ACCEPTED MANUSCRIPT
Na2CO3 aq. until the aqueous phase was at pH = 11 and washed
Methyl (R)-3-(4-chlorophenyl)-4,4-difluorobutanoate ((R)-4e)
1H NMR (300 MHz, CDCl3) δ 2.75 (dd, 1H, J = 16.5, 9.1 Hz),
2.93 (dd, 1H, J = 16.5, 35.7 Hz), 3.52-3.69 (m, 1H), 3.62 (s, 3H),
5.91 (td, 1H, JH-F = 56.2, J = 3.2 Hz), 7.22 (d, 2H, J = 8.5 Hz),
7.33 (d, 2H, J = 8.5 Hz); 19F NMR (282 MHz, CDCl3) δ -123.4
(ddd, 1F, JF-F = 279.6, JF-H = 55.4, 18.0 Hz), -120.1 (ddd, 1F, JF-F
with Et2O (5 mL). The aqueous phase was acidified until pH = 1,
extracted with CH2Cl2 (5 mL × 4), and the combined organic
phases were dried with anhydrous MgSO4. After filtration and
concentration under vacuum, the crude carboxylic acid was ob-
tained.
= 278.9, JF-H = 57.7, 15.1 Hz); [α]24 +16.53 (c 1.71, CHCl3), 48%
D
Esterification
ee; HPLC (column, CHIRALPAK AS-H, Hexane/2-Propanol =
99/1, flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) tR of
major (R)-isomer 11.8 min, tR of minor (S)-isomer 16.5 min.
The crude carboxylic acid was dissolved in dry DMF (2.0 mL)
and treated with MeI (19 ꢀL, 0.3 mmol) or benzyl bromide (36
ꢀL, 0.3 mmol) and K2CO3 (55.3 mg, 0.4 mmol) under argon at-
mosphere. The mixture was stirred for 3 h at room temperature,
then the resulting mixture was directly passed through silica-gel
column to isolate the difluoromethylated ester 4.
Methyl (R)-4,4-difluoro-3-(4-nitrophenyl)butanoate ((R)-4f)
1H NMR (300 MHz, CDCl3) δ 2.82 (dd, 1H, J = 16.8, 9.1 Hz),
3.02 (dd, 1H, J = 16.8, 5.7 Hz), 3.63 (s, 3H), 3.68-3.84 (m, 1H),
5.99 (td, 1H, JH-F = 55.9, J = 3.1 Hz), 7.48 (d, 2H, J = 8.7 Hz),
8.22 (d, 2H, J = 8.8 Hz); 19F NMR (282 MHz, CDCl3) δ -122.4
(ddd, 1F, JF-F = 281.4, JF-H = 55.8, 15.4 Hz), -120.8 (ddd, 1F, JF-F
Methyl (R)-4,4-difluoro-3-(4-methoxyphenyl)butanoate ((R)-
4a)
1H NMR (300 MHz, CDCl3) δ 2.75 (dd, 1H, J = 16.2, 9.0 Hz),
2.94 (dd, 1H, J = 16.3, 5.8 Hz), 3.49-3.66 (m, 1H), 3.62 (s, 3H),
3.79 (s, 3H), 5.89 (td, 1H, JH-F = 56.4, J = 3.3 Hz), 6.88 (d, 2H, J
= 8.8 Hz), 7.20 (d, 2H, J = 8.6 Hz); 19F NMR (282 MHz, CDCl3)
δ -123.9 (ddd, 1F, JF-F = 278.7, JF-H = 56.2, 18.1 Hz), -119.5 (ddd,
= 281.8, JF-H = 55.8, 16.3 Hz); [α]24 +7.5 (c 0.85, CHCl3), 20% ee;
D
HPLC (column, CHIRALPAK AS-H, Hexane/2-Propanol = 96/4,
flow rate 0.8 mL/min, 20 °C, detection UV 254 nm) tR of major
(R)-isomer 33.4 min, tR of minor (S)-isomer 53.7 min.
