Vinyl esters as ethylene equivalents in the Khand annulation reaction

Article abstract of DOI:10.1039/a906660h

A preparatively convenient and mild method for modified Khand cycloadditions is described; vinyl esters are employed as the olefinic reaction partner to provide cyclopentenone products more normally obtained with ethylene.

Full text of DOI:10.1039/a906660h

Vinyl esters as ethylene equivalents in the Khand annulation reaction
William J. Kerr,* Mark McLaughlin, Peter L. Pauson and Sarah M. Robertson
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK
G1 1XL. E-mail: cbas69@strath.ac.uk
Received (in Liverpool, UK) 13th August 1999, Accepted 6th September 1999
Table 1 Modified Khand reactions of vinyl substrates with phenylethyne
complex 1a
A preparatively convenient and mild method for modified
Khand cycloadditions is described; vinyl esters are employed
as the olefinic reaction partner to provide cyclopentenone
products more normally obtained with ethylene.
The simple one step cobalt carbonyl mediated annulation of an
alkyne, an alkene, and carbon monoxide to form substituted
cyclopentenones (the Khand reaction)1 has emerged as one of
the most widely used organometal-based transformations in
X
Yield of 3 (%)
organic synthesis. Indeed, in recent years the development of
modified techniques for promoting this reaction has led to its
increased utilisation in a wide variety of synthetic en-
deavours.1,2 In particular, the application of amine N-oxide
promoters has allowed the annulations to be performed under
mild reaction conditions to deliver highly improved product
yields.3 More specifically, studies in our own laboratory have
led to N-oxide techniques which allow the application to both
asymmetric cyclisation strategies4 and to the establishment of
markedly improved procedures for use with gaseous alkenes
such as ethylene.2h,5 Here we report the discovery of a novel use
of non-gaseous ethylene equivalents in the Khand cyclisation.
With a view to gaining access to (poly)oxygenated cyclo-
pentenones and, more especially, with the advent of the mild
amine N-oxide strategies, we envisaged that it would be
possible to employ relatively sensitive vinyl esters as olefinic
substrates. Since the phenylethyne–cobalt complex 1 was
known6,7 to give mixtures of 4- and 5-ethoxy-1-phenyl-
cyclopent-2-en-1-one in poor yield when treated with ethyl
vinyl ether under the generally less effective traditional reaction
conditions, this complex was utilised in our initial experiments
with vinyl acetate 2. To our surprise, under the N-oxide
conditions shown in Scheme 1 the only organic product isolated
was the monosubstituted 2-phenylcyclopent-2-en-1-one 3,
lacking the anticipated acetate functional unit. Despite the
moderate 53% yield, we recognised that this result had
considerable potential as the basis for the development of a
procedure which would employ what could be considered as a
non-gaseous ethylene equivalent in Khand cycloadditions. To
this end, we sought to optimise this modified Khand process by
varying the reaction promoter, the vinyl ester, and the general
reaction conditions.
2
4
5
6
7
AcO
52
50
58
31
54
CF3CO2
BzO
ButCO2
Br
a 9–10 equiv. of NMO·H2O employed.
Based on the results shown in Table 1, vinyl benzoate 5 was
selected for further optimisation. Subsequently, it was estab-
lished that slow (syringe pump) addition of the N-oxide
promoter (NMO·H2O) over a 3 h period led to an excellent 80%
yield of 3 at room temperature.‡ Indeed, the enhanced
efficiency of this modified Khand process now compares
favourably with the optimum yields achieved when using
ethylene gas with Me3N+–O2·2H2O and complex 1; ethylene
reaction at 40 °C and 25–30 atm provides a 71% yield of 3
whilst reaction at room temperature and 1 atm proceeds in 55%
yield.2h,5b
Having developed the slow addition procedure, these condi-
tions were applied to a range of alkyne complexes (Table 2).§
Overall, we have found that the efficiency of the new vinyl
benzoate technique is at least comparable with the optimum
ethylene methods and, in most instances (where a comparison
can be made), significant enhancement in the yield of
cyclopentenone can be realised. A particularly vivid example of
the improved efficacy of the ethylene equivalent method is
provided when THP-protected propargyl alcohol is utilised as
the alkyne substrate; using vinyl benzoate with NMO·H2O at
Table 2 Modified Khand reactions of vinyl benzoate 5 with alkynesa
In the reaction shown in Scheme 1, the ketone 3 had been
obtained using trimethylamine N-oxide dihydrate at 45 °C. On
the other hand, by employing the alternative mild oxidant, N-
methylmorpholine N-oxide monohydrate (NMO·H2O),3a we
found that the same class of transformation could be promoted
at room temperature. In turn, this N-oxide was adopted for use
in comparative experiments. As can be seen from Table 1, in
reactions with complex 1, a range of vinyl esters (2, 4–6) all
successfully afforded the cyclopentenone 3. Additionally, use
of vinyl bromide 7 also led to the formation of the same enone
product.†
R
Product
Yield (%)
Ph
n-C5H11
3
8
9
10
11
12
13
80
77
45
87
80
61
33
Me3SiCH2
THPOCH2
THPO(CH2)2
HO(CH2)2
HOCH2
a Typically the alkyne Co2(CO)6 complex and excess vinyl benzoate (as co-
solvent)¶ are stirred as NMO·H2O (8–10 equiv.) is added over 0.5–3 h as a
solution in CH2Cl2 before stirring is continued at room temp.
Scheme 1 Reagents and conditions: i, Me3N+–O2·2H2O (9 equiv.),
toluene–MeOH (10:1), 45 °C.
Chem. Commun., 1999, 2171–2172
This journal is © The Royal Society of Chemistry 1999
2171

