Page 11 of 17
The Journal of Organic Chemistry
corresponding Suzuki reaction was performed following LC/MS (24 h), the crude Suzuki product was purified via silica
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Method E using 4-bromoanisole as the cross-coupling partner
at 50 °C. Upon consumption of the boronic acid based on
LC/MS (20 h), the reaction was cooled to room temperature and
filtered, the wet cake was rinsed with warm (55 °C) DI H2O (2
x 3 mL) and then allowed to dry under house vacuum to afford
the cross-coupled product 16 as a tan solid (307 mg, 0.71 mmol,
gel column chromatography done using 5 % MeOH/ DCM as
eluent to afford 19 as a pale yellow solid (296 mg, 0.62 mmol,
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62 %). H NMR (500 MHz, DMSO-d6) δ 7.59 (d, J = 8.7 Hz,
2H), 7.24 – 7.13 (m, 5H), 7.07 (d, J = 8.0 Hz, 1H), 7.02 (d, J =
8.8 Hz, 2H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 4.33 (s, 1H), 4.02 (t,
J = 6.8 Hz, 2H), 3.80 (s, 3H), 3.44 (q, J = 5.7, 5.3 Hz, 2H), 2.35
(m, 12H), 1.82 (p, J = 6.8 Hz, 2H). 13C{1H} NMR (126 MHz,
DMSO) δ 159.5, 145.7, 145.1, 140.0, 132.7, 128.2, 128.0,
127.8, 127.5, 124.0, 122.9, 122.5, 120.9, 116.5, 114.8, 114.2,
60.7, 58.9, 55.7, 55.4, 53.7, 53.4, 45.0, 27.5, 24.3. HRMS (ESI,
m/z): calcd. for C28H33N3O2S, [M+H]+: 476.2366; found:
476.2356.
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71 %). H NMR (500 MHz, Acetone-d6) δ 11.84 (s, 1H), 8.35
(d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.92
(d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 2.4
Hz, 1H), 7.16 – 7.06 (m, 2H), 3.90 (s, 3H), 1.55 (s, 9H), 1.42 (s,
9H). 13C{1H} NMR (126 MHz, Acetone) δ 160.0, 146.6, 143.5,
142.0, 141.7, 140.7, 138.5, 132.5, 128.5, 128.3, 125.1, 125.1,
117.8, 116.0, 114.5, 113.6, 54.8, 35.4, 34.3, 30.8, 29.0. HRMS
(ESI, m/z): calcd. for C27H31N3O2, [M+H]+: 430.2489; found:
430.2477.
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1-(4-Fluorophenyl)-4-(4-hydroxy-4-(4'-methoxy-[1,1'-bi-
phenyl]-4-yl)piperidin-1-yl)butan-1-one (20). The borylation
of the corresponding aryl chloride (haloperidol) was performed
using Method C at room temperature and complete in 4 h based
on LC/MS. The corresponding Suzuki reaction was performed
following Method E using 4-bromoanisole as the cross-cou-
pling partner at 50 °C. Upon consumption of the boronic acid
based on LC/MS (20 h), the reaction was cooled to room tem-
perature and filtered, the wet cake was rinsed with warm (55
°C) DI H2O (2 x 3 mL) and then allowed to dry under house
vacuum to afford 20 as an off-white/pale grey solid (329 mg,
0.73 mmol, 73 %). 1H NMR (500 MHz, DMSO-d6) δ 8.09 (dd,
J = 8.6, 5.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.3
Hz, 2H), 7.47 – 7.31 (m, 4H), 7.02 (d, J = 8.7 Hz, 2H), 4.74 (s,
1H), 3.80 (s, 3H), 2.99 (t, J = 6.8 Hz, 2H), 2.60 (d, J = 12.0 Hz,
2H), 2.44 – 2.27 (m, 4H), 1.86 (p, J = 6.8 Hz, 2H), 1.73 (td, J =
12.8, 4.3 Hz, 2H), 1.51 (d, J = 12.4 Hz, 2H). 13C{1H} NMR (126
MHz, DMSO) δ 198.8, 166.3, 164.3, 159.2, 149.1, 138.1, 134.5,
132.9, 131.3 (d, JC-F = 9.3 Hz), 128.0, 126.0, 125.7, 116.1,
116.0, 114.8, 70.0, 57.8, 55.6, 49.5, 38.4, 36.2, 22.5. 19F NMR
(471 MHz, DMSO-d6) δ -106.90. HRMS (ESI, m/z): calcd. for
C28H30FNO3, [M+H]+: 448.2282; found: 448.2274.
