Pd-catalyzed coupling reaction of acid chlorides with terminal alkynes using 1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene ligand

Article abstract of DOI:10.1016/j.tetlet.2012.01.105

In the presence of 1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene as a ligand, the direct synthesis of alkynones has accomplished by a Pd-catalyzed coupling reaction of acid chlorides with terminal acetylenes under mild conditions.

Full text of DOI:10.1016/j.tetlet.2012.01.105

Tetrahedron Letters 53 (2012) 1764–1767
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Pd-catalyzed coupling reaction of acid chlorides with terminal alkynes using
1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene ligand
⇑
Shingo Atobe, Haruna Masuno, Motohiro Sonoda , Yuki Suzuki, Hiroyuki Shinohara, Satoshi Shibata,
Akiya Ogawa
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuencho, Nakaku, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of 1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene as a ligand, the direct synthesis of
alkynones has accomplished by a Pd-catalyzed coupling reaction of acid chlorides with terminal acety-
lenes under mild conditions.
Received 28 December 2011
Revised 20 January 2012
Accepted 23 January 2012
Available online 31 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
trans-Spanning ligand
Acetylene
Acid chloride
Alkynone
Alkynones are useful intermediate in organic synthesis, espe-
cially for the synthesis of cyclic compounds such as N-heterocy-
cles,1 furans,2 and others,3,4 though the synthetic methods of
alkynones have not been developed markedly. A general procedure
for the synthesis of alkynones has been established by using an
oxidation of propargylic alcohols which are obtained from a nucle-
ophilic addition reaction of anionic acetylide to aldehydes.5 With
regard to a transition-metal-catalyzed reaction, Sonogashira et al.
reported that a direct coupling reaction of acid chlorides with ter-
minal acetylenes afforded various alkynones directly under mild
conditions.6,7 Despite of the convenience of this method, the reac-
tion often suffered from the formation of diynes, generated from
terminal acetylenes due to the presence of Cu co-catalysts. From
this viewpoint, there are some reports of Pd-catalyzed coupling
reactions of acid chlorides with acetylenes under copper-free con-
ditions.8 Recently, we have reported a copper-free Sonogashira
coupling reaction9 using a rigid trans-spanning ligand 1 or 2
(Fig. 1). In the course of the study, we examined the direct synthe-
sis of alkynones using trans-spanning ligands. Here, we disclose a
Pd-catalyzed coupling reaction of acid chlorides with terminal
acetylenes using 1-(2-pyridylethynyl)-2-(2-thienylethynyl)ben-
zene (3) as a trans-spanning ligand.9b,10
S
N
S
S
N
N
1
2
3
Figure 1. Rigid trans-spanning ligands.
(0.01 mmol), and triethylamine (1.7 mmol) was stirred in acetoni-
trile (1.5 mL) at 40 °C, the desired coupling product 6a was ob-
tained in 56% yield (Table 1, entry 1). To optimize the reaction
conditions, several solvents, bases, or catalysts were also exam-
ined. The use of diisopropylethylamine, pyridine, or K2CO3 as a
base was not effective for this reaction (entries 2–4). Chloroform
and toluene were found to be favorable solvents. When the reac-
tion was conducted in chloroform or toluene, 6a was obtained in
71% or 81% yields, respectively, though the reaction in DMF did
not proceed at all (entries 5–7). In the presence of Pd(PPh3)4 or
Pd(OAc)2 as a catalyst, the desired coupling reaction proceeded
to give 6a in 72% or 44% yield, respectively (entries 8 and 9). From
these results, the reaction conditions in entry 7 were employed as
the optimized conditions unless otherwise noted.
First, we examined a coupling reaction of benzoyl chloride (4a)
with 1-octyne (5a) using the ligand 3. When a mixture of 4a
(0.6 mmol), 5a (0.5 mmol), PdCl2(PPh3)2 (0.01 mmol),
3
Next, other trans-spanning ligands were employed under the
optimized conditions (Scheme 1). In contrast to the result of the
reaction using 3, the use of ligand 1, which would coordinate
⇑
Corresponding author. Tel.: +81 72 254 9295; fax: +81 72 254 9290.
E-mail address: sonoda@chem.osakafu-u.ac.jp (M. Sonoda).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.105

