Influence of the catalytic conditions on the selectivity of the Pd-catalyzed Heck arylation of acrolein derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.03.186

The Heck arylation of acrolein with a variety of condensed aryl and heteroaryl halides is described. Depending on the substrate, up to 87% isolated yield to the expected aldehydes was achieved. When the reaction was run on diethylacetal acrolein, the choice of catalytic system dramatically affected the selectivity of the reaction: the catalyst system based on Herrmann's palladacycle complex gave mainly saturated esters 2, whereas Cacchi's conditions led to the formation of α,β-unsaturated aldehydes 1.

Full text of DOI:10.1016/j.tetlet.2006.03.186

Tetrahedron Letters 47 (2006) 3839–3842
Influence of the catalytic conditions on the selectivity of the
Pd-catalyzed Heck arylation of acrolein derivatives
*
´
Sebastien Noe¨l, Laurent Djakovitch and Catherine Pinel
Institut de Recherches sur la Catalyse, UPR-CNRS 5401, 2 Avenue Albert Einstein, 69626 Villeurbanne, France
Received 1 March 2006; revised 24 March 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—The Heck arylation of acrolein with a variety of condensed aryl and heteroaryl halides is described. Depending on the
substrate, up to 87% isolated yield to the expected aldehydes was achieved. When the reaction was run on diethylacetal acrolein,
the choice of catalytic system dramatically affected the selectivity of the reaction: the catalyst system based on Herrmann’s palla-
dacycle complex gave mainly saturated esters 2, whereas Cacchi’s conditions led to the formation of a,b-unsaturated aldehydes 1.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Cinnamaldehyde and its derivatives are important
intermediates in the cosmetic, pharmaceutical, and
agrochemical industries.1–3 For example, cinnamalde-
hyde is commonly used as cinnamon flavoring
compound in the food industry, and the trans-cinnam-
aldehyde derivatives possess antifungal or antibacterial
properties.
we demonstrated that both mono- or di-arylation were
possible.9 The scope of this initial study was limited to
the uses of simple aryl bromides. In the present contri-
bution, we report the Heck arylation of acrolein using
a large variety of condensed aryl halides and heteroaryl
halides, and compare the result to those issued from the
Heck arylation of diethyl acetal acrolein under strictly
the same reaction conditions.
Several methods based on the Perkin and Claisen
condensations of aromatic aldehydes have been reported
for the synthesis of cinnamaldehyde derivatives at the
industrial scale.4 However, the applicability of these
methods remains limited due to the difficult and costly
synthesis of the starting materials.5 Recently several
palladium catalyzed syntheses, based on the Heck
reaction, have been reported from the acrolein.6–8
However, this arylation was found in some cases to lead
to a mixture of aldehyde and saturated ester under
different reaction conditions. Thus, the selective synthe-
sis of aldehydes via the direct palladium-catalyzed Heck
arylation of acrolein, under standard reaction condi-
tions (polar solvent, base, commercially available palla-
dium catalyst), would undoubtedly represent a route of
choice.
Initially, the Heck arylation of acrolein using various
aromatic and heteroaromatic bromides was studied
using the reaction conditions optimized for bromo-
benzene (1 equiv aryl bromide, 3 equiv acrolein, 1.5
equiv NaOAc, 2 mol % [Pd] cat., 8 mL NMP, 140 ꢁC)
(Scheme 1).9,10 The results are reported in Table 1.
After 6 h, the conversions of the bromoaryl derivatives
and the selectivities toward the expected aldehydes are
high, with the exception of 1-bromonaphthalene and
9-bromoanthracene: the former led to a low (32%) but
O
O
O
O
Pd
Pd
P
P
oTol
oTol
oTol
oTol
We previously reported results on the Heck arylation of
a,b-unsaturated aldehydes, including acrolein, in which
"Palladacyle"
O
O
Ar
ArX
NMP, NaOAc, 140 °C
1
Ar = aryl, heteroaryl
Keywords: Heck arylation; Acrolein; Acrolein diethyl acetal; Cinna-
Scheme 1. Heck arylation of acrolein. Reaction conditions: 2.4 mmol
aryl halide, 7.2 mmol acrolein, 3.6 mmol NaOAc, 2 mol % Pd-catalyst,
8 mL NMP, 140 ꢁC.
mon derivatives; Aromatic compounds; Heteroaromatic compounds.
