A short synthesis of conjugated unsaturated amides and esters via triphenylphosphine-catalysed isomerisation of acetylenic pentafluorophenyl esters

Article abstract of DOI:10.1039/a704927g

Isomerisation of acetylenic pentafluorophenyl esters in the presence of phosphines gives rise to activated dienoic acids, which can be coupled directly with amines and alcohols in a simple one-pot procedure.

Full text of DOI:10.1039/a704927g

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A short synthesis of conjugated unsaturated amides and esters via
triphenylphosphine-catalysed isomerisation of acetylenic pentafluorophenyl
esters†
Uli Kazmaier
Organisch-Chemisches Institut der Universita¨t, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Isomerisation of acetylenic pentafluorophenyl esters in the
presence of phosphines gives rise to activated dienoic acids,
which can be coupled directly with amines and alcohols in a
simple one-pot procedure.
especially for the syntheses of strained cyclic peptides.18 The
isomerisation of these esters proceeds under much milder
conditions (Table 1), because of the strong electron-with-
drawing effect of the fluorine atoms and the resulting activation
of the triple bond.
Highly unsaturated carboxylic and fatty acids are very common
in different types of natural products.1 Many of these sometimes
very complex compounds show interesting biological activities
and are applied as antibiotics.2 Unsaturated esters are found as
side-chains of sugars,3 such as the antifungal active papula-
candins,4 or as parts of macrocyclic lactones.5 Unsaturated
amides find application as insecticides,6 and modified peptides7
and cyclopeptides8 are highly interesting from a pharmaceutical
point of view.
Using 10 mol% of PPh3 the isomerisation can be carried out
at room temperature and under neutral conditions, which is
important for the application of this procedure to sensitive
substrates. Various acetylenic esters were investigated and, in
general, the isomerisation was complete after stirring the
reaction mixture overnight. The (E,E)-diene is formed almost
exclusively (93–99%, as determined by NMR or GC analyses).
If the esters tolerate higher temperatures, the amount of
phosphine can be dramatically reduced, as shown with the last
entries.‡ The higher temperatures are necessary for acceptable
turnovers. From a synthetical point of view, it is convenient to
carry out the isomerisation with 5% of phosphine at 50 °C,
because under these conditions most reactions are complete
after 4–5 h. The isomerisation only occurs in the presence of
phosphines. No reaction was observed in the presence of tertiary
amines, as determined by GC analysis, which is especially well-
suited to monitoring the reaction progress. Obviously, the
isomerisation proceeds directly from the acetylene to the
conjugated diene. Allenic intermediates, as postulated in
transition metal catalysed isomerisations,13 could not be
detected in any of the investigated examples.
In general, the isomerisation proceeds in a very clean manner
and without side reactions. Therefore the isomerised active
esters can be coupled directly with nucleophiles in a one-pot
procedure (Scheme 2).§ Thus conversion to the corresponding
amides 7, e.g. by reaction with amino acid esters 8 and peptides
9, occurs at room temperature. To use this protocol in peptide
syntheses, it would also be of interest to couple the dienoic acid
to free amino acids, because the acylated amino acids obtained
can be used directly for the next coupling step with further
amino acids or peptides. This approach can be realized by
heating the desired amino acid in toluene with bis(trimethyl-
silyl)acetamide (until the amino acid is completely dissolved)
giving rise to the corresponding silyl ester 10. The acylated
amino acid 11 is obtained after acidic workup of the reaction
mixture. The increased reactivity of the pentafluorophenol
esters towards alkyl esters also allows their regioselective
isomerisation and coupling, as illustrated with substrate 12
(Scheme 3).
Apart from eliminations9 and Knoevenagel condensations,10
Wittig and Horner–Emmons11 reactions are used frequently for
the synthesis of conjugated unsaturated carboxylic acids.
Besides these well established approaches, organometallic
transformations, such as cross coupling reactions12 or metal-
catalysed isomerisations of acetylenes to dienes,13 are also
becoming more and more important.
Recently we described a new isomerisation of acetylenic
carbonyl compounds in the presence of triphenylphosphine.14
Similar results were obtained by Guo and Lu.15 While
acetylenic ketones can easily be isomerised in the presence of
5–10% of PPh3 at 80–100 °C (Scheme 1), the corresponding
less reactive esters react only in the presence of weak acids (e.g.
acetic acid). If the reaction is applied to activated enynes or
diynes, conjugated trienes or tetraenes can be obtained as
well.16
The reaction probably starts with a nucleophilic addition of
the phosphine on the activated triple bond, followed by a set of
proton transfer steps. Perhaps these steps are accelerated by
weak acids. This mechanism seams reasonable, because several
of the possible intermediates could be trapped and used for
further reactions, e.g. Michael additions.17
This procedure gives easy and cheap access to these
interesting compounds, although problems may arise during the
isomerisation process with acid- or thermo-labile compounds.
Acetylenic amides only react, if at all, under even more drastic
conditions,14 which may not be ‘survived’ by sensitive amides,
like peptides.
For an application of this process to natural product synthesis
it would be desirable to work under mild conditions and/or to
combine the isomerisation of an activated acetylene with a
successive esterification (or amide formation), probably in a
one-pot procedure. This approach can be realized by using the
corresponding acetylenic pentafluorophenol esters. These rela-
tively stable esters are used frequently in peptide syntheses,
Table 1 PPh3-catalysed isomerisations of 5
PPh3 (%)
T/°C
t/h
Conversion (%)
10
10
10
5
25
25
25
50
50
2
14
14
4
43
67
97
quant.
46
R
R
R′
PPh3
heat
R′
O
O
1
4
0.1
100
40
59
Scheme 1
Chem. Commun., 1997
2305

