A domino copper-catalyzed C-O coupling-Claisen rearrangement process

Article abstract of DOI:10.1021/ja034809y

A practical method for the diastereoselective generation of two adjacent quarternary stereocenters by combining a copper-catalyzed C-O coupling reaction with a subsequent Claisen rearrangement in a one-pot domino process is described. Furthermore, an experimentally simple method for the stereoselective synthesis of a variety of different types of vinyl ethers is delineated using the same catalyst system. Copyright

Full text of DOI:10.1021/ja034809y

Published on Web 04/04/2003
A Domino Copper-Catalyzed C-O Coupling-Claisen Rearrangement Process
Gero Nordmann and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 21, 2003; E-mail: sbuchwal@mit.edu
Table 1. Preparation of Allyl Vinyl Ether 3
The Claisen rearrangement is among the most powerful methods
for the construction of carbon-carbon bonds.1 Since its discovery
in 1912,2 the lack of a general process for the stereoselective
synthesis of simple allyl vinyl ethers for the classical aliphatic
Claisen rearrangement3 has frustrated synthetic chemists.1d,4 Herein,
we describe a novel domino process that consists of a copper-
catalyzed C-O bond coupling and a subsequent Claisen rearrange-
ment (Scheme 1).5,6 Additionally, we describe the synthesis of a
isolated yield (%)
Scheme 1
entry
ligand
temp (°C)
atm
air
air
air
air
air
argon
argon
conv. (% GC)
3
4
1
2
3
4
5
6
7
II
II
II
III
III
II
80
100
120
80
60
80
78
92
95
>98
74
66
>95
40
31
1
68
56
42
5
7
32
63
4
0
6
variety of different vinyl ethers applying similar methodology.
An experimentally attractive means for the preparation of allyl
vinyl ethers I involves the stereospecific coupling of a vinyl halide
and the appropriate allylic alcohol. In 1992 Keegstra reported the
coupling of sodium methoxide and butoxide with a variety of vinyl
halides in the presence of catalytic amounts of copper bromide.7
To our knowledge, this is the only report of a copper-catalyzed
coupling of alcohols with vinyl halides.8 We recently described
the Ullmann-type coupling of aliphatic alcohols with aryl iodides.9
The reaction conditions for this transformation (10 mol % CuI, 20
mol % 1,10-phenanthroline II, 1.5 equiv of Cs2CO3)10 also proved
to be successful for the coupling of allylic alcohol 1 with vinyl
iodide 211 at 80 °C to give 40% of the allyl vinyl ether 3.
Interestingly, the corresponding Claisen rearrangement product was
also isolated in 7% yield (Table 1, entry 1). Complete retention of
configuration of the double bond geometry in the vinyl ether
product, as seen by Keegstra,7 supports the hypothesis that a
catalytic process, rather than a simple nucleophilic substitution is
operative. Raising the reaction temperature from 80 to 100 °C led
to an increased overall yield (3 + 4, combined 63% isolated yield).
Enal 4 was isolated in 32% yield as a mixture of diastereoisomers
in a 1:1 ratio, the formation of which is presumably due to
epimerization of the rearrangement product under the basic reaction
conditions. Performing the reaction at 120 °C led to almost exclusive
formation of 4 in 63% yield (1:1 mixture of diastereomers). In a
preliminary screening of different ligands, we found that tetra-
methyl-1,10-phenanthroline III is superior to 1,10-phenanthroline
II. Its use, at 80 °C, for the coupling of 1 and 2 led to full conversion
of the substrates and an improved yield of the desired allyl vinyl
ether 3.
II
120
62
resulted in a decrease of the diastereoselectivity or in lower yields.
The same transformation could also be induced through microwave
irradiation (results in brackets) in a much shorter time.13
To evaluate the scope of the coupling-rearrangement process,
we set out to apply the method to the diastereoselective generation
of a compound with a tertiary center vicinal to a quarternary one,
as well as one with two adjacent quarternary stereocenters.14
Particularly appealing in this context was the idea of a domino
process15 combining copper-catalyzed C-O bond formation and
thermal Claisen rearrangement. Subjecting allylic alcohol 6 and
vinyl iodide 816 to the reaction conditions shown in Table 2 led to
the clean formation of the desired rearrangement product 9 in 55%
yield with high stereochemical purity (dr ) 92:8, Table 2, entry
1). Using alcohol 7, in which the double bond geometry is of the
(Z)-configuration, produced the expected diastereomeric product
10 of opposite relative configuration in 68% isolated yield. To
further extend the scope of the chemistry to the synthesis of ketones,
vinyl iodide 1116 was used as a substrate and the corresponding
ketone 12 was isolated in 59% yield. Surprisingly, alcohol 7 did
not lead to consistent results in the analogous transformation.
Several attempts to convert it to 13 led to very low conversion of
the starting vinyl iodide 11 (<40%). We next subjected geraniol
14 and nerol 15 to the aforementioned reaction conditions. In
separate experiments, the aldehydes 16 and 17 as well as the ketones
1817 and 19, bearing two adjacent quarternary stereocenters, could
be isolated in good yields and stereoselectivities. That the dr of
the ketone products (Table 2, entries 3, 4, 7, and 8) were slightly
lower than for the corresponding aldehydes (Table 2, entries 1, 2,
5, and 6), can be attributed to the lower stereochemical purity of
the starting vinyl iodide 11 (E/Z ) 88:12) compared to that of 8
(E/Z > 95:5).
As expected, the allyl vinyl ether 3 could be transformed in a
separate step to the aldehyde 5 in high yield and high diastereo-
selectivity (eq 1).12 Longer reaction times or higher temperatures
The Cu/III catalyst was also able to successfully concatenate a
variety of other types of alcoholssaliphatic, propargylic and
benzylicswith vinyl iodides (Table 3, entries 1-3) under mild
9
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J. AM. CHEM. SOC. 2003, 125, 4978-4979
10.1021/ja034809y CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Domino C-O Bond Formation-Claisen Rearrangement
these reaction conditions, presumably via â-elimination due to the
presence of a hydrogen atom in the trans-position at the double
bond of the vinyl halide; no coupling products could be isolated in
these cases.
In summary we have described a simple method for the formation
of allyl vinyl ethers and their in situ Claisen rearrangement to form,
in a diastereoselective fashion, compounds with vicinal quarternary
stereocenters.
Acknowledgment. We thank the National Institutes of Health
(GM 45906) for supporting this work. We are grateful to Pfizer,
Merck, Bristol-Myers Squibb, and Lundbeck for additional funds.
We also thank Personal Chemistry AB for loaning us the Smith-
Synthesizer.
Supporting Information Available: Experimental procedures,
characterization data for all unknown compounds, and X-ray crystal-
lographic data for the semicarbazone of 16 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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conditions. A vinyl bromide was also successfully subjected to the
reaction conditions, albeit in slightly lower yield. The reaction times
for the different types of alcohols vary significantly, generally in
the order aliphatic > allylic = propargylic > benzylic. One
limitation that we note is that (Z)-vinyl iodides decompose under
(17) In this case, using 1,10-phenanthroline II instead of 3,4,7,8-tetramethyl
1,10-phenanthroline III as the ligand led to a significantly lower yield
for the transformation (31% isolated yield).
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