Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery

Article abstract of DOI:10.1002/chem.201705708

Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF₃/NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.

Full text of DOI:10.1002/chem.201705708

A Journal of
Accepted Article
Title: Synthesis of functionalized difluorocyclopropanes: unique
building blocks for drug discovery
Authors: Roman Bychek, Vadym Levterov, Iryna Sadkova, Andrey
Tolmachev, and Pavel Mykhailiuk
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.201705708
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10.1002/chem.201705708
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Synthesis of functionalized difluorocyclopropanes:
unique building blocks for drug discovery
Roman M. Bychek,a Vadym V. Levterov,a Iryna V. Sadkova,a Andrey A. Tolmachev,a,b
Pavel K. Mykhailiuka,b*
Abstract: Difluorocyclopropane-containing building blocks for drug
Our
work
previous
discovery were synthesized from the functionalized alkenes and
TMSCF3/NaI. Novel fluorinated acids, amines, amino acids,
alcohols, ketones and sulfonyl chlorides were obtained.
F
F
a)
R
n
CF2ClCO2Na
F
F
n
or
N
CO2Me
N
N
FSO2CF2CO2TMS
51-78%
Boc
Boc
1-3
Boc
n =
activated alkenes
Introduction
CF2ClCO2Na
b)
no
reaction
or
N
The incorporation of fluorinated units into organic
compounds can profoundly change their physico-chemical and
biological properties. In particular, incorporation even of a single
fluorine atom can significantly increase the bioavailability,
metabolic stability and the lipophilicity of the corresponding
bioactive molecules. Moreover, up to 20% of all modern
marketed drugs and even 30% of all agrochemicals are fluorine-
containing organic compounds.[1-3] Fluorine-substituted amino
acids have also found another practical application – as
19F-labels in structural and functional studies of peptides.[4,5,6]
Given the high popularity of cyclopropane motif in drugs, it is
not surprising therefore that difluorocyclopropane-containing
compounds also gained popularity in drug discovery in recent
years (Figure 1).[7,8] They also proved to be valuable starting
materials in organic synthesis.[9,10]
FSO2CF2CO2TMS
PG
PG:
Bn
Boc, Bz,
non-activated alkenes
This work
F
F
c)
R
n
TMSCF3/NaI
64-86%
R
n
+
esters, nitriles,
ketals
N
ethers,
n =
1-3
N
Boc
Boc
Scheme 1. Background and historical context of our research.
Diverse applications of fluorinated cyclopropanes promoted
the development of general methods for their synthesis.[11-17]
Recently, we performed the difluorocyclopropanation of cyclic N-
Boc protected enamides - activated alkenes - with CF2ClCO2Na
or Dolbier reagent (FSO2CF2CO2TMS). We used these
fluorinated amines as building blocks for drug discovery, and the
fluorinated amino acids as 19F-NMR labels for studying peptides
(Scheme 1).[6] However, all previous attempts to perform this
transformation on non-activated alkenes with the N-protected
amino group, failed.
In 2011, Prakash reported that the combination CF3TMS/NaI
efficiently converted the non-activated alkenes into the gem-
difluorocyclopropanes.[8] Most of the starting alkenes, however,
contained no functional groups. Herein, we used this procedure
to convert the functionalized non-activated alkenes - amines,
esters, nitriles, ethers and ketals - into the functionalized
difluorocyclopropanes: novel building blocks for drug
discovery.[18]
F
F
F
F
F
HN
F
O
HN
NH
N
NH
F
O
CO2H
NH2
N
O
HO2C
N
N
CO2H
O
H
Anti-cancer
WO 2016/202755 A1
of the 5-HT2C
WO 2017/50807 A1
agent
Selective mGluR2
Agonist
receptor
agonist
456
J. Med. Chem.
2004, 47,
Pharm
AbbVie
Bayer
N
F
HO
O
F
O
O
F
N
N
N
O
F
Cl
O
or
treatment of
obesity
Zosuquidar
antineoplastic drug
reached Phase III clinical trials
for the
Agent
prophylaxis
EP 2015/2848622 A1
Takeda Pharm
Eli Lilli
Figure 1. Bioactive compounds with a difluorocyclopropane motif.
