Synthesis of cis -1,2-dihaloalkenes featuring palladium-catalyzed coupling of haloalkynes and α,β-unsaturated carbonyls

Article abstract of DOI:10.1021/jo102406j

A highly regio- and stereoselective method for the synthesis of cis-1,2-dihaloalkenes through Pd-catalyzed coupling of haloalkynes and α,β-unsaturated carbonyls has been reported. Excellent stereoselectivities (Z/E up to >98:2) were observed in most cases. This method was subsequently applied to synthesize the functionalized conjugated enyne via the mono-Sonogashira coupling reaction of cis-1-chloro-2-iodoalkene.

Full text of DOI:10.1021/jo102406j

NOTE
pubs.acs.org/joc
Synthesis of cis-1,2-Dihaloalkenes Featuring Palladium-Catalyzed
Coupling of Haloalkynes and r,β-Unsaturated Carbonyls
Dongxu Chen, Yi Cao, Zheliang Yuan, Haiting Cai, Renwei Zheng, Lichun Kong, and Gangguo Zhu*
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
S Supporting Information
b
ABSTRACT: A highly regio- and stereoselective method for the synthesis of
cis-1,2-dihaloalkenes through Pd-catalyzed coupling of haloalkynes and R,
β-unsaturated carbonyls has been reported. Excellent stereoselectivities (Z/E up
to >98:2) were observed in most cases. This method was subsequently applied
to synthesize the functionalized conjugated enyne via the mono-Sonogashira
coupling reaction of cis-1-chloro-2-iodoalkene.
alogenated organic compounds are naturally occurring in
living organisms, and they have also been frequently used as
result, we further examined the reaction conditions and the
results were summarized in Table 1.
H
important building blocks in multistep synthesis, material
science, and the chemical industry.1 In particular, 1,2-dihaloalk-
enes have attracted considerable attention in the past decades,
mainly due to the coupling reactions of the two adjacent
carbonꢀhalide bonds with various nucleophiles for the rapid
formation of stereodefined tri- or tetrasubstituted alkenes.2
The synthesis of trans-1,2-dihaloalkenes is accomplished
normally by the electrophilic halogenation of alkynes (eq 1,
Scheme 1).3 For example, Ogilvie et al. described a highly
selective iodochlorination reaction of alkynes employing tetra-
butylammonium iodide and dichloroethane,3c,d in which trans-1-
chloro-2-iodoalkene was obtained as the single isomer. Despite
the great prevalence of preparing trans-1,2-dihaloalkenes in the
literature, interestingly, there are rather limited methods for the
effective synthesis of stereoselectively pure cis-1,2-dihaloalkene
derivatives (eq 2, Scheme 1).4 A promising report for the
stereoselective synthesis of cis-1,2-dihaloalkenes came from
Whiting’s group, where the iodochlorination of alkynes occurred
with iodine monochloride and tetraethylammonium iodide.5
However, this method is not stereoselective yet in some cases.
Apart from the selectivity issue, the conventional electrophilic
halogenation reactions involve hazardous, toxic, and corrosive
electrophilic halogen sources, which further limits their applica-
tions in organic synthesis. As such, it is highly desirable to
develop an environmentally benign and selective method for
the preparation of cis-1,2-dihaloalkenes from the readily available
starting materials. Herein, we report a highly regio- and stereo-
selective protocol for the synthesis of cis-1,2-dihaloalkenes
featuring the Pd-catalyzed haloalkynesꢀR,β-unsaturated carbo-
nyls coupling reaction.6
As shown in Table 1, among all the palladium sources we
examined, Pd(OAc)2 proved to be the best, affording product 4
in 91% GC yield and with excellent stereoselectivity (Z/E >
98:2) (entries 1ꢀ4, Table 1). The stereochemistry of the product
was determined by NOE measurements and further confirmed
by its conversion into the literature-known (Z)-1,2-dibromo-1-
phenylpropene.7 Increasing the amount of LiBr only slightly
improved the yields, for example, the use of 2.0 and 5.0 equiv of
LiBr gave 4 in 91% and 92% yields, respectively (entries 5 and 6,
Table 1). The replacement of LiBr by other bromide sources,
such as KBr and NaBr, resulted in lower yields (entries 7 and 8,
Table 1). We also screened the solvents for the reaction, and of all
the solvents we tested, HOAc turned out to be the best (entries
8ꢀ10, Table 1).
