3-arylpropanoate esters through the palladium-catalyzed reaction of aryl halides with acrolein diethyl acetal

Article abstract of DOI:10.1055/s-2003-39900

The reaction of aryl halides with acrolein diethyl acetal in the presence of Pd(OAc)₂, n-Bu₃N, and n-Bu₄NCl in DMF at 90°C affords ethyl 3-arylpropanoates. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, nitrile, and nitro groups. ortho-Substituents do not hamper the reaction. 3-Arylpropanoate esters were isolated in good to excellent yields with many neutral, electron-rich and electron-poor aryl iodides and electron-poor aryl bromide. Neutral and electron-rich aryl bromides gave the desired ester in moderate yields.

Full text of DOI:10.1055/s-2003-39900

LETTER
1133
3
-Arylpropanoate Esters through the Palladium-Catalyzed Reaction of Aryl
Halides with Acrolein Diethyl Acetal
a
a
a
b
P
G
d-Catalyze
d
Synt
i
hesis 3
a
-
Arylpropa
n
noate Esters
f
from
A
r
r
H
alide
a
s
and Acro
n
lein
D
iethyl
cA
cetal o Battistuzzi, Sandro Cacchi,* Giancarlo Fabrizi, Roberta Bernini
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’,
P.le A. Moro 5, 00185 Roma, Italy
Fax +39(6)49912780; E-mail: sandro.cacchi@uniroma1.it
b
Dipartimento A.B.A.C., Università degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
Received 12 May 2003
with acrolein diethyl acetal as a high-yielding, virtually
one-step procedure for the preparation of a wide variety of
cinnamaldehydes.2
Abstract: The reaction of aryl halides with acrolein diethyl acetal
in the presence of Pd(OAc) , n-Bu N, and n-Bu NCl in DMF at
2
3
4
,3
9
0 °C affords ethyl 3-arylpropanoates. A variety of functional
groups are tolerated in the aryl halides, including ether, aldehyde,
ketone, ester, nitrile, and nitro groups. ortho-Substituents do not
hamper the reaction. 3-Arylpropanoate esters were isolated in good
to excellent yields with many neutral, electron-rich and electron-
poor aryl iodides and electron-poor aryl bromide. Neutral and elec-
tron-rich aryl bromides gave the desired ester in moderate yields.
Our success in controlling the reactivity of 3 so as to favor
the formation of cinnamaldehydes prompted us to investi-
gate further the reaction with the aim of tuning reaction
conditions so as to obtain, from the same carbopalladation
intermediate, 3-arylpropanoate esters. On the other hand,
3
-arylpropanoate esters are useful intermediates in organ-
Key words: palladium, alkenes, esters, aryl halides, Heck reaction
4
ic synthesis and have also been used for the preparation
5
of biologically active compounds, and this appears to jus-
tify efforts to develop simple and general methodologies
for their preparation, particularly when these methodolo-
gies accommodate considerable functionalities.
The palladium-catalyzed reaction of aryl halides with ac-
rolein acetals has undoubtedly a great synthetic potential.
Readily available starting materials as well as simple re-
action conditions should make it a very useful tool for the
preparation of cinnamaldehydes and/or 3-arylpropanoate
Here we report just such a process, in which a vast array
of 3-arylpropanoate esters is prepared through the palladi-
um-catalyzed reaction of aryl iodides and bromides with
acrolein diethyl acetal.
1
esters. However, since the pioneering work of Heck, this
chemistry has not found application. Indeed, its useful-
ness is strongly flawed by the fact that cinnamaldehydes
and 3-arylpropanoate esters are usually obtained as mix-
tures. This is due to the involvement of both the available
b hydrogens in the key elimination of HPdX species from
the carbopalladation intermediate 3 (Scheme 1).
On the basis of our previous findings, initial attempts were
made by using p-iodoanisole and acrolein diethyl acetal as
the model system, Pd(OAc) as the precatalyst, n-Bu NCl
2
4
as the added salt, as well as a variety of phosphine ligands
and bases at temperatures ranging from 60 °C to 90 °C in
DMF. Some results from that study are summarized in
Table 1 and show that carbonate and acetate bases, with or
without phosphine ligands, usually afford moderate yields
of propanoate ester 5a (ketene acetals 4 have been report-
ed to be unstable under vinylic substitution conditions and
to form ester derivatives even under careful anhydrous
OR
O
hydrolysis
Ar
OR
Ar
OR
4
5
HPdX
OR
OR
Pd(0)
OR
1
conditions). In addition, mixtures of 5a and cinnamalde-
ArX
Ar
OR
hyde acetal 6a were always obtained.
