Palladium-catalyzed cross-couplings of unsaturated halides bearing relatively acidic hydrogen atoms with organozinc reagents

Article abstract of DOI:10.1055/s-0028-1083286

A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using palladium(II) acetate (1 mol%), and S-Phos (2 mol%) as catalyst without the need of prot

Full text of DOI:10.1055/s-0028-1083286

PRACTICAL SYNTHETIC PROCEDURES
681
Palladium-Catalyzed Cross-Couplings of Unsaturated Halides Bearing
Relatively Acidic Hydrogen Atoms with Organozinc Reagents
Coupling
React
h
ions of
A
ryl
i
H
alides
b
B
earingAc
i
idic Hy
n
drogenAtom
g
s
Dong,a,b Georg Manolikakes,a Jinshan Li,b Paul Knochel*a
a
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München,
Butenandtstraße 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. of China
b
PSP
Received 4 August 2008; revised 22 August 2008
No147
Abstract: A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides
bearing an acidic NH or OH proton, using palladium(II) acetate (1 mol%), and S-Phos (2 mol%) as catalyst without the need of protecting
groups.
Key words: palladium catalysis, cross-coupling, functionalized zinc reagents, polyfunctional biaryls
Procedure 1:
I
ZnI⋅LiCl
Br
NH2
2a (1.0 equiv)
Zn, LiCl
EtO2C
NH2
Pd(OAc)2 (1 mol%)
S-Phos (2 mol%)
THF, 25 °C, 1 h
THF, 25° C
24 h
CO2Et
CO2Et
1a (1.2 equiv)
3a: 95%
PCy2
OMe
OH
MeO
Procedure 2:
Br
Cl
S-Phos
2f (1.0 equiv)
OH
Zn, LiCl
ZnCI⋅LiCl
Cl
Pd(OAc)2 (1 mol%)
S-Phos (2 mol%)
THF, 25 °C, 2.5 h
THF, 25° C
24 h
Cl
Cl
3f: 91%
1c (1.3 equiv)
slow addition over
90 min
Scheme 1
Introduction
difficulties concerning their tendency to form boroxines
and competitive deboronation remain.3 Also, due to the
covalent nature of the C–B bond, these cross-couplings
proceed under harsher conditions compared to the corre-
sponding Negishi cross-coupling using organozinc re-
agents,4 which also display a high functional group
compability.5 Recently, we have reported reaction condi-
tions and a catalytic system allowing the cross-coupling of
organozinc reagents with unsaturated aryl halides bearing
relatively acidic hydrogens without the use of protecting
groups.6 No excess of the zinc reagent and no additional
base for deprotonation of the acidic proton prior to the
cross-coupling were necessary. We found that the use of
palladium(II) acetate (1 mol%) and S-Phos (2 mol%), in-
troduced by Buchwald7 as a catalytic system, allowed an
efficient cross-coupling between various organozinc re-
Palladium-catalyzed cross-coupling reactions between or-
ganometallic reagents and unsaturated halides are of cen-
tral importance in modern synthetic organic chemistry.
The resulting cross-coupling products are highly relevant
as phamaceuticals, agrochemicals, natural products, or
new materials.1 The most popular palladium-catalyzed
cross-coupling, the Suzuki reaction, uses organoboronic
acids or derivatives as nuleophiles,2 due to the commer-
cial availability, air stability, and functional group com-
patibility of the organoboron reagents. However,
SYNTHESIS 2009, No. 4, pp 0681–0686
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083286; Art ID: T13108SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

682
Z. Dong et al.
PRACTICAL SYNTHETIC PROCEDURES
agents and unsaturated halides bearing relatively acidic (Table 1, entry 1). We also scaled up this cross-coupling
NH groups. By adding the zinc reagent slowly (typically reaction starting with 20 mmol of the aryl bromide with a
over 90 min via a syringe pump), also more acidic alcohol slightly increased yield (Procedure 1). The relatively acid-
and phenol protons were tolerated. Herein, we wish to re- ic NH2 protons9 do not disturb the cross-coupling reac-
port a typical practical procedure illustrating this method. tion, which obviously occurs faster than the competitive
deprotonation. Interestingly, the reaction can be extended
to 2,5-dibromoanilines, although with moderate yields.
