Two-directional cross-metathesis

Article abstract of DOI:10.1039/b907720k

Two-directional cross-metathesis of a range of α,ω dienes 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 h

Full text of DOI:10.1039/b907720k

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Two-directional cross-metathesis†
Annabella F. Newton,a Stephen J. Roe,b Jean-Christophe Legeay,a Pooja Aggarwal,a Camille Gignoux,a
Nicola J. Birch,b Robert Nixon,c Marie-Lyne Alcarazc and Robert A. Stockman*a
Received 16th April 2009, Accepted 20th April 2009
First published as an Advance Article on the web 28th April 2009
DOI: 10.1039/b907720k
Table 1 Optimisation of conditions
Two-directional cross-metathesis of a range of a,x dienes 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
elongation.
Two-directional synthesis, wherein a symmetrical substrate chain
is elongated either sequentially or simultaneously in two-directions
by the same reaction, has become a widely used tactic in organic
synthesis.1 As two reactions are taking place on the same substrate,
it is preferable for efficient synthesis that the type of reaction
used to homologate is robust and high yielding. Over the past
few years we have explored the tactic of combining two-directional
synthesis and tandem reactions for the concise synthesis of natural
products.2 These syntheses used Horner-Wadsworth Emmons
reactions for two-directional homologation of dialkenes by a
two-step process involving initial oxidative cleavage followed by
reolefination. More recently we have sought to shorten this
sequence by the use of cross-metathesis.3 Our recent synthesis
of histrionicotoxin4 used this approach, resulting in the shortest
synthetic route to this natural product to date. With this initial
success, we set about investigating the scope and generality of
this type of process,5 and herein we disclose our findings on the
two-directional homologation of a,w-dienes by cross-metathesis.
The conversion of diene 1 to dienoate 2 was used as our
optimisation platform, as this transformation forms part of our
strategy towards the synthesis of pinnaic acid,6 and previously
required 4 steps to accomplish (ketone protection, oxidative
cleavage, olefination, deprotection). We investigated two cross-
metathesis catalysts, Grubbs second-generation catalyst7 (3) and
the Hoveyda-Blechert catalyst8 4 (also known as the Grubbs-
Hoveyda second generation catalyst). The results of our study
are shown in Table 1.
Cat.
Loadinga
Temp Time
Yield mono Yield double
Entry Cat.
n
X
(◦C)
(h)
CM (%)
CM (%)
1
2
3
4
5
3
4
4
4
4
2
2
4
2
2
2.5 20
2.5 20
1.0 20
0.5 20
2.5 40
120
120
120
120
60
44
—
—
31
90
83
67
79
—
a n = number of additions of catalyst portion, X = catalyst portion in
mol%.
portions, with the second portion being added in all cases 24 hours
after the start of the reaction. It was found that having more
additions of catalyst were not beneficial (entry 3). Similarly heating
of the reaction was not found to influence the rate significantly.
Thus it was determined that two additions of 2.5 mol% of catalyst
4, with the reaction being run at room temperature gave an
excellent yield of the dienoate 2. With this information in hand, we
then turned our attention to the exploration of the two-directional
cross-metathesis of diene 1 with other alkenes. Our results are
summarised in Table 2.
Acrylate esters were found to be good substrates for the reaction,
with even the bulky tert-butyl acrylate participating well. Acrolein
was also found to undergo the cross metathesis in 63% yield, with
no mono-cross metathesis product being observed. Methyl vinyl
ketone was found to be a less reactive substrate, with substantial
amounts of mono-cross metathesis product being isolated under
the standard conditions. It was found, however, that upon heating
the reaction in a microwave (120 ◦C, 3.5 hours), good yields
could be achieved. This is in contrast to ethylvinylketone, which
reacted slowly but cleanly under the standard conditions to yield
87% of the doubly homologated product. It is unclear as to
why there is such a difference between these two examples, and
one can only surmise that methylvinylketone is more prone to
The reactions were all carried out at room temperature in
dichloromethane using 6 equivalents of ethyl acrylate. It was found
that the reactions were relatively slow, but very clean, with minimal
byproducts being formed when catalyst 4 was used. The use of
catalyst 3 resulted in slower reaction, with incomplete conversion
to the dihomologated product. Due to the length of the reactions,
it was found that addition of the catalyst was best achieved in two
aSchool of Chemistry, University of Nottingham, Nottingham, NG7
2RD, UK. E-mail: robert.stockman@nottingham.ac.uk; Fax: +44 (0)115
9513564; Tel: +44 (0)115 9513252
bSchool of Chemistry, University of East Anglia, Norwich, NR4 7TJ, UK
cAstraZeneca, Bakewell Road, Loughborough, Leics, LE11 5RH, UK
† Electronic supplementary information (ESI) available: Experimental
procedures and data. See DOI: 10.1039/b907720k
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Table 2 Investigation into range of cross-metathesis partners for ketone1
Entry
1
Substrate
Time (hrs)
120
Yield (%)
78
Major Product
2
3
4
5
6
7
8
120
