Copper-Catalyzed Negishi Coupling of Diarylzinc Reagents with Aryl Iodides

Article abstract of DOI:10.1055/s-0035-1560397

We report an efficient copper(I) iodide catalyzed cross-coupling of diarylzinc reagents with aryl iodides. The reaction proceeds under ligand-free conditions at low catalyst loading (5 mol%) and tolerates a variety of functional groups.

Full text of DOI:10.1055/s-0035-1560397

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 504–511
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S. Thapa et al.
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Synthesis
Copper-Catalyzed Negishi Coupling of Diarylzinc Reagents with
Aryl Iodides
Surendra Thapa
tolerates CO2R, CN, Br, Cl and o-Me among other functional groups
Adarsh S. Vangala
Ramesh Giri*
CuI (5 mol%)
no ligand
I
+
Zn
Department of Chemistry & Chemical Biology,
The University of New Mexico, Albuquerque,
NM 87131, USA
LiCl (1.0 equiv)
R1
R1
0.5–1.0 equiv
R2
DMF, 100 °C, 12 h
R1
R2
rgiri@unm.edu
19 examples; up to 84% yield
Received: 04.10.2015
Accepted after revision: 04.11.2015
Published online: 04.01.2016
very little is known on the application of copper as a cata-
lyst for the Negishi coupling.16 In 2004, Ready and Malosh
demonstrated that copper could catalyze the reaction of al-
kylzinc reagents with α-chloro ketones by an SN2 process
(Scheme 1, a).17 Recently, we also reported that copper(I)
iodide could catalyze the cross-couplings of alkyl-, aryl-,
and alkynylzinc reagents with heteroaryl iodides under li-
gand-free conditions (Scheme 1, b).18 However, we found
that when arylzinc bromides were coupled with non-het-
erocyclic aryl iodides, the reactions afforded the biaryl
products in low yields only. In this article, we report the op-
timization of reaction conditions that enabled the cross-
coupling of arylzinc reagents with aryl iodides to afford bi-
aryl products (Scheme 1, c). We demonstrate that the cur-
rent copper-catalyzed Negishi coupling tolerates a wide va-
riety of functional groups and affords the cross-coupled
products in good to excellent yields under ligand-free con-
ditions.
DOI: 10.1055/s-0035-1560397; Art ID: st-2015-z0576-fa
Abstract We report an efficient copper(I) iodide catalyzed cross-
coupling of diarylzinc reagents with aryl iodides. The reaction proceeds
under ligand-free conditions at low catalyst loading (5 mol%) and toler-
ates a variety of functional groups.
Key words copper, cross-coupling, diarylzinc, ligand-free, Negishi
coupling
The Negishi coupling represents one of the most power-
ful synthetic methods for the construction of carbon–car-
bon (C–C) bonds in organic molecules.1 The synthetic ver-
satility of this transformation stems from the use of or-
ganozinc reagents that are tolerant of a wide variety of
functional groups encountered in organic synthesis.1d In
addition, organozinc reagents are also readily prepared
from the reaction of organo halides with metallic zinc.2 As
such, tremendous progress has been made over the course
of the last three decades in the context of the scope of this
reaction as well as its application to the synthesis of natural
products,3 pharmaceuticals4 and materials.5 While palladi-
um and nickel have remained the ‘gold-standard’ catalysts
for various cross-couplings including the Negishi coupling,
copper, which is earth-abundant and has low toxicity, has
recently gained popularity as an alternative catalyst.6 In
this respect, copper has already been shown to enable the
cross-couplings of the organometallic reagents of magne-
sium,7 tin,8 boron,9 silicon,10 zirconium,11 and indium12
with alkyl and aryl halides. Surprisingly, despite clear evi-
dence of the ability of organozinc reagents to transmetalate
to copper halides, as demonstrated both in the stoichiomet-
ric syntheses of organocopper(I) complexes13 and catalytic
reactions such as conjugate,14 allylic,2a and 1,2-additions,15
(a) Ready and Malosh
O
O
CuI
Cl
Alkyl
alkyl ZnX
+
SN2
(b) Giri and co-workers
alkyl/aryl/alkynyl ZnX
