Selective arylation of 1,1-disubstituted olefins using a biphenyl-based phosphine in Heck coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2009.07.052

The biphenyl-based phosphine, 2-diphenylphosphino-2′-methylbiphenyl is an effective ligand for palladium-catalyzed terminal arylation of 1,1-disubstituted olefins with aryl bromides in DMF and K₂CO₃ as base. The yields of products are independent of the electronic properties of the aryl bromides, however, the nature of the olefin has a major effect.

Full text of DOI:10.1016/j.tetlet.2009.07.052

Tetrahedron Letters 50 (2009) 5470–5473
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Tetrahedron Letters
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Selective arylation of 1,1-disubstituted olefins using a biphenyl-based
phosphine in Heck coupling reactions
a,b
Shirin Nadri a, Mohammad Joshaghani a,b, , Ezzat Rafiee
*
a Faculty of Chemistry, Razi University, Kermanshah 67149, Iran
b Kermanshah Oil Refining Company, Kermanshah, Iran
a r t i c l e i n f o
a b s t r a c t
The biphenyl-based phosphine, 2-diphenylphosphino-20-methylbiphenyl is an effective ligand for palla-
dium-catalyzed terminal arylation of 1,1-disubstituted olefins with aryl bromides in DMF and K2CO3 as
base. The yields of products are independent of the electronic properties of the aryl bromides, however,
the nature of the olefin has a major effect.
Article history:
Received 5 May 2009
Revised 30 June 2009
Accepted 10 July 2009
Available online 15 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
C–C Coupling
Heck reaction
1,1-Disubstituted olefins
Biphenyl-based phosphine
Palladium-catalyzed cross-coupling reactions are important
methods for the construction of carbon–carbon bonds. An example
is the Heck reaction, the Pd-catalyzed reaction of an olefin with an
aryl derivative in the presence of a base, where formally a vinylic
hydrogen is replaced by an aryl group.1,2 The Heck coupling has
been applied to a wide variety of monosubstituted olefins. How-
ever, only a few examples of the use of 1,1-disubstituted olefins
have been reported to date.3–9 Heck reaction of aryl halides with
1,1-disubstituted olefins affords bulky aryl olefins which display
interesting pharmacological and physical properties.10–13
carbon–carbon and carbon–heteroatom bond forming reac-
tions.18–22
The stability of catalysts based on these phosphines is believed
to be due to
p-interactions between the non-phosphine-containing
ring of the biphenyl ligand and the Pd(0) center. This
p
-interaction
may stabilize any intermediate in the catalytic cycle thereby
increasing the lifetime of the catalyst.23–28
We are interested in developing highly active palladium
catalysts, and in this context we have focused on C–C coupling
reactions.29–32 Herein, we report that the sterically bulky biphe-
nyl-based phosphine (4)–Pd complex is sufficiently active to
promote Heck reactions of 1,1-disubstituted olefins with aryl
bromides. We have reported that phosphine 4 can be successfully
applied in the palladium-catalyzed Suzuki coupling of aryl halides
as well as bromoarylphosphines and bromoarylphosphine oxides,
with low catalyst loading and in good to excellent conversions.31
The biphenyl-based phosphine 4 was prepared in almost quan-
titative yield by Suzuki coupling of o-tolylboronic acid with either
bromophenylphosphine or its corresponding oxide using Pd(OAc)2
and various monophosphine ligands, as described earlier30,31
(Scheme 2).
Based on our recent success with biphenyl-based phosphine 4
as a ligand in Heck coupling reactions of monosubstituted olefins
with aryl bromides, we employed the same experimental protocol
for the Heck reactions of 1,1-disubstituted olefins.33 Thus, N,N-
dimethylformamide (DMF) was chosen as the solvent and sodium
carbonate (K2CO3) as the base for the reaction of aryl bromides
The arylation of 1,1-disubstituted olefins such as methacrylates,
depending on the direction of b-hydride elimination, can give two
possible isomers: (a)
nal double bond, the stereochemistry of which can be E or Z and,
(b) -benzylacrylates 2 with a terminal double bond, which is sus-
a-methylcinnamic acid esters 1 with an inter-
a
ceptible to further arylation to give 3 (Scheme 1).
Generally, the combination of a palladium catalyst with various
phosphine ligands results in excellent yields and high efficiency in
the Heck reaction.14–17 Inspired by the discovery that electron-rich
and bulky phosphines are important ligands, several researchers
have synthesized a number of Pd complexes associated with bulky
and electron-rich phosphines. Among them, biphenyl-based phos-
phines are of significant interest in organic synthesis. Catalysts
based on this class of ligands have not only displayed high stability,
but have also shown increased reactivity in palladium-catalyzed
with n-butyl methacrylate and
a-methyl styrene at 135 °C using
* Corresponding author. Tel./fax: +98 831 4274559.
E-mail address: mjoshaghani@razi.ac.ir (M. Joshaghani).
0.025 mol% of Pd(OAc)2.34
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.052

