Letter Cite This: ACS Catal. 2019, 9, 6896−6902
pubs.acs.org/acscatalysis
Enantioselective Construction of Chiral Sulfides via Catalytic Electrophilic Azidothiolation and Oxythiolation of N‑Allyl Sulfonamides Yaoyu Liang and Xiaodan Zhao* Institute of Organic Chemistry and MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China Downloaded via GUILFORD COLG on July 18, 2019 at 07:26:20 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: An efficient and convenient pathway was developed for enantioselective synthesis of chiral sulfides by chiral bifunctional selenide-catalyzed electrophilic azidothiolation and oxythiolation of N-allyl sulfonamides. By this protocol, a variety of chiral vicinal azidosulfides and oxysulfides were obtained in good yields with high enantioselectivities and diastereoselectivities. In this transformation, not only electrophilic arylthiolating reagents but also a wide range of electrophilic alkylthiolating reagents worked very well. The practical application of this method was elucidated by further transformations of the products into the diversified compounds. KEYWORDS: electrophilic thiolation, azidation, alkene difunctionalization, Lewis base catalysis, asymmetric catalysis
S
intermediate was an exceptionally convenient pathway for the preparation of chiral functionalized sulfides, because both the thio group and another valuable functional group could be introduced simultaneously into the parent molecules under mild conditions. Usually, a wide range of functional groups were well-tolerated in the reaction. Despite these great advantages, exploration on this area remains relatively rare. As an early step, stoichiometric enantiopure thiosulfonium salts were utilized for the electrophilic aminomethylthiolation of alkenes.10 The products of chiral sulfides were obtained with up to 86% enantiomeric excess (ee). To avoid the employment of stoichiometric chiral thiolating reagents and improve stereocontrol, Denmark developed chiral chalcogenophosphoramide-catalyzed electrophilic arythiolation of alkenes for the synthesis of chiral sulfides.11 Alternatively, Shi reported chiral Brønsted acid-catalyzed electrophilic oxysulfenylation and aminosulfenylation of alkenes for similar purposes.12 Furthermore, our group developed chiral chalcogenide-catalyzed synthesis of optically active CF3S molecules by transferring a specific fluorinated sulfur group, CF3S+, to alkenes in intramolecular and intermolecular manners.13 Although great advances have been gained, these catalytic electrophilic thiolations suffered from the limitations of substrate scope and reaction type. These limitations include the following:
ynthesis of chiral organosulfur compounds has been a long-standing goal in organic synthesis, because of the prevalence of thioether structural units in natural products, drugs, and bioactive molecules.1,2 In addition, chiral organosulfur compounds are an important class of synthetic intermediates3 and ligands (Figure 1).4 Consequently, many
Figure 1. Selected examples of valuable sulfur-containing molecules.
efforts have been devoted to their synthesis, especially with alkenes.5−12 For example, synthesis of chiral sulfides via the transition-metal-catalyzed hydrothiolation of alkenes and catalytic sulfa-Michael additions of thiols to activated alkenes has been documented.7,8 Moreover, electrophilic thiolation of alkenes has emerged as a powerful strategy for the synthesis of chiral sulfides.10−13 Compared with other methods, this electrophilic thiolation reaction via a thiiranium ion © XXXX American Chemical Society
(i) the incorporated sulfur groups are restricted to arylthio and strong electron-withdrawing CF3S groups; Received: May 8, 2019 Revised: June 29, 2019 Published: July 2, 2019 6896
DOI: 10.1021/acscatal.9b01900 ACS Catal. 2019, 9, 6896−6902
Letter
ACS Catalysis
allylamine 1b gave the desired product with 48% ee, albeit in low yield. By replacing the protecting group with the Ts group, the reactivity and enantioselectivity largely increased (3c, 62% ee). When the nitrogen on substrate was further protected by a methyl group, the enantioselectivity of reaction decreased dramatically (3d, 29% ee). To further improve the reactivity and enanioselectivity, different solvents, scaffolds carrying on n-hexylthio group, and catalysts were screened (Table 1). The mixed solvents of dichloromethane and toluene gave product 3c in slightly better ee (entry 1 in Table 1). Other sulfur reagents based on the scaffolds, such as phthalimide, pyrrolidinone, and imidazolidinedione, were much less efficient than 2a (Table 1, entries 2− 4). The protecting groups such as Ts, Ns, and Bz on the nitrogen of catalyst were less effective than the Tf group