Results and Discussion
Optimization. Our previous attempts to perform the
difluorocyclopropanation of alkene
1
by reaction with
a*
b
Enamine Ltd., Chervonotkatska 78, Kyiv 02094, Ukraine,
www.mykhailiukchem.org, www.enamine.net
E-mail:Pavel.Mykhailiuk@gmail.com
Department of Chemistry, Taras Shevchenko National University of
Kyiv, Volodymyrska 64, Kyiv 01601, Ukraine.
Supporting information for this article is available on the Internet
CF2ClCO2Na, (CF3)2Hg or FSO2CF2CO2TMS/LiF failed (Scheme
2). However, following the procedure of Prakash - heating a
solution of alkene 1, TMSCF3 (2.5 equiv), and NaI (0.2 equiv) in
THF, - product 1a was obtained in 67% yield. It is worth
mentioning that for unclear reasons the reaction did not proceed
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10.1002/chem.201705708
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in acetonitrile or dioxane.[8] Cleavage of the N-Boc protecting
group under the acidic conditions provided the target amine 1b.
The procedure was scalable, as we easily synthesized 10 g of
amine 1b in one run.
*HCl
F
F
83
85
85
6
7
6b
7b
N
N
oc
B
H
or
CF2ClCO2Na
(CF )
2Hg
3
*HCl
F
or
FSO2CF2CO2TMS
TMSCF3
N
F
F
F
F
F
N
*HCl
oc
B
H
NaI
HCl
dioxane
96%
(cat)
F
F
*HCl
F
F
reflux
THF,
67%
N
N
N
Boc
F
F
H
Boc
8
8b
1
1a
1b 10
g
N
N
oc
B
H
Scheme 2. Optimized synthesis of amine 1b.
[a]
Reaction conditions: (i) TMSCF3 (2.5 equiv), NaI (0.5 equiv), alkene (1
Reaction scope. Carbamates. We next explored the high
potential of this procedure to synthesize other secondary
fluorinated amines.[19] In fact, all carbamates 1-8 smoothly gave
the corresponding difluorocyclopropanes 1a-8a after the work-up
(see SI). Acidic N-Boc deprotection resulted in the fused amines
1b-3b and the spirocyclic amines 4b-8b in 64-87% isolated yield
over two steps (Table 1).
equiv), THF, reflux for 4 h. (ii) alkene, 5M HCl, MeOH, rt, 12h. [b] Isolated yield
over two steps.
Unexpectedly, the corresponding reaction of N-Boc-
protected azetidine 9 gave the monofluoro-substituted pyrrole 10
in 60% yield. The reaction might have proceeded via the ring-
opening of the highly strained intermediate 9a followed by an
elimination of HF (Scheme 3).
F
Table 1. Reaction scope. Carbamates.
F
F
F
F
1
TMSCF
)
*HCl
R
a
ca 3
t
)
F
*HCl
TMSCF3
ca
N I
(
R
R
-
HF
a
N I
t
)
R
(
re ux
THF fl
,
N
oc
B
N
F
N
re ux
60%
THF fl
,
n
n
wor -u
k
p
n
N
N
oc
B
n
N
oc
B
N
e
M OH
,
-
2
)
H
oc
B
oc
B
H
HCl 0 o
C
a
9
9
10
64 87%
-
-
1 8
1b 8b
Scheme 3. Unexpected synthesis of pyrrole 10.
Yield
(%)a,b
Alkene
Product
Esters and nitriles. The reported conditions for the
difluorocyclopropanation were relatively mild, and compatible
with many functional groups: esters, nitriles, ethers and ketals
(Table 2, Table 3).
F
F
*HCl
1
2
3
1b
2b
3b
64
83
86
N
oc
B
N
H
We studied the reaction of esters 11-17 and nitriles 18-21
with CF3TMS/NaI (Table 2) to afford the corresponding
difluorocyclopropanes. The trisubstituted amine 19 reacted
slowly, and the conversion of the reaction reached only 10%.
The final carboxylic acids 11b-21b were synthesized by alkali
hydrolysis of nitrile and ester groups in 10-89% combined yield.
