Copper-catalyzed allylation of a,a-difluoro-substituted organozinc reagents

Article abstract of DOI:10.1021/jo4024705

A method for the coupling of organozinc reagents, difluorocarbene, and allylic electrophiles is described. The reaction involves insertion of difluorocarbene into the carbon-zinc bond followed by copper-catalyzed allylic substitution.

Full text of DOI:10.1021/jo4024705

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Note
Copper-catalyzed allylation of alpha,alpha-
difluoro-substituted organozinc reagents
Artem A. Zemtsov, Nikolay S. Kondratyev, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 28 Nov 2013
Downloaded from http://pubs.acs.org on December 1, 2013
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Copperꢀcatalyzed allylation of α,αꢀdifluoroꢀsubstituted organozinc reagents
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Artem A. Zemtsov,† Nikolay S. Kondratyev,†,‡ Vitalij V. Levin,† Marina I. Struchkova,† Alexander
D. Dilman*,†
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† N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation
‡ Higher Chemical College, Russian Academy of Sciences, 125047 Moscow, Miusskaya sq. 9,
Russian Federation
adil25@mail.ru
F
F
a) CF2-insertion
C
R2
F
F
R2
b) Cu-catalyzed allylation
R3
R1
X
R3
R1 ZnY
R4
R4
Abstract. A method for the coupling of organozinc reagents, difluorocarbene, and allylic
electrophiles has been described. The reaction involves insertion of difluorocarbene into carbonꢀ
zinc bond followed by copperꢀcatalyzed allylic substitution.
Due to ability of CF2 fragment to serve as bioisoster of ether oxygen and a carbonyl group,
compounds containing difluoromethylene unit have gained increasing attention in medicinal
chemistry.1 At the same time, existing methodologies for the synthesis of organofluorine
compounds of this type2 suffer from a number of disadvantages such as hazardous/harsh reagents
(deoxofluorination process)3 or multiꢀstep synthetic sequence starting from widely available
fluorinated chemicals.4,5 Recently, we introduced a concept for assembling CF2ꢀcontaining products
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from three independent components — difluorocarbene, nucleophile, and electrophile6 (Scheme 1).
Organozinc reagents 1 were used as nucleophiles generating gemꢀdifluorinated organozinc species 2
which were quenched by halogen or a proton.6 Herein, we demonstrate the use of allylic
electrophiles as a final component. Notably, this oneꢀpot protocol for assembling of fluorinated
products from three parts involves the formation of two CꢀC bonds.7
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Fluorinated organozinc reagents typically exhibit low reactivity towards various carbonꢀ
centered electrophiles.8 However, the presence of copper (I) salts may induce zinc/copper exchange
generating fluorinated organocopper species, which is expected to undergo coupling with allylic
electrophiles.9ꢀ11
Scheme 1. Synthesis of CF2ꢀcontaining products.
F
F
F
F
C
Nu
E
Nu
R
E
E = I, Br, H
F
F
previous work
F
F
C
E
F F
ZnBr
R
ZnBr
R
E
X
E =
1
2
this work
(Bromodifluoromethyl)trimethylsilane (Me3SiCF2Br) in the presence of basic activator was
used as a source of difluorocarbene.12 Organozinc reagent 2a generated from 4ꢀ
methoxycarbonylbenzylzinc bromide under typical conditions6 was selected as a model substrate,
and its reaction with allyl bromide 3a was evaluated (Table 1). The coupling of 1a and 3a
proceeded cleanly within 2 hours at –25 °C in the presence of 10 mol % of copper iodide/1,10ꢀ
phenanthroline combination, as well as 2 equiv of dimethylformamide as additive, affording
product 4a in 88% yield (entry 1). 1,10ꢀPhenanthroline is a typical ligand in copper catalyzed
processes,13 whereas the role of dimethylformamide is to stabilize reagents 2 through coordination
with zinc.6 Allyl chloride can be used instead of allyl bromide leading to the product in slightly
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reduced yield (entry 5). Interestingly, even in the absence of copper the coupling product was
slowly formed (entry 2). Presumably, the copperꢀfree reaction proceeds due to Lewis acidic nature
of the organozinc reagent.14
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Table 1. Allylation of reagent 1a.
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Me3SiCF2Br, NaOAc
Ar
ZnBr
–25 °C, 18 h, MeCN
1a, Ar = 4-MeO2CC6H4
3a, (2 equiv)
Br
CuI (10%), phen (10%)
DMF (2.0 equiv)
ZnBr
Ar
Ar
4a
–25 °C, 2 h
F
F
F F
2a
Entry
Deviation from standard conditions
Yield of
4a, %
88
1
2
3
4
5
none
no CuI, phen, DMF
no phen
16a
41a
no DMF
68a
allyl chloride instead of 3a
82
a Determined by 19F NMR with PhCF3 as an internal standard.