Therefore, the optimal reaction conditions consisted of 5 mol %
of Pd(OAc)2 as the catalyst, 2.0 equiv of lithium halides as
halide sources, and HOAc as the solvent. As demonstrated in
Table 2, the reaction could be scaled up to 10 mmol to give
product 4 in 80% yield (entry 1, Table 2). Then, we turned our
attention to the stereoselective synthesis of various cis-1,2-
dihaloalkenes using our protocol, and the scope and limits of
this reaction were illustrated in Table 2. Various aryl and alkyl
ethynyl bromides could react with 2 to give the desired cis-1,2-
dibromoalkene products in good to excellent yields, and parti-
cularly noteworthy was that excellent stereoselectivity (Z/E >
98:2) was observed (entries 1ꢀ3, Table 2).
Due to the readily easy elimination process2d of cis-1,2-dibro-
moalkenes occurring in Pd-catalyzed cross-coupling reactions,8
we set up to prepare cis-1-chloro-2-haloalkenes, in recognition of
the chemically more stable feature of the CꢀCl bond than the
CꢀBr bond. In addition, the well-established differentiated
reactivity of CꢀCl and CꢀBr or CꢀI bonds may provide us a
better chance to install different groups in a regioselective
To test the feasibility, phenylethynyl bromide (1a) and
acrolein (2a) were chosen for the initial screening. In the
presence of 5 mol % of PdCl2 and 1.0 equiv of LiBr (3a) as an
additive, 1a was completely consumed within 1 h at room
temperature in HOAc, providing 4 in 75% yield with a high
Z-stereoselectivity (Z/E = 90:10). Inspired by this promising
Received: December 5, 2010
Published: April 11, 2011
r
2011 American Chemical Society
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NOTE
Table 2. Scope and Limits of the Reactiona
Scheme 1. Two Possible Pathways for 1,2-Dihaloalkenes
Table 1. Selected Results of Screening the Reaction
Conditionsa
entry
PdX2
solvent
MX (equiv) yield (%)b,c
Z/Ed
1
2
PdCl2
PdBr2
HOAc
HOAc
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (1.0)
LiBr (2.0)
LiBr (5.0)
NaBr (2.0)
KBr (2.0)
75
90:10
>98:2
96:4
79
3
Pd(CF3CO2)2 HOAc
75
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
HOAc
HOAc
HOAc
HOAc
HOAc
85
91 (82c)
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
5
6
92
7
84
8
42
9
HCOOH LiBr (2.0)
1 N HCl LiBr (2.0)
52
10
6
a Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), MX and Pd
catalyst (0.025 mmol) in 2.5 mL of solvent at 23 °C. b GC yields, with
naphthalene as the internal standard. Isolated yield. d Determined by
c
GC.
fashion. Thus, we focused on chloroalkynes as the substrates to
synthesize all kinds of 1,2-dihaloalkenes, with the emphasis on
the differentially halogenated ones.
As expected, different types of cis-1-bromo-2-chloroalkenes
bearing either electron-deficient or electron-rich groups were
successfully generated in good yields and with excellent stereo-
selectivities under the optimal reaction conditions (entries 4ꢀ9,
Table 2). Furthermore, cis-1-chloro-2-iodoalkenes were pre-
pared with excellent stereoselectivities in the presence of LiI
(3b), albeit in moderate yields and at elevated temperature
(80 °C) (entries 10ꢀ15, Table 2). Lithium chloride (3c) was
also smoothly incorporated into the reaction and afforded the
desired cis-1,2-dichloroalkenes in good yields and excellent
stereoselectivities (Z/E > 98:2), except that 1,2-dichloroalkene
products 23 and 24 were obtained with 94:6 and 67:33 mixture
of Z/E isomers, respectively (entries 20 and 21, Table 2).
Aliphatic haloalkynes also participated well in this reaction,
and resulted in the cis-1-bromo-2-chloro-, cis-1-chloro-2-iodo-
, and cis-1,2-dichloroalkenes in a highly stereoselective fashion
and with good yields. For instance, the cis-1-bromo-2-chlor-
oalkene 25 was generated in 81% yield and with excellent
stereoselectivity (Z/E > 98:2) in the presence of LiBr, whereas
cis-1,2-dichloroalkene 27 was obtained as a single Z-isomer in
77% yield with LiCl as the halide source (entries 22ꢀ24,
Table 2).
a Reaction conditions: 1 (0.5 mmol), 2 (0.75ꢀ2.5 mmol), LiX2
(1.0 mmol), and Pd(OAc)2 (0.025 mmol) in 2.5 mL of HOAc at
23 °C (80 °C for LiI). b Isolated yields. c Determined by GC. d Isolated
yield on 10 mmol scale.
