Nickel-Catalyzed Decarboxylative Coupling of Alkynyl Carboxylates with Aryl Tosylates and Mesylates

Article abstract of DOI:10.1055/s-0037-1609636

A method for the nickel-catalyzed coupling of alkynyl carboxylates or acids with aryl tosylates and mesylates is described. Electronically varied carboxylates and aryl electrophiles participate in these transformations to afford the desired diarylalkyne p

Full text of DOI:10.1055/s-0037-1609636

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
A. Howard et al.
Paper
Synthesis
Nickel-Catalyzed Decarboxylative Coupling of Alkynyl Carboxylates
with Aryl Tosylates and Mesylates
Anna Howard §
Samantha Klemann §
Sarah Kolling §
Katrina Little §
Erin Plasek §
O
Ni(COD)2 (10 mol%)
PMe3HBF4 (30 mol%)
Ar
OK
R1O Ar
OR1 = OTs, OMs
+
dioxane or diglyme
80–140 °C
47–99% yield
R2
R2
R2 = H, Me, OMe, F, CF3
Ar = Aryl
Dipannita Kalyani*
St. Olaf College, Department of Chemistry, 1520 St. Olaf Ave.,
Northfield, MN 55057, USA
kalyani@stolaf.edu
§ These authors contributed equally
Received: 29.09.2018
Accepted after revision: 07.10.2018
Published online: 20.11.2018
Previous work:
O
(a)
DOI: 10.1055/s-0037-1609636; Art ID: ss-2018-m0546-op
Pd or Pd/Cu cat.
Ar2
Ar1
OR'
Ar1 Ar2
+
+
RO
Abstract A method for the nickel-catalyzed coupling of alkynyl car-
boxylates or acids with aryl tosylates and mesylates is described. Elec-
tronically varied carboxylates and aryl electrophiles participate in these
transformations to afford the desired diarylalkyne products. In general,
electrophiles bearing an extended π-system lead to products in higher
yields than sulfonates with only one aromatic ring.
R' = H or K
O
OR = OTf, OTs, OMs
(b)
Pd cat.
Ar2
Ar2
OH
TsO
Ar1
Ar1
OR = OTf, OTs
This work:
Key words alkynes, arenes, carboxylic acids, cross-coupling, nickel ca-
(c)
O
talysis, decarboxylative
Ni cat.
Ar2
Ar2
RO
OK
+
Ar1
Ar1
OR = OTs, OMs
Decarboxylative cross-coupling of aryl electrophiles
with carboxylates is a well-established method for the for-
mation of carbon–aryl bonds.1 The use of carboxylic acids
obviates the need for the preparation and use of often sen-
sitive organometallic reagents.2 Additionally, structurally
diverse carboxylic acids are readily available bench-stable
compounds. In lieu of these advantages, several reports on
decarboxylative cross-couplings with aryl halides have
been published.2–8 In recent years there has been increasing
interest in developing cross-coupling methods using phe-
nolic electrophiles in place of aryl halides.9 However, only a
few sporadic reports have detailed decarboxylative cross-
couplings using C–O electrophiles.10 These include the pal-
ladium-catalyzed coupling of aryl sulfonates with aryl car-
boxylates (Scheme 1a) or alkynyl carboxylic acids (Scheme
1b).1,10 As part of our program on C–C bond formations us-
ing C–O electrophiles,11 herein, we report the first example
of nickel-catalyzed decarboxylative couplings of alkynyl
carboxylates with aryl tosylates and mesylates (Scheme
1c).12 A brief scope of these transformations with alkynyl
carboxylic acids in place of the corresponding carboxylates
is also presented.13
Scheme 1 Decarboxylative cross-couplings with aromatic C–O electro-
philes
We commenced our studies with optimization of the
cross-coupling of potassium phenylpropiolate with 2-naph-
thyl tosylate (Table 1). A screen of ligands revealed that
PMe3 (20 mol%) led to the desired product 1a in 68% yield
using Ni(COD)2 as the catalyst and 1,4-dioxane as the sol-
vent at 80 °C (entries 1–4). Increasing the equivalents of
PMe3 enhanced the yield of 1a (entries 2 and 5). Bench-sta-
ble Ni(II) catalysts afforded 1a in comparable yields to that
obtained using Ni(COD)2 (entries 5–7). However, Ni(COD)2
was employed for further studies because it was the most
efficient for reactions with electronically varied tosylates.
