Transition Metal-free gem-difluorocyclopropanation of Alkenes with CF3SiMe3?NaI System: a Recipe for Electron-deficient Substrates

Article abstract of DOI:10.1002/adsc.201801006

Reaction of various electron-deficient alkenes, as well as functionalized styrene derivatives with CF₃SiMe₃?NaI system is studied. Relative reactivity of the substrates is established. It is shown that many α,β-unsaturated esters can

Full text of DOI:10.1002/adsc.201801006

Title: Transition metal-free <i>gem</i>-difluorocyclopropanation of
alkenes with CF₃SiMe₃ – NaI system:
a recipe for electron-deficient substrates
Authors: Pavel Nosik, Sergey Ryabukhin, Oleksandr Grygorenko, and
Dmitriy Volocnyuk
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801006
Link to VoR: http://dx.doi.org/10.1002/adsc.201801006

10.1002/adsc.201801006
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition metal-free gem-difluorocyclopropanation of alkenes
with CF3SiMe3 – NaI system: a recipe for electron-deficient
substrates
Pavel S. Nosik,a,b Sergey V. Ryabukhin,b Oleksandr O. Grygorenko,a,b* Dmitriy M.
Volochnyukc
a
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine, www.enamine.net
National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
b
[Tel.: +38-044-239-3315; fax: +380-44-537-3253; e-mail: gregor@univ.kiev.ua]
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Reaction of various electron-deficient alkenes, as spirocyclic gem-difluorocyclopropyl-substituted carboxylic
well as functionalized styrene derivatives with CF3SiMe3 – acids with good yields (36–79% for two steps) on up to
NaI system is studied. Relative reactivity of the substrates is 100 g scale.
established. It is shown that many ,-unsaturated esters can
be difluorocyclopropanated efficiently under “slow addition
protocol” conditions, which provides access to mono- and
Keywords: Difluorocarbene; Cycloaddition; Cycloalkanes;
Spiro compounds; Ruppert–Prakash reagent
kinase A inhibitor 4 (IC50 = 0.18 nM),[16] nanomolar
LPAR2 (lysophosphatidic acid receptor 2) antagonist
5,[17] or TBK1 (TANK binding kinase 1) inhibitor
(IC50 =0.86 nM) can be mentioned (Figure 1).[18]
Introduction
Modern medicinal chemistry widely exploits two
structural motifs to improve physicochemical
characteristics of the compounds: fluorine atoms and
small rings.[1–8] Gem-difluorocyclopropanes combine
both these structural features and are therefore
considered as very promising building blocks for
early drug discovery.[9–12] Among the most prominent
examples, experimental antineoplastic drug zosuqui-
dar (1), which has reached Phase III clinical trials,[13]
glutamate analogue 2 – selective mGluR2 (metabo-
tropic glutamate receptor 2) agonist,[14] one more
mGluR2 modulator 3 (EC50 = 6.2 nM),[15] Aurora
A common approach to the construction of the
gem-difluorocyclopropane core relies on the difluoro-
cyclopropanation of alkenes. Such transformations
have been known for more than 50 years; never-
theless, their widespread application was hampered
until recently due to low efficiency and limited
substrate scope, or the use of toxic and hardly
available reagents (see the previous work and
references cited therein for more information).[19] In
2011, Prakash, Olah, and co-workers published a
convenient protocol for the alkene difluorocyclopro-
Figure 1. Some biologically active gem-difluorocyclopropanes.
1
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
this procedure with ether, ketal, as well as non-
conjugated ester and nitrile functions.[25]
All the previously reported data on the relative
substrate reactivity in the alkene difluorocypropana-
tion with the CF3SiMe3 – NaI system reveal that the
method is especially efficient for electron-rich double
bonds.[19,20] Electron-deficient alkenes (such as
acrylates) are poor substrates for this transformation
which do not react under the standard conditions
(see[26] and references cited therein). Recently, it was
shown that the CF3SiMe3 – NaI system can be
effective for electron-poor double bonds if catalysis
with a cobalt(II) porphyrin complex is applied.[26] The
utility of this protocol was demonstrated for a single
example (namely, n-butyl acrylate).
In our previous paper, we have described a
modification of the original procedure by Prakash,
Olah and co-workers, which involved the gradual
introduction of CF3SiMe3 into the reaction system
and allowed extending the substrate scope towards
double bonds with modest reactivity (e.g. mono- and
dialkyl-substituted).[19] These results inspired us to
check if the further extension of the reaction scope is
possible with this “slow addition protocol”. In
particular, electron-deficient substrates 7a–r with
diverse electronic properties were included in this
study (Figure 2). In addition to that, phenyl-
substituted alkenes 7s–v, as well as N-Boc-protected
amines 7w and 7x from our previous work[19] were
evaluated as the control substrates. Finally, styrene
derivatives 7y and 7z bearing an additional functional
group in the aromatic ring were also studied.
Scheme 1. Difluorocyclopropanation of alkenes with the
CF3SiMe3 – NaI system
panation which involved CF3SiMe3 (known as the
Ruppert – Prakash reagent) – NaI system (Scheme
1).[20] Several papers appeared since then describing
analogous transformations;[21–24] nevertheless, most of
them had reported the use of non-functionalized
alkenes (e.g. styrenes) which provided little
possibilities for further functionalization. Recently,
we have extended the original protocol of Prakash,
Olah, and co-workers towards alkenes bearing N-Boc
protected secondary amino function.[19] Another
recent publication demonstrated the compatibility of
Results and Discussion
First of all, the reaction of esters 7a–e and 7j, as
well as control substrates 7u–x and p-7z with the
CF3SiMe3 – NaI system was studied under the “slow
addition protocol” conditions. In particular, the
Ruppert – Prakash reagent (0.1 mol/h) was added
Figure 2. Substrates 7a–z studied in this work
2
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
slowly to a mixture of the substrate (0.4 mol) and NaI
(0.14 mol) in refluxing THF. Conversion of the
substrates 7 was analyzed as a function of CF3SiMe3
carbon atom in 8 by alkyl groups R1/R2; in the case of
substrates 7d and especially 7e, ring strain relief
might be also involved. Surprisingly, compound 7b
amount added using 1H NMR spectroscopy (Figure 3). appeared to be the least reactive in the series 7a–e,
According to these data, relative reactivity of the
substrates was as following (Figure 4):
7u > 7e > 7d  7c > 7a > 7b >
whereas “push-pull” ester 7j did not react at all.
These results show that the mechanism shown in
Scheme 2 is oversimplified and cannot rationalize all
the facts observed. This conclusion is further
supported by the fact that trans-stilbene (7u) had
modest reactivity towards the CF3SiMe3 – NaI system.
Low reactivity was also observed for carboxymethyl-
substituted styrene derivative p-7z (which might be
expected though). In the case of substrates 7w and 7x,
the results obtained were in accordance with our
previous findings.[19]
> 7w > 7x > 7v > p-7z >> 7j
Scheme 2. Previously described the mechanism of alkene
difluorocyclopropanation with CF3SiMe3 – NaI system
Using the developed procedure, difluorocyclo-
propyl-substituted carboxylates 9a–g were obtained
in 75–92% yields (Table 1). It should be noted that
the reaction could be scaled up to 100 g without
significant changes in the yield of the product
(although in some cases, it proceeded vigorously after
addition of the first 1–1.5 mol of CF3SiMe3 per 1 mol
of 7). The reaction occurred even with methyl
cinnamate (7h), although its conversion into the
product 9h using the standard slow addition protocol
was low (less than 15%). Nevertheless, an interesting
observation was made during optimization of the
latter procedure; in particular, the yield of 9h could
be improved to 37% if not only CF3SiMe3 but also
NaI was introduced into the reaction mixture in
several portions (20.35 mol per 1 mol of 7h).