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The reaction is almost independent of the solvent used.
Alcohols, especially sterically hindered ones, do not react under
the conditions of amide formation, and they can be used as
solvents for amines which are not soluble in less polar solvents.
Nevertheless, esterification is possible under transesterification
conditions, as described by Seebach et al.19 (Scheme 4). In the
presence of LiBr and 1,4-diazabicyclo[2.2.2]octane (DABCO)
or DBU, acylated polyols (e.g. 14) and steroids (e.g. 15) can be
obtained. The formation of the corresponding Weinreb am-
ides20 also needs higher temperatures (80 °C) in comparison to
the reaction of other amines.
Forschungsgemeinschaft and the Fonds der Chemischen In-
dustrie is gratefully acknowledged.
Footnotes and References
* E-mail: ck1@ix.urz.uni-heidelberg.de
† Dedicated to Professor Huttner on the occasion of his 60th birthday.
‡ In these cases the reaction should be carried out under argon to avoid
oxidation (deactivation) of the catalyst.
§ General procedure for the isomerisation/amide formation: 1 mmol each of
alkynoic acid and pentafluorophenol were dissolved in 5 ml CH2Cl2 and,
after addition of 0.1 mmol of DMAP, the solution was cooled to 220 °C. A
solution of 1 mmol DCC in 1 ml CH2Cl2 was added and the mixture was
allowed to warm to room temperature overnight. After filtration and
evaporation of the solvent the residue was dissolved in 5 ml of toluene. After
addition of 0.05 mmol of PPh3 the solution was warmed to 50 °C for 5 h.
After cooling to room temperature, 1–1.5 mmol of the corresponding amine
were added and the mixture was stirred at room temperature overnight. The
obtained crude product was purified by flash chromatography or crystal-
lisation.
Professor Dr G. Helmchen is thanked for his generous
support of this work. Financial support by the Deutsche
R
OSiMe3
OPFP
Phe +
NSiMe3
O
v
N
H2N
CO2SiMe3
Ph
i
CO2Bn
R
O
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O
H
N
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N
H
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Pri
O
9
Scheme 2 Reagents and conditions: i, PPh3, toluene, 50 °C, 5 h; ii, Pro-
OBn, 74%; iii, piperidine, 81%; iv, Val-Gly-OMe, 75%; v, toluene, 110 °C,
4 h; vi, H3O+, 63%
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Ph
O
CO2But
CO2But
NH2
CO2PFP
i, ii
N
H
O
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12
13
Scheme 3 Reagents and conditions: i, PPh3 (5%), 50 °C, 5 h; ii, Phe-NH2,
room temp., 14 h, 66% over two steps
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O
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OPFP
O
OH
O
i
H
OSiMe2But
O
H
H
O
O
O
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O
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14
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Scheme 4 Reagents and conditions: i, Cortison, DBU, LiBr, DMF, toluene,
80 °C, 14 h, 64%; R*OH, DBU, LiBr, toluene–THF, 80 °C, 10 h
Received in Liverpool, UK, 9th July 1997; 7/04927G
2306
Chem. Commun., 1997