Synthesis of chiral N-heterocyclic carbene ligands with rigid backbones and application to the palladium-catalyzed enantioselective intramolecular α-arylation of amides

Article abstract of DOI:10.1021/ol200149s

Chiral N-heterocyclic carbene (NHC) ligands having a 2,2′- bisquinoline-based C₂ symmetric skeleton were developed. The ligands exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.

Full text of DOI:10.1021/ol200149s

Supporting Information
Synthesis of Chiral N-Heterocyclic Carbene Ligands with Rigid Backbones"and
Application to the Palladium-Catalyzed Enantioselective Intramolecular
!-Arylation of Amides
Lantao Liu, Naoki Ishida, Shinji Ashida, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto
University, Katsura, Kyoto 615-8510, Japan
Table of Contents
S2
Generals and Materials
Synthesis of Chiral Diamines (R,R)-10 and (S,S)-10
Spectroscopic data (8-10)
S5
S8
Synthesis of the Chiral Carbene Precursors 6a, 6b and 7
Spectroscopic data (6a, 6b, 11a, 11b, and 7)
Synthesis of Chiral NHC-Copper Complexe 13
Spectroscopic data (13)
Detail of the Single-Crystal X-Ray Analysis (13)
S22
S24
Synthesis of Amides 14
Spectroscopic data (14)
Catalytic Asymmetric Intramolecular !-Arylation Reactions
Spectroscopic data (15)
S28
S29
S71
References
1
13
Copies of H and C NMR
Copies of HPLC
!
1

1
General. NMR spectra were recorded on a Varian Gemini 2000 ( H at 300 MHz
1
3
and C at 75 MHz), or Varian Mercury-400 spectrometers. Unless otherwise noted,
CDCl was used as a solvent. Chemical Shifts are recorded in " ppm referenced to a
residual CDCl
3
1
13
3
(" = 7.26 for H, " = 77.0 for C). High-resolution mass spectra
were recorded on Applied Biosystems Voyager Elite or JEOL JMS-HX110A
spectrometer. Infrared spectra were recorded on a SHIMADZU FT-IR 8100.
Optical rotation was measured by a JASCO P-1020 polarimeter. HPLC analysis was
performed by 4.6 # 250 mm column. Column chromatography was performed with
silica gel 60 N (Kanto). Preparative thin-layer chromatography was performed with
Silica gel 60 PF254 (Merck). Gel permeation chromatography (GPC) was carried out
with Japan Analytical Industry LC-908 or LC-9204 equipped with JAIGEL-1H.
1
,2,3
4
Materials. Amides 14
and TMEDA·PdMe
2
were prepared by the reported
1
1
2
1
procedures. 14a, 14c, 14e, and 14g are known compounds. Toluene and
hexane were dried over sodium benzophenone ketyl.
Chlorobenzene and
1
,2-dichloroethane were dried over CaH . Unless otherwise noted, all chemicals and
2
anhydrous solvents were obtained from commercial suppliers.
Synthesis of Chiral Diamines (R,R)-10 and (S,S)-10
Diimine 8
!
2

To a stirred solution of aminodiphenylmethane (25 g, 137 mmol) in hexane (60
mL) at room temperature was added glyoxal (40 wt.% solution in water, 7.8 mL, 68
mmol). After being stirred at room temperature overnight, the white precipitate
generated was collected by filtration, washed with hexane and then dried under
vacuum to give dimine 8 as a white solid (25.2 g, 65 mmol, 96% yield).
1
H NMR " 8.23 (s, 2H), 7.33 (d, J = 4.4 Hz, 16H), 7.22-7.30 (m, 4H), 5.60 (s, 2H);
1
3
C NMR " 162.1, 142.6, 128.6, 127.6, 127.3, 78.1; IR (KBr) 1628, 1492, 1448, 748,
–
1
+
6
3
96 cm ; HRMS (ESI): Calcd for C28
89.2005.
25 2
H N ([M+H] ): 389.2012. Found m/z
9
To a stirred solution of 8 (23.2 g, 64 mmol) in THF (240 mL) at -78 ˚C was
added dropwise the 2-methylallylmagnesium choloride (1.0 M in THF, 192mL, 192
mmol). The mixture was allowed to increase gradually to room temperature and
stirred for 10 hours. The reaction was quenched with water, the aq. layer was
3 4
extracted with CHCl , and the combined organic layers were dried over MgSO and
concentrated to give diamine 9 as brown oil (30.4 g, 60.8 mmol, 95% yield) which
was pure enough for next step.
1
H NMR " 7.16-7.40 (m, 20H), 4.76 (s, 2H), 4.65 (s, 2H), 4.42 (s, 2H), 2.77 (t, J = 6.0
Hz, 2H), 2.46 (dd, J = 13.2, 4.8 Hz, 2H), 2.04 (dd, J = 13.6, 8.0 Hz, 2H), 1.62 (br, 2H),
1
3
1
.45 (s, 6H); C NMR " 144.6, 144.5, 144.1, 128.4, 128.2, 127.8, 127.4, 126.9, 126.8,
–
1
1
12.8, 64.6, 53.3, 38.7, 21.9; IR (neat) 1642, 1599, 1492, 1451, 893, 745, 699 cm ;
+
41 2
HRMS(ESI): Calcd for C36H N ([M+H] ): 501.3264. Found m/z 501.3250.
Chiral Diamines (R,R)-10 and (S,S)-10
!
3

3
Racemic-10: To 9 (30.0 g, 60 mmol) at room temperature was added Et SiH
(
˚
(
28.6 mL, 180 mmol) and TFA (60 mL) subsequently. The mixture was stirred at 60
C for 6 hours. The reaction was cooled with ice bath and quenched with aq. NaOH
6 M, 150 mL, 900 mmol). The aq. layer was extracted with CHCl
3
, and the
combined organic layers were dried over Na
2
SO and concentrated to brown oil
4
containing racemic-4 which was used for next step without further purification.
5
(
R,R)-10: To the mixture containing Racemic-10 that was obtained from last
step was added (L)-tartaric acid (9.0 g, 60 mmol) and ethanol (300 mL). The
mixture was refluxed for 2 hours. The salt of (L)-tartaric acid and Racemic-10 was
collected by suction filtration. To the solid was added ethanol 300 ml and water 100
mL. The mixture was refluxed for 2 hours and cooled to room temperature gradually.
The (R,R)-10-(L)-tartrate was precipitated as white solid while (S,S)-10-(L)-tartrate
remained in the mother liquid. To the white solid was added aq. NaOH (6 M, 5 mL,
3
2
0 mmol) and stirred for 5 minutes. The mixture was extracted with Et
2
O (30 mL #
), and the combined organic layers were dried over Na SO and concentrated to
2
4
afford chiral diamine (R,R)-10 (1.86 g, 11 mmol, 37% yield) as colorless liquid.
(R,R)-10:
1
H NMR " 4.80-4.86 (m, 2H), 4.73-4.79 (m, 2H), 2.72-2.82 (m, 2H), 2.20 (dd, J =
1
3
1
3.5, 2.7 Hz, 2H), 1.96-2.08 (m, 2H), 1.72 (s, 6H), 1.28 (br, 4H); C NMR " 143.2,
–
1
1
12.9, 52.3, 43.7, 22.1; IR (neat) 3373, 2932, 1648, 1445, 1375, 890 cm ;
+
25
HRMS(ESI): Calcd for C10
H
21
N
2
([M+H] ): 169.1699. Found m/z 169.1699; [!]
D
=
3
-23.0 (c = 1.0 in CHCl ).
(S,S)-10: To the mother liquid was added aq. NaOH (6 M, 20 mL, 120 mmol) and
stirred for 5 minutes. The mixture was extracted with Et O (30 mL # 2), and the
2
!
4

