A very simple synthesis of chloroalkenes and chlorodienes by selective Suzuki couplings of 1,1- and 1,2-dichloroethylene

Article abstract of DOI:10.1002/adsc.200505302

Chloroalkenes, important building blocks for cross-coupling reactions, are prepared in one step by the Suzuki reaction of 1,1-dichloroethylene and 1,2-dichloroethylene with alkenyl- and arylboronic acids. Under the proper reaction conditions, it is possible to obtain the monocoupling reaction to provide the corresponding chloroalkenes with good yields. This method represents an excellent route for the preparation of chloroalkenes and chlorodienes from commercially available starting materials.

Full text of DOI:10.1002/adsc.200505302

FULL PAPERS
DOI: 10.1002/adsc.200505302
A Very Simple Synthesis of Chloroalkenes and Chlorodienes by
Selective Suzuki Couplings of 1,1- and 1,2-Dichloroethylene
´
´
Jose Barluenga,* Patricia Moriel, Fernando Aznar, Carlos Valdes
´
´
Instituto Universitario de Química Organometalica “Enrique Moles”, Universidad de Oviedo, Julian Clavería 8,
33006, Oviedo, Spain
Fax: (þ34)-985-103-450, e-mail: barluenga@uniovi.es
Received: July 28, 2005; Accepted: November 28, 2005
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Chloroalkenes, important building blocks yields. This method represents an excellent route for
for cross-coupling reactions, are prepared in one the preparation of chloroalkenes and chlorodienes
step by the Suzuki reaction of 1,1-dichloroethylene from commercially available starting materials.
and 1,2-dichloroethylene with alkenyl- and arylboron-
ic acids. Under the proper reaction conditions, it is
possible to obtain the monocoupling reaction to pro- Keywords: boronic acids; chloroalkenes; cross-cou-
vide the corresponding chloroalkenes with good pling; palladium; Suzuki reaction
Introduction
A general strategy for the synthesis of 1-chloroal-
kenes[7] and 2-chloroalkenes[8] could be the selective
Transition-metal catalyzed cross-coupling reactions are cross-coupling reaction between inexpensive and com-
amongst the most powerful transformations for the for- mercially available 1,2-dichloroethylene and 1,1-di-
mation of C C and C heteroatom bonds.[1] In a cross- chloroethylene, respectively, and the corresponding or-
coupling process, the formation of the new bond is ach- ganometallic derivatives (Scheme 1). Palladium-cata-
ieved from two coupling partners: a nucleophile, typical- lyzed selective monosubstitutions of 1,1- and 1,2-diha-
ly an organometallic derivative (organoboron, organo- loalkenes have been reported employing organomagne-
tin, organozinc) and an electrophile, usually an organic sium,[9] organozinc,[10] organoboron,[11] and organotin[12]
halide or pseudohalide. In spite of the enormous devel- reagents, as well as in Sonogashira couplings with acety-
opment of increasingly efficient cross-coupling proto- lenes.[13] Moreover, selective monosubstitutions on
cols in recent years, the usefulness of these methodolo- mixed 1,2-dihaloethylenes such as 1-bromo-2-iodoethy-
gies is very often hampered by the availability of the lene and 1-chloro-2-iodoethylene have been recently
starting materials. In this context, the development of ef- employed by Neghisi,[14] and Organ[15] for the prepara-
ficient methodologies for the preparation of organic hal- tion of 1-haloalkenes. However, the simplest and most
ꢀ
ꢀ
ides appears to be a field of great interest.
readily available members of the family, 1,1- and 1,2-di-
We have recently disclosed the palladium-catalyzed chloroethylene,[16] have been less studied. The ability of
amination of alkenyl bromides and chlorides as a new 1,2-dichloroethylene to participate in selective mono-
method for the synthesis of imines and enamines.[2] In couplings has been applied in Sonogashira couplings,[17]
particular, we have shown that the amination of 1- and and also in Ni-catalyzed couplings with Grignard re-
2-chlorobutadienes represents a new entry to the prepa- agents,[18] in Pd-catalyzed reactions with alkenyl-
ration of 1- and 2-aminobutadienes, respectively,[2c,3] ver- alanes,[19] and to the best of our knowledge, only one ex-
satile reagents for cycloaddition reactions.[4] In the ample of reaction of 1,2-dichloroethylene with an alke-
course of our research, we surprisingly realized that sim- nylboronic acid has been previously reported, providing
ple 1- and 2-chloroethylenes and specially 1-chloro-1,3- only a moderate yield of the corresponding chloro-
butadienes[5] and 2-chloro-1,3-butadienes,[6] are not as diene.[20] The use of 1,1-dichloroethylene in cross-cou-
readily available as one might initially imagine. Most pling processes is more scarce, and only a Sonogashira
of the methods described for their synthesis are not gen- coupling and a single example of a Pd-catalyzed cou-
eral, require several steps from commercial sources, and pling of a vinylalane have been previously reported.[21]
usually provide low yields and lack stereoselectivity.
