Discovery of a novel palladium catalyst for the preparation of enynes with a copper- and ligand-free Sonogashira reaction

Article abstract of DOI:10.1055/s-0031-1290938

A new palladium(II) complex based on N,N-dimethylethanolamine, (SP-4-1)-bis[N,N-dimethylaminoethoxy-kN,O]palladium(II) which coordinates with two moles of AcOH, has been synthesized. The structure of the complex has been established by X-ray diffraction a

Full text of DOI:10.1055/s-0031-1290938

LETTER
▌1257
lDettierscovery of A Novel Palladium Catalyst for the Preparation of Enynes with a
Copper- and Ligand-Free Sonogashira Reaction
Novel Palladium Catalyst for Preparation of Enynes
Xia Mi, Mengmeng Huang,* Yujian Feng, Yangjie Wu*
Chemistry Department, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan
Universities, Zhengzhou University, Zhengzhou 450052, P. R. of China
Fax +86(371)67979408; E-mail: wyj@zzu.edu.cn; E-mail: hmm@zzu.edu.cn
Received: 01.01.2012; Accepted after revision: 17.03.2012
the preparation method for alkoxypalladium complex
Abstract: A new palladium(II) complex based on N,N-dimethyle-
based on N,N-dimethylethanolamine, X-ray diffraction
thanolamine, (SP-4-1′)-bis[N,N-dimethylaminoethoxy-kN,O]palla-
analysis of bis[N,N-dimethylaminoethoxy-κN,O]palladi-
um(II) (2), and its catalytic activities in copper- and li-
dium(II) which coordinates with two moles of AcOH, has been
synthesized. The structure of the complex has been established by
X-ray diffraction analysis. Using this complex as a catalyst, a series gand-free Sonogashira reaction for preparation of the
of conjugated enynes were successfully synthesized by Sonogashira
cross-coupling reaction in the absence of co-catalyst CuX and any
enynes.
The di(aminoalkoxy)palladium complex 2 can be ob-
ligand at room temperature during 20 hours affording the corre-
tained with the reaction between Pd(OAc)2 and N,N-di-
methylethanolamine by elimination of two equivalents of
acetic acid to give a good yield (Scheme 1).
sponding products in moderate to excellent yields. The optimized
catalytic systems are tolerant in the presence of a broad variety of
functional groups in the substrates. The catalytic system was found
to be ineffective for vinyl chloride. Moreover, it was found that (Z)-
β-bromostyrene reacts with terminal alkynes with retention of the
steric configuration and the transformation of most of the Z-isomer
did not occur in this reaction.
O
Me
Pd(OAc)2
Me
Me
N
N
Me
Pd
O
2 Me2NCH2CH2OH
1
Key words: N,N-dimethylethanolamine, copper-free, ligand-free,
Sonogashira reaction, enyne, β-bromostyrene, stereochemistry
2 (80%)
Scheme 1 Synthesis of palladium complex 2
The palladium-catalyzed Sonogashira reaction is an im-
portant method in organic synthesis.1 In particular, enynes
– the main products of this reaction – can be used to syn-
thesize heterocyclic compounds2 and conjugated alkenes.3
In addition, the conjugated enyne is a structure of high in-
terest owing to its presence in many natural products and
biologically active compounds.4 For example, this struc-
ture is present in trans-kumausyne, calicheamycin and
terbinafine.5 The Sonogashira coupling reaction usually
requires co-catalyst CuX(I) and other activator.6 More-
over, there have been a large number of publications con-
cerning Sonogashira reaction catalyzed by other metal
complexes, e.g. Ni,7 Cu(I)8 and Cu(II)9 complexes, but the
reactions usually proceed under severe reaction condi-
tions or with phosphorus-containing additives.10 In the
last decade, copper- and ligand-free palladium-catalyzed
Sonogashira coupling reaction has been a novel indepen-
dent research direction.Therefore, design and synthesis of
novel and active catalysts are at the core of our research.
Recently, only one paper has reported that alkoxypalladi-
um complex [(HOCH2CH2)2NCH2CH2O]2Pd has been
used as an effective catalyst in Suzuki11 reaction. But
there is no report concerning the catalytic activity in the
reaction of β-bromostyrene with terminal alkynes. In our
continuous research12 on this reaction, we intend to study
Complex 2 was adequately characterized by NMR spec-
troscopy, mass spectrometry, and elemental analysis.
