N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

The synthesis of bifunctional N-sulfinylureas and thioureas with an appended pyrrolidine unit is presented. These organocatalysts were evaluated in Michael additions of aldehydes to nitroalkenes both under solvent-free conditions and in solution. The N-sulfinylurea catalyst was more efficient than the corresponding thiourea. For some substrates, enantioselectivities reached 98% ee. The stereogenic center on the sulfur did not have a considerable influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of aldehydes and hydrogen-bond activation of nitroalkenes.


Introduction
Asymmetric organocatalysis became one of the strategic ways for the efficient synthesis of chiral compounds [1]. Bifunctional catalysis has proven to be a successful concept in asymmetric organocatalysis [2][3][4][5][6][7][8]. An amine unit with a hydrogen-bond donating skeleton is highly efficient from among various possible combinations of catalytic moieties within an organocatalyst. This idea has been inspired by proline catalysis itself, in which the carboxylic function acts as an ancillary hydrogen-bond donor for the direction of one of the reagents [9]. Amines serve as basic units and nucleophilic components capable of carbonyl compounds activation via enamine or iminium ion formation [10,11]. In particular, pyrrolidine became a privileged structural motif central to many catalyst designs [12]. This fact stems from the success of diarylprolinol silyl ethers as chiral organocatalysts, which were independently introduced by Hayashi [13] and Jørgensen [14]. These compounds were used in a large number of stereoselective syntheses, including total syntheses of natural compounds [15]. The pyrrolidine moiety has been successfully combined with thiourea [16][17][18] and the squaramide unit [19,20]. Thioureas and squaramides often feature the electron-withdrawing group attached to one of the nitrogen atoms to increase the acidity of the hydrogen-bond donating unit. This notion has often been realized with substituted aryls such as 3,5-bis(trifluoromethyl)phenyl. Ellman introduced a different approach and developed N-sulfinylureas. An additional potentially useful feature is the stereogenic center on sulfur. tert-Butanesulfinamide is highly useful in stereoselective synthesis as a stereoinducing group [21]. Thus, N-sulfinylureas and thioureas are a new class of organocatalysts, with the sulfinyl group acting both as an acidifying and a chiral controlling moiety. A variety of N-sulfinylureas catalyzed aza-Henry reaction, including enantioselective H-bonding-catalyzed additions to aliphatic N-Boc-imines with high stereoselectivity [22]. A broad range of β-aminonitroolefins were reduced to chiral β-aminonitroalkanes in high yields and excellent enantioselectivities using trichlorosilane as a reducing agent and an N-sulfinylurea as bifunctional organocatalyst [23]. The enantioand diastereoselective addition of Meldrum's acids to nitroalkenes via N-sulfinylurea catalysis gave products that were readily converted to pharmaceutically relevant compounds [24,25]. A sulfinylurea organocatalyst catalyzed a highly selective Michael addition of thioacetic acid to aromatic and aliphatic nitroalkenes to produce chiral β-aminothiols, compounds of pharmaceutical interest [26]. Similarly, the enantioselective addition of thioacids to trisubstituted nitroalkenes was catalyzed by several N-sulfinylureas providing the 1,2-nitrothioacetates in good yields and enantioselectivities [27]. A sulfinylurea catalyst was also applied to catalyze the addition of 3-substituted pyrazol-5-ones to trisubstituted nitroalkenes. The adducts were obtained with good yields and enantioselectivities up to 91:9 er [28].
Inspired by the previous successful applications of sulfinylureas and thioureas as organocatalysts, we have designed four new N-sulfinyl-N'-(pyrrolidinylmethyl)urea and N-sulfinyl-N'-(pyrrolidinylmethyl)thiourea bifunctional organocatalysts. The main design principles are outlined in Figure 1. The catalysts feature a pyrrolidine unit, which should engage in enamine activation of enolizable carbonyl compounds. The urea or thiourea moiety shall provide hydrogen-bond donating ability. Furthermore, these compounds possess a sulfinyl group with an additional stereogenic center on the sulfur. To verify the influence of a matched/mismatched combination of chirality, we employed both enantiomers of tert-butyl sulfinamide with the (S)enantiomer of the pyrrolidine building block.
