Functionalisation of cycloalkanes: The photomediated reaction of cycloalkanes with alkynes

Article abstract of DOI:10.1016/S0040-4039(01)00390-2

Using a standard mercury vapour lamp or sunlight, and in the presence of a soluble or polymer-bound photomediator such as benzophenone, cycloalkanes can be functionalised by insertion of alkynes containing electron-withdrawing groups into a C-H bond.

Full text of DOI:10.1016/S0040-4039(01)00390-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3211–3213
Functionalisation of cycloalkanes: the photomediated reaction of
cycloalkanes with alkynes
Niall W. A. Geraghty* and John J. Hannan
Chemistry Department, National University of Ireland, Galway, Ireland
Received 20 February 2001; revised 23 February 2001; accepted 7 March 2001
Abstract—Using a standard mercury vapour lamp or sunlight, and in the presence of a soluble or polymer-bound photomediator
such as benzophenone, cycloalkanes can be functionalised by insertion of alkynes containing electron-withdrawing groups into a
CꢀH bond. © 2001 Elsevier Science Ltd. All rights reserved.
The functionalisation of an unactivated alkane is a
fundamental synthetic process of enormous practical
importance.1 It can be achieved using heme and non-
heme based enzyme systems,1 ‘Gif chemistry’2 and a
number of other diverse methods.3 In 1969 Buchi, and
independently Grovenstein, noted that the irradiation
of a cyclohexane solution of ethyl propiolate4 or
dimethyl acetylenedicarboxylate5 gave very small
amounts of products resulting from alkyne insertion
into a CꢀH bond of the cycloalkane. In view of the
reaction times and yields involved—24 h and 5%, and
10% and 14 days, respectively—it is not surprising that
the system has not been revisited for over 30 years. We
have now found that the use of a photomediator such
as benzophenone has a dramatic effect on this system,
reducing the reaction time to a few hours and, in the
case of cyclopentane, giving yields as high as 70%
(Scheme 1). The further observations that the reaction
proceeds in sunlight and that an easily removed, and
potentially recyclable, polymer-bound mediator can be
used, support the conclusion that this photochemical
functionalisation is a potentially important way of acti-
vating a saturated system.
of E- and Z-alkenes as a result of a secondary photo-
isomerization process, the precise ratio being a function
of the reaction time and mediator used. An electron-
withdrawing group on the alkyne appears to be a
prerequisite for reaction, as alkynes with electronically
neutral (phenylacetylene, diphenylacetylene and 3-
hexyne) and electron-donating groups (ethyl ethynyl
ether) do not react. The reaction of monosubstituted
alkynes results in regiospecific reaction at the unsubsti-
tuted alkyne carbon. The process is most efficient for
cyclopentane, with C6ꢀC8 cycloalkanes giving lower
yields of approximately the same size. This effect may
be an example of I strain,6 a concept normally associ-
ated with reactions involving carbocation intermediates,
but which has also been applied to radical reactions.
Disubstituted alkynes are less reactive giving poorer
yields with cyclopentane and cyclohexane, and failing
to react with higher cycloalkanes.
The separation of the product from the mediator
requires chromatography, thus making the process less
attractive from the synthetic point of view. The poly-
mer-bound mediator 17 can however be used thus
allowing pure product to be isolated by a simple filtra-
tion/evaporation sequence. The yield obtained is lower
The reaction is carried out by irradiating a cycloalkane
solution of the alkyne (0.15 M) and the mediator (1
equiv.) through pyrex, using a medium pressure mer-
cury lamp, until none of the alkyne remains (GC).
Evaporation of the cycloalkane and removal of the
mediator by chromatography gives a substituted alkene
as the only low molecular weight product formed. The
synthetic scope of the reaction has been explored in
terms of both the alkyne and the cycloalkane compo-
nent. In general, the reaction (Table 1) gives a mixture
* Corresponding author.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00390-2

