Halogenative difluorohomologation of ketones

Article abstract of DOI:10.1021/acs.joc.5b00904

A method for the difluorohomologation of ketones accompanied by halogenation of a C-H bond is described. The reaction involves silylation, difluorocarbene addition using Me₃SiCF₂Br activated by a bromide ion, and halogenation of intermediate cyclopropanes with N-bromo- or N-iodosuccinimide. The whole process is performed without isolation of intermediates. The resulting α,α-difluoro-β-halo-substituted ketones can be readily converted into fluorine containing pyrazole derivatives and oxetanes.

Full text of DOI:10.1021/acs.joc.5b00904

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Article
Halogenative difluorohomologation of ketones
Oleg V. Fedorov, Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00904 • Publication Date (Web): 12 May 2015
Downloaded from http://pubs.acs.org on May 15, 2015
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The Journal of Organic Chemistry
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Halogenative difluorohomologation of ketones
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Oleg V. Fedorov, Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova, Alexander D.
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Dilman*
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N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
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Federation
adil25@mail.ru
(a) silylation
F
F
(b)
C
O
O
X
(c) X
X = Br, I
R2
R1
R1
R2
F
F
Abstract. A method for the difluorohomologation of ketones accompanied by halogenation of a Cꢀ
H bond is described. The reaction involves silylation, difluorocarbene addition using Me3SiCF2Br
activated by bromide ion, and halogenation of intermediate cyclopropanes with Nꢀbromoꢀ or Nꢀ
iodosuccinimide. The whole process is performed without isolation of intermediates. The resulting
α,αꢀdifluoroꢀβꢀhaloꢀsubstituted ketones can be readily converted into fluorine containing pyrazole
derivatives and oxetanes.
Introduction
α,αꢀDifluoroketones represent an important subclass of organofluorine compounds, useful for
medicinal chemistry,1,2 and other fields.3 Due to significant electron withdrawing effect of two
fluorine atoms, the carbonyl group can react with water to form hydrate adducts. The hydration not
only alters the polarity of the starting molecule, but also changes the shape of the carbonyl
functionality from planar to tetrahedral. The hydrate adducts can mimic the transition state of
peptide hydrolysis thereby serving as inhibitors of proteases. This phenomenon has been exploited
for the identification of inhibitors of various enzymes.2aꢀc Moreover, other mechanisms of biological
activities of α,αꢀdifluorinated carbonyl compounds have been discovered.2d,e
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Conventional methods for the synthesis of α,αꢀdifluoroketones involve functionalization of
difluorocarbonyl fragment4 or electrophilic fluorination of parent ketones and their derivatives5
(Scheme 1). Recently, we proposed a concept for difluorohomologation of ketones 1 based on
generation of silyloxyꢀsubstituted cyclopropanes 2 followed by their protonation.6 Herein we report
that cyclopropanes 2 may undergo halogenation leading to βꢀhalogenꢀsubstituted α,αꢀ
difluoroketones 3, and demonstrate the utility of the latter for the preparation of other gemꢀ
difluorinated products.
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Scheme 1. Synthesis of α,αꢀdifluoroketones.
Conventional methods
O
Y R2
X
R1
+
O
F
F
R2
R1
O
F
F
R2
+
" F
"
R1
O
Our approach
O
H
R1
R2
(a) silylation
(b) CF2
F
F
OSiMe3
R2
Previous work
R2
R1
F
R1
1
2
F
O
Hal
R2
Hal
R1
F
F
3
This work
The halogenation of nonꢀfluorinated cyclopropanols and their derivatives was well documented,7
and frequently employed in combination with subsequent halogen elimination to afford α,βꢀ
unsaturated ketones.7,8 While halogen elimination is facile in nonꢀfluorinated series,9 it is not
feasible for products 3 due to the presence of two fluorine atoms. However, for halogenation of
fluorinated cyclopropyl ethers, the data available in the literature are scarce. Thus, in a single
example, the reaction of a cyclopropane, derived from difluorocarbene addition to 2ꢀ
methoxypropene, with an excess of bromine in water was reported to afford a tribromoꢀsubstituted
product (the primary ringꢀopened product underwent subsequent dibromination at methyl group).10
On the other hand, perfluorinated cyclopropyl ethers reacted with bromine at very harsh conditions
(temperatures exceeding 150 °C, long reaction times).11
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Cyclopropanes 2 can be accessed by difluorocarbene addition to silyl enol ethers. However, the
limited stability of cyclopropanes 2 is a key problem determining the scope of their applications.6
Indeed, compounds 2 are prone to transformation into αꢀfluoroenones, and this process can proceed
either at elevated temperatures,12 or under neutral or basic conditions even at room temperature.13
Conventional chromatographic isolation of 2 may also be problematic.6a Therefore, compounds 2
must be generated under mildest conditions possible, and subsequently immediately employed,
preferably in the same reaction flask.
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Results and Discussion
Wide variety of reagents for the generation of difluorocarbene have been described in the
literature.14 However, a silicon reagent, (bromodifluoromethyl)trimethylsilane (Me3SiCF2Br), was
selected for our study on the following reasons: (a) it can effect difluorocyclopropanation of alkenes
under virtually nonꢀbasic and anhydrous conditions;15,16 (b) it is airꢀstable and easyꢀtoꢀhandle
compound;17 (c) it is now commercially available from several suppliers, or can be prepared in one
or two steps from readily available (trifluoromethyl)trimethylsilane.15a,17a
Silyl enol ether 4a, derived from pꢀbromoacetophenone, was selected as a model substrate. First,
enol ether 4a was converted into cyclopropane 2a using Me3SiCF2Br and
hexamethylphosphoramide (HMPA) according to previously developed procedure,6a followed by
addition of bromine (Table 1). However, there was only 19% conversion of 2a to 3a within 10
minutes, which did not increase with time even on mild heating (entry 1). The use of Nꢀ
bromosuccinimide (NBS) gave similar result (entry 2). Presumably, Lewis basic HMPA inhibits
bromination reaction.18 Then we switched to cyclopropanation conditions involving bromide ion as
an activator of the silicon reagent. It was reported that combination of Me3SiCF2Br with catalytic
amounts (3 mol %) of Bu4NBr works well at 110 °C for various alkenes.15a In our case, the
moderate stability of cyclopropane 2a prompted us to employ lower temperatures with concomitant
increase of concentration of the bromide activator. When the reaction was performed in hot 1,2ꢀ
dichloroethane (82 °C) using Me3SiCF2Br and 0.2 equiv of Bu4NBr, the cyclopropane was formed
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in about 60% yield. Surprisingly, 19F NMR analysis indicated the formation of less reactive
Me3SiCF2Cl, which likely originates from initial Br/Cl exchange between bromide ion and
dichloroethane followed by Br/Cl exchange between appeared chloride ion and Me3SiCF2Br.19
Nevertheless, subsequent addition of NBS gave rapid conversion of 2a into 3a (entry 3). To exclude
halogen exchange, acetonitrile was used as a solvent, with the cyclopropanation being complete
within 1.5 h at 80 °C. After cooling to room temperature, NBS was added that within 10 minutes
effected clean conversion of 2a into product 3a finally isolated in 89% yield (entry 4).
