Reagent-free Nazarov cyclisations

Article abstract of DOI:10.1039/b415463k

A new protocol for Nazarov cyclisation is described that involves simple heating of dienones in the absence of any external Lewis acid. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b415463k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Reagent-free Nazarov cyclisations{
Frederic Douelle, Lauren Tal{ and Michael F. Greaney*
Received (in Cambridge, UK) 5th October 2004, Accepted 25th October 2004
First published as an Advance Article on the web 8th December 2004
DOI: 10.1039/b415463k
A new protocol for Nazarov cyclisation is described that
involves simple heating of dienones in the absence of any
external Lewis acid.
The Nazarov cyclisation of dienones to produce 2-cyclopentenones
has become one of the most powerful methods for cyclopentan-
nulation in recent years (Scheme 1).1–10 Since its discovery in
1941,11 the reaction has been subject to a steady stream of
innovations such that the contemporary procedure delivers good
yields of cyclopentenones under mild conditions, can operate with
complete regiocontrol and displays reasonable functional group
Scheme 2 Thermal Nazarov cyclisation of dienone 1 in the absence of
tolerance. In addition, the dienone substrates are easy to synthesise
and the sound mechanistic picture that underpins the reaction
permits the accurate prediction of substituent effects.
added Lewis acid.
the generality of this transformation as a method for five-
membered ring synthesis. Additionally, we were interested to see
whether the electrocyclisation proceeds under simple thermal
conditions; or whether an as-yet unidentified acidic component is
acting as a catalyst for the process. With these two aims in mind,
we began to optimise the reaction by replacing the conventional
oil-bath heating conditions with microwave irradiation with a view
to reducing the reaction time. A brief survey of reaction solvent
indicated that polar aprotic solvents such as DMA or DMF
worked well in the microwave, producing high yields of 2 after
15 min irradiation. DCM, methanol and acetonitrile were poor
solvents for the reaction, producing none of the desired
cyclopentenone. By far the best solvent, however, was the ionic
liquid 1-ethyl-3-methylimidazolium tetrafluoroborate (EMImBF4),
giving an 82% yield of 2 after just 1 min of microwave irradiation.
This, along with DMA, was chosen as the solvent to take forward
for further study on the scope of this transformation with
alternative substrates.
The dienones 3–11 were synthesised by literature methods12 and
subjected to thermal Nazarov cyclisation in EMImBF4 or DMA,
and the results shown in Table 1. We were pleased to observe the
expected cyclopentenones being produced in good to excellent
yields for a range of a,a9-dialkyl or oxyalkyl dienone substrates.
Although EMImBF4 produced some excellent yields of alkyl-
substituted cyclopentenones in very short reaction times (entries 1
and 2), DMA proved to be the more versatile solvent overall. The
reaction works well for cyclic and acyclic dienones, producing
monocyclic (entries 1, 2 and 3), bicyclic (entries 5, 6 and 7) and
tricyclic (entry 4) cyclopentanoid products. In all cases the
cyclopentenone regioisomer having the most substituted double
bond was the only isolated product from the reaction. We found
disubstitution a- to the ketone group to be a necessary criterion for
successful reaction, as both mono- and unsubstituted substrates
failed to undergo ring closure. This substitution pattern is common
in Nazarov substrates, and is thought to promote the population
Scheme 1 The Nazarov cyclisation.
The development of progressively milder acid promoters has
played an important role in the evolution of the Nazarov
cyclisation as a versatile synthetic methodology. The original
harsh, mineral acid promoters were largely superseded by strong
Lewis acids such as AlCl3, SnCl4 and FeCl3. Although generally
effective, they were necessarily restricted to robust substrates that
could tolerate the stoichiometric amounts of reagent that were
usually required for complete reaction.1 Recent reports in this area
have described catalytic protocols for the cyclisation, as well as
milder Lewis acids with non-nucleophilic counter-ions.2,3,5,8 In this
report, we describe the Nazarov cyclisation of dienones in the
absence of any acid promoters, producing
transformation.
a reagent-free
As part of a research program looking at new methods for
cyclopentannulation, we noticed that the ketone 1 underwent
thermal Nazarov cyclisation when heated in DMF, in the absence
of any external acid. Despite the robust reaction conditions, the
transformation was clean, producing the product cyclopentenone 2
in a respectable 71% yield (Scheme 2).
We were unaware of any precedent for Nazarov cyclisation in
the absence of external acid promoters, and wanted to investigate
{ Electronic supplementary information (ESI) available: Synthetic proce-
dures and characterisation data for all new compounds. See http://
www.rsc.org/suppdata/cc/b4/b415463k/
{ Visiting undergraduate from Barnard College, NY, USA.
*Michael.Greaney@ed.ac.uk
660 | Chem. Commun., 2005, 660–662
This journal is ß The Royal Society of Chemistry 2005

