfortunately, reaction of both Et- and t-Bu-esters 23 with dimethyloxosulfonium methylide led
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to complex mixtures of products instead of 24. An alternative Simmons–Smith cyclopropanation
of allyl alcohol 25 into 26 also appeared to be unfruitful.
7
8
9
Finally, carboxylic acid cis-7 was obtained by a three-step reaction sequence along with its
isomer trans-7 (Scheme 4, B). Cyclization of 27 with ethyl 2-cyanoacetate afforded
cyclopropane derivative 28 (28% yield),37 which was further subjected to alkaline hydrolysis of
both ester and nitrile groups (79% yield). Unfortunately, we could not avoid formation of
stereoisomeric mixtures of the final product upon the decarboxylation step. The best result was
achieved by heating 29 until it became completely melted, and then distilling the formed 50:50
mixture of cis-7 and trans-7 at 170–185 °C. Alternative decarboxylation methods that were
tested (e.g. refluxing of 29 in pyridine or heating at 80 °C with Cu2O in DMF) usually led to a
higher ratio of trans-product (up to 70%) and a greater content of by-products; furthermore, the
conversion was lowered significantly when the reaction time was reduced to 1 h. The obtained
isomers of 7 were next separated by column chromatography to provide cis-7 and trans-7 in 30%
and 41% yield, respectively.
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Synthesis of amines 8–10 was achieved via a modified Curtius rearrangement of the
corresponding carboxylic acids 5–7, followed by N-Boc deprotection of the intermediate
carbamates (Table 1). The two non-fluorinated derivatives trans-31 and cis-31 were obtained by
the same procedure for further evaluation of their physicochemical properties.
Table 1. Preparation of amines 8–10 and 31
1) ClCO2Et, NaN3
O
t-BuOH, PhMe
NH3+Cl
and
R
R
OH
and
2) HCl, MeOH
5 7
8 10


31
30
(R = CH3)
(R = CH3)
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Entry
Amine
cis-8
R
Yield, %
68
1
2
3
4
5
6
7
8
CH2F
CH2F
CHF2
CHF2
CF3
trans-8
cis-9
72
60
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trans-9
cis-10
62
67
trans-10
cis-31
CF3
72
CH3
54
trans-31
CH3
66
Physicochemical Properties. In order to evaluate an impact of the degree of fluorination and
the spatial orientation of the fluoroalkyl moiety and either carboxylic acid or amine group at the
cyclopropane ring, pKa values were measured for compounds 5–7 and 8–10 (Figure 4, A). In the
case of carboxylic acid cis-5, an undesired cyclization to lactone 16 occurred upon deprotonation
with base. Since this side reaction prevented the accurate measurement of the pKa value for cis-5,
this experiment was excluded. In addition, it was also noted that the fluoromethyl-substituted
amines 8 were unstable as free bases and therefore could not be used for reliable measurements
of the dissociation constants.
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Figure 4. Measured pKa values for 5–7, 9, 10 and 30, 31 (A); oak ridge thermal ellipsoid plot
(ORTEP) diagrams for compounds cis-6 (B). Thermal ellipsoids are shown at the 50%
probability level.
It turned out that in the case of carboxylic acids 6 and 7, the relative configuration of the two
substituents had no significant impact on the acidity. The difference of pKa values for isomers of
6 and 7 is comparable to that for non-fluorinated derivatives 30 (∆pKa = 0.01, 0.12, and 0.04,
respectively). This result indicates that the acidity of 5–7 and 30 is influenced almost exclusively
by the extent of polarization through bonds. By contrast, the basicity of all amines cis-9, 10, and
31 was noted to be lower than of their corresponding trans-isomers. This may relate to the steric
effect of the (fluoro)alkyl groups in the cis isomers, which interferes with the protonation ability
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of amine group and disfavors solvatation of the cationic forms. The maximum difference of 0.60
pKa units was observed for cis-/trans-9 pair. This effect can be explained by additional
polarization of the N+–H bond through space due to the proximate position and the favorable
relative orientation of the fluoroalkyl moiety dipol. Yet, such interaction had little impact on the
acidity of cis-6 because of the greater distance between the CHF2-group and the O–H bond
(Figure 4, B). Besides, the difference in pKa values for CH3-/CF3-substituted pairs cis-10/cis-31
and trans-10/trans-31 was estimated to be 2.23 and 2.26 units, respectively. This observation is
in compliance with a general rule of thumb that introduction of fluorine atoms into the γ-position
of aliphatic amine leads to the decrease of dissociation constant by ca. 0.7 units per γ-F.10,17
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PhNH2, HATU
i-Pr2NEt
O
O
OH
R
R
R
HN
Ph
DMF
7387%
5 7
and
32 35


30
O
BzCl, Et3N
NH3+Cl
N
Ph
R
CH2Cl2
H
7490%
8 10

36 39

31
and
Scheme 5. Synthesis of amides 32–35 and 36–39.