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Table 1. Preparation of ketone 3a.
OSiMe3
F
F
O
Br
C
OSiMe3
"Br
(b)
"
Ar
Ar
3a
Ar
(a)
F
F
F
F
2a
4a, Ar = 4-BrC6H4
no Conditions
2a : 3aa Yield of
3a, %a
1
2
3
4
(a) TMSCF2Br (2 equiv),
81 : 19
16
13
60
89b
HMPA (3 equiv), dioxane, rt, 2h
(b) Br2 (1.5 equiv), rt, 10 min
(a) TMSCF2Br (2 equiv),
75 : 25
HMPA (3 equiv), dioxane, rt, 2h
(b) NBS (1.5 equiv), rt, 10 min
(a) TMSCF2Br (1.3 equiv), Bu4NBr – : 100
(0.2 equiv), dichloroethane, ꢀ, 2 h
(b) NBS 1.3 equiv, rt, 10 min
(a) TMSCF2Br (1.5 equiv), Bu4NBr – : 100
(0.2 equiv); MeCN, 80 °C, 1.5 h
(b) NBS 1.3 equiv, rt, 10 min
a Determined by 19F NMR of reaction mixtures.
b Isolated yield
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We also attempted chlorination of intermediate cyclopropane 2a using Nꢀchlorosuccinimide
(NCS) (Scheme 2). Thus, when NCS was added to the cyclopropane generated from enol ether 4a
under typical conditions, only brominated product along with Me3SiCF2Cl were observed by 19F
NMR. Apparently, the combination of NCS and bromide ion served as a brominating reagent along
with the formation of chloride ion, which reacted with excess of Me3SiCF2Br. Unfortunately, use of
combination Me3SiCF2Cl/chloride/NCS provided a complex mixture containing significant
amounts of unreacted cyclopropane 2a along with its decomposition product — αꢀfluoroenone 5a,
and a minor amount of expected chlorination compound.
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Scheme 2. Reactions using NCS.
(a) Me3SiCF2Br, Bu4NBr
O
Br
MeCN, 80 °C, 1.5 h
Me3SiCF2Cl
+
F
Ar
3a
(b) NCS, rt, 10 min
F
F
4a
(a) Me3SiCF2Cl, BnNEt3Cl
O
O
Cl
MeCN, ꢀ, 2 h
+
2a +
Ar
Ar
(b) NCS, rt, 10 min
F
F
5a
ratio 10 : 3 : 1
Under the optimized conditions, a series of silyl enol ethers 4 were converted into bromoꢀ or
iodoꢀsubstituted products 3 employing NBS or NIS, respectively (Table 2). High yields of products
were obtained from enol ethers derived from pꢀmethoxyacetophenone, αꢀtetralone and
cyclohexanone.
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Table 2. Synthesis of 3 from silyl enol ethers 4.
3
4
5
O
6
7
8
9
(a) Me3SiCF2Br, Bu4NBr
MeCN, 80 °C, 1.5 h
OSiMe3
R2
F
F
R1
R1
(b) NXS, rt, 10 min
R2
X
4
3
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substrate
X
product
yield of
3, %a
OSiMe3
O
F
Br
4b Br
3b 95
3c 82
3d 97
F
MeO
MeO
O
F
I
4b
I
F
MeO
O
OSiMe3
4c Br
F
F
F
Br
O
4c
I
I
3e
3f
85
80
F
I
OSiMe3
O
F
4d
F
I
a Isolated yield
Despite the fact that silyl enol ethers can be readily prepared from ketones,20 we decided to
perform the whole sequence of transformations of ketones into final products without timeꢀ
consuming isolation and purification of enol ethers. For this purpose, ketones 1 were silylated using
chlorosilane/NaI/NEt3 combination,20a and the crude silyl enol ethers 4, which were produced in
virtually quantitative yields, were subjected to further reactions without purification (Table 3). This
halogenative difluorohomologation worked well for acyclic and cyclic ketones affording final
products 3 in good overall yields.
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Table 3. Synthesis of 3 from ketones 1.
3
4
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9
(a) Me3SiCl (1.3 equiv), NaI (1.4 equiv),
NEt3(1.5 equiv) , rt, 12 h
O
(b) Me3SiCF2Br (1.5 equiv)
O
F
F
R1
Bu4NBr (0.2 equiv), 80 °C, 1.5 h
R3
R1
R2
X
R2
(c) NXS (1.3 equiv), rt, 10 min
R3
1
3
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no. substrate
1
X
product
yield of
3, %a
O
O
Br
1a Br
3a 78
3b 89
3c 80
F
F
Br
Br
O
O
Br
2
1b Br
1b I
F
F
MeO
MeO
O
I
3
F
F
MeO
O
O
Br
4
1e Br
1f Br
3g 92
3h 65
Ph
Ph
F
F
5b
6c
O
O
Br
F
F
O
O
Br
1g Br
3i 56
F
F
O2N
O2N
O
O
Br
7
8
1h Br
1h I
3j 91
3k 90
F
F
O
I
F
F
9b
1i Br
1j Br
3l 69
3m 71
O
O
Br
Ph
Ph
F
F
10b
O
O
Br
F
F
MeO
MeO
O
O
11
12
13
1c Br
1d I
F
3d 85
3f 77
3nd 76
F
Br
O
O
F
F
I
O
1k I
O
F
F
I
O
O
14
1l Br
3o 96
F
F
Br
a Isolated yield based on ketone 1.
b Cyclopropanation conditions: 70 °C, 2.5 h.
c Cyclopropanation conditions: Me3SiCF2Br (2 equiv), Bu4NBr (0.3 equiv), 80 °C, 2 h.
d Mixture of isomers 5:1.
