The Journal of Organic Chemistry
Note
gel chromatography. A 1.0 mmol scale reaction was performed with this
procedure for the synthesis of compound 5.
with DCM/pentane (5:95). Compound 6 was obtained as a yellow
solid (55 mg, 48% yield); mp 59−60 °C; 1H NMR (500 MHz, CDCl3)
δ 8.59 (s, 1H), 8.47 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 8.01 (t,
J = 54.0 Hz, 1H), 7.62−7.59 (multiple peaks, 2H), 7.53−7.50 (multiple
peaks, 2H); 13C{1H} NMR (176 MHz, CDCl3) δ 131.7 (t, J = 2.0 Hz),
131.4, 129.8 (t, J = 3.6 Hz), 129.4, 127.6, 125.5, 123.5−123.3 (two
overlapping peaks), 114.3 (t, J = 236 Hz); 19F NMR (470 MHz,
CDCl3) δ −106.7 (d, J = 54.0 Hz, 2F); HRMS (EI/magnetic sector)
calcd for C15H10F2 [M]+ m/z 228.0745, found 228.0756.
General Procedure B for the Difluoromethylation of Aryl
Chlorides/Bromides. In a glovebox, the aryl halide substrate (0.500
mmol, 1 equiv), Pd(PtBu3)2 (12.8 mg, 0.025 mmol, 0.05 equiv), CsF
(152 mg, 1.0 mmol, 2 equiv), dioxane (1.5 mL, 0.33 M), and
TMSCF2H (136 μL, 1.0 mmol, 2 equiv) were combined in a 4 mL vial.
The vial was sealed with a Teflon-lined screw cap and brought out of the
glovebox. The reaction was allowed to stir vigorously at 120 °C (100 °C
for aryl bromides) for 16 h (24 h for aryl bromides). The reaction
mixture was allowed to cool to room temperature, filtered through a
plug of Celite that was then washed with Et2O or DCM, and
concentrated under vacuum. The crude residue was purified via silica
gel chromatography. In a separate reaction, 19F NMR yields were obtained
using 0.1 mmol scale of aryl chloride/bromide under analogous conditions.
Trifluoromethoxybenzene (1 equiv, 0.5 M in THF) was used as internal
standard.
2-(Difluoromethyl)biphenyl (7).18 Synthesized using Method B
and 2-chlorobiphenyl (94.3 mg, 0.500 mmol). The crude residue was
purified by flash chromatography on silica gel (pentane). This
1
procedure afforded 7 as a colorless oil (48 mg, 47% yield); H NMR
(500 MHz, CDCl3) δ 7.81−7.79 (multiplet, 1H), 7.54−7.41 (multiple
peaks, 5H), 7.38−7.35 (multiple peaks, 3H), 6.55 (t, J = 55.0 Hz, 1H).
13C{1H} NMR (176 MHz, CDCl3) δ 141.6 (t, J = 6.7 Hz), 138.8, 131.9
(t, J = 22 Hz), 130.7 (t, J = 1.9 Hz), 130.4, 129.7, 128.6, 128.1, 128.1,
125.8 (t, J = 5.2 Hz), 113.3 (t, J = 236). 19F NMR (470 MHz, CDCl3) δ
−107.4 (d, J = 55.0 Hz, 2F). HRMS (EI/magnetic sector) calcd for
C13H10F2 [M]+ m/z 204.0745, found 204.0742.
1-Butyl-4-(difluoromethyl)benzene (2).9a Synthesized using
Method A and 1-butyl-4-chlorobenzene (84 mg, 0.5 mmol). The
crude mixture was purified by flash chromatography on silica gel
(hexanes/Et2O, 99:1). This procedure afforded 2 as a colorless oil (76
2-Difluoromethyl-1,3-dimethylbenzene (8).9a Synthesized
using Method B and 2-chloro-1,3-dimethylbenzene (70 mg, 0.5
mmol). The crude residue was purified by flash chromatography on
silica gel (pentane). This procedure afforded 8 as a colorless oil (29 mg,
37% yield); 1H NMR (500 MHz, CDCl3) δ 7.21 (t, J = 7.7 Hz, 1H),
7.05 (d, J = 7.7 Hz, 2H), 6.98 (t, J = 54.0 Hz, 1H), 2.48 (s, 6H);
13C{1H} NMR (176 MHz, CDCl3) δ 137.3 (t, J = 3.9 Hz), 130.5 (t, J =
1.8 Hz), 130.2 (t, J = 20 Hz), 129.4, 114.7 (t, J = 236 Hz), 19.7 (t, J = 1.8
Hz); 19F NMR (470 MHz, CDCl3) δ −112.0 (d, J = 54.0 Hz, 2F).
