Pd0-Catalyzed carbonylation of 1,1-dichloro-1-alkenes, a new selective access to Z-α-chloroacrylates

Article abstract of DOI:10.1039/c0cc02517h

A novel and fully chemo- and stereoselective three component strategy leading to Z-α-chloroacrylates by a Pd⁰-catalyzed reaction of CO (1 atm) with 1,1-dichloro-1-alkenes and various alcohols is disclosed. This catalytic approach compares favourably with the Wittig type strategies as α-chloroacrylates of pure Z configuration are obtained in high yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc02517h

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Pd0-Catalyzed carbonylation of 1,1-dichloro-1-alkenes, a new selective
access to Z-a-chloroacrylatesw
Martin Arthuis, Anne Lecup and Emmanuel Roulland*
Received 12th July 2010, Accepted 3rd September 2010
DOI: 10.1039/c0cc02517h
A novel and fully chemo- and stereoselective three component
strategy leading to Z-a-chloroacrylates by a Pd0-catalyzed
reaction of CO (1 atm) with 1,1-dichloro-1-alkenes and various
alcohols is disclosed. This catalytic approach compares
favourably with the Wittig type strategies as a-chloroacrylates
of pure Z configuration are obtained in high yield.
a-Haloacrylates are fairly useful and versatile building
blocks, allowing a wide variety of transformations. Among
these we can mention: Michael reaction,8 cycloadditions leading
to oxazoles,9 pyrazoles,10 or to cycloglutamates.11 The enantio-
selective hydrogenation of the C–C double bond of a-halo-
acrylates has also been described,12 and classical ester reduction
can be performed leading to a-chlorinated, a,b-unsaturated
aldehydes or allylic alcohols. This large array of reactivity has
been used for the preparation of pharmaceutical drugs or for
natural products synthesis such as a-amino-acids,13 aziridines,14
amino-alcohols,14 nucleosides,15 heterocycles,16 as well as
in polymer chemistry.17 With a-bromoacrylates or a-iodo-
acrylates, substitution of the halogen atom can be easily mediated
by transition metals (Pd0, SmII),18,19 leading to very valuable
trisubstituted alkenes of controlled configuration. Oddly enough,
nothing has been reported about the Pd0-catalyzed cross-coupling
reactions of the corresponding a-chloroacrylates 2.
In the literature various entries to Z-a-haloacrylates 2 are
reported, but only few are stereoselective and none are cata-
lytic processes. Among those, one can mention dehydrohalo-
genation of a,b-halogenated esters,20 and transition-metal
promoted reactions using dissuasive stoichiometric amounts
of Mn,21 Cr,22 Fe,23 or Sm.24 The Wittig25 and Horner–
Wadsworth–Emmons26 reactions have been extensively used
to access both E- and Z-a-bromoacrylates with acceptable E/Z
selectivity, but the HWE pathway to a-chloroacrylates 2 is
poorly documented27 and has been reported to occur with
medium or even no E/Z selectivity at all.26b,27b More recently
Mukaiyama et al. have reported a stereoselective synthesis of 2
by reaction of a chlorosilylketene derivative with aldehydes.28
The most widely utilized protocols to prepare 1,1-dichloro-1-
alkenes 1, our starting material, are neither straightforward nor
general and all lead to significant amount of toxic by-products
(CHCl3–DBU/Ac2O–pyridine/Zn–AcOH,29 CCl4–Al–PbBr2/
Ac2O–pyridine/Zn–AcOH30 or CHCl3–PPh331). To render our
methodology even more valuable, we adopted the Normant
procedure.32 This method furnished 1,1-dichloro-1-alkenes 133
in good yields along with rather innocuous and water-soluble
by-products, allowing facile purification and easy scale-up.
Furthermore, this method works with equal efficiency with
aromatic as well as with enolisable aldehydes.
New chemo-, regio- and stereoselective functional group
transformations by transition metal catalysis are challenging
motivations for synthetic chemists.1 In this context, we
previously developed two efficient methods to access Z-chloro-
alkenes of pure configuration based on Pd0 chemistry.2 Among
these methods, the Pd0-catalyzed cross-coupling of 1,1-di-
chloro-1-alkenes 1 with alkyl-9-BBN2a displayed an interesting
potential, highlighted by our total synthesis of the chlorinated
macrolide (+)-oocydin A/haterumalide NA.3 From this we
imagined that this potential could be advantageously exploited
for the stereoselective preparation of Z-a-chloroacrylates 2 by
Pd0-catalyzed reaction of 1,1-dichloro-1-alkenes 1 with carbon
monoxide and an alcohol, featuring then a straightforward and
simple three-component reaction (Scheme 1).
Carbon monoxide has been extensively used in palladium
chemistry4 but surprisingly, such an approach has never been
reported so far either with 1 or with their 1,1-dibromo-1-alkenes
analogues. As a consequence, there was no insight on how 1,1-
dichloro-1-alkenes 1 would react with CO in the presence of Pd0
and how the chemoselectivity (i.e., mono- vs. bis-substitution) or
the E/Z-selectivity of the reaction would be. Nevertheless an high
Z selectivity was expected for this carbonylation as the less
hindered trans chlorine atom of 1 showed more reactivity in
previously reported Suzuki–Miyaura2a and Negishi5 cross-
couplings. We found only very loosely related examples in the
literature in which 1,1-dibromo-1-alkenes are transformed into
2-carboxyindoles6 or 2-aroyl-heteroaroylindoles7 using CO. How-
ever, these two transformations are actually domino processes in
which CO reacts only secondarily with a 2-bromoindole inter-
mediate arising from a primary Pd0-catalyzed cyclization of the
1,1-dibromoalkene on the aniline function at the ortho position.
To set the carbonylation conditions we chose to work under
an atmospheric pressure of CO using a balloon and selected
(2,2-dichlorovinyl)benzene (1a)2a as model substrate (Table 1).
The first trial was conducted with Pd2(dba)3 and the PPh3 ligand
but, surprisingly no reaction was observed (entry 1). We also
tried dppf, dppe, dppp, dppb and Ruphos, in the same conditions
but with no result. The use of large bite angle bisphosphines such
as Xantphos 3 gave 2aa23a in 15% yield (entry 2) but tert-
Bu-Xantphos gave no reaction. The use of Binap led to some
Scheme 1
CNRS, Institut de Chimie des Substances Naturelles (ICSN),
UPR 2301, Avenue de la Terrasse, 91198, Gif-sur-Yvette, France.
E-mail: emmanue.roulland@icsn.cnrs-gif.fr; Fax: (+33)-16907-7247;
Tel: (+33)-16982-4572
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data for new compounds.
See DOI: 10.1039/c0cc02517h
c
7810 Chem. Commun., 2010, 46, 7810–7812
This journal is The Royal Society of Chemistry 2010