Figure 3. Conversion of the substrates 7 as a function of
CF3SiMe3 amount added (conditions: alkene (0.4 mol),
CF3SiMe3 (0.1 mol/h), NaI (0.14 mol), THF, 65 C)
As it follows from these data, ,-unsaturated
esters 7a–e could be difluorocyclopropanated with
good efficiency using the slow addition protocol.
Moreover, they were even slightly more reactive than
“electron-neutral” alkenes 7w and 7x studied in our
previous work on the difluorocyclopopanation of
carbamates[19] (although they were still less reactive
than styrene (7u)). This fact is not consistent with the
electrophilic nature of singlet difluorocarbene which
is widely documented in the literature.[27] The relative
reactivity of the substrates 7a, 7c, 7d, and 7e still
could be explained assuming non-symmetrical
transition structure 8 resulting from a non-concerted
approach of the reagent to the double bond of the
substrate, which was described in our previous work
(Scheme 2; for 7a–e: R3 = EWG, R4 = H).[19] Indeed,
the increased reactivity of 7c–e might be addressed to
stabilization of partial positive charge at one of the
Unfortunately, neither this modified nor standard
slow addition protocol allowed extending applica-
bility of the method to ,-unsaturated 7i–o having
an additional strong donor or acceptor substituent.
The approach was also inefficient with ,-
unsaturated nitrile 7p and nitro derivative 7r.
Finally, several styrene derivatives 7s, 7t, 7y and
Figure 4. Relative reactivity of the substrates 7a–e, 7u–x, and p-7z
3
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
Table 1. Synthesis of carboxylic acids 10a–h bearing gem-difluorocyclopropane fragment
#
1
Substrate 7
Ester 9b)
Carboxylic acid 10b)
Yield of 9 (%)
Yield of 10 (%)
89
85
2
3
4
5
6
75
76
78
84
92
93
93
91
89
94
7
8
86
92
96
37b)
a) Relative configurations are shown. b) NaI was introduced into the reaction mixture in two portions
7z were studied in the reaction with the CF3SiMe3 –
NaI system, in addition to the control substrates 7u,
7v, and p-7z mentioned above. Most of these
substrates demonstrated an expected level of reacti-
vity. In particular, -methylstyrene (7s) gave the
corresponding cyclopropane 9s in 96% yield. Three
isomeric carboxylates 7z reacted with the CF3SiMe3 –
NaI system slowly; nevertheless, the corresponding
products 9z were isolated in 34–94% yield (Scheme
3). Phenols 7y demonstrated high reactivity, and the
cyclopropanes 9y were obtained in 90–92% yield
(Scheme 4). Notably, protection of the free hydroxy
group in their molecules was not necessary since its
silylation occurred under the reaction conditions in
situ. This was confirmed by isolation of silyl ether 11
(95%). To obtain free phenols 9y, the crude products
of difluorocyclopropanation were treated with tetra-n-
butylammonium fluoride.
Scheme 3. Synthesis of carboxylic acids 12
4
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
Surprisingly, -methoxystyrene (7t) did not react
an additional strong donor or acceptor substituent, as
well as ,-unsaturated nitrile and nitro derivatives
were inefficient substrates in the reaction with the
CF3SiMe3 – NaI system and the corresponding gem-
difluorocyclopropanes could not be obtained. Difluo-
rocyclopropanation of methyl cinnamate can be
performed with satisfactory yield (37%) if excess of
both CF3SiMe3 and NaI are introduced into the
reaction mixture gradually.
with CF3SiMe3 – NaI under any of the conditions
described above. This result is analogous to that
observed for methoxyacrylates 7j and 7k and can be
considered as one more experimental fact which
cannot be explained assuming the non-symmetrical
transition structure 8.
Mono- and spirocyclic difluorocyclopropane-
substituted carboxylic acids obtained by hydrolysis of
the above-mentioned products are promising
advanced low-molecular-weight building blocks for
medicinal chemistry, which can be considered now as
readily available to the scientific community (on up
to 100 g scale).
Reaction of various functionalized styrene
derivatives with the CF3SiMe3 – NaI system occurs in
an expected manner: in particular, carboxymethyl
derivatives demonstrate lowered reactivity. On the
contrary, styrenes bearing phenolic group are reactive
substrates, which do not require protection of the
hydroxyl function.
Scheme 4. Synthesis of phenols 9y
To demonstrate the synthetic potential of the
products obtained, all the esters 9a–z described above
were subjected to alkaline hydrolysis. It was found
that in all cases, the difluorocyclopropane moiety
tolerated the reaction conditions, and the
corresponding carboxylic acids 10a–h (Table 1) and
12 (Scheme 3) were obtained in 85–96% yield. It
should be noted that the products 9b and 10h were
obtained in a diastereospecific manner as trans
isomers, which was confirmed by 2D NMR
experiments (Figure 5).
Experimental Section
The solvents were purified according to the standard
procedures. All starting materials were obtained from
Enamine Ltd. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography
was performed using Kieselgel Merck 60 (230–400
1
13
19
mesh) as the stationary phase. H, C, and F NMR
spectra were recorded on a Bruker 170 Avance 500
spectrometer (at 500 MHz for Protons and 126 MHz
for Carbon-13) and Varian Unity Plus 400
spectrometer (at 400 MHz for protons, 101 MHz for
Carbon-13, and 376 MHz for Fluorine-19).
Tetramethylsilane (1H, 13C) or C6F6 (19F) were used as
standards. Elemental analyses were performed at the
Laboratory of Organic Analysis, Institute of Organic
Chemistry, National Academy of Sciences of Ukraine,
their results were found to be in good agreement
(±0.4%) with the calculated values. Mass spectra
were recorded on Agilent 1100 LCMSD SL
instrument (chemical ionization (APCI)) and Agilent
5890 Series II 5972 GCMS instrument (electron
impact ionization (EI)).
Figure 5. Significant correlations in 1H-19F NOESY
spectra of 9b and 10h
Conclusions
The reaction of ,-unsaturated esters with the
CF3SiMe3 – NaI system under “slow addition
protocol” conditions, followed by hydrolysis of the
ester function is an efficient method for the
preparation of gem-difluorocyclopropylcarboxylic
acids (36–79% yields for two steps). ,-Unsaturated
esters demonstrate significant reactivity under the
aforementioned conditions, which is comparable to
(and even slightly higher than) that of non-conjugated
mono- and 1,2-disubstituted alkenes. This fact, as
well as the relative reactivities of substrates (i.e.
isobutenoate > acrylate > crotonate) shows that the
published mechanism of the difluorocyclopropa-
nation which includes partially non-synchronous
cycloaddition of difluorocarbene to the double bond
of the substrate is oversimplified and does not explain
all the experimental data. ,-Unsaturated esters with
General procedure for the preparation of 9a–g, 9s,
9u, 9v, 9z, and 11:
Sodium iodide (21.0 g, 0.140 mol) was added to a
solution of alkene 7 (0.400 mol) in anhydrous THF
(1000 mL) under a nitrogen atmosphere, and the
mixture was heated to reflux. Trimethyl(trifluoro-
methyl)silane (198 g, 1.39 mol) was added dropwise
over 12–16 h at this temperature (CAUTION! In
some cases, the reaction proceeded vigorously after
addition of ca. 0.4–0.6 mol of CF3SiMe3). The
reaction mixture was heated overnight, and the
5
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
1
19
conversion was checked by H NMR and/or GCMS.