The introduction of green chemistry principles into chemical transformations is an important goal toward sustainable production and manufacturing. Asymmetric organocatalysis can benefit and accommodate many sustainability techniques [29]. Mechanochemistry can increase the sustainability profile of a chemical process by reducing potentially harmful organic solvents and bring other benefits such as substantially shortened reaction times. A handful of asymmetric organocatalytic transformations were successfully performed under solvent-free ballmilling conditions [30,31]. In this context, we describe the synthesis of new pyrrolidine appended sulfinylurea and thiourea organocatalysts and their assessment in Michael additions of aldehydes to nitroalkenes. Furthermore, we have evaluated the suitability of these catalysts under solvent-free conditions. With the help of DFT calculations, we elucidated the mode of action of these catalysts.

Synthesis of catalysts
We have started the synthesis of the catalysts from Boc-protected (S)-prolinol (1), from which the key intermediate, pyrrolidine derivative 2, can be obtained in three steps according to the literature procedure [32]. Using this method, we obtained the product 2 in a yield comparable (56% overall yield) to that described in the literature. However, the difficult chromatographic separation after each step prompted us to apply a Mitsunobu and Staudinger reaction for the preparation of amine 2 (Scheme 1) [33]. This one-pot reaction gave the desired amine 2 in 56% yield. Then, the corresponding isothiocyanate 3a was prepared by reaction of amine 2 with CS 2 and DCC according to the reported procedure. However, this method gave product 3a in only 44% yield. Therefore, we decided to prepare isothiocyanate 3a using thiophosgene in dry THF with Et 3 N. This procedure afforded the corresponding isothiocyanate 3a in 86% yield (Scheme 1). Isocyanate 3b was also synthesized from amine 2. The reaction with bis(trichloromethyl)carbonate (BTC) afforded the crude product 3b, which was sufficiently pure for use in the next reaction step without further purification (Scheme 1).
The next steps of the catalyst synthesis were the attachment of tert-butanesulfinamide 4 to iso(thio)cyanates 3a and 3b with Application of thioureas C1 and ureas C2 in the Michael addition of aldehydes to nitroalkenes

Michael addition in solution
As the first benchmark transformation, we opted for the Michael addition of butanal (6a) to β-nitrostyrene (7a) catalyzed by (S,R)-C2 (Scheme 3). The reaction in CH 2 Cl 2 at 5 °C with Et 3 N as a base gave 45% of adduct 8a with 86:14 dr and 24:76 er for both diastereomers. Slightly better yields (63%) were achieved in CHCl 3 at room temperature with Et 3 N or NMP as a base, but both diastereoselectivity as well as enantioselectivity remained unchanged. We have used thiourea (S,R)-C1 for this Michael addition, too, but the catalyst was not successful for this reaction (not shown).