CuI
I
R
+
Het
Het
(c) this work
I
CuI
ZnX
+
no ligand
Scheme 1 Copper-catalyzed Negishi cross-couplings
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We began our investigation by attempting to couple
commercially available phenylzinc bromide (1) with 4-io-
dotoluene (2) under our previously reported standard reac-
tion conditions (Table 1, entry 1). However, the cross-
coupling product, 4-methylbiphenyl (3), was formed in 42%
GC yield only. Replacing N,N-dimethylformamide with oth-
er polar, mid-polar, and non-polar solvents did not improve
the product yield (entries 2 and 3). We also examined the
effects of a wide variety of bases, fluoride sources, and
counteranions in the reaction, which also did not improve
the product yield (entries 4 and 5). A variety of ligands such
as neutral nitrogen- and phosphorus-based monodentate
and bidentate ligands, carbene ligands as well as anionic li-
gands, which afforded the product only in 11–49% yields
(entries 6–8). Increasing the amount of lithium chloride
and phenylzinc bromide, or running the reaction for a lon-
ger time or at a higher temperature either did not improve
the reaction or formed the product in only a slightly higher
yield (entries 9–13). Surprisingly, when the organozinc re-
agent was changed from phenylzinc bromide (1) to di-
phenylzinc, the reaction furnished the cross-coupled prod-
uct 3 in 87% GC yield (entry 14) under the standard reaction
conditions using copper(I) iodide (5 mol%) and lithium
chloride (1 equiv) in N,N-dimethylformamide at 100 °C
without the need for the addition of ancillary ligands. This
reaction required only 0.5 equivalents of diphenylzinc. Lith-
ium chloride plays a crucial role in this cross-coupling be-
cause the reaction conducted in its absence afforded 3 in
only in 45% GC yield (entry 15). Lithium chloride is general-
ly considered to generate more reactive organozinc spe-
cies.19
After optimizing the reaction conditions, we examined
the substrate scope of the current cross-coupling reaction
for aryl–aryl bond formation. The reactions proceed well
for the coupling of electron-rich as well as electron-poor
aryl iodides with electron-neutral, electron-poor, and elec-
tron-rich diarylzinc reagents affording the products in good
yield (Table 2). The reactions require only 0.5 equivalents of
diphenylzinc (entries 1–4). However, reactions with other
diarylzinc reagents required 1.0 equivalents (entries 5–18).
Biographical Sketches
Ramesh Giri was born in Chit-
wan, Nepal and graduated with
distinction from Tribhuvan Uni-
versity (Nepal) with an M.Sc. in
organic chemistry in 2000 un-
der the supervision of Prof. S. M.
Tuladhar. He then moved to the
University of Cambridge (UK) as
a Shell Centenary Scholar and
received an M.Phil. in bioorgan-
ic chemistry in 2003 with Prof. J.
B. Spencer. He earned his Ph.D.
in chemistry from The Scripps
Research Institute in 2009 with
Prof. Jin-Quan Yu, where he
studied palladium-catalyzed C–
H functionalization. As a post-
doctoral fellow in the research
laboratory of Prof. John F.
Hartwig at UC Berkeley/UIUC,
he studied the mechanisms of
Ullmann amination and biaryl
ether forming processes. In
2012, he joined the faculty of
the Department of Chemistry &
Chemical Biology at the Univer-
sity of New Mexico as an Assis-
tant Professor. His research
group is interested in develop-
ing organic transformations
based on first row late transition
metals and investigating their
reaction mechanisms.
Surendra Thapa was born and
raised in Kathmandu, Nepal. Af-
ter graduating with a B.A. in
chemistry from South Dakota
State University in Brookings
(SD, USA), he began his gradu-
ate studies in 2012 at New Mex-
ico Highlands University in Las
Vegas, NM, where he worked
with Dr. Tatiana Timofeeva, Dr.
Kaiguo Chang, and Dr. Carol
Linder. He joined the Giri group
in the summer of 2013 as a
graduate student where he is
currently conducting research
on copper-catalyzed cross-
couplings and mechanistic in-
vestigations.
