Efficient synthesis of unsymmetrical 1,3-diynes utilizing a palladium-catalyzed cross-coupling reaction without homo-coupling

Full text of DOI:10.1002/bkcs.10004

Note
DOI: 10.1002/bkcs.10004
BULLETIN OF THE
B. Kim et al.
KOREAN CHEMICAL SOCIETY
Efficient Synthesis of Unsymmetrical 1,3-Diynes Utilizing a Palladium-
Catalyzed Cross-Coupling Reaction Without Homo-Coupling
*
Boyoung Kim, Sunyoung You, Namgeol Lee, and Sungwook Choi
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejon 305-764,
Korea. *E-mail: swchoi2010@cnu.ac.kr
Received July 2, 2014, Accepted September 1, 2014, Published online December 19, 2014
Keywords: Palladium-catalyzed cross-coupling, Conjugated 1,3-diyne
Conjugated 1,3-diynes are important building blocks in the
fields of chemistry, biology, and material science because they
are found in a variety of natural products,1–5 pharmaceuticals,6
electronic and optical materials,7 and molecular recognition
systems.8 Numerous efficient methods for the construction
of conjugated 1,3-diynes have been developed. The Glaser–
Hay coupling reaction was the first method used to construct
symmetric 1,3-diynes, which were obtained using a Cu-
mediated oxidative homo-coupling reaction of two terminal
alkynes.9,10 Later, improved methods, including Cu-catalyzed
homo-coupling11–14 and Pd-catalyzed homo-coupling,15–21
have been developed for the construction of symmetrical
1,3-diynes. Furthermore, numerous studies have attempted
to construct unsymmetrical 1,3-diynes. The method devel-
oped by Cadiot and Chodkiewicz has been utilized for the syn-
thesis of unsymmetrical 1,3-diynes via Cu-catalyzed coupling
of a 1-haloalkyne and a terminal alkyne.22 However, the
Cadiot–Chodkiewicz coupling showed a limitation in the
construction of unsymmetrical 1,3-diynes because of its
low selectivity, yielding a mixture of homo-coupled and
cross-coupled products. Recently, Cu- and Pd-catalyzed
cross-coupling reactions have been reported.23–27 Although
modified coupling methods have been developed for more
efficient and selective preparation of unsymmetrical 1,3-
diynes, these methods suffer from several drawbacks, such
as the generation of undesired homo-coupled by-products
and difficulty in isolation of the desired product.
Here, we describe the solid-phase synthesis of various
unsymmetrical 1,3-diynes bearing carboxylic acid via Pd-
catalyzed cross-coupling reaction. Unsymmetrical 1,3-diyne
5a was synthesized using the solid-phase route described in
Scheme 1. The compound 4-iodobenzoic acid was attached
to commercially available Wang resin using 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and Hydroxyben-
zotriazole (HOBT) in DMF. The reaction of iodobenzoate 1
with trimethylsilyl acetylene catalyzed by Pd(PPh3)4 and
CuI, followed by desylilation of intermediate 2 with tetrabu-
tylammonium fluoride (TBAF) in Tetrahydrofuran (THF),
yielded aryl acetylene3. Asa starting point for the development
of our solid-phase-based method, we chose phenylethynyl
bromide to construct unsymmetrical 1,3-diyne 5a, and the con-
version and purity were determined using high-performance
liquidchromatography (HPLC) analysis (Table 1). The effects
of the catalyst, solvent, and additive were initially investigated
for the solid-phase cross-coupling reaction.
As shown in entries 1–4 in Table 1, a variety of palladium
catalysts were examined in the presence of CuI at room tem-
perature for 24 h. The use of Pd2(dba)3 afforded the desired
unsymmetrical 1,3-diyne 5a in 27% overall yield with 86%
purity over five steps. Further optimization revealed that the
solvent played an important role in this process (Table 1,
entries 5–7). Thebestyield(49% overallyieldand92%purity)
was obtained when a catalytic amount of Pd2(dba)3 and CuI in
Et3N was used (Table 1, entry 6). Based on these results, we
next explored the effect of ligands while maintaining constant
concentration of Pd2(dba)3 and CuI in Et3N (Table 1, entries
8–10). Although the use of PPh3 and 1,3-bis(diphenylpho-
sphino)propane (Dppp) showed low reactivity, the addition
of tri(o-tolyl)phosphine (P(o-tol)3) furnished 5a in 45% yield.
Only a trace amount of the cross-coupled product 5a was
detected in the absence of the palladium catalyst, and low con-
version was observed with a catalytic amount of Pd2(dba)3 and
CuI in Et3N at higher temperatures (data not shown).
