Enantioselective Addition of Dialkyl Malonates to β-Arylethenesulfonyl Fluorides under High-Pressure Conditions

Application of high-pressure conditions enables enantioselective Michael-type addition of dialkyl malonates to β-arylethenesulfonyl fluorides. The reaction is efficiently catalyzed with 5 mol % of tertiary amino-thiourea at 9 kbar. Chiral alkanesulfonyl fluorides are formed in yields of up to 96% and enantioselectivities of up to 92%. Functionalization of the adducts via sulfur fluoride exchange (SuFEx) reaction and desulfonylative cyclization is demonstrated.

S ulfonyl fluorides 1 are valuable class of compounds applied as protein inhibitors, 2 polymer building blocks, and substrates for organic transformations. 3Their unique combination of stability and reactivity triggered with hydrogen bonds or silicon species enables "click"-type transformations known as the sulfur fluoride exchange (SuFEx) reaction. 4As activation of the sulfonyl group toward substitution is a key aspect of studies, both "actor" and "spectator" reactions in which the fluoride is being replaced or remains intact are of particular interest.For β-arylethenesulfonyl fluorides (ArCH� CHSO 2 F), both types of the processes are known and give, for example, sulfonates with aryl silyl ethers, conjugate addition products with secondary amines, or cyclic sultams, via sequence of addition−substitution with hydrazines. 5In contrast to ethenesulfonyl fluoride (CH 2 �CHSO 2 F, ESF), 6 known as "the most perfect Michael-acceptor ever found," βarylsubstituted analogues are ∼4.5 orders of magnitude less electrophilic, 7 thus, their reactions with C-nucleophiles remain a challenging task.Key literature examples of such processes are presented in Scheme 1. Lupton et al. reported NHCcatalyzed addition of silyl ethers of dimedone, which gave δsultones. 8,9Qin et al. tested similar DBU-promoted reactions with pyrazolones and 1,3-diketones, whereas diethyl malonate was shown to react with 4-nitrosubstituted substrate by following a pathway of addition−elimination of the fluorosulfonyl group. 10The same author also reported reactions with malononitrile and cyanomalonate, which resulted in substituted cyclopropanes. 11Only recently has water-accelerated phosphazene-catalyzed addition of dithiomalonates been demonstrated in a racemic variant. 12However, under these conditions, an adduct with dibenzyl malonate was formed in only trace amount (<3% of yield), despite presence of advantageous biphasic medium and superbase catalysis.Interestingly, the "on-water" acceleration 13 postulated by Cheong and Bae et al. 12,14 was attributed to confined water-embraced organic cages formed upon vigorous stirring, which display a pressure-like effect. 15In our report, we present addition of dialkyl malonates to a series of β-arylethenesulfonyl fluorides in an enantioselective 16 organocatalyzed variant under homogeneous high-pressure conditions.We conclude about action of the catalytic system on the basis of product configuration and demonstrate transformations of the chiral adducts via SuFEx and desulfonylative cyclization.
Recently, we reported synthesis of ArCH�CHSO 2 F via olefination 17 of arylaldehydes with methanedisulfonyl fluoride (FSO 2 CH 2 SO 2 F, MDSF). 18With the set of substrates in hand, we tested a model reaction of β-phenylethenesulfonyl fluoride (1a) with diethyl malonate (Table 1), thereby giving adduct 2a in the presence of chiral thiourea, urea, and squaramide organocatalysts 3a−l 19 (Figure 1).First, screening of the catalysts in toluene solutions at 9 kbar led to identification of thioureas 3d and 3k as the most promising variants in terms of enantioselectivity and conversion (Table 1, entries 1−12). 20Changes of the solvent (entries 4, 13, and 14) also controlled the reaction course, with toluene combining the highest ee values and reasonable solubility of substrates (model reaction mixture at c 1a = 1.0 M formed a quasi-saturated solution).When the process was run at a lower pressure of 6 kbar (entry 15) and for a shortened time (2 h, entry 17), it remained highly efficient, and substrate conversion decreased only when catalyst loading was lowered to 2 mol % (entries 16 and 18).Finally, we observed that in a more diluted solution (c 1a = 0.5 M) enantioselectivity was improved, and in preparative experiment, adduct 2a was isolated in 94% and 89% ee (entry 19). 20Importantly, the same reaction repeated under atmospheric pressure gave only traces of 2a (∼4% after 7 days, entry 20), which clearly demonstrated effect of the high pressure on the reaction rate.It is noteworthy that despite hydrogen bond complexation with the organocatalyst, the fluorosulfonyl group remained perfectly stable toward substitution on the reaction course.The observation corroborates literature data on sulfonyl fluorides 1a,4 which under the high-pressure conditions, yet unprecedented for SuFEx chemistry, fully support the term 'sleeping beauties'. 3ext, we studied scope of the reaction for various βarylethenesulfonyl fluorides, 1a−r (Scheme 2).After 20 h, we observed practically complete conversion 21 of all sulfonyl fluorides, except 1p and 1r, which were less soluble in toluene.
Although the problem of solubility can be overcome by using less concentrated reaction mixtures, this approach is not recommended because of limited working volume of the highpressure reactors and demand for use of higher catalyst and nucleophile loading. 20In turn, use of a solvent in which solubility is better, e.g., THF, resulted in a lower enantiomeric purity of the adduct (60% ee for 2r).In the remaining substrate series, presence of substituents at the aromatic ring was well-tolerated, and enantioselectivity ranged from 82 to 92%.Only for adduct 2o, which bears two fluorine atoms at the ortho positions, was the ee lowered (73%).Moreover, a very good result was obtained with dimethyl malonate, where product 4 was isolated in 95% yield and 92% ee.