3
PdX
OR
1
2
KOAc was the first base examined. In the absence of
phosphine ligands, at 60 °C, 6a was obtained as the main
product (Table 1, entry 1). Na CO was the next base ex-
HPdX
O
hydrolysis
Ar
OR
Ar
H
2
3
6
7
amined and, though the result was still unsatisfactory
from a synthetic point of view, 5a was obtained as the
main product (Table 1, entry 2). The addition of phos-
phine ligands such as P(o-MeO-C H ) , PPh , P(p-Cl-
Scheme 1
6
4 3
3
Recently, we have shown that a proper choice of catalysts,
bases, and added salts allows for the utilization of the pal-
ladium-catalyzed reaction of aryl bromides and iodides
C H ) , and P(o-Me-C H ) did not provide any beneficial
6
4 3
6
4 3
effect (Table 1, entries 3–6). On the contrary, with the lat-
ter, no reaction was observed after 20 hours. Increasing
the temperature to 90 °C provided slightly better results
with Na CO3 in the absence of phosphine ligands
(Table 1, entry 7) while a poor 5a to 6a ratio was still ob-
tained when NaOAc was employed as the base (Table 1,
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1133,1136,ftx,en;G10703ST.pdf.
2
©
Georg Thieme Verlag Stuttgart · New York

1
134
G. Battistuzzi et al.
LETTER
Table 1 Bases, Ligands, and Added Salts in the Palladium-Catalyzed Reaction of p-Iodoanisole with Acrolein Diethyl Acetala
Entry
Base (equiv)
Ligand
Temp (°C)
Time (h)
Yield (%)b
5
a
6ac
1
2
3
4
5
6
7
8
9
KOAc (2)
–
60
60
60
60
60
60
90
90
90
90
90
90
90
90
90
90
90
90
3
3.5
18
18
18
20
3.5
3
34
47
43
55
58
–
47
Na CO (2.5)
–
28
2
3
Na CO (2.5)
P(o-MeO-C H )
4 3
25
2
3
6
Na CO (2.5)
PPh3
33
2
3
Na CO (2.5)
P(p-Cl-C H )
33
2
3
6
4 3
Na CO (2.5)
P(o-Me-C H )
4 3
–
2
3
6
Na CO (2.5)
–
–
61
55
56
65
55
61
83
55
74
59
68
91
30 (5)
2
3
NaOAc (3.5)
Na CO (2.5)
35
P(o-Me-C H )
4 3
3
36 (1)
2
3
6
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
Na CO (2.5)
ttmpp
PPh3
16
6
22 (4)
2
3
Et N (2)
10 (23)
3
Et N(2)
P(o-Me-C H )
4 3
5
9 (24)
3
6
Et N (2)
–
–
–
–
–
–
20
20
22
21
24
3
–
–
–
–
–
–
3
d
Et N (2)
3
Et N (2) e
3
p.s. (1.2)f,g
p.s. (1.5)f,g
1
n-Bu N (2)
3
a
Unless otherwise stated, reactions were conducted on a 0.5 mmol scale in starting p-iodoanisole in DMF (2 mL) using 1 equiv of p-iodo-
anisole, 3 equiv of acrolein diethyl acetal, 1 equiv of n-Bu NCl and 0.03 equiv of Pd(OAc) in the presence of a base (Table 1).
4
2
b
c
d
e
f
Yields are given for isolated products.
Figures in parentheses refer to isolated p-methoxycinnamaldehyde.
In the absence of n-Bu NCl.
4
In the presence of n-Bu NBr. Compound 5a was isolated in 66% yield after 9 h.
p.s. = proton sponge [1,8-bis(dimethylamino)naphthalene].
Essentially no change was observed after 9 h.