Under the optimized conditions benzyl and alkyl zinc reagents were coupled with allyl
bromides or chlorides (Table 2). The coupling tolerates ester and nitrile functional groups and
provides products 4 in good yields. With respect to allylic component, the reaction afforded
products in which fluorinated nucleophile is attached to less substituted carbon (entries 5ꢀ8). It
should be pointed out, that Eꢀgeranyl bromide 3h afforded product 4h as inseparable mixture of
geometrical isomers in a ratio of 3 : 1 (assignment of configurations of the components of 4h was
problematic due to overlap of signals from both isomers).
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Table 2. Allylation of organozinc reagents.
R2 R5
5
6
7
8
a) Me3SiCF2Br, NaOAc, –25 °C, 18 h, MeCN
R1
R1 ZnY
R4
R2 R5
R3
CuI (10%), phen (10%),
F
F
1
b)
4
X
R4
(2 equiv) DMF (2.0 equiv), –25 °C, 2 h
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R3
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Entry
1
1
3
4
Yield of 4, %a
4b 76
ZnBr
Cl
Br
1a
1a
3b
3c
F
F
F
MeO2C
MeO2C
MeO2C
2
3
4c
76
F
Br
Br
1a
1a
3d
4d 90
Br
F
F
MeO2C
4
3eb
4e
76
Br
Cl
F
F
F
F
Ph
Ph
MeO2C
MeO2C
Ph
3fb
3gb
3hb
3i
4f
75
66
Ph
5
6
7
8
1a
1a
1a
1a
Ph
Ph
4g
Br
Br
F
F
CO2Me
CO2Me
MeO2C
MeO2C
4h 71c
F
F
4i
4j
80
76
Br
Br
F
F
F
F
MeO2C
MeO2C
MeO2C
ZnBr
9
1b
1c
1d
3a
3a
3a
ZnBr
ZnBr
10
11
4k 80
F
F
F
NC
Br
NC
Br
4l
81
F
12
1e
3a
4m 78
4n 74
ZnCl
F
F
Br
Br
Br
13
14
1f
3c
3a
Ph
F
Ph
ZnBr
Br
F
Br
BzO
1g
4o
70
BzO
ZnI
F
F
15
1i
3e
4p 66d
Me ZnI
F
F
Ph
Ph
a Yield based on organozinc halide.
b 1.33 equiv of allylating reagent were used.
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c 3 : 1 mixture of geometrical isomers.
d 1.5 equiv of MeZnI relative to 3e; the yield based on 3e.
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Concerning reaction mechanism, we may propose the initial formation of organocopper
intermediate 5.15 The interaction of copper center with a double bond leads to πꢀcomplex 6 followed
by slow generation of copper (III) species 7α or 7γ. The formation of only one product may be
associated either with rapid interconversion between 7α and 7γ, or with exclusive formation of
isomer 7α. Nevertheless, the loss of double bond geometry observed for Eꢀgeranyl bromide 3h
supports the former pathway.16
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Scheme 2. Proposed mechanism.
R2
X
R2
R1
X
R1
ZnBr
R1
CuL
CuI, L
Zn(II)
CuL
F
F
F
F
2
F F
5
6
R2
R1
CuL
F
F
X
7α
R1
F
R2
F
R2
Cu(I)
R1
CuL
X
F
F
7γ
In summary, a method for the synthesis of CF2ꢀcontaining compounds from three components
— organozinc reagent, difluorocarbene, and allylic electrophile — has been described. The reaction
is performed under mild reaction conditions and results in the formation of two CꢀC bonds within
one synthetic step.
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Experimental section
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General methods. All reactions were performed in Schlenk flasks under an argon atmosphere.
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 aq.
KMnO4 solution. For NMR measurements, CDCl3 was distilled from CaH2. Commercial allyl
halides and methyl iodide were distilled prior to use. Organozinc reagents (1aꢀg),6
(Bromodifluoromethyl)trimethylsilane,7 methyl (2Z)ꢀ2ꢀ(bromomethyl)ꢀ3ꢀphenylacrylate (3g),17
(2E)ꢀ1ꢀbromoꢀ3,7ꢀdimethyloctaꢀ2,6ꢀdiene (3h)18 were prepared according to literature procedures.