(ii) the nucleophiles that attack the thiiranium ions are generally confined to conventional functional groups such as amides, carboxylic acids, alcohols, and aromatic rings; (iii) the scope of alkenes is limited; and (iv) the reaction type almost focuses on intramolecular reactions. As a result, the wider application of chiral sulfides has been severely hampered. Thus, developing new and efficient methods for their synthesis is in great demand. In the aforementioned limitations, we noticed that catalytic enantioselective electrophilic thiolation of alkenes with electrophilic long-chain-alkylthio (AlkylS+) reagents has not been successfully reached, although dialkylthioether moieties are prevalent in molecules as arylthioether moieties.1−4,11a The main reason might stem from the different properties of AlkylS+ species, in comparison with ArS+ species. AlkylS+ species has different reactivity and smaller steric hindrance, which could lead to low yields of products and the issue of enantioselectivity. In the past several years, when we studied enantioselective trifluoromethylthiolation of alkenes with CF3S+ reagents,13 it was discovered that the CF3S+ species was highly reactive, but could be successfully controlled to give the products by adjusting the substituents on the phenyl ring of chalcogenide catalysts. When the substituents of chalcogenide catalyst were adjusted, the basicity of the chalcogen center and steric hindrance were subsequently changed. This made control of the reactivity of CF 3 S + species and the enantioselectivity of the reaction possible. Inspired by this fact, we reasoned that the control of AlkylS+ species might be feasible to afford the products by choosing proper chalcogenide catalysts. Herein, we report our discovery that a bifunctional selenide catalyst enabled enantioselective intermolecular electrophilic azidoalkylthiolation and oxyalkylthiolation of N-allyl sulfonamides. The similar conditions were also suitable for arylthiolation of N-allyl sulfonamides. Enantioselective incorporation of an azido group into the parent molecules to synthesize chiral organic azides has been paid more and more attention in recent years, because the azido group is capable of undergoing functional group interconversions.14 By reduction, cycloaddition, or radical pathway, chiral organic azides could be converted to chiral nitrogen-containing compounds such as amines, 1,2,3-triazoles, and aziridines. However, until now, catalytic enantioselective azidothiolation of alkenes, a potentially important reaction, has never been realized. To challenge this restriction, we initiated our studies on alkylthiolation of alkenes by using N-allylaminetype compounds as substrates,15 N-nHex-succinimide as an electrophilic sulfur source, and TMSN3 as a nucleophile. When azidoalkylthiolation of Bz-protected (E)-3-phenyl-2-propenylamine (1a) was performed at −78 °C using chiral selenide C1 as a catalyst, no desired product was observed and most starting material remained (eq 1). To our delight, Tf-protected
Table 1. Screening of Reaction Conditionsa
entry
catalyst
sulfur source
yieldb (%)
enantiomeric excess, eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d
C1 C1 C1 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C14
2a 2b 2c 2d 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a
38 − − 15 22 42 46 32 64 88 92 59 82 62 73 96 95 (92) 91
65 − − 43 32 48 99:1. bNMR yield using quinoline as the internal standard. Isolated yield is given in parentheses in 0.1 mmol scale. cDetermined by HPLC analysis. dTMSOTf (2.0 equiv) instead of Tf2NH.
6897
DOI: 10.1021/acscatal.9b01900 ACS Catal. 2019, 9, 6896−6902
Letter
ACS Catalysis Scheme 2. Azidothiolation with Different N-Allyl Sulfonamidesa
(Table 1, entries 5−7). In contrast, sulfide catalyst C5 gave the product in slightly lower enantioselectivity (Table 1, entry 8). Based on these results, selenide catalysts showed promise. Various selenide catalysts were then tested. To increase the steric hindrance of the catalyst, a methoxy group was placed at the ortho position of the phenyl ring. The enantioselectivity improved very slightly (Table 1, entry 9). When groups were placed at the two ortho positions, the enantioselectivity decreased dramatically (Table 1, entries 10 and 11). In order to relatively reduce the steric hindrance of catalyst, groups were installed on the meta position (Table 1, entries 12 and 13). The enantioselectivity improved to 76% when two phenyl groups were placed at the meta positions (Table 1, entry 14). tert-Butyl groups at the meta positions resulted in slightly better ee (Table 1, entry 15). When an ethoxyl group was additionally installed at the ortho position, the enantioselectivity increased to 94% (Table 1, entry 17). Other acids such as TMSOTf and TfOH were less effective (Table 1, entry 18). With the optimal conditions in hand, the scope of electrophilic sulfur reagents was evaluated (Scheme 1). All
a
Conditions: 1 (0.1 mmol); other conditions as same as those in Scheme 1. Unless note, all the diastereoselectivities are >99:1. bWith 32:1 dr. cToluene (4.0 mL) as solvent. dWith 19:1 dr. eWith 21:1 dr.