Thus the arylzinc reagent 1a (2.4 equiv) reacts with the di-
bromoaniline 2b, affording the 2,4,6-trisubstituted phenyl-
Scope and Limitations
A variety of functionalized zinc reagents were coupled
with unsaturated aryl halides bearing acidic hydrogen at-
oms under mild conditions (1–3 h, 25 °C). Thus, the ester-
substituted arylzinc reagent 1a (1.2 equiv), prepared by
direct zinc insertion into the corresponding aryl iodide,8
with 4-bromoaniline (2a) in the presence of palladium(II)
acetate (1 mol%) and S-Phos (2 mol%) led within 1 hour
at 25 °C to the biphenyl aniline 3a in 88% isolated yield
amine 3b, a useful intermediate for the synthesis of
thioarylaminyls,10 in 47% yield (entry 2). Unprotected 5-
bromoindole (2c) was also suitable for the cross-coupling
procedure and the arylated indole 3c was obtained in 85%
yield (entry 3) after the reaction with 4-cyanophenylzinc
Table 1 Palladium-Catalyzed Cross-Couplings between Functionalized Zinc Reagents and Unsaturated Halides Bearing an Acidic NH or OH
Function
Entry Zinc reagent
Unsaturated halide
Product
Yield (%)a
88 (95)b
1
1a
2a
3a
EtO2C
ZnI⋅LiCl
Br
NH2
EtO2C
Ar
NH2
Br
2
1a
2b
3bc
47d
H2N
CO2Et
H2N
NC
CO2Et
Br
Ar
Br
3
4
1b
1c
2c
3c
85
81
NC
ZnI⋅LiCl
N
H
N
H
NH2
ZnCl⋅LiCl
Br
2d
3d
Cl
H2N
Cl
OH
OH
5
6
1b
1d
2e
3e
3f
78e
65e
I
NC
OH
ZnCl⋅LiCl
2f
Br
OH
OH
OH
7
8
1c
1e
2g
3g
3h
91e
75e
Br
Cl
O
O
ZnCl⋅LiCl
H
Br
2h
H
OH
OH
O
Bu
O
Bu
OH
Me
OH
Me
88e
I
9
1f
2i
3i
NC
NC
ZnBr⋅LiCl
a Yield of analytically pure product.
b Reaction was carried out on a 20 mmol scale.
c Ar = 4-EtO2CC6H4.
d Amount of zinc reagent used: 2.4 equiv.
e The zinc reagent was added slowly over 90 min via a syringe pump.
Synthesis 2009, No. 4, 681–686 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Coupling of Aryl Halides Bearing Acidic Hydrogens
683
lution of 1a was carefully separated from the remaining Zn powder
by using a syringe and transferred to another dry and argon-flushed
flask. Titration of the Zn reagent (typically 1 mL) with I2,13 indicat-
ed a concentration of 0.94 M.
iodide reagent 1b. Also, 2-chlorobenzylzinc chloride re-
agent 1c, prepared by direct zinc insertion into the benzyl-
ic chloride,11 reacted smoothly with 2-bromoaniline (2d;
27 mmol) within two hours at 25 °C, leading to the diaryl-
methane 3d in 81% yield (entry 4). For the coupling of un-
saturated halides bearing more acidic OH functions, it was
found that the slow addition of the zinc reagent was cru-
cial for obtaining a high yield. Thus, adding the arylzinc
1b reagent (1.2 equiv) slowly over 90 minutes (via syringe
pump) to a solution of the iodobenzyl alcohol 2e, palladi-
um(II) acetate (1 mol%), and S-Phos (2 mol%) led to the
functionalized biaryl 3e in 78% yield (entry 5).
Zinc Reagent 1b
Anhyd LiCl (56 mmol, 2.38 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (76 mmol, 4.98 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (50 mL) was added and the
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
TMSCl (2.5 mmol, 0.32 mL). 4-Iodobenzonitrile (50 mmol, 11.5 g)
was added neat and the mixture stirred at 25 °C for 24 h. The solu-
tion of 1b was carefully separated from the remaining Zn powder by
using a syringe and transferred to another dry and argon-flushed
flask. Titration of the Zn reagent (typically 1 mL) with I2,13 indicat-
ed a concentration of 0.95 M.
Similarly, the reaction of benzylzinc chloride reagent 1d
with the alkenyl bromide 2f, bearing an acidic OH group,
furnished the desired coupling product 3f in 65% yield
(entry 6). In the case of benzylic zinc reagents, even more
acidic phenolic protons were tolerated by our protocol.12
Adding the benzylzinc chloride reagent 1c (1.3 equiv)
slowly (over 90 min) to a solution of 3-bromophenol (2g;
32 mmol), palladium(II) acetate (1 mol%), and S-Phos (2
mol%) provided the phenol 3g in 91% yield (entry 7).
