Palladium(II)-catalyzed Heck reaction of aryl halides and arylboronic acids with olefins under mild conditions

Article abstract of DOI:10.3762/bjoc.9.180

A series of general and selective Pd(II)-catalyzed Heck reactions were investigated under mild reaction conditions. The first protocol has been developed employing an imidazole-based secondary phosphine oxide (SPO) ligated palladium complex (6) as a precatalyst. The catalytic coupling of aryl halides and olefins led to the formation of the corresponding coupled products in excellent yields. A variety of substrates, both electron-rich and electron-poor olefins, were converted smoothly to the targeted products in high yields. Compared with the existing approaches employing SPO-Pd complexes in a Heck reaction, the current strategy features mild reaction conditions and broad substrate scope. Furthermore, we described the coupling of arylboronic acids with olefins, which were catalyzed by Pd(OAc)₂ and employed N-bromosuccinimide as an additive under ambient conditions. The resulted biaryls have been obtained in moderate to good yields.

Full text of DOI:10.3762/bjoc.9.180

Palladium(II)-catalyzed Heck reaction
of aryl halides and arylboronic acids with olefins
under mild conditions
Tanveer Mahamadali Shaikh and Fung-E Hong*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1578–1588.
Department of Chemistry, National Chung Hsing University, 250
Kuo-Kuang Road, Taichung, Taiwan (R.O.C.)
doi:10.3762/bjoc.9.180
Received: 15 May 2013
Accepted: 10 July 2013
Published: 05 August 2013
Email:
Fung-E Hong* - fehong@dragon.nchu.edu.tw
* Corresponding author
Associate Editor: T. P. Yoon
Keywords:
© 2013 Shaikh and Hong; licensee Beilstein-Institut.
License and terms: see end of document.
aryl halides; Heck reaction; olefins; palladium-complex; phosphine
Abstract
A series of general and selective Pd(II)-catalyzed Heck reactions were investigated under mild reaction conditions. The first
protocol has been developed employing an imidazole-based secondary phosphine oxide (SPO) ligated palladium complex (6) as a
precatalyst. The catalytic coupling of aryl halides and olefins led to the formation of the corresponding coupled products in excel-
lent yields. A variety of substrates, both electron-rich and electron-poor olefins, were converted smoothly to the targeted products in
high yields. Compared with the existing approaches employing SPO–Pd complexes in a Heck reaction, the current strategy features
mild reaction conditions and broad substrate scope. Furthermore, we described the coupling of arylboronic acids with olefins, which
were catalyzed by Pd(OAc)2 and employed N-bromosuccinimide as an additive under ambient conditions. The resulted biaryls have
been obtained in moderate to good yields.
Introduction
Substituted olefins are important structural motifs in natural the most commonly employed arylpalladium precursors in the
products, pharmaceuticals, bioactive compounds and organic Heck reaction.
materials [1,2]. Olefins such as stilbene derivatives normally
show antitumor [3], antiinflammatory [4], neuroprotective [5], In the early 1970s, Mizoroki [10] and Heck [11] developed a
and cardioprotective [6] properties. Due to its importance in the palladium(0)-catalyzed cross-coupling of olefins with organic
synthesis of leading molecules, a variety of preparative method- halides. Later, several other catalytic protocols were used with
ologies have been developed. Particularly, the Heck reaction is variations in their coupling procedures by changing metal
one of the most chosen methods in the synthesis of aryl-substi- sources, ligands, additives or substrates [12-16]. The class of
tuted olefins [7-9]. Aryl halides or arylboronic acids are among phosphine-ligated palladium complexes [17-21] represents the
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most frequently employed precatalysts to achieve high reactivi- catalyzed cross-coupling of aryl halides 1 with olefins 2 at
ties and selectivities for such reactions. However, such trisubsti- 60 °C; and (ii) Pd(OAc)2 catalyzed arylation of arylboronic
tuted phosphines in the palladium complexes are often air-sensi- acids 4 with olefins at 25 °C (Scheme 1).
