An electron-deficient diene as ligand for palladium-catalyzed cross-coupling reactions: An efficient alkylation of aryl iodides by primary and secondary alkylzinc reagents

Article abstract of DOI:10.1002/adsc.200800118

An electron-deficient diene, L₁, was found to be an effective ligand in facilitating palladium-catalyzed Negishi couplings involving primary and secondary alkylzinc reagents. The reactions took place readily at 60 °C in THF with 5 mol% of a catalyst generated in situ from bis(acetonitrile) palladium dichloride [PdCl₂(MeCN)₂] and L₁, and functional groups such as chloro, bromo, etc. attached to phenyl ring as well as β-H atoms adjacent to the reaction site were well tolerated. The problematic isomerizations in secondary alkyzinc reagents involved in the reactions reported in the literature were also observed in our system when isopropylzinc chloride was employed alone as the nucleophile. However, the isomerization was significantly suppressed when i-Pr₂Zn was utilized in the presence of L₁.

Full text of DOI:10.1002/adsc.200800118

FULL PAPERS
DOI: 10.1002/adsc.200800118
An Electron-Deficient Diene as Ligand for Palladium-Catalyzed
Cross-Coupling Reactions: An Efficient Alkylation of Aryl
Iodides byPrimaryand SecondaryAlkylzinc Reagents
Qiang Liu,a Hui Duan,a Xiancai Luo,a Yang Tang,a Gang Li,a Rong Huang,a
and Aiwen Leia,*
a
The College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067
Phone: (+86)-27-6875-4672; e-mail: aiwenlei@whu.edu.cn
Received: February 22, 2008; Published online: May 19, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An electron-deficient diene, L1, was found tions in secondary alkyzinc reagents involved in the
to be an effective ligand in facilitating palladium-cat- reactions reported in the literature were also ob-
alyzed Negishi couplings involving primary and sec- served in our system when isopropylzinc chloride
ondary alkylzinc reagents. The reactions took place was employed alone as the nucleophile. However,
readily at 608C in THF with 5 mol% of a catalyst the isomerization was significantly suppressed when
generated in situ from bis(acetonitrile)palladium di- i-Pr2Zn was utilized in the presence of L1.
chloride [PdCl
2ACHTREUNG(MeCN)2] and L1, and functional
groups such as chloro, bromo, etc. attached to phenyl
ring as well as b-H atoms adjacent to the reaction Keywords: alkylation; alkylzinc reagents; C C cou-
site were well tolerated. The problematic isomeriza- pling; diene ligand; palladium
À
Introduction
and sterically hindered phosphine and carbene ligands
3
À
have enabled the difficult oxidative addition of Csp
During the past three decades, Pd-catalyzed cross- X,[23] but the formed Csp Pd species is exposed to
coupling reactions have been explored energetically the risk of b-H elimination at the initial step and the
and now rank among the most fruitful transition electronic properties of the ligands are disadvanta-
metal-catalyzed bond formation processes in organic geous to the reductive elimination step.[22]
À
3
À
chemistry.[1,2] The methods for the formation of Csp
The other option is to use ArX as the electrophile
2
2
2
Csp , Csp Csp and C N, etc. bonds have become and Csp3Mas the nucleophile, in which the oxidative
well established after the development of various or- addition of ArX to Pd(0) to form II is facile, but after
ganometallic reagents to facilitate transmetallation transmetallation with a secondary alkylzinc reagent,
processes in the 1970s[3–7] and the applications of elec- the resultant complex III might undergo reductive
tron-rich and/or sterically hindered ligands to mainly elimination to afford the desired product IV (path a),
enhance oxidative additions since the 1990s.[8–20] How- or b-H elimination to form V (path b). Since the alkyl
ever, Csp3-related bond formations are still immature group is a good sigma donor ligand, the reductive
due to sluggish reductive elimination and competitive elimination path is not easy. Consequently, path b is
À
À
fast b-hydride elimination, although the methodolo- very competitive. At this point, V might go through
3
À
gies, especially those invovling Csp Ar bond forma- olefin insertion and reductive elimination to give the
tions, are of great importance both in laboratory syn- isomerized product VIII, or undergo direct reductive
thesis and industrial application.10,21,22
elimination to form the dehalogenated compound VI.
