Synthesis of P,N-2,2′-biphenyl derivatives with central chirality

Article abstract of DOI:10.1007/s11426-010-4056-2

Enantiopure 2-(dicyclohexylphosphino)-1,1′-biphenyl derivatives substituted in the 2′-position by a chiral amino group were prepared. For the compound bearing an acyclic chiral chain, the key step was a Suzuki coupling between bromobenzeneboronic acid and N-Boc-iodoaniline whereas an aromatic nucleophilic substitution allowed the introduction of a chiral pyrrolidine in the 2′-position of the biphenyl backbone. The efficiency of the P,N-biphenyl pyrrolidine derivatives as ligands in Pd-catalyzed arylaminations compares well with that of DavePhos ligand.

Full text of DOI:10.1007/s11426-010-4056-2

SCIENCE CHINA
Chemistry
September 2010 Vol.53 No.9: 1907–1913
doi: 10.1007/s11426-010-4056-2
• ARTICLES •
Synthesis of P,N-2,2′-biphenyl derivatives with central chirality
JEAN Ludovic, POULIQUEN Michael, BLANCHET Jérôme,
LASNE Marie-Claire & ROUDEN Jacques*
Laboratoire de Chimie Moléculaire et Thioorganique, UMR 6507 CNRS-ENSICAEN & Université de Caen-Basse Normandie, 6 Boulevard du
Maréchal Juin, 14050 Caen, Institut Normand de Chimie Moléculaire, Médicinale et Macromoléculaire (INC3M), FR CNRS 3038, France
Received April 6, 2010; accepted May 26, 2010
Enantiopure 2-(dicyclohexylphosphino)-1,1′-biphenyl derivatives substituted in the 2′-position by a chiral amino group were
prepared. For the compound bearing an acyclic chiral chain, the key step was a Suzuki coupling between bromobenzenebo-
ronic acid and N-Boc-iodoaniline whereas an aromatic nucleophilic substitution allowed the introduction of a chiral pyrrolidine
in the 2′-position of the biphenyl backbone. The efficiency of the P,N-biphenyl pyrrolidine derivatives as ligands in
Pd-catalyzed arylaminations compares well with that of DavePhos ligand.
3-aminopyrrolidines, Suzuki coupling, biphenyls, chiral ligand, arylamination
1 Introduction
Chiral P,N compounds have been mainly prepared as
asymmetric inducers owing to their steric and electronic
properties [1–2]. 2,2′-Substituted biphenyls with a carbon [3]
or a phosphorus [4] stereogenic center are little known,
while this type of compound was widely developed in
achiral transition metal mediated reactions [5–6].
Herein, we report the synthesis of two P,N-ligands con-
taining a biphenyl moiety and for the first time a central
chirality either on a flexible chain (1) or in a five-membered
ring (2) (Figure 1).
Figure 1 DavePhos ligand and target compounds.
ketyl. Hexane, 1,2-dichloroethane, benzene and chloroben-
zene were distilled from calcium hydride and stored over
molecular sieves 4 Å. Thin layer chromatography (TLC)
was performed on Merck 60F254 silica gel plates and visual-
ized with a UV lamp (254 nm). Flash column chromatography
was carried out with silica gel SI 60 (0.040–0.063 mm, Merck).
Uncorrected melting points were obtained using a Köfler
bench apparatus. Infrared spectra (IR) were recorded with a
16 PC FT-IR spectrometer. Elementary analyses were per-
formed on a Thermoquest apparatus. Mass and high resolution
mass spectra (HRMS) were obtained on a Waters-Micromass
2 Experimental
General experimental
Dichloromethane, acetonitrile, ether and toluene were dried
with a PURESOLVTM apparatus (Innovative Technology Inc.).
THF was dried and distilled from sodium benzophenone
1
Q-Tof micro instrument. H NMR, 13C NMR and 31P NMR
spectra were recorded on a Bruker Avance DPX-250.
Chemical shifts are expressed in  (ppm) units downfield
from TMS. 31P NMR chemical shifts are reported in ppm
*Corresponding author (email: jacques.rouden@ensicaen.fr)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
www.springerlink.com

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JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
relative to H3PO4 (0 ppm). Optical rotations were measured
at 20 °C on a Perkin-Elmer 241 LC polarimeter in a 1 dm cell.
2-Bromo and 2-aminobenzeneboronic acids, 2-iodoaniline,
2-aminobiphenyl 3 are commercially available. 2-Iodo-N-
(t-butoxycarbonyl)aniline 9b [7], 2-bromo-2′-aminobiphenyl
17 [8], dimesylate 18 [9], 3-N,N-dimethylaminopyrrolidine
14 [10], 1-benzyl-3-(phenylamino)pyrrolidine 26 [11] and
1-Boc-3-(phenylamino)piperidine 28 [11] are known com-
pounds.
80%) as a pale yellow oil. IR (film) 3022, 2972, 2930, 2878,
1
1594, 1500, 1482, 1452, 1434, 1102 cm1; H NMR (400
MHz, CDCl3)  : 0.94 (d, J = 6.1 Hz, 3H), 2.68 (s, 3H), 2.79
(dd, J = 13.7, 5.3 Hz, 1H), 2.92 (dd, J = 13.7, 6.5 Hz, 1H),
3.28 (s, 3H), 3.29–3.35 (m, 1H), 7.06 (td, J = 7.4, 0.9 Hz,
1H), 7.14 (d, J = 8.1 Hz, 1H), 7.24 (dd, J=7.5, 1.6 Hz, 1H),
7.28–7.35 (m, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.56 (d, J=8.5
Hz, 2H) ppm; 13C NMR (62.9 MHz, CDCl3)  : 17.8, 42.6,
56.5, 60.8, 76.0, 119.8, 122.2, 126.9, 127.5, 128.4, 129.3,
129.4, 129.7, 132.0, 135.6, 142.3, 151.3 ppm.
