Direct α-acyloxylation of organic sulfides with the hypervalent (diacyloxyiodo)benzene/tetra-n-butylammonium bromide (TBAB) reagent combination

Abstract

A novel metal-free approach to directly synthesize α-acyloxy sulfides from readily available alkyl sulfides utilizing the hypervalent (diacyloxyiodo)benzene and TBAB reagent combination is reported. This transformation is characterized by its broad substrate scope in moderate to excellent yields, convenient operating conditions and outstanding functional group tolerance.

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Sulfur-containing organic compounds have been attracting more and more interest due to their essential role in the fields of modern organic synthesis,¹ drug design and discovery,² food chemistry³ and material science.⁴ Among common organosulfur compounds, α-acyloxy sulfides⁵ and their further oxidative derivatives (α-acyloxy sulfones)⁶ have been widely employed as aldehyde or ketone synthons in organic synthesis. Moreover, the ester parts of bifunctional α-acyloxy sulfides can subsequently react with a large variety of external or internal nucleophiles, which provide a convenient method for regiospecific carbon–carbon bond formation.^7c,f Therefore, α-acyloxy sulfides are widely used as valuable synthetic precursors and intermediates, especially in the construction of biologically and industrially useful carbocycles and heterocylces (naturally occurring or unnatural), such as lamivudine,^8a strychnine^8b and asteltoxin.^8c

Over the past decades, there were five general methods for the preparation of α-acyloxy sulfides (Scheme 1): (1) Pummerer-type rearrangement of alkyl sulfoxides;⁷ (2) the nucleophilic reaction of α-substituted alkyl sulfides;⁹ (3) the anti-Markovnikov addition of vinyl esters with arylthiols;¹⁰ (4) addition of aryl disulfides with (acyloxymethyl)magnesium chlorides;¹¹ (5) the anodic oxidation of sulfides.¹²

Scheme 1 Exiting methods for synthesize the α-acyloxy sulfides.

Stoichiometric hypervalent (diacyloxyiodo)benzene has been frequently used in the direct acyloxylation of C(sp³)–H bonds recently. In this regard, various directing groups, such as picolinamide,¹³ pyridine,¹⁴ oxime,^14,15 8-aminoquinoline,¹⁶ S-methyl-S-2-pyridyl-sulfoximine,¹⁷ Boc-protected N-methylamine,¹⁸ N²-pyridine-1,2,3-triazole-4-carboxylic acid¹⁹ and 1-aminoanthraquinone,²⁰ have been successfully utilized for transition-metal-catalyzed chelate-directed oxidative functionalization of C(sp³)–H bonds in conjunction with PhI(OAc)₂, giving rise to acetoxylated products in excellent yields and extremely high selectivities. In addition, the acyloxylation reactions of substrates with activated C_sp³–H bonds (benzylic position²¹ or α-position relative to an electron-withdrawing group²²) in presence of PhI(OAc)₂ have also been emphasized in literatures. Despite the advances in this field, the ability of hypervalent (diacyloxyiodo)benzene to introduce an acyloxy group into organic sulfides has been virtually unexplored, which is probably because organic sulfides are easily oxidized to the corresponding sulfoxides.²³ As a continuation of our research interest in the application of hypervalent iodine reagents in the rapid and efficient preparation of useful sulfur-containing compounds,²⁴ this work herein report a direct and selective acyloxylation of a variety of sulfides with the combination of hypervalent (diacyloxyiodo)benzene and tetra-n-butyl ammonium bromide (TBAB). It is noteworthy that sulfoxides as the traditional precursors of Pummerer reaction⁸ need not be synthesized, whilst most of organic sulfides are commercially available or easily prepared. To the best of our knowledge, only relatively rare electrochemical approaches¹² have been reported thus far to construct the high-value α-acyloxy sulfides from readily available sulfides (Fig. 1).

Fig. 1 Examples of α-acyloxy sulfides as valuable intermediates in natural products.