Polar solvents such as 1,4-dioxane, DMSO, and diglyme af-
forded 1a in similar yields (entries 5, 9 and 10) while non-
polar solvents such as p-xylene gave 1a in low yield (entry
8). A temperature screen showed that higher temperatures
are detrimental to these decarboxylative couplings (entries
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
A. Howard et al.
Paper
Synthesis
5, 11 and 12). Finally, no product was obtained in the ab-
sence of the nickel catalyst and the ligand (entries 13 and
14).14
Ni(COD)2
(10 mol%)
PMe3HBF4
(30 mol%)
O
Ar
OK
TsO
+
dioxane,
80 °C
Table 1 Optimization of Decarboxylative Alkynylation
R
R
(2.0 equiv)
(1.0 equiv)
Ar = 2-naphthyl
Ni catalyst
(10 mol%)
ligand
O
Ar
Ar
Ar
Ar
Ar
Ar
(20 mol%)
OK
+
TsO
solvent [0.25 M]
temperature,
16 h
Me
MeO
1 (2.0 equiv)
(1.0 equiv)
(1a)
Ar = 2-naphthyl
1a, 89%
4a, 83%
2a, 99%
5a, 67%
3a, 86%
6a, 85%
Ar
Entry
Solvent
Ligand
Ni catalyst
Temp (°C)GC yield (%)a
MeO
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
p-xylene
dppf
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(acac)2
NiBr2
80
80
0
68
0
F
F3C
2b
PMe3
PCy3
3b
80
Me
Ar
4b
Pt-Bu3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
PMe3
none
none
80
0
5b,c
6b,c
7b,c
8b,c
9b,c
10b,c
11b,c
12b,c
13
80
84
90
87
14
72
79
83
62
0
80
7a, 78%
80
Scheme 2 Scope of salts for cross-coupling with 2-naphthyl tosylate
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
none
80
(isolated yields)
DMSO
80
diglyme
80
O
Ni(COD)2 (10 mol%)
PMe3HBF4 (30 mol%)
Ar
Ar
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
100
120
80
OK
+
TsO
Ph
Ph
dioxane or diglyme
80 °C
Ph
(2.0 equiv)
(1.0 equiv)
14
80
0
N
a Calibrated GC yields against hexadecane as the internal standard.
b The HBF4 salt of the ligand was used.
N
OMe
Ph
c Ligand (30 mol%) was used.
Ph
1b, 94%a
1c, 88%a
1f, 57%d,e
1h, 47%d,e
1d, 59%b
1g, 62%d
The optimal conditions for the formation of 1a were ap-
plied to the use of electronically diverse alkynyl carboxyl-
ates for coupling with 2-naphthyl tosylate. As shown in
Scheme 2, the desired diarylalkynes were obtained in good
to excellent yields.
Electronically varied tosylates also participate in these
reactions (Scheme 3). However, the highest yields were ob-
tained with electrophiles bearing an extended aromatic
system, such as for the formation of 1a–c. Furthermore,
electron-deficient tosylates (1d, 1f, and 1g) afforded the
products in somewhat higher yields than electron-rich elec-
trophiles (cf. 1h). Additionally, reactions leading to prod-
ucts 1d–h required higher temperatures (120 or 140 °C)
than those leading to diarylalkynes 1a–c (80 °C).15
OMe
Ph
CF3
Me
CO2Et
Ph
Ph
1e, 41%b,c
Ph
Scheme 3 Scope of tosylates for cross-coupling (isolated yields). a Re-
action conducted at 80 °C with dioxane as solvent. b Reaction conduct-
ed at 120 °C with diglyme as solvent. c Carboxylate (3.0 equiv) used.
d Reaction conducted at 140 °C with diglyme as solvent. e Carboxylate
(4.0 equiv) used.
These decarboxylative cross-couplings can be expanded
to the use of more atom-economical aryl mesylates. As
shown in Scheme 4, in general, electronically varied alkynyl
carboxylates coupled with 2-naphthyl mesylate to afford
the desired products in comparable yields to those obtained
using 2-naphthyl tosylate (Scheme 2).
Furthermore, the cross-couplings using electronically
varied aryl mesylates often afforded the diarylalkyne prod-
ucts in lower yields than those obtained using the corre-
sponding tosylates (Scheme 5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
A. Howard et al.
Paper
Synthesis
Ni(COD)2
(10 mol%)
PMe3HBF4
(30 mol%)
(a)
Ni(COD)2
O
(10 mol%)
PMe3HBF4
(30 mol%)
O
Ar
OK
+
MsO
Ar
OH
dioxane
80 °C
+
TsO
R
R
base (2.5 equiv)
dioxane
(2.0 equiv)
(1.0 equiv)
Ar = 2-naphthyl
1a
80 °C
(2.0 equiv)
(1.0 equiv)
Ar = 2-naphthyl
K3PO4, 67%
K2CO3, 21%
Cs2CO3, 76%
Ar
Ar
Ar
Ar
Ar
Ar
Me
MeO
MeO
(b)
1a, 91%
4a, 99%
2a, 95%
3a, 80%
6a, 82%
Ni(COD)2
(10 mol%)
PMe3HBF4
(30 mol%)
O
Ar
OH
+
MsO
F
F3C
K3PO4 (2.5 equiv)
dioxane
5a, 66%
7a, 48%
80 °C
(2.0 equiv)
(1.0 equiv)
1a
Me
Ar
Ar = 2-naphthyl
47%
Scheme 6 Screen of bases for direct coupling with phenylpropiolic
acid
Scheme 4 Scope of salts for cross-coupling with 2-naphthyl mesylate
(isolated yields)
efficiencies than reactions with the corresponding carbox-
ylates (Scheme 7).
