Three-component synthesis of fluorinated pyrazoles from fluoroalkylamines, NaNO2 and electron-deficient alkynes

Article abstract of DOI:10.1039/c4ob02670e

Three-component reaction between RCF₂CH₂NH₂·HCl, NaNO₂ and electron-deficient alkynes significantly depends on substituent R . The reaction gives the fluorinated pyrazoles in high yields when R is a fluorine atom or a fluoroalkyl group. With other R unexpected products are formed.

Full text of DOI:10.1039/c4ob02670e

View Article Online
View Journal
Organic &
Biomol ec ular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. K. Mykhailiuk,
Org. Biomol. Chem., 2015, DOI: 10.1039/C4OB02670E.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Page 1 of 8
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C4OB02670E
Organic & Biomolecular Chemistry
RSCPublishing
ARTICLE
Three-component synthesis of fluorinated
pyrazoles from fluoroalkylamines, NaNO and
2
Cite this: DOI: 10.1039/x0xx00000x
electron-deficient alkynes
a,b∗
Pavel K. Mykhailiuk
Received 00th January 2014,
Accepted 00th January 2014
Threeꢀcomponent reaction between RCF CH NH *HCl, NaNO and alkynes drastically
2
2
2
2
1
DOI: 10.1039/x0xx00000x
depends on substituents “R” and “R ”. The reaction gives the fluorinated pyrazoles in high
1
yields when “R” is fluorine atom or fluoroalkyl group, and “R ” is an electronꢀwithdrawing
www.rsc.org/
substituent. With other “R” unexpected products are formed.
Introduction
(Scheme 1, a) towards CF
3
ꢀsubstituted pyrazoles was
elaborated. Mechanistically, the reaction proceeded via in situ
generated of CF CHN , followed by [3+2]ꢀcycloaddition with
9
ꢀ
Fluorinated heterocycles play a role in medicinal chemistry
and agrochemistry.
3
2
1
,2
In particular, pyrazoles with diverse
alkynes. Later, this transformation was expanded towards C F ꢀ
2
5
fluoroalkyl groups often comprise to bioactive molecules
10
pyrazoles starting from amine
2 (Scheme 1, a). In both cases,
3,4
(
Figure 1). Therefore, elaboration of practical and general
however, only the electronꢀdeficient alkynes reacted. Given that
the target CF ꢀ/C F ꢀpyrazoles were synthesized in high yield
methods to novel fluoroalkylꢀsubstituted pyrazoles is truly
important.
3
2 5
and gram scale, herein I wanted to answer the following
questions: is this reaction universal? Can other fluoroalkyl
amines (scope of “R”) be used? Can other alkynes (scope of
“R”) be used (Scheme 1, b)?
CF
3
S
C
2
F
5
CF
3
N
O
N
CF
3
NH
N
NH
N
NH
2
N
N
O
Previous work (a)
N
CN
SO
2
NH
2
*HCl
CF3,
C2F5
CF3
N
C2F5
N
rt
Cl
Celecoxib
Antiinflamatory drug
Penthiopyrad
Fungicide
WO2012/80376
Insecticide
EWG
CH
2
2
/H
2
O
or
NH2
EWG
EWG
refs. 9, 10a
N
N
Pfizer
Mitsui
Syngenta
NaNO2
H
H
1, 2
Br
O
O
HCF
2
CF
2
C
2
F
5
This work (b)
2 2
HCF CF
N
*HCl
NH2
RCF2
rt
Is this reaction universal?
N
R1
1
N
CH Cl /H2O
What is the scope of "R" / "R "?
NH
2
2
2
N
NaNO2
WO2005/95351
Insecticide
Bayer CS
O
US2011/124660
R
N
Insecticide
Bayer CS
N
9,10a
Scheme 1. (a) Literature data.
(b) Aim of this work.
Fig. 1. Drugs and agrochemicals – derivatives of pyrazoles with diverse
fluoroalkyl groups.
Results and Discussion
Among other methods to introduce fluoroalkyl groups into
Scope of amines
5
organic compounds, CF CHN is worth mentioning. In 1943
3
2
To study the scope of the reaction, a model alkyne was
selected first – methyl propyolate. Then, diverse amine
Gilman and Jones synthesized this reagent from trifluoroethyl
6
amine hydrochloride and sodium nitrite. Since than CF CHN
3
2
7
hydrochlorides RCF CH NH *HCl (3ꢀ10*HCl) were tested
2 2 2
blossoms in organic chemistry and many research groups have
9
8
under the previously discovered conditions. In particular, a
been using it. In particular, recently a threeꢀcomponent
mixture of an amine, NaNO and methyl propyolate was stirred
2
reaction between CF CH NH *HCl (1), NaNO and alkynes
2
3
2
2
This journal is © The Royal Society of Chemistry 2013
J. Name., 2014, 00, 1-3 | 1

Organic & Biomolecular Chemistry
Page 2 of 8
View Article Online
ARTICLE
DOI: 10.1039/C B02670E
Jou4Ornal Name
in dichloromethane/water at room temperature for three days. Obviously, the reaction proceeded via in situ formation of
The obtained unexpected results are summarized in Table 1.
RCF CHN (Scheme 2, Path “
a
”).
2
2
Table 1. Scope of the reaction: amines.
Path "e"
one-pot
CF2
O
F
F
X-Ray
*
HCl
reaction
CH Cl /H
rt, 72 h
RCF
2
NaNO
2
+
2
2
2
O
?
HN
O
N
2
2
CO Me
-
C
4
H
8
HN
O
NH
2
-N
2
+
2.0 eq.
3.0 eq.
1.0 eq.
-H
O
(1-10)*HCl
11
H
Path "a"
RCF
2
X-Ray
CO
2
Me
a
Amine
R
Product
Yield
Path
N
[
3+2]
2
CO Me
R = R
f
N
H
RCF
2
RCF
2
+
-
H+
O
N
Path "d"
FCF
2
N2
N
2
Path "b"
X-Ray
O
9
X
Y
R
1
F
1a
2a
3a
4a
5b
99% (X-Ray) “a”
H
O
CO2Me
[3+2]
N
3
2
CO Me
N
R
H
NaNO2
O
-HF
H
2
N2
N
2
CO Me
H
HNO
2
*
HCl
RCF
2
3
CF CF
2
2
-H O
Path "c"
1
0a
O
N
2
3
4
5
6
7
8
9
CF
3
99%
“a”
“a”
“a”
NH
2
N
O
X-Ray
CO
2
Me
O
N
R
H
NO
CO
2
Me
R
R
-N
2
[3+2]
+N
N
2
O-
2
CO Me
O
CF
2
C
2
F
4
CF
2
Z
W
b
H
2
NCH
2
C
3
F
6
N
N
87%
MeO
2
C
CO
2
Me
Scheme 2. Proposed mechanistic profile of the reaction.
