Samarium(ii) iodide-mediated intramolecular pinacol coupling reactions with cyclopropyl ketones

Article abstract of DOI:10.1039/b712542a

The first reported intramolecular pinacol coupling of cyclopropyl ketones has been achieved, demonstrating that cyclisation competes favourably with ring-opening of the cyclopropyl ketyl radical. The Royal Society of Chemistry.

Full text of DOI:10.1039/b712542a

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Samarium(II) iodide-mediated intramolecular pinacol coupling
reactions with cyclopropyl ketones{
Sarah L. Foster, Sandeep Handa,* Michael Krafft and David Rowling
Received (in Cambridge, UK) 15th August 2007, Accepted 28th August 2007
First published as an Advance Article on the web 5th September 2007
DOI: 10.1039/b712542a
an oxyradical (path B) which is subsequently reduced to the
The first reported intramolecular pinacol coupling of cyclopro-
pyl ketones has been achieved, demonstrating that cyclisation
competes favourably with ring-opening of the cyclopropyl ketyl
radical.
corresponding anion. Alternatively, metal oxirane intermediates
may be produced followed by anionic addition to the carbonyl
(path C). Due to the fast rates for 5- and 6-exo-trig radical
cyclisations onto a carbonyl group, pathway B is thought to be the
dominant mechanism for reactions forming small rings.7,9
However, there are no literature examples of intramolecular
pinacol reactions employing cyclopropyl ketones to investigate the
mechanism of this key transformation.{ We have sought to
address this and in this communication report the first examples of
SmI2-mediated pinacol coupling reactions of cyclopropyl ketones,
showing that cyclisation to form a 5-membered ring can compete
favourably with cyclopropyl ring-opening.
Samarium(II) iodide is one of the most widely used single electron
transfer (SET) agents in organic synthesis. Since its introduction to
the synthetic community by Kagan and co-workers,1 this reagent
has been utilised for a variety of transformations, including ketyl–
olefin coupling, Barbier- and Reformatsky-type reactions amongst
many others.2 Despite detailed investigations, the mechanisms of
many reactions mediated by SmI2 remain ambiguous, although
they have been shown to involve a variety of radical, anionic and
organosamarium intermediates.2,3 In this regard, cyclopropyl
ketones have often been employed as mechanistic probes for
SmI2-promoted reactions of ketones, with ring-opening of the
cyclopropane (or lack thereof) taken as evidence for (or against)
the involvement of ketyl radical anions.4 Several examples of
synthetic strategies employing the SmI2-mediated reductive ring-
opening of cyclopropyl ketones have also been reported.5
The three key cyclopropyl ketones 1–3 employed in this study
were produced using the route we have described previously.8 The
diketone 1, was first submitted to our standard pinacol cyclisation
conditions (SmI2 (2.5 equiv.), tBuOH (3 equiv.), 278 uC to room
temperature over 12 h). The only product from this reaction was
the cis-diol 4, isolated in 73% yield after column chromatography
(Scheme 2). The yield and stereoselectivity (established from
NOESY spectroscopy) seen in the formation of 4 is in agreement
with our previous results for an analogue of 1 in which the
One particularly common transformation mediated by SmI2 is
the pinacol coupling reaction of carbonyls to produce 1,2-diols.6
The intramolecular reaction has been widely employed for the
synthesis of carbocyclic systems,2,7 and we have reported its use to
access N-heterocyclic diols.8 The typical mechanisms that have
been proposed for low-valent metal-mediated pinacol reactions are
shown in Scheme 1.6,9 Initial formation of an anionic ketyl radical
can be followed by either dimerisation (path A) to produce the
diol, or by radical addition to another carbonyl group producing
cyclopropyl substituent is replaced by
a
methyl group.8
Surprisingly, we saw no evidence (by 1H and 13C NMR
spectroscopy or MS analysis of the crude reaction mixture) of
the ring-opened product 5, nor of any products that might
conceivably arise from it by subsequent reductions, pinacol
cyclisations or intramolecular aldol reactions.
Although the sole formation of 4 was unexpected, we could not
rule out the possibility of selective reduction of the methyl ketone
in 1, followed by addition of the resulting ketyl radical anion onto
the cyclopropyl ketone. To address this issue, we therefore
examined the pinacol cyclisation of 2 where reduction of the
cyclopropyl ketone is necessitated (Scheme 3). To our surprise, we
again found no evidence for any ring-opened products in this
reaction and the heterocyclic cis-diol 6 was isolated in 71% yield.10
The lack of any ring-opened products from 1 or 2 led us next to
explore the reaction of ketone 3 (Scheme 4). Treatment of 3 with
Scheme 1 Proposed mechanisms for pinacol coupling reactions.
Department of Chemistry, University of Leicester, Leicester, UK
LE1 7RH. E-mail: s.handa@le.ac.uk; Fax: +44 (0)116 252 3789;
Tel: +44 (0)116 252 2128
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data. See DOI: 10.1039/b712542a
Scheme 2
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Scheme 3
Scheme 4
t
Scheme 5
SmI2 (1.25 equiv.) and BuOH (1.5 equiv.) resulted in a low yield
(10%) of the ring-opened product 7, together with appreciable
amounts (60%) of recovered starting material. The yield of 7 could
be increased to 25% by using excess reagents (SmI2 3 equiv.,
tBuOH 4 equiv.) although a significant quantity of 3 was still re-
isolated from this reaction, together with small amounts of 8,
which arises from reductive cleavage of the a-heteroatom from
ketone 3 and/or 7.11 The poor conversion of 3 to 7 is at first glance
