(Het)aryl Difluoromethyl-Substituted β-Alkoxyenones: Synthesis and Heterocyclizations

Article abstract of DOI:10.1002/ejoc.201901833

An efficient approach to the preparation of β-alkoxyenones bearing (het)aryl difluoromethyl substituents is described. The method included acylation of acyclic or cyclic vinyl ethers with (het)aryl difluoroacetyl chlorides. The method worked well for most

Full text of DOI:10.1002/ejoc.201901833

A Journal of
Accepted Article
Title: (Het)aryl difluoromethyl-substituted β-alkoxyenones: synthesis
and heterocyclizations
Authors: Maksym Ya. Bugera, Karen V. Tarasenko, Ivan S. Kondratov,
Igor I. Gerus, Bohdan V. Vashchenko, Viktor E. Ivasyshyn,
and Oleksandr O Grygorenko
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901833
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
(Het)aryl difluoromethyl-substituted β-alkoxyenones: synthesis
and heterocyclizations
Maksym Ya. Bugera,[a,b] Dr. Karen V. Tarasenko,[b,c] Dr. Ivan S. Kondratov,*[a,b] Dr. Igor I. Gerus,[b]
Bohdan V. Vashchenko,[a,d] Viktor E. Ivasyshyn,[b]† Dr. Oleksandr O. Grygorenko*[a,d]
Dedicated to Professor Dr. Günter Haufe on the occasion of his 70th birthday
Abstract: An efficient approach to the preparation of β-alkoxy-
enones bearing (het)aryl difluoromethyl substituents is described.
The method included acylation of acyclic or cyclic vinyl ethers with
(het)aryl difluoroacetyl chlorides. The method worked well for most
substrates, except aryl-substituted derivatives bearing electron-
donating groups in o- or p-positions, and heteroaromatic compounds
bearing sufficiently basic nitrogen atom. Synthetic utility of (het)aryl
difluoromethyl-substituted β-alkoxyenones as CCC bis-electrophiles
was demonstrated by heterocyclizations with common 1,2- and 1,3-
bis-nucleophiles leading to compounds with (het)aryl–CF2–(het)aryl
motif, in particular (het)aryl difluoromethyl-substituted pyrazoles, iso-
xazoles, and pyrimidines – promising chemotypes for drug discovery.
known approaches rely on gem-difluorination reactions, i.e.
deoxofluorination of diarylketones (Scheme 1, A),[3,26–33] flu-
orodesulfurization of thioketones (B)[33–35] or thioketals (C).[36–42]
Alternative strategy implies the use of building blocks already
containing the (het)aryl difluoromethyl moiety; it is represented
by [4+2] or [3+2] cycloadditions of 4,4-difluorobutynoates (D).[43]
Introduction
Introducing gem-difluoromethylene unit into organic compounds
is an important design approach in medicinal,[1–5] agricultural,[6,7]
and synthetic,[8–17] chemistry in view of improving physico-
chemical properties of derivatives.[18–22] The CF2 moiety was
considered as a bioisosteric replacement of methylene, carbonyl,
or ether groups with improved metabolic stability.[23–25]
Incorporation of the difluoromethylene linker between
(hetero)aromatic rings improved activity and/or pharmacokinetic
properties of the compounds as compared to their non-
fluorinated counterparts.[26–29] In addition to that, the CF2 frag-
ment can be found in several marketed drugs including Gemcita-
bine, Ledipasvir, Lubiprostone, and Tafluprost (Figure 1).[3]
Figure 1. Marketed drugs bearing gem-difluoromethylene unit
O
S
difluorodi(het)arylmethanes
Although synthesis of CF2-substituted derivatives attracted
considerable interest in recent years, methods for preparation of
difluorodi(het)arylmethanes (i.e. compounds with CF2-linker bet-
ween two (het)aryl rings) are scarce in the literature. Most
(Het)Ar
(Het)Ar
CO2Et
A
B
Ar
Ar
F
F
F
F
(Het)Ar
(Het)Ar
D
C
R1S SR2
Ar Ar
Ar
R1 = R2 = Ph
R1 + R2 = (CH2)2 3
[a]
M. Ya. Bugera, Dr. I. S. Kondratov, B. V. Vashchenko,
Dr. O. O. Grygorenko
Scheme 1. Known syntheses of difluorodi(het)arylmethanes
Enamine Ltd. (www.enamine.net),
Chervonotkatska Street 78, Kyiv 02094, Ukraine
E-mail: kondratov@mail.enamine.net (I.S.K.)
M. Ya. Bugera, Dr. K. V. Tarasenko, Dr. I. S. Kondratov,
Dr. I. I. Gerus, V. E. Ivasyshyn
[b]
V.P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS
of Ukraine, Murmanska Street 1, Kyiv 02660, Ukraine
Dr. K. V. Tarasenko
Chemspace, Ilukstes iela 38-5, Riga, LV-1082, Latvia
B. V. Vashchenko, Dr. O. O. Grygorenko
[c]
[d]
Taras Shevchenko National University of Kyiv
Volodymyrska Street 60, Kyiv 01601, Ukraine
E-mail: gregor@univ.kiev.ua (O.O.G.)
†
Current address: Stratingh Institute for Chemistry, University of
Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Scheme 2. -Alkoxyenones 1 in the synthesis of fluorinated heterocycles
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
In this work, we considered another approach to difluorodi(het)-
arylmethanes, which also relied on the use of (het)aryl difluoro
methyl-substituted building blocks, namely, β-alkoxyenones of
the type 1 (X = (het)aryl, Scheme 2). It should be noted that
heterocyclizations of various fluorinated β-alkoxyenones 1 (X =
H, F, Cl, CF3, CHF2) were reported in recent publications descri-
bing synthesis of fluoroalkyl-substituted pyrazoles,[44–60]
isoxazoles,[54] and pyrimidines,[47,57,61–67] as well as other hetero-
cycles.[31,68–73] However, no examples of (het)aryl difluoromethyl -
substituted enones of the type 1 were reported to date.
substrates with electron-donating substituents in o- and p-
positions of the aryl group. Thus, in the case of substrates 3g
and 3i bearing p- and o-tolyl substituents, the yield of enones 1g
and 1i was moderate (54% and 51%, respectively), whereas
with m-tolyl-substituted derivative 3h, the reaction has significan-
tly better outcome (80% yield). This effect could be somewhat
countervailed by incorporation of the fluorine atom: reaction with
3j gave the target product 1j in 61% yield. In the case of
stronger electron-donating groups (i.e. methoxyl), the reaction
did not take place in the case of o- and p-isomers (substrates 3k
and 3m, respectively); even introducing the halogen atom
(substrate 3n) did not overcome this effect. Meanwhile, m-me-
thoxy-substituted carboxylic acid 3l gave corresponding enone
1l in 67% yield. The observed deactivating effect of electron-
donating groups is presumably related to diminished electro-
philicity of the intermediate acyl chlorides.