2 4
combined organic layers were dried over Na SO to afford enantioenriched (S,S)-10
as colorless liquid. The enantioenriched (S,S)-10 was further purified by the
complexation with (D)-tartaric acid: To the enantioenriched (S,S)-10 was added
(D)-tartaric acid (2.25 g, 15 mmol), ethanol (210 mL) and water (70 mL). The
mixture was refluxed for 2 hours and then cooled to room temperature gradually.
(
S,S)-10-(D)-Tartrate was precipitated as white solid. To the white solid of
S,S)-10-(D)-Tartrate was added aq. NaOH (6 M, 5 mL, 30 mmol) and stirred for 5
(
minutes. The mixture was extracted with Et
organic layers were dried over Na SO and concentrated to afford chiral diamine
S,S)-10 (1.76 g, 10.5 mmol, 35% yield) as colorless liquid. [!]
CHCl ).
2
O (15 ml # 2), and the combined
2
4
2
5
(
D
= +23.0 (c = 1.0 in
3
Synthesis of the Chiral Carbene Precursors 6a, 6b and 7
6
General procedure for synthesis of chiral diamines 11: To a dried Schlenk tube
2
were added Pd(OAc) (22.4 mg, 0.1 mmol, 5 mol %), racemic-BINAP (62.3 mg, 0.1
t
mmol, 5 mol %), BuONa (576 mg, 6.0 mmol, 3.0 equiv), (S,S)-10 (336 mg, 2.0 mmol,
1
.0 equiv), 2-alkyl bromobenzene (4.4 mmol, 2.2 equiv), and toluene (4 mL). The
mixture was stirred at 100 ˚C for 20 hours. After cooling to room temperature,
volatiles were removed under vacuum and the residue was purified by flash
chromatography (f.c.) (hexane/ether 100/3) to give diamine 11a (647 mg, 93% yield)
and 11b (728 mg, 90% yield).
!
5

11a
1
H NMR " 7.18 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H),
.71 (t, J = 7.2 Hz, 2H), 4.89 (d, J = 1.2 Hz, 2H), 4.85 (d, J = 0.4 Hz, 2H), 4.00
psedo t, J = 7.2 Hz, 2H), 3.55 (s, 2H), 2.49 (dd, J = 14, 6.4 Hz, 2H), 2.34 (dd, J = 14,
6
(
1
3
7
.2 Hz, 2H), 2.18 (s, 6H), 1.74 (s, 6H); C NMR " 145.8, 143.1, 130.4, 127.3, 122.2,
1
1
3
16.9, 113.0, 110.1, 52.6, 41.0, 22.3, 17.5; IR (KBr) 3421, 1607, 1586, 1513, 1316,
–
1
+
263, 1124, 1055, 904, 746 cm ; HRMS(ESI): Calcd for C24
H
33
N
2
([M+H] ):
2
5
49.2638. Found m/z 349.2642; [!]
D
= +20.0 (c = 1.0 in CHCl ); HPLC [Daicel
3
Chiralcel OD-H, hexane/i-PrOH = 98/2, flow rate = #.$ mL/min, $ = 254 nm): t1 =
.0 min (minor), t2 = 6.6 min (major), ee: > 99%].
6
11b
1
H NMR " 7.10-7.22 (m, 4H), 6.81 (d, J = 8.0 Hz, 2H), 6.76 (t, J = 7.6 Hz, 2H), 4.87
s, 2H), 4.82 (s, 2H), 3.98 (d, J = 5.6 Hz, 2H), 3.73 (s, 2H), 2.88 (sept, J = 6.8 Hz, 2H),
(
2
6
.40 (dd, J = 14, 7.2 Hz, 2H), 2.32 (dd, J = 14, 7.2 Hz, 2H), 1.72 (s, 6H), 1.31 (d, J =
1
3
.8 Hz, 6H), 1.26 (d, J = 6.8 Hz, 6H); C NMR " 144.5, 143.2, 132.6, 126.9, 125.3,
1
1
17.4, 113.1, 111.0, 52.3, 40.9, 27.5, 22.5, 22.4, 22.2; IR (neat) 2963, 1604, 1583,
–
1
41 2
504, 1451, 1311, 1256, 1041, 891, 744 cm ; HRMS(ESI): Calcd for C28H N
+
25
([M+H] ): 405.3264. Found m/z 405.3246; [!]
D
3
= +27.7 (c = 1.0 in CHCl ).
General procedure for synthesis of chiral cyclic diamines 12: To a dried Schlenk
tube were added 5 (1 mmol), chlorobenzene (40 mL) and AlCl (665 mg, 5 mmol).
3
The mixture was stirred at 100 ˚C for 1 hour. After cooling to 0 ˚C, to the mixture
was added aq. NaOH (6 M, 5 mL, 30 mmol) and stirred for 20 minutes. The mixture
2
was extracted with Et O (30 mL # 3), the combined organic layers were dried over
Na SO . The volatiles were removed under vacuum, and the residue was purified by
2
4
!
6

flash chromatography (f.c.) (hexane/ether 100/3) to give diamine 12 which were used
without characterization.
General procedure for synthesis of chiral imidazolidiniums 6 and 7: To a dried
Schlenk tube were added the diamines 11b (1 mmol) or 12 (obtained from last step),
CH(OEt)
hours. After cooling to room temperature, the volatiles were removed under
vacuum, and the residue was purified by flash chromatography (f.c.) (DMC/CH OH
0/1) to give chiral imidazolidiniums 6a (350 mg, 75 % yield over two steps), 6b
361 mg, 72 % yield over two steps) and 7 (447 mg, 89 % yield).
3 4 4
(2 ml), and NH BF (1.2 mmol). The mixture was stirred at 120 ˚C for 5
3
1
(
6
a
1
H NMR " 8.39 (s, 1H), 7.20-7.40 (m, 4H), 7.14 (d, J = 7.2 Hz, 2H), 4.34 (d, J = 12.6
1
3
Hz, 2H), 2.42 (s, 6H), 2.16-2.38 (m, 4H), 1.47 (s, 6H), 1.39 (s, 6H); C NMR " 150.3,
1
39.4, 130.2, 129.7, 129.1, 128.1, 126.0, 62.2, 42.6, 34.2, 32.2, 30.9, 19.2; IR (KBr)
–
1
2
969, 1607, 1577, 1453, 1303, 1257, 1058, 790, 749 cm ; HRMS(ESI): Calcd for
+
25
C
25
H
31
N
2
([M-BF
4
] ): 359.2482. Found m/z 359.2479; [!]
D
= -96.5 (c = 0.2 in
CHCl
3
).
6
b
1
H NMR " 7.85 (s, 1H), 7.20-7.42 (m, 6H), 4.47 (d, J = 14.4 Hz, 2H), 2.94 (sept, J =
.6 Hz, 2H), 2.20-2.43 (m, 4H), 1.50 (s, 6H), 1.43 (s, 6H), 1.32 (d, J = 6.6 Hz, 6H),
6
1
3
1
.27 (d, J = 6.9 Hz, 6H); C NMR " 151.1, 140.0, 139.7, 128.7, 128.2, 126.0, 125.6,
6
2.7, 42.4, 34.6, 32.4, 30.9, 27.4, 24.7, 24.2; IR (KBr) 2960, 1609, 1581, 1438, 1300,
–
1
+
1
39 2 4
255, 1050, 752 cm ; HRMS(APCI): Calcd for C29H N ([M-BF ] ): 415.3108.
2
5
Found m/z 415.3088; [!]
D
3
= -59.0 (c = 0.6 in CHCl )
7
!
7

