D
J. H. Pang et al.
Special Topic
Synthesis
nucleophilic amination of biaryl ethers was found to be
very sensitive to steric factors (Scheme 8D): installation of
an ortho-methyl group (in substrate 18) made the reaction
progress sluggish, resulting in incomplete conversion to af-
ford a mixture of 11 and 19 in 2:1 ratio in only 21% total
yield even after stirring for 24 h.
To summarize, this work validated that the methoxy
group, which is commonly considered as a poor leaving
group, is most superior for nucleophilic aromatic substitu-
tion reactions under the NaH–LiI system from the point of
view of reaction efficiency and atom economy. Although
the aryoxy group generally possesses a better leaving group
ability than methoxy, the regioselectivity of the amination
of unsymmetrical biaryl ethers is heavily affected by elec-
tronic and steric factors.
13C NMR (100 MHz, CDCl3): = 151.5, 141.1, 131.6, 128.7, 127.7,
126.5, 126.3, 116.4, 50.4, 25.8, 24.4.
1-(Biphenyl-4-yl)piperidine (3)9a and 1-(Biphenyl-3-yl)piperidine
(4)24
Scheme 3B with 1-Br: reaction time: 23 h; eluent system: 2%
EtOAc/hexane; 3 and 4 were obtained as an inseparable mixture as a
light brown solid; yield: 99.9 mg (0.421 mmol, 85%; 3: 38%, 4: 47%).
The spectroscopic data for 3 and 4 are identical to those reported in
the literature.
1H NMR (400 MHz, CDCl3): = 7.59–7.54 (d, J = 8.2 Hz, 2 × 0.45 H + 2 ×
0.55 H), 7.49 (d, J = 8.8 Hz, 2 × 0.45 H), 7.43–7.37 (dd, J = 8.2, 8.1 Hz, 2
× 0.45 H + m, 2 × 0.55 H), 7.34–7.24 (t, J = 8.2 Hz, 1 × 0.45 H + m, 2 ×
0.55 H), 7.14 (t, J = 2.0 Hz, 1 × 0.55 H), 7.07 (d, J = 7.6 Hz, 1 × 0.55 H),
6.99 (d, J = 8.2 Hz, 2 × 0.45 H), 6.93 (dd, J = 8.5 Hz, 2.4 Hz, 1 × 0.55 H),
3.22–3.19 (t, J = 5.5 Hz, 4 × 0.45 H + t, J = 5.5 Hz, 4 × 0.55 H), 1.75–1.69
(m, 4 × 0.45 H + m, 4 × 0.55 H), 1.62–1.55 (m, 2 × 0.45 H + m, 2 × 0.55
H).
13C NMR (100 MHz, CDCl3): = 152.7, 151.5, 142.2, 142.0, 141.1,
131.6, 129.4, 128.7, 128.6, 127.7, 127.2, 127.1, 126.5, 126.3, 118.3,
116.4, 115.6, 115.5, 50.8, 50.4, 25.9, 25.8, 24.4 (overlapped).
Biphenyl (5)25 was formed in 5% yield based on 1H NMR of the crude
material using 1,2-dibromoethane as the internal standard. The spec-
troscopic data are identical to those reported in the literature.
All experiments were carried out under a N2 atmosphere with anhy-
drous solvents. THF was taken from a solvent purification system (PS-
400-5, innovative technology Inc.). NaH (60% dispersion in mineral
oil), LiI were purchased from Sigma-Aldrich, Inc. LiI was dried over
P2O5 under reduced pressure at 120 °C. Due to the moisture sensitivi-
ty of NaH, it was consistently handled under an argon atmosphere in
a glovebox or with Schlenk techniques under a N2 atmosphere. The
arene substrates 1-Br,16 1-Cl,17 1-OTf,18 7-Br,19 12,20 14,21 16,22 and
1823 were prepared using the reported methods. The substrates 1-
OMe, 7-OMe, 10-OMe, 10-SMe, and 10-OPh were commercially
available and used as received. TLC analyses were performed on silica
gel glass plates (Merck silica gel 60), and the spots were visualized
with UV light (254 and 365 nm). Flash chromatography was per-
formed using Merck silica gel 60 with distilled solvents. Shimadzu
GC-2010 was used for the GC analyses. 1H NMR spectra (400 MHz)
were recorded on a Bruker Avance 400 spectrometer in CDCl3 [using
TMS (for 1H, = 0.00) as internal standard]. 13C NMR spectra (100
MHz) were recorded on a Bruker Avance 400 spectrometer in CDCl3
[using CDCl3 (for 13C, = 77.00) as internal standard].