1-(Biphenyl-2-yl-methylamino)-propan-2-ol (4a)
(2′-Bromo-biphenyl-2-yl)-carbamic acid tert-butyl ester (7)
To a suspension of sodium hydride (50% in mineral oil,
850 mg, 17.7 mmol) in dry THF (5 mL) was added
2-aminobiphenyl 3 (2 g, 11.8 mmol) in dry THF (10 mL) at
room temperature. The mixture was stirred for 1 h and
iodomethane (2 mL, 32.1 mmol) was added. After 12 h at
room temperature, Et2O (15 mL) and water (10 mL) were
added. The organic layer was separated and the aqueous
layer was extracted with Et2O (2  15 mL). The combined
organic layers were dried over MgSO4 and concentrated
under reduced pressure to give a mixture (2.4 g) of
2-(N-methylamino)-1,1′-biphenyl (85%) and 2-(N,N-
dimethylamino)-1,1′-biphenyl (15%) (The ratios were deter-
mined by 1H NMR).
A Schlenk flask, evacuated and backfilled with nitrogen,
was charged with Pd(OAc)2 (196 mg, 5 mol% Pd), triphenyl-
phosphine (945 mg, 20 mol%), dioxane/H2O (4:1, 90 mL),
2-iodo-N-(t-butoxycarbonyl)aniline 9b (5.6 g 17.5 mmol),
2-bromobenzeneboronic acid 10 (5.25 g, 26.5 mmol) and
Na2CO3 (4.0 g, 38.5 mmol). The flask was evacuated and
backfilled with nitrogen then capped with a rubber septum.
The mixture was heated to 95 °C for 12 h. The crude prod-
uct was extracted with CH2Cl2, dried over MgSO4 and con-
centrated under reduced pressure. Flash chromatography
(n-hexane/EtOAc = 90:10) afforded 7 (5.0 g, yield: 82 %) as
a colorless powder. Mp 66 °C; IR (film): 1724, 1584, 1516,
1
1444 cm1. H NMR (400 MHz, CDCl3)  : 1.49 (s, 9H),
To the crude mixture (2.4 g) in CH2Cl2 (20 mL) under
nitrogen was added triethylaluminium in hexanes (1 M, 15
mL, 15 mmol) at 0 °C. After 30 min, propylene oxide (850 L,
12.1 mmol) was added and the mixture was stirred at room
temperature for 3 h. Aqueous sodium hydroxide (6 N, 15 mL,
90 mmol) was carefully added at 0 °C (vigorous gas evolu-
tion). The mixture was then stirred vigorously for 1 h. The
organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure.
Flash chromatography (EtOAc/n-heptane = 20:80) afforded
4a (1.4 g, yield: 55%) as a pale yellow oil. IR (film) 3426,
6.17 (br s, NH), 7.14 (d, J = 3.24 Hz, 2H), 7.31 (d, J = 8.1
Hz, 2H), 7.40–7.50 (m, 2H), 7.74 (d, J = 8.1 Hz, 1H), 8.11
(br d, J = 8.1 Hz, 1H) ppm; 13C NMR (62.9 MHz, CDCl3) :
28.4, 80.6, 120.3, 123.0, 124.3, 128.0, 129.0, 129.8, 130.0,
130.8, 131.9, 133.3, 135.7, 138.9, 152.9 ppm; GC/MS (EI)
(m/z) 349 (15), 347 (15), 294 (16), 293 (81), 292 (22), 291
(84), 212 (100), 213 (15), 194 (12), 168 (94), 167 (41), 166
(34), 57 (74); Anal. calcd for C17H18BrNO2: C, 58.63; H,
5.21; N, 4.02. Found: C, 59.02; H, 5.34; N, 4.08.
(2'-Bromo-biphenyl-2-yl)-methyl-amine (8) [12]
1
1592, 1482 cm1; H NMR (400 MHz, CDCl3) : 1.04 (d,
A solution of aniline 7 (8.3 g, 23.7 mmol) in dry THF (100 mL)
was added slowly at room temperature to a suspension of
LiAlH4 (2 g, 52.6 mmol) in dry THF (100 mL). The mixture
was refluxed for 2 h under N2, cooled to room temperature
and carefully treated with water (2 mL), aqueous sodium
hydroxyde (15%, 2 mL) and water (6 mL). The mixture was
dried over MgSO4 and concentrated under reduced pressure.
Flash chromatography (n-hexane/EtOAc = 90:10) afforded 8
J = 6.1 Hz, 3H), 2.51 (s, OH), 2.60 (s, 3 H), 2.65 (dd, J =
12.6, 10.2 Hz, 1H), 2.84 (dd, J = 2.9, 12.6 Hz, 1H), 3.75 (m,
1H), 7.47–7.20 (m, 9H) ppm; 13C NMR (62.9 MHz, CDCl3)
: 19.8, 42.4, 63.7, 64.4, 121.6, 124.1, 127.0, 128.4, 129.1,
131.1, 138.2, 140.9, 151.2 ppm.