Next, compounds 5–7, 30 and 8–10, 31 were converted into their corresponding amides 32–35
and 36–39 (Scheme 5), which were used for the determination of LogP. Previously, it was found
that the common tendency in lipophilicity of n-propyl-substituted compounds containing the
fluorine atoms at the C-3 position is CH3 >> CH2F ≤ CHF2 << CF3.17 This trend was fully
retained for amides trans-32–35 and 36–39 (Figure 5). However, amides cis-32–35 demonstrated
a different pattern: CH2F < CF3 < CHF2 < CH3. The decrease in lipophilicity of cis-34 as
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compared to trans-34 (∆logP = 0.86) was noted to be significantly higher than the logP gap for
the cis-38/trans-38 pair (∆logP = 0.37). An analysis of X-ray crystal structures of amides cis-34
and cis-38 was used to provide a possible explanation to this observation (Figure 6). In
particular, it was noticed that there is a weak attractive interaction between the fluorine atom of
CF3 group and the carbonyl moiety of cis-substituted amides. This assumption was supported by
short F···C(=O) (r1) and F···O (r2) distances (r1 = r2 = 3.07 Å) and by F···C(=O) angle of 78.5° in
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cis-34 that are typical for such interactions.38–40 In addition, C NMR spectra of these studied
amides revealed a greater shielding of carbonyl C-atom in cis-34 (δ = 165.3 ppm) as compared to
trans-34 and cis-/trans-38 (δ = 168.1–168.9 ppm). This attractive F···C(=O) interaction may
stabilize the preferred position of carbonyl group of cis-34 at ca. 39.5° to C–CF3 bond and
facilitate the co-orientation of C=O and CF3 derived dipole moments (Figure 5, displayed as
vectors n1 and n2, respectively). By contrast, a similar interaction in cis-38 orients C=O moiety at
ca. 102.9° with respect to the CF3-group and does not lead to a similar significant increase in
polarity, which was indicated for cis-34. This observation was also consistent with calculated
dipole moment of 4.4766 Debye for more lipophilic compound cis-38, and a greater value of
5.2968 Debye for the more polar compound cis-34.
For other types of fluorinated substituents, it was noted that amides derived from amines cis-8
and 9 were also more polar than their trans-counterparts (Figure 4, ∆logP = 0.29 and 0.28,
respectively). Yet, the amides derived from carboxylic acids 5 and 6 had a negligible difference
of the logP values between their cis- and trans-isomers (∆logP = 0.08 and 0.07, respectively).
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Figure 5. Measured logP values for 32–35 and 36–39.
Figure 6. Oak ridge thermal ellipsoid plot (ORTEP) diagrams for compounds cis-34 and cis-
38. Thermal ellipsoids are shown at the 50% probability level.
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CONCLUSIONS
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All twelve isomeric CH2F-, CHF2-, CF3-substituted cyclopropanecarboxylic acids and
cyclopropanamines were synthesized by three different synthetic approaches on a multigram
scale. One of the described approaches relied on deoxofluorination of either aldehyde or
hydroxymethyl moieties in the cyclopropanecarboxylic acid esters. Two other reaction sequences
involved cyclopropanation of fluoroalkyl-substituted alkene as the key synthetic step.
Comparison of pKa values for cis- and trans-fluoroalkyl substituted cyclopropanecarboxylic
acids revealed that their acidity is not influenced by the configuration of groups on the
cyclopropane ring. On the contrary, the basicity of the corresponding amines was slightly
lowered by the presence of a proximate fluorinated methyl moiety in the cis-position.
Examination of logP values of the obtained amides demonstrated that all representatives
followed CH3 >> CH2F ≤ CHF2 << CF3 lipophilicity pattern except for amide cis-34 derived
from cis-CF3-substituted cyclopropanecarboxylic acid. Additional X-ray crystallographic studies
allowed detecting a weak attractive interaction between the fluorine atoms of the CF3 group and
the carbonyl moiety of the cis-substituted amides that could contribute to the notable increase in
polarity. Overall, the synthesized compounds present valuable fluoroalkyl-substituted
cyclopropane-derived building blocks which can be used for modulation of physicochemical
properties upon lead optimization.
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EXPERIMENTAL SECTION
General Methods. The solvents were purified according to the standard procedures.41 All
starting materials were purchased from commercial sources. Melting points were measured on
automated melting point system. Column chromatography was performed using Kieselgel Merck
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60 (230–400 mesh) as the stationary phase. H, 19F and 13C NMR spectra were recorded at
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500 MHz or 400 MHz, 470 or 376 MHz, and 126 MHz or 101 MHz, respectively. Chemical
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. High-resolution mass spectra (HRMS) were recorded on an
LC/MSD TOF mass spectrometer by electrospray ionization time-of-flight reflectron
experiments. 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.42 X-ray diffraction studies were performed on an automatic
diffractometer (graphite monochromated Mo Kα radiation, CCDdetector, ω-scanning, 2θmax =
60°). CCDC 2020315 (cis-6), 2020316 (trans-9), 2020372 (cis-34), and 2020373 (cis-38) 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.
Dipole moments were calculated using Gaussian 09 set of programs43 at the M06-2X/aug-cc-
pVTZ approximation level.44–46 Atomic coordinates were extracted from the XRDA data and
used without optimization.
