Cobalt-xantphos-catalyzed, LiCl-mediated preparation of arylzinc reagents from aryl iodides, bromides, and chlorides

Article abstract of DOI:10.1021/jo102417x

A cobalt-Xantphos-catalyzed, LiCl-mediated system has been developed for the direct and expedient preparation of arylzinc reagents in THF from the corresponding aryl iodides, bromides, and chlorides. Owing to the use of THF as a versatile solvent, the thus-formed arylzinc reagents displayed a high degree of compatibility with a variety of conventional as well as newly emerging metal-catalyzed cross-coupling reactions.

Full text of DOI:10.1021/jo102417x

FEATURED ARTICLE
pubs.acs.org/joc
Cobalt-Xantphos-Catalyzed, LiCl-Mediated Preparation of Arylzinc
Reagents from Aryl Iodides, Bromides, and Chlorides
Meng-Yi Jin and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S Supporting Information
b
ABSTRACT: A cobalt-Xantphos-catalyzed, LiCl-mediated system
has been developed for the direct and expedient preparation of arylzinc
reagents in THF from the corresponding aryl iodides, bromides, and
chlorides. Owing to the use of THF as a versatile solvent, the thus-
formed arylzinc reagents displayed a high degree of compatibility with a
variety of conventional as well as newly emerging metal-catalyzed cross-
coupling reactions.
Scheme 1. Cobalt-Xantphos-Catalyzed, LiCl-Mediated
Zinc Insertion into Aryl Halides
’ INTRODUCTION
The preparation of organozinc reagents is an important
synthetic task owing to the versatility of the reagents in a wide
range of C-C bond-forming reactions.1 In light of operational
simplicity and atom efficiency, direct insertion of zinc into
organic halides is the most attractive method. Furthermore, with
the continuous development of transition-metal catalysis of
organozinc reagents beyond conventional Pd and Cu catalysis,2,3
their preparative methods featuring convenience, broad substrate
scope, and wide applicability are highly desirable. However,
existing methods, particularly for arylzinc reagents, have not
yet displayed all of the aforementioned features. Early methods,
except the one employing less convenient Rieke zinc,4 required
the use of aryl iodides and highly polar solvents,5,6 the latter being
potentially detrimental to subsequent transition-metal-catalyzed
reactions. The LiCl-mediated zinc insertion in THF recently
developed by the Knochel group7 has gained popularity among
the synthetic community due to its convenience and wide
applicability.2,8 Nevertheless, the substrates used are limited to
aryl iodides and highly activated aryl bromides. While the
preparation of arylzinc reagents from the corresponding bro-
mides and chlorides has been achieved by the CoBr2-catalyzed
method of Gosmini and co-workers,9 the use of acetonitrile as the
solvent (and pyridine as the cosolvent for aryl chlorides) narrows
the potential applicability of the resulting zinc reagents. We
report herein a cobalt-Xantphos-catalyzed, LiCl-mediated sys-
tem that allows for the expedient synthesis of arylzinc reagents in
THF from a series of aryl iodides, bromides, and chlorides
(Scheme 1). Furthermore, the thus-formed arylzinc reagents
have proven to be applicable to conventional as well as newly
emerging cross-coupling reactions catalyzed by various transition
metal complexes (i.e., Cu, Pd, Fe, Rh).
’ RESULTS AND DISCUSSION
Optimization of Reaction Conditions. Prompted by Gosmi-
ni’s work on CoBr2-catalyzed zinc insertion in acetonitrile,9 we
set out to explore cobalt complexes that could accelerate the
Knochel zinc insertion in THF. We initially focused on the zinc
insertion into 4-iodoanisole 1, which was reported to complete
after 90 h at 50 °C.7 Screening of a variety of cobalt precatalysts
and ligands led us to find that a combination of CoCl2 and
Xantphos greatly accelerates the reaction. Thus, the reaction
of 1 with Zn LiCl (1.5 equiv/1.0 equiv; zinc was preactivated by
3
1,2-dibromoethane and Me3SiCl) in the presence of CoCl2 and
Xantphos (5 mol % each) in THF completed within 16 h at
20 °C, and after quenching with 1 M HCl afforded anisole 2 in
97% yield, together with a small amount of a homocoupling
Received: December 7, 2010
Published: March 08, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
FEATURED ARTICLE
Table 1. Zinc Insertion into 4-Iodoanisolea
Table 2. Zinc Insertion into Unactivated Aryl Iodidesa
yieldb (%)
entry
Ar-I
time (h)
ArZnI
ArH
ArAr
1
4-MeC6H4I
6
6
86
84
16
0
9
11
81
95
12
10
7
4
3
0
0
4
0
1
8
5
1
2
3-MeC6H4I
3c,d
4 c,d
5
6c
7c
8
2-MeC6H4I
16
24
5
2,4,6-Me3C6H2I
3-MeOC6H4I
2-MeOC6H4I
2,4-(MeO)2C6H3I
4-Me2NC6H4I
3-NCC6H4I
83
90
92
67
89
91
6
7
12
8
4
9
5
10
3-EtO2CC6H4I
5
8
a Reaction conditions in Table 1, entry 20, were employed unless
otherwise noted. b Determined by GC after iodolysis. For each reaction,
full conversion of the starting material was confirmed by GC. c 5 mol % of
CoCl2 and 5 mol % of Xantphos were used. d Reaction was run at 50 °C.
yieldb (%)
entry
CoXn
ligand
LiY
2
3
1
1
CoCl2
CoCl2
Xantphos LiCl 97 (12) 2 (3) 0 (84)
LiBr and LiI also assisted the zinc insertion, while the absence of
a lithium salt resulted in no rate acceleration (entries 16-18).
