Large-Scale Cobalt-Catalyzed Cross-Couplings of Functionalized Bench-Stable Arylzinc Pivalates with (Hetero)Aryl and Alkenyl Halides

Article abstract of DOI:10.1055/s-0036-1588986

A robust and scalable CoCl ₂ -catalyzed cross-coupling between functionalized arylzinc pivalates and various electron-poor (hetero)aryl and alkenyl halides is reported.

Full text of DOI:10.1055/s-0036-1588986

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
special topic
A
de
M. S. Hofmayer et al.
Special Topic
Synthesis
Large-Scale Cobalt-Catalyzed Cross-Couplings of Functionalized
Bench-Stable Arylzinc Pivalates with (Hetero)Aryl and Alkenyl
Halides
CoCl2
(1 mol% or 5 mol%)
X
X
Maximilian S. Hofmayer
Jeffrey M. Hammann
Ferdinand H. Lutter
Paul Knochel*
ZnOPiv
X
X
+
R
X
THF, 40 °C, 16 h
R
X
Hal
Hal = Cl, Br, I
X = C, N
(1.5 equiv)
60–94% yield
11 examples
gram scale
Department of Chemistry, Ludwig-Maximilians-Universität
München, Butenandtstraße 5-13, Haus F, 81377 München,
Germany
Paul.Knochel@cup.uni-muenchen.de
Published as part of the Special Topic Cobalt in Organic Synthesis
Received: 13.02.2017
Accepted after revision: 09.03.2017
Published online: 18.04.2017
a palladium catalyst.9 However, the high price10 and/or
toxicity11 of Pd and other commonly used transition metals
are a major drawback.
DOI: 10.1055/s-0036-1588986; Art ID: ss-2017-c0090-st
In contrast, cobalt salts have many beneficial character-
istics. Cobalt(II) chloride is fairly inexpensive when com-
pared to palladium(II) chloride (price: CoCl2 ca. 45 €/100 g;
PdCl2 ca. 2500 €/100 g)12 and relatively non-toxic when
compared to nickel(II) chloride13a and palladium(II) chlo-
Abstract A robust and scalable CoCl2-catalyzed cross-coupling be-
tween functionalized arylzinc pivalates and various electron-poor (hete-
ro)aryl and alkenyl halides is reported.
Key words cobalt, zinc pivalate, catalysis, cross-coupling, N-heterocy-
cles
ride13b [LD50(CoCl2, rat oral)
= 418 mg/kg; LD50(NiCl2,
rat oral) = 186 mg/kg; LD50(PdCl2, rat oral) = 200 mg/kg]. Re-
cently, there has been much progress in Co-catalyzed cou-
pling reactions.14 It was demonstrated, that Co salts are
convenient catalysts for C–C bond forming reactions and
highly attractive for extensive academic and industrial use.
Thus, we recently developed a CoCl2-catalyzed cross-
coupling of solid organozinc pivalates with unsaturated ha-
lides.15 Herein, we report further scope extensions for per-
forming these cross-coupling reactions on a gram scale of
up to 20 mmol. To our delight, we found that the amount of
cobalt catalyst can even be reduced from 5 mol% to only 1
mol% CoCl2 when 2-halogenated N-heterocycles were used
as electrophiles.
Thus, a range of substituted N-heterocyclic chlorides
and bromides were readily employed in this reaction
(Table 1, entries 1–6). 4-Methoxyphenylzinc pivalate (2a)
reacted smoothly with 2-bromoquinoline (1a) leading to
the arylated quinoline 3a in 78% yield on a 10-mmol scale
(entry 1). Similarly, the cross-coupling of methyl 2-chloro-
nicotinate (1b) and the organozinc reagent 2b bearing and
NMe2 group led to the desired pyridine 3b in 83% yield on a
20-mmol scale (entry 2). The coupling of the electron-rich
zinc reagent 2c with 2-chloro-5-(trifluoromethyl)pyridine
(1c) afforded the pyridine 3c in 82% yield (10-mmol scale;
entry 3). Furthermore, pyrimidines and triazines were also
good substrates, furnishing the arylated coupling products
3d and 3e in 65–76% yield on a 10-mmol scale (entries 4
Transition-metal-catalyzed cross-coupling reactions are
valuable tools for the construction of C–C bonds, especially
for the synthesis of pharmaceuticals and agrochemicals.1
The air and water stability of boronic esters,2 boronic acids,3
as well as trifluoroborates4 makes their use in Suzuki–
Miyaura cross-coupling reactions highly attractive. Thus,
boron organometallics have found broad applications in
medicinal chemistry.5 However, in 2011, O’Donovan and co-
workers described boron-organometallics as a novel class of
bacterial mutagens.6 They showed that boron reagents are
genotoxic by direct covalent binding to DNA. With the
growing awareness within the pharmaceutical industry of
boron-organometallics being potentially toxic, new alterna-
tives should be developed for cross-coupling reactions in a
medicinal chemistry setting.