4
g
entry 8). With Na CO and the electron-rich sterically en- satisfactory results (Table 1, entries 16 and 17) but the
2
3
cumbered ligand tris(2,4,6-trimethoxyphenyl)phosphine best result was obtained by using n-Bu N (Table 1, entry
3
(
ttmpp) the ester was isolated in good yield and an encour- 18).
aging 2.5 was observed for the ratio of 5a to 6a (Table 1,
entry 10), but a major step forward in controlling the se-
lectivity of the reaction was achieved by switching to
The best conditions developed so far [Pd(OAc) , n-Bu N,
2
3
6
n-Bu NCl, 90 °C in DMF] were applied to other aryl
4
halides. As shown by the results summarized in Table 2,
under these conditions the reaction proceeds very smooth-
ly with high regioselectivity. The elimination of HPdX
species from 3 occurs so as to favor the formation of
the propanoate esters. In practice, the base and additives
Et N in the absence of phosphine ligands (Table 1, entry
3
1
3). The use of Et N in the presence of phosphine ligands
3
(
7
Table 1, entries 11 and 12) gives mixtures of 5a and 6a/
a (the latter derived from the hydrolysis of 6a).
Omitting n-Bu NCl leads to lower yields; even prolong- (n-Bu NOAc, K CO , and KCl in the synthesis of
4
4
2
3
2
ing the reaction time to 20 hours (Table 1, entry 14), es- cynnamaldehydes and n-Bu N and n-Bu NCl in the
3
4
sentially no change was observed after 8 hours. n-Bu NBr present synthesis of propanoate esters), using Pd(OAc) in
4
2
proved clearly inferior to n-Bu NCl (Table 1, compare en- DMF at 90 °C, completely inverse the selectivity of the
4
try 13 with entry 15). The use of proton sponge also gave reaction.
Synlett 2003, No. 8, 1133–1136 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Synthesis 3-Arylpropanoate Esters from Aryl Halides and Acrolein Diethyl Acetal
1135
Table 2 Palladium-Catalyzed Synthesis of Ethyl 3-Arylpro-
panoates 5 from Aryl Iodides or Bromides 1 and Acrolein Diethyl
Acetal
The formation of 5 through the base-catalyzed isomeriza-
tion of 6 to 4 is ruled out by the following experiment.
Compound 6i was subjected to our standard reaction con-
ditions omitting palladium and aryl halide for 20 hours:
only trace amounts, if any, of the ester were observed, part
of 6i was recovered unchanged and part of 6i was convert-
ed to cinnamaldehyde 7i (during the reaction and non
acidic work-up). A similar result was obtained when the
experiment was carried out in the presence of Pd(OAc)2
and omitting the aryl halide.
a
7
Entry Aryl iodide or bromide 1 Time (h) Yield (%) of 5b
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
p-MeO-C H -I
3
19
6
91
5a
5a
5b
5c
5d
5e
5f
6
4
42c
p-MeO-C H -Br
6
4
m-MeO-C H -I
89
80
84
82
81
6
4
o-MeO-C H -I
7.5
6
4
A variety of functional groups are tolerated in the aryl ha-
lides, including ether, aldehyde, ketone, ester, nitrile, and
nitro groups. 3-Arylpropanoate esters were isolated in
good to excellent yields with many neutral, electron-rich
and electron-poor aryl iodides and electron-poor aryl
bromides. ortho-Substituents do not hamper the reaction
(Table 2, entries 4, 7, 13, 16, 22, 27, 28). Only neutral
and electron-rich aryl bromides gave the desired ester in
moderate yields (Table 2, entries 2 and 9).
p-Me-C H -I
3
6
4
m-Me-C H -I
3
6
4
o-Me-C H -I
2.5
5.5
6
4
3,5-Me -C H -I
75
5g
5h
5i
2
6
3
41d
p-Ph-C H -Br
50
6
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
PhI
p-F-C H -I
2.5
3
70
98
92
94
81
85
89
92
84
87
78
76
92
85
85
83
68
47
92
81
86
85
5j
The methodology can be successfully applied to the syn-
6
4
8
thesis of the diesters 8 (Scheme 2).
m-F-C H -I
2.5
6.5
1
5k
5l
6
4
o-F-C H -I
O
6
4
Pd(OAc)2
I
OEt
OEt
n
n
p-Br-C H -I
5m
5n
5o
5p
5q
5r
5s
3
Bu N, Bu NCl
OEt
OEt
6
4
4
DMF, 90 °C
m-Br-C H -I
1
6
4
I
8
o-Br-C H -I
5
6
4
O
p-Cl-C H -I
2.5
1
ortho
para
8a (61%, 24 h)
8b (77%, 3 h)
6
4
m-CF -C H -I
3
6
4
Scheme 2
p-EtOOC-C H -I
1
6
4
p-CN-C H -Br
23
6
4
In conclusion, we have shown that an appropriate selec-
tion of catalysts, bases, and added salts can provide an
efficient and straightforward route for the palladium-cata-
lyzed synthesis of 3-arylpropanoate esters from acrolein
diethyl acetal and a variety of aryl iodides or bromides.