O
Ni(COD)2 (10 mol%)
PMe3HBF4 (30 mol%)
Ar
Ar
In summary, we have described the first general exam-
ple of nickel-catalyzed decarboxylative cross-couplings of
alkynyl carboxylates with aryl tosylates and mesylates. In
general, electron-rich carboxylates are more effective for
these reactions than their electron-deficient counterparts.
Furthermore, aryl electrophiles bearing an extended π-sys-
tem lead to products in higher yields than aryl electrophiles
with only one aromatic ring. The scope of aryl tosylates is
broader than aryl mesylates. Finally, arylpropiolic acids can
be used in place of the arylpropiolate salts, albeit with low-
er reaction efficiencies than the latter.
OK
MsO
+
Ph
Ph
dioxane or diglyme
80 °C
(2.0 equiv)
(1.0 equiv)
N
OMe
Ph
CO2Et
Ph
Ph
1c, 64%a
1e, 49%b
1g, 17%c
Scheme 5 Scope of mesylates for cross-coupling (isolated yields).
a Reaction conducted at 80 °C with dioxane as solvent. b Reaction con-
ducted at 120 °C with diglyme as solvent; carboxylate (3.0 equiv) used.
c Reaction conducted at 140 °C with diglyme as solvent.
Ni(COD)2
(10 mol%)
PMe3HBF4
(30 mol%)
Having explored the scope of these decarboxylative
cross-couplings with alkynyl carboxylates, we next exam-
ined the use of their precursor alkynyl acids in these trans-
formations. Importantly, the direct use of acids instead of
salts enhances the step economy of the process by obviating
the synthesis and purification of the carboxylate salts. A
screen of bases revealed that both Cs2CO3 and K3PO4 effect-
ed the coupling of phenylpropiolic acid with 2-naphthyl to-
sylate to afford 1a in synthetically useful yields (Scheme 6).
However, the direct coupling with phenylpropiolic acid was
less effective than the reactions using the corresponding
carboxylate for couplings with both tosylates and
mesylates.
O
Ar
OH
+
TsO
K3PO4
(2.5 equiv)
dioxane or diglyme
80 or 120 °C
R
R
(2.0 equiv)
(1.0 equiv)
Ar = 2-naphthyl
Ar
Ar
Ar
MeO
F
F3C
3a, 45%a
4a, 22%b
5a, 21%b
Scheme 7 Cross-couplings with arylpropiolic acids (isolated yields).
a Reaction conducted at 80 °C with dioxane as solvent. b Reaction con-
ducted at 120 °C with diglyme as solvent.
Electronically varied arylpropiolic acids coupled with 2-
naphthyl tosylate to afford the diarylalkynes, albeit in lower
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
A. Howard et al.
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Synthesis
NMR spectra were obtained on a Bruker 400 (399.96 MHz for 1H;
100.57 MHz for 13C) spectrometer. 1H NMR chemical shifts are report-
ed in parts per million (ppm) relative to TMS, with the residual sol-
vent peak used as an internal reference. Multiplicities are reported as
follows: singlet (s), doublet (d), doublet of doublets (dd), and multi-
plet/multiple peaks (m). IR spectra were obtained on a Thermo Scien-
tific Nicolet iS5 iD5 ATR spectrophotometer. Melting points were ob-
tained on a Thomas Hoover melting point apparatus. Phenylpropiolic
acid was obtained from Aldrich, Ni(COD)2 and ligands were obtained
from Strem Chemicals, and anhydrous cesium carbonate, potassium
carbonate, and potassium phosphate were obtained from Acros; all
materials were used as received. The acids,13d carboxylates,16a to-
sylates,16b and mesylates16c were prepared using literature proce-
dures. Anhydrous p-xylene, DMSO, diglyme, and 1,4-dioxane were
obtained from Aldrich and used as received. Other solvents were ob-
tained from Fisher Chemical or VWR Chemical and used without fur-
ther purification. Flash chromatography was performed on EM Sci-
ence silica gel 60 (0.040–0.063 mm particle size, 230–400 mesh) and
TLC was performed on Analtech TLC plates precoated with silica gel
Couplings with Arylpropiolic Acids; General Procedure D
Arylpropiolic acid and electrophile (tosylate or mesylate) were
weighed in an oven-dried 4-mL scintillation vial containing a magnet-
ic stir bar. The vial was taken into a glovebox, and Ni(COD)2,
PMe3HBF4, and base were added. The vial was sealed with a Teflon-
lined cap, then taken out of the glovebox, and the reaction mixture
was stirred at the indicated temperature for the indicated time. The
reaction mixture was cooled to room temperature and filtered
through a 1.5-inch plug of silica gel, eluting with Et2O (100 mL). The
filtrate was concentrated and chromatographed on a silica gel column
to afford the product.
