Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety

Article abstract of DOI:10.1002/adsc.201700857

The synthesis of monocyclic, spirocyclic and fused bicyclic secondary amines bearing a gem-difluorocyclopropane moiety via difluorocyclopropanation of unsaturated N-Boc derivatives using the trifluoromethyl(trimethyl)silane/sodium iodide [CF₃SiMe₃-NaI] system is described. The relative order of the substrate reactivity is established. It is shown that for the reactive alkenes the standard reaction conditions can be used, whereas for the substrates with low reactivity, slow addition of the Ruppert–Prakash reagent is necessary. (Figure presented.).

Full text of DOI:10.1002/adsc.201700857

Title: Gram-scale synthesis of amines bearing gem-
difluorocyclopropane moiety
Authors: Pavel Nosik, Andrii Gerasov, Rodion Boiko, Eduard Rusanov,
Sergey Ryabukhin, Oleksandr Grygorenko, and Dmitriy
Volocnyuk
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700857
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gram-scale synthesis of amines bearing
gem-difluorocyclopropane moiety
Pavel S. Nosik,a.b Andrii O. Gerasov,c Rodion O. Boiko,c Eduard Rusanov,a Sergey V.
Ryabukhin,b Oleksandr O. Grygorenko,b* Dmitriy M. Volochnyuka
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine
b
[Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua]
Spectrum Info Ltd., Life Chemicals Group, 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. Synthesis of monocyclic, spirocyclic and fused conditions can be used, whereas for the substrates with low
bicyclic secondary amines bearing gem-difluorocyclo- reactivity, slow addition of the Ruppert–Prakash reagent is
propane moiety via difluorocyclopropanation of unsaturated necessary.
N-Boc derivatives using CF3SiMe3–NaI system is described.
Relative order of the substrate reactivity is established. It is
shown that for the reactive alkenes, the standard reaction
Keywords: Difluorocarbene; Cycloaddition; Cycloalkanes;
Bicyclic compounds; Ruppert–Prakash reagent
Introduction
Organofluorine compounds and derivatives of small
ring can be undoubtedly named among the hallmarks
of modern drug discovery.[1–8] Gem-difluoro-
cyclopropanes which combine these structural
features are promising building blocks for medicinal
chemistry.[9–11] In particular, they were used in design
of experimental antineoplastic drug zosuquidar (1),
which has reached Phase III clinical trials,[12]
glutamate analogue 2 – selective mGluR2 agonist,[13]
DDR1 inhibitor 3,[14] potential insecticide 4,[15] or
fumagillol derivative 5 – a possible antiobesity agent
(Figure 1).[16]
Figure 2. Distribution of papers and patents on
difluorocyclopropanation of alkenes over the last 50 years.
Figure 1. Biologically active gem-difluorocyclopropanes.
1
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
Figure 3. Discovery of alkene difluorocyclopropanation reagents.
A general approach to gem-difluorocyclopropanes
relies on the reaction of alkenes with difluorocarbene
source. Although the difluorocyclopropanation of
alkenes has been known for more than 50 years, it
represented mainly academic interest until recently
(Figure 2).[17] In 2010s, this reaction has attracted
attention of industrial chemists, which has been
reflected in more than 30 recent patent applications.
The main reason behind this is the fact that despite
many reagents were known for the difluorocyclo-
propanation of alkenes prior 2010s (Figure 3),[18–35]
most of them either showed low efficiency and
limited substrate scope, or were toxic and hardly
available.
spirocyclic amines bearing gem-difluorocyclopropane
moiety starting from unsaturated amine derivatives
and using the Ruppert–Prakash reagent (CF3SiMe3) –
a readily available, non-toxic difluorocyclopropana-
tion agent. It should be noted that since the first
publication of Prakash, Olah and co-workers on the
use of CF3SiMe3 for the difluorocyclopropanation of
alkenes,[33] several papers appeared describing
analogous transformations.[45–48] Nevertheless, none
of them reported the use of unsaturated amine
derivatives as the substrates (with a few exceptions:
one described in a patent[49] and another mentioned
above (compound 8)[44]).
As a part of our ongoing research on the synthesis
of various fluorinated building blocks for medicinal
chemistry,[36–41] we have become interested in mono-
and bicyclic amines containing gem-difluorocyclo-
propane fragment. To our surprise, although the use
of such amines was documented in patents,[14–16] their
syntheses are quite rarely encountered in the literature.
In particular, unstable bicyclic amines 6 were
prepared via reaction of the corresponding enecarba-
mates with trimethylsilyl fluorosulfonyldifluo-
roacetate (TFDA) (Figure 4).[42] cis- and trans-4,5-
Difluoromethanoproline derivatives 7a,b were
prepared by an analogous method using CF2ClCO2Na
as the difluorocarbene source.[43] Recently, synthesis
Results and Discussion
Primary screen for the difluorocyclopropanation
reaction conditions started from the original protocol
Prakash, Ola and co-workers (i. e. alkene (1 mol),
TMSCF3 (2.5 mol), NaI (0.2 mol), THF, 65 C,
2 h)[33] using N-Boc-4-methylenepiperidone (9a)
(described in the patent mentioned above[49]) and
several allyl amine derivatives 9b–e as the model
substrates (Figure 5). It was found that in the case of
9a, the product 10a was obtained in 87% yield.
Derivatives 9b,c gave only trace amounts of the
target products, whereas in the case of 9d,e, no target
compounds were detected at all.
of N-Boc protected amines 8 was described via
difluorocyclopropanation of the corresponding
alkenes with Ruppert–Prakash reagent.[44]
Figure 5. Substrates 9a–e checked under the original
conditions of Prakash, Olah and co-workers (alkene
(1 mol), TMSCF3 (2.5 mol), NaI (0.2 mol), THF, 65 C,
2 h)[33]
Figure 4. Literature examples of (N-protected) amines
bearing gem-difluorocyclopropane moiety
Since the previous studies on the Ruppert–Prakash
reagent showed significant solvent effect on the
reaction outcome,[33,50] we have performed difluoro-
In this work, we describe our study towards
synthesis of monocyclic, fused bicyclic and
2
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
cyclopropanation of 9a with TMSCF3–NaI system in
conversion of these substrates as a function of the
reaction time under standard conditions (alkene
(1 mol), TMSCF3 (2.5 mol), NaI (0.2 mol), THF,
65 C) (Figures 6 and 7). It was found that for the
alkenes 9a and 9f, nearly complete conversion was
observed after 1 h of the reaction. In the case of 9g,
the same situation was achieved after ca. 3 h. For the
substrates 9b, 9h and 9i, 10%, 34% and 29%
conversion, respectively, was achieved after 5 h of
the reaction, and these values did not improve further
significantly even after 24 h.
several solvents (Table 1). The literature results on
C–H perfluoroalkylation of aromatic compounds with
[50]
TMSCF3
showed 1,2-dimethoxyethane to be the
solvent of choice for the reaction. However, in the
case of 9a, the previous results of Prakash, Olah and
co-workers were confirmed:[33] using THF gave the
best conversion of the substrate to the target product.