Also the benzylic zinc reagent 1e (1.2 equiv), bearing a
keto function, reacts smoothly with 5-bromosalicylalde-
hyde (2h), leading to the polyfunctional diarylmethane 3h
Zinc Reagent 1c
Anhyd LiCl (84 mmol, 3.57 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (114 mmol, 7.47 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (75 mL) was added and the
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
in 75% yield (entry 8). Finally the cyano-substituted TMSCl (2.5 mmol, 0.32 mL). The mixture was cooled in a water
bath. 2-Chlorobenzyl chloride (75 mmol, 12.07 g) was added neat
and the mixture and stirred for 2 h. The solution of 1c was carefully
alkylzinc bromide reagent 1f could be coupled with the
secondary iodobenzyl alcohol 2i to give the benzylic alco-
separated from the remaining Zn powder by using a syringe and
hol 3i in 88% yield (entry 9).
transferred to another dry and argon-flushed flask. Titration of the
Zn reagent (typically 1 mL) with I2,13 indicated a concentration of
0.92 M.
In summary, an efficient cross-coupling of various func-
tionalized zinc reagents with unsaturated halides bearing
acidic protons was demonstrated. No use of protecting
groups or deprotonation by an additional base prior to the
cross-coupling of these acidic protons is required. We
have extended our previous work to the scaled-up and op-
timized cross-coupling of aryl- and alkenyl halides, bear-
Zinc Reagent 1d
Anhyd LiCl (56 mmol, 2.38 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (76 mmol, 4.98 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
ing acidic NH or OH functions. These reactions could be vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (50 mL) was added and the
performed with standard laboratory glassware and did not
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
require the use of expensive chemicals or catalysts. Fur-
TMSCl (2.5 mmol, 0.32 mL). The mixture was cooled in a water
ther studies are underway in our laboratory to extend this
bath. Benzyl chloride (50 mmol, 6.33 g) was added neat and the
mixture and stirred for 12 h. The solution of 1c was carefully sepa-
method.
rated from the remaining Zn powder by using a syringe and trans-
ferred to another dry and argon-flushed flask. Titration of the Zn
All reactions were carried out under argon in dried glassware. All
reagent (typically 1 mL) with I2,13 indicated a concentration of 0.93
starting materials were purchased from commercial suppliers and
M.
used without further purification, unless otherwise stated. THF was
continuously refluxed and freshly distilled from sodium benzophe-
Zinc Reagent 1e
none ketyl under N2. S-Phos was purchased from Strem or prepared
according to the literature.8 Yields refer to isolated compounds es-
Anhyd LiCl (56 mmol, 2.38 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (76 mmol, 4.98 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (50 mL) was added and the
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
TMSCl (2.5 mmol, 0.32 mL). The mixture was cooled to 0 °C. 1-(3-
Chloromethylphenyl)pentan-1-one (50 mmol, 10.54 g) was added
neat and the mixture was warmed to 25 °C and stirred for 4 h. The
solution of 1c was carefully separated from remaining Zn powder
by using a syringe and transferred to another dry and argon-flushed
flask. Titration of the Zn reagent (typically 1 mL) with I2,13 indicat-
ed a concentration of 0.87 M.
1
timated to be >95% pure as determined by H NMR spectroscopy
and capillary GC analysis.
Zinc Reagent 1a
Anhyd LiCl (56 mmol, 2.38 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (76 mmol, 4.98 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (50 mL) was added and the
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
TMSCl (2.5 mmol, 0.32 mL). Ethyl 4-iodobenzoate (50 mmol, 13.8
g) was added neat and the mixture stirred at 25 °C for 24 h. The so-
Synthesis 2009, No. 4, 681–686 © Thieme Stuttgart · New York

684
Z. Dong et al.
PRACTICAL SYNTHETIC PROCEDURES
Zinc Reagent 1f
13C NMR (100 MHz, CDCl3, 25 °C): d = 155.5, 141.5, 138.3, 134.2,
Anhyd LiCl (56 mmol, 2.38 g) was placed in an argon-flushed flask
and dried for 30 min at 150 °C under high vacuum (1 mbar). Zn
powder (76 mmol, 4.98 g) was added under argon and the hetero-
geneous mixture was dried again for 30 min at 150 °C under high
vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (50 mL) was added and the
Zn was activated with 1,2-dibromoethane (2.5 mmol, 0.22 mL) and
TMSCl (2.5 mmol, 0.32 mL). 4-Bromobutyronitrile (50 mmol, 7.40
g) was added neat and the mixture stirred at 50 °C for 24 h. The so-
lution of 1f was carefully separated from the remaining Zn powder
by using a syringe and transferred to another dry and argon-flushed
flask. Titration of the Zn reagent (typically 1 mL) with I2,13 indicat-
ed a concentration of 1.0 M.