Using the Pd2(dba)3-catalyzed system (Table 1, entry 6),
we examined the generality and feasibility of our method
with a variety of substituted phenylethynyl bromides. All pro-
ducts were isolated via column chromatography and charac-
terized using HPLC and NMR. As shown in Table 2, the
solid-phase cross-coupling reaction allowed us to prepare var-
ious unsymmetrical 1,3-diynes bearing carboxylic acid with
electron-donating groups (Table 2, entries 2, 5, and 6) and
electron-withdrawing groups (Table 2, entries 3 and 4) on
the benzene ring. In general, electron-deficient phenylethynyl
bromide yielded higher amounts of 1,3-diynes compared to
electron-rich phenylethynyl bromide. Furthermore, terminal
alkynes containing the aminopyridine moiety could be con-
verted into the corresponding unsymmetrical 1,3-diyne scaf-
fold (Table 2, entry 7).
Overall, we developed a simple and robust synthetic
approach to prepare unsymmetrical 1,3-diynes bearing car-
boxylic acid utilizing a variety of substituted phenylethynyl
bromides under mild conditions. To the best of our knowl-
edge, this is the first example of unsymmetrical 1,3-diyne pre-
pared by solid-phase synthesis. Although overall yields are
Bull. Korean Chem. Soc. 2015, Vol. 36, 360–362
© 2014 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
moderate, this approach may be used to synthesize a broad
range of unsymmetrical 1,3-diynes bearing carboxylic acid,
and may be extended to prepare conjugated triynes or poly-
ynes in natural products or to generate combinatorial chemical
libraries.
(3×), DMF (3×), and THF (2×). This resin was then suspended
with THF and stirred with TBAF (1 M in THF, 2 equiv.) for 1
h. The resin was filtered, washed repeatedly with THF (5×)
and CH2Cl2 (2×), and dried in vacuo. Resin-bound alkyne 3
was swelled in degassed Et3N for 10 min. To this resin were
added phenylethynyl bromide (3 equiv.), CuI (0.1 equiv.),
andPd2(dba)3 (0.1 equiv.). Theresin wasstirred for24 hunder
Experimental
All reactions were run under N2 atmosphere except especially
indicated experiments. Anhydrous solvents were used for
most reactions. Solvents were purified by common distillation
methods. Some distilled solvents were degassed under N2 gas
flow through the solvent. 1H and 13C spectra were recorded on
BRUKER 300 and 600 MHz spectrometers. Chemical shifts
Table 1. Optimization of palladium-catalyzed cross-coupling of
polymer-bound alkyne 3 and phenylethynyl bromide.a
Total
Entry
Catalyst
Additive and solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Et3N (4 equiv.)/DMF
Et3N (4 equiv.)/DMF
Et3N (4 equiv.)/DMF
Et3N (4 equiv.)/DMF
Et3N/DMF (1:1)
Et3N
i-Pr2NH
PPh3 (0.2 equiv.)/Et3N
P(o-tol)3 (0.2 equiv.)/Et3N
Dppp (0.2 equiv.)/Et3N
24
14
27
26
10
49
37
11
45
37
1
are reported relative to internal CDCl3 (Me4Si, δ 0.0 for H
1
and CDCl3, 77.16 for 13C) and DMSO-d6 (δ 2.50 for H
and 39.52 for 13C). Analytical reverse-phase HPLC (RP-
HPLC) was performed on a Waters Alience 2695 separation
module, using a Waters 2487 dual λ absorbance detector
(Waters, MA, USA), equipped with Alience 2695 autosampler
and a Watchers® 120 ODS-BP Columns (120 Å pore size, 5 μ
M particle size, mobile phase A = 0.1% TFA in 95% H2O +
4.9% MeCN; mobile phase B = 0.1% TFA in 95% MeCN +
4.9% H2O). Linear gradients were run from 100:0 to 0:100
A:B over 25 min.
a Palladium-catalyzed cross-coupling reactions were performed with
0.08 mmol of alkyne 3, 0.1 equiv. of Pd catalyst, 0.1 equiv. of Cul,
additive, and solvent.
GeneralProcedureforthePreparationof1,3-diynes5a–5g
b Total yields were based on loading of 4-iodobenzoic acid on the Wang
resin and determined by HPLC analysis.
The Wang resin (0.9 mmoL/g) was swelled in CH2Cl2 for ~10
min. In sequential order, 4-iodobenzoic acid (2 equiv.), Et3N
(1.5 equiv.), EDCIÁHCl (2 equiv.), and HOBT (0.3 equiv.)
were added to the reaction vessel, and the reaction was stirred
for 18 h. The resin was filtered and washed repeatedly with
DMF (3×), CH2Cl2 (3×), and oxygen-free THF. The resin
was then suspended in degassed THF/Et3N (1:1) and stirred
with Pd(PPh3)4 (0.1 equiv.), CuI (0.1 equiv.), and trimethylsi-
lylacetylene (7 equiv.) for 48 h under a nitrogen atmosphere.