1
H NMR " 8.21 (s, 1H), 7.55 (dd, J = 8.0, 0.8 Hz, 2H), 7.41-7.51 (m, 4H), 7.30-7.37
m, 2H), 4.99 (t, J = 1.6 Hz, 2H), 4.91 (s, 2H), 4.48-4.56 (m, 2H), 3.11 (sept, J = 6.8
(
Hz, 2H), 2.60 (dd, J = 13.2, 11.2 Hz, 2H), 2.42 (dd, J = 13.2, 2.8 Hz, 2H), 1.59 (s, 6H),
1
3
1
1
2
C
.37 (d, J = 6.8 Hz, 6H), 1.32 (d, J = 6.8 Hz, 6H); C NMR " 156.8, 144.9, 138.4,
31.1, 130.5, 128.8, 127.9, 127.4, 117.3, 66.2, 40.2, 28.4, 24.4, 24.0, 21.5; IR (KBr)
–
1
971, 1637, 1491, 1448, 1253, 1050, 920, 763 cm ; HRMS(APCI): Calcd for
+
25
29
H
39
N
2
([M-BF
4
] ): 415.3108. Found m/z 415.3087. [!]
D
= -227 (c = 0.6 in
CHCl
3
).
Synthesis of chiral NHC-copper complex 13: To a dried schlenk tube were added
t
6
b (0.1 mmol, 50 mg), BuONa (0.1 mmol, 9.6 mg), CuCl (0.1 mmol, 9.9 mg), and
THF (2 mL). The mixture was stirred at room temprature for 3 hours. The
volatiles were removed under vacuum, and the residue was purified by preparative
thin layer chromatography on silica gel (DCM/EtOH 10/1) to give 13 (16.2 mg, 33%
yield). A single crystal suitable for an X-ray structural analysis was obtained by
3
recrystallization from CHCl /hexane
1
3
1
H NMR " 7.19 (dd, J = 8.0, 1.2 Hz, 4H), 7.03 (t, J = 8.0 Hz, 4H), 6.42 (dd, J = 8.0,
1
.2 Hz, 4H), 3.81 (t, J = 7.6 Hz, 4H), 3.70 (sept, J = 6.8 Hz, 4H), 3.70 (sept, J = 6.8
Hz, 4H), 1.90 (d, J = 6.4 Hz, 8H), 1.47 (s, 12H), 1.29 (s, 12H), 0.92 (d, J = 6.8 Hz,
1
3
1
2H), 0.89 (d, J = 6.4 Hz, 12H); C NMR " 200.5, 139.7, 139.5, 133.0, 128.0, 124.6,
1
23.8, 62.7, 43.1, 34.6, 33.9, 30.2, 29.0, 26.1, 20.8; IR (KBr) 2963, 1441, 1405, 1388,
–
1
+
1
299, 1052, 749 cm ; HRMS(ESI): Calcd for C58
H
4 4
76CuN ([M-BF ] ): 891.5361.
2
5
Found m/z 891.5344; [!]
D
= -462.4 (c = 0.1 in CHCl
3
).
!
8

The single crystal was mounted on a plastic loop. Data were collected on
Rigaku/MSC Saturn CCD diffractometer with confocal monochromated Mo KR
radiation ($ = 0.7107 Å) and processed using the CrystalClear program (Rigaku). The
structure was solved by a direct method and refined by full matrix least-squares
refinement cycles on F2 for all data using the SHELX-97. Details of crystal and data
collection parameters are shown in Table S1–S5.
Table S1. Crystal data and structure refinement
Identification code
1
Empirical formula
Formula weight
C60 H78 B Cl6 Cu F4 N4
1218.31
Temperature
296(2) K
Wavelength
0.71075 A
Crystal system, space group
Unit cell dimensions
P212121
a = 11.9578(3) A alpha = 90 deg.
b = 16.9032(4) A
beta = 90
deg.
deg.
c = 31.2535(9) A gamma = 90
6317.1(3) A^3
Volume
Z, Calculated density
Absorption coefficient
F(000)
4, 1.281 Mg/m^3
0.651 mm^-1
2552
Crystal size
0.10 x 0.10 x 0.10 mm
Theta range for data collection 3.02 to 27.49 deg.
Limiting indices -13<=h<=15, -21<=k<=21,
40<=l<=40
-
Reflections collected / unique
Completeness to theta = 27.49
Max. and min. transmission
Refinement method
59307 / 14109 [R(int) = 0.0292]
98.2 %
0.9378 and 0.9378
Full-matrix least-squares on F^2
14109 / 0 / 701
Data / restraints / parameters
Goodness-of-fit on F^2
1.065
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0536, wR2 = 0.1539
R1 = 0.0638, wR2 = 0.1641
0.020(11)
Absolute structure parameter
Largest diff. peak and hole
0.613 and -0.493 e.A^-3
!
9

Table S2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement
parameters (A^2 x 10^3) for 1. U(eq) is defined as one third of the trace of the
orthogonalized Uij tensor.
_
_______________________________________________________________
x
y
z
U(eq)
_
_______________________________________________________________
Cu(1)
C(19)
N(1)
6921(1)
7313(2)
6636(2)
5900(2)
3311(2)
4690(3)
6576(2)
8357(2)
7760(2)
6730(2)
6994(2)
5042(2)
5707(2)
5560(2)
7810(3)
3948(2)
3619(2)
4467(3)
4785(3)
4626(2)
5337(3)
9709(3)
9699(3)
7320(5)
5415(3)
7884(3)
3114(3)
6726(4)
4398(4)
2910(3)
3360(3)
6280(4)
68(1)
210(2)
1515(1)
921(1)
40(1)
40(1)
44(1)
38(1)
143(1)
51(1)
39(1)
48(1)
50(1)
43(1)
41(1)
42(1)
42(1)
46(1)
202(2)
48(1)
53(1)
64(1)
58(1)
49(1)
51(1)
65(1)
61(1)
247(2)
54(1)
49(1)
66(1)
64(1)
70(1)
181(1)
72(1)
63(1)
383(1)
591(1)
N(2)
352(1)
2359(1)
-1037(1)
839(1)
Cl(1)
C(24)
C(25)
N(3)
820(1)
346(2)
-95(2)
2113(1)
763(1)
123(2)
C(27)
C(28)
N(4)
-165(2)
-529(2)
-667(1)
886(2)
3017(1)
2821(1)
2365(1)
2205(1)
2783(1)
629(1)
C(30)
C(31)
C(32)
Cl(4)
C(34)
C(35)
C(36)
C(37)
C(38)
C(39)
C(40)
C(41)
Cl(5)
C(43)
C(44)
C(45)
C(46)
C(47)
Cl(2)
C(49)
C(50)
-10(2)
744(2)
-2173(1)
728(2)
-730(1)
2333(1)
2645(1)
1819(1)
947(1)
71(2)
2032(2)
-529(2)
-467(2)
1560(2)
-939(2)
92(3)
2752(1)
1965(1)
797(1)
1356(1)
-1578(1)
438(1)
-1859(2)
1489(2)
-1206(2)
1235(2)
-1849(2)
1873(3)
-796(1)
1854(2)
1863(2)
2283(1)
2179(1)
1690(1)
511(1)
-815(1)
1922(1)
137(1)
!
10

