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

Abstract

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.

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Metallocarbenes underpin a broad range of powerful chemo- and stereoselective transformations in modern organic synthesis.¹ α-Sulfinyl metal carbenes, 1, position a readily-elaborated functional group^2–5 bearing a stereogenic centre at the reactive site (Scheme 1a).⁶ However this attractive proposition has yet to be realised using conventional approaches to metal carbene reactivity. Maguire and co-workers established that α-diazo sulfoxides are only isolable when constrained as part of a cyclic system and that they and their resulting α-sulfinyl rhodium carbenes undergo rapid Wolff-like rearrangement (Scheme 1b).⁷ Here we demonstrate how the reactivity patterns of α-sulfinyl carbenes can be accessed from alkynyl sulfoxides under gold catalysis.

Scheme 1 Approaches to access α-sulfinyl metal carbene type reactivity.

The use of a π-acid to chemoselectively activate alkynes in the presence of a nucleophilic oxidant provides an attractive route into α-oxo metal carbene reactivity patterns without the need to install or handle diazo groups.^8–11 One intriguing aspect is that some reactions appear to bypass the actual gold carbene 4 and proceed directly from the vinyl gold carbenoid intermediate 3 (Scheme 1c).¹² We hypothesised that broader applications of α-sulfinyl metal carbene chemistry might therefore be accessible if α-sulfinyl vinyl gold carbenoid 7 could be accessed from alkynyl sulfoxide 6, quenched prior to expulsion of the nucleofuge, and proved less vulnerable to rearrangement than the corresponding metal carbene. This approach presents an interesting challenge as sulfoxides are effective nucleophiles and oxygen-transfer agents in the presence of alkyne–gold complexes¹³ or metal carbenes.¹⁴ For successful application of alkynyl sulfoxide 6 as an α-sulfinyl carbene equivalent, effective π-activation and regioselective oxidation is required, but 6 and 8 must not act as nucleophilic oxidants.¹⁵

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-N-oxide (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 SPhosAuNTf₂ 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).¹⁶ Changing the temperature had little effect on dr, though conversion stalled at much lower temperatures: at 80 °C 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).

Table 1 Survey of reaction conditions

Entry	Ligand	Solvent	T (°C)	Oxidant	Yield of 10a^a (%)
a Reactions performed on a 0.1 mmol scale; yields of the major diastereomer 10a determined by ^1H NMR analysis of the crude reaction mixture using 1,2,4,5-tetramethylbenzene as an internal reference. Overlap prevented accurate determination of dr. b 62% at 2.5 mol% cat. 27% at 1.0 mol% cat. L1 = (tris(2,4-di-tertbutylphenyl)phosphite). L2 = 1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene). L3 = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. L4 = 2-ditertbutylphosphinobiphenyl. L5 = 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos). c Higher concentrations afforded lower yields (42% 10a at 0.2 M).
1	L1	Dioxane	65	11	42
2	L2	Dioxane	65	11	45
3	L3	Dioxane	65	11	47
4	L4	Dioxane	65	11	59
5	L5	Dioxane	65	11	66
6	L5	1,2-DCE	60	11	45
7	L5	THF	60	11	37
8	L5	CH2Cl2	rt	11	26
9	L5	Toluene	60	11	39
10	L5	Dioxane	80	11	69^b^,^c
11	L5	Dioxane	80	11 (2.0 eq.)	54
12	L5	Dioxane	80	12	63
13	L5	Dioxane	80	13	59

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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 °C (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 ¹H 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).¹⁷

Table 2 Substrate scope

Entry	R	9	T (°C)	Time (h)	% Yield of 10^a
a Isolated yields after purification by column chromatography. The yields refer to a single diastereomer apart from when diastereomeric ratios are given. b 9c is a 1 : 1 mixture of diastereomers. c Incomplete conversion. d The same yield and d.r. were obtained at room temperature. e 2.5 mol% SPhosAuNTf2.
1	^nBu	9a	50	17	72 (6 : 1)
2	PhCH2CH2	9b	50	3.5	63 (6 : 1)
3		9c	50	21	70 (10 : 10 : 1 : 1)
4	Cyclohexyl	9d	50	24^c	45 (7 : 1)
5	^tBu	9e	50	25	70 (12 : 1)
6	Cyclopropyl	9f	50	17	86^d (10 : 1)
7	Ph	9g	65	0.75	80
8^e	4-MeC6H4	9h	23	28	75
9	4-MeOC6H4	9i	40	1	78
10^e	4-AcNH-C6H4	9j	50	20	79
11	4-F3CC6H4	9k	50	17	63
12	4-MeO2CC6H4	9l	50	20	64
13	4-FC6H4	9m	50	17	68
14	3-MeOC6H4	9n	50	18	70
15	4-BrC6H4	9o	50	3	74
16^e	2-BrC6H4	9p	23	28	50
17	2-^iPr-C6H4	9q	50	28	52 (7 : 1)
18	2-Naphthyl	9r	50	28	70
19	2-Furyl	9s	50	28	74
20		9t	50	28	73
21		9u	50	21	63 (10 : 1)
22		9v	50	21	65 (10 : 1)

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The relative stereochemistry of the major diastereomers 10 and minor diastereomers 10′ were assigned using characteristic chemical shifts in the ¹H 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.

Fig. 1 X-ray crystal structure of major diastereomer 10g.

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 allow full characterisation. We hypothesised that 1,5-hydride transfer from the benzylic position may be competing with cyclopropanation.¹⁸ To 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.

Scheme 2 An alternative reaction pathway consistent with 1,5-hydride transfer.

