Palladium(II)-catalyzed highly regio- and stereoselective synthesis of 2Chloro-1,3-diene derivatives from alkynols and alkenes

Article abstract of DOI:10.1002/chem.201001318

(Chemical Equation Presented) Diene or not diene: A facile and efficient palladium-catalyzed highly regioand stereoselective strategy is depicted for the synthesis of chloro-substituted 1,3-dienes from alkynols and alkenes (see scheme). This protocol provides a good alternative for the construction of halo-substituted 1,3-dienes.

Full text of DOI:10.1002/chem.201001318

DOI: 10.1002/chem.201001318
Palladium(II)-Catalyzed Highly Regio- and Stereoselective Synthesis of 2-
Chloro-1,3-diene Derivatives from Alkynols and Alkenes
Huanfeng Jiang,* Chunli Qiao, and Weibing Liu[a]
Over the past decade, transition-metal-catalyzed reactions
have emerged as powerful and general methods for the syn-
methyl acrylate (2a) to synthesize (E)-methyl 5-chloro-6-
methylhepta-3,5-dienoate (3aa) (Table 1) by using cop-
AHCTUNTGRENpNGNU er(II) chloride dihydrate CuCl2·2H2O as the additive. As
thesis of organic compounds.[1] C C or C heteroatom bond-
formation processes, which are typically mediated by well-
defined, air-stable palladium catalysis, are now ubiquitous in
both academia and industry.[2] Recently, our group has de-
À
À
Table 1. Optimization of reaction conditions.[a]
À
veloped an efficient C C coupling reaction for diene synthe-
sis by directly utilizing chloropalladation chemistry
(Scheme 1).[3] On the basis of our work, we herein disclose a
Entry
Catalyst
(5 mol%)
Additive
(2.0 equiv)
Solvent
Yield[b]
[%]
N
1
2
3
4
5
6
7
8
Pd(OAc)2
G
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
ZnCl2
CuCl
none
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
toluene
DMSO
THF
DCE
52
28
57
32
0
A
CHTUNGTRENNUNG
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
0
trace
trace
trace
50
46
43
9
Scheme 1. Highly regio- and stereoselective intermolecular reaction to
synthesize chloro-substituted dienes.
10
11
12[d]
13[e]
14[f]
1,4-dioxane
1,4-dioxane
1,4-dioxane
47
85
highly regio- and stereoselective synthetic method to con-
struct (E)-2-chloro-1,3-dienes from alkynols and alkenes by
using a PdCl2/CuCl2 catalyst system.[4] The 1,3-diene unit is
an important synthon in organic synthesis[4] and many natu-
ral products that contain the 1,3-diene framework have
showed potential biological activities, such as cell-cycle regu-
lating properties and apoptotic, antifungal, and antiviral ac-
tivities.[5]
[a] Reaction conditions: 1a (0.25 mmol) and 2a (0.25 mmol) in solvent
(2 mL) at 808C for 4 h. [b] GC yields. [c] dba=dibenzylideneacetone.
[d] Reaction temperature: 608C. [e] 1008C. [f] Reaction time: 10 h.
shown in Table 1, PdACHTUNRGTNEUNG(OAc)2 and PdCl2 were suitable cata-
lysts for this reaction in dioxane (entries 1 and 3). Changing
the additives, we found that copper(II) chloride dihydrate
(CuCl2·2H2O) led to preferable result (Table 1, entries 3–6).
Among the various solvents examined, dioxane gave the
best result (Table 1, entries 7–14). The optimal reaction tem-
perature was 808C. Higher and lower reaction temperatures
led the decrease in the yield. (Table 1, entries 12 and 13; cf.
entry 3). However, there was a significant increase in the
yield when prolonging the reaction time to 10 h and the de-
sired product was obtained in 85% yield (Table 1, entry 14).
Under the optimized conditions, the reaction was applied
to a range of substrates. A wide variety of tert-propargylic
Initial efforts were focused on the evaluation of palladium
catalysts for the reaction of 2-methylbut-3-yn-2-ol (1a) with
[a] Prof. Dr. H. Jiang, C. Qiao, W. Liu
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (China)
Fax : (+86)20-8711-2906
E-mail: jianghf@scut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001318.
10968
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Chem. Eur. J. 2010, 16, 10968 – 10970