Coupled Products 1a–7a Using 2-Naphthyl Tosylate (Scheme 2)
2-(2-Phenylethynyl)naphthalene (1a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropiolate (92.1 mg,
0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv),
PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous dioxane
(1.0 mL) was stirred at 80 °C for 16 h. Chromatography (hexanes) gave
1a as a white solid; yield: 50.6 mg (89%).
60 F254
.
Decarboxylative Cross-Couplings; General Procedures
Rf = 0.32 (hexanes).
1H NMR (CDCl3): δ = 8.06 (s, 1 H), 7.86–7.78 (m, 3 H), 7.61–7.56 (m, 3
H), 7.53–7.47 (m, 2 H), 7.41–7.33 (m, 3 H); the spectroscopic data are
consistent with the literature.17
Couplings with Solid Tosylates or Mesylates; General Procedure A
Carboxylate and electrophile (tosylate or mesylate) were weighed in
an oven-dried 4-mL scintillation vial containing a magnetic stir bar.
The vial was taken into a glovebox, and Ni(COD)2 and PMe3HBF4 were
added. Anhydrous 1,4-dioxane or diglyme was added, the vial was
sealed with a Teflon-lined cap, then taken out of the glovebox, and the
reaction mixture was stirred at the indicated temperature for the in-
dicated time. The reaction mixture was cooled to room temperature
and filtered through a 1.5-inch plug of silica gel, eluting with Et2O
(100 mL). The filtrate was concentrated and chromatographed on a
silica gel column to afford the product.
2-[2-(4-Methylphenyl)ethynyl]naphthalene (2a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-(p-tolyl)propiolate (99.1 mg,
0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv),
PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous dioxane
(1.0 mL) was stirred at 80 °C for 17 h. Chromatography (hexanes) gave
2a as a light yellow solid; yield: 60.0 mg (99%).
Rf = 0.44 (hexanes).
Couplings with Mesylates; General Procedure B
1H NMR (CDCl3): δ = 8.04 (s, 1 H), 7.85–7.78 (m, 3 H), 7.57 (d, J = 6.8
Hz, 1 H), 7.53–7.44 (m, 4 H), 7.18 (d, J = 7.6 Hz, 2 H), 2.38 (s, 3 H); the
spectroscopic data are consistent with the literature.17
Carboxylate was weighed in an oven-dried 4-mL scintillation vial con-
taining a magnetic stir bar. The vial was taken into a glovebox, and
mesylate, Ni(COD)2, and PMe3HBF4 were added. Anhydrous 1,4-diox-
ane or diglyme was added, the vial was sealed with a Teflon-lined cap,
then taken out of the glovebox, and the reaction mixture was stirred
at the indicated temperature for the indicated time. The reaction mix-
ture was cooled to room temperature and filtered through a 1.5-inch
plug of silica gel, eluting with Et2O (100 mL). The filtrate was concen-
trated and chromatographed on a silica gel column to afford the prod-
uct.
2-[2-(4-Methoxyphenyl)ethynyl]naphthalene (3a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-(4-methoxyphenyl)propio-
late (108 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhy-
drous dioxane (1.0 mL) was stirred at 80 °C for 14 h. Chromatography
(EtOAc/hexanes, 2:98) gave 3a as a white solid; yield: 55.7 mg (86%).
Rf = 0.30 (EtOAc/hexanes, 2:98).
Couplings with Liquid Tosylates or Mesylates; General Procedure C
1H NMR (CDCl3): δ = 8.03 (s, 1 H), 7.83–7.79 (m, 3 H), 7.58–7.46 (m, 5
H), 6.90 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H); the spectroscopic data are
consistent with the literature.17
Carboxylate was weighed in an oven-dried 4-mL scintillation vial con-
taining a magnetic stir bar. The vial was taken into a glovebox, and
Ni(COD)2 and PMe3HBF4 were added. Electrophile (tosylate or
mesylate) was added as a solution in the solvent (anhydrous 1,4-diox-
ane or diglyme). The vial was sealed with a Teflon-lined cap, then tak-
en out of the glovebox, and the reaction mixture was stirred at the
indicated temperature for the indicated time. The reaction mixture
was cooled to room temperature and filtered through a 1.5-inch plug
of silica gel, eluting with Et2O (100 mL). The filtrate was concentrated
and chromatographed on a silica gel column to afford the product.
2-[2-(4-Fluorophenyl)ethynyl]naphthalene (4a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-(4-fluorophenyl)propiolate
(102 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhy-
drous dioxane (1.0 mL) was stirred at 80 °C for 16 h. Chromatography
(hexanes) gave 4a as a pale yellow solid; yield: 51.2 mg (83%).
