Generation of 1,2-oxathiolium ions from (arysulfonyl)- and (arylsulfinyl)allenes in Brønsted acids. NMR and DFT study of these cations and their reactions

Introduction

Allenes are widely explored in organic synthesis for the construction of various molecules [1-7]. In particular, arylsulfonyl (ArSO₂) allenes are usefull building blocks in miscellaneous transformations. For instance, addition of such allenes to Michael acceptors leading to terminal acetylenes has been recently shown [8]. These allenes give rise to pyrrolidines [9], pyrroles [10], chromenes [11], benzoazepinones [12], macrolides [13], and some other carbo- and heterocycles [14-16]. It should be specially emphasized that many compounds containing SO₂ groups are drugs, such as, dapson [17], oxicams [18], or amisulpride [19]. Substantial contribution in this area was made by Harmata et al. [20-24]. However, to the best of our knowledge, electrophilic reactions of (arylsulfonyl)allenes have not been widely studied yet. It has been shown by Ma et al. that ArSO₂-allenes take part into halogenohydroxylation (Hal = I, Br) or addition–elemination of bromine (forming bromobutadienes) with high stereoselectivity [25,26]. Apart from that, reactions of sulfur containing allenes were studied in acidic media [27,28]. Despite promising results, there was no further research in this area.

Based on our recent work on transformations of phosphonoallenes under the action of strong Brønsted or Lewis acids [29-32], we undertook a special study on reactions of (arylsulfonyl)allenes 2a–j and (arylsulfinyl)allenes 1a,b (Scheme 1).

The reaction between proparylic alcohols and arylsulfanyl chlorides followed by acetylene–allene rearrangement was used to prepare (arylsulfinyl)allenes 1 according to the literature procedure [24,25]. The latter were in situ oxidized to (arylsulfonyl)allenes 2 (see X-ray structure of 2h in Figure 1). Allenes 1a,b were specially isolated to compare their reactivity with allenes 2.

The main goals of this work were the investigation of reactions of sulfur-containing allenes 1 and 2 under electrophilic activation with Brønsted or Lewis (super)acids, and the study on cationic intermediates of these reactions by means of NMR and DFT calculations.

Results and Discussion

First, the behavior of allenes 1a,b and 2a–h in Brønsted acids (TfOH, D₂SO₄) was studied by means of NMR (Table 1). Dissolving these allenes in TfOH or D₂SO₄ directly in NMR tubes at room temperature gave intensively colored red solutions of cationic species, which were stable for a long time. The NMR data, including ¹H, ¹³C, DEPT, COSY, and HSQC spectra (see Supporting Information File 1), demonstrated unambiguously that compounds 1a,b and 2a–h underwent cyclization into the corresponding ions Aa,b and Ba–h via protonation (deuteration for D₂SO₄, Bd-d) of the central carbon allenic triad followed by nucleophilic attack of oxygen of the SO₂ group (for Ba–h) or SO group (for Aa,b) onto the carbocationic center. The similar cyclization was observed for phosphonoallenes (see P1, P2, Table 1) by us previously [30,32]. A new signal of the attached proton H4 at δ 8.05–6.83 ppm range appeared in ¹H NMR spectra of species A, B. The comparison of ¹³C NMR spectra of oxathiolylium A, B and oxaphospholium P1, P2 ions shows that for the former species the signal of carbon C5 is about 10–15 ppm downfield shifted relatively the same signal in the cations P1, P2 (Table 1). This reveals that carbon C5 bears a rather large positive charge in cations A, B. For dication Bh, different signals were detected for quaternary carbons C5 and C5', and vinyl carbons C4 and C4', etc., that, probably, indicates formation of two diastereomers (one meso-form and one pair of enantiomers) due to the stereogenic sulfur centers.

In the case of the cation Bf, the signals of two isomers were found in the spectra in a ratio of 5 to 1. These isomers appear due to cis-, trans-orientation of t-Bu and ArS groups in the five-membered ring.

To the best of our knowledge, this is one of the first examples of full NMR characterization of such broad series of cyclic sulfur containing cations Aa,b and Ba–h. Allenes 2i,j did not react with acids at room temperature, however, they react with TfOH at higher temperature (see below).