C(51)
C(52)
C(53)
C(54)
C(55)
C(56)
C(57)
C(58)
C(59)
C(60)
C(61)
C(62)
C(63)
C(64)
C(65)
B(1)
8778(3)
6548(3)
9257(3)
3567(3)
7815(3)
3693(3)
8402(4)
9425(4)
10558(4)
2703(3)
8762(3)
9850(3)
7288(3)
7399(3)
5797(5)
9268(5)
3197(3)
8703(5)
9393(3)
8749(4)
8366(3)
10912(4)
5890(6)
6091(3)
9197(6)
9805(5)
6763(5)
4059(5)
9608(4)
6873(4)
10510(4)
6465(5)
9590(5)
10142(6)
4560(7)
2630(5)
6911(7)
9199(6)
-718(2)
1825(2)
-250(2)
1514(3)
-1749(2)
758(3)
2991(1)
1911(1)
981(1)
57(1)
56(1)
51(1)
75(1)
62(1)
66(1)
71(1)
79(1)
90(1)
76(1)
61(1)
84(1)
52(1)
62(1)
82(1)
80(1)
73(1)
93(2)
66(1)
73(1)
57(1)
89(1)
103(2)
271(3)
107(2)
167(2)
102(2)
102(2)
89(1)
94(2)
85(1)
93(2)
102(2)
118(2)
110(2)
89(1)
115(2)
178(2)
747(1)
1945(1)
896(1)
-772(2)
-1200(3)
-1310(3)
-454(3)
-1218(2)
-212(3)
538(2)
169(1)
343(1)
1034(2)
2459(2)
2584(1)
3011(2)
193(1)
1423(2)
1795(3)
557(4)
156(1)
-321(1)
-949(1)
3063(1)
1892(2)
1482(1)
3381(1)
289(1)
C(67)
C(68)
C(69)
C(70)
C(71)
C(72)
C(73)
Cl(6)
C(75)
F(1)
448(3)
-2274(3)
931(2)
-1271(3)
105(2)
-1038(3)
-2313(3)
-1174(2)
-2105(3)
692(3)
1419(2)
1954(2)
-941(2)
334(2)
-599(1)
1502(2)
1328(2)
2517(2)
2319(2)
1575(2)
243(2)
C(77)
C(78)
C(79)
C(80)
C(81)
C(82)
C(83)
C(84)
C(85)
C(86)
C(87)
F(2)
2299(3)
-755(4)
-1758(3)
2275(3)
-326(3)
2737(2)
-2272(4)
1485(4)
-1013(3)
161(3)
2167(2)
1220(2)
551(2)
-690(2)
1239(2)
-1248(2)
-2175(4)
1108(3)
!
11

F(3)
8225(4)
9484(10)
10431(5)
9517(5)
7365(7)
2997(2)
293(4)
-98(5)
-818(2)
-1157(2)
56(2)
173(2)
256(4)
123(2)
103(2)
128(3)
121(1)
F(4)
C(91)
C(92)
C(94)
Cl(3)
-1016(5)
1103(4)
-1470(4)
381(1)
1958(2)
-1083(2)
-163(1)
_
_______________________________________________________________
Table S3. Bond lengths [A] and angles [deg]
____________________________________________________________
_
Cu(1)-C(19)
Cu(1)-C(25)
C(19)-N(1)
C(19)-N(3)
N(1)-C(32)
N(1)-C(63)
N(2)-C(25)
N(2)-C(30)
N(2)-C(31)
Cl(1)-C(86)
C(24)-C(56)
C(24)-C(32)
C(24)-C(37)
C(25)-N(4)
N(3)-C(53)
N(3)-C(71)
C(27)-C(28)
C(27)-C(51)
C(28)-N(4)
C(28)-C(31)
N(4)-C(44)
C(30)-C(34)
C(30)-C(39)
C(31)-C(38)
C(32)-C(43)
Cl(4)-C(94)
C(34)-C(45)
1.929(3)
1.934(2)
1.344(3)
1.350(4)
1.428(4)
1.490(3)
1.348(3)
1.447(3)
1.480(3)
1.756(6)
1.392(5
1.402(5)
1.521(5)
1.344(3)
1.422(4)
1.480(4)
1.506(4)
1.537(4)
1.478(3)
1.510(4)
1.424(4)
1.394(4)
1.410(4)
1.508(4)
1.404(4)
1.707(7)
1.401(4)
!
12

C(34)-C(35)
C(35)-C(60)
C(35)-C(67)
C(35)-C(38)
C(36)-C(39)
C(36)-C(49)
C(37)-C(85)
C(37)-C(78)
C(39)-C(52)
C(40)-C(59)
C(40)-C(53)
C(40)-C(58)
C(41)-C(81)
C(41)-C(53)
C(41)-C(69)
Cl(5)-C(94)
C(43)-C(47)
C(43)-C(50)
C(44)-C(55)
C(44)-C(61)
C(45)-C(49)
C(46)-C(73)
C(46)-C(87)
C(46)-C(55)
C(47)-C(54)
Cl(2)-C(86)
C(50)-C(82)
C(50)-C(64)
C(50)-C(65)
C(51)-C(61)
C(51)-C(70)
C(51)-C(62)
C(52)-C(77)
C(52)-C(80)
C(54)-C(56)
C(55)-C(68)
C(57)-C(58)
C(57)-C(71)
1.528(5)
1.524(5)
1.539(5)
1.545(4)
1.389(5)
1.395(6)
1.506(6)
1.522(6)
1.524(5)
1.406(6)
1.406(5)
1.525(6)
1.380(6)
1.409(5)
1.517(6)
1.682(8)
1.397(5)
1.537(5
1.403(5)
1.409(5)
1.352(6)
1.514(7)
1.530(6)
1.535(6)
1.378(6)
1.698(6)
1.531(6)
1.532(5)
1.547(6)
1.528(6)
1.536(5)
1.541(5)
1.531(5)
1.534(6)
1.369(7)
1.394(6)
1.521(6)
1.529(5)
!
13

C(58)-C(91)
1.532(8)
1.553(8)
1.354(8)
1.379(5)
1.506(5)
1.512(5)
1.288(6)
1.310(9)
1.323(7)
1.387(7)
1.364(8)
1.521(6)
1.534(6)
1.385(8)
1.664(10)
1.397(8)
1.743(5)
177.98(11)
107.5(2)
128.2(2)
124.26(19)
124.9(2)
111.2(2)
117.8(2)
125.9(2)
111.9(2)
116.4(2)
117.1(3)
121.4(3)
121.0(3)
107.0(2)
126.19(19)
126.83(19)
125.0(2)
112.0(2)
117.7(2)
112.2(3)
106.4(2)
C(58)-C(75)
C(59)-C(72)
C(61)-C(79)
C(63)-C(64)
C(63)-C(71)
B(1)-F(1)
B(1)-F(4)
B(1)-F(2)
B(1)-F(3)
C(68)-C(83)
C(69)-C(92)
C(69)-C(84)
C(72)-C(81)
Cl(6)-C(94)
C(79)-C(83)
C(86)-Cl(3)
C(19)-Cu(1)-C(25)
N(1)-C(19)-N(3)
N(1)-C(19)-Cu(1)
N(3)-C(19)-Cu(1)
C(19)-N(1)-C(32)
C(19)-N(1)-C(63)
C(32)-N(1)-C(63)
C(25)-N(2)-C(30)
C(25)-N(2)-C(31)
C(30)-N(2)-C(31)
C(56)-C(24)-C(32)
C(56)-C(24)-C(37)
C(32)-C(24)-C(37)
N(4)-C(25)-N(2)
N(4)-C(25)-Cu(1)
N(2)-C(25)-Cu(1)
C(19)-N(3)-C(53)
C(19)-N(3)-C(71)
C(53)-N(3)-C(71)
C(28)-C(27)-C(51)
N(4)-C(28)-C(27)
!
14