2-(Biphenyl-2-yl)-(2-methoxypropyl)methyl-amine (4b)
1
To a suspension of sodium hydride (50% in mineral oil,
224 mg, 4.7 mmol) in dry THF (2 mL) was added amino
alcohol 4a (750 mg, 3.1 mmol) in dry THF (8 mL). The
mixture was stirred at room temperature for 15 min before
adding iodomethane (400 L, 6.4 mmol). The mixture was
stirred at room temperature for 2 h. Et2O (10 mL) and water
(5 mL) were then added. The organic layer was separated
and the aqueous layer was extracted with Et2O. The com-
bined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. Flash chromatography (pe-
troleum ether/EtOAc = 90:10) yielded 4b (630 mg, yield:
as a yellow oil (3.3 g, yield: 53%). H NMR (400 MHz,
CDCl3) : 2.91 (s, 3H), 3.55 (br s, NH), 6.85 (br d, J=7.9 Hz,
1H), 6.91 (td, J = 7.4, 1.0 Hz, 1H), 7.14 (dd, J=7.4, 1.7 Hz,
1H), 7.34 (td, J = 7.9, 1.9 Hz, 1H), 7.42–7.51 (m, 3H), 7.83
(dd, J = 8.0, 1.1 Hz, 1H) ppm; 13C NMR (62.9 MHz, CDCl3)
: 30.8, 109.9, 116.6, 124.7, 126.8, 128.0, 129.3, 129.4,
129.8, 132.1, 133.2, 140.0, 146.2 ppm; GC/MS (EI) (m/z)
263 (97), 261 (100), 182 (96), 180 (29), 167 (63).
(S)-1-[(2'-Bromo-biphenyl-2-yl)-methylamino]-propan-2-ol (S-11)
To a solution of aniline 8 (576 mg, 2.2 mmol) in CH2Cl2

JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
1909
(5 mL) under nitrogen was added triethylaluminium in
hexane (1 M, 3.1 mL, 3.1 mmol) at 0 °C. After 30 min,
(S)-propylene oxide (170 L, 2.43 mmol) was added and
the mixture was stirred at room temperature for 2 h. Aque-
ous sodium hydroxide (6 N, 3 mL, 18 mmol) was carefully
added (vigorous gas evolution) at 0 °C. The mixture was
stirred vigorously for 1 h. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (215 mL).
The combined organic layer was dried over MgSO4 and
concentrated under reduced pressure. Flash chromatography
(n-heptane/EtOAc = 80:20) afforded (S)-11 (430 mg, yield:
61%) as a pale yellow oil. []25D: + 26 (c 1.3 in CHCl3); 1H
NMR [400 MHz, CDCl3], 2 conformers A and B (A/B =
50:50),  : 1.05 (d, J = 5.9 Hz, 0.5H), 1.07 (d, J = 5.9 Hz,
0.5H), 2.59 (s, 1.5 HA), 2.60 (s, 1.5 HB) 2.65 (s, OH),
2.65–2.78 (m,1H), 2.79–2,83 (m, 1H), 3.75–3.85 (m, 1H),
7.15–7.28 (m, 4H), 7.34–7.45 (m, 3H), 7.71 (s, 0.5HA), 7.73
(s, 0.5HB) ppm; 13C NMR (62.9 MHz, CDCl3)  : 20.2 and
20.3, 41.8 and 42.1, 63.8, 64.5 and 64.8,121.3, 121.8, 123.9
and 124.1, 124.3, 127.6 and 127.8, 129.3, 129.4 and 129.5,
131.9 and 132.0, 133.4 and 133.5, 137.4, 142.0 and 142.1,
151.9 and 152.1; GC/MS (EI) (m/z) 319 (11), 276 (100),
274 (97), 195 (85), 194 (38), 152 (6); HRMS calcd for
C16H18NOBr (MH+): 320.0650, found: 320.0660.
added dropwise n-BuLi (1.6 M in hexane, 900 L, 1.4
mmol) at 78 °C. The yellow solution was stirred at 78 °C
for 20 min before adding ClPCy2 (350 L, 1.6 mmol). The
mixture was stirred for 12 h with gradual warming to room
temperature. The reaction mixture was quenched with
NH4Cl (saturated solution) and diluted with Et2O. The or-
ganic layer was separated, washed with brine (saturated),
dried over MgSO4 and concentrated under reduced pressure.
Flash chromatography (n-heptane/EtOAc = 90:10) afforded
(S)-1 (250 mg, yield: 42%) as a colorless oil. []25D: 2.0 (c
5.5 in CHCl3).1H NMR (400 MHz, CDCl3), 2 conformers A
and B (A/B =58/42), : 0.71 and 0.73 [d, J=6.2 Hz, 3H (A,
B)], 1.00–2.10 (m, 22H), 2.48–2.55 [m, 1H (A, B)],
2.55–2.70 [m, 1H (A, B)], 2.78 (s, 1.36, 3HB), 2.92 (s,
1.74 3HA), 3.16 (s, 1.36 3HB), 3.18 [s, 1.74 3HA], 6.90–7.10
(m, 3H), 7.30–7.40 (m, 4H), 7.58 (bs, 1H) ppm; 13C NMR
(400 MHz, CDCl3)  : 17.3, 26.9, 27.5, 27.9, 28.1, 29.0,
30.2, 30.4, 30.6, 31.1, 33.6, 36.9, 42.4, 41.5, 62.3, 59.9,
119.3, 120.5, 121.3, 126.3, 128.4, 128.8, 130.4, 131.1,
132.8, 133.1, 135.7, 150.0, 152.3 ppm (observed complexity
due to P-C splitting); 31P NMR (101.2 MHz, CDCl3)  :
8.8 and 9.0; MS (CI) (m/z) 452 (100) (MH+) 435 (5), 420
(9), 349 (38); HRMS calcd for C29H42NOP (MH+):
452.3082, found: 452.3091.
