Mechanistic insights into the gold(I)-catalyzed [3,3]-sigmatropic rearrangement of sulfoniums for the formation of chiral 1,4-dicarbonyls or formal α-arylation of carbonyl compounds

Abstract

Starting with vinyl sulfoxides and propargyl silane, the Au(I)-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfonium intermediates furnished, after a protodemetallation step and hydrolysis of a thionium ion, the corresponding 4-oxo-2-aryl-2-alkyl-pentanal derivatives. From the fine analysis of crude mixtures representative of this transformation, formal α-arylated products of acetone (1-arylpropan-2-one derivatives) and aryl sulfanes were also isolated and characterized, depending on the substrates and reaction conditions used. Therefore, a tentative mechanistic explanation of the formation of these unexpected products was highlighted and DFT calculations have also streamlined the reactivity of these cationic gold(I)-catalyzed transformations.

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Introduction

Among the major reactions frequently used in organic chemistry, pericyclic transformations historically occupy a prominent place. In this context, the formation of carbon–carbon bonds by charge accelerated [3,3] sigmatropic rearrangements has long enthused the scientific community, both for synthetic applications and from a theoretical point of view to better understand these fascinating transformations.^1,2 By “charge accelerated rearrangements”, we would like to refer to reaction intermediates involving a charged atom in their reactive intermediate structure, such as cationic aza-Cope transformations or the 2-oxonia-Cope rearrangement of oxocarbenium ions. In the context of this study, we will focus on sulfonium-Claisen rearrangements.³ It is important to note that this key positively charged sulfur intermediate could be formed either via electrophilic activation of aryl sulfoxides and then by the addition of a nucleophile via an “interrupted Pummerer reaction” or by the nucleophilic addition of the oxygen atom of a sulfoxide to a vinyl cation intermediate or a gold-activated alkyne, as in the preliminary work of Toste and Zhang (Scheme 1a).^4a,b In these transformations, mechanistic studies were subsequently carried out. Indeed, when these articles were published in 2007, a mechanism involving α-oxo gold carbenoids was prioritized. But then, with the work of Asensio^4c (Scheme 1b) and further DFT studies by Zhang,^4d the mechanism involving a sulfonium [3,3] sigmatropic rearrangement was much more favoured.

Scheme 1 Examples of charge accelerated [3,3] sigmatropic rearrangements of sulfoniums.

Later on, Maulide and collaborators detailed precisely the mechanism of triflic acid-catalyzed oxoarylation of ynamides using DFT and mass spectrometry studies (Scheme 1c, top).^5a,b Interestingly, these in-depth studies allowed them to propose a stepwise or concerted rearrangement mechanism, depending on the substituents of the substrates used. Thus, they were able to understand why in some cases the reaction was not totally regioselective. Later, they extended this reactivity using chiral vinyl sulfoxide substrates (Scheme 1c, bottom).^5c Highly functionalized 1,4-dicarbonyls have been isolated and mechanistic insights into this transformation have been provided recently.^5d Yorimitsu and Yanagi also scrutinized the mechanism of the sigmatropic rearrangement of arylsulfonium intermediates (Scheme 1d).^6a In addition to these in-depth studies of Maulide⁵ and Yorimitsu,⁶ other relevant studies in this field include the work of Kita,⁷ Procter,⁸ Peng,⁹ and others as well.¹⁰ As for us, we were interested in the development of an Au(I)-catalyzed reaction between vinyl sulfoxides 1 and triisopropyl(prop-2-yn-1-yl)silane 2 (Scheme 2).¹¹

Scheme 2 Divergent reactivity in the Au(I)-catalyzed [3,3]-sigmatropic rearrangement of sulfoniums.