The process is quite general, tolerates many important
functional groups, and compares well with most common
procedures for the preparation of this class of com-
pounds.9
m-EtOOC-C H -I
1
5t
6
4
o-MeOOC-C H -I
5
5u
5v
5v
5w
5y
5x
5z
5za
5zb
5zb
6
4
p-MeOC-C H -I
0.5
6
4
p-MeOC-C H -Br
29
6
4
p-OHC-C H -Br
24
31
31
1
6
4
–13
m-OHC-C H -Br
6
4
o-OHC-C H -Br
6
4
Acknowledgment
2-Me-5-NO -C H -I
Work carried out in the framework of the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’ sup-
ported by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica, Rome. The authors are also greatly indebted to the
University ‘La Sapienza’ for financial support of this research.
2
6
3
3-NO -4-Me-C H -I
4
2
6
3
p-NO -C H -I
1
2
6
4
3
p-NO -C H -Br
7
2
6
4
a
Unless otherwise stated, 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 acetal, 2 equiv of n-Bu N,
3
1
equiv of n-Bu NCl, and 0.03 equiv of Pd(OAc) .
Yields are given for isolated products.
4
2
b
c
In the presence of 6 equiv of n-Bu N. p-Bromoanisole was recovered
3
in 56% yield.
d
4
-Bromobiphenyl was recovered in 52% yield.
Synlett 2003, No. 8, 1133–1136 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
136
G. Battistuzzi et al.
LETTER
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(
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(
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(
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(
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(
+
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(
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(
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1
(
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(
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esters via reduction of cinnamate esters, see: (a) Taylor, R.
A.; Santora, B. P.; Gagne, M. R. Org. Lett. 2000, 2, 1781.
(b) Chauhan, M.; Boudjouk, P. Can. J. Chem. 2000, 78,
nitrotoluene (0.132 g, 0.501 mmol), acrolein diethylacetal
(
0.229 mL, 1.50 mmol), n-Bu NCl (0.139 g, 0.50 mmol), n-
4
Bu N (0.238 mL, 1.00 mmol) in 2.0 mL of DMF, Pd(OAc)
3
2
(
0.003 g, 0.015 mmol) was added. The mixture was warmed
at 90 °C and stirred for 1 h. After cooling, the reaction
mixture was diluted with 2 N HCl and extracted with Et O.
1396. (c) Couturier, M.; Andresen, B. M.; Tucker, J. L.;
Dube, P.; Brenek, S. J.; Negri, J. T. Tetrahedron Lett. 2001,
42, 2763. (d) Vinson, S. L.; Gagne, M. R. Chem. Commun.
2001, 1130. (e) Desai, B.; Danks, T. N. Tetrahedron Lett.
2
The organic layer was dried over Na SO and concentrated
2
4
under reduced pressure. The residue was purified by
chromatography (n-hexane/EtOAc 85/15 v/v) to give 0.109
g of 5z (92% yield) as an oil. IR (KBr): 1733, 1521, 1348
2001, 42, 5963. (f) Shibata, I.; Suwa, T.; Ryu, K.; Baba, A.
J. Org. Chem. 2001, 66, 8690. (g) Concellon, J. M.;
Rodriguez-Solla, H. Chem.–Eur. J. 2001, 7, 4266. (h)Basu,
M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K. Synlett
2002, 319. (i) Bremeyer, N. B.; Ley, S. V.; Ramarao, C.;
Shirley, I. M.; Smith, S. C. Synlett 2002, 1843.
–
1 1
cm . H NMR (CDCl ): d = 8.01 (d, J = 2.3 Hz, 1 H), 7.95
3
1
(
dd, J = 8.3 Hz, J = 2.4 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H),
1 2
4
.14 (q, J = 7.1 Hz, 2 H), 3.01 (t, J = 7.5 Hz, 2 H), 2.64 (t,
1
1
J = 7.5 Hz, 2 H), 2.42 (s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).
1
1
13
C NMR (CDCl ): d = 172.3, 146.5, 144.2, 140.3, 131.0,
3
Synlett 2003, No. 8, 1133–1136 ISSN 1234-567-89 © Thieme Stuttgart · New York