Rf = 0.46 (hexanes).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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A. Howard et al.
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1H NMR (CDCl3): δ = 8.04 (s, 1 H), 7.85–7.78 (m, 3 H), 7.58–7.47 (m, 5
H), 7.06 (t, J = 8.8 Hz, 2 H); the spectroscopic data are consistent with
the literature.17
Coupled Products 1b–h Using Aryl Tosylates (Scheme 3)
2-Methoxy-7-(2-phenylethynyl)naphthalene (1b)
Following general procedure A, a mixture of 7-methoxy-2-naphthyl
tosylate (82.0 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropio-
late (92.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h. Chroma-
tography (hexanes) gave 1b as a light yellow solid; yield: 61.1 mg
(94%); mp 104–106 °C.
2-[2-[4-(Trifluoromethyl)phenyl]ethynyl]naphthalene (5a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-[4-(trifluoromethyl)phe-
nyl]propiolate (126 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg,
0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 14.5 h.
Chromatography (hexanes) gave 5a as a pale yellow solid; yield: 49.6
mg (67%).
Rf = 0.30 (hexanes).
IR (neat): 3011, 2924, 1625, 1593, 1569, 1508, 1489, 1458, 1450,
1409, 1391, 1371, 1329, 1269, 1249, 1214, 1171, 1143, 1130, 1114,
1072, 1030, 968, 952, 919, 889, 843, 835, 824, 806, 754, 724, 693 cm–
Rf = 0.55 (hexanes).
1H NMR (CDCl3): δ = 8.08 (s, 1 H), 7.91–7.79 (m, 3 H), 7.68–7.51 (m, 7
H); the spectroscopic data are consistent with the literature.17
.
1
1H NMR (CDCl3): δ = 7.95 (s, 1 H), 7.74–7.71 (m, 2 H), 7.60–7.54 (m, 2
H), 7.44 (d, J = 7.8 Hz, 1 H), 7.40–7.33 (m, 3 H), 7.16 (dd, J = 9.3, 2.8 Hz,
1 H), 7.11 (s, 1 H), 3.93 (s, 3 H).
13C NMR (CDCl3): δ = 158.06, 134.19, 131.61, 130.21, 129.21, 128.33,
128.23, 127.70, 126.24, 123.32, 121.02, 119.44, 105.57, 89.91, 89.62,
55.31.
2-[2-(3-Methoxyphenyl)ethynyl]naphthalene (6a)
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-(3-methoxyphenyl)propio-
late (107 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhy-
drous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h. Chromatogra-
phy (EtOAc/hexanes, 1:99) gave 6a as a white solid; yield: 55.1 mg
(85%); mp 67–68 °C.
HRMS: m/z [M+] calcd for C19H14O: 258.1045; found: 258.1049.
6-(2-Phenylethynyl)quinoline (1c)
Rf = 0.28 (EtOAc/hexanes, 1:99).
Following general procedure A, a mixture of quinolin-6-yl 4-methyl-
benzene sulfonate (74.8 mg, 0.250 mmol, 1.0 equiv), potassium 3-
phenylpropiolate (92.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90
mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h.
Chromatography (EtOAc/hexanes, 20:80) gave 1c as a tan solid; yield:
50.4 mg (88%).
IR (neat): 3003, 2960, 2936, 1592, 1579, 1489, 1461, 1443, 1415,
1345, 1323, 1312, 1272, 1249, 1225, 1179, 1157, 1145, 1136, 1109,
1076, 1037, 990, 960, 950, 930, 905, 865, 855, 816, 784, 771, 747, 691,
655 cm–1
.
1H NMR (CDCl3): δ = 8.06 (s, 1 H), 7.83–7.80 (m, 3 H), 7.58 (dd, J = 8.5,
1.6 Hz, 1 H), 7.52–7.48 (m, 2 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.6
Hz, 1 H), 7.11 (s, 1 H), 6.91 (ddd, J = 8.0, 2.5, 0.8 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (CDCl3): δ = 159.36, 132.98, 132.79, 131.46, 129.42, 128.38,
127.98, 127.74, 126.65, 126.52, 124.25, 124.21, 120.46, 116.35,
114.98, 89.66, 89.60, 55.26.
Rf = 0.32 (EtOAc/hexanes, 20:80).
1H NMR (CDCl3): δ = 8.92 (d, J = 3.0 Hz, 1 H), 8.15–8.03 (m, 3 H), 7.82
(d, J = 8.6 Hz, 1 H), 7.58 (d, J = 3.6 Hz, 2 H), 7.44–7.38 (m, 4 H); the
spectroscopic data are consistent with the literature.18
HRMS: m/z [M+] calcd for C19H14O: 258.1045; found: 258.1040.