N
H
N
H
The reaction of amine hydrochloride
5*HCl with nonꢀ
CHF
2
97%
fluorinated electronꢀwithdrawing substituent (CO Me),
2
unexpectedly gave the pure diazo ketone 5b (X-Ray, Figure 2)
in 51% yield and the starting alkyne. Presumably, the initially
formed fluorinated diazo intermediate “Y” underwent acidꢀ
catalyzed aqueous hydrolysis (Scheme 2, Path “b”). Individual
diazo ketone 5b, in turn, did not react with methyl propyolate
even under heating.
O
c
CO
2
Me
MeO C
2
51% (X-Ray) “b”
N
2
O
O
d
6
b
Ph
17%
“b”
Ph
H
Ph
d
Amine hydrochloride
results: along with many unidentified products, diazo ketone
, and pure isoxazole 6c X-Ray, Figure 2) were isolated in
poor yields. Although the mechanism of formation of isoxazole
6*HCl gave even more astonishing
6c
10% (X-Ray) “c”
N
2
N
2
CO Me
O
6
b
(
O
H
e
7b
8c
[ca. 50%]
“b”
6
6
c
b
is not totally clear, it seems that the initially formed ketone
N
2
reacted with HNO to give intermediate “Z” that further
2
transformed into nitriloxide “W”. [3+2]ꢀcycloaddition of “W”
O
with methyl propyolate might have given isoxazole 6c (Scheme
c
HOCH
2
HO
31% (X-Ray) “c”
11
N
O
2, Paths “b” and “c”). Indeed, additional mechanistic studied
are needed to support/reject this suggestion (that is outside the
scope of this work).
Reaction of amine hydrochloride 7*HCl gave no pyrazoleꢀ
containing products, but unidentified side materials, the starting
CO
2
Me
O
O
N
Et
Et
9c
7%
21%
“c”
“d”
Et
9
d
N
CO
2
Me
F
2
CO Me
O
N
H
alkyne and diazo acetaldehyde 7b. The pure compound 7b was
F
described in the literature before – in CDCl it exists as a
3
c
10
BocNHCH
2
10e
47% (X-Ray) “e”
mixture of cisꢀ and transꢀrotamers that have very characteristic
HN
O
1
12
O
signals in H NMR. Worth mentioning, that previously
Atherton Fields, and Haszeldine also tried to generate
CF HCHN
Amine hydrochloride
Ray, Figure 2) as a main reaction product (Scheme 2, Path “c”).
Amine hydrochloride *HCl with an alkyl substituent (Et)
*HCl with fluorinated provided the complex mixture from which the two pure
electronꢀwithdrawing substituents gave the expected pyrazoles products were obtained: minor isoxazole 9c and major pyrazole
,
a
c
b
Isolated yields. 0.5 eq. of amine (H
.0 eq. of amine RCF CH NH
0% purity. Yield according to NMR of the reaction mixture.
2
NCH
2
2
C F
4
)
2
*2HCl were used.
13
d
2
2
, but with no success.
*HCl also afforded isoxazole 8d (X-
1
2
2
2
*HCl was used. Product 6b was of
e
8
8
9
Amine hydrochlorides 3*HCl and 4
3
a
and 4a in good yields of 87% and 97%, respectively. 9d (Scheme 2, Paths “c” and “d”). Presumably, the initially
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 8
Journal Name
Organic & Biomolecular Chemistry
View Article Online
ART70ICLE
DOI: 10.1039/C4OB026 E
formed alkyl diazo ketone EtCOCHN2 was quite active to While heterocyclic alkyne 20 gave pyrazole 20a in good yield
rapidly react with methyl propyolate (9d), rather than to be of 73%, aromatic lessꢀ (21) or none activated (22) alkynes did
transformed into nitriloxide (and subsequently into 9c).
Amine hydrochloride 10*HCl gave pure cyclic product 10e
not react, however.
Table 2. Scope of the reaction: alkynes.
(
X-Ray, Figure 2) in 59% yield (Scheme 2, Path “e”). In this
*HCl
2 2
HCF CF
NaNO
2
reaction no pyrazole/isoxazoleꢀcontaing products was observed
in any significant amounts.
CH Cl /H O
?
R1
2
2
2
NH
2
rt, 72 h
one-pot
reaction
2.0 eq.
3.0 eq.
1.0 eq.
In a short summary, the studied reaction (Scheme 1) gives
the needed fluorinated pyrazoles only if substituent “R” is Fꢀ
4*HCl
11-22
a
Alkyne
Product
Yield (%)
atom (
1) or fluoroalkyl group (2ꢀ4). Although only three groups
ꢀ
CF , C F H and C F X ꢀ were tested, it seems that the reaction
3
2
4
3
6
HCF CF
2
2
2
2
2
2
2
would also work for all fluoroalkyl substituents “R”. With other
substitutents “R” ꢀ H, Alk, Ar, CO Alk ( 10), ꢀ the reaction
11
4a
97
CO
2
Me
N
2
CO Me
N
H
5
ꢀ
2
gives unexpected products in low to moderate yields. Although,
detailed mechanistic studies are needed to explain formation of
these compounds (which is outside of the scope of the current
project), the putative overall mechanistic profile is summarized
in Scheme 2. These suggestions are supported by X-Ray data of
all products and stable intermediates (Figure 2).
HCF
HCF
HCF
HCF
HCF
CF
2
12
13
14
15
16
17
18
19
20
21
22
12a
13a
14a
15a
16a
17a
18a
19a
20a
97
CO
2
Et
N
2
CO Et
N
H
CF
2
96 (X-Ray)
CO
2
iPr
N
2
CO iPr
N
H
CF
2
N
96
N
H
O
O
O
O
O
CF
2
Ph
95
N
Ph
N
H
5
b
6c
CF
2
Ph
Ph
N
94
91
O
N
H
HCF
HCF
HCF
2
2
2
CF
2
2
CO Me
2
MeO C
N
CO
2
Me
CO
2
Me
N
H
7
c
10e
Fig. 2. X-Ray crystallographic structures of compounds 5b, 6c, 7c, and
1
1
4
CF
2
2
CO Et
0e
.
2
EtO C
92
N
CO
2
Et
2
CO Et
N
H
CF
2
Ph
Ph
Scope of alkynes
P
Ph
Ph
N
93 (X-Ray)
P
O
N
H
O
Previously, we showed that in situꢀgenerated FCF CHN2
2
and CF CF CHN reacted at room temperature only with
electronꢀdeficient
HCF CF CHN , however, could differ much, because HCF ꢀ
substituent is a significantly weaker acceptor than the Fꢀ and
HCF CF2
3
2
2
2
9
,10a
N
N
N
b
alkynes.
The
reactivity
of
73
N
N
H
2
2
2
2
N
15
CF ꢀones.
Therefore, amine hydrochloride
4*HCl was
3
b
no reaction
no reaction
selected next, and its reactivity was tested towards diverse
CF3
16
alkynes (Table 2).