If necessary, additional trimethyl(trifluoromethyl)-
silane (198 g, 1.39 mol) was added, and the reaction
mixture was refluxed for an additional 24 h. The
latter manipulations were repeated once again if
necessary. Then the solvent was evaporated, the
residue was diluted with CH2Cl2 (500 mL), and the
precipitate was filtered off. The filtrates were
triturated with 5% aq KMnO4 (500 mL), the organic
phase was separated, washed with H2O (150 mL),
dried over Na2SO4, and evaporated in vacuo. The
crude product was distilled under reduced pressure or
purified by column chromatography.
20.4 (d, J = 6.3 Hz), 13.2 (d, J = 7.7 Hz) ppm. F
NMR (CDCl3, 376 MHz) δ –133.2 (d, J = 152.3 Hz),
–145.8 (d, J = 152.3 Hz) ppm. Anal. Calcd. for
C7H10F2O2: C 51.22; H 6.14. Found: C 50.92; H 5.97.
MS (EI, 70 eV): m/z (rel. int.) = 149 [M–CH3]+ (67);
144 [M–HF]+ (11); 143 [M–HF–H]+ (41); 133 [M–
OCH3]+ (40); 113 [M–OCH3–HF]+ (32); 105 [M–
COOCH3]+ (100); 104 (14); 91 [CH2C(CH3)CF2]+
(58); 85 [M–COOCH3–HF]+ (42); 77 (56); 65 (32);
59 (35); 39 (31).
Methyl 2,2-difluorospiro[2.3]hexane-1-carboxylate
(9d)
Butyl 2,2-difluorocyclopropanecarboxylate (9a)[28]
1
Yield 147 g, 78%. Colorless oil. H NMR (CDCl3,
400 MHz) δ 3.68 (s, 3H), 2.47 – 1.80 (m, 7H) ppm.
13C NMR (CDCl3, 101 MHz) δ 166.4, 111.8 (dd, J =
293.4, 288.3 Hz), 51.8, 34.4 (t, J = 10.8 Hz), 32.5 (dd,
J = 12.8, 10.0 Hz), 24.5 (d, J = 4.1 Hz), 22.3 (d, J =
1
Yield 123.7 g, 89%. Colorless oil. H NMR (CDCl3,
500 MHz) δ 4.16 (t, J = 6.7 Hz, 2H), 2.43 (dddd, J =
13.6, 10.7, 7.9, 2.8 Hz, 1H), 2.10 – 1.99 (m, 1H), 1.78
– 1.68 (m, 1H), 1.64 (quint, J = 6.8 Hz, 2H), 1.40
(sext, J = 7.5 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H) ppm.
13C NMR (CDCl3, 101 MHz) δ 166.7, 110.7 (dd, J =
288.3, 282.9 Hz), 65.4, 30.5, 25.6 (t, J = 11.6 Hz),
19.0, 16.4 (t, J = 11.4 Hz), 13.6 ppm. 19F NMR
(CDCl3, 470 MHz) δ –126.1 (dtd, J = 153.6, 12.4, 6.2
Hz), –140.9 (ddd, J = 153.6, 12.7, 5.2 Hz) ppm. Anal.
Calcd. for C8H12F2O2: C 53.93; H 6.79. Found: C
54.18; H 6.93. MS (EI, 70 eV): m/z (rel. int.) = 122
[M–C4H8]+ (100); 105 [M–OC4H9]+ (77); 77 (28); 76
[M–COOC4H9]+ (10); 57 [C4H9]+ (75); 56 [C3H3F]+
(19); 55 [C3H2F]+ (48); 41 (61).
19
4.0 Hz), 16.7 ppm. F NMR (CDCl3, 376 MHz) δ –
132.7 (d, J = 151.5 Hz), –145.6 (d, J = 151.5 Hz)
ppm. Anal. Calcd. for C8H10F2O2: C 54.54; H 5.72.
Found: C 54.19; H 5.90. MS (EI, 70 eV): m/z (rel.
int.) = 148 [M–C2H4]+ (100); 145 [M–OCH3]+ (15);
141 [M–CH3–HF]+ (12); 133 [M–C2H4–CH3]+ (45);
117 [M–COOCH3]+ (19); 97 [M–COOCH3–HF]+
(56); 91[CF2CHCO]+ (32); 89 [M–COOCH3–C2H4]+
(18); 77 (38); 59 (29); 39 (36).
Ethyl 2,2-difluorospiro[2.2]pentane-1-carboxylate
(9e)
Methyl 2,2-difluoro-3-methylcyclopropanecarbo-
xylate (9b)
1
Yield 46.9 g, 84%. Colorless oil. H NMR (CDCl3,
400 MHz) δ 4.23 – 4.11 (m, 2H), 2.64 (d, J = 9.5 Hz,
1H), 1.39 – 1.30 (m, 2H), 1.30 – 1.15 (m, 5H) ppm.
13C NMR (CDCl3, 126 MHz) δ 166.9, 112.4 (dd, J =
293.0, 289.0 Hz), 61.1, 30.2 (t, J = 11.9 Hz), 20.0 (t,
J = 9.6 Hz), 14.2, 7.6 (d, J = 2.1 Hz), 6.7 (d, J = 2.3
1
Yield 224 g, 75%. Colorless oil. H NMR (CDCl3,
400 MHz) δ 3.70 (s, 3H), 2.33 – 2.20 (m, 1H), 2.00
(dd, J = 13.0, 7.3 Hz, 1H), 1.22 (d, J = 9.7 Hz, 3H)
ppm. 13C NMR (CDCl3, 101 MHz) δ 167.4, 112.7 (dd,
J = 292.1, 286.4 Hz), 52.2, 31.9 (t, J = 11.5 Hz), 24.1
19
Hz) ppm. F NMR (CDCl3, 376 MHz) δ –128.0 (dd,
J = 146.3, 4.1 Hz), –140.4 (dd, J = 146.3, 4.0 Hz)
ppm. Anal. Calcd. for C8H10F2O2: C 54.54; H 5.72.
Found: C 54.14; H 5.46. MS (EI, 70 eV): m/z (rel.
int.) = 148 [M–C2H4]+ (13); 131 [M–OC2H5]+ (33);
128 [M–C2H4–HF]+ (10); 103 [M–COOC2H5]+ (24);
101 [M–COOC2H5–H2]+ (15), 100 [M–COOC2H5–
H2–H]+ (100); 99 (25); 91 [CF2CHCO]+ (29); 83 [M–
COOC2H5–HF]+ (22); 72 (56).
19
(t, J = 9.9 Hz), 10.1 (d, J = 4.7 Hz) ppm. F NMR
(CDCl3, 376 MHz) δ –136.7 (d, J = 152.4 Hz), –
137.6 (d, J = 152.4 Hz) ppm. Anal. Calcd. for
C6H8F2O2: C 48.00; H 5.37. Found: C 47.71; H 5.30.
MS (EI, 70 eV): m/z (rel. int.) = 135 [M–CH3]+ (100);
119 [M–OCH3]+ (44); 107 (27); 99 [M–OCH3–HF]+
(15); 91 [M–COOCH3]+ (89); 77 [CH2CHCF2]+ (10);
71 [CH3C3HF]+ (54); 69 (36); 59 (34); 52 (28); 39
(32).