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347

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Motivated by the need for a simple and efficient meth-
od for the synthesis of structurally diverse 1-chloroal-
kenes and 2-chloroalkenes to broaden the scope of the
alkenylamination reaction, we decided to carry out an
extensive study on the Pd-catalyzed cross-coupling reac-
tions of dichloroethylenes. We decided to focus on the
Suzuki–Miyaura reaction,[22,23] owing to the wide availa-
bility and also low toxicity of the required boronic acids.
Surprisingly, in spite of its popularity, the Suzuki–
Miyaura cross-coupling with dichloroethylenes had re-
mained almost unexplored.[20] In this paper, we report
Scheme 1. General strategy for the synthesis of 1-chloroal-
kenes and 2-chloroalkenes.
our findings regarding the employment of 1,1-dichloroe- Results and Discussion
thyene (1) and trans-1,2-dichloroethylene (2) as sub-
strates in Suzuki cross-couplings oriented to the prepa- We selected the coupling of (E)-1-octenylboronic acid
ration of chloroalkenes and chlorodienes (Scheme 1).
(3a) with 1 as prototype reaction to develop suitable
conditions. A large array of reactions was carried out us-
ing Pd2(dba)3 as metal source, different supporting li-
gands, solvents, and bases, and under different molar ra-
tios of the dichloroethylene (Table 1). Preliminary ex-
periments using 1:1 molar ratio of both coupling part-
Table 1. Reaction of alkenylboronic acid 3a with 1,1-dichloroethylene 1.[a] Selected data from the optimization of the reaction
conditions.
Entry
Ligand
Solvent
Base
T [8C]
T [h]
Ratio 4a : 5[b]
Yield[c] [%]
1
2
3
3
4
5
6
7
8
PPh3
Dioxane
Dioxane
Dioxane
Toluene
Toluene
Toluene
Dioxane
Toluene
Toluene
Dioxane
Dioxane
Toluene
Toluene
Dioxane
CsF
CsF
CsF
100
100
70
80
80
5
5
7
6
6
5
4
4
5
4
4
5
24
24
32: 68
70: 30
62: 38
>95: 5
>95: 5
>95: 5
>95: 5
>95: 5
>95: 5
–
not determined
not determined
not determined
BINAP
BINAP
DavePhos
DPPDAB
SPhos
JohnPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
K3PO4
K3PO4
K3PO4
CsF
K3PO4
Cs2CO3
K3PO4
CsF
40
58
16
28
92[d]
70
0
100
70
100
100
100
100
100
25
9
10
11[e]
12
13
>95: 5
>95: 5
–
86[d]
46
0
K3PO4
K3PO4
CsF
XPhos
25
–
0
[a]
General reaction conditions: 0.5 mmol alkenylboronic acid; 2.0 mmol (4 equivs.) 1,1-dichloroethylene; Pd2(dba)3 0.5 mol %;
2: 1 molar relationship Pd :Ligand; 2 equivs. base; 2 mL solvent.
Determined by analysis of the H NMR spectra of the reaction.
Isolated yields.
Reaction conversion was complete.
Pd2(dba)3 0.25 mol % was used.
[b]
[c]
[d]
[e]
1
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Adv. Synth. Catal. 2006, 348, 347 – 353

Simple Synthesis of Chloroalkenes and Chlorodienes
FULL PAPERS
ners afforded always considerable amounts of triene 5, out in the presence of an aryl chloride (entry 6), given
derived from the second coupling of chloride 4a with the higher reactivity of vinyl chlorides over aryl chlor-
the boronic acid. Therefore, our optimization study ides towards oxidative addition reactions. However,
was directed towards a set of reaction conditions that the utilization of electron-poor arylboronic acids
would maximize the conversion of the coupling reac- seemed to be a limitation of the reaction due to unde-
tion, but minimizing the formation of the triene 5. It sired side reactions of the boronic acid (entry 12).[25b,26]
was found that a 4:1 molar ratio of dichloroethylene: Thus, when 3-acetylphenylboronic acid was used, the re-
boronic acid was a prerequisite to avoid the second cou- action proceeded with very low yield, with acetophe-
pling process.
