A. M. Maj et al. / Tetrahedron 63 (2007) 2657–2663
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4.2.2. 3,5-Dimethyl-30,50-bis(trifluoromethyl)biphenyl-4-
amine (6b). Brown oil, yield: 82%. H NMR (400 MHz,
MgSO4 and evaporated. The crude product was recrystal-
lized from CHCl3/n-hexane.
1
CDCl3, 25 ꢀC): d¼2.26 (s, 6H, ortho-CH3), 3.78 (s, 2H,
NH2), 7.21 (s, 2H, CHar), 7.72 (s, 1H, CHar), 7.94 (s, 2H,
4.4.1. N-(30,50-Difluoro-3,5-dimethylbiphenyl-4-yl)-2,2,2-
13
1
CHar) ppm. C NMR (100 MHz, CDCl3, 25 ꢀC): d¼18.7
trifluoroacetamide (8a). White-grey solid, yield: 34%. H
(ortho-CH3), 120.3 (para-CHar), 123.2 (CF3), 125.9 (Car),
127.1 (CHar), 127.9 (Car), 128.5 (CHar), 132.6 (CarCF3),
132.9 (Car), 144.7 (CarN) ppm.
NMR (400 MHz, CDCl3, 25 ꢀC): d¼2.26 (s, 6H, ortho-
CH3), 6.77–6.81 (m, 1H, CHar), 7.04 (d, J¼16 Hz, 2H,
CHar), 7.25 (s, 2H, CHar), 7.72 (s, 1H, NH) ppm. 13C
NMR (100 MHz, CDCl3, 25 ꢀC): d¼18.3 (ortho-CH3),
103.0 (para-CHar), 109.9 (CHar), 110.1 (Car), 122.4 (CF3),
127.3 (Car), 131.1 (CHar), 136.1 (Car), 139.2 (Car), 162.2
(CO), 164.7 (CarF) ppm.
4.2.3. 40-Methoxy-3,5-dimethylbiphenyl-4-amine (6c).
Brown oil, yield: 53%. 1H NMR (400 MHz, CDCl3,
25 ꢀC): d¼2.23 (s, 6H, ortho-CH3), 3.60 (s, 2H, NH2),
3.82 (s, 3H, OCH3), 6.92 (d, J¼8.6 Hz, 2H, CHar), 7.15 (s,
2H, CHar), 7.47 (d, J¼8.6 Hz, 2H, CHar) ppm. 13C NMR
(100 MHz, CDCl3, 25 ꢀC): d¼18.0 (ortho-CH3), 55.3
(OCH3), 114.0 (CHar), 122.0 (Car), 124.7 (Car), 126.8
(CHar), 127.3 (CHar), 130.7 (Car), 141.8 (CarN), 150.7
(CarO) ppm.
4.4.2. N-(3,5-Dimethyl-30,50-bis(trifluoromethyl)bi-
phenyl-4-yl)-2,2,2-trifluoroacetamide (8b). White-grey
1
solid, yield: 38%. H NMR (400 MHz, CDCl3, 25 ꢀC): d¼
2.19 (s, 6H, ortho-CH3), 7.26 (s, 2H, CHar), 7.35 (s, 2H,
CHar), 7.50 (m, 1H, CHar), 7.87 (s, 1H, NH) ppm. 13C
NMR (100 MHz, CDCl3, 25 ꢀC): d¼18.6 (ortho-CH3),
114.3 (CF3), 126.6 (CHar), 126.8 (CF3), 127.3 (Car), 127.6
(CHar), 128.1 (CHar), 133.3 (Car), 137.6 (Car), 148.8 (Car),
159.2 (Car), 163.6 (CO) ppm.
4.3. Synthesis of N-(4-bromo-2,6-dimethylphenyl)-
2,2,2-trifluoroacetamide (7)
A two-necked 100-mL round-bottom flask equipped with a
magnetic stirring bar and capped with a three-way stopcock
was charged with 4-bromo-2,6-dimethylaniline (5) (1 g,
5 mmol) and Na2CO3 (5.83 g, 55 mmol). The reactor was
purged of air by applying three vacuum/argon cycles. Dry
Et2O (50 mL) was added and the resulting suspension was
cooled in an ice–water bath before trifluoroacetic anhydride
(7.5 mL, 55 mmol) was carefully added. The mixture was
first stirred for 5 min at 0 ꢀC then for 40 min at room temper-
ature. Next, 40 mL of CHCl3 was added and the excess of
trifluoroacetic anhydride was destroyed by slow addition
of ice (50 mL). The resulting biphasic mixture was trans-
ferred into a separation funnel. The organic phase was col-
lected and the aqueous phase was extracted with CHCl3
(3ꢁ50 mL). All the organic phases were gathered, dried
over MgSO4 and evaporated. Crude N-(4-bromo-2,6-di-
methylphenyl)-2,2,2-trifluoroacetamide (7) was obtained
as a white-grey solid in 95% yield and used without any
4.4.3. N-(40-Methoxy-3,5-dimethylbiphenyl-4-yl)-2,2,2-
1
trifluoroacetamide (8c). White-grey solid, yield: 90%. H
NMR (400 MHz, CDCl3, 25 ꢀC): d¼2.26 (s, 6H, ortho-
CH3), 3.84 (s, 3H, OCH3), 6.95 (d, J¼8.0 Hz, 2H, CHar),
7.27 (s, 2H, CHar), 7.47 (d, J¼8.4 Hz, 2H, CHar), 7.57 (s,
13
1H, NH) ppm. C NMR (100 MHz, CDCl3, 25 ꢀC): d¼
17.9 (ortho-CH3), 55.5 (OCH3), 114.4 (CHar), 117.4 (CF3),
127.0 (CHar), 128.3 (CHar), 129.5 (Car), 132.9 (Car), 135.6
(Car), 141.2 (Car), 155.7 (CO), 159.5 (CarO) ppm.