Ethyl 1-ethyl-2,2-difluorocyclopropanecarboxylate
(9f)
Methyl 2,2-difluoro-3,3-dimethylcyclopropanecarbo-
xylate (9c)[29]
Yield 12.8 g, 92%. Orange oil. 1H NMR (CDCl3, 400
MHz) δ 4.25 – 4.11 (m, 2H), 2.19 – 2.05 (m, 2H),
1.49 – 1.35 (m, 1H), 1.30 – 1.19 (m, 4H), 0.98 (t, J =
7.3 Hz, 3H) ppm. 13C NMR (CDCl3, 101 MHz) δ
167.9, 112.8 (t, J = 289.4 Hz), 61.6, 36.3, 21.5 (d, J =
5.2 Hz), 20.3 (t, J = 9.6 Hz), 14.1, 10.9 (d, J = 2.6
1
Yield 21.8 g, 76%. Colorless oil. H NMR (CDCl3,
400 MHz) δ 3.69 (s, 3H), 2.04 (dd, J = 13.1, 1.6 Hz,
1H), 1.37 (s, 3H), 1.32 (s, 3H) ppm. 13C NMR
(CDCl3, 126 MHz) δ 166.6, 114.2 (t, J = 291.7 Hz),
51.7, 33.8 (dd, J = 13.0, 9.8 Hz), 30.2 (t, J = 9.7 Hz),
6
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10.1002/adsc.201801006
Advanced Synthesis & Catalysis
Hz) ppm. 19F NMR (CDCl3, 470 MHz) δ –134.6 (d, J
= 152.9 Hz), –135.7 (d, J = 152.9 Hz) ppm. Anal.
Calcd. for C8H12F2O2: C 53.93; H 6.79. Found: C
53.55; H 7.03. MS (EI, 70 eV): m/z (rel. int.) = 150
[M–C2H4]+ (12); 135 (100); 133 [M–OC2H5]+ (28);
130 [M–C2H5–F]+ (15); 102 [M–C2H4–C2H5–F]+
(18); 87 (38); 77 [M–C2H4–COOC2H5]+ (29); 55 (34);
39 (34).
(100); 153 [M–H]+ (63); 133 [M–HF–H]+ (76); 127
(27); 104 (41); 103 (29); 77 (25).
(3,3-Difluorocyclopropane-1,2-diyl)dibenzene (9v)[30]
1
Yield 5.20 g, 82%. White solid. Mp 45–46 °C. H
NMR (CDCl3, 500 MHz) δ 7.48 – 7.34 (m, 10H),
13
3.10 (t, J = 7.6 Hz, 2H) ppm. C NMR (CDCl3, 126
MHz) δ 133.0, 128.2, 127.7 (t, J = 1.5 Hz), 127.0,
112.4 (t, J = 291.6 Hz), 34.0 (t, J = 10.6 Hz) ppm. 19F
NMR (CDCl3, 470 MHz) δ –134.1 (t, J = 5.3 Hz)
ppm. Anal. Calcd. for C15H12F2: C 78.24; H 5.25.
Found: C 78.16; H 5.46. MS (EI, 70 eV): m/z (rel.
int.) = 210 [M–HF]+ (100); 209 [M–HF–H]+ (53);
180 [PhCHCHPh]+ (12); 179 (42); 178
[PhCCPh]+(42); 153 [M–C6H5] (27); 152 [M–C6H5–
H] (92); [M–C6H5–HF–H] 132 (79); 127 (30); 89
(32); 63 (36); 51 (31).
Methyl 2,2-difluoro-1-phenylcyclopropanecarbo-
xylate (9g)
1
Yield 85.5, 86%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.46 – 7.29 (m, 5H), 3.70 (s, 3H), 2.64
(ddd, J = 12.4, 7.9, 6.1 Hz, 1H), 1.93 (ddd, J = 12.4,
7.9, 4.8 Hz, 1H) ppm. 13C NMR (CDCl3, 101 MHz) δ
167.6, 132.3, 130.4, 128.5, 128.4, 111.0 (dd, J =
290.4, 288.9 Hz), 53.2, 39.4, 22.2 (dd, J = 10.6, 8.6
Hz) ppm. 19F NMR (CDCl3, 376 MHz) δ –129.1 (d, J
= 148.3 Hz), –134.7 (d, J = 148.3 Hz) ppm. Anal.
Calcd. for C11H10F2O2: C 62.26; H 4.75. Found: C
61.92; H 4.61. MS (EI, 70 eV): m/z (rel. int.) = 197
[M–CH3]+ (24); 180 [M–OCH3–H]+ (21); 178 [M–
CH3–F]+ (29); 152 [M–COOCH3–H]+ (21); 151 [M–
COOCH3–H2]+ (50); 150 [M–COOCH3–H2–H]+ (49);
148 (43); 133 [M–COOCH3–HF]+ (72); 126 (39); 103
[C6H5CCH2]+ (100); 102 [C6H5CCH]+ (21); 77 (44).
Methyl 2-(2,2-difluorocyclopropyl)benzoate (o-9z)
1
Yield 118.1 g, 86%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.97 (d, J = 9.5 Hz, 1H), 7.48 (t, J = 7.6
Hz, 1H), 7.40 – 7.30 (m, 2H), 3.92 (s, 3H), 3.24 (dd,
J = 21.3, 12.4 Hz, 1H), 1.87 – 1.75 (m, 1H), 1.61 –
1.49 (m, 1H) ppm. 13C NMR (CDCl3, 101 MHz) δ
167.4, 134.6, 132.3, 131.3, 130.8, 129.5 (d, J = 3.9
Hz), 127.5, 112.4 (dd, J = 286.8, 281.4 Hz), 52.2,
19
(2,2-Difluoro-3-methylcyclopropyl)benzene (9s)[30]
27.0 (t, J = 11.3 Hz), 16.5 (t, J = 10.6 Hz) ppm. F
NMR (CDCl3, 376 MHz) δ –127.4 (d, J = 154.3 Hz),
–140.8 (d, J = 154.3 Hz) ppm. Anal. Calcd. for
C11H10F2O2: C 62.26; H 4.75. Found: C 61.94; H 5.01.
MS (EI, 70 eV): m/z (rel. int.) = 151 [M–COOCH3–
H2]+ (13); 148 (31); 134 [M–COOCH3–F]+ (12); 133
[M–COOCH3–HF]+ (100).
1
Yield 2.10 g, 96%. Yellowish oil. H NMR (CDCl3,
500 MHz) δ 7.40 – 7.21 (m, 5H), 2.30 (dd, J = 13.7,
7.6 Hz, 1H), 1.92 – 1.83 (m, 1H), 1.40 (ddd, J = 6.4,
2.6, 1.2 Hz, 3H) ppm. 13C NMR (CDCl3, 126 MHz) δ
133.8, 128.0, 127.4 (t, J = 1.7 Hz), 126.4, 114.2 (dd, J
= 290.9, 289.6 Hz), 33.6 (t, J = 10.9 Hz), 23.8 (t, J =
10.0 Hz), 10.9 (d, J = 5.0 Hz) ppm. 19F NMR (CDCl3,
470 MHz) δ –137.47 (dd, J = 153.2, 14.8 Hz), –
138.31 (dd, J = 153.2, 17.5 Hz) ppm. Anal. Calcd. for
C10H10F2: C 71.41; H 5.99. Found: C 71.54; H 5.66.