131.07, 129.6, 129.5, 127.8, 126.9, 121.5, 115.8, 113.3, 39.0.
MS (EI, 70 eV): m/z (%) = 220 (18), 218 (55, [M+]), 184 (15), 183
(100), 182 (17), 181 (20), 165 (49), 153 (20), 152 (22).
HRMS: m/z calcd for C13H11ClO: 218.0498; found: 218.0496.
2¢-Amino-[1,1¢;3¢,1¢¢]terphenyl-4,5¢,4¢¢-tricarboxylic Acid Tri-
ethyl Ester (3b)
4-(Ethoxycarbonyl)phenylzinc iodide (1a; 7.7 mL, 0.94 M in THF,
7.2 mmol) was added to a solution of 2-amino-5-bromobenzoic acid
methyl ester (2b; 969 mg, 3 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol),
and S-Phos (24.6 mg, 0.06 mmol) in THF (2 mL), according to Pro-
cedure 1. The mixture was stirred for 3 h at 25 °C. Then, the mixture
was quenched with sat. aq NH4Cl (15 mL) and extracted with Et2O
(3 × 15 mL). The combined organic phases were washed with sat.
aq thiourea (15 mL) and dried (Na2SO4). Purification of the crude
residue obtained after evaporation of the solvents by flash chroma-
tography (pentane–Et2O, 9:1) yielded 3b as a yellow solid (651 mg,
47%); mp 129.5–131.6 °C.
Procedure 1
4¢-Aminobiphenyl-4-carboxylic Acid Ethyl Ester (3a)
A dry and argon flushed 100 mL Schlenk-tube was charged with 4-
bromoaniline (2a; 3.44 g, 20 mmol), Pd(OAc)2 (45 mg, 0.2 mmol),
S-Phos (164 mg, 0.4 mmol), and THF (20 mL). After stirring the
mixture for 5 min, 4-(ethoxycarbonyl)phenylzinc iodide (1a; 25.5
mL, 0.94 M in THF, 24 mmol) was added (Caution! The reaction
is exothermic. For conducting the reaction on a bigger scale we rec-
ommend the use of a reflux condenser and addition of the Zn re-
agent over 10–15 min). The mixture was stirred for 1 h at 25 °C.
Then, the mixture was quenched with a sat. aq NH4Cl (40 mL), ex-
tracted with Et2O (3 × 50 mL). The combined organic phases were
washed with sat. aq thiourea (50 mL) and dried (Na2SO4). Purifica-
tion of the crude residue obtained after evaporation of the solvents
by flash chromatography (pentane–Et2O, 7:3) yielded 3a as a white
solid (4.58 g, 95%); mp 86.8–88.4 °C.
IR (KBr): 3453 (w), 3357 (w), 2979 (w), 1705 (vs), 1605 (s), 1464
(m), 1399 (m), 1366 (s), 1336 (m), 1283 (s), 1232 (vs), 1177 (s),
1098 (vs), 1048 (s), 1017 cm–1 (s).
1H NMR (CDCl3, 600 MHz, 25 °C): d = 8.12 (d, J = 8.2 Hz, 4 H),
7.82 (s, 2 H), 7.56 (d, J = 8.2 Hz, 4 H), 4.39 (q, J = 7.1 Hz, 4 H),
4.31 (q, J = 7.1 Hz, 2 H), 4.26 (s, 2 H), 1.40 (t, J = 7.1 Hz, 6 H), 1.34
(t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz, 25 °C): d = 166.5, 166.2, 144.7, 143.2,
131.7, 130.3, 129.9, 129.2, 126.1, 120.1, 61.1, 60.6, 14.4, 14.4.
MS (EI, 70 eV): m/z (%) = 461 (100, [M+]), 416 (22), 388 (5), 287
(8), 241 (6).
IR (KBr): 3421 (w), 3334 (w), 2985 (w), 1693 (vs), 1629 (w), 1595
(m), 1532 (w), 1495 (m), 1473 (w), 1364 (m), 1276 (s), 1197 (m),
1132 (m), 1115 (m), 1023 cm–1 (m).