The method was also suitable for heterocylic derivatives, i.e.
2-pyridyl-, 1-methylpyrazol-5-yl- and thiazol-2-yldifluoroacetic
acids (3q–s). The corresponding hetaryl-substituted -ethoxy-
enones 1q–s were obtained in 63–78% yield. Unexpectedly, the
reaction was not successful for the case of 3- and 4-pyridyl
counterparts 3o and 3p. We address this to limited stability of
the corresponding acyl halides, which is probably defined by the
nitrogen atom basicity.
Results and Discussion
Two synthetic approaches to the title compounds were
evaluated in this work, namely, sp2–sp3 coupling of (het)aryl
halides with bromodifluoromethyl-substituted enones (e.g. 2), as
well as acylation of vinyl ethers with activated derivatives of
difluoro(het)arylacetic acids 3 (Scheme 3).
The method was successfully extended to other vinyl ethers, e.g.
1-ethoxyprop-1-ene (4a), 2-methoxypropene (4b), 2,3-dihy-
drofuran (4c), and 3,4-dihydro-2H-pyran (4d). Likewise to the
case of ethoxyethene, the reaction with model p-fluorophenyl
difluoroacetic acid 3b led to the target enones 1t–w in 74–88%
yield (Scheme 6).
Scheme 3. Retrosynthetic analysis of enones 1
First of all, reaction of compound 2 with phenyl iodide was
performed under conditions described previously for ethyl bro-
modifluoroacetate (Cu, DMSO, 60 °C, 12 h).[74–76] Unfortunately,
complete decomposition of the starting enone was observed,
and no traces of target product 1a were detected in the reaction
mixture. Meanwhile, acylation of ethoxyethene with acyl chloride
obtained in situ from phenyl difluoroacetic acid 3a proceeded
smoothly in the presence of pyridine in CH2Cl2[45] and resulted in
in 86% yield of 1a (Scheme 4).
Scheme 4. Synthesis of enone 1a
In order to study the scope and limitation of the method we
extended the aforementioned approach to a series of aryldi-
fluoroacetic acids bearing electron-withdrawing (3b–f) and
electron-donating substituents (3g–n), as well as heteroaromatic
counterparts, i.e. derivatives of pyridine (1o–q), pyrazole (1r),
and thiazole (1s) (Scheme 5). In the case of electron-poor aryl-
substituted compounds, the procedure worked well, and the
corresponding enones 1b–f were obtained in good yields (70–
88%). On the contrary, deactivating effect was apparent for the
Scheme 5. Synthesis of enones 1b–s
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
R1
1. (COCl)2, DMF
CH2Cl2, 2 h, rt
proceeded slowly at rt, so that only traces of the product 5w
were detected after 96 h, while a complex mixture was formed
when the reaction was performed at 60 °C.
F
F
F
F
OR3
Ar
Ar
CO2H
2. 4a d, pyridine,
CH2Cl2, 5 °C to rt
overnight
O
R2
3b, Ar = p-FC6H4
1t w
R4
R1
F
F
F
F
.
N2H4 H2O
OR3
OMe
R2
(Het)Ar
OEt
Me
(Het)Ar
HOAc, rt, 12 h
O
R2
HN
O
Me
N
O
4a
4b
4c
4d
1a e and 1q w
5a e and 5q w
F
F
Me
F
F
O
F
F
F
F
F
F
OEt
O
O
F
HN
HN
F
N
N
HN
N
F
Cl
1v, 88%
1t, 77%
5a, 78%
5b, 81%
5c, 87%
F
F
F
F
O
F
F
OMe
Me
F
F
F
F
O
O
F
F
HN
HN
N
N
N
HN
1w, 74%
O2N
N
1u, 86%
Br
5d, 84%
5e, 85%
5q, 73%
Scheme 6. Synthesis of enones 1t–w
Me
F
F
Me
F
F
F
F
N
N
N
Stereochemistry of the products 1 was confirmed by 1H – 1H
HN
N
HN
S
HN
N
N
F
1
NOE and H – 19F HOESY experiments (Figure 2). In particular,
5r, 78%
5s, 86%
5t, 82%
considerable nuclear Overhouser effect was observed for the
CH2 unit protons upon irradiation of H-3 or Me-3 moieties of the
compounds 1b, 1t, and 1u. In addition to that, significant
heteronuclear NOE correlations between the H-4 and fluorine
atoms of the CF2 group were found for all these products. Finally,
values of vicinal coupling constants for the protons attached to
the double bond were characteristic for the trans configuration
(3J = 12.3 Hz for all derivatives 1a–s).
OH
OH
F
F
F
F
F
F
Me
HN
HN
HN
N
N
N
F
F
F
5u, 83%
5v, 57%
5w, traces
Scheme 7. Synthesis of pyrazoles 5a–e and 5q–w
Figure 2. NOE experiments with compounds 1b, 1t, and 1u
Synthetic utility of enones 1 as the CCC bis-electrophiles was
demonstrated by condensation with common 1,2- and 1,3-
binucleophiles. In particular, reaction of enones 1a–e and 1q–w
with hydrazine hydrate in AcOH proceeded smoothly at rt and
led to corresponding pyrazoles 5a–e and 5q–u in 73–87% yield
(Scheme 7). Under these conditions, reaction of 1v was
accompanied by the dihydrofuran ring opening leading to pyra-
zole 5v (57% yield). Notably, analogous transformation of 1w
Scheme 8. Synthesis of heterocycles 7–9
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
scale) downfield from TMS as an internal standard and are referenced
Heterocyclization of enone 1b with another 1,2-bis-nucleophile,
NH2OH,·in H2O at rt led to isoxazolinol 6 in 74% yield, which did
not underwent spontaneous dehydration (Scheme 8). Treatment
of 6 with SOCl2 and pyridine in CH2Cl2 resulted in the target
isoxazole 7 in excellent yield (92%).