S. Atobe et al. / Tetrahedron Letters 53 (2012) 1764–1767
1765
Table 1
PdCl2(PPh3)2 2 mol%
additive 2 mol%
O
O
Optimization of the reaction conditions
n
+
C6H13
Cl
toluene, NEt3
40 oC, 5 h
cat. [Pd] 2 mol%
2 mol%
O
O
n
C6H13
3
+
nC6H13
Cl
base, solvent
40 oC, 5 h
4a
5a
6a
nC6H13
additive:
1
2
3
32%
16%
81%
11%
42%
32%
11%
4a
Entry
5a
6a
Cat. [Pd]
Base
Solvent
Yielda (%)
S
N
7 (4 mol%)
8 (4 mol%)
8
7
1
2
3
4
5
6
7
8
9
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
NEt3
CH3CN
CH3CN
CH3CN
CH3CN
DMF
56
ND
9
ND
ND
71
81
72
44
NEtiPr2
Pyridine
K2CO3
NEt3
7 (2 mol%) + 8 (2 mol%)
none
Scheme 1. Coupling reactions in the presence of ethynylbenzenes.
NEt3
NEt3
NEt3
NEt3
CHCl3
Toluene
Toluene
Toluene
simultaneously, an enhancement of the reactivity was not ob-
served. This implied that the trans-bidentatable structure of the li-
gand was important for this coupling reaction. In the absence of
any ligand, the desired product 6a was obtained in 11% yield.
The reactions of various acid chlorides with 1-octyne were
examined and the results were summarized in Table 2.11 4-Meth-
ylbenzoyl chloride (4b) showed good reactivity to give the
corresponding product 6b in 94% yield (entry 2). Both 4-methoxy-
benzoyl chloride (4c) and 4-chlorobenzoyl chloride (4d) were also
converted into the corresponding products 6c (99%) and 6d (73%),
respectively (entries 3 and 4). Unfortunately, the reaction of
Pd(OAc)2
a
Determined by 1H NMR.
relatively weakly to palladium, or 2, which would coordinate
strongly, was found to be ineffective and most of the starting mate-
rial 5a was recovered. Both 2-(phenylethynyl)pyridine (7) and 2-
(phenylethynyl)thiophene (8), which are the half structure of the
bidentatable ligand 3, were employed instead of 3 to give 6a in
11% and 42% yields, respectively. Even when 7 and 8 were used
Table 2
Coupling reaction using various acid chlorides
PdCl2(PPh3)2 2 mol%
O
3 2 mol%
O
nC6H13
+
R
R
Cl
NEt3, toluene
40 oC, 5 h
nC6H13
4
5a
6
Entry
1
4
Product
Yielda (%)
O
O
O
O
6a, 78
Cl
Cl
Cl
4a
4b
nC6H13
O
2
3
6b, 94
6c, 99
nC6H13
O
4c
4d
nC6H13
MeO
Cl
MeO
O
O
O
Cl
Cl
4
5
6d, 73
6e, 15
nC6H13
Cl
O
4e
4f
nC6H13
OMe
O
OMe
O
6
6f, 77
Cl
nC6H13
O
O
7b
8
6g, 76
4g
4h
Cl
nC6H13
O
O
6h, Tracec
Cl
nC6H13
a
b
c
Isolated yield.
80 °C, 17 h.
Determined by 1H NMR.