1-(4-(Difluoromethyl)phenyl)-1H-pyrrole (9).10 Synthesized
using Method A and 1-(4-chlorophenyl)-1H-pyrrole (89 mg, 0.5
mmol). The crude mixture was purified by flash chromatography on
silica gel (gradient of hexanes/Et2O from 98:2 to 90:10). This
procedure afforded 9 as a white solid (58 mg, 60% yield); mp 85−87
°C; 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J = 8.2 Hz, 2H), 7.48 (d, J =
8.2 Hz, 2H), 7.14 (t, J = 2.2 Hz, 2H), 6.68 (t, J = 56.4 Hz, 1H), 6.41 (t, J
= 2.2 Hz, 2H); 13C{1H} NMR (CDCl3, 176 MHz) δ 142.6, 131.6 (t, J =
22.8 Hz), 127.3 (t, J = 6.0 Hz), 120.4, 119.3, 114.6 (t, J = 238.5 Hz),
111.4; 19F NMR (CDCl3, 376 MHz) δ −110.3 (d, J = 56.3 Hz, 2F);
HRMS (EI/magnetic sector) calcd for C11H9F2N [M]+ m/z 193.0703,
found 193.0706.
1
mg, 83% yield); H NMR (CDCl3, 500 MHz) δ 7.41 (d, J = 7.7 Hz,
2H), 7.26 (d, J = 7.7 Hz, 2H), 6.61 (t, J = 56.7 Hz, 1H), 2.65 (t, J = 7.8
Hz, 2H), 1.60 (tt, J = 7.8, 6.8, 2H), 1.35 (tq, J = 7.3, 6.8 Hz, 2H), 0.94 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 146.1 (t, J = 1.9
Hz), 132.0 (t, J = 22.5 Hz), 128.9, 125.7 (t, J = 5.9 Hz), 115.7 (t, J =
237.9 Hz), 35.7, 33.7, 22.5, 14.1; 19F NMR (CDCl3, 376 MHz) −109.7
(d, J = 56.7 Hz, 2F); HRMS (EI/magnetic sector) calcd for C11H14F2
[M]+ m/z 184.1064, found 184.1070.
4-(Difluoromethyl)biphenyl (3).9a Synthesized using Method A
and 4-chlorobiphenyl (94 mg, 0.5 mmol). The crude mixture was
purified by flash chromatography on silica gel (hexanes). This
procedure afforded 3 as a white solid (89 mg, 87% yield); mp 79−80
°C; 1H NMR (CDCl3, 500 MHz) δ 7.69 (d, J = 8.0 Hz, 2H), 7.64−7.57
(multiple peaks, 4H), 7.49−7.47 (multiple peaks, 2H), 7.40 (m, 1H),
6.71 (t, J = 56.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 143.9 (t,
J = 2.1 Hz), 140.4, 133.4 (t, J = 22.5 Hz), 129.1, 128.1, 127.6, 127.5,
126.3 (t, J = 6.0 Hz), 115.0 (t, J = 238.5 Hz); 19F NMR (CDCl3, 376
MHz) δ −110.4 (d, J = 56.5 Hz, 2F); HRMS (EI/magnetic sector)
calcd for C13H10F2 [M]+ m/z 204.0751, found 204.0759.
4-(Difluoromethyl)diphenyl Ether (4).12b Synthesized using
Method B and 4-chlorodiphenyl ether (102 mg, 0.5 mmol). The crude
residue was purified by flash chromatography on silica gel (pentane).
5-(Difluoromethyl)benzo[d][1,3]dioxole (10).18 Synthesized
using Method A and 5-chlorobenzo-[d][1,3]dioxole (78 mg, 0.5
mmol). The crude mixture was purified by flash chromatography on
silica gel (hexanes/Et2O, 98:2). This procedure afforded 10 as a
colorless oil (52 mg, 60% yield); 1H NMR (CDCl3, 400 MHz) δ 6.99−
6.97 (multiple peaks, 2H), 6.85 (d, J = 7.8 Hz, 1H), 6.54 (t, J = 56.6 Hz,
1H), 6.01 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 149.5 (t, J = 1.4
Hz), 148.0, 128.3 (t, J = 22.6 Hz), 120.1 (t, J = 7.1 Hz), 114.6 (t, J =
238.1 Hz), 108.2, 105.8 (t, J = 5.4 Hz), 101.5; 19F NMR (CDCl3, 376
MHz) δ −108.0 (d, J = 56.6 Hz, 2F); HRMS (EI/magnetic sector)
calcd for C8H6F2O2 [M]+ m/z 172.0336, found 172.0339.