To estimate the charge distribution in species Aa, Ba we carried out DFT calculations (Table 2). The calculations confirm the experimental NMR data (Table 1) and prove that C5 does have a large positive charge 0.25 e, which should make this carbon a highly reactive electrophilic center. Another electrophilic center is the sulfur atom, which also bears a large positive charge (1.21–2.06 e). Apart from that, the atomic coefficient of contribution in the LUMO for sulfur is much higher than for C5. Thus, the electrophilic reactivity of sulfur may be explained by both charge and orbital control. Also, ortho-carbons in the phenyl group bear a negative charge −0.17 to −0.16 e; this means that intramolecular cyclization on these atoms is possible.

To conclude the study on electronic characteristics of 1,2-oxathiolylium ions A, B by means of NMR and DFT calculations, one should expect that these species may react in several pathways. First, they may undergo nucleophilic attack on sulfur or on carbon C5, due to a high positive charge on it. Another pathway may be an electrophilic cyclization at the ortho-carbon in the S-phenyl ring.

Then, the preparative reactions of allene 2a under the action of different electrophilic reagents were conducted. Transformations of 2a using an excess of various Brønsted acids followed by aqueous quenching of the reaction mixture are shown in Table 3. These reactions resulted in the formation of three different products, Z-3a, Z-4a and 5a, depending on the reaction conditions. At room temperature in CF₃SO₃H or H₂SO₄ for a short time, 10 min or 1 h, respectively, butadiene Z-3a and alcohol Z-4a were formed (Table 3, entries 1 and 3). Increasing the reaction temperature to 60 °C and the time to 8 h in CF₃SO₃H led to the formation of thiochromene 1,1-dioxide 5a (Table 3, entry 2). Decreasing the reaction temperature down to −60 °C in FSO₃H with work-up of the superacidic reaction solution with a low nucleophilic medium (frozen aqueous HCl at −60 °C) gave almost quantitatively butadiene Z-3a with a small admixture of its E-isomer (Table 3, entry 4). Weaker acids, CF₃CO₂H or aqueous HCl, did not activate allene 2a, no reactions took place (Table 3, entries 5 and 6). Apart from that, Lewis acids of various strength (AlCl₃, AlBr₃, FeCl₃, CeCl₃, BF₃-Et₂O, In(OTf)₃) were found to be ineffective for this transformation, no reactions of allenes 2 occurred with them.

Taking into account the data on the formation of cations B (Table 1), their electronic characteristics (Table 2), and reactions of allene 2a in Brønsted acids (Table 3), one may propose a plausible mechanism for the transformation of 2a (Scheme 2). Protonation of the allene system gives cation C, which is cyclized into stable species Ba. Upon work-up of the acidic reaction solution, the fate of the cation Ba strongly depends on the nucleophilicity of the quenching medium. Under the conditions of low nucleophilic work-up with aqueous HCl (Table 3, entry 4), the deprotonation takes place leading to butadiene Z-3a. The predominant formation of the Z-isomer of 3a may reveal that cation Ba undergoes deprotonation and recyclization, rather than species C. Quenching of species Ba with water (high nucleophilicity) affords alcohol Z-4a. The formation of compound 4a in exclusively Z-configuration may indicate that cation Ba reacts with H₂O in S_N2 manner, keeping in mind that carbon C5 in Ba possesses a large positive charge (see data in Table 1 and Table 2). An alternative mechanism of the formation of alcohol 4a includes the attack of H₂O on the sulfur electrophilic center giving intermediate D, which is rearranged into alcohol Z-4a. Preparation of sulfur heterocycle 5a at high reaction temperature (Table 3, entry 2) shows that the intramolecular cyclization to the ortho-carbon of phenyl ring occurs, most probably, through cation C (Scheme 2). And this reaction has a high activation barrier, analogously to the similar cyclization of phosphonoallenes to the corresponding phosphonoheterocycles [30].

We decided to achieve the selective formation of each of these different products, butadienes 3, adducts with nucleophiles 4, and thiochromene 1,1-dioxides 5, from allenes 2. The preparation of compounds 3a–h was done by the following method (Scheme 3). Reactions of 2a–h were carried out in CH₂Cl₂ with 1 equivalent of TfOH to generate the corresponding cations Ba–h. Then, the reaction mixture was cooled down to −35 °C and quenched under very mild and low nucleophilic conditions with frozen aqueous HCl at −60 °C, that finally led quantitatively to butadienes 3a–h (see X-ray structure of 3e in Figure 1). Worth noting, that compounds 3a–h have strictly cis-configuration of SO₂Ar group and a vinyl substituent at C2 carbon. It should be mentioned that palladium-catalyzed isomerization of such (arylsulfonyl)allenes 2 into trans-butadienes 3 was described recently [23]. Herein, we have developed a novel metal-free approach for the synthesis of cis-isomers of 3.