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trans-2-(Fluoromethyl)cyclopropanecarboxylic Acid (trans-5). To a solution of NaOH (24.2
g, 0.606 mol) in H2O (300 mL), a solution of ester 11 (40.0 g, 0.303 mol) in THF (300 mL) was
added. The reaction mixture was stirred overnight, acidified with aq. NaHSO4 and extracted with
EtOAc (2×300 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated
1
under reduced pressure. Yield 26.8 g (75%). White crystalline solid, mp = 49–51 °C. H NMR
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(400 MHz, CDCl3) δ 11.61 (s, 1H), 4.42 (ddd, J = 47.9, 9.9, 5.9 Hz, 1H), 4.22 (ddd, J = 47.5,
9.9, 7.0 Hz, 1H), 1.98 – 1.82 (m, 1H), 1.67 (dt, J = 8.7, 4.5 Hz, 1H), 1.34 (tt, J = 8.7, 3.8 Hz,
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1H), 1.07 – 0.93 (m, 1H) ppm. C{1H} NMR (126 MHz, CDCl3) δ 179.9, 84.5 (d, J = 169.3
19
Hz), 22.3 (d, J = 24.7 Hz), 18.2 (d, J = 5.6 Hz), 13.0 (d, J = 6.8 Hz) ppm. F{1H} NMR (376
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MHz, CDCl3) δ –215.7 ppm. GC–MS (m/z): 85 (M+ – CH2F). HRMS (ESI–TOF) m/z: [M + H]+
Calcd for C5H8FO2 119.0503; Found 119.0502.
cis-2-(Fluoromethyl)cyclopropanecarboxylic Acid (cis-5). To a solution of acid 14 (120 g,
0.70 mol) in THF (1.7 L), a 10 M solution of BH3·Me2S in THF (175 mL, 1.75 mol) was added
dropwise under Ar at –20 °C. The reaction mixture was warmed to rt, stirred overnight and after
that poured into cold saturated aq. NH4Cl (1 L). After extraction with EtOAc (3×1 L), the
combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced
pressure to give crude isopropyl cis-2-(hydroxymethyl)cyclopropanecarboxylate (15), which was
used in the next step without additional purification. BF3·OEt2 (111 g, 99.0 mL, 781 mmol) was
added dropwise to an ice-cold solution of morpholinosulfur trifluoride (137 g, 783 mmol) in
anhydrous CH2Cl2 (1.4 L) under Ar, while keeping the reaction temperature below 5 °C. The
resulting suspension was stirred for 15 min at the same temperature, then Et3N·3HF (252 g, 255
mL, 1.57 mol) was added in one portion. The reaction mixture was stirred for 15 min at 5 °C and
then a solution of alcohol 15 (90.0 g, 523 mmol) in CH2Cl2 (100 mL) was added dropwise. The
resulting solution was stirred for 1 h at the same temperature, then diluted with aq. NaHCO3 (1
L). The aqueous layer was extracted with CH2Cl2 (2×600 mL), the combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
subjected to vacuum distillation (bp 56 – 60 °C / 7 mbar) to give 50.2 g of the compound 17
(colorless liquid, ca. 45% yield), which was used in the next step without additional purification.
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1H NMR (400 MHz, CDCl3) δ 5.00 (sept, J = 6.3 Hz, 1H), 4.72 (ddd, J = 48.2, 9.7, 6.1 Hz, 1H),
4.43 (dt, J = 47.1, 9.7 Hz, 1H), 1.90 – 1.76 (m, 1H), 1.76 – 1.61 (m, 1H), 1.23 (t, J = 7.1 Hz,
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6H), 1.16 – 1.06 (m, 2H) ppm. C{1H} NMR (126 MHz, CDCl3) δ 171.6, 82.1 (d, J = 164.0
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Hz), 68.2, 21.9, 21.8, 20.4 (d, J = 25.5 Hz), 18.1 (d, J = 4.5 Hz), 11.3 (d, J = 8.3 Hz) ppm.
19F{1H} NMR (376 MHz, CDCl3) δ –212.4 ppm.
To a solution of 17 (50.0 g, 312 mmol) in the mixture of MeOH (250 mL) and H2O (250 mL),
NaOH (50.0 g, 1.25 mol) was added in one portion at 20 °C. The reaction mixture was stirred for
15 min, diluted with H2O (1 L) and extracted with t-BuOMe (650 mL). The aqueous phase was
separated, acidified with NaHSO4 and extracted with EtOAc (650 mL). The organic phase was
dried over anhydrous Na2SO4 and concentrated under reduced pressure at 33–35 °C. The
obtained solids were washed with pentane and filtered to give the target product. Compound cis-
5 started to decompose gradually after 3 week of storing at –10 °C. Yield: 31.9 g (ca. 55% from
1
17, or 25% from 14). White solid, unstable upon heating. H NMR (500 MHz, CDCl3) δ 4.74
(ddd, J = 47.9, 9.6, 6.1 Hz, 1H), 4.55 (dt, J = 47.1, 9.6 Hz, 1H), 1.91 – 1.85 (m, 1H), 1.85 – 1.77
13
(m, 1H), 1.27 – 1.21 (m, 1H), 1.20 – 1.14 (m, 1H) ppm. C{1H} NMR (126 MHz, CDCl3) δ
178.7, 81.8 (d, J = 164.4 Hz), 21.6 (d, J = 25.9 Hz), 17.5 (d, J = 4.4 Hz), 12.5 (d, J = 8.0 Hz)
ppm. 19F NMR (470 MHz, CDCl3) δ –212.4 (t, J = 47.5 Hz) ppm. HRMS (ESI–TOF) m/z: [M +
H]+ Calcd for C5H8FO2 119.0503; Found 119.0501.
