JOURNAL OF CHEMICAL RESEARCH 2016 383
Table 1 Scaled-up PEPPSI-catalysed synthesis of functionalised biaryls
at 25 °C for 24 h. The solution of 1a was carefully separated from
remaining zinc powder by using a syringe and transferred to another
dry and Ar-flushed flask. Titration of the zinc reagent (typically 1 mL)
with iodine, indicated a concentration of 0.80 M.
by using Knochel type organozinc reagents
X
ZnX.LiCl
X
R2
Zn, LiCl
20–30 mmol
Synthesis of substituted biaryls; general procedure
PEPPSI (1%)
THF, r.t.
R2
Yield: 80–96 %
R1
THF, 25 °C
R1
R1
Synthesis of 3,4’-(dimethoxy)biphenyl (Table 1, entry 1, 3a):
4-(Methoxy)bromobenzene (2a, 3.74 g, 20 mmol), PEPPSI (0.136 g,
0.2 mmol) and THF (20 mL) were placed in a dry and argon flushed
250 mL Schlenk-flask. The reaction mixture was stirred for 5 min,
and then 3-(methoxy)phenylzinc bromide (1a, 30 mL, 0.80 M in
THF, 24 mmol) was added. The reaction mixture was stirred for 1 h
at 25 °C and then quenched with aqueous saturated NH4Cl solution,
and extracted with ether. The combined organic phases were washed
with an aqueous thiourea solution and dried with Na2SO4. The crude
residue obtained after evaporation of the solvent was purified by flash
chromatography (pentane/ether = 10:1) to yield 3,4’-(dimethoxy)
biphenyl (3a) as a white solid (4.07 g, 95%).
X =Br, I
Entry R1
R2
Products
Yield/%a
1
2
3
4
5
6
7
8
1a 3-OMe
1b 4-OMe
1c 2-OMe
1b
1d 3-CO2Et
1e 4-CO2Et
1f 4-Me
1f
1f
1f
1f
1f
2a 4-OMe
2b 3-OMe
2a
3a
3a
3b
3b
3c
3c
3d
3e
3f
95
96
82
84
89
80
90
80
86
94
90
88
2c 2-OMe
2d 4-CO2Et
2e 3-CO2Et
2f 4-CO2Et
2a
3,4’-(Dimethoxy)biphenyl (Table 1, entry 1, 3a): White solid; m.p.:
1
60–61 °C (lit.12 58–59 °C). H NMR (600 MHz, CDCl3): δ 7.47–7.42
9
2g 4-CF3
2h 4-CN
2i 3-CN
2j 2-CN
(m, 2H), 7.27–7.22 (m, 1H), 7.08–7.04 (m, 1H), 7.02–7.00 (m, 1H),
6.91–6.86 (m, 2H), 6.80–6.75 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 159.90, 159.21, 142.33, 133.58, 129.67,
128.16, 119.25, 114.13, 112.49, 111.99, 55.34, 55.28; HRMS m/z for
C14H14O2 calcd 214.0994; found: 214.0990.
10
11
12
3g
3h
3i
aIsolated yield of analytically pure product.
2,4’-(Dimethoxy)biphenyl (Table 1, entry 3, 3b): White solid; m.p.:
70 °C (lit.13 68–70 °C). H NMR (600 MHz, CDCl3): δ 7.42–7.35 (m,
1
with excellent yields. Sensitive functional groups, such as CN
and COOEt groups, were tolerated in the coupling reaction.
2H), 7.24–7.18 (m, 2H), 6.96–6.84 (m, 4H), 3.72 (s, 3H), 3.75 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 158.60, 156.40, 130.85, 130.59, 130.54,
130.28, 128.12, 120.77, 113.44, 111.14, 55.49, 55.22; HRMS m/z for
C14H14O2 calcd 214.0994; found: 214.0999.
Conclusions
A practical scaled up synthetic procedure for the preparation
of functionalised biaryls by using Knochel type organozinc
reagents in the presence of PEPPSI is reported. All the reactions
were performed on the 20–30 mmol scale, and with low PEPPSI
loading (1 mol%). The reactions were clean and the desired
products were isolated in excellent yields. Sensitive functional
groups, such as CN and COOEt groups, were tolerated in the
coupling reaction. The protocol, which enabled the Negishi
reaction to proceed smoothly and rapidly, may be a practical
and interesting synthetic procedure to prepare important
organic intermediates or precursors.
3,4’-Di(ethoxycarbonyl)biphenyl (Table 1, entry 5, 3c): Pale yellow
oil; 1H NMR (600 MHz, CDCl3): δ 8.30 (t, J = 1.8 Hz, 1H), 8.14–8.12
(m, 2H), 8.07–8.06 (m, 1H), 7.81–7.79 (m, 1H), 7.70–7.67 (m, 2H), 7.53
(t, J = 7.8 Hz, 1 H), 4.43–4.38 (m, 4H), 1.42 (td, J = 7.2, 0.6 Hz, 6H).
