Direct synthesis of protected arylacetaldehydes by palladium- tetraphosphine-catalyzed arylation of ethyleneglycol vinylether

Article abstract of DOI:10.1055/s-2004-829063

Through the use of [PdCl(C₃H₅)]₂/cis,cis, cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclopentane as a catalyst, a range of aryl bromides undergo Heck reaction with ethyleneglycol vinylether to give regioselectively protected arylacetaldehydes in good yields. The β-arylation products were obtained in the range 93-98% selectivity with electron-poor aryl bromides. Furthermore, this catalyst can be used at low loading, even for reactions of sterically hindered aryl bromides. The arylvinyl ethers intermediates undergo subsequent ketalization to give the corresponding 2-benzyl-1,3-dioxolane derivatives.

Full text of DOI:10.1055/s-2004-829063

LETTER
1561
Direct Synthesis of Protected Arylacetaldehydes by Palladium-Tetra-
phosphine-Catalyzed Arylation of Ethyleneglycol Vinylether
P
alladium
s
-Tetraph
a
osphine-Ca
b
talyzed
A
ryl
e
ation of
E
th
l
yleneg
l
lycol
V
e
inylether Kondolff, Henri Doucet,* Maurice Santelli*
Laboratoire de Synthèse Organique UMR 6180 CNRS and Université d’Aix-Marseille III: ‘Chirotechnologies: Catalyse et Biocatalyse’,
Faculté des Sciences de Saint Jérôme, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Fax +33(4)91983865; E-mail: henri.doucet@univ.u-3mrs.fr; E-mail: m.santelli@univ.u-3mrs.fr
Received 15 April 2004
cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cy-
Abstract: Through the use of [PdCl(C3H5)]2/cis,cis,cis-1,2,3,4-tet-
clopentane or Tedicyp18 (Scheme 1) in which four diphe-
nylphosphino groups are stereospecifically bound to the
rakis(diphenylphosphinomethyl) cyclopentane as a catalyst, a range
of aryl bromides undergo Heck reaction with ethyleneglycol vi-
nylether to give regioselectively protected arylacetaldehydes in
same face of a cyclopentane ring. We have already report-
good yields. The b-arylation products were obtained in the range ed the results obtained in allylic substitution,18 for Suzuki
cross-coupling,19 and for Sonogashira alkynylation20 us-
93–98% selectivity with electron-poor aryl bromides. Furthermore,
this catalyst can be used at low loading, even for reactions of steri-
ing Tedicyp as the ligand. We have also reported several
cally hindered aryl bromides. The arylvinyl ethers intermediates un-
results obtained for Heck vinylation reaction.21 We had
dergo subsequent ketalization to give the corresponding 2-benzyl-
observed that with n-butylvinyl ether in the presence of
1,3-dioxolane derivatives.
the tetraphosphine Tedicyp associated to [Pd(C3H5)Cl]2,
Key words: palladium, catalysis, tetraphosphine, Heck reaction,
high reaction rates but moderate to good regioselectivities
aryl bromides, ethyleneglycol vinylether, arylacetaldehydes
in favour of b-arylation could be obtained,21c but in many
cases these selectivities were not high enough to provide
a useful process for the preparation of protected arylacet-
Palladium-catalyzed functionalization of aromatic halides
aldehydes. In order to improve the selectivity of the reac-
has become an important method in preparative organic
tion in favor of the b-addition with our catalyst, we have
decided to investigate arylation reactions with enol ethers
containing a coordinating substituent in order to achieve
higher regiochemical control. Here, we report our studies
involving an alcohol-containing substrate derived from
ethyl vinyl ether: ethylene glycol vinylether.
For this study, based on previous results,21c DMF was
chemistry.1 Nevertheless, arylation of electron-rich ole-
fins such as enol ethers is often limited by poor a:b regio-
selectivity.2–6 High a-regioselective arylations in the
presence of n-butylvinylether have been reported by Cabri
et al. and Hallberg et al. in the presence of Pd(OAc)2/
dppp.7–10 In some procedures, TlOAc was added in order
to improve the regioselectivity of the reaction. The re-
chosen as the solvent and potassium carbonate as the base.
action performed in ionic liquids as solvent also led
selectively to the a-arylation.11 On the other hand,
The reactions were performed at 130 °C under argon in
the presence of a ratio 1:2 of [Pd(C3H5)Cl]2–Tedicyp as
catalyst.
poly(ethylene glycol) used as solvent with Pd(OAc)2 as
catalyst led selectively to the b-arylated products.12 It has
been demonstrated that the regioselectivity of the addition
of organopalladium intermediates can be influenced by
coordinating groups adjacent to the substrate double
bond.13–16 For example, Hallberg et al. have described that
the nitrogen containing vinyl ethers [2-(dimethylami-
no)ethoxy]-ethene in the presence of palladium acetate
led to regioselective b-arylation of several aryl ha-
lides.13,15 On the other hand, in the presence of ethylene
glycol vinylether with Pd(OAc)2/dppp as catalyst they ob-
tained selectively the a-arylations to give aryl vinyl
ethers, which undergo subsequent ketalization to form se-
lectively the isomer e in Scheme 1.17 Surprisingly, to our
knowledge, the selective b-arylation in the presence of
ethylene glycol vinylether has never been described.
First, we investigated the Heck reaction of electron-poor
and electron-rich aryl bromides with ethyleneglycol vi-
nylether in the presence of the system Pd–Tedicyp cata-
lyst (Scheme 1, Table 1). The results presented in Table 1
disclose a strong influence of the substituents on the aryl
bromides on the regioselectivity of the addition and on the
reaction rate. We obtained high efficiency and good regio-
selectivities in favor of b-arylation with electron-poor aryl
bromides such as 4-bromoacetophenone, 4-bromo-
benzonitrile, 4-nitrobromobenzene, or 4-trifluoromethyl-
bromobenzene. The b-selectivities observed were in the
range 93–98% (entries 1–8). Even electron-poor ortho-
substituted aryl bromides gave satisfactory results (entries
6–8). Moreover, most of these reactions were performed
with high ratios substrates:catalyst (up to 10 000). On
the other hand, the reaction performed with the electron-
rich aryl bromides: 4-t-butylbromobenzene or 2-methyl-
bromobenzene led to lower selectivities. With these sub-
strates, larger amounts of a-arylated products were
obtained (entries 13 and 14). Bromobenzene or iodo-
benzene also led to mixtures of a- and b-arylated products
In order to obtain stable and efficient palladium catalysts,
we have prepared the new tetraphosphine ligand,
SYNLETT 2004, No. 9, pp 1561–1564
2
2.
0
7.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829063; Art ID: G13104ST
© Georg Thieme Verlag Stuttgart · New York