Change of the cobalt/Xantphos ratio from 1:1 to 1:2 did not
affect the reaction (entry 19). A catalyst loading of 2.5 mol %
was sufficient for full conversion of 1 within 8 h (entry 20). A
preformed complex, CoCl2(Xantphos),10 showed a similar cat-
alytic activity to the in situ generated catalyst (entry 21). Note
that reactions performed in polar solvents such as DMF and
acetonitrile gave much poorer results, affording the product 2 in
31% and 38% yields, respectively. No reaction took place when
toluene was used as the solvent.
Zinc Insertion into Aryl Iodides, Bromides, and Chlorides.
The optimized catalytic system (Table 1, entry 13) was applicable to
a series of unactivated aryl iodides (Table 2). Thus, 4- and 3-iodo-
toluenes underwent zinc insertion smoothly within 6 h to afford the
corresponding zinc reagents in ca. 85% yields (entries 1 and 2). The
reaction of 2-iodotoluene completed within 16 h at 50 °C with a
catalyst loading of 5 mol %. However, toluene was formed as the
main product (entry 3). Similarly, 2-iodomesitylene afforded
the reduction product exclusively (entry 4). A methoxy group
on the 3- or 2-position did not interfere with the reaction
(entries 5-7). A strongly donating dimethylamino substituent
was also tolerated (entry 8). In addition, moderately reactive
3-cyano- and 3-ethoxycarbonyl-substituted iodides afforded the
corresponding functionalized arylzinc reagents in good yields
(entries 9 and 10).
The Co-Xantphos catalyst also allowed the facile conversion
of a variety of aryl bromides to the corresponding arylzinc
reagents (Table 3). Thus, bromobenzene underwent complete
conversion within 14 h, affording PhZnBr in 82% yield (entry 1).
Electron-withdrawing halogen and CF3 substituents accelerated
the reaction, affording the zinc reagents within 5-6 h (entries
2-7). Note that the C-Cl bonds of 1-bromo-3,5-dichloroben-
zene remained intact at room temperature (entry 7; see also entry
16). Electron-rich or neutral aryl bromides also afforded the
corresponding zinc reagents in good yield, albeit after longer
reaction times (entries 8-11). In addition, activated substrates
such as ethyl 4-bromobenzoate reacted smoothly within 5 h
(entry 12). Unexpectedly, the reaction of 3-bromobenzonitirle
was rather sluggish, and afforded the zinc reagent in a moderate
yield after 35 h (entry 13).
2
LiCl
LiCl
9
5
0
89
95
90
0
3
0
4
Xantphos LiCl 10
DPEphos LiCl 89
0
5
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoBr2
CoI2
11
3
6
dppbz
dppf
dppe
PPh3
bpy
LiCl 67
LiCl 40
LiCl 29
27
52
67
95
46
0
7
5
8
0
9c
10
11
12
13
14
15
16
17
18
19d
LiCl
5
0
LiCl 26
LiCl 51
17
47
2
phen
Xantphos LiCl 95
Xantphos LiCl 96
Xantphos LiCl 94
Xantphos LiCl 94
Xantphos LiBr 99
0
1
0
Co(acac)2
Co(acac)3
CoCl2
2
0
4
0
<1
2
0
CoCl2
Xantphos LiI
Xantphos
97
2
0
CoCl2
0
97
0
CoCl2
Xantphos LiCl 97
Xantphos LiCl 98 (9)
LiCl (6)
1
20e,f CoCl2
21f,g CoCl2(Xantphos)
a Reaction was performed on a 2 mmol scale. b Determined by GC using
n-tridecane as an internal standard. Values in parentheses refer to yields
obtained for reactions quenched with I2. c 10 mol % of PPh3 was used. d 10
mol % of Xantphos was used. e 2.5 mol % of CoCl2 and Xantphos were used.
f Reaction completed in 8 h. g 2.5 mol % of CoCl2(Xantphos) was used.
2 (3) 0 (88)
(<1) (93)
product 3 (Table 1, entry 1). When the same reaction was
quenched with I2, 1 was recovered in 84% yield. This confirmed
efficient zinc insertion. Unlike the Gosmini protocol,9b-d in-
dividually, CoCl2 (and other cobalt salts) or Xantphos did not
exhibit any rate acceleration in THF (entries 2-4).
Although other diphosphines such as DPEphos, dppbz, dppf,
and dppe also accelerated the zinc insertion, their effects were
less pronounced than that of Xantphos (entries 5-8). Mono-
dentate phosphines such as PPh3 were not effective (entry 9).
The use of bipyridine and phenanthroline ligands resulted in the
formation of considerable amounts of 3 (entries 10 and 11).
Other cobalt sources such as CoBr2, CoI2, Co(acac)2, and
Co(acac)3 performed equally well as CoCl2 (entries 12-15).
