The Pauson-Khand reaction of medium sized trans-cycloalkenes

Article abstract of DOI:10.1039/c3cc41005f

Medium sized trans-cycloalkenes are unusually reactive in the intermolecular Pauson-Khand reaction (PKR) with regard to typical monocyclic alkenes. This is due to the ring strain imparted by the E stereochemistry. The PKR of these alkenes offers a modular, regioselective and straightforward entry to trans fused [n.3.0] bicyclic scaffolds (n = 6-8). The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc41005f

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The Pauson–Khand reaction of medium sized
trans-cycloalkenes†
Cite this: Chem. Commun., 2013,
49, 3055
a
a
a
ab
Agust´ı Lledo,* Aida Fuster, Marc Reves, Xavier Verdaguer and Antoni Riera*ab
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Received 5th February 2013,
Accepted 26th February 2013
DOI: 10.1039/c3cc41005f
www.rsc.org/chemcomm
Medium sized trans-cycloalkenes are unusually reactive in the
intermolecular Pauson–Khand reaction (PKR) with regard to typical
monocyclic alkenes. This is due to the ring strain imparted by the
E stereochemistry. The PKR of these alkenes offers a modular,
regioselective and straightforward entry to trans fused [n.3.0]
bicyclic scaffolds (n = 6–8).
Fig. 1 Reactive alkenes for the intermolecular PKR.
The Pauson–Khand reaction (PKR) is the method of choice for a
straightforward assembly of cyclopentenone fragments from an
alkene and an alkyne.1 When executed in an intramolecular fashion, modular access to a trans fused bicyclo[6.3.0]undecane scaffold,
this cobalt(0) mediated co-cyclization is an extremely efficient way to which is a common motif among terpenes (Scheme 1).10
build up complexity and ring strain in a single synthetic step from
There is a burgeoning interest in the use of (E)-cyclooctene
relatively simple precursors. Its continued use in the total synthesis derivatives – which easily engage in cycloaddition reactions – as tools
of complex organic molecules speaks for its reliability.2 Conversely, for bioconjugation,11 radiolabelling12 and other biotechnological
the intermolecular version of the PKR has not found widespread use applications. Although metal-mediated transformations of
despite its potential for bringing together readily available building (E)-cyclooctene are scarce in the literature,13 several efficient
blocks (alkenes, alkynes) into an elaborated cyclopentanic scaffold in methods for its preparation are available, including flow processes
a single step.3,4 This is basically due to limitations in the substrate based on the photosensitized isomerization of (Z)-cyclooctene.14 For
scope, particularly concerning the alkene counterpart. Accordingly, our purpose, we chose to prepare (E)-cyclooctene by a more
much effort has been devoted to unveiling suitable reaction partners conventional two-step route from cyclooctene oxide.15
beyond the classical norbornene derivatives that the pioneering work
Initial attempts to perform the PKR of (E)-cyclooctene under
of Pauson and co-workers focused on.5 A key feature of reactive thermal activation were unsuccessful. For most alkyne hexacarbonyl
unfunctionalized alkenes—not purposely decorated with coordinating cobalt complexes the cycloaddition reaction does not occur signifi-
groups—6 is that they contain considerable ring strain embedded in cantly below 50 1C, temperature at which (E)-cyclooctene already
the form of a polycyclic structure or a small ring7 (Fig. 1). Because of isomerizes back to (Z)-cyclooctene at a reasonable rate. The reactivity
such restraints, general and successful examples of intermolecular of (Z)-cyclooctene is, in turn, very sluggish: when subjected to
PKRs inevitably yield cis fused adducts.8 During our efforts for reaction with complex 1a, it does not furnish any product.
finding synthetically useful substrates for the intermolecular PKR,9
To avoid alkene isomerization processes we centered our efforts
we hypothesized whether we could capitalize on ring strain arising on the N-oxide promoted reactions.16 Gratifyingly, we found that
from a trans linkage in medium sized cycloalkenes such as the trimethylsilylacetylene hexacarbonyl dicobalt complex 1a
(E)-cyclooctene. This transformation would enable a direct and smoothly reacted with an excess of the alkene under the presence
a Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10,
08028 Barcelona, Spain. E-mail: agusti.lledo@irbbarcelona.org,
antoni.riera@irbbarcelona.org; Fax: +34 934037095; Tel: +34 934037093
b
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´
Departament de Quımica Organica, Universitat de Barcelona,
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Martı i Franques 1–11, 08028 Barcelona, Spain
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for new compounds; 2D NOESY spectrum of 2a. See
DOI: 10.1039/c3cc41005f
Scheme 1 Intermolecular PKR with trans-cycloalkenes.
c
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Scheme 2 N-Oxide promoted PKRs of (E)-cyclooctene.