Two options are viable for construction of the Therefore, accelerating the reductive elimination of
3
À
Csp Ar bond utilizing cross-coupling methods. One III is the key to selectively gain the desired product
is to use Csp X as electrophile and ArMas nucleo-
3
IV.[24] p-Acidic ligands, which can accept electrons
À
phile, which would involve oxidative addition of from the metal center, are known from many stoichio-
3
À
Csp X to Pd(0). Recent applications of electron-rich metric studies to be able to facilitate reductive elimi-
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Table 1. The ligand effect in the Csp3-related Negishi cou-
nations.[25–34] For example, olefins were found to be
able to accelerate reductive elimination in the
1960s.[35] However, as a labile type of ligand, olefins
have rarely been applied in catalytic processes.[36–52]
Recently, we have unexpectedly observed that
pling.[a]
3
À
Pd
A
mation with b-hydrogen in high yields,[53] indicating
that dba might play an important role in forming the
3
À
Csp Csp bond. Afterwards, we designed a novel
phosphine-olefin ligand and successfully applied it in
2
3
[54]
À
Csp Csp Negishi coupling. But when a secondary
alkylzinc chloride was used as nucleophile, isomeriza-
tion to form VIII remained problematic. To further
challenge the Csp3-related bond formations and probe
the application of olefin-type ligands in Csp3-related
cross-coupling reactions, we synthesized a bidentate
olefin ligand L1 (Figure 1). Herein, we report our at-
Figure 1. The diene ligand.
[a]
Reactions were carried out with ArI (0.5 mmol), Pd cat.
(0.0025 mmol) and the zinc reagent (1.0 mmol) in THF
at 608C for 2 h.
The selectivity was determined by GC.
DPPBz=1,2-bis(diphenylphosphino)benzene.
tempt to use L1 in Negishi couplings involving pri-
mary and secondary alkylzinc reagents.
[b]
[c]
Results and Discussion
entries 8–13). It was noteworthy that when PdACHTREUNG(dab)2
Ethyl 2-iodobenzoate 1a and cyclohexylzinc chloride was utilized as catalyst, the reaction between 2c and
2a were chosen as benchmark substrates, different 1a resulted in only 58% yield, and the reaction be-
catalytic systems were tested at 608C in THF, and the tween 2d and 1a gave 88% desired product, both
results are compiled in Table 1. PPh3 as ligand gave being inferior to those catalyzed by PdCl
(MeCN)2
(dba)2
3a in 43% yield with 57% 4a, and P(t-Bu)3 promoted and L1, indicating the generality problem of PdACHTREUNG
G
both the yield and selectivity to midrange (Table 1, in this reaction. In addition, the reaction of 1a with 2f
entries 1 and 4). Bidentate ligand dppbz resulted in on a 10-mmol scale was tested with 1 mol% catalyst
poor results, yet dppf achieved a moderate result loading, a 95% isolated yield of the desired cross-cou-
(Table 1, entries 2 and 3). To our delight, the combi- pling product was obtained after 3 h.
nation of 1 equivalent of PdCl
2A
In cross-coupling reactions involving secondary al-
lents of L1 furnished the best result with a 92% yield kylzinc reagents, isomerization could hardly be
of the desired product 3a and only 8% dehalegenated evaded, i.e., path b in Scheme 1 is difficult to
side product 4a (Table 1, entry 6). Pd
well too albeit with slightly inferior yield and selectiv- PdCl
ity (Table 1, entry 5). and 1.5 equiv. of isopropylzinc chloride, the ratio be-
The substrate scope was next investigated under tween ethyl 2-isopropylbenzoate 5a and ethyl 2-pro-
the optimized conditions with PdCl2A(MeCN)2 and L1 pylbenzoate 6a was determined by GC to be 5:1 and
(dab)2 behaved block.[24,54] When the catalyst generated in situ from
ACHTREUNG
2ACHTREU(NG MeCN)2 and L1 was tested in the reaction of 1a
CTHREUNG
as catalysts in THF at 608C, and the results are listed the total yield was 91%. Using dba as the ligand re-
in Table 2. The couplings between 2a and primary sulted in even poorer selectivity (5a:6a=2:1) and
zinc reagents with b-H atoms (2c, 2d, 2e, 2g), without lower total yield (56%). However, the isomerization
b-H atoms (2f) and secondary zinc reagents (2a, 2b) was almost completely inhibited when diisopropylzinc
all took place readily and the yields were good to ex- 4a was used as the nucleophile and the selectivity for
cellent (Table 2, entries 1–7). Furthermore, functional the desired product 5a over the isomerized product 6a
groups such as chloro, bromo, and trifluoromethyl, was up to 97:3 (Table 3, entry 1). Dba afforded 74:26
etc. in the aryl part were all well tolerated (Table 2, selectivity under similar conditions (Table 3, entry 2).