1766
S. Atobe et al. / Tetrahedron Letters 53 (2012) 1764–1767
Table 3
Next, the reactions of various terminal acetylenes with 4a were
examined. The results were summarized in Table 3.11 5-Hexynenit-
rile (5b) showed a good reactivity to give 9b in good yield (entry 1).
When 1-ethynylcyclohexene (5c) was employed as a conjugated
enyne for this reaction, the corresponding coupling product 9c
was obtained in 68% yield (entry 2). Aromatic acetylenes, such as
phenylacetylene (5d), 4-tolylacetylene (5e), 4-methoxyphenyl-
acetylene (5f), and 4-trifluoromethylphenylacetylene (5g) were
all favorable substrates and the corresponding products 9d, 9e,
9f, and 9g were obtained in high yields, respectively (entries 3–
6). In contrast, the reaction of 2-ethynylpyridine (5h) with 4a affor-
ded the coupling product 9h in relatively low yield (39%) (entry 7).
A coordination of nitrogen atom in pyridine ring to the palladium
might have inhibited the desired reaction. Both mono-protected
alkynes, 2-methyl-3-butyn-2-ol (5i) and triisopropylsilyl acetylene
(5j), reacted effectively with 4a to give the corresponding alkynon-
es 9i and 9j, which can be employed in further transformation after
deprotection, in high yields, respectively (entries 8 and 9). In the
case of the reaction of 5-hexyn-1-ol (5k) with 4a, a trace amount
of the desired product 9k was detected (entry 10).12 Interestingly,
in this reaction an esterification of 4a prior to the coupling reaction
proceeded to afford an ester 10 and its coupling product 11 in 32%
and 10% yields, respectively. Therefore, when the reaction was con-
ducted by using 2 equiv of 4a, a tandem esterification and the fol-
lowing coupling product 11 was obtained in 62% yield (Scheme 2).
Although a role of the trans-spanning ligand 3 is unclear, trans-
[PdCl{C(@O)R}Á3] complex, which would be formed after oxidative
addition of acid chloride to palladium metal and the following
isomerization from cis- to trans-form of complex by the aid of 3,
might be a key intermediate in the catalytic cycle.
Coupling reaction using various terminal acetylenes
PdCl2(PPh3)2 2 mol%
O
3 2 mol%
O
+
R
R
Ph
Cl
NEt3, toluene
40 oC, 5 h
Ph
4a
5
9
Entry
1
5
Product
Yielda (%)
O
CN
CN
9b, 82
5b
5c
Ph
O
2
9c, 68
9d, 94
9e, 85
9f, 84
Ph
O
3
5d
5e
Ph
O
4
Ph
O
OMe
CF3
5
OMe
CF3
5f
5g
5h
Ph
O
6
9g, 85
9h, 39
9i, 99
Ph
O
7b
8
Ph
O
N
N
OH
5i
5j
OH
Ph
O
TIPS
9
9j, 71
TIPS
In summary, we have developed the direct synthesis of the con-
jugated alkynones by the palladium-catalyzed coupling reaction of
acid chlorides with terminal acetylenes using the rigid trans-
spanning ligand 3. Mechanistic studies to clarify the role of
trans-spanning ligand are now in progress.
Ph
O
OH
10
9k, Tracec
OH
5k
Ph
a
b
c
Isolated yield.
Ambient temperature, 2 h.
Determined by 1H NMR.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.105.
O
PdCl2(PPh3)2 2 mol%
Cl
O
3 2 mol%
References and notes
O
NEt3, toluene
40 oC, 5 h
4a
5k
, 1.0 mmol
1. For N-heterocycles, see; (a) Willy, B.; Müller, T. J. J. Org. Lett. 2011, 13, 2082–
2085; (b) Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626–
1632; (c) Grotjahn, D. B.; Van, S.; Combs, D.; Lev, D. A.; Schneider, C.; Rideout,
M.; Meyer, C.; Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200–9209;
(d) Obrecht, D.; Zumbrunn, C.; Müller, K. J. Org. Chem. 1999, 64, 6891–6895.
2. For furan derivatives, see; (a) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J.
T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452; (b)
Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850–852; (c) Wills, M. S. B.;
Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378–9379; (d) Jeevanandam, A.;
Narkunan, K.; Ling, Y.-C. J. Org. Chem. 2001, 66, 6014–6020.
+
10
OH
coupling
reaction
, 0.5 mmol
O
O
O
3. For other heterocycles, see; (a) Egi, M.; Azechi, K.; Saneto, M.; Shimizu, K.; Akai,
S. J. Org. Chem. 2010, 75, 2123–2126; (b) Ciesielski, J.; Canterbury, D. P.;
Frontier, A. J. Org. Lett. 2009, 11, 4374–4377; (c) Chen, G.; Zeng, R.; Gu, Z.; Fu, C.;
11
, 62%
´
Ma, S. Org. Lett. 2008, 10, 4235–4238; (d) Doubsky, J.; Streinz, L.; Šaman, D.;
Zedník, J.; Koutek, B. Org. Lett. 2004, 6, 4909–4911.
Scheme 2. A tandem esterification and coupling reaction of 5k.
4. For other usage of alkynones, see; (a) Masaki, T.; Kawano, K.; Sugimura, T. J. Am.
Chem. Soc. 2011, 133, 5695–5697; (b) Wender, P. A.; Stemmler, R. T.; Sirois, L. E.
J. Am. Chem. Soc. 2010, 132, 2532–2533; (c) Brummond, K. M.; Chen, D. Org. Lett.
2008, 10, 705–708; (d) Leung, L. T.; Leung, S. K.; Chiu, P. Org. Lett. 2005, 7, 5249–
5252; (e) Pu, X.; Ma, D. J. Org. Chem. 2003, 68, 4400–4405; (f) Pastine, S. J.;
Sames, D. Org. Lett. 2003, 5, 4053–4055; (g) Nielsen, T. E.; de Dios, M. A. C.;
Tanner, D. J. Org. Chem. 2002, 67, 7309–7313; (h) Dodero, V. I.; Koll, L. C.;
Faraoni, M. B.; Mitchell, T. N.; Podestá, J. C. J. Org. Chem. 2003, 68, 10087–10091;
(i) Van den Hoven, B. G.; Ali, B. E.; Alper, H. . J. Org. Chem 2000, 65, 4131–4137;
(j) Spino, C.; Barriault, N. J. Org. Chem. 1999, 64, 5292–5298.
2-methoxybenzoyl chloride (4e) resulted in a formation of com-
plex mixture including 6e (15%) (entry 5). Aliphatic acid chloride
such as cyclohexanecarboxylic acid chloride (4f) reacted with 5a
to give 6f in good yield (77%) (entry 6). Although the reaction of
sterically hindered pivaloyl chloride (4g) did not proceed at
40 °C, higher temperature (80 °C) and prolonged reaction time re-
sulted in the formation of the corresponding product 6g in 76%
yield (entry 7). Acetyl chloride (4h) was found to be unsuitable
for this reaction, and a complex mixture, including a trace amount
of 6h, was obtained (entry 8).
5. For the approach for alkynones via propargyl alcohols, see; (a) Maeda, Y.;
Kakiuchi, N.; Matsumura, S.; Nishimura, T.; Kawamura, T.; Uemura, S. J. Org.
Chem. 2002, 67, 6718–6724; (b) Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem.
1996, 61, 4439–4449.
6. Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977, 777–778.