It was experimentally found that amine
the previously reported amines and
4
behaved similar to
b
1
2 (Table 2). In fact,
electronꢀdeficient alkynes 12-19 smoothly reacted to give
pyrazoles 12a-19a in excellent yields of 91ꢀ97%. The reaction
was extremely clean ꢀ no side products, ꢀ and practical ꢀ
evaporation of organic phase afforded the pure pyrazoles
without any further purification. For monoꢀsubstituted alkynes,
a
b
Isolated yields. 5.0 eq. of amine
4
were used
In short summary, the studied reaction (Scheme 1) gives the
regioselective formation of only 3,5ꢀdisubstituted pyrazoles needed fluorinated pyrazoles only with electronꢀdeficient
was observed, that was supported by X-Ray studies (Figure 3). alkynes. The nature of fluoroalkylꢀsubstituent “R” (F, CF3,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem. 2014, 00, 1-3 | 3

Organic & Biomolecular Chemistry
Page 4 of 8
View Article Online
ARTICLE
DOI: 10.1039/C B02670E
Jou4Ornal Name
CHF2, etc) in amines does not have any significant impact on
To a stirred suspension of C F CH NH ·HCl (120 mg, 0.64
2 5 2 2
the reactivity of the corresponding diazo intermediate mmol, 2.0 eq.) in CH Cl (8.0 mL) / water (0.4 mL), sodium nitrite
2
2
RCF CHN , and hence on the selection of alkynes.
(64 mg, 0.96 mmol, 3.0 eq.) and methyl propyolate (26 mg, 0.32
mmol, 1.0 eq.) were added. The reaction mixture was vigorously
stirred 72 h at 20 ºC. Water (2.0 mL) and CH Cl (6 mL) were
2
2
2
2
added. The organic layer was separated. The aqueous layer was
washed with CH Cl (2 × 6 mL). The combined organic layers were
2
2
dried over Na SO and evaporated under vacuum to provide the pure
2
4
product 2a as a white solid (78 mg, 99%). M.p. = 79ꢀ80 ºC.
1
H NMR (500 MHz; CDCl ; Me Si), δ: 11.81 (broad s, 1H, NH),
3 4
1
3a
19a
7
.11 (s, 1H, CH), 3.96 (s, 3H, CH ).
3
1
7
Fig. 3. X-Ray crystallographic structures of compounds 13a
,
19a
.
13
C NMR (125 MHz; CDCl ; Me Si), δ: 159.0 (s, CO), 142.8
3
4
1
2
(broad s, C), 135.5 (broad s, C), 118.6 (qt, J = 285 Hz, J = 36
CꢀF CꢀF
1
2
Hz, CF CF ), 110.2 (tq, J = 250 Hz, J = 39 Hz, CF CF ),
2
3
CꢀF
CꢀF
2
3
1
08.6 (s, CH), 52.7 (s, CH ).
3
Conclusions
19
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ85.1 (s, 3F, CF CF ), ꢀ
3
3
2
3
1
13.8 (s, 2F, CF CF ).
2
3
The studied reaction towards fluorinated pyrazoles
+
MS (CI): m/z (%) = 245 [M+1] .
Anal. calcd for C : C, 34.44; H, 2.06; N, 11.48. Found:
C, 34.14; H, 2.34; N, 11.68.
(
Schemes 1, 3) is universal. It ideally works if substituent “R”
1
H F N O
7 5 5 2 2
is Fꢀatom or fluoroalkyl group, and substituent R is an
electronꢀwithdrawing group (EWG). With other “R” the
reaction gives unexpected products in low yields. This method
is highly practical: it works under air, in common solvents
Dimethyl
3,3'-(1,1,2,2,3,3,4,4-octafluorobutane-1,4-
diyl)bis(1H-pyrazole-5-carboxylate) (3a)
(
water, dichloromehane), without any catalysts and at room
The reaction was performed following the general procedure,
except for: 0.5 eq. (H NCH CF CF ) *2HCl + 1.0 eq. methyl
temperature. Moreover, it gives pyrazoles in excellent yields,
and mostly without purification (just evaporation of an organic
phase). Gram quantities of the products can be rapidly
synthesized. I believe that the developed useful protocol will
find very soon wide practical application in medicinal
chemistry and agrochemistry – areas, where fluoroalkyl
pyrazoles play an important role.
2
2
2
2 2
propyolate + 2 eq. NaNO . After 72 h at 20 ºC, the reaction mixture
2
was placed into the fringe at 0 ºC for 12h. The formed lightꢀyellow
precipitate was filtered off, washed with water, and dried on air.
Yellow solid (125 mg, 87%). M.p. > 200 ºC.
1
H NMR (500 MHz; DMSOꢀd ; Me Si), δ: 7.20 (s, 2H, CH), 3.86
6
4
(
s, 6H, CH ).
3
RCF
2
13
*
HCl
rt
RCF
2
C NMR (125 MHz; DMSOꢀd
6
; Me Si), δ: 158.9 (s, CO), 140.8
4
NaNO
2
R1
CH
2
Cl
2
/H
2
O
N
R1
1
NH
2
N
(
=
broad s, C), 135.6 (broad s, C), one CF is not seen, 109.4 (tt, J
2
CꢀF
H
2
250 Hz, J = 38 Hz, CF ), 108.6 (s, CH), 52.5 (s, CH ).
CꢀF
2
3
19
The reaction perfectly works, when
"R" = F, RF
F NMR (375 MHz; DMSOꢀd ; CFCl ), δ: ꢀ108.1 (t, J = 11.3 Hz,
6
3
1
"
R " = EWG
4
F, CF ), ꢀ121.5 (t, J = 11.3 Hz, 4F, CF ).
2 2
+
Scheme 3. Scope of three-component synthesis of fluorinated pyrazoles.
MS (CI): m/z (%) = 451 [M+1] .
Anal. calcd for C H F N O : C, 37.35; H, 2.24; N, 12.44.
14
10
8
4
4
Found: C, 37.11; H, 2.03; N, 12.78.
Methyl 3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-5-carboxylate
4a)
The reaction was performed following the general procedure.
Experimental part
(
Dichloromethane was purified by distillation. All reagents were
1
available from Enamine Ltd. Melting points are uncorrected. Hꢀ and
White solid (70 mg, 97%). M.p. 67ꢀ68 ºC.
13
CꢀNMR spectra were recorded on
a
Bruker Avance 500
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.12 (s, 1H, CH), 6.13 (t,
3
4
19
spectrometer (at 499.9 MHz and 124.9 MHz, respectively). Fꢀ
NMR spectra were recorded on a Varian Unity Plus 400
spectrometer (at 376.7 Hz). Chemical shifts are reported in ppm
J = 52.0 Hz, 1H, CHF ), 3.97 (s, 3H, CH ).
2
3
13
C NMR (125 MHz; CDCl ; Me Si), δ: 159.1 (s, CO), 143.2 (t, J
30 Hz, C), 135.1 (s, C), 109.3 (tt, J = 250 Hz, J = 38 Hz,
CꢀF CꢀF
3
4
1
2
=
1
13
19
downfield from Me Si ( H, C) or upfield from CFCl ( F) using
4
3
CF ), tetrꢀCF is not seen, 108.1 (s, CH), 52.4 (s, CH ).