The solvent effect on the reaction outcome is not
clear; it might be related to the differences in Na+
solvatation, however, the detailed mechanism of the
reaction (and hence the role of Na+) is currently
unknown.
We anticipate that upon action of NaI, partial
decomposition of TMSCF3 occurs, presumably via
difluorocarbene or carbenoid intermediate. Such
process becomes an important side reaction with less
reactive substrates (like 9b, 9h and 9i). This
hypothesis is supported by recent positive results on
the difluorocyclopropanation with TMSCF3–NaI in
continuous flow, published by Charette and co-wor-
kers.[45] Indeed, decomposition of the reagent can be
alleviated under continuous flow conditions.
Moreover, we have performed a control experiment
without alkene (TMSCF3 (0.4 M in THF), NaI (10 %
mol), rt to reflux) (Figure 8). It was found that at
these conditions, TMSCF3 was transformed into a
mixture containing mainly CF2=CF2 and Me3SiF;
formation of hexafluorocyclopropane was also
observed (according to 19F NMR data) (Scheme 1).[51–
Table 1. Difluorocyclopropanation of the substrate 9a in
various solvents
Solventa)
Conversion, (%)
after 2 h
after 4 h
THF
1,4-Dioxane
t-BuOMe
MeCN
1,2-Dimethoxyethane
a) Conditions: 7a (1 mol), TMSCF3 (2.5 mol), NaI
(0.2 mol), 65 C.
>99
0
0
0
33
>99
N/A
N/A
N/A
77
53]
Notably, more than 90% decomposition of the
reagent was observed after 1–1.5 h at reflux, and the
ratio of CF2=CF2 and hexafluorocyclopropane in the
resulting mixture was ca. 25:1.
Figure 6. Conversion of the substrates 7a,b,f–i as a
function of the reaction time (conditions: alkene (1 mol),
TMSCF3 (2.5 mol), NaI (0.2 mol), THF, 65 C)
Figure 8. Decomposition of the Ruppert–Prakash reagent
(conditions: TMSCF3 (0.4 M in THF), NaI (10 % mol), rt
to reflux)
In the next part of this work, we have aimed at
optimization of the reaction time for the substrates
9a,b, as well as for four additional unsaturated N-Boc
derivatives 9f–i. To achieve this, we have studied
Figure 7. Relative reactivity of the substrates 9a,b,f–i towards TMSCF3–NaI system
3
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
The procedures developed were used for the
synthesis of monocyclic, spirocyclic and fused
bicyclic gem-difluorocyclopropanes 10a,b,f–p (Table
2). The products were obtained in 50–91 % yields
after flash chromatography or distillation under
reduced pressure. Finally, deprotection of 10 using
ethereal HCl led to the formation of the title amines
11 (isolated as hydrochlorides in 85–94 % yields).
The structures of hydrochlorides 11aHCl, 11jHCl
and 11kHCl, as well as Boc derivative 10g were
confirmed using X-Ray single crystal diffraction
studies (Figure 9).
Scheme 1. Reactions describing decomposition of the
Ruppert–Prakash reagent.
To diminish the negative effect of the reagent
decomposition without using significant excess of
TMSCF3, we used slow addition technique for the
substrates 9b, 9h and 9i. Thus, TMSCF3 was added
slowly to a refluxing solution of the substrate and NaI
in THF over the period of 6–8 h. Under these
conditions, we could achieve nearly complete
conversion for each of these substrates.
An important result obtained in this part of the
study is the order of the substrate reactivity towards
TMSCF3–NaI system:
9a  9f > 9g > 9h  9i > 9b
Apparently, gem-disubstituted alkenes (9a, 9f and
9g) show the best reactivity, and this part of the series
correlates with steric effects observed in the substrate
molecules. However, the rest of the series
demonstrate an opposite correlation. In our opinion, a
possible explanation might include (partially) non-
synchronous formation of the two  bonds by the
difluorocarbene or carbenoid during cycloaddition
(Scheme 2). The (partial) positive charge at one of
the carbon atoms is stabilized best in the transition
state formed from the gem-disubstituted substrates
(“tertiary carbocationoid center”), whereas in the case
of monosubstituted alkenes like 9b, the poorest
stabilization is observed.
It should be noted that to the best of our knowledge,
the relative reactivity of various alkenes towards
TMSCF3–NaI system was not studied thoroughly to
date, and the mechanism of this reaction remains
unclear. Nevertheless, most of the examples
described in the previous works included
difluorocyclopropanation of aryl-substituted double
bonds,[33,45–48] which supports the above hypothesis
since the aryl groups can provide even better
stabilization of the positive charge (“benzylic
carbocationoid center”). Our results are also
consistent with well-established electrophilic nature
of singlet difluorocarbene, i. e. its preference to react
with electron-rich alkenes.[54] A more thorough
investigation of the reaction mechanism involving the
TMSCF3–NaI system is ongoing and will be
published elsewhere.
Figure 9. Molecular structure of 11aHCl, 11jHCl,
11kHCl and 10g.
Conclusion
Reaction of N-Boc protected unsaturated amines with
CF3SiMe3 – NaI system, followed by deprotection is
an efficient method for the synthesis of monocyclic,
spirocyclic and fused bicyclic secondary amines
bearing gem-difluorocyclopropane moiety. The
optimal conditions for the difluorocyclopropanation
include refluxing of the starting materials in THF as
the solvent. At these conditions, a remarkable
decomposition of the Ruppert–Prakash reagent occurs
to give a mixture of gaseous by-products (mainly
CF2=CF2 and Me3SiF), which compete with the main
reaction. While this side process is not a problem for
the reactive substrates (possessing 1,1-disubstituted,
tri- or tetrasubstituted double bond), in the case of
mono- and 1,2-disubstituted alkenes, it prevents the
Scheme 2. Possible explanation of the substrate reactivity
order in the reaction with TMSCF3–NaI system.