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The key possible side reaction for the difluorohomologation process is the known rearrangement
of cyclopropanes 2 into fluoroenones 512 (Scheme 3). This rearrangement is favored by temperature
and proceeds during difluorocarbene addition step, whereas formed fluoroenones 5 undergo
bromination at the next step leading to byꢀproducts 6, which are difficult to get rid of by flash
chromatography. In particular, this side reaction was feasible for cyclopropanes 2 derived from
acyclic alkyl substituted ketones (R2 = Alk, entries 9 and 10). Similar processes were noted when
difluorocarbene addition is disfavored by sterics (R1 is orthoꢀsubstituted aryl group, entry 5) or
electronic effects (R1 contains pꢀnitro group, entry 6). For this reason, difluorocarbene addition for
substrates 1f,i,j (entries 5, 9, 10) was carried out at a bit milder conditions (70 °C, 2.5 h). For pꢀ
nitroacetophenone 1g, cyclopropanation was slow and, for complete conversion of silyl enol ether,
higher loading of Me3SiCF2Br and Bu4NBr was used (entry 6). In the latter case, fluoroenone
formation cannot be suppressed, and corresponding dibrominated byꢀproduct 6a was also isolated in
7% yield (see Scheme 3, structure 6, R1 = 4ꢀNO2C6H4, R2 = H).
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Scheme 3. Side reaction.
OSiMe3
R2
O
O
Br
NBS, Br
R1
F
R1
R2
R1
R2
F
Br
F
2
5
6
F
For silyl enol ether 4m, derived from deoxybenzoin 1m, cyclopropane 2m was unstable under
the cyclopropanation conditions (Scheme 4). As a result, the reaction of enol ether 4m afforded
fluoroenone 5m and product 7. The latter was formed from enone 5m by nucleophilic addition of
CF2Brꢀanion at the carbonyl group.17d
Scheme 4. Reaction of substrate 1m.
Me3SiCF2Br (3 equiv)
Me3SiCl, NaI
NEt3, rt, 12 h
Bu4NBr (0.4 equiv)
O
OSiMe3
Ph
MeCN, ꢀ, 10 h
Ph
Ph
Ph
O
1m
4m
F
F
F
OSiMe3
Ph
Me3SiO
Ph
Br
Ph
+
Ph
5m, 66%
Ph
F
Ph
F
F
2m
7, 14%
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Compounds 3 may provide easy access to fluorineꢀsubstituted heterocycles, as was exemplified
by reactions of ketone 3b (Scheme 5). Thus, treatment of 3b with phenylhydrazine and potassium
carbonate afforded either pyrazoline 8 or pyrazole 9 depending on reaction conditions. Addition of
a hydride or a Grignard reagent to the carbonyl group furnished alcohols 10, which under basic
conditions were cyclized into gemꢀdifluorinated oxetanes 11. It should be pointed out that no
methods have been described in the literature for the synthesis of 3,3ꢀdifluorinated oxetanes of this
type, whereas by our approach these interesting products21 can be straightforwardly obtained
starting from simple ketones.
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Scheme 5. Synthesis of heterocycles.
Ph
N N
rt, 12 h
Ar
MeOH
PhNHNH2
F
F
O
Br
8, 95%
K2CO3
Ar
Ph
rt, 12 h;
F
F
N N
F
130 °C, 1 h
3b, Ar = 4-MeOC6H4
Ar
DMF
9, 91%
NaBH4
O
OH Br
or MeMgI
K2CO3, DMF
90 °C, 4 h
3b
F
Ar
Ar
F
R
R
F
F
10a, R = H, 89%
10b, R = Me, 80%
11a, R = H, 78%
11b, R = Me, 74%
In summary, a practical method for halogenative difluorohomologation of ketones is described.
The process efficiency is determined by difluorocarbene addition step, which is performed in warm
acetonitrile by using a silicon reagent as a difluorocarbene source. At the same time, halogenation
of the cyclopropanes occurs rapidly and selectively affording ringꢀopened products. The whole
sequence can be conveniently performed without isolation of intermediate compounds. The
products of halogenative difluorohomologation can be converted into valuable fluorine substituted
heterocycles.
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Experimental section
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General Methods. All reactions were performed under an argon atmosphere. Acetonitrile was
distilled from CaH2 and stored over MS 4A. Hexamethylphosphoramide (HMPA) and
dimethylformamide (DMF) were distilled under vacuum from CaH2 and stored over MS 4A.
Column chromatography was carried out employing silica gel (230ꢀ400 mesh). Precoated silica gel
plates Fꢀ254 were used for thinꢀlayer analytical chromatography visualizing with UV and/or acidic
aq. KMnO4 solution. (Bromodifluoromethyl)trimethylsilane (Me3SiCF2Br)17a and compounds 4a-
d,m20a were prepared according to literature procedures.
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Reactions of silyl enol ethers 4a-d (General Procedure 1). Me3SiCF2Br (305 mg, 1.5 mmol,
1.5 equiv) and Bu4NBr (64.5 mg, 0.2 mmol, 0.2 equiv) were added to a solution of silyl enol ether 4
(1 mmol, 1 equiv) in MeCN (1 mL) at room temperature, and the mixture was stirred for 1.5 h at 80
°С. Then the mixture was cooled to room temperature, and NBS or NIS (1.3 mmol, 1.3 equiv) was
added, and the mixture was stirred for 10 min at room temperature. For the workup, the mixture was
diluted with water (8 mL) and aqueous phase was extracted with hexane (3×5 mL). The combined
organic layers were filtered through Na2SO4, concentrated under vacuum, and the residue was
purified by column chromatography.
Reactions of ketones 1a-h,i-l (General Procedure 2).
Preparation of silyl enol ether. NaI (210 mg, 1.4 mmol, 1.4 equiv) was placed in a tube, and
dried under vacuum using heat gun. After cooling to room temperature, the tube was filled with
argon. Then, MeCN (1 mL), ketone 1 (1 mmol, 1 equiv), and Et3N (152 mg, 1.5 mmol, 1.5 equiv)
were successively added. The mixture was cooled with ice/water bath, and Me3SiCl (1.66 mL, 13
mmol, 1.3 equiv) was added at 0 °С. The cooling bath was removed, and the mixture was stirred for
12 h at room temperature. Then, volatile components were evaporated under vacuum [the vacuum
of about 10ꢀ20 Torr was applied with heating in water bath at about 50 °C]. The solid residue was
washed with hexane (3×15 mL) [the hexane layers were decanted and filtered through a cotton
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plug]. The combined filtrates were concentrated under vacuum using rotary evaporator, furnishing
silyl enol ether which was used without purification.