We gratefully acknowledge financial support from the
Carnegie Trust for a postgraduate scholarship (M. M.) and
Pfizer Central Research, Sandwich, for generous funding of our
research endeavours. We also thank the EPSRC Mass Spec-
trometry Service, University of Wales, Swansea, for analyses.
Notes and references
Scheme 2 Reagents and conditions: i, NMO·2H2O (10 equiv.), CH2Cl2, 2 h
addition, room temp.
† Under more traditional conditions of elevated temperature with no N-
oxide promoters, in reaction with complex 1, vinyl bromide had been shown
to give the product of reductive debromination, cyclopentenone 3, in the low
yield of 19% (ref. 8).
‡ Performing the NMO slow addition experiments for the reaction of
complex 1 with vinyl benzoate 5 at a range of higher or lower temperatures
(from 270 to 40 °C) led to less efficient cyclisations and lower yields of
3.
§ All compounds exhibited satisfactory analytical and spectral data.
¶ Excess vinyl benzoate is readily recoverable on completion of the
reaction.
∑ Using thermal conditions with no promoter, THP-protected propargyl
alcohol completely failed to yield any cyclopentenone products when
reacted with ethylene (ref. 9).
room temperature an excellent 87% yield of cyclopentenone 10
is achieved, whereas the maximum yield obtained under the
optimum ethylene conditions was only 33%.2h,5b
∑
As a final example, and to show the utility of the modified
methods in natural product synthesis, we chose to employ
alkyne complex 14. In our previously reported total synthesis of
(+)-taylorione,2h,5a the key step in our sequence towards this
target had been the Khand reaction of 14 with ethylene. When
reacted with vinyl benzoate under the conditions described here
(Scheme 2), complex 14 gave cyclopentenone 15 in a 60%
yield.** This result constitutes an improvement in the carefully
optimised yield of 41% obtained for the same transformation
with ethylene under ambient conditions. On the other hand, it is
not equal to the best autoclave yield of 81% achieved with
Me3N+–O2·2H2O at 40 °C and 25 atm. Nonetheless, it is worth
noting that, in the instances where higher yields are achievable
using gaseous alkenes, autoclave facilities and conditions of
elevated temperature and pressure are required. In contrast, the
ethylene equivalent procedures disclosed here show how cheap,
readily available and easily handled vinyl esters can be
employed under ambient conditions to provide cyclopentenone
products in yields which are at least competitive with and, more
usually, improved over those of the equivalent optimised
ethylene process.
** This result provides the ketal protected form of the recently reported
(+)-nortaylorione (ref. 10) and constitutes a formal total synthesis of this
natural product, which has been prepared from 15 by our novel PPh3/CBr4
ketal deprotection method [ref. 2(h), 5(a), 11].
1 For reviews see: O. Geis and H.-G. Schmalz, Angew. Chem., Int. Ed.,
1998, 37, 911; N. E. Schore, Org. React., 1991, 40, 1; N. E. Schore, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991, vol. 5, p. 1037.
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587; (c) M. M. Bruendl, S. G. Van Ornum, T.-M. Chan and J. M. Cook,
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Motherwell, Chem. Commun., 1999, 183; (f) L. M. Harwood and
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Kerr and U. Lange, Tetrahedron, 1996, 52, 7391 and references cited
therein.
3 (a) S. Shambayati, W. E. Crowe and S. L. Schreiber, Tetrahedron Lett.,
1990, 31, 5289; (b) N. Jeong, Y. K. Chung, B. Y. Lee, S. H. Lee and
S.-E. Yoo, Synlett, 1991, 204; (c) Y. K. Chung, B. Y. Lee, N. Jeong, M.
Hudecek and P. L. Pauson, Organometallics, 1993, 12, 220; (d) M. E.
Krafft, I. L. Scott, R. H. Romero, S. Feibelmann and C. E. Van Pelt,
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McLaughlin, A. S. Nicol, P. L. Pauson and S. M. Robertson,
unpublished observations.
In the developed modified Khand process it is clear that the
isolated cyclopentenones are the products of reduction. In this
respect, the C–O cleavage and subsequent replacement of the
ester oxygen with H must involve a low oxidation state cobalt
species, as this would be expected, under the reaction
conditions, to be the only available reducing agent. Addition-
ally, the reaction only proceeds to give the reduced products
under inert (N2) atmospheres. However, when using vinyl
acetate 2 with complex 1 in air only a very low yield (7%) of the
5-acetoxycyclopentenone is obtained. We believe that the
required hydrogen atom to complete the reduction process is
supplied from water (e.g. from the hydrated N-oxide). This
theory was supported when the reaction of 1 and 2, promoted by
anhydrous NMO, was performed in the presence of excess D2O
and exclusively yielded 5-deuterio-2-phenylcyclopent-2-en-
1-one. Such regioselective incorporation of deuterium also
implies that the reductive cleavage occurs after the coupling of
the alkyne and alkene.
In summary, we have developed a novel method by which
vinyl esters can be utilised as non-gaseous ethylene equivalents
in the Khand annulation. The mild conditions and simple
techniques employed provide significant advantages, both in
terms of practical convenience and, in the majority of cases
explored, reaction yield, over the corresponding gaseous alkene
procedures.
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9 H. J. Jaffer, PhD Thesis, University of Strathclyde, 1982.
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A. J. Marsaioli, Tetrahedron: Asymmetry, 1997, 8, 1833.
11 C. Johnstone, W. J. Kerr and J. S. Scott, Chem. Commun., 1996, 341.
Communication 9/06660H
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Chem. Commun., 1999, 2171–2172