formation of 7 can be explained by a gold-promoted hydration
of the alkyne in the presence of adventitious water to afford
diketones 8.18 Using 6b a small quantity of 8b was isolated from the
reaction mixture. Subsequently, intramolecular aldol dehydration
with preferential formation of a five-membered ring would afford
the observed product and regenerate water. The latter step may be
promoted by the gold catalyst or traces of Brønsted acid generated
in situ from it.13,19
In light of this result, we considered the possibility that a similar
hydration–aldol dehydration pathway could account for all the
cyclisations rather than direct carbon–carbon bond-formation.
Subjecting keto-alkyne 1a to the hydrative conditions developed
by Liu [PtCl2, CO (1 atm), dioxane–H2O, 100 ◦C, 2.5 h] afforded
complete conversion with the cyclic enone 2a formed in 66% NMR
yield alongside several byproducts at 6 mol% catalyst loading.20,21,22
As previously seen in our study, larger quantities of water shut
down the gold-catalysed reaction completely (Table 1, entry 5).
Similarly, when 1 equivalent of water was added to the reaction
mixture, the reaction progress was significantly retarded, and a
lower overall combined yield of product and recovered starting
material was obtained (Scheme 4).
confirms that both keto-alkyne 1a and diketone 10 are converted
into enone 2a under the reaction conditions (See Supporting
Information†). The formation of a small amount of 10 was
observed when the gold-catalysed cyclisation of 1a was performed
in an NMR tube and monitored regularly by 1H NMR (See
Supporting Information). Addition of independently synthesised
10 to this reaction confirmed this observation. On depletion of the
keto-alkyne, remaining diketone was also consumed. These results
prove that, despite the low levels of water, intermolecular alkyne
hydration occurs under the reaction conditions. Furthermore, a
species generated in the reaction of 1a is capable of mediating
aldol dehydration of 10. While the direct carbon–carbon bond
forming process (Scheme 2) can not be eliminated as a possibility,
as water would also aid the required keto–enol tautomerisation,
the alkyne-hydration aldol-dehydration pathway is shown to be at
least competitive with this intramolecular cyclisation.
In summary, we have demonstrated the overall cycloisomeri-
sation of unactivated ketones with alkynes at room temperature
under gold catalysis. This straightforward process has been used
to assemble a range of fused and spiro carbocyclic structures from
simple precursors under mild conditions. The role of water is finely
poised between being an integral component of the reaction system
and contributing to catalyst and substrate degradation. Further
investigations into the precise role of water in these reactions are
under way alongside a wider study of gold-catalysed reactions of
keto-alkynes. These results will be reported in due course.
We thank the University of Birmingham and EPSRC
(EO/F031254) for financial support and Johnson Matthey plc for
a generous loan of metal salts. This research was part supported
through Birmingham Science City: Innovative Uses for Advanced
Materials in the Modern World (West Midlands Centre for
Advanced Materials Project 2), with support from Advantage West
Midlands (AWM) and part funded by the European Regional
Development Fund (ERDF).
Notes and references
Scheme
4 Study of the possible hydration–aldol-dehydration pro-
1 (a) R. Bloch, P. le Perchec, F. Rouessac and J.-M. Conia, Tetrahedron,
1968, 24, 5971; (b) G. Mandville, F. Leyendecker and J.-M. Conia, Bull.
Soc. Chim. Fr., 1973, 963.
cess. Yields determined by 1H NMR against a known quantity of
1,2,4,5-tetramethylbenzene.
2 J.-M. Conia and P. le Perchec, Synthesis, 1975, 1.
However, the use of degassed yet undistilled CH2Cl2 gave the
same yield of 2a as did using distilled CH2Cl2.23 When using dry
solvent the hygroscopic silver salts employed in these reactions
are a potential source of adventitious water. No product was
observed when the reaction was run in the presence of activated
molecular sieves to counter this issue. These results confirm that
a small amount of water is necessary for the cyclisation of 1a.
However, larger proportions of water have a negative effect which
is apparently due to catalyst deactivation and increasing levels of
either product or starting material degradation.
To further explore the role of water, the immediate product
of alkyne hydration, diketone 10, was independently prepared.
Unoptimised NaAuCl4-promoted hydration gave 10 in moderate
yields alongside a mixture of 1a and 2a. No reaction was observed
when 10 was subjected to the standard gold-catalysed cyclisation
conditions. However, when a small amount of 1a was added to
a solution of Ph3PAuCl–AgOTf and 10 in CH2Cl2 after 2 h,
a reaction was initiated and product 2a was formed. On near
complete consumption of 10, analysis of the product mixture
3 J. Drouin, M. A. Boaventura and J. M. Conia, Synthesis, 1983, 801.
4 The use of enol ethers alongside stoichiometric mercury salts (a) M. A.
Boaventura and J. Drouin, Bull. Soc. Chim. Fr., 1987, 1015; (b) J.
Drouin, M. A. Boaventura and J. M. Conia, J. Am. Chem. Soc., 1985,
107, 1726; (c) For representative applications see: H. Huang and C. J.
Forsyth, J. Org. Chem., 1995, 60, 2773; (d) A. J. Frontier, S. Raghavan
and S. J. Danishefsky, J. Am. Chem. Soc., 2000, 122, 6151.
5 For representative transition-metal catalysed use of alkyl and silyl enol
ethers see: (a) K. Maeyama and N. Iwasawa, J. Am. Chem. Soc., 1998,
120, 1928; (b) N. Iwasawa, K. Maeyama and H. Kusama, Org. Lett.,
2001, 3, 3871; (c) J. W. Dankwardt, Tetrahedron Lett., 2001, 42, 5809;
(d) H. Kusama, H. Yamabe and N. Iwasawa, Org. Lett., 2002, 4, 2569;
(e) C. Nevado, D. J. Ca´rdenas and A. M. Echavarren, Chem.–Eur. J.,
2003, 9, 2627; (f) B. K. Corkey and F. D. Toste, J. Am. Chem. Soc.,
2007, 129, 2764.
6 Examples of cycloisomerisation of 1,3-dicarbonyl compounds and
b-keto esters onto alkynes: Gold catalysis: (a) J. J. Kennedy-Smith,
S. T. Staben and F. D. Toste, J. Am. Chem. Soc., 2004, 126, 4526;
(b) S. T. Staben, J. J. Kennedy-Smith and F. D. Toste, Angew. Chem.,
Int. Ed., 2004, 43, 5350; (c) For an asymmetric palladium-catalysed
process: B. K. Corkey and F. D. Toste, J. Am. Chem. Soc., 2005, 127,
17168; (d) Copper/Silver co-catalysed: C.-L. Deng, R.-J. Song, S.-M.
Guo, X.-Q. Wang and J.-H. Li, Org. Lett., 2007, 9, 5111; (e) C.-L. Deng,
T. Zou, Z.-Q. Wang, R.-J. Song and J.-H. Li, J. Org. Chem., 2009, 74,
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