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Reaction of silyl enol ethers. The crude silyl enol was transferred into a reaction tube, the tube
was evacuated and filled with argon. Then, MeCN (1 mL), Me3SiCF2Br (305 mg, 1.5 mmol, 1.5
equiv) and Bu4NBr (64.5 mg, 0.2 mmol, 0.2 equiv) were successively added at room temperature.
The mixture was stirred for 1.5 h at 80 °С (for substrates 1a-e,h,k,l) or 2.5 h at 70 °C (for substrates
1f,i,j), and then cooled to room temperature. NBS or NIS (1.3 mmol, 1.3 equiv) was added, and the
mixture was stirred for 10 min at room temperature. For the workup, the mixture was diluted with
water (8 mL) and aqueous phase was extracted with hexane (3×5 mL). The combined organic layers
were filtered through Na2SO4, concentrated under vacuum, and the residue was purified by column
chromatography.
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3-Bromo-1-(4-bromophenyl)-2,2-difluoropropan-1-one (3a). General procedure 1, yield 292 mg
(89%). General procedure 2, yield 257 mg (78%). Colorless crystals. Mp 45–46 °С. Rf 0.39
(hexane/EtOAc, 8:1). 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, 2H, J = 8.2 Hz), 7.66 (d, 2H, J = 8.2
Hz), 3.89 (t, 2H, JHꢀF = 14.7 Hz). 13C{1H} NMR (75 MHz, CDCl3), δ: 28.9 (t, J = 28.1 Hz), 115.3 (t,
J = 256.4 Hz), 130.3 (t, J = 3.4 Hz), 130.7, 131.7 (t, J = 3.4 Hz), 132.4, 186.9 (t, J = 31.0 Hz). 19F
NMR (282 MHz, CDCl3) δ: –100.5 (t, 2F, J = 14.7 Hz). Calcd for C9H7Br2F2O (327.95): C, 32.96;
H, 1.84. Found: C, 32.93; H, 1.91.
3-Bromo-2,2-difluoro-1-(4-methoxyphenyl)propan-1-one (3b). General procedure 1, yield 265
mg (95%). General procedure 2, yield 248 mg (89%). Colorless crystals. Mp 47–48 °С. Rf 0.36
(hexane/EtOAc, 8:1). 1H NMR (300 MHz, CDCl3) δ: 8.10 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 9.2 Hz,
1H), 3.89 (t, JHꢀF = 14.7 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3), δ: 29.7 (t, J = 28.2
Hz), 55.7, 114.3, 115.4 (t, J = 256.5 Hz), 124.4 (t, J = 3.3 Hz), 132.9 (t, J = 3.3 Hz), 165.0, 185.9 (t,
J = 29.9 Hz). 19F NMR (282 MHz, CDCl3) δ: –100.3 (t, 2F, J = 14.7 Hz). Calcd for C10H9BrF2O2
(279.08): C, 43.04; H, 3.25. Found: C, 42.74; H, 3.36.
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2,2-Difluoro-3-iodo-1-(4-methoxyphenyl)propan-1-one (3c). General procedure 1, yield 267 mg
(82%). General procedure 2, yield 262 mg (80%). Colorless crystals. Mp 55–56 °С. Rf 0.33
(hexane/EtOAc, 8:1). 1H NMR (300 MHz, CDCl3) δ: 8.08 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.8 Hz,
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2H), 3.89 (s, 3H), 3.75 (t, JHꢀF = 16.1 Hz, 2H). C{1H} NMR (75 MHz, CDCl3), δ: 1.3 (t, J = 27.6
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Hz), 55.8, 114.3, 115.9 (t, J = 255.1 Hz), 124.4 (t, J = 3.0 Hz), 133.0 (t, J = 3.5 Hz), 165.0, 185.3 (t,
J = 31.1 Hz). 19F NMR (300 MHz, CDCl3) δ: –94.8 (t, 2F, J = 16.1 Hz). Calcd for C10H9F2IO2
(326.08): C, 36.83; H, 2.78. Found: C, 36.77; H, 2.90.
7-Bromo-6,6-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (3d). General procedure 1,
yield 267 mg (97%). General procedure 2, yield 235 mg (85%). Yellow oil. Rf 0.32 (hexane/EtOAc,
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8:1). H NMR (300 MHz, CDCl3) δ: 7.68 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.36 (t, J =
7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.69–4.46 (m, 1H), 3.37 (dd, J = 16.5, 11.0 Hz, 1H), 2.94 (dd,
J = 16.5, 7.3 Hz, 1H), 2.70–2.37 (m, 2H). 13C NMR (75 MHz, CDCl3), δ: 30.8, 33.3 (t, J = 2.3 Hz),
49.5 (dd, J = 27.6, 23.0 Hz), 115.6 (dd, J = 253.4, 255.7 Hz), 127.3,130.2, 130.3, 133.2, 134.3,
140.5, 191.3 (dd, J = 28.8, 31.1 Hz). 19F NMR (282 MHz, CDCl3) δ: –99.3 (dd, J = 243.7, 6.4 Hz),
–106.4 (dd, J = 243.7, 14.8 Hz). Calcd for C11H9BrF2O (275.09): C, 48.03; H, 3.30. Found: C,
48.04; H, 3.31.
6,6-Difluoro-7-iodo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (3e). General procedure 1,
yield 274 mg (85%). Yellow oil. Rf 0.30 (hexane/EtOAc, 8:1). 1H NMR (300 MHz, CDCl3) δ: 7.69
(d, J = 7.3 Hz, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 4.77–
4.56 (m, 1H), 3.30–3.11 (m, 1H), 3.04–2.85 (m, 1H), 2.63–2.45 (m, 2H). 13C NMR (75 MHz,
CDCl3), δ: 27.0 (t, J = 24.2 Hz), 32.6, 35.4 (t, J = 4.6 Hz), 116.3 (t, J = 253.4 Hz), 127.2, 130.2,
130.3, 133.1, 134.2, 140.9, 190.0 (t, J = 27.0 Hz). 19F NMR (282 MHz, CDCl3) δ: –95.1 (dd, J =
238.5, 6.3 Hz), –97.8 (dd, J = 238.5, 19.1 Hz). Calcd for C11H9F2IO (322.09): C, 41.02; H, 2.82.
Found: C, 41.11; H, 2.91.