After the formation of 1,4-dicarbonyl compounds 3 and a crotonization step, the corresponding cyclopentenones with C4-quaternary stereocenters were isolated and used as key building blocks in the total synthesis of seven sesquiterpenoids (Scheme 2a).^11a,b Interestingly, depending on the nature of the substituents of the sulfoxides and the reaction conditions, it has sometimes been possible to isolate and characterize formal α-arylated products 4 or 4′via another [3,3] sigmatropic rearrangement (Scheme 2b). In order to better understand this transformation and the factors that could influence (or annihilate) this divergent reactivity, in the present study different substrates were tested and reaction mechanisms supported by DFT calculations were proposed.

Results and discussion

Influence of the reaction conditions and the nature of substrates 2a–d on the reaction outcome

In order to have a better understanding of the influence of the reaction conditions and the structure of the silyl group of 2 on the reaction outcome, different tests were initiated, starting with (R,Z)-1a and TIPS-propargyl 2a as substrates (Table 1). At 30 °C, even though the reaction rate was slow, the expected product 3a was delivered in 70% ¹H NMR yield, accompanied by vinyl sulfide 5a ^10c (14% yield) (Table 1, entry 1). No compounds 4a′ (or the silylated analogue 4a) were detected in the crude ¹H NMR spectra.

Table 1 Influence of the reaction conditions and the nature of propargyl silanes 2a–d on the reaction outcome

Entry	SiR2R′	T (°C)	Time (h)	Conversion^a (%)	Yields^a (%)
					(S)-3a	4a′	5a
Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), JohnPhosAu(MeCN)SbF6 catalyst (10 mol%) in dichloroethane (2 mL).a Conversion and yields were determined by ^1H-NMR analysis of the crude mixture using dibromomethane as an internal standard (isolated yield in brackets).b Water (3.0 equiv.) was added.c 1 (0.12 mmol) and 2 (0.10 mmol).d HNTf2 (10 mol%) was used as the catalyst, 1 (0.10 mmol), 2 (0.15 mmol) in dichloroethane (2 mL).
1	Si(iPr)3 (TIPS) 2a	30	144	99	70	0	14
2	Si(iPr)3 (TIPS)	40	46	92	64	0	14
3	Si(iPr)3 (TIPS)	40	60	99	68	0	15
4	Si(iPr) 3 (TIPS)	40	60	99	73 (70)	0	15
5	Si(iPr)3 (TIPS)	50	46	99	63	0	14
6^c	Si(iPr)3 (TIPS)	50	46	95	57	0	18
7	SiMe 3 (TMS) 2b	40	60	66	4	53 (44)	5
8	SitBuMe2 (TBDMS) 2c	40	110	84	51	9	15
9	SitBuPh2 (TBDPS) 2d	40	96	26	11	0	8
10^d	Si(iPr)3 (TIPS) 2a	40	60	99	52	0	10
11^d	SiMe3 (TMS) 2b	40	62	86	26	11	7

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In order to accelerate the rearrangement process and possibly reduce the formation of undesirable sulfide 5, the reaction temperature was increased to 40 °C. After 46 hours, the conversion of 1a was not complete, but that was accomplished after 60 h reaction time (entries 2 and 3). To our delight, when 3 equivalents of water were added to favor the hydrolysis of the thionium ion intermediate, 3a was isolated in 70% yield, with the formation of sulfide 5a always (entry 4). Increasing the reaction temperature to 50 °C did not improve this result, even by changing the relative stoichiometry of substrates 1a and 2a (entries 5 and 6). It is noteworthy that in all the previous catalytic tests, the chirality transfer from the chiral sulfoxide to the newly formed stereogenic center was always excellent. Starting with substrate (R,Z)-1a with 99% ee, product (S)-3a was isolated with the same enantiomeric excess. We next turned our attention to the effect of silyl substituents of 2b–d (entries 7–9). Trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS) groups were examined to compare their behaviour in this transformation, with the results obtained with triisopropylsilyl (TIPS). Very interestingly, the TMS-substituent reversed the reactivity of the [3,3]-sigmatropic rearrangement. The major compound 4a′ (53% NMR yield, 44% isolated yield) was obtained, along with trace amounts of products 3a and 5a (entry 7). This is not the case with bulkier TBDMS and TBDPS silyl groups. Indeed, the TBDMS silyl group led to the formation of 3a in 51% yield, along with a small amount of product 4a′ (9% yield) (entry 8). Propargyl silane with the TBDPS group only afforded 3a and 5a in low yields (∼10%) (entry 9). It should be noted that with these three substrates 2b–d, the conversion rate is lower than that with TIPS-propargyl 2a.