Adarsh Vangala was born in
Albuquerque, New Mexico
(USA) in 1995. He attended
high school at Albuquerque
Academy, and after graduating
he started attending the Univer-
sity of New Mexico in the fall of
2012. Adarsh joined the Giri
group during the summer of
2013 where he has been con-
ducting research in the areas of
transition-metal catalysis.
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Table 1 Optimization of the Reaction Conditionsa
CuI (5 mol%)
PhZnBr + Me
I
Me
Ph
LiCl (1.0 equiv)
DMF, 100 °C, 12 h
1
2
3
Entry
Modified conditionsb
none
Yield (%)c
1
2
42
change the solvent to: DMSO, DMA, HMPA, or DMPU
change the solvent to: toluene, benzene, NMP, or dioxane
change LiCl to: CsF, Cs2CO3, K3PO4, NaOMe, or NaOAc
trace
10–25
10–40
8–30
35–49
8
3
4
5
addition of: [Bu4N]PF6, [Bu4N]BF4, KPF6, Na2SiF6, or (NH4)2TiF6
addition of: Ph3P, dppda, tmopd, tmeda, phen
addition of: dppbe
6
7
8
addition of: 8-HQ, tmhd, SIMes·HCl
change LiCl (1.0 equiv) to: LiCl (2.0 equiv)
change time to: 18 h
11–25
42
9
10
11
12
13
14
15
45
change time to: 24 h
50
change temperature to: 120 °C
51
used PhZnBr (2.0 equiv)
47
change PhZnBr to: Ph2Zn (0.5 equiv)
change PhZnBr to: Ph2Zn (0.5 equiv) without the use of LiCl
87 (82)d
45
a Using DMF (0.5 mL). Ph2Zn was generated from the reaction of PhLi with ZnCl2 (99.999% purity). CuI (99.999%) was used.
b dppda: 2-(diphenylphosphino)-N,N-dimethylaniline; tmopd = N,N,N′,N′-tetramethyl-o-phenylenediamine; phen = 1,10-phenanthroline; dppbe = 1,2-bis(diphenyl-
phosphino)benzene; 8-HQ = 8-hydroxyquinoline; tmhd = 2,2,6,6-tetramethylheptane-3,5-dione.
c Calibrated GC yields using 2-nitrobiphenyl as a standard.
d Reaction performed on a 1.0-mmol scale in DMF (5 mL); isolated yield. Addition of LiBr (1 equiv) instead of LiCl under the standard reaction conditions de-
creased the yield of 3 to 76% suggesting that Br– could inhibit the reaction.
The reaction tolerates a variety of functional groups such as
ester, trifluoromethyl, and nitrile on the aryl iodide (entries
2–6, 10–12, and 14–17) and alkoxy and alkyl on the aryl-
zinc reagent (entries 5–17). The reaction also tolerates ha-
lides such as chloride and bromide, and ortho-substituents
on both aryl iodides (entries 7, 8, 13, and 18) and arylzinc
reagents (entries 6–14 and 18). The tolerance of these func-
tional groups demonstrates the versatility of the current
coupling reaction and its potential synthetic utility.
per(I) complexes.13 We have previously shown that the
[CuPh] complex reacts with aryl iodides to afford biaryl
products.10b,21 Therefore, we believe that a similar mecha-
nistic scenario can also be envisioned in the current
copper-catalyzed cross-coupling of diarylzinc reagents with
aryl iodides that involves [CuAr] as the reaction intermedi-
ate.