1F, JF-F = 276.2, JF-H = 55.9, 13.8 Hz); [α]2D4 +22.2 (c 1.09,
CHCl3), 72% ee; HPLC (column, CHIRALPAK AS-H, Hexane/2-
Propanol = 99/1, flow rate 0.8 mL/min, 20 °C, detection UV 254
nm) tR of major (R)-isomer 18.3 min, tR of minor (S)-isomer 33.7
min.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
Benzyl (R)-4,4-difluoro-3-phenylbutanoate ((R)-4b)
1H NMR (300 MHz, CDCl3) δ 2.85 (dd, 1H, J = 16.2, 9.1 Hz),
3.02 (dd, 1H, J = 16.2, 5.8 Hz), 3.56-3.73 (m, 1H), 5.00-5.09 (m,
2H), 5.93 (td, 1H, JH-F = 56.3, J = 3.4 Hz), 7.18-7.23 (m, 2H),
7.27-7.37 (m, 8H); 19F NMR (282 MHz, CDCl3) δ -123.7 (ddd,
AUTHOR INFORMATION
Corresponding Author
1F, JF-F = 277.5, JF-H = 56.8, 18.0 Hz), -119.3 (ddd, 1F, JF-F
=
279.6, JF-H = 55.3, 13.6 Hz); [α]2D4 +9.7 (c 1.71, CHCl3), 46% ee;
* E-mail for K. M.: mikami.k.ab@m.titech.ac.jp.
HPLC (column, CHIRALPAK AD-3, Hexane/2-Propanol = 98/2,
flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) tR of major
(R)-isomer 15.4 min, tR of minor (S)-isomer 18.5 min.
ACKNOWLEDGMENT
This research was supported by the Japan Science and Technolo-
gy Agency (JST) (ACT-C: Creation of Advance Catalytic Trans-
formation for the Sustainable Manufacturing at Low Energy, Low
Environmental Load).
Methyl (R)-4,4-difluoro-3-(naphthalen-1-yl)butanoate ((R)-4c)
1H NMR (300 MHz, CDCl3) δ 2.97 (dd, 1H, J = 16.4, 8.0 Hz),
3.16 (dd, 1H, J = 16.4, 6.4 Hz), 3.60 (s, 3H), 4.55-4.71 (m, 1H),
6.07 (td, 1H, JH-F = 56.3, J = 3.3 Hz), 7.47-7.63 (m, 4H), 7.81-
7.90 (m, 2H), 8.16 (d, 1H, J = 8.5 Hz); 19F NMR (282 MHz,
CDCl3) δ -123.6 (ddd, 1F, JF-F = 277.7, JF-H = 56.9, 12.6 Hz), -
REFERENCES
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118.0 (ddd, 1F, JF-F = 277.4, JF-H = 57.2, 7.3 Hz); [α]2D4 -13.1 (c
1.14, CHCl3), 82% ee; HPLC (column, CHIRALCEL OJ-3, Hex-
ane/2-Propanol = 99/1, flow rate 0.8 mL/min, 20 °C, detection
UV 220 nm) tR of major (R)-isomer 44.6 min, tR of minor (S)-
isomer 59.3 min.
Methyl
(R)-3-(3,4-dimethoxyphenyl)-4,4-difluorobutanoate
((R)-4d)
1H NMR (300 MHz, CDCl3) δ 2.75 (dd, 1H, J = 16.3, 9.0 Hz),
2.94 (dd, 1H, J = 16.3, 5.8 Hz), 3.48-3.64 (m, 1H), 3.62 (s, 3H),
3.86 (s, 3H), 3.88 (s, 3H), 5.91 (td, 1H, JH-F = 56.4, J = 3.2 Hz),
6.78-6.83 (m, 3H); 19F NMR (282 MHz, CDCl3) δ -123.8 (ddd,
1F, JF-F = 276.1, JF-H = 55.7, 18.1 Hz), -119.2 (ddd, 1F, JF-F
=
277.9, JF-H = 57.0, 13.6 Hz); [α]24 +8.36 (c 0.90, CHCl3), 29% ee;
D
(3) For selected reviews, see: (a) Gao, B.; Ni, C.; Hu, J. Selective
Incorporation of Difluoromethylene Moieties into Arenes As-
sisted by Transition Metals. Chimia 2014, 68, 414. (b) Liang, T.;
Neumann, C. N.; Ritter, T. Introduction of Fluorine and Fluo-
rineꢁContaining Functional Groups. Angew. Chem. Int. Ed.
2013, 52, 8214. (c) Sugiishi, T.; Amii, H.; Aikawa, K.; Mikami,
HPLC (column, CHIRALPAK AS-H, Hexane/2-Propanol = 96/4,
flow rate 0.8 mL/min, 20 °C, detection UV 220 nm) tR of major
(R)-isomer 16.9 min, tR of minor (S)-isomer 19.6 min.