Terminal Heck Arylation of Vinyl Ethers
as Ar-Pd precursor under decarbonylative reflux conditions.11
Fair â-selectivities (up to â/R ) 90:10) and good yields (40-
SCHEME 1
6
0%) were obtained with aryl moieties carrying electron-
withdrawing aryl groups. The authors also concluded that the
type of halide coordinating to the metal center in the oxidative
addition intermediate had a profound influence on the regiose-
lectivity, with chloride giving highest selectivity for the linear
1
2
â-product. Since the direct use of aryl chlorides species was
not generally possible at this time, a series of alkyl vinyl ethers
equipped with palladium-presenting amino groups was instead
introduced, allowing highly selective â-arylations via a pseudo
intramolecular insertion process.1 However, for effective use
in synthesis, the development of â-selective procedures for
arylation of electron-rich standard olefins without metal-
coordinating auxiliaries is desirable.
3,14
impressive outcome of the latter reaction, the unique properties
of the P(t-Bu)3 ligand and the high sensitivity of the Heck
reaction to experimental parameters raised a number of impor-
tant questions: (a) Can fine-tuning of a P(t-Bu)3-based arylation
system furnish a general â-selective Heck protocol for unfunc-
tionalized alkyl vinyl ethers and aryl chlorides equipped with
both electron-withdrawing and electron-donating substit-
uents? (b) Is it possible to reduce the long reaction time and
identify a more convenient non-inert procedure? (c) How can
an improved regiochemical outcome be analyzed and under-
stood?
By addition of a novel tetraphosphine-palladium catalyst,
Doucet and Santelli obtained high regioselectivities favoring
the linear isomer using sterically demanding cyclohexyl or tert-
1
5
butyl vinyl ether and electron-deficient aryl bromides. With
unhindered n-butyl vinyl ether only poor R/â ratios were
obtained. In contrast, with a particular poly(ethylene glycol)
polymer (PEG-2000), high terminal selectivities were recently
reported with both aryl bromides carrying EWGs (electron-
withdrawing groups) or EDGs (electron-donating groups) and
simple palladium acetate.16
We have now specifically addressed the transformation
depicted in Scheme 1, following a combined experimental and
computational approach. We herein report that palladium-
catalyzed arylation of the less-substituted â-position of the vinyl
ether double bond can be efficiently and rapidly performed under
air using aryl chlorides, P(t-Bu)3 liberating [(t-Bu3)PH]BF4, and
high-density microwave processing, providing rapid and smooth
A substantial improvement in Heck methodology was the
pioneering discovery by Fu that the electron-rich and bulky P(t-
Bu)3 ligand promotes smooth oxidative addition of aryl chlo-
rides, thus enabling Heck reactions with this class of readily
available starting materials.1 Since the first reports, there has
been a notable interest in further exploring this versatile ligand,
and the corresponding air-stable preligand [(t-Bu3)PH]BF4, both
7,18
2
5,26
in situ heating.
[
Enhanced â-selectivities are observed with
1
9-23
from a mechanistic point of view
and from a preparative
(t-Bu3)PH]BF4 compared to PPh3 and with PEG-200,27 carrying
2
4
perspective. Importantly, Fu investigated the effect of P(t-
Bu)3 with n-butyl vinyl ether in two isolated entries using
p-(dimethylamino)bromobenzene and p-chloroacetophenone as
free hydroxyl terminals, compared to aqueous DMF. Comple-
mentary DFT calculations provide an explanation for the
experimental regiochemical outcome with respect to the para-
substituent of the aryl chloride and the properties of the
phosphine ligand. In addition, the preparative usefulness of this
arylation procedure is illustrated in the key step of a new
synthetic route to Betaxolol, an approved well-known clinically
used â-blocker.
1
7
substrates and Pd2(dba)3 as the palladium source. Both
arylations were performed under an inert atmosphere at ambient
temperature in 1,4-dioxane for 33-48 h. The reaction with the
electron-rich aryl bromide led to a â/R ratio of 20:80, whereas
the activated chloride furnished a higher â/R-selectivity of 91:9
with 5% remaining p-chloroacetophenone. The products were
isolated in high yields, 97% and 87%, respectively, although
not as individual regioisomers but as mixtures. Based on the
Results
Experimental Results. We decided to initiate the investiga-
tion using a series of electronically and sterically different aryl
chlorides (1a-i) with n-butyl vinyl ether (2a) as the model olefin
and aqueous DMF as the solvent in microwave-transparent
reaction vessels sealed under air. The first set of reactions
demonstrated that Cy2NMe was a useful base and that [(t-Bu3)-
PH]BF4 served as a reliable source of P(t-Bu)3 under non-
inert microwave conditions. Among different alternatives of
(
(
11) Andersson, C. M.; Hallberg, A. J. Org. Chem. 1988, 53, 235-239.
12) Andersson, C. M.; Hallberg, A. J. Org. Chem. 1988, 53, 2112-
2
8
114.
(
13) Oestreich, M. Eur. J. Org. Chem. 2005, 783-792.
(
14) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123,
217-8225.
(
15) Kondolff, I.; Doucet, H.; Santelli, M. Synlett 2004, 1561-1564.
(16) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S.; Reddy, N. R.
Org. Lett. 2002, 4, 4399-4401.
(
(
17) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
18) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-
28
palladium(0) sources, Herrman’s palladacycle repeatedly
delivered higher yields and better â-selectivities with slug-
gish p-anisyl chloride than other alternatives [Pd(OAc)2,
Pd(PCy3)2, and Pd2(dba)3]. Without [(t-Bu3)PH]BF4 no produc-
4
211.
(19) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed.
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003, 42, 5749-5752.
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20) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178-13179.
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1
(
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J. Org. Chem, Vol. 71, No. 10, 2006 3897