COMMUNICATION
alcohols could successfully react with alkenes to afford the
corresponding 2-chloro-1,3-diene derivatives (Scheme 2). As
revealed in Scheme 2, alkenes with electron-withdrawing or
results. The transformation of 3-methylnon-1-yn-3-ol (1d)
with 2j was a typical example and only gave (3E, 5Z)-5-
chloro-6-methyldodeca-3,5-dienenitrile (3dj) in 42% isolat-
ed yield. Interestingly, this strategy can also be applied to
synthesize other halosubstituted 1,3-dienes. For example, the
reaction can proceed smoothly and give the corresponding
product in good isolated yield when using PdBr2 and CuBr2
as the catalyst system (Scheme 3).
Scheme 3.
To probe the credibility of our proposed mechanism and
shed more light on the formation of 2-chloro-1,3-diene de-
rivatives, several experiments were carried out. First, we
tested the acidity of the reaction solution after the reactions
were completed. The results indicated that the reaction solu-
tion was slightly acidic and the pH value was among in the
range 5–6. Next, deuterium-labeled 3-methyl-3-[(trimethylsi-
lyl)oxy]-1-butyne was used as a modified substrate to distin-
guish the hydrogen position of the terminal alkyne. As de-
picted in Scheme 4, deuterium product 6 was obtained ex-
clusively in 69% isolated yield and the deuterium atom
1
(96% examined by H NMR spectroscopy) was still present.
Scheme 4.
Scheme 2. Synthesis of 2-chloro-1,3-dienes from alkynols and alkenes.
On the basis of these preliminary results, a mechanistic
proposal for this transformation, exemplified by the forma-
tion of 3aa, is depicted in Scheme 5. Vinylpalladium inter-
mediate I is initially formed by trans-chloropalladation of
the alkyne in the presence of excess halide ions,[6] followed
by the insertion of methyl acrylate to generate an alkylpalla-
dium species II.[7] Further palladium b-hydride elimination
of intermediate II afforded the intermediate III, which un-
derwent re-addition of the palladium hydride to the double
bond with the opposite regiochemistry and produced anoth-
er alkylpalladium species IV.[8] Subsequent allylic rearrange-
ment of intermediate IV would generate alkylpalladium
compound V.[9] Finally, b-hydroxyelimination[10] produced
the observed 1,3-diene product 3aa and PdCl2 were regener-
ated in the presence of CuCl2 for the next cycle.
-donating groups are suitable for this protocol; the electron-
ic properties of the substituents on the alkenes has no signif-
icant influence on the reaction (3aa–3aj). For example, the
coupling reaction of 1a with acrylonitrile (2j) or 1-(allyl-
ACHTUNGTRENNUNGoxy)benzene (2b) as well as 1-ethynylcyclohexanol (1c)
with methyl acrylate (2a) or 1-(allyloxy)benzene (2b) all led
to the corresponding 2-chloro-1,3-dienes in reasonable yield
(3aj, 3ab, 3ca, and 3cb). This transformation proceeded
smoothly with high regio- and stereoselectivity and afforded
the desired product in moderate to excellent yields for those
alkynols substituted with the same groups (R1 =R2). For ex-
ample, the reaction of 1a, 3-ethylpent-1-yn-3-ol (1b), and 1-
ethynylcyclohexanol (1c) with 2b led to the corresponding
product in 67, 70, and 71% isolated yields, respectively.
When R1 and R2 were different, the reaction led to inferior
In conclusion, we have described a facile and efficient
method for the synthesis of 2-chloro-1,3-diene derivatives by
Chem. Eur. J. 2010, 16, 10968 – 10970
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10969

H. Jiang et al.
Acknowledgements
The authors are grateful to the National Natural Science Foundation of
China (nos. 20625205, 20772034 and 20932002) and Doctoral Fund of
Ministry of Education of China (20090172110014) for financial support.
Keywords: alkenes · homogeneous catalysis · palladium ·
regioselectivity · stereoselectivity
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a Pd-catalyzed intermolecular reaction from alkynols and al-
kenes. The high regio- and stereoselectivity and tolerance
for a range of functional groups as well as the mild reaction
conditions and good to excellent yields make the present
protocol very attractive. It is a good alternative for the syn-
thesis of halosubstituted-1,3-diene derivatives. The scope
(including the asymmetrically substituted propargylic alco-
hols, the symmetrically and the asymmetrically polysubsti-
tuted alkenes), mechanism, and applications of this strategy
are under investigation in our group, and the results will be
reported in due course.
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Experimental Section
Full experimental details and characterization data are given in the Sup-
porting Information.
General method: All of the reactions were carried out at 808C in a
Schlenk tube equipped with magnetic stirrer bar for 10 h. All solvents
and reagents were used as received. 1H NMR spectra were recorded in
CDCl3 at 400 or 600 MHz and 13C NMR spectra were recorded in CDCl3
at 100 or150 MHz. GC-MS was performed by using electron ionization
(EI). TLC was performed by using commercially prepared 100–400 mesh
silica gel plates (GF254), and visualization was effected at 254 nm. All the
other chemicals were purchased from Aldrich Chemicals.
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Typical procedure for the reaction of 1a and 2a (Table 1, 3aa): A mix-
ture of PdCl2 (8.85 mg, 0.05 mmol), CuCl2·2H2O (336 mg, 2.0 mmol), 1,4-
dioxane (2 mL), 1a (84 mg, 1.0 mmol), and 2a (86 mg, 1 mmol) were
added successively in Schlenk tube. After stirring for 10 h at 808C, the
solution was directly subjected to isolation by PTLC (GF254) eluted with
a 50:1 n-hexane/ethyl acetate mixture, which gave 3aa as a pale yellow
oil (152.2 mg, 81%).
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Received: May 15, 2010
Published online: August 16, 2010
10970
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Chem. Eur. J. 2010, 16, 10968 – 10970