2
2
3
conventional deuterium lock referencing as internal standards. MS
analysis was performed on an LCMS instrument with chemical
ionization, or on GCMS with ionization by electrospray.
General procedure
19
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.6 (broad s, 2F, CF ),
3
3
2
2
2
ꢀ
136.4 (dt, J = 52.0 Hz, J = 7.5 Hz).
MS (CI): m/z (%) = 227 [M+1] .
Anal. calcd for C H F N O : C, 37.18; H, 2.67; N, 12.39. Found:
FꢀH FꢀF
+
7
6
4
2
2
Representative synthesis:
Methyl 3-(pentafluoroethyl)-1H-pyrazole-5-carboxylate (2a)
C, 37.45; H, 2.32; N, 12.71.
Methyl 3-diazo-2-oxopropanoate (5b)
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 8
Journal Name
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C4OB026 E
ART LE
70IC
1
The reaction was performed following the general procedure,
H NMR (500 MHz; DMSOꢀd ; Me Si), δ: 7.58 (s, 1H, CH), 5.50
6
4
except for: 1 eq. MeO CCF CH NH *HCl + 1.0 eq. methyl (broad s, 1H, OH), 4.77 (broad s, 2H, CH ), 3.92 (s, 3H, CH ).
2
2
2
2
2
3
1
13
propyolate + 3.0 eq. NaNO . H NMR of the crude reaction mixture
C NMR (125 MHz; DMSOꢀd ; Me Si), δ: 192.6 (s, CO), 161.0
6 4
2
revealed the starting alkyne, diazo compound 5b and an unidentified (s), 160.3 (s), 156.3 (s), 108.1 (s), 66.1 (s, CH ), 53.3 (s, CH ).
2
3
+
side product (5ꢀ10% mol). The isolated reaction mixture was left at
0 ºC for 24 h, whereas the partial crystallization occurred. The
mixture was washed with cyclohexane (0.5 mL) to remove the liquid 45.05; H, 4.12; N, 7.33.
products (the alkyne and the side product). The remaining white The experiment was also successfully performed on 4ꢀtimes
MS (ES): m/z (%) = 185 [M] .
2
Anal. calcd for C H NO : C, 45.41; H, 3.81; N, 7.57. Found: C,
7
7
5
solid was dried on air to afford the diazo ketone 5b (42 mg, 51%). larger scale.
M.p. 44ꢀ45 ºC (dec.)
1
H NMR (500 MHz; CDCl ; Me Si), δ: 6.18 (s, 1H, CH), 3.88 (s,
Methyl 3-propionylisoxazole-5-carboxylate (9c),
3
4
3
H, CH ).
Methyl 3-propionyl-1H-pyrazole-5-carboxylate (9d)
The reaction was performed following the general procedure. The
crude reaction mixture was purified by column chromatography
3
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 176.1 (s, CO), 160.4 (s,
3
4
CO), 56.7 (s, CH), 53.0 (s, CH ).
3
+
MS (ES): m/z (%) = 128 [M] .
using hexane/EtOAc = 1/1 as an eluent. The fraction with R = 0.7
F
Anal. calcd for C H N O : C, 37.51; H, 3.15; N, 21.87. Found: C, contained the pure isoxazole 9c (4 mg, 7%) as a white crystalline.
4
4
2
3
3
7.15; H, 3.38; N, 21.69.
The experiment was also performed on 4ꢀtimes larger scale, all
results being reproducible.
M.p. 53ꢀ54 ºC.
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.26 (s, 1H, CH), 4.00 (s,
3
4
3H, OCH ), 3.12 (q, J = 8.0 Hz, 2H, CH CH ), 1.24 (q, J = 8.0 Hz,
3
2
3
3
H, CH CH ).
2
3
13
2
-Diazo-1-phenylethanone (6b),
C NMR (125 MHz; CDCl ; Me Si), δ: 193.7 (s, CO), 161.5 (s),
3 4
Methyl 3-benzoylisoxazole-5-carboxylate (6c)
161.0 (s), 144.3 (s), 107.4 (s), 52.8 (s, OCH ), 33.1 (s, CH ), 6.7 (s,
3 2
The reaction was performed following the general procedure, CH3).
+
except for: 1 eq. PhCF CH NH *HCl + 1.0 eq. methyl propyolate +
MS (ES): m/z (%) = 183 [M] .
Anal. calcd for C H NO : C, 52.46; H, 4.95; N, 7.65. Found: C,
2
2
2
3
.0 eq. NaNO . The crude reaction mixture was purified by column
2
8
9
4
chromatography using hexane/EtOAc = 5/1 as an eluent. The 52.22; H, 5.27; N, 7.31.
fraction with R = 0.4 (11 mg) contained ca. 90% of isoxazole 6c. The fraction with R = 0.3 contained the pure isoxazole 9d (12
F
F
This fraction was recrystallized from cyclohexane to afford the pure mg, 21%) as a white solid. M.p. 116ꢀ117 ºC.
1
isoxazole 6c (8 mg, 10%) as a white solid. M.p. 95ꢀ96 ºC.
H NMR (500 MHz; CDCl ; Me Si), δ: 7.33 (s, 1H, CH), 3.96 (s,
3 4
1
H NMR (500 MHz; CDCl ; Me Si), δ: 8.32 (d, J = 8.0 Hz, 2H, 3H, CH ), 2.99 (q, J = 7.0 Hz, 2H, CH ), 1.23 (t, J = 7.0 Hz, 3H,
3
4
3
2
Ph), 7.69 (t, J = 8.0 Hz, 1H, Ph), 7.55 (t, J = 8.0 Hz, 2H, Ph), 7.41 (s, CH ).
3
1
3
1
H, CH), 4.02 (s, 3H, CH ).
C NMR (125 MHz; CDCl ; Me Si), δ: 193.7 (s, CO), 160.6 (s,
3 4
3
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 184.0 (s, CO), 161.8 (s), CO), 109.5 (s, CH), tertꢀC are not seen, 53.3 (s), 32.2 (s), 7.4 (s).
3
4
+
1
60.4 (s), 156.3 (s), 134.8 (s), 134.1 (s), 130.3 (s), 128.4 (s), 109.9
MS (CI): m/z (%) = 183 [M+1] .
(
s), 52.8 (s, CH3).
MS (ES): m/z (%) = 231 [M] .
Anal. calcd for C H N O : C, 52.74; H, 5.53; N, 15.38. Found:
C, 52.41; H, 5.25; N, 15.69.
8
10
2
3
+
Anal. calcd for C H NO : C, 62.34; H, 3.92; N, 6.06. Found: C,
The experiment was also performed on 5ꢀtimes larger scale.
12
9
4
6
2.71; H, 3.59; N, 6.44.
Fraction with RF = 0.3 (8 mg, 17%) contained ca. 90% of
diazoketone 6b.