In comparison, organozinc reagents (RZnX, X = Hal) al-
low fast transmetalation from Zn to Pd or other transition
metals and additionally display excellent functional group
tolerance and better reactivity in coupling reactions.7 How-
ever, their high sensitivity towards air and moisture limits
synthetic applications. In 2011, we demonstrated that or-
ganozinc pivalates (RZnOPiv)8 show a greatly improved air
and moisture stability. In addition, these organozinc re-
agents are solids after solvent evaporation, allowing them
to be weighed out on the benchtop. Organozinc pivalates
readily undergo cross-coupling reactions in the presence of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
M. S. Hofmayer et al.
Special Topic
Synthesis
and 5). Additionally, 3-bromoquinoline (1f) reacted with 2f,
providing the expected product 3f in 63% yield (15-mmol
scale; entry 6). Moreover, various electron-poor aryl halides
also proved to be good substrates for this cross-coupling
(Table 1, entries 7–9). Thus, 4-bromo-2-fluorobenzonitrile
(1g) reacted regio- and chemoselectively with the electron-
rich arylzinc pivalate 2g furnishing the substitution product
3g in 93% yield on a 10-mmol scale (entry 7). Similarly, the
reaction of 4-iodobenzonitrile (1h) with 2h or 2f provided
the coupling products 3h,i in 71–90% yield on a 10–15
mmol scale (entries 8 and 9). Additionally, this cobalt-cata-
lyzed procedure was also scalable for the performance of
aryl–alkenyl cross-couplings. Thus, ethyl (Z)-3-bromoacry-
late (1i; E/Z 1:99) undergoes a stereoselective reaction with
2i under our standard conditions providing 3j in 61% yield
with almost complete retention of the double bond geome-
try (E/Z 4:96, entry 10). Similarly, the (E)-styryl bromide 1j
(E/Z 99:1) cross-couples with the arylzinc pivalate 2c lead-
ing to the (E)-stilbene 3k in 83% yield (E/Z 99:1, entry 11).
Table 1 Cobalt-Catalyzed Cross-Couplings of (Hetero)Aryl and Alkenyl Halides with Arylzinc Pivalates
ZnOPiv
R
X
X
(1.5 equiv)
X
X
X
CoCl2
(1 mol% or 5 mol%)
THF, 40 °C, 16 h
R
X
Hal
Hal = Cl, Br, I
Entry
1
Electrophile
Metal species
Product
Catalyst loading (mol%) Scale (mmol)
Yield (%)
ZnOPiv
ZnOPiv
5
1
1
1
1
10
84
77
78
N
N
Br
MeO
2a
OMe
1a
3a
CO2Me
CO2Me
1
1
1
20
85
83
2
3
N
N
Cl
Me2N
NMe2
1b
2b
3b
F3C
Me
ZnOPiv
F3C
Me
N
1
1
1
10
81
82
MeO
N
Cl
OMe
Me
1c
Me
2c
3c
N
TBSO
ZnOPiv
ZnOPiv
N
OTBS
1
1
1
10
74
76
N
4
5
N
Br
2d
1d
3d
Ph
N
Ph
BocO
N
N
1
1
1
10
70
65
N
N
OBoc
Ph
Ph
N
Cl
2e
1e
3e
N
N
ZnOPiv
O
5
5
1
15
65
63
O
O
6
O
2f
Br
1f
3f
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
M. S. Hofmayer et al.
Special Topic
Synthesis
Table 1 (continued)
Entry
7
Electrophile
Metal species
Product
Catalyst loading (mol%) Scale (mmol)
Yield (%)
NC
MeO
ZnOPiv
NC
OMe
OMe
F
5
5
1
10
94
93
MeO
F
1g
Br
OMe
OMe
2g
3g
NC
NC
TBSO
ZnOPiv
OTBS
5
5
1
10
91
90
8
I
I
2h
1h
3h
NC
NC
ZnOPiv
ZnOPiv
ZnOPiv
O
5
5
1
15
72
71
O
O
9
O
2f
1h
3i
MeS
SMe
Br
5
5
1
15
60
61
10
EtO2C
1i; E/Z 1:99
EtO2C
3j; E/Z 4:96
2i
MeO
Me
MeO
Me
5
5
1
10
89
83
11
MeO
Br
OMe
Me
1b; E/Z 99:1
Me
2c
3k; E/Z 99:1
In summary, we have shown practical scalable cobalt-
catalyzed cross-coupling reactions between N-heterocyclic
halides as well as halogenated aromatics with various aryl-
zinc pivalates using only 1–5% cobalt(II) chloride.