3212
N. W. A. Geraghty, J. J. Hannan / Tetrahedron Letters 42 (2001) 3211–3213
Table 1. The photomediateda reaction of alkynes with
Mechanistically, the reaction can be viewed simply as
an example of photosensitization. This would involve
energy transfer from benzophenone, or its equivalent, to
the alkyne which acting as a 1,2-biradical in its triplet
state, could be involved in the key abstraction of hydro-
gen from the cycloalkane. The failure of either phenyl-
acetylene (ET=300 kJ mol−1)8 or diphenylacetylene
(ET=260 kJ mol−1)8 to react in the presence of benzophe-
none (ET=287 kJ mol−1)8 suggests that this is not the
case. Although reaction of the former is precluded on
energy grounds, the sensitisation mechanism fails to
account for the lack of reactivity of the latter. A
mechanism (Scheme 2) in which the benzophenone
abstracts a hydrogen atom from the cycloalkane9 is thus
preferred. In addition to providing a basis for the
reaction in general, this mechanism also accounts for the
significance of an electron-withdrawing group in the
alkyne, as it would allow attack of the nucleophilic10
cycloalkyl radical to be more competitive relative to
hydrogen abstraction. In the absence of an electron-with-
drawing group the latter process occurs exclusively,
resulting in reversion to starting materials. In terms of
how the vinyl radical proceeds to products, the data
currently available do not distinguish between a cage
effect promoted hydrogen abstraction from the benz-
hydryl radical, and hydrogen abstraction from a
cycloalkane molecule which would occur as part of a
chain mechanism.
cycloalkanes: representative examples
Cycloalkane Alkyne
Time (h)
Yield (%)b E:Zc
C5
C6
C7
C8
C5
C6
C7
Ethyl propiolate
2.5
4.5
2.5
3.5
2.5
20
70
43
40
47
50
15
36
1.33
1.53
1.00
1.14
Z only
0.29
1.25
Ethyl propiolate
Ethyl propiolate
Ethyl propiolate
DMAD
DMADd
Isopropyl
2.75
propiolate
3-Butyn-2-one
Methyl propiolate 7.5
Methyl propiolate 32
C5
C5
C7
C5
11.5
18
54
26
3.90e
1.3e,f
1.4g
Ethyl ethynyl
ether
No reaction
C5
C5
Phenylacetylene
Diphenylacetylene No reaction
No reaction
a Rayonet reactor, pyrex vessel, 350 nm lamps, mediator: benzophe-
none, unless otherwise indicated.
b Isolated yield; all compounds were identified spectroscopically and
all new compounds gave satisfactory elemental analyses.
c
For isolated products, unless otherwise indicated.
d Mediator: acetophenone.
e
GC.
f
Polymer-bound mediator.
g Light source: sunlight.
but the experimentally facile nature of the procedure
makes the use of a polymer-bound mediator very
attractive. Another interesting aspect of the system is
the possibility of carrying out the reactions in sun-
light. Although under these conditions the reactions
were again slower and resulted in lower yields, the
experimental set-up used for solar irradiation was not
optimised and so the potential of this approach
remains to be assessed. The formation of small
amounts of two, as yet, unidentified by-products was
also observed in this case.
The range of materials available from this system is
increased by the fact that photochemistry can also be
used to isomerize the a,b-unsaturated ester products
(Scheme 3). Thus, irradiation of the enoates through
quartz (254 nm lamps) gave b,g-unsaturated esters as
expected, whereas under the same conditions the ene-
dioates, derived from the disubstituted acetylenes,
underwent a novel double isomerization. Initially
these reactions were carried out conventionally11 in
the presence of a trace of amine, however, it subse-
quently became clear that this is not required in
many cases.
Thus, in general terms, this photomediated reaction
of cycloalkanes with alkynes constitutes a novel way
of carrying out a fundamentally important process,
the functionalisation of a saturated hydrocarbon. Our
Scheme 2.

N. W. A. Geraghty, J. J. Hannan / Tetrahedron Letters 42 (2001) 3211–3213
3213
Scheme 3.
experiments suggest that the process is synthetically
useful for alkynes with electron-withdrawing sub-
stituents, and for hydrocarbons, which for reasons of
symmetry or reactivity, give a unique radical following
hydrogen abstraction. It is particularly attractive from
the green/clean chemistry point of view as it can utilise
solar radiation and a potentially recyclable polymer-
bound photomediator. Further synthetic and mechanis-
tic studies relating to these aspects of the reaction, and
to the basic reaction itself, are currently under way.
3. (a) Crabtree, R. H.; Habib, A. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 7, pp. 1–38; (b) Taber, D. F. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp.
1046–1047.
4. Buchi, G.; Feairheller, S. H. J. Org. Chem. 1969, 34,
609–612.
5. Grovenstein, E.; Campbell, T. C.; Shibata, T. J. Org.
Chem. 1969, 34, 2418–2428.
6. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1993; p. 769.
7. Blossey, E. C.; Neckers, D. C. Tetrahedron Lett. 1974, 15,
323–326.
Acknowledgements
8. Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of
Photochemistry, 2nd ed.; Marcel Dekker: New York,
1993.
9. Evans, T. R. In Techniques of Organic Chemistry; Leer-
makers, P. A.; Weissberger, A., Eds. Energy Transfer and
Organic Photochemistry. Interscience: New York, 1969;
Vol. 14, p. 312.
The support provided to J.J.H. by the Irish science and
technology agency, Enterprise Ireland, and Limerick
Corporation is gratefully acknowledged.
References
10. Giese, B.; Lachhein, S. Angew. Chem., Int. Ed. Engl.
1982, 21, 768–775.
11. Duhaime, R. M.; Lombardo, D. A.; Skinner, I. A.;
Weedon, A. C. J. Org. Chem. 1985, 50, 873–879.
1. MacFaul, P. A.; Arends, I. W. C. E.; Ingold, K. U.;
Wagner, D. D. M. J. Chem. Soc., Perkin Trans. 2 1997,
135–145 and references cited therein.
2. Barton, D. H. R. Synlett 1997, 229–230.
.
.