cis-Isopropyl 2-(Difluoromethyl)cyclopropanecarboxylate (19). To a solution of acid 14
(120 g, 0.70 mol) in THF (1.7 L), a 10 M solution of BH3·Me2S in THF (175 mL, 1.75 mol) was
added dropwise under Ar at –20 °C. The reaction mixture was warmed to rt, stirred overnight
and after that poured into cold saturated aq. NH4Cl (1 L). After extraction with EtOAc (3×1 L),
the combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced
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pressure to give crude isopropyl cis-2-(hydroxymethyl)cyclopropanecarboxylate (15), which was
used in the next step without additional purification. To a pre-cooled to 0 °C mixture of crude
alcohol 15 (92.0 g, 0.58 mol), TEMPO (1.80 g, 11.5 mmol) and CH3CO2Na (71.5 g, 0.87 mol) in
CH2Cl2 (1.4 L), trichloroisocyanuric acid (54.0 g, 0.23 mol) was added portionwise. The reaction
mixture was warmed to rt and stirred for 4 h. K2CO3 (400 g, 2.90 mol) was then added and the
mixture was stirred for additional 30 min. The resulting solution was filtered and washed with
aq. K2CO3 (700 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The difluorinated derivative 18 was additionally subjected to vacuum
distillation (bp 68–70 °C / 22 mbar) and was isolated in a pure form containing up to 33 mol% of
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CH2Cl2. Yield 84.9 g (78%). Colorless oil. H NMR (500 MHz, CDCl3) δ 9.31 (d, J = 6.4 Hz,
1H), 5.00 (hept, J = 6.3 Hz, 1H), 2.17 (td, J = 8.2, 6.4 Hz, 1H), 2.01 (tt, J = 8.2, 6.6 Hz, 1H),
1.89 (td, J = 6.6, 5.0 Hz, 1H), 1.51 (td, J = 8.2, 5.0 Hz, 1H), 1.24 (d, J = 6.3 Hz, 3H), 1.22 (d, J =
6.3 Hz, 3H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 199.7, 170.0, 69.1, 30.0, 23.0, 21.7, 13.0
ppm. The compound 18 was used further as a synthetic intermediate for the preparation of 19.
Morpholinosulfur trifluoride (202 g, 1.15 mol) was added dropwise to an ice-cold solution of
aldehyde 18 (82.0 g, 0.53 mol) in anhydrous CH2Cl2 (1 L). The resulting solution was gradually
warmed to rt and stirred for 24 h, and then poured into aq. NaHCO3 (700 mL). The organic phase
was separated, whereas aqueous phase was extracted with CH2Cl2 (2×300 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by vacuum distillation (bp 51–55 °C / 9 mbar). Yield 35.7 g (38%
1
from 18, or 30% from 14). Colorless oil. H NMR (400 MHz, CDCl3) δ 5.82 (td, J = 55.7, 7.6
Hz, 1H), 5.00 (sept, J = 6.2 Hz, 1H), 1.92 – 1.83 (m, 1H), 1.77 – 1.65 (m, 1H), 1.33 – 1.27 (m,
13
1H), 1.22 (t, J = 6.2 Hz, 6H), 1.21 – 1.16 (m, 1H) ppm. C{1H} NMR (101 MHz, CDCl3) δ
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171.1, 116.5 (dd, J = 236.1, 233.6 Hz), 68.8, 22.4 (dd, J = 34.4, 30.3 Hz), 21.8, 21.8, 17.4 (d, J =
7.3 Hz), 10.4 (d, J = 8.9 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ –108.7 (dd, J = 289.0, 55.7 Hz,
1F), –114.3 (ddd, J = 289.0, 55.7, 8.6 Hz, 1F) ppm. GC–MS (m/z): 163 (M+ – CH3), 127 (M+ –
CHF2), 119 (M+ – OCH(CH3)2), 91 (M+ – CO2CH(CH3)2). Anal. Calcd. for C8H12F2O2: C, 53.93;
H, 6.79. Found: C, 54.17; H, 7.02.
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cis-2-(Difluoromethyl)cyclopropanecarboxylic Acid (cis-6). To a solution of NaOH (15.3 g,
0.38 mmol) in H2O (300 mL), a solution of ester 19 (34.0 g, 0.19 mol) in THF (100 mL) was
added. The reaction mixture was stirred overnight, acidified with aq. NaHSO4 and extracted with
EtOAc (2×200 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by vacuum distillation (bp 68–70 °C / 2
mbar). Yield 25.1 g (95%). White solid, mp 68–70 °C. 1H NMR (500 MHz, CDCl3) δ 11.75 (br
s, 1H), 5.87 (td, J = 55.5, 7.6 Hz, 1H), 1.96 (td, J = 8.2, 6.0 Hz, 1H), 1.91 – 1.80 (m, 1H), 1.43 –
1.30 (m, 2H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 178.4, 116.1 (dd, J = 236.0, 234.6), 23.6
19
(dd, J = 35.0, 30.7 Hz), 17.0 (d, J = 7.5 Hz), 11.6 ppm. F NMR (376 MHz, CDCl3) δ –108.9
(dd, J = 290.9, 55.5 Hz, 1F), –114.1 (ddd, J = 290.9, 55.5, 8.5 Hz, 1F) ppm. GC–MS (m/z): 136
(M+), 116 (M+ – HF), 91 (M+ – CO2H), 85 (M+ – CHF2). HRMS (ESI–TOF) m/z: [M – H]– Calcd
for C5H5F2O2 135.0263; Found 135.0266.