The structure and absolute configuration of representative adduct 2g was established using X-ray crystallography 20 (Scheme 3, left).Accordingly, use of catalyst (1R,2R)-3d afforded enantiomerically enriched product (R)-2g.The result shed some light on mechanism of the asymmetric induction by comparison with course of similar reactions, described in the literature (vide infra).Chiral thioureas containing a tertiary amino group are well-known organocatalysts applied to, for example, the addition of malonates to ω-nitrostyrenes (ArCH�CHNO 2 ) with the parent dimethylamino derivative 3a introduced by Takemoto et al. (Figure 1). 22Importantly, the same direction of asymmetric induction with (1R,2R)-3a is observed in the addition of malonates to ω-nitrostyrenes 22b and to β-arylethenesulfonyl fluorides (Table 1, entry 1), which suggests a similar mode of complexation and mechanism of action.In this context, NO 2 and SO 2 groups can be considered as f unctional isosteres 23 in accordance with early crystallographic studies, 24 addition reactions to α,β-unsaturated sulfones, 25 and enantioselective bond formation between ESF and indolone derivatives. 26Therefore, on the basis of mechanistic studies by Paṕai et al. 27 and Vetticat et al. 28 on conjugate addition to nitroalkenes, 22b we reckon that bifunctional catalyst 3d complexes malonate anion with two hydrogen bonds of the thiourea motif, whereas protonated amino group interacts with oxygen atom of the SO 2 F (Scheme 3, right).
In the last part of the project, we focused on atmospheric pressure addition reactions and postsynthetic functionalizations of chiral adduct 2a.First, we tested model reaction of 1a with diethyl malonate under atmospheric pressure and more vigorous conditions (Scheme 4, top).A stoichiometric amount of NEt 3 in 0.5 M toluene solution was used at rt for 4 days, and rac-2a was formed in 34% yield, whereas the yield increased to a reasonable level of 70% at 60 °C.In turn, an organocatalyzed variant was tested with 20 mol % of thiourea 3d, and the reaction time was extended to 14 days.In this case, we isolated adduct 2a in 55% yield and 81% ee, but at a higher temperature (60 °C), the enantioselectivity decreased to 70% ee.The data demonstrate that malonate adducts can be synthesized under atmospheric pressure using high catalyst loading and prolonged reaction time.However, yields and enantioselectivities of products are questionable (considering, e.g., cost and molecular mass of 3d), and substrate conversions remain incomplete in all cases.
Scheme 2. High-Pressure Organocatalytic Addition of Malonates to β-Arylethenesulfonyl Fluorides (1a−r) a Substrates 1p and 1r were less soluble in toluene.b The reaction was carried out at c 1r = 0.15 M with 10 mol % of 3d and 3 equiv of diethyl malonate.c The reaction repeated under standard conditions in THF afforded 2r, with an isolated yield of 83% and 60% ee. 20The mechanistic model was based on theoretical studies of enolate addition to ω-nitrostyrenes by Paṕai et al. 27 and Vetticat et al. 28 Scheme 4. Atmospheric Pressure Addition Experiments (Top) and Follow-up Studies (Bottom) a Optical rotation of 7 was consistent with the literature data of Senantiomer. 30hen, we studied transformations of model adduct (R)-2a (Scheme 4, bottom).An attempt at decarboxylation with aqueous HCl in acetic acid solution at 100 °C gave a mixture of sulfonyl fluoride (5a, 56%) and sulfonic acid (5b, 43%), with both bearing a free carboxyl group.Synthesis of sulfonamides via SuFEx with (R)-and (S)-1-phenylethylamines (DIPEA, MeCN, 80 °C) gave diastereoisomeric sulfonamides 6a,b isolated in 97% and 90% yield, respectively.Finally, inspired by a report of Qin et al., 11 we tested DBUpromoted cyclization via substitution of the fluorosulfonyl group. 29Interestingly, diethyl 2-phenylcyclopropane-1,1-dicarboxylate (7) was isolated in 83%, and its enantiomeric excess was essentially the same as that of the substrate 2a (89% ee).Optical rotation of 7 was consistent with the literature data of S-enantiomer, 30 thereby supporting a mechanism of nucleophilic substitution in which adjacent stereogenic center remains intact.The synthesis of chiral cyclopropane supplements metal-catalyzed carbene addition methods 30,31 and is of particular interest because of numerous applications of the small ring structures in stereospecific expansion reactions. 32n conclusion, we presented reactions of β-arylethenesulfonyl fluorides with dialkyl malonates catalyzed with chiral amino-thiourea under high-pressure conditions (9 kbar).A set of 19 enantioenriched products was isolated in yields up to 96% and ee values up to 92%.Although unsaturated sulfonyl fluorides are less electrophilic than nitroalkenes 7,33 and react at reasonable rates only under high-pressure conditions, mechanism of action of the organocatalyst is likely the same for both classes of the substrates.Importantly, the enantioselective addition of malonates to ArCH�CHSO 2 F delivers products potent for further transformations, such as SuFEx and cyclization to cyclopropanes.

Scheme 3 .
Scheme 3. X-ray Structure of Adduct 2g (Left) and One of the Plausible Mechanistic Models a of the Observed Asymmetric Induction (Right)