The use of a strong Brønsted acid namely triflimide (Tf₂NH) as a catalyst resulted in a slight yield erosion of 3a (52% NMR yield) and 10% yield of sulfide product 4a′ (entry 10). In the presence of this acid, the use of 2b (with the TMS group) led to the formation of products 3/4′/5 in 26/11/7% NMR yields (entry 11). Overall, the selectivity outcome during the sigmatropic rearrangement varies as well with the Brønsted acid, even if the catalyst effect is less pronounced than with the gold catalyst.

As a partial conclusion to Table 1, we can remarkably observe that with (R,Z)-1a and TIPS-propargyl 2a, we never observed α-arylketone derivatives 4a/4a′ resulting from the aryl-[3,3]-sigmatropic rearrangement pathway (entries 1–6). The results discussed above apparently revealed that the silyl group was able to selectively modulate the orientation of sulfonium [3,3] sigmatropic rearrangement in the gold-catalyzed process.

The influence of the E/Z configuration and the nature of the aromatic groups of olefinic substrates 1 was studied in this transformation (Table 2). For comparison purposes, we provided the results obtained with (R,Z)-1a (entry 1). Starting from (R,E)-1a, products (R)-3a and (E)-5a were solely isolated, in 56% and 21% yield, respectively (entry 2). This test means that with this aryl substituent, both olefinic isomers of 1a give preferentially compound 3a. With (R,E)-1b, substituted with a bulky 1-naphthyl aromatic ring, the major compound remained (R)-3b (39% yield, 96% ee) but the sigmatropic rearrangement also occurred on the para-tolyl part of the substrate, providing 4b in 31% yield (entry 3). In the presence of (rac,Z)-1c, substituted with a 2,4,5-trimethylbenzene group, the major compound becomes (Z)-4c (42% yield), with 3c as the minor compound (18% yield, entry 4). Thus, the steric factor seems very important in the regioselectivity of the reaction. Indeed, with a simple phenyl substituent ((R,E)-1d), the isolated yield of (R)-3d increased to 63%, with only a small amount of 4d (13% yield, entry 5). With the Z-isomer, (rac,Z)-1d, the results are overall the same (65% yield of 3d and 12% yield of 4d, entry 6). Thus, the E/Z-geometry of olefin does not seem to be a decisive point in the reaction outcome, unlike the effects of the steric bulk of substituents on vinylsulfoxides. (Rac,Z)-1e, with a small “R” methyl group, follows the same trends as substrate (rac,Z)-1d, with a propyl chain (entry 7).

Table 2 Reactivity of different vinyl-sulfoxide derivatives 1a–e

Entry	Substrate 1, ee (%)	Ar	R	Yield 3 ^a (%), ee (%)	Yield 4 ^a (%)	Yield 5 ^b (%)
Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), H2O (3.0 equiv.), JohnPhosAu(MeCN)SbF6 catalyst (10 mol%) in dichloroethane (2 mL).a Isolated yields.b Yields were determined by ^1H-NMR analysis of the crude mixture using dibromomethane as an internal standard.
1	(R,Z)-1a, 99% ee	2,5-OMe-4-Me-C6H2	Me	(S)-3a, 70%, 99% ee	(Z)-4a, 0%	(Z)-5a, 15%
2	(R,E)-1a, 97% ee	2,5-OMe-4-Me-C6H2	Me	(R)-3a, 56%, 96% ee	(E)-4a, 0%	(E)-5a, 21%
3	(R,E)-1b, 98% ee	1-Naphthyl	nPr	(R)-3b, 39%, 96% ee	(E)-4b, 31%	(E)-5b, 12%
4	(rac,Z)-1c	2,4,5-Me-C6H2	Me	rac-3c, 18% (27%)^b	(Z)-4c, 42%	(Z)-5c, 15%
5	(R,E)-1d, 98% ee	Ph	nPr	(R)-3d, 63%, 97% ee	(E)-4d, 13%	(E)-5d, 14%
6	(rac,Z)-1d	Ph	nPr	rac-3d, 65%	(Z)-4d, 12%	(Z)-5d, 11%
7	(rac,Z)-1e	Ph	Me	rac-3e, 41% (51%)^b	(Z)-4e, 5%	(Z)-5e, 11%

