Alkynyl sulfoxides as α-sulfinyl carbene equivalents: gold-catalysed oxidative cyclopropanation.

Alkynyl sulfoxides are shown to act as α-sulfinyl metallocarbene synthons under oxidative gold catalysis, enabling reactions that are not available from diazo-precursors. This strategy is exemplified in the synthesis of fused α-sulfinyl cyclopropanes.

We tested this hypothesis in the oxidative cyclopropanation reaction of readily accessible ene-alkynyl sulfoxides.‡ A reaction survey with 9a identified that the desired cyclopropane-fused thiolane S-oxide was formed as an approximately 6 : 1 mixture of diastereomers 10a and 10b using 3,5-dichloropyridine-Noxide (11) as stoichiometric oxidant in the presence of various cationic Au(I) catalysts.Phosphite, N-heterocyclic carbene and bulky phosphine ligands all proved effective on the gold, with SPhosAuNTf 2 giving highest yield (Table 1, entries 1-5).Dioxane proved superior to other solvents (entries 5-9) while 11 was more effective than other commonly used pyridine-N-oxide derivatives 12 and 13 (entries 10-13). 16Changing the temperature had little effect on dr, though conversion stalled at much lower temperatures: at 80 1C the catalyst loading could be halved with little effect, though dropping further was detrimental to conversion of 9a (entry 10).Increasing oxidant loading saw lower yields, likely due to over-oxidation pathways (entry 11).
A range of ene-alkynyl sulfoxides 9a-v were prepared to explore the effect of the alkyne substituent on the reaction (Table 2).Primary, secondary and tertiary alkyl substituents were all accommodated with good conversions at 50 1C (entries 1-6).Notably, cyclopropyl-substituted alkyne 3q gave the same yield and d.r. at room temperature (entry 6).Aryl substituted alkynes were also more reactive, proceeding at room temperature, although higher yields were obtained under the standard conditions (entries 7-20, see ESI † for reactions at room temperature).
In these cases the d.r. was approximately 8 : 1 as determined by 1 H NMR analysis of the reaction mixture before purification.The aromatic substituent can be either electron-rich or -poor and will accommodate a variety of functionality across all positions.The tolerance of this chemistry is highlighted by the ready inclusion of a 3-bromothiophen-2-yl moiety (entry 20).Furthermore, the reactions of diene-alkynyl sulfoxides 9u/v proceeded smoothly to the desired sulfur heterocycles despite the possibility of competing cycloisomerisation prior to oxidation across one or both of the two 1,6-enyne motifs embedded in the substrates (entries 21 and 22). 17he relative stereochemistry of the major diastereomers 10 and minor diastereomers 10 0 were assigned using characteristic chemical shifts in the 1 H NMR spectra (see ESI †).
In addition a crystal structure was obtained for major diastereomer 10g (Fig. 1), § confirming the NMR analysis that the sulfoxide oxygen and cyclopropyl methylene are on the same side of the thiolane ring.
The reaction of 9q, bearing an ortho-isopropyl substituent, saw formation of a side-product alongside 10q (Table 2, entry 17) although this was not isolated in sufficient quantity or purity to a Reactions performed on a 0.1 mmol scale; yields of the major diastereomer 10a determined by 1 H NMR analysis of the crude reaction mixture using 1,2,4,5-tetramethylbenzene as an internal reference.
Overlap prevented accurate determination of dr.allow full characterisation.We hypothesised that 1,5-hydride transfer from the benzylic position may be competing with cyclopropanation. 18To test this hypothesis we prepared the methylsulfoxide 12 where cyclopropanation is not possible.The formation of stilbene 13 under the standard reaction conditions is indeed consistent with 1,5-hydride transfer onto a vinyl gold carbenoid (cf.7) followed by elimination of a proton and protodeauration (Scheme 2).Key resonances in 13 also correlate to those in the side-product from 9q.
The feasibility of using a disubstituted alkene in the cyclopropanation was then explored using styrene 14 (Scheme 3).Under the standard reaction conditions the more heavily substituted cyclopropane 15 was indeed formed, 19 alongside hydroxylated ringopened product 16.Formation of 16 is consistent with the cationic character of a gold carbenoid extending through the alkene and enabling a hydrative cyclisation in the presence of adventitious water. 20 preliminary investigation shows that using alkynyl sulfoxides as a-sulfinyl carbene equivalents is not limited to sulfur heterocycle formation.Under unoptimised conditions, which saw incomplete conversion, 1,5-enyne 17 gave fused carbocyclic ring system 18 as a 1.6 : 1 mixture of diastereomers (Scheme 4).
In conclusion, the synthetic limitations that have prevented access to desirable aspects of a-sulfinyl metallocarbene reactivity can be bypassed by an oxidative gold catalysis strategy using readily accessed alkynyl sulfoxides.For the first time a-sulfinyl carbene-like activity is demonstrated through intramolecular cyclopropanation reactions, affording ring-fused cyclopropanes containing a-sulfinylcarbonyl motifs. 21Future work will address the use of this approach in the wider context of carbene reactivity and explore the opportunities arising from the use of enantiopure sulfoxides. 22he authors acknowledge support from the Centre for Chemical and Materials Analysis in the School of Chemistry at University of Birmingham (UoB) and thank Dr Louise Male (UoB) for X-ray crystallography.We thank the UoB for a studentship (MJB).

Table 1
Survey of reaction conditions