Esters, ethers and ketals. Next, we performed the
synthesis of alcohols 22b-26b and ketones 27b, 28b with a
difluorocyclopropanane moiety. We used an optimized above
procedure: heating a mixture of alkene, CF3TMS and NaI in
acetonitrile at reflux for 12 h. After a standard work-up, the
intermediate difluorocyclopropane-containing esters, ethers and
ketals 11a-21a – were obtained in good to high yields. The
second step – hydrolysis of the functional groups – was
performed under various conditions. In particular, phenol 22b
was obtained by cleaving the OMe-group in cyclopropane 22a
with BBr3 at -35 ºC. Alcohols 23b-26b were obtained by basic
hydrolysis of the ester group in cyclopropanes 23a-26a. Finally,
ketones 27b and 28b were synthesized by an acidic cleavage of
the ketal moiety in difluorocyclopropanes 27a and 28a,
correspondingly.
Ph
*HCl
F
Ph
F
N
oc
B
N
H
F
*HCl
Ph
F
Ph
N
N
oc
B
H
F
*HCl
F
4
5
4b
5b
87
86
N
oc
N
H
B
*HCl
F
F
N
N
oc
H
B
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10.1002/chem.201705708
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Table 2. Reaction scope. Esters and nitriles.
Table 3. Reaction scope. Esters, ethers and ketals.
1
TMSCF
,
3
)
1
ca
TMSCF
3
a
ca
re ux
f
THF l
,
)
N I
t
,
)
(
a
N I
re ux
t
THF fl
,
)
,
wor -u
k
(
p
F
F
H
CO2
e
M
wor -u
k
p
CO2
R
R2
ro s s o
2
)
H d l i
y y
f FG
F
R
R2
BB CH Cl 35 oC
ro s s o
H d
f
2
)
l
y
i
r
-
,
2
22b
y
,
3
2
F
R1
F
G
es er rou
t
g
p
or
or
f
R1
F
G
r
t
,
LiOH THF/H O
,
-
-
11b 21b
2
11 21
e
r
t
K2CO3 M OH/H O
,
,
2
-
-
22b 28b
22 28
-
or
23b 26b
f
Yield
or
Alkene
Product
(%)a,b,c
HCl/H O
t
r
,
2
or
27b 28b
f
,
H
CO2
F
e
M
CO2
89
(4:1)
Yield
11
12
11b
12b
Alkene
Product
(%)a,b
F
F
F
F
F
F
e
H
CO2
M
CO2
87
(1:1)
F
F
22
22b
35
F
e
M
O
H
O
F
F
F
F
88
(2:1)
z
23
24
25
26
27
28
B
23b
24b
25b
26b
27b
28b
48
55
76
75
73
88
O
13
14
13b
Et
CO2
N
H
O
H
CO2
N
oc
B
oc
B
F
F
z
B
O
H
CO2
O
O
Et
CO2
H
O
O
82
(1:1)
14b
15b
F
O
F
F
z
B
O
F
F
H
O
H
CO2
e
M
CO2
F
87
(3:1)
15
16
F
F
OBz
H
O
F
F
n
B
CO2
16b
56
F
O
O
H
CO2
F
O
e
CO2H
M
CO2
F
17
17b
86
O
F
O
F
O
F
O
O
H
CO2
N
C
C
75
(2:1)
F
18
19
20
21
18b
19b
20b
21b
[a]
Reaction conditions: (i) TMSCF3 (2.5 equiv), NaI (0.5 equiv), alkene (1
F
equiv), THF, reflux for 4 h. (ii) Hydrolysis under different conditions. [b] Isolated
yield over two steps.
H
CO2
F
N
10
72
12
Synthesis of building blocks. Having synthesized the
difluorocyclopropyl-containing carboxylic acids (Table 2), we
next converted some of them into the corresponding amines by
Curtius reaction. In particular, compounds 11b, 12b, 15b and
18b were treated with diphenylphosphoryl azide (DPPA) in the
presence of tert-butanol. Acidic cleavage of the N-Boc group in
the intermediate carbamates afforded the target amines 11c,
12c, 15c and 18c as hydrochlorides in 78-84% combined yield
(Scheme 4).