Michael acceptors containing heterocyclic groups have been studied only sparingly, but the corresponding chiral compounds with heterocyclic substituents are of high biological and medicinal relevance [34,35]. Therefore, we have decided to evaluate sulfinylurea and thiourea catalysts C1 and C2 also with (E)-2-(2-nitrovinyl)furan (9)  with PhCO 2 H as acid additive gave product 10a in 31% yield after 72 hours with a diastereomeric ratio of 86:14 and high enantiomeric purity of 95:5 er for the major diastereomer (Table 1, entry 1). Using chloroform/isopropyl alcohol 9:1 as the solvent mixture afforded after 120 hours, aldehyde 10a in 45% yield with 83:17 dr and 97:3 er (Table 1, entry 2). The Michael addition in methanol catalyzed by only 3 mol % (S,R)-C1 after 72 hours provided only 18% yield, but with high enantiomeric purity (99:1, Table 1, entry 5). The reaction without a base did not provide the desired product 10a (Table 1,  entry 6). Moreover, a reaction performed with other acidic additives (phenylboronic acid, p-toluenesulfonic acid) provided after 72 hours only 18% and 23% yield of the product with compromised diastereomeric and enantiomeric purity (Table 1, entries 3 and 4). When, we applied 3 mol % of catalyst (S,R)-C1 during 48 hours, we obtained 73% yield with diastereomeric purity 83:17 and high enantiomeric purity, similar to the reaction performed in methanol (99:1 er, Table 1, entry 7). Using the same conditions as with catalyst (S,R)-C1, we also used 3 mol % (S,S)-C1 (Table 1, entry 8). The yield and diastereomeric and enantiomeric purity were very similar as with catalyst (S,R)-C1. However, a further reduction of the catalyst loading to 1 mol % of (S,S)-C1, required a longer reaction time, up to 216 hours and this Michael addition gave only 27% yield of the product (Table 1, entry 11). Additionally, attempting the Michael addition of 3-phenylpropanal (6c) to nitroalkene 9 catalyzed by (S,S)-C1 without any acid additive resulted in a very low yield after 48 hours (29%, Table 1, entry 9) with a diastereomeric purity of 80:20 dr. We also tested the Boc-pro-tected derivative (S,S)-5b as the catalyst (Table 1, entry 10). The Michael addition catalyzed by (S,S)-5b provided racemic product 10a in 23% yield. This result confirms the essential role of the pyrrolidine unit in the enamine formation during the reaction. Michael addition reactions catalyzed with sulfinylureas (S,R)-C2 and (S,S)-C2 provided the products within 24 hours in good yields (63% and 88%, respectively) but with lowered diastereomeric and enantiomeric purities (Table 1, entries 12 and 13).
In terms of the stereochemical outcome, both sulfinylthioureas C1 and urea C2 afforded the same enantiomer as the main product. Furthermore, both diastereomers of both catalysts also directed the Michael addition toward the same enantiomer. These results suggest that the main stereogenic element in the catalyst structure is the pyrrolidine unit. The stereogenic center on the sulfur plays only a minor role, probably because it is far away from the reaction center.
Catalyst (S,R)-C2 catalyzed the Michael addition of propanal (6d) and hexanal (6b) to nitroalkene 9. The reaction in the presence of 3 mol % (S,R)-C2 provided the product 10b in 70% yield and 85:15 dr and 75:25 er (Table 1, entry 14). Here, we have also tested the influence of only basic additive on the reaction and the product was obtained with 73% yield (Table 1, entry 15). The reaction without a base went much less efficiently (Table 1, entry 16), similarly to the reaction performed without acid additive and base (Table 1, entry 17). The product 10c by Michael addition of hexanal 6b to nitroalkene 9 was ob- tained with only 40% yield with comparable diastereoselectivity (Table 1, entry 18). The aliphatic aldehydes propanal (6d) and hexanal (6b) provided medium yields and diastereoselectivity and enantioselectivity.

Michael additions under solvent-free reaction conditions
To evaluate the applicability of the new catalysts C1 and C2, we decided to test them in the Michael addition under solventfree conditions. Ball-milling experiments were conducted in a mixer mill, in which the milling vessels perform radial oscillations with vibrational frequencies from 3 to 30 Hz. These reactions were realized in stainless steel milling jars with an internal volume of 5 mL and with stainless steel balls (Ø 5 mm). We  have started with an evaluation of the solvent-free conditions for the reaction of butanal (6a) and nitrostyrene (7a) using sulfinylurea catalyst (S,R)-C2.
