Page 2 - From -Arylation of Olefins to Acylation with Aldehydes: A Journey in Regiocontrol of the Heck Reaction

R-Arylation of Olefins to Acylation with Aldehydes Ruan and Xiao

SCHEME 1. Orientation of Addition of Bromobenzene to Olefins SCHEME 2. Orientation of Arylation of Electron-Rich and Neutral
Prior to 1979 Olefins Prior to 1995

using ArOTf or ArX (X = Br, I) in the presence of a silver or
The Heck reaction can give rise to two regioisomeric thallium salt. 5a
products (eq 1). 35 With electron-deficient olefins, such It is now generally accepted that the regioselectivity
as acrylonitriles and acrylates, the linear β-arylated issue exists because there are two competing reaction
products are formed with few exceptions. However, pathways in the Heck reaction, as illustrated by the simpli-
electron-rich olefins, such as acyclic enol ethers and fied mechanism in Scheme 3. 3,5,7,8 The neutral pathway A
enamides, are problematic, usually affording a mixture produces the β product, which is triggered by the dissocia-
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of R-and β-arylated products. In his study of the aryla- tion of a neutral ligand from Pd . In contrast, the ionic
tion, Heck already noted “Double bonds substituted with pathway B, featuring halide dissociation instead, yields the
electron-donating substituents tend to produce signifi- R product.
cant amount of 2-aryl adducts in addition to the major The R-regioselectivity is probably a result of the polarized
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1-aryl isomers.” In a 1979 Account, he summarized the nature of the CdC double bond in an electron-rich olefin
4
orientation of ArBr addition to various olefins. Scheme 1 such as vinyl ethers, in which the HOMO orbital is primarily
shows the results concerning electron-rich and neutral located on the β-carbon and the R-carbon is more positively
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olefins. charged. Coordination to the cationic Pd center would
Since the early studies by Heck and others, extensive enhance this polarization, as illustrated by the resonance
effort has been devoted to controlling the regioselectivity in structures shown in eq 2, rendering the R-carbon more
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the Heck reaction of electron-rich olefins, that is, those susceptible to attack by the migrating aryl moiety. DFT
bearing a heteroatom adjacent to the CdC double bond. calculations show that, when following pathway B, electron-
The progress made in the 197080s was documented by rich olefins indeed tend to afford the R-arylated olefin, and
Daves and Hallberg, 5b revealing that the regioselectivity of this is driven primarily by electrostatic and frontier orbital
the arylation is governed by a range of parameters, includ- interactions. 10 Theoretical studies also revealed how an
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ing the electronic properties of the aromatic rings, ligands, electron-rich olefin is polarized by Pd . Thus, 2,3-dihydrofur-
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∧
and halide additives. an coordinates to a Pd P N complex almost exclusively
A significant advance was made by Cabri in the early through one of the two olefinic carbons, the C 4 atom,
1990s. 5a He found that the regioselectivity could be con- supporting eq 2. 11
trolled by the choice of ligands and the leaving groups of aryl
substrates, regardless of other variables. Thus, enol ethers
were arylated with regioselectivities of >99/1 as measured
by the R/β ratios in DMF, when a bidentate ligand was
employed and the arylating halides were replaced by tri- The mechanism in Scheme 3, although simple, explains
flates, or when a stoichiometric silver or thallium salt was the salient features of the methods used by Hallberg and
added in the case of aryl halides being the arylating Larhed, 3e,12 Cabri, 5a,7a,13 and other researchers 3a,e in their
reagents. This approach has since been exploited in a effort to promote the R-selectivity. Thus, acting as halide
number of reactions including those that lead to bioactive scavengers for aryl halides, silver and thallium salts promote
compounds. 3ce Scheme 2 shows examples highlighted by the ionic pathway B. Similarly, the lability of the PdOTf
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Cabri and Candiani in a 1995 Account which were obtained bond facilitates the formation of the cationic Pd olefin

Vol. 44, No. 8 ’ 2011 ’ 614–626 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 615