5,5-Difluoro-1,3-oxazinan-2-one (10e)
The reaction was performed following the general procedure,
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.75 (d, J = 8.0 Hz, 2H, except for: 1 eq. BocNHCH CF CH NH *HCl + 1.0 eq. methyl
3
4
2
2
2
2
Ph), 7.55 (t, J = 8.0 Hz, 1H, Ph), 7.45 (t, J = 8.0 Hz, 2H, Ph), 7.91 (s, propyolate + 3.0 eq. NaNO . The oil+crystalline crude reaction
2
1
H, CH).
mixture was washed with cyclohexane (0.5 mL) to give the pure
1
H NMR of 6b was identical to that described for the individual product 10e (21 mg, 47%) as a white crystalline. M.p. 66ꢀ67 ºC.
1
compound.
H NMR (500 MHz; CDCl ; Me Si), δ: 6.41 (broads, 1H, NH),
3 4
The experiment was also performed on 10ꢀtimes larger scale, all 4.37 (t, J = 10.5 Hz, 4H, CH ), 3.69 (t, J = 10.5 Hz, 4H, CH ).
2
2
13
results being reproducible.
C NMR (125 MHz; CDCl ; Me Si), δ: 152.0 (s, CO), 113.6 (t, J
3 4
=
244 Hz, CF ), 67.2 (t, J = 33 Hz, CH CF ), 46.4 (t, J = 33 Hz,
2 2 2
Methyl 3-glycoloylisoxazole-5-carboxylate (8c)
The reaction was performed following the general procedure,
CH CF ).
2
2
19
3
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ112.3 (qv, J(F,H) =
3 3
except for: 1 eq. HOCH CF CH NH *HCl + 1.0 eq. methyl 11.3 Hz, 2F, CF2).
2
2
2
2
1
+
propyolate + 3.0 eq. NaNO . H NMR of the crude reaction mixture
MS (ES): m/z (%) = 137 [M] .
Anal. calcd for C H F NO : C, 35.05; H, 3.68; N, 10.22. Found:
2
revealed ca. 50% of isoxazole 8c. The oil+crystalline reaction
4
5
2
2
mixture was washed with cyclohexane (0.5 mL) to give the pure C, 35.43; H, 3.46; N, 10.57.
isoxazole 8c (18 mg, 31%) as a white solid. M.p. 158ꢀ159 ºC.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem. 2014, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 8
View Article Online
ARTICLE
DOI: 10.1039/C B02670E
Jou4Ornal Name
1
Ethyl 3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-5-carboxylate
12a)
Compound 12a was obtained as a white solid (74 mg, 97%) CHF CF ), 4.16 (s, 2H, CH ).
H NMR (500 MHz; CDCl ; Me Si), δ: 7.36ꢀ7.26 (m, 5H, Ph),
3 4
2
3
(
7.05 (s, 1H, CH), 6.12 (tt, J = 52.0 Hz, J = 16.0 Hz, 1H,
HꢀF HꢀF
2
2
2
13
following the general procedure. M.p. = 67ꢀ68 ºC.
C NMR (125 MHz; CDCl ; Me Si), δ: 188.0 (s, CO), 143.4 (t, J
3 4
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.09 (s, 1H, CH), 6.11 (t, = 28.7 Hz, CCF ), 141.5 (s, C), 132.0 (s, Ph), 129.1 (s, Ph), 128.6 (s,
J = 52.0 Hz, 1H, CHF ), 4.40 (q, J = 7.0 Hz, 2H, CH CH ), 1.38 (t, J Ph), 127.2 (s, Ph), 111.6 (tt, J = 245 Hz, J = 28 Hz, CF2),
3
4
2
1
2
2
2
3
CꢀF
CꢀF
1
2
=
7.0 Hz, 3H, CH CH ).
109.3 (tt, J = 250 Hz, J = 38 Hz, CF ), 107.8 (s, CH), 46.1 (s,
CꢀF CꢀF 2
2
3
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 158.6 (s, CO), 143.5 (t, J CH ).
3
4
2
19
1
2
=
30 Hz, C), 135.3 (s, C), 111.7 (tt, J = 245 Hz, J = 28 Hz,
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.4 (pseudo q, J = 4.0
3 3
CꢀF
CꢀF
1
2
2
2
CF ), 109.3 (tt, J = 250 Hz, J = 38 Hz, CF ),107.9 (s, CH), Hz, 2F, CF ), ꢀ136.4 (dt, J = 52.0 Hz, J = 4.0 Hz).
2
CꢀF
CꢀF
2
2
FꢀH
FꢀF
+
6
1.8 (s. OCH ), 13.8 (s, CH ).
MS (CI): m/z (%) = 287 [M+1] .
Anal. calcd for C H F N O: C, 54.55; H, 3.52; N, 9.79. Found:
13 10 4 2
2
3
1
9
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.6 (pseudo q, J = 4.0
3
3
2
2
Hz, 2F, CF ), ꢀ136.5 (dt, J = 52.0 Hz, J = 4.0 Hz).
C, 54.21; H, 3.78; N, 9.61.
2
FꢀH
FꢀF
+
MS (CI): m/z (%) = 241 [M+1] .
Anal. calcd for C H F N O : C, 40.01; H, 3.36; N, 11.66. Found:
1-[3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-5-yl]-3-phenyl-1-
propanone (16a)
8
8
4
2
2
C, 40.33; H, 3.72; N, 11.47.
Compound 16a was obtained as a colorless oil (91 mg, 94%)
Isopropyl
carboxylate (13a)
3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-5- following the general procedure.
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.33ꢀ7.21 (m, 5H, Ph),
3 4
2
3
Compound 13a was obtained as a white solid (78 mg, 96%) 7.02 (s, 1H, CH), 6.12 (tt, J = 52.0 Hz, J = 16.0 Hz, 1H,
HꢀF
HꢀF
following the general procedure. M.p. = 72ꢀ73 ºC.
CHF CF ), 3.22 (t, J = 7.5 Hz, 2H, CH ), 3.06 (t, J = 7.5 Hz, 2H,
2 2 2
1
H NMR (500 MHz; CDCl ; Me Si), δ: 7.08 (s, 1H, CH), 6.11 (tt, CH ).
3
4
2
2
3
13
JHꢀF = 52.0 Hz, J = 16.0 Hz, 1H, CHF CF ), 5.27 (m, J = 6.5 Hz,
C NMR (125 MHz; CDCl ; Me Si), δ: 190.0 (s, CO), 143.4 (t, J
3 4
HꢀF
2
2
1
H, CHCH ), 1.36 (t, J = 6.5 Hz, 6H, CHCH ).