2,2-Difluoro-3-iodocycloheptanone (3f). General procedure 1, yield 219 mg (80%). General
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procedure 2, yield 210 mg (77%). Colorless oil. Rf 0.29 (hexane/EtOAc, 5:1). H NMR (300 MHz,
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CDCl3) δ: 4.32 (dddd, JHꢀF = 21.1 Hz, J = 8.3, 4.1, 2.3 Hz), 2.94–2.74 (m, 1H), 2.73–2.53 (m, 1H),
2.43–2.26 (m, 1H), 2.25–2.06 (m, 1H), 1.96–1.66 (m, 3H), 1.58 (m, 1H). 13C NMR (75 MHz,
CDCl3) 22.0, 26.6 (dd, J = 26.1, 23.9 Hz), 27.0, 36.1 (t, J = 2.8 Hz), 38.3, 116.2 (dd, J = 255.6,
254.4 Hz), 197.9 (dd, J = 29.0, 26.5 Hz). 19F NMR (282 MHz, CDCl3) δ: –92.47 (d, J = 241.6 Hz),
–110.04 (dd, J = 241.6, 21.1 Hz). Calcd for C7H9F2IO (274.05): C, 30.68; H, 3.31. Found: C, 30.51;
H, 3.19.
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3-Bromo-2,2-difluoro-1-phenylpropan-1-one (3g).23 General procedure 2, yield 229 mg (92%).
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Colorless oil. Rf 0.33 (hexane/EtOAc, 25:1). H NMR (300 MHz, CDCl3) δ: 8.11 (d, J = 8.2 Hz,
2H), 7.66 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 3.91 (t, JHꢀF = 14.7 Hz, 2H). 13C{1H} NMR
(75 MHz, CDCl3), δ: 29.2 (t, J = 27.6 Hz), 115.3 (t, J = 256.5 Hz), 128.9, 130.3 (t, J = 3.3 Hz),
131.7 (t, J = 3.2 Hz), 134.9, 187.7 (t, J =30.4 Hz). 19F NMR (282 MHz, CDCl3) δ: –100.6 (t, J =
14.7 Hz). Calcd for C9H7BrF2O (249.05): C, 43.40; H, 2.83. Found: C, 43.27; H, 2.71.
3-Bromo-1-(2,4-dimethylphenyl)-2,2-difluoropropan-1-one (3h). General procedure 2, yield 180
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mg (65%). Colorless crystals
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Mp 38–37 °С. Rf 0.32 (hexane/EtOAc, 12:1). H NMR (300 MHz,
CDCl3) δ: 7.81 (d, J = 8.2 Hz, 1H), 7.17–7.05 (m, 2H), 3.89 (t, JHꢀF = 13.7 Hz, 2H), 2.48 (s, 3H),
2.38 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3), δ: 21.3, 21.7, 29.2 (t, J = 29.3 Hz), 115.2 (t, J =
258.2 Hz), 126.4, 129.1, 130.2 (t, J = 5.7 Hz), 133.2, 141.1, 144.0, 190.4 (t, J = 28.7 Hz). 19F NMR
(282 MHz, CDCl3) δ: –100.2 (t, J = 13.7 Hz). Calcd for C11H11BrF2O (277.11): C, 47.68; H, 4.00.
Found: C, 47.54; H, 3.91.
3-Bromo-2,2-difluoro-1-(4-nitrophenyl)propan-1-one (3i) The reaction of 4ꢀnitroacetophenone
1g was performed according to General procedure 2 using modified condition at
difluorocyclopropanation step: Me3SiCF2Br (406 mg, 2 mmol, 2 equiv), Bu4NBr (96 mg, 0.3 mmol,
0.3 equiv), heating for 2 h at 80 °C. The crude material was separated by column chromatography
(hexane/EtOAc, gradient from 4:1 to 2:1) affording compounds 3i (172 mg) and 6a (23 mg).
Compound 3i was subsequently distilled in a short path apparatus at 139–141 °C (bath temp.)/0.7
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Torr furnishing 165 mg (56%). Colorless oil. Rf 0.31 (hexane/EtOAc, 2:1). H NMR (300 MHz,
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CDCl3) δ: 8.34 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 8.5 Hz, 2H), 3.91 (t, JHꢀF = 14.7 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3), δ: 28.2 (t, J = 28.1), 115.1 (t, J = 256.4 Hz), 124.0, 131.3 (t, J = 3.4 Hz),
136.1, 151.2, 186.6 (t, J = 32.1 Hz). 19F NMR (282 MHz, CDCl3) δ: –100.5 (t, J = 14.7 Hz). Calcd
for C9H6BrF2NO3 (294.05): C, 36.76; H, 2.06; N, 4.76; Found: C, 36.82; H, 2.09; N, 4.74.
3-Bromo-2,2-difluoro-1-(naphthalen-2-yl)propan-1-one (3j). General procedure 2, yield 272 mg
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(91%). Colorless crystals.
Mp 61–65 °С. Rf 0.30 (hexane/EtOAc, 8:1). 1H NMR (300 MHz, CDCl3)
δ: 8.72 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.97–7.84 (m, 2H), 7.76–7.52 (m,
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2H), 3.99 (t, JHꢀF = 14.6 Hz, 2H). C{1H} NMR (75 MHz, CDCl3), δ: 20.5 (t, J = 28.1 Hz), 115.5
(t, J = 256.4 Hz), 124.7, 124.8, 127.3, 128.0, 128.9, 130.0, 130.3, 132.4, 133.2 (t, J = 4.6 Hz),
136.3, 187.6 (t, J = 30.4 Hz). 19F NMR (282 MHz, CDCl3) δ: –99.9 (t, J = 14.6 Hz). Calcd for
C13H9BrF2O (299.11): C, 52.20; H, 3.03. Found: C, 52.11; H, 2.98.
2,2-Difluoro-3-iodo-1-(naphthalen-2-yl)propan-1-one (3k). General procedure 2, yield 311 mg
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(90%). Colorless crystals
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Mp 73–74 °С. Rf 0.29 (hexane/EtOAc, 16:1). H NMR (300 MHz,
CDCl3) δ: 8.69 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.94–7.83 (m, 2H), 7.70–
7.57 (m, 2H), 3.84 (t, JHꢀF = 16.1 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3), δ: 1.2 (t, J = 27.6 Hz),
115.9 (t, J = 255.4 Hz), 142.7 (t, J = 2.2 Hz), 127.2, 127.9, 128.6 (t, J = 2.8 Hz), 128.8, 129.7,
130.2, 132.3, 133.1 (t, J = 5.0 Hz), 136.2, 186.8 (t, J = 31.0 Hz). 19F NMR (282 MHz, CDCl3) δ: –
94.4 (t, J = 16.1 Hz). Calcd for C13H9F2IO (346.11): C, 45.11; H, 2.62. Found: C, 45.12; H, 2.51.