2,3-Dibromoprop-1-ene (3c). To a solution of allyl bromide (5.0 g, 41.3 mmol) in CCl4 (40
mL) was added bromine (2.1 mL, 41.3 mmol) at a rate that the reaction temperature did not exceed
30 °C. The solution was stirred for 2 h until complete decoloration, then all volatile compounds
were removed under reduced pressure furnishing 1,2,3ꢀtribromopropane (10.4 g, 90% yield) as a
slightlyꢀyellow oil which was used without further purification. Water (0.54 mL, 30.0 mmol) was
added to the resulting 1,2,3ꢀtribromopropane, and to a stirred mixture solid NaOH (4.0 g, 70.0
mmol) was slowly added at room temperature. The resulting suspension was stirred for 18 h and
then the product was distilled from the reaction flask under reduced pressure (65–75 °C, 70 mm
Hg). Subsequent recrystallization of the resulting oil from MeOH (5 mL) at –78oC followed by
distillation under reduced pressure (79–81 °C, 80 mm Hg) gave 2.97 g (40% yield) of 3c as a clear
oil. 1H NMR (300 MHz, CDCl3), δ: 4.20 (s, 2H), 5.65 (br, 1H), 6.04 (br, 1H).19
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(6-Bromocyclohex-1-en-1-yl)benzene (3e). PhMgCl (1.9 M in THF, 25 mL, 47.5 mmol) was
added to a solution of cyclohexanone (3.7 mL, 36.0 mmol) in THF (25 mL) at –30 °C. The cooling
bath was removed and the thick white suspension was stirred for 1 h at room temperature. Then
water (10 mL) and hexane (40 mL) were added, and the biphasic mixture was vigorously shaken.
The organic layer was separated, the residual inorganic cake was extracted with hexane (2×20 mL),
and the combined organic phase was concentrated on a rotary evaporator. The resulting solid was
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dissolved in toluene (30 mL), TsOHꢁH2O (20 mg) was added, and the mixture was refluxed with
DeanꢀStark trap for 1 h. Most part of toluene was evaporated at atmospheric pressure, while the
residual toluene was evaporated under reduced pressure (15 mm Hg). The crude 1ꢀphenylcyclohexꢀ
1ꢀene was dissolved in acetone (60 mL) and water (30 mL), followed by addition of Nꢀ
bromosuccinimide (6.41 g, 36.0 mmol), and the mixture was stirred for 3 h at 10 °C. Then acetone
was evaporated under vacuum, water (20 mL) was added, and the mixture was extracted with
hexane (3×30 mL). The combined organic phase was successively washed with water and brine,
dried over Na2SO4 and concentrated on rotary evaporator. The crude bromohydrin was dissolved in
hexane (10 mL), and the solution was added to a mixture of 20% H2SO4 (10 mL) and AcOH (40
mL). The reaction mixture was stirred for 5 min, then the iced water (50 mL) was added, and the
product was extracted with ether (3×30 mL). The combined organic phase was successively washed
with water and saturated solution of NaHCO3, and concentrated on rotary evaporator. The resulting
oil was dissolved in hexane/CH2Cl2 (2/1), cooled to 0 °C. The precipitate was filterred affording
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1
compound 3e (3.92 g, 46% yield) as a lightlyꢀlilac solid. Mp 43–44 °C. H NMR (300 MHz,
CDCl3), δ: 1.77–1.93 (m, 1H), 2.05–2.24 (m, 2H), 2.31–2.55 (m, 3H), 5.35 (t, 1H, J = 2.8 Hz); 6.21
(dd, 1H, J = 4.8; 3.1 Hz) 7.27–7.47 (m, 5H).20
General procedure for difluorocarbene insertion/allylation reaction. A freshly titrated THF
solution of 1 (1.5 mmol)6 was concentrated in vacuo until the solid or viscious residue was formed,
and the residue was dissolved in freshly distilled MeCN (1.5 mL). To the resulting solution was
added NaOAc (148 mg, 1.8 mmol for 1aꢀd,fꢀi, or 172 mg, 2.1 mmol for 1e) at room temperature,
the reaction flask was immersed in a cold bath at –25 °C, and the mixture was stirred for 10 minutes
at this temperature. Then, Me3SiCF2Br (365 mg, 1.8 mmol for 1aꢀd,fꢀi, or 426 mg, 2.1 mmol for 1e)
was added dropwise at –25 °C, and the reaction mixture was stirred at this temperature (18 h for 1aꢀ
d,fꢀi, 21 h for 1e). To the resulting white suspension at –25 °C were successively added DMF (231
ꢂL, 3.0 mmol), allyl reagent 3 (3.0 mmol for 3aꢀd,g,i; 2.0 mmol for 3e,f,h; 1.0 mmol of 3e for
combination 1i/3e), 1,10ꢀphenanthroline (27 mg, 0.15 mmol) and CuI (29 mg, 0.15 mmol). The
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reaction mixture was stirred for 2 h at –25 °C, the cooling bath was removed, and the reaction was
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quenched with water (10 mL). The resulting suspension was extracted with hexane (3×10 mL) [or
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pentane (3×10 mL) in case of volatile products 4n,p]. The combined organic phase was filtered
through Na2SO4, concentrated under vacuum (or under ambient pressure in case of 4n,p). The
residue was purified by column chromatography on silica gel.