none, coming from the protodeborination of the boronic
The set of ligands included in the optimization round acid, being the main product isolated. In spite of this lim-
consisted of PPh3, the chelating diphosphine BINAP, itation, this procedure represents a very efficient ap-
and several electron-rich bulky biphenyls. As represent- proach to a wide variety of a-chlorostyrenes and 2-
ed in Table 1, the best results were obtained from the chloro-1,3-butadienes, which competes favourably
Pd(0)/XPhos[24] catalytic combination (entries 7 and with the very few alternative methods available for their
10), which provided high yield of the desired chloro- preparation.[6,7]
diene 4a without formation of the triene 5. Interestingly,
We next turned our attention to the coupling reactions
PPh3 and BINAP, which are expected to generate less with 1,2-dichloroethylene, which would allow for the
active catalysts also promoted the cross-coupling, but preparation of 2-substituted-1-chloroethylenes. In con-
the reactions always afforded mixtures of chlorodiene trast with the successful results obtained in most cases
4a and triene 5. Other ligands which are known to be for 1,1-dichloroethylene, the coupling of 1,2-dichloro-
very active in the Suzuki–Miyaura reaction (DavePhos, ethylene turned out to be more challenging. Again, an
SPhos)[25] afforded the desired chlorodienebut with low- extensive screening of ligands and reaction conditions
er conversions and overall yield (entries 3 and 5).
was carried out in an attempt to overcome the limita-
On the other hand, it was observed that a proper com- tions observed, using the coupling of 2-phenylethenyl-
bination of base and solvent is very important for the boronic acid with 1,2-dichloroethyene as prototype re-
success of the reaction (entries 7 to 10). After some ex- action. The best reaction conditions again consisted in
perimentation it was determined that the best combina- Pd2(dba)3 as metal source, JohnPhos as supporting li-
tions were K3PO4/toluene and CsF/dioxane. Typically, gand, CsF as additive in dioxane at 708C.
the optimized reaction conditions required 1 mol % of
As depicted in Table 3, results ranging from excellent
Pd at 1008C. A decrease in the catalyst loading to to good were obtained for the coupling of 1,2-dichloro-
0.5 mol % slowed the reaction down significantly (entry ethylene with electron-rich alkenylboronic acids (en-
11), while the reaction at room temperature did not pro- tries 1–3 and 5) and electron-rich arylboronic acids (en-
ceed to any extent (entries 12 and 13). Moreover, when tries 10 and 11). In those cases, the monocoupling reac-
the molar relationship of dichloroethylene:boronic acid tion proceeds selectively and with total retention of con-
was reduced from 4:1 to 2:1, a small amount of triene 5 figuration of the trans double bond. However, a slight
was always detected.
decrease in the electron-donor character of the substitu-
The scope of the reaction was studied with a variety of ents of the boronic acid gave rise to very poor results due
alkenyl- and arylboronic acids (Table 2). In several cas- to an increase of the double coupling product 7 as well as
es, when XPhos was employed as supporting ligand, sig- other undesired side products derived from protode-
nificant amounts of the double coupled product were boronation, 8, and homocoupling, 9, of the boronic
obtained. After some experimentation, it was deter- acids.[26] The increase in the formation of 7 can be ration-
mined that in such examples reactions in the presence alized considering the relative reactivity of the different
of JohnPhos (Table 2, Method C) provided the best re- chloroalkenes towards oxidative addition to the Pd cen-
sults.
ter. Apparently, there is a very slight reactivity differ-
Under the optimized reaction conditions, the cross- ence between 1,2-dichloroethyene (2) and the 1-chlor-
coupling reaction could be achieved successfully with oalkenes 6 formed in the coupling reaction. For elec-
different alkenyl- and arylboronic acids 3 giving rise to tron-rich alkenylboronic acids, the coupling reaction
the desired 2-chloro-1,3-butadienes and a-chlorostyr- gives rise to electron-donating-substituted chloroal-
enes 4 (Table 2). In most of the examples the alkenyl kenes 6, that are less reactive towards oxidative addition
chloride 4 was obtained cleanly as the sole reaction than 1,2-dichloroethylene, and therefore, the selective
product as judged by 1H and 13C NMR. However, the in- monocoupling occurs. However, the coupling of elec-
stability of these type of compounds towards chroma- tron-neutral and electron-poor boronic acids with 1,2-
tography gave rise, in some examples, to relatively re- dichloroethylene affords a new chloroethylene 6 which
duced isolated yields.
is substantially more reactive than 1,2-dichloroethylene
The coupling reaction provides excellent results for towards oxidative addition, and therefore it was not pos-
electron-rich and electron-neutral substitutents on the sible to carry out the selective monocoupling under the
boronic acid. Moreover, the reaction can be carried present reaction conditions.