NMR data revealed that in spite of the presence of two
moles of AcOH, the Pd–O bonds did not cleave even in a
solution. The structure of 2 in crystalline state was estab-
lished by X-ray diffraction analysis (Figure 1).13
Figure 1 Molecular structure of complex 2. Displacement ellip-
soids are shown at the 50% probability level. Hydrogen bonds are de-
picted as dashed open lines.
We examined the catalytic activity of the complex 2 in the
modified Sonogashira reaction between (E/Z)-β-bromo-
styrene 3a (E/Z = 85:15) and phenylacetylene (4a; Table
SYNLETT 2012, 23, 1257–1261
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-1290938; Art ID: ST-2011-W0819-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1258
X. Mi et al.
LETTER
1). The results indicate that the reaction of 3a with 4a pro- found that the functional group of terminal alkynes did not
ceeds smoothly at room temperature in the presence of have an influence on the steric ratio of their corresponding
Cs2CO3 in polar solvents DMF or DMSO (Table 1, entries products (Table 2, entries 1–6). This ratio remained con-
4 and 7). An increase in the polarity of the aprotic solvent stant (E/Z = 97:3). In addition, it was found that (Z)-β-bro-
resulted in an impressive increase of the yield (Table 1, mostyrene (Z/E = 86:14)14 could react smoothly with
entries 7–10). When using the relative strong or weak base terminal alkynes, and the product yields were higher than
in this reaction, the desired product 5aa was only obtained those of the analogous E-isomers (Table 2, entries 9 and
in middle yield (Table 1, entries 1–3, 5 and 6). In addition, 10). The transformation of some of the Z-isomeric product
the obtained product 5aa was obtained as a mixture of (E)- to E-isomer was also obtained from the reaction of (Z)-
and (Z)-1,4-diphenylbut-1-en-3-yne (E/Z = 93:7). The re- bromostyrene with terminal alkynes (Table 2, entries 9
sult indicates that a part of the Z-isomeric product trans- and 10). The same catalytic system also gives excellent re-
formed into the E-isomer.
sults in case of aliphatic alkyne 4h (Table 2, entry 8).
However, in the presence of a proton-donating group in a
substrate (propargyl-type alcohol 4g), the examined cata-
lyst lost the catalytic ability (Table 2, entry 7). In addition,
this catalyst could be used in the reaction of aliphatic vinyl
bromide with phenylacetylene, but the product yield was
only 28% (Table 2, entry 12).
Table 1 Screening Bases and Solvents for the Coupling of (E)-β-
Bromostyrene and Phenylacetylenea
Br
Pd (1 mol%)
base (2 equiv)
3a
+
In addition, we examined the reaction of 1,1-dibromo-2,2-
diphenylethene (6)15 with phenylacetylene (4a). While at
the room temperature there was no sign of the reaction, at
50 °C the expected product 7 was formed and could be
isolated in a 58% yield. The molecular structure of the
compound 7 was established by X-ray diffraction analysis
(Scheme 2).16
R
solvent (2 mL)
r.t., N2, 20 h
5aa
R
4a
Yield (%)b
Entry
Base
Solvent
1
2
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
57
69
47
99
77
76
99
88
68
11
K2CO3
KOAc
Cs2CO3
KOH
3
4
5
6
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
8
9
1,4-dioxane
toluene
10
a Reaction conditions: (E)-β-bromostyrene (1 mmol), phenylacety-
lene (1.5 mmol), complex 2 (1 mol%), base (2 mmol) in solvent (2
mL) at 25 °C for 20 h, N2.
b GC yield.