N(4)-C(28)-C(31)
C(27)-C(28)-C(31)
C(25)-N(4)-C(44)
C(25)-N(4)-C(28)
C(44)-N(4)-C(28)
C(34)-C(30)-C(39)
C(34)-C(30)-N(2)
C(39)-C(30)-N(2)
N(2)-C(31)-C(38)
N(2)-C(31)-C(28)
C(38)-C(31)-C(28)
C(24)-C(32)-C(43)
C(24)-C(32)-N(1)
C(43)-C(32)-N(1)
C(30)-C(34)-C(45)
C(30)-C(34)-C(35)
C(45)-C(34)-C(35)
C(60)-C(35)-C(34)
C(60)-C(35)-C(67)
C(34)-C(35)-C(67)
C(60)-C(35)-C(38)
C(34)-C(35)-C(38)
C(67)-C(35)-C(38)
C(39)-C(36)-C(49)
C(85)-C(37)-C(24)
C(85)-C(37)-C(78)
C(24)-C(37)-C(78)
C(31)-C(38)-C(35)
C(36)-C(39)-C(30)
C(36)-C(39)-C(52)
C(30)-C(39)-C(52)
C(59)-C(40)-C(53)
C(59)-C(40)-C(58)
C(53)-C(40)-C(58)
C(81)-C(41)-C(53)
C(81)-C(41)-C(69)
C(53)-C(41)-C(69)
C(47)-C(43)-C(32)
100.9(2)
117.2(3)
129.2(2)
111.9(2)
115.7(2)
122.8(3)
116.8(2)
120.2(3)
106.7(2)
100.60(19)
113.7(2)
122.4(3)
120.2(3)
117.3(3)
116.9(3)
124.3(2)
118.8(3)
111.4(3)
109.2(3)
109.0(3)
107.5(3)
111.4(2)
108.3(3)
120.8(3)
109.4(3)
113.8(4)
112.0(4)
112.4(3)
116.9(3)
120.4(3)
122.2(3)
115.5(4)
121.6(4)
122.4(3)
117.7(4)
121.2(4)
120.7(3)
117.2(3)
!
15

C(47)-C(43)-C(50)
C(32)-C(43)-C(50)
C(55)-C(44)-C(61)
C(55)-C(44)-N(4)
C(61)-C(44)-N(4)
C(49)-C(45)-C(34)
C(73)-C(46)-C(87)
C(73)-C(46)-C(55)
C(87)-C(46)-C(55)
C(54)-C(47)-C(43)
C(45)-C(49)-C(36)
C(82)-C(50)-C(64)
C(82)-C(50)-C(43)
C(64)-C(50)-C(43)
C(82)-C(50)-C(65)
C(64)-C(50)-C(65)
C(43)-C(50)-C(65)
C(61)-C(51)-C(70)
C(61)-C(51)-C(27)
C(70)-C(51)-C(27)
C(61)-C(51)-C(62)
C(70)-C(51)-C(62)
C(27)-C(51)-C(62)
C(39)-C(52)-C(77)
C(39)-C(52)-C(80)
C(77)-C(52)-C(80)
C(40)-C(53)-C(41)
C(40)-C(53)-N(3)
C(41)-C(53)-N(3)
C(56)-C(54)-C(47)
C(68)-C(55)-C(44)
C(68)-C(55)-C(46)
C(44)-C(55)-C(46)
C(54)-C(56)-C(24)
C(58)-C(57)-C(71)
C(57)-C(58)-C(40)
C(57)-C(58)-C(91)
C(40)-C(58)-C(91)
119.6(3)
123.1(3)
122.5(3)
120.6(3)
116.6(3)
121.6(4)
114.2(5)
109.6(3)
113.3(4)
120.6(4)
120.7(3)
109.5(4)
111.2(4)
111.3(3)
109.1(4)
109.1(3)
106.6(3)
108.8(3)
111.7(3)
108.1(3)
110.6(3)
108.9(3)
108.6(3)
113.9(4)
107.1(3)
113.0(4)
122.4(3)
117.5(3)
120.0(3)
120.9(4)
117.4(4)
121.0(4)
120.9(3)
121.2(4)
113.3(4)
111.9(3)
109.0(4)
108.1(5)
!
16

C(57)-C(58)-C(75)
C(40)-C(58)-C(75)
C(91)-C(58)-C(75)
C(72)-C(59)-C(40)
C(79)-C(61)-C(44)
C(79)-C(61)-C(51)
C(44)-C(61)-C(51)
N(1)-C(63)-C(64)
N(1)-C(63)-C(71)
C(64)-C(63)-C(71)
C(63)-C(64)-C(50)
F(1)-B(1)-F(4)
108.7(5)
109.9(4)
109.1(5)
122.9(5)
117.0(4)
119.0(3)
123.8(3)
106.5(3)
101.3(2)
115.0(3)
114.1(3)
118.2(7)
120.5(6)
104.8(5)
104.8(5)
93.0(7)
F(1)-B(1)-F(2)
F(4)-B(1)-F(2)
F(1)-B(1)-F(3)
F(4)-B(1)-F(3)
F(2)-B(1)-F(3)
112.3(6)
121.1(4)
114.3(4)
106.9(4)
110.4(4)
100.5(2)
105.4(3)
116.4(3)
119.9(4)
121.3(4)
121.0(5)
120.4(4)
111.8(3)
111.7(3)
109.4(3)
109.5(5)
108.8(5)
109.4(5)
C(83)-C(68)-C(55)
C(41)-C(69)-C(92)
C(41)-C(69)-C(84)
C(92)-C(69)-C(84)
N(3)-C(71)-C(63)
N(3)-C(71)-C(57)
C(63)-C(71)-C(57)
C(59)-C(72)-C(81)
C(61)-C(79)-C(83)
C(41)-C(81)-C(72)
C(68)-C(83)-C(79)
Cl(2)-C(86)-Cl(3)
Cl(2)-C(86)-Cl(1)
Cl(3)-C(86)-Cl(1)
Cl(6)-C(94)-Cl(5)
Cl(6)-C(94)-Cl(4)
Cl(5)-C(94)-Cl(4)
_
____________________________________________________________
Symmetry transformations used to generate equivalent atoms:
!
17

Table S4. Anisotropic displacement parameters (A^2 x 10^3) The anisotropic
displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a*
b* U12 ]
_
_
____________________________________________________________________
_
U11
U22
U33
U23
U13
U12
_
___________________________________________________________________
__
_
Cu(1)
C(19)
N(1)
45(1)
43(1)
51(1)
37(1)
44(1)
43(1)
48(1)
43(1)
154(2)
61(2)
40(1)
60(1)
62(2)
54(1)
44(1)
45(1)
52(1)
51(2)
107(1)
54(2)
67(2)
54(2)
57(2)
58(2)
42(1)
70(2)
80(2)
124(2)
53(2)
53(2)
78(2)
42(1)
68(2)
100(1)
32(1)
35(1)
32(1)
34(1)
90(1)
42(1)
36(1)
37(1)
42(1)
33(1)
34(1)
36(1)
34(1)
41(1)
223(3)
47(2)
55(2)
64(2)
57(2)
47(1)
45(1)
65(2)
60(2)
139(2)
44(2)
46(1)
72(2)
49(2)
68(2)
169(2)
4(1)
5(1)
6(1)
5(1)
0(1)
-2(1)
0(1)
1(1)
1(1)
3(1)
4(1)
N(2)
0(1)
Cl(1) 184(2)
-6(1)
16(1)
-5(1)
-3(1)
2(1)
-48(2)
C(24)
C(25)
N(3)
50(2)
40(1)
48(1)
44(1)
44(1)
45(1)
45(1)
41(1)
47(1)
4(1)
4(1)
-4(1)
-2(1)
4(1)
1(1)
5(1)
6(1)
6(1)
0(1)
4(1)
4(1)
C(27)
C(28)
N(4)
3(1)
-7(1)
-1(1)
-1(1)
-4(1)
1(1)
6(1)
3(1)
C(30)
C(31)
C(32)
0(1)
4(1)
2(1)
-8(1)
-157(3)
-6(1)
3(1)
Cl(4) 275(3)
10(1)
1(1)
-20(2)
C(34)
C(35)
C(36)
C(37)
C(38)
C(39)
C(40)
C(41)
43(1)
39(1)
74(2)
60(2)
42(1)
64(2)
59(2)
43(1)
9(1)
4(2)
6(2)
9(2)
-8(2)
-11(2)
1(1)
14(2)
-12(2)
-3(1)
6(1)
12(1)
11(1)
3(1)
-5(1)
8(2)
1(2)
18(2)
-6(2)
-94(3)
6(2)
2(2)
-8(1)
-59(3)
-5(1)
3(1)
Cl(5) 476(7)
8(1)
C(43)
C(44)
C(45)
65(2)
49(2)
47(2)
7(1)
6(1)
15(1)
19(2)
10(2)
19(2)
28(2)
5(2)
-9(2)
-8(2)
-8(2)
-30(2)
C(46) 100(3)
C(47) 75(2)
Cl(2) 273(3)
-3(1)
12(2)
-46(1)
!
18