tive in nature and easily oxidized [22,23]. Therefore, a new
Results and Discussion
class of secondary phosphine oxide ligands (SPO) has been
explored for these ligand-assisted palladium-catalyzed cross- Heck reaction of aryl halides with olefins
coupling reactions [24-27]. This type of SPO ligand is stable In the presence of solvents, secondary phosphine oxide
towards air and moisture and convenient to handle compared to (RR'P(O)H) might undergo tautomerization, which generates a
the conventional trisubstituted phosphine ligands. Despite this less stable phosphinous acid (RR'POH) species. Subsequently,
advantage, the potential of these ligands has not been fully real- its coordination to the metal center through the phosphorus
ized in Heck arylation reactions. Up to now, only a few exam- atom forms a phosphinous acid–metal complex [54-56]. Thus,
ples of utilizing SPO-ligated palladium complexes in oxidative the resulting transition-metal complex might function as an
Heck reactions have been demonstrated [28-31]. Previously, we active catalyst in various C–C-bond-forming reactions. Acker-
also reported the synthesis of cobalt-containing SPO ligands mann et al. reported the synthesis of stable N-aryl-substituted
and their palladium complex. This was successfully applied as a pyrrole and indole-derived SPO-preligands, which were utilized
catalytic precursor in oxidative Heck reactions [32]. However, in Kumada–Corriu cross-coupling reactions [57]. Recently, we
these reactions were carried out at high temperatures with reported the synthesis and characterization of imidazole-based
limited substrate scope. Therefore, the development of an alter- secondary phosphine oxide ligand 5 and its application in C–C-
native general and mild procedure employing a stable and inex- bond-forming reactions (Scheme 2) [58]. Furthermore, the
pensive ligand is still in great demand.
application of complex 6 in cross-coupling reactions has been
carefully studied. We found that complex 6 is an active catalyst
Furthermore, the application of palladium complexes in the for the Heck reaction of aryl halides with olefins under mild
oxidative coupling of organo-boron compounds with olefins has conditions.
attracted much attention in recent years [33-38]. Various
catalytic systems have been developed by Jung [39] and Larhed To optimize the reaction conditions, a series of reactions under
et al. [40-43] by employing diverse variations in oxidants, various combinations of bases, solvents and temperatures,
ligands or palladium complexes [44-47]. Nowadays, several employing complex 6 as precatalyst, was pursued. Bromoben-
competent methods are also known to achieve this transforma- zene (1a) and styrene (2a) were chosen as the model substrates
tion with different reaction conditions employing base-free, in this coupling reaction and the results are presented in
ligand-free conditions or by using conventional oxidants such as Table 1.
oxygen, benzoquinone, Cu salts, etc. [48-53].
Initially, the coupling was carried out by using 1 mol % loading
In this article we report two new protocols for Heck cross-cou- of Pd-complex 6 as a precatalyst, with styrene (2a, 1 mmol),
pling reactions: (i) a stable SPO ligated palladium complex 6 and bromobenzene (1a, 1 mmol) in DMSO (2 mL), and at
Scheme 1: Heck reaction of olefins with aryl halides and arylboronic acids.
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Scheme 2: Synthesis of imidazole-based SPO–Pd complex 6.
Table 1: Palladium complex (6) catalyzed Heck reaction of bromobenzene and styrene: Optimization of reaction conditions.a
Entry
Complex 6 (mol %)
Base (equiv)
Solvent
Temp (°C)
Yield (%)b
1
2
1
2
2
1
1
1
1
1
1
2
2
2
2
2
2
NaOH (1)
NaOAc (1)
Et3N (2)
DMSO
DMSO
DMSO
toluene
CH3CN
THF
rt
rt
–
–
3
40
rt
–
4
K2CO3 (1)
K2CO3 (1)
K3PO4 (1)
K3PO4 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (1)
K2CO3 (2)
K2CO3 (2)
–
5
rt
–c
17
24
46
65
84
92
73
89
96
82
6
40
60
60
100
100
80
50
60
60
60
7
THF
8
THF
9
DMF
10
11
12
13
14
15
DMF
DMF
DMF
DMF
DMF
no solv.
aReaction conditions: styrene (1.0 mmol), bromobenzene (1.0 mmol), base, solvent (1 mL), stirred for 12 h. bIsolated yield. cReaction mixture was
stirred for 24 h.