3-(2-Phenylethynyl)pyridine (1d)
2-[2-(2-Methylphenyl)ethynyl]naphthalene (7a)
Following general procedure A, a mixture of 3-pyridyl tosylate (62.3
mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropiolate (92.1 mg,
0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv),
PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous diglyme
(1.0 mL) was stirred at 120 °C for 4 h. Chromatography (EtOAc/hex-
anes, 20:80) gave 1d as a tan solid; yield: 26.6 mg (59%).
Following general procedure A, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), potassium 3-(o-tolyl)propiolate (99.6 mg,
0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv),
PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous dioxane
(1.0 mL) was stirred at 80 °C for 19 h. Chromatography (hexanes) gave
7a as a white solid; yield: 46.9 mg (78%); mp 108–109 °C.
Rf = 0.22 (EtOAc/hexanes, 20:80).
Rf = 0.50 (hexanes).
1H NMR (CDCl3): δ = 8.77 (s, 1 H), 8.55 (d, J = 4.0 Hz, 1 H), 7.81 (d, J =
7.8 Hz, 1 H), 7.56–7.54 (m, 2 H), 7.38–7.36 (m, 3 H), 7.30–7.26 (m, 1
H); the spectroscopic data are consistent with the literature.19
IR (neat): 2920, 1598, 1498, 1483, 1454, 1435, 1142, 944, 899, 863,
819, 754, 743, 717 cm–1
.
1H NMR (CDCl3): δ = 8.05 (s, 1 H), 7.87–7.77 (m, 3 H), 7.59–7.49 (m, 4
H), 7.30–7.19 (m, 3 H), 2.57 (s, 3 H).
1-Methoxy-3-(2-phenylethynyl)benzene (1e)
13C NMR (CDCl3): δ = 140.22, 133.03, 132.75, 131.66, 131.17, 129.46,
128.39, 128.32, 127.96, 127.74, 127.73, 126.57, 126.52, 125.59,
123.01, 120.83, 93.72, 88.68, 20.78.
Following general procedure A, a mixture of m-methoxyphenyl to-
sylate (69.6 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropio-
late (138.2 mg, 0.750 mmol, 3.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous diglyme (1.0 mL) was stirred at 120 °C for 15 h. Chroma-
tography (EtOAc/hexanes, 1:99) gave 1e as an orange oil; yield: 21.4
mg (41%).
HRMS: m/z [M+] calcd for C19H14: 242.1096; found: 242.1089.
Rf = 0.35 (EtOAc/hexanes, 1:99).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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A. Howard et al.
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Synthesis
1H NMR (CDCl3): δ = 7.55–7.53 (m, 2 H), 7.35–7.34 (m, 3 H), 7.26 (t, J =
7.6 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.06 (s, 1 H), 6.90 (d, J = 7.4 Hz, 1
H), 3.83 (s, 3 H); the spectroscopic data are consistent with the litera-
ture.20
0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhy-
drous dioxane (1.0 mL) was stirred at 80 °C for 16 h. Chromatography
(hexanes) gave 2a as a light yellow solid; yield: 57.4 mg (95%);
Rf = 0.44 (hexanes). The spectroscopic data are consistent with those
of the product obtained using the tosylate.
1-(2-Phenylethynyl)-3-(trifluoromethyl)benzene (1f)
2-[2-(4-Methoxyphenyl)ethynyl]naphthalene (3a)
Following general procedure A, a mixture of m-(trifluoromethyl)phe-
nyl tosylate (79.0 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenyl-
propiolate (184.2 mg, 1.00 mmol, 4.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous diglyme (1.0 mL) was stirred at 140 °C for 4 h. Chromatog-
raphy (hexanes) gave 1f as a pale yellow solid; yield: 35.1 mg (57%).
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-(4-methoxyphe-
nyl)propiolate (107 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg,
0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h.
Chromatography (EtOAc/hexanes, 1:99) gave 3a as a light yellow sol-
id; yield: 51.9 mg (80%); Rf = 0.30 (EtOAc/hexanes, 2:98). The spectro-
scopic data are consistent with those of the product obtained using
the tosylate.
Rf = 0.60 (hexanes).
1H NMR (CDCl3): δ = 7.80 (s, 1 H), 7.70 (d, J = 7.7 Hz, 1 H), 7.60–7.54
(m, 3 H), 7.48 (t, J = 7.8 Hz, 1 H), 7.38–7.36 (m, 3 H); the spectroscopic
data are consistent with the literature.21
2-[2-(4-Fluorophenyl)ethynyl]naphthalene (4a)
Ethyl 3-(2-Phenylethynyl)benzoate (1g)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-(4-fluorophe-
nyl)propiolate (101 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg,
0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 14 h.
Chromatography (hexanes) gave 4a as a yellow solid; yield: 61.5 mg
(99%); Rf = 0.46 (hexanes). The spectroscopic data are consistent with
those of the product obtained using the tosylate.
