Highly stereoselective synthesis of (Z)-1,2-dihaloalkenes by a Pd-catalyzed hydrohalogenation of alkynyl halides

Article abstract of DOI:10.1039/c2cc31553j

An unprecedented Pd-catalyzed hydrohalogenation of alkynyl halides for the regio- and stereoselective synthesis of (Z)-1,2-dihaloalkenes has been realized using [(allyl)PdCl]₂ as the catalyst and cis,cis-1,5-cyclooctadiene as the ligand. The advantages of this protocol are well illustrated by the assembly of trisubstituted (Z)-enynes and multifunctional benzenes via iterative cross-coupling reactions or tandem Diels-Alder-aromatization reactions, respectively.

Full text of DOI:10.1039/c2cc31553j

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COMMUNICATION
Highly stereoselective synthesis of (Z)-1,2-dihaloalkenes by
a Pd-catalyzed hydrohalogenation of alkynyl halidesw
Gangguo Zhu,* Dongxu Chen, Yuyi Wang and Renwei Zheng
Received 1st March 2012, Accepted 19th April 2012
DOI: 10.1039/c2cc31553j
An unprecedented Pd-catalyzed hydrohalogenation of alkynyl
halides for the regio- and stereoselective synthesis of (Z)-1,2-
dihaloalkenes has been realized using [(allyl)PdCl]2 as the
catalyst and cis,cis-1,5-cyclooctadiene as the ligand. The
advantages of this protocol are well illustrated by the assembly
of trisubstituted (Z)-enynes and multifunctional benzenes via
iterative cross-coupling reactions or tandem Diels–Alder–
aromatization reactions, respectively.
Table 1 Optimization of the reaction conditionsa
Entry PdX2
Additive/equiv. Time/h Yieldb/%
1
2
3
4
5
6
7
8
Pd(OAc)2
4a/0.2
4b/0.2
4c/0.2
4d/0.2
4e/0.2
4f/0.2
4g/0.2
4h/0.2
4h/0.1
4h/0.1
4h/0.05
—
8
8
8
8
8
8
8
8
8
5
4
8
5
8
8
8
8
Tracec
20
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[(Allyl)PdCl]2
[(Allyl)PdCl]2
Pd(COD)Cl2
[(Allyl)PdCl]2
—
Tracec
30
26
Alkenyl halides are one of the most important building blocks
in organic chemistry due to their versatile reactivity in a number
of chemical transformations.1 In this regard, 1,2-dihaloalkenes
have received more and more interest because of their wide
applications for the effective construction of stereodefined
multifunctional alkenes via the transition-metal-catalyzed
coupling reactions.2 Consequently, the stereoselective synthesis
of 1,2-dihaloalkenes is highly desirable. Along this line, the
halogenation of alkynes appears to be a straightforward approach
to 1,2-dihaloalkenes.3 However, this method often provides
(E)-1,2-dihaloalkenes as the major products. In contrast, there
are only limited methods for the stereoselective formation of
(Z)-1,2-dihaloalkenes.3a,4 Recently, the Jiang group disclosed an
elegant method for the preparation of (Z)-2-halo-1-iodoalkenes by
treating haloalkynes with KI in acetic anhydride.5 Pursuing our
interest in the Pd-catalyzed functionalization of heteroatom-
substituted acetylenes,6 we report here an unprecedented
Pd-catalyzed hydrohalogenation7 of haloalkynes, allowing access
to (Z)-1,2-dihaloalkenes in good yields with excellent regio- and
stereoselectivity.
5c
37
68
44
85 (84)d
81
9
10
11
12
13
14
15
16
17
10c
15c
n.p.
10c
20
—
4h/0.1
[(Cinnamyl)PdCl]2 4h/0.1
PdCl2
PdBr2
4h/0.1
4h/0.1
22
a
Reaction conditions: 1a (0.5 mmol), 4 (0.025–0.1 mmol), LiCl
(1.0 mmol), and Pd catalyst (0.025 mmol) in 1 mL of HOAc at 80 1C.