MS (EI, 70 eV): m/z (rel. int.) = 153 [M–CH3]+ (100);
133 [M–CH3–HF]+ (77); 118 [M–CF2]+ (14); 117
[M–CF2–H]+ (55).
Methyl 3-(2,2-difluorocyclopropyl)benzoate (m-9z)
1
Yield 135 g, 94%. Colorless oil. H NMR (CDCl3,
500 MHz) δ 7.97 – 7.88 (m, 2H), 7.45 – 7.33 (m, 2H),
3.90 (s, 3H), 2.82 – 2.73 (m, 1H), 1.89 – 1.76 (m, 1H),
1.71 – 1.61 (m, 1H) ppm. 13C NMR (CDCl3, 126
MHz) δ 166.2, 133.6, 132.0, 130.0, 128.6, 128.0,
127.9, 111.8 (dd, J = 287.3, 283.7 Hz), 51.6, 26.4 (t, J
= 11.5 Hz), 16.5 (t, J = 10.6 Hz) ppm. 19F NMR
(CDCl3, 376 MHz) δ –126.6 (d, J = 154.4 Hz), –
142.7 (d, J = 154.4 Hz) ppm. Anal. Calcd. for
C11H10F2O2: C 62.26; H 4.75. Found: C 62.65; H 4.80.
API-ES MS, positive mode, m/z (rel. int.): 213
[M+H]+ (100).
(2,2-Difluorocyclopropyl)benzene (9u)[30]
1
Yield 7.28 g, 98%.Yellowish oil. H NMR (CDCl3,
500 MHz) δ 7.43 – 7.23 (m, 5H), 2.80 (ddd, J = 13.4,
11.7, 8.0 Hz, 1H), 1.85 (tdd, J = 12.3, 8.0, 4.9 Hz,
1H), 1.66 (dtd, J = 12.1, 8.0, 3.9 Hz, 1H) ppm. C
13
NMR (CDCl3, 126 MHz) δ 133.7, 128.5, 128.1 (t, J =
1.6 Hz), 127.2, 112.6 (dd, J = 286.7, 284.0 Hz), 27.2
(t, J = 11.4 Hz), 17.0 (t, J = 10.6 Hz) ppm. F NMR
(CDCl3, 470 MHz) δ –125.8 (dtd, J = 154.3, 13.8, 4.6
Hz), –142.4 (ddd, J = 154.3, 13.5, 5.3 Hz) ppm. Anal.
Calcd. for C9H8F2: C 70.12; H 5.23. Found: C 70.38;
H 5.30. MS (EI, 70 eV): m/z (rel. int.) = 154 [M]+
Methyl 4-(2,2-difluorocyclopropyl)benzoate (p-9z)
19
1
Yield 0.455 g, 34%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.96 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 7.9
Hz, 2H), 3.87 (s, 3H), 2.74 (td, J = 12.3, 8.1 Hz, 1H),
1.84 (tdd, J = 12.2, 8.0, 5.1 Hz, 1H), 1.65 (dtd, J =
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801006
Advanced Synthesis & Catalysis
1
12.2, 8.0, 3.9 Hz, 1H) ppm. 13C NMR (CDCl3, 126
MHz) δ 166.2, 138.5, 129.2, 128.5, 127.4, 111.8 (dd,
J = 287.6, 284.1 Hz), 51.6, 26.7 (t, J = 11.6 Hz), 16.9
Yield 2.27 g, 37%. Yellowish oil. H NMR (CDCl3,
500 MHz) δ 7.41 – 7.22 (m, 5H), 3.82 (s, 3H), 3.51
(ddd, J = 13.6, 7.9, 2.7 Hz, 1H), 2.74 (ddd, J = 13.3,
7.9, 1.0 Hz, 1H) ppm. 13C NMR (CDCl3, 101 MHz) δ
166.8, 131.1, 128.7, 128.1, 128.0, 52.7, 33.4 (t, J =
10.7 Hz), 32.2 (t, J = 11.1 Hz) ppm. 19F NMR (CDCl3,
376 MHz) δ –133.4 (d, J = 151.7 Hz), –134.7 (d,
J = 151.7 Hz) ppm. Anal. Calcd. for C11H10F2O2: C
62.26; H 4.75. Found: C 62.51; H 4.70. MS (EI, 70
eV): m/z (rel. int.) = 192 [M–HF]+ (21); 153 [M–
COOCH3]+ (89); 151 [M–COOCH3–H2]+ (12); 134
[M–COOCH3–F]+ (13); 133 [M–COOCH3–HF]+
(100).
19
(t, J = 10.5 Hz) ppm. F NMR (CDCl3, 376 MHz) δ
–126.1 (d, J = 154.5 Hz), –142.8 (d, J = 154.5 Hz)
ppm. Anal. Calcd. for C11H10F2O2: C 62.26; H 4.75.
Found: C 62.66; H 5.14. API-ES MS, positive mode,
m/z: 213 [M+H]+.
(4-(2,2-Difluorocyclopropyl)phenoxy)trimethylsilane
(11)
The residue after evaporation of the reaction mixture
obtained from p-7y (5.00 g, 41.6 mmol) using a
general procedure described above was triturated
with dry CH2Cl2 (50 mL), the solid was filtered off,
and the filtrates were evaporated in vacuo. The
product was used in the next step without further
purification. If any further manipulations were
performed with the product (e.g. aqueous work-up),
its partial deprotection occurred.
General procedure for the preparation of 9y
Sodium iodide (4.36 g, 29.1 mmol) was added to a
solution of styrene 7 (10.0 g, 83.2 mmol) in
anhydrous THF (100 mL) under nitrogen atmosphere,
and the mixture was heated to reflux.
Trimethyl(trifluoromethyl)silane (41.4 g, 0.291 mol)
was added dropwise over 12–16 h at this temperature.
The reaction mixture was heated overnight. The
solvent was evaporated, triturated with dry CH2Cl2
(100 mL), and the solid was filtered off. A solution of
TBAF3H2O (8.50 g, 27.4 mmol) in THF (20 mL)
was added to the filtrate, and the resulting mixture
was stirred at rt overnight, then washed with 10% aq
HCl (30 mL), dried over Na2SO4, and evaporated in
vacuo. The crude product was purified by column
chromatography (EtOAc – hexanes (1:4) as eluent).
1
Yield 9.63 g, 95%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.07 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.6
Hz, 2H), 2.67 (td, J = 12.6, 7.9 Hz, 1H), 1.75 (tdd, J
= 12.6, 7.9, 4.8 Hz, 1H), 1.52 (dtd, J = 16.1, 7.9, 3.9
Hz, 1H), 0.24 (s, 9H) ppm. 13C NMR (CDCl3, 101
MHz) δ 154.4, 129.1 (t, J = 1.6 Hz), 126.5, 120.0,
112.7 (dd, J = 286.5, 284.0 Hz), 26.6 (t, J = 11.5 Hz),
17.0 (t, J = 10.5 Hz), 0.2 ppm. 19F NMR (CDCl3, 376
MHz) δ –126.6 (d, J = 153.8 Hz), –143.0 (d, J =
153.8 Hz) ppm. Anal. Calcd. for C12H16F2OSi: C
59.47; H 6.66. Found: C 59.09; H 6.90. MS (EI, 70
eV): m/z (rel. int.) = 227 [M–CH3]+ (18); 226 [M–
CH4]+ (100); 206 [M–CH4–HF]+ (19); 176 (26); 149
[M–Si(CH3)3–HF]+ (13); 134 [M–OSi(CH3)3–HF]+
(10); 77 (45); 73 (57).