(S)-(2′-Bromo-biphenyl-2-yl)-(2-methoxy propyl)methylamine
(S-12)
(±)-[1-(2-Bromo-phenyl)-pyrrolidin-3-yl]dimethylamine (13a)
In a Schlenk tube under an argon atmosphere, Pd2dba3
(4.42 mg, 0.005 mmol, 0.005 equiv), BINAP (9.34 mg,
0.015 mmol, 0.015 equiv) and t-BuONa (300 mg, 3.1 mmol,
3.1 equiv) were dissolved in degassed toluene (5 mL). Di-
hydrochloride of pyrrolidine 14 (187 mg, 1.0 mmol) and
dibromobenzene 15a (96 L, 0.8 mmol, 0.8 equiv) were
added and the mixture was heated to 105 °C for 24 h. An
aqueous solution of ammonia (14%, 10 mL) was added and
the aqueous layer was extracted with CH2Cl2. The solvent
was removed under reduced pressure and the crude product
was purified by column chromatography [CH2Cl2/MeOH/
NH4OH (28%) = 95:5:1] to afford pyrrolidine 13a as a col-
orless oil (172 mg, yield: 80%). IR (film): 2948, 2816, 2770,
To a suspension of sodium hydride (50% in mineral oil, 50 mg,
0.84 mmol) in dry THF (2 mL) was added (S)-11 (180 mg,
0.56 mmol) in dry THF (2 mL). The mixture was stirred at
room temperature for 1 h before adding iodomethane (39 L,
0.62 mmol). The mixture was stirred for 12 h, and then di-
luted with Et2O (10 mL) and water (5 mL). The aqueous
layer was extracted with Et2O (2  10 mL). The combined
organic layers were dried over MgSO4 and concentrated
under reduced pressure. Flash chromatography (n-heptane/
EtOAc = 85:15) afforded (S)-12 (156 mg, yield: 83%) as a
1
pale yellow oil. H NMR (400 MHz, CDCl3), 2 conformers
A and B (A/B = 53:47),  : 0.83 [d, J = 6.2 Hz, 3H (A, B)],
2.65–2.70 [m, 1H, (A, B)], 2.71 [s, 3H (A, B)], 2.80 [dd, J=
13.2, 5.9 Hz, 0.53 HA] and 2.89 (dd, J = 13.2, 5.9 Hz, 0.47
HB), 2.99–3.05 [m, 1H (A or B)], 3.18–3.22 [m, 1H (A or
B)], 3.22 and 3.23 [s, 3H (A, B)], 7.00–7.08 [m, 1H (A, B)],
7.12–7.20 [m, 3H (A, B)], 7.30–7.38 [m, 3H (A, B)], 7.65
(0.53HA) and 7.67 (0.47 HB) ppm; 13C NMR (62.9 MHz,
CDCl3)  : 17.5 and 17.6, 42.02 and 42.06, 56.7, 61.4 and
61.8, 76.3 and 76.7, 119.7 and 120.1, 121.6 and 121.8,
124.4 and 124.5, 127.5, 128.7, 129.1, 132.2, 132.7 and
132.5, 133.35 and 133.30, 135.0 and 134.8, 143.0 and 142.7,
151.7 and 152.1 ppm.
1
1586, 1474, 1336, 1154, 1042, 1022, 746 cm1; H NMR
(250 MHz, CDCl3)  : 1.87 (m, 1H), 2.11–2.25 (m, 1H),
2.32 (s, 6H), 2.87 (quint, J = 7.6 Hz, 1H), 3.25 (td, J = 8.7,
3.6 Hz, 1H), 3.35–3.47 (m, 2H), 3.62 (dt, J = 8.7, 7.2 Hz,
1H), 6.78 (dt, J = 7.6, 1.5 Hz, 1H), 6.93 (dd, J=8.0, 1.5 Hz,
1H), 7.21 (dt, J = 7.6, 1.5 Hz, 1H), 7.51 (dd, J=8.0, 1.5 Hz,
1H) ppm; 13C NMR (62.9 MHz, CDCl3)  : 29.6, 44.0, 50.3,
55.6, 65.4, 114.4, 118.2, 121.9, 127.8, 134.5, 148.1 ppm;
MS (EI) (m/z) 269 (100, M+H+), 268 (60, M+H+), 225 (6),
169 (4), 145 (4), 84 (60), 70 (30).
(±)-[1-(2-Iodo-phenyl)-pyrrolidin-3-yl]-dimethylamine (13b)
(S)-(2′-(Dicyclohexylphosphanyl-biphenyl-2-yl)-(2-methoxy-
propyl)-methyl-amine (S-1)
Using the same procedure as for 13a, diamine 13b was ob-
tained as a colorless oil (215 mg, yield: 85%). IR (film)
1
2952, 2820, 2775, 1580, 1469, 1264, 1212, 737 cm1; H
To (S)-12 (436 mg, 1.3 mmol) in dry THF (3 mL) was

1910
JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
equiv). The mixture was heated to 110 °C for 4 h. After
cooling, the aqueous layer was extracted with Et2O. The
combined organic extracts were dried over MgSO4 and
evaporated under reduced pressure. The crude product was
purified by flash chromatography (CH2Cl2/MeOH =98:2) to
afford (R)-22 as a yellow oil (1.40 g, yield: 76%). []D =
+34.6 (c 0.7 in CHCl3); IR (film): 2951, 2868, 2776, 2420,
1598, 1571, 1469, 1302, 1268, 1108, 727 cm1; 1H NMR
(250 MHz, CDCl3), 2 conformers A and B (A/B=50:50), :
1.65–1.80 (m, 1H), 1.99–2.11 (m, 1H), 2.13 (s, 3H), 2.14 (s,
3H), 2.52–2.68 (m, 1H), 2.77 (t, J = 9.1 Hz, 0.5H), 2.91 (t,
J = 9.1 Hz, 0.5H), 3.06–3.32 (m, 3H), 6.64 (d, J = 7.6 Hz,
0.5H), 6.68 (d, J = 7.6 Hz, 0.5H), 7.18–7.26 (m, 1.5H),
7.28–7.34 (m, 0.5H), 7.37 (dd, J = 7.4, 1.2 Hz, 0.5H), 7.45
(dd, J = 7.6, 1.8 Hz, 0.5H), 7.58 (dd, J = 8.0, 1.2 Hz, 0.5H),
7.63–7.69 (m, 0.5H), 7.95 (d, J = 2.8 Hz, 0.5H), 7.97 (d, J=
3.5 Hz, 0.5H), 8.10 (t, J = 3.5 Hz, 0.5H), 8.14 (t, J=2.8 Hz,
0.5H); 13C NMR (62.9 MHz, CDCl3), 2 conformers, : 30.2,
30.3, 44.2, 44.3, 49.7, 49.8, 55.2, 55.3, 65.2, 65.3, 112.4,
113.0, 124.7, 124.9, 125.0, 125.2, 125.3, 125.4, 127.0,
127.1, 129.0, 129.3, 129.4, 131.9, 132.9, 132.3, 132.7,
136.8, 137.1, 141.5, 142.0, 150.8, 151.1; MS (ESI) (m/z)
390 (27, M+H+), 362 (80), 345 (97), 266 (46), 265 (100),
226 (36), 225 (15); HRMS (M+H+): calcd for C18H21N3O2Br:
390.0793, found: 390.0802.