5-(4-Methoxyphenyl)-2-methylbenzo[d]thiazole (17). The
borylation of the corresponding aryl chloride (5-chloro-2-
methylbenzothiazole) was performed using Method C at 55 °C
and complete in 4.5 h based on LC/MS. The corresponding Su-
zuki reaction was performed following Method E using 4-bro-
moanisole as the cross-coupling partner at 55 °C. Upon con-
sumption of the boronic acid based on LC/MS (19 h), the crude
Suzuki product was purified via silica gel column chromatog-
raphy using a gradient of EtOAc/hexanes (10-20 %) to provide
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17 as a white solid (195 mg, 0.76 mmol, 76%). H NMR (500
MHz, DMSO-d6) δ 8.12 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.4 Hz,
1H), 7.71 (d, J = 8.7 Hz, 2H), 7.66 (dd, J = 8.4, 1.8 Hz, 1H),
7.06 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.82 (s, 3H). 13C{1H}
NMR (126 MHz, DMSO) δ 168.1, 159.5, 154.3, 138.6, 134.1,
132.6, 128.5, 123.8, 122.7, 119.6, 114.9, 55.7, 20.3. HRMS
(ESI, m/z): calcd. for C15H13NOS, [M+H]+: 256.0791; found:
256.0790.
2-(4-Methoxyphenyl)-9H-thioxanthen-9-one
(18).
The
borylation of the corresponding aryl chloride (2-chlorothioxan-
thone) was performed using Method C at room temperature and
complete in 22 h based on LC/MS. The corresponding Suzuki
reaction was performed following Method E using 4-bromoan-
isole as the cross-coupling partner at 55 °C. Upon consumption
of the boronic acid based on LC/MS (24 h), the reaction was
cooled to room temperature and filtered, the wet cake was
rinsed with warm (55 °C) DI H2O (2 x 3 mL) and then allowed
to dry under house vacuum to afford solids that were slightly
impure. The solids were recrystallized with nitromethane (1.2
mL) to afford the cross-coupling product 18 as a pale yellow
solid (175 mg, 0.54 mmol, 54 %). 1H NMR (500 MHz, DMSO-
d6) δ 8.65 (d, J = 2.2 Hz, 1H), 8.50 (dd, J = 8.1, 1.5 Hz, 1H),
8.06 (dd, J = 8.4, 2.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.87
(dd, J = 8.2, 1.2 Hz, 1H), 7.79 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H),
7.74 (d, J = 8.8 Hz, 2H), 7.61 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H),
7.09 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H). 13C{1H }NMR (126 MHz,
DMSO) δ 179.3, 159.9, 138.7, 137.0, 135.2, 133.5, 131.4,
131.3, 129.6, 129.1, 128.8, 128.4, 127.8, 127.3, 127.1, 126.1,
115.1, 55.7. HRMS (ESI, m/z): calcd. for C20H14O2S, [M+H]+:
319.0787; found: 319.0778.
6-(4-Methoxyphenyl)-2-methyl-4H-chromen-4-one
(21).
The borylation of the corresponding aryl bromide (6-bromo-2-
methylchromone) was performed using Method B at 40 °C and
complete in 7 h based on LC/MS. The corresponding Suzuki
reaction was performed following Method E using 4-bromoan-
isole as the cross-coupling partner at 55 °C. Upon consumption
of the boronic acid based on LC/MS (16 h), the crude Suzuki
product was purified via silica gel column chromatography
done using 10-20 % EtOAc/hexanes as eluent to afford the
cross-coupling product 21 as a pale yellow/orange solid (219
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mg, 0.82 mmol, 82%). H NMR (500 MHz, DMSO-d6) δ 8.15
(d, J = 2.4 Hz, 1H), 8.04 (dd, J = 8.7, 2.5 Hz, 1H), 7.73 – 7.63
(m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 6.28 (d, J = 1.0 Hz, 1H), 3.82
(s, 3H), 2.42 (s, 3H). 13C{1H} NMR (126 MHz, DMSO) δ
177.2, 167.3, 159.7, 155.5, 137.3, 132.4, 131.3, 128.4, 123.7,
121.7, 119.2, 115.0, 110.3, 55.7, 20.5. HRMS (ESI, m/z): calcd.
for C17H14O3, [M+H]+: 267.1016; found: 267.1013.
5-(4-Methoxyphenyl)-1H-indole33 (22). The corresponding
Suzuki product was made using multiple methods: Table 3:
The borylation of 5-bromoindole was performed using Method
A at 40 °C and complete in 4.5 h based on LC/MS. The corre-
sponding Suzuki reaction was performed following Method E
using 4-bromoanisole as the cross-coupling partner at 55 °C.
Upon consumption of the boronic acid based on LC/MS, the
crude Suzuki product was purified via column chromatography
using 10 % EtOAc/hexanes as eluent to afford 22 as an off-
white solid (195 mg, 0.87 mmol, 87%).
2-(4-(3-(2-(4-Methoxyphenyl)-10H-phenothiazin-10-yl)pro-
pyl)piperazin-1-yl)ethan-1-ol (19). The borylation of the cor-
responding aryl chloride (perphenazine) was performed using
Method C at 40 °C and complete in 4.5 h based on LC/MS. The
corresponding Suzuki reaction was performed following
Method E using 4-bromoanisole as the cross-coupling partner
at 55 °C. Upon consumption of the boronic acid based on
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