Pd(II)-catalyzed dehydrogenative olefination of terminal arylalkynes with allylic ethers: General and selective access to linear (Z)-1,3-enynes

Article abstract of DOI:10.1021/ol302400p

This work demonstrates a green and efficient method to prepare 1,3-enynes via Pd(II)-catalyzed direct dehydrogenative olefination of terminal arylalkynes with unactived allylic ethers. Various terminal arylalkynes can participate in the reaction, stereoselectively affording the desired conjugated (Z)-1,3-enynes in moderate to good yields.

Full text of DOI:10.1021/ol302400p

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5242–5245
Pd(II)-Catalyzed Dehydrogenative
Olefination of Terminal Arylalkynes with
Allylic Ethers: General and Selective
Access to Linear (Z)‑1,3-Enynes
Yin-Lin Shao,† Xiao-Hong Zhang,*,† Jiang-Sheng Han,† and Ping Zhong*,†,‡
College of Chemistry and Materials Engineering and Oujiang College,
Wenzhou University, Wenzhou 325035, China
kamenzxh@163.com; zhongp0512@163.com
Received August 29, 2012
ABSTRACT
This work demonstrates a green and efficient method to prepare 1,3-enynes via Pd(II)-catalyzed direct dehydrogenative olefination of terminal
arylalkynes with unactived allylic ethers. Various terminal arylalkynes can participate in the reaction, stereoselectively affording the desired
conjugated (Z)-1,3-enynes in moderate to good yields.
The conjugated 1,3-enyne moiety is an important unit
found in many naturally occurring and pharmaceutically
active compounds.1 For example, terbinafine, bearing the
1,3-enyne moiety, is used in the treatment of superficial
fungal infections due to its biological activity.2 In addition,
1,3-enynes are also efficient precursors to naphthalenes,3
heterocyclic compounds,4 and conjugated alkenes.5 Owing
to their great importance, the preparation of 1,3-enynes
has been an area of considerable activity in recent years.6
Among various methods available for 1,3-enynes, the tra-
ditional PdÀCu-catalyzed7 or Pd-catalyzed8 Sonogashira
coupling reaction of terminal alkynes with vinyl halide is
the most convenient and prevalent. At present, most
investigations were mainly aimed toward the development
of inexpensive catalysts such as copper9 and iron10 instead
† College of Chemistry and Materials Engineering.
‡ Oujiang College.
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(7) For selected papers on the PdÀCu-catalyzed Sonogashira cou-
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G. Eur. J. Org. Chem. 2008, 377. (b) Li, J. H.; Zhang, X. D.; Xie, Y. X.
Eur. J. Org. Chem. 2005, 4256. (c) Novak, Z.; Szabo, A.; Repasi, J.;
Kotschy, A. J. Org. Chem. 2003, 68, 3327.
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Org. Biomol. Chem. 2012, 10, 2960. (b) Chen, J. L.; Zheng, F.; Huang,
Y. G.; Qing, F. L. J. Org. Chem. 2011, 76, 6525.
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(6) For selected papers on the synthesis of 1,3-enyne, see: (a) Haug,
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r
10.1021/ol302400p
Published on Web 10/01/2012
2012 American Chemical Society