5% phenylmethylpolysiloxane; length: 15 m, diameter: 0.25 mm; film
thickness: 0.25 μm). CoCl2 (97% purity) was purchased from Sigma-
Aldrich.
Preparation of Zn(OPiv)2
Pivalic acid (20.4 g, 22.6 mL, 200 mmol) was placed in a dry and ar-
gon-flushed 500-mL three-necked round-bottom flask, equipped
with a magnetic stirring bar, a septum, and a pressure equalizer, and
dissolved in dry THF (120 mL). The mixture was cooled to 0 °C, and a
solution of Et2Zn (13.0 g, 10.8 mL, 105 mmol) in dry THF (120 mL)
was added over a period of 30 min under vigorous stirring. Then, the
ice-bath was removed and stirring was continued at 25 °C for a fur-
ther 1 h at which point bubbling had ceased (a thick slurry was
formed). The solvent was removed in vacuo and the solid residue was
dried for at least a further 4 h. Zn(OPiv)2 was obtained in quantitative
yield, as a puffy amorphous colorless solid.
Unless otherwise indicated, all reactions were carried out with mag-
netic stirring and in flame-dried glassware under argon. Syringes
used to transfer reagents and solvents were purged with argon prior
to use. Reactions were monitored by gas chromatography (GC and
GC-MS) or TLC. TLC were performed using aluminum plates covered
with silica gel (Merck 60, F-254) and visualized by UV detection. Puri-
fication via column chromatography was performed using Merck sili-
ca gel 60 (40–63 mm 230–400 mesh ASTM from Merck). THF was
continuously refluxed and freshly distilled from Na benzophenone
ketyl under N2. Yields refer to isolated yields of compounds estimated
to be >95% pure as determined by 1H NMR (25 °C) and capillary GC
analysis. Melting points were measured using a Büchi B 540 appara-
tus and are uncorrected. NMR spectra were recorded in CDCl3. Mass
spectra and HRMS were recorded on Finnigan MAT 90 or Finnigan
MAT 95 instruments using electron ionization (EI) except where oth-
erwise noted. Infrared spectra (IR) were recorded on a Perkin Elmer
spectrum BX-59343 instrument. For detection, a Smiths Detection
DuraSamplIR II Diamond ATR sensor was used. GCs were recorded on
machines of the type Hewlett-Packard 6890 (Hewlett Packard,
Organozinc Pivalates; General Procedure 1 (GP1)
A dry and argon flushed Schlenk tube equipped with a magnetic stir-
ring bar and a septum was charged with Mg turnings (1.1 equiv), dry
LiCl (1.1 equiv), and dry THF (1 M solution with respect to the aryl
halide). The aryl halide (1.0 equiv) was added. If necessary the
Schlenk tube was placed in a water bath and cooled during the initial
heat evolution from the insertion reaction. The progress of the inser-
tion reaction was monitored by GC-analysis of reaction aliquots
quenched with I2. Upon completion of the insertion, solid Zn(OPiv)2
(1.0 equiv) was added in one portion and the mixture was stirred at
r.t. for 15 min. Solvent removal afforded the solid organozinc pivalate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
M. S. Hofmayer et al.
Special Topic
Synthesis
Cobalt-Catalyzed Cross-Couplings; General Procedure 2 (GP2) for
10-mmol Scale with 1 mol% CoCl2
2-(4-Methoxy-3,5-dimethylphenyl)-5-(trifluoromethyl)pyridine
(3c)
A dry and argon-flushed 50-mL Schlenk flask, equipped with a stir-
ring bar and a septum, was charged with dry CoCl2 (13 mg, 0.01
mmol, 1 mol%) and dry THF (10 mL). The aryl halide (10.0 mmol,
1.0 equiv) was added at r.t. Then, a solution of the (hetero)aryl zinc
pivalate (15 mmol, 1.5 equiv) was added dropwise over 5 min via sy-
ringe. The reaction was stirred at 40 °C and monitored by GC analysis
(C11H24 was used as an internal standard). Upon consumption of the
starting material, sat. aq NH4Cl solution (50 mL) and EtOAc (50 mL)
were added, the phases were separated and the aqueous phase was
extracted with EtOAc (3 × 50 mL). The combined organic layers were
washed with 2 M aq NaOH solution (50 mL) and dried (Na2SO4). The
solvents were evaporated and the residue was subjected to column
chromatography purification (silica gel) yielding the product.
Following GP2, 2-chloro-5-(trifluoromethyl)pyridine [1c, 1.81 g,
10 mmol, 1 equiv, in THF (10 mL)] was reacted with 2c (15 mmol,
1.5 equiv), prepared according to GP1, using CoCl2 (13 mg, 0.1 mmol,
1 mol%) as catalyst. The solution was stirred at 40 °C for 16 h and was
worked up as usual. The crude product was purified by column chro-
matography (silica gel, isohexane/EtOAc, 4:1) to afford 3c as a color-
less oil (2.30 g, 8.2 mmol, 82%).