[Ar1ZnCl]–[Li]+
[Ar1Zn(Cl)(I)]–[Li]+
Ar1Zn + LiCl
Based on literature reports and our recent mechanistic
work on copper-catalyzed cross-couplings,9a,10b,12 we pro-
pose a catalytic cycle for the current reaction (Scheme 2). It
is evident from the optimization of the reaction conditions
that the use of lithium chloride is critical in this coupling of
diarylzinc reagents with aryl iodides (Table 1, entries 14
and 15). As such, we envision that diarylzincate complexes
such as 21, generated from the binding of lithium chloride
to the diarylzinc reagent, are the actual species in solution
that undergo transmetalation with copper(I) iodide to gen-
erate [CuAr] complexes as the reaction intermediates. Or-
ganozinc complexes are known to form organozincate spe-
cies in the presence of lithium halides in solution.19b,20 In
addition, diarylzinc reagents have been demonstrated to
undergo transmetalation with copper salts to form arylcop-
21
22
CuI(solv)
23
[CuAr1(solv)]
24
Ar1 Ar2
Scheme 2 Proposed catalytic cycle
Ar2
I
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Table 2 Coupling of Diarylzinc Reagents with Aryl Iodidesa
CuI (5 mol%)
Ar12Zn
Ar2
I
Ar1 Ar2
+
LiCl (1.0 equiv)
DMF, 100 °C, 12 h
Entry
1
Ar1
Ar2I
Ar1–Ar2
Yieldb (%)
OMe
I
72c
79c
83c
78c
MeO
4
5
6
7
CF3
I
2
3
4
5
F3C
CN
I
NC
CO2Me
I
MeO2C
CO2Me
I
74
84
72
76
MeO2C
Me
Me
Me
Me
Me
Me
Me
Me
8
CN
I
6
7
8
NC
9
Cl
I
Cl
10
11
Br
I
Br
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Table 2 (continued)
Entry
9
Ar1
Ar2I
Ar1–Ar2
Yieldb (%)
OMe
I
55
82
57
67
51
Me
MeO
Me
12
13
14
15
16
CF3
I
10
11
12
13
F3C
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CO2Me
I
MeO2C
CN
I
NC
Br
I
Br
OMe
OMe
CF3
F3C
I
14
15
16
59
73
71
CF3
CF3
OMe
17
CO2Me
I
MeO2C
OMe
OMe
18
CN
I
NC
OMe
OMe
19
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Table 2 (continued)
Entry
17
Ar1
Ar2I
Ar1–Ar2
Yieldb (%)
CF3
I
75
77
F3C
Me
20
Me
Cl
I
18
Me
Me
Cl
10
a Performed on a 1.0-mmol scale using Ar12Zn (1 equiv) in DMF (5 mL) unless otherwise stated. Ar12Zn was prepared in situ from ZnCl2 with Ar1Li (2 equiv) in THF
at r.t.
b Isolated yield.
c Ph2Zn (0.5 equiv) was used.
In summary, we have developed an efficient ligand-free
copper(I) iodide catalyzed Negishi coupling of diarylzinc re-
agents with aryl iodides that furnishes cross-coupled biaryl
products in good to excellent yields. The reaction tolerates a
variety of functional groups, such as chloride, bromide,
ester, trifluoromethyl, and nitrile on the aryl iodide and
alkoxy, alkyl, and chloro on the arylzinc reagent.
4-Methylbiphenyl (3)
Purification by column chromatography (silica gel) gave 3 as a white
solid; yield: 137.9 mg (82%).
1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3 H), 7.33 (d, J = 7.8 Hz, 2 H),
7.40–7.43 (m, 1 H), 7.50 (t, J = 8.1 Hz, 2 H), 7.58 (d, J = 8.1 Hz, 2 H),
7.65–7.68 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.2, 127.1, 128.8, 129.6, 137.1, 138.5,
141.3.
GC-MS: m/z = 168.1.
All the reactions and handling of chemicals were done inside a N2-
filled glovebox unless stated otherwise. All the glassware were prop-
erly dried in an oven before use. Bulk solvents and reagents were ob-
tained from commercial sources and used directly without further
4-Methoxybiphenyl (4)
Purification by column chromatography (silica gel) gave 4 as a white
solid; yield: 132.6 mg (72%).
1H NMR (300 MHz, CDCl3): δ = 3.91 (s, 3 H), 7.08 (d, J = 9.0 Hz, 2 H),
7.41 (t, J = 7.2 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 2 H), 7.61–7.68 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 55.3, 114.3, 126.7, 126.8, 128.2, 128.8,
1
purification. H, 13C, and 19F NMR spectra were recorded on a Bruker
instrument (300, 75, and 282 MHz, respectively) and internally refer-
enced to the residual solvent signals (1H NMR: CDCl3, δ = 7.26; 13C
NMR: CDCl3, δ = 77.16; for 19F NMR: C6F6, δ = –164.9).