surprising, although Skrydstrup and co-workers have recently
unlikely at 0.1 M concentrations of SmI2.I Therefore, the most
likely explanation is that 10 undergoes 5-exo-trig cyclisation at a
faster rate than cyclopropyl ring opening. The rate constant for
ring opening of the methyl cyclopropyl ketyl radical has been
shown to have a lower limit of 107 s21 at 25 uC.14 Whilst data is
not available for the 5-exo-trig cyclisation of ketyl radicals onto
carbonyls, the rate for the corresponding cyclisation of a primary
radical onto an aldehyde is 8.7 6 105 s21 (at 80 uC).15 The fact
that 5-exo-trig cyclisation of 10 competes so successfully with ring-
opening is no doubt due to the nucleophilic nature of the ketyl
radical anion together with chelation by Sm3+, which increases the
electrophilicity of the remaining carbonyl and lowers the entropic
barrier to the cyclisation.
reported similar low reactivity for the ring-opening of
a
cyclopropyl N-acyl oxazolidinone.4b Therefore, as a control
experiment we exposed a 1 : 1 mixture of 2 and 3 to
1
SmI2–tBuOH. Analysis of the crude reaction mixture using H
NMR spectroscopy confirmed our findings on the relative
reactivity of the two substrates, with complete conversion of 2
A 6, compared to ca. 10% conversion of 3 A 7.
In summary, we have shown for the first time that cyclopropyl
ketones can be successfully employed in intramolecular SmI2-
mediated pinacol coupling reactions. The fact that no ring-opened
products are observed in these reactions suggests that the rate of
5-exo-trig cyclisation of a ketyl radical anion onto a ketone is faster
than cyclopropyl ring-opening. In addition, our results point to the
crucial role played by samarium chelation in increasing the rate of
the pinacol cyclisation as well as in reduction of the carbonyl
group by inner-sphere SET.16
On the basis of the successful SmI2-mediated pinacol cyclisation
of diketone 2 (and to a lesser extent 1), we can make the following
observations as to the mechanism of the reaction. The lack of any
ring-opened products seemingly points to reaction path (C)
(Scheme 1) which avoids the formation of ketyl radicals.
However, whilst metal oxirane species have been observed with
transition metals such as vanadium or niobium,12 the direct
formation of these species by Sm(II) has not been reported and so
this pathway is unlikely.§ A plausible reaction pathway (based on
path (B) in Scheme 1) is presented in Scheme 5." In this proposal,
initial co-ordination of the oxophilic Sm(II) to both ketone groups
gives 9 and facilitates inner-sphere13 single electron transfer
generating 10. This would explain the comparatively low reactivity
of 3 to SET as formation of an analogous chelated complex is not
possible. The ketyl radical anion 10 subsequently undergoes 5-exo-
trig cyclisation producing 11 which eventually leads to the product
6. Ring-opening products would potentially arise from the
sequence 10 A 12 A 13. The lack of ring-opened products in
the reaction of 2 may be explained by slow reduction of 12 under
the reaction conditions, allowing ring-opening to be reversible.
However, whilst there is no data available on the reversibility of
ring-opening for alkyl cyclopropyl ketyl radicals, a consideration
of estimated rate constants for the processes involved has led
Guibe´ and co-workers4a to suggest that reversible ring-opening is
We would like to thank the University of Leicester and the
Erasmus programme (MK) for financial support.
Notes and references
{ There are a limited number of reports of successful intermolecular
pinacol coupling reactions of cyclopropyl ketones without ring-opening.
The reactions have been mediated by low-valent Ti reagents, Bu3SnH–
AIBN, or electro- and photochemical methods. However, two cases
involved an aryl-substituted cyclopropyl ketone,17 and aryl cyclopropyl
ketyl anions have been shown to undergo slow and reversible ring-
opening.18 Two further examples involved the dimerisation of dicyclopro-
pyl ketone19 and cyclopropyl 1,2-diketones,20 and the ketyl anions of both
systems are apparently stable.21 In the final example with acetylcyclopro-
pane,22 the authors suggest vicinal association of the ketones to polymeric
low-valent titanium species and concerted electron transfer, thereby
avoiding the formation of discrete ketyl radicals.
§ A Sm(II)-species has been shown to undergo reaction with benzophenone
to give a disamarium(III) benzophenone-dianion complex.23
4792 | Chem. Commun., 2007, 4791–4793
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" The intermediates shown in Scheme 5 may undergo protonation by
tBuOH, although this is presumably discouraged by the chelate effect. We
also cannot rule out reduction of radical 10 to the corresponding anion
followed by anionic cyclisation, although this is unlikely in the presence of a
proton donor.
7 For selected examples, see: G. A. Molander and C. Kenny, J. Org.
Chem., 1988, 53, 2132; J. L. Chiara, W. Cabri and S. Hanessian,
Tetrahedron Lett., 1991, 32, 1125.
8 S. Handa, M. S. Kachala and S. R. Lowe, Tetrahedron Lett., 2004, 45,
253.
I The rate constant for the reduction of 12 may be approximated to 7 6
106 s21 at 25 uC, whilst the rate constant for cyclisation for the free
3-butenyl radical is 0.8 6 104 s21—for a detailed discussion see ref. 4a.
9 H. L. Pedersen, T. B. Christensen, R. J. Enemærke, K. Daasbjerg and
T. Skrydstrup, Eur. J. Org. Chem., 1999, 565.
10 The cis-stereochemistry of diol 6 was established from the alternative
synthesis shown:
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16 Samarium coordination has frequently been invoked to explain the cis-
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ref. 7.
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