(E)-tert-Butyl 4,4-Difluorobut-2-enoate (20). To a solution of NaOH (67.3 g, 1.68 mol) in
H2O (600 mL), ethyl ester 22 (67.3 g, 0.45 mol) was added and stirred at 50 °C for 2 h using oil
bath as a heat source. After cooling the reaction mixture to rt, the solution was neutralized with
aq NaHSO4 and then extracted with EtOAc (2×400 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
recrystallized from hexane and then subjected to the next step. To a solution of obtained (E)-4,4-
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difluorobut-2-enoic acid (44.5 g) in THF (450 mL), Boc2O (95.5 g, 0.44 mol) was added at 0 °C.
DMAP (8.91 g, 72.9 mmol) was then added in small portions at the same temperature, after
which the reaction mixture was warmed to rt and stirred overnight. The resulting solution was
diluted with EtOAc (450 mL), washed with H2O (300 mL), aq. NaHSO4 (300 mL) and aq.
NaHCO3 (300 mL). The organic phase was dried over anhydrous Na2SO4, evaporated under
reduced pressure and distilled in vacuo (bp 56–58 °C / 7 mbar). Yield 52.7 g (66%). Colorless
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oil. H NMR (400 MHz, CDCl3) δ 6.69 (dtd, J = 16.0, 9.9, 4.5 Hz, 1H), 6.23 – 6.13 (m, 1H),
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6.19 (dd, J = 55.1, 4.5 Hz, 1H), 1.49 (s, 9H) ppm. C{1H} NMR (101 MHz, CDCl3) δ 163.9,
135.5 (t, J = 24.1 Hz), 129.4 (t, J = 10.5 Hz), 112.9 (t, J = 236.8 Hz), 82.0, 28.1 ppm. 19F NMR
(376 MHz, CDCl3) δ –116.0 (ddd, J = 55.1, 9.9, 2.5 Hz) ppm. GC–MS (m/z): 163 (M+ – CH3),
105 (M+ – OC(CH3)3). Anal. Calcd. for C8H12F2O2: C, 53.93; H, 6.79. Found: C, 54.27; H, 6.99.
trans-tert-Butyl 2-(Difluoromethyl)cyclopropanecarboxylate (21). To a suspension of NaH
(12.8 g, 0.32 mol, 60% dispersion in oil) in dry DMSO (500 mL) under Ar,
trimethylsulfoxonium iodide (70.4 g, 0.32 mol) was added portionwise. After stirring at rt for 1
h, a solution of 20 (51.0 g, 0.29 mol) in DMSO (250 mL) was added dropwise. The reaction
mixture was stirred overnight, poured into aq. NaHCO3 (600 mL) and extracted EtOAc (3×600
mL). The combined organic layers were washed with H2O (2×500 mL), dried over anhydrous
Na2SO4, evaporated under reduced pressure and distilled in vacuo (bp 56–57 °C / 7 mbar.). Yield
25.5 g (45%). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 5.73 (td, J = 57.2, 3.5 Hz, 1H), 1.88 –
1.80 (m, 1H), 1.78 (dt, J = 9.3, 4.8 Hz, 1H), 1.42 (s, 9H), 1.21 – 1.15 (m, 1H), 1.09 – 1.03 (m,
1H) ppm. 13C{1H} NMR (126 MHz, CDCl3) δ 171.4, 115.0 (t, J = 238.8 Hz), 81.3, 28.2, 22.6 (t,
J = 26.9 Hz), 17.1 (t, J = 4.1 Hz), 9.7 (t, J = 4.5 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ –117.9
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(dt, J = 57.2, 11.3 Hz) ppm. Anal. Calcd. for C9H14F2O2: C, 56.24; H, 7.34. Found: C, 56.49; H,
6.94.
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trans-2-(Difluoromethyl)cyclopropanecarboxylic Acid (trans-6). To a solution of ester 21
(25.0 g, 0.13 mol) in CH2Cl2 (200 mL), CF3CO2H (25 mL) was added. The reaction mixture was
stirred overnight, concentrated under vacuum and dried under reduced pressure. Yield 16.5 g
(92%). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 10.68 (br s, 1H), 5.79 (td, J = 57.0, 3.4 Hz,
1H), 2.03 – 1.95 (m, 1H), 1.91 (dt, J = 9.2, 4.7 Hz, 1H), 1.38 – 1.30 (m, 1H), 1.28 – 1.20 (m, 1H)
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ppm. C{1H} NMR (126 MHz, CDCl3) δ 179.0, 114.4 (t, J = 239.4 Hz), 23.8 (t, J = 27.1 Hz),
15.9 (t, J = 4.5 Hz), 10.7 (t, J = 4.3 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3) δ –118.2 (d, J =
285.4 Hz), –119.4 (d, J = 285.4 Hz) ppm. LC–MS (m/z): 135 (M – H+). HRMS (ESI–TOF) m/z:
[M + H]+ Calcd for C5H7F2O2 137.0409; Found 137.0404.