120
120
3.5
120
96
85
78
63a
76b
87
73c
47
264
9
120
120
—
—
No reaction
No reaction
10
11
192
35
a 5 equivalents of acrolein were used. b This reaction was found to give mainly mono-CM product at room temperature, so microwave conditions (120 ◦C)
were used. c Elevated temperatures (50 ◦C) were required to observe CM, and 2 ¥ 5 mol% catalyst was used.
self-condensation and polymerization, and thus the long reac-
tion times required at ambient temperatures allow these other
processes to take place. Vinyl sulfone was also found to require
heating, but this time 50 ◦C was found to be sufficient. Vinyl
pinacol borane was found to give predominantly the mono-
substituted product. Electron rich alkenes styrene and allyl
trimethylsilane were found not to participate in the reaction,
although allyl bromide was a successful substrate for double cross-
metathesis, albeit in only 35% yield.
Having looked at the two-directional cross-metathesis of ketone
1, we now set out to explore the effect of chain length and
centrepiece functionality on the two-directional cross metathesis
process. Our results are described in Table 3.
In general, substrates with alcohol functionality (entries 1, 3,
8, Table 3) were found to be detrimental to the reaction when
compared with the corresponding ketone substrates (entries 2,
5, 11). Indeed, in the case of Entry 8 it was found that the
alcohol substrate gave the product of mono cross-metathesis
as the main product. The lack of reactivity is likely due to
internal co-ordination of the alcohol to the alkylidene carbene,
slowing the cross-metathesis. The reactions with alcohols were
also noticeably more prone to decomposing the starting materials
compared to the ketone substrates. The exception to this was
Entry 2, where due to the proximity of the ketone functionality
to the alkenes, the majority of product was the result of the
alkene functionality moving into conjugation with the ketone,
thus generating a mixture of products, whereas the alcohol variant,
(entry 1), actually underwent double cross-metathesis in moderate
yield. Protected alcohol functions (Entry 8) and protected amines
(Entries 5, 6, 9) were found to be good substrates, as was an amide
function (Entry 11). It was found that if the starting material
allowed the formation of a 6-membered ring through ring-closing
metathesis, then this was the major product obtained (Entry 6).
This observation might suggest that the reaction proceeds via
initial ring-closing metathesis, followed by ring-opening cross
metathesis. However, ring-closing metathesis products were not
observed in any of the other experiments, although a few percent
of mono-cross metathesis products were occasionally observed.
We suggest therefore, that in the case of Entry 7, ring-closing
metathesis is a competitive pathway to the first cross-metathesis,
but the 6-membered product of ring-closing metathesis acts as
a thermodynamic sink. Around 18% of double-cross metathesis
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Table 3 Investigation into range of cross-metathesis partners for ethyl acrylate
Entry
1
Substrate
Time (hrs)
89
Yield (%)
44a
Major Product
2
3
89
8
120
14
4
5
6
7
120
190
48
57
66b
77
77
48
8
9
96
120
144
120
144
35
67
89
90
79
10
11
12
13
14
144
144
—
—
No reaction
No reaction
a 12 equivalents of ethyl acrylate were used. b 2 ¥ 4.3 mol% catalyst and 6 equivalents of ethyl acrylate were used. c This reaction was carried out at reflux.
product was observed in this reaction. Polar functionalities such as
oxime and amine (entries 12,13) were found to not be compatible.
Presumably these functionalities bind the catalyst, thus removing
it from the catalytic cycle.
The authors thank EPSRC (EP/D500877, EP/E055346), As-
traZeneca, University of East Anglia and University of Notting-
ham for funding.
In conclusion, two-directional cross-metathesis offers a conve-
nient, fairly functional group tolerant and high-yielding method
of doubly homologating a,w dialkenes to give exclusively the E,E-
dienes, with the exception of 1,7-dienes, which preferentially give
the product of ring-closing metathesis.
Notes and references
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Schreiber, Acc. Chem. Res., 1994, 27, 9.
2 (a) R. A. Stockman, A. Sinclair, L. G. Arini, P. Szeto and D. L. Hughes,
J. Org. Chem., 2004, 69, 1598; (b) M. Rejzek, R. A. Stockman and
2276 | Org. Biomol. Chem., 2009, 7, 2274–2277
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D. L. Hughes, Org. Biomol. Chem., 2005, 3, 73; (c) S. J. Roe and R. A.
Stockman, Chem. Commun., 2008, 3432.
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Beilstein J. Org. Chem., 2008, 4, 4; J.-C. Legeay, W. Lewis and R. A.
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5 For some one-off examples of two-directional metathesis see: J. S. Clark
and O. Hamelin, Angew. Chem., Int. Ed., 2000, 112, 380; S. Purser,
T. D. W. Claridge, B. Odell, P. R. Moore and V. Gouverneur, Org. Lett.,
7 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
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Tetrahedron Lett., 2000, 41, 9973.
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The Royal Society of Chemistry 2009
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