The resin was filtered and washed repeatedly with THF
Table 2. Palladium-catalyzed cross-coupling of polymer-bound
alkyne 3 and a variety of substituted phenylethynyl bromides.a
O
R
X
HO
5
Entry
Phenylethynyl bromide
Product
5a
Total yield (%)b
Br
Br
1
2
3
4
5
6
48
24
53
57
47
33
I
I
a
b
d
5b
O
OH
HO
+
O
1
F3C
EtO2C
O
Br
O
5c
TMS
c
Br
5d
Br
5e
O
O
Br
O
5f
O
2
3
Br
7
5g
42
N
a Palladium-catalyzed cross-coupling reactions were performed with
0.25 mmoL of polymer-bound alkyne 3, 0.1 equiv. of Pd2(dba)3, 0.1
equiv. of Cul, and 3 equiv. of phenylethynyl bromide in 4 mL of
degassed Et3N.
e
HO
O
O
O
b Isolated yield. Total yields were based on loading of 4-iodobenzoic acid
on the Wang resin.
4
5a
Scheme 1. Synthesis of conjugated 1,3-diynes.
Bull. Korean Chem. Soc. 2015, Vol. 36, 360–362
© 2014 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
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a nitrogen atmosphere. The resin was filtered, washed succes-
sively with DMF (2×), CH2Cl2 (2×), a solution of sodium
diethyldithiocarbamate (377 mg) and DIEA (0.33 mL) in
DMF, DMF (4×), CH2Cl2, and MeOH, and dried in vacuo.
The final compounds were cleaved from the resin by treatment
of TFA/ CH2Cl2 (1:1) for 1 h.
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5a: 1H-NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.97
(d, J = 8.0 Hz, 2H), 7.7 (d, J = 8.0 Hz, 2H), 7.63–7.66 (m,
2H), 7.43–7.53 (m, 3H); 13C-NMR (75 MHz, DMSO-d6) δ
166.48, 132.57, 132.48, 131.62, 130.24, 129.55, 128.95,
124.65, 120.11, 83.07, 80.87, 75.78, 73.17.
5b: 1H-NMR (300 MHz, DMSO-d6) δ 7.95 (d, J = 8.7 Hz,
2H), 7.68 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.26 (d,
J = 8.1 Hz, 2H); 13C-NMR (75 MHz, DMSO-d6) δ 171.19,
166.67, 140.38, 132.41, 129.58, 129.50, 124.20, 117.10,
83.26, 80.79, 75.71, 72.76, 21.18.
5c: 1H-NMR (300 MHz, DMSO-d6) δ 7.98 (d, J = 8.4 Hz,
2H), 7.90–7.88 (m, 4H), 7.75 (d, J = 8.4 Hz, 2H); 13C-NMR
(150 MHz, DMSO-d6) δ 166.18, 133.07, 132.46, 131.78,
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122.65, 81.92, 81.09, 75.20, 75.06.
5d: 1H-NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H),
7.97–8.01 (m, 4H), 7.72–7.78 (m, 4H), 4.33 (q, J = 7.1 Hz,
2H), 1.33 (t, J = 7.1 Hz, 3H); 13C-NMR (75 MHz, DMSO-
d6) δ 166.44, 164.87, 132.79, 132.76, 131.91, 130.74,
129.55, 129.38, 124.76, 124.27, 82.20, 81.85, 75.68, 75.31,
61.12, 14.06.
5e: 1H-NMR (300 MHz, DMSO-d6) δ 13.22 (s, 1H), 7.95
(d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.58 (d, J =
8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 3.80 (s, 3H); 13C-
NMR (75 MHz, DMSO-d6) δ 166.99, 161.15, 134.82,
132.93, 131.86, 130.03, 125.47, 115.17, 112.29, 84.09,
80.82, 76.76, 72.61, 55.91.
5f: 1H-NMR (300 MHz, DMSO-d6) δ 7.97 (d, J = 8.1 Hz,
2H), 7.71–7.78 (m, 8H), 7.39–7.52 (m, 3H); 13C-NMR (75
MHz, DMSO-d6) δ 174.74, 166.50, 141.68, 138.83, 133.16,
132.61, 131.59, 129.59, 129.11, 127.12, 126.81, 124.73,
119.05, 83.07, 81.22, 75.93, 73.90.
5g: 1H-NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 8.64
(d, J = 4.7 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.86–7.92 (m,
3H), 7.74–7.77 (m, 3H), 7.48–7.52 (m, 1H); 13C-NMR (75
MHz, DMSO-d6) δ 166.46, 150.59, 140.52, 137.01, 132.80,
132.02, 129.58, 128.64, 124.75, 124.13, 82.02, 81.44,
75.15, 71.96.
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Acknowledgments. This study was financially supported by
research fund of Chungnam National University in 2010.
Bull. Korean Chem. Soc. 2015, Vol. 36, 360–362
© 2014 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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