A relatively high yield (81%) of Michael adduct 8a was formed in 3 hours of milling, with triethylamine as the base (Table 3, entry 1). The diastereoselectivity and enantioselectivity reached comparable values as in the solvent conditions. The chemical yield of adduct 8a dropped to 51%, when the excess of butanal (6a) was reduced from 3 to 1.5 equivalents. The diastereoselectivity increased to 93:7 and the enantioselectivity for the major enantiomer was 19:81 and 16:84 for the minor enantiomer, re- The catalyst (2.5-10 mol %), base (10 mol %) and a half volume of aldehyde (total 5 equiv used), were added to a 10 mL vial vessel. After 5 min, the remaining volume of aldehyde was added to the mixture. Benzoic acid (10 mol %) was added after 5 min stirring and 10 min later, nitroalkene (1 equiv) was added. spectively (  Table 3, entries 3-8) proceeded with yields of 53-82%. The highest value of diastereoselectivity was achieved only with triethylamine as the base (dr 93:7) but unfortunately with a comparable enantioselectivity (Table 3, entry 2). When the excess of butanal (6a) was reduced from 3 to 1.5 equivalents, the yield again decreased (Table 3, cf. entries 2 and 7). The Michael addition of aldehyde 6a to nitroalkene 7a with K 2 CO 3 and pyrrole (10 mol %) as the base, respectively, afforded adduct 8a in 71 and 75% yield, with diastereoselectivity of 60:40 and 62:38 and in a racemic form ( Table 3, entries 9 and 10). Only traces of adduct 8a were detected in the reaction mixture when the reaction in the ball mill was carried out without any base and any acid additive (Table 3, entry 11).
Furthermore, we have continued with the evaluation of catalyst (S,R)-C2 in the Michael addition of aldehydes 6a-c to functionalized nitrostyrenes 7b and 7c. These reactions were conducted using a ball-milling set-up as well as solvent-free stirring at 30 °C. The experimental results of the addition reactions of aldehydes 6a-c with nitrostyrenes 7b,c catalyzed with (S,R)-C2 are summarized in Table 4.
The aliphatic aldehyde 6a in the Michael addition with 4-methoxy-β-nitrostyrene (7b) catalyzed by catalyst (S,R)-C2 gave the corresponding Michael adduct exclusively by using the ballmill method. The Michael addition was carried out in the presence of Et 3 N as the base and provided only 32% yield of the product with low diastereoselectivity and enantioselectivity ( Table 4, entry 1). The aliphatic aldehyde 6b with 4-methoxy-βnitrostyrene (7b) gave the Michael addition product 8c by the solvent-free method by stirring at 30 °C. Ten mol % of catalyst (S,R)-C2 gave 32% yield after 48 hours. The best result in terms of yield and diastereoselectivity was obtained by a small amount of catalyst (S,R)-C2. Already 2.5 mol % of (S,R)-C2 provided the product in 75% yield and 71:29 dr and 33:67 er, respectively. A higher catalyst loading of 5 mol % under solvent-free stirring gave 67% yield and 55:45 dr and 50:50 er ( Table 4, entries 2-4). Hexanal (6b) also reacted successfully with 4-fluoro-β-nitrostyrene (7c) and gave the product 8d under solvent-free and ball-mill conditions. Again a small amount of catalyst (S,R)-C2 (2.5 mol %) gave the best chemical yield, 70% using solvent-free, neat stirring at 30 °C. In comparison, the ball-mill reaction afforded 66% of the product (Table 4, entries 5-7). The Michael addition of aldehyde 6c gave under dry stirring products 8e and 8f in 76 and 79% yield with comparable diastereoselectivity and enantioselectivity ( Table 4, entries 8 and 9).

DFT calculations of catalyst structure and reaction stereo-course
To understand the catalyst operation, we have conducted DFT calculations of its structure and reaction course. All calculations were realized using Turbomole program package [36,37]. Geometric optimizations were performed using PBEh-3c functional [38]. This functional is a composite scheme based on the well-known PBE0 functional [39,40]. PBEh-3c corrects for the basis set superposition error and accounts for the long-range London dispersion interactions. Geometrical optimizations were performed with the Karlsruhe split-valence def2-SV(P) basis set [41]. Energies were refined using the Minnesota M06-2X functional [42] and valence triple-zeta def2-TZVP basis set [43]. After the Michael addition, the initial products formed are iminium salts with the catalysts, which are hydrolyzed to the isolated Michael adducts 10. A representative reaction profile is depicted in Figure 4.