of PdÀCu (or Pd) as catalyst to improve the Sonogashira
coupling reaction. Although remarkable progress has been
achieved in terms of catalysts, these reactions are depen-
dent on preactivation of alkene with halide to form the
substrate of vinyl halide, which requires several extra
synthetic steps and generate waste. The overall process is
neither atom-economical nor green. Therefore, more effi-
cient and green protocols to prepare 1,3-enyne would be
highly desirable.
Recently, significant progress has been achieved for the
synthesis of conjugated dienes via Pd-catalyzed direct
dehydrogenative olefination of sp2 CÀH bonds with allylic
esters.11 These excellent works urged us to postulate that
1,3-enyne could be obtained via Pd-catalyzed direct dehy-
drogenative olefination of terminal alkynes (sp CÀH
bonds) with unactived alkene (sp2 CÀH bonds, such as
allylic ethers, etc.), which exemplifies the ideals of atom
and step economy. Fortunately, we successfully accom-
plished the first example of Pd(OAc)2-catalyzed direct
dehydrogenative olefination of terminal arylalkynes with
the commercially available allylic ether, stereoselectively
affording (Z)-1,3-enyne derivatives as the sole products.
Herein, we report the results in detail.
be dramatically increased to 76% when the reaction was
conducted under N2 atmosphere (entry 15). To our de-
light, the reaction stereoselectively afforded the conjugated
(Z)-(5-methoxypent-3-en-1-ynyl)benzene (3), whose con-
figuration was confirmed based on the Noesy spectra and
J value. Unfortunately, decreasing the amount of allyl
methyl ether 2a to 1.5 mmol (5 equiv) resulted in a lower
yield of 51% (entry 16). As the amount of allyl methyl
ether 2a was further increased to 4.5 mmol (15 equiv), no
obvious increase of the yield was observed (entry 17). The
reaction temperature and time were next screened, and it
was found that lower or higher reaction temperature led
to the low conversion as well as shortening the reaction
time to 24 h (entries 18À20). Thus the optimal condi-
tion was finally identified as follows: phenylacetylene
(1.0 equiv), allyl methyl ether (10 equiv), Pd(OAc)2
(5 mol %), DPPP (6 mol %), HOAc/MeCN (v/v = 1:3),
80 °C, 48 h under N2. Notably, entries 1À20 are only a
sampling of over 50 reactions that have been screened by
using different catalysts, ligands, additives, oxidants, bases,
and solvents (see Supporting Information).
We chose phenylacetylene 1a and allyl methyl ether 2a as
the model substrates to optimize suitable conditions for
this reaction. First, the amount of allyl methyl ether 2a was
selected as 2 equiv, while the homocoupled product 3a
dominated in the reaction and only a few of target product
3 can be detected by GC-MS, which may result from the
instability of the allyl methyl ether under such a catalytic
system. So a large excess of allyl methyl ether (2a, 10 equiv)
was used to detect the optimal reaction conditions. During
the investigation, it was found that the solvents, catalysts,
temperature, and ligands critically affected the dehydro-
genative cross-coupling reaction efficiency (Table 1). Sol-
vents such as HOAc/DMF, HOAc/DCE, HOAc, MeCN,
and DMSO were ineffective (entries 2À6), whereas 15%
yield of 3 was obtained by the addition of 25 vol % HOAc
as cosolvent into MeCN (entry 1) when using Pd(OAc)2
as catalyst and bpy as ligand at 80 °C. The solvent effect
indicates that a specified volume of HOAc plays an
important role in this reaction. The low yield of 15%
urged us to seek optimal reaction conditions. Then
different catalysts such as Pd(PPh3)4, Pd2(dba)3, PdCl2,
and Pd(CF3COO)2 were screened to give worse results
than Pd(OAc)2 (entries 7À10). After a series of tests, we
were pleased to find that the ligands had a dramatic
effect on the yield. Among the ligands screened, 1,3-
bis(diphenylphosphino)propane (DPPP) turned out to
be the best, affording 3 in 43% yield, while 1,10-phenan-
throline, tetramethylethylenediamine (TMEDA), and triphe-
nylphosphine (PPh3) were not that effective (entries 11À14).
Remarkably, the yield of cross-coupling product 3 could
Table 1. Reaction Condition Optimizationa
entry
catalyst
ligand
solventb
yield (%)c
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
PdCl2
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
HOAc/MeCN
HOAc
15
trace
trace
NR
MeCN
DMSO
HOAc/DMF
HOAc/DCE
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
trace
trace
trace
NR
11
10 Pd(CF3COO)2 bpy
NR
11 Pd(OAc)2
12 Pd(OAc)2
13 Pd(OAc)2
14 Pd(OAc)2
15d Pd(OAc)2
16d Pd(OAc)2
17d Pd(OAc)2
18d Pd(OAc)2
19d Pd(OAc)2
20d Pd(OAc)2
1,10-phenanthroline HOAc/MeCN
15
TMEDA
PPh3
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
trace
trace
43
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
HOAc/MeCN 76
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
HOAc/MeCN
51e
77f
66g
51h
30i
a Reaction conditions: phenylacetylene 1a (0.3 mmol), allyl methyl
ether 2a (3.0 mmol), catalyst (5 mol %), ligand (6 mol %), solvent
(2 mL), 80 °C, 48 h. b v/v = 1:3. c Isolated yields. d Reaction carried out
under N2. e Allyl methyl ether 2a (1.5 mmol). f Allyl methyl ether 2a
(4.5 mmol). g Shorten the reaction to 24 h. h At 40 °C. i 110 °C.
(11) For selected dehydrogenative olefination reactions, see: (a)
Rodriguez, A.; Moran, W. J. Eur. J. Org. Chem. 2009, 1313. (b) Zhang,
Y. Z.; Li, Z. J.; Liu, Z. Q. Org. Lett. 2012, 14, 226. (c) Chen, F.; Feng, Z.;
He, C. Y.; Wang, H. Y.; Guo, Y. L.; Zhang, X. G. Org. Lett. 2012, 14,
1176. (d) Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012,
14, 1760. (e) Zhang, Y. X.; Cui, Z. L.; Li, Z. J.; Liu, Z. Q. Org. Lett. 2012,
14, 1838.
With the optimal catalytic system in hand, the scope of
terminal alkynes was next investigated (Table 2). As
expected, various arylacetylenes worked well under the
reaction conditions. A range of functional groups, such as
Org. Lett., Vol. 14, No. 20, 2012
5243

