Azulenesulfonium and azulenebis(sulfonium) salts: Formation by interrupted Pummerer reaction and subsequent derivatisation by nucleophiles

Azulenes undergo either single or dual SEAr reactions depending on the nature of the sulfur(IV) electrophile employed. These electrophiles are generated in situ from either sulfoxides or sulfides. The resultant cationic or dicationic azulene products can undergo further derivatisation by means of nucleophilic attack at the sulfonium a-carbon. In the case of cycloalkyl azulenylsulfonium salts, this leads to ring-opened azulenylsulfide products. © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).


Introduction
Sulfonium salts, trivalent cationic sulfur(IV) species, have a rich chemistry which has seen them exploited in various applications. They are used as photoacid generators [1], for purposes including microlithography [2], initiation of polymerisation [3], optical data storage [4], and oxygen-independent photodynamic therapy [5]. In organic synthesis, sulfonium salts may be employed in crosscoupling, where they have been shown to be competent pseudohalide electrophilic coupling partners [6e12]. They have been used to enable versatile derivatisation reactions using photoredox catalysis [11b,c], [13e22], as well as via S N Ar processes and/or aryne intermediates [23,24], and via sulfurane intermediates [46,47]. Synthetic applications of sulfonium salts (and other sulfur(IV) species derived from them, such as sulfur ylides) have been reviewed [25].
Methods for preparing sulfonium salts have been reviewed [26], and include approaches such as the direct alkylation of thiols and sulfides [27]. One strategy is to employ a sulfoxide starting material in a so-called "Interrupted Pummerer" reaction [25,28,29]. As shown in Scheme 1, a sulfoxide 1 may be activated with an electrophilic activating agent 2 (commonly an acid anhydride) to give cationic intermediate 3. In a classical Pummerer reaction, intermediate 3 undergoes deprotonation a-to sulfur, with concomitant SeO bond cleavage to give thionium ion 4. This in turn undergoes addition of the carboxylate nucleophile to give a-acyloxysulfide 5 as the final product. However, in the presence of a sufficiently nucleophilic additive, the reaction pathway may be "interrupted", with nucleophilic substitution at sulfur occurring in preference to deprotonation, thereby forming sulfonium salt 6. The interrupted Pummerer reaction has been utilised in [3,3]-sigmatropic reaction cascades [30], in carbohydrate synthesis [31], and in heterocycle synthesis [32].
If an aromatic ring is sufficiently electron-rich, it may act as the nucleophile in the interrupted Pummerer reaction, by an S E Ar mechanism. Azulene (7), a bicyclic, non-alternant arene, fulfils this criterion. Known for its blue colour [33] and anomalous fluorescence [34], azulene has a dipole of 1.08 D, unusually high for a hydrocarbon. This may be rationalised through considerations of resonance, with the resonance structures 7′-7 000 shown in Scheme 2 all possessing a seven-membered ring that is itself aromatic (6p tropylium cation). It follows from these resonance structures that the 1-and 3-positions of azulene are the most electron rich and hence the preferred sites for S E Ar reactions.
Formation of a sulfonium salt by an interrupted Pummerer reaction with azulenes was first reported by Shoji,Ito,Morita and coworkers [35]. As part of our ongoing interest in the chemistry of azulene [36,48,49], we previously reported the synthesis of cyclic sulfonium salts bearing an azulene substituent. These were highly stable and applicable in cross-coupling (Scheme 3) [10]. The crosscoupling of azulenes had previously been difficult, due to instability of most azulenyl halides; this necessitated other approaches [37]. We now wish to report on the scope of the interrupted Pummerer reaction of azulenes, on a variant employing sulfide starting materials, as well as on reactions of azulenesulfonium salts other than in cross-coupling.

