Organic Process Research & Development
Article
100 g scale: 3a (320 mmol, 102.7 g), ClPPh2 (352 mmol, 65
mL), THF (1 L), 76% yield (103.8 g).
%, 0.1 mmol, 0.0439 g), and NaOt-Bu (150 mmol, 14.4 g)
were loaded into a Schlenk flask equipped with a Teflon-coated
magnetic stir bar. The flask was evacuated and flushed with
nitrogen for three cycles. 2-Chloro-1,3-dimethylbenzene (50
mmol, 6.63 mL), 2,6-diisopropylaniline (100 mmol, 18.9 mL),
toluene (25 mL), and hexane (25 mL) were added with
stirring at room temperature, and stirring was continued for
several minutes. The flask was then placed into a preheated oil
bath (110 °C) and stirred for 18 h. After completion of the
reaction as judged by GC−MS and TLC, the reaction flask was
allowed to cool to room temperature, and 50 mL of water was
added to the mixture. The resulting mixture was extracted with
EtOAc, and the organic layer was collected and extracted with
20 mL of aqueous 10 M hydrochloric acid at least 4 times to
remove the unreacted 2,6-diisopropylaniline (as monitored by
TLC). The solvent was then removed by rotary evaporation to
afford the desired product (98% yield, 15.7 g, 16.1 mL) as a
dark-brown oil. 1H NMR (500 MHz, CDCl3) δ 7.16−7.10 (m,
3H), 6.94 (d, J = 7.5 Hz, 2H), 6.72 (t, J = 7.5 Hz, 1H), 3.17−
3.12 (m, 2H), 1.98 (s, 6H), 1.11 (d, J = 7.0 Hz, 12H); 13C
NMR (125 MHz, CDCl3) δ 144.1, 143.1, 138.8, 129.5, 125.6,
124.8, 123.2, 119.6, 28.0, 23.4, 19.3.
(2S,6′R)-2′,4,6-Trimethoxy-6′-methyl-7-(o-tolyl)-3H-
spiro[benzofuran-2,1′-cyclohexan]-2′-ene-3,4′-dione
(10). Pd(OAc)2 (1 mol %, 0.3 mmol, 0.067 g), 8a (4 mol %,
1.2 mmol, 0.66 g), griseofulvin (30 mmol, 10.58 g), o-
tolylboronic acid (60 mmol, 8.16 g), and K3PO4·H2O (90
mmol, 20.7 g) were loaded into a Schlenk flask equipped with
a Teflon-coated magnetic stir bar. The flask was evacuated and
flushed with nitrogen for three cycles. Dioxane (50 mL) was
added with stirring at room temperature, and stirring was
continued for several minutes. The flask was then placed into a
preheated oil bath (120 °C) and stirred for 24 h. After
completion of the reaction as judged by GC-MS and TLC, the
reaction flask was allowed to cool to room temperature, and 50
mL of water was added to the mixture. The resulting mixture
was extracted with EtOAc, and the organic layer was collected
and extracted with 1 M NaOH solution at least three times.
Water and brine were further used for extraction. The organic
layer was concentrated by rotary evaporation to afford the
desired product (93% yield, 11.4 g) as a pale-yellow solid (mp
120.0−122.2 °C). 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J =
4.0 Hz, 2H), 7.22−7.15 (m, 1H), 6.17 (s, 1H), 5.45 (s, 1H),
4.01 (s, 3H), 3.86 (s, 3H), 3.57 (d, J = 15.5 Hz, 3H), 3.04 (dd,
J = 13.5, 16.5 Hz, 1H), 2.68−2.63 (m, 1H), 2.36−2.31 (m,
1H), 2.18 (d, J = 2 Hz, 3H), 0.94−0.93 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 197.2, 197.2, 193.0, 171.6, 171.6, 171.5,
166.5, 166.5, 158.7, 158.6, 137.9, 137.6, 131.0, 130.9, 130.6,
130.6, 129.8, 129.7, 128.0, 128.0, 125.4, 125.4, 106.8, 104.3,
104.2, 103.8, 89.6, 88.6, 88.5, 77.3, 77.0, 76.7, 56.4, 56.4, 56.1,
56.1, 39.9, 39.8, 36.2, 36.0, 19.8, 19.5, 14.1, 14.1; HRMS
(ESI+) m/z [M + Na]+ calcd for C24H25O6 431.14651, found
431.14631.
9-(2-Bromophenyl)-3,6-di-tert-butyl-9H-carbazole
(7).4b The general procedure of the improved synthetic
method was followed. 3,6-Di-tert-butyl-9H-carbazole (6) (1
equiv), KOH (total of 10 equiv), and 1-bromo-2-fluoroben-
zene (4 equiv) were mixed in DMF and heated at 155 °C for a
total of 12 h. After extraction and recrystallization, 9-(2-
bromophenyl)-3,6-di-tert-butyl-9H-carbazole (7) was obtained
1
in 76−88% yield as a pale-yellow solid. H NMR (500 MHz,
CDCl3) δ 8.17 (s, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.52−7.45
(m, 4H), 7.39 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H),
1.48 (s, 18H); 13C NMR (125 MHz, CDCl3) δ 142.7, 139.3,
137.3, 134.1, 131.0, 129.8, 128.7, 123.7, 123.5, 123.2, 116.3,
109.4, 34.7, 32.0.
