Palladium-catalyzed arylation of vinylic acetates. Phosphine ligand influenced regioselectivity

Article abstract of DOI:10.1016/j.tetlet.2009.09.048

A palladium-catalyzed coupling reaction of aryl bromides with vinylic acetates in the presence of tributyltin methoxide h as been described. The α-arylation aldehyde product and the aryl ketone were obtained in the presence of P(t-Bu)₃ and P(o-

Full text of DOI:10.1016/j.tetlet.2009.09.048

Tetrahedron Letters 50 (2009) 6546–6548
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed arylation of vinylic acetates. Phosphine ligand influenced
regioselectivity
*
Mickaël Jean, Jacques Renault, Pierre van de Weghe
EA Substances Lichéniques et Photoprotection, Faculté des Sciences Biologiques et Pharmaceutiques, Université de Rennes 1, 2 avenue du Prof. Léon Bernard,
F-35043 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2009
Revised 4 September 2009
Accepted 9 September 2009
Available online 12 September 2009
A palladium-catalyzed coupling reaction of aryl bromides with vinylic acetates in the presence of tribu-
tyltin methoxide has been described. The
a-arylation aldehyde product and the aryl ketone were
obtained in the presence of P(t-Bu)3 and P(o-Tol)3, respectively.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl bromides
Arylation
Palladium
Tri-tert-butylphosphine
Tri(o-tolyl)phosphine
Aldehydes
Ketones
Regioselectivity
During the last decade, the palladium-catalyzed
a
-arylation of
xantphos or SPhos in wet dioxane (24 ppm H2O) in the presence
of Cs2CO3, good to excellent yields were obtained for various alde-
hydes with electron-rich aryl bromides. More recently, according
to these previous studies they described an asymmetric intramo-
lecular version of this reaction with phosphanyloxazoline-based li-
gands.6 The high yields and enantioselectivities reach this protocol
attractive for applications in total synthesis. In the same time, Xiao
and co-workers reported a palladium-catalyzed direct acylation of
aryl bromides with aldehydes.7 While in the presence of palladium
carbonyl derivatives has become a versatile tool for advanced or-
ganic synthesis. The importance of this C–C bond construction
method is evident from the huge number of publications that ap-
peared recently.1 Due to reactivity issues and despite considerable
progress made in this field, the
less explored.
a-arylation of aldehydes remains
In 2002, Miura and co-workers disclosed the first Pd-catalyzed
a
-arylation of aldehydes with aryl bromides.2 The reaction was
carried out using palladium diacetate as catalyst with the bulky
P(t-Bu)3 as phosphine ligand and cesium carbonate as base.
Although the dioxane was used as a solvent to limit the formation
of aldol by-products, the yields were generally modest. Based on
these pioneering findings, the groups of Buchwald3 and later Har-
and ligand the reaction of aryl halides and aldehydes lead to the a-
arylation as shown by Buchwald and Hartwig, the addition of pyr-
rolidine and 4 Å MS in the reaction mixture gives the aryl ketone
via the formation in situ of an enamine followed by a Heck-type
reaction.
twig4 developed an efficient and general protocol for the
a
-aryla-
In 2007, relying on palladium-catalyzed
tones via tin enolates described by Migita and co-workers,8 we
investigated the -arylation of aldehydes. Surprisingly, no ex-
a-phenylation of ke-
tion of aldehydes with aryl bromides and chlorides in dioxane in
the presence of cesium carbonate using Pd(OAc)2/racemic BINAP
or [{Pd(allyl)Cl}2]/dppf or Q-phos as catalytic system. Despite bet-
ter yields and increasing the scope of aldehydes, these protocols
suffer from some limitations (the coupling between aldehydes
and electron-rich aryl bromides and aryl chlorides still remains dif-
ficult). In 2008, Buchwald and co-workers proposed an improved
protocol for this palladium-catalyzed reaction.5 Using Pd(OAc)2/
a
pected product was observed but only acylation of the aromatic
group was achieved affording unexpected aryl ketones.9 We found
that 5 mol % of PdCl2[P(o-Tol)3]2 in DMSO at 100 °C in the presence
of 2 equiv of vinylic acetate and 2 equiv of Bu3SnOMe are the best
reaction conditions to obtain a complete conversion of aryl bro-
mides (Scheme 1).
In this study, various phosphine ligands were tested and we no-
ticed the formation of the product of
using the tri-tert-butylphosphine. Intrigued by this observation,
a-arylation of aldehydes
* Corresponding author. Tel.: +33 2 23 23 38 03; fax: +33 2 23 23 44 25.
E-mail address: pierre.van-de-weghe@univ-rennes1.fr (P. van de Weghe).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.048