Finally, NCN bis-nucleophiles were studied in reaction with
enone 1b (Scheme 8). In particular, condensation of 1b with
urea in aq HCl gave pyrimidin-2(1H)-one 8 (63% yield), whereas
reaction with guanidine hydrochloride afforded the correspond-
ding 2-aminopyrimidine 9 in 41% yield.
using residual NMR solvent peaks at 7.26 and 77.16 ppm for 1H and 13
C
in CDCl3, 2.50 and 39.52 ppm for 1H and 13C in DMSO-d6. Coupling
constants (J) are shown in Hz. Spectra are reported as follows: chemical
shift (δ, ppm), multiplicity, integration, coupling constants (Hz). Elemental
analyses were performed at the Laboratory of Organic Analysis,
Department of Chemistry, Taras Shevchenko National University of Kyiv.
Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument
(chemical ionization (CI)) and Agilent 5890 Series II 5972 GCMS
instrument (electron impact ionization (EI)).
General procedure for the preparation of enones 1a–x.
To a stirred solution of the corresponding difluoro(hetero)aryl acetic acid
3a–t (5.00 mmol) in CH2Cl2 (10 mL), oxalyl chloride (1.26 g, 0.858 mL,
10.0 mmol) and DMF (1 drop) were added at rt. The solution was stirred
at rt for 2 h until gas evolution ceased. Then the solvent was evaporated
in vacuo to give crude acyl chloride, which was dissolved in CH2Cl2 (10
mL) and added dropwise to a solution of ethoxyethene (541 mg, 0.713
mL, 7.50 mmol) or the corresponding enol ether 4a–d (7.50 mmol) and
pyridine (791 mg, 0.805 mL, 10.0 mmol) in CH2Cl2 (20 mL) at 0 °C. The
solution was stirred at rt overnight and then diluted with H2O (30 mL).
The organic layer was separated, washed with H2O (220 mL), saturated
aq NaHCO3 (220 mL), and brine (20 mL), dried over Na2SO4 and
evaporated in vacuo. If necessary, the product was purified by flash
chromatography on silica gel using hexanes as eluent.
Conclusions
Acylation of vinyl ethers with acyl chlorides generated in situ
from difluoro(het)arylacetic acids was found to be an efficient
method for the preparation of (het)aryl difluoromethyl-substituted
β-alkoxyenones. In the case of ethoxyethene, the method
worked well for the parent difluorophenylacetic acid, as well as
its derivatives bearing electron-withdrawing groups at the
aromatic ring. Substrates with donor substituents (e.g. methyl or
methoxy) at the aryl moiety were less efficient; for the o- and p-
methoxyphenyl-substituted derivatives, the method did not work
at all. This effect might be addressed to diminished reactivity of
the corresponding acyl chloride intermediates towards electro-
philic attack at the vinyl ether.
Further extension of the substrate scope included difluoro-
hetarylacetic acids, namely, 2-pyridyl-, 2-thiazolyl-, and 1-me-
thyl-5-pyrazolyl-substituted derivatives. The method did not work
for the 3- and 4-pyridyl counterparts having a slightly more basic
nitrogen atom, possibly due to low stability of the corresponding
acyl chlorides. Moreover, methyl-substituted and cyclic vinyl
ethers could be introduced into the reaction successfully.
The target (het)aryl difluoromethyl-substituted β-alkoxyenones
were obtained in 51–88% yield. They appeared to have
sufficient reactivity as CCC bis-electrophiles towards hydrazine,
hydroxylamine, urea, and guanidine (except dihydropyrane
derivative), providing the corresponding fluorinated pyrazoles,
isoxazoles, and pyrimidines in 41–92% yield. Thus, the title
(het)aryl difluoromethyl-substituted β-alkoxyenones are conve-
nient building blocks for the construction of various frameworks
with (het)aryl-CF2-(het)aryl motif – promising chemotypes for
drug discovery.
(E)-4-Ethoxy-1,1-difluoro-1-phenylbut-3-en-2-one (1a).[68] Yield 973
mg (86%). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 12.3
Hz, 1H), 7.57 (d, J = 7.3 Hz, 2H), 7.49 – 7.40 (m, 3H), 5.96 (d, J = 12.3
Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 188.6 (t, J = 31.1 Hz), 166.4, 133.2 (t, J = 25.8 Hz), 130.7,
128.7, 125.6 (t, J = 6.2 Hz), 116.1 (t, J = 253 Hz), 98.9, 68.5, 14.5. 19F
NMR (470 MHz, CDCl3) δ –106.7. GC/MS (EI): m/z = 127 [C6H5CF2]+,
207 [M–F]+. Anal. Calcd. for C12H12F2O2: C 63.71; H 5.35. Found: C
64.07; H 5.11.
(E)-4-Ethoxy-1,1-difluoro-1-(4-fluorophenyl)but-3-en-2-one (1b). Yield
952 mg (78%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J =
12.3 Hz, 1H), 7.55 (dd, J = 8.4, 5.3 Hz, 2H), 7.11 (t, J = 8.4 Hz, 2H), 5.96
(d, J = 12.3 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) δ 188.5 (t, J = 31.4 Hz), 166.7, 164.2 (d, J = 250
Hz), 129.2 (t, J = 25.1 Hz), 128.0 (dt, J = 8.7, 6.3 Hz), 115.9 (d, J = 22.2
Hz), 115.8 (t, J = 254 Hz), 98.6, 68.7, 14.5. 19F NMR (376 MHz, CDCl3) δ
–105.6, –110.2 (t, J = 2.5 Hz). GC/MS (EI): m/z = 145 [p-FC6H4CF2]+,
225 [M–F]+. Anal. Calcd. for C12H11F3O2: C 59.02; H 4.54. Found: C
58.83; H 4.33.
(E)-1-(4-Chlorophenyl)-4-ethoxy-1,1-difluorobut-3-en-2-one
(1c).
Yield 912 mg (70%). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d,
J = 12.3 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 5.95
(d, J = 12.3 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 188.2 (t, J = 31.0 Hz), 166.8, 137.1, 131.7 (t, J
= 26.3 Hz), 129.0, 127.2 (t, J = 6.1 Hz), 115.7 (t, J = 254 Hz), 98.6, 68.7,
14.5. 19F NMR (470 MHz, CDCl3) δ –106.4. GC/MS (EI): m/z = 161/163
[p-ClC6H4CF2]+, 241/243 [M–F]+. Anal. Calcd. for C12H11ClF2O2: C 55.30;
H 4.25; Cl 13.60. Found: C 54.93; H 4.42; Cl 13.55.