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Methyl 4-(2,2-difluoropent-4-enyl)benzoate (4a). 317 mg (88%). Colorless crystals. Mp 52–54
1
°C. Rf = 0.24 (hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3), δ: 2.57 (td, 2H, J = 15.9, 7.2
Hz), 3.20 (t, 2H, J = 15.9 Hz), 3.93 (s, 3H), 5.20 (dd, 1H, J = 17.2, 1.5 Hz), 5.27 (dd, 1H, J = 10.3,
1.5 Hz), 5.84 (ddt, 1H, J = 17.2, 10.3, 7.2 Hz), 7.36 (d, 2H, J = 8.2 Hz), 8.01 (d, 2H, J = 8.2 Hz).
13C NMR (75 MHz, CDCl3) δ: 40.6 (t, J = 25.6 Hz), 42.2 (t, J = 24.9 Hz), 52.0, 120.6, 122.7 (t, J =
244.6 Hz), 129.1, 129.2, 129.3, 129.6, 130.4, 138.3 (t, J = 4.3 Hz), 166.7. 19F NMR (282 MHz,
CDCl3) δ: –96.4 (tt, 2F, J = 15.9, 15.9 Hz). Calcd for C13H14F2O2 (240.25): C 64.99, H 5.87. Found:
C 65.05, H 5.84.
Methyl 4-(2,2-difluoro-4-methylpent-4-enyl)benzoate (4b). 290 mg (76%). Colorless oil. Rf =
0.33 (hexanes/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3), δ: 1.84 (s, 3H), 2.54 (t, 2H, J = 15.9 Hz),
3.21 (t, 2H, J = 15.9 Hz), 3.92 (s, 3H), 4.85 (d, 1H, J = 1.3 Hz), 5.01 (d, 1H, J = 1.3 Hz), 7.36 (d,
2H, J = 8.2 Hz), 8.00 (d, 2H, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3) δ: 23.4 (t, J = 2.2 Hz), 42.6
(t, J = 25.7 Hz), 44.4 (t, J = 25.9 Hz), 52.1, 117.0, 123.1 (t, J = 244.6 Hz), 129.3, 129.7, 130.6,
138.1 (t, J = 3.9 Hz), 138.6 (t, J = 3.9 Hz), 166.9. 19F NMR (282 MHz, CDCl3) δ: –94.6 (tt, 2F, J =
15.9, 15.9 Hz). Calcd for C14H16F2O2 (254.27): C 66.13, H 6.34. Found: C 66.07, H 6.31.
Methyl 4-(4-bromo-2,2-difluoropent-4-enyl)benzoate (4c). 364 mg (76%). Colorless crystals.
1
Mp 40–42 °C. Rf = 0.19 (hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3), δ: 3.01 (t, 2H, J =
16.3 Hz), 3.31 (t, 2H, J = 16.3 Hz), 3.93 (s, 3H), 5.75 (d, 1H, J = 1.7 Hz), 5.82 (d, 1H, J = 1.7 Hz),
13
7.39 (d, 2H, J = 8.4 Hz), 8.02 (d, 2H, J = 8.4 Hz). C NMR (75 MHz, CDCl3) δ: 41.9 (t, J = 25.4
Hz), 46.8 (t, J = 26.8 Hz), 51.6, 121.0 (t, J = 245.7 Hz), 121.8 (t, J = 5.3 Hz), 122.8, 129.0, 129.2,
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130.0, 137.2 (t, J = 3.6 Hz), 166.3. 19F NMR (282 MHz, CDCl3) δ: –95.4 (tt, 2F, J = 16.3, 16.3 Hz).
Calcd for C13H13BrF2O2 (319.14): C 48.92, H 4.11. Found: C 49.07, H 4.18.
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Methyl 4-(2-cyclohex-2-en-1-yl-2,2-difluoroethyl)benzoate (4d). 378 mg (90%). Paleꢀyellow
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crystals. Mp 74–76 °C. Rf = 0.24 (hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3), δ: 1.43–
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1.68 (m, 2H), 1.78–1.98 (m, 2H), 1.99–2.10 (m, 2H), 2.51–2.73 (m, 1H), 3.20 (t, 2H, J = 17.2 Hz),
3.92 (s, 3H), 5.71 (dd, 1H, J = 10.1 Hz, 2.5 Hz), 5.94 (ddd, 1H, J = 10.1, 3.6, 2.5 Hz), 7.37 (d, 2H, J
= 8.2 Hz), 8.01 (d, 2H, J = 8.2 Hz).13C NMR (75 MHz, CDCl3) δ: 21.1, 23.0 (t, J = 4.4 Hz), 24.8,
40.3 (t, J = 26.0 Hz), 42.0 (t, J = 23.8 Hz), 52.1, 123.1 (t, J = 5.5 Hz), 124.4 (t, J = 245.5 Hz),
129.2, 129.6, 130.6, 131.3, 138.7 (t, J = 3.3 Hz), 167.0. 19F NMR (282 MHz, CDCl3) δ: –102.7 (m,
2F). Calcd for C16H18F2O2 (280.31): C 68.56, H 6.47. Found: C 68.84, H 6.66.
