New odourless protocols for efficient Pauson-Khand annulations

Article abstract of DOI:10.1039/b506947p

An inexpensive and commercially available odourless additive, dodecyl methyl sulflde, has been shown to be a highly effective promoter in the Pauson-Khand cyclisation of both intra- and intermolecular substrates, affording good to excellent yields of cycl

Full text of DOI:10.1039/b506947p

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C O M M U N I C A T I O N
New odourless protocols for efficient Pauson–Khand annulations
Jack A. Brown, Stephanie Irvine, William J. Kerr* and Colin M. Pearson
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde,
295 Cathedral Street, Glasgow, Scotland, UK G1 1XL. E-mail: w.kerr@strath.ac.uk;
Fax: +44 141 548 4246; Tel: +44 141 548 2959
Received 16th May 2005, Accepted 19th May 2005
First published as an Advance Article on the web 9th June 2005
An inexpensive and commercially available odourless ad-
ditive, dodecyl methyl sulfide, has been shown to be a
highly effective promoter in the Pauson–Khand cyclisation
of both intra- and intermolecular substrates, affording good
to excellent yields of cyclopentenone products.
employment within any P–K processes. Initially, we decided
to investigate the optimum number of equivalents of DodSMe
required, using the N-tosyl 1,6-enyne substrate (Entry 1,
Table 1). Pleasingly, from the outset of this study it appeared
that DodSMe had the desired beneficial promotion effect in
the intramolecular P–K reaction. Furthermore, from these
preliminary reactions we identified that 3.5 equivalents of the
sulfide was optimum, with a good 66% yield of the product
being obtained in this initial example.‡
Following the establishment of this procedure, we examined
several alternative intramolecular P–K annulations and the
results from this study are shown in Table 1. Entries 2 and 3
clearly exemplify that DodSMe is a highly effective promoter
of the intramolecular cyclisation of 1,6-enyne substrates to
produce [5,5]-fused bicyclic cyclopentenones. Furthermore, the
1,7-enyne example (Entry 4) also demonstrates the efficacy of
this technique with the preparation of the less accessible [6,5]-
fused bicyclic system in good yield.
The transition metal-mediated [2+2+1] cycloaddition involving
an alkyne, an alkene, and carbon monoxide represents one of the
most effective and widely utilised methods of generating highly
substituted cyclopentenones in a single step.1 The stoichiometric
cobalt-mediated process, the Pauson–Khand (P–K) reaction,
was first reported in 1971 and was conducted under relatively
harsh thermal conditions.2 Given that the originally utilised
procedures generally only produced low yields, it is perhaps
unsurprising that considerable effort has been exerted on the
development of milder and higher yielding protocols for the
P–K annulation.
In this regard, although the use of dry state absorption,3
ultrasound,4 and phosphine oxides4a have, in certain cases, led to
yield and rate enhancements, their applicability is somewhat lim-
ited. Unquestionably the most significant advance in promotion
techniques has arisen from the use of tertiary amine N-oxides as
promoters,5 allowing reactions to be carried out with elevated
levels of efficiency at room temperature or below. The use of
amines as additives has also been reported by Sugihara and co-
workers,6 however, more recently the same workers have shown
that alkyl methyl sulfides can be employed as effective promoters
of the P–K cyclisation.7 In particular, n-butyl methyl sulfide (n-
BuSMe) in 1,2-dichloroethane was found to be the optimum
additive over the examples presented. This sulfide additive
technique is particularly noteworthy for its ability to promote
several P–K reactions which fail completely or perform poorly
under alternative conditions. Having stated this, although highly
effective, the main drawback of this technique is the volatility,
extremely unpleasant odour, and lachrymatory effect of the low
molecular weight sulfide employed. Moreover, n-butyl methyl
sulfide is both expensive and unrecoverable from the reaction
mixture, and thus cannot be potentially recycled. To circumvent
these issues somewhat, in 2000 we reported on the use of a high
loading polymer-supported sulfide analogue, which was both
odourless and recyclable over a minimum of 5 cycles.8 Although
this proved to be a highly efficient additive and paralleled
the promotion efficacy of n-BuSMe, we were keen to develop
a more economical and practically acceptable solution-phase
sulfide promoter strategy, where the additive would possess
little detectable obnoxious odour. In this respect, we noted
that Node and co-workers had recently reported the use of n-
dodecyl methyl sulfide (DodSMe) and dodecyl methyl sulfoxide
as completely odourless alternatives for Corey–Kim and Swern
oxidations, respectively.9 Given the low volatility and negligible
odour of DodSMe, coupled with its commercial availability and
low cost,† we felt that this agent could be exploited as a more
readily applicable promoter of P–K reactions. We now report
the results from our preliminary studies in this area.