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FEATURED ARTICLE
Table 3. Zinc Insertion into Aryl Bromides and Chloridesa
Scheme 3. Proposed Catalytic Cycle
yieldb (%)
entry
Ar-X
time (h) ArZnX ArH ArAr
1
C6H5Br
14
6
82
89
90
87
92
95
96
87
79
82
79
85
68
89
92
83
80
86
85
60
62
ND
7
3
4
2
4-F3CC6H4Br
3
3,5-(CF3)2C6H3Br
3-FC6H4Br
6
ND
6
0
4
5c
6c
7c
5
2
3,4-F2C6H3Br
5
<7
<5
<4
5
<1
0
C6F5Br
5
3,5-Cl2C6H3Br
4-PhC6H4Br
5
0
8
10
24
14
22
5
0
9
1-C10H7Br
20
10
21
9
0
10
11d
12e
13d
14c
15c
16
17c
18c,d,f
4-MeOC6H4Br
2-MeOC6H4Br
4-EtO2CC6H4Br
3-NCC6H4Br
4
0
6
35
5
14
<5
<6
4
9
reaction of 2-iodomesitylene in THF-d8, followed by quenching
with 1 M HCl, afforded deuterated mesitylene with a deuterium
incorporation rate of 76%, demonstrating that hydrogen
abstraction from THF solvent is the major pathway leading to
the reduction product. This observation suggests the radical
nature of the reaction (vide infra).
2-bromothiophene
3-bromothiophene
2-bromo-5-chlorothiophene
3-bromoquinoline
2-chlorothiophene
<4
<2
3
8
5
20
24
24
24
24
<1
9
0
5
19 c,d,f 3-chlorothiophene
20 c,d,g 3-EtO2CC6H4Cl
21c,d,g
9
3
Cross-Coupling Reactions of Arylzinc Reagents. The
arylzinc reagents prepared by the present method are amenable
to a variety of transition-metal-catalyzed cross-coupling reactions
in one pot, without apparent interference from the cobalt catalyst
(Table 4). Allylation and acylation reactions in the presence of
19
15
3-F3CC6H4Cl
14
15
a Reaction conditions in Table 1, entry 20, were employed unless
otherwise noted. b Determined by GC after iodolysis unless otherwise
noted. ND = not detemined. c Reaction was run on a 4-5 mmol scale,
and yield of ArZnX was determined by iodine titration.11 d 5 mol % of
CoCl2 and 5 mol % of Xantphos was used. e 5 mol % of Xantphos
was used. f Reaction was run at 50 °C. g Reaction was run at 80 °C.
CuCN 2LiCl12 were successfully applied to 3-tosyloxyphenyl-
3
zinc bromide, 3,5-dichlorophenylzinc bromide, and 3-thienylzinc
bromide to afford the products 4-6 in good yields (entries
1-3).13 The copper catalyst also allowed for the electrophilic
trapping of 3,5-bis(trifluoromethyl)phenylzinc bromide with
chlorodiphenylphosphine, affording the triarylphopshine 7 in
53% yield (entry 4).14 Negishi coupling reactions of 4-biphenyl-
zinc bromide, 3-cyanophenylzinc iodide, and 2-methoxyphenyl-
zinc iodide with aryl halides using Pd(PPh3)4 or Pd-SPhos
catalyst15 gave the biaryl compounds 8-10 in 65-95% yields
(entries 5-7). The preparation and Negishi coupling of 4-bi-
phenylzinc bromide could be performed on a 10 mmol scale
without significant decrease in the product yield (entry 5).
Besides the application to the well-established Cu- and Pd-
catalyzed reactions, our zinc reagents are ready for use in the
emerging cross-coupling reactions. Reactions of 2,4-dimethox-
yphenylzinc iodide, 3-quinolylzinc bromide, and 3,4-difluoro-
phenylzinc bromide with primary or secondary alkyl bromides
were achieved in good yields by the iron-diamine or iron-
diphosphine catalyzed protocols of Nakamura and co-workers
(entries 8-10).3b,g Note that 3,4-difluorophenylzinc bromide
prepared according to the Gosmini method9c failed to participate
in the iron-catalyzed cross-coupling reaction (1% GC yield)
presumably due to the adverse effect of the acetonitrile solvent,
highlighting the advantage of the present protocol. Applications
to the Rh-catalyzed three-component coupling with an allene
and acetonitrile2f and the MgCl2-mediated addition to an
aldehyde,8e recently reported by the Oshima and Knochel
groups, respectively, were also successful (entries 11 and 12).
Proposed Reaction Mechanism. At present, we suggest a
mechanistic scenario similar to that proposed by Gosmini and
co-workers for CoBr2-catalyzed zinc insertion (Scheme 3).9b,c
Scheme 2
A smooth zinc insertion was also observed for heteroaryl
bromides. Thus, bromothiophenes underwent complete conver-
sion within 5-8 h to afford the thienylzinc reagents in 83-92%
yields (entries 14-16). 3-Quinolylzinc bromide was obtained in
80% yield after 20 h (entry 17). Unfortunately, the attempted
zinc insertion to 2-bromopyridine afforded mostly pyridine as
the reduced product (data not shown).