Methyl 4-[2,2-difluoro-2-(2-phenylcyclohex-2-en-1-yl)ethyl]benzoate (4e). 406 mg (76%).
Colorless crystals. Mp 74–75 °C. Rf = 0.21 (hexanes/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3), δ:
1.63–1.97 (m, 3H), 2.13–2.23 (m, 1H), 2.24–2.33 (m, 2H), 2.91 (ddd, 1H, J = 14.6, 13.8, 11.2 Hz),
3.01 (ddd, 1H, J = 14.6, 13.8, 11.2 Hz), 3.21–3.37 (m, 1H), 3.90 (s, 3H), 6.09 (t, 1H, J = 3.7 Hz),
7.16 (d, 2H, J = 8.2 Hz), 7.22–7.38 (m, 5H), 7.94 (d, 2H, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3)
δ: 18.5 (t, J = 1.9 Hz), 23.7 (dd, J = 4.8, 3.5), 25.5, 42.2 (t, J = 22.7 Hz), 42.4 (t, J = 25.7 Hz), 52.2,
124.3 (t, J = 248.5 Hz), 126.7, 126.9, 128.4, 129.0, 129.4, 130.7, 132.7, 135.0 (t, J = 3.6 Hz), 138.7
(t, J = 3.0 Hz), 143.9, 167.1. 19F NMR (282 MHz, CDCl3) δ: –96.2 (dddd, 1F, J = 243.7, 23.3, 14.6,
13.8 Hz), –94.5 (dddd, 1F, J = 243.7, 23.8, 14.6, 13.8 Hz). Calcd for C22H22F2O2 (356.41): C 74.14,
H 6.22. Found: C 73.95, H 6.24.
Methyl 4-[(4E)-2,2-difluoro-5-phenylpent-4-enyl]benzoate (4f). 356 mg (75%). Colorless
crystals. Mp 85–86 °C. Rf = 0.23 (hexanes/EtOAc, 10/1). 1H NMR (300 MHz, CDCl3), δ: 2.72 (td,
2H, J = 15.7, 7.7 Hz), 3.25 (t, 2H, J = 15.7 Hz), 3.94 (s, 3H), 6.19 (dt, 1H, J = 16.0, 7.7 Hz), 6.49
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(d, 1H, J = 16.0 Hz), 7.24–7.44 (m, 7H), 8.04 (d, 2H, J = 8.2 Hz). C NMR (75 MHz, CDCl3), δ:
40.1 (t, J = 26.0 Hz), 42.6 (t, J = 26.0 Hz), 52.2, 120.5 (t, J = 5.8 Hz), 123.1 (t, J = 244.1 Hz),
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126.4, 127.9, 128.7, 129.5, 129.8, 130.6, 135.6, 136.8, 138.5 (t, J = 4.4 Hz), 166.9. F NMR (282
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MHz, CDCl3), δ: –95.8 (tt, 2F, J = 15.7, 15.7 Hz). Calcd for C19H18F2O2 (316.34): C 72.14, H 5.74.
Found: C 72.16, H 5.84.
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Methyl 4-[(4E)-2,2-difluoro-4-(methoxycarbonyl)-5-phenylpent-4-enyl]benzoate (4g). 371 mg
(66%). Colorless oil. Rf = 0.04 (hexanes/EtOAc, 15/1). Configuration determined by NOESY
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experiment. H NMR (300 MHz, CDCl3), δ: 3.19 (t, 2H, J = 16.3 Hz), 3.25 (t, 2H, J = 16.3 Hz),
3.83 (s, 3H), 3.92 (s, 3H), 7.29–7.33 (m, 5H), 7.32 (d, 2H, J = 8.2 Hz), 7.88 (s, 1H), 8.00 (d, 2H, J =
8.2 Hz). 13C NMR (75 MHz, CDCl3) δ: 34.0 (t, J = 25.4 Hz), 43.5 (t, J = 25.4 Hz), 52.0, 52.2, 122.6
(t, J = 245.7 Hz), 124.7 (t, J = 3.3 Hz), 128.5, 128.9, 129.0 (t, J = 1.7 Hz), 129.3, 129.5, 130.5,
134.7, 138.1 (t, J = 3.9 Hz), 143.6, 166.8, 168.5. 19F NMR (282 MHz, CDCl3) δ: –94.5 (tt, 2F, J =
16.3, 16.3 Hz). Calcd for C21H20F2O4 (374.38): C 67.37, H 5.38. Found: C 67.25, H 5.49.