Table 1 Dodecyl methyl sulfide (DodSMe) promoted intramolecular
Pauson–Khand (P–K) annulations
Entrya
1
Product
Yield (%)b
66
2
3
81
71
4
75
a All reactions carried out in 1,2-DCE (0.1 M) at 83 ◦C for 30 minutes.
b Isolated yields following purification.
It should be noted that for each of the examples shown we
also employed the more volatile n-BuSMe. In every case, the
yields obtained utilising our odourless and less costly DodSMe
protocol were at least comparable with those from use of the
considerably less practically convenient sulfide.
To further test this protocol, the stench-free conditions were
applied to a more elaborate system. In this regard, the key P–K
cyclisation of a total synthesis programme currently on-going
within our laboratory, aimed towards the preparation of 2-epi-
a-cedren-3-one, employs the enyne substrate shown in Scheme 1.
Pleasingly, the reaction proceeded to stereospecifically construct
the tricyclic system shown in an excellent 92% yield. Moreover,
when n-BuSMe was employed with the same substrate, a lower
yield of 83% was obtained.
To initiate these studies, DodSMe (97%, Avocado†) was
firstly dried and purified via Kugelrohr distillation prior to
2 3 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 6 – 2 3 9 8
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
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As an additional test of this methodology, we investigated
the use of DodSMe in a regioselective P–K process, recently
developed within our laboratories.11 In the example shown in
Scheme 2, the odour-free technique allowed the acyclic diethyl
allyl phosphonate to react with the alkyne cobalt complex of
phenylacetylene to give the cyclopentenone products in 65%
yield and with a regioselectivity of 3.3 : 1.¶ The use of n-BuSMe
led to a lower 54% yield and a similar level of regioselection.
Scheme 1 DodSMe promoted construction of the core [5.3.1.0] unde-
cane skeleton of 2-epi-a-cedren-3-one.
Following successful application with a panel of intramolec-
ular substrates, we next examined a range of, normally more
demanding, intermolecular reactions. Gratifyingly, as the results
in Table 2 display, the newly developed DodSMe stench-free
promotion conditions operated equally well for the intermolec-
ular processes tested. Utilising the reactive olefin, norbornene,
with various alkyne cobalt complexes led to the requisite
cyclopentenone products in high yield (Entries 1, 2, and 3).
More notably, this technique also produces good yields of cy-
clopentenone products when unstrained and, thus, generally less
reactive alkenes are employed. In this regard, when cycloheptene
was employed (Entry 4), the DodSMe promoter system gave a
yield of 66% with this unreactive alkene.§ As Entries 5 and 6
illustrate, good yields were also obtained with cyclopentene and
2,5-dihydrofuran. These results are particularly pleasing as these
olefinic substrates have previously required dual ultrasound–
amine N-oxide promotion techniques to deliver similar levels of
cyclisation efficiency.4b
Scheme 2 Odour-free sulfide promotion in a regioselective P–K
reaction. Reagents and conditions: DodSMe (3.5 eq.), 1,2-DCE, 83 ◦C,
18 h.
To further enhance the overall practical utility of this
methodology, we attempted to employ the DodSMe additive
in unpurified form and as supplied. Taking the allyl propargyl
ether as a suitable P–K example substrate (Scheme 3), undistilled
sulfide was used in, otherwise, identical fashion to that described
above. Subsequently, the anticipated cyclopentenone product
was obtained in only a slightly reduced yield of 73% (cf. 81%
when using the purified DodSMe). Therefore, this feature further
adds to the practical accessibility of this protocol, especially
when compared to the alternative sulfide promotion techniques.