Experimental Section
General. The solvents were purified according to the standard
procedures.[77] Compounds 3a–t were provided by Enamine Ltd. All other
starting materials were purchased from commercial sources. Melting
points were measured on MPA100 OptiMelt automated melting point
system. Analytical TLC was performed using Polychrom SI F254 plates.
Column chromatography was performed using Kieselgel Merck 60 (230–
400 mesh) as the stationary phase. 1H and 13C NMR spectra were
recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1H
NMR, 126 MHz for 13C NMR and 470 MHz for 19F NMR) and Varian Unity
Plus 400 spectrometer (at 400 MHz for 1H NMR, 101 MHz for 13C NMR
and 376 MHz for 19F NMR). NMR chemical shifts are reported in ppm (δ
(E)-1-(4-Bromophenyl)-4-ethoxy-1,1-difluorobut-3-en-2-one
(1d).
Yield 1.34 g (88%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J
= 12.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.95 (d,
J = 12.3 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 188.2 (t, J = 31.0 Hz), 166.8, 132.3 (t, J = 26.4
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
Hz), 132.0, 127.4 (t, J = 6.1 Hz), 125.4, 115.7 (t, J = 254 Hz), 98.6, 68.7,
14.5. 19F NMR (376 MHz, CDCl3) δ –106.6. GC/MS (EI): m/z = 205/207
[p-BrC6H4CF2]+, 285/287 [M–F]+. Anal. Calcd. for C12H11BrF2O2: C 47.24;
H 3.63; Br 26.19. Found: C 47.61; H 3.68; Br 25.84.
163.8 (d, J = 250 Hz), 140.0 (dt, J = 8.4, 3.1 Hz), 128.5 (q, J = 9.2 Hz),
127.6 (td, J = 24.0, 3.0 Hz), 118.8 (d, J = 21.7 Hz), 116.5 (t, J = 254 Hz),
112.8 (d, J = 21.5 Hz), 99.01, 68.6, 20.1, 14.5. 19F NMR (376 MHz,
CDCl3)
δ –103.4, –111.5. GC/MS (EI): m/z = 159 [4-fluoro-2-
methylphenylCF2]+, 221 [M–F]+, 239 [M]+. Anal. Calcd. for C13H13F3O2: C
60.46; H 5.07. Found: C 60.30; H 5.32.
(E)-4-Ethoxy-1,1-difluoro-1-(4-nitrophenyl)but-3-en-2-one (1e). Yield
1.08 g (80%). Brownish solid; mp 50–52 °C. 1H NMR (400 MHz, CDCl3) δ
8.28 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 12.3 Hz, 1H), 7.75 (d, J = 8.7 Hz,
2H), 6.00 (d, J = 12.3 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 187.5 (t, J = 30.5 Hz), 167.5, 149.4,
139.4 (t, J = 26.1 Hz), 127.2 (t, J = 6.1 Hz), 123.8, 115.1 (t, J = 255 Hz),
98.3, 69.0, 14.5. 19F NMR (376 MHz, CDCl3) δ –106.6. GC/MS (EI): m/z
= 172 [p-O2NC6H4CF2]+. Anal. Calcd. for C12H11F2NO4: C 53.14; H 4.09;
N 5.16. Found: C 53.12; H 4.29; N 4.78.
(E)-4-Ethoxy-1,1-difluoro-1-(3-methoxyphenyl)but-3-en-2-one
(1l).
Yield 858 mg (67%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d,
J = 12.3 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.08 (s,
1H), 6 7.02 – 6.94 (m, 1H), 5.94 (d, J = 12.3 Hz, 1H), 4.00 (q, J = 7.1 Hz,
2H), 3.81 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
188.4 (t, J = 31.0 Hz), 166.4, 159.8, 134.5 (t, J = 25.9 Hz), 129.9, 117.8 (t,
J = 6.2 Hz), 116.6, 115.9 (t, J = 254 Hz), 111.0 (t, J = 6.3 Hz), 98.8, 68.5,
55.4, 14.5. 19F NMR (470 MHz, CDCl3) δ –106.8. GC/MS (EI): m/z = 157
[m-MeOC6H4CF2]+, 237 [M–F]+, 256 [M]+. Anal. Calcd. for C13H14F2O3: C
60.93; H 5.51. Found: C 60.92; H 5.67.
(E)-1-(3-Bromophenyl)-4-ethoxy-1,1-difluorobut-3-en-2-one (1f). Yield
1.19 g (78%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J =
12.3 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.7 Hz,
1H), 7.30 (t, J = 7.9 Hz, 1H), 5.96 (d, J = 12.3 Hz, 1H), 4.04 (q, J = 7.1 Hz,
2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 188.0 (t, J =
30.8 Hz), 166.9, 135.3 (t, J = 26.2 Hz), 133.9, 130.3, 128.9 (t, J = 6.5 Hz),
124.5 (t, J = 6.1 Hz), 122.8, 115.2 (t, J = 255 Hz), 98.6, 68.8, 14.4 (d, J =
40.1 Hz). 19F NMR (376 MHz, CDCl3) δ –106.6. GC/MS (EI): m/z =
205/207 [m-BrC6H4CF2]+. Anal. Calcd. for C12H11BrF2O2: C 47.24; H 3.63;
Br 26.19. Found: C 47.24; H 3.31; Br 26.15.
(E)-4-Ethoxy-1,1-difluoro-1-(pyridin-2-yl)but-3-en-2-one (1q). Yield
738 mg (65%). Brownish oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J =
4.5 Hz, 1H), 7.83 – 7.76 (m, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.35 (dd, J =
7.2, 5.1 Hz, 1H), 6.06 (d, J = 12.3 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 1.32
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 188.4 (t, J = 29.3 Hz),
166.2, 152.4 (t, J = 27.9 Hz), 149.6, 137.3, 125.3, 121.1 (t, J = 4.0 Hz),
114.0 (t, J = 254 Hz), 99.6, 68.3, 14.4. 19F NMR (376 MHz, CDCl3) δ –
108.9. GC/MS (EI): m/z = 128 [pyridin-2-ylCF2]+, 227 [M]+. Anal. Calcd.
for C11H11F2NO2: C 58.15; H 4.88; N 6.16. Found: C 58.48; H 4.65; N
6.19.