Methyl 4-(2,2-difluoro-4,9-dimethyldeca-4,8-dienyl)benzoate (4h). 358 mg (71%). Isolated as
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3/1 mixture of isomers. Colorless oil. Rf = 0.28 (hexanes/EtOAc, 25/1). H NMR (300 MHz,
CDCl3), δ: major, 1.55 (s, 3H), 1.63 (s, 3H), 1.69 (s, 3H), 5.11 (t, 1H, J = 7.2 Hz); minor, 1.58 (s,
3H), 1.67 (s, 3H), 1.77 (s, 3H), 5.06 (t, 1H, J = 7.2 Hz); both isomers, 1.91–2.20 (m, 4H), 2.50 (td,
2H, J = 15.9, 7.2 Hz), 3.17 (t, 2H, J = 15.9 Hz), 3.92 (s, 3H), 5.21 (t, 1H, J = 7.2 Hz). 13C NMR (75
MHz, CDCl3) δ: both isomers, 16.4, 17.7, 17.8, 23.7, 25.7, 25.8, 26.3, 26.5, 32.2, 35.0 (t, J = 25.4
Hz), 35.1 (t, J = 25.4 Hz), 42.2 (t, J = 26.0 Hz), 42.5 (t, J = 26.0 Hz), 52.1, 110.1, 115.0 (t, J = 5.8
Hz), 115.4 (t, J = 5.8 Hz), 123.6 (t, J = 243.5 Hz), 123.8, 124.0 (t, J = 243.3 Hz), 124.1, 129.3,
129.7, 130.5, 131.8, 132.0, 138.7 (t, J = 4.2 Hz), 138.8 (t, J = 4.2 Hz), 140.5, 140.7, 167.0. 19F
NMR (282 MHz, CDCl3) δ: major, –95.7 (tt, 2F, J = 15.9, 15.9 Hz), minor: –96.3 (tt, 2F, J = 15.9,
15.9 Hz). Calcd for C20H26F2O2 (336.42): C 71.40, H 7.79. Found: C 71.19, H 7.55.
Methyl 4-(2,2-difluoro-5-methylhex-4-enyl)benzoate (4i). 322 mg (80%). Colorless oil. Rf =
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0.26 (hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3), δ: 1.56 (s, 3H), 1.77 (s, 3H), 2.57 (td,
2H, J = 15.8, 7.2 Hz), 3.18 (t, 2H, J = 16.3 Hz), 3.92 (s, 3H), 5.15–5.25 (m, 1H), 7.34 (d, 2H, J =
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8.2 Hz), 8.00 (d, 2H, J = 8.2 Hz). C NMR (75 MHz, CDCl3), δ: 18.0, 25.9, 35.3 (t, J = 25.4 Hz),
42.3 (t, J = 26.0 Hz), 52.0, 115.0 (t, J = 5.8 Hz), 123.8 (t, J = 243.3 Hz), 129.3, 129.6, 130.5, 137.0,
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138.8 (t, J = 4.4 Hz), 166.9. 19F NMR (282 MHz, CDCl3) δ: –95.9 (tt, 2F, J = 16.3, 15.8 Hz). Calcd
for C15H18F2O2 (268.30): C 67.15, H 6.76. Found: C 67.09, H 6.66.
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Methyl 3-(2,2-difluoropent-4-enyl)benzoate (4j). 274 mg (76%). Colorless oil. Rf = 0.26
(hexanes/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3), δ: 2.57 (dt, 2H, J = 15.8, 7.3 Hz), 3.19 (t, 2H,
J = 15.8 Hz), 3.92 (s, 3H), 5.21 (dd, 1H, J = 17.4, 1.6 Hz), 5.27 (dd, 1H, J = 10.5, 1.7 Hz), 5.85
(ddt, 1H, J = 17.4, 10.5, 7.3 Hz), 7.40 (dd, 1H, J = 7.3, 7.3 Hz), 7.48 (d, 1H, J = 7.3 Hz), 7.96 (d,
1H, J = 1.5 Hz), 7.97 (dd, 1H, J = 7.3, 1.5 Hz). 13C NMR (75 MHz, CDCl3), δ: 40.6 (t, J = 25.6 Hz),
42.0 (t, J = 25.6 Hz), 52.0, 120.5, 122.7 (t, J = 243.6 Hz), 128.4, 128.5, 129.2 (t, J = 5.8 Hz), 130.3,
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131.4, 133.5 (t, J = 4.3 Hz), 134.8, 166.7. F NMR (282, CDCl3), δ: –96.9 (tt, 2F, J = 15.8. 15.8
Hz). Calcd for C13H14F2O2 (240.25): C 64.99, H 5.87. Found: C 65.05, H 5.87.