FT-IR (ATR): 2929, 1606, 1567, 1476, 1326, 1199, 1164, 1125, 1075,
1012, 839, 718 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.90 (dt, J = 2.5, 0.9 Hz, 1 H), 7.93 (ddd,
J = 8.3, 2.4, 0.7 Hz, 1 H), 7.82–7.75 (m, 1 H), 7.69 (2 H), 3.77 (s, 3 H),
2.37 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 160.5 (d, J = 1.5 Hz), 158.9, 146.4 (q, J =
4.1 Hz), 133.8 (q, J = 3.5 Hz), 133.4, 131.5, 127.9, 124.3 (q, J = 33.0 Hz),
123.9 (q, J = 272.8 Hz), 119.6, 59.7, 16.3.
2-(4-Methoxyphenyl)quinoline (3a)
Following GP2, 2-bromoquinoline [1a, 2.08 g, 10 mmol, 1 equiv, in
THF (10 mL)] was reacted with 2a (15 mmol, 1.5 equiv), prepared ac-
cording to GP1, using CoCl2 (13 mg, 0.1 mmol, 1 mol%) as catalyst. The
solution was stirred at 40 °C for 16 h and was worked up as usual. The
crude product was purified by column chromatography (silica gel,
isohexane/EtOAc, 7:3) to afford 3a as a colorless crystals (1.83 g, 7.8
mmol, 78%); mp 123.7–124.5 °C.
MS (EI, 70 eV): m/z (%) = 282 (16), 281 (100), 280 (3), 267 (16), 266
(79), 238 (34), 222 (15), 61 (12).
HRMS (EI, 70 eV): m/z [M] calcd for
C15H14ClF3NO: 281.1027;
found: 281.1020.
2-[3-(tert-Butyldimethylsiloxy)phenyl]pyrimidine (3d)
FT-IR (ATR): 2960, 2920, 1594, 1495, 1467, 1430, 1289, 1247, 1174,
Following GP2, 2-bromopyrimidine [1d, 1.59 g, 10 mmol, 1 equiv, in
THF (10 mL)] was reacted with 2d (15 mmol, 1.5 equiv), prepared ac-
cording to GP1, using CoCl2 (13 mg, 0.1 mmol, 1 mol%) as catalyst. The
solution was stirred at 40 °C for 16 h and was worked up as usual. The
crude product was purified by column chromatography (silica gel,
isohexane/EtOAc, 9:1) to afford 3d as a colorless oil (2.17 g, 7.6 mmol,
76%).
1156, 1028, 975, 948, 811, 789, 748, 726 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.20–8.09 (m, 4 H), 7.84–7.76 (m, 2 H),
7.71 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.49 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H),
7.08–6.99 (m, 2 H), 3.87 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 160.8, 156.9, 148.3, 136.6, 132.3, 129.6,
129.5, 128.9, 127.5, 126.9, 125.9, 118.5, 114.2, 55.4.
FT-IR (ATR): 2931, 2858, 1713, 1553, 1450, 1422, 1409, 1281, 1250,
MS (EI, 70 eV): m/z (%) = 237 (2), 236 (16), 235 (100), 234 (3), 220
(21), 192 (23), 191 (24), 190 (6).
1225, 1177, 1150, 939, 834, 816, 796, 779, 690 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.80 (d, J = 4.8 Hz, 2 H), 8.04 (ddd, J =
7.8, 1.6, 1.0 Hz, 1 H), 7.94 (dd, J = 2.5, 1.6 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1
H), 7.18 (t, J = 4.8 Hz, 1 H), 6.97 (ddd, J = 8.1, 2.6, 1.0 Hz, 1 H), 1.01 (s, 9
H), 0.24 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 164.6, 157.2, 156.1, 139.1, 129.5,
122.6, 121.2, 119.8, 119.1, 25.7, 18.2, –4.4.
HRMS (EI, 70 eV): m/z [M] calcd for
C16H13ON: 235.0997;
found: 235.0998.
Methyl 2-[4-(Dimethylamino)phenyl]nicotinate (3b)
Following GP2, methyl 2-chloronicotinate [1b, 3.44 g, 20 mmol, 1
equiv, in THF (20 mL)] was reacted with 2b (30 mmol, 1.5 equiv), pre-
pared according to GP1, using CoCl2 (26 mg, 0.2 mmol, 1 mol%) as cat-
alyst. The solution was stirred at 40 °C for 16 h and was worked up as
usual. The crude product was purified by column chromatography
(silica gel, isohexane/EtOAc, 9:1 to 2:1) to afford 3b as a yellow oil
(4.24 g, 16.5 mmol, 83%).
