Two-directional ring-opening cross-metathesis

Article abstract of DOI:10.1039/b906301c

Two-directional ring-opening cross-metathesis of a range of cyclic alkenes with a variety of electron deficient alkenes has been accomplished; it was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a

Full text of DOI:10.1039/b906301c

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Two-directional ring-opening cross-metathesisw
Stephen J. Roe,a Jean-Christophe Legeay,b Diane Robbins,b Pooja Aggarwalb
and Robert A. Stockman*b
Received (in College Park, MD, USA) 31st March 2009, Accepted 15th May 2009
First published as an Advance Article on the web 10th June 2009
DOI: 10.1039/b906301c
Two-directional ring-opening cross-metathesis of a range of
cyclic alkenes with a variety of electron deficient alkenes has
been accomplished; it was found that the process is quite general
and gives complete selectivity for the E,E-dienes, making this a
very useful and high-yielding protocol for two-directional chain
synthesis.
Table 1 Investigation into range of ring-opening cross-metathesis
partners for ketone 1
Over the past 20 years, the two-directional synthesis of
symmetrical chains1 followed by their desymmetrisation2 has
become an established and popular strategy for the synthesis
of complex molecules.3 Cyclic alkenes have long been
exploited as potential long-chain precursors, usually with the
scission of the alkene with ozonolysis4 or Johnson–Lemieux5
type oxidative cleavage to yield chains terminated with carboxylic
acids, aldehydes or acetals.6 Olefin metathesis7 is another type
of reaction which can use cyclic alkenes as substrates to yield
long-chain molecules. Mostly attention in this area has been
on ring-opening metathesis polymerisation (ROMP)8 or on
asymmetric ring-opening metathesis and cross-metathesis
(AROM-CM),9 wherein a cyclic alkene is ring-opened and
just one cross-metathesis is carried out in an asymmetric
fashion. There are surprisingly few examples of using ring-
opening metathesis and double cross-metathesis (RO-CM)10
to furnish non-differentially terminated chains. Our synthetic
programme on developing desymmetrising tandem reactions11
required a range of substrates with chains containing a
functional group in the centre of the chain with identical
electron deficient alkenes at the chain termini. Thus we
decided to investigate further two-directional ring-opening
cross-metathesis of a range of cyclic alkenes decorated with
a range of typical functional groups in order to ascertain the
scope and generality of this approach towards the synthesis of
long-chain molecules.
Yield
t/h (%) Major product
Entry Substrate
1
48 77
2
3
48 72
48 60
4
5
48 30
48 89
4a 73b
6
7
8
144c
48
—
—
Complex mixture
No reaction
9
48 14
a
b
Our initial investigation looked at the RO-CM of cyclooct-
4-en-1-one with a range of singly substituted alkenes. These
results are shown in Table 1. It was found that the acrylate
esters were all successful substrates, with the keto-dienoate
products being isolated in very good yields after 2–3 days at
room temperature. Acrolein was a less reactive coupling
partner giving 30% yield of RO-CM product after two
days. Acrylonitrile was not a good substrate, and gave no
discernable reaction at room temperature. However, good
This reaction was carried out in a microwave at 140 1C. A mixture
of alkene isomers was obtained (2 : 1 : 1 Z,Z : Z,E : E,Z). Elevated
c
temperatures (50 1C) were required to observe CM, and 2 Â 5 mol%
catalyst was used.
yields were obtained with microwave heating.12,3j All of the
reactions were found to be selective for forming E,E-products,
except the acrylonitrile reaction (entry 6), which gave a 2 : 1 : 1
mixture of Z,Z : Z,E : E,Z alkene isomers, which is consistent
with previous observations for acrylonitrile cross-metathesis.13
In the case of the vinylsulfone metathesis, the major products
were of ‘‘dimeric’’ and ‘‘trimeric’’ type, wherein the ruthenium
carbene product of the initial ring-opening metathesis itself
undergoes a ring-opening metathesis with another molecule of
cyclooct-4-en-1-one before a final cross-metathesis, as seen
a School of Chemistry, University of East Anglia, Norwich,
UK NR4 7TJ
b School of Chemistry, University of Nottingham, Nottingham,
UK NG7 2RD. E-mail: robert.stockman@nottingham.ac.uk;
Fax: +44 (0)115 9513564; Tel: +44 (0)115 9513252
w Electronic supplementary information (ESI) available: Experimental
procedures and data. See DOI: 10.1039/b906301c
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Table 2 Two-directional ring-opening cross-metathesis
Entry
1
Substrate
t/h
Yield (%)
20
Major product
72
2
3
48
89
66
52
4
5
48
72
No reaction
50
6
7
48
48
79
63
8
9
89
89
74
72
10
11
48
48
67
58
previously by Grubbs et al.14 Separation of these compounds
and their regioisomers was not possible. It is surmised that the
vinyl sulfone is a slow participant in the cross-metathesis
process, thus resulting in the partial oligermerisation of the
cycloalkene.
alkenes were the least reactive substrates for the reactions,
although with extended reaction times, decent yields of
product could be obtained. In our cases (entries 1–4), we
had substitution on the rings, thus the reactions were slower
than those noted by Blechert et al. on unsubstituted cyclo-
pentene and cyclohexene (6 hours).10a It was found that
7-, 8- and 10-membered rings all underwent the ROM-CM
reaction well. Trans-decene was found to react more slowly
than the other cis-alkene substrates. Cycloocta1,4-diene was
found to undergo a double RO-CM reaction to give the
product which would have required a cyclobutene substrate.
In a previous report by Grubbs et al., cycloocta-1,4-diene was
found to only undergo reaction at one alkene,10b thus this new
Having looked at the two-directional cross-metathesis of
cyclooct-4-en-1-one, we now set out to explore the effect
of ring size and ring substituents on the two-directional
ROM-CM process. Our results are described in Table 2.
We chose to limit the coupling partner to ethyl acrylate
for the investigation into ring size and functional group
compatability. As found by Blechert et al. in their pioneering
work on RO-CM,10a the less strained 5- and 6-membered ring
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procedure offers a complementary type of reactivity for this
substrate. Alcohols, ketones protected amines and epoxides
were found to be tolerated by the reaction conditions.
In conclusion, two-directional ring-opening cross-metathesis
offers a convenient, functional group tolerant and high-yielding
method of forming long-chain dialkenes to give exclusively the
E,E-dienes.
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The authors thank EPSRC (ARF EP/E055346), University
of East Anglia and University of Nottingham for funding.
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