Then, we tried to get selectively products of the nucleophilic attack onto cations B (like structure Z-4a in Scheme 2) by quenching of the acidic reaction solutions (in TfOH) with various nucleophiles (water, methanol, benzene, acetonitrile). But, in all cases, these reactions were unselective. For instance, for allene 2a, mixtures of butadiene Z-3a and alcohol Z-4a were obtained. To overcome this obstacle we decided to use 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), which was known to form the corresponding ether for further substitution reactions [33]. Indeed, the use of HFIP and a catalytic amount of TfOH (0.1 equiv) followed by hydrolysis allowed to achieve an exclusive formation of allyl alcohols Z-4a,b and E-4c from allenes 2a,b,d, respectively, in high yields (Scheme 4). The most probably, this reaction proceeds through intermediate formation of ethers E from the corresponding species B. The ethers E are hydrolyzed to compounds 4. Reactions of allenes 2 with other nucleophiles (methanol, benzene, acetonitrile) led to the formation of complex mixtures of reaction products. It must be noted that no reaction proceeded in HFIP without TfOH.

The assignment of the cis-configuration of the ArSO₂ group and the C3-substituent in compounds 3 and 4 was based on the low spin–spin interaction constant of 8.0–11.8 Hz between the vinyl protons in the ¹H NMR spectrum (see Supporting Information File 1) and on comparison with the known trans-isomers of 3 [23].

Compounds Z-3a and Z-4a could be interconverted in acids through species Ba (Scheme 2). Thus, both Z-3a and Z-4a give cation Ba upon dissolving in TfOH. Then, a different quenching of solution of the cation affords Z-3a (Scheme 3) or Z-4a (Scheme 5). Heating of the solution of Ba leads to 5a (see Scheme 5).

The exclusive formation of thiochromene 1,1-dioxides 5a–c was obtained by running the reaction of 2a,c,d with 1 equivalent of CF₃SO₃H at high temperature (reflux in ortho-dichlorobenzene at 144 °C) for 2 h (Scheme 5, see X-ray structure of 5c in Figure 1). It was found by H,H-NOESY and COSY correlations, that there was a [6,7]-shift of the methyl group in the thiochromene system of 5b obtained from allene 2c, which, at first, should give 6-methyl substituted thiochromene. This shift is caused by the action of superacid at high reaction temperature. Phenyl-substituted allenes 2e,f did not afford the corresponding thiochromenes, due to oligomerization under the harsh reaction conditions. Other allenes 2g,h gave the corresponding heterocycles 5 in very poor yields (<4%, by GC–MS and ¹H NMR data).

As it was mentioned above, unsubsituted allenes 2i,j did not react with TfOH at room temperature (see discussion on NMR of cations B, Table 1). Under the heating in TfOH at 100 °C for 0.5 h, these allenes afforded (arylsulfonyl)acetones 6a,b, which may be formed under the hydrolysis of the formed vinyl triflates F (Scheme 6).

Finally, in this study, we carried out reactions of (arylsulfinyl)allenes 1a,b under superelectrophilic activation with TfOH or AlX₃ (X = Cl, Br). The corresponding cations Aa,b generated from 1a,b in TfOH were subjected to quenching with various nucleophiles followed by hydrolysis (Scheme 7). In all the cases, allyl alcohols 7a,b were isolated (see X-ray structure of 7b in Figure 1). The same alcohols were obtained in reactions of 1a,b with AlX₃ (X = Cl, Br) after the hydrolysis of reaction solutions. In these reactions, presumably, intermediate adducts G, which are formed upon interaction of species Aa,b with nucleophiles, are easily hydrolazible and give rise to alcohols 7a,b.

Conclusion

Transformations of (arylsulfonyl)- and (arylsulfinyl)allenes under the action of the Brønsted superacid TfOH, or strong Lewis acids AlX₃ (X = Cl, Br) have been studied. Under electrophilic conditions, these allenes form the corresponding 1,2-oxathiolium ions, which have been studied by NMR and DFT calculations. Depending on electrophilic activator, reaction conditions (temperature, time), and nucleophilicity of media for quenching of solutions of 1,2-oxathiolium ions, these species may undergo various transformations leading to the selective formation of one of the reaction products: conjugated dienes, allyl alcohols, or thiochromene 1,1-dioxides. These reactions open new opportunities for organic synthesis based on electrophilic activation of sulfur containing allenes.