Organocatalyzed Asymmetric Reaction Using α-Isothiocyanato Compounds

Organocatalyzed asymmetric reaction using α-isothiocyanato compounds has received much attention in the past 5 years, and significant progress has been made for three types of isothiocyanato compounds, including α-isothiocyanato amides, esters, and phospho‐ nates. This chapter covers the recent advances of α-isothiocyanato compounds in the organocatalytic asymmetric reaction.


Cascade aldol/cyclization
In 2008, Seidel and coworkers successfully established the first cascade aldol/cyclization reaction of α-isothiocyanato imides (1b) and various aldehydes (11) with a chiral bifunctional thiourea-tertiary amine (7a) as catalyst (Scheme 2) [10]. With this method, a wide range of protected syn β-hydroxyl-α-amino acids (12) could be readily generated in very good results (up to 99% yield, 98:2 dr, and 96% ee) with low catalyst loading ( 5 mol%) and under mild reaction conditions. More importantly, in some instances, due to the product precipitation, the corresponding products even could be directly isolated with high diastereoselectivities and enantioselectivities by simple filtration.
Using the rosin-derived amine-thiourea 7c as a bifunctional catalyst, a highly efficient and convenient cascade aldol/cyclization of α-isothiocyanato amides (1b and 1c) or α-isothiocyanato ester (5) with isatins (15) was disclosed by Wang's group (Scheme 3) [13]. In this process, optically active spirocyclic thiocarbamates (16 or 17) were obtained in good to excellent results. Additionally, the products were readily transformed into biologically active spirooxazolines. Importantly, using a model of acute neuroinflammation, several of the spirooxazolines were found to significantly reduce LPS-induced fever. Shortly after this report, a similar protocol was reported by Zhao's group in 2011 (Scheme 3) [14]. Using catalyst 8h derived from cinchonidine in diethyl ether at room temperature, a series of spirocyclic thiocarbamate compounds 18 were obtained in high yields (up to 99%) with good diastereoselectivities and enantioselectivities (up to 86:14 dr and 98% ee).
Although isothiocyanates have previously been applied in the synthesis of cyclic aldol products [10][11][12][13][14], this represents the first example in the construction of spirocyclic oxindoles using 3-isothiocyanato oxindoles through direct aldol reaction. In the reaction of 3-isothiocyanato oxindoles (2) with simple ketones (19), a range of spirooxindole derivatives (20) containing two highly congested adjacent tetrasubstituted carbon stereocenters were obtained in good to excellent results (up to 95% yield, 95:5 dr, and 98% ee). Moreover, the utilities of this method were also demonstrated by the transformation of product 20a to more structurally diverse spirooxindoles (21-25) (Scheme 5). It is worthy to note that there is no change in the stereoselectivities during the various transformations.  Following this work, our group further disclosed a highly efficient approach for the synthesis of spiro[oxazolidine-2-thione-oxindoles] (26) with 3-isothiocyanato oxindoles (2) and aldehydes (11) via a cascade aldol/cyclization reaction process (Scheme 6) [18]. In this process, spiro[oxazolidine-2-thione-oxindole] compounds 26 were obtained in up to 95% yield, 98:2 dr, and 89% ee. Importantly, in most instances, high reactivity was observed and the reaction could be completed even within 1. 0 min. Scheme 7. Asymmetric synthesis of β-hydroxyl-α-amino phosphonic acid derivatives via organocatalytic direct aldol reaction of α-isothiocyanato phosphonates with aldehydes.
In 2013, our group firstly developed an asymmetric cascade aldol/cyclization reaction between α-isothiocyanato phosphonates (6) and aldehydes (11) for the construction of β-hydroxyl-αamino phosphonic acid derivatives (27) [19]. Using bifunctional thiourea catalyst 8d derived from quinine, a range of protected β-hydroxyl-α-amino phosphonates derivatives (27) containing contiguous quaternary-tertiary stereocenters was obtained in up to 93% yield, >99:1 dr, and 81% ee. The potential application of this method was demonstrated by a large-scale experiment and by the further transformation of one product.
