Palladium-catalyzed regiocontrolled internal heteroarylation of electron-rich olefins with heteroaryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.08.005

A highly efficient palladium-catalyzed Heck coupling reaction of heteroaryl halides with electron-rich vinyl ether and hydroxyalkyl vinyl ethers is described. It was found that the choice of solvent, ligand, and reaction temperature had a fundamental influence on the regioselectivity and reactivity of the reaction, and the combination of Pd(OAc)₂ and DPPF in ethylene glycol led to the most effective catalytic system. Under these conditions, a variety of heteroaryl halides reacted very quickly with electron-rich olefins to afford exclusively the branched products in good to excellent yields without employing triflates, halide scavengers, or ionic liquids.

Full text of DOI:10.1016/j.tetlet.2008.08.005

Tetrahedron Letters 49 (2008) 6104–6107
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed regiocontrolled internal heteroarylation
of electron-rich olefins with heteroaryl halides
b
b,
Dan Xu a, Zhihua Liu a, Weijun Tang a, Lijin Xu a, , Zeynab Hyder , Jianliang Xiao
*
*
a Department of Chemistry, Renmin University of China, Beijing 100872, China
b Liverpool Centre for Materials and Catalysis, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient palladium-catalyzed Heck coupling reaction of heteroaryl halides with electron-rich
vinyl ether and hydroxyalkyl vinyl ethers is described. It was found that the choice of solvent, ligand,
and reaction temperature had a fundamental influence on the regioselectivity and reactivity of the reac-
tion, and the combination of Pd(OAc)2 and DPPF in ethylene glycol led to the most effective catalytic sys-
tem. Under these conditions, a variety of heteroaryl halides reacted very quickly with electron-rich
olefins to afford exclusively the branched products in good to excellent yields without employing
triflates, halide scavengers, or ionic liquids.
Received 25 April 2008
Revised 29 July 2008
Accepted 5 August 2008
Available online 8 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The Pd-catalyzed Heck olefination of heteroaryl halides has
emerged as a powerful tool for the synthesis of functionalized
heteroaryls.1 However, most of the published Heck reactions
focused on the heteroarylation of electron-deficient olefins, and
the coupling reactions of electron-rich olefins with heteroaryl
halides have remained largely unexplored.1,2 This is understand-
able since the latter is frequently complicated by the formation
of mixtures of linear b- and branched a-products due to two pos-
sible reaction pathways (Eq. 1).3,4 Several methods have been suc-
cessfully developed to circumvent the problem of regioselectivity,
but they usually suffer from the use of expensive substrates, or
toxic additives or limitations to particular olefins.5 Considering
Table 1
Solvent and ligand effect on the Heck heteroarylation of vinyl ethera
OBu
Br
OBu
Pd(OAc)2/Ligand
+
+
N
OBu
NEt3, solvent
N
N
1a
2a
3a
4a
Entry
Solvent
Ligand
Temperature (°C)
Time (h)
Conv. (%)b
a
/bb
E/Zb
1
2
3
4
5
6
7
8
9
Isopropanol
Ethanol
DPPP
DPPP
DPPP
DPPB
Reflux
Reflux
115
115
115
115
115
115
140
20
20
20
20
20
20
20
12
2
Nd
Nd
40
32
28
<1
50
100
100
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
>99/1
>99/1
>99/1
DPPE
DPPM
rac-BINAP
DPPF
95/5
>99/1
>99/1
70/30
DPPF
a
Conditions: 1a (1.0 mmol.), 2a (2.0 mmol), Pd(OAc)2 (3 mol %), ligand (6 mol %), NEt3 (2.0 mmol), solvent (2 mL).
Determined by 1H NMR. When no b product was detected, a value >99/1 was assigned.
b
* Corresponding authors. Tel.: +86 10 62511528; fax: +86 10 62516444 (L.X.).