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We also tried to completely avoid the rearrangement to the p-tolyl part of the substrate by using alkyl- and benzyl-sulfoxide derivatives. Indeed, if the substituent linked to the sulfur atom is replaced by alkyl or benzylic substituents, it becomes impossible to follow the path of the aryl-[3,3]-sigmatropic rearrangement for the formation of non-desired compounds 4/4′. Therefore, benzyl and n-octyl-substituted vinyl sulfoxides 1f–g were subjected to the optimal conditions of Table 1 and compared to the results obtained with (R,Z)-1a (73% NMR yield, 99% ee) (Scheme 3). Unfortunately, relatively low conversion of such substrates was observed. Indeed, vinyl sulfoxide (S,Z)-1f with a benzyl substituent could be converted slowly (118 h reaction time) to the desired product (S)-3a in comparable NMR yield (66%), with total chirality transfer.

Scheme 3 Examination of different vinyl sulfoxide substrates (isolated yield in brackets).

Substrate (rac,Z)-1g exhibited a rather poor reactivity (13% NMR yield in 160 h), while using a di-ortho-substituted arylsulfoxide group, namely a 1,3,5-trimethylbenzene group in substrate 1h, if the formal arylation was still not possible, the isolated yield of the desired product 3a was unfortunately not improved. In both cases, only trace amounts (<5%) of sulfide products 5 were detected. These results showed that the steric and electronic properties of the substituent on sulfoxide have a significant influence on the reactivity of the substrates. In 1a–e, we can conclude that even the presence of by-products with para-tolyl-sulfoxides can be observed, and so far, they remain the best substrates for the reaction we have just developed.

Proposed mechanism

The already proposed mechanism^11a of this catalytic transformation for the formation of compound 3 begins with the gold-activation of propargyl silane 2 (Scheme 4, right). The presence of the silicon atom is very important for the success of this transformation, due to the well-known properties of silicon to stabilize β-positive charge by hyperconjugation (intermediates I/I′).¹²

Scheme 4 Proposed divergent mechanism for the formation of compounds 3, 4/4′ and 5.

For example, the use of prop-1-yne as a substrate proved to be unsuccessful unlike 2, which has already been used for [3,3]-sigmatropic rearrangements of sulfoxide derivatives by our group and others.¹³ Subsequent addition of vinyl sulfoxide 1 to intermediates I/I′ furnished a sulfonium intermediate (II). After [3,3]-sigmatropic rearrangement through a chair-like transition state, the thionium ion (III) could be formed. In the presence of water in the reaction mixture, hydrolysis of the thionium ion and protodesilylation and protodemetallation steps gave chiral 1,4-dicarbonyl compounds 3. Moreover, this transformation with the traceless chiral sulfoxide auxiliary is fully stereospecific: the double bond geometry of vinyl sulfoxide determines the absolute configuration of the carbon stereogenic center. In the presented case, starting from the Z-isomer, (S)-2-methyl-4-oxo-2-arylpentanal derivative 3 was obtained with an almost perfect transfer of chirality from the chiral sulfoxide to the newly formed quaternary stereogenic center. If in most cases, this desired compound was isolated after crotonization in 50–70% yield, some unexpected products appear to be forming in significant proportions. Indeed, compounds 4/4′ were identified, embedding all carbons of both starting materials 1 and 2. An alternative mechanism that can explain the formation of products 4/4′ is proposed in Scheme 4, left. Based on previous reports on sulfonium chemistry,³ we considered that rearrangement could occur on the para-tolyl moiety, and not exclusively on the vinyl part. After the formation of intermediate IV and consecutive [3,3]-sigmatropic rearrangement, the new thionium ion (V) was putatively formed. At this step, a new C–C bond was formed and the oxygen–sulfur bond was broken. With the formation of this dearomative intermediate (V) with a high energy barrier, after rearomatization and protodemetallation steps, ortho-alkylated compound 4 and the corresponding desilylated product 4′ could be formed. In addition to the formation of these products, (2-arylprop-1-en-1-yl)(p-tolyl)sulfane 5 was also isolated. A mechanism was postulated to account for the formation of this compound (Scheme 5).