5 g scale: 6 (15 mmol, 4.2 g), KOH (45 mmol, 2.52 g, start
of reaction; 30 mmol, 1.68 g, first hour; 30 mmol, 1.68 g,
second hour; 30 mmol, 1.68 g, third hour; 30 mmol, 1.68 g,
fourth hour; total 165 mmol, 9.3 g), DMF (50 mL), 1-bromo-
2-fluorobenzene (60 mmol, 6.6 mL), total reaction time of 8 h,
reaction temperature of 155 °C, 88% yield (5.7 g).
100 g scale: 6 (0.35 mol, 97.7 g), KOH (1.05 mol, 58.9 g,
start of reaction; 0.7 mol, 39.3 g, first hour; 0.7 mol, 39.3 g,
second hour; 0.7 mol, 39.3 g, third hour; 0.7 mol, 39.3 g,
fourth hour; 0.7 mol, 39.3 g, fifth hour; 0.7 mol, 39.3 g, sixth
hour; total 5.25 mol, 295.0 g), DMF (2.5 L), 1-bromo-2-
fluorobenzene (1.4 mol, 153 mL), total reaction time of 12 h,
reaction temperature of 155 °C, 76% yield (115 g).
3,6-Di-tert-butyl-9-(2-(dicyclohexylphosphino)-
phenyl)-9H-carbazole (8a).4b The general procedure for the
synthesis of phosphine ligands was followed. Precursor 7 and
ClPCy2 were used to afford 3,6-di-tert-butyl-9-(2-
(dicyclohexylphosphino)phenyl)-9H-carbazole (8a) as a
1
white solid. H NMR (500 MHz, C6D6) δ 8.38 (s, 2H), 7.58
(d, J = 7.5 Hz, 2H), 7.52 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.5
Hz, 2H), 7.12 (d, J = 7.0 Hz, 2H), 1.73−1.53 (m, 12H), 1.42
(s, 18H), 1.18−0.96 (m, 10H); 13C NMR (125 MHz, C6D6) δ
145.0, 144.8, 142.4, 138.4, 138.2, 134.0, 134.0, 130.3, 130.3,
128.3, 128.1, 127.9, 124.0, 123.5, 116.6, 110.8, 110.8, 34.8,
34.4, 34.2, 32.2, 30.4, 30.3, 30.0, 30.0, 27.6, 27.5, 27.4, 27.4,
27.4, 26.6; 31P NMR (162 MHz, C6D6) δ −14.598.
5 g scale: 7 (12 mmol, 5.2 g), ClPCy2 (13.2 mmol, 2.91
mL), THF (20 mL), 88% yield (5.83 g).
100 g scale: 7 (250 mmol, 108.4 g), ClPCy2 (275 mmol,
60.7 mL), THF (800 mL), 78% yield (107.6 g).
3,6-Di-tert-butyl-9-(2-(diphenylphosphino)phenyl)-
9H-carbazole (8b).11 The general procedure for the synthesis
of phosphine ligands was followed. Precursor 7 and ClPPh2
w e r e u s e d t o a ff o r d 3 , 6 - d i - t e r t - b u t y l - 9 - ( 2 -
(diphenylphosphino)phenyl)-9H-carbazole (8b) as a white
solid. 1H NMR (500 MHz, C6D6) δ 8.31 (d, J = 2.0 Hz, 2H),
7.44−7.41 (m, 1H), 7.34 (dd, J = 8.5, 2 Hz, 2H), 7.19−7.17
(m, 4H); 7.10−7.03 (m, 3H), 6.98−6.92 (m, 8H), 1.41 (s,
18H); 13C NMR (125 MHz, C6D6) δ 142.3, 141.1, 137.1,
137.0, 135.0, 134.3, 134.2, 130.6, 130.4, 130.4, 128.9, 128.7,
128.5, 128.5, 128.3, 123.9, 123.6, 116.3, 110.4, 110.4, 34.7,
32.2; 31P NMR (162 MHz, C6D6) δ −16.202.
2,3,4,5,6-Pentafluoro-2′,6′-dimethyl-1,1′-biphenyl
(11).13 Pd(OAc)2 (2 mol %, 1.2 mmol, 0.27 g), 8b (8 mol %,
4.8 mmol, 2.59 g), 2,6-dimethylphenylboronic acid (120
mmol, 18.0 g), and K3PO4 (180 mmol, 38.2 g) were loaded
into a Schlenk flask equipped with a Teflon-coated magnetic
stir bar. The flask was evacuated and flushed with nitrogen for
three cycles. Chloropentafluorobenzene (60 mmol, 7.75 mL)
and dioxane (60 mL) were added with stirring at room
temperature, and stirring was continued for several minutes.
The flask was then placed into a preheated oil bath (110 °C)
5 g scale: 7 (15 mmol, 6.5 g), ClPPh2 (16.5 mmol, 3.05
mL), THF (30 mL), 70% yield (5.67 g).
100 g scale: 7 (300 mmol, 130.0 g), ClPPh2 (330 mmol, 61
mL), THF (1 L), 66% yield (106.7 g).
N-(2,6-Diisopropylphenyl)-2,6-dimethylaniline (9).12
Pd(OAc)2 (0.1 mol %, 0.025 mmol, 0.0056 g), 4a (0.4 mol
F
Org. Process Res. Dev. XXXX, XXX, XXX−XXX