F
H
CO2
F
N
C
O
O
F
N
C
H
CO2
F
O
O
F
[a]
Reaction conditions: (i) TMSCF3 (2.5 equiv), NaI (0.5 equiv), alkene (1
equiv), THF, reflux for 4 h. (ii) alkene (1 equiv), 1 M LiOH (2 equiv), THF, rt,
12h. [b] Isolated yield over two steps. cDiastereomeric ratio according to NMR.
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10.1002/chem.201705708
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NH2
H
CO2
1
2
Et N DPPA
,
F
F
,
thioacetates 23i-26i. Oxidation of 23i-26i with gaseous chlorine
yielded sulfonyl chlorides 23j-26j in 40-82% overall yield
(Scheme 6).
)
3
u
-
re ux
t B OH fl
,
F
F
oxane-
di
HCl
)
r
t
12b
c
12
Representative synthesis of sulfonamide 26k was
performed by treating sulfonyl chloride 26j with aq. ammonia at
room temperature (Scheme 6).
NH2
F
NH2
F
F
F
R
R
F
s
M
N
c
11
c
12
(
:
:
R
F
nO
R2
c
n
S
A
R2
7
8
1 1
80 4 1
%,
R
F
%,
(
)
)
n
l
SO2C
n
NH2
SO2
Cl2
F
a
c
SA
F
NH H
4O
F
R2
F
R2
CH2Cl2/H2O
CH2Cl2
DMF
r
t
F
R1
0 5 oC
R1
NH2
NH2
r
t
-
R1
R1
F
n=
1 2
F
,
-
-
26k
23i 26i
23 26
-
23d 26d
j
j
F
F
c
15
c
8
(
:
:
2
)
18
l
NH2
SO2
75
%,
(
1
)
4
3
%,
SO2C
3
l
SO2C
Scheme 4. Synthesis of amines via the Curtius rearrangement.
F
F
F
F
F
F
The high synthetic utility of the obtained difluorocyclopropane-
containing alcohols (Table 3) was demonstrated by converting
some of them into the primary amines (Scheme 5). We used
three synthetic strategies (Scheme 5). Method A: the alcohols
were converted into mesylates with MsCl, followed by an
exchange of the leaving group with KCN in DMF at 60 ºC. The
obtained nitriles were treated with in situ generated AlH3 (LiAlH4
+ TMSCl) in THF to obtain the desired amines 20f and 25f.
Method B: alternatively, we converted alcohols into the
corresponding bromides with BBr3. The bromides were next
treated with NaN3 (3 equiv) in DMF at 50 °C. The obtained
azides were reduced with PPh3 into the needed amines 23f and
24f. Method C: in this approach, the mesylates were first
converted into the azides with NaN3, followed by a reduction with
PPh3 into the target amines 25fb and 26f.
26
26k
25
82
j
(
58
41
%
%
%
j
(
)
(
)
)
F
F
l
SO2C
O
l
SO2C
F
F
23
24
64
j
(
40
%
)
%
j
(
)
Scheme 6. Synthesis of sulfonyl chlorides and sulfonamides.
Compound 13b was easily separated into the individual
diastereomers 13b-1 and 13b-2 by the standard column
chromatography on silicagel. The stereoconfiguration of the
isolated compounds was determined by 2D-NMR experiments
(SI). These novel fluorinated prolines have a potential for the
applications as 19F-labels in peptides studies[21] and building
blocks for drug discovery.[22,23] For example, the corresponding
none-fluorinated motif comprises to a structure of the anti-
hepatitis C drug Ledipasvir (Scheme 7).
e
o
M th d A
R
F
R
F
R
F
s
M Cl
s
LiAlH4
M
nO
R2
n
N
H
C
R
F
nO
R2
n
NH2
F
F
F
F
F
KCN
DMF
Et3N
TM
SC
l
F
F
R2
F
F
R2
CH2Cl2
0 o
THF
0 o
o umn
l
C
60 o
C
R1
R1
R1
C
C
R1
c rom.