Azulenebis(sulfonium) dications
Both the 1-and 3-positions of azulene are highly nucleophilic (c.f. Scheme 2), which can lead to problems of over-reaction in S E Ar reactions. For example, electrophilic halogenation of azulene with N-halosuccinimides inevitably leads to mixtures of 1-halo-and 1,3dihaloazulenes. In contrast, the interrupted Pummerer reaction shown in Scheme 3 provides monosubstitution product 10 cleanly, with no second S E Ar reaction occurring. The introduction of a (positively charged) sulfonium substituent in 10 strongly deactivates the azulene ring towards further S E Ar reactions. Nevertheless, Shoji, Ito, Morita and co-workers have previously demonstrated [35a] that a second interrupted Pummerer reaction may be induced by use of a stronger activating agent, thereby producing an azulenebis(sulfonium) dication. Specifically, use of a sulfonic acid anhydride (triflic anhydride) instead of a carboxylic acid anhydride can provide a Pummerer intermediate 12 (Scheme 4) which is electrophilic enough to react a second time with monosulfonium salts such as 13. (Use of triflic anhydride to activate DMSO for S E Ar reactions with arenes was first reported by Balenkova [38] We have employed triflic anhydride with other azulenes and sulfoxides to obtain novel azulenebis(sulfonium) dications 16e18 that have been characterised crystallographically, as shown in Table 1 and Figs. 1e3. While the procedure in Scheme 4 provides the products as their triflate salts in the first instance, a salt swap with aqueous KPF 6 may be readily effected to give the corresponding hexafluorophosphate salts.
In order to expand further the synthetic accessibility of azulenebis(sulfonium) salts, we investigated other ways to generate reactive electrophiles such as 3 (Scheme 1). Species of type 3 can react with azulenes to give the desired products as they are trivalent sulfur(IV) species bearing a good leaving group. Generation of 3 from a sulfoxide is redox-neutral with respect to sulfur, i.e. starting material 1 is also a sulfur(IV) species. We considered the alternative possibility of generating a reactive sulfur(IV) species in an oxidative process from a sulfur(II) precursor (Scheme 5). In order to activate a sulfide such as 19, selection of the correct activating agent is crucial. Whereas an acylating agent such as 20 (e.g. carboxylic acid anhydride) is the most common choice for sulfoxide activation in interrupted Pummerer reactions, this is not a productive pathway for sulfides. Although acylsulfonium salts such as 21 are known species [39], they would not be expected to undergo the desired S E Ar process at sulfur as the acyl group is not a viable leaving group. Rather, nucleophiles reportedly effect addition/elimination at the carbonyl of 21, and/or attack on the R 1 /R 2 substituents a-to sulfur. In contrast, a sulfonic acid anhydride such as 22 will activate sulfide 19 to give a disulfur species 23, in which a viable leaving group (the sulfone) is attached to the sulfonium. In this case, attack of a nucleophile at the sulfonium centre leads to SeS bond cleavage and loss of a sulfinate anion to give 24.
Reaction of arenes with electrophiles of type 23 in an S E Ar process was first reported by Balenkova and co-workers [40], but to date has not been reported for azulenes. At the outset it was unclear whether sulfonylsulfonium electrophiles of type 23 would be sufficiently electrophilic to react twice and form an azulenebis(sulfonium) dication (as is the case for sulfonyloxysulfonium electrophiles 12) or whether only a single S E Ar reaction would occur. We first attempted formation of the monosubstitution product by treating a mixture of azulene and excess 1,4-oxathiane 25 with only 1.25 eq. of triflic anhydride (Scheme 6A). This provided the expected product 26, thus demonstrating the viability of this alternative approach to the preparation of azulenesulfonium salts. The reaction was repeated with 2.2 eq. of triflic anhydride (Scheme 6B), which led to the formation of azulenebis(sulfonium) dication 27, thereby showing that sulfonylsulfonium electrophiles (23) can indeed effect a second S E Ar reaction on azulene. However, the yield of 27 was low, and a second product predominated, unexpected trifluoromethyl sulfoxide 28. We rationalise the formation of 28 on the basis of the sulfinate anion produced by the first S E Ar process reacting with triflic anhydride to produce mixed sulfonic/sulfinic anhydride 31 [41], which is itself a viable electrophile for a second S E Ar process that introduces the sulfoxide at the azulene 3-position (Scheme 6C). A somewhat analogous process was proposed by Gunji and co-workers to explain the unexpected formation of a sulfoxide upon the attempted sulfonylation of 2-aminoazulene [42]. The structures of 26e28 were confirmed crystallographically ( Fig. 4).
We also evaluated 1,4-dithiane 33 as the sulfide in this process, for which an additional mechanistic pathway can operate. It has  [35a] for this product. been reported that cyclic bis(sulfides) can undergo electrophilic activation and transannular reaction to give disulfonium dications and this pathway operates even for 33, when the product is the highly strained bicyclo[2.2.0] dication 35 [43]. The mechanism proceeding via 35 is depicted in Scheme 7A, although both 34 and 35 would be viable electrophiles for the S E Ar step and we have not attempted to determine whether this mechanism is operative or the one in Scheme 5. Regardless, these reaction conditions are able to effect either monosubstitution (Scheme 7B-C) or disubstitution (Scheme 7D), depending on stoichiometry with respect to triflic anhydride, as was the case for 1,4-oxathiane in Scheme 6. In contrast to the 1,4-oxathiane case, no sulfoxide-containing byproduct was isolated from the disubstitution reaction, although its formation is mechanistically viable in this case also [42]. The structures of 37 and 39 were confirmed crystallographically (Fig. 5).

Sulfonium ring-opening
It has previously been shown that azulenyl dimethyl sulfonium salts react readily with amine nucleophiles at the methyl group, undergoing demethylation to afford the corresponding azulenyl methyl sulfides (Scheme 8A) [35]. As the azulenesulfonium salts we report here are all cycloalkyl structures, the corresponding transformation would effect a ring opening, as opposed to dealkylation, in these cases [44]. We applied this procedure to a selection of azulene monosulfonium and bis(sulfonium) salts, using phenylthiolate as a model nucleophile, as shown in Scheme 8B. In each instance the reaction proceeded to give products 45e50 in good to excellent yield; no chromatography was necessary. The structure of 48 was confirmed crystallographically (Fig. 6).
We also evaluated representative nitrogen nucleophiles (benzhydrylamine, potassium phthalimide) in the azulenesulfonium ring-opening process and found them to be equally competent nucleophiles (Scheme 9), giving 51e52 (Scheme 9A). In contrast, reaction with sodium ethoxide did not effect nucleophilic substitution to give 53, but instead gave a small amount of impure material tentatively assigned as homoallyl sulfide 54, which could arise from an elimination/ring-opening process (Scheme 9B).