S. Nadri et al. / Tetrahedron Letters 50 (2009) 5470–5473
5471
Ar
R1
[Cat.]
Ar
Ar
+
Ar
+
Ar
X
+
R1
R1
R1
1
1
n
2
3
R = CO Bu
2
Scheme 1. Heck arylation of 1,1-disubstituted olefins.
ucts in all cases (KTI ꢀ 99/1), and only a small amount of the dou-
ble arylated product was formed (KMD ꢀ 99/1) (Table 1).
PPh2
Br
PPh2
Ar
4: Ar = o-tolyl
Pd(OAc)2
Phosphine
+ ArB(OH)2
Using a phosphinito Pd complex in DMF at 180 °C, Jensen
observed that in the Heck arylation of olefins in the presence of
both inorganic and organic bases, the internal olefin was obtained
as the major product.3 In contrast, Beller found that in the Heck
arylation of olefins, catalyzed by Herrmann’s palladacycle, the
nature of the base had a significant effect on the regioselectivity.
Inorganic bases such as sodium acetate gave a mixture of the two
regioisomers with the terminal olefin as the major product,
whereas the internal olefin was favored by organic bases such
Scheme 2. Synthesis of biphenyl-based phosphine 4.
We observed that n-butyl methacrylate in the presence of
K2CO3 as base, gave terminal olefins as the major coupling prod-
Table 1
Heck reaction of n-butyl methacrylate with aryl bromidesa
Br
CO2nBu
Pd(OAc)2 / phosphine 4
R
CO2nBu
CO2nBu
+
CO2nBu
+
+
R
R
R
°
K2CO3, DMF, 135 C
internal
terminal
double arylated
R
c
d
Entry
1
Aryl bromide
Terminalb (%)
80
KTI
KMD
TON
>99/1
14.6
>99/1
>99/1
3200
H3C
Br
2
3
4
5
6
73
2920
OHC
Br
95
>99/1
>99/1
3800
Br
17 (45)
49 (50)
90
1.7 (>99/1)
16 (5.5)
>99/1
2.7 (>99/1)
>99/1 (6.5)
>99/1
1840 (1800)
2040 (2720)
3600
MeOC
MeO
Br
Br
H3C
Br
7
8
5 (42)
40
>99/1 (8.4)
>99/1
>99/1 (6.71)
>99/1
200 (2160)
1600
O2N
Br
Br
9
20
>99/1
>99/1
800
Br
a
Reaction conditions: aryl bromide (4 mmol), n-butyl methacrylate (4 mmol), K2CO3 (4 mmol), Pd(OAc)2 (0.025 mol %), phosphine 4 (0.05 mol %), DMF (3 mL), 135 °C, 1 h, N2.
GC yield. The numbers in parentheses are from 24 h reactions.
KTI = terminal/internal.
b
c
d
KMD = mono arylated/double arylated, mono arylated = sum of terminal and internal isomers.