h
F
N
an
d
n=
1 2
,
a
D
B
H
CO2
N
H
CO2
M
B
N
N
3
H
CO2
r
C
F
N
oc
B
e
o
3
e o
M th d
C
M th d B
H
,
5
0
-
h 3
2 C
oc
B
4
oc
B
P
o
C
c
0
l
o
C
P
2
A
O
t
T
R
F
R
F
E
13b
r
nB
R2
R
nN3
R2
-
13b 1
42
%
)
(
-
13b 2
24
%
)
a
N
N3
(
F
DMF
50 o
-
ro nes
R1
F
R1
F
2 P li
C
C
e
o
e
o
e o
C
M th d A
M th d B
M th d
F
F
NH2
NH2
O
F
F
F
N
F
N
NH2
F
NH
O
F
25fb
N
H
N
20f
23f
70
%
( )
N
56
29
%
%
O
(
(
)
(
)
)
NH2
e
asv r
i
L di
p
F
an - e a
s
ru
C
d
g
ti h titi
p
F
NH2
F
F
NH2
ea
c enc es
Gil d S i
i
O
F
F
25f
24f
26f
(
7
48
72
8
%
%
%
)
(
)
Scheme 7. Synthesis of fluorine-containing prolines 13b-1 and 13b-2.
Scheme 5. Synthesis of difluorocyclopropane-containing amines from alcohols.
Acid 11b was efficiently separated into the individual
diastereomers 11b-1 and 11b-2 by fractional crystallization from
hexane (Scheme 8). The structure of compounds was proven by
an X-Ray analysis (Figure 2).[24]
We next expanded our collection of building blocks into
sulfonyl chlorides.[20] Reaction of mesylates 23d-26d with
sodium thioacetate in DMF at room temperature gave
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10.1002/chem.201705708
Chemistry - A European Journal
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rac ona
ti
f
l
central CDCl3 (δ = 77.16 ppm) or DMSO-d6 (δ = 39.52 ppm). Coupling
constants are given in Hz. MS analysis was performed on an LCMS
instrument with chemical ionization or GCMS with electrospray ionization.
H
CO2
H
CO2
H
CO2
F
F
cr s a za on
lli ti
t
F
y
an
d
exane
h
F
F
F
11b
-
-
(
11b 1
11b 2
64
-
a
X R
y
16
%
%
)
(
a
)
-
X R
y
2.
General
procedure
for
synthesis
of
protected
Scheme 8. Synthesis of single diastereomers 11b-1 and 11b-2.
difluorocyclopropanes
TMSCF3 (0.25 mol) and NaI (0.05 mol, 0.5 equiv) were added in one
portion to a solution containing the appropriate alkene (0.10 mol, 1 equiv)
in 200 mL of dry THF (freshly distilled from LiAlH4). The mixture was
refluxed for 4 h and monitored by TLC. If the reaction was incomplete
after this time, additional TMSCF3 (0.25 mol, 2.5 equiv) was added, and
the mixture was heated for 4 h until the starting material was completely
consumed. Upon completion of the reaction, the mixture was
concentrated under reduced pressure in the following manner: the
residue was dissolved in CH2Cl2, washed with water, a 0.1 M solution of
sodium thiosulfate, brine, dried over Na2SO4, filtered, and the solvent
was removed under reduced pressure to afford the desired product. In
some cases the product required purification by column chromatography
(gradient, hexane/MTBE) or distillation.
11b-1
11b-2
Figure 2. X-Ray crystal structure of acids 11b-1 and 11b-2.
The C-H bond in the cyclic N-Boc-protected amine 1b was
oxidized using a modified procedure from a recent patent.[25] This
reaction yielded γ-lactam 29. Base-catalyzed hydrolysis of
lactam 29 produced the N-Boc protected fluorinated GABA-
analogue 30 in 53% overall yield (Scheme 9).
7,7-Difluoro-6-phenyl-3-azabicyclo[4.1.0]heptane hydrochloride (2b).