4
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
Table 2. Synthesis of amines 11 bearing gem-difluorocyclopropane fragment
#
1
Substrate 9
Boc derivative 10
Amine 11a)
Methodb)
A
Yield of 10 (%) Yield of 11HCl (%)
91
94
2
3
B
A
50
88
95
92
4
A
82
93
5
6
B
B
81
87
91
96
7
8
A
A
64
81
85
90
9
A
A
75
88
89
91
10
11
12
A
A
88
81
92
85
13
B
76
96
a) Isolated as hydrochlorides. b) Method A: TMSCF3 is added in one portion; Method B: slow addition of TMSCF3
5
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
complete conversion, so that slow addition of
CF3SiMe3 becomes necessary. The reactivity order of
the substrates shows that the process is governed
mainly by electronic and to lesser extent – by steric
factors, which can be explained by partially non-
synchronous transition state during addition of
difluorocarbene (carbenoid) to the double bond.
The method includes only two operationally simple
steps, relies on the readily available and non-toxic
starting materials, gives 48–85% overall yields of the
target products, have been used effectively on up to
40 gram scale and in our opinion, has potential for
further scale-up. This makes secondary amines
bearing gem-difluorocyclopropane moiety readily
available to the chemical community, first of all for
the use as building blocks for medicinal chemistry
programs.
(300 mL) under nitrogen atmosphere. Trimethyl-
(trifluoromethyl)silane (48.9 g, 0.344 mol) was added,
and the reaction mixture was heated at reflux
overnight, at which time GCMS indicated complete
conversion. The solid was filtered, and the solvent
was evaporated. The crude product was dissolved in
hexanes (100 mL), filtered through a pad of silica gel
(100 g), and washed with hexanes (300 mL). The
combined filtrates were evaporated to give the
product 10, which was used in the next step without
further purification.
Method B:
Sodium iodide (0.540 g, 3.60 mmol) was added to a
solution of alkene 9 (10.0 mmol) in anhydrous THF
(20 mL) under nitrogen atmosphere and heated to
reflux. Trimethyl(trifluoromethyl)silane (4.93 g, 34.7
mmol) was added dropwise over 6–8 h. The reaction
mixture was heated overnight, at which time the
conversion was detected by GCMS. If necessary,
additional trimethyl(trifluoromethyl)silane (4.93 g, ,
34.7 mmol) was added, and the reaction mixture was
refluxed for additional 24 h. When the conversion
was complete, the solvent was evaporated, and the
crude product was distilled under reduced pressure.
Experimental Section
The solvents were purified according to the standard
procedures. Alkenes 9a–p were prepared via Wittig
olefination of the corresponding ketones using the
methods reported in the literature. All other starting
materials were purchased from commercial sources.
Analytical TLC was performed using Polychrom SI
F254 plates. Column chromatography was performed
using Kieselgel Merck 60 (230–400 mesh) as the
tert-Butyl
1,1-difluoro-6-azaspiro[2.5]octane-6-
1
13
19
stationary phase. H, C, and F NMR spectra were
recorded on a Varian Gemini 2000 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 internal 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 an Agilent 1100 LCMSD SL instrument
(electrospray ionization (ESI)) or Agilent 7820A gas
chromatograph system (electron impact ionization
(EI), ionization energy – 70 eV)). Conversion
measurements were performed using the same GCMS
instrument (column: HP-5ms UI, 30 m0.25 mm,
0.25 µm; carrier gas: helium at 1 mL/min;
temperatures: injector – 250 °C, oven program –
50 °С initial temperature for 1 min, then ramp to
300 °С at 20 °С/min, then hold final temperature for
5 min; MSD transfer line – 280 °C, MSD source –
230 °C, MSD quad – 150 °C; injection parameters:
split ratio 200:1, 0.5 µL injected; MS parameters:
mass scan range – 35–550, ionization energy – 70eV).
carboxylate (10a)
Yield 66.7 g, 91% (Method A). Off-white crystalline
powder. Mp 46–48 °C. 1H NMR (CDCl3, 400 MHz) δ
3.57 – 3.42 (m, 2H), 3.40 – 3.27 (m, 2H), 1.66 – 1.47
(m, 4H), 1.44 (s, J = 2.3 Hz, 9H), 1.08 (t, J = 8.3 Hz,
2H). 13C NMR (CDCl3, 101 MHz,) δ 154.2, 115.4 (t, J
= 288.1 Hz), 79.3, 42.8, 28.4, 28.1, 26.8 (t, J = 10.0
Hz), 21.0 (t, J = 10.1 Hz). 19F NMR (CDCl3, 376
MHz) δ –140.6. MS (EI): m/z = 247 (M+), 192 (M+–t-
Bu), 174 (M+–t-BuO), 147 (M+–Boc), 127 (M+–Boc–
HF). Anal. Calcd. for C12H19F2NO2: C, 58.29; H,
7.74; N, 5.66. Found: C, 58.49; H, 8.02; N, 5.30.
tert-Butyl ((2,2-difluorocyclopropyl)methyl)(methyl)-
carbamate (10b)
The crude product obtained by Method B was
dissolved in CH2Cl2 (100 mL) and treated with 5% aq
KMnO4 (100 mL). The mixture was stirred at rt
overnight. The obtained solid was filtered, the phases
were separated, and the organic layer was dried over
Na2SO4, and evaporated in vacuo. Yield 1.05 g, 50%.
1
Brownish oil. H NMR (CDCl3, 400 MHz) δ 3.95 –
3.72 (m, 1H), 3.71 – 3.46 (m, 1H), 3.10 – 2.93 (m,
1H), 2.88 (s, 3H), 1.90 – 1.66 (m, 1H), 1.45 (s, 9H),
General procedure for the preparation of 10:
13
1.17 – 0.93 (m, 1H). C NMR (CDCl3, 101 MHz) δ
154.7, 79.4, 45.8, 33.8, 28.1, 27.7, 21.1 (t, J = 8.0 Hz),
14.5 (t, J = 11.1 Hz). F NMR (CDCl3, 376 MHz) δ
Method A:
19
–130.3 (dd, J = 157.9, 62.0 Hz), –143.3 (d, J = 158.6
Sodium iodide (5.30 g, 0.0354 mol) was added to a
solution of alkene 9 (0.100 mol) in anhydrous THF
Hz). MS (EI): m/z = 206 (M+), 165 (M+–t-Bu), 148
6
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
(M+–t-BuO), 121 (M+–Boc), 101 (M+–Boc–HF).