HRMS: m/z calcd for C27H27NO6: 461.1838; found: 481.1846.
1H NMR (CDCl3, 300 MHz, 25 °C): d = 8.05 (ddd, J = 8.5, 2.0, 1.9
Hz, 2 H), 7.59 (ddd, J = 8.5, 2.0, 1.9 Hz, 2 H), 7.48–7.43 (m, 2 H),
6.78–6.73 (m, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 3.79 (s, 2 H), 1.40 (t,
J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz, 25 °C): d = 166.7, 146.7, 145.4, 130.1,
130.0, 128.2, 128.1, 125.9, 115.3, 60.8, 14.4.
4-(1H-Indol-5-yl)benzonitrile (3c)
4-Cyanophenylzinc iodide (1b; 3.8 mL, 0.95 M in THF, 3.6 mmol)
was added to a solution of 5-bromoindole (2c; 588 mg, 3 mmol),
Pd(OAc)2 (6.7 mg, 0.06 mmol), and S-Phos (24.6 mg, 0.06 mmol)
in THF (2 mL), according to Procedure 1. The mixture was stirred
for 1 h at 25 °C. Then, the mixture was quenched with sat. aq NH4Cl
(15 mL) and extracted with Et2O (3 × 15 mL). The combined organ-
ic phases were washed with sat. aq thiourea (15 mL) and dried
(Na2SO4). Purification of the crude residue obtained after evapora-
tion of the solvents by flash chromatography (pentane–Et2O, 3:2)
yielded 3c as a colorless solid (558 mg, 85%); mp 122.6–123.7 °C.
MS (EI, 70 eV): m/z (%) = 241 (100, [M+]), 213 (49), 196 (38), 167
(20), 139 (9).
HRMS: m/z calcd for C15H15NO2: 241.1103; found: 241.1101.
Procedure 2
3-(2-Chlorobenzyl)phenol (3g)
IR (KBr): 3371 (br w), 2981 (w), 2904 (w), 2871 (w), 1704 (s), 1615
(m), 1586 (m), 1507 (s), 1465 (m), 1442 (m), 1367 (m), 1276 (vs),
1187 (s), 1105 (s), 1081 (s), 1018 cm–1 (s).
1H NMR (CDCl3, 300 MHz, 25 °C): d = 7.90–7.83 (m, 2 H), 7.39–
7.27 (m, 2 H), 7.14–7.02 (m, 2 H), 6.65–6.55 (m, 1 H), 4.53 (s, 2 H),
4.34 (q, J = 7.2 Hz, 2 H), 3.91 (s, 2 H), 3.06 (br s, 3 H), 1.36 (t,
J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 75 MHz, 25 °C): d = 166.6, 144.1, 139.5, 132.9,
131.3, 130.8, 130.1, 129.6, 128.7, 127.6, 127.2, 124.4, 116.0, 65.2,
61.0, 37.6, 14.3.
A dry and argon-flushed 100 mL Schlenk-tube was charged with 3-
bromophenol (2g; 5.53 g, 32 mmol), Pd(OAc)2 (71 mg, 0.32 mmol),
S-Phos (262 mg, 0.64 mmol), and THF (30 mL). After stirring the
mixture for 5 min, 2-chlorobenzylzinc chloride (1c; 45.6 mL, 0.92
M in THF, 42 mmol) was added slowly over 90 min with a syringe
pump. The mixture was stirred for 1 h at 25 °C. Then, the mixture
was quenched with sat. aq NH4Cl (50 mL) and extracted with Et2O
(3 × 75 mL). The combined organic phases were washed with sat.
aq thiourea (60 mL) and dried (Na2SO4). Purification of the crude
residue obtained after evaporation of the solvents by flash chroma-
tography (pentane–Et2O, 2:1) yielded 3g as a colorless oil (6.37 g,
91%).
MS (EI, 70 eV): m/z (%) = 285 (100, [M+]), 267 (32), 238 (55), 194
(86), 165 (32).
HRMS: m/z calcd for C17H19NO3: 285.1365; found: 285.1359.
IR (film): 3327 (br m), 1610 (m), 1587 (m), 1470 (m), 1453 (m),
1441 (m), 1244 (m), 1148 (m), 1050 (m), 1036 (m), 953 (m), 873
(w), 742 (vs), 679 cm–1 (s).
1H NMR (400 MHz, CDCl3, 25 °C): d = 7.39–7.36 (m, 1 H), 7.19–
7.13 (m, 4 H), 6.80–6.78 (m, 1 H), 6.69–6.64 (m, 2 H), 4.96 (s, 1 H),
4.06 (s, 2 H).