Adv. Synth. Catal. 2006, 348, 347 – 353
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Table 2. Synthesis of 2-chloroalkenes by cross-coupling of 1,1-dichloroethylene (1) with alkenyl- and arylboronic acids 3.
Entry
R-B(OH)2
Product
Method[a]
Yield(%)[b]
1
2
3a
4a
A
B
92
86
3
4
3b
3c
4b
4c
A
C
87
76
5
6
7
8
3d
3e
3f
4d
4e
4f
C
C
C
C
72
49
61
64
3g
4g
9
3h
3i
4h
4i
C
C
87
66
10
11
12
[a]
3j
4j
C
C
83
3k
4k
21[c]
Method A: 0.5 mmol boronic acid; 2.0 mmol (4 equivs.) dichloroethylene 1; Pd2(dba)3 0.5 mol %; XPhos 2 mol %; 1 mmol
(2 equiv.) K3PO4; 2 mL toluene; 1008C. Method B: 0.5 mmol boronic acid; 2.0 mmol (4 equivs.) dichloroethylene 1; Pd2
(dba)3 0.5 mol %; XPhos 2 mol %; 1 mmol (2 equivs.) CsF; 2 mL dioxane, 1008C. Method C: 0.5 mmol boronic acid;
2.0 mmol (4 equivs.) dichloroethylene 1; Pd2(dba)3 0.5 mol %; JohnPhos 2 mol %; 1 mmol (2 equivs.) CsF; 2 mL dioxane,
708C.
Isolated yields, after flash chromatography.
A 4k:acetophenone, 31: 69, mixture was obtained.
[b]
[c]
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Simple Synthesis of Chloroalkenes and Chlorodienes
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Table 3. Synthesis of 1-chloroalkenes by cross-coupling of 1,2-dichloroethylene (2) with alkenyl- and arylboronic acids 3.
Entry
Product
Method[a]
Ratio 6: 7: 8: 9
Yield [%][b]
1
2
6a
A
B
100: 0: 0: 0
100: 0: 0: 0
89
94
3
4
5
6b
6c
6d
A
C
C
100: 0: 0: 0
69: 31: 0: 0
79: 0: 21: 0
90
44
65
6
7
6e
6f
C
C
100: 0: 0: 0
60
33
56: 22: 0: 22
8
9
6g
6h
C
C
41: 59:: 0
14
50
66: 32: 1: 0
10
6i
C
100: 0: 0: 0
67
11
12
6j
C
C
100: 0: 0: 0
82
31
6k
44: 12: 44: 0
[a]
Method A: 0.5 mmol boronic acid; 2.0 mmol (4 equivs.) dichloroethylene 2; Pd2(dba)3 0.5 mol %; XPhos 2 mol %; 1 mmol
(2 equivs.) K3PO4; 2 mL toluene; 1008C. Method B: 0.5 mmol boronic acid; 2.0 mmol (4 equivs.) dichloroethylene 2; Pd2
(dba)3 0.5 mol %; XPhos 2 mol %; 1 mmol (2 equivs.) CsF; 2 mL dioxane, 1008C. Method C: 0.5 mmol boronic acid;
2.0 mmol (4 equivs.) dichloroethylene (1 or 2); Pd2(dba)3 1 mol %; JohnPhos 2 mol %; 1 mmol (2 equivs.) CsF; 2 mL diox-
ane, 708C.
[b]
Isolated yields, after flash chromatography.
Conclusion
other hand, the selective coupling of trans-1,2-dichloro-
ethylene with alkenylboronic acids and electron-rich ar-
In summary, we have carried out an extensive study of ylboronic acids, is a very straightforward and efficacious
the usefulness of 1,1- and trans-1,2-dichloroethylene in method for the stereoselective synthesis of trans-1-
selective Suzuki couplings with boronic acids. The cou- chloro-1,3-butadienes and trans-b-chlorostyrenes, re-
pling reaction of 1,1-dichloroethylene represents a spectively. In both cases, the present methodology com-
very general and efficient method for the preparation pares favourably with the existing methods for the prep-
of a-chlorostyrenes and 2-chloro-1,3-butadienes in one aration of these types of chlorides, important building
step and from commercial starting materials. On the blocks for cross-coupling reactions.
Adv. Synth. Catal. 2006, 348, 347 – 353
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ratus at 10ꢀ3 Torr for 1–3 hours to eliminate the protodebori-
nation product.
Experimental Section
Specific experimental details and characterization data for
compounds 4 and 6 are available in the Supporting Informa-
tion.