NMR (250 MHz, CDCl3) : 1.87 (dq, J = 12.1, 7.9 Hz, 1H),
2.11–2.24 (m, 1H), 2.31 (s, 6H), 2.90 (quint, J=7.5 Hz, 1H),
3.17 (td, J = 8.8, 4.5 Hz, 1 H), 3.25–3.39 (m, 2H), 3.53 (dt,
J = 9.1, 7.5 Hz, 1H), 6.70 (dt, J = 7.5, 1.4 Hz, 1H), 6.98 (dd,
J = 8.0, 1.4 Hz, 1H), 7.26 (dt, J = 7.5, 1.4 Hz, 1H), 7.82 (dd,
J = 8.0, 1.4 Hz, 1H) ppm; 13C NMR (62.9 MHz, CDCl3) :
28.8, 43.2, 50.4, 55.4, 64.7, 91.4, 118.4, 123.0, 128.1, 140.1,
150.7 ppm; MS (EI) m/z: 317 (100, M+H+), 316 (13),
271(19), 146 (3), 84 (16).
(1R)-(3-Bromo-1-bromomethyl-propyl)-carbamic acid tert-
butyl ester (19)
To the dimesylate (S)-18 (480 mg, 1.33 mmol) was added
LiBr (690 mg, 7.84 mmol, 5.9 equiv) in dry acetone (10 mL).
The mixture was heated to 45 °C for 24 h, filtered and the
acetone was removed. An aqueous solution of ammonia
(28%) was added and the mixture was extracted with
CH2Cl2. The combined organic extracts were dried over
MgSO4 and concentrated under reduced pressure to give
compound (S)-19 as a colorless solid (255 mg, 58%). Mp
68 °C; IR (film): 3431, 2251, 1708, 1499, 1367, 1243, 1163,
907, 731, 650 cm1. 1H NMR (250 MHz, CDCl3)  : 1.45 (s,
9H), 2.08–2.20 (m, 2H), 3.40–3.50 (m, 2H), 3.50–3.64 (m,
2H), 4.00–4.12 (m, 1H), 4.73 (m, 1H) ppm.13C NMR (62.9
MHz, CDCl3)  : 28.3, 29.0, 36.4, 37.9, 49.2, 80.1, 155.0
ppm.
(R)-[1-(2′-Bromo-5-amino-biphenyl-2-yl)-pyrrolidin-3-yl]-
dimethyl-amine (23)
2′-Bromo-2-fluoro-5-nitro-1,1′-biphenyl (20)
To compound (R)-22 (100 mg, 0.26 mmol) in ethanol (5 mL)
were added zinc powder (336 mg, 5.13 mmol, 19.7 equiv)
and calcium chloride (43 mg, 0.39 mmol, 1.5 equiv). The
reaction mixture was heated under reflux for 16 h. The reac-
tion mixture was filtered and the filtrate was diluted with
water and extracted with EtOAc. The organic layer was
washed with water, brine, dried over MgSO4, filtered and
evaporated to afford (R)-23 as a brown oil (85 mg, yield:
91%) which required no purification. []D = +40.1 (c 0.8 in
CHCl3); IR (film): 3332, 3206, 2949, 2818, 1621, 1505,
1468, 1315, 1156, 1018, 807, 733 cm1; 1H NMR (250 MHz,
CDCl3), (2 conformers 50:50), : 1.54–1.72 (m, 1H),
1.82–1.98 (m, 1H), 2.10 (s, 6H), 2.53–2.76 (m, 2H),
2.77–3.00 (m, 3H), 3.30 (br s, 2H), 6.50 (dd, J=8.3, 2.8 Hz,
1H), 6.64 (dd, J = 4.2, 2.9 Hz, 0.5 H), 6.70 (dd, J = 3.9, 2.8
Hz, 0.5H), 6.72–6.78 (m, 1H), 7.08–7.16 (m, 1H), 7.21–7.26
(m, 1H), 7.27–7.39 (m, 1H), 7.58 (dd, J=7.8, 1.1 Hz, 0.5H),
7.63 (br d, J = 7.8 Hz, 0.5H) ppm; 13C NMR (62.9 MHz,
CDCl3), 2 conformers, : 29.4, 29.8, 43.6, 43.8, 49.9, 50.5,
55.0, 55.3, 65.2, 65.4, 115.9, 116.0, 116.2, 116.5, 119.0,
119.5, 124.0, 124.4, 126.8, 127.0, 128.0, 128.2, 131.3,
131.9, 131.7, 132.3, 132.2, 132.7, 138.4, 138.6, 140.4,
140.7, 142.9, 143.3 ppm; MS (ESI) (m/z) 360 (24, M+H+),
315 (96), 287 (52), 275 (11), 261 (11), 236 (32), 235 (100),
208 (11), 196 (17), 182 (9); HRMS (M+H+): calcd for
C18H23N3Br: 360.1075, found: 360.1068.