C(49)
C(50)
C(51)
C(52)
C(53)
C(54)
C(55)
C(56)
C(57)
C(58)
C(59)
C(60)
C(61)
C(62)
C(63)
C(64)
C(65)
B(1)
69(2)
83(2)
42(1)
65(2)
43(1)
58(2)
75(2)
45(2)
90(3)
90(3)
69(2)
43(2)
50(2)
43(2)
62(2)
68(2)
99(3)
79(3)
65(2)
65(2)
54(2)
73(2)
41(1)
60(2)
94(3)
55(2)
92(3)
76(2)
87(3)
91(3)
93(3)
74(2)
116(4)
63(2)
69(2)
90(3)
113(4)
94(3)
79(3)
78(2)
87(3)
70(2)
108(4)
82(3)
190(3)
79(3)
205(5)
93(3)
106(4)
99(3)
100(3)
101(3)
53(2)
109(4)
90(4)
60(2)
96(3)
82(3)
53(2)
56(2)
63(2)
51(2)
72(2)
54(2)
62(2)
47(2)
60(2)
108(4)
91(3)
59(2)
93(3)
30(1)
48(2)
57(2)
48(2)
60(2)
77(3)
67(2)
65(2)
38(1)
94(3)
98(4)
477(8)
93(3)
94(2)
108(4)
109(4)
90(3)
106(4)
89(3)
104(4)
102(4)
131(5)
85(3)
78(3)
9(2)
15(1)
11(2)
1(1)
-21(2)
1(2)
24(2)
4(2)
-6(1)
7(2)
6(2)
0(1)
5(1)
4(1)
6(1)
4(2)
-2(2)
6(2)
22(2)
21(2)
2(2)
5(1)
8(2)
-2(1)
4(2)
-10(2)
-6(2)
11(3)
13(2)
11(2)
18(3)
8(1)
23(2)
36(2)
32(3)
-9(2)
16(2)
-5(2)
-1(2)
-5(2)
9(3)
3(2)
0(2)
-5(2)
-3(1)
-11(2)
5(1)
15(2)
24(2)
-7(2)
5(2)
4(2)
-9(2)
-5(2)
13(2)
15(3)
-2(2)
-15(2)
7(1)
-16(3)
16(2)
43(3)
-15(2)
8(2)
C(67)
C(68) 122(4)
-9(2)
-4(2)
17(2)
1(1)
C(69)
C(70)
C(71)
C(72)
53(2)
68(2)
64(2)
67(2)
8(2)
12(3)
25(3)
125(4)
-20(3)
19(3)
52(3)
48(3)
3(3)
-23(2)
-22(3)
46(3)
-19(3)
-57(3)
24(3)
13(3)
-10(2)
8(3)
13(2)
-24(3)
11(2)
40(4)
-82(4)
4(3)
C(73) 128(5)
Cl(6) 145(2)
C(75) 147(5)
F(1)
203(5)
C(77) 106(4)
C(78)
C(79)
C(80)
C(81)
91(3)
76(3)
76(3)
64(2)
-23(3)
46(3)
-21(3)
1(2)
-43(3)
7(3)
-25(2)
13(3)
5(3)
C(82) 121(4)
C(83) 94(3)
22(2)
0(3)
-3(2)
61(3)
-41(4)
-11(3)
-2(3)
C(84) 133(5)
C(85) 184(6)
1(3)
39(4)
-44(4)
-12(2)
-3(2)
-8(2)
C(86)
92(3)
!
19

C(87) 158(6)
110(4)
171(4)
220(5)
221(7)
160(6)
152(5)
93(4)
77(3)
110(3)
162(4)
166(5)
89(4)
-41(3)
55(3)
23(4)
-73(5)
9(4)
-11(4)
-20(3)
17(3)
39(4)
-66(4)
-43(4)
15(8)
69(5)
2(3)
F(2)
F(3)
F(4)
253(6)
138(3)
380(11)
49(6)
C(91) 119(4)
C(92) 81(3)
37(3)
76(3)
-24(3)
18(3)
-7(1)
-26(2)
-57(5)
-31(1)
C(94) 166(7)
Cl(3) 170(2)
123(5)
76(1)
-44(4)
8(1)
116(1)
_
_
____________________________________________________________________
_
Table S5. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters
A^2 x 10^3).
(
_
_______________________________________________________________
U(eq)
x
y
z
_
______________________________________________________________
H(63)
H(64)
H(71)
H(72)
H(3)
7611
7930
6545
5680
4624
5563
4487
4699
2374
6411
4281
2786
7012
2911
3102
7734
8394
10892
2972
2060
2501
-40
326
3315
2870
2964
3011
1650
1029
3022
2532
2255
1655
399
59
59
-1028
389
52
51
2472
-627
-733
-868
1144
-1317
2376
2164
1347
1789
515
77
H(75)
H(65)
H(66)
H(4)
70
59
59
79
H(76)
H(5)
77
84
H(6)
1812
1898
805
86
H(77)
H(7)
67
90
H(8)
1038
278
80
H(67)
H(68)
H(9)
-1029
-819
-1762
-705
-137
-851
85
-140
923
85
108
113
113
113
H(57)
H(58)
H(59)
2204
2393
2665
!
20

H(60)
H(61)
H(62)
H(73)
H(69)
H(70)
H(15)
H(16)
H(17)
H(18)
H(19)
H(20)
H(10)
H(78)
H(21)
H(22)
H(23)
H(74)
H(11)
H(24)
H(25)
H(26)
H(27)
H(28)
H(29)
H(30)
H(31)
H(32)
H(33)
H(34)
H(35)
H(12)
H(36)
H(37)
H(38)
H(13)
H(39)
H(40)
9834
9891
10491
6914
7824
7820
6276
5063
5752
2933
2598
3798
8691
8613
9356
8053
8820
9013
11424
5149
5936
6055
8527
9816
9109
6344
7546
6535
3286
4252
4181
10203
6466
7661
6696
10790
7017
6720
112
119
3263
2762
3021
-58
126
126
126
62
-553
315
1545
1617
2070
2025
1248
40
-99
74
400
74
-518
-328
-401
3252
3000
3198
1666
1401
3363
3385
3638
174
123
123
123
109
109
109
111
79
807
730
-2631
1026
-1641
-1554
-965
389
110
110
110
68
-1329
-2216
-2150
-2868
-2218
-2379
-2276
2073
2284
2838
-676
-430
-1301
-1781
2764
2384
1959
-125
2954
2786
1578
1848
2248
1933
491
107
154
154
154
160
160
160
153
153
153
153
153
153
106
141
141
141
102
139
139
462
43
1270
1435
1545
1257
1569
1398
2708
2331
2315
2565
1830
53
533
!
21