Anal. Calcd. for C10H17F2NO2: C, 54.29; H, 7.74; N,
6.33. Found: C, 54.30; H, 8.10; N, 6.66.
1H NMR (CDCl3, 400 MHz) δ 3.92 – 2.81 (m, 4H),
1.97 – 1.52 (m, 4H), 1.45 (s, 9H). C NMR (CDCl3,
13
101 MHz) δ 154.1, 113.6 (t, J = 285.9 Hz), 79.4, 39.4
(d, J = 95.6 Hz), 35.7 (d, J = 107.9 Hz), 28.2, 16.8,
15.7. 19F NMR (CDCl3, 376 MHz) δ –128.0 (d, J =
158.5 Hz), –153.4 (dd, J = 158.4, 94.9 Hz). MS (EI):
m/z = 233 (M+), 218 (M+–CH3), 178 (M+–t-Bu), 160
(M+–t-BuO), 133 (M+–Boc), 113 (M+–Boc–HF).
Anal. Calcd. for C11H17F2NO2: C, 56.64; H, 7.35; N,
6.00. Found: C, 56.69; H, 7.48; N, 5.71.
tert-Butyl
1,1-difluoro-2-methyl-6-azaspiro[2.5]-
octane-6-carboxylate (10f)
1
Yield 60.6 g, 88% (Method A). Yellowish oil. H
NMR (CDCl3, 400 MHz) δ 3.58 – 3.43 (m, 2H), 3.14
(qd, J = 8.0, 5.0 Hz, 2H), 1.47 (m, 4H), 1.37 (s, 9H),
1.19 – 1.06 (m, 1H), 0.98 (dd, J = 6.5, 2.9 Hz, 3H).
13C NMR (CDCl3, 101 MHz) δ 154.2, 116.2 (dd, J =
295.9, 289.2 Hz), 79.1, 42.8, 29.9, 27.9, 24.7 (t, J =
tert-Butyl
1,1-difluoro-5-azaspiro[2.3]hexane-5-
carboxylate (10j)
19
9.8 Hz), 23.4, 5.3 (d, J = 4.9 Hz). F NMR (CDCl3,
376 MHz) δ –139.7 (dd, J = 153.7, 14.2 Hz), –151.4
(d, J = 153.7 Hz). MS (EI): m/z = 261 (M+), 206
(M+–t-Bu), 188 (M+–t-BuO), 141 (M+–Boc–HF).
Anal. Calcd. for C13H21F2NO2: C, 59.75; H, 8.10; N,
5.36. Found: C, 59.91; H, 7.93; N, 5.18.
1
Yield 45.3 g, 64% (Method A). Light brown oil. H
NMR (CDCl3, 400 MHz) δ 4.11 (d, J = 9.2 Hz, 2H),
3.96 (dt, J = 9.3, 2.3 Hz, 2H), 1.45 (s, 9H), 1.44 –
1.40 (m, 2H). 13C NMR (CDCl3, 101 MHz) δ 155.4,
110.4 (t, J = 285.5 Hz), 79.7, 52.0, 33.6, 29.5, 28.1,
18.1, 0.9. 19F NMR (CDCl3, 376 MHz,) δ –140.4. MS
(EI): m/z = 219 (M+), 204 (M+–CH3), 164, 146 (M+–
t-BuO), 118, 103. Anal. Calcd. for C10H15F2NO2: C,
54.79; H, 6.90; N, 6.39. Found: C, 54.80; H, 6.69; N,
6.33.
tert-Butyl
undecane-8-carboxylate (10g)
11,11-difluoro-8-azadispiro[3.0.55.14]-
1
Yield 2.07 g, 82%. Yellowish oil. H NMR (CDCl3,
400 MHz) δ 3.66 – 3.53 (m, 2H), 3.28 – 3.17 (m, 2H),
2.07 (s, 4H), 2.05 – 1.89 (m, 2H), 1.46 (s, 9H), 1.44 –
1.39 (m, 4H). 13C NMR (CDCl3, 101 MHz) δ 154.3,
114.9 (t, J = 294.3 Hz), 79.3, 42.9, 32.4 (t, J = 11.1
Hz), 28.2, 24.6, 20.1, 15.8. 19F NMR (CDCl3, 376
MHz) δ –148.9. MS (EI): m/z = 287 (M+), 231 (M+–t-
Bu), 214 (M+–t-BuO), 166. Anal. Calcd. for
C15H23F2NO2: C, 62.70; H, 8.07; N, 4.87. Found: C,
62.31; H, 8.10; N, 4.68.
tert-Butyl
carboxylate (10k)
1,1-difluoro-5-azaspiro[2.4]heptane-5-
1
Yield 26.4 g, 81% (Method A). Light brown oil. H
NMR (CDCl3, 400 MHz) δ 3.64 – 3.22 (m, 4H), 2.12
– 2.02 (m, 1H), 1.97 – 1.84 (m, 1H), 1.44 (s, 9H),
1.32 (dd, J = 11.1, 6.5 Hz, 2H). 13C NMR (CDCl3,
101 MHz) δ 153.7, 112.8 (t, J = 287.1 Hz), 79.2, 47.8
(d, J = 28.3 Hz), 45.5 (d, J = 35.1 Hz), 28.1, 18.6. 19F
NMR (CDCl3, 376 MHz) δ –138.7 (d, J = 152.6 Hz),
–140.4 (d, J = 158.9 Hz). MS (EI): m/z = 233 (M+),
178, 160 (M+–t-BuO), 133 (M+–Boc), 113 (M+–Boc–
HF). Anal. Calcd. for C11H17F2NO2: C, 56.64; H,
7.35; N, 6.00. Found: C, 56.78; H, 7.36; N, 5.63.
tert-Butyl 6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-
carboxylate (10h)
The crude product obtained by Method B was
distilled under reduced pressure (bp 75–78 °C /
1 mbar) to give 10h. Yield 18.1 g, 81%. Yellowish
1
solid. Mp 52–54 °C. H NMR (CDCl3, 400 MHz) δ
3.76 (dd, J = 32.4, 11.2 Hz, 2H), 3.65 – 3.51 (m, 2H),
2.23 (dd, J = 12.2, 5.1 Hz, 2H), 1.45 (s, 9H). 13C
NMR (CDCl3, 101 MHz) δ 153.2, 112.9 (dd, J =
295.0, 276.9 Hz), 79.5, 45.1, 28.2, 26.0 (t, J = 12.0
Hz), 25.3 (t, J = 12.1 Hz). 19F NMR (CDCl3, 376
MHz) δ –131.3 (dt, J = 162.0, 12.1 Hz), –157.6 (d, J
= 162.0 Hz). MS (EI): m/z = 219 (M+), 204 (M+–
CH3), 164, 146 (M+–t-BuO), 119 (M+–Boc). Anal.
Calcd. for C10H15F2NO2: C, 54.79; H, 6.90; N, 6.39.