Pd(OAc)2 (112 mg, 0.5 mmol, 0.05 equiv) and PPh3 (540 mg,
2.0 mmol, 0.2 equiv) were dissolved in degassed dioxane
(30 mL). Fluorobenzene 21 (2.67 g, 10.0 mmol), 2-bromoben-
zeneboronic acid 10 (2.00 g, 10 mmol, 1.0 equiv) and CsF
(2.70 g, 18 mmol, 1.8 equiv) were added. The mixture was
heated to 120 °C in a sealed tube for 24 h. After cooling,
water (15 mL) was added and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
Purification by flash column chromatography (pentane/
EtOAc = 98:2) afforded biphenyl 20 as a colorless solid
(2.40 g, yield: 81%). Mp 73 °C; IR (film): 3100, 1626, 1578,
1562, 1527, 1492, 1469, 1434, 1344, 1248, 1102, 744 cm1.
1H NMR (250 MHz, CDCl3) : 7.12–7.26 (m, 3H),
7.28–7.38 (m, 1H), 7.60–7.64 (m, 1H), 8.14–8.31 (m, 2H)
ppm. 13C NMR (62.9 MHz, CDCl3)  : 116.8 (d, JC-F =24.9
Hz), 123.3, 125.7 (d, JC-F = 10.1 Hz), 127.5, 127.6, 129.9 (d,
JC-F = 18.6 Hz), 130.5, 131.3, 133.0, 134.6, 143.9 (d, JC-F
=
2.8 Hz), 163.0 (d, JC-F = 258.5 Hz). HRMS (M+H+): calcd
for C12H8BrFNO2: 295.9722, found 295.9727.
(R)-[1-(2′-Bromo-5-nitro-biphenyl-2-yl)-pyrrolidin-3-yl]-di-
methyl-amine (22)
To compound 20 (1.40 g, 4.72 mmol) in DMF (8 mL) were
added K2CO3 (2.93 g, 21.24 mmol, 4.5 equiv) and di-
methylaminopyrrolidine (R)-14 (1.33 mg, 7.08 mmol, 1.5

JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
1911
31P NMR (101.2 MHz, CDCl3),  : 9.52 (A), 10.75 (B)
ppm; MS (ESI) (m/z) 463 (49, M+H+), 435 (40), 418 (43),
390 (23), 378 (66), 349 (100), 336 (30), 308 (60), 267 (30),
226 (25), 221 (29), 220 (99), 214 (25), 185 (27), 115 (37);
HRMS (M+H+): calcd for C30H44N2P 463.3242, found
463.3239.
(R)-[1-(2′-Bromo-biphenyl-2-yl)-pyrrolidin-3-yl]-dimethyl-
amine (24)
To compound (R)-23 (400 mg, 1.16 mmol) in THF/H2O
(1:1, 10 mL) were added H3PO2 (50% aqueous solution,
450 L, 8.1 mmol, 7.0 equiv), then Cu2O (20.2 mg, 0.14
mmol, 0.12 equiv) and NaNO2 (104 mg, 1.51 mmol, 1.3
equiv) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h. A saturated aqueous solution of Na2CO3
was added and the aqueous layer was extracted with EtOAc.
The organic layer was washed with brine, dried over
MgSO4, and evaporated. The residue was purified by flash
chromatography (pentane/EtOAc = 80:20) to afford (R)-24
(280 mg, yield: 70%) as a colorless oil. []D =+62.2 (c 1.15
3 Results and discussion
The functionalization of aminobiphenyls 4 (Scheme 1) was
the first strategy we envisaged to prepare compound 1. We
assumed that an aminoethanol or ether moiety could direct a
remote lithiation of the biphenyl backbone [13, 14]. In order
to test this hypothesis and to know the potential sites of de-
protonation, we treated the alcohol 4a and the ether 4b eas-
ily prepared from aminobiphenyl with an alkyllithium. The
reaction mixture was then allowed to react with chloro-
trimethylsilane. With 4a, the complex mixtures of products
were formed including the trimethylsilyl protected alcohol.
No reaction took place under the same conditions with the
ether 4b.
1
in CHCl3); H NMR (250 MHz, CDCl3), 2 conformers A
and B (A/B = 50:50), : 1.58–1.76 (m, 1H), 1.89–2.03 (m,
1H), 2.13 (s, 3H), 2.14 (s, 3H), 2.52–2.74 (m, 1.5H), 2.80
(t, J = 8.5 Hz, 0.5H), 2.92–3.12 (m, 3H), 6.77–6.87 (m, 2H),
7.01–7.20 (m, 2H), 7.23–7.36 (m, 2.5H), 7.42 (dd, J = 7.6,
1.8 Hz, 0.5H), 7.63 (dd, J = 7.9, 1.2 Hz, 0.5H), 7.68 (d, J=
7.9 Hz, 0.5H).
(R)-[1-(2′-Dicyclohexyphosphanyl)-biphenyl-2-yl]-pyrrolidin-
3-yl]-dimethyl-amine (2)
Palladium mediated Suzuki-coupling has been widely
developed for the synthesis of biaryls [15, 16], we thus ex-
amined the cross-coupling of o-bromoiodobenzene 6 and
boronic acid 5 (Scheme 2). The reaction [Pd(OAc)2 (5
mol%), PPh3 (20 mol%) in DMF/H2O or DME/H2O/EtOH
and K3PO4 or Na2CO3, under reflux] between these partners
led to biphenyl 7 in low yields (26%–30%). Conversely, the
coupling between bromobenzeneboronic acid 10 and N-Boc
iodoaniline 9b under identical catalytic conditions afforded
the expected compound 7 in 82% yield after optimization.