Scheme 5 Mechanistic proposal for the formation of compound 5.

After the formation of sulfonium intermediates (II)/(IV), two pathways could be proposed. Intermediate VII could be formed after the addition of another vinyl sulfoxide molecule 1 on the electrophilic site of II/IV (Path a). This could explain the formation of sulfide 5 and 2-oxo-3-(silyl)propanal 6 ¹⁴via this intermediate (VII). Alternatively, the same intermediate (VII) could be possibly formed via the putative formation of gold carbenoid (VI) (Path b).

DFT calculations were performed to shed more light on the reaction pathways of this transformation, including the role of the gold complex during the catalytic cycle.

DFT computations

The Gaussian 16 software package¹⁵ was used to perform all DFT calculations. The chosen level of theory was taken from a recent mechanistic study on gold-catalyzed cycloisomerizations.¹⁶ Minima and transition states were optimized using the PBE0 functional,¹⁷ the SDD (ECP) basis set for Au and the 6-311G(d,p) basis set for the other elements.¹⁸ Thermal correction to the Gibbs free energy was obtained at this level at 313.15 K.¹⁹ Single point energy calculations were performed at the PCM/BMK-D3(BJ)/def2-TZVPP level, which includes a solvation model for dichloroethane and the dispersion effect. The discussed values are relative Gibbs free energies at 313.15 K (ΔG₃₁₃, kcal mol⁻¹).

DFT computations were performed to shed light on the selectivity of the reaction. (R)-Sulfoxide 1 and propargyl silane 2a were used as model reagents. Since HNTf₂ is a potent catalyst, we started our investigations using H⁺ as a promoter (Fig. 1). Compound 1 and the vinyl cation 2′, which corresponds to the protonation of 2, were chosen as references for the free energies.

Fig. 1 Free energy profile (ΔG₃₁₃, kcal mol⁻¹) using H⁺ as the catalyst (some hydrogen atoms have been omitted for clarity; selected distances in Å).

Modeling of the nucleophilic addition of 1 to 2′ led to TS1, lying 5.9 kcal mol⁻¹ above the reference system. The resulting sulfoxonium 7 is more stable than 1 and 2′ by 25.1 kcal mol⁻¹. The σ[3,3] transition state TS2 was located at −13.0 kcal mol⁻¹ (i.e. 12.1 kcal mol⁻¹ above 7). Interestingly, because of the spontaneous addition of the expected ketone functionality onto the doubly bonded sulfonium moiety, the stereochemically defined cyclic carbocation 8 was obtained instead of the postulated thionium ion intermediate (III) shown in Scheme 4, in a strongly exergonic fashion (−68.5 kcal mol⁻¹). Nevertheless, it seems clear that the hydrolysis of such an intermediate would also lead to the experimentally observed keto-aldehyde 3. The 3,3-sigmatropic shift was also computed from compound 9, which is a slightly less stable conformer of 7 preorganized for the functionalization of the tolyl group. The corresponding σ[3,3] transition state TS3 (−4.2 kcal mol⁻¹) was located 8.8 kcal mol⁻¹ above TS2. This result is consistent with the fully regioselective reaction observed experimentally.