Isolated yield. Byproducts resulting from oligomerization of 1a
b
c
d
were observed. Yield on a 10 mmol scale.
the effects of ligands (Fig. 1) on this reaction employing Pd(OAc)2
as the catalyst. We were pleased to find that the use of cis,cis-1,5-
cyclooctadiene (4h) led to the formation of 5 in 68% yield, while a
dramatic decrease in the yield was observed when the amount of
4h was reduced to 10 mol% (entries 8 and 9, Table 1).
To this end, phenylethynyl chloride (1a) was chosen for the
initial screening. After several trials, (Z)-1,2-dichloro-l-phenyl-
ethene (5) was obtained in 20% yield using butyl acrylate (4b) as
the promoter (entry 2, Table 1). Notably, the reaction presented
here represents the first Pd-catalyzed hydrochlorination of
haloacetylenes. Encouraged by this promising result, we further
investigated other reaction parameters for this transformation
(entries 3–17, Table 1). Firstly, we focused on investigations of
Pleasingly, the yield of 5 was boosted to 85% by simply
switching the palladium sources from Pd(OAc)2 to [(allyl)PdCl]2
(entries 9 and 10, Table 1). Moreover, the reaction could be
scaled up to 10 mmol to produce 5 in 84% isolated yield
(entry 10, Table 1). The control experiments indicated that
both [(allyl)PdCl]2 and cis,cis-1,5-cyclooctadiene were crucial
for the occurrence of this reaction (entries 12–14, Table 1).
Other palladium sources, such as [(cinnamyl)PdCl]2, PdCl2
and PdBr2, all led to the product in inferior yields (entries
15–17, Table 1). Hence, running the reaction in HOAc at 80 1C
with 2.5 mol% of [(allyl)PdCl]2 as the catalyst and 10 mol% of
cis,cis-1,5-cyclooctadiene (4h) as the ligand appeared to be the
optimal reaction conditions.
Department of Chemistry, Zhejiang Normal University,
688 Yingbin Road, Jinhua 321004, China. E-mail: gangguo@zjnu.cn;
Fax: +86-579-82282610; Tel: +86-579-82283702
w Electronic supplementary information (ESI) available: Experimental
details and characterization of compounds 5–40. See DOI: 10.1039/
c2cc31553j
c
5796 Chem. Commun., 2012, 48, 5796–5798
This journal is The Royal Society of Chemistry 2012

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(R = 3-NMe2–C6H4 and 4-CO2H–C6H4), various functional
groups, such as F, Cl, Br, OMe, OH, OBn, OTBDPS, CO2Et,
AcNH, CHO and alkenyl groups, were found to be well
tolerated under the standard conditions.
Notably, besides (Z)-1,2-dichloroalkenes, (Z)-1-bromo-2-
chloroalkenes could also be synthesized in good yields by this
protocol. For instance, Pd-catalyzed hydrochlorination of
bromoalkynes afforded (Z)-1-bromo-2-chloroalkenes 23 and
24 in yields of 87% and 76%, respectively (entries 18 and 19,
Table 2). On the other hand, the hydrobromination of alkynyl
chlorides 1a and 1g generated 34 and 35 in good yields
(entries 29 and 30, Table 2), thus providing an alternative
pathway for assembling (Z)-1-bromo-2-chloroalkenes. More-
over, the hydrobromination of alkynyl bromides occurred as
well, giving rise to (Z)-1,2-dibromoalkenes in reasonable yields
(entries 31 and 32, Table 2).8 In contrast, either the hydro-
chlorination of phenylacetylene iodide (3) or the hydroiodina-
tion of phenylethynyl chloride (1a) failed to form the desired
product under the standard conditions (entries 33 and 34,
Table 2). The stereochemistry of (Z)-1,2-dihaloalkenes was
determined by the HMBC, NOE, 1H NMR and 13C NMR
analysis of the known compounds (see ESIw).