4-(2,2-Difluoropent-4-enyl)benzonitrile (4k). 249 mg (80%). Colorless crystals. Mp 40–42 °C.
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Rf = 0.27 (hexanes/EtOAc, 15/1). H NMR (300 MHz, CDCl3), δ: 2.60 (td, 2H, J = 15.6, 7.2 Hz),
3.20 (t, 2H, J = 16.2 Hz), 5.22 (dd, 1H, J = 17.4, 1.2 Hz), 5.28 (dd, 1H, J = 10.2, 1.2 Hz), 5.83 (ddt,
1H, J = 17.4, 10.2, 7.2 Hz), 7.40 (d, 2H, J = 7.8 Hz), 7.63 (d, 2H, J = 7.8 Hz). 13C NMR (75 MHz,
CDCl3), δ: 40.9 (t, J = 25.6 Hz), 42.3 (t, J = 25.9 Hz), 111.5, 118.6, 120.9, 122.5 (t, J = 243.9 Hz),
129.1 (t, J = 6.1 Hz), 131.3, 132.1, 138.6 (t, J = 4.0 Hz). 19F NMR (282 MHz, CDCl3), δ: –96.8 (tt,
2F, J = 16.2, 15.6 Hz). Calcd for C12H11F2N (207.22): C 69.55, H 5.35, N 6.76. Found: C 69.59, H
5.38, N 6.69.
1-Bromo-4-(2,2-difluoropent-4-enyl)benzene (4l). 317 mg (81%). Colorless oil. Rf = 0.33
(hexane). 1H NMR (300 MHz, CDCl3), δ: 2.58 (td, 2H, J = 15.9, 7.1 Hz), 3.12 (t, 2H, J = 15.9 Hz),
5.22 (dd, 1H, J = 17.0, 1.5 Hz), 5.29 (dd, 1H, J = 10.1, 1.5 Hz), 5.86 (ddt, 1H, J = 17.0, 10.1, 7.1
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Hz), 7.18 (d, 2H, J = 8.2 Hz), 7.49 (d, 2H, J = 8.2 Hz). C NMR (75 MHz, CDCl3), δ: 40.5 (t, J =
25.6 Hz), 41.7 (t, J = 25.9 Hz), 120.5, 121.4, 122.7 (t, J = 243.6 Hz), 129.3 (t, J = 5.8 Hz), 131.5,
132.0, 132.1 (t, J = 5.0 Hz). 19F NMR (282 MHz, CDCl3), δ: –96.8 (tt, 2F, J = 15.9, 15.9 Hz). Calcd
for C11H11BrF2 (261.11): C 50.60, H 4.25. Found: C 50.61, H 4.29.
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1-(2,2-Difluoropent-4-enyl)naphthalene (4m). 272 mg (78%). Colorless oil. Rf = 0.24
(hexane). 1H NMR (300 MHz, CDCl3), δ: 2.70 (td, 2H, J = 15.9, 7.0 Hz), 3.68 (t, 2H, J = 15.9 Hz),
5.26 (dd, 1H, J = 17.8, 1.3 Hz), 5.32 (dd, 1H, J = 11.0, 1.3 Hz), 5.96 (ddt, 1H, J = 17.8, 11.0, 7.0
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Hz), 7.42–7.65 (m, 4H), 7.82–7.90 (m, 1H), 7.92 (d, 1H, J = 7.8 Hz), 8.12 (d, 1H, J = 7.8 Hz). C
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NMR (75 MHz, CDCl3), δ: 39.0 (t, J = 25.9 Hz), 41.1 (t, J = 25.6 Hz), 120.5, 123.5 (t, J = 243.9
Hz), 124.4 (t, J = 1.8 Hz), 125.3, 125.7, 126.2, 128.3, 128.8, 129.4, 129.6 (d, J =5.5 Hz), 129.6,
132.9, 134.0. 19F NMR (282 MHz, CDCl3), δ: –95.4 (tt, 2F, J = 15.9, 15.9 Hz). Calcd for C15H14F2
(232.27): C 77.57, H 6.08. Found: C 77.17, H 5.55.