1562
I. Kondolff et al.
LETTER
Ph2P
Ph2P
PPh2
PPh2
OH
O
O
O
Br
R
R
Tedicyp
R
R
O
R
a
e
d
½ [Pd(C3H5)Cl]2,
+
K2CO3, DMF, 130 °C
OH
O
O
HO
O
Z: b
E: c
Scheme 1
Table 1 Tedicyp–Palladium-Catalyzed Selective Synthesis of Protected Arylacetaldehydes from Ethyleneglycol Vinylether and Aryl
Halidesa,23,24
Entry
Aryl halide
Ratio
Selectivity
Ratio
Isomer d
Yield of isomer
substrate:catalyst a:b:c:d:e (%)
b+c+d:a+e
product number d (%)
1
2
4-Bromoacetophenone
4-Bromobenzaldehyde
4-Bromobenzonitrile
4-Nitrobromobenzene
4-Trifluoromethylbromobenzene
2-Bromobenzaldehyde
2-Bromobenzonitrile
2-Trifluoromethylbromobenzene
3,4-Difluorobromobenzene
4-Fluorobromobenzene
Bromobenzene
10 000
10 000
10 000
1 000
10 000
250
0:0:0:93:7
93:7
1d
2d
87
91
92
87
90
77
91
88
79
52
89b
52
87b
57
74
79
83
88
85
81
76
0:0:0:97:3
97:3
3
0:0:0:98:2
98:2
3d
4
0:0:0:98:2
98:2
4d
5
0:0:0:94:6
94:6
5d
6
0:0:0:96:4
96:4
6d
7
1 000
10 000
250
3:0:0:97:0
97:3
7d
8
0:0:0:94:6
94:6
8d
9
0:0:0:85:15
0:0:0:57:43
0:13:41:13:33
0:10:11:57:22
0:10:29:27:34
17:6:15:62:0
0:0:0:78:22
0:0:0:90:10
12:0:0:88:0
3:0:0:97:0
85:15
57:43
67:33
78:22
66:34
83:17
78:22
90:10
88:12
97:3
9d
10
11
12
13
14
15
16
17
18
19
20
21
250
10d
11d
11d
12d
13d
14d
15d
16d
17d
18d
19d
20d
100
Iodobenzene
100
4-t-Butylbromobenzene
2-Methylbromobenzene
1-Bromonaphthalene
9-Bromoanthracene
250
100
1 000
1 000
1 000
1 000
10 000
1 000
1 000
3-Bromopyridine
4-Bromopyridine
3-Bromoquinoline
10:0:0:90:0
12:0:0:88:0
0:0:0:100:0
90:10
88:12
100:0
4-Bromoisoquinoline
5-Bromopyrimidine
a Conditions: catalyst: [Pd(C3H5)Cl]2–Tedicyp 1:2, aryl halide (1 mmol), ethyleneglycol vinylether (2 mmol), K2CO3 (2 mmol), DMF, 130 °C,
20 h, under argon, isolated yields of isomer d, ratio of isomers determined by GC and 1H NMR of the crude mixtures.
b Yield of the mixture containing all the isomers b–e.
Synlett 2004, No. 9, 1561–1564 © Thieme Stuttgart · New York