To explore the synthetic utility of this reaction, we examined
the generated products in the transition-metal-catalyzed cross-
coupling reactions. For example, the Sonogashira coupling9 of
23 with phenylacetylene furnished 81% of (Z)-chloroenyne 38
without touching the C–Cl bond, which was further converted
into the trisubstituted conjugated (Z)-enyne 39 in 70% yield
via the Suzuki–Miyaura coupling10 (Scheme 1). As such, this
protocol provided a promising method for the synthesis of
trisubstituted (Z)-enyne,11 a challenging target in organic
synthesis, through the iterative cross-coupling reactions by
taking advantage of the differentiated reactivity of the C–Br
and C–Cl bonds.
Fig. 1 Selected promoters.
With the optimized reaction conditions in hand, we then
evaluated the scope and generality of this reaction. As shown
in Table 2, in general, the reaction provided (Z)-1,2-dihalo-
alkenes in reasonable to excellent yields with excellent regio-
and stereoselectivity. For example, aromatic chloroalkynes 1c
and 1d afforded (Z)-1,2-dichloroalkenes 7 and 8 in 88% and
90% yields, respectively (entries 2 and 3, Table 2). As for
aliphatic haloalkynes, the reaction formed the corresponding
products in good yields and excellent stereoselectivities (entries 12,
13, 17, 27 and 28, Table 2). Moreover, alkenyl haloalkynes, such
as 1o, 1p, and 2a, were also good substrates for this reaction
(entries 14–16, Table 2). Except amino and carboxylic substituents
Table 2 Scope and limitations of the reactiona
Entry
R/X1
X2
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
4-F–C6H4/Cl (1b)
4-Cl–C6H4/Cl (1c)
2,4-Cl2–C6H3/Cl (1d)
4-Br–C6H4/Cl (1e)
4-Me–C6H4/Cl (1f)
4-i-Pr–C6H4/Cl (1g)
4-MeO–C6H4/Cl (1h)
3,4-MeO2–C6H3/Cl (1i)
2-Thienyl/Cl (1j)
2-Naphthyl/Cl (1k)
1-Naphthyl/Cl (1l)
BnOCH2/Cl (1m)
n-C8H17/Cl (1n)
(E)-Styryl/Cl (1o)
1-Cyclohexenyl/Cl (1p)
1-Cyclohexenyl/Br (2a)
Cinnamyl/Br (2b)
Ph/Br (2c)
4-F–C6H4/Br (2d)
4-Cl–C6H4/Br (2e)
4-Me–C6H4/Br (2f)
3,4-MeO2–C6H3/Br (2g)
4-CHO–C6H4/Br (2h)
4-CO2Et–C6H4/Br (2i)
3-AcNH–C6H4/Br (2j)
3-OH–C6H4/Br (2k)
TBDPSO(CH2)2/Br (2l)
BnOCH2/Br (2m)
Ph/Cl (1a)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Cl
I
3
6
4
5
5
5
6
6
8
5
5
6
8
5
6
6
6
6
8
8
8
8
5
5
4
5
8
8
5
8
8
8
8
8
72 (6)
88 (7)
90 (8)
76 (9)
84 (10)
90 (11)
80 (12)
78 (13)
75 (14)
83 (15)
80 (16)
73 (17)
80 (18)c
60 (19)
68 (20)
72 (21)
75 (22)
87 (23)
76 (24)
92 (25)
81 (26)
77 (27)
86 (28)
83 (29)
82 (30)
85 (31)
95 (32)
84 (33)
62 (34)d
72 (35)d
53 (36)d
45 (37)d
Trace
Furthermore, (Z)-1,2-dihalo-1,3-dienes turned out to be
effective substrates for the Diels–Alder reaction. For instance,
treatment of 20 with diethyl acetylenedicarboxylate led to the
elaboration of functionalized benzene 40 in 66% yield via the
tandem Diels–Alder–aromatization process (Scheme 2).