(4-Bromo-2,2-difluoro-1-methylpent-4-enyl)benzene (4n). 306 mg (74%). Colorless oil. Rf =
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0.19 (pentane). H NMR (300 MHz, CDCl3), δ: 1.50 (d, 3H, J = 7.2 Hz), 2.85–2.99 (m, 2H), 3.30
(ddq, 1H, J = 19.6, 10.5, 7.2 Hz), 5.72 (d, 1H, J = 1.7 Hz), 5.74 (d, 1H, J = 1.7 Hz), 7.29–7.42 (m,
5H). 13C NMR (75 MHz, CDCl3), δ: 14.4 (t, J = 5.3 Hz), 45.59 (dd, J = 24.2, 22.1 Hz), 45.62 (dd, J
= 27.1, 25.4 Hz), 122.1 (dd, J = 5.2, 3.3 Hz), 122.3, 122.7 (t, J = 248.8 Hz), 127.0, 128.1, 128.2 (t, J
= 1.4 Hz), 138.8 (d, J = 6.1 Hz). 19F NMR (282 MHz, CDCl3), δ: –105.8 (ddt, 1F, J = 245.8, 19.6,
12.7 Hz), –101.7 (dtd, 1F, J = 245.8, 15.4, 10.5 Hz). Calcd for C12H13BrF2 (275.13): C 52.39, H
4.76. Found: C 52.11, H 4.88.
4,4-Difluorohept-6-enyl benzoate (4o). 267 mg, 70%. Colorless oil. Rf = 0.41 (hexanes/EtOAc
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15/1). H NMR (300 MHz, CDCl3), δ: 1.87–2.15 (m, 4H), 2.65 (td, 2H, J = 16.0, 7.3 Hz), 4.36 (t,
2H, J = 5.7 Hz), 5.23 (dd, 1H, J = 16.1, 1.2 Hz), 5.24 (dd, 1H, J = 10.3, 1.2 Hz), 5.82 (ddt, 1H, J =
16.0, 10.3, 7.3 Hz), 7.45 (dd, 2H, J = 7.9, 7.2 Hz), 7.57 (dd, 1H, J = 7.2 Hz), 8.06 (d, 2H, J = 7.9
Hz). 13C NMR (75 MHz, CDCl3), δ: 21.8 (t, J = 4.6 Hz), 32.7 (t, J = 25.6 Hz), 41.4 (t, J = 26.2 Hz),
64.2, 120.3, 123.9 (t, J = 241.8 Hz), 128.4, 129.5 (t, J = 6.1 Hz), 129.6, 130.3, 133.0, 166.4. 19F
NMR (282, CDCl3), δ: –98.6 (tt, 2F, J = 16.0, 16.0 Hz). Calcd for C14H16F2O2 (254.27): C 66.13, H
6.34. Found: C 66.09, H 6.38.
[6-(1,1-Difluoroethyl)cyclohex-1-en-1-yl]benzene (4p). 147 mg (66%). Colorless oil. Rf = 0.28
(pentane).1H NMR (300 MHz, CDCl3), δ: 1.39 (t, 3H, J = 18.8 Hz), 1.62–1.76 (m, 1H), 1.77–1.97
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(m, 2H), 2.10–2.21 (m, 1H), 2.22–2.33 (m, 2H), 3.19–3.39 (m, 1H), 6.04–6.12 (m, 1H), 7.19–7.44
(m, 5H). 13C NMR (75 MHz, CDCl3), δ: 18.5 (dd, J = 2.8, 1.4 Hz), 23.2 (t, J = 28.2), 23.7 (dd, J =
5.0, 3.8 Hz), 25.5, 42.9 (t, J = 23.5 Hz), 125.4 (t, J = 243.5 Hz), 126.59, 126.62, 128.1, 132.2, 135.5
(t, J =3.9 Hz), 143.8. 19F NMR (282 MHz, CDCl3), δ: –90.4 (dqd, 1F, J = 243.0, 18.8, 17.0 Hz), –
85.4 (dqd, 1F, J = 243.0, 18.8, 12.7 Hz). Calcd for C14H16F2 (222.27): C 75.65, H 7.26. Found: C
75.59, H 7.21.
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Acknowledgement
This work was supported by the Ministry of Science (project MDꢀ1151.2011.3), Russian
Foundation for Basic Research (project 13ꢀ03ꢀ12074), and the Russian Academy of Sciences.
Supporting Information
Copies of NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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(14) The reaction of allyl chlorides with πꢀnucleophiles promoted by ZnCl2 has been described,
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Chem. Ber. 1984, 117, 322–335.
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(15) Attempted observation of intermediate 5 was unsuccessful. Thus, mixing of reagent 2a with
stoichiometric amounts of phen and CuI at –25 °C gave a precipitate, while subsequent
recording of 19F NMR spectrum at room temperature gave no signals.
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(16) For a similar erosion of double bond configuration along with αꢀattack in reaction of
trifluoromethyl copper species, see ref. 10a.
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