133.8, 140.8, 159.2.
GC-MS: m/z = 184.1.
Biphenyls; General Procedure
Diarylzinc reagents were generated in situ as described below. In all
reactions, 1 equiv of diarylzinc reagent was used except for reactions
with diphenylzinc reagent, where only 0.5 equiv was used.
4-(Trifluoromethyl)biphenyl (5)
Purification by column chromatography (silica gel) gave 5 as a white
solid; yield: 175.5 mg (79%).
1H NMR (300 MHz, CDCl3): δ = 7.39–7.51 (m, 3 H), 7.59–7.62 (m, 2 H),
7.70 (s, 4 H).
13C NMR (75 MHz, CDCl3): δ = 122.7, 125.9 (q, JCF = 3.5 Hz), 127.4,
127.6, 128.3, 129.1, 129.7, 139.9, 144.9.
19F NMR (282 Hz, CDCl3): δ = –60.8.
In a glovebox, ZnCl2 (136.3 mg, 1.0 mmol) and aryllithium (2.0 mmol)
were weighed into a 4-dram and a 1-dram vial, respectively. Then a
solution of aryllithium in THF (2 mL) was added dropwise to the sus-
pension of ZnCl2 in THF (2 mL) at r.t. The mixture was stirred for 1 h,
THF was removed, and the in situ generated diarylzinc reagent was
dissolved in DMF (5 mL). CuI (9.5 mg, 0.050 mmol), aryl halide (1.0
mmol), and LiCl (42.3 mg, 1.0 mmol) were weighed into a 15-mL
pressure vessel and the diarylzinc reagent was added. The pressure
vessel was then tightly capped, taken out of the glovebox, and placed
in an oil bath preheated to 100 °C with vigorous stirring. After 12 h,
the mixture was cooled to r.t., diluted with EtOAc (15 mL) and washed
with H2O (3 × 5 mL); the aqueous fraction was back-extracted with
EtOAc (3 × 5 mL). All of the EtOAc extracts were combined and dried
(Na2SO4), and the solvent was removed on a rotary evaporator. The
product was purified by column chromatography (silica gel, 0–10%
EtOAc–hexanes).
GC-MS: m/z = 222.1.
Biphenyl-4-carbonitrile (6)
Purification by column chromatography (silica gel) gave 6 as a white
solid; yield: 148.7 mg (83%).
1H NMR (300 MHz, CDCl3): δ = 7.43–7.51 (m, 3 H), 7.58–7.60 (m, 2 H),
7.67–7.74 (m, 4 H).
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13C NMR (75 MHz, CDCl3): δ = 111.0, 119.1, 127.3, 127.8, 128.8, 129.2,
1H NMR (300 MHz, CDCl3): δ = 2.29 (s, 3 H), 3.86 (s, 3 H) 6.94–6.97 (m,
132.7, 139.3, 145.8.
2 H), 7.22–7.28 (m, 6 H).
GC-MS: m/z = 179.1.
13C NMR (75 MHz, CDCl3): δ = 20.6, 55.4, 113.6, 125.8, 127.1, 130.0,
130.3, 134.5, 135.6, 141.7, 158.6.
Methyl Biphenyl-4-carboxylate (7)
GC-MS: m/z = 198.1.
Purification by column chromatography (silica gel) gave 7 as a white
solid; yield: 165.5 mg (78%).
2-Methoxy-4′-(trifluoromethyl)biphenyl (13)
1H NMR (300 MHz, CDCl3): δ = 3.95 (s, 3 H), 7.44–7.52 (m, 3 H), 7.64–
7.69 (m, 4 H), 8.11 (dd, J = 6.6, 1.8 Hz, 2 H).
Purification by column chromatography (silica gel) gave 13 as a color-
less oil; yield: 206.8 mg (82%).