= 28.5 Hz, CCF ), 141.6 (s, C), 139.7 (s, Ph), 128.3 (s, Ph), 128.0 (s,
2
3
3
1
3
1
2
C NMR (125 MHz; CDCl ; Me Si), δ: 158.1 (s, CO), 143.6 (t, J Ph), 126.1 (s, Ph), 111.6 (tt, J = 245 Hz, J = 28 Hz, CF2),
3
4
CꢀF
CꢀF
1
2
1
2
=
30 Hz, C), 135.6 (s, C), 111.6 (tt, J = 245 Hz, J = 28 Hz, 109.3 (tt, J = 250 Hz, J = 38 Hz, CF ), 107.3 (s, CH), 40.9 (s,
CꢀF CꢀF CꢀF CꢀF 2
1
2
CF ), 109.3 (tt, J = 250 Hz, J = 38 Hz, CF ),107.7 (s, CH), CH ), 29.2 (s, CH ).
6
2
CꢀF
CꢀF
2
2
2
19
9.9 (s, OCH), 21.3 (s, CH ).
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.5 (pseudo q, J = 4.0
3 3
3
1
9
2
2
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.7 (pseudo q, J = 4.0 Hz, 2F, CF ), ꢀ136.4 (dt, J = 52.0 Hz, J = 4.0 Hz).
3
3
2
FꢀH
FꢀF
2
2
+
Hz, 2F, CF ), ꢀ136.5 (dt, J = 52.0 Hz, J = 4.0 Hz).
MS (CI): m/z (%) = 301 [M+1] .
Anal. calcd for C H F N O: C, 56.00; H, 4.03; N, 9.33. Found:
2
FꢀH
FꢀF
+
MS (CI): m/z (%) = 255 [M+1] .
Anal. calcd for C H F N O : C, 42.53; H, 3.97; N, 11.02. Found: C, 56.34; H, 3.76; N, 9.52.
14
12
4
2
9
10
4
2
2
C, 42.84; H, 4.31; N, 11.25.
Dimethyl
3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-4,5-
Cyclobutyl[3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-5-
yl]methanone (14a)
dicarboxylate (17a)
Compound 17a was obtained as a yelowish oil (83 mg, 91%)
Compound 14a was obtained as a colorless oil (77 mg, 96%) following the general procedure.
1
2
following the general procedure.
H NMR (500 MHz; CDCl ; Me Si), δ: 6.28 (tt, J = 52.0 Hz,
3 4 HꢀF
1
3
H NMR (500 MHz; CDCl ; Me Si), δ: 6.97 (s, 1H, CH), 6.15 (tt,
JHꢀF = 16.0 Hz, 1H, CHF CF ), 3.92 (s, 3H, CH ), 3.90 (s, 3H,
2 2 3
3
4
2
3
JHꢀF = 52.0 Hz, J = 16.0 Hz, 1H, CHF CF ), 3.82 (qv, J = 7.0 CH ).
HꢀF
2
2
3
1
3
Hz, 1H, CH), 2.46 (m, 2H), 2.33 (m, 2H), 2.14 (m, 2H).
C NMR (125 MHz; CDCl ; Me Si), δ: 161.9 (s, CO), 158.0 (s,
3 4
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 191.4 (s, CO), 143.8 (t, J CO), 141.3 (t, J = 28.7 Hz, CCF ), 134.7 (s, C), 115.6 (s, C), 111.4
3
4
2
1
2
1
2
1
2
=
30 Hz, C), 140.2 (s, C), 111.5 (tt, J = 245 Hz, J = 28 Hz, (tt, J = 245 Hz, J = 28 Hz, CF ), 109.1 (tt, J = 250 Hz, J
CꢀF CꢀF CꢀF CꢀF 2 CꢀF Cꢀ
1
2
CF ), 109.3 (tt, J = 250 Hz, J = 38 Hz, CF ),107.0 (s, CH),
= 38 Hz, CF ), 53.8 (s, CH ), 53.7 (s, CH ).
2 3 3
2
CꢀF
CꢀF
2
F
1
9
4
2.4 (s), 26.5 (s), 24.3 (s), 17.8 (s, CH ).
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ114.9 (pseudo q, J = 4.0
3 3
3
1
9
2
2
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ113.5 (pseudo q, J = 4.0 Hz, 2F, CF ), ꢀ137.4 (dt, J = 52.0 Hz, J = 4.0 Hz).
3
3
2
FꢀH
FꢀF
2
2
+
Hz, 2F, CF ), ꢀ136.6 (dt, J = 52.0 Hz, J = 4.0 Hz).
MS (CI): m/z (%) = 285 [M+1] .
Anal. calcd for C H F N O : C, 38.04; H, 2.84; N, 9.86. Found:
2
FꢀH
FꢀF
+
MS (CI): m/z (%) = 251 [M+1] .
Anal. calcd for C H F N O: C, 48.01; H, 4.03; N, 11.20. Found: C, 38.37; H, 3.05; N, 9.51.
9
8
4
2
4
10
10
4
2
C, 48.35; H, 3.82; N, 11.49.
Diethyl
3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole-4,5-
1
-[3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-5-yl]-2-
dicarboxylate (18a)
phenylethanone (15a)
Compound 18a was obtained as colorless oil (92 mg, 92%)
Compound 15a was obtained as a colorless oil (87 mg, 95%) following the general procedure.
following the general procedure.
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 8
Journal Name
Organic & Biomolecular Chemistry
View Article Online
ART70ICLE
DOI: 10.1039/C4OB026 E
1
2
H NMR (500 MHz; CDCl ; Me Si), δ: 6.27 (tt, J = 52.0 Hz, and to O. Mashkov, R. Iminov, V. Arkhipov, B. Chalyk for the
3
4
HꢀF
3
JHꢀF = 16.0 Hz, 1H, CHF CF ), 4.41 (m, 4H, CH +CH ), 1.37 (m, help in managing this project.
2
2
2
2
6
H, CH +CH ).
3 3
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 161.4 (s, CO), 157.5 (s,
3
4
CO), 141.5 (t, J = 28.7 Hz, CCF ), 134.5 (s, C), 116.1 (s, C), tertꢀ
2
1
2
CF is not seen, 109.4 (tt, J = 250 Hz, J = 38 Hz, CF ), 62.3 Notes and references
2
CꢀF
CꢀF
2
a
b
Enamine Ltd., vul. Matrosova 23, 01013 Kyiv, Ukraine
Faculty of Chemistry, Taras Shevchenko National University of Kyiv,
(
s, OCH ), 61.9 (s, OCH ), 13.6 (s, CH ), 13.5 (s, CH ).
2 2 3 3
1
9
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ114.7 (pseudo q, J = 4.0
3
3
vul. Volodymyrska 62a, 01601 Kyiv, Ukraine
2
2
Hz, 2F, CF ), ꢀ137.4 (dt, J = 52.0 Hz, J = 4.0 Hz).
2
FꢀH
FꢀF
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
+
MS (CI): m/z (%) = 313 [M+1] .
Anal. calcd for C H F N O : C, 42.32; H, 3.87; N, 8.97. Found:
11
12
4
2
4
C, 42.05; H, 4.23; N, 9.36.
5
-(Diphenylphosphoryl)-3-(1,1,2,2-tetrafluoroethyl)-1H-
pyrazole (19a)
Compound 19a was obtained as a white solid (109 mg, 93%)
following the general procedure. M.p. > 200 ºC.