(E)-4-Ethoxy-1,1-difluoro-1-(p-tolyl)but-3-en-2-one (1g). Yield 649 mg
(54%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 12.3 Hz,
1H), 7.43 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 5.93 (d, J = 12.3
Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 188.8 (t, J = 31.3 Hz), 166.2, 141.0, 130.3
(t, J = 26.0 Hz), 129.4, 125.6 (t, J = 6.1 Hz), 116.3 (t, J = 253 Hz), 99.0,
68.5, 21.4, 14.5. 19F NMR (376 MHz, CDCl3) δ –106.4. GC/MS (EI): m/z
(E)-4-Ethoxy-1,1-difluoro-1-(1-methyl-1H-pyrazol-5-yl)but-3-en-2-one
(1r). Yield 886 mg (77%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.84
(d, J = 12.3 Hz, 1H), 7.42 (s, 1H), 6.43 (s, 1H), 5.92 (d, J = 12.3 Hz, 1H),
4.04 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 186.5 (t, J = 30.0 Hz), 167.1, 138.2, 134.1 (t, J =
31.2 Hz), 112.3 (t, J = 251 Hz), 107.8 (t, J = 3.8 Hz), 98.6, 68.8, 38.6,
14.5. 19F NMR (376 MHz, CDCl3) δ –103.4. GC/MS (EI): m/z = 131 [1-
methyl-1H-pyrazol-5-ylCF2]+, 211 [M–F]+, 230 [M]+. Anal. Calcd. for
=
141 [p-MeC6H4CF2]+, 221 [M–F]+, 240 [M]+. Anal. Calcd. for
C13H14F2O2: C 64.99; H 5.87. Found: C 64.78; H 5.55.
(E)-4-Ethoxy-1,1-difluoro-1-(m-tolyl)but-3-en-2-one (1h). Yield 961 mg
(80%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 12.3 Hz,
1H), 7.35 (d, J = 6.4 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.26 – 7.21 (m, 1H),
5.94 (d, J = 12.3 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.32 (t, J
= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 188.7 (t, J = 31.1 Hz), 166.3,
138.7, 133.1 (t, J = 25.6 Hz), 131.5, 128.6, 126.2 (t, J = 6.0 Hz), 122.7 (t,
J = 6.2 Hz), 116.2 (t, J = 253 Hz), 98.9, 68.5, 21.5, 14.5. 19F NMR (376
MHz, CDCl3) δ –106.7. GC/MS (EI): m/z = 141 [m-MeC6H4CF2]+, 221 [M–
F]+, 240 [M]+. Anal. Calcd. for C13H14F2O2: C 64.99; H 5.87. Found: C
65.34; H 6.18.
C10H12F2N2O2: C 52.17; H 5.25; N 12.17. Found: C 52.06; H 4.89; N
12.20
(E)-4-Ethoxy-1,1-difluoro-1-(thiazol-2-yl)but-3-en-2-one (1s). Yield
910 mg (78%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.93 – 7.87 (m,
1H), 7.86 (d, J = 12.3 Hz, 1H), 7.54 (d, J = 3.1 Hz, 1H), 6.08 (d, J = 12.3
Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 186.1 (t, J = 28.8 Hz), 167.0, 160.8 (t, J = 33.0 Hz), 144.0,
122.4, 112.42 (t, J = 253 Hz), 99.0, 68.6, 14.4. 19F NMR (376 MHz,
CDCl3) δ –99.9. GC/MS (EI): m/z = 134 [thiazol-2-ylCF2]+, 214 [M–F]+,
233 [M]+. Anal. Calcd. for C9H9F2NO2S: C 46.35; H 3.89; N 6.01; S 13.75.
Found: C 46.36; H 4.21; N 5.97; S 14.10.
(E)-4-Ethoxy-1,1-difluoro-1-(o-tolyl)but-3-en-2-one (1i). Yield 613 mg
(51%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 12.3 Hz,
1H), 7.56 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.3 Hz,
1H), 7.20 (d, J = 7.3 Hz, 1H), 5.89 (d, J = 12.3 Hz, 1H), 3.98 (q, J = 7.1
Hz, 2H), 2.35 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 188.2 (t, J = 31.2 Hz), 166.2, 136.9 (t, J = 3.2 Hz), 132.0, 131.4
(t, J = 23.5 Hz), 130.7, 126.3 (t, J = 9.0 Hz), 126.0, 116.8 (t, J = 253 Hz),
99.3, 68.5, 20.1, 14.5. 19F NMR (376 MHz, CDCl3) δ –104.4. GC/MS (EI):
m/z = 141 [o-MeC6H4CF2]+, 221 [M–F]+, 240 [M]+. Anal. Calcd. for
C13H14F2O2: C 64.99; H 5.87. Found: C 65.09; H 5.54.
(E)-4-Ethoxy-1,1-difluoro-1-(4-fluorophenyl)-3-methylbut-3-en-2-one
(1t). Yield 994 mg (77%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.62
(s, 1H), 7.50 (dd, J = 8.3, 5.3 Hz, 2H), 7.11 (t, J = 8.3 Hz, 2H), 4.10 (q, J
= 7.1 Hz, 2H), 1.75 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 188.4 (t, J = 30.3 Hz), 164.0 (d, J = 250 Hz), 163.8 (t, J = 7.8
Hz), 130.4 (td, J = 25.8, 3.0 Hz), 127.9 (dt, J = 8.6, 6.1 Hz), 117.1 (t, J =
253 Hz), 115.8 (d, J = 22.0 Hz), 113.1, 71.1, 15.4, 8.7. 19F NMR (470
MHz, CDCl3) δ –94.3, –110.2 – –110.7 (m). GC/MS (EI): m/z = 145 [p-
FC6H4CF2]+, 258 [M]+. Anal. Calcd. for C13H13F3O2: C 60.46; H 5.07.
Found: C 60.81; H 4.85.