13C NMR (75 MHz, CDCl3): δ = 52.1, 127.0, 127.3, 128.1, 128.9, 130.1,
140.0, 145.6, 167.0.
1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 7.00–7.09 (m, 2 H), 7.33
(dt, J = 8.4, 1.8 Hz, 1 H), 7.38–7.41 (m, 1 H), 7.63–7.69 (m, 4 H).
GC-MS: m/z = 212.1.
13C NMR (75 MHz, CDCl3): δ = 55.7, 111.5, 121.2, 125.0 (d, JCF = 3.6 Hz),
129.3, 129.4, 129.6, 129.9, 130.9, 142.4, 156.6.
19F NMR (282 Hz, CDCl3): δ = –60.8.
Methyl 2′-Methylbiphenyl-4-carboxylate (8)
Purification by column chromatography (silica gel) gave 8 as a white
solid; yield: 167.5 mg (74%).
GC-MS: m/z = 252.1.
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H), 3.96 (s, 3 H), 7.24–7.29
(m, 4 H), 7.41 (d, J = 8.1 Hz, 2 H), 8.11 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 20.4, 52.2, 126.0, 127.9, 128.7, 129.3,
Methyl 2′-Methoxybiphenyl-4-carboxylate (14)
Purification by column chromatography (silica gel) gave 14 as a white
solid; yield: 138.1 mg (57%).
129.5, 129.6, 130.6, 135.2, 140.9, 146.8, 167.1.
1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H), 3.94 (s, 3 H), 6.99–7.08
(m, 2 H), 7.33–7.40 (m, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 8.09 (d, J = 8.7 Hz,
2 H).
GC-MS: m/z = 226.2.
13C NMR (75 MHz, CDCl3): δ = 52.2, 52.6, 111.4, 121.0, 128.6, 129.4,
2′-Methylbiphenyl-4-carbonitrile (9)
129.5, 129.6,130.8, 143.5, 156.5, 167.2.
Purification by column chromatography (silica gel) gave 9 as a white
solid; yield: 162.3 mg (84%).
GC-MS: m/z = 242.1.
1H NMR (300 MHz, CDCl3): δ = 2.26 (s, 3 H), 7.19 (d, J = 6.6 Hz, 1 H),
7.27–7.32 (m, 3 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H).
2′-Methoxybiphenyl-4-carbonitrile (15)
13C NMR (75 MHz, CDCl3): δ = 20.4, 110.8, 119.1, 126.2, 128.4, 129.5,
Purification by column chromatography (silica gel) gave 15 as a white
130.1, 130.8, 132.1, 135.1, 140.1, 146.9.
solid; yield: 140.2 mg (67%).
GC-MS: m/z = 193.2.
1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 7.00–7.09 (m, 2 H), 7.31
(d, J = 7.5 Hz, 1 H), 7.39 (t, J = 8.4 Hz, 1 H), 7.66 (q, J = 8.4 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 55.5, 110.4, 111.4, 119.2, 121.1, 128.7,
4-Chloro-2′-methylbiphenyl (10)
129.9, 130.2, 130.6, 131.8, 143.4, 156.4.
Reaction of di-2-tolylzinc reagent and 1-chloro-4-iodobenzene fol-
lowed by purification by column chromatography (silica gel) gave 10
as a colorless oil; yield: 145.9 mg (72%). Reaction of di-4-chloro-
phenylzinc reagent and 2-iodotoluene followed by purification by
column chromatography (silica gel) gave 10; yield: 156.1 mg (77%).
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H), 7.24–7.33 (m, 6 H), 7.44
(d, J = 8.4 Hz, 2 H).
GC-MS: m/z = 209.1.
4-Bromo-2′-methoxybiphenyl (16)
Purification by column chromatography (silica gel) gave 16 as a color-
less oil; yield: 134.2 mg (51%).
1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H), 6.97–7.06 (m, 2 H), 7.27–
7.37 (m, 2 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 55.5, 111.3, 120.9, 121.1, 129.0, 129.5,
13C NMR (75 MHz, CDCl3): δ = 20.5, 126.0, 127.7, 128.4, 129.8, 130.5,
130.6, 132.9, 135.4, 140.5, 140.8.