MS (EI, 70 eV): m/z (%) = 287 (3), 286 (12), 230 (6), 229 (20), 288
(100), 213 (5), 167 (5).
HR-MS (EI, 70 eV): m/z [M] calcd for
C16H22N2OSi: 286.1501;
found: 286.1496.
FT-IR (ATR): 1717, 1607, 1579, 1565, 1525, 1422, 1356, 1313, 1282,
tert-Butyl [3-(4,6-Diphenyl-1,3,5-triazin-2-yl)phenyl] Carbonate
(3e)
1216, 1193, 1169, 1122, 1094, 1053, 945, 824, 777, 751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.71 (dd, J = 4.8, 1.8 Hz, 1 H), 7.98 (dd,
J = 7.7, 1.8 Hz, 1 H), 7.54–7.45 (m, 2 H), 7.20 (dd, J = 7.8, 4.8 Hz, 1 H),
6.81–6.70 (m, 2 H), 3.76 (s, 3 H), 3.01 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 158.4, 151.1, 150.9, 137.7,
129.7, 127.4, 126.1, 120.1, 111.8, 52.4, 40.4.
Following GP2, 2-chloro-4,6-diphenyl-1,3,5-triazine [1e, 2.68 g,
10 mmol, 1 equiv, in THF (10 mL)] was reacted with 2e (15 mmol, 1.5
equiv), prepared according to GP1, using CoCl2 (13 mg, 0.1 mmol, 1
mol%) as catalyst. The solution was stirred at 40 °C for 16 h and was
worked up as usual. The crude product was purified by column chro-
matography (silica gel, isohexane/EtOAc, 4:1) to afford 3e as a color-
less solid (2.77 g, 6.5 mmol, 65%); mp 182.3–183.0 °C.
MS (EI, 70 eV): m/z (%) = 257 (17), 256 (100), 255 (53), 241 (43), 225
(14), 98 (12), 44 (15).
FT-IR (ATR): 2982, 1757, 1519, 1447, 1363, 1253, 1218, 1147, 909,
HR-MS (EI, 70 eV): m/z [M] calcd for
C15H16N2O2: 256.1212;
770, 732, 689 cm–1
.
found: 256.1208.
1H NMR (400 MHz, CDCl3): δ = 8.81–8.73 (m, 4 H), 8.67 (dt, J = 7.8, 1.3
Hz, 1 H), 8.56 (dd, J = 2.5, 1.6 Hz, 1 H), 7.67–7.54 (m, 7 H), 7.46 (ddd,
J = 8.1, 2.5, 1.1 Hz, 1 H), 1.62 (s, 9 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
M. S. Hofmayer et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): δ = 171.7, 170.8, 151.8, 151.5, 138.0,
136.1, 132.6, 129.6, 129.0, 128.7, 126.3, 125.5, 121.7, 83.9, 27.8.
crude product was purified by column chromatography (silica gel,
isohexane/EtOAc, 100:2) to afford 3h as a colorless solid (2.79 g, 9.0
mmol, 90%); mp 44.4–46.0 °C.
MS (EI, 70 eV): m/z (%) = 426 (1), 326 (21), 325 (100), 104 (18), 103
(21), 57 (33).
FT-IR (ATR): 2958, 2929, 2910, 2856, 2225, 1597, 1577, 1478, 1468,
1310, 1302, 1260, 1254, 1217, 940, 932, 827, 784, 701 cm–1
.
HRMS (EI, 70 eV): m/z [M + H]+ calcd for C26H24N3O3: 426.1812;
found: 426.1811.
1H NMR (400 MHz, CDCl3): δ = 7.73–7.70 (m, 2 H), 7.67–7.63 (m, 2 H),
7.33 (t, J = 7.9 Hz, 1 H), 7.17 (ddd, J = 7.7, 1.8, 1.0 Hz, 1 H), 7.05 (t, J =
2.1 Hz, 1 H), 6.90 (ddd, J = 8.1, 2.4, 1.0 Hz, 1 H), 1.01 (s, 9 H), 0.24 (s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 145.6, 140.8, 132.7, 130.2,
127.9, 120.4, 119.1, 119.1, 111.1, 25.8, 18.4, –4.2.
3-(1,3-Benzodioxol-5-yl)quinoline (3f)
Following GP2, 3-bromoquinoline [1f, 3.12 g, 15 mmol, 1 equiv, in
THF (15 mL)] was reacted with 2f (22.5 mmol, 1.5 equiv), prepared
according to GP1, using CoCl2 (65 mg, 0.5 mmol, 5 mol%) as catalyst.
The solution was stirred at 40 °C for 16 h and was worked up as usual.
The crude product was purified by column chromatography (silica
gel, isohexane/EtOAc, 6:4) to afford 3f as a yellow solid (2.34 g, 9.4
mmol, 63%); mp 104.9–105.9 °C.