5472
S. Nadri et al. / Tetrahedron Letters 50 (2009) 5470–5473
Table 2
Heck reaction of
a
-methylstyrene with aryl bromidesa
Br
Pd(OAc)2 / phosphine 4
R
R
R
R
+
+
+
°
K2CO3, DMF, 135 C
internal
terminal
double arylated
R
c
d
Entry
1
Aryl bromide
Terminalb (%)
KTI
KMD
TON
78
9.75
19
>99/1
>99/1
>99/1
>99/1
3440
H3C
Br
2
3
4
95
4000
Br
10 (40)
40
2 (>99/1)
>99/1
600 (600)
1600
MeOC
Br
MeO
H3C
Br
5
6
7
82
35
40
15
9.1
>99/1
4.9
3640
2120
1600
600
Br
3.9
O2N
Br
Br
>99/1
>99/1
8
>99/1
>99/1
Br
a
Reaction conditions: aryl bromide (4 mmol), a-methylstyrene (4 mmol), K2CO3 (4 mmol), Pd(OAc)2 (0.025 mol %), phosphine 4 (0.05 mol %), DMF (3 mL), 135 °C, 1 h, N2.
NMR yield. The numbers in parentheses are from 24 h reactions.
KTI = terminal/internal.
b
c
d
KMD = mono arylated/double arylated, mono arylated = sum of terminal and internal isomers.
as Bu3N and diisopropylethylamine (DIPEA).4 Sun and co-work-
ers5 reported that during the arylation of 1,1-disubstituted olefins
catalyzed by Co hollow nanospheres, only internal olefins were
obtained, in contrast to the palladium nanoparticle-catalyzed
reaction reported by Caló et al. in which isomerized products
(terminal isomer) were generated.6
If in the Heck coupling reaction oxidative addition of the aryl
halide to the Pd(0) species is the rate-determining step, electron-
withdrawing groups on the aryl halide should lead to improved
rates, whereas electron-donating groups should decrease reaction
rates. As shown in Tables 1 and 2 aryl bromides with both elec-
tron-withdrawing and electron-donating groups showed no obvi-
ous difference in reactivity. In addition, reasonable yields were
observed with electron-donating Me and OMe substituents on
the bromobenzene. On the other hand, the nature of the olefin
has a dominating effect on the yield and selectivity of the reaction.
These results lead to some doubts about the effect of the aryl bro-
mide on the rate-determining step and infer a greater contribution
of the coordination and/or insertion of the olefin in the rate-deter-
mining step.
We considered a-methylstyrene a suitable candidate for further
evaluation of the influence of biphenyl-based phosphine 4 on the
Heck reactions with 1,1-disubstituted olefins because it has excel-
lent NMR monitorable protons. Analogous to the reactions with
n-butyl methacrylate, high selectivity was observed for the termi-
nal olefin albeit with slower reaction rates (Table 2). In addition,
selectivity toward the mono-arylated product was better than that
with n-butyl methacrylate and no double-arylated products were
observed apart from the case of 1-bromo-4-nitrobenzene in which
a small amount of the double arylated product was formed (Table
2, entry 6). It would seem that the existence of a strong electron-
withdrawing NO2 group on the aryl bromide makes it more suscep-
tible to further oxidative addition to the Pd species.
In summary, the use of biphenyl-based phosphine 4 as a ligand
and K2CO3 as a base in Heck reactions, leads to the terminal iso-
mers of 1,1-disubstituted olefins, selectively, and in reasonable
yields in most cases regardless of the nature of the substituents
on the arylbromides.

S. Nadri et al. / Tetrahedron Letters 50 (2009) 5470–5473
5473
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Acknowledgments
The authors thank the Razi University Research Council and
Kermanshah Oil Refining Company for support of this work.
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