methyl, ethyl, n-butyl, methoxyl, chloro, fluoro, bromo,
and nitro groups, were tolerated in this dehydrogenative
olefination procedure. In generally, the electron-donating
substituents on the phenyl ring of arylacetylene were
beneficial for the transformation, whereas an electron-
withdrawing group decreased the efficiency. For example,
the arylacetylenes with methyl, ethyl, n-butyl, and meth-
oxyl groups (entries 1À6) gave the dehydrogenative pro-
ducts in more than 65% yields, while their chloro, fluoro,
bromo, and nitro equivalents generated the corresponding
products in less than 50% yields (entries 7À11). However,
steric hindrance affected the efficiency slightly. Substrates
with para-methyl and para-chloro gave similar yields as
their meta-methyl and meta-chloro equivalents (entries 2,
3, 7, and 8). To our delight, treatment of phenylacetylene
with allyl methyl sulfide also afforded the 1,3-enyne product
14, but the yield was decreased to 25% (entry 12). Unfortu-
nately, the aliphatic terminal alkyne such as 1-hexyne was
intolerant to the catalytic system (entry 13).
Subsequently, promoted by the successful Pd-catalyzed
direct dehydrogenative olefination of arylacetylene with
allyl methyl ether, allyl phenyl ether was also examined
with respect to various arylacetylenes to synthesize 1,3-
eyene compounds (Table 3). Evidently, allyl phenyl ether
was found to be more reactive than allyl methyl ether,
which may be attributed to the more stable nature of allyl
phenyl ether. The targeted 1,3-enyne products were obtained
in good yields ranging from 49 to 88%. Similarly, arylacety-
lenes possessing electron-donating functional groups favored
the dehydrogenative cross-coupling reaction (entries 1À6)
more than those with electron-withdrawing groups (entries
7À11). When the substrate scope was extended to 4-nitro-
phenylacetylene, the corresponding 1,3-enyne was obtained
in a lower 49% yield (entry 11). Furthermore, the reaction
between allyl phenyl ether and 1-hexyne cannot be observed
in the optimal condition (entry 12).
Table 2. Pd-Catalyzed Dehydrogenative Olefination of Term-
inal Alkynes with Allyl Methyl Ethers (Sulfide)a,b
Table 3. Pd-Catalyzed Dehydrogenative Olefination of
Terminal Alkynes with Allyl Phenyl Ethersa,b
a Reaction conditions: arylacetylene (0.3 mmol), allyl methyl ether
(3.0 mmol), Pd(OAc)2 (5 mol %), DPPP (6 mol %), solvent (2 mL, v/v =
1:3), 80 °C, 48 h. b Isolated yields.
a Reaction conditions: arylacetylene (0.3 mmol), allyl phenyl ether
(3.0 mmol), Pd(OAc)2 (5 mol %), DPPP (6 mol %), solvent (2 mL, v/v =
1:3), 80 °C, 48 h. b Isolated yields.
5244
Org. Lett., Vol. 14, No. 20, 2012

In conclusion, we have developed an efficient and
green protocol to synthesize 1,3-enyne compounds via
Pd(OAc)2-catalyzed direct dehydrogenative olefination
of terminal arylalkynes with unactived allylic ethers
(10 equiv), which does not require the preactivation of
alkene with halide to form the substrate of vinyl halide
and exemplifies the ideals of atom and step economy.
Various terminal arylalkynes can participate in the
reaction, stereoselectively affording the desired conju-
gated (Z)-1,3-enynes in moderate to good yield. Further
studies on the mechanism of the reaction are ongoing in
our laboratory.
Acknowledgment. The authors thank the National Nat-
ural Science Foundation of China (No. 20972114), the
Zhejiang Provincial Natural Science Foundation of China
(Y4100578), and the Opening Foundation of Zhejiang
Provincial Top Key Discipline (100061200140).
Supporting Information Available. Description of ex-
perimental procedures and full characterization of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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