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NOTE
Scheme 2. The Mono-Sonogashira Coupling of 16
via the palladium-catalyzed coupling of alkynyl halides and R,β-
unsaturated carbonyls under mild reaction conditions. It repre-
sents a highly regio- and stereoselective halopalladation process
of haloalkynes. Further investigations of the synthetic applica-
tions of this reaction for the establishment of tri- or tetrasub-
stituted alkenes are currently underway in this group.
’ EXPERIMENTAL SECTION
General Procedure for the Synthesis of cis-1,2-Dihaloalk-
enes. To a solution of LiBr (87.0 mg, 1.0 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol), and 2a (0.11 mL, 2.5 mmol) in 2.5 mL of HOAc was
added 1a (91.0 mg, 0.5 mmol). After the reaction mixture was stirred at
room temperature for 1 h, it was quenched with water, extracted with
ethyl acetate, dried over Na2SO4, and concentrated. The residue was
purified by column chromatography on silica to give 130.1 mg (yield:
82%) of 4 as a colorless oil: Z/E > 98:2; 1H NMR (CDCl3, 400 MHz) δ
2.73 (s, 4H), 7.28ꢀ7.37 (m, 5H), 9.68 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 31.3, 42.8, 123.9, 127.8, 128.3 (2C), 128.7 (2C), 129.0, 138.9,
199.7; IR (neat, cmꢀ1) 3049, 2923, 1724, 1622; MS (EI, m/z) 320 (1),
318 (2), 316 (Mþ, 1), 239 (100), 237 (Mþ ꢀ 79Br, 88); HRMS (ESI)
calcd for C11H10Br2O 315.9089, found 315.9097.
Scheme 3. Proposed Mechanism for Pd-Catalyzed Coupling
of Haloalkynes and R,β-Unsaturated Carbonyls
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
Finally, we checked other R,β-unsaturated carbonyls as the
electrophiles for this reaction. For example, the reaction of
1-cyclohexyl-2-propenone (2b) afforded cis-1-bromo-2-chlor-
oalkene 31 in 67% yield and excellent setereoselectivity (Z/E >
98:2), while substituted R,β-unsaturated carbonyls, such as
2-methylacrolein (2c) and crotonaldehyde (2d), only led to 32
and 33 in 42% and 50% yields, respectively (entries 28ꢀ30,
Table 2). The sharp contrast suggested distinctive steric effect on
the electrophiles.
dures and spectroscopic data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: gangguo@zjnu.cn.
’ ACKNOWLEDGMENT
As such, we have developed a rather practical and versatile
method for the synthesis of cis-1,2-dihaloalkene derivatives. As
we mentioned above, 1,2-dihaloalkenes could serve as useful
intermediates for the rapid synthesis of highly functionalized
alkenes. Thus, we made some primary efforts along this line. For
instance, treatment of cis-1-chloro-2-iodoalkene 16 with 2 equiv
of phenylacetylene in the presence of 5 mol % of Pd(PPh3)2Cl2
and 15 mol % of CuI in toluene at 40 °C gave the conjugated
enyne 34 in 65% yield, and the untouched CꢀCl bond of 34 may
be further utilized for late-stage modification in organic synthesis.
In sharp contrast, the reaction of cis-1,2-dibromoalkene product
4 failed to give the desired product under the Sonogashira
coupling9 conditions (Scheme 2).
The possible mechanism for this Pd-catalyzed coupling of
alkynyl halides with R,β-unsaturated carbonyls is proposed in
Scheme 3. Pioneered by Kaneda10a and Lu,11aꢀc the halopallada-
tion reaction10,11 has had great success in the past decades. It is
widely accepted that the halopalladation reaction may undergo
trans-addition in the presence of excess halide sources.12 As such,
the haloalkyne 1 underwent the trans-addition pathway in the
presence of an excess of halides to form the trans-halopalladation
adduct I, followed by the carbopalladation reaction with R,β-
unsaturated carbonyls to afford an alkyl palladium intermediate
II or the enolate intermediate III. Finally, the protonolysis of the
OꢀPd or CꢀPd bonds furnished the cis-dihaloalkene products
and regenerated the palladium catalyst (Scheme 3).
We greatly thank the National Natural Science Foundation of
China (No. 20902084), Qianjiang Talents Project of the Science
and Technology Office in Zhejiang Province (2010R10016), and
Zhejiang Normal University for their financial support. We also
thank Dr. Zhihong Huang for help with the preparation of the
manuscript.
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