13C NMR (150 MHz, CDCl3): δ 166.33, 144.39, 140.25, 131.47, 131.19,
130.11, 129.66, 129.00, 128.29, 127.08, 61.16, 61.01, 14.32; HRMS m/z
for C18H18O4 calcd 298.1205; found: 298.1208.
4-Methyl-4’-(ethoxycarbonyl)biphenyl (Table 1, entry 7, 3d): White
1
solid; m.p.: 75–77 °C (lit.14 78–79 °C). H NMR (400 MHz, CDCl3):
δ 8.11–8.05 (m, 2H), 7.65–7.60 (m, 2H), 7.54–7.47 (m, 2H), 7.30–7.24
(m, 2H), 4.38 (q, J = 6.8 Hz, 2H), 2.39 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz): δ 166.56, 145.45, 138.05, 137.15, 130.02, 129.63,
128.95, 127.09, 126.73, 60.91, 21.14, 14.37; HRMS m/z for C16H16O2
calcd 240.1150; found: 240.1152.
4-Methyl-4’-(methoxy)biphenyl (Table 1, entry 8, 3e): White solid;
m.p.: 111–112 °C (lit.15 115–118 °C). 1H NMR (400 MHz): δ 7.46–7.41
(m, 2H), 7.40–7.35 (m, 2H), 7.17–7.13 (m, 2H), 6.92–6.87 (m, 2H), 3.77
(s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz): δ 158.89, 137.93, 136.30,
133.72, 129.38, 127.90, 126.54, 114.12, 55.30, 21.00; HRMS m/z for
C14H14O calcd 198.1045; found: 198.1050.
Experimental
Melting points were determined on the Kofler micro melting point
1
apparatus and were not corrected. H NMR (in CDCl3) and 13C NMR
(in CDCl3) spectra were measured using TMS as internal standard on
a Bruker 600 AC NMR or Bruker 400 AC NMR spectrometer. A high-
resolution mass spectra (ESI–HRMS) were determined on an Ion Spec
(7.0 T) spectrometer.
All reactions were carried out under an argon atmosphere in dried
glassware. All starting materials were purchased from commercial
suppliers and used without further purification unless otherwise stated.
THF was continuously refluxed and freshly distilled from sodium
benzophenone ketyl under nitrogen. Yields refer to isolated compounds
4-Methyl-4’-(trifluoromethyl)biphenyl (Table 1, entry 9, 3f): White
1
solid; m.p.: 121–122 °C (lit.16 120 °C). H NMR (600 MHz, CDCl3):
δ 7.68–7.67 (m, 4H), 7.53–7.49 (m, 2H), 7.31–7.26 (m, 2H), 2.42 (s,
3H). 13C NMR (150 MHz, CDCl3): δ 144.62 (q, 4JC–F = 1.5 Hz), 138.13,
2
136.84, 129.68, 129.01 (q, JC–F = 32 Hz), 127.15, 127.08, 125.64
1
estimated to be > 95% pure as determined by H NMR and capillary
3
1
(q, JC–F = 3.7 Hz), 124.33 (q, JC–F = 270 Hz), 21.13; HRMS m/z for
C14H11F3 calcd 236.0813; found: 236.0820.
GC analysis.
Synthesis of Knochel type organozinc reagents; general procedure
4-Methyl-4’-(cyano)biphenyl (Table 1, entry 10, 3g): White solid;
1
m.p.: 110–112 °C (lit.14 110–111 °C). H NMR (400 MHz, CDCl3): δ
Synthesis of organozinc reagent 1a: Anhydrous LiCl (33 mmol, 1.40 g)
was placed in an Ar-flushed flask and dried for 30 min at 250 °C under
high vacuum (1 mbar). Zinc powder (90 mmol, 5.88 g) was added
under Ar and the heterogenous mixture was dried again for 30 min at
250 °C under high vacuum (1 mbar). After cooling to 25 °C, the flask
was evacuated and refilled with Ar three times. THF (30 mL) was
added and the zinc was activated with 1,2-dibromoethane (5% mmol)
and TMSCl (1–2% mmol). 3-Methoxylbromobenzene (30 mmol,
5.61 g) was added carefully and the reaction mixture was stirred
7.66–7.56 (m, 4H), 7.44–7.39 (m, 2H), 7.24–7.19 (m, 2H), 2.34 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 145.59, 138.73, 136.25, 132.54, 129.81,
127.44, 127.03, 119.00, 110.54, 21.16; HRMS m/z for C14H11N calcd
193.0891; found: 193.0899.
4-Methyl-3’-(cyano)biphenyl (Table 1, entry 11, 3h): White solid;
1
m.p.: 74–75 °C (lit.17 66–68 °C). H NMR (400 MHz, CDCl3): δ
7.80–7.70 (m, 2H), 7.58 (td, J = 7.6, 1.4 Hz, 1H), 7.52–7.43 (m, 3H),
7.28–7.25 (m, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3): δ