2-(2,2-Difluorocyclopropyl)phenol (o-9y)
1
Yield 13.1 g, 92%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.20 – 7.08 (m, 2H), 6.98 – 6.76 (m, 2H),
4.91 (s, 1H), 2.79 (td, J = 12.4, 8.0 Hz, 1H), 1.85 (tdd,
J = 12.0, 8.0, 4.7 Hz, 1H), 1.59 (dtd, J = 11.9, 8.0, 3.7
13
Hz, 1H) ppm. C NMR (CDCl3, 126 MHz) δ 154.4,
Methyl 2,2-difluoro-3-phenylcyclopropanecarbo-
128.5, 128.3, 120.4, 119.4, 114.8, 112.4 (dd, J =
285.6, 283.1 Hz), 21.5 (t, J = 11.6 Hz), 15.7 (t, J =
10.8 Hz) ppm. 19F NMR (CDCl3, 376 MHz) δ –127.2
(d, J = 152.3 Hz), –141.5 (d, J = 152.3 Hz) ppm.
Anal. Calcd. for C9H8F2O: C 63.53; H 4.74. Found: C
63.82; H 5.03. MS (EI, 70 eV): m/z (rel. int.) = 170
[M]+ (100); 169 [M–H]+ (20); 151[M–F]+ (30); 150
[M–HF]+ (16); 131 [M–HF–F]+ (12); 120 [M–CF2]+
(15); 91 [C6H4OH] (34).
xylate (9h)[31]
Sodium iodide (1.62 g, 10.8 mmol) was added to a
solution of methyl cinnamate (5.00 g, 30.8 mmol) in
anhydrous THF (50 mL) under nitrogen atmosphere
and heated to reflux. Trimethyl(trifluormethyl)silane
(15.3 g, 107.8 mmol) was added dropwise over 12–16
h. Additional trimethyl(trifluoromethyl)silane (15.3 g,
107.8 mmol) and sodium iodide (1.62 g, 10.8 mmol)
were added, and the reaction mixture was refluxed for
additional 24 h. Then the solvent was evaporated, the
residue was diluted with CH2Cl2 (500 mL), and the
precipitate was filtered off. 5% aq KMnO4 (500 mL)
was added to the filtrate, and the mixture was stirred
at rt overnight. The organic phase was separated,
washed with H2O (150 mL), dried over Na2SO4, and
evaporated. The crude product was purified by
column chromatography (hexanes – EtOAc (8:1) as
eluent).
3-(2,2-Difluorocyclopropyl)phenol (m-9y)
1
Yield 6.47 g, 91%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 7.19 (t, J = 7.7 Hz, 1H), 6.85 – 6.65 (m,
3H), 5.11 (s, 1H), 2.69 (td, J = 12.3, 8.0 Hz, 1H),
1.79 (tdd, J = 12.4, 8.0, 4.7 Hz, 1H), 1.58 (dtd, J =
12.1, 8.0, 3.5 Hz, 1H) ppm. 13C NMR (CDCl3, 101
MHz) δ 155.5, 135.6, 129.7, 120.7, 115.0, 114.2,
112.52 (dd, J = 286.4, 284.2 Hz), 27.0 (t, J = 11.5
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801006
Advanced Synthesis & Catalysis
Hz), 17.1 (t, J = 10.5 Hz) ppm. 19F NMR (CDCl3, 376
MHz) δ –126.2 (d, J = 154.2 Hz), –142.7 (d, J =
154.2 Hz) ppm. Anal. Calcd. for C9H8F2O: C 63.53;
H 4.74. Found: C 63.24; H 4.66. MS (EI, 70 eV): m/z
(rel. int.) = 170 [M]+ (100); 169 [M–H]+ (25); 151
[M–F]+ (23); 150 [M–HF]+ (37); 149 [M–HF–H]+
(56); 122 (52); 121 (34); 120[M–CF2]+ (37); 119[M–
CF2–H]+ (12); 91 [C6H4OH] (35).
2,2-Difluoro-3-methylcyclopropanecarboxylic acid
(10b)
1
Yield 42.1 g, 93%. White solid. Mp 51–53 °C. H
NMR (CDCl3, 500 MHz) δ 11.88 (br s, 1H), 2.38 –
2.29 (m, 1H), 2.04 (dd, J = 11.3, 7.2 Hz, 1H), 1.28 (d,
J = 6.1 Hz, 3H) ppm. 13C NMR (CDCl3, 126 MHz) δ
173.2, 112.2 (dd, J = 292.2, 287.0 Hz), 31.4 (t, J =
12.0 Hz), 24.5 (t, J = 9.7 Hz), 9.7 (d, J = 3.3 Hz) ppm.
19F NMR (CDCl3, 376 MHz) δ –136.1 (d, J = 152.2
Hz), –136.6 (d, J = 152.2 Hz) ppm. Anal. Calcd. for
C5H6F2O2: C 44.13; H 4.44. Found: C 44.41; H 4.07.
MS (EI, 70 eV): m/z (rel. int.) = 121 [M–CH3]+ (71);
101 [M–CH3–HF]+ (45); 91 [M–COOH]+ (100); 88
(38); 77 [CH2CHCF2]+ (17); 71 [M–COOH–HF]+
(48); 69 [M–COOH–HF]+ (62); 65 (26); 51 (39); 45
(33); 41 (28).
4-(2,2-Difluorocyclopropyl)phenol (p-9y)
1
Yield 63.6 g, 90%. White solid. Mp 55–58 °C. H
NMR (CDCl3, 500 MHz) δ 7.12 (d, J = 8.2 Hz, 2H),
6.81 (d, J = 8.4 Hz, 2H), 4.81 (s, 1H), 2.71 (td, J =
12.6, 7.9 Hz, 1H), 1.79 (tdd, J = 12.2, 7.9, 4.8 Hz,
13
1H), 1.55 (dtd, J = 12.0, 7.9, 3.8 Hz, 1H) ppm. C
NMR (CDCl3, 126 MHz) δ 154.2, 128.9, 125.4, 114.9,
112.2 (dd, J = 286.7, 283.7 Hz), 25.9 (t, J = 11.4 Hz),
16.4 (t, J = 10.7 Hz) ppm. 19F NMR (CDCl3, 470
MHz) δ –126.2 (dtd, J = 153.6, 13.6, 4.0 Hz), –142.3
(ddd, J = 153.6, 13.6, 5.3 Hz) ppm. Anal. Calcd. for
C9H8F2O: C 63.53; H 4.74. Found: C 63.76; H 4.91.
MS (EI, 70 eV): m/z (rel. int.) = 171 (10); 170 [M]+
(100); 169 [M–H]+ (67); 150 [M–HF]+ (25); 120
[M–CF2]+ (56); 119 [CH2=CHC6H4=O]+ (19); 91
[C6H4OH] (24).
2,2-Difluoro-3,3-dimethylcyclopropanecarboxylic
acid (10c)[29]
Yield 8.54 g, 93%. White solid. Mp 68–70 °C (Lit.
1
66.5–67.5 °C). H NMR (CDCl3, 500 MHz) δ 11.54
(s, 1H), 2.07 (dd, J = 12.6, 1.5 Hz, 1H), 1.42 (s, 3H),
1.37 (s, 3H) ppm. 13C NMR (CDCl3, 126 MHz) δ
173.0, 114.1 (t, J = 291.7 Hz), 33.9 (dd, J = 13.7, 9.9
Hz), 31.4 (t, J = 9.6 Hz), 20.6 (d, J = 6.1 Hz), 13.2 (d,
19
General procedure for the preparation of 10 and 12
J = 6.4 Hz) ppm. F NMR (CDCl3, 376 MHz) δ –
132.2 (d, J = 152.3 Hz), –145.1 (d, J = 152.3 Hz)
ppm. Anal. Calcd. for C6H8F2O2: C 48.00; H 5.37.