Table 1 Scope of the PKR of (E)-cyclooctenea
Scheme 4 PKRs of (E)-1-methylcyclooctene.
reactivity to norbornene, one of the best alkenes for the PKR.
In sharp contrast, (Z)-cyclooctene furnishes the corresponding
cyclopentenone only in combination with the more reactive phenyl-
acetylene complex 1b, after an extended reaction time and in low
yield (Scheme 3, bottom).
Next, we sought to explore the scope of this approach with
regard to the alkene counterpart. We were pleased to find that
the PKR of (E)-1-methylcyclooctene with terminal alkynes
(Scheme 4) occurs in a regioselective manner, something which
is very rare.17 When we treated complexes 1a and 1b with
(E)-1-methylcyclooctene, we could only isolate one regioisomer
from the crude, corresponding to the 1-methyl substituted
bicyclo[6.3.0]undec-10-en-9-one (5a and 5b). In the case of
complex 1c a 77 : 23 mixture of regioisomers was obtained,
favoring again the g substituted cyclopentenone 5c. The lower
yields obtained here are due to the slim excess of alkene used in
these experiments.
Gratifyingly, larger trans-cycloalkenes also participate in the
reaction, although significant erosion in the yields is observed
as the ring strain diminishes. We subjected (E)-cyclonon-5-en-1-one
(A, prepared in two steps from 2-chlorocyclopentanone)18 to reaction
with various alkyne hexacarbonyl dicobalt complexes under our
standard set of conditions (Scheme 5). Whereas no product
formation was observed for the less reactive complexes (bearing
internal and/or electron rich alkynes), those derived from
terminal alkynes with a phenyl or an electron withdrawing
substituent furnished the expected cycloalkenediones 7 in moderate
yields (Table 2). In a rather anticipated outcome, the even less
strained (E)-cyclodecene (B) only furnished the desired Pauson–
Khand adduct 8 with N-Boc-propargylamine complex 1f, under
the same set of conditions used for (E)-cyclooctene (Table 1). For
these less reactive alkenes we reasoned that decomposition of
the unsaturated cobalt complex occurring from amine N-oxide
mediated decarbonylation might effectively compete with the
Pauson–Khand reaction manifold, thus leading to significant
yield erosion. To overcome this shortcoming we assessed
Complex
R
R0
T
Product Yieldb (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
TMS
Ph
n-Bu
CH2CH2Ph
n-Pr
CH2NHBoc
CMe2OH
CH2OTBS
CH2OTIPS CH2OTIPS ꢀ30 1C - r.t. 2i
H
H
H
H
n-Pr
H
H
0 1C - r.t. 2a
84
69
79
92
78
98
80
38
86
ꢀ20 1C - r.t. 2b
ꢀ20 1C - r.t. 2c
ꢀ25 1C - r.t. 2d
ꢀ20 1C - r.t. 2e
ꢀ45 1C - r.t. 2f
ꢀ50 1C - r.t. 2g
0 1C - r.t. 2h
H
a
Conditions: 3 eq. alkene, 6 eq. N-methylmorpholine N-oxide (NMO).
Isolated yield.
b
of N-methylmorpholine N-oxide (NMO) to yield the corresponding
cyclopentenone in excellent yield (Scheme 2). The trans stereo-
chemistry at the ring fusion of the adduct was corroborated by a 2D
NOESY experiment (see ESI†). We then extended this chemistry to a
series of alkyne hexacarbonyl dicobalt complexes with varying
degrees of substitution and stereoelectronic properties (Table 1).
Good yields of the desired compounds were obtained with most of
the substrates, including aliphatic alkynes, alcohols and protected
amines. In some instances lowering the reaction temperature
resulted in improved yields of the cyclopentenone. For the
propargyl derivative 1h, a particularly challenging substrate for
the PKR, we were able to isolate the desired cyclopentenone,
albeit in much diminished yields. Lower temperatures did not
lead to any improvement in this case.