2-(2-Chlorobenzyl)phenylamine (3d)
2-Chlorobenzylzinc chloride (1c; 34.8 mL, 0.92 M in THF, 32
mmol) was added to a solution of 2-bromoaniline (2d; 4.64, 27
mmol), Pd(OAc)2 (60 mg, 0.27 mmol), and S-Phos (221 mg, 0.54
mmol) in THF (25 mL), according to Procedure 1. The mixture was
stirred for 2 h at 25 °C. Then, the mixture was quenched with sat. aq
Synthesis 2009, No. 4, 681–686 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Coupling of Aryl Halides Bearing Acidic Hydrogens
685
NH4Cl (50 mL) and extracted with Et2O (3 × 75 mL). The combined
organic phases were washed with sat. aq thiourea (60 mL) and dried
(Na2SO4). Purification of the crude residue obtained after evapora-
tion of the solvents by flash chromatography (pentane–Et2O, 5:1)
yielded 3d as a pale yellow oil (4.76 g, 81%).
MS (EI, 70 eV): m/z (%) = 148 (35, [M+]), 133 (17), 119 (9), 91
(100), 77 (12).
2-Hydroxy-5-(3-pentanoylbenzyl)benzaldehyde (3h)
3-Pentanoylbenzylzinc chloride (1e; 2.8 mL, 0.87 M in THF, 2.4
mmol) was added to a solution of 5-bromosalicylaldehyde (2h; 402
mg, 2 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S-Phos (16.4 mg,
0.04 mmol) in THF (2 mL), according to Procedure 2. The mixture
was stirred for 1 h at 25 °C. Then, the mixture was quenched with
sat. aq NH4Cl (15 mL) and extracted with Et2O (3 × 15 mL). The
combined organic phases were washed with sat. aq thiourea (15
mL) and dried (Na2SO4). Purification of the crude residue obtained
after evaporation of the solvents by flash chromatography (pen-
tane–Et2O, 1:1) yielded 3h as a colorless oil (450 mg, 75%).
IR (film): 3372 (w), 3022 (w), 1742 (w), 1619 (m), 1493 (m), 1455
(m), 1442 (m), 1276 (w), 1189 (w), 1120 (w), 1048 (m), 1036 (s),
743 (vs), 682 cm–1 (m).
1H NMR (600 MHz, CDCl3, 25 °C): d = 7.43–7.41 (m, 1 H), 7.20–
7.12 (m, 3 H), 7.04–6.99 (m, 2 H), 6.80–6.73 (m, 2 H), 3.99 (s, 2 H),
3.67 (s, 2 H).
13C NMR (150 MHz, CDCl3, 25 °C): d = 144.4, 136.8, 134.3, 130.8,
130.0, 129.4, 127.8, 127.8, 127.0, 123.6, 118.96, 115.89, 34.9.
MS (70 eV, EI): m/z (%) = 217 (27, [M+]), 183 (16), 182 (100), 181
(19), 180 (69), 167 (12), 165 (16), 106 (11), 90 (13).
IR (film): 3459 (m), 3049 (w), 2951 (m), 2922 (m), 2868 (m), 1664
(vs), 1582 (m), 1450 (w), 1434 (m), 1367 (m), 1274 (m), 1232 (m),
1189 (s), 1136 cm–1 (m).
HRMS: m/z calcd for C13H12ClN: 217.0658; found: 217.0657.
1H NMR (300 MHz, CDCl3, 25 °C): d = 10.9 (s, 1 H), 9.80 (s, 1 H),
7.84 (dt, 3JH,H = 7.7 Hz, 4JH,H = 1.5 Hz, 1 H), 7.81 (d, 4JH,H = 1.4 Hz,
4¢-(1-Hydroxy-1-methylethyl)biphenyl-4-carbonitrile (3e)
4-Cyanophenylzinc iodide (1b; 2.5 mL, 0.95 M in THF, 2.4 mmol)
was added to a solution of 2-(4-iodophenyl)propan-2-ol (2e; 524
mg, 2 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S-Phos (16.4 mg,
0.04 mmol) in THF (2 mL), according to Procedure 2; The mixture
was stirred for 1 h at 25 °C. Then, the mixture was quenched with
sat. aq NH4Cl (15 mL) and extracted with Et2O (3 × 15 mL). The
combined organic phases were washed with sat. aq thiourea (15
mL) and dried (Na2SO4). Purification of the crude residue obtained
after evaporation of the solvents by flash chromatography (pen-
tane–Et2O, 3:2) yielded 3e as a colorless solid (371 mg, 78%); mp
165.8–167.4 °C.