Scheme 1. Azidothiolation with Different Electrophilic Sulfur Reagentsa
94%−96% ee). Steric hindrance of substrates had an impact on the enantioselectivity of reactions. For instance, when placing a fluorine atom at the ortho position of the phenyl ring, product 3w was formed with 85% ee, which was lower than 4-fluorosubsitituted 3u compounds. Naphthyl-substituted allyl sulfonamide gave product 3y with excellent ee. However, when alkyl-substituted allyl sulfonamides were utilized as substrates, the desired products were obtained only with less than 80% ee. In comparison, their azidoarylthiolation gave the corresponding products with high enantioselectivities (3z−3ab, 89%− 91% ee). When the method was applied to oxyalkylthiolation of Nallyl sulfonamides with different oxygen nucleophiles, the desired products were obtained in high yields with excellent enantioselectivities (Scheme 3). Note that water could act as a nucleophile under the acidic conditions. The product of thiolated 1,3-aminoalcohol 4a was obtained in good yield with
a
Conditions: 1c (0.1 mmol), 2 (1.5 equiv), TMSN3 (2.0 equiv), C14 (10 mol %), Tf2NH (2.0 equiv), CH2Cl2 (2.0 mL) + toluene (2.0 mL), −78 °C, 24 h. Unless note, all the diastereoselectivities are >99:1. bWith 31:1 diastereomeric ratio (dr). cWith 49:1 dr.
Scheme 3. Oxyalkylthiolation of N-Allyl Sulfonamidesa
the alkylthiolating reagents generated the azidoalkylthiolation products in good to excellent yields with excellent enantioselectivities and disatereoselectivities (3c−3l, 90%− 96% ee). Various functional groups were well-tolerated under the conditions. For example, when the electrophilic sulfur reagents contained the halo substituents such as Br− and Cl−, double bond, and nitrile group, the reactions still proceeded smoothly to give the desired products in high yields. These functional groups could offer a convenience for the further transformations of products. Not surprisingly, the conditions were also suitable for arylthiolation of 1c. By similar electrophilic three-component reactions, aryl sulfides were obtained in excellent yields with excellent enantioselectivities (3m−3p, 96%−97% ee). Note that the steric hindrance of aromatic sulfur reagent did not affect the reactivity and selectivity of reaction. Next, we turned our attention to examining different N-allyl sulfonamides under similar conditions (Scheme 2). A range of arylpropenylsulfonamides gave the azidohexylthiolation products in good yields with excellent enantioselectivities (3q−3v,
a Conditions: 1c (0.1 mmol), 2a (1.5 equiv), ROH (2.0 equiv), C14 (10 mol %), Tf2NH (2.5 equiv), CH2Cl2 (2.0 mL) + toluene (2.0 mL), −78 °C, 48 h. Unless note, all the diastereoselectivities are >99:1.
6898
DOI: 10.1021/acscatal.9b01900 ACS Catal. 2019, 9, 6896−6902
Letter
ACS Catalysis
more stable thiosulfonium intermediate, which was not easy to react with alkene substrate and then resulted in low reactivity. It was surprising that, using the mixed catalysts of C14 and 3m, the product was obtained with almost the same enantioselectivity using only catalyst C14 (eq 4). Why did product 3m not affect the reaction? We investigated the correlation between yield and reaction time (Figure 2). It was found that the reaction was completed in 60 min using selenide catalyst C14 (10 mol %). In contrast, using product 3m (10 mol %) as a catalyst led to only 4% NMR yield in 60 min. These results suggest that the catalyst is much more efficient than the sulfide products as catalysts.
high enantioselectivity. Moreover, different functional groups such as Br− and alkyne were well-tolerated under the conditions (4c, 94% ee; 4f, 92% ee). These results indicated the generality of this method. The achieved products with multiple functional groups allowed for further transformations (Scheme 4). For instance, Scheme 4. Further Transformations of Productsa
(a) P(OMe)3, toluene, 80 °C, 8 h. (b) Dimethyl but-2-ynedioate, toluene, 115 °C, 6 h. (c) NaH, DMF, rt, 8 h. (d) PPh3, THF/H2O, rt, overnight, and then CS2, NaOH, ClCH2COONa, H2O, rt, 12 h. (e) m-CPBA, CH2Cl2, rt, overnight, and then LiHMDS, THF, reflux, 24 h. a
product 3c bearing an azido group was either reduced to form phosphoramidate 5 or underwent cycloaddition to give triazole 6. Bromo-substituted alkylthio product 3i went through an intramolecular SN2 substitution to give thiomorpholine derivative 7 in high yield. Product 3g was reduced to an primary amine and then gave thiourea 8, an analogue of bioactive molecules,16 in 66% total yield by linking two amino groups. In addition, the thio group on substrate could be removed. For example, sulfide 3m was converted to aziridine 9 bearing an azido group in high yield by a sequence of oxidation of the PhS group to the corresponding sulfone group and intramolecular substitution. The enantioselectivities of products in these transformations were not eroded. These results revealed that the obtained sulfide products were readily modified, which provides a good route for the diversified synthesis of molecules. In the above thiolation reactions, the formed chiral products 3 have an amino sulfide moiety and an H-bond donor. They could be a potential sulfide catalyst to catalyze the thiolation reactions. To reveal whether the sulfide products have an impact on the reactions, control experiments were conducted. When product 3c was used as a catalyst, the reaction of 1c with n HexS+ reagent and TMSN3 gave product 3c′ in