Following general procedure C, a mixture of ethyl 3-(tosyloxy)benzo-
ate (80.0 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropiolate
(92.1 mg, 0.50 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10
equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous
diglyme (1.0 mL) was stirred at 140 °C for 4 h. Chromatography (EtO-
Ac/hexanes, 1:99) gave 1g as an orange oil; yield: 38.8 mg (62%).
Rf = 0.16 (EtOAc/hexanes, 1:99).
1H NMR (CDCl3): δ = 8.21 (s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.70 (d, J =
7.8 Hz, 1 H), 7.58–7.51 (m, 2 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.39–7.34 (m,
3 H), 4.40 (q, J = 7.2 Hz, 2 H), 1.41 (t, J = 7.1 Hz, 3 H); the spectroscopic
data are consistent with the literature.19
2-[2-[4-(Trifluoromethyl)phenyl]ethynyl]naphthalene (5a)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-[4-(trifluorometh-
yl)phenyl]propiolate (126 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90
mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h.
Chromatography (hexanes) gave 5a as a pale yellow solid; yield: 48.5
mg (66%); Rf = 0.55 (hexanes). The spectroscopic data are consistent
with those of the product obtained using the tosylate.
1-Methyl-4-(2-phenylethynyl)benzene (1h)
Following general procedure A, a mixture of p-tolyl tosylate (65.6 mg,
0.250 mmol, 1.0 equiv), potassium 3-phenylpropiolate (184 mg, 1.00
mmol, 4.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv),
PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous diglyme
(1.0 mL) was stirred at 140 °C for 15.5 h. Chromatography (hexanes)
gave 1h as a light orange solid; yield: 22.4 mg (47%).
2-[2-(3-Methoxyphenyl)ethynyl]naphthalene (6a)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-(3-methoxyphe-
nyl)propiolate (107 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg,
0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30
equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for 15.5 h.
Chromatography (EtOAc/hexanes, 1:99) gave 6a as a white solid;
yield: 52.7 mg (82%); Rf = 0.28 (EtOAc/hexanes, 1:99). The spectro-
scopic data are consistent with those of the product obtained using
the tosylate.
Rf = 0.60 (hexanes).
1H NMR (CDCl3): δ = 7.54–7.50 (m, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.37–
7.30 (m, 3 H), 7.15 (d, J = 7.8 Hz, 2 H), 2.37 (s, 3 H); the spectroscopic
data are consistent with the literature.12b
Coupled Products 1a–7a Using 2-Naphthyl Mesylate (Scheme 4)
2-(2-Phenylethynyl)naphthalene (1a)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropiolate (92.1
mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10
equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhydrous
dioxane (1.0 mL) was stirred at 80 °C for 14 h. Chromatography (hex-
anes) gave 1a as a yellow solid; yield: 51.7 mg (91%); Rf = 0.32 (hex-
anes). The spectroscopic data are consistent with those of the product
obtained using the tosylate.
2-[2-(2-Methylphenyl)ethynyl]naphthalene (7a)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-(o-tolyl)propiolate
(99.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and anhy-
drous dioxane (1.0 mL) was stirred at 80 °C for 17 h. Chromatography
(hexanes) gave 7a as a white solid; yield: 29.0 mg (48%); Rf = 0.50
(hexanes). The spectroscopic data are consistent with those of the
product obtained using the tosylate.
2-[2-(4-Methylphenyl)ethynyl]naphthalene (2a)
Following general procedure A, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-(p-tolyl)propiolate
(99.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025 mmol,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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Synthesis
Coupled Products 1c, 1e, 1g Using Aryl Mesylates (Scheme 5)
6-(2-Phenylethynyl)quinoline (1c)
Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg,
0.075 mmol, 0.30 equiv), and anhydrous dioxane (1.0 mL) was stirred
at 80 °C for 15 h. Chromatography (EtOAc/hexanes, 1:99) gave 3a as a
white solid; yield: 29.3 mg (45%); Rf = 0.30 (EtOAc/hexanes, 2:98). The
spectroscopic data are consistent with those of the product obtained
using the carboxylate.
Following general procedure A, a mixture of quinolin-6-yl-methane
sulfonate (55.8 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenyl-
propiolate (92.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous dioxane (1.0 mL) was stirred at 80 °C for 19 h. Chromatog-
raphy (EtOAc/hexanes, 20:80) gave 1c as a yellow solid; yield: 36.8 mg
(64%); Rf = 0.31 (EtOAc/hexanes, 20:80). The spectroscopic data are
consistent with those of the product obtained using the tosylate.
2-[2-(4-Fluorophenyl)ethynyl]naphthalene (4a)
Following general procedure D, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), 3-(4-fluorophenyl)propiolic acid (82.1
mg, 0.500 mmol, 2.0 equiv), K3PO4 (133 mg, 0.625 mmol, 2.5 equiv),
Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg,
0.075 mmol, 0.30 equiv), and anhydrous diglyme (1.0 mL) was stirred
at 120 °C for 14 h. Chromatography (hexanes) gave 4a as a pale yellow
solid; yield: 13.4 mg (22%); Rf = 0.46 (hexanes). The spectroscopic
data are consistent with those of the product obtained using the car-
boxylate.