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Table 1 Conditions for the Pd0-catalyzed carbonylation of 1
Unfortunately, n-BuNH2 failed to provide the targeted amide
2ag. Other Z-a-chloroacrylates were obtained in good yields
from electron rich (2ae, 2cb,35 2ce) as well as from electron poor
(2be, 2de, 2fe, 2ge) aromatic 1,1-dichloro-1-alkenes 1. In
addition, a 1,1-dichloro-1-alkene bearing a 2-pyridyl function
was successfully carbonylated, as 2ee was obtained in 62% yield.
Biselectrophilic substrates such as 1-chloro-4-(2,2-dichlorovinyl)-
benzene led exclusively to 2fe whereas its corresponding
brominated analogue, 1-bromo-4-(2,2-dichlorovinyl)benzene, led
as expected, to a mixture of mono- (2ge) and bis- (2gee)
carbonylated products, the gem-dichloalkene function displaying
more reactivity than the bromine. One limitation of our method
appeared with the carbonylation of (E)-(4,4-dichlorobuta-
1,3-dienyl)benzene which led to acrylates 2he as an 65/35 E/Z
mixture but interestingly, 2ie was obtained with a 95/5 E/Z ratio.
As expected, the aliphatic 1,1-dichloro-1-alkenes 1 showed a
slightly lower reactivity giving products 2je to 2le with lower
yields but still as the pure Z isomer.
Entry Pd source, ligand Conditions
Result
d
1
Pd2(dba)3, PPh3
Et3N, THF–MeOH,
60 1C, 86 h
Et3N, THF–MeOH,
1a (recovered
unchanged)
2aa, 15%c
2
Pd2(dba)3, 3e
60 1C, 86 h
3
Pd2(dba)3, Binape i-Pr2EtN, THF–MeOH, 2aa, 30%c
60 1C, 65 h
4
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd2(dba)3, 4e
Pd(OAc)2, 4f
Pd2(dba)3, 4g
i-Pr2EtN, THF–MeOH, 2aa, 37%c
60 1C, 86 h
i-Pr2EtN, MeOH,
(50% conv.)h
2aa, 68%c
5
(70% conv.)h
2ab, 87%c
Even though a-iodo- and a-bromoacrylates are well-known
Pd0-catalyzed cross-coupling partners,18 and albeit the recent and
vast development of cross-coupling methods of chlorinated
electrophiles,36 a careful examination of the literature shows that
a-chloroacrylates 2 have apparently never been used in Pd0-
catalyzed cross-couplings. So, we focused on the Suzuki–Miyaura
reaction37 and found that the conditions we previously adapted
for the cross-couplings of non-conjugated vinylic chlorides2b using
60 1C, 70 h
6
i-Pr2EtN, EtOH,
70 1C, 65 h
i-Pr2EtN, n-PrOH,
(90% conv.)h
2ac, 65%c
7
85 1C, 65 h
(90% conv.)h
2ad, 69%c,i
8
i-Pr2EtN, n-BuOH,
105 1C, 65 h
i-Pr2EtN, BnOH,
(100% conv.)h
2ae, 87%c
9
70 1C, 24 h
(100% conv.)h
2af, 91%c
10
11
12
i-Pr2EtN, MPMOH,
70 1C, 24 h
i-Pr2EtN, BnOH,
70 1C, 24 h
i-Pr2EtN, BnOH,
70 1C, 70 h
(100% conv.)h
2ae, 55%c
Table 2 Pd0-catalyzed carbonylation of various 1,1-dichloro-1-alkenes 1
(100% conv.)h
2ae, (blocking
at 55% conv.)h
a 1 atm of CO (balloon). b 3.0 equiv. Isolated yield. PPh3: 10 mol%,
Pd2(dba)3: 2.5 mol%. e Bisphosphine: 5 mol%, Pd2(dba)3: 2.5 mol%.
c
d
Pd(OAc)2: 5 mol%, 4: 5 mol%. g Pd2(dba)3: 1 mol% and 4: 2 mol%.
Evaluated by 1H NMR. 17% of bis-carbonylated product has also been
isolated.
f
h
i
improvement (entry 3) but still incomplete conversion. Dpephos
4 in THF–MeOH led to a 37% yield and a conversion of 50%
(entry 4). We found that using MeOH without any co-solvent
along with Dpephos 4 and the Hunig’s base, gave improved yield
¨
(68%) and better but still incomplete conversion (70%) (entry 5).
Finally, the use of less polar alcohol solvents led to better
(entries 6, 7) or even total conversion along with high yields of
pure Z-carbonylated compounds 2 (entries 8–11). Of particular
interests are BnOH and (4-MeO)BnOH which furnished respec-
tively ester 2ae (87%) and ester 2af (91%) with full conversion.
Carbon monoxide being more soluble in non-polar solvents,34
may explain why lipophilic alcohols allow working at
atmospheric pressure (BnOH 4 EtOH c MeOH). Importantly,
E/Z-selectivity and chemoselectivity of this reaction are total in
all cases, but higher reaction temperatures (105 1C) led to 17% of
two-fold carbonylated product (entry 8). The use of a cheaper Pd
source such as Pd(OAc)2 or lower Pd2(dba)3 loadings unfortu-
nately led to yield erosion (entries 11, 12).
To determine the scope of this reaction, we implemented it to
various 1,1-dichloroalkenes 1 and alcohols, which led to a series
of Z-a-chloroacrylates 2 (Table 2). We have already shown
above that this reaction works efficiently with various alcohols
(2ab19 to 2af), BnOH and (4-MeO)BnOH giving the best results.
a Reaction time: 48 h. b 1-Bromo-4-(2,2-dichlorovinyl)benzene can react
twice leading to a 65/35 mixture of mono- 2ge and bis-ester 2gee after
24 h, and 35/65 after 72 h at 70 1C, 57%. c 100 1C, 17 h. d 100 1C, 24 h.
c
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Chem. Commun., 2010, 46, 7810–7812 7811