3
1 H), 7.41–7.30 (m, 3 H), 7.28 (t, JH,H = 7.7 Hz, 1 H), 6.94 (d,
3JH,H = 8.2 Hz, 1 H), 4.04 (s, 2 H), 2.95 (t, 3JH,H = 7.4 Hz, 2 H), 1.72
(quint, 3JH,H = 7.5 Hz, 2 H), 1.41 (sext, 3JH,H = 7.4 Hz, 2 H), 0.96 (t,
3JH,H = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3, 25 °C): d = 200.4, 196.4, 160.2, 140.9,
137.6, 137.5, 133.3, 133.2, 131.9, 128.8, 128.2, 126.3, 120.4, 117.9,
40.5, 38.3, 26.4, 22.4, 13.9.
MS (EI, 70 eV): m/z (%) = 296 (4, [M+]), 254 (11), 239 (18), 176
(100), 165 (17).
HRMS: m/z calcd for C20H19O3: 296.1412; found: 296.1416.
IR (KBr): 3486 (m), 3068 (w), 2971 (w), 2230 (m), 1604 (m), 1492
(m), 1471 (w), 1395 (m), 1361 (m), 1316 (w), 1285 (w), 1214 (w),
1167 (m), 1092 (m), 1024 cm–1 (m).
1H NMR (CDCl3, 300 MHz, 25 °C): d = 7.71 (dd, J = 8.2, 1.6 Hz, 2
H), 7.67 (dd, J = 8.2, 1.6 Hz, 2 H), 7.61–7.58 (m, 2 H), 7.57–7.55
(m, 2 H), 1.80 (br s, 1 H), 1.62 (s, 6 H).
13C NMR (CDCl3, 75 MHz, 25 °C): d = 149.8, 145.3, 137.5, 132.8,
132.6, 127.9, 127.6, 127.0, 125.2, 118.9, 110.8, 72.4, 31.8.
MS (EI, 70 eV): m/z (%) = 237 (12, [M+]), 222 (100), 180 (19), 151
(14), 111 (7).
4-[3-(1-Hydroxyethyl)phenyl]butyronitrile (3i)
4-Cyanobutylzinc bromide (1f; 2.4 mL, 1.0 M in THF, 2.4 mmol),
was added to a solution of 1-(3-iodophenyl)ethanol (2i; 496 mg, 2
mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S-Phos (16.4 mg, 0.04
mmol) in THF (2 mL), according to Procedure 2. The mixture was
stirred for 1 h at 25 °C. Then, the mixture was quenched with sat. aq
NH4Cl (15 mL) and extracted with Et2O (3 × 15 mL). The combined
organic phases were washed with sat. aq thiourea (15 mL) and dried
(Na2SO4). Purification of the crude residue obtained after evapora-
tion of the solvents by flash chromatography (pentane–Et2O, 3:2)
yielded 3i as a colorless oil (332 mg, 88%).
HRMS: m/z calcd for C16H15NO: 237.1154; found: 237.1144.
IR (film): 3416 (w), 2969 (w), 2928 (w), 2868 (w), 2248 (w), 1608
(w), 1590 (w), 1488 (w), 1448 (w), 1424 (w), 1368 (w), 1259 (w),
1160 (w), 1074 (s), 1012 cm–1 (m).
(E)-4-Phenylbut-2-en-1-ol (3f)
Benzylzinc chloride (1d, 1.57 mL, 1.56 M in THF, 2.4 mmol) was
added to a solution of (E)-3-bromoprop-2-en-1-ol (2f; 247 mg, 2
mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and S-Phos (16.4 mg, 0.04
mmol) in THF (2 mL), according to Procedure 2: The mixture was
stirred for 1 h at 25 °C. Then the mixture was quenched with sat. aq
NH4Cl (15 mL) and extracted with Et2O (3 × 15 mL). The combined
organic phases were washed with sat. aq thiourea (15 mL) and dried
(Na2SO4). Purification of the crude residue obtained after evapora-
tion of the solvents by flash chromatography (pentane–Et2O, 1:1)
yielded 3f as a yellow oil (190 mg, 65%).