1-Methoxy-3-(2-phenylethynyl)benzene (1e)
Following general procedure C, a mixture of m-methoxyphenyl
mesylate (50.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropi-
olate (138.2 mg, 0.750 mmol, 3.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous diglyme (1.0 mL) was stirred at 120 °C for 16 h. Chroma-
tography (EtOAc/hexanes, 1:99) gave 1e as a yellow oil; yield: 25.4 mg
(49%); Rf = 0.35 (EtOAc/hexanes, 1:99). The spectroscopic data are
consistent with those of the product obtained using the tosylate.
2-[2-[4-(Trifluoromethyl)phenyl]ethynyl]naphthalene (5a)
Following general procedure D, a mixture of 2-naphthyl tosylate (74.5
mg, 0.250 mmol, 1.0 equiv), 3-[4-(trifluoromethyl)phenyl]propiolic
acid (108 mg, 0.500 mmol, 2.0 equiv), K3PO4 (133 mg, 0.625 mmol, 2.5
equiv), Ni(COD)2 (6.90 mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3
mg, 0.075 mmol, 0.30 equiv), and anhydrous diglyme (1.0 mL) was
stirred at 120 °C for 16 h. Chromatography (hexanes) gave 5a as a pale
yellow solid; yield: 15.4 mg (21%); Rf = 0.55 (hexanes). The spectro-
scopic data are consistent with those of the product obtained using
the carboxylate.
Ethyl 3-(2-Phenylethynyl)benzoate (1g)
Following general procedure B, a mixture of ethyl 3-(mesyloxy)ben-
zoate (60.5 mg, 0.250 mmol, 1.0 equiv), potassium 3-phenylpropio-
late (92.1 mg, 0.500 mmol, 2.0 equiv), Ni(COD)2 (6.90 mg, 0.025
mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol, 0.30 equiv), and
anhydrous diglyme (1.0 mL) was stirred at 140 °C for 4 h. Chromatog-
raphy (EtOAc/hexanes, 1:99) gave 1g as an orange oil; yield: 10.8 mg
(17%); Rf = 0.21 (EtOAc/hexanes, 1:99). The spectroscopic data are
consistent with those of the product obtained using the tosylate.
Funding Information
This work was supported by the NSF (CHE-1554630) Research Corpo-
ration for Science Advancement, Organic Syntheses Inc. PUI Summer
Coupled Products 1a, 3a–5a Using Acids (Schemes 6 and 7)
2-(2-Phenylethynyl)naphthalene (1a)
Research Grant, and St. Olaf College.
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Following general procedure D, a mixture of 2-naphthyl tosylate (74.5
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mmol, 2.0 equiv), K3PO4 (133 mg, 0.625 mmol, 2.5 equiv), Ni(COD)2
(6.90 mg, 0.025 mmol, 0.10 equiv), PMe3HBF4 (12.3 mg, 0.075 mmol,
0.30 equiv), and anhydrous dioxane (1.0 mL) was stirred at 80 °C for
17 h. Chromatography (hexanes) gave 1a as a white solid; yield: 32.0
mg (67%); Rf = 0.38 (hexanes). The spectroscopic data are consistent
with those of the product obtained using the carboxylate.
Supporting Information
for this article is available online at http://www.thieme-con-
nect.com/products/ejournals/journal/10.1055/s-0037-1609636.
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References
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2-(2-Phenylethynyl)naphthalene (1a)
Following general procedure D, a mixture of 2-naphthyl mesylate
(55.5 mg, 0.250 mmol, 1.0 equiv), 3-phenylpropiolic acid (73.1 mg,
0.500 mmol, 2.0 equiv), K3PO4 (133 mg, 0.625 mmol, 2.5 equiv),
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are consistent with those of the product obtained using the carboxyl-
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mg, 0.250 mmol, 1.0 equiv), 3-(4-methoxyphenyl)propiolic acid (88.1
mg, 0.500 mmol, 2.0 equiv), K3PO4 (133 mg, 0.625 mmol, 2.5 equiv),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
A. Howard et al.
Paper
Synthesis
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(14) The reactions are heterogeneous. The carboxylate is less soluble
in p-xylene than in dioxane or diglyme. The lower yields at
higher temperature might be in part due to decarboxylative
dimerization (mass consistent with this byproduct was
observed by GCMS). The Aldrich specification sheet for dioxane
or diglyme did not mention the presence of any inhibitors.
(15) The carboxylate equivalence is largely empirical. The products
were isolated using reaction conditions that showed highest
conversion and least byproducts by GCMS. The reaction using p-
methoxyphenyl tosylate led to the product in low yield and we
were unable to isolate a clean sample of the desired product.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H