(E)-4-Ethoxy-1,1-difluoro-1-(4-fluoro-2-methylphenyl)but-3-en-2-one
(1j). Yield 788 mg (61%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.81
(d, J = 12.3 Hz, 1H), 7.55 (dd, J = 8.4, 5.8 Hz, 1H), 7.02 – 6.80 (m, 2H),
5.91 (d, J = 12.3 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.35 (t, J
= 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 187.9 (t, J = 31.5 Hz), 166.4,
(E)-1,1-Difluoro-1-(4-fluorophenyl)-4-methoxypent-3-en-2-one (1u).
Yield 1.05 g (86%). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.56 (dd,
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
J = 8.4, 4.8 Hz, 2H), 7.11 (t, J = 8.4 Hz, 2H), 5.82 (s, 1H), 3.73 (s, 3H),
2.34 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 187.6 (t, J = 29.7 Hz), 179.6,
164.1 (d, J = 250 Hz), 129.8 (t, J = 26.3 Hz), 128.0 (dd, J = 14.7, 6.3 Hz),
116.1 (t, J = 255 Hz), 115.8 (d, J = 22.1 Hz), 92.5, 56.3, 20.8. 19F NMR
(470 MHz, CDCl3) δ –104.8, –110.3– –110.7 (m). GC/MS (EI): m/z = 145
[p-FC6H4CF2]+, 244 [M]+. Anal. Calcd. for C12H11F3O2: C 59.02; H 4.54.
Found: C 59.37; H 4.71.
229/231 [M+H]+. Anal. Calcd. for C10H7F3N2: C 56.61; H 3.33; N 13.2.
Found: C 56.85; H 3.15; N 12.99.
5-((4-Bromophenyl)difluoromethyl)-1H-pyrazole (5d). Yield 229 mg
(84%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 13.25 (br s, 1H), 7.57
(d, J = 8.4 Hz, 2H), 7.50 – 7.43 (m, 3H), 6.42 (d, J = 1.9 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 148.5 (t, J = 32.8 Hz), 135.9 (t, J = 27.9 Hz),
131.8, 130.1, 127.7 (t, J = 5.4 Hz), 124.9, 117.8 (t, J = 238 Hz), 104.3 (t,
J = 2.7 Hz). 19F NMR (470 MHz, CDCl3) δ –87.8. LC/MS (CI): m/z =
253/255 [M–F]+, 273/275 [M+H]+. Anal. Calcd. for C10H7BrF2N2: C 43.98;
H 2.58; N 10.26; Br 29.26. Found: C 44.25; H 2.76; N 10.48; Br 29.06.
1-(4,5-Dihydrofuran-3-yl)-2,2-difluoro-2-(4-fluorophenyl)ethanone
(1v). Yield 1.06 g (88%). Colorless solid; mp 80–83 °C. 1H NMR (400
MHz, CDCl3) δ 7.67 (s, 1H), 7.55 (dd, J = 8.4, 5.3 Hz, 2H), 7.12 (t, J = 8.4
Hz, 2H), 4.56 (t, J = 9.8 Hz, 2H), 2.90 (t, J = 9.8 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 184.9 (t, J = 32.6 Hz), 164.2 (d, J = 251 Hz), 162.5 (t, J =
9.7 Hz), 129.6 (td, J = 26.1, 3.1 Hz), 127.9 (dt, J = 8.7, 6.2 Hz), 116.4 (t,
J = 253 Hz), 115.9 (d, J = 22.1 Hz), 115.2, 73.2, 27.6. 19F NMR (470 MHz,
CDCl3) δ –99.4, –110.1 – –110.2 (m). GC/MS (EI): m/z = 145 [p-
FC6H4CF2]+, 223 [M–F]+, 242 [M]+. Anal. Calcd. for C12H9F3O2: C 59.51;
H 3.75. Found: C 59.35; H 4.09.
5-(Difluoro(4-nitrophenyl)methyl)-1H-pyrazole (5e). Yield 203 mg
(85%). Brownish solid; mp 83–86 °C. 1H NMR (400 MHz, CDCl3) δ 12.67
(br s, 1H), 8.28 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 7.63 – 7.57
(m, 1H), 6.49 (d, J = 2.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 149.1,
148.2 (t, J = 32.7 Hz), 142.8 (t, J = 28.0 Hz), 130.3, 127.2 (t, J = 5.5 Hz),
123.8, 117.2 (t, J = 239 Hz), 104.3. 19F NMR (376 MHz, CDCl3) δ –89.3.
LC/MS (CI): m/z = 240 [M+H]+. Anal. Calcd. for C10H7F2N3O2: C 50.22; H
2.95; N 17.57. Found: C 49.88; H 3.30; N 17.34.
1-(3,4-Dihydro-2H-pyran-5-yl)-2,2-difluoro-2-(4-fluorophenyl)-
ethanone (1w). Yield 948 mg (74%). Yellowish oil. 1H NMR (400 MHz,
CDCl3) δ 7.88 (s, 1H), 7.51 (dd, J = 8.5, 5.3 Hz, 2H), 7.11 (t, J = 8.5 Hz,
2H), 4.10 (t, J = 4.9 Hz, 2H), 2.28 (t, J = 6.3 Hz, 2H), 1.89 (p, J = 6.1 Hz,
2H). 13C NMR (126 MHz, CDCl3) δ 187.5 (t, J = 30.6 Hz), 164.1 (d, J =
250 Hz), 161.8 (t, J = 9.1 Hz), 130.2 (td, J = 25.8, 3.0 Hz), 127.9 (dt, J =
8.6, 6.1 Hz), 116.9 (t, J = 253 Hz), 115.8 (d, J = 22.1 Hz), 112.4, 67.5,
21.0, 18.6. 19F NMR (470 MHz, CDCl3) δ –95.2, –109.7 – –110.8 (m).
GC/MS (EI): m/z = 145 [p-FC6H4CF2]+, 237 [M–F]+, 256 [M]+. Anal. Calcd.
for C13H11F3O2: C 60.94; H 4.33. Found: C 60.86; H 4.22.
2-(Difluoro(1H-pyrazol-5-yl)methyl)pyridine (5q). Yield 142 mg (73%).
