An efficient palladium-catalyzed synthesis of cinnamaldehydes from acrolein diethyl acetal and aryl iodides and bromides

Article abstract of DOI:10.1021/ol034071p

(Matrix presented) The reaction of aryl iodides and bromides with acrolein diethyl acetal in the presence of Pd(OAc)₂, ⁿBu ₄NOAc, K₂CO₃, KCl, and DMF, at 90°C until the disappearance of the acetal followed by the addition of 2 N HCl to the crude reaction mixture, affords cinnamaldehydes in good to high yields. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, dialkylamino, nitrile, and nitro groups. The presence of substituents close to the oxidative addition site does not hamper the reaction.

Full text of DOI:10.1021/ol034071p

ORGANIC
LETTERS
2003
Vol. 5, No. 5
777-780
An Efficient Palladium-Catalyzed
Synthesis of Cinnamaldehydes from
Acrolein Diethyl Acetal and Aryl Iodides
and Bromides
Gianfranco Battistuzzi, Sandro Cacchi,* and Giancarlo Fabrizi
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received January 15, 2003
ABSTRACT
The reaction of aryl iodides and bromides with acrolein diethyl acetal in the presence of Pd(OAc)2, nBu4NOAc, K2CO , KCl, and DMF, at 90 °C
3
until the disappearance of the acetal followed by the addition of 2 N HCl to the crude reaction mixture, affords cinnamaldehydes in good to
high yields. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, dialkylamino, nitrile, and
nitro groups. The presence of substituents close to the oxidative addition site does not hamper the reaction.
Cinnamaldehyde and its derivatives are widely used in food1
and cosmetic1a,1d industries. For example, cinnamaldehyde
is the main component of cassia oil as well as cinnamon
bark oil and is used in flavoring compounds to impart a
cinnamon flavor. Antifungal activities2 of trans-cinnamal-
dehyde derivatives as well as their antibacterial3 and anti-
termitic4 activities were also investigated. p-Dialkylamino-
cinnamaldehydes are important compounds for nonlinear
optics5 and titration of active aldehyde dehydrogenases.6
The palladium-catalyzed vinylic substitution of acrolein
with aryl halides would represent a useful and straighforward
approach to this class of compounds. Indeed, there has been
a report by Jeffery wherein phenyl, m-tolyl, and p-chloro-
phenyl iodides were treated with acrolein, Pd(OAc)2, nBuN4-
Cl, and NaHCO3 in DMF at 20 °C for 60 h to yield the
corresponding cinnamaldehydes in high yields.7 The reaction,
however, requires long reaction times, and in some cases,
the desired products are obtained in low yield.8,9
Furthermore, formation of cinnamaldehydes from aryl
bromides, which would greatly widen the scope of the
synthetic procedure, still remains a challenge. At the required
elevated temperatures, under basic conditions, the unsaturated
carbonyl compound appears to undergo extensive polymer-
(1) (a) Wijesekera, R. O. Historical Overview of the Cinnamon Industry.
In CRC Critical ReViews in Food Science and Nutrition 1978, 10, 1-30.
(b) Sato, M.; Nagane, Y.; Kawasaki, T. Ger. Offen DE 3003096, 1980;
Chem. Abstr. 1981, 94, 29060. (c) Fang, J. M.; Chen, S. A.; Cheng, Y. S.
J. Agric. Food Chem. 1989, 37, 744. (d) Yamada, N.; Matsubara, S. JP
Patent 05179283, 1993; Chem. Abstr. 1994, 120, 14902.
Acta Crystallogr. C 2000, C56, 976. (e) Panja, S.; Bangal, P. R.; Chakravorti,
S. Chem. Phys. Lett. 2000, 329, 377. (f) Bangal, P. R.; Panja, S.; Chakravorti,
S. J. Photoch. Photobio. A 2001, 139, 5. (g) Panja, S.; Chakravorti, S.
Spectrochim. Acta A 2002, 58A, 113.
(2) (a) Ishida, S.; Matsuda, A.; Kawamura, Y.; Yamanaka, K. Chemo-
therapy 1960, 8, 157. (b) Ferhout, H.; Bohatier, J.; Guillot, J.; Chalchat, J.
C. J. Essent. Oil Res. 1999, 11, 119.
(3) Friedman, M.; Henika, P. R.; Mandrell, R. E. J. Food Protect. 2002,
65, 1545.
(4) Chang, S.-T.; Cheng, S.-S. J. Agric. Food Chem. 2002, 50, 1389.
(5) For some recent references, see for example: (a) Schmalzlin, E.;
Bitterer, U.; Langhals, H.; Brauchle, C.; Meerholz, K. Chem. Phys. 1999,
245, 73. (b) Tretiak, S.; Chernyak, V.; Mukamel, S. Chem. Phys. 1999,
245, 145. (c) Goller, A.; Grummt, U.-W. Int. J. Quant. Chem. 2000, 77,
727. (d) Nesterov, V. N.; Timofeeva, T. V.; Antipin, M. Y.; Clark, R. D.
(6) (a) Dryjanski, M.; Lehmann, T.; Abriola, D.; Pietruszko, R. J. Protein
Chem. 1999, 18, 627. (b) Wroczynski, P.; Wierzchowski, J. Analyst 2000,
125, 511.
(7) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(8) Unroe, M. R.; Reinhardt, B. A. Synthesis 1987, 981.
(9) Our attempts to prepare cinnamaldehydes from p-iodoanisole and
o-iodotoluene under Jeffery’s conditions [2 equiv of acrolein, 0.03 equiv
of Pd(OAc)2, 1 equiv of nBuN4Cl, and 2.5 equiv of NaHCO3 in DMF at 20
°C] produced the desired products in 18 and 26% yields (96 h), respectively.
p-Iodoanisole and o-iodotoluene were recovered in 79 and 54% yields,
respectively.
10.1021/ol034071p CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/11/2003