ambient temperature in the presence of NaOH (1 equiv, Table 1, (2 equiv) and DMF (2 mL) resulted in the formation of 84% of
entry 1). The reaction did not give the coupled product 3a. 3a at 100 °C (Table 1, entry 10). A further increase in the reac-
Moreover, the use of other bases such as NaOAc, Et3N and tion temperature would lead to decomposition of the palladium
K2CO3 in the presence of the solvents, DMSO, toluene or complex, which was formed in situ, thus lowered the yield of
acetonitrile were not useful and no coupled product was the product. Therefore, the loading of the precatalyst 6 was
observed. Interestingly, the reaction showed little progress in increased to 2 mol % and resulted in the formation of trans-stil-
the presence of K3PO4 and tetrahydrofuran at 40 °C to obtain bene in 92% yield at 80 °C (Table 1, entry 11). Synthetically, it
3a in 17% yield (Table 1, entry 6). The yield was slightly im- is important to carry out reactions under mild reaction condi-
proved when the reaction was heated at 60 °C (Table 1, entry tions. Nevertheless, low yield (73%) of the product was
7). When K2CO3 (1.0 equiv) in THF was employed under obtained by reducing the reaction temperature to 50 °C. Thus, a
similar reaction conditions, the yield of trans-stilbene was im- substrate survey was conducted at 60 °C. The optimized reac-
proved to 46% (Table 1, entry 8). Once K2CO3 had been tion conditions were found to be the use of styrene (2a,
selected as the most effective base, the next step involved the 1 mmol), bromobenzene (1a, 1 mmol), K2CO3 (2 mmol), and
enhancement of the product yield. The combination of K2CO3 precatalyst 6 (2 mol %) with heating at 60 °C in DMF (1 mL,
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Table 1, entry 14). It is worthy of noting that the coupling reac- Both aryl bromide and aryl iodide performed well (Table 2,
tion was also performed in the absence of solvent, which gave entries 1 and 2) under these conditions. However, the aryl chlo-
82% yield (Table 1, entry 15) of the coupled product.
ride was found to be less reactive giving the corresponding
product 3a in 62% yield (Table 2, entry 3). The oxidative cou-
A wide range of olefins with different and diversely substituted pling was found to be selective in the case of 4-bromostyrene
aryl bromides were subjected to cross-coupling to produce the (2b), which gives 90% yield of 4-bromo trans-stilbene (3b)
corresponding 1,2-disubstituted olefins. The results are summa- without the observation of any side product (Table 2, entry 4).
rized in Table 2.
The presence of either an electron-withdrawing or electron-
Table 2: Heck reaction of olefins and aryl halides: Scope of substrate.a
Entry
1
Olefin (2)
Aryl halide (1)
Product (3)
Yield (%)b,c
96
2a
2a
2a
1a
1b
1c
3a
3a
3a
2
3
98
62
4
90
2b
1a
3b
5
6
92
88
1a
1d
2c
2a
3c
3d
7
8
90
1a
1a
2d
3e
95 (35)d
2e
2f
3f
3d
3g
9
91
80
1a
1a
10
2g
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Table 2: Heck reaction of olefins and aryl halides: Scope of substrate.a (continued)
11
85
2h
1a
1a
3h
12
87
2i
2j
3i
13
14
90
1a
1a
3j
89
2k
3k
15
16
88
1a
2l
2a
3l
90
1e
1a
3m
17
18
78
2m
3n
95
1a
1a
1a
2n
2o
2p
3o
19
20
90
3p
92
3q
aReaction conditions: olefin (1.0 mmol), aryl halide (1.0 mmol), Pd-complex 6 (2.0 mol %), K2CO3 (2.0 mmol), DMF (1 mL), 60 °C, 12 h. bIsolated
yield. cProducts were characterized by 1H, 13C NMR and GC–MS. dThe yield corresponds to employing 4-chloro anisole as the aryl halide source.
donating group on the aromatic ring of olefin did not affect the in 90% and 95% yields, respectively (Table 2, entries 7 and 8).
reactivity and yield of product. The reactions led to the forma- As known, aromatic rings having substituents such as, -CH2OH,
tion of excellent yields of the corresponding products 3e and 3f -CHO, -COCH3 -CN and -CF3 are rather useful in organic syn-
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Heck reaction of arylboronic acids with
thesis. However, in earlier reported oxidative coupling condi-
tions these functional groups were not compatible and gave low olefins
yields of products. Therefore, these highly modifiable groups The phosphine- and base-free coupling of arylboronic acids
were screened under these catalytic conditions. Thus, 4-vinyl- with olefins under mild reaction conditions were studied as well
benzyl alcohol (2g), 4-vinyl benzaldehyde (2h), 4-vinylace- to broaden the scope of cross-coupling reactions. To search for
tophenone (2i), 4-cyanostyrene (2j) and 4-trifluoromethyl- the optimized reaction conditions, phenylboronic acid (4a) and
styrene (2k) were smoothly converted to their corresponding styrene (2a) were chosen as the model substrates and Pd(OAc)2
coupled products 3g–3k in excellent yields (Table 2, entries was employed as the catalyst. Various reaction conditions were
10–14). The selectivities and yields of the coupled products tested and the results are presented in Table 3. Initially, a
were excellent regardless of ortho-, meta-, or para-substitution Pd(OAc)2 catalyzed Heck reaction was performed employing
patterns on either styrenes or aryl halides under these catalytic polar sovents, dimethylacetamide (DMAc) and DMF, at 25 °C
conditions. For example, the coupling of substituted methyl- in the presence of 0.5 equiv of N-bromosuccinimide (NBS).