GC-MS: m/z = 202.1.
130.6, 131.1, 131.2, 137.4, 156.3.
GC-MS: m/z = 262.0.
4-Bromo-2′-methylbiphenyl (11)
Purification by column chromatography (silica gel) gave 11 as a color-
less oil; yield: 187.8 mg (76%).
1H NMR (300 MHz, CDCl3): δ = 2.29 (s, 3 H), 7.21–7.30 (m, 6 H), 7.57
(d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 20.5, 121.1, 126.0, 127.7, 129.7, 130.6,
2-Methoxy-3′,5′-bis(trifluoromethyl)biphenyl (17)
Purification by column chromatography (silica gel) gave 17 as a color-
less oil; yield: 188.9 mg (59%).
1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H), 7.04–7.12 (m, 2 H), 7.35
(dd, J = 7.5, 1.5 Hz, 1 H), 7.43 (dt, J = 8.4, 1.8 Hz, 1 H), 7.85 (s, 1 H), 8.02
(s, 2 H).
131.0, 131.3, 135.3, 140.7, 140.9.
GC-MS: m/z = 245.9.
13C NMR (75 MHz, CDCl3): δ = 55.7, 111.5, 120.7 (t, JCF = 4.1 Hz), 121.3,
123.7 (d, JCF = 270.9 Hz), 127.7, 129.1, 130.6 (d, JCF = 28.6 Hz), 131.4 (d,
JCF = 33.0 Hz), 132.0, 140.7, 156.5.
4-Methoxy-2′-methylbiphenyl (12)
19F NMR (282 Hz, CDCl3): δ = –61.2.
Purification by column chromatography (silica gel) gave 12 as a color-
less oil; yield: 109.0 mg (55%).
GC-MS: m/z = 320.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 504–511

511
S. Thapa et al.
Feature
Synthesis
Methyl 3′-Methoxybiphenyl-4-carboxylate (18)
(2) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 6040. (b) Huo, S. Org. Lett. 2003,
5, 423.
(3) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed.
2005, 44, 4442.
(4) Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
(5) Getmanenko, Y. A.; Twieg, R. J. J. Org. Chem. 2008, 73, 830.
(6) For reviews, see: (a) Thapa, S.; Shrestha, B.; Gurung, S. K.; Giri,
R. Org. Biomol. Chem. 2015, 13, 4816. (b) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
Purification by column chromatography (silica gel) gave 18 as a white
solid; yield: 176.9 mg (73%).
1H NMR (300 MHz, CDCl3): δ = 3.87 (s, 3 H), 3.94 (s, 3 H), 6.94 (dd, J =
8.1, 1.8 Hz, 1 H), 7.15 (t, J = 2.4 Hz, 1 H), 7.21 (d, J = 7.5 Hz, 1 H), 7.38
(t, J = 7.8 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 52.2, 55.4, 113.1, 113.6, 119.8, 127.2,
129.1, 130.0, 130.1, 141.5, 145.5, 160.1, 167.0.
GC-MS: m/z = 242.1.
(7) For selected examples, see: (a) Yang, C.-T.; Zhang, Z.-Q.; Liang, J.;
Liu, J.-H.; Lu, X.-Y.; Chen, H.-H.; Liu, L. J. Am. Chem. Soc. 2012,
134, 11124. (b) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.;
Kambe, N. Angew. Chem. Int. Ed. 2007, 46, 2086. (c) Cahiez, G.;
Gager, O.; Buendia, J. Angew. Chem. Int. Ed. 2010, 49, 1278.
(d) Hintermann, L.; Xiao, L.; Labonne, A. Angew. Chem. Int. Ed.
2008, 47, 8246.
(8) For selected examples, see: (a) Takeda, T.; Matsunaga, K. I.;
Kabasawa, Y.; Fujiwara, T. Chem. Lett. 1995, 771. (b) Falck, J. R.;
Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117, 5973. (c) Allred, G.
D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748. (d) Kang,
S.-K.; Kim, J.-S.; Choi, S.-C. J. Org. Chem. 1997, 62, 4208.