1
H NMR (500 MHz; DMSOꢀd6; Me Si), δ: 14.66 (broad s, NH),
4
7
.67 (broad s, 6H, Ph+Ph), 7.59 (broad s, 4H, Ph+Ph), 6.84 (pseudo
2
t, J = 52.0 Hz, 2H, CHF CF + CH).
HꢀF
2
2
1
3
C NMR (125 MHz; CDCl ; Me Si), δ: 142.7 (broad s, C), 137.9
3
4
1
1
(d, J(C,P) = 111.9 Hz, C), 132.9 (s, pꢀCH, Ph), 132.5 (d, J(C,P) =
3
2
1
=
16.5 Hz, C), 131.2 (d, J(C,P) = 11.3 Hz, CH, Ph), 120.1 (d, J(C,P)
2
1
12.5 Hz, CH, Ph), 111.8 (d, J(C,P) = 16.3 Hz, CH).
F NMR (375 MHz; CDCl ; CFCl ), δ: ꢀ111.1 (pseudo q, J = 4.0 Applications, Petrov, V. A., Ed.; John Wiley & Sons, Inc., Publishers:
(a) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and
1
9
3
3
2
2
Hz, 2F, CF ), ꢀ136.7 (dt, J = 52.0 Hz, J = 4.0 Hz).
New Jersey, 2009. (b) Bioorganic and Medicinal Chemistry of Fluorine
(Eds.: J.ꢀP. Bégué, D. BonnetꢀDelpon), John Wiley & Sons, New Jersey,
2008; (c) Fluorine in Medicinal Chemistry and Chemical Biology (Ed.: I.
2
FꢀH
FꢀF
3
1
P NMR (202 MHz DMSOꢀd6; H PO ), δ: 14.7 (broad s, P).
3
4
+
MS (CI): m/z (%) = 369 [M+1] .
Anal. calcd for C H F N OP: C, 55.45; H, 3.56; N, 7.51. Found: Ojima), Blackwell Publishing, 2009; (d) Fluorine in Pharmaceutical and
17
13
4
2
C, 55.11; H, 3.87; N, 7.72.
Medicinal Chemistry: From Biophysical Aspects to Clinical Applications
(
Eds.: V. Gouverneur, K. Müller), Imperial College Press, London, 2012.
2
2
-[3-((1,1,2,2-tetrafluoroethyl)-1H-pyrazol-5-yl]-quinoxaline
20a)
The reaction was performed following the general procedure, Chem. Rev. 2014
except for: 5.0 eq. HCF CF CH NH *HCl + 1.0 eq. alkyne + 8.0 eq. Chem. 2014 167, 16. (c) O’Hagan, D. J. Fluorine Chem. 2010
NaNO . The formed product was washed out with CHCl (0.5 mL) 1071. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Recent reviews: (a) Wang, J.; SánchezꢀRoselló, M.; Aceña, J. L.; del
(
Pozo, C.; Sorochinsky, A. E.; Fusteero, S.; Soloshonok, V. A.; Liu. H.
114, 2432. (b) Fujiwara, T.; O’Hagan, D. J. Fluorine
131,
,
,
,
2
2
2
2
2
3
to afford the pure pyrazole 20a a grey solid (69 mg, 73%). M.p. > Soc. Rev. 2008, 37, 320. (e) Hagmann, W. K. J. Med. Chem. 2008, 51,
2
00 ºC.
4359.
1
3
H NMR (500 MHz; DMSOꢀd ; Me Si), δ: 14.19 (broad s, 1H,
For reviews on fluorinated pyrazoles, see: (a) Fustero, S.; Sanchezꢀ
6
4
NH), 9.55 (s, 1H, CH), 8.14 (d, J = 8.0 Hz, 2H, CH), 7.91 (m, 2H, Rosello, M.; Barrio, P.; SimonꢀFuentes A. Chem. Rev. 2011
,
111, 6984.
2
CH), 7.75 (s, 1H, CH), 6.91 (t, J = 52.0 Hz, 1H, CHF CF ).
(b) Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.ꢀP.; Leroux F.
152, 2. (c) Fustero, S. SimonꢀFuentes, A.;
HꢀF
2
2
1
3
C NMR (125 MHz; DMSOꢀd ; Me Si), δ: 143.7 (s), 142.5 (s), R. J. Fluorine Chem. 2013
,
6
4
1
41.5 (s), 141.1 (s), 131.2 (s), 130.6 (s), 129.2 (s), 128.9 (s), tertꢀCF
SanzꢀCervera, J. F. Org. Prep. Proced. Int.
,
2009
,
41, 253
2
1
2
4
is not seen, 110.0 (tt, J = 250 Hz, J = 38 Hz, CF ), 105.1 (s).
For some recent papers on fluoroalkyl pyrazoles, see: (a) Sha, Q.; Liu, H.;
CꢀF
CꢀF
2
1
9
F NMR (375 MHz; DMSOꢀd ; CFCl ), δ: ꢀ111.3 (broad s, 2F, Wei, Y. Eur. J. Org. Chem. 2014, 34, 7707. (b) Iminov, R. T.; Mashkov, A.
6
3
2
2
CF ), ꢀ136.5 (dt, J = 52.6 Hz, J = 7.6 Hz).
V.; Vyzir, I. I.; Chalyk, B. A.; Tverdokhlebov, A. V.; Mykhailiuk, P. K.;
Babichenko, L. N.; Tolmachev, A. A.; Volovenko, Y. M.; Biitseva, A.;
2
FꢀH
FꢀF
+
MS (CI): m/z (%) = 297 [M+1] .
Anal. calcd for C H F N : C, 52.71; H, 2.72; N, 18.91. Found: C, Shishkin, O. V.; Shishkina, S. V. Eur. J. Org. Chem. 2014, in press, DOI:
13
8
4
4
5
2.34; H, 2.58; N, 19.22.
10.1002/ejoc.201403295. (c) Giornal, F.; Landelle, G.; Lui, N.; Vors, J.ꢀP.;
Pazenok, S.; Leroux, F. R. Org. Process Res. Dev. 2014, 18, 1002. (d)
Roman, R.; Navarro, A.; Wodka, D.; AlvimꢀGaston, M.; Husain, S.;
Franklin, N.; SimónꢀFuentes, A.; Fustero, S. Org. Process Res. Dev. 2014,
Acknowledgements
1
8, 1027. (e) Pazenok, S.; Giornal, F.; Landelle, G.; Lui, N.; Vors, J.ꢀP.;
All amines and alkynes were generously provided by Enamine
Ltd. I am very grateful to O. Ishenko and V. Stepanenko for the
Leroax, F. R. Eur. J. Org. Chem. 2013, 4249. (f) Gerus, I. I.; Mironetz, R. X.;
Kondratov, I. S.; Bezdudny, A. V.; Dmytriv, Y. V.; Shishkin, O. V.; Starova,
kind gift of 2. I also thank Dr. S. Shishkina for Xꢀray studies;
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem. 2014, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 8
View Article Online
ARTICLE
DOI: 10.1039/C B02670E
Jou4Ornal Name
1
0
V. S.; Zaporozhets, O. A.; Tolmachev, A. A.; Mykhailiuk, P. K. J. Org.
Chem. 2012, 77, 47.