On the basis of the abovementioned results, the scope and
limitation of the coupling reaction were explored by using
various bromostyrenes and terminal alkynes, and the re-
sults are summarized in Table 2. It was found that this
coupling reaction can be applied to all aryl terminal al-
kynes, affording the corresponding products in moderate
to excellent yields. Generally, electron-donating terminal
alkynes give higher yields (Table 2, entries 1 and 2). Com-
pared to phenylacetylene, the terminal alkyne 4f bearing
an electron-withdrawing group o-CF3 gave a considerably
lower yield owing to the steric hindrance (Table 2, entry
6). But this catalytic system was found to be ineffective
for vinyl chloride (Table 2, entry 11). Besides that, we
Scheme 2 Molecular structure of compound 7
We surmise that the mechanism of the complex 2 cata-
lyzed Sonogashira reaction is similar to that of the reac-
tion using Pd(OAc)2 as a catalyst. The proposed
mechanism is shown in Scheme 3. In the process, we
found that under reaction conditions using 1 mol% Pd
(OAc)2 as a catalyst and 4 mol% Me2NCH2CH2OH as a li-
Synlett 2012, 23, 1257–1261
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Palladium Catalyst for Preparation of Enynes
1259
gand, the yield reduced to 90%. After Pd(OAc)2 is re- In conclusion, we have synthesized a new cyclopalladated
duced to Pd(0), Pd(0) cannot easily coordinate with the complex based on N,N-dimethylethanolamine.17 The
ligand, which results in the deactivation of the Pd(0) spe- structure of the obtained complex was studied by X-ray
cies. Thus, the above results demonstrated that the com- crystallography. As an effective catalyst it can be used to
plex 2 was an efficient catalyst for the coupling reaction.
prepare conjugated enynes by Sonogashira cross-coupling
reaction in the absence of co-catalyst CuX and any ligand
at room temperature in 20 hours to give the corresponding
products in moderate to excellent yields.18 Moreover, it
was found that (Z)-β-bromostyrene reacts with terminal
alkynes with retention of the steric configuration. The ma-
jor part of the Z-isomer did not transform to the E-isomer
in this reaction.
II
R2 Pd
X
HC CR1
HX
R2X
R1C CH
base
II
L2Pd
Pd(0)
R2
C
II
Pd
CR1
R2
C C
R1
Scheme 3 Plausible reaction mechanism
Table 2 Modified Sonogashira Cross-Coupling Reaction of Halogenated Alkene with Terminal Alkynesa
R3
R3
Pd (1 mol%), Cs2CO3 (2 equiv)
DMF (2 mL), r.t., N2, 20 h
X
+
R1
R4
R1
R4
R2
3a–d
R2
4a–h
5
Yield (%)b
Entry
1
Halogenated alkene
Terminal alkyne
Product
97 (E/Z = 93:7)
Br
E
4a
4b
3a
3a
5aa
5ab
2
3
93 (E/Z = 93:7)
40 (E/Z = 93:7)
3a
3a
3a
3a
4c
5ac
5ad
5ae
4
5
6
92 (E/Z = 93:7)
77 (E/Z = 93:7)
12 (E/Z = 93:7)
F
F
4d
Br
Br
4e
F3C
F3C
4f
5af
NRc
7
3a
–
HC
C
OH
4g
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1257–1261

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X. Mi et al.
LETTER
Table 2 Modified Sonogashira Cross-Coupling Reaction of Halogenated Alkene with Terminal Alkynesa (continued)
R3
R3
Pd (1 mol%), Cs2CO3 (2 equiv)
DMF (2 mL), r.t., N2, 20 h
X
+
R1
R4
R1
R4
R2
3a–d
R2
4a–h
5
Yield (%)b
Entry
8
Halogenated alkene
Terminal alkyne
Product
3a
95 (E)
HC
C
(CH2)4Me
(CH2)4Me
4h
5ah
Z
9
97 (E/Z = 22:78)
Br
4a
4b
3b
5ba
10
3b
97 (E/Z = 19:81)
5bb
Cl
NRc
11
12
–
CHO
4a
4a
3c
H
Br
28
3d
5da
a Reaction conditions: halogenated alkene (1 mmol), terminal alkyne (1.5 mmol), complex 2 (1 mol%), Cs2CO3 (2 mmol) in DMF (2 mL) at 25
°C for 20 h, N2.
b Isolation yield containing E- and Z-isomers based on 3.
c No reaction.
(3) Mohamed, Y. M. A.; Hansen, T. V. Tetrahedron Lett. 2011,
Acknowledgment
52, 1057.
We thank the National Science Foundation of China (No.