(9) For selected examples, see: (a) Gurung, S. K.; Thapa, S.; Kafle, A.;
Dickie, D. A.; Giri, R. Org. Lett. 2014, 16, 1264. (b) Yang, C.-T.;
Zhang, Z.-Q.; Liu, Y.-C.; Liu, L. Angew. Chem. Int. Ed. 2011, 50,
3904. (c) Thathagar, M. B.; Beckers, J.; Rothenberg, G. J. Am.
Chem. Soc. 2002, 124, 11858. (d) Zhou, Y.; You, W.; Smith, K. B.;
Brown, M. K. Angew. Chem. Int. Ed. 2014, 53, 3475. (e) You, W.;
Brown, M. K. J. Am. Chem. Soc. 2014, 136, 14730.
(10) For selected examples, see: (a) Gurung, S. K.; Thapa, S.;
Shrestha, B.; Giri, R. Synthesis 2014, 46, 1933. (b) Gurung, S. K.;
Thapa, S.; Vangala, A. S.; Giri, R. Org. Lett. 2013, 15, 5378.
(c) Tsubouchi, A.; Muramatsu, D.; Takeda, T. Angew. Chem. Int.
Ed. 2013, 52, 12719. (d) Cornelissen, L.; Lefrancq, M.; Riant, O.
Org. Lett. 2014, 16, 3024. (e) Cornelissen, L.; Cirriez, V.;
Vercruysse, S.; Riant, O. Chem. Commun. 2014, 50, 8018.
(11) (a) Thapa, S.; Basnet, P.; Gurung, S. K.; Giri, R. Chem. Commun.
2015, 51, 4009. (b) Takahashi, T.; Li, Y.; Stepnicka, P.; Kitamura,
M.; Liu, Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
576.
3′-Methoxybiphenyl-4-carbonitrile (19)
Purification by column chromatography (silica gel) gave 19 as a color-
less oil; yield: 148.5 mg (71%).
1H NMR (300 MHz, CDCl3): δ = 3.87 (s, 3 H), 6.97 (dd, J = 7.8, 2.1 Hz, 1
H), 7.10 (t, J = 2.1 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1
H), 7.66–7.73 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 55.5, 111.1, 113.2, 114.0, 119.0, 119.8,
127.9, 130.3, 132.7, 140.7, 145.6, 160.2.
GC-MS: m/z = 209.1.
4-Methyl-4′-(trifluoromethyl)biphenyl (20)
Purification by column chromatography (silica gel) gave 20 as a white
solid; yield: 177.2 mg (75%).
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H), 7.29 (d, J = 8.4, 2 H), 7.49–
7.52 (m, 2 H), 7.69 (s, 4 H).
13C NMR (75 MHz, CDCl3): δ = 21.3, 122.7, 125.8 (d, JCF = 3.8 Hz), 126.1
(d, JCF = 3.8 Hz), 127.2, 127.3, 127.8, 129.2 (d, JCF = 32.3 Hz), 129.9,
137.0, 138.3, 144.8.
19F NMR (282 Hz, CDCl3): δ = –60.8.
GC-MS: m/z = 236.1.
Acknowledgment
We thank the University of New Mexico (UNM) for financial support,
and upgrades to the NMR Facility (NSF grants CHE08-40523 and
CHE09-46690).
(12) Thapa, S.; Gurung, S. K.; Dickie, D. A.; Giri, R. Angew. Chem. Int.
Ed. 2014, 53, 11620.
Supporting Information
(13) Hofstee, H. K.; Boersma, J.; Van Der Kerk, G. J. M. J. Organomet.
Chem. 1978, 144, 255.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560397.
(14) Thaler, T.; Knochel, P. Angew. Chem. Int. Ed. 2009, 48, 645.
(15) Hjelmgaard, T.; Tanner, D. Org. Biomol. Chem. 2006, 4, 1796.
(16) Karstens, W. F. J.; Moolenaar, M. J.; Rutjes, F. P. J. T.; Grabowska,
U.; Speckamp, W. N.; Hiemstra, H. Tetrahedron Lett. 1999, 40,
8629.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 504–511