trans-Ethyl 1-Cyano-2-(trifluoromethyl)cyclopropanecarboxylate (28).47,48 Alkene 27 (420
g, 2.40 mol) was added dropwise to a solution of ethyl cyanoacetate (226 g, 2.00 mol), K2CO3
(552 g, 4.00 mol) and KF (348 g, 6.00 mol) in DMF (5 L) at 0oC. The mixture was allowed to
warm to rt and was left to stir overnight. The mixture was extracted with t-BuOMe (5 L) and
H2O (10 L). Organic layer was washed with H2O (3×1.5 L), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The product was purified by vacuum distillation (bp 60–65
°C / 1 mbar). Yield 116 g (28%). Colorless liquid. For physical and spectral data see ref.47,48
2-(Trifluoromethyl)cyclopropane-1,1-dicarboxylic Acid (29). Compound 28 (29.0 g, 0.14
mol) was added to a solution of KOH (39.2 g, 0.70 mol) in H2O (300 mL), and the mixture was
refluxed for 96 h using oil bath as a heat source. After cooling to rt, the solution was acidified
with NaHSO4 to pH = 1–2 and then extracted with EtOAc (300 mL). Organic layer was washed
with H2O (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure.
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Yield 22.1 g (79%). Brown solid, which decomposed upon heating. 1H NMR (400 MHz, DMSO-
d6) δ 2.69 – 2.54 (m, 1H), 1.62 (dd, J = 7.2, 5.4 Hz, 1H), 1.55 (dd, J = 9.4, 5.4 Hz, 1H) ppm.
13C{1H} NMR (151 MHz, DMSO-d6) δ 169.5, 166.6, 124.7 (q, J = 272.0 Hz), 33.1, 25.8 (q, J =
37.4 Hz), 14.5 ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ –62.8 ppm. LC–MS (m/z): 197 (M –
H+). Anal. Calcd. for C6H5F3O4: C, 36.38; H, 2.54. Found: C, 36.12; H, 2.89.
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cis-2-(Trifluoromethyl)cyclopropanecarboxylic Acid (cis-7). Dicarboxylic acid 29 (22.0 g,
0.111 mol) was melted and heated at 220 °C (using oil bath as a heat source) until the evolution
of gas ceased. The resulting two isomeric carboxylic acids cis-7 and trans-7 were distilled at
170–185 °C. The collected fraction contained 13.2 g (85.7 mol) of ca. 1:1 mixture of cis-7 and
trans-7. The cis-isomer was isolated by flash column chromatography (Hex : EtOAc : Formic
Acid = 10 : 1 : 0.3 as eluent, Rf(cis-7) = 0.17, Rf(trans-7) = 0.26) to give pure title compound as
a colorless liquid which crystallizes upon standing. Yield 5.13 g (30%). White solid, mp 42–44
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°C. H NMR (400 MHz, CDCl3) δ 10.89 (br s, 1H), 2.11 – 1.94 (m, 2H), 1.70 (q, J = 6.6 Hz,
13
1H), 1.32 (q, J = 7.8 Hz, 1H) ppm. C{1H} NMR (126 MHz, CDCl3) δ 175.2, 125.0 (q, J =
272.7 Hz), 23.0 (q, J = 39.3 Hz), 18.5, 9.3 ppm. 19F{1H} NMR (376 MHz, CDCl3) δ –61.4 ppm.
GC–MS (m/z): 137 (M+ – OH), 109 (M+ – OH – CO). Anal. Calcd. for C5H5F3O2: C, 38.97; H,
3.27. Found: C, 39.32; H, 3.03.
trans-2-(Trifluoromethyl)cyclopropanecarboxylic Acid (trans-7).34,35 The compound was
obtained by the same procedure described for cis-7. Yield 7.02 g (41%). Colorless oil. For
physical and spectral data see ref.35
General Procedure for the Preparation of Hydrochlorides 8–10, 31. To a solution of the
corresponding acid 5–7 or 30 (0.18 mmol) and Et3N (56.4 g, 0.56 mol) in THF (400 mL), ethyl
chloroformate (40.0 g, 0.370 mol) was added dropwise at –20 °C. The reaction mixture was
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stirred at the same temperature for 1 h and then 100 mL of aq NaN3 (35.8 g, 0.550 mol) was
added at –10 °C. The mixture was stirred at rt for 2 h, poured into water and extracted with
EtOAc (400 mL). The organic phase was washed with aq. NaHCO3 (150 mL), dried over
anhydrous Na2SO4, evaporated to 70 mL and added to 200 mL of toluene. t-BuOH (155 g, 1.85
mol) was added in one portion to the reaction mixture. The mixture was refluxed overnight and
then evaporated to give the corresponding Boc-protected amine. The obtained crude product was
dissolved in 2M HCl in MeOH (400 mL). The reaction mixture was stirred at rt for 1.5 h and
then concentrated under vacuum. The residue was triturated in Et2O and the resulting solid was
filtered to give the target product.
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cis-2-(Fluoromethyl)cyclopropanaminium Chloride (cis-8). The deprotection step of the
intermediate N-Boc amine by 2M HCl in MeOH should be carried out for 15 min. Yield 5.78 g
(68%) from 8.00 g of cis-5. Beige solid, mp = 76–78 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.76
(s, 3H), 4.77 (quint, J = 10.3 Hz, 1H), 4.65 (quint, J = 10.3 Hz, 1H), 2.77 – 2.65 (m, 1H), 1.57 –
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1.41 (m, 1H), 1.10 – 0.96 (m, 1H), 0.91 (q, J = 6.0 Hz, 1H) ppm. C{1H} NMR (126 MHz,
DMSO-d6) δ 81.9 (d, J = 162.1 Hz), 26.2 (d, J = 6.2 Hz), 14.7 (d, J = 25.4 Hz), 7.4 (d, J = 8.1
Hz) ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ –211.2 ppm. LC–MS (m/z): 90 (M – Cl–).