Preliminary studies demonstrated that the present catalytic
system is also effective for aryl chlorides (Table 3). With a catalyst
loading of 5 mol %, chlorothiophenes were converted to the
corresponding zinc reagents within 24 h at 50 °C in ca. 85%
yields (entries 18 and 19). Activated aryl chlorides such as those
bearing 3-ethoxycarbonyl and 3-trifluoromethyl groups partici-
pated in the reaction at 80 °C to afford the zinc reagents in
moderate yields of ca. 60% (entries 20 and 21). Unactivated
substrates such as 4-chloroanisole reacted very sluggishly (<30%
conversion under the same conditions).
To probe the source of the hydrogen atom in the reduction
product, we performed a labeling experiment (Scheme 2). The
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FEATURED ARTICLE
Table 4. Metal-Mediated Electrophilic Trapping of Arylzinc
Halidesa
species to an arylcobalt(II) species by Zn, (3) transmetalation of
the arylcobalt(II) species with zinc(II) halide, which is generated
through the preceding reduction steps, to afford arylzinc halide
and cobalt(II) halide, and (4) reduction of cobalt(II) halide by Zn
to regenerate the cobalt(I) species. On the basis of the deuterium
labeling experiment (Scheme 2), we consider that the arylcobalt-
(II) species has a radical character. Thus, when the transmetalation
between the arylcobalt(II) species and zinc(II) halide is slow, it
would behave as an aryl radicalto abstract the hydrogen atom from
THF, affording the reduction product as the major product (see
entries 3 and 4 in Table 2). More details, including the roles of
Xantphos and LiCl, will be subjects of further studies.16
’ CONCLUSION
In summary, we have developed a Co-Xantphos-catalyzed,
LiCl-mediated protocol for the efficient preparation of arylzinc
reagents. With Xantphos as the key ligand and THF as the
compatible solvent, the present method fulfills the requirements
for operational simplicity, broad substrate scope, and applicabil-
ity to a variety of transition metal-catalyzed cross-coupling
reactions in a well-balanced manner. Further investigations into
the transition metal-catalyzed metal insertion into organic ha-
lides are in progress in our laboratory.
’ EXPERIMENTAL SECTION
General Procedure for the Zinc Insertion into Aryl Halides.
Anhydrous LiCl (84.8 mg, 2 mmol) was placed in a 10 mL Schlenk tube,
dried under vacuum (1 mbar) at 150 °C for 20 min, and cooled to room
temperature (20 °C) under N2. To the Schlenk tube was added zinc
powder (196 mg, 3 mmol), and the heterogeneous mixture of Zn and
LiCl was dried under vacuum (1 mbar) at 150 °C for 15 min. While
cooling to room temperature, the reaction tube was evacuated and
backfilled with N2 for three times. The mixture was suspended with THF
(2 mL), followed by the activation of Zn with BrCH2CH2Br (10 μL, 0.1
mmol) and Me3SiCl (3 μL, 0.02 mmol) and stirring for 5 min. Then
Xantphos (28.9 mg, 0.05 mmol) and CoCl2 (6.5 mg, 0.05 mmol) were
added sequentially. After the mixture was stirred for an additional 5 min,
an aryl halide (2 mmol) was added in one portion. The reaction was
stirred at room temperature and monitored by GC analysis of hydro-
lyzed aliquots. After complete conversion of the starting material, the
reaction was quenched by the addition of I2 (0.76 g, 3 mmol) and stirred
for 30 min. The resulting mixture was analyzed by GC using n-tridecane
or n-tetradecane as an internal standard to determine the yield of the
arylzinc reagent. For some entries in Table 3, the reaction was performed
on a 4-5 mmol scale in a 25 mL three-necked round-bottom flask, and
the yield of the arylzinc reagent was determined by iodine titration
(average of three runs) according to the literature procedure.11
Procedures for Metal-Mediated Electrophilic Trapping of
Arylzinc Halides (Table 4). The electrophilic trapping reactions
were performed in one pot after preparation of the arylzinc reagents
according to the typical procedure (2 mmol scale) unless otherwise
noted. The copper (entries 1-4),12 palladium (entries 5-7),15 iron
(entries 8-10),3b,g rhodium (entry 11),2f and magnesium (entry 12)8e-
catalyzed/mediated reactions were performed according to the literature
procedures with slight modifications in some cases (see below).
3-Allylphenyl 4-methylbenzenesulfonate (4). To 3-tosylox-
yphenylzinc bromide (prepared according to the typical procedure, 7 h)
a Performed on a 2 mmol scale (starting aryl halide) unless otherwise noted.
See the Experimental Section for the detailed procedure for each case.
b Based on the starting aryl halide. c Isolated yield based on the electrophile.
In parentheses is shown the yield of a 10 mmol scale reaction. d CuCN 2
3
e
LiCl (10-20 mol %) was used. Pd2(dba)3 (0.25 mol %) and S-Phos
(1 mol %) were used. f Pd(PPh3)4 (2 mol %) was used. g Me3SiCH2MgCl
(1 equiv), N,N,N0,N0-tetramethylethylenediamine (1 equiv), and FeCl3
(2.5 mol %) were used. h Me3SiCH2MgCl (1 equiv), FeCl3 (2.5 mol %),
and dppbz (7.5 mol %) were used. i [RhCl(cod)]2 (1.25 mol %), PtBu3
3
HBF4 (5 mol %), and KOtBu (5 mol %) were used. Performed on a
1 mmol scale. j MgCl2 (1 equiv) was used.