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An Electron-Deficient Diene as Ligand for Palladium-Catalyzed Cross-Coupling Reactions
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Table 2. The Negishi coupling promoted by L1.[a]
[a]
Reactions were carried out with ArI (1.0 mmol), PdCl2ACHTRE(UNG MeCN)2 (0.05 mmol), L1
(0.1mmol) and the zinc reagent (1.5 mmol) in THF at 608C for 2 h.
RZnX was prepared in situ from RMgX and ZnCl2.
Isolated yields.
GC yields.
PdACHTER(UNG dba)2 was used as the catalyst.
[b]
[c]
[d]
[e]
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Qiang Liu et al.
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Scheme 1. Competitive paths of Negishi coupling involving secondary alkylzinc reagents.
Table 3. The Negishi coupling of secondary alkylzinc reagents.[a]
[a]
Reactions were carried out with ArI (0.5 mmol), PdCl2ACHTRE(UNG MeCN)2 (0.025 mmol), L1
(0.05 mmol) and the zinc reagent (1.5 mmol) in THF at 608C for 2 h.
Isolated yields.
GC yields.
R’2Zn was prepared in situ from R’MgBr and ZnCl2.
Determined by GC.
[b]
[c]
[d]
[e]
Yet the catalyst generated in situ from PdACHTRE(UGN dba)2 and sis. So further analysis is ongoing regarding the exact
3 equiv, L1 improved the selectivity to 91:9 (Table 3, effect of L1 in the reaction.
entry 3), clearly exhibiting the effectiveness of L1 in
promoting the reductive elimination over the b-H
elimination pathway (vide supra). Further extensions Conclusions
to diethylzinc 4b and diACHTREU(NG n-hexyl)zinc 4c resulted in
similar selectivities and yields (Table 3, entries 4 and In summary, we have designed and synthesized an
5). electron-deficient olefin ligand L1, and applied it in
Whatꢀs more, a black powder, Catalyst 1, was pre- Pd-catalyzed cross-coupling reaction of aryl iodides
pared from PdCl2 and L1 in MeOH following a similar and alkylzinc reagents. b-H atoms and functional
procedure for synthesis of Pd
tested and found to be similar to that of the catalyst and L1 exhibited obvious effects in inhibiting isomeri-
generated in situ from PdCl2A(MeCN)2 and L1 in sever- zation when secondary dialkylzinc reagents were em-
ACHTREU(NG dba)2. Its activity was groups such as bromo, chloro, etc. were well tolerated,
CTHREUNG
al reactions. However, the spectroscopic data of the ployed as the nucleophiles. Further studies on mecha-
powder were difficult to assign, and it was not stable nistic aspects and extension of the scope are ungoing
enough in solution to get a crystal for structure analy- in our laborotary and will be reported in due course.
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An Electron-Deficient Diene as Ligand for Palladium-Catalyzed Cross-Coupling Reactions
FULL PAPERS
Experimental Section
Supporting Information
The characterization data is available in a Supporting Infor-
mation file.
Synthesis of L1
Dicyclopentadiene (5 g) was heated to 180 8C, the cyclopen-
ta-1,3-diene was then distilled out. To this cyclopenta-1,3-
diene (3.3 g, 50 mmol), diethyl but-2-ynedioate (8.5 g,
50 mmol) was added dropwise. The color of the solution
turned to light yellow. The reaction was exothermic. The
product was distilled under vacuum to afford a colorless
liquid; yield:. 10.4 g (88%).
Acknowledgements
This work was support by National Natural Science Founda-
tion of China (20502020) and the startup fund from Wuhan
University.
Synthesis of Catalyst 1
Palladium(II) chloride (1.58 g, 8.94 mmol), ligand L1 (7.4 g,
31.3 mmol), anhydrous sodium acetate (5.87 g, 71 mmol)
and anhydrous methanol (200 mL) were charged into a 500-
mL oven-dried three-necked flask purged with N2. The mix-
ture was heated to reflux and stirred overnight. The solution
was washed with degassed water. The aqueous phase was
extracted with CH2Cl2. The organic phrase was dried with
anhydrous sodium sulfate and the solvent evaporated under
vacuum. Removal of further solvent using an oil pump pro-
vided a black crystalloid material; yield: 6.7 g.
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