Yield = 91% (19.1 g). The product is a beige powder, mp 233 ºC. 1H
NMR (400 MHz, DMSO): δ 9.23 (br s, 2H), 7.50 (d, 2H, 3J = 7.0 Hz, Ph),
7.39 (t, 2H, 3J = 7.5 Hz, Ph), 7.33 (t, 1H, 3J = 7.3 Hz, Ph), 3.78 - 7.72 (m,
1H), 3.17 - 3.09 (m, 2H), 2.71 - 2.65 (m, 1H), 2.46 - 2.38 (m, 2H), 2.15 -
2
2.07 (m, 1H). 19F NMR (376 MHz, DMSO-d6): δ -129.6 (dd, JFF = 152.1
3
2
Hz, JFH = 13.5 Hz), -142.6 (d, JFF = 152.8 Hz). 13C NMR (101 MHz,
DMSO-d6): δ 137.6, 128.6, 128.5, 127.7, 113.4 (t, 1JCF = 292.2 Hz, CF2),
38.0 (d, JCF = 5.1 Hz), 34.9, 29.2 (t, JCF = 10.3 Hz, CPh), 22.7, 19.7 (t,
JCF = 10.7 Hz, CCF2). MS (APCI) m/z [M+H]+ calculated for C12H14F2N:
210.1; found: 210.1. Anal. calcd. for C12H14ClF2N: C, 58.66; H, 5.74; N,
5.70. Found: C, 58.47; H, 5.85; N, 5.58.
F
F
F
F
F
a
F
N IO4
u
ca .
t
)
LiOH
R Cl *H O
(
3
2
c
r
t
EtOA /H O
,
O
r
THF/H O
t
,
2
2
H
CO2
N
N
75
%
70
%
oc
NHB
oc
B
oc
B
30
1b
2
9
3-(2,2-Difluorocyclopropyl)propanoic acid (16b).
-
F
ABA
C
2 G
Yield = 60% (9.0 g) after recrystallization from hexanes. The product is a
white solid, mp 36 ºC. 1H NMR (400 MHz, CDCl3): δ 10.81 (br s, 1H,
OH), 2.52 - 2.48 (m, 2H, CH2C(O)), 1.83 – 1.80 (m, 2H, CH2), 1.65 – 1.57
(m, 1H, CH), 1.46 – 1.39 (m, 1H, CHHCF2), 0.99 – 0.95 (m, 1H,
CHHCF2). 19F NMR (376 MHz, CDCl3): δ -128.9 (dt, 2JFF = 156.9 Hz, 3JFH
Scheme 9. Synthesis of GABA-analogue 30.
Conclusions
2
3
= 12.6 Hz), -145.5 (dd, JFF = 156.9 Hz, JFH = 12.8 Hz). 13C NMR (126
MHz, CDCl3): δ 179.3 (C=O),, 114.1 (t, 1JCF = 291.8 Hz, CF2), 33.1, 22.1
We
synthesized
difluorocyclopropane-containing
2
2
carboxylic acids, ketones, nitriles, alcohols, and amines from the
functionalized alkenes and TMSCF3/NaI. We believe that these
novel fluorinated building blocks will find soon a wide application
in drug discovery projects.
(d, JCF = 4.5 Hz), 21.5 (t, JCF = 10.8 Hz, CCF2), 16.0 (t, JCF = 11.0 Hz,
CH2CF2). MS (APEI) m/z [M] calculated for C6H8F2O2: 150.1; found:
150.1. Anal. calcd. for C6H8F2O2: C, 48.00; H, 5.37. Found: C, 48.14; H,
5.20.
2-(2,2-Difluorocyclopropyl)ethane-1-sulfonyl chloride (23j).
1
Yield = 90% (18.4 g). The product is a colorless oil. H NMR (400 MHz,
Experimental Section
CDCl3): δ 3.82 – 3.73 (m, 2H, CH2S), 2.25 – 2.18 (m, 2H), 1.75 – 1.55
(m, 2H, CH, CHHCF2), 1.13 – 1.08 (m, 1H, CHHCF). 19F NMR (376 MHz,
2
2
CDCl3): δ -129.4 (d, JFF = 160.9 Hz), -145.1 (d, JFF = 159.2 Hz). 13C
1. General. All chemicals were provided by Enamine Ltd
1
1
(www.enamine.net).