MS (EI, 70 eV): m/z (%) = 253 (6), 252 (38), 236 (16), 190 (4), 179 (4),
165 (4), 75 (4).
HRMS (EI, 70 eV): m/z [M] calcd for
C19H23NOSi: 309.1549;
found: 309.1546.
FT-IR (ATR): 2893, 1608, 1504, 1493, 1464, 1419, 1374, 1339, 1293,
1242, 1218, 1126, 1106, 1040, 964, 936, 903, 859, 843, 809, 786, 725,
4-(1,3-Benzodioxol-5-yl)benzonitrile (3i)
693 cm–1
.
Following GP2, 4-iodobenzonitrile [1h, 3.44 g, 15 mmol, 1 equiv, in
THF (15 mL)] was reacted with 2f (22.5 mmol, 1.5 equiv), prepared
according to GP1, using CoCl2 (65 mg, 0.5 mmol, 5 mol%) as catalyst.
The solution was stirred at 40 °C for 16 h and was worked up as usual.
The crude product was purified by column chromatography (silica
gel, isohexane/EtOAc, 9:1) to afford 3i as a colorless solid (2.37 g,
10.7 mmol, 71%); mp 125.6–126.7 °C.
1H NMR (400 MHz, CDCl3): δ = 9.12 (d, J = 2.3 Hz, 1 H), 8.21 (d, J = 1.8
Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.85 (d, J = 8.2 Hz, 1 H), 7.71 (ddd, J =
8.4, 6.9, 1.4 Hz, 1 H), 7.57 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 H), 7.20–7.17 (m,
2 H), 6.98–6.94 (m, 1 H), 6.06–6.03 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 150.0, 148.7, 148.0, 147.3, 133.7,
132.8, 132.2, 129.3, 128.2, 128.0, 127.2, 121.3, 109.1, 107.9, 101.5.
MS (EI, 70 eV): m/z (%) = 250 (20), 249 (100), 248 (22), 191 (10), 189
(18), 164 (5), 163 (6), 125 (9), 124 (7), 43 (6).
FT-IR (ATR): 2898, 2227, 1604, 1501, 1480, 1442, 1412, 1341, 1306,
1294, 1275, 1252, 1228, 1181, 1108, 1038, 1011, 932, 906, 871, 841,
808, 729 cm–1
.
HRMS (EI, 70 eV): m/z [M] calcd for
C16H11O2N: 249.0790;
found: 249.0756.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.66 (m, 2 H), 7.62–7.57 (m, 2 H),
7.10–7.04 (m, 2 H), 6.91 (d, J = 7.9 Hz, 1 H), 6.03 (s, 2 H).
13C NMR (101 MHz, CDCl3): δ = 148.6, 148.4, 145.4, 133.5, 132.7,
3-Fluoro-3′,4′,5′-trimethoxybiphenyl-4-carbonitrile (3g)
127.5, 121.3, 119.1, 110.6, 109.0, 107.6, 101.6.
Following GP2, 4-bromo-2-fluorobenzonitrile [1g, 2.00 g, 10 mmol, 1
equiv, in THF (10 mL)] was reacted with 2g (15 mmol, 1.5 equiv), pre-
pared according to GP1, using CoCl2 (65 mg, 0.5 mmol, 5 mol%) as cat-
alyst. The solution was stirred at 40 °C for 16 h and was worked up as
usual. The crude product was purified by column chromatography
(silica gel, isohexane/EtOAc, 8:2) to afford 3g as a colorless solid
(2.67 g, 9.3 mmol, 93%); mp 124.6–125.2 °C.
MS (EI, 70 eV): m/z (%) = 224 (14), 223 (100), 222 (47), 164 (25), 112
(6), 111 (6).
HRMS (EI, 70 eV): m/z [M] calcd for
found: 223.0629.
C14H9NO2: 223.0633;
Ethyl (Z)-3-[3-(Methylthio)phenyl]acrylate (3j)
FT-IR (ATR): 2941, 2842, 2233, 1588, 1491, 1400, 1349, 1236, 1129,
Following GP2, ethyl (Z)-3-bromoacrylate [1i, 2.68 g, 15 mmol, 1
equiv, in THF (15 mL), E/Z 1:99] was reacted with 2i (22.5 mmol, 1.5
equiv), prepared according to GP1, using CoCl2 (97 mg, 0.75 mmol, 5
mol%) as catalyst. The solution was stirred at 40 °C for 16 h and was
worked up as usual. The crude product was purified by column chro-
matography (silica gel, isohexane/EtOAc, 100:2) to afford 3j as a col-
orless oil (2.03 g, 9.1 mmol, 61%, E/Z 4:96).