HRMS (ESI–TOF) m/z: [M – Cl]+ Calcd for C4H9FN 90.0714; Found 90.0718.
trans-2-(Fluoromethyl)cyclopropanaminium Chloride (trans-8). Yield 11.5 g (72%) from
15.0 g of trans-5. Beige solid, mp = 126–128 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 3H),
4.36 (ddd, J = 42.0, 9.9, 6.9 Hz, 1H), 4.23 (ddd, J = 42.4, 9.9, 7.7 Hz, 1H), 2.63 – 2.54 (m, 1H),
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1.78 – 1.64 (m, 1H), 1.14 – 1.00 (m, 1H), 0.78 (q, J = 6.6 Hz, 1H) ppm. C{1H} NMR (126
MHz, DMSO-d6) δ 84.0 (d, J = 164.0 Hz), 26.3 (d, J = 8.9 Hz), 16.4 (d, J = 25.2 Hz), 7.8 (d, J =
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7.2 Hz) ppm. 19F{1H} NMR (376 MHz, DMSO-d6) δ –212.0 ppm. GC–MS (m/z): 68 (M+ – HCl
– F – H2). HRMS (ESI–TOF) m/z: [M – Cl]+ Calcd for C4H9FN 90.0714; Found 90.0717.
cis-2-(Difluoromethyl)cyclopropanaminium Chloride (cis-9). Yield 15.8 g (60%) from 25.0
g of cis-6. White solid, mp 146–148 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 3H), 6.37 (td,
J = 54.1, 7.2 Hz, 1H), 2.87 – 2.74 (m, 1H), 1.77 – 1.55 (m, 1H), 1.29 – 1.20 (m, 1H), 1.18 – 1.09
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(m, 1H) ppm. C{1H} NMR (101 MHz, DMSO-d6) δ 116.4 (t, J = 234.7 Hz), 25.3 (d, J = 8.9
19
Hz), 17.7 (t, J = 30.3 Hz), 6.2 (d, J = 7.6 Hz) ppm. F NMR (376 MHz, DMSO-d6) δ –106.0
(ddd, J = 288.0, 54.1, 7.9 Hz), –112.9 (ddd, J = 288.0, 54.1, 9.9 Hz) ppm. LC–MS (m/z): 108 (M
– Cl–). HRMS (ESI–TOF) m/z: [M – Cl]+ Calcd for C4H8F2N 108.0619; Found 108.0620.
trans-2-(Difluoromethyl)cyclopropanaminium Chloride (trans-9). Yield 8.50 g (62%) from
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13.0 g of trans-6. White solid, mp 123–125 °C. H NMR (500 MHz, D2O) δ 5.95 (td, J = 56.6,
3.9 Hz, 1H), 3.00 – 2.94 (m, 1H), 2.01 – 1.91 (m, 1H), 1.30 – 1.25 (m, 2H) ppm. 13C{1H} NMR
(126 MHz, D2O) δ 114.8 (t, J = 236.8 Hz), 24.5 (t, J = 6.7 Hz), 18.6 (t, J = 27.5 Hz), 6.1 (t, J =
19
4.5 Hz) ppm. F{1H} NMR (376 MHz, D2O) δ –118.1 (d, J = 300.8 Hz), –118.9 (d, J = 300.8
Hz) ppm. LC–MS (m/z): 108 (M – Cl–). HRMS (ESI–TOF) m/z: [M – Cl]+ Calcd for C4H8F2N
108.0619; Found 108.0621.
cis-2-(Trifluoromethyl)cyclopropanaminium Chloride (cis-10). Yield 1.76 g (67%) from
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2.50 g of cis-7. White solid, mp 190–192 °C. H NMR (400 MHz, D2O) δ 3.06 (q, J = 7.1 Hz,
13
1H), 2.17 (quint, J = 8.4 Hz, 1H), 1.57 – 1.37 (m, 2H) ppm. C{1H} NMR (126 MHz, D2O) δ
125.3 (q, J = 270.6 Hz), 25.7, 16.7 (q, J = 36.8 Hz), 7.2 ppm. 19F{1H} NMR (376 MHz, D2O) δ –
61.7 ppm. LC–MS (m/z): 126 (M – Cl–). HRMS (ESI–TOF) m/z: [M – Cl]+ Calcd for C4H7F3N
126.0525; Found 126.0529.
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trans-2-(Trifluoromethyl)cyclopropanaminium Chloride (trans-10). Yield 1.89 g (72%)
from 2.50 g of trans-7. For physical and spectral data see ref.49
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cis-2-Methylcyclopropanaminium Chloride (cis-31). Yield 1.74 g (54%) from 3.00 g of cis-
30. 1H NMR (400 MHz, D2O) δ 2.71 – 2.59 (m, 1H), 1.26 – 1.11 (m, 4H), 1.07 – 0.97 (m, 1H),
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0.54 – 0.42 (m, 1H) ppm. C{1H} NMR (126 MHz, D2O) δ 26.8, 10.8, 10.1, 8.7 ppm. Anal.