styrenes (Table 2, entry 15) or alkyl-substituted aryl halides This resulted in the formation of trans-stilbene (3a) in 52% and
(Table 2, entry 16) gave 88–90% isolated yields of 3l and 3m. 40% yield, respectively (Table 3, entries 1 and 2). However, the
To investigate whether the reaction was compatible with a same reaction under the control conditions (i.e., in the absence
heteroaryl olefin, 2-vinylpyridine (2m) was subjected to this of NBS) resulted in production of a trace amount of the coupled
reaction. It produced the corresponding coupled product 3n in product 3a (Table 3, entry 3). When the coupling reaction was
78% yield (Table 2, entry 17). Furthermore, using these opti- carried out at 90 °C in DMAc solvent, the yield of 3a decreased,
mized conditions, bromobenzene (1a) was examined with due to the formation of side product, such as bromobenzene,
different vinyl esters to determine the scope of this procedure. from the corresponding phenylboronic acid (Table 3, entry 4).
The results are given in Table 2, entries 18–20. Notably, the Therefore, it is believed that NBS plays an important role in this
performances were in agreement with the previous expectations catalytic reaction. Furthermore, we focused our attention to
and yields are excellent in the preparation of α,β–unsaturated other solvents such as MeOH, CH2Cl2, CH3CN, Me2O, t-Bu2O,
esters. The corresponding α,β-unsaturated esters 3o–3q were THF, DMSO and 1,4-dioxane, which resulted in low yields of
obtained in 90–95% yields, respectively.
arylated product. Subsequently, the reaction was subjected to
Table 3: Heck reaction of phenylboronic acid and styrene: Optimization of the reaction conditions.a
Entry
Additive (equiv)
Solvent
Time (h)
Temp. (°C)
Yield (%)b,c
1
2
NBS (0.5)
NBS (0.5)
–
DMAc
DMF
18
18
24
18
18
24
18
18
18
12
18
12
12
12
25
25
25
90
25
25
25
80
25
25
25
25
25
25
52
40
3
DMAc
trace
34
4
NBS (0.5)
NBS (0.5)
NBS (0.5)
NBS (0.1)
NBS (0.1)
NBS (1)
DMAc
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
68
6
69
7
30
8
47
9
40
10
11
12
13
14
NBS (0.3)
NBS/K2CO3 (0.3:1)
NBS/4 Å MS (0.3:2)
LiBr (0.3)
76
nrd
15
nr
CuBr
42
aReaction conditions: styrene (0.5 mmol), phenylboronic acid (0.5 mmol), Pd(OAc)2 (5 mol %), additive and dry solvent (1 mL) for 12 h at 25 °C.
bIsolated yield. cProduct was characterized by GC–MS, 1H and 13C NMR. dReaction was stirred under air.
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the apolar solvent toluene. The expected product trans-stilbene yield of trans-stilbene (3a) (Table 3, entry 14). Thus, the opti-
(3a) was obtained in 68% yield at 25 °C for 18 h (Table 3, mized reaction conditions for the Heck reaction here is the use
entry 5). The yield of the desired product did not improve even of arylboronic acid (1 mmol), olefin (1 mmol), Pd(OAc)2
when the reaction was stirred for 24 h (Table 3, entry 6). On the (5 mol %), NBS (30 mol %), toluene (1 mL) at 25 °C under stir-
other hand, lowering the additive (NBS) to 10 mol % did not ring for 12 h.
show any improvement to the formation of trans-stilbene (3a)
(Table 3, entries 7 and 8). A sharp decline in the formation of The optimized Heck cross-coupling conditions were employed
trans-stilbene (3a) (Table 3, entry 9) was observed on to examine the arylation of substituted olefins and phenyl-
increasing the quantity of NBS to a stoichiometric amount boronic acid. The results are presented in Table 4. As shown in
(1.0 equiv). This was probably due to the formation of other Table 4, this coupling procedure tolerates various functional
competitive side product(s). Interestingly, the coupled product groups to afford the desired product (3). The compatibility of
was obtained with improved yield of 76% by using 30 mol % halo-substituted styrenes is synthetically useful since the prod-
NBS (Table 3, entry 10). Next, we turned our attention to the ucts could be easily modified further to form synthetic building
improvement of the yields of trans-stilbene by adjusting other blocks. Thus, the coupling of 4-fluorostyrene (2q), 4-bromo-
reaction parameters. Thus, the addition of K2CO3 as base along styrene (2b) and 4-chlorostyrene (2r) through oxidative Heck
with NBS under similarly performed reaction conditions led to reaction led to the corresponding products in 65–69% yields,
no formation of the targeted product. The addition of molecular respectively (Table 4, entries 2–4). Furthermore, the electron-
sieves was not a good choice either [59]. The other additives withdrawing groups on styrene, such as 3-nitrostilbene (2d) and
such as LiBr and CuBr were also examined. Still, no coupled 4-trifluorostilbene (2k) resulted in the formation 3e and 3k in
product was obtained in the presence of LiBr (30 mol %, 76% and 70% yields, respectively (Table 4, entries 5 and 6).