H(41)
H(14)
H(42)
H(43)
H(44)
H(45)
H(46)
H(47)
H(1)
5775
10186
10885
9847
3021
-2615
1480
2013
1309
-1526
-751
210
2121
1336
1232
928
139
122
177
177
177
164
16
10161
4896
582
4874
307
3768
-1071
243
513
164
107
173
173
173
184
184
184
155
155
155
153
1822
-720
1255
1073
1105
-232
159
H(48)
H(49)
H(50)
H(51)
H(52)
H(53)
H(54)
H(55)
H(56)
H(2)
7322
-2661
-1797
-2269
-1180
-1296
-458
7326
6200
10271
11075
10576
8928
61
846
2112
2004
2056
-1079
9476
1664
910
10227
7879
-1019
_
_______________________________________________________________
1
,2,3
Synthesis of Amides 14
The 2-methyl-arylacetic acid derivatives the acids were prepared according to
7
literature. The acid (1.0 eq.) was refluxed with 2.0 eq. SOCl
2
for 2 hours. After
, the resulting acyl chloride was diluted with CH Cl
Then the mixture was cooled to 0 ˚C before the addition of 2.0 eq. NEt and 1.0 eq.
evaporation of excess SOCl
2
2
2
.
3
arylamine. The mixture was allowed to increase to room temperature stirred for 12
hours. The N-H amide was purified by flash chromatography. The amide in THF
was dropped to a suspension of 1.1 eq. NaH in THF at 0 ˚C and the micxture was
!
22

stirred for 1 h at room temperature, followed by the addition of 1.1 eq. MeI or
benzylbromide at 0 ˚C. Stirring was continued for 12 h at room temperature. The
product was purified by flash chromatography to give 14.
1
4b
1
7
7
0% yield. H NMR " 7.69 (d, J = 7.6 Hz, 0.70H), 7.59 (d, J = 8.0 Hz, 0.27H),
.39-7.46 (m, 0.26H), 7.35 (dd, J = 8.0, 1.6 Hz, 0.29H), 7.11-7.31 (m, 2.03H), 7.00 (d,
J = 8.0 Hz, 1.97H), 6.92 (d, J = 8.0 Hz, 0.55H), 6.85 (d, J = 8.0 Hz, 1.50H), 6.75 (dd,
J = 7.6, 1.6 Hz, 0.76H), 3.48 (q, J = 6.8 Hz, 0.28H), 3.30 (q, J = 6.8 Hz, 0.82H), 3.18
1
3
(
s, 0.80H), 3.16 (s, 2.30H), 2.25-2.32 (m, 3.00H), 1.36-1.46 (m, 3.13H); C NMR "
1
1
3
74.1, 173.9, 142.6, 142.3, 138.6, 137.6, 136.20, 136.19, 134.0, 133.5, 130.9, 130.0,
29.7, 129.6, 129.0, 128.8, 128.6, 128.4, 127.9, 127.3, 124.1, 123.6, 43.5, 42.7, 36.10,
6.06, 21.00, 20.97, 20.63, 20.59; IR (KBr) 1654, 1513, 1477, 1379, 1283, 1254,
–
1
+
1124, 1050, 828, 772, 730 cm ; HRMS(ESI): Calcd for C17H19BrNO ([M+H] ):
3
32.0645. Found m/z 332.0649.
1
4d
1
7
9% yield. H NMR " 7.63-7.69 (m, 0.81H), 7.45-7.51 (m, 0.28H), 7.37 (d, J = 7.6
Hz, 0.91H), 7.00-7.26 (m, 7.68H), 6.93 (d, J = 7.2 Hz, 0.14H), 6.74-6.89 (m, 1.71H),
.75-5.84 (m, 0.95H), 5.68 (d, J = 14.4 Hz, 0.84H), 3.93 (dd, J = 14.4, 1.2 Hz, 1.01
5
1
3
H), 3.76-3.84 (m, 0.15H), 3.47-3.56 (m, 0.88H), 1.30-1.50 (m, 6.00H); C NMR "
1
1
1
1
73.8, 173.7, 140.3, 140.0, 139.9, 138.8, 137.1, 137.0, 135.0, 134.8, 134.0, 133.2,
32.2, 132.1, 130.0, 129.8, 129.4, 129.3, 129.0, 128.25, 128.16, 127.9, 127.6, 127.4,
27.3, 126.5, 126.4, 126.3, 126.2, 124.4, 124.2, 51.6, 51.2, 40.5, 39.1, 20.1, 19.2, 18.2,
–
1
8.1; IR (neat) 1667, 1475, 1389, 1270, 1245, 1205, 1030, 762, 727, 699 cm ;
+
HRMS(ESI): Calcd for C23
H
23BrNO ([M+H] ): 408.0958. Found m/z 408.0956.
!
23

1
4f
1
8
5% yield. H NMR " 7.65 (dd, J = 8.0, 0.8 Hz, 0.76H), 7.46-7.52 (m, 0.38H), 7.33
(
dd, J = 7.6, 1.6 Hz, 0.80H), 7.04-7.27 (m, 7.15H), 6.76-6.93 (m, 2.01H), 6.63 (d, J =
.0 Hz, 0.20H), 6.57 (d, J = 8.4 Hz, 0.79H), 6.00 (dd, J = 7.6, 1.2 Hz, 0.77H), 5.74 (d,
J = 14.4 Hz, 0.21H), 5.67 (d, J = 14.4 Hz, 0.82H), 4.14 (q, J = 7.2 Hz, 0.23H),
8
1
3
3
1
1
3
.82-3.99 (m, 1.86H), 1.33-1.38 (m, 3.00H); C NMR " 174.5, 155.6, 140.1, 137.3,
33.4, 133.1, 132.2, 132.0, 130.2, 129.3, 129.1, 129.0, 128.8, 128.2, 128.1, 127.62,
27.59, 127.3, 127.20, 127.18, 124.2, 120.7, 120.5, 109.6, 109.4, 54.6, 51.6, 51.2,
–
1
6.6, 34.5, 19.8, 18.7; IR (neat) 1661, 1493, 1475, 1390, 1246, 1030, 754, 727 cm ;
+
HRMS(ESI): Calcd for C23
H
23BrNO
2
([M+H] ): 424.0907. Found m/z 424.0902.
1
4h
1
8
9
0
1
1
1
1
3% yield. H NMR " 7.63-7.70 (m, 0.90H), 7.45-7.54 (m, 0.93H), 7.02-7.29 (m,
.00H), 6.79-6.87 (m, 1.09H), 5.86 (dd, J = 7.6, 1.6 Hz, 0.76H), 5.76 (d, J = 14.0 Hz,
.24H), 5.66 (d, J = 14.4 Hz, 0.80H), 4.15 (q, J = 6.8 Hz, 0.22H), 3.84-4.01 (m,
1
3
.76H), 1.34-1.42 (m, 3.00H); C NMR " 173.2, 139.55, 139.48, 137.0, 134.1, 133.5,
33.4, 132.0, 131.6, 129.6, 129.4, 129.3, 129.1, 128.9, 128.3, 128.2, 128.1, 127.84,
27.77, 127.5, 127.4, 127.2, 127.0, 124.1, 51.8, 51.4, 40.9, 39.2, 20.0, 18.9; IR (neat)
–
1
667, 1475, 1394, 1270, 1032, 753, 726 cm ; HRMS(ESI): Calcd for C22H20BrClNO
+
(
[M+H] ): 428.0411. Found m/z 428.0407.
Catalytic asymmetric intramolecular !-arylation reactions
General procedure: In an N
2
2
-filled glove-box, TMEDA·PdMe (2.5 mg, 0.01 mmol,
t
5
mol %), 6b (5.0 mg, 0.01 mmol, 5 mol %), BuONa (29 mg, 0.3 mmol, 1.5 equiv),
amide 14a (63.6mg, 0.2 mmol, 1.0 equiv), and toluene (2 mL), were added to an
oven-dried Schlenk tube containing a stirrer bar. The tube was sealed and taken out of
!
24

the glove box. After being heated at 50 ˚C for 20 h, the reaction mixture was cooled to
room temperature. The solvent were evaporated under vacuum and the residue was
purified by preparative thin layer chromatography (hexane/ethyl acetate 5:1) on silica
gel to give 15a (47.1 mg, 0.199 mmol, 99% yield).
1
5a
1
H NMR " 7.17-7.35 (m, 7H), 7.09 (td, J = 7.6, 0.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
1
3
3
1
.24 (s, 3H), 1.79 (s, 3H); C NMR " 179.4, 143.2, 140.7, 134.7, 128.5, 128.0, 127.1,
26.6, 124.1, 122.7, 108.2, 52.1, 26.4, 23.7; HPLC [(Daicel Chiralcel OD-H,
hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min, $ = 254 nm): t1 = 14.2 min (major),
t2 = 16.9 min (minor) ee = 86%].
1
5b
1
H NMR " 7.33 (t, J = 7.6 Hz, 1H), 7.16-7.25 (m, 3H), 7.07-7.15 (m, 3H), 6.92 (d, J =
1
3
8
1
.0 Hz, 1H), 3.25 (s, 3H), 2.31 (s, 3H), 1.79 (s, 3H); C NMR " 179.5, 143.2, 137.8,
36.8, 134.9, 129.2, 128.0, 126.4, 124.1, 122.7, 108.2, 51.8, 26.4, 23.7, 20.9; [(Daicel
Chiralcel AD-H, hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min, $ = 254 nm): t1 =
1
4.4 min (major), t2 = 18.7 min (minor) ee = 84%].
1
5c
!
25