View Article Online
Table 1 Thermal Nazarov cyclisationsa
Entry Starting material
Product
Yield (%)
98
1a
Scheme 3 Conformational equilibrium illustrated for dienone 4.
of the U-shaped conformation necessary for cyclisation by raising
the energy of the unreactive S and W-shaped conformers
(Scheme 3).4d Substitution at the b-position by contrast is not as
important (entries 2 and 3).
3
12 trans/cis 5 : 1
2a
85
We synthesised dienone 8 with a view to examining possible
alkyl shifts in the reaction, as b,b-disubstituted dienones are
especially vulnerable to producing rearranged products under the
acidic conditions of the classical Nazarov.13 Under the neutral
conditions employed here, no such rearrangement products could
be detected and the expected cyclopentenone 17 was produced
smoothly in 60% yield. This moderate yield, and that of the
diphenyl cyclopentenone 18, is likely due to a failure of the minor
Z-isomer in the starting dienones to undergo the desired ring
closure. The requisite U-shaped conformation that the dienones
must adopt for cyclisation is subject to severe steric hindrance in
both Z-8 and Z-9.
4
5
6
13
14
15
3b
4b
5b
68
71
61
The reaction conditions could not be extended to all substrates.
Ketone 10 (entry 8) was resistant to all attempts at achieving an
aromatic Nazarov cyclisation, being recovered unchanged from
the microwave vessel after prolonged irradiation. b-Keto esters
such as 11 were also poor substrates, undergoing extensive
decomposition under the microwave conditions.
The possibility of Brønsted acid catalysis was investigated by
cyclising dienone 6 in freshly distilled DMA in the presence of one
equivalent of proton sponge, using a base-washed microwave
vessel. A slightly attenuated 60% yield was recorded, indicating
that in DMA, genuine thermal cyclisation can occur in the absence
of any acid catalysis. The success of the reaction in ionic liquids, by
contrast, may in part be due to their weakly Lewis acidic character
reinforcing their qualities as superb microwave solvents.14,15
To conclude, we have discovered a new reagent-free protocol for
Nazarov cyclisation that produces highly substituted cyclopente-
nones in good to excellent yields. In addition to the economic and
environmental benefits of conducting reagent-free carbon-carbon
bond formation, the neutral reaction conditions may enable the
extension of Nazarov methodology to acid-sensitive substrates that
have been previously inaccessible.
7
16 9 : 1 unassigned
6b
60
8 E/Z 5 : 1
17 trans/cis 1 : 1
7b
56
9 E/Z 7 : 3
18
8a,b
Recovered starting material
We thank AstraZeneca and Pfizer for research support, and
acknowledge the EPSRC mass spectrometry service at Swansea.
Frederic Douelle, Lauren Tal{ and Michael F. Greaney*
University of Edinburgh, School of Chemistry, Joseph Black Building,
King’s Buildings, West Mains Rd, Edinburgh, UK EH9 3JJ.
E-mail: Michael.Greaney@ed.ac.uk
10
9a,b
Decomposition
Notes and references
1 K. L. Habermas, S. Denmark and T. K. Jones, in Organic Reactions, ed.
L. A. Paquette, John Wiley & Sons, New York, 1994, vol. 45, pp. 451–
458.
2 (a) G. Liang and D. Trauner, J. Am. Chem. Soc., 2004, 126, 9544–9545;
(b) G. Liang, S. N. Gradl and D. Trauner, Org. Lett., 2003, 5,
4931–4934.
11
a
b
EMImBF4; DMA; see electronic supplementary information
(ESI) for reaction details.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 660–662 | 661

View Article Online
3 (a) M. Janka, W. He, A. J. Frontier and R. Eisenberg, J. Am. Chem.
Soc., 2004, 126, 6864–6865; (b) W. He, X. Sun and A. J. Frontier, J. Am.
Chem. Soc., 2003, 125, 14278–14279.
8 D. J. Kerr, C. Metje and B. L. Flynn, Chem. Commun., 2003, 1380.
9 M. Harmata and D. R. Lee, J. Am. Chem. Soc., 2002, 124,
14328–14329.
4 (a) B. K. Tokeshi and M. A. Tius, Synthesis, 2004, 786–790; (b) C. Bee,
E. Leclerc and M. A. Tius, Org. Lett., 2003, 5, 4927–4930; (c) J. Forest,
C. Bee, F. Cordaro and M. A. Tius, Org. Lett., 2003, 5, 4069–4072; (d)
M. A. Tius, Acc. Chem. Res., 2003, 36, 284–290.
5 V. K. Aggarwal and A. J. Belfield, Org. Lett., 2003, 5, 5075–5078.
6 E. G. Occhiato, C. Prandi, A. Ferrali, A. Guarna and P. Venturello,
J. Org. Chem., 2003, 68, 9728–9741.
10 A. Fernandez Mateos, E. M. Martin de la Nava and R. Rubio Gonzalez,
Tetrahedron, 2001, 57, 1049–1057.
11 I. N. Nazarov and I. I. Zaretskaya, Izv. Akad. Nauk SSSR Ser. Khim.,
1941, 211–224. For a full list of Nazarov’s papers in this area, see ref. 1.
12 See ESI{ for the preparation of dienones 1 and 3–11.
13 J. Motoyoshiya, T. Yazaki and S. Hayashi, J. Org. Chem., 1991, 56,
735–740.
7 (a) C. C. Browder, F. P. Marmsaeter and F. G. West, Can. J. Chem.,
2004, 82, 375–385; (b) Y. Wang, B. D. Schill, A. M. Arif and F. G. West,
Org. Lett., 2003, 5, 2747–2750; (c) S. Giese and F. G. West, Tetrahedron,
2000, 56, 10221–10228.
14 J. Howarth, K. Hanlon, D. Fayne and P. McCormac, Tetrahedron
Lett., 1997, 38, 3097–3100.
15 J. Hoffmann, M. Nuechter, B. Ondruschka and P. Wasserscheid, Green
Chem., 2003, 5, 296–299.
662 | Chem. Commun., 2005, 660–662
This journal is ß The Royal Society of Chemistry 2005