3-Bromo-2,2-difluoro-1-phenylbutan-1-one (3l). General procedure 2, yield 182 mg (69%).
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Colorless oil. Rf 0.32 (hexane/EtOAc, 20:1). H NMR (300 MHz, CDCl3) δ: 8.09 (d, J = 7.8 Hz,
2H), 7.66 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 4.64 (ddq, JHꢀF = 14.7 Hz, J = 11.0, 6.4 Hz,
1H), 1.84 (d, J = 6.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3), δ: 18.5 (t, J = 3.4 Hz), 43.6 (dd, J =
25.2, 26.7 Hz), 116.3 (t, J = 258.7 Hz), 129.0, 130.2 (t, J = 3.4 Hz), 132.6, 134.6, 188.5 (dd, J =
28.7, 31.0 Hz). 19F NMR (282 MHz, CDCl3) δ: –103.8 (dd, J = 277.1, 11.0 Hz), –108.1 (dd, J =
276.1, 14.7 Hz). Calcd for C10H9BrF2O (263.08): C, 45.65; H, 3.45. Found: C, 45.59; H, 3.37.
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3-Bromo-2,2-difluoro-1-(4-methoxyphenyl)-3-methylbutan-1-one (3m). General procedure 2.
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yield 218 mg (71%). Colorless oil
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Rf 0.27 (hexane/EtOAc, 20:1). H NMR (300 MHz, CDCl3) δ:
8.14 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 3.89 (s, 3H), 1.98 (s, 6H). 13C{1H} NMR (75
MHz, CDCl3), δ: 28.8 (t, J = 2.8 Hz), 55.7, 60.9 (t, J = 25.2 Hz), 114.0, 117.5 (t, J = 261.7 Hz),
126.7 (t, J = 2.3 Hz), 133.3 (t, J = 4.6 Hz), 164.6, 187.0. 19F NMR (282 MHz, CDCl3) δ: –103.1 (s).
Calcd for C12H13BrF2O2 (307.13): C, 46.93; H, 4.27. Found: C, 46.84; H, 4.23.
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5-(tert-Butyl)-2,2-difluoro-3-iodocycloheptanone (3n). Mixture of diastereoisomers, 5:1. General
procedure 2, yield 251 mg (76%). Colorless oil. Rf 0.28 (hexane/EtOAc, 15:1). 1H NMR (300 MHz,
CDCl3) δ: 4.74–4.58 (m, major) and 4.19–3.98 (m, minor) (1H), 3.06–2.41 (m) and 2.35–2.15 (m)
(3H), 2.11–1.77 (m) and 1.69–1.33 (m) (4H), 0.92 (s, major) and 0.88 (s, minor) (9H). 13C{1H}
NMR (75 MHz, CDCl3), δ: Major: 24.2 (d, J = 2.8 Hz), 27.0 (t, J = 25.7 Hz), 27.6, 33.6, 35.8 (dd, J
= 4.6, 1.8 Hz), 38.5 (t, J = 1.7 Hz), 46.9, 116. 1 (dd, J = 256.5, 254.1 Hz), 197.4 (dd, J = 27.9,
24.6); Minor: 24.3 (d, J = 2.8 Hz), 27.9 (dd, J = 25.7, 23.7 Hz), 21.2, 34.2, 37.6 (t, J = 1.7 Hz), 39.9
(d, J = 5.2 Hz), 50.8. 19F NMR (282 MHz, CDCl3) δ: Major: –99.9 (dd, 1F, J = 250.0, 4.2 Hz), –
101.4 (dd, 1F, J = 250.0, 10.6 Hz); Minor: –89.9 (d, J = 231.5 Hz), –114.2 (dd, J = 231.5, 29.0 Hz).
Calcd for C11H17F2IO (330.15): C, 40.02; H, 5.19. Found: C, 39.97; H, 5.02.
3-Bromo-2,2-difluorocyclotridecanone (3o). General procedure 2, yield 299 mg (96%). Colorless
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crystals
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Mp 35.5–36.5 °С. Rf 0.29 (hexane/EtOAc, 30:1). H NMR (300 MHz, CDCl3) δ: 4.28–
4.04 (m, 1H), 3.00 (ddt, J = 19.2, 10.1, 2.8 Hz, 1H), 2.63 (ddd, J = 19.2, 7.3, 2.8 Hz, 1H), 2.01–1.82
(m, 1H), 1.83–1.51 (m, 4H), 1.50–1.05 (m, 13H). 13C{1H} NMR (75 MHz, CDCl3), δ: 21.2, 23.2,
23.9, 24.2, 24.6, 24.7, 25.5, 26.4, 30.6 (d, J = 2.7 Hz), 36.6, 51.1 (dd, J = 24.0, 22.2 Hz), 115.1 (dd,
J = 260.4, 255.3 Hz), 201.2 (dd, J = 32.1, 25.8 Hz). 19F NMR (282 MHz, CDCl3) δ: –96.7 (d, J =
243.7 Hz), –125.3 (dd, J = 243.7, 25.4 Hz). Calcd for C13H21BrF2O (311.21): C, 50.17; H, 6.80.
Found: C, 50.14; H, 6.96.
2,3-Dibromo-2-fluoro-1-(4-nitrophenyl)propan-1-one (6a). Obtained in reaction of 4ꢀ
nitroacetophenone 1g as a byꢀproduct to 3i (see procedure for the synthesis of 3i). Yield 23 mg
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(7%). Colorless crystals. Mp 88–89 °С. Rf. 0.23 (hexane/EtOAc, 4:1). 1H NMR (300 MHz, CDCl3)
δ: 8.36–8.32 (m, 2H), 8.31–8.25 (m, 2H), 4.47 (dd, JHꢀF = 29.7 Hz, J = 11.7 Hz, 1H), 4.20 (dd, J =
11.7, 8.1, 1H). 13C{1H} NMR (75 MHz, CDCl3), δ: 33.7 (d, J = 22.7 Hz), 98.2 (J = 276 Hz), 123.9,
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(dd, J = 29.7, 8.1 Hz). Calcd for C9H6Br2FNO3 (354.96): C, 30.45; H, 1.70; N, 3.95. Found: C,
30.30; H, 1.81; N, 3.88.