In an attempt to ascertain the relative reactivity of (E)-cyclooctene
in a qualitative manner, we then performed a competition experi-
ment (Scheme 3, top). Complex 1a was subjected to reaction with an
equimolar mixture of competing alkenes in large excess with respect
to the complex. The results show that (E)-cyclooctene is similar in
Scheme 3 Relative reactivities of trans- and cis-cycloalkenes.
3056 Chem. Commun., 2013, 49, 3055--3057
Scheme 5 PKRs of 9- and 10-membered trans-cycloalkenes.
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Table 2 Scope of the PKR with larger ring cycloalkenesa
(c) K. Fujioka, H. Yokoe, M. Yoshida and K. Shishido, Org. Lett.,
2011, 14, 244–247.
3 S. E. Gibson and N. Mainolfi, Angew. Chem., Int. Ed., 2005, 44,
3022–3037.
Complex
R
Alkene
T
Product Yieldb (%)
1b
1f
1f
1h
1h
1f
Ph
A
A
A
A
A
B
B
B
ꢀ20 1C - r.t. 7b
ꢀ45 1C - r.t. 7f
43
4 (a) A. Vazquez-Romero, L. Cardenas, E. Blasi, X. Verdaguer and
A. Riera, Org. Lett., 2009, 11, 3104–3107; (b) A. Vazquez-Romero,
J. Rodriguez, A. Lledo, X. Verdaguer and A. Riera, Org. Lett., 2008, 10,
4509–4512; (c) M. Iqbal, P. Evans, A. Lledo, X. Verdaguer,
M. A. Pericas, A. Riera, C. Loeffler, A. K. Sinha and M. J. Mueller,
ChemBioChem, 2005, 6, 276–280; (d) X. Verdaguer, A. Lledo,
C. Lopez-Mosquera, M. A. Maestro, M. A. Pericas and A. Riera,
J. Org. Chem., 2004, 69, 8053–8061.
5 (a) I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts and
M. I. Foreman, J. Chem. Soc., Perkin Trans. 1, 1973, 977–981;
(b) I. U. Khand, G. R. Knox, P. L. Pauson and W. E. Watts,
J. Chem. Soc., Perkin Trans. 1, 1973, 975–977; (c) I. U. Khand,
G. R. Knox, P. L. Pauson and W. E. Watts, J. Chem. Soc., Chem.
Commun., 1971, 36.
6 (a) K. Itami, K. Mitsudo and J.-i. Yoshida, Angew. Chem., Int. Ed.,
2002, 41, 3481–3484; (b) J. A. Brown, T. Janecki and W. J. Kerr,
Synlett, 2005, 2023–2026; (c) M. R. Rivero, J. C. de la Rosa and
J. C. Carretero, J. Am. Chem. Soc., 2003, 125, 14992–14993;
(d) M. E. Krafft, C. A. Juliano, I. L. Scott, C. Wright and
M. D. McEachin, J. Am. Chem. Soc., 1991, 113, 1693–1703.
7 (a) A. de Meijere, H. Becker, A. Stolle, S. I. Kozhushkov, M. T. Bes,
J. Salauen and M. Noltemeyer, Chem.–Eur. J., 2005, 11, 2471–2482;
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A. Riera, Org. Lett., 2001, 3, 3193–3196.
CH2NHBoc
CH2NHBoc
CH2OTBS
CH2OTBS
CH2NHBoc
CH2NHBoc
Ph
49
ꢀ20 1C
7f
67c
43
ꢀ30 1C - r.t. 7h
ꢀ20 1C 7h
61c
38
ꢀ45 1C - r.t. 8f
1f
1b
ꢀ20 1C
ꢀ20 1C
8f
8b
65c
19c
a
Conditions: 3 eq. alkene, 6 eq. N-methylmorpholine N-oxide (NMO).