We initiated our investigation by choosing thioanisole 1a and 2 equivalents of PhI(OAc)₂ as the model substrates for the target α-acyloxylation reaction in the presence of 1 equivalent of TBAB in CH₂Cl₂ at room temperature for 6 h (Table 1, entry 1). To our delight, the desired product 2a was isolated, albeit in only 22% yield. Importantly, the controlled reaction in the absence of tetra-n-butyl ammonium bromide (Table 1, entry 2) was carried out and clearly showed that only trace amount of expected product 2a was formed. By adjusting the amount of TBAB (Table 1, entries 3 and 4) to 3 equivalents, the α-acyloxylation product 2a can be formed as the dominant product (60% yield; Table 1, entry 4). The excessive amounts of TBAB is necessary because of the competing oxidation of the sulfur with the PhI(OAc)₂. The increase of the amount of TBAB is beneficial to the production of tetra-n-butylammonium [di(acyloxy)bromated (I)], which might be the critical intermediate in this reaction. In stark contrast, the replacement of TBAB by other additives was completely unsuccessful and led to the formation of expected product 2a in less than 5% yield (Table 1, entries 5–9), confirming the unique reactivity of the PhI(OAc)₂/TBAB system. Subsequently, other solvents, including toluene and THF, were also surveyed but substantially decreased the reaction efficiency (Table 1, entries 10 and 11). Finally, the amount of PhI(OAc)₂ can be reduced to 1.75 equivalents, which led to improvement in both starting material consumption and product formation providing a slightly higher yield of 66% (Table 1, entry 12). Interestingly, it was found that the improper substrates ratio between thioanisole 1a and PhI(OAc)₂ had negative effects on the reaction (Table 1, entries 13–17). Therefore, the condition described in entry 12 in Table 1 was chosen as the standard condition to verify the general applicability of the present methodology. To our disappointment, methyl phenyl sulfone or methyl phenyl sulfoxide failed to yield the corresponding α-acyloxylated sulfone or sulfoxide under the optimized condition, suggesting the requirement of two lone pairs on the sulfur for the α-acyloxylation transformation.

Table 1 Optimization of the reaction conditions^ab

Entry	PhI(OAc)2 (equiv.)	Additive (equiv.)	Solvent	Yield^b (%)
a Reaction conditions: thioanisole (0.5 mmol), PhI(OAc)2, additive, solvent (2.0 mL), room temperature.b Isolated yield.
1	2.0	n-Bu4NBr (1.0)	CH2Cl2	22
2	2.0	—	CH2Cl2	<5
3	2.0	n-Bu4NBr (0.5)	CH2Cl2	<10
4	2.0	n-Bu4NBr (3.0)	CH2Cl2	60
5	2.0	n-Bu4NF (3.0)	CH2Cl2	0
6	2.0	n-Bu4NCl (3.0)	CH2Cl2	0
7	2.0	n-Bu4NI (3.0)	CH2Cl2	<5
8	2.0	n-Bu4NOAc (3.0)	CH2Cl2	<5
9	2.0	NaBr (3.0)	CH2Cl2	0
10	2.0	n-Bu4NBr (3.0)	Toluene	36
11	2.0	n-Bu4NBr (3.0)	THF	0
12	1.75	n-Bu4NBr (3.0)	CH2Cl2	66
13	4.0	n-Bu4NBr (3.0)	CH2Cl2	<10
14	3.0	n-Bu4NBr (3.0)	CH2Cl2	19
15	2.5	n-Bu4NBr (3.0)	CH2Cl2	35
16	1.5	n-Bu4NBr (3.0)	CH2Cl2	57
17	1.0	n-Bu4NBr (3.0)	CH2Cl2	35

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With the optimized reaction condition in hand, we first examined the scope of sulfide substrates (Table 2). Various alkyl phenyl sulfides (1a–1i) with different substituents on the phenyl ring, including electron-donating and electron-withdrawing groups, can react smoothly with the combination of PhI(OAc)₂ and TBAB to afford the corresponding α-acyloxylation products in yields from 32% to 80%. Moreover, the introduction of the substituents in ortho, meta, and para positions of the phenyl group is in fact also tolerated under the standard reaction condition (1j, 1k and 1b). Remarkably, this transformation is compatible with a variety of synthetically valuable functional groups (1b–1o), including fluoro, chloro, bromo, methoxy, nitro, cyano, carbonyl, alkenyl and alkynyl, thus offering ample opportunities for further derivation. Among these, there are still several sulfide substrates containing cyano (1e), nitro (1f) and carbonyl (1g), can get corresponding α-acyloxylation products with low yields, which is mainly because of the competing oxidation of the sulfur with the PhI(OAc)₂. In particular, sulfide 1p, possessing the important dibenzo[b,e]thiepin framework²⁵ with a broad-ranging pharmacological potential, can also provide the desired α-acyloxylation product 2p in 72% yield. Besides the benzene ring, naphthyl-substituted sulfide (1q) and heteroaryl-substituted sulfide (1r) are also amenable to this transformation. Likewise, unsymmetrical alkyl methyl sulfides also proved to be suitable substrates for this transformation. For n-decyl methyl sulfide 1s, excellent regioselectivity favoring functionalization of the less hindered C–H bond was observed and sole α-acyloxylation product 2s was achieved in 32% yield. On the contrary, acetoxylation of 2-(methylthio)-1-phenylethan-1-one 1t took place only at the more sterically accessible position, which is mainly because of the further advantage in the formation of the more stable thionium ion, and a 58% isolated yield of α-acyloxylation product 2t was obtained. Notably, α-acyloxy β-ketosulfide products 2o and 2t might be easily rearranged into α-acyloxy thioesters as versatile building blocks via acyl migration in enolate form.²⁶ Based on the results for the above different regioselectivities between 2° and 3° C–H bonds, we presumed that it perhaps originated from the stability of the thioniumion intermediates.