Conclusion
We have designed and synthesized bifunctional pyrrolidinecontaining sulfinylureas and thioureas. These catalysts operate via enamine activation of aldehydes and hydrogen-bond activation of the electrophilic component, in this study -nitrostyrenes. These catalysts were effective in the Michael addition of aldehydes to nitroalkenes, affording the corresponding adducts in medium to high diastereomeric and enantiomeric  purities. The reactions under solvent-free conditions performed considerably faster than those under classical conditions in solution, with comparable or better yields, without any significant effect on selectivity. Sulfinylurea catalysts were more active than the corresponding thioureas. The additional stereogenic center on the sulfur plays only a minor role on the stereoselectivity of the reaction, which is governed mainly by the configuration of the proline moiety. DFT calculations elucidated the stereochemical action of the catalysts in organocatalytic Michael addition and suggested the possibilities of further improvement in catalyst design.

Experimental
Synthesis of catalysts The solution of PPh 3 (1.64 g, 6.3 mmol) and N-Boc-(S)-prolinol (1, 1.0 g, 5.0 mmol) in dry THF (10 mL) was cooled in an icewater bath, and subsequently, diisopropyl azodicarboxylate (DIAD, 1.21 g, 6.0 mmol) and diphenylphosphoryl azide (DPPA, 1.65 g, 6.0 mmol) were added dropwise under argon atmosphere. The mixture was allowed to reach room temperature and stirred for 20 h. The reaction mixture was then warmed to 75 °C and refluxed for 2 h, subsequently, PPh 3 (1.64 g, 6.3 mmol) in THF (10 mL) was added, and the reaction mixture was refluxed for further 2 h. After that, the reaction mixture was cooled to room temperature, water (1 mL) was added, and the mixture was stirred for 3 h. Then, the solvent was removed under vacuum and the pH of the residue was adjusted to around 2 with 1 M HCl. General procedure for preparation of N-sulfinylthiourea pre-catalysts (S,R)-5a and (S,S)-5a A stirred solution of (R)-tert-butanesulfinamide or (S)-tertbutanesulfinamide (0.09 g, 0.75 mmol) in THF (5 mL) was cooled to 0 °C under argon atmosphere. Butyllithium in hexane (0.35 g, 0.82 mmol) was added dropwise, and the solution was stirred for 15 min. The cooling bath was removed and the solution of (S)-tert-butyl 2-(isothiocyanatomethyl)pyrrolidine-1carboxylate (3a, 0.20 g, 0.82 mmol) in dry THF (5 mL) was added dropwise over 15 min and stirring continued at rt for four days. The reaction was quenched with water (0.3 mL) and the mixture was stirred for 30 min. The resulting mixture was concentrated in vacuo and the desired product was isolated by column chromatography on silica gel (EtOAc/MeOH/NH 4 OH 60:1:0.6→50:1:0.5). General procedure for the preparation of N-sulfinylurea pre-catalysts (S,R)-5b and ((S,S)-5b) A stirred solution of (R)-tert-butanesulfinamide or (S)-tertbutanesulfinamide (0.07 g, 0.6 mmol) in THF (5 mL) was cooled to −30 °C under argon atmosphere. Butyllithium in hexane (0.28 g, 0.66 mmol) was added dropwise and the solution was stirred for 15 min. The solution of (S)-tert-butyl 2-(isocyanatomethyl)pyrrolidine-1-carboxylate (3b, 0.15 g, 0.66 mmol) in dry THF (5 mL) was added dropwise during 15 min, the cooling bath was removed, and stirring was continued at rt for 22 h. The reaction was then quenched with water (0.3 mL) and the mixture was stirred for 30 min. The resulting mixture was concentrated and the desired product was isolated by column chromatography on silica gel (EtOAc/ MeOH/NH 4 OH 60:1:0.6→50:1:0.5).