21172200) and the Graduate Student Science Research Foundation
of Zhengzhou University (11L00303) for financial support given to
this research.
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Synlett 2012, 23, 1257–1261
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Palladium Catalyst for Preparation of Enynes
1261
(12) Huang, M. M.; Feng, Y. J.; Wu, Y. J. Tetrahedron 2012, 68,
376.
(13) CCDC 869934 contains the supplementary crystallographic
data of compound 2 for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Center via
http://www.ccdc.cam.ac.uk/data_request/cif.
(14) Kim, S. H.; Wei, H. X.; Willis, S.; Li, G. Synth. Commun.
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(18) Palladium-Catalyzed Sonogashira Reaction of β-
Bromostyrene and Terminal Acetylene (Table 1 and
Table 2): Table 2, entry 2, is given as an example: β-
Bromostyrene (183 mg, 1.0 mmol), p-tolyacetylene (174
mg, 1.5 mmol), alkoxypalladium complex (4 mg, 1 mol%),
Cs2CO3 (652 mg, 2.0 mmol) and DMF (2 mL) were added in
Schlenk flask under nitrogen atmosphere. The reaction
mixture was stirred at r.t. for 20 h. Then H2O (50 mL) was
added and the resulting mixture was extracted with CH2Cl2
(3 × 20 mL). The combined organic layer was dried over
anhyd Na2SO4. After filtration, the solvent was removed
under reduced pressure. The residue was purified by TLC
using petroleum ether as an eluent to give the pure diphenyl
acetylene. Yield: 93%; white solid; mp 75–76 °C (lit.19 75–
76 °C). For E-isomer: 1H NMR (400 MHz, CDCl3): δ = 2.38
(s, 3 H, Me), 6.41 (d, J = 16.1 Hz, 1 H, CH=), 7.04 (d, J =
16.1 Hz, 1 H, CH=), 7.16 (d, J = 7.8 Hz, 2 H), 7.29–7.46 (2
× m, 7 H, ArH). For Z-isomer: 1H NMR (400 MHz, CDCl3):
δ = 2.39 (s, 3 H, Me), 5.93 (d, J = 12.2 Hz, 1 H, CH=), 6.70
(d, J = 11.7 Hz, 1 H, CH=), 7.29–7.46 (2 × m, 7 H, ArH),
7.94 (d, J = 7.3 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ =
21.49 (Me), 88.24, 91.97 (C≡ group), 108.31, 120.32,
126.25, 128.50, 128.71, 129.11, 131.40, 136.41, 138.34,
140.85 (CH=CH, ArC). Anal. Calcd for C17H14: C, 93.54; H,
6.46. Found: C, 93.47; H, 6.40.
(16) CCDC 869935 contains the supplementary crystallographic
data of compound 7 for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Center via
http://www.ccdc.cam.ac.uk/data_request/cif.
(17) Synthesis of (Me2NCH2CH2O)2Pd⋅2AcOH: A solution of
Me2NCH2CH2OH (0.24 g, 2.68 mmol) in toluene (10 mL)
was add to a stirred solution of Pd(OAc)2 (0.3 g, 1.34 mmol)
in toluene (10 mL), and the mixture was stirred at r.t. After
2 d all volatiles were removed under reduced pressure to
give 2 as a yellow crystalline solid. Yield: 0.54 g (80%); mp
93–95 °C. 1H NMR (400 MHz, C6D6): δ = 1.92–2.00 (m, 4
H, CH2N), 2.01 (s, 6 H, CH3COOH), 2.17 (s, 12 H, CH3N),
3.37–3.75 (m, 4 H, CH2O), 11.00–11.15 (br s, 2 H,
CH3COOH). 13C NMR (100 MHz, C6H6): δ = 22.08
(CH3COOH), 49.63 (CH3N), 63.87 (CH2N), 68.50 (CH2O),
174.27 (C=O). Anal. Calcd for C8H20N2O2Pd⋅2AcOH: C,
35.78; H, 7.01; N, 6.96. Found: C, 35.20; H, 6.79; N, 6.88.
(19) Ghosh, R.; Zhang, X.; Achord, P.; Emge, T. J.; Krogh-
Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2007, 129,
853.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1257–1261

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