Found: C, 54.97; H, 6.89; N, 6.14.
tert-Butyl
carboxylate (10l)
1,1-difluoro-5-azaspiro[2.5]octane-5-
1
Yield 21.0 g, 75% (Method A). Light brown oil. H
NMR (CDCl3, 400 MHz) δ 3.59 – 3.15 (m, 4H), 1.73
– 1.61 (m, 1H), 1.61 – 1.44 (m, 3H), 1.38 (s, 9H),
1.25 – 1.02 (m, 1H), 1.03 – 0.89 (m, 1H). 13C NMR
(CDCl3, 101 MHz) δ 155.7, 115.0 (t, J = 287.6 Hz),
79.2, 46.1, 43.1, 27.9, 27.4 (t, J = 10.3 Hz), 27.1 (d, J
19
= 4.7 Hz), 23.9, 20.4. F NMR (CDCl3, 376 MHz) δ
–140.1 (dd, J = 157.5, 12.7 Hz), –141.8 (d, J = 158.1
Hz). MS (EI): m/z = 247 (M+), 191 (M+–t-Bu), 174
(M+–t-BuO), 147 (M+–Boc), 127 (M+–Boc–HF).
Anal. Calcd. for C12H19F2NO2: C, 58.29; H, 7.74; N,
5.66. Found: C, 58.60; H, 7.91; N, 5.41.
tert-Butyl 7,7-difluoro-3-azabicyclo[4.1.0]heptane-3-
carboxylate (10i)
The crude product obtained by Method B was
distilled under reduced pressure (bp 85–93 °C /
1 mbar) to give 10i. Yield 20.1 g, 87%. Yellowish oil.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700857
Advanced Synthesis & Catalysis
tert-Butyl
carboxylate (10m)
1,1-difluoro-6-azaspiro[2.6]nonane-6-
31.7, 30.3, 28.1, 27.2 (dd, J = 10.8, 9.8 Hz), 14.9 (t, J
= 10.9 Hz). 19F NMR (CDCl3, 376 MHz) δ –128.1 (d,
J = 157.3 Hz), –146.2 (dd, J = 157.3, 13.1 Hz). MS
(EI): m/z = 261 (M+), 204 (M+–t-Bu), 188 (M+–t-
BuO), 160 (M+–Boc), 140 (M+–Boc–HF–H). Anal.
Calcd. for C13H21F2NO2: C, 59.75; H, 8.10; N, 5.36.
Found: C, 59.90; H, 8.15; N, 5.46.
1
Yield 14.2 g, 88% (Method A). Light brown oil. H
NMR (CDCl3, 400 MHz) δ 3.61 – 3.17 (m, 4H), 1.88
– 1.55 (m, 6H), 1.46 (s, 9H), 1.10 – 0.95 (m, 2H). 13C
NMR (CDCl3, 101 MHz) δ 154.9, 115.9 (t, J = 287.7
Hz), 78.9, 46.5 (d, J = 75.4 Hz), 44.5 (d, J = 29.1
Hz), 31.4 (d, J = 50.7 Hz), 29.2, 28.5 (d, J = 21.2
Hz), 28.1, 24.8 (d, J = 9.9 Hz), 21.3 (dt, J = 40.0, 9.2
Hz). 19F NMR (CDCl3, 376 MHz) δ –138.1 (dd, J =
152.4, 97.1 Hz), –139.7 (dd, J = 152.0, 115.5 Hz).
MS (EI): m/z = 261 (M+), 188 (M+–t-BuO), 140 (M+–
Boc–HF). Anal. Calcd. for C13H21F2NO2: C, 59.75; H,
8.10; N, 5.36. Found: C, 59.45; H, 8.45; N, 5.37.
Decomposition of CF3SiMe3 upon action of NaI:
TMSCF3 (3.00 g, 0.0211 mol) and PhCF3 (3.08 g,
0.0211 mol) were dissolved in THF (50 mL). NaI
(0.315 g, 2.10 mmol) was added, and the mixture was
heated at reflux with efficient condenser. The
evaluated gases were trapped at –78 C by a THF
solution (25 mL) containing PhCF3 (1.00 g, 6.85
mmol). The temperature of the reaction mixture was
monitored, and 19F NMR spectra were recorded for
both THF solutions each 10 min and then used to
build the graph shown in Figure 8.
tert-Butyl
decane-7-carboxylate (10n)
10,10-difluoro-7-azadispiro[2.0.54.13]-
Yield 6.14 g, 88% (Method A). Pale yellow
crystalline powder. Mp 83-84 °C. H NMR (CDCl3,
1
400 MHz) δ 3.59 – 3.42 (m, 2H), 3.35 – 3.24 (m, 2H),
1.75 – 1.62 (m, 2H), 1.58 – 1.49 (m, 2H), 1.45 (s, 9H),
1.07 – 0.92 (m, 4H). C NMR (CDCl3, 101 MHz) δ
154.2, 116.7 (t, J = 293.4 Hz), 79.3, 42.9, 28.2, 27.8
(t, J = 10.2 Hz), 27.3, 22.9 (t, J = 9.7 Hz), 4.2. 19F
NMR (CDCl3, 376 MHz) δ –144.1. MS (EI): m/z =
200 (M+–t-BuO), 172 (M+–Boc), 145, 109. Anal.
Calcd. for C14H21F2NO2: C, 61.52; H, 7.74; N, 5.12.
Found: C, 61.35; H, 7.34; N, 5.44.
General procedure for the preparation of 11a–11o:
13
To a solution of 10 (45.0 mmol) in dry Et2O (100
mL), 3.5 M HCl in Et2O (100 mL) was added, and
the reaction mixture was stirred overnight. The solid
formed was filtered, washed with Et2O (350 mL)
and dried under reduced pressure.
1,1-Difluoro-6-azaspiro[2.5]octane
hydrochloride
(11a∙HCl)
tert-Butyl
decane-6-carboxylate (10o)
10,10-difluoro-6-azadispiro[2.0.54.13]-
Yield 41.2 g, 94%. Pale yellow crystalline powder.