ization10 and product yields are quite low. To avoid the
polymerization problem, acrolein acetals have been used by
Heck as three-carbon components.10 However, this procedure
is flawed by the formation of mixtures of the desired vinylic
substitution products 4 and ester derivatives 7,11 due to the
fact that the palladium hydride elimination from the carbo-
palladation intermediate 3 can involve both the available â
hydrogens (Scheme 1). For example, the reaction of bromo-
C6H4)3P. Omitting phosphine ligands did not provide any
beneficial effect, the ester 7a still being the main reaction
product (Table 1, entries 1 and 2). Only after switching to
Table 1. Bases and Salts in the Reaction of p-Iodoanisole and
a
Acrolein Diethyl Acetal in the Presence of Pd(OAc)2
% yieldb
4a c 7a
salt
T
time
entry
base (equiv)
Na2CO3 (2.5)
(1 equiv) (°C) (h)
1
2
nBu4NCl 60 18
28
3.5 30
47
61
Na2CO3 (2.5)
nBu4NCl 90
Scheme 1
3
4
5
6
7
8
9
10
KOAc (2)
KOAc (2)
KOAc (2), NaHCO3 (1.5)
KOAc (2), K2CO3 (1.5)
KOAc (2), K2CO3 (1.5)
KOAc (2), K3PO4 (1.5)
nBu4NCl 60 17
51 (2) 33
47
56 (5) 29
43 (4) 28
78
nBu4NCl 90
3
34
nBu4NCl 60 18
nBu4NCl 60
nBu4NCl 90
nBu4NCl 90
4
2
21
3.5 59 (6) 21
4
3
nBu4NOAc (2), K2CO3 (1.5) nBu4NCl 90
57 (4) 14
73 (8)
nBu4NOAc (2), K2CO3 (1.5) KCl
90
5
a Reactions were conducted on a 0.5 mmol scale in starting p-iodoanisole
in DMF (2 mL) using 1 equiv of p-iodoanisole, 3 equiv of acrolein diethyl
acetal, and 0.03 equiv of Pd(OAc)2. b Yields are given for isolated products.
c Figures in parentheses refer to isolated p-methoxycinnamaldehyde.
KOAc (and omitting phosphine ligands) did the mixture
contain predominantly the desired 4a (Table 1, entries 3 and
4). Of the possible (E)- and (Z)-isomers, only the (E)-isomer
was present, as indicated by the large coupling constant (16
Hz) of the vinyl hydrogens. The yield increased to 78% in
benzene with acrolein dimethyl acetal gave the corresponding
derivatives 4 and 7 in 56 and 39% yields, respectively.
Some interesting results have been obtained by slightly
modifying the original Heck conditions.12 However, only two
substituents have been explored (Me and iPr) and, apparently,
no mention has been made of propanoate ester byproducts.
When we subjected m-bromotoluene to the modified Heck
conditions, the reaction produced the corresponding
cinnamaldehyde and propanoate ester in 62 and 35% yields,
respectively.
Therefore, it appeared to be of interest to investigate further
the palladium-catalyzed reaction of aryl halides with a three-
carbon component so as to turn it into a general synthetically
useful route to cinnamaldehydes. Particularly because of their
higher thermal stability, we decided to explore the use of
dialkyl acetals. Consequently, our task was to find conditions
to control the direction of the key palladium hydride
elimination.
13
2 h by adding 1.5 equiv of K2CO3 (Table 1, entry 7). But