Recently, a novel cascade aldol/cyclization reaction of 3-isothiocyanato oxindoles with αketophosphonates was disclosed by Mukherjee's group (Scheme 8) [21]. This protocol provides an alternative approach to the β-amino-α-hydroxyphosphonate derivatives which contains a spirooxindole scaffold bearing two contiguous quaternary stereogenic centers in high yields with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to >99:1 er). In addition, the products of this reaction can be modified to allow easy access to differently functionalized spirooxindoles. Scheme 8. Enantioselective synthesis of β-amino-α-hydroxyphosphonates between 3-isothiocyanato oxindoles and α-ketophosphonates.
In 2011, Feng's group [24] and Wang's group [25] independently reported highly efficient asymmetric cascade Mannich-cyclization reaction of α-isothiocyanato imides (1a and 1b) with N-Ts-protected imines (30) (Scheme 10). A highly efficient chiral bisguanidine catalyst (9) was used into the reaction of 1a with 30 in Feng's group. In that reaction, significant progress including broad substrate scope, affording chiral α,β-diamino acid derivatives in excellent yields (up to 99%) with high diastereoselectivities (up to >95:5 dr) and excellent enantioselectivities (up to >99% ee) had been made. Notably, the additive (p-CNC 6 H 4 CO 2 H) in the reaction had an important influence on the reactivity and asymmetric induction, which attribute to the hydrogen and the guanidine moiety both played crucial roles in the process. On the other hand, Wang's group used the bifunctional catalyst (8g) derived from rosin affording corresponding Mannich products 31b in high yields (up to 94%) with good to high stereoselectivities (up to 20:1 dr, and 99% ee). And preliminary biological studies revealed that several of the methylthioimidazoline derivatives showed extremely promising antipyretic activity.
Feng and Wang also gave a proposed active model for the reaction in their work, respectively (Scheme 10). Feng proposed that the weakly acidic additive (p-CNC 6 H 4 CO 2 H) could protonate one of the guanidine moieties leading to a guanidinium salt, which activates the N-Ts-imine via hydrogen bond to the nitrogen of the N-Ts-imine. Meanwhile, the active hydrogen atom of α-isothiocyanato imide was deprotonated by the other guanidine group, and then, an intermolecular hydrogen bond stabilizes the α-isothiocyanato imide. Simultaneously, the N-H group of the amide on the same side of guanidine moiety might play as a Brønsted acid to locate α-isothiocyanato amide (1a). In this active model, the activated α-isothiocyanato imide (1a) preferentially attacked the activated N-Ts-imine from the Si-face, affording the desired major product with (4S,5R) configuration. On the other hand, Wang proposed that the rosinderived tertiary amine-thiourea (8g) would act in a bifunctional fashion. The α-carbon atom of α-isothiocyanato amide (1b) was enolized by the tertiary amine moiety of the catalyst (8g). Concurrently, N-Ts-imine (30) was located and activated by two hydrogen atoms of the thiourea moiety through hydrogen-bond interaction. Afterwards, the nucleophile would preferentially attack at the N-Ts-imine (30) from the Re-face, since the Si-face of the N-Ts-imine (30) was restricted by the quinine moiety of the catalyst.
Meanwhile, a similar strategy to access spirooxindole derivatives using quinine 8a as catalyst for the reaction of 3-isothiocyanato oxindoles (2) and N-Ts imines (30) was discovered in our group (Scheme 12) [27]. With the developed protocol, a range of structurally complex spirocyclic oxindoles derivatives (34′) was obtained in good results (up to 99% yield, >99:1 dr, and 97% ee). Importantly, N-PMP aldimine, N-diphenylphosphinoyl aldimine, and N-Boc isatinimine were also good substrates for reacting with 3-isothiocyanato oxindoles (2). A possible model for explaining the stereochemistry of the domino Mannich-cyclization reaction was proposed.