1
H NMR " 7.63-7.70 (m, 1H), 7.25-7.34 (m, 2H), 7.20 (td, J = 7.6, 1.2 Hz, 1H), 7.04
d, J = 7.2 Hz, 1H), 6.99 (td, J = 7.6, 1.2 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.83-6.89
(
(
1
3
m, 1H), 3.33 (s, 3H), 1.78 (s, 3H), 1.62 (s, 3H); C NMR " 180.0, 142.9, 137.8,
1
1
2
36.8, 135.0, 131.6, 127.7, 127.6, 127.4, 126.0, 122.9, 122.8, 108.0, 52.3, 26.4, 25.7,
9.1; [(Daicel Chiralcel OD-H, hexane/i-PrOH = 98/2, flow rate = 1.0 mL/min, $ =
54 nm): t1 = 20.7 min (major), t2 = 32.3 min (minor) ee = 96%].
1
5d
1
H NMR " 7.68 (d, J = 7.6 Hz, 1H), 7.39-7.45 (m, 2H), 7.25-7.39 (m, 4H), 7.15-7.25
m, 2H), 7.04 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.82-6.92 (m, 2H), 5.24 (d,
(
1
3
J = 15.2 Hz, 1H), 4.80 (d, J = 15.6 Hz, 1H), 1.84 (s, 3H), 1.61 (s, 3H); C NMR "
1
1
1
3
80.0, 142.1, 137.7, 137.0, 136.1, 135.2, 131.7, 128.8, 127.81, 127.78, 127.75, 127.69,
27.6, 126.0, 122.97, 122.96, 109.1, 52.5, 44.1, 26.3, 19.5; IR (neat) 1714, 1611, 1486,
–
1
+
464, 1343, 1173, 752, 745 cm ; HRMS(ESI): Calcd for C23
H
22NO ([M+H] ):
2
5
28.1696. Found m/z 328.1704; [!]
D
= +76.1 (c = 2.3 in CHCl ). [(Daicel Chiralcel
3
OD-H, hexane/i-PrOH = 98/2, flow rate = 1.0 mL/min, $ = 254 nm): t1 = 20.9 min
major), t2 = 31.0 min (minor) ee = 98%].
(
1
5e
1
H NMR " 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.25-7.30 (m, 2H), 7.05 (td, J = 7.6, 1.2 Hz,
H), 6.93 (td, J = 7.6, 1.2 Hz, 1H), 6.83-6.92 (m, 2H), 6.76 (dd, J = 8.0, 1.2 Hz, 1H),
1
1
3
3
1
.41 (s, 3H), 3.32 (s, 3H), 1.71 (s, 3H); C NMR " 181.0, 156.9, 143.5, 135.6, 129.7,
28.7, 127.5, 127.2, 122.13, 122.10, 120.8, 112.0, 107.3, 55.8, 49.8, 26.3, 23.3.
[(Daicel Chiralcel OD-H, hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min, $ = 254
nm): t1 = 11.9 min (major), t2 = 26.3 min (minor) ee = 92%].
!
26

1
5f
1
H NMR " 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.44-7.52 (m, 2H), 7.25-7.40 (m, 4H), 7.13
td, J = 8.0, 1.6 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 6.90 (td, J = 7.6, 1.2 Hz, 1H),
(
6
3
1
1
C
.80-6.87 (m, 2H), 6.76 (td, J = 8.0, 1.2 Hz, 1H), 5.01 (s, 2H), 3.22 (s, 3H), 1.77 (s,
1
3
H); C NMR " 180.6, 157.0, 142.5, 136.6, 135.9, 129.3, 128.8, 128.6, 127.9, 127.7,
27.4, 127.1, 122.10, 122.07, 120.7, 111.8, 108.3, 55.4, 49.9, 44.0, 24.0; IR (KBr)
–
1
710, 1611, 1470, 1341, 1174, 1081, 912, 883, 750 cm ; HRMS(ESI): Calcd for
+
25
23
H
22NO
2
([M+H] ): 344.1645. Found m/z 344.1652; [!]
). [(Daicel Chiralcel OD-H, hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min, $
254 nm): t1 = 12.8 min (major), t2 = 19.9 min (minor) ee = 94%].
D
= +76.1 (c = 2.3 in
CHCl
3
=
1
5g
1
H NMR " 7.76-7.94 (m, 3H), 7.56 (t, J = 7.6 Hz, 1H), 7.28-7.40 (m, 2H), 7.13-7.24
m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.88-6.99 (m, 2H), 6.80-6.88 (m, 1H), 3.45 (s, 3H),
(
1
3
1
1
.92 (s, 3H); C NMR " 180.4, 142.2, 136.7, 135.1, 134.3, 131.3, 129.1, 129.0, 127.9,
26.2, 125.2, 125.0, 123.4, 123.0, 122.8, 108.6, 52.4, 26.8, 26.7. [(Daicel Chiralcel
AD-H, hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min, $ = 254 nm): t1 = 17.0 min
major), t2 = 32.9 min (minor) ee = 97%].
(
1
5h
!
27

1
H NMR " 7.72-7.78 (m, 1H), 7.23-7.48 (m, 8H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 6.95
td, J = 7.2, 1.2 Hz, 1H), 6.80-6.87 (m, 2H), 5.22 (d, J = 15.2 Hz, 1H), 4.82 (d, J =
(
1
3
1
1
2
C
5.6 Hz, 1H), 1.84 (s, 3H); C NMR " 179.2, 142.8, 137.5, 136.0, 134.4, 134.0,
30.7, 129.3, 129.0, 128.6, 127.8, 127.7, 127.6, 126.8, 122.6, 122.3, 109.1, 52.3, 44.3,
–
1
5.7; IR (KBr) 1720, 1611, 1480, 1341, 1174, 1081, 750 cm ; HRMS(ESI): Calcd for
+
25
22
H
19ONCl ([M+H] ): 348.1150. Found m/z 348.1155.; [!]
). [(Daicel Chiralcel OD-H, hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min, $
254 nm): t1 = 12.8 min (major), t2 = 19.0 min (minor) ee = 97%].
D
= +80.0 (c = 0.5 in
CHCl
3
=
References
1
2
. S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402.
. E. P. Kündig, T. M. Seidel, Y.-X. Jia, G. Bernadinelli, Angew. Chem. 2007, 119, 8636; Angew.
Chem., Int. Ed. 2007, 46, 8484.
3
4
5
. S. Würtz, C. Lohre, R. Fröhlich, K. Bergander, F. Glorius, J. Am. Chem. Soc. 2009, 131, 8344.
. A. M.Taylor, R. A. Altman, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 9900.
. a) T. A. Whitney, J. Org. Chem. 1980, 45, 4214; b) J. F. Larrow, E. N. Jacobsen, Org. Synth.
1
998, 75, 1; c) H. J. Schanz, M. A. Linseis, D. G. Gilheany, Tetrahedron Asymmetry 2003, 14,
2
763.
6
. J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 7215.
!
28

!
29

!
30