Conclusions
This work describes the synthesis of cyclic azulenesulfonium and azulenebis(sulfonium) salts having diversity in both the azulene and the cyclic sulfonium motifs. Two different methods are exploited to synthesise these compounds, namely the redoxneutral interrupted Pummerer process employing sulfoxides, and the oxidative direct electrophilic activation of sulfides. Either of these processes can be made to favour either the mono-or bis(sulfonium) product, through appropriate choice of reaction stoichiometry and/or activating agent. The cyclic sulfonium salts are bench-stable, highly crystalline and readily prepared in good yield. They also undergo facile ring-opening when treated with a variety of nucleophiles, introducing a third point of diversity into the final products (Schemes 8 and 9).

General information
Reactions were carried out under an atmosphere of nitrogen unless stated otherwise. Petrol refers to petroleum ether, bp 40e60 C. Dichloromethane was dried and degassed by passing through anhydrous alumina columns using an Innovative Technology Inc. PS-400-7 solvent purification system. N,N-Dimethylformamide was supplied stored under argon, over 4 Å molecular sieves; no further drying was performed. TLCs were performed using aluminium-backed plates precoated with Alu-gram®SIL G/UV or aluminium backed plates precoated with Alu-gram®ALOX N/UV 254 nm and visualised by the naked eye (for coloured azulene compounds) UV light (254 nm). Flash column chromatography was carried out using Davisil LC 60 Å silica gel (35e70 mm) purchased from Sigma Aldrich. All reagents were purchased from Sigma-Aldrich Chemical Co., Fluorochem Ltd, or Fisher Scientific Ltd.; all reagents were used as received without further purification. IR spectra were recorded on a Perkin-Elmer Spectrum 1600 FT IR spectrometer with universal ATR sampling accessory, with absorbances quoted as n in cm À1 . NMR spectra were run on an Agilent ProPulse 500 MHz instrument or Bruker Avance 500 MHz instruments at 298 K, unless otherwise specified. In tabulated NMR data, "p" refers to a pentet/quintet, "hept" refers to a heptet, and "app" is an abbreviation of "apparent". Capillary melting points were recorded on a Büchi 535 melting point apparatus, and are uncorrected. High resolution mass spectrometry (HRMS) was carried out using a micrOTOF ESI-TOF spectrometer coupled to an Agilent 1200 LC system for autosampling. X-ray crystallography was carried out at 150 K on a RIGAKU SuperNova, Dual, Cu at zero, EosS2 single crystal diffractometer using a microfocus sealed X-ray tube with Cu-Ka radiation l ¼ 1.51484 Å and a Rigaku New Xcalibur, EosS2 using graphite monochromated Mo-Ka radiation (l ¼ 0.71073 Å).

General procedure A: synthesis of azulenebis(sulfonium) salts by interrupted Pummerer reaction
The required azulene (1.0 eq.) and sulfoxide (14.0 eq.) were added to a 100 mL round bottomed flask. The flask was sealed, evacuated and filled with N 2 . 10 mL of CH 2 Cl 2 was added and the reaction mixture stirred for 5 min. Triflic anhydride (2.4 eq.) was diluted in 10 mL of CH 2 Cl 2 , then this solution was added dropwise to the reaction flask. The reaction was stirred at room temperature for 2 h, then solvent was removed in vacuo. The crude product was dissolved in the minimum amount of CH 2 Cl 2 and precipitated after addition excess of Et 2 O. The precipitate was then recrystallised from EtOH to give the desired product.

General procedure B: synthesis of azulenesulfonium or azulenebis(sulfonium) salts by electrophilic activation of a sulfide
The required sulfide and azulene were dissolved in CH 2 Cl 2 under a nitrogen atmosphere and cooled to À78 C in an acetone/dry ice bath. The required quantity of triflic anhydride was dissolved in 5 mL of dry CH 2 Cl 2 and added dropwise to the reaction mixture. After vigorous stirring for the specified period, the reaction mixture was allowed to warm to room temperature, then worked up as specified.

General procedure C: nucleophilic ring-opening of cyclic sulfonium salts
The required sulfonium salt and nucleophile were added to a 50 mL round bottomed flask with a magnetic stirrer bar. The flask was evacuated and filled N 2 gas. 5 mL of DMF was added to the flask and the reaction mixture was stirred at the specified temperature for the specified time. The reaction mixture was diluted with diethyl ether (30 mL), and washed with water (2 Â 30 mL) and 5% LiCl (aq) solution (30 mL). The organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and if necessary, the crude product was purified as indicated.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.