Another kind of asymmetric cascade Michael/cyclization reaction between dimethylpyrazole isothiocyanato imides (3) and methyleneindolinones (35) using bifunctional catalyst (8i) derived from cinchonidine was also explored by Barbas and coworkers in 2012 (Scheme 13) [29]. Dimethylpyrazole was selected as the directing group, because there would have interaction between the pyrazole group and the thiourea moiety of the catalyst. Additionally, the acetyl protecting group played a crucial role in the enantioselectivity. The reaction provided smoothly a range of highly functionalized spirocyclic oxindoles (39) in excellent results (up to 95% yield, >25:1 dr, and 98% ee). Notably, for this kind of asymmetric cascade Michael/cyclization reactions with bifunctional thiourea-tertiary amine catalyst, although two substrates were simultaneously activated by the catalyst, Wang and Barbas gave their respective transition states (Scheme 13). Wang proposed that the oxindole scaffold was activated by double H-bonding, and the α-carbon atom of isothiocyanate imide was activated via enolate anion by the tertiary amine moiety of the catalyst. However, Barbas thought that the oxindole scaffold was activated by the tertiary amine moiety of catalyst and that the αcarbon atom of isothiocyanato imide was deprotonated by double H-bonding.
On the basis of the works from Wang's and Barbas' group (Scheme 13) [28,29], organocatalytic asymmetric cascade Michael/cyclization reaction of α-isothiocyanato imides and esters (1a, 1b, and 4a) with various unsaturated pyrazolones (40) was also explored by Wang and coworkers in 2012 (Scheme 14) [30]. With the developed method, a series of spirocyclic pyrazolone compounds were observed (41a, 41b, and 42) in high diastereoselectivity and enantioselectivity (up to 20:1 dr, and >99% ee). Undoubtedly, this methodology provides a convenient and highly efficient approach for the construction of spiropyrazolone skeletons with high enantioselectivities.
The following examples illustrate the progress in this area.
To further investigate the versatility of 3-isothiocyanato oxindoles for constructing more complex spirocyclic oxindole scaffolds, the cascade Michael/cyclization reaction of 3-isothiocyanato oxindoles (2) with 3-methyl-4-nitro-5-alkenyl-isoxazoles (46) was subsequently explored in our laboratory (Scheme 15) [33]. To our delight, optically active 3,3′-pyrrolidonyl spirooxindole derivatives (47) could be smoothly obtained in high yields (up to 97%) with excellent stereoselectivities (up to >99:1 dr and 98% ee) with cinchona alkaloid quinine as catalyst. Nevertheless, the potential application of this method was also demonstrated by the large-scale experiment and the versatile transformation of the product into other heterocyclic compounds.
Encouraged by our these progresses using 3-isothiocyanato oxindoles (2) as powerful and versatile precursors in the organocatalytic asymmetric cascade Michael/cyclization reactions [32,33], we further attempted to investigate the reactions of 3-isothiocyanato oxindoles (2) with unsaturated isoxazolones (48) and pyrazolones (40) (Scheme 15) [34]. It was observed that the reaction also worked well with quinine as catalyst under mild reaction conditions, delivering two kinds of spirooxindole derivatives (49 and 50) in high to excellent yields with moderate to good stereoselectivities.
Recently, an organocatalytic asymmetric Michael/cyclization cascade reaction of 3-isothiocyanato oxindoles (2) with 3-nitroindoles (51) was disclosed by our groups [35]. With the developed protocol, a wide range of polycyclic spirooxindoles (52), containing three contiguous chiral centers with two of them having quaternary stereocenters, could be obtained with satisfactory results (up to 99% yield, >99:1 dr, and 96% ee). This method is very promising because the reaction is scalable, and the versatile transformations of the products into other spirocyclic oxindoles are also feasible.
At the same year, a similar reaction between isothiocyanato oxindoles (2) and methyleneoxindoles (35) through a cascade Michael/cyclization process for the construction of bispirooxindole scaffolds (45d) was also successfully explored in Huang's group (Scheme 16) [39]. In this process, trifunctional organocatalyst (8n) based on BINAM and quinine scaffolds was efficient for the methyleneoxindole substrates bearing ketone moieties. However, bifunctional organocatalyst (8d) derived from quinine was the optimal catalyst for the methyleneoxindole substrates bearing different ester substituents. It should be noted that all of the reactions could complete in less than 1. 0 min, providing structurally complex bispirooxindole derivatives (45d) in high yields (up to 99% yield) with excellent stereoselectivities (up to >20:1 dr, and 99% ee).