Brownish solid; mp 76–78 °C. 1H NMR (400 MHz, CDCl3) δ 13.31 (br s,
1H), 8.64 (d, J = 4.5 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz,
1H), 7.57 (d, J = 1.0 Hz, 1H), 7.38 – 7.29 (m, 1H), 6.51 (d, J = 1.8 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 154.6 (t, J = 29.5 Hz), 149.6, 147.5 (t,
J = 31.7 Hz), 137.3, 130.4, 125.0, 120.5 (t, J = 4.2 Hz), 116.3 (t, J = 239
Hz), 104.1. 19F NMR (376 MHz, CDCl3) δ –93.5. LC/MS (CI): m/z = 196
[M+H]+. Anal. Calcd. for C9H7F2N3: C 55.39; H 3.62; N 21.53. Found: C
55.75; H 3.62; N 21.41.
General procedure for the preparation of pyrazoles 5a–e and 5q–v.
To a solution of enone 1a–e or 1q–v (1.00 mmol) in HOAc (10 mL),
hydrazine hydrate (551 mg, 1.10 mmol) was added, and the mixture was
stirred at rt for 12 h. Then the solvent was evaporated in vacuo, and the
residue was dissolved in CH2Cl2 (10 mL). The organic layer was washed
with H2O (210 mL), saturated aq NaHCO3 (210 mL), and brine (10 mL),
dried over Na2SO4, and evaporated in vacuo to give the target product 5.
5-(Difluoro(1H-pyrazol-5-yl)methyl)-1-methyl-1H-pyrazole (5r). Yield
154 mg (78%). Colorless oil. 1H NMR (400 MHz, CDCl3) δ 13.26 (br s,
1H), 7.52 (d, J = 1.4 Hz, 1H), 7.42 (s, 1H), 6.52 (d, J = 1.9 Hz, 1H), 6.35
(s, 1H), 3.94 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.2 (t, J = 32.0 Hz),
137.9, 137.5 (t, J = 32.1 Hz), 130.3, 114.1 (t, J = 234 Hz), 108.4 (t, J =
3.5 Hz), 104.3, 38.5. 19F NMR (376 MHz, CDCl3) δ –86.1. LC/MS (CI):
m/z = 199 [M+H]+. Anal. Calcd. for C8H8F2N4: C 48.49; H 4.07; N 28.27.
Found: C 48.17; H 3.91; N 27.90
5-(Difluoro(phenyl)methyl)-1H-pyrazole (5a). Yield 151 mg (78%).
Yellowish oil. 1H NMR (500 MHz, CDCl3) δ 13.58 (br s, 1H), 7.62 (d, J =
6.7 Hz, 2H), 7.50 – 7.41 (m, 4H), 6.41 (d, J = 2.0 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 148.8 (t, J = 32.7 Hz), 136.9 (t, J = 27.4 Hz), 130.4, 130.1,
128.6, 125.9 (t, J = 5.5 Hz), 118.3 (t, J = 238 Hz), 104.2 (t, J = 2.7 Hz).
19F NMR (376 MHz, CDCl3) δ –87.4. LC/MS (CI): m/z = 175 [M–F]+, 193
[M–H]–. Anal. Calcd. for C10H8F2N2: C 61.85; H 4.15; N 14.43. Found: C
61.72; H 4.06; N 14.57.
2-(Difluoro(1H-pyrazol-5-yl)methyl)thiazole (5s). Yield 173 mg (86%).
Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 13.53 (br s, 1H), 8.04 – 7.75
(m, 1H), 7.63 (s, 1H), 7.50 (d, J = 3.1 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H).
13C NMR (126 MHz, CDCl3) δ 163.9 (t, J = 35.4 Hz), 146.6 (t, J = 31.8
Hz), 143.8, 130.4, 121.8, 114.8 (t, J = 238 Hz), 104.3. 19F NMR (470
MHz, CDCl3) δ –83.5. LC/MS (CI): m/z = 202 [M+H]+. Anal. Calcd. for
C7H5F2N3S: C 41.79; H 2.51; N 20.89; S 15.94. Found: C 41.85; H 2.57;
N 21.06; S 15.63.
5-(Difluoro(4-fluorophenyl)methyl)-1H-pyrazole (5b). Yield 172 mg
(81%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 13.49 (br s, 1H), 7.59
(dd, J = 8.3, 5.4 Hz, 2H), 7.51 – 7.46 (m, 1H), 7.11 (t, J = 8.3 Hz, 2H),
6.41 (d, J = 1.8 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.9 (d, J = 250
Hz), 148.7 (t, J = 32.3 Hz), 132.9 (td, J = 28.0, 3.0 Hz), 130.1, 128.2 (dt,
5-(Difluoro(4-fluorophenyl)methyl)-4-methyl-1H-pyrazole (5t). Yield
185 mg (82%). Yellowish oil. 1H NMR (400 MHz, CDCl3) δ 13.12 (br s,
1H), 7.55 (dd, J = 8.0, 5.5 Hz, 2H), 7.26 (s, 1H), 7.11 (t, J = 8.5 Hz, 2H),
1.99 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.7 (d, J = 250 Hz), 145.5 (t,
J = 31.9 Hz), 132.8 (td, J = 28.3, 3.2 Hz), 130.0, 128.1 (dt, J = 8.8, 5.3
Hz), 118.7 (t, J = 238 Hz), 115.5 (d, J = 22.0 Hz), 114.34, 8.4. 19F NMR
(376 MHz, CDCl3) δ –87.1, –110.6 – –111.4 (m). LC/MS (CI): m/z = 207
[M–F]+, 227 [M+H]+. Anal. Calcd. for C11H9F3N2: C 58.41; H 4.01; N 12.38.
Found: C 58.28; H 4.16; N 12.19.
J = 8.8, 5.4 Hz), 117.9 (t, J = 238 Hz), 115.6 (d, J = 22.0 Hz), 104.3. 19
F
NMR (470 MHz, CDCl3) δ –86.4, –110.5 – –111.4 (m). LC/MS (CI): m/z =
193 [M–F]+, 211 [M–H]–. Anal. Calcd. for C10H7F3N2: C 56.61; H 3.33; N
13.20. Found: C 56.41; H 2.99; N 13.39.
5-((4-Chlorophenyl)difluoromethyl)-1H-pyrazole (5c). Yield 199 mg
(87%). Yellowish oil. 1H NMR (500 MHz, CDCl3) δ 13.41 (br s, 1H), 7.54
(d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 7.41 (d, J = 8.2 Hz, 2H), 6.42 (s, 1H).