M. Jean et al. / Tetrahedron Letters 50 (2009) 6546–6548
6547
Table 1
5 mol%
O
Palladium-catalyzed arylation of 2-methyl-1-propen-1-yl acetate 2
R1
PdCl2[(o-Tol)3P]2
R1
OAc
ArBr
+
Ar
O
Method A or B
Me
Me Me
Ar CHO
Bu3SnOMe (2 equiv)
DMSO, 100 °C
R2
R2
OAc
Me
ArBr
+
+ Bu3SnOMe
+
Ar
DMSO, 100 °C, 14 h
Me
2
Me
1
3
4
5
(2 equiv)
(2 equiv)
Scheme 1. Pd-catalyzed acylation of arylbromides.
Entry
Aryl bromide 1
Methoda
Ratio 4/5b
Yieldc (%)
Br
we set out to examine the influence of the phosphine on the regi-
oselectivity of this palladium-catalyzed reaction. We compared the
coupling reaction of 2-methyl-1-propen-1-yl acetate 2 with vari-
ous aryl bromides 1 using either tri-tert-butylphosphine (method
A) or tri(o-tolyl)phosphine (method B). The results are shown in
Table 1.
1
2
A
B
95/5
5/95
68
57
Br
3
4
A
B
97/3
3/97
75
75d
As can be seen the reaction afforded low to good yields of cou-
pling products. The formation of the aldehyde 4 or the aryl ketone
5 appears to be both dependent on the aryl bromide and the
phosphine. As previously reported,9 in the presence of tri(o-
tolyl)phosphine (Method B), the aryl ketone 5 was obtained as
the major product (ratio 5:4 >90/10 except with 4-nitro-bromo-
benzene, entry 24). Using the tri-tert-butylphosphine (method A),
a complete inversion of selectivity was observed in most cases (ra-
tio 4:5 >80/20, entries 1, 3, 5, 9 and 13). For the 4-nitro-bromoben-
zene, the conversion and the yield are too low to conclude (entry
23). On the other hand it is noteworthy that the regioselectivity
of the coupling reaction in the presence of the tri-tert-butylphos-
phine is very sensitive to the steric hindrance. A slight decrease
of the selectivity of the formation of aldehyde 4 was observed with
Br
5
6
A
B
80/20
3/97
70
76d
Br
7
8
A
B
70/30
3/97
36
75
d
MeO
Br
9
10
A
B
92/8
3/97
60
51
OMe
a-bromonaphthalene, o-methoxy-bromobenzene, and o-methyl-
bromobenzene (entries 5, 9, and 17). In the case of more sterically
hindered aromatic derivatives as 2-bromo-N,N-dimethylaniline
and o,o0-dimethyl-bromobenzene the aryl ketones 5 were achieved
in high selectivities (ratio 5:4 >97/3).
Br
11
12
A
B
55/45
3/97
48
42
Me2N
Aware of the influence of ligand on the outcome of the reaction,
the tricyclohexylphosphine was also used instead of P(t-Bu)3.
Br
Unfortunately, as Miura and coll. noticed in the a-arylation of alde-
hydes with aryl bromides,2a we did not observe any coupling reac-
tion between the b-bromonaphthalene and 2.
13
14
A
B
97/3
10/90
78
69
NMe2
Based on our previous work,9 two concurrent mechanisms can
be considered. In the presence of tri(o-tolyl)phosphine (cycle B)
the aryl ketone 5 was produced via the addition of the aryl group
to a ketene whereas in the presence of tri-tert-butylphosphine (cy-
cle A) the aldehyde 4 was obtained as the major product following
Br
15
16
A
B
3/97
3/97
79
75
NMe2
the classical catalytic cycle of a-arylation of aldehydes (Scheme 2).
Hartwig and Roy reported that reductive elimination of aryl halide
is made easy by the addition of tri-tert-butylphosphine to a dimeric
tri(o-tolyl)phosphine arylpalladium (II) halide complexe.10 Conse-
quently, the difference of reactivity in our reaction would be due
to a faster reductive elimination with P(t-Bu)3 than with P(o-
Tol)3 after the formation of the intermediate A. Moreover, the bulk-
iest phosphine11 P(o-Tol)3 helps the b-H-elimination to give the
palladium-ketene intermediate B. This is also consistent with the
preferential formation of the aryl ketone 5 when sterically hin-
dered ortho-substituted aryl bromides are used.
Br
17
18
A
B
65/35
3/97
64
41
Me
Me
Br
19
20
A
B
3/97
3/97
57
43
Me
Having established that the tri-tert-butylphosphine leads to the
-arylation product, we turned our attention to the reactivity of
aryl bromides in the presence of vinyl acetate and monosubsti-
tuted vinylic acetates. Reaction of b-bromonaphthalene with vinyl
acetate under the method A reaction conditions (Scheme 3) affor-
Br
21
22
A
B
Inextricable mixture
a
3/97
62
MeO2C
O2N
Br
ded a complex mixture from which the a,b-unsaturated aldehyde 6
23
24
A
B
97/3
45/55
21
39
was isolated in 28% yield (in the presence of P(o-Tol)3, method B,9
the corresponding aryl ketone was isolated in 41% yield). The alde-
hyde 6 was probably formed through a palladium-catalyzed cou-
pling reaction followed by enolization of the aldehyde-
aldolization–crotonization cascade reactions. The use of 3-phe-
nyl-1-propen-1-yl acetate instead of vinyl acetate also provided a
a
Method A: 5 mol % PdCl2(CH3CN)2, 10 mol % P(t-Bu)3. Method B: 5 mol %
PdCl2[P(o-Tol)3]2.
Ratio determined by 1H NMR from the crude mixture.
Isolated yield (average of two runs).
b
c
d
See Ref. 9.