Calcd. for C4H10ClN: C, 44.66; H, 9.37; N, 13.02; Cl, 32.95. Found: C, 44.83; H, 9.06; N, 12.79;
Cl, 33.21.
trans-2-Methylcyclopropanaminium Chloride (trans-31). Yield 2.13 g (66%) from 3.00 g of
trans-30. Yellow solid, mp = 60–62 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 3H), 2.21 (dt,
J = 7.5, 3.6 Hz, 1H), 1.21 – 1.09 (m, 1H), 0.98 (d, J = 6.2 Hz, 3H), 0.88 (ddd, J = 9.5, 5.7, 3.6
Hz, 1H), 0.45 (dt, J = 7.5, 5.7 Hz, 1H) ppm. 13C{1H} NMR (126 MHz, DMSO-d6) δ 28.4, 16.1,
10.9, 10.8 ppm. GC–MS (m/z): 56 (M+ –HCl – CH3). Anal. Calcd. for C4H10ClN: C, 44.66; H,
9.37; N, 13.02; Cl, 32.95. Found: C, 44.75; H, 9.21; N, 13.10; Cl, 33.08.
General procedure for the preparation of the amides 32–35. DIPEA (323 mg, 2.50 mmol),
HATU (418 mg, 1.10 mmol) and PhNH2 (102 mg, 1.10 mmol) were sequentially added to a
stirred solution of acid (1.00 mmol) in dry DMF (15 mL) at 0 °C. The reaction mixture was
stirred at rt overnight, then poured into 50 mL of H2O and extracted with EtOAc (35 mL). The
organic phase was separated, washed with aq. NaHSO4 (10 mL), aq. Na2CO3 (10 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by HPLC.
cis-2-(Fluoromethyl)-N-phenylcyclopropanecarboxamide (cis-32). Yield 1.21 g (74%) from
1.00 g of cis-5. White solid, mp = 111–113 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.48
(d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 4.78 (ddd, J = 48.5, 9.9, 5.8
Hz, 1H), 4.55 (dt, J = 47.0, 9.5 Hz, 1H), 1.88 – 1.74 (m, 1H), 1.75 – 1.62 (m, 1H), 1.33 – 1.18
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(m, 1H), 1.16 – 1.02 (m, 1H) ppm. C{1H} NMR (151 MHz, CDCl3): δ 168.9, 138.1, 129.1,
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124.4, 120.1, 82.2 (d, J = 163.0 Hz), 20.6 (d, J = 19.2 Hz), 20.5, 10.2 (d, J = 8.6 Hz) ppm.
19F{1H} NMR (376 MHz, CDCl3): δ –211.6 ppm. LC–MS (m/z): 194 (M + H+). Anal. Calcd. for
C11H12FNO: C, 68.38; H, 6.26; N, 7.25. Found: C, 68.64; H, 6.64; N, 7.49.
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trans-2-(Fluoromethyl)-N-phenylcyclopropanecarboxamide (trans-32). Yield 1.31 g (80%)
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from 1.00 g of trans-5. White solid, mp = 100–102 °C. H NMR (400 MHz, CDCl3): δ 7.85 (s,
1H), 7.49 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 4.50 (ddd, J =
48.4, 9.8, 5.6 Hz, 1H), 4.15 (ddd, J = 47.7, 9.8, 7.4 Hz, 1H), 1.94 – 1.84 (m, 1H), 1.67 – 1.54 (m,
1H), 1.42 – 1.30 (m, 1H), 0.88 (dt, J = 9.4, 5.4 Hz, 1H) ppm. 13C{1H} NMR (151 MHz, CDCl3):
δ 170.3, 138.0, 129.1, 124.4, 120.0, 85.0 (d, J = 168.1 Hz), 21.1, 20.9 (d, J = 23.4 Hz), 11.8 (d, J
= 7.4 Hz) ppm. 19F{1H} NMR (376 MHz, CDCl3): δ –214.7 ppm. LC–MS (m/z): 194 (M + H+).
Anal. Calcd. for C11H12FNO: C, 68.38; H, 6.26; N, 7.25. Found: C, 68.19; H, 6.13; N, 7.33.
cis-2-(Difluoromethyl)-N-phenylcyclopropanecarboxamide (cis-33). Yield 1.35 g (87%) from
1.00 g of cis-6. White solid, mp = 116–119 °C. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.46
(d, J = 8.0 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 5.99 (td, J = 55.8, 7.4 Hz,
1H), 1.86 – 1.78 (m, 1H), 1.78 – 1.67 (m, 1H), 1.54 – 1.43 (m, 1H), 1.28 – 1.16 (m, 1H) ppm.
13C{1H} NMR (151 MHz, CDCl3): δ 168.3, 137.6, 129.2, 124.9, 120.4, 116.3 (t, J = 234.7 Hz),
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22.7 (dd, J = 34.0, 30.2 Hz), 19.8 (d, J = 7.2 Hz), 9.7 (d, J = 8.9 Hz) ppm. F{1H} NMR (376
MHz, CDCl3): δ –108.4 (d, J = 288.7 Hz, 1F), –113.7 (d, J = 288.7 Hz, 1F) ppm. LC–MS (m/z):
212 (M + H+). Anal. Calcd. for C11H11F2NO: C, 62.55; H, 5.25; N, 6.63. Found: C, 62.61; H,
5.14; N, 6.94.
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