(a) P. K. Mykhailiuk Beilstein. J. Org. Chem. 2015, 11, 16. (b) P.
Mykhailiuk Chem. Eur. J. 2014
11
,
17, 4942.
5
Some reviews on fluoroalkylation, see: (a) Maa, J.ꢀA.; Cahard, D.
For a review on [3+2]ꢀcycloadditions, see: G. Maas in Synthetic
Chem. Rev. 2004
Chem. 2012, 2479. (c) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2014
DOI: 10.1021/cr5002386 (d) Tomashenko, O. A.; Gruushin, V. V. Chem. Wiley, New York, 2002, pp. 539ꢀ621.
Rev. 2011 111, 4475. (e) Charpentier, J.; Fru
015 in press, DOI: 10.1021/cr500223h. (f) BarataꢀVallejo, S.; Lantano, 1999, 1107.
B.; Postigo, A. Chem. Eur. J. 2014
Gribble, G. W.; Le, V.ꢀD.; Roy, S. Tetrahedron 2011
,
104, 6119. (b) Macé, Y.; Magnier, E. Eur. J. Org. Applications of 1,3-Dipolar Cycloaddition Chemistry toward
,
in press Heterocycles and Natural Products (Eds.: A. Padwa, W. H. Pearson),
,
.
12
,
̈
Y. Chiang, A. J. Kresge, V. V. Popik J. Chem. Soc. Perkin Trans. 2,
2
,
1
3
4
,
20, 16806. (g) Roy, S.; Gregg, B. T.;
J. H. Atherton, R. Fields, R. N. Haszeldine J. Chem. Soc. C
, 1971, 366.
1
,
67, 2161. (h) Nie,
111, 455.
CCDC numbers: 1036133 (5b), 1036138 (6c), 1036139 (7c), 1036137
J.; Guo, H.ꢀC.; Cahard, D.; Ma, J.ꢀA. Chem. Rev. 2011
,
(10e) 1036136 (13a), 1036134 (19a) and 1036135 (23a).
6
15
Gaseous CF
3
CHN
2
was first described in: Gilman, H.; Jones, R. G. J.
65, 1458.
CHN
Some recent papers on CF CHN
Morandi, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2010
Morandi, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2010
Morandi, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50, 1101. (d) 20. (c) Chernykh, Y.; Jurasek, B.; Beier, P. J. Fluorine Chem. 2014
ꢀI inductive effects of substituents: F (4.0), CF
3
(3.5), CHF
2
(2.9):
Am. Chem. Soc. 1943
,
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991
,
91, 165.
7
16
More than 70 papers on CF
3
2
have been published so far (Reaxys DB).
For other methods on incorporation of tetrafluoroethyl group into
8
3
2
by different research groups: (a) organic compounds, see: (a) Chernykh, Y.; HlatꢀGlembova, K.;
49, 938. (b) Klepetarova, B.; Beier, P. Eur. J. Org. Chem. 2011, 4528. (b) Sokolenko,
,
,
49, 4294. (c) T. M.; Davydova, Y. A.; Yagupolskii, Y. L. J. Fluorine Chem. 2012
,
136
,
,
in
Zhang, F.ꢀG.; Wei, Y.; Yi, Y.ꢀP.; Nie, J.; Ma, J.ꢀA. Org. Lett. 2014
,
16
16
,
,
press, DOI: 10.1016/j.jfluchem.2014.08.004. (d) Vaclavık, J.; Chernykh,
Y.; Jurasek, B.; Beier, P. J. Fluorine Chem. 2015 169, 24.
CCDC numbers: 1036133 (5b), 1036138 (6c), 1036139 (7c), 1036137
10e) 1036136 (13a), 1036134 (19a) and 1036135 (23a).
3
1
122. (e) Wang, S.; Nie, J.; Zheng, Y.; Ma, J.ꢀA. Org. Lett. 2014
,
,
1
7
606. (f) Li, F.; Nie, J.; Sun, L.; Zheng, Y.; Ma, J.ꢀA. Angew. Chem. Int.
2013 52, 6255. (g) Argintaru, O. A.; Ryu, D.; Aron, I.; Molander, G.
A. Angew. Chem. Int. Ed 2013 52, 13656. (h) Molander, G. A.;
Cavalcanti, L. N. Org. Lett. 2014 15, 3166. (i) Molander, G. A.; Ryu, D.
Angew. Chem. Int. Ed 2014 53 14181. (j) Artamonov, O. S.;
Ed
.
,
(
.
,
,
.
,
,
Mykhailiuk, P. K.; Voievoda, N. M.; Volochnyuk, D. M.; Komarov I. V.
Synthesis 2010, 443. (k) Artamonov, O. S.; Slobodyanyuk, E. Y.;
Shishkin, O. V.; Komarov, I. V.; Mykhailiuk, P. K. Synthesis 2013, 225.
(
l) Artamonov, O. S.; Slobodyanyuk, E. Y.; Volochnyuk, D. M.;
Komarov I. V.; Tolmachev, A.A.; Mykhailiuk, P. K. Eur. J. Org. Chem.
014, 3592. (m) Mykhailiuk, P. K.; Afonin, S.; Palamarchuk, G. V.;
Shishkin, O. V.; Ulrich, A. S.; Komarov, I. V. Angew. Chem. Int. Ed
2
.
2
008
,
,
45, 5765. (n) Le Maux, P.; Juillard, S.; Simonneaux, G. Synthesis
10, 1701. (o) Duncton, M. A. J.; Ayala, L.; Kaub, C.; Janagani, S.;
2006
Edwards, W. T.; Orike, N.; Ramamoorthy, K.; Kincaid, J.; Kelly, M. G.
Tetrahedron Lett 2010 51, 1009. (p) Chai, Z.; Bouillon, J.ꢀP.; Caharrd,
D. Chem. Commun. 2012 48, 9471. (q) Duncton, M. A. J.; Singh, R. Org.
Lett. 2013 15, 4284. (r) Wu, G.; Deng, Y.; Wu, C.; Wang, X.; Zhang, Y.;
.
,
,
,
Wang, J. Eur. J. Org. Chem. 2014, 4477. (s) Li, T.ꢀR.; Duan, S.ꢀW.;
Ding, W.; Liu, Y.ꢀY.; Chen, J.ꢀR.; Lu, L.ꢀQ.; Xiao, W.ꢀJ. J. Org. Chem.
2
014
,
79, 2296.
9
Slobodyanyuk, E. Y.; Artamonov, O. S.; Shishkin, O. V.; Mykhailiuk,
P. K. Eur. J. Org. Chem. 2014, 2487.
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012