*
Corresponding author. Tel.: +33 4 72 44 53 81; fax: +33 4 72 44 53
99; e-mail: laurent.djakovitch@catalyse.cnrs.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.186

3840
S. Noe¨l et al. / Tetrahedron Letters 47 (2006) 3839–3842
Table 1. Heck arylation of acrolein10 (Scheme 1)
O
O
Ar
Ar
1
2
ArX
Conversiona
(%)
Product/selectivitya
(%)
Isolated
yield (%)
or
1) Heck coupling
2) Hydrolysis
OEt
OEt
Ar = aryl, heteroaryl
ArX
Br
96
32
1a/100
1b/100
87
21
OEt
or
Br
Br
Ar-H
3
Scheme 2. Heck arylation of acrolein diethyl acetal. Reaction condi-
tions: (1) 2.4 mmol aryl halide, 7.2 mmol acrolein, 3.6 mmol base,
2–5 mol % Pd-catalyst (i.e., palladacycle or Pd(OAc)2, KCl,
n-Bu4NOAc), 8 mL solvent, 90–140 ꢁC. (2) HCl (1 N), H2O.
35
Mixtureb
—
Br
selective conversion to the expected aldehyde, while the
latter led to the formation of a mixture of products
with low conversion. Analysis of the product mixture
in the latter case showed that anthracene, formed by
dehalogenation, was the major product (48%, identified
by GC–MS analysis), with the remainder apparently
composed of two cross-coupling isomers (further purifi-
cation and analysis was not undertaken).
90
98
63
1d/90
67
82
83
Br
1e/100
1f/100
N
Br
N
No reports concerned the Heck reaction between hetero-
aryl halides and acrolein, while such coupling products
would be highly valuable for the synthesis of important
ketolide antibiotics like Cethromycin.11 As reported in
Table 1, all heteroaryl halides, including the benzo-
thiophene, gave reasonable to high isolated yield
(40–83%) to the expected aldehydes, thanks to the high
conversions (>80%) and selectivities (>70%).
Br
73
1h/70
40
S
a Conversion and selectivity were determined by GC (Drel
=
5%).
b This reaction gave a mixture of three products (3c: 48% and coupling
compounds: 52%) that could not be separated from each other.
Table 2. Heck arylation of acrolein diethyl acetal (Scheme 2)
Conditionsa
Conv.b (%)
Selectivityc (%) Ar
O
Ar-H
O
Ar
ArX
3
1
OEt
2
Br
Cacchi’s A
Herrmann’s B
70
82
83 (32)
17
15
85 (75)
95
Br
Br
Cacchi’s A
Herrmann’s B
73
90
86
5
14
Cacchi’s A
85
40
60
Herrmann’s B
100
100 (84)
Br
Cacchi’s A
Herrmann’s B
90
95
67 (42)
33
100 (95)
Br
Cacchi’s A
Herrmann’s B
100
100
79
15
21
85
N
Br
Cacchi’s A
Herrmann’s B
100
85
33
17
100
50
N
Br
Cacchi’s A
Herrmann’s B
100
35
7
5
3
90
90
5
S
a Reaction conditions: (A) Pd(OAc)2 5 mol %, K2CO3, n-Bu4NOAc, KCl, DMF, 90 ꢁC, 6 h. (B) ‘palladacycle’ 2 mol %, NaOAc, NMP, 140 ꢁC, 6 h.
b Conversion based on unreacted aryl halide were determined by GC (Drel
5%).
c Selectivity determined by GC. When available, isolated yields (%) are given in brackets.
=

S. Noe¨l et al. / Tetrahedron Letters 47 (2006) 3839–3842
3841
Given these initial results, we were interested in compar-
ing the direct arylation of acrolein to that of its diethyl-
acetal derivative, both methods affording the same
compounds (Scheme 2). Particularly, we compared the
methodology used previously (‘palladacycle’,12 NaOAc,
NMP) to that reported by Cacchi and co-workers,6
which was based on Jeffery’s13 phase transfer reaction
conditions (Pd(OAc)2, n-Bu4NOAc, K2CO3, KCl,
DMF), which had been found to be very efficient for
the preparation of cinnamaldehydes.