The development of efficient methods to construct complex molecules containing the F atoms has been attracting considerable interest due to the potential applications of this kind of compounds in biology, medicine, and agricultural chemistry as well as in materials science.

Asymmetric [3+2] cycloaddition of 3-isothiocyanato oxindoles with 2butynedioic acid diesters
Encouraged by the achievements in the enantioselective construction of two classes of spirooxindole derivatives (63 and 64) (Scheme 18) [43], Xu and coworkers further investigated the asymmetric [3+2] cycloaddition reaction of 3-isothiocyanato oxindoles (2) and acetylenedicarboxylic acid diesters (65) for the construction of another kinds of spirooxindoles (Scheme 19) [43]. Similarly, two kinds of spirocyclic oxindoles derivatives (66 and 67) were also respectively obtained in good to high yields with good to excellent diastereoselectivities and enantioselectivities by changing the ratio of the two substrates. Additionally, the application of this approach was also demonstrated by a large-scale experiment and by the further conversion of the cycloadduct into other more spirocyclic oxindoles.
In the developed method, the desired spirooxindoles (69) could be obtained in high yields (up to >99% yield) with high enantioselectivities (up to 98% ee) in diethyl ether with the ratio of 2 -68 in 1.3:1 (Scheme 20) [44]. Similarly, another kind of spirooxindoles (70) could also be afforded in excellent results (up to 99% yield and 99% ee) in toluene with the ratio of 2 -68 in 1:2. Nevertheless, various transformations of the cycloadduct into other highly functionalized spirooxindole derivatives were also realized, and some products showed promising antitumor activity via the MTT assays.
In Wang's report [45], a plausible mechanism was proposed. As shown in Scheme 21, the enolized α-isothiocyanato intermediate A might self-cyclize by trapping the oxygen anions in the enolate. The enolized intermediate might exist in two α-isothiocyanate-thiooxazole states, such as B and C tautomerisms (Scheme 21). Subsequently, the sulfur-based nucleophiles in Scheme 21. Catalytic enantioselective ring-opening reaction of meso-aziridines with α-isothiocyanato imides.
the thiooxazole intermediate C attack the activated meso-aziridines (71), and consequently with the aziridine ring-opening process, leading to a series of β-aminothiooxazole compounds (72). Notably, this methodology extends the scope of sulfur-based nucleophiles for asymmetric ring opening of meso-aziridines.

Summary and outlook
Using α-isothiocyanato amides, esters, and phosphonates as new type of versatile reagents for the organic synthesis have been extensively studied and significant process has been made in this area over the past ten years. With these α-isothiocyanato compounds as powerful precursors, the scope of the asymmetric cascade reactions with various organocatalysts has been greatly expanded. Importantly, these developed protocols provided new access to structurally diverse and complex heterocyclic compounds which were difficult to obtain with other reactions. Despite rapid progress in organocatalytic asymmetric cascade reactions with α-isothiocyanato compounds as reagents has been made, the types of chemical reaction in this area are still limited in number. Accordingly, it might be one promising and exciting research field to develop novel asymmetric cascade reactions between the α-isothiocyanato compounds and other accepters, such as nitrosoarenes [46], N-sulfinylanilines [47], oxaziridines [48], nitrones [49], azomethine imines [50], α-halo N-acyl hydrazones [51], epoxidation [52], et al. Moreover, making further insight into the reaction mechanism concerning α-isothiocyanato reagents will facilitate the rapid development of the new methodology in this realm. In summary, the research by employing α-isothiocyanato compounds for the construction of complex heterocyclic compounds via organocatalytic asymmetric cascade process has broad development space. Further ground-breaking and exciting discoveries regarding to the application of the powerful and versatile will be reported in the near future.