E-mail address: xulj@chem.ruc.edu.cn (L. Xu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.005

D. Xu et al. / Tetrahedron Letters 49 (2008) 6104–6107
6105
Table 2
the synthetic potential of this reaction in heterocyclic chemistry, a
more effective catalytic system for regioselective heteroarylation
of electron-rich olefins would be attractive.
Regioselective Heck heteroaryaltion of vinyl ether in ethylene glycola
O
H+
Pd(OAc)2/DPPF
+
Ar-Br
Ar
OBu
Ar
P
P
Ar
OBu
R
Ethylene glycol
NEt3 , 140 ºC
Pd
Ar
R
1
2a
Ar-Br
3
5
A
B
P
P
Pd
Yieldb (%)
α
β
Entry
Product
Time (h)
2
Ar X
ð1Þ
R
P
P
COMe
N
Ar
R
1
1a
95
Pd
Ar
5a
X
R
During the course of our research on regiocontrolled arylation
of electron-rich olefins,6 we discovered that Pd-catalyzed highly
regioselective Heck reactions of heteroaryl halides with electron-
rich olefins could be achieved in an imidazolium ionic liquid
[bmim][BF4].6c However, these reactions proceeded slowly, requir-
ing about 30 h for completion. Another concern is that in these
reactions pure ionic liquid was used as the bulk solvent, which
may create a problem since ionic liquids are by no means cheap
as solvents. Following our pursuit for a cleaner, more economic
method for the regioselective Heck heteroarylation, herein we
report that heteroaryl halides can be efficiently olefinated
with electron-rich olefins in a highly regioselective manner in
ethylene glycol, which is a low-cost and environmentally benign
solvent, without recourse to ionic liquids, triflates, or halide
scavengers.7
COMe
2
3
4
5
1b
1c
1d
1e
2
85
92
86
95
5b
N
COMe
5c
0.5
1
N
AcHN
COMe
5d
N
COMe
5e
OMe
0.3
N
MeO
The preliminary experiments were performed with 4-bromo-
isoquinoline 1a as the model substrate, and the results are summa-
rized in Table 1. We first investigated the heteroarylation of the
benchmark electron-rich olefin butyl vinyl ether 2a, in different
alcohols under the previously established conditions, where the
catalyst was generated in situ from DPPP (1,3-bis(diphenylphos-
phino)propane) and Pd(OAc)2.6 No reaction was observed in either
isopropanol or ethanol after 20 h; however, ethylene glycol
COMe
6
7
1f
1g
1h
1i
0.3
1
96
89
90
87
89
5f
N
MeO
COMe
5g
N
N
MeOC
COMe
5h
provided
a
40% conversion with the exclusive formation of
-substituted product 3a (entries 1–3). The better reactivity and
-regioselectivity observed in ethylene glycol may be partly as-
8
2
a
a
MeOOC
COMe
cribed to its higher boiling point (bp: ethanol, 78 °C; isopropanol,
81–83 °C; and ethylene glycol, 196–198 °C) and better capability
to form hydrogen bond with the bromide anion,8 enhancing the
concentration of the cationic Pd(II)-olefin species. In order to im-
prove the rate of this reaction, we then examined the catalytic per-
formance of other bidentate phosphines in ethylene glycol. High
regioselectivity was obtained with DPPE (1,2-bis(diphenylphos-
phino)ethane), DPPB (1,4-bis(diphenylphosphino)butane), or DPPF
(1,10-bis(diphenylphosphino)ferrocene) as the ligand; but DPPM
(1,1-bis(diphenylphosphino)methane) inhibited the reaction and
rac-BINAP (( )-2-20-Bis(diphenylphosphino)-1,10-binaphthalene)
displayed an inferior regioselectivity (entries 4–8). Delightfully,
the combination of Pd(OAc)2 and DPPF afforded the most efficient
catalyst (entry 8), which may be related to the large bite angle of
DPPF.6e Ethylene glycol allows operation at a higher temperature,
and a faster reaction rate is expected at elevated temperature.