and later Cacchi and co-workers,7 correlated the forma-
tion of the ester to the hydridic character of the benzylic
hydrogen in the carbopalladated adduct type 9 (Fig. 1,
route B). However, as can be observed in Table 2, the
aldehyde/ester selectivity was affected by the reaction
conditions. Cacchi’s conditions involved phosphine free
catalytic system, for which it is generally admitted that
‘naked’ palladium acted as active species. The use of a
stoichiometric amount of KCl as an additive would
favor the formation of the so-called ‘anionic’ palladium
species {[L2Pd(0)Cl]À, K+} 4 as the active species in the
catalytic cycle, as has been proposed by Jutand
(Fig. 1a).15–19
As reported in Table 2, the catalytic system (A) de-
scribed by Cacchi and co-workers6,7 led to good conver-
sions, and the selectivity was favorable to the formation
of the aldehydes, except for the case of 9-bromoanthra-
cene, that afforded a mixture of aldehyde 1 and ester 2 in
a 40:60 ratio. High reactivity of heteroarylbromides was
also observed with this catalytic system, but in those
cases dehalogenation was observed, especially with ben-
zothiophenic bromide.
In the presence of a phosphine ligand, neutral palladium
complexes (type 7) would be involved as the catalytically
active species. However, using the Hermann’s pallada-
cycle as catalyst precursor would result in the initial for-
mation of palladium active species coordinated by only
one phosphine ligand; these species being stabilized by
solvent coordination, as reported recently by Jutand.20
In that case, we suggest the existence of additional
strong interactions between the Pd(II) center and the
aromatic ring of the bromo substrates in the carbopalla-
dated adduct 9 (Fig. 1, route B). These interactions
would prevent the internal rotation along the ArCH–
CH(Pd)CHR bond that is usually reported in the Heck
mechanism. As a consequence, the syn b-hydrogen
elimination would mainly occur via the H gem to the
diacetal, thus yielding the ester.
The nature of the catalytic system dramatically influ-
enced the selectivity of this coupling reaction: in the
presence of the Herrmann’s palladacycle (system B),
ester 2 was formed as the main product whatever the
substrate.
The formation of saturated ester 2, rather than aldehyde
1, for these aryl halides was expectable from previous
works described in the literature. Heck and Zebovitz,14
Pd(II)X2
(S)2Pd(0)
L2Pd(II)X2
KCl
H
H
OEt
(S) Pd (S)
Ar
LPd(0)(S)
7
Oxidative
addition
L
Pd (S)
X
(S)2Pd(0)Cl
O
1
Ar
O
X
Oxidative
addition
4
2
syn-
β
-H
β
syn- -H
elimination
Ar
elimination
(S)
L
Pd (S)
X
Cl
X
X
Pd Ar
Route A
no phosphine
KCl
X
(S) Pd (S)
Pd
L
8
Route B
(S)
5
Ar
H
H
H
L = phosphine ligand
Olefin
coordination
Olefin
coordination
OEt
OEt
EtO
EtO
Ar
H
Ar
(S)
L
Pd
X
Cl
X
X
*
X
No interaction
Internal rotation
Strong π-interaction:
Cl
(S) Pd (S)
Pd Ar
OEt
no internal rotation
(S) Pd
Ar
L
OEt
Ar
H
H
OEt
Olefin
insertion
Olefin
insertion
EtO
OEt
OEt
EtO
EtO
H
H
6
9
X
Cl
(S) = Solvent
L
Pd L
H
OEt
EtO
H
* Limitations for anthracylderivatives
Figure 1. Proposed routes for the Heck arylation of acrolein diethyl acetal depending on the catalyst used.

3842
S. Noe¨l et al. / Tetrahedron Letters 47 (2006) 3839–3842
4. Rosen, T. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; pp
395–432.
5. Garbe, D. In Ullmann’s Encyclopedia of Industrial Chem-
istry; Arpe, H.-J., Ed.; VCH: Weinheim, 1992; p 99.
6. Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003, 5,
777.
7. Battistuzzi, G.; Cacchi, S.; Fabrizi, G.; Bernini, R. Synlett
2003, 1133.
8. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2004,
60, 11533.
Such interactions would be restricted where anionic
palladium(II) complexes were involved due to the initial
formation of the pentacoordinated Pd(II)-complex 5 by
the oxidative addition of the aryl halide; as a conse-
quence, the formation of the aldehyde would be pre-
dominant (Fig. 1, route A). However, the rotation was
also limited with the anthracene derivative due to steric
hindrance induced by the condensed aromatic group.