the best result in terms of reaction time, yield (including the
isolated cinnamaldehyde derivative), and ratio of 4a to 7a
n
was obtained by using 2 equiv of Bu4NOAc, 1.5 equiv of
K2CO3, and 1 equiv of KCl (Table 1, entry 10).
The cinnamaldehyde product could be obtained upon
exposing 4a to 2 N HCl at room temperature. However, the
preparation of 6a was conveniently carried out as a one-pot
process, omitting the isolation of 4a (2 N HCl was added to
the crude reaction mixture). Compound 6a, in this case, was
isolated in 88% overall yield. Therefore, the one-pot protocol
was employed when the reaction was extended to include
other aryl iodides and bromides.
Under the best conditions developed so far [Pd(OAc)2,
nBu4NOAc, K2CO3, KCl, and DMF, at 90 °C until the
disappearance of 1 followed by the addition of 2 N HCl to
the crude reaction mixture],14 the reaction proceeds very
p-Iodoanisole and acrolein diethyl acetal 2 (R ) Et) were
employed as the model system. Initial attempts were carried
out using Pd(OAc)2 as the precatalyst, Na2CO3 as the base
(employment of nitrogen bases has been reported to afford
a mixture of products),10 nBu4NCl as the added salt, and a
variety of phosphine ligands at temperatures ranging from
60 to 90 °C in DMF. However, formation of mixtures of
the aryl acetal 4a and the ester 7a (the major component)
was still observed with PPh3, (o-tol)3P, (p-MeO-C6H4)3P,
[2,6-(MeO)2-C6H3]3P, [2,4,6-(MeO)3-C6H2]3P, and (p-Cl-
(12) Lee, J. T.; Kim, J. I. Daehan Hwahak Hwoejee 1984, 28, 335.
Conditions used: ArBr (1 equiv), acrolein diethyl acetal (1.2 equiv), Pd-
(OAc)2 (0.01 equiv), (o-tol)3P (0.02 equiv), and Et3N (3 equiv) at 100 °C.
Heck conditions:10 ArBr (1 equiv), acrolein dimethyl acetal (1 equiv),
Pd(OAc)2 (0.008 equiv), (o-tol)3P (0.064 equiv), and Et3N (1 equiv) at 100
°C.
(13) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Synlett
1996, 568.
(14) Typical Procedure for the Preparation of Cinnamaldehydes. To
a stirred solution of p-iodoanisole (0.117 g, 0.5 mmol) in 2.0 mL of DMF
were added acrolein diethyl acetal (0.229 mL, 1.5 mmol), nBu4NOAc (0.302
g, 1.0 mmol), K2CO3 (0.104 g, 0.75 mmol), KCl (0.037 g, 0.5 mmol), and
Pd(OAc)2 (0.003 g, 0.015 mmol). The mixture was stirred for 1.5 h at 90
°C. After the mixture was cooled, 2 N HCl was slowly added and the
reaction mixture was stirred at room temperature for 10 min. Then, the
mixture was diluted with ether and washed with water. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure. The residue
was purified by chromatography (silica gel, 35 g; 90/10 v/v n-hexane/ethyl
(10) Zebovitz, T. C.; Heck, R. F. J. Org. Chem. 1977, 42, 3907.
(11) Ketene acetals 5 have been reported to be unstable under vinylic
substitution conditions and to form ester derivatives even under careful
anhydrous conditions; see: ref 10.
778
Org. Lett., Vol. 5, No. 5, 2003