Autoclaves
were
provided
by
UOSLab
NMR (126 MHz, CDCl3): δ 113.1 (dd, JCF = 282.1 Hz, JCF = 282.1 Hz,
CF2), 64.0 (d, JCF = 2.0 Hz, CH2S), 22.5 (d, JCF = 5.1 Hz, CH2C), 19.8 (t,
2JCF = 11.1 Hz, CH), 16.4 (t, 2JCF = 11.1 Hz, CH2CF2). MS (APEI) m/z [M]
calculated for C5H7ClF2O2S: 204.0; found: 204.0. Anal. calcd. for
C5H7ClF2O2S: C, 29.35; H, 3.45; S, 15.67. Found: C, 29.51; H, 3.24; S,
15.83.
(en.uoslab.com). All solvents were treated according using standard
methods. All reactions were monitored by thin-layer chromatography
(TLC) and were visualized using UV light. Product purification was
performed using silica gel column chromatography. TLC-characterization
was performed with pre-coated silica gel GF254 (0.2 mm), while column
chromatography characterization was performed with silica gel (100-200
mesh).1H-NMR, 19F-NMR, 13C-NMR spectra were recorded with
tetramethylsilane (TMS, δ = 0.00 ppm) as the internal standard. 1H-NMR
spectra were recorded at 400 or 500 MHz (Varian); 19F-NMR spectra
were recorded at 376 MHz (Varian), 13C NMR spectra were recorded at
100 or 126 MHz (Varian). 1H-NMR chemical shifts are reported downfield
from CDCl3 (δ = 7.26 ppm), D2O (δ = 4.79 ppm) or DMSO-d6 (δ = 2.50
ppm). 13C-NMR chemical shifts for 13C-NMR are reported relative to the
3-(((tert-Butoxycarbonyl)amino)methyl)-2,2-difluorocyclopropane-1-
carboxylic acid (30).
The crude product was dissolved in THF (20 mL) and an aqueous
solution of 1 M LiOH (0.2 g, 0.0075 mol, 2 equiv) was added. The
resulting solution was stirred overnight. The mixture was partially
concentrated under reduced pressure, and washed several times with
CH2Cl2. The aqueous layer was acidified with a saturated solution of
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10.1002/chem.201705708
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12. J. Xu, E.-A. Ahmed, B. Xiao, Q.-Q. Lu, Y.-L. Wang, C.-G. Yu, Y. Fu
Angew. Chem. Int. Ed. 2015, 54, 8231.
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P. Lyssikatos, D. Shore, V. Verma, et al., Substituted Heterocyclic
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17. J. Baudoux, D.Cahard, Electrophilic Fluorination with N–F
Reagents, Chapter 2, John Wiley & Sons, 2008, p 347.
NaHSO4 and extracted with CH2Cl2. The organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue was
solidified in hexanes to give the final product as a white powder, mp 117
1
°C, (1.3 g, 70%). H NMR (400 MHz, DMSO-d6): δ 12.85 (br s, 1H, OH),
3
7.07 (br s, 1H, NH), 3.47 – 3.33 (m, 2H, CH2), 2.65 (t, J = 11.6 Hz, 1H,
CH), 2.28 (s, 1H, CH), 1.39 (br s, 9H, t-Bu). 19F NMR (376 MHz, DMSO-
2
2
d6): δ -122.1 (d, 1F, JFF = 153.6 Hz), -148.9 (d, JFF = 153.7 Hz). 13C
NMR (126 MHz, DMSO-d6): δ 166.6 (COOH), 155.5 (C=O), 112.3 (t, 1JCF
= 286.7 Hz, CF2), 77.9 (C, t-Bu), 32.7 – 32.6 (m), 28.2 (3×CH3), 27.3 –
26.7 (m). MS Anal. calcd. for C10H15F2NO4: C, 47.81; H, 6.02; N, 5.58.
Found: C, 47.61; H, 6.27; N, 5.44.
Acknowledgements
Authors are very grateful to Dr. V. Iaroshenko for the help in
the preparation of the manuscript.