1-(Biphenyl-4-yl)piperidine (3)9a and 1-(Biphenyl-3-yl)piperidine
(4)24
Scheme 3B with 1-Cl: reaction time: 23 h; eluent system: 2% EtO-
Ac/hexane; 3 and 4 were obtained as an inseparable mixture as a light
brown solid; yield: 97.0 mg (0.409 mmol, 81%; 3: 37%, 4: 44%). The
spectroscopic data for 3 and 4 are identical to those reported in the
literature.
1H NMR (400 MHz, CDCl3): = 7.59–7.54 (d, J = 8.2 Hz, 2 × 0.45 H + 2 ×
0.55 H), 7.49 (d, J = 8.8 Hz, 2 × 0.45 H), 7.43–7.37 (dd, J = 8.2, 8.1 Hz, 2
× 0.45 H + m, 2 × 0.55 H), 7.34–7.24 (t, J = 8.2 Hz, 1 × 0.45 H + m, 2 ×
0.55 H), 7.14 (t, J = 2.0 Hz, 1 × 0.55 H), 7.07 (d, J = 7.6 Hz, 1 × 0.55 H),
6.99 (d, J = 8.2 Hz, 2 × 0.45 H), 6.93 (dd, J = 8.5 Hz, 2.4 Hz, 1 × 0.55 H),
3.22–3.19 (t, J = 5.5 Hz, 4 × 0.45 H + t, J = 5.5 Hz, 4 × 0.55 H), 1.75–1.69
(m, 4 × 0.45 H + m, 4 × 0.55 H), 1.62–1.55 (m, 2 × 0.45 H + m, 2 × 0.55
H).
13C NMR (100 MHz, CDCl3): = 152.7, 151.5, 142.2, 142.0, 141.1,
131.6, 129.4, 128.7, 128.6, 127.7, 127.2, 127.1, 126.5, 126.3, 118.3,
116.4, 115.6, 115.5, 50.8, 50.4, 25.9, 25.8, 24.4 (overlapped).
Biphenyl (5)25 was formed in 5% yield based on 1H NMR of the crude
material using 1,2-dibromoethane as the internal standard. The spec-
troscopic data are identical to those reported in the literature.
Piperidin-1-ylarenes; General Procedure
To a mixture of NaH (60% dispersion, 100 mg, 2.50 mmol) and LiI (134
mg, 1.00 mmol) in a 25-mL sealed tube was added a solution of arene
substrate (0.50 mmol) in THF (0.5 mL) and piperidine (85.2 mg, 99 L,
1.00 mmol). The reaction was stirred at 60 °C (the reaction time is in-
dicated in the respective scheme) and was quenched with water at
0 °C. The organic materials were extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were washed brine and dried
(MgSO4). The volatile materials were removed in vacuo and the re-
sulting crude residue was purified by flash column chromatography
(the eluent system is indicated for each substrate) to give the product.
Biphenyl-4-ol (6)26
Scheme 3C: reaction time: 24 h; eluent system: 10% EtOAc/hexane;
white solid; yield: 22.1 mg (0.130 mmol, 26%); mp 164–166 °C. The
spectroscopic data for 6 are identical to those reported in the litera-
ture.
1H NMR (400 MHz, CDCl3): = 7.54 (d, J = 7.4 Hz, 2 H), 7.48 (d, J = 8.7
Hz, 2 H), 7.41 (dd, J = 7.4, 7.4 Hz, 2 H), 7.30 (t, J = 7.4 Hz, 1 H), 6.90 (d,
J = 8.7 Hz, 2 H), 4.88 (s, 1 H).
1-(Biphenyl-4-yl)piperidine (3)9a
Scheme 3A: reaction time: 23 h; eluent system: 2% EtOAc/hexane;
white solid; yield: 103 mg (0.434 mmol, 87%); mp 124–126 °C. The
spectroscopic data for 3 are identical to those reported in the litera-
ture.
1H NMR (400 MHz, CDCl3): = 7.56 (d, J = 8.2 Hz, 2 H), 7.50 (d, J = 8.8
Hz, 2 H), 7.39 (dd, J = 8.2, 8.2 Hz, 2 H), 7.26 (t, J = 8.2 Hz, 1 H), 6.99 (d,
J = 8.8 Hz, 2 H), 3.21 (t, J = 5.5 Hz, 4 H), 1.75–1.69 (m, 4 H), 1.62–1.55
(m, 2 H).
13C NMR (100 MHz, CDCl3): = 155.0, 140.7, 134.0, 128.7, 128.4, 126.7
(overlapped), 115.6.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–F