Table 2. Palladium-Catalyzed Synthesis of Cinnamaldehydes 6 from Aryl Halides 1 and Acrolein Diethyl Acetala
a Reactions were conducted on a 0.5 mmol scale in starting aryl halides in DMF (2 mL) at 90 °C using 1 equiv of aryl halide, 3 equiv of acrolein diethyl
n
acetal, 0.03 equiv of Pd(OAc)2, 2 equiv of Bu4NOAc, 1.5 equiv of K2CO3, and 1 equiv of KCl. b Yields are given for isolated products.
smoothly with high regioselectivity. The elimination of
HPdXLn species from 3 occurs so as to favor the formation
of the aryl acetal 4. Propanoate esters have been obtained in
yields ranging from traces to 10%.
of p-bromonitrobenzene with acrolein dimethyl acetal gave
exclusively (59% yield) the corresponding propanoate ester,
as it might be expected on the basis of a presumed weaker
hydridic character of the benzylic hydrogen in the corre-
sponding carbopalladation adduct 4.10 Under our conditions,
p-bromonitrobenzene gives the cinnamaldehyde product in
70% yield (Table 2, entry 33).
Remarkably, our process can be successfully applied to
the preparation of cinnamaldehydes bearing para dialkyl-
amino substituents (Table 2, entry 5), an important class of
compounds5,6 that cannot be prepared by using the Heck
conditions (dark tar-like nonvolatile products were ob-
tained)10 or the vinylogation of p-dialkylaminobenzaldehydes
(they have been reported not to react at all).15 The presence
of substituents close to the oxidative addition site does not
hamper the reaction (Table 2, entries 4, 10, 11, 17, 24, 31).
In conclusion, we have shown that an appropriate selection
of bases and added salts can provide an efficient and
straightforward route for the palladium-catalyzed synthesis
As shown in Table 2, a variety of functional groups are
tolerated in the aryl halides, including ether, aldehyde, ketone,
ester, dialkylamino, nitrile, and nitro groups. Cinnamalde-
hydes were isolated in good to high yields, with many
neutral, electron-rich, and electron-poor aryl iodides and
bromides. No significant influence of the substituents in the
aryl halides on the ratio of 6 to 7 was observed. Both
electron-poor and electron-rich aryl halides yielded cinna-
maldehydes as the main products. On the contrary, under
typical Heck conditions, the reaction appears to be influenced
by the nature of the aryl halide. For example, the reaction
acetate) to give 0.071 g (88% yield) of p-methoxycinnamaldehyde 6a: mp
56-7 °C.; lit. mp 57-58.5 °C (Gulyi, S. E. Zhurnal Organicheskoi Khimii
1
1983, 19, 808); IR (KBr) 1667, 1250, 1018, 977 cm-1; H NMR (CDCl3)
δ 9.62 (d, J1 ) 7.8 Hz, 1H), 7.55-7.49 (m, 2H), 7.43 (d, J ) 15.8 Hz,
1H), 6.98-6.93 (m, 2H), 6.61 (dd, J1 ) 15.8 Hz, J2 ) 7.8 Hz, 1H), 3.86
(s, 3H); 13C NMR (CDCl3) δ 194.0, 162.6, 153.1, 130.7, 127.1, 126.8, 114.9,
55.8. Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found C, 74.11; H,
6.24.
(15) Daubrasse, N.; Francesch, C.; Rolando, C. Tetrahedron 1998, 54,
10761.
Org. Lett., Vol. 5, No. 5, 2003
779

of cinnamaldehydes from acrolein diethyl acetal and a variety
of aryl iodides or bromides. The process is quite general and
tolerates many important functional groups.
Institutes for Applied Research, Ben-Gurion University of
the Negev (Israel), for helpful discussions on the applications
of our procedure.
Acknowledgment. Work carried out in the framework
of the National Project “Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni” supported by the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica,
Rome. The authors are also greatly indebted to the University
“La Sapienza” for financial support of this research. One of
the authors gratefully acknowledges Dr. Jacob Klug of the
Supporting Information Available: Typical experimen-
tal procedure for the preparation of cinnamaldeydes and
characterization data for all the compounds listed in Table
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL034071P
780
Org. Lett., Vol. 5, No. 5, 2003