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 ring-opened 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

Scheme 3 Use of 1,2-disubstituted alkene in oxidative cyclopropanation.

A preliminary investigation shows that using alkynyl sulfoxides as α-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).

Scheme 4 Synthesis of an α-sulfinyl cyclopropyl-fused cyclopentanone.

In conclusion, the synthetic limitations that have prevented access to desirable aspects of α-sulfinyl metallocarbene reactivity can be bypassed by an oxidative gold catalysis strategy using readily accessed alkynyl sulfoxides. For the first time α-sulfinyl carbene-like activity is demonstrated through intramolecular cyclopropanation reactions, affording ring-fused cyclopropanes containing α-sulfinylcarbonyl motifs.²¹ Future 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.²²

The 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).

Notes and references

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9. For examples in oxidative cyclopropanation, see: (a) H. Chen and L. Zhang, Angew. Chem., Int. Ed., 2015, 54, 11775–11779; (b) K. Ji, Z. Zheng, Z. Wang and L. Zhang, Angew. Chem., Int. Ed., 2015, 54, 1245–1249; (c) H.-S. Yeom and S. Shin, Org. Biomol. Chem., 2013, 11, 1089–1092; (d) A. Homs, M. E. Muratore and A. M. Echavarren, Org. Lett., 2015, 17, 461–463; (e) D. Qian, H. Hu, F. Liu, B. Tang, W. Ye, Y. Wang and J. Zhang, Angew. Chem., Int. Ed., 2014, 53, 13751–13755; (f) K.-B. Wang, R.-Q. Ran, S.-D. Xiu and C.-Y. Li, Org. Lett., 2013, 15, 2374–2377; (g) D. Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade, A. Das and R.-S. Liu, Angew. Chem., Int. Ed., 2011, 50, 6911–6914; (h) D. Qian and J. Zhang, Chem. Commun., 2011, 47, 11152–11154 and references therein.
10. For prior work in this area from one of us, see: (a) M. Dos Santos and P. W. Davies, Chem. Commun., 2014, 50, 6001–6004; (b) P. W. Davies, A. Cremonesi and N. Martin, Chem. Commun., 2011, 47, 379–381; (c) P. W. Davies, Pure Appl. Chem., 2010, 82, 1537–1544; (d) P. W. Davies and S. J. C. Albrecht, Angew. Chem., Int. Ed., 2009, 48, 8372–8375.
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14. See ref. 13d and C. A. Witham, P. Mauleon, N. D. Shapiro, B. D. Sherry and F. D. Toste, J. Am. Chem. Soc., 2007, 129, 5838–5839.
15. Alkynyl sulfoxides have been scarcely employed in gold catalysis. For a single example, see G. Zhang and L. Zhang, J. Am. Chem. Soc., 2008, 130, 12598–12599.
16. (a) D. B. Huple, S. Ghorpade and R.-S. Liu, Chem. – Eur. J., 2013, 19, 12965–12969; (b) R. Liu, G. N. Winston-McPherson, Z.-Y. Yang, X. Zhou, W. Song, I. A. Guzei, X. Xu and W. Tang, J. Am. Chem. Soc., 2013, 135, 8201–8204.
17. For a review, see: R. Dorel and A. M. Echavarren, J. Org. Chem., 2015, 80, 7321–7332.
18. In keeping with the oxidative cyclisation of o-benzylalkynes, where C–C bond formation precedes the elimination observed here, see ref. 12b.
19. The methylene protons on the non-fused cyclopropane in 15 are desymmetrised to 4 distinct resonances, consistent with an interaction with the superimposed phenyl group in an exo position and retention of starting alkene geometry.
20. For example of alkoxycyclisation of enynes in the presence of water C. Nieto-Oberhuber, M. P. Muñoz, S. López, E. Jiménez-Núñez, C. Nevado, E. Herrero-Gómez, M. Raducan and A. M. Echavarren, Chem. – Eur. J., 2006, 12, 1677–1693.
21. All the reaction outcomes are consistent with the sequence of sulfinyl-directed oxidation followed by cyclopropanation. For instance, an inverted order of steps would be expected to give rise to vinylcyclopropanes through fast 1,2-CH insertion from alkylalkynes.
22. Although not the focus of this report, analogous cyclopropane-fused sulfolanes can be prepared under the reported reaction conditions starting from the alkynyl sulfone equivalent.
    For examples of gold-catalysed oxidative transformations of alkynyl sulfones see: L. Cui, G. Zhang, Y. Peng and L. Zhang, Org. Lett., 2009, 11, 1225–1228 and ref. 9b.

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures and analytical data for new compounds. ¹H and ¹³C NMR spectra. Structural determination and additional catalysis results. CCDC 1528851. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc02244a

‡ All sulfoxides were prepared in the racemic series.

§ Crystal structure determination of 10g: crystal data for C₁₂H₁₂O₂S (M = 220.28 g mol⁻¹): triclinic, space group P1̄ (no. 2), a = 6.2782(3) Å, b = 7.1917(3) Å, c = 12.4920(6) Å, α = 86.275(4)°, β = 75.966(4)°, γ = 66.086(4)°, V = 499.87(4) ų, Z = 2, T = 100.01(11) K, μ(CuKα) = 2.667 mm⁻¹, D_calc = 1.463 g cm⁻³, 7653 reflections measured (7.3° ≤ 2Θ ≤ 144.236°), 1939 unique (R_int = 0.0218, R_sigma = 0.0170) which were used in all calculations. The final R₁ was 0.0390 (I > 2σ(I)) and wR₂ was 0.0963 (all data). The CIF for the crystal structure of 10g has been deposited with the CCDC and have been given the deposition number CCDC 1528851.

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