Mp 199–203 °C (dec.). H NMR (DMSO-d6, 400
1
1
MHz) δ 9.33 (br s, 1H), 9.23 (br s, 1H), 3.16 – 2.93
(m, 4H), 1.95 – 1.80 (m, 2H), 1.78 – 1.58 (m, 2H),
1.42 (t, J = 8.9 Hz, 2H). 13C NMR (DMSO-d6, 101
MHz) δ 116.1 (t, J = 287.2 Hz), 42.3, 25.0 (t, J = 10.5
Yield 0.668 g, 81% (Method A). Yellowish oil. H
NMR (CDCl3, 400 MHz) δ 3.58 – 3.19 (m, 4H), 1.82
– 1.71 (m, 1H), 1.65 – 1.52 (m, 3H), 1.42 (s, 9H),
13
1.09 – 0.88 (m, 4H). C NMR (CDCl3, 101 MHz) δ
19
Hz), 24.5, 20.7 (t, J = 9.8 Hz). F NMR (DMSO-d6,
153.9, 116.1 (t, J = 293.0 Hz), 79.2, 45.4, 43.0, 28.4
(s, J = 9.9 Hz), 28.0, 25.8, 23.9, 22.5 (t, J = 9.6 Hz),
4.4, 3.9. F NMR (CDCl3, 376 MHz) δ –143.5 (d, J
= 152.0 Hz), –144.5 (d, J = 151.8 Hz). MS (EI): m/z
= 217 (M+–t-Bu), 197, 172 (M+–Boc), 158. Anal.
Calcd. for C14H21F2NO2: C, 61.52; H, 7.74; N, 5.12.
Found: C, 61.41; H, 7.89; N, 5.08.
376 MHz) δ –139.1 (t, J = 8.1 Hz). MS (EI): m/z =
147 (M+), 127 (M+–HF), 82. Anal. Calcd. for
C7H12ClF2N: C, 45.79; H, 6.59; N, 7.63; Cl, 19.31.
Found: C, 46.03; H, 6.96; N, 7.71; Cl, 19.04.
19
1-(2,2-difluorocyclopropyl)-N-methylmethanamine
hydrochloride (11b∙HCl)
tert-Butyl
carboxylate (10p)
4-(2,2-difluorocyclopropyl)piperidine-1-
Yield 0.641 g, 95%. White solid. Mp 106-121 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.50 (brs,
1
2H), 3.01 (d, J = 61.2 Hz, 2H), 2.51 (s, 3H), 2.10 (s,
1H), 1.69 (d, J = 42.2 Hz, 2H). 13C NMR (DMSO-d6,
101 MHz) δ 113.5 (t, J = 282.5 Hz), 44.6 (d, J = 4.7
Hz), 31.7, 17.9 (t, J = 11.4 Hz), 15.2 (t, J = 10.8 Hz).
19F NMR (DMSO-d6, 376 MHz) δ –128.3 (d, J =
155.9 Hz), –140.8 (dd, J = 156.0, 10.1 Hz). MS (EI):
m/z = 121 (M+), 99, 91. Anal. Calcd. for C5H10ClF2N:
The crude product obtained by Method B was
distilled under reduced pressure (bp 104–107 °C /
0.1 mbar) to give 10p. Yield 17.3 g, 76%. Yellowish
1
oil. H NMR (CDCl3, 400 MHz) δ 4.17 – 3.90 (m,
2H), 2.75 – 2.55 (2, 1H), 1.80 – 1.57 (m, 2H), 1.42 (s,
9H), 1.37 – 1.15 (m, 5H), 0.97 – 0.86 (m, 1H). 13C
NMR (CDCl3, 101 MHz) δ 154.3, 113.4 (dd, J =
346.1, 221.0 Hz), 79.0, 43.3, 34.7 (d, J = 2.8 Hz),
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700857
Advanced Synthesis & Catalysis
C, 38.11; H, 6.40; N, 8.89; Cl, 22.50. Found: C,
37.89; H, 6.14; N, 8.72; Cl, 22.58.
286.3, 284.2 Hz), 37.9, 34.3, 14.8 (t, J = 11.4 Hz),
13.5 (dd, J = 13.1, 10.2 Hz), 12.9. 19F NMR (DMSO-
d6, 376 MHz) δ –127.9 (d, J = 156.1 Hz), –148.1 (d, J
= 156.2 Hz). MS (EI): m/z = 133 (M+), 113 (M+–HF–
H), 85. Anal. Calcd. for C6H10ClF2N: C, 42.49; H,
5.94; N, 8.26; Cl, 20.90. Found: C, 42.75; H, 5.77; N,
8.65; Cl, 20.91.
1,1-Difluoro-2-methyl-6-azaspiro[2.5]octane
hydrochloride (11f∙HCl)
Yield 29.2 g, 92%. White solid. Mp 171–174 °C
1
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.26 (br s,
2H), 3.20 – 2.88 (m, 4H), 1.93 – 1.63 (m, 4H), 1.63 –
1.43 (m, 1H), 1.06 (dd, J = 6.5, 2.6 Hz, 3H). 13C
NMR (101 DMSO-d6, 101 MHz) δ 116.6 (dd, J =
295.5, 288.1 Hz), 42.4 (d, J = 4.4 Hz), 26.2 (t, J =
10.1 Hz), 26.0 (d, J = 5.3 Hz), 24.6 (t, J = 9.6 Hz),
19.8 (d, J = 4.9 Hz), 5.6 (d, J = 4.7 Hz). 19F NMR
(DMSO-d6, 376 MHz) δ –138.0 (dd, J = 152.5, 14.8
Hz), –149.5 (d, J = 152.5 Hz). MS (EI): m/z = 161
(M+), 141 (M+–HF), 126. Anal. Calcd. for
C8H14ClF2N: C, 48.61; H, 7.14; N, 7.09; Cl, 17.94.
Found: C, 48.94; H, 6.77; N, 6.75; Cl, 18.15.
1,1-Difluoro-5-azaspiro[2.3]hexane hydrochloride
(11j∙HCl)
Yield 26.1 g, 85%. Light brown crystalline powder.
1
Mp 143–146 °C (dec.). H NMR (DMSO-d6, 400
MHz) δ 9.66 (br s, 2H), 4.29 – 4.06 (m, 2H), 4.06 –
3.89 (m, 2H), 1.81 (t, J = 9.4 Hz, 2H). 13C NMR
(DMSO-d6, 101 MHz) δ 110.7 (t, J = 286.3 Hz), 47.0,
19
23.7, 17.3 (t, J = 9.9 Hz). F NMR (DMSO-d6, 376
MHz) δ –138.6. MS (EI): m/z = 119 (M+), 98 (M+–
HF–H), 90. Anal. Calcd. for C5H8ClF2N: C, 38.60; H,
5.18; N, 9.00; Cl, 22.79. Found: C, 38.74; H, 5.11; N,
9.10; Cl, 23.16.