Isolated yield. Slow addition of NMO (see ESI).
b
c
qualitatively – by TLC monitoring – the lowest temperature at
which product formation was taking place significantly. For
complex 1f this turned out to be around ꢀ20 1C. Subsequently,
we performed the reaction again, but adding the N-oxide
solution slowly by means of a syringe pump while keeping
the reaction at ꢀ20 1C, in order to minimize the accumulation
of the unsaturated cobalt complex in solution. Employing this
methodology, useful yields could be obtained with both A and B
(Table 2). Even the less reactive complex of this series, 1b,
furnished the corresponding adduct with (E)-cyclodecene,
albeit in low yield.
8 Examples of intermolecular PKR’s yielding trans fused adducts,
other than those involving directing groups (ref. 5), are almost
inexistent.
A recent exception: S. Su, R. A. Rodriguez and
P. S. Baran, J. Am. Chem. Soc., 2011, 133, 13922–13925.
In conclusion, we have shown that the ring strain contained
in medium sized trans-cycloalkenes can be exploited in the
intermolecular Pauson–Khand reaction to access functiona-
lized bicyclic structures in a stereo- and regioselective manner.
Given the fact that 8-, 9-, and 10-membered trans-cycloalkenes
can be accessed with certain ease (in comparison with norbor-
nene derivatives for instance), this transformation contributes
significantly to expand the synthetic utility of the
intermolecular PKR.
´
´
9 M. Reves, A. Lledo, Y. Ji, E. Blasi, A. Riera and X. Verdaguer, Org.
Lett., 2012, 14, 3534–3537.
10 This system is typically accessed by indirect routes involving ring
expansion reactions: (a) X. Fan, L.-G. Zhuo, Y. Q. Tu and Z.-X. Yu,
Tetrahedron, 2009, 65, 4709–4713; (b) I. Shinohara and H. Nagaoka,
Tetrahedron Lett., 2004, 45, 1495–1498; (c) C. J. Roxburgh, Tetra-
hedron, 1993, 49, 10749–10784.
11 (a) N. K. Devaraj, R. Upadhyay, J. B. Haun, S. A. Hilderbrand and
R. Weissleder, Angew. Chem., Int. Ed., 2009, 48, 7013–7016;
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and J. M. Fox, Chem. Commun., 2010, 46, 8043–8045.
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42, 599–605; (b) W. Adam and R. M. Bargon, Chem. Commun., 2001,
1910–1911.
14 M. Royzen, G. P. A. Yap and J. M. Fox, J. Am. Chem. Soc., 2008, 130,
3760–3761.
15 (E)-Cyclooctene was obtained on a 12 g scale with 5% residual (Z)-
cyclooctene after distillation: K. J. Shea and J. S. Kim, J. Am. Chem.
Soc., 1992, 114, 4846–4855.
16 (a) N. Jeong, Y. K. Chung, B. Y. Lee, S. H. Lee and S. E. Yoo, Synlett,
1991, 204–206; (b) S. Shambayati, W. E. Crowe and S. L. Schreiber,
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We are grateful to MINECO (CTQ2011-23620), Generalitat de
Catalunya (2009SGR 00901) and IRB Barcelona for financial
support. A.L. acknowledges MINECO (Juan de la Cierva con-
tract) and EU (PEOPLE-2011-CIG-294045) for funding.
Notes and references
1 (a) The Pauson-Khand Reaction, ed. R. R. Torres, John Wiley & Sons,
Ltd, 2012; (b) H.-W. Lee and F.-Y. Kwong, Eur. J. Org. Chem., 2010,
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G. Dominguez and J. Perez-Castells, Chem. Soc. Rev., 2004, 33, 32–42.
2 Recent examples: (a) Q. Xiao, W.-W. Ren, Z.-X. Chen, T.-W. Sun,
Y. Li, Q.-D. Ye, J.-X. Gong, F.-K. Meng, L. You, Y.-F. Liu, M.-Z. Zhao, 17 L. M. Harwood and L. S. A. Tejera, Chem. Commun., 1997,
L.-M. Xu, Z.-H. Shan, Y. Shi, Y.-F. Tang, J.-H. Chen and Z. Yang,
1627–1628.
Angew. Chem., Int. Ed., 2011, 50, 7373–7377; (b) Y. Hayashi, 18 K. Tomooka, T. Ezawa, H. Inoue, K. Uehara and K. Igawa, J. Am.
F. Inagaki and C. Mukai, Org. Lett., 2011, 13, 1778–1780;
Chem. Soc., 2011, 133, 1754–1756.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3055--3057 3057