was added CuCN 2LiCl (0.20 mL of 1.0 M solution in THF, 0.20
3
Thus, the reaction may be initiated by reduction of CoCl2
(Xantphos) to a cobalt(I) species by Zn and involves the following
steps: (1) oxidative addition of an aryl halide to cobalt(I) to afford
an arylcobalt(III) species, (2) reduction of the arylcobalt(III)
mmol) at -20 °C, followed by the addition of allyl bromide (208.5 mg,
1.72 mmol). The reaction mixture was then stirred at 0 °C for 4 h,
followed by the addition of saturated aqueous NH4Cl solution (4 mL)
and 10% aqueous NH3 solution (2 mL). The resulting mixture was
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The Journal of Organic Chemistry
FEATURED ARTICLE
extracted with ethyl acetate (3 ꢀ 6 mL). The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. Purification of the crude product by silica gel
chromatography (eluent: hexane/EtOAc = 50/1, 30/1) afforded the
title compound as a colorless oil (479.6 mg, 97%): Rf 0.48 (hexane/
EtOAc = 3/1); 1H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 3.29 (d, J =
6.8 Hz, 2H), 4.97 (ddt, J = 1.6 Hz, 1.6 Hz, 17.2 Hz, 1H), 5.03 (ddt, J = 1.2
Hz, 1.6 Hz, 10.0 Hz, 1H), 5.82 (ddt, J = 6.8 Hz, 10.0 Hz, 17.2 Hz, 1 H),
6.77-6.78 (m, 1H), 6.80-6.83 (m, 1H), 7.04-7.06 (m, 1H), 7.16-
7.20 (m, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 21.5, 39.5, 116.3, 119.9, 122.4, 127.3, 128.4,
129.3, 129.6, 132.3, 136.2, 141.9, 145.2, 149.6; FTIR (NaCl, neat): 3082,
2980, 2924, 1736, 1639, 1609, 1599, 1483, 1445, 1373, 1294, 1242, 1223,
1190, 1179, 1128, 1094, 1045, 955, 907, 818, 729, 692, 664; HRMS
(ESI) calcd for C16H17O3S [M þ H]þ 289.0898, found 289.0893.
(3,5-Dichlorophenyl)(phenyl)methanone (5). To 3,5-dichloro-
phenylzinc bromide (prepared according to the typical procedure, 5 h)
NH4Cl solution (4 mL) and 10% aqueous NH3 solution (2 mL). The
resulting mixture was extracted with ethyl acetate (3 ꢀ 6 mL). The
combined organic phase was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the crude product
by silica gel chromatography (eluent: hexane) afforded the title com-
pound as a colorless oil (340.8 mg, 53%): Rf 0.47 (hexane/EtOAc =
50/1); 1H NMR (400 MHz, CDCl3) δ 7.31-7.36 (m, 4H), 7.39-7.43
(m, 6H), 7.71 (d, 3JH-P = 6.0 Hz, 2H), 7.83 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 122.4 (septet, 3JC-F = 3.7 Hz), 123.2 (q, 1JC-F = 271
Hz), 129.0 (d, 3JC-P = 7.5 Hz), 129.7, 131.6 (dq, 3JC-P = 5.9 Hz, 2JC-F
=
33 Hz), 133.0 (dq, 2JC-P = 20 Hz, 3JC-F = 3.4 Hz), 133.8 (d, 2JC-P = 20
Hz), 134.9 (d, 1JC-P = 10 Hz), 142.1 (d, 1JC-P = 18 Hz); 31P{1H} NMR
(162 MHz, CDCl3): δ -4.6; FTIR (NaCl, neat) 3073, 3057, 1740,
1614, 1477, 1435, 1356, 1279, 1184, 1134, 1105, 1096, 1026, 999, 897,
843, 745, 696, 681, 665; HRMS (ESI) calcd for C20H14F631P [M þ H]þ
399.0737, found 399.0737.