Found: C 47.98; H 5.49. MS (EI, 70 eV): m/z (rel.
int.) = 135 [M–CH3]+ (94); 130 [M–HF]+ (13); 129
[M–HF–H]+ (93); 115 [M–CH3–HF]+ (61); 105 [M–
COOH]+ (100); 91 [CH2C(CH3)CF2]+ (57); 87 (33);
85 [M–COOH–HF]+ (30); 83 (31); 77 (85); 65 (39);
59 (74); 41 (49); 39 (67).
To a solution of ester 9 (0.142 mol) in MeOH (250
mL), NaOH (8.50 g, 0.213 mol) in H2O (10 mL) was
added, and the reaction mixture was stirred at rt
overnight. Then the solvent was evaporated in vacuo,
the residue was diluted with H2O (150 mL) and
washed with Et2O (350 mL). The aqueous layer was
acidified with 10% aq HCl to pH = 4 and extracted
with EtOAc (3100 mL). The combined organic
layers were dried over Na2SO4 and evaporated in
vacuo.
2,2-Difluorospiro[2.3]hexane-1-carboxylic
acid
(10d)
1
2,2-Difluorocyclopropanecarboxylic acid (10a)[28]
Yield 41.9 g, 91%. White solid. Mp 49–53 °C. H
NMR (CDCl3, 400 MHz) δ 10.49 (br s, 1H), 2.53 –
2.21 (m, 4H), 2.18 – 2.01 (m, 3H) ppm. 13C NMR
(CDCl3, 101 MHz) δ 172.3, 111.3 (dd, J = 294.0,
288.1 Hz), 34.8 (t, J = 10.7 Hz), 32.2 (dd, J = 13.4,
10.2 Hz), 24.1 (d, J = 3.8 Hz), 22.0 (d, J = 3.7 Hz),
16.2 ppm. 19F NMR (CDCl3, 376 MHz) δ –131.7 (d, J
= 151.3 Hz), –144.9 (d, J = 151.3 Hz) ppm. Anal.
Calcd. for C7H8F2O2: C 51.86; H 4.97. Found: C
52.01; H 5.23. MS (EI, 70 eV): m/z (rel. int.) = 141
[M–HF–H]+ (10); 134 [M–C2H4]+ (100); 115 [M–
C2H4–F]+ (11); 114 [M–C2H4–HF]+ (46); 97 [M–
COOH–HF]+ (55); 91 [CF2CHCO]+ (19); 89 [M–
C2H4–COOH]+ (13); 86 (41); 77 (33); 45 (28); 39
(75).
Yield 72.0 g, 85%. White solid. Mp 62–63 °C (Lit.
61–62 °C). 1H NMR (CDCl3, 400 MHz) δ 11.80 (br s,
1H), 2.44 (ddd, J = 12.7, 10.6, 7.9 Hz, 1H), 2.07 (dtd,
J = 12.2, 7.9, 6.3 Hz, 1H), 1.80 (tdd, J = 11.0, 7.9, 5.0
13
Hz, 1H) ppm. C NMR (CDCl3, 101 MHz) δ 173.3,
110.6 (dd, J = 289.1, 283.2 Hz), 25.4 (dd, J = 13.2,
10.8 Hz), 17.1 (dd, J = 10.7, 10.1 Hz) ppm. 19F NMR
(CDCl3, 376 MHz) δ –125.9 (d, J = 153.6 Hz), –
140.8 (d, J = 153.6 Hz) ppm. Anal. Calcd. for
C4H4F2O2: C 39.36; H 3.30. Found: C 39.65; H 3.54.
MS (EI, 70 eV): m/z (rel. int.) = 105 [M–OH]+ (11);
104 [M–OH2]+ (42); 77 [M–COOH]+ (86); 76 [M–
COOH–H]+ (34); 75 [M–COOH–H2]+ (34); 57 [M–
COOH–HF]+ (29); 56 (100); 51 (55); 46 (45).
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801006
Advanced Synthesis & Catalysis
2,2-Difluorospiro[2.2]pentane-1-carboxylic acid
(10e)
Yield 1.80 g, 96%. Yellowish powder. Mp 93–94 °C
(Lit. 92–94 °C). 1H NMR (CDCl3, 400 MHz) δ 7.53 –
7.09 (m, 5H), 3.69 – 3.38 (m, 1H), 2.76 (dd, J = 13.3,
8.3 Hz, 1H) ppm. 13C NMR (CDCl3, 126 MHz) δ
172.7, 130.6, 128.8, 128.2, 128.1, 110.7 (dd, J =
294.8, 288.0 Hz), 33.9 (dd, J = 10.7, 9.2 Hz), 32.1 (t,
1
Yield 18.7 g, 89%. White solid. Mp 92–95 °C. H
NMR (CDCl3, 400 MHz) δ 10.93 (br s, 1H), 2.71 –
2.63 (m, 1H), 1.42 – 1.30 (m, 3H), 1.29 – 1.21 (m,
1H) ppm. 13C NMR (CDCl3, 101 MHz) δ 173.7,
112.3 (dd, J = 293.7, 289.4 Hz), 30.2 (t, J = 9.2 Hz),
20.8 (t, J = 9.4 Hz), 7.9 (d, J = 2.0 Hz), 7.0 (d, J = 2.1
Hz) ppm. 19F NMR (CDCl3, 376 MHz) δ –126.9 (d, J
= 145.6 Hz), –139.4 (d, J = 145.6 Hz) ppm. Anal.
Calcd. for C6H6F2O2: C 48.66; H 4.08. Found: C
48.44; H 4.14. MS (EI, 70 eV): m/z (rel. int.) = 103
[M–COOH]+ (15); 101 [M–COOH–H2]+ (14); 100
[M–COOH–H2–H]+ (44); 99 (42); 91 [CF2CHCO]+
(36); 83 [M–COOH–HF]+ (21); 75 [M–COOH–
C2H4]+ (34); 72 (100); 53 (30); 45 (27); 40 (29); 39
(57).
19
J = 11.5 Hz) ppm. F NMR (CDCl3, 376 MHz) δ –
132.8 (d, J = 151.6 Hz), –133.7 (d, J = 151.6 Hz)
ppm. Anal. Calcd. for C10H8F2O2: C 60.61; H 4.07.
Found: C 60.96; H 4.20. MS (EI, 70 eV): m/z (rel.
int.) = 178 [M–HF]+ (11); 153 [M–COOH]+ (22); 134
[M–COOH–F]+ (35); 133 [M–COOH–HF]+ (100).