General Remarks
All reactions were carried out under nitrogen atmosphere in an
RR98030 12 place Carousel Reaction StationTM from Radleys
Discovery Technologies, equipped with gas-tight threaded
caps with a valve, cooling reflux head system, and digital tem-
perature controller. Toluene, dioxane, pentane and hexanes
were continuously refluxed and freshly distilled from sodium/
benzophenone under nitrogen. Pd2(dba)3 was purchased
form Strem Chemical Co. and used without further purifica-
tion. All phosphine ligands used are commercially available
from Strem or Aldrich and were used without further purifica-
tion. K3PO4 and CsF were purchased from Aldrich Chemical
Co., stored in a flask purged with nitrogen and weighed in
the air. The boronic acids employed are commercially availa-
ble from Aldrich or Acros, and were used without further pu-
rification. The boronic acid 3b was prepared according to a lit-
erature procedure.[27] 1,1-Dichloroethylene and 1,2-dichloro-
ethylene are commercially available from Fluka and Acros, re-
spectively, and were used without further purification.
Acknowledgements
´
´
Financial support of this work byFundacion Ramon Areces and
DGI (Grant MCT-04-CTQ2004-08077-C02-01). P. M. wishes to
thank MEC of Spain for a predoctoral fellowship.
References and Notes
[1] For general reviews on Pd-catalyzed cross-coupling reac-
tions, see: a) E. Negishi, (Ed.), Handbook of Organopal-
ladium Chemistry for Organic Synthesis, Wiley-Inter-
science, New York, 2002, Vol. I, Part III, pp 215–1119;
b) A. de Meijere, F. Diederich, (Eds.), Metal-Catalyzed
Cross Coupling Reactions, VCH, Weinheim, 2004.
´
´
[2] a) J. Barluenga, F. Aznar, M. A. Fernandez, C. Valdes,
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´
´
M. A. Fernandez, F. Aznar, C. Valdes, Chem. Eur. J.
General Procedure for the Cross-Coupling of Boronic
Acids 3 with 1,1-Dichloroethylene (1) or trans-1,2-
Dichloroethylene (2)
2004, 10, 494–507; c) J. Barluenga, F. Aznar, M. A. Fer-
nandez, C. Valdes, Chem. Commun. 2004, 1400–1401.
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[4] For a review on the synthesis and application of hetero-
Method A: A carousel reaction tube under nitrogen atmos-
phere was charged with dicyclohexylphosphino-2’,4’,6’-triiso-
propylbiphenyl (XPhos) (0.02 mmol, 2 mol %), tris(dibenzyli-
deneacetone)dipalladium(0) (0.005 mmol, 1 mol %), potassi-
um phosphate (2 mmol), the boronic acid 3a, b (1 mmol) and
toluene (4 mL). After 1 minute, the dichloroethylene 1 or 2
(4 mmol) was added. The system was heated at 1008C with stir-
ring and reflux until the starting boronic acid had been com-
pletely consumed as judged by TLC analysis. The mixture
was allowed to cool to room temperature, taken up in dry pen-
tane or hexanes (15 mL), and filtered through Celite. The sol-
vents were evaporated under reduced pressure. The residue
was redissolved in dry hexanes (15 mL), filtered again through
Celite, concentrated under reduced pressure and dried under
high vacuum to afford a residue which consisted of the essen-
tially pure chlorodiene 4a, b or 5a, b.
´
substituted dienes, see: J. Barluenga, A. Suarez-Sobrino,
´
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Method B: This is the same as that of Method A, using CsF
(2 mmol) instead of K3PO4 as base and dioxane (4 mL) as sol-
vent.
Method C: A carousel reaction tube under nitrogen atmos-
phere was charged with 1,1’-bis(di-tert-butylphosphino)bi-
phenyl (JohnPhos) (0.02 mmol, 2 mol %), tris(dibenzylidene-
acetone)dipalladium(0) (0.005 mmol, 1 mol %), cesium fluo-
ride (2 mmol), the boronic acid 3c–k (1 mmol) and dioxane
(4 mL). After 1 minute, the dichloroethylene 1 or 2 (4 mmol)
was added. The system was heated at 708C with stirring and re-
flux until the starting boronic acid had been completely con-
sumed as judged by TLC analysis. The mixture was allowed
to cool to room temperature, taken up in dry pentane, hexanes
or dichloromethane (15 mL), and filtered through Celite. The
solvents were evaporated under reduced pressure and the res-
idue was purified by flash chromatography. In some cases, the
crude residue was heated neat at 42–658C in a kugelrçhr appa-
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Simple Synthesis of Chloroalkenes and Chlorodienes
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Adv. Synth. Catal. 2006, 348, 347 – 353
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