3-Methoxy-1,10:40,100-terphenyl (8). To 4-biphenylzinc bro-
mide (prepared according to the typical procedure, 10 h) was added a
THF solution of Pd2(dba)3/SPhos (0.25 mL, 0.02 M/0.08 M, 0.005
mmol/0.020 mmol) at 20 °C, followed by the addition of 1-iodo-3-
methoxybenzene (1.41 mL of 1.13 M solution in THF, 372.1 mg, 1.59
mmol). THF (0.34 mL) was added to rinse the walls of the tube. The
reaction mixture was stirred for 20 min and then quenched with
saturated aqueous NH4Cl solution (4 mL), followed by extraction with
ethyl acetate (3 ꢀ 5 mL). The combined organic phase was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
Purification of the crude product by silica gel chromatography (eluent:
hexane/EtOAc = 80/1) afforded the title compound as a white solid
(394.6 mg, 95%). The same reaction was also performed on a 10 mmol
scale in a 100 mL three-necked flask to afford the title compound in 88%
yield. The spectral data showed good agreement with the literature data
(see the Supporting Information).17
Ethyl 30-Cyano(1,10-biphenyl)-4-carboxylate (9). To 3-cya-
nophenylzinc iodide (prepared according to the typical procedure, 8 h)
was added Pd(PPh3)4 (47.0 mg, 0.04 mmol) at 20 °C, followed by the
addition of ethyl 4-iodobenzoate (1.34 mL of 1.19 M solution in THF,
439.0 mg, 1.59 mmol). THF (0.8 mL) was added to rinse the walls of the
tube. The reaction mixture was stirred for 2 h and quenched with
saturated aqueous NH4Cl solution (4 mL), followed by extraction with
ethyl acetate (3 ꢀ 5 mL). The combined organic phase was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
Purification of the crude product by silica gel chromatography (eluent:
hexane/EtOAc = 10/1) afforded the title compound as a white solid
(352.3 mg, 88%). The spectral data showed good agreement with the
literature data (see the Supporting Information).18
2-(2-Methoxyphenyl)pyridine (10). To 2-methoxyphenylzinc
iodide (prepared according to the typical procedure, 6 h) was added a
THF solution of Pd2(dba)3/SPhos (0.25 mL, 0.02 M/0.08 M, 0.005
mmol/0.020 mmol) at 20 °C, followed by the addition of 2-bromopyr-
idine (1.33 mL of 1.20 M solution in THF, 252.8 mg, 1.60 mmol). THF
(0.42 mL) was added to rinse the walls of the tube. The reaction mixture
was stirred for 7 h and quenched with saturated aqueous NH4Cl solution
(4 mL). Saturated aqueous NaHCO3 solution (4 mL) was added,
followed by extraction with ethyl acetate (3 ꢀ 8 mL). The combined
organic phase was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. Purification of the crude product by silica
gel chromatography (eluent: hexane/EtOAc = 10/1, 8/1) afforded the
title compound as a colorless oil (192.3 mg, 65%). The spectral data
showed good agreement with the literature data (see the Supporting
Information).19
was added CuCN 2LiCl (0.40 mL of 1.0 M solution in THF, 0.40
3
mmol) -20 °C. The resulting mixture was stirred at 0 °C for 10 min,
followed by the addition of benzoyl chloride (242.9 mg, 1.73 mmol) at -
20 °C. The reaction mixture was then stirred at 20 °C for 2 h, followed
by the addition of saturated aqueous NH4Cl solution (4 mL) and
10% aqueous NH3 solution (2 mL). The resulting mixture was extracted
with ethyl acetate (3 ꢀ 6 mL). The combined organic phase was washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. Purification of the crude product by silica gel chromatography
(eluent: hexane/EtOAc = 100/1) afforded the title compound as a white
solid (312.1 mg, 72%): Rf 0.56 (hexane/EtOAc = 3/1); mp 62.2-
63.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.48-7.52 (m, 2H), 7.54-7.55
(m, 1H), 7.60-7.64 (m, 3H), 7.76-7.78 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 128.1, 128.6, 129.9, 132.0, 133.1, 135.2, 136.2, 140.2,
193.6; FTIR (NaCl, CHCl3) 3076, 1663, 1597, 1562, 1447, 1416, 1395,
1314, 1275, 1180, 1161, 1099, 974, 872, 810, 756 (overlapped with
CHCl3 band), 719, 692, 652; HRMS (ESI) calcd for C13H835Cl2O [M
þ H]þ 251.0030, found 251.0025.
Thiophen-3-yl(4-(trifluoromethyl)phenyl)methanone (6).
To 3-thienylzinc bromide (prepared according to the typical procedure,
8 h) was added CuCN 2LiCl (0.40 mL of 1.0 M solution in THF, 0.40
3
mmol) at -20 °C. The resulting mixture was stirred at 0 °C for 10 min,
followed by the addition of 4-(trifluoromethyl)benzoyl chloride (343.8
mg, 1.65 mmol) at -20 °C. The reaction mixture was then stirred at
20 °C for 2 h, followed by the addition of saturated aqueous NH4Cl
solution (4 mL) and 10% aqueous NH3 solution (2 mL). The resulting
mixture was extracted with ethyl acetate (3 ꢀ 6 mL). The combined
organic phase was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. Purification of the crude product by silica
gel chromatography (eluent: hexane/EtOAc = 100/1, 70/1) afforded
the title compound as a white solid (337.2 mg, 80%): Rf 0.51 (hexane/
1
EtOAc = 3/1); mp 113.8-114.9 °C; H NMR (400 MHz, CDCl3)
δ 7.41 (dd, J = 2.8 Hz, 5.2 Hz, 1H), 7.60 (dd, J = 1.2 Hz, 5.2 Hz, 1H),
7.76 (d, J = 8.0 Hz, 2H), 7.92-7.94 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 123.6 (q, 1JC-F = 271 Hz), 125.4 (q, 3JC-F = 3.6 Hz), 126.7,
128.3, 129.5, 133.6 (q, 2JC-F = 32 Hz), 134.6, 140.7, 141.6, 188.7; FTIR
(NaCl, CHCl3) 3103, 1639, 1508, 1420, 1408, 1325, 1277, 1206, 1171,
1153, 1134, 1119, 1109, 1067, 1013, 972, 856, 831, 754 (overlapped with
CHCl3 band), 706, 687; HRMS (ESI) calcd for C12H8F3OS [M þ H]þ
257.0248, found 257.0253.
(3,5-Bis(trifluoromethyl)phenyl)diphenylphosphine (7).