LETTER
Palladium-Tetraphosphine-Catalyzed Arylation of Ethyleneglycol Vinylether
1563
(entries 11 and 12) indicating that the lower regioselectiv- nylether the formation of only 6% of a-arylated product
ities observed with electron-rich aryl bromides does not had been observed (Table 1, entry 5).
comes from a slower oxidative addition of the aryl halide.
Finally, we compared our catalytic system with the sys-
The sterically hindered substrates 1-bromonaphthalene
tem PPh3 (4 equiv) and [Pd(C3H5)Cl]2 (1 equiv) for this re-
and 9-bromoanthracene gave b-arylated products in 78
action with 9-bromoanthracene. In the presence of 0.4%
catalyst, the ratio of products b+c+d:a+e was 72:28.
Moreover, compound 15d was isolated in a low yield
(21%). With this catalyst, a very important debromation
and 90% selectivities, respectively, indicating that the re-
gioselectivity of the addition is partially controlled by
steric factors (entries 15 and 16).
Next, we studied the reaction in the presence of heteroaryl of 9-bromoanthracene was observed and the major prod-
bromides (entries 17–21). Pyridines or quinolines are p- uct of the reaction was anthracene.
electron deficient, so we could expect similar results with
In summary, we have established that the Tedicyp–palla-
bromopyridines or bromoquinolines than with electron-
dium system provides a convenient catalyst for the syn-
poor aryl bromides. With 3-bromopyridine, 3-bromoquin-
thesis of protected arylacetaldehyde derivatives by
oline and 4-bromoisoquinoline selectivities of 88%, 90%
coupling of aryl bromides with ethyleneglycol vinylether
followed by intramolecular ketalization. The electronic
control of the regioselectivity of the addition encountered
with n-butylvinylether appears to be partially suppressed
and 88% in favor of b-arylation were obtained, respective-
ly. The highest selectivities with heteroaromatic sub-
strates were observed with 4-bromopyridine and 5-
bromopyrimidine (98% and 100%, respectively).
by an adjacent alcohol function. Anchoring the enol to the
The intramolecular cyclization of the arylalkenes a, b and metal by an alcohol function probably imposes a confor-
c (Scheme 1) was generally observed to give the corre- mational change in the structure of the (aryl)Pd(enol) in-
sponding 2-benzyl-1,3-dioxolane d and 2-methyl-2-phe- termediate and stabilizes a neutral Pd-complex favoring
nyl-1,3-dioxolane e derivatives. This ketal formation is the formation of the b-arylated products.1c The best selec-
not palladium-catalyzed, but arise through internal nu- tivities in favor of b-arylations were observed with elec-
cleophilic attack of the hydroxyl group.22 Faster cycliza- tron-poor aryl bromides. With bromobenzene or electron-
tion reactions were observed with electron-deficient rich aryl bromides mixtures or regioisomers were ob-
substrates. For example, when 4-t-butylbromobenzene served. In all cases, only traces (<1%) of homocoupling
was used, mixtures of cyclized and uncyclized products products were observed with this catalyst. Ethyleneglycol
were obtained. On the other hand, in the presence of 4- vinylether is commercially available, moreover, the reac-
bromoacetophenone or 3,5-bis(trifluoromethyl)bromo- tion can be performed with as little as 0.01% catalyst with
benzene only ketal products were detected.
several substrates, so this catalyst appears to be among the
most active and stable ones reported so far for this reac-
tion. Due to the high price of palladium, the practical ad-
vantage of such low catalyst loading reactions can become
increasingly important for industrial processes.
In order to determine if an ether function instead of an al-
cohol on the vinylether would have an effect on the con-
trol of the regioselectivity of the addition, we performed
the reaction in the presence of ethyleneglycol n-butylvinyl
diether and n-butylvinylether (ratio substrat–catalyst:
1000, see Scheme 2). We observed that very similar mix-
tures of isomers were obtained and in both case large
amounts of a-arylated products were formed (24% and
25%, respectively). In the presence of ethyleneglycol vi-
Acknowledgment
I. K. is grateful to the Ministère de l’Education Nationale, de la
Recherche et de la Technologie for a grant. We are grateful to Dr
R. Snowden and Firmenich, SA (Genève, Switzerland) for their
support.
F3C
Br
Tedicyp
½ [Pd(C3H5)Cl]2
O
F3C
+
+
F3C
R
O
R
K2CO3, DMF, 130 °C, 20 h
R
O
a
Z: b E: c
R = nBu:
R = CH2CH2OnBu: a: 24%, b: 24%, c: 52%
a: 25%, b: 25%, c: 50%
Scheme 2
Synlett 2004, No. 9, 1561–1564 © Thieme Stuttgart · New York

1564
I. Kondolff et al.
LETTER
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Synlett 2004, No. 9, 1561–1564 © Thieme Stuttgart · New York