In view of our previous results,4c,6 a plausible mechanism for
this Pd-catalyzed trans-hydrohalogenation of alkynyl halides is
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Scheme 1 Synthesis of trisubstituted (Z)-enyne.
4-i-Pr–C6H4/Cl (1g)
Ph/Br (2c)
4-Cl–C6H4/Br (2e)
Ph/I (3)
Ph/Cl (1a)
Trace
a
Reaction conditions: 1–3 (0.5 mmol), 4h (0.05 mmol), LiX2
(1.0 mmol), and [(allyl)PdCl]2 (0.013 mmol) in 1 mL of HOAc at 80 1C.
Isolated yield. Z/E=11/1. 4h (0.5 mmol) was used.
b
c
d
Scheme 2 Synthesis of substituted benzene.
Chem. Commun., 2012, 48, 5796–5798 5797
c
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Trans. 1, 2000, 395; (d) C. Chiappe, D. Capraro, V. Conte and
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Scheme 3 Proposed mechanism.
4 (a) S. Hara, T. Kato, H. Shimizu and A. Suzuki, Tetrahedron Lett.,
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7 For selected hydrohalogenation reactions of alkynes, see:
(a) S. Ma, X. Lu and Z. Li, J. Org. Chem., 1992, 57, 709;
(b) W. Yu and Z. Jin, J. Am. Chem. Soc., 2000, 122, 9840;
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M. O. Frederick, L. Shen and C. A. Zificsak, Org. Lett., 2003,
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proposed in Scheme 3. In the presence of cis,cis-1,5-cyclo-
octadiene (4h), the neutral allylpalladium(II) chloride dimer is
converted into an active cationic palladium species A, followed
by the trans-halopalladation6,12 of haloalkynes to give an alkenyl
palladium intermediate B. Finally, protonolysis13 of the alkenyl
C–Pd bond of B provides (Z)-1,2-dihaloalkenes with concurrent
regeneration of the species A (Scheme 3). Notably, as one of the
fundamental processes for trapping the C–Pd bond, protonolysis
is mainly limited to the alkyl C–Pd bond connecting with
electron-withdrawing groups.14 As such, this reaction represents
a significant advance in the protonolysis process.
In conclusion, we have developed a stereospecific Pd-catalyzed
hydrohalogenation of haloalkynes for the first time. The reaction
provides a facile access to (Z)-1,2-dihaloalkenes in good yields
with excellent stereoselectivities and good functional group
compatibility. The synthetic utility of this method was illustrated
by the preparation of trisubstituted (Z)-enyne via the selective C1
Sonogashira coupling followed by the C2 Suzuki coupling of
(Z)-1-bromo-2-chloroalkenes. In addition, (Z)-1,2-dihaloalkenes
could be converted into multisubstituted benzenes through the
Diels–Alder–aromatization tandem process. Further investiga-
tions on the mechanism of this protocol are underway.
8 It was found that the use of stoichiometric cis,cis-1,5-cyclooctadiene
improved the yields of hydrobromination of alkynyl halides.
9 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
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10 N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979,
20, 3437.
11 J. M. Tour, Chem. Rev., 1996, 96, 537 and references therein.
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20902084 and
21172199) and the Program for Changjiang Scholars and
Innovative Research Team in Chinese Universities (IRT0980).
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¨
Y. I. M. Nilsson and R. G. P. Gatti, Organometallics, 1995, 14, 4242.
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see: (a) Y. Fukuda, H. Shiragami, K. Utimoto and H. Nozaki,
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bond, see: (a) Z. Wang and X. Lu, J. Org. Chem., 1996, 61, 2254;
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c
5798 Chem. Commun., 2012, 48, 5796–5798
This journal is The Royal Society of Chemistry 2012