To 3,5-bis(trifluoromethyl)phenylzinc bromide (prepared according
to the typical procedure) was added CuCN 2LiCl (0.40 mL of 1.0 M
3
solution in THF, 0.40 mmol) at -20 °C. The resulting mixture was
stirred at 0 °C for 10 min, followed by the addition of chlorodiphenyl-
phosphine (355.4 mg, 1.61 mmol) at -20 °C. The reaction mixture was
stirred at 20 °C for 2 h, followed by the addition of saturated aqueous
Ethyl 5-(2,4-Dimethoxyphenyl)pentanoate (11). To 2,4-
dimethoxyphenylzinc iodide (prepared according to the typical proce-
dure, 7 h) was added Me3SiCH2MgCl (0.89 M solution in THF, 2.2 mL,
2.0 mmol) at 0 °C. The resulting mixture was stirred for 2 h, followed by
1976
dx.doi.org/10.1021/jo102417x |J. Org. Chem. 2011, 76, 1972–1978

The Journal of Organic Chemistry
FEATURED ARTICLE
the addition of TMEDA (0.30 mL, 2.0 mmol), ethyl 5-bromovalerate
(186.5 mg, 0.89 mmol), and FeCl3 (0.1 M solution in THF, 0.5 mL, 0.05
mmol). The reaction mixture was warmed to 30 °C, stirred for 6 h, and
then quenched with saturated aqueous NH4Cl solution (5 mL). The
resulting mixture was extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic phase was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the crude product
by silica gel chromatography (eluent: hexane/EtOAc = 25/1, 20/1,
15/1) afforded the title compound as a colorless oil (220.8 mg, 93%): Rf
0.30 (hexane/EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 1.25 (t,
J = 7.2 Hz, 3H), 1.54-1.70 (m, 4H), 2.32 (t, J = 7.4 Hz, 2H), 2.55 (t, J =
7.4 Hz, 2H), 3.78 (s, 6H), 4.12 (q, J = 7.2 Hz, 2H), 6.41 (dd, J = 2.4 Hz,
8.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.2, 24.7, 29.0, 29.5, 34.2, 55.1, 55.2, 60.0, 98.4,
103.6, 122.9, 129.8, 158.2, 159.0, 173.8; FTIR (NaCl, neat) 2938, 2860,
2835, 1732, 1614, 1587, 1506, 1464, 1439, 1418, 1373, 1288, 260, 1207,
1180, 1155, 1121,1038, 935, 924, 833, 785, 665; HRMS (ESI) calcd for
C15H23O4 [M þ H]þ 267.1596, found 267.1593.
according to the typical procedure) (1.0 mL, 0.85 mmol, 0.85 M in
THF) under nitrogen. Then, acetonitrile (20.2 mg, 0.492 mmol) and
nona-1,2-diene (98.8 mg, 0.795 mmol) were added. The mixture was
stirred at 25 °C for 2 h, followed by the addition of saturated aqueous
NH4Cl solution (4 mL). The resulting mixture was extracted with ethyl
acetate (3 ꢀ 5 mL). The combined organic phase was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure. Purifica-
tion of the crude product by silica gel chromatography (eluent: hexane/
EtOAc = 100/1, 50/1) afforded the title compound as a colorless oil
(91.2 mg, 71%): Rf 0.19 (hexane/EtOAc = 50/1); 1H NMR (400 MHz,
CDCl3) δ 0.86 (t, J = 7.0 Hz, 3H), 1.25-1.28 (m, 8H), 1.60-1.65
(m, 1H), 1.88-1.94 (m, 1H), 2.12 (s, 3H), 3.52 (t, J = 7.4 Hz, 1H), 5.21
(s, 1H), 5.49 (s, 1H), 6.97-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.13-
7.16 (m, 1H), 7.27-7.33 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.0, 22.5, 27.6, 28.4, 29.2, 30.8, 31.6, 58.6, 113.4 (d, 2JC-F = 22.1 Hz),
114.6 (d, 2JC-F = 21.2 Hz), 116.2, 122.0 (d, 4JC-F = 2.6 Hz), 130.0 (d,
3JC-F = 8.4 Hz), 143.5 (d, 3JC-F = 7.3 Hz), 145.9, 162.9 (d, 1JC-F = 244.4
Hz), 208.1; FTIR (NaCl, neat) 3088, 2955, 2928, 2855, 1715, 1611, 1580,
1487, 1435, 1354, 1265, 1196, 1163, 908, 874, 787, 725, 652; HRMS
(ESI) calcd for C17H24FO [M þ H]þ 263.1811, found 263.1808.