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Table 3 Pd0-catalyzed substitution of the chlorine atom of various
Z-a-chloroacrylates 2
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the Ruphos ligand 5, were efficient. So we demonstrated that the
cross-coupling of Z-a-chloroacrylates 2 worked successfully even
with various types of organoboron reagents (boronic acid, boronic
ester, potassium trifluoroborate and trimethylboroxine), affording
disubstituted acrylates 6 with a similar efficiency in all cases
(Table 3). Thus we prepared some stilbene derivatives
(known 6a,38 6b, 6c39) featuring the skeleton of combretastatine
analogues.40 In the last example, trimethylboroxine was used as a
methyl donor with a-chloroacrylate trans-2ke leading to cross-
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valuable stereoselective access to the 1,2-propenylidene motif
which is frequently encountered in natural products.41
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¨
In summary, we have demonstrated the feasibility of the
Pd0-catalyzed carbonylation of 1,1-dichloro-1-alkenes 1, and set
efficient conditions for this very useful transformation. This
provides a novel and highly chemo- and stereoselective access to
Z-a-chloroacrylates 2 that compares favourably with the
Wittig-type methods. For this reaction, the use of a large bite
angle bisphosphine palladium ligand appeared to be instru-
mental, which is in full accordance with what was previously
observed for the cross-coupling of 1 with alkyl-9-BBN2a or with
alkylzinc.5 We also successfully investigated the unexplored
Pd0-catalyzed cross-coupling reaction of a-chlororacrylates 2
using various boron nucleophilic coupling partners, affording
disubstituted acrylates 6 of pure configuration.
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7812 Chem. Commun., 2010, 46, 7810–7812
This journal is The Royal Society of Chemistry 2010