Table 2 Scope of thioether derivatives^ab

a Reaction conditions: thioether (0.5 mmol), TBAB (1.5 mmol), PhI(OAc)₂ (0.875 mmol), DCM (2.0 mL), room temperature.b Isolated yield.

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Next, we evaluated α-acyloxylation between methyl phenyl sulfide 1a and other hypervalent (diacyloxyiodo)benzenes with the aid of tetra-n-butyl ammonium bromide. As expected, all four hypervalent (diacyloxyiodo)benzenes smoothly participated in this transformation leading to the desired products in good yields (Table 3). Higher yields obtained than PhI(OAc)₂ implied that we can select the appropriate hypervalent iodine reagents as the acylate source (e.g., hypervalent (dipivaloxyiodo)benzene) to efficiently afford the analogous α-acyloxy sulfide products, which might give a handgrip for a variety of further transformations in organic synthesis. Actually, the clearly improved yields were indeed observed as illustrated in Table 3 (3eb and 3fb).

Table 3 Scope of hypervalent iodine(III) reagents derivatives^ab

a Following the general procedure.b Isolated yield.

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Although further studies may be still required to discover and understand the mechanism in more detail, on the basis of our present results and the previously reported literatures,²⁷ a plausible mechanism for this α-acyloxylation transformation, exemplified by the reaction of organic sulfides with PhI(OAc)₂/TBAB system, is proposed in Scheme 2. Initially, a highly active intermediate tetra-n-butylammonium [di(acyloxy)bromated (I)], which might be really responsible for the α-acyloxylation reactions, is generated by the interaction of hypervalent (diacyloxyiodo)benzene with tetra-n-butyl ammonium bromide. As a matter of fact, subjection of methyl phenyl sulfide 1a in the presence of other tetra-n-butyl ammonium salts and NaBr (Table 1, entries 5–9) resulted in less than 5% of the desired product, which is likely a result of inexistence of tetra-n-butylammonium [di(acyloxy)bromated (I)] and competitive undesired oxidation.²⁸ Then, organic sulfides undergoes Br-activation by the nucleophilic attack at the electrophilic bromine centre to form an bromosulfonium salt. Afterwards, deprotonation next to the positively charged sulfur by the acetate anion would lead to the generation of acetic acid and a new thionium ion. The existence of acetic acid has been confirmed by the in situ ¹H and ¹³C NMR investigation. Finally, the nucleophilic addition of acetate anion to the double C=S bond completes the formation of the α-acyloxy sulfide products. The excess of TBAB for this α-acyloxylation transformation would be indispensable and helpful to avoid the alternative and competing undesired oxidation.²³

Scheme 2 Proposed mechanism for the reaction.

In summary, we have developed an unprecedented metal-free α-acyloxylation process of a broad range of alkyl sulfides with the combination of hypervalent (diacyloxyiodo)benzenes and tetra-n-butyl ammonium bromide. The key features of the present protocol are metal-free reaction condition, operational simplicity, a wide ranging substrate scope and tolerance of various synthetically useful functional groups. This methodology could also potentially streamline the synthesis by minimizing the unnecessary oxidation operation to organic sulfoxides as the traditional precursors of Pummerer reaction⁸ and reducing the number of steps. Preliminary studies have shown that the success of this reaction might be mainly attributed to the generation of the tetra-n-butylammonium [di(acyloxy)bromated (I)]. Further investigations on mechanistic details as well as other related transformation events are currently underway in our laboratory.

Acknowledgements

The work was supported by the “Hundred Talents Program” of Harbin Institute of Technology (HIT), the “Fundamental Research Funds for the Central University” (HIT.BRETIV.201502), the NSFC (21202027), the NCET (NCET-12-0145), and the “Technology Foundation for Selected Overseas Chinese Scholar” of Ministry of Human Resources and Social Security of China (MOHRSS).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed synthetic procedures and characterization of new compounds. See DOI: 10.1039/c6ra01799a

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