6548
M. Jean et al. / Tetrahedron Letters 50 (2009) 6546–6548
ArX
Me
OAc
Ar
Pd
X
+
Bu3SnOMe
- AcOMe
Me Me
Ln
Me
oxidative addition
H
LnPd
LnPdX2
Me
Me
O
Bu3SnO
Bu3Sn
transmetallation
H
CYCLE A
L = P(t-Bu)3
Bu3SnX
Ar
transmetallation
Ar
Ln Pd
Me
Me
reductive
elimination
L Pd L
X
H
O
Me Me
A
oxidative addition
ArX
Ar
CHO
β-H elimination
4
CYCLE B
L
L = P(o-Tol)3
L2PdX2
L2Pd
O
C
Ar
reductive
elimination
L Pd
O
ligand
exchange
Me Me
H
Me
Me
L
L Pd
H
Me
Me
B
Ar
5
L
O
Ar
Scheme 2. Working catalytic cycle.
Acknowledgments
CH3
5 mol%
PdCl2(CH3CN)2
Br
10 mol% P(t-Bu)3
We gratefully acknowledge the CRMPO for mass measurements
and the Université de Rennes 1, Région Bretagne, and Rennes
Métropole for financial support of this project.
CHO
28%
OAc
Bu3SnOMe (2 equiv)
DMSO, 100 °C, 14 h
6
+
Supplementary data
Scheme 3. Pd-catalyzed reaction with vinyl acetate.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.048.
complex mixture from which no aldehyde could be isolated (72%
yield of aryl ketone with method B).9
References and notes
Miura and co-workers2a reported that the formation of aldol
products was overcome by the use of dioxane instead of the
DMF. Relying on these observations, we decided to check our reac-
tion in dioxane. Whatever the phosphine and palladium source
used, no reaction occurred in these reaction conditions.
In summary, we have shown that a change of ligand can lead to
a dramatic inversion of the regioselectivity in the palladium-cata-
lyzed addition of aryl bromides to vinylic acetate. However, the
reaction conditions described here in the presence of tri-tert-butyl-
phosphine are not satisfactory. At this stage of work, the scope of
the reaction remains limited to disubstituted vinylic acetates. Fur-
ther investigations of the reaction conditions, as well as mechanis-
tic studies are currently underway and will be reported in due
course.
1. (a) Culkin, D. C.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245; (b) Hartwig, J.
F. Synlett 2006, 1283–1294.
2. (a) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
2002, 43, 101–104; See also an intramolecular version: (b) Muratake, H.;
Natsume, M.; Nakai, H. Tetrahedron 2004, 60, 11783–11803.
3. Martin, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236–7239.
4. Vo, G. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127–2130.
5. Martin, R.; Buchwald, S. L. Org. Lett. 2008, 10, 4561–4564.
6. Garcia-Fortanet, J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 8108–8111.
7. Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 10510–10511.
8. (a) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. J. Chem. Soc., Chem. Commun.
1983, 344–345; (b) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem.
Soc. Jpn. 1984, 57, 242–246.
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3623–3625.
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11. Tolman’s cone angle: P(o-Tol)3 = 194°; P(t-Bu)3 = 182°; P(Cy)3 = 170°.