Preparation of compounds 5m and 7. Silyl enol ether 4m was prepared according to General
Procedure 2 from deoxybenzoine 1m (268 mg, 1 mmol). A solution of crude 4m in MeCN (1 mL)
was treated with Me3SiCF2Br (609 mg, 3 mmol, 3 equiv) and Bu4NBr (128 mg, 0.4 mmol, 0.4
equiv) were successively added at room temperature. The mixture was heated at reflux for 10 h, and
then cooled to room temperature. For the workup, the mixture was diluted with water (8 mL) and
aqueous phase was extracted with hexane (3×5 mL). The combined organic layers were filtered
through Na2SO4, concentrated under vacuum. The residue was separated by semiꢀpreparative HPLC
(reversed phase column C18ꢀreprosil ultra, 10 ꢁ, 21×250 mm, H2O/MeCN gradient 30/70 to 70/30).
Retention time: 5m, 9 min; 7, 12 min.
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(Z)-2-Fluoro-1,3-diphenylprop-2-en-1-one (5m).22 Yield 149 mg (66%). Colorless oil. H NMR
(300 MHz, CDCl3) δ: 7.98–7.36 (m, 10 H), 6.86 (d, JHꢀF = 36.7 Hz, 1H). 13C{1H} NMR (75 MHz,
CDCl3), δ: 120.2 (d, J = 5.7 Hz), 128.6, 129.0, 129.5 (d, J = 3.5 Hz), 130.1 (d, J = 3.5 Hz), 130.8 (d,
J = 9.2 Hz), 131.5 (d, J = 4.6 Hz), 133.0, 136.4, 154.6 (d, J = 271.9 Hz), 188.0 (d, J = 28.7 Hz). 19F
NMR (282 MHz, CDCl3) δ: –120.1 (d, J = 36.7 Hz). Calcd for C15H11FO (226.25): C, 79.63; H,
4.90. Found: C, 79.67; H, 4.87.
({(2Z)-1-[Bromo(difluoro)methyl]-2-fluoro-1,3-diphenylprop-2-enyl}oxy)(trimethyl)silane (7).
Yield 58 mg (14%). Yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.75–7.65 (m, 2H), 7.57 (d, J = 7.3
Hz, 2H), 7.47–7.29 (m, 7H), 6.27 (d, JHꢀF = 39.6 Hz), 0.24 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3), δ: 1.6 (d, J = 1.6 Hz), 84.6 (m), 111.9 (dt, J = 6.9, 2.3 Hz), 125.7 (m), 128.17, 128.23 (t, J
= 1.9 Hz), 128.4 (d, J = 2.3 Hz), 128.8, 129.3 (d, J = 8.0 Hz), 129.5, 132.3 (d, J = 2.3 Hz), 137.1,
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155.4 (d, J = 269.6 Hz). 19F NMR (282 MHz, CDCl3) δ: –53.3 (dd, J = 162.4, 13.1 Hz), –54.74 (dd,
J = 162.4, 4.2 Hz), –111.0 (dd, J = 39.6, 13.1 Hz). Calcd for C19H20BrF3OSi (429.35): C, 53.15; H,
4.70. Found: C, 53.01; H, 4.71.
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4,4-Difluoro-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (8). Phenylhydrazine (108
mg, 1.05 mmol, 1.05 equiv) and potassium acetate (300 mg, 3 mmol, 3 equiv) were added to a
solution of ketone 3b (279 mg, 1 mmol, 1 equiv) in methanol (1.5 mL), and the mixture was stirred
for 12 h at room temperature. Then, water (9 mL) water was added with stirring, and the mixture
was kept without stirring for additional 10 min. The precipitate was filtered and washed with cold
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ethanol, and dried under vacuum. Yield 274 mg (95%). Yellow crystals. Mp 105–106 °С (dec.). H
NMR (300 MHz, CDCl3) δ: 7.86 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz,
2H), 7.04–6.92 (m, 3H), 4.24 (t, JHꢀF = 21.9 Hz, 2H), 3.86 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3), δ: 55.5, 56.7 (t, J = 31.0 Hz), 113.0, 114.5, 121.0, 127.4, 128.4 (t, J = 249.4 Hz), 129.5,
141.5 (t, J = 24.1 Hz), 141.8, 143.6, 160.6. 19F NMR (282 MHz, CDCl3) δ: –92.7 (t, J = 21.9 Hz).
Calcd for C16H14F2N2O (288.29): C, 66.66; H, 4.89; N, 9.72. Found: C, 66.64; H, 4.90; N, 9.68.
4-Fluoro-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole (9). Phenylhydrazine (108 mg, 1.05 mmol,
1.05 equiv) and K2CO3 (300 mg, 3 mmol, 3 equiv) were added to a solution of ketone 3b (279 mg, 1
mmol, 1 equiv) in DMF (1.5 mL), and the mixture was stirred for 12 h at room temperature and for
1 h at 130 °C. The mixture was cooled to room temperature, diluted with water (9 mL), and
extracted with diethyl ether (3×4 mL). The combined organic layers were filtered through Na2SO4,
concentrated under vacuum, and the residue was purified by column chromatography. Yield 244 mg
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(91%). Colorless crystals. Mp 102–103 °С. Rf 0.27 (hexane/EtOAc, 7:1). H NMR (300 MHz,
CDCl3) δ: 7.94 (d, J = 8.7 Hz, 2H), 7.85 (d, JHꢀF = 4.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.47 (t, J =
7.6, 2H), 7.30 (t, J = 7.6, 1H), 7.02 (t, J = 8.7 Hz, 2H), 3.87 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3), δ: 55.4, 114.1 (d, J = 29.8 Hz), 114.2, 118.5, 123.6 (d, J = 3.4 Hz), 126.4, 127.7 (d, J = 3.4
Hz), 129.5, 139.0 (d, J = 6.9 Hz), 140.2, 148.8 (d, J = 252.4 Hz), 159.8. 19F NMR (282 MHz,
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CDCl3) δ: –173.6 (d, J = 4.6 Hz). Calcd for C16H13FN2O (268.29): C, 71.63; H, 4.88; N, 10.44.
Found: C, 71.48; H, 4.77; N, 10.34.