4.4.4. N-(3,5-Dimethyl-40-phenoxybiphenyl-4-yl)-2,2,2-
trifluoroacetamide (8d). White-grey solid, yield: 31%,
1
mp 134 ꢀC. H NMR (400 MHz, CDCl3, 25 ꢀC): d¼2.27
(s, 6H, ortho-CH3), 6.97–7.11 (m, 4H, CHar), 7.13–7.24
(m, 2H, CHar), 7.34–7.48 (m, 2H, CHar), 7.51–7.72 (m,
3H, CHar), 8.16 (s, 1H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 25 ꢀC): d¼19.2 (CH3), 115.6 (CF3), 119.9 (CHar),
120.0 (CHar), 124.4 (CHar), 128.1 (CHar), 129.4 (CHar),
131.1 (CHar), 136.2 (Car), 136.5 (Car), 141.9 (Car), 141.2
(Car), 157.9 (CO), 158.1 (CarO), 159.0 (CarO) ppm.
1
further purification, mp 140–141 ꢀC. H NMR (400 MHz,
CDCl3, 25 ꢀC): d¼2.10 (s, 6H, ortho-CH3), 7.19 (s, 2H,
CHar), 7.48 (s, 1H, NH) ppm. 13C NMR (100 MHz,
CDCl3, 25 ꢀC): d¼18.0 (CH3), 114.7 (CF3), 122.4 (Car),
129.9 (CHar), 131.6 (Car), 137.5 (Car), 155.6 (CO) ppm.
4.4.5. N-(40-tert-Butyl-3,5-dimethylbiphenyl-4-yl)-2,2,2-
trifluoroacetamide (8e). White-grey solid, yield: 74%, mp
1
4.4. Preparation of N-protected biphenylamines
via Suzuki cross-coupling
113–114 ꢀC. H NMR (400 MHz, CDCl3, 25 ꢀC): d¼1.36
(s, 9H, C(CH3)3), 2.28 (s, 6H, ortho-CH3), 7.31 (d, 2H,
CHar), 7.44–7.50 (m, 4H, CHar), 7.55 (s, 1H, NH) ppm.
13C NMR (100 MHz, CDCl3, 25 ꢀC): d¼18.4 (ortho-CH3),
31.5 (C(CH3)3), 34.7 (C(CH3)3), 125.9 (CHar), 126.9
(CHar), 127.4 (CHar), 129.7 (Car), 131.6 (CF3), 135.6 (Car),
137.5 (Car), 141.6 (Car), 150.8 (Car), 155.6 (CO) ppm.
A two-necked 100-mL round-bottom flask equipped with
a reflux condenser capped with a three-way stopcock was
charged with a phenylboronic acid (4.4 mmol), N-(4-bromo-
2,6-dimethylphenyl)-2,2,2-trifluoroacetamide (7) (1.1843 g,
4 mmol), Pd(OAc)2 (45 mg, 0.2 mmol) and Na2CO3 (0.9 g,
8.5 mmol). The reactor was purged of air by applying three
vacuum/argon cycles before degassed methanol (50 mL)
was added. The reaction mixture was sonicated for 4 h in
an ultrasound cleaning bath initially at room temperature.
The temperature slightly increased during the run due to
the sonication process. The resulting suspension was filtered
through a Celite pad and the filtrate was evaporated. The
residue was dissolved in CHCl3 (20 mL) and washed with
water (2ꢁ30 mL). The organic layer was dried over
4.5. Cleavage of the trifluoroacetamide group
A 250-mL round-bottom flask was charged with a substituted
N-(3,5-dimethylbiphenyl-4-yl)-2,2,2-trifluoroacetamide
(5 mmol), water (10 mL) and concentrated hydrochloric acid
(10 mL). The reaction mixture was heated to reflux for 17 h.
The resulting solution was brought back to room tempera-
ture and evaporated to dryness. The residue was taken up
with water (100 mL) and refluxed with Ba(OH)2$8H2O