(3-Chlorophenyl)(3,4-difluorophenyl)methanol (15). To
3,4-difluorophenylzinc bromide (prepared according to the typical
procedure) was added a THF/toluene solution (8/3, 4.5 mL) of MgCl2
(0.45 M, 2.0 mmol) at 20 °C. The resulting mixture was stirred for 2 h,
followed by the addition of 3-chlorobenzaldehyde (237.5 mg, 1.69
mmol). The reaction mixture was stirred for 6 h. Then, the reaction
mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl
solution (5 mL), and extracted with ethyl acetate (3 ꢀ 5 mL). The
combined organic phase was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the crude product
by silica gel chromatography (eluent: hexane/EtOAc = 20/1, 15/1, 10/
1) afforded the title compound as a colorless oil (312.8 mg, 73%): Rf 0.22
(hexane/EtOAc = 5/1); 1H NMR (400 MHz, CDCl3) δ 2.30 (brs, 1H),
5.76 (s, 1H), 7.05-7.24 (m, 4H), 7.26-7.31 (m, 2H), 7.36 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 74.4, 115.4 (d, 2JC-F = 18 Hz), 117.2
(d, 2JC-F = 17 Hz), 122.4 (dd, 4JC-F = 3.5 Hz, 3JC-F = 6.4 Hz), 124.5,
3-Cyclohexylquinoline (12). To 3-quinolylzinc bromide (prepared
according to the typical procedure, 20 h) was added Me3SiCH2MgCl
(0.89 M solution in THF, 2.2 mL, 2.0 mmol) at 0 °C. The resulting
mixture was stirred for 2 h, followed by the addition of TMEDA
(0.30 mL, 2.0 mmol), bromocyclohexane (146.0 mg, 0.90 mmol), and
FeCl3 (0.1 M solution in THF, 0.5 mL, 0.05 mmol). The reaction
mixture was warmed to 30 °C, stirred for 6 h, and then quenched with
saturated aqueous NH4Cl solution (5 mL). The resulting mixture was
extracted with ethyl acetate (3 ꢀ 5 mL). The combined organic phase
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. Purification of the crude product by silica gel
chromatography (eluent: hexane/EtOAc = 20/1, 15/1, 10/1) afforded
the title compound as a colorless oil (172.3 mg, 91%): Rf 0.21 (hexane/
EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 1.26-1.37 (m, 1H),
1.41-1.59 (m, 4H), 1.78-1.84 (m, 1H), 1.89-1.93 (m, 2H), 1.98-
2.01 (m, 2H), 2.73 (tt, J = 3.3 Hz, 11.5 Hz, 1H), 7.51 (ddd, J = 0.8 Hz, 6.8
Hz, 8.4 Hz, 1H), 7.64 (ddd, J = 1.2 Hz, 6.8 Hz, 8.4 Hz, 1H), 7.77
(dd, J = 0.8 Hz, 8.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 8.4 Hz,
1H), 8.82 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 25.9,
26.7, 34.1, 42.0, 126.4, 127.4, 128.2, 128.4, 129.0, 132.2, 140.3, 146.8,
151.3; FTIR (NaCl, neat) 3063, 2924, 2851, 1736, 1639, 1570, 1493,
1449, 1371, 1331, 1263, 1238, 1125, 1047, 1018, 974, 881, 860, 787, 752;
HRMS (ESI) calcd for C15H18N [M þ H]þ 212.1439, found 212.1439.
(3,4-Difluorophenyl)cycloheptane (13). The reaction was
performed with a slight modification of the original procedure. To
(3,4-difluorophenyl)zinc bromide (prepared according to the typical
procedure, 5 h) was added Me3SiCH2MgCl (0.92 M solution in THF,
2.2 mL, 2.0 mmol) at 0 °C. The resulting mixture was stirred for 2 h,
followed by the addition of 1,2-bis(diphenylphosphino)benzene
(DPPBz, 67.0 mg, 0.15 mmol) and bromocycloheptane (189.4 mg,
1.07 mmol) at 0 °C. After 10 min, FeCl3 (0.25 mL, 0.20 M solution in
THF, 0.05 mmol) was added at the same temperature. The reaction
mixture was stirred at 60 °C for 5 h. After the mixture was cooled to
ambient temperature, aqueous ammonium chloride (saturated, 5.0 mL)
was added. The resulting mixture was extracted with Et2O (3 ꢀ 5 mL).
The combined organic phase was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. Purification of the crude
product by silica gel chromatography (eluent: hexane/EtOAc = 100/1)
afforded the title compound as a colorless oil (169.5 mg, 75%). The
spectral data showed good agreement with the literature data (see the
Supporting Information).3g
4
3
126.4, 128.0, 130.0, 134.5, 139.9 (t, JC-F = JC-F = 4.2 Hz), 144.8,
149.7 (dd, 2JC-F = 13 Hz, 1JC-F = 247 Hz), 150.2 (dd, 2JC-F = 13 Hz,
1JC-F = 247 Hz); FTIR (NaCl, neat) 3420, 2988, 1707, 1638, 1622,
1612, 1574, 1518, 1474, 1433, 1375, 1279, 1207, 1192, 1113, 1045, 959,
943, 881, 824, 799, 766, 750, 719, 691; HRMS (ESI) calcd for
C13H935ClF2O23Na [M þ Na]þ 277.0208, found 277.0201.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental informa-
b
tion and NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
’ ACKNOWLEDGMENT
We thank the National Research Foundation, Singapore
(NRF-RF2009-05 to N.Y.) and Nanyang Technological Uni-
versity for generous financial support and Boon-Hong Tan for
technical assistance.
3-(1-(3-Fluorophenyl)vinyl)nonan-2-one (14). The reaction
was performed with a slight modification of the original procedure. To a
heterogeneous mixture of [RhCl(cod)]2 (6.4 mg, 0.013 mmol), PtBu3
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3
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1977
dx.doi.org/10.1021/jo102417x |J. Org. Chem. 2011, 76, 1972–1978

The Journal of Organic Chemistry
FEATURED ARTICLE
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3
sluggish.
1978
dx.doi.org/10.1021/jo102417x |J. Org. Chem. 2011, 76, 1972–1978