The gold ion (Ph₃P)Au⁺ was next used as the promoter (Fig. 2). The formation of the Claisen precursor 12 requires 8.9 kcal mol⁻¹ of free energy of activation to reach TS4 and is exergonic by 3.7 kcal mol⁻¹. From 12, the pathway to the cyclic carbocation 15 is distinct from the protocatalyzed series. The expected intermediate 14 (corresponding to III in Scheme 4) could be optimized this time without spontaneous cyclization.

Fig. 2 Free energy profile (ΔG₃₁₃, kcal mol⁻¹) using AuL⁺ as the catalyst (L = PPh₃; some hydrogen atoms have been omitted for clarity; selected distances in Å).

However, it was not obtained from 12 but from complex 13, which seems like a cyclopropane exhibiting a long C–C distance of 2.08 Å. The latter can be viewed as the result of the condensation of a gold oxo-carbenoid on the vinyl sulfide double bond. This electrophilic cyclopropanation occurs concomitantly with the breaking of the S–O bond of 12, hence the stereoselectivity of the process. The corresponding transition state TS5, lying at 1.6 kcal mol⁻¹, is readily accessible (5.3 kcal mol⁻¹ from 12) and the formation of 13 is markedly exergonic (−37.3 kcal mol⁻¹). The formation of carbocation 14 through TS6 (−29.6 kcal mol⁻¹; 7.7 kcal mol⁻¹ above 13) is also straightforward. Nucleophilic addition of the carbonyl group requires only 1.3 kcal mol⁻¹ to reach TS7 (−33.7 kcal mol⁻¹), leading to the cyclic intermediate 15 (−55.6 kcal mol⁻¹) with the release of 20.6 kcal mol⁻¹. Thus, the same type of cyclic structure is achieved as in the protocatalyzed pathway, but via distinct intermediates due to the ability of the gold ion to stabilize carbocations. Nevertheless, this pathway remains clearly more favorable than the one involving isomer 16 (−2.9 kcal mol⁻¹) and the corresponding σ[3,3] transition state TS8 (13.1 kcal mol⁻¹; 4.2 kcal mol⁻¹ above TS4). This is in line with the experimentally observed regioselectivity. Overall, reaching intermediate 8 or 15 is a thermodynamic trap, and the regeneration of the catalyst from these intermediates could be slow. The hydrolysis of 8 or 15 by the low amount of water available could benefit from a higher temperature.

Conclusions

The combined results above highlight the following key points:

(1) Gold-catalyzed sulfonium [3,3]-sigmatropic rearrangement on sulfoxides 1, in reaction with TIPS-propargyl 2a, preferentially occurs on the C(sp²)-vinylic part of the substrate.

(2) The use of alkyl sulfoxides could possibly solve the problem of the formation of rearrangement products on the aryl part, but for now, the conversions are unfortunately very low.

(3) Increasing the steric hindrance around the alkenyl group (1-naphthyl or 2,4,5-trimethylbenzene vs. phenyl groups) favors the sigmatropic rearrangement on the p-tolyl group and the formation of compound 4.

(4) E/Z-geometry of olefin 1 has little influence on the selectivity of the rearrangement.

(5) In gold-catalyzed processes, the silyl group (TIPS or TMS) of 2a–b can selectively control the rearrangement on the vinyl or aromatic side. This effect seems less drastic in the presence of a Brønsted acid.

(6) Each case exhibits a nearly impartial reactivity to the competitive formation of sulfide derivatives 5 in 5–21% yield.

(7) In all cases, with the presence of more or less by-products, the transfer of chirality on the desired product 3 is always excellent.

With the mechanistic understanding of this transformation and thanks to DFT calculations, we envisage extending this methodology to other substrates and, in particular, applying it to the total synthesis of natural products in the future.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the CSC (China Scholarship Council) for PhD grants to W. Z. and Y.-Q. H., ICSN, CNRS and Paris-Saclay University for financial support. This work was granted access to the HPC resources under the allocation 2020-A0070810977 made by GENCI.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data. See DOI: https://doi.org/10.1039/d4qo01061b

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