11,11-Difluoro-8-azadispiro[3.0.55.14]undecane
hydrochloride (11g∙HCl)
1,1-Difluoro-5-azaspiro[2.4]heptane hydrochloride
(11k∙HCl)
Yield 1.27 g, 93%. White solid. Mp 228–232 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 3.16 – 2.97
1
(m, 4H), 2.23 – 2.09 (m, 2H), 2.05 – 1.94 (m, 4H),
1.71 – 1.61 (m, 2H), 1.61 – 1.51 (m, 2H), NH2 are
exchanged with HDO. 13C NMR (DMSO-d6, 101
MHz) δ 115.0 (t, J = 294.9 Hz), 42.2, 32.4 (t, J = 10.7
Hz), 26.2 (t, J = 9.1 Hz), 20.9, 19.6, 15.2. 19F NMR
(DMSO-d6, 376 MHz) δ –147.2. MS (EI): m/z = 187
(M+), 167, 139. Anal. Calcd. for C10H16ClF2N: C,
53.69; H, 7.21; N, 6.26; Cl, 15.85. Found: C, 53.89;
H, 7.33; N, 6.63; Cl, 15.50.
Yield 19.6 g, 90%. Brownish crystalline powder. Mp
130–133 °C (dec.). 1H NMR (DMSO-d6, 400 MHz) δ
9.71 (br s, 2H), 3.49 – 3.12 (m, 4H), 2.25 – 1.88 (m,
13
1H), 1.91 – 1.45 (m, 1H). C NMR (DMSO-d6, 101
MHz) δ 113.1 (t, J = 287.1 Hz), 45.9 (d, J = 5.7 Hz),
45.1, 28.8 (t, J = 9.8 Hz), 27.3, 18.7 (t, J = 10.0 Hz).
19F NMR (DMSO-d6, 376 MHz) δ –136.5 (dd, J =
377.8, 160.5 Hz). MS (EI): m/z = 133 (M+), 82, 68.
Anal. Calcd. for C6H10ClF2N: C, 42.49; H, 5.94; N,
8.26; Cl, 20.90. Found: C, 42.53; H, 5.73; N, 8.39; Cl,
20.56.
6,6-Difluoro-3-azabicyclo[3.1.0]hexane
hydrochloride (11h∙HCl)
1,1-Difluoro-5-azaspiro[2.5]octane
(11l∙HCl)
hydrochloride
Yield 11.6 g, 91%. White solid. Mp 183–185 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.94 (br s,
1
2H), 3.58 (d, J = 12.4 Hz, 2H), 3.42 (d, J = 12.4 Hz,
2H), 2.80 (d, J = 11.3 Hz, 2H). 13C NMR (DMSO-d6,
101 MHz) δ 113.2 (dd, J = 292.3, 281.5 Hz), 44.7,
26.4 (t, J = 12.1 Hz). 19F NMR (DMSO-d6, 376 MHz)
δ –128.3 (d, J = 160.1 Hz), –149.3 (d, J = 160.1 Hz).
MS (EI): m/z = 119 (M+), 98, 90. Anal. Calcd. for
C5H8ClF2N: C, 38.60; H, 5.18; N, 9.00; Cl, 22.79.
Found: C, 38.91; H, 5.19; N, 9.30; Cl, 22.40.
Yield 18.6 g, 89%. Light brown crystalline powder.
Mp 143-151 °C (dec.). H NMR (DMSO-d6, 400
1
MHz) δ 9.30 (br s, 2H), 3.22 – 2.90 (m, 4H), 1.87 –
1.66 (m, 3H), 1.66 – 1.52 (m, 2H), 1.52 – 1.37 (m,
13
1H). C NMR (DMSO-d6, 101 MHz) δ 115.1 (t, J =
286.8 Hz), 44.0 (d, J = 6.6 Hz), 43.0, 24.7 (dd, J =
22.9, 7.0 Hz), 20.9. 19F NMR (DMSO-d6, 376 MHz)
δ –137.3 (d, J = 169.5 Hz), –139.8 (d, J = 167.8 Hz).
MS (EI): m/z = 147 (M+), 126 (M+–HF–H), 96, 82.
Anal. Calcd. for C7H12ClF2N: C, 45.79; H, 6.59; N,
7.63; Cl, 19.31. Found: C, 45.86; H, 6.96; N, 8.03; Cl,
19.10.
7,7-Difluoro-3-azabicyclo[4.1.0]heptane
hydrochloride (11i∙HCl)
Yield 13.9 g, 96%. White solid. Mp 98–102 °C (dec.).
1H NMR (DMSO-d6, 400 MHz) δ 9.27 (br s, 1H),
3.61 – 3.46 (m, 1H), 3.07 – 2.93 (m, 1H), 2.93 – 2.81
(m, 1H), 2.22 – 1.95 (m, 3H), 1.91 – 1.78 (m, 1H).
13C NMR (DMSO-d6, 101 MHz) δ 113.9 (dd, J =
1,1-Difluoro-6-azaspiro[2.6]nonane hydrochloride
(11m∙HCl)
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700857
Advanced Synthesis & Catalysis
Yield 10.2 g, 91%. White solid. Mp 113-121 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.41 (br s,
(DMSO-d6, 101 MHz) δ 116.1 (t, J = 292.4 Hz), 43.4,
43.0, 26.0 (dd, J = 11.5, 10.0 Hz), 23.7, 23.3 (t, J =
9.5 Hz), 20.6, 5.3, 4.4. 19F NMR (DMSO-d6, 376
MHz) δ –139.9 (dd, J = 151.7, 7.7 Hz), –142.2 (dd, J
= 151.7, 8.3 Hz). MS (EI): m/z = 173 (M+), 158, 144,
82. Anal. Calcd. for C9H14ClF2N: C, 51.56; H, 6.73;
N, 6.68; Cl, 16.91. Found: C, 51.23; H, 6.92; N, 7.05;
Cl, 17.02.
1
2H), 3.21 – 2.99 (m, 4H), 2.08 – 1.94 (m, 1H), 1.94 –
1.73 (m, 4H), 1.73 – 1.51 (m, 1H), 1.47 – 1.19 (m,
13
2H). C NMR (DMSO-d6, 101 MHz) δ 116.1 (t, J =
292.4 Hz), 43.4, 43.0, 26.1 (t, J = 292.6 Hz), 23.7,
23.3 (t, J = 9.5 Hz), 20.6, 5.3, 4.4. 19F NMR (DMSO-
d6, 376 MHz) δ –136.9. MS (EI): m/z = 161 (M+),
140 (M+–HF–H), 96, 56. Anal. Calcd. for
C8H14ClF2N: C, 48.61; H, 7.14; N, 7.09; Cl, 17.94.
Found: C, 48.78; H, 7.08; N, 7.47; Cl, 18.07.