Table 3, entry 13). On the other hand, the employment of CuBr However, the electron-donating substituent on olefin lessened
(30 mol %) with the presence of Pd(OAc)2 resulted in a 42% the reaction rate and thus led to poor yield of product 3f
Table 4: Substrate scope in the Heck arylation reaction of phenylboronic acids with olefins.a
Entry
1
Substrate (2)
Product (3)b
Yield (%)c
76
2a
2q
2b
2r
3a
3r
2
3
4
65d
69
3b
3s
66
5
76
2d
3e
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Table 4: Substrate scope in the Heck arylation reaction of phenylboronic acids with olefins.a (continued)
6
70
30
70
2k
2e
3k
3f
7
8
2c
2n
3c
3o
9
50
42
10
2o
2s
3p
3t
11
12
38
44e
2t
3u
aReaction conditions: styrene (1.0 mmol), phenylboronic acid (1.0 mmol), catalyst (5 mol %), N-bromosuccinimide (30 mol %), and toluene (2 mL)
under nitrogen for 12 h. bProduct was characterized by GC–MS, 1H and 13C NMR. cIsolated yield. dDetermined by GC–MS. eE/Z ratio 20:1 by
1H NMR, terminal/internal 4/1.
(Table 4, entry 7). The reaction with aliphatic alkenes, such as To expand the scope of this cross-coupling, these conditions
tert-butyl acrylate (2n) or ethyl acrylate (2o), allyl acetate (2s) were then applied to a variety of boronic acids and styrene
and n-heptene (2t) afforded the corresponding coupled prod- (Table 5). For a diverse set of boronic acids, cross-coupling
ucts in moderate yields, respectively (Table 4, entries 9–12). proceeded smoothly with 2a in moderate to good yields. In this
Table 5: Substrate scope in Heck arylation reaction of phenylboronic acids with olefins.a
Entry
1
Substrate
Productb
Yield (%)c
76
4a
3a
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Table 5: Substrate scope in Heck arylation reaction of phenylboronic acids with olefins.a (continued)
2
69
67
72
75
4b
4c
3b
3c
3k
3v
3
4
5
4d
4e
6
7
73
60
4f
3e
4g
4h
4i
3l
3s
3f
8
9
62
40
aReaction conditions: similar to Table 4. bProduct was characterized by GC–MS, 1H and 13C NMR. cIsolated yield.
case, the procedure also tolerated a range of functional groups, various olefins and aryl halides utilizing an imidazole-based
such as bromo, chloro, nitro, methoxy, and alkyl groups. The secondary phosphine oxide ligated palladium complex (6) under
arylboronic acids with electron-withdrawing substituents mild conditions. The yields of products obtained were excellent
furnished good yields of coupled product as compared to the and in high regioselectivity. Compared with the previously
electron-donating substituents. For example, 4-nitro (4e) and described procedures for the Heck reaction of aryl halides as
3-nitrophenylboronic acid (4f) were reacted smoothly with substrates employing a SPO–Pd complex as a catalyst, the
styrene to afford the corresponding products in 75% and 73% method reported here has the advantages of having a stable
yields, respectively (Table 5, entries 5 and 6).
catalyst system, general substrate scope, and mild reaction
conditions (60 °C). Secondly, we also developed the Heck reac-
tion of arylboronic acids with various alkenes employing
Conclusion
In summary, we have developed two new protocols for oxida- N-bromosuccinimide as an additive and catalyzed by Pd(OAc)2,
tive Heck reactions employing Pd(OAc)2 as a catalytic under base- and ligand-free conditions at 25 °C. The yields of
precursor. The first method is based on coupling between the coupled products are moderate to good.
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Supporting Information File 1
General procedure for Heck reactions, preparation of
complex 6 and characterization data.
doi:10.1002/anie.200600442
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-180-S1.pdf]
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Acknowledgements
The authors are grateful to the National Science Council of
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