S. Atobe et al. / Tetrahedron Letters 53 (2012) 1764–1767
1767
7. For synthesis of alkynones, see; (a) Kawaguchi, S-i.; Srivastava, P.; Engman, L.
Tetrahedron Lett. 2011, 52, 4120–4122; (b) Wu, X.-F.; Sundararaju, B.;
Neoumann, H.; Dixneuf, N. P.; Beller, M. Chem. Eur. J. 2011, 17, 106–110; (c)
Nishihara, Y.; Saito, D.; Inoue, E.; Okada, Y.; Miyazaki, M.; Inoue, Y.; Takagi, K.
Tetrahedron Lett. 2010, 51, 306–308; (d) Liu, J.; Peng, X.; Sun, W.; Zhao, Y.; Xia,
C. Org. Lett. 2008, 10, 3933–3936; (e) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.;
Charmant, J. P. H.; Kantacha, A. Chem. Commun. 2005, 1037–1039; (f) Liang, B.;
Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem.
2005, 70, 6097–6100; (g) Ahmed, M. S. M.; Sekiguchi, A.; Masui, K.; Mori, A.
Bull. Chem. Soc. Jpn. 2005, 78, 160–168; (h) Oh, C. H.; Reddy, V. R. Tetrahedron
Lett. 2004, 45, 8545–8548; (i) Jackson, M. M.; Leverett, C.; Toczko, J. F.; Roberts,
J. C. J. Org. Chem. 2002, 67, 5032–5035.
Acta 2008, 91, 259–264; (b) Palimkar, S. S.; Kumar, P. H.; Jogdand, N. R.; Daniel,
T.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron Lett. 2006, 47, 5527–5530; (c)
Alonso, D. A.; Nájera, C.; Pacheco, M. C. J. Org. Chem. 2004, 69, 1615–1619.
9. (a) Atobe, S.; Sonoda, M.; Suzuki, Y.; Shinohara, H.; Yamamoto, T.; Ogawa, A.
Chem. Lett. 2011, 40, 925–927; (b) Atobe, S.; Sonoda, M.; Suzuki, Y.; Yamamoto,
T.; Masuno, H.; Shinohara, H.; Ogawa, A. Res. Chem. Intermed. , in press.
10. Unfortunately, we could not achieve the crystal structure analysis. However,
DFT calculation indicated that trans-[Pd(PPh3)2Á3] is comfortable than the cis-
complex.
11. In most cases, neither diynes nor enynes, generated from 5, were detected by
1H NMR, whereas acid anhydrides, elaborated from acid chlorides, were
observed.
8. For examples of Pd-catalyzed coupling reactions of acid halides with alkynes,
see; (a) Likhar, P. R.; Subhas, M. S.; Roy, M.; Roy, S.; Kantam, M. L. . Helv. Chim.
12. Formation of the coupling product 9k was confirmed by 1H NMR, though it
could not be isolated from the resulting reaction mixture.