Table 2 DodSMe promoted intermolecular P–K annulations
Entry
1
Time
Product
Yield (%)c
89
120 mina
Scheme 3 Use of unpurified DodSMe promoter.
2
3
30 mina
40 mina
86
86
In conclusion, conditions have now been developed that
allow inexpensive, commercially available, and directly utilisable
dodecyl methyl sulfide to be employed as an efficient promoter
of both intra- and intermolecular Pauson–Khand cyclisations.
Moreover, this technique is particularly notable as it avoids the
obnoxious smell associated with the previously reported sulfide
promoters, whilst mirroring and, in many cases, enhancing the
excellent promotion efficiencies associated with this class of
reagent.
We thank the University of Strathclyde for a University
Postgraduate Scholarship (J.A.B.), the C.K. Marr Trust for a
Postgraduate Scholarship, Pfizer Global Research and Devel-
opment, Sandwich for generous funding of our research, and
the ESPRC Mass Spectrometry Service, University of Wales,
Swansea for analyses.
4
90 mina
66d
5
6
5 daysb
5 daysb
62e
55e
Notes and references
† DodSMe: £21.90 per 50 g, Avocado Research Chemicals, Heysham,
Lancashire, LA3 2XY, UK; n-BuSMe: £72.00 per 5 mL, TCI Organic
Chemicals, TCI Europe, B-2070 Zwijndrecht, Belgium.
‡ Representative experimental procedure: To a solution of hexacarbonyl-
[l-[4-methyl-N-[2-propen-1-yl]-N-[(2,3-g:2,3-g)-2-propyn-1-yl]benzenesul-
fonamide]]dicobalt-(Co–Co) (0.16 g, 0.3 mmol) in 1,2-DCE (3 ml,
0.1 M) under an atmosphere of N2 was added DodSMe (0.227 g,
1.05 mmol). The reaction mixture was then heated to reflux (83 ◦C) for
30 minutes. After this time, the 1,2-DCE was removed under reduced
pressure and the residue purified directly by silica chromatography
using Et2O as the eluant. The product, 2,3,3a,4-tetrahydro-(p-toluene-
sulfonyl)cyclopenta[c]pyrrol-5(1H)-one, was obtained as a colourless
solid (55 mg, 66%), mp 143–145 ◦C. Analysis was consistent with that
a Reactions carried out in 1,2-DCE (0.1 M) at 83 ◦C. b Reactions carried
out in 1,2-DCE (0.1 M) at 35 ◦C. c Isolated yields following purification.
d Four equivalents of DodSMe employed. e Five equivalents of DodSMe
employed.
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2
2H), 5.99 (s, 1H), 4.34 (d, J = 16.5 Hz, 1H), 4.01–4.06 (m, 2H), 3.15
2
(m, 1H), 2.57–2.66 (m, 2H), 2.45 (s, 3H), 2.06 (dd, J = 17.9 Hz, J =
3.7 Hz, 1H) ppm. All other compounds exhibited satisfactory spectral
and analytical data.
§ It should be noted that Sugihara has reported that cycloheptene cyclises
with the dicobalthexacarbonyl complex of phenylacetylene under n-
BuSMe promoted conditions to give the expected cyclopentenone
product in an 85% yield.7 However, in our hands, we found this to be a
capricious process and, over 5 attempts, the maximum yield obtained for
this cyclisation, with n-BuSMe as the additive, was only a moderate 49%.
In every other instance where n-BuSMe had been previously employed,
the yields obtained with this additive within our laboratory were in line
with those obtained by Sugihara et al.
¶ The specific cyclopentenone regioisomers from the allyl phosphonate
process were identified by 1H NMR spectroscopy and, in particular,
from the splitting patterns of the olefinic and adjacent protons.
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2 3 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 6 – 2 3 9 8