2-(2,2-Difluorocyclopropyl)benzoic acid (o-12)
1
Yield 45.7 g, 98%. White solid. Mp 131–134 °C. H
NMR (CDCl3, 400 MHz) δ 12.00 (br s, 1H), 8.14 (d,
J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 – 7.33
(m, 2H), 3.36 (td, J = 12.5, 8.7 Hz, 1H), 1.88 (tdd, J =
11.8, 8.0, 5.0 Hz, 1H), 1.61 (dtd, J = 11.7, 8.0, 3.3 Hz,
1H) ppm. 13C NMR (CDCl3, 126 MHz) δ 171.9,
135.7, 133.2, 131.6, 130.1, 129.6, 127.6, 112.4 (dd, J
= 287.3, 281.6 Hz), 26.9 (t, J = 11.2 Hz), 16.6 (t, J =
10.5 Hz) ppm. 19F NMR (CDCl3, 470 MHz) δ –126.8
(dt, J=154.8, 14.8 Hz), –139.9 (ddd, J = 154.8, 13.9,
5.7 Hz) ppm. Anal. Calcd. for C10H8F2O2: C 60.61; H
4.07. Found: C 60.88; H 3.88. API-ES MS, positive
mode, m/z (rel. int.): 199 [M+H]+ (100); 191 (26);
157 (73); 129 (27); 101 (35). API-ES MS, negative
mode, m/z (rel. int.): 197 [M–H]– (100); 157 (84).
1-Ethyl-2,2-difluorocyclopropanecarboxylic acid
(10f)
Yield 7.51 g, 94%. Yellowish oil. 1H NMR (CDCl3,
400 MHz) δ 11.88 (br s, 1H), 2.26 – 2.00 (m, 2H),
1.57 – 1.44 (m, 1H), 1.36 (dt, J = 10.6, 7.4 Hz, 1H),
13
1.03 (t, J = 7.4 Hz, 3H) ppm. C NMR (CDCl3, 101
MHz) δ 175.0, 112.8 (dd, J = 290.7, 289.2 Hz), 35.8
(t, J = 10.5 Hz), 21.2, 22.1 (t, 9.5 Hz), 10.9 (d, J = 2.0
Hz) ppm. 19F NMR (CDCl3, 470 MHz) δ –134.2 (ddd,
J = 152.0, 12.8, 6.7 Hz), –134.2 (d, J = 152.0) ppm.
Anal. Calcd. for C6H8F2O2: C 48.00; H 5.37. Found:
C 47.84; H 4.97. MS (EI, 70 eV): m/z (rel. int.) = 133
[M–OH]+ (100); 115 (25); 102 [M–C2H4–HF]+ (15);
86 [M–COOH–F]+ (90); 59 (36); 55 (27); 40 (32).
3-(2,2-Difluorocyclopropyl)benzoic acid (m-12)
1
Yield 46.2 g, 99%. White solid. Mp 129–131 °C. H
NMR (CDCl3, 400 MHz) δ 10.64 (br s, 1H), 8.00 (d,
J = 7.4 Hz, 1H), 7.95 (s, 1H), 7.49 – 7.38 (m, 2H),
2.79 (td, J = 12.3, 8.0 Hz, 1H), 1.86 (tdd, J = 12.3,
8.0, 5.0 Hz, 1H), 1.67 (dtd, J = 12.2, 8.0, 3.9 Hz, 1H)
ppm. 13C NMR (CDCl3, 101 MHz) δ 171.8, 134.3,
133.3, 129.9, 129.8, 129.0, 128.7, 112.2 (dd,
J = 287.3, 283.7 Hz), 26.9, 17.1 ppm. 19F NMR
(CDCl3, 376 MHz) δ –126.6 (d, J = 154.8 Hz), –
142.7 (d, J = 154.8 Hz) ppm. Anal. Calcd. for
C10H8F2O2: C 60.61; H 4.07. Found: C 60.24; H 3.77.
API-ES MS, negative mode, m/z (rel. int.): 197.1 [M–
H]– (100).
2,2-Difluoro-1-phenylcyclopropanecarboxylic acid
(10g)[32]
Yield 47.9 g, 92%. Yellowish powder. Mp 102–
1
103 °C (Lit. 102 °C). H NMR (CDCl3, 500 MHz) δ
11.33 (br s, 1H), 7.42 – 7.35 (m, 5H), 2.66 (dt, J =
12.4, 7.1 Hz, 1H), 2.02 (ddd, J = 12.4, 7.9, 4.8 Hz,
1H) ppm. 13C NMR (CDCl3, 126 MHz) δ 173.5,
131.6, 130.4 (d, J = 1.9 Hz), 128.7, 128.5, 111.0 (dd,
J = 292.0, 288.6 Hz), 39.1 (t, J = 11.2 Hz), 22.6 (dd,
J = 10.5, 8.4 Hz) ppm. 19F NMR (CDCl3, 376 MHz) δ
–127.9 (d, J = 147.4 Hz), –134.6 (d, J = 147.4 Hz)
ppm. Anal. Calcd. for C10H8F2O2: C 60.61; H 4.07.
Found: C 60.38; H 3.83. MS (EI, 70 eV): m/z (rel.
int.) = 198 [M]+ (59); 153 [M–COOH]+ (13); 152
[M–COOH–H]+ (47); 151 [M–COOH–H2]+ (64); 150
(86); 134 [M–COOH–F]+ (25); 133 [M–COOH–HF]+
(100); 103 [C6H5CCH2]+ (70); 102 [C6H5CCH]+ (24);
77 (45).
4-(2,2-Difluorocyclopropyl)benzoic acid (p-12)
Yield 0.403 g, 95%. White solid. Mp 139–142 °C. 1H
NMR (CDCl3, 500 MHz) δ 8.08 (d, J = 8.3 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 2.81 (td, J = 12.3, 8.2 Hz,
1H), 1.99 – 1.85 (m, 1H), 1.76 – 1.65 (m, 1H) ppm.
13C NMR (CDCl3, 101 MHz) δ 171.2, 140.1, 132.1,
130.4, 128.1, 112.2 (dd, J = 287.9, 284.4 Hz), 27.3 (t,
J = 11.6 Hz), 17.6 (t, J = 10.5 Hz) ppm. 19F NMR
(CDCl3, 376 MHz) δ –126.0 (d, J = 154.9 Hz), –
2,2-Difluoro-3-phenylcyclopropanecarboxylic acid
(10h)[31]
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801006
Advanced Synthesis & Catalysis
[15]
[16]
H. Urabe, R. Shimono, T. Tamita, N. Hattori, K.
Sakagami, Y. Matsuda, A. Yasuhara, S. Masuda, K.
Konishi, T. Nakamura, S. Yamamoto, PCT. Int.
Pat. WO2013/062079, 2013.
142.6 (d, J = 154.9 Hz) ppm. Anal. Calcd. for
C10H8F2O2: C 60.61; H 4.07. Found: C 60.98; H 3.82.
API-ES MS, positive mode, m/z (rel. int.): 201 (100);
173 (30); 155 (35); 123 (30); 111 (28). API-ES MS,
negative mode, m/z (rel. int.): 197 [M–H]– (100).
A. E. Sutton, T. E. Richardson, B. R. Huck, S. R.
Karra, X. Chen, Y. Xiao, A. Goutopoulos, R. LAN,
D. Perrey, G. Vandeveer, Harold, L. Liu-Bujalski,
F. Stieber, B. L. Hodous, H. Qiu, R. C. Jones, B.
Heasley, PCT Int. Pat. WO 2010/093419, 2010.
Acknowledgements
The work was supported by Enamine Ltd. The authors thank Prof.
Andrey A. Tolmachev for his encouragement and support, Yuliya
Kuchkovska and Halyna Buvailo for their help with manuscript
preparation.
[17]
W. Staehle, M. Schultz, K. Schiemann, WO
2013/020622, 2013.
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P. S. Nosik, A. O. Gerasov, R. O. Boiko, E.
Rusanov, S. V. Ryabukhin, O. O. Grygorenko, D.
M. Volochnyuk, Adv. Synth. Catal. 2017, 359,
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