1H NMR (CDCl3, 300 MHz, 25 °C): d = 7.31–7.19 (m, 3 H), 7.10–
7.07 (m, 1 H), 4.88 (q, J = 6.5 Hz, 1 H), 2.78 (t, J = 7.3 Hz, 2 H),
7.32 (t, J = 7.2 Hz, 2 H), 2.03–1.94 (m, 2 H), 1.81 (br s, 1 H), 1.48
(d, J = 6.5 Hz, 3 H).
13C NMR (CDCl3, 75 MHz, 25 °C): d = 146.3, 140.0, 128.8, 127.5,
125.4, 123.6, 119.4, 70.3, 34.4, 26.9, 25.3, 16.5.
MS (EI, 70 eV): m/z (%) = 189 (20, [M+]), 174 (73), 146 (100), 129
(52), 91 (41).
HRMS: m/z calcd for C12H15NO: 189.1154; found: 189.1149.
IR (film): 3324 (br w), 3026 (w), 2864 (w), 1658 (w), 1598 (w),
1577 (w), 1494 (m), 1448 (m), 1370 (w), 1296 (w), 1202 (w), 1091
(m), 964 cm–1 (s).
1H NMR (300 MHz, CDCl3, 25 °C): d = 7.32–7.25 (m, 2 H), 7.22–
7.15 (m, 3 H), 5.85 (dtt, J = 15 Hz, 6.5, 1.3 Hz, 1 H), 5.68 (dtt,
J = 15, 6.8, 1.2 Hz, 1 H), 4.10 (dd, J = 5.8, 1.2 Hz, 2 H), 3.37 (d,
J = 6.5 Hz, 2 H), 1.45 (br s, 1 H).
Acknowledgment
We thank the Fonds der Chemischen Industrie and the DFG (SFB
749) for financial support. We thank Chemetall GmbH (Frankfurt)
and BASF AG (Ludwigshafen) for the generous gift of chemicals.
Z. Dong acknowledges the Chinese Scholarship Council for finan-
cial support.
13C NMR (75 MHz, CDCl3, 25 °C): d = 139.9, 131.5, 130.3, 128.5,
128.4, 126.1, 63.5, 38.6.
Synthesis 2009, No. 4, 681–686 © Thieme Stuttgart · New York

686
Z. Dong et al.
PRACTICAL SYNTHETIC PROCEDURES
(6) Manolikakes, G.; Schade, M. A.; Muñoz Hernandez, C.;
Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765.
(7) (a) Altman, R. A.; Buchwald, S. L. Nature Protocols 2007,
2, 3115. (b) Barder, T. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 5096. (c) Milne, J. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2004, 126, 13028. (d) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685.
References
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (b) Tsuji, J. Transition Metal Reagents and Catalysis:
Innovations in Organic Synthesis; Wiley: Chichester, 1995.
(c) Transition Metals for Organic Synthesis, 2nd ed.; Beller,
M.; Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37,
3387. (c) Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int.
Ed. 1999, 38, 2413. (d) Zapf, A.; Ehrentraut, A.; Beller, M.
Angew. Chem. Int. Ed. 2000, 39, 4153. (e) Molander, G. A.;
Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(3) (a) Handy, S. T.; Zhang, Y.; Bregman, H. J. Org. Chem.
2004, 69, 2362. (b) Chaumeil, H.; Signorella, S.; Le Drian,
C. Tetrahedron 2000, 56, 9655. (c) Wanatabe, T.; Miyaura,
N.; Suzuki, A. Synlett 1992, 207.
(4) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982,
15, 340. (c) Zeng, X.; Quian, M.; Hu, Q.; Negishi, E. Angew.
Chem. Int. Ed. 2004, 43, 2259.
(8) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 6040.
(9) Typical pKa values (in DMSO) for anilines range between
20–30; for a comprehensive compilation of pKa data see
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
and references cited therein.
(10) For the possible use of thioarylaminyls as spin source or
building block for organic magnets, see: Magnetic
Properties of Organic Materials; Lathi, P. M., Ed.; Marcel
Dekker: New York, 1999.
(11) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10,
1107.
(12) Our experiments indicate a relative kinetic basicity of zinc
reagents: arylzinc halide > alkylzinc halide > benzylic zinc
halide. For further experimental details, see ref. 7.
(13) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
(5) For selected examples from our group, see: (a) Sase, S.;
Jaric, M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org.
Chem. 2008, 73, 7380. (b) Gavryushin, A.; Kofink, C.;
Manolikakes, G.; Knochel, P. Org. Lett. 2005, 7, 4871.
Synthesis 2009, No. 4, 681–686 © Thieme Stuttgart · New York