Reaction of 1,1ꢀdifluoroalkylzinc halides
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 11, November, 2014 2565
[4ꢀ(Methoxycarbonyl)benzyl]zinc chloride (6a). To a suspenꢀ
sion of zinc dust (1.21 g, 18.5 mmol) in THF (8 mL), two drops
of Me3SiCl were added and the mixture was heated to reflux.
After cooling the mixture using iceꢀwater, methyl 4ꢀ(chloroꢀ
methyl)benzoate (1.66 g, 9.0 mmol) was added. The mixture was
stirred at 0 С for 2 h and then at room temperature for 16 h. The
0.94 М solution (iodometry data) was obtained.
dominant product. Apparently, chlorinating reagents oxiꢀ
dize the bromide ions both present in the reagent 2a and
formed from Me3SiCF2Br. However, addition of silver
acetate capable of acting as a bromide ion scavenger reꢀ
sults in decomposition of reagent 2a. It should be noted
that separation of a mixture of compounds 4a and 5a is
very complicated due to the similarity of their physicoꢀ
chemical properties.
To exclude the possibility of bromination, we employed
the corresponding organozinc chlorides 6a,b together with
(chlorodifluoromethyl)thrimethylsilane as a source of
the CF2 species in the presence of sodium acetate as an
activator. Chlorination of intermediate reagents 7a,b was
achieved with sulfuryl chloride (Scheme 3). This proceꢀ
dure allows us to obtain compounds 5a,b bearing the
chlorodifluoromethyl group in 57—64% yields.
Methyl 4ꢀ(2ꢀchloroꢀ2,2ꢀdifluoroethyl)benzoate (5a). A solution
of [4ꢀ(methoxycarbonyl)benzyl]zinc chloride 6a (0.47 mmol,
0.50 mL, 0.94 М solution in THF) was diluted with diglyme (0.5 mL)
and anhydrous NaOAc (50.7 mg, 0.62 mmol) was added.
The mixture was cooled to –25 С and Me3SiCF2Cl (98 mg,
0.62 mmol) was added with stirring. The reaction mixture was
stirred at –25 С for 45 h and at 0 С for 1 h. Then, SO2Cl2
(80.4 mg, 0.60 mmol) was added and stirring was continued at
0 С for 30 min. The volatiles were removed in vacuo (~15 Torr),
and the residue was diluted with hexane (5 mL) and 1 М H2SO4
(5 mL). Aqueous layer was extracted with hexane (2×3 mL).
Combined organics were washed with 1 М H2SO4 (3 mL), dried
with Na2SO4, and concentrated in vacuo. Purification of the
residue by silica gel column chromatography (gradient elution
with EtOAc—hexane, 1 : 40 1 : 20) afforded compound 5a in
the yield of 71 mg (64%), colorless oil, Rf 0.29 (EtOAc—hexane,
1 : 8). 1H NMR (300 MHz), : 8.04 (d, 2 H, CHAr, J = 8.1 Hz);
7.39 (d, 2 H, CHAr, J = 8.1 Hz); 3.92 (s, 3 H, OMe); 3.62 (t, 2 H,
CH2, J = 13.0 Hz). 13C NMR (75 MHz), : 166.7; 136.0
(t, J = 2.9 Hz); 130.7, 130.2, 129.9; 128.2 (t, J = 292.5 Hz); 52.3;
47.8 (t, J = 25.3 Hz). 19F NMR (282 MHz), : –51.8 (t, J = 13.0 Hz).
Found (%): C, 51.08; H, 4.01. C10H9ClF2O2. Calculated (%):
C, 51.19; H, 3.87.
Scheme 3
1ꢀ(2ꢀChloroꢀ2,2ꢀdifluoroethyl)naphthalene (5b). A solution
of (1ꢀnaphthyl)zinc chloride (1.25 mmol, 1.0 mL, 1.25 М soluꢀ
tion in THF) was diluted with Nꢀmethylpyrrolidone (1.0 mL),
and anhydrous NaOAc (130 mg, 1.59 mmol) was added. After
cooling the mixture to –25 С, Me3SiCF2Cl (239 mg, 1.51 mmol)
was added with stirring and stirring was continued for 24 h at the
same temperature. Then, SO2Cl2 (201 mg, 1.49 mmol) was addꢀ
ed and stirring was continued for 20 min. The cooling was reꢀ
moved, the stirred reaction mixture was treated with hexane
(3 mL) and saturated aqueous NaHCO3 (5 mL). After warming
up to room temperature, the organic layer was separated and the
aqueous layer was extracted with hexane (2×5 mL). The comꢀ
bined organics was dried with Na2SO4, and concentrated in vacuo.
Purification of the residue by silica gel column chromatography
(elution with hexane) afforded compound 5b in the yield of
162 mg (57%), colorless oil, crystallized on standing. Rf 0.28
(hexane), m.p. 38—41 С. 1H NMR (300 MHz), : 8.06 (d, 1 H,
CHAr, J = 8.2 Hz); 7.94—7.85 (m, 2 H, CHAr); 7.63—7.44 (m, 4 H,
CHAr); 4.10 (t, 2 H, CH2, J = 13.3 Hz). 13C NMR (75 MHz),
: 134.1, 132.6, 130.1, 129.3; 129.1 (t, J = 293.4 Hz); 129.0;
127.4 (t, J = 2.3 Hz); 126.7; 126.0; 125.3; 123.9 (t, J = 1.7 Hz);
44.5 (t, J = 25.1 Hz). 19F NMR (282 MHz), : –50.5 (t, J = 13.3 Hz).
Found (%): C, 63.71; H, 4.09. C12H9ClF2. Calculated (%):
C, 63.59; H, 4.00.
5—7: Ar = 4ꢀMeO2CC6H4 (a), 1ꢀnaphthyl (b)
In summary, we demonstrated that compounds bearꢀ
ing the chlorodifluoromethyl group are readily available
via reactions involving organozinc reagents. It should be
emphasized that this method can be accomplished only
with organozinc chlorides since organozinc bromides lead
to undesired bromodifluoroꢀsubstituted products due
to oxidation of the bromide ions with the chlorinating
reagents.
Experimental
1
H, 13C, and 19F NMR spectra were run on a Bruker AMꢀ
300 instrument in CDCl3. Acetonitrile was distilled over CaH2.
(1ꢀNaphthylmethyl)zinc chloride5 and (chlorodifluoromethyl)ꢀ
trimethylsilane8 were synthesized by the known procedure.
Methyl 4ꢀ(chloromethyl)benzoate. A mixture of methyl
4ꢀ(bromomethyl)benzoate (5.13 g, 22.4 mmol) and LiCl (1.90 g,
44.8 mmol) in diglyme (20 mL) was stirred at 0 С for 18 h.
Then, ice water (10 mL) and hexane (10 mL) were added. The
organic layer was separated, filtered through Na2SO4, and conꢀ
centrated in vacuo. To the residue, diglyme (10 mL) and LiCl
(0.95 g, 22.4 mmol) were added and the mixture was stirred at
0 C for 5 h. The stirred reaction mixture was diluted with water
(30 mL), the precipitate formed was collected, dried in vacuo,
and recrystallized form methanol. Methyl 4ꢀ(chloromethyl)ꢀ
benzoate was obtained in the yield of 2.89 g (70%).9
This work was financially supported by the Russian
Science Foundation (Project No. 14ꢀ23ꢀ00150).
References
1. (a) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem., Int.
Ed., 2013, 52, 8214; (b) Organofluorine Chemistry, Ed. K. Uneꢀ
Smirnov