18. While we were putting our hands at the manuscript, a related work
on difluorocyclopropane-containing amines appeared: P. S. Nosik,
A. O. Gerasov, R. O. Boiko, E. Rusanov, S. V. Ryabukhin, O. O.
Grygorenko, D. M. Volochnyuk Adv. Synth. Catal. 2017, 18, 3126.
19. Our previous interest in fluorinated amines: a) V. S. Yarmolchuk,
P. K. Mykhailiuk, I. V. Komarov Tetrahedron Lett. 2011, 52, 1300;
b) V. S. Yarmolchuk, O. V. Shishkin, V. S. Starova, O. A.
Zaporozhets, O. Kravchuk, S. Zozulya, I. V. Komarov, P. K.
Mykhailiuk Eur. J. Org. Chem. 2013, 3086; c) V. S. Yarmolchuk, V.
L. Mykhalchuk, P. K. Mykhailiuk Tetrahedron 2014, 70, 3011; d) A.
V. Bezdudny, A. N. Alekseenko, P. K. Mykhailiuk, O. V.
Manoilenko, O. V. Shishkin, Y. M. Pustovit Eur. J. Org. Chem.
2011, 1782; e) O. S. Artamonov, E. Y. Slobodyanyuk, D. M.
Volochnyuk, I. V. Komarov, A. A. Tolmachev, P. K. Mykhailiuk Eur.
J. Org. Chem. 2014, 3592; f) O. S. Artamonov, E. Y.
Slobodyanyuk, O. V. Shishkin, I. V. Komarov, P. K. Mykhailiuk
Synthesis 2013, 45, 225; g) A. V. Shcherbatiuk, O. S. Shyshlyk, D.
V. Yarmoliuk, O. V. Shishkin, S. V. Shishkina, V. S. Starova, O. A.
Zaporozhets, S. Zozulya, R. Moriev, O. Kravchuk, O. Manoilenko,
A. A. Tolmachev, P. K. Mykhailiuk Tetrahedron 2013, 13, 3796.
20. A. V. Bogolubsky, Y. S. Moroz, P. K. Mykhailiuk, S. E. Pipko, A. I.
Konovets, I. V. Sadkova, A. Tolmachev ACS Comb. Sci. 2014, 16,
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A. S. Ulrich, I. V. Komarov Angew. Chem. Int. Ed. 2008, 47, 5765;
b) D. Dietz, V. Kubyshkin, N. Budisa ChemBioChem 2015, 16,
403; c) V. S. Kubyshkin, S. Afonin, S. Kara, N. Budisa, P. K.
Mykhailiuk, A. S. Ulrich Org. Biomol. Chem. 2015, 13, 3171.
22. Our previous interest in unique Proline analogues: a) P. K.
Mykhailiuk, S. V. Shishkina, O. V. Shishkin; O. A. Zaporozhets, I.
V. Komarov Tetrahedron 2011, 67, 3091; b) K. Levchenko, O. P.
Datsenko, O. Serhiichuk, A. Tolmachev, V. O. Iaroshenko, P. K.
Mykhailiuk J. Org. Chem. 2016, 81, 5803; c) A. N. Tkachenko, D.
S. Radchenko, P. K. Mykhailiuk, O. O. Grygorenko, I. V. Komarov
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Keywords: fluorine • difluorocyclopropane • CF3TMS • amines •
cycloaddition
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Fluorinated heterocycles*
Roman M. Bychek, Vadym V. Levterov,
Iryna V. Sadkova, Andrey A. Tolmachev,
Pavel K. Mykhailiuk*
F
F
R
R2
a
TMSCF3/N I
unc ona ze
ti
li
F
F2
d
R
R2
-c c o ro anes
l
y
p
p
re ux
THF fl
,
or ru
scover
di
R1
F
G
f
d
g
y
R1
F
G
exam es
28
l
p
Page No. – Page No.
F
F
F
F
F
Synthesis of functionalized
difluorocyclopropanes: unique
building blocks for drug discovery
F
H
CO2
N
N
N
oc
B
H
H
ze ne
A
tidi
rro ne
P lidi
y
-
ro ne
L P li
Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF3/NaI. Novel
fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.
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