998, 820, 811 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.66 (dd, J = 8.1, 6.7 Hz, 1 H), 7.44 (dd,
J = 8.1, 1.7 Hz, 1 H), 7.39 (dd, J = 10.2, 1.6 Hz, 1 H), 6.75 (s, 2 H), 3.93 (s,
6 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.5 (d, J = 258.7 Hz), 153.9, 148.8 (d,
J = 8.1 Hz), 139.4, 133.9 (d, J = 2.0 Hz), 133.8, 123.4 (d, J = 3.2 Hz),
114.9 (d, J = 20.3 Hz), 114.2, 104.7, 99.8 (d, J = 15.7 Hz), 61.1, 56.5.
Signals of the major isomer are given (Z-isomer).
MS (EI, 70 eV): m/z (%) = 288 (17), 287 (100), 272 (80), 244 (45), 229
(31), 214 (19), 212 (45), 201, (21).
FT-IR (ATR): 2981, 2923, 1714, 1628, 1565, 1160, 1113, 1096, 1027,
824, 787, 678 cm–1
.
HRMS (EI, 70 eV): m/z [M] calcd for
found: 287.0952.
C16H14FNO3: 287.0958;
1H NMR (400 MHz, CDCl3): δ = 7.52 (q, J = 1.3, 0.8 Hz, 1 H), 7.34 (dt, J =
7.4, 1.3 Hz, 1 H), 7.29 (d, J = 7.7 Hz, 1 H), 7.24 (dt, J = 7.7, 1.7 Hz, 1 H),
6.91 (d, J = 12.6 Hz, 1 H), 5.98 (d, J = 12.6 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2
H), 2.51 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H).
3′-(tert-Butyldimethylsiloxy)biphenyl-4-carbonitrile (3h)
13C NMR (100 MHz, CDCl3): δ = 166.2, 142.3, 138.4, 135.6, 128.5,
127.7, 127.3, 126.6, 120.7, 60.5, 16.0, 14.2.
Following GP2, 4-iodobenzonitrile [1h, 2.29 g, 10 mmol, 1 equiv, in
THF (10 mL)] was reacted with 2h (15 mmol, 1.5 equiv), prepared ac-
cording to GP1, using CoCl2 (65 mg, 0.5 mmol, 5 mol%) as catalyst. The
solution was stirred at 40 °C for 16 h and was worked up as usual. The
MS (EI, 70 eV): m/z (%) = 222 (100), 177 (46), 149 (26), 134 (39), 131
(30), 116 (16), 115 (16), 102 (17).
HRMS (EI, 70 eV): m/z [M] calcd for
C12H14O2S: 222.0715;
found: 222.0708.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
M. S. Hofmayer et al.
Special Topic
Synthesis
(E)-1-Methoxy-4-(4-methoxystyryl)-2,6-dimethylbenzene (3k)
(6) O’Donovan, M. R.; Mee, C. D.; Fenner, S.; Teasdale, A.; Phillips, D.
H. Mutat. Res. 2011, 724, 1.
(7) Haas, D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal.
2016, 6, 1540.
Following GP2, (E)-1-(2-bromovinyl)-4-methoxybenzene [1j, 2.13 g,
10 mmol, 1 equiv, in THF (10 mL), E/Z 99:1] was reacted with 2c (15
mmol, 1.5 equiv), prepared according to GP1, using CoCl2 (65 mg,
0.5 mmol, 5 mol%) as catalyst. The solution was stirred at 40 °C for
16 h and was worked up as usual. The crude product was purified by
column chromatography (silica gel, isohexane/EtOAc, 100:2) to afford
3k as a colorless solid (2.22 g, 8.3 mmol, 83%, E/Z 99:1); mp 96.7–
97.2 °C.
(8) NMR experiments and crystallographic data showed that the
structure of these zinc reagents is RZnX·Mg(OPiv)2·LiCl. How-
ever, for the sake of clarity, we have named these reagents
RZnOPiv, see: Hernán-Gómez, A.; Herd, E.; Hevia, E.; Kennedy,
A. R.; Knochel, P.; Koszinowski, K.; Manolikakes, S. M.; Mulvey,
R. E.; Schnegelsberg, C. Angew. Chem. Int. Ed. 2014, 53, 2706.
(9) (a) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew.
Chem. Int. Ed. 2011, 50, 9205. (b) Stathakis, C. I.; Bernhardt, S.;
Quint, V.; Knochel, P. Angew. Chem. Int. Ed. 2012, 51, 9428.
(c) Colombe, J. R.; Bernhardt, S.; Stathakis, C.; Buchwald, S. L.;
Knochel, P. Org. Lett. 2013, 15, 5754. (d) Stathakis, C. I.;
Manolikakes, S. M.; Knochel, P. Org. Lett. 2013, 15, 1302.