1
This procedure afforded 4 as a colorless oil (54 mg, 45% yield); H
NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.2 Hz, 2H), 7.40−7.36
(multiple peaks, 2H), 7.19−7.15 (m, 1H), 7.06−7.04 (multiple peaks,
4H), 6.63 (t, J = 57.1 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3) δ
159.8 (t, J = 2.0 Hz), 156.4, 130.2, 129.1 (t, J = 23 Hz), 127.5 (t, J = 6.0
Hz), 124.3, 119.8, 118.5, 114.8 (t, J = 238 Hz); 19F NMR (470 MHz,
CDCl3) δ −109.1 (d, J = 57.1 Hz, 2F); HRMS (EI/magnetic sector)
calcd for C13H10F2O [M]+ m/z 220.0694, found 220.0697.
1-(Difluoromethyl)naphthalene (5).8c Synthesized using Meth-
od A and 1-chloronaphthalene (81 mg, 0.5 mmol). The crude mixture
was purified by flash chromatography on silica gel (pentane). This
procedure afforded 5 as a colorless oil (75.5 mg, 85% yield). Using
Method A and 1-chloronaphthalene (162 mg, 1.0 mmol), 5 was obtained as
a colorless oil (156 mg, 88% yield); 1H NMR (CDCl3, 400 MHz) δ 8.18
(d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.91 (m, 1H), 7.69 (dd, J =
7.1, 1.4 Hz, 1H), 7.62−7.48 (multiple peaks, 2H), 7.50 (dd, J = 7.7, 1.4
Hz, 1H), 7.14 (t, J = 55.2 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz)
δ 134.0, 131.7 (t, J = 1.8 Hz), 129.9 (t, J = 3.0 Hz), 129.8 (t, J = 20.8
Hz), 129.0, 127.4, 126.6, 125.0 (t, J = 8.7 Hz), 124.9, 123.8 (t, J = 1.2
Hz), 115.6 (t, J = 238.4 Hz); 19F NMR (CDCl3, 376 MHz) δ −110.9 (d,
J = 55.2 Hz, 2F); HRMS (EI/magnetic sector) calcd for C11H8F2 [M]+
m/z 178.0594, found 178.0598.
4-(Difluoromethyl)dibenzofuran (11).18 Synthesized using
Method B and 4-chlorodibenzofuran (101.3 mg, 0.500 mmol). The
crude residue was purified by flash chromatography on silica gel
(gradient of pentane to pentane/Et2O 95:5). This procedure afforded
11 as a colorless oil (63 mg, 58% yield); 1H NMR (500 MHz, CDCl3) δ
8.06 (dd, J = 7.7, 1.4 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.6
Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.53−7.49 (m, 1H), 7.43 (t, J = 7.8
Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 55.6 Hz, 1H); 13C{1H}
NMR (176 MHz, CDCl3) δ 156.6, 153.3 (t, J = 5.1 Hz), 128.1, 125.4,
124.0 (t, J = 5.7 Hz), 123.6, 123.5, 123.3 (t, J = 1.8 Hz), 123.0, 121.0,
118.7 (t, J = 24 Hz), 112.2, 112.1 (t, J = 237 Hz); 19F NMR (376 MHz,
CDCl3) δ −113.1 (d, J = 55.6 Hz, 2F); HRMS (EI/magnetic sector)
calcd for C13H8F2O [M]+ m/z 218.0538, found 218.0532.
1-(Difluoromethyl)methylnaphthalene (12).19 Synthesized
using Method B and 1-(chloromethyl)-naphthalene (88 mg, 0.5
mmol). The crude residue was purified by silica gel column
chromatography (pentane). This procedure afforded compound 12
as a colorless oil (35 mg, 36% yield); 1H NMR (500 MHz, CDCl3) δ
9-(Difluoromethyl)anthracene (6). Synthesized using Method B
and 4-chloroanthracene (106 mg, 0.5 mmol). The crude mixture was
purified via two sequential silica gel columns as follows. In the first
column, the product was eluted with a gradient of pentane to 2.5%
Et2O/97.5% pentane. In the second column, the product was eluted
D
J. Org. Chem. XXXX, XXX, XXX−XXX