4-(2,2-Difluorocyclopropyl)piperidine hydrochloride
(11p∙HCl)
Yield 12.3 g, 96%. White solid. Mp 216–218 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.36 (br s,
10,10-Difluoro-7-azadispiro[2.0.54.13]decane
hydrochloride (11n∙HCl)
1
1H), 9.17 (br s, 1H), 3.20 (t, J = 12.0 Hz, 2H), 2.89 –
2.71 (m, 2H), 1.79 (t, J = 14.8 Hz, 2H), 1.69 – 1.30
(m, 5H), 1.24 – 1.02 (m, 1H). 13C NMR (DMSO-d6,
101 MHz) δ 114.9 (t, J = 282.8 Hz), 42.7, 42.4, 31.9
(d, J = 2.8 Hz), 28.2, 26.9, 26.5 (t, J = 10.0 Hz), 14.8
Yield 4.36 g, 92%. White solid. Mp 245-252 °C
(dec.). H NMR (DMSO-d6, 400 MHz) δ 9.18 (br s,
1
2H), 3.14 – 3.04 (m, 2H), 3.04 – 2.91 (m, 2H), 1.99 –
1.85 (m, 2H), 1.80 – 1.63 (m, 2H), 1.27 – 1.17 (m,
13
19
2H), 1.08 – 0.99 (m, 2H). C NMR (DMSO-d6, 101
(t, J = 10.4 Hz). F NMR (DMSO-d6, 376 MHz) δ –
MHz) δ 117.0 (t, J = 293.3 Hz), 42.0, 25.9 (t, J = 10.6
Hz), 23.7, 23.3 (t, J = 9.3 Hz), 4.4. 19F NMR (DMSO-
d6, 376 MHz) δ –142.0. MS (EI): m/z = 173 (M+),
158, 145, 109. Anal. Calcd. for C9H14ClF2N: C,
51.56; H, 6.73; N, 6.68; Cl, 16.91. Found: C, 51.84;
H, 6.44; N, 6.63; Cl, 17.20.
125.8 (d, J = 153.6 Hz), –143.5 (dd, J = 153.6, 13.1
Hz). MS (EI): m/z = 161 (M+), 132, 96, 68, 56. Anal.
Calcd. for C8H14ClF2N: C, 48.61; H, 7.14; N, 7.09; Cl,
17.94. Found: C, 48.41; H, 7.28; N, 7.33; Cl, 17.61.
X-Ray structure determination
10,10-Difluoro-6-azadispiro[2.0.54.13]decane
hydrochloride (11o∙HCl)
Single crystals were obtained by slow evaporation of
the solutions in MeCN (11aHCl, 11jHCl and 11kHCl)
or hexanes (10g). All crystallographic measurements
for 11aHCl, 11kHCl and 10g were performed at
173 K, for 11jHCl – at 123 K on a Bruker Smart
Apex II diffractometer operating in the  scans mode.
The intensity data were collected with graphite-
monochromated Mo-K radiation ( = 0.71078 Å).
Yield 0.334 g, 85%. Light brown crystalline powder.
1
Mp 157–160 °C (dec.). H NMR (DMSO-d6, 400
MHz) δ 9.38 (br s, 1H), 9.20 (br s, 1H), 3.25 – 3.08
(m, 1H), 3.08 – 2.78 (m, 3H), 1.86 – 1.65 (m, 3H),
1.61 – 1.45 (m, 2H), 1.16 – 0.94 (m, 3H). 13C NMR
Table 3. Crystal data, data collection and structure refinement details for 10g, 11jHCl, 11aHCl and 11kHCl
11aHCl
11kHCl
Parameter
10g
11jHCl
Formula
M
C14H21F2NO2
273.32
C5H8ClF2N
155.57
C7H12ClF2N
183.63
C6H10ClF2N
279.31
Crystal system
Space group, Z
a, Å
b, Å
c, Å
Monoclinic
P21/c, 4
13.723(3)
10.149(2)
10.666(2)
105.924(8)
1428.5(5)
1.271
Monoclinic
Cm, 2
Orthorhombic
Cmca, 8
9.783(4)
7.335(3)
24.443(12)
90
1754.0(13)
1.391
0.405
Orthorhombic
P212121, 4
5.3683(10)
10.4694(19)
13.742(3)
90
772.3(3)
1.459
0.454
10.332(4)
7.205(4)
5.670(3)
121.987(9)
358.0(3)
1.443
β, º
V, Å3
Dc, g·cm–1
μ(Mo-Kα), mm−1
θmax, º
0.101
26.48
0.482
28.39
28.38
28.28
Measured/unique reflections
Rint
13924/2953
0.0535
2020/ 913
0.0236
9037/1162
0.0622
4797/1739
0.0352
Parameters refined
R1[I >2σ(I)]
wR2 (all data)
Goof on F2
Max, min peak, Å–3
172
0.045
0.1269
1.054
68
0.0233
0.0517
1.066
68
0.0383
0.0873
0.989
92
0.037
0.081
1.07
0.26/–0.22
0.26/–0.20
0.41/–0.19
0.24/–0.25
10
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10.1002/adsc.201700857
Advanced Synthesis & Catalysis
[12]
L. D. Cripe, H. Uno, E. M. Paietta, M. R. Litzow,
R. P. Ketterling, J. M. Bennett, J. M. Rowe, H. M.
Lazarus, S. Luger, M. S. Tallman, Blood 2010, 116,
4077–4085.
The data were corrected for Lorentz-polarization
effects and for the effects of absorption (numerical
for 11jHCl, 11kHCl and multi-scans method for
11kHCl, 10g). The structures were solved by direct
methods and refined by the full-matrix least-squares
technique in the anisotropic approximation for non-
hydrogen atoms using the Bruker SHELXTL
program package.[55] All CH hydrogen atoms were
placed at calculated positions and refined as ‘riding’
model. Crystal data, data collection and structure
refinement details are summarized in Table 3.
CCDC-1556358, CCDC-1556359, CCDC-1556360,
and CCDC-1556361 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge
[13] I. Collado, C. Pedregal, A. B. Bueno, A. Marcos, R.
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Centre
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The work was supported by Ukrainian Government Funding
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Gram-scale synthesis of amines bearing
gem-difluorocyclopropane moiety
Adv. Synth. Catal. 2017, Volume, Page – Page
Pavel S. Nosik, Andrii O. Gerasov, Rodion O.
Boiko, Eduard Rusanov, Sergey V. Ryabukhin,
Oleksandr O. Grygorenko,*
Dmitriy M. Volochnyuk
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