(e) Manolikakes, S. M.; Ellwart, M.; Stathakis, C. I.; Knochel, P.
Chem. Eur. J. 2014, 20, 12289.
FT-IR (ATR): 2920, 2832, 1510, 1478, 1452, 1302, 1251, 1219, 1176,
1138, 1111, 1037, 1010, 966, 849, 807, 761 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46–7.41 (m, 2 H), 7.17 (s, 2 H), 6.97
(d, J = 16.3 Hz, 1 H), 6.95–6.86 (m, 2 H), 6.88 (d, J = 16.3 Hz, 1 H), 3.83
(s, 3 H), 3.74 (s, 3 H), 2.32 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 159.2, 156.6, 133.3, 131.1, 130.6,
127.6, 127.3, 126.8, 126.4, 114.2, 59.9, 55.4, 16.3.
MS (EI, 70 eV): m/z (%) = 268 (88), 253 (100), 195 (25), 179 (12), 178
(17), 165 (29), 152 (17).
(10) World market prices: Pd ca. 22700 €/kg, Co ca. 35 €/kg;
http://www.infomine.com/; retrieved February 2017.
(11) (a) Handbook on the Toxicology of Metals; Friberg, L.; Nordberg,
G. F.; Vouk, V. B., Eds.; Elsevier: Amsterdam, 1986. (b) Hughes,
HRMS (EI, 70 eV): m/z [M] calcd for
C18H20O2: 268.1463;
found: 268.1460.
M. N. Comprehensive Coordination Chemistry;
6
V
o.
l
Wilkinson, G.;
Gillard, R. D.; McCleverty, J. A., Eds.; Pergamon: Oxford, 1987,
643–648. (c) Nickel and the Skin: Absorption, Immunology, Epi-
demiology, and Metallurgy; Hostynek, J. J.; Maibach, H. I., Eds.;
CRC: Boca Raton, 2002.
Acknowledgment
We thank the DFG (SFB749) and the LMU for financial support. We
also thank Albemarle (Hoechst, Germany) for the generous gift of
chemicals.
(12) Prices retrieved from Alfa Aesar; February 2017.
(13) (a) Egorova, K. S.; Ananikov, V. P. Angew. Chem. Int. Ed. 2016, 55,
12150. (b) Moore, W.; Hysell, D.; Hall, L.; Campbell, K.; Stara, J.
Environ. Health Perspect. 1975, 10, 63.
Supporting Information
(14) For selected examples, see: (a) Xu, W.; Yoshikai, N. Angew.
Chem. Int. Ed. 2016, 55, 12731. (b) Yan, J.; Yoshikai, N. ACS Catal.
2016, 6, 3738. (c) Wang, H.; Moselage, M.; Gonzalez, M. J.;
Ackermann, L. ACS Catal. 2016, 6, 2705. (d) Zell, D.; Bu, Q.; Feldt,
M.; Ackermann, L. Angew. Chem. Int. Ed. 2016, 55, 7408.
(e) Nicolas, L.; Izquierdo, E.; Angibaud, P.; Stansfield, I.;
Meerpoel, L.; Reymond, S.; Cossy, J. J. Org. Chem. 2013, 78,
11807. (f) Barre, B.; Gonnard, L.; Campagne, R.; Reymond, S.;
Marin, J.; Ciapetti, P.; Brellier, M.; Guerinot, A.; Cossy, J. Org.
Lett. 2014, 16, 6160. (g) Gonnard, L.; Guerinot, A.; Cossy, J. Chem.
Eur. J. 2015, 21, 12797. (h) Corpet, M.; Bai, X.-Z.; Gosmini, C. Adv.
Synth. Catal. 2014, 356, 2937. (i) Cai, Y.; Qian, X.; Gosmini, C.
Adv. Synth. Catal. 2016, 358, 2427. (j) Pal, S.; Chowdhury, S.;
Rozwadowski, E.; Auffrant, A.; Gosmini, C. Adv. Synth. Catal.
2016, 358, 2431. (k) Cahiez, G.; Chaboche, C.; Duplais, C.;
Giulliani, A.; Moyeux, A. Adv. Synth. Catal. 2008, 350, 1484.
(l) Cahiez, G.; Chaboche, C.; Duplais, C.; Moyeux, A. Org. Lett.
2009, 11, 277. (m) Kobayashi, T.; Ohmiya, H.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2008, 130, 11276. (n) Murakami, K.;
Yorimitsu, H.; Oshima, K. Chem. Eur. J. 2010, 16, 7688.
(o) Gensch, T.; Klauck, F. J. R.; Glorius, F. Angew. Chem. Int. Ed.
2016, 55, 11287. (p) Lerchen, A.; Vásquez-Céspedes, S.; Glorius,
F. Angew. Chem. Int. Ed. 2016, 55, 3208.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588986.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F