Indeed, when the reaction temperature was increased to 140 °C,
we were pleased to find that the heteroarylation of 2a with 1a
was completed in 2 h (entry 9). These results indicate that alco-
holic solvents are capable of quenching the halides by hydrogen
bonding, thus blocking the pathway to the linear product, and
rendering the branched product favorably (Eq. 2).
9
2
5i
N
COMe
5j
10
1j
1
S
11
1k
1l
5k
COMe
2
90
81
N
COMe
12c
15
5l
N
Br
COMe
13c
1m
1n
1.5
1.5
86
90
5ma
S
MeOC
COMe
5mb
14c,d
S
a
Conditions: 1 (1.0 mmol), 2a (2.0 mmol), Pd(OAc)2 (3 mol%), DPPF (6 mol%),
NEt3 (2.0 mmol), ethylene glycol (2 mL), 140 °C. Compound 5 was obtained after
acidification of 4. 100% conversion and no linear products were observed as shown
by 1H NMR analysis.
P
P
Ar
X
P
P
Ar
X- H OR
Pd
+
+
H OR
+
Pd
ð2Þ
R
R
b
Isolated yields.
c
To study the substrate scope of this efficient catalytic system,
we then extended the chemistry to other heteroaryl halides. In a
Compounds 1l: 4-bromopyridine hydrochloride; 1m: 3,4-dibromothiophene.
d
Four equivalents of olefins were employed.

6106
D. Xu et al. / Tetrahedron Letters 49 (2008) 6104–6107
Table 3
typical reaction, a mixture of 1, 2a, Pd(OAc)2, DPPF, and NEt3 was
heated in 2 mL ethylene glycol at 140 °C in an inert atmosphere
of N2; the ketone 5 was obtained following the hydrolysis of 3.
As shown in Table 2, all the reactions reached completion with
>99/1 regioselectivity in favor of the branched products with good
to excellent isolated yields.11 Nearly all the reactions were com-
pleted within 2 h, regardless of the nature of the heteroaryl rings.
This outcome is remarkable in comparison with our previous re-
sults in ionic liquid, in which the reactions required as long as
36 h to complete.6c It appeared that the reaction proceeded slightly
faster in the olefination of electron-rich heteroaryl bromides (en-
tries 3, 5–7), and somewhat longer reaction times were needed
for the electron-deficient ones (entries 8 and 9). For example, only
0.3 h was needed to finish the coupling reaction of 1f and 2a (entry
6), while it took 2 h to complete the olefination of 1j (entry 9),
although the former is sterically less favorable. It is notable that
the heteroaryl bromides, 1k and 1l (4-bromopyridine hydrochlo-
ride), which have long been considered as difficult substrates for
Heck couplings,9 could undergo the regioselective olefination
smoothly (entries 11 and 12). The slow olefination of 1l is probably
due to the presence of chloride anion, which has been found to in-
hibit the regioselective coupling of aryl halides with electron-rich
olefins.6b
Regioselective heteroarylation of hydroxyalkyl vinyl ethers in ethylene glycola
O
Pd(OAc)2/DPPF
OH
+
Ar-Br
Ar
O
Ethylene glycol
NEt3 , 140 ºC
O
n
2b (n=1)n
2c (n=2)
1
6
Entry Ar–Br Olefin Product
Time (h) Yieldb (%)
O
1
1b
2b
2
92
O
N
O
6bb
O
O
2
3
4
1d
1f
2b
2b
2b
1
1
1
91
89
92
6db
N
O
O
6fb
N
O
MeO
1g
N
6gb
The catalytic system also worked effectively for the olefination
of a polyhalohetero-aryl, furnishing mono- or poly-olefinated
products in good yields (entries 13 and 14). For example, in the
presence of 2 equiv 2a, compound 1m (3,4-dibromothiophene)
was mono-olefinated to provide the product 5ma as the main
product, leaving another position for further functionalization (en-
try 13). Indeed, using 4 equiv 2a led to the di-olefinated product
5mb (entry 14).