The selectivity of the ester/aldehyde is not affected by
the nature of the aryl halide, the use of the palladacycle
as catalyst leading almost exclusively to the formation of
ester 2, while the use of the Cacchi’s catalytic system
gives mainly aldehyde 1. For the latter catalytic system,
given that the pentacoordinated anionic Pd(II)-complex
5 center is in equilibrium with the original ‘naked’
neutral species (type 8), the ratio of aldehyde 1 to ester
2 probably also depends on the hindrance of the
aromatic moiety.
9. Nejjar, A.; Pinel, C.; Djakovitch, L. Adv. Synth. Catal.
2003, 345, 612.
10. Typical procedure for the reaction with acrolein:
2.4 mmol of aryl halide, 7.2 mmol of acrolein, 3.6 mmol
of NaOAc and 2 mol % [Pd] as of ‘palladacycle’ were
introduced in a pressure tube under argon. Eight milliliter
of solvent NMP previously deaerated were added, and
the mixture was deaerated by an argon flow for 5 min.
The reactor was then placed in a pre-heated oil bath at
140 ꢁC for 6 h under vigorous stirring and then cooled to
room temperature before the reaction mixture was
analyzed by GC. At completion of the reaction, the
mixture was diluted with 150 mL of water and the
resulting mixture was extracted with 4 · 20 mL CH2Cl2
or EtOAc. The combined organic layers were washed
three times with 15 mL H2O, then 15 mL brine, dried
over MgSO4 and evaporated. The residue was then
purified by flash chromatography on silica gel. Similar
procedure was used for acrolein diethylacetal, except that
at completion of the reaction, the mixture was diluted
with 150 mL HCl 1 N.
In conclusion, we have shown that the direct arylation
of acrolein in the context of the synthesis of cinnam-
aldehyde derivatives is an efficient procedure. Using
the Herrmann’s palladacycle as catalyst, aldehydes 1
were prepared with up to 87% isolated yield from
condensed aryl halides, and that was extended success-
fully to heteroaryl halides, like bromoquinolines and
bromobenzothiophene (40–83% yield). Using diethyl
acetal acrolein as substrate, the selective formation of
saturated ester 2 was attained under the same reaction
conditions, leading to a very efficient synthesis of the
industrially important arylpropionate esters.
11. Henninger, T. C.; Xu, X.; Abbanat, D.; Baum, E. Z.;
Foleno, B. D.; Hilliard, J. J.; Bush, K.; Hlasta, D. J.;
Macielag, M. J. Bio. Med. Chem. Lett. 2004, 14, 449.
¨
12. Herrmann, W. A.; Broßmer, C.; Ofele, K.; Reisinger,
C.-P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem.
Int. Ed. Engl. 1995, 34, 1844.
Acknowledgment
13. Jeffery, T. Tetrahedron Lett. 1994, 35, 4103.
14. Zebovitz, T. C.; Heck, R. F. J. Org. Chem. 1977, 42, 3907.
15. Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.;
Meyer, G. Organometallics 1995, 14, 5605.
`
S.N. thanks the ‘Ministere de l’Education Nationale,
´
de l’Enseignement Superieur et de la Recherche’ for
funding.
16. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
´
17. Amatore, C.; Carre, E.; Jutand, A.; Medjour, Y. Organo-
metallics 2002, 21, 4540.
References and notes
18. Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.;
Meyer, G. In Novel Trends in Electroorganic Synthesis;
Torii, S., Ed.; Springer: Tokyo, 1997; pp 379–382.
19. Under Cacchi’s conditions, anionic palladium(II) complex
[L2Pd(0)OAc]À may be formed due to the use of n-
Bu4OAc.
1. Wijesekera, R. O. Crit. Rev. Food. Sci. Nut. 1978, 10, 1.
2. Fang, J. M.; Chen, S. A.; Cheng, Y. S. J. Agric. Food
Chem. 1989, 37, 744.
3. Friedman, M.; Henika, P. R.; Mandrell, R. E. J. Food
Prot. 2002, 65, 1545.
´
20. d’Oryle, F.; Jutand, A. Tetrahedron 2005, 61, 9670.