It is noteworthy that no Suzuki coupling occurred with
N-Boc-bromoaniline 9a. Introduction of the chiral lateral
chain was performed by ring opening of the (S)-propylene
oxide in the presence of triethylaluminium [17]. The alcohol
function was then transformed into ether and a halogen-
metal exchange followed by reaction with chlorodicyclo-
hexylphosphane led to the chiral biphenyl. Unexpectedly,
To compound (R)-24 (120 mg, 0.35 mmol) in dry THF (2 mL)
was added dropwise n-BuLi (2.5 M in hexane, 155 L, 0.38
mmol, 1.1 equiv) at 78 °C. The yellow solution was stirred
at 78 °C for 20 min. Then ClP(Cy)2 (94 L, 0.45 mmol,
1.3 equiv) was added and the mixture was stirred for 12 h
with gradual warming to room temperature. The reaction
mixture was quenched with a saturated aqueous solution of
NH4Cl and diluted with Et2O. The organic layer was sepa-
rated, washed with brine, dried over MgSO4 and concen-
trated under reduced pressure. The crude product was puri-
fied by flash chromatography (CH2Cl2/MeOH = 99:1) to
afford (R)-2 as a colorless oil (104 mg, yield: 64%). []D =
+51.3 (c 2.0 in CHCl3); IR (film): 3049, 2923, 2850, 1595,
1
1567, 1496, 1481, 1462, 1446, 1160, 726 cm1; H NMR
(400 MHz, CDCl3), 2 conformers A and B (A/B=60:40), :
0.80–2.00 (m, 23H), 2.01–2.06 (m, 1H), 2.07 (s, 2.4HB),
2.13 (s, 3.6HA), 2.45–2.56 (m, 1H), 2.64 (t, J = 8.9 Hz,
0.4HB), 2.69 (t, J = 8.9 Hz, 0.6HA), 2.79 (dt, J=9.8, 6.7 Hz,
0.6HA), 2.91 (dt, J = 9.1, 1.8 Hz, 0.6HA), 2.96 (dd, J = 9.1,
7.2 Hz, 0.4HB), 3.06 (dt, J = 9.1, 6.9 Hz, 0.4HB), 3.12 (dd,
J = 8.1, 7.3 Hz, 0.6HA), 3.15 (dt, J = 9.0, 3.1 Hz, 0.4HB),
6.75–6.84 (m, 2H), 6.99 (m, 1H), 7.20–7.40 (m, 4H),
7.47–7.52 (m, 0.6HA), 7.52–7.57 (m, 0.4HB) ppm; 13C NMR
(100.6 MHz, CDCl3),  : 26.4–28.4 (6 C), 29.5–30.9 (6 C),
32.5, 33.9, 35.7, 36.3, 44.0, 44.2, 49.4, 49.9, 55.1, 55.3,
65.5, 65.7, 113.6, 114.2, 116.6, 117.5, 125.9, 126.0, 127.8,
127.9, 128.0, 128.2, 129.5, 129.6, 130.7, 130.8, 131.3,
131.4, 131.5, 132.0, 132.1, 132.4, 132.5, 132.6, 133.6,
133.7, 135.3, 135.6, 135.8, 136.1, 146.8, 148.0, 150.0,
150.5 ppm (observed complexity due to PC splitting and
conformers; definitive assignments have not yet been made);
1
the H NMR spectra of alcohol 11, ether 12 and target
Scheme 1 Synthesis of biphenyls 4a and 4b. Reagents and conditions: (i)
NaH, THF, 1 h then MeI, THF, RT 12 h; (ii) AlEt3 in hexanes, CH2Cl2, 0 °C,
30 min then propylene oxide, RT, 3 h, 55% for (i) and (ii); (iii) NaH, THF,
rt, 15 min then MeI, RT, 2 h 80%; (iv) t-Bu-Li (3 equiv), THF, 78 °C (or
20 °C or 0 °C) ; (v) Me3SiCl (3 equiv), 2 h.

1912
JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
X = I) afforded aminopyrrolidine 13a and 13b in 80% and
85% yields, respectively. A Suzuki coupling of these pyr-
rolidines 13a and 13b was attempted under different condi-
tions (Pd2dba3 or Pd(OAc)2, Na2CO3 or K3PO4, dioxane/
H2O, toluene or dioxane, and ligands [18, 19], 95–110 °C).
When a reaction occurred, either a complex mixture of
products or the dehalogeno derivative 16 was formed.
All the attempts to transform the bromo derivative 13a
into a boronate, a trimethylstannyl or an organozinc deriva-
tive failed. The only product isolated was the phenylpyr-
rolidine 16.
The difficulties encountered to introduce a phenyl ring in
the ortho-position to the pyrrolidine led us to study the route
B in which the pyrrolidine ring could be appended to the
biphenyl backbone. Reaction of aniline 17 and dimesylate
18 at 45 °C in THF in the presence of HNa for 48 h yielded
the expected compound in poor yield (14%). This poor re-
activity may be due to the ortho-substitution of the aniline
and the instability of the reagents. Attempts to use the di-
bromide 19 failed, and a complex mixture was formed. The
route C was thus studied.
A Suzuki coupling between 2-iodo 4-nitro fluorobenzene
[20] and boronic acid 10 yielded the biaryl 20 in 81% yield.