O
MeOOC
5
6
1i
2b
2b
2
2
94
87
O
N
6ib
O
1k
N
O
6kb
Given the success with 2a, we hoped that this efficient coupling
process could also be extended to other electron-rich olefins. Hall-
berg and his coworkers first reported the synthesis of cyclic ketals
of acetophenones via internal Heck arylation of hydroxyalkyl vinyl
ethers with aryl triflates, but the reactions were slow and addi-
tional hydrolysis with dry acetic acid to complete ring closing
was required.10 Recently with aryl halides as the substrates, similar
regioselective arylation has been successfully carried out in ionic
liquids without subsequent hydrolysis.6b,6d Very recently, Larhed
and his coworkers reported regioselective heteroarylation of
hydroxyalkyl vinyl ethers in water, but they only obtained the
ketones.5d So far there has been no report about the synthesis of
cyclic ketals via regioselective heteroarylation of hydroxyalkyl
vinyl ethers. To our delight, under the same reaction conditions
as for vinyl ether 2a, the hydroxyalkyl vinyl ethers 2b and 2c have
proved to be viable substrates. Examples of heteroarylation with
different heteroaryl halides are given in Table 3.11 It is notable that
all the reactions were completed again within 2 h with excellent
regioselectivities, affording the 5-membered and 7-membered
cyclic ketals in good yields without subsequent hydrolysis. Also
noteworthy is the successful olefination of 1m (Table 3, entries 7
and 8). In the presence of 2 equiv 2b, the compound underwent
mono-olefination to produce 6mba as the main product (entry
7), while using 4 equiv 2b led to the di-olefinated product 6mbb
O
O
Br
7
1m
1m
1b
2b
2b
2c
2c
1
2
2
2
83
89
70
75
6mba
S
O
O
8c
O
S
6mbb
O
9
O
6bc
N
O
MeOOC
10
1i
O
6ic
N
a
Conditions:
1 (1.0 mmol), 2b or 2c (2.0 mmol), Pd(OAc)2 (3 mol%), DPPF
(6 mol%), NEt3 (2.0 mmol), ethylene glycol (2 mL), 140 °C. 100% conversion and no
linear products were observed as shown by 1H NMR analysis.
b
Isolated yields.
c
Four equivalents of olefins were employed.
(entry 8). The formation of
compound may be due to the steric effects.
a mono-rather than a di-ketal
Acknowledgments
In summary, we have developed a general and efficient method
for the internal heteroarylation of vinyl ether and hydroxyalkyl
vinyl ethers in a green solvent, ethylene glycol. This method allows
for highly regioselective heteroarylation of these electron-rich ole-
fins with heteroaryl halides with no necessity for triflates, halide
scavengers, or ionic liquids. Ethylene glycol is expected to facilitate
the formation of the ionic palladium intermediate, enabling the
reaction to proceed via the ionic route and hence to preferentially
afford the branched products.
We thank the Renmin University of China and the National Nat-
ural Science Foundation of China (Nos. 20542009 and 20672139)
for financial support.
References and notes
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11. General procedure for the olefination of heteroaryls: An oven-dried, two-necked
round-bottomed flask containing a stir bar was charged with heteroaryl halide
1 (1.0 mmol), Pd(OAc)2 (7 mg, 0.03 mmol), DPPF (25 mg, 0.06 mmol), and
ethylene glycol (2 mL) under nitrogen at room temperature. Following
degassing three times, olefin
2 (2.0 mmol) and NEt3 (2.0 mmol) were
injected sequentially. The flask was placed in an oil bath, and the mixture
was stirred and heated at 140 °C. The reaction was monitored by TLC. After the
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extracted with dichloromethane 3 times. For products requiring acid
hydrolysis, aqueous HCl (5%, 5 mL) was added and following stirring for
0.5 h, dichloromethane was added. The combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified via flash chromatography on silica gel using a mixture of ethyl acetate
and hexane (5:95–20:80).