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3-Bromo-2,2-difluoro-1-(4-methoxyphenyl)propan-1-ol (10a). NaBH4 (57 mg, 1.5mmol, 3
equiv) was added to a solution of ketone 3b (140 mg, 0.5 mmol, 1 equiv) in ethanol (5 mL), and the
mixture was stirred for 3 h at room temperature. The reaction was quenched by addition of saturated
aqueous NH4Cl (6 mL), and the mixture as concentrated under vacuum to 1/3 of its volume. The
resulting mixture was diluted with water (3 mL) followed by extraction with methyl tertꢀbutyl ether
(3×4 mL). The combined organic layers were filtered through Na2SO4, concentrated under vacuum,
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and the residue was purified by column chromatography. Yield 125 mg (89%). Colorless oil. H
NMR (300 MHz, DMSOꢀd6) δ: 7.34 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 5.8
Hz, 1H), 4.92 (dt, JHꢀF = 16.4, 5.8 Hz, 2H), 4.05–3.77 (m, 2H), 3.75 (s, 3H). 13C{1H} NMR (75
MHz, DMSOꢀd6), δ: 31.3 (dd, J =29.8, 26.4 Hz), 55.1, 71.7 (dd, J =29.8, 25.2 Hz), 113.4, 119.4
(dd, J =248.4, 245.0 Hz), 128.9, 129.4, 159.3. 19F NMR (282 MHz, DMSOꢀd6) δ: –107.7 (ddt, 1F, J
= 241.7, 23.3, 8.5 Hz), –112.9 (dddd, 1F, J = 241.7, 38.1, 16.4, 5.8 Hz). Calcd for C10H11BrF2O2
(281.09): C, 42.73; H, 3.94. Found: C, 42.75; H, 4.04.
4-Bromo-3,3-difluoro-2-(4-methoxyphenyl)butan-2-ol (10b). MeMgBr (3M in diethyl ether, 400
µl, 1.5 mmol, 1.5 equiv) was added dropwise to a solution of ketone 3b (279 mg, 1 mmol, 1 equiv)
in THF (400 ꢁL) at 0 °C. The cooling bath was removed, and the mixture was stirred for 30 min.
The reaction was quenched by addition of saturated aqueous NH4Cl (3 mL) by extraction with
diethyl ether (3×4 mL). The combined organic layers were filtered through Na2SO4, concentrated
under vacuum, and the residue was purified by column chromatography. Yield 236 mg (80%).
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Colorless crystals. 70–71 °C. Rf 0.29 (hexane/EtOAc, 5:1). H NMR (300 MHz, CDCl3) δ: 7.45 (d,
J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.78 (dddd, JHꢀF = 29.0 Hz, J = 12.4, 3.0, 0.8
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Hz, 2H), 3.19 (dddd, JHꢀF = 29.0, 12.4, 3.0, 0.8 Hz, 1H), 2.31 (s, 1H), 1.75 (s, 3H). C{1H} NMR
(75 MHz, CDCl3), δ: 24.4 (t, J = 2.8 Hz), 30.4 (t, J =26.5 Hz), 55.4, 76.0 (dd, J = 26.9, 26.0 Hz),
114.0, 120.0 (t, J = 251.0 Hz), 127.2, 132.2 (d, J = 3.3 Hz), 159.6. 19F NMR (282 MHz, CDCl3) δ: –
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111.6 (dd, 1F, J = 243.7, 29.0 Hz), –114.9 (dd, 1F, J = 243.7, 29.0 Hz). Calcd for C11H13BrF2O2
(295.12): C, 44.77; H, 4.44. Found: C, 44.67; H, 4.46.
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Synthesis of oxetanes 11a,b. K2CO3 (336 mg, 3 mmol, 3 equiv) was added to a solution of
alcohol 10 (1 mmol, 1 equiv) in DMF (2 mL) at room temperature, and the mixture was stirred for 4
h at 90°C. The mixture was cooled to room temperature, diluted with water (8 mL), and extracted
with diethyl ether (3×4 mL). The combined organic layers were filtered through Na2SO4,
concentrated under vacuum, and the residue was purified by column chromatography.
3,3-Difluoro-2-(4-methoxyphenyl)oxetane (11a). Yield 157 mg (78%). Colorless oil. Rf 0.29
(hexane/EtOAc, 5:1). 1H NMR (300 MHz, CDCl3) δ: 7.35 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 9.2 Hz,
2H), 5.80 (t, JHꢀF = 11.0 Hz, 1H), 5.01–4.75 (m, 2H), 3.83 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3), δ: 55.4, 78.7 (dd, J =26.4,24.1 Hz), 91.7 (dd, J =26.4, 23.0 Hz), 114.1, 118.0 (dd, J =
282.3, 280.0 Hz), 125.7 (t, J = 2.9 Hz), 128.6, 160.6. 19F NMR (282 MHz, CDCl3) δ: –99.5 (dq, J =
192.9, 11.0 Hz, 1F), –112.4 (ddt, J = 192.9, 17.1, 11.0 Hz, 1F). Calcd for C10H10F2O2 (200.18): C,
60.00; H, 5.04. Found: C, 59.84; H, 4.92.
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3,3-Difluoro-2-(4-methoxyphenyl)-2-methyloxetane (11b). Yield 158 mg (74%). Colorless oil. Rf
0.33 (hexane/EtOAc, 4:1). 1H NMR (300 MHz, CDCl3) δ: 7.36 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7
Hz, 2H), 4.88–4.65 (m, 2H), 3.83 (s, 3H), 1.77 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3), δ: 23.2,
55.4, 76.5 (t, J = 26.0 Hz), 95.2 (t, J = 23.2Hz), 113.9, 118.6 (dd, J = 284.4, 282,6 Hz), 126.4,
131.2, 159.6. 19F NMR (282 MHz, CDCl3) δ: –108.3 (dt, J = 187.5, 12.7 Hz, 1F), –113.5 (dt, J =
187.5, 12.7 Hz, 1F). Calcd for C11H12F2O2 (214.21): C, 61.68; H, 5.65. Found: C, 61.76; H, 5.71.
Acknowledgement
This work was supported by the Ministry of Science (project MDꢀ3256.2015.3), Russian
Foundation for Basic Research (projects 15ꢀ33ꢀ20133, 14ꢀ03ꢀ00293), and the Russian Academy of
Sciences.
Supporting Information
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Copies of NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
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References
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(14) Ni, C.; Hu, J. Synthesis 2014, 46, 842–863.
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(21) Oxetanes have recently emerged as valuable fragments in drug discovery, see: Burkhard, J.
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