Aromatic nucleophilic substitution of the fluorine atom by
(R)-(3-N,N-dimethylamino)pyrrolidine (R)-14 afforded com-
pound 22 in a satisfactory yield. Reduction of the nitro
group followed by diazotation in the presence of a reducing
agent, bromine-lithium exchange and reaction with chlorodi-
cyclohexylphosphane led to the expected compound 2 as two
conformers in six steps and 18% overall yield from
4-fluoronitrobenzene.
Scheme 2 Synthesis of compound 1. Reagents and conditions: (i)
Na2CO3, DME/H2O/EtOH (4/1/0.1), PPh3 (20 mol%), Pd(OAc)2 (5 mol%),
85 °C, 12 h, 7: 30%; (ii) the same as (i) but dioxane/H2O (4:1), 95 °C, 7:
82%; (iii) LiAlH4 (2 equiv), THF, reflux, 2 h, 8 [12]: 53%; (iv) (S)-propylene
oxide, AlEt3, CH2Cl2, RT, 1 h, 11: 52%; (v) NaH, THF, RT, 1 h, then MeI,
rt, 12 h, 12: 85%; (vi) n-BuLi, THF, 78 °C, then ClPCy2, THF, 78 °C to
RT, 12 h, 1: 42%.
compound 1 show the formation of two conformers.
The synthesis of compound 2 was envisaged according to
three routes summarized in Scheme 3. The first one was
based on a coupling reaction between ortho-halogenoaniline
13 and dihalogenobenzene, whereas in the second and third
approaches, the pyrrolidine moiety was built on preformed
biphenyl derivatives 17 or 20. Reaction of a slight excess of
N,N-dimethylaminopyrrolidine dihydrochloride 14·2HCl
and dibromo or diiodobenzene 15a or 15b in toluene at
100 °C in the presence of t-BuONa, Pd2dba3 (3 mol%), and
a ligand (4.5 mol%, BINAP for X = Br and Xantphos for
Palladium catalyzed amination of a dibromo cyclophane
[21] and arylation of binaphthyl(di)amines [22, 23] have
previously shown the possibility of a kinetic resolution in
palladium mediated reactions. The synthesized compounds
were thus evaluated in palladium mediated arylaminations.
Aminopyrrolidine 25 and bromobenzene in the presence of
Scheme 4 Synthesis of compound 2. Reagents and conditions: (i)
Pd(OAc)2 (5 mol%), Ph3P (0.2 equiv), 10 (1 equiv), CsF (1.8 equiv), dioxane,
120 °C, sealed tube, 24 h, 81%; (ii) 3-(R)-(N,N-dimethylamino)pyrrolidine
dihydrochloride, DMF, K2CO3 (4 equiv), 110 °C, 4 h, 76%; (iii) Zn (22
equiv), CaCl2 (1.5 equiv), EtOH, 80 °C, 16 h, 91%; (iv) NaNO2 (1.3 equiv),
Cu2O (0.12 equiv), H3PO2 (7 equiv), THF/H2O (1:1), 70%; (v) n-BuLi (1.1
equiv), ClPCy2 (1.3 equiv), THF, 78 °C, 64%.
Scheme 3 Retrosynthetic analysis of compound 2.

JEAN Ludovic, et al. Sci China Chem September (2010) Vol.53 No.9
1913
addition of diethylzinc to N-phosphinoylimines: Discovery of new
effective chiral ligands. J Org Chem, 2008, 73: 6330–6340
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Pd2dba3 and ligand 1 under the conditions shown in Scheme
5 gave no reaction. However, chlorobenzene under the same
catalytic conditions afforded N-arylpyrrolidine 26 in 54%
yield. Compared to DavePhos (Figure 1), the cross-coupling
was slightly less efficient (yield with DavePhos: 80%). It is
noteworthy that using Pd(OAc)2 as a source of Pd, only
traces of the coupled product 26 were formed. Ligand 2 was
tested in the palladium mediated reaction of bromobenzene
with N-Boc-3-aminopiperidine 27. The expected arylamine
28 was formed in 88% yield, a value which compares well
with that obtained when ligand DavePhos was used (90 %
yield under the same conditions).
5
6
7
8
These results are encouraging in view of undertaking
arylation of racemic amines 25 and 27 under kinetic resolu-
tion conditions.
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Scheme 5 Evaluation of ligands 1 and 2. (i) PhCl (1 mmol), 25 (1.2
mmol), t-BuONa (1.4 mmol), Pd2dba3 (1 mol%), 1 (1.5 mol%), toluene,
95 °C, 24 h, 54%; (ii) PhBr (1 mmol), 27 (1.2 mmol), t-BuONa (1.4 mmol),
Pd2dba3 (1 mol%), 2 (1.5 mol%), toluene, 110 °C, 24 h, 88%.
14 Choppin S, Gros P, Fort Y. First regioselective C-2 lithiation of 3-and
4-chloropyridines. Eur J Org Chem, 2001: 603–606
4 Conclusions
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In summary, we have synthesized the first 2,2′ biphenyl P,N
compounds bearing central chirality. The study demon-
strated the good reactivity of 2-bromoboronic acid com-
pared to that of 2-N-Boc aminoboronic acid in the Suzuki
coupling with 2-iodosubstituted benzene. A bulky pyr-
rolidine was introduced in the 2-position of 2′-substituted
biphenyl via an aromatic nucleophilic substitution. Prelimi-
nary experiments have shown that these ligands, in the
presence of a palladium source, are able to catalyze
arylaminations efficiently, with the best results obtained
with the more rigid compound 2.
We gratefully acknowledge the CNRS/Region Basse Normandie and
Network PUNCH'Orga for fellowships to LJ and MP, respectively, the
Ministry of Education, the CNRS and the European Union (FEDER
funding) for financial supports.
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