13C NMR (126 MHz, CDCl3) δ 148.5 (t, J = 32.6 Hz), 136.6, 135.4 (t, J =
27.9 Hz), 130.1, 128.9, 127.4 (t, J = 5.3 Hz), 117.8 (t, J = 238 Hz), 104.2.
19F NMR (470 MHz, CDCl3) δ –87.5. LC/MS (CI): m/z = 209/211 [M–F]+,
5-(Difluoro(4-fluorophenyl)methyl)-3-methyl-1H-pyrazole (5u). Yield
188 mg (83%). Yellowish solid; mp 50–53 °C. 1H NMR (400 MHz, CDCl3)
δ 12.03 (br s, 1H), 7.52 (dd, J = 8.5, 5.4 Hz, 2H), 7.04 (t, J = 8.5 Hz, 2H),
6.13 (s, 1H), 2.17 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.7 (d, J = 249
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10.1002/ejoc.201901833
European Journal of Organic Chemistry
FULL PAPER
Hz), 149.2 (t, J = 33.2 Hz), 140.9, 133.0 (td, J = 28.0, 3.1 Hz), 128.1 (dt,
J = 8.7, 5.4 Hz), 117.7 (t, J = 237 Hz), 115.4 (d, J = 21.9 Hz), 103.2, 10.7.
19F NMR (470 MHz, CDCl3) δ –86.8, –110.7 – –112.2 (m). LC/MS (CI):
m/z = 207 [M–F]+, 227 [M+H]+. Anal. Calcd. for C11H9F3N2: C 58.41; H
4.01; N 12.38. Found: C 58.74; H 3.82; N 12.29.
The residue was diluted with H2O (10 mL) and EtOAc (10 mL), the
organic layer was separated, dried over Na2SO4, and evaporated in
vacuo. The residue was recrystallized from hexanes. Yield 201 mg (41%).
Yellowish solid; mp 181–183 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d,
J = 4.0 Hz, 1H), 7.60 (t, J = 6.7 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.02 (s,
2H), 6.93 – 6.84 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.5, 163.1
(d, J = 248 Hz), 162.5 (t, J = 31.0 Hz), 160.5, 131.6 (t, J = 27.4 Hz),
128.1 (dt, J = 8.9, 5.8 Hz), 117.4 (t, J = 243 Hz), 115.8, 104.9. 19F NMR
(470 MHz, DMSO-d6) δ –95.4, –109.9. LC/MS (CI): m/z = 240 [M+H]+.
Anal. Calcd. for C11H8F3N3: C 55.23; H 3.37; N 17.57. Found: C 55.61; H
3.49; N 17.55.
2-(5-(Difluoro(4-fluorophenyl)methyl)-1H-pyrazol-4-yl)ethanol
(5v).
Yield 146 mg (57%). Yellowish solid; mp 101–102 °C. 1H NMR (400 MHz,
DMSO-d6) δ 12.93 (br s, 1H), 7.68 (s, 1H), 7.56 (dd, J = 8.3, 5.6 Hz, 2H),
7.30 (t, J = 8.3 Hz, 2H), 4.66 (t, J = 5.2 Hz, 1H), 3.54 (q, J = 6.9 Hz, 2H),
2.66 (t, J = 6.9 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 162.9 (d, J =
247 Hz), 144.9 (t, J = 33.4 Hz), 133.0 (td, J = 27.1, 2.2 Hz), 129.3, 128.2
(dd, J = 14.0, 5.3 Hz), 119.3 (t, J = 235 Hz), 115.5, 115.2 (d, J = 22.0 Hz),
61.3, 27.2. 19F NMR (470 MHz, DMSO-d6) δ –83.5, –110.5 – –111.3 (m).
LC/MS (CI): m/z = 257 [M+H]+. Anal. Calcd. for C12H11F3N2O: C 56.25; H
4.33; N 10.93. Found: C 55.97; H 4.11; N 10.55.
Acknowledgements
The work was funded by Enamine Ldt. O.O.G. was also funded
by Ministry of Education and Science of Ukraine (Grant No.
19BF037-03). The authors thank Prof. Andrey A. Tolmachev for
his encouragement and support, and Dr. Andriy Kozytskyi for
NOE measurements.
5-(Difluoro(4-fluorophenyl)methyl)-4,5-dihydroisoxazol-5-ol
(6).
Na2CO3 (607 mg, 5.73 mmol) was added to a mixture of enone 1b (2.00
g, 8.19 mmol) and hydroxylamine hydrochloride (743 mg, 10.7 mmol) in
H2O (15 mL) at rt. The resulting mixture was stirred at rt for 12 h, and
then t-BuOMe was added. The organic layer was separated, dried over
Na2SO4, and evaporated in vacuo. The residue was recrystallized from
CHCl3. Yield 1.41 g (74%). Yellowish solid; mp 139–141 °C. 1H NMR
(500 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.64 (dd, J = 8.7, 6.1 Hz, 2H), 7.54
(d, J = 1.3 Hz, 1H), 7.31 (t, J = 8.7 Hz, 2H), 3.43 (d, J = 19.0 Hz, 1H),
2.94 (d, J = 19.0 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.3 (d, J =
247 Hz), 147.9, 129.4 (dd, J = 15.1, 6.4 Hz), 129.1 (td, J = 26.4, 3.2 Hz),
118.6 (t, J = 249 Hz), 115.0 (d, J = 22.0 Hz), 104.3 (t, J = 33.1 Hz), 42.9.
19F NMR (376 MHz, DMSO-d6) δ –105.1 (d, J = 14.7 Hz), –110.5. LC/MS
(CI): m/z = 232 [M+H]+. Anal. Calcd. for C10H8F3NO2: C 51.96; H 3.49; N
6.06. Found: C 52.23; H 3.74; N 6.42.
Keywords: organofluorine compounds, heterocycles,
diarylmethanes, condensation
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FULL PAPER
Synthesis of β-alkoxyenones
decorated with (het)aryl difluoromethyl
substituents, as well as utility of these
substrates for heterocyclizations
leading to fluorinated pyrazoles,
oxazoles and pyrimidines is
described.
Organofluorine compounds
Maksym Ya. Bugera,
Karen V. Tarasenko,
Ivan S. Kondratov,* Igor I. Gerus,
Bohdan V. Vashchenko,
Viktor E. Ivasyshyn,
Oleksandr O. Grygorenko*
Page No. – Page No.
(Het)aryl difluoromethyl -substituted
β-alkoxyenones: synthesis and
heterocyclizations
This article is protected by copyright. All rights reserved.