Synthesis and Properties of Chiral Thioureas Bearing an Additional Function at a Remote Position Tethered by a 1,5-Disubstituted Triazole

The synthesis and properties of multifunctional thioureas bearing a variety of functional groups at a position remote from the thiourea moiety are described. A 1,5-disubstituted triazole tether connected with a thiourea and another functional group was synthesized via ruthenium catalyzed Huisgen cycloaddition. We demonstrate the utility of the synthetic thioureas as asymmetric catalysts and probes for the mechanistic elucidation of the course of the Michael reaction of an α,β-unsaturated imide.


Introduction
The development of organocatalysts represents an important field in asymmetric synthesis [1]. Over the past decade, thiourea-based bifunctional catalysts such as 1 (Figure 1) have emerged as promising chiral catalysts due to ease of accessibility and their high efficiency in various asymmetric transformations [2][3][4][5][6][7][8][9]. Thiourea 1 has isolated acidic and basic functional groups in the same molecule. The combination of two functional groups within a chiral space of the catalyst leads to synergistic effects on the activation of substrates, providing high stereoselectivity and/or acceleration of the reaction rates. In most bifunctional thiourea catalysts, another functional partner is placed at a neighboring position so as to entropically activate the bimolecular reaction. Thioureas bearing another OPEN ACCESS activating site at comparably remote positions have not been explored thoroughly [10]. On the other hand, in case of well-designed enzymes, sequentially distant functional groups can synergistically participate in the activation of the enzymatic reaction through the organization of an adequate chiral space. We envisioned that thiourea catalysts tethered with the third functional group at a remote position would provide further advantages with regard to molecular catalysis ( Figure 1). One of the important and challenging matters would be the adequate design of the tether, which must appropriately display conformational flexibility/rigidity in order to provide an organized reaction space. Additionally, synthetic accessibility in the formation of the tether would be valuable. 1,3-Dipolar cycloaddition of alkynes with alkyl-or arylazides, also known as the Huisgen cycloaddition [11], affords substituted 1,2,3-triazole compounds. A great deal of attention has been paid to the Cu(I)-catalyzed Huisgen cycloaddition giving 1,4-disubstituted triazoles (known as "click chemistry") due to several synthetic advantages, including a wide tolerance for various functional groups, high chemical yield, simple reaction operation and easy purification [12]. Ru(II) catalysts are also known to activate the cycloaddition, but the catalyst results in the exclusive formation of 1,5disubstituted triazoles [13][14][15]. Thus, both substituents of Ru-catalyzed cycloadducts, 1,5-triazoles, direct at the same side, whereas those of 1,4-disubstituted triazoles are oriented at opposite sides ( Figure 2). We envisioned that the 1,5-disubstituted triazole core would be suitable for the tether for the following reasons: 1) conformational rigidity of the aromatic ring, 2) both substituents of 1,5disubstituted triazoles directing to the same side, and 3) synthetic convenience. Herein we wish to report on the synthesis of chiral thioureas bearing acidic, basic or neutral functional groups at a remote position using Ru-catalyzed Huisgen cycloaddition and their utility as chiral organocatalysts and probes for the mechanistic elucidation of the course of the Michael reaction of an α,β-unsaturated imide [16].
We envisioned synthesizing thioureas bearing a variety of functional groups at remote positions. Preparative procedures of azide partners 8, 10, 12, 15 are depicted in Scheme 2. Azide 8 bearing a phenolic function was synthesized from alcohol 7 according to the reported procedure [18]. Azide 10 possessing a carboxylate equivalent was prepared from bromide 9 [19]. Both enantiomers of proline derivative 12 were obtained from the corresponding enantiomeric alcohols 11 [20] in two steps. Azides 15a,b having α,β-unsaturated imide moieties were prepared in two steps from 13a,b [21,22] We next examined the Ru-catalyzed Huisgen reaction of alkynes 6 with benzylazide (16) in the presence of Cp * Ru(PPh 3 ) 2 Cl or [Cp * RuCl] 4 , which were reported to be highly active catalysts in the Huisgen cycloaddition [13][14][15]. Unfortunately, almost no formation of the desired cycloadduct was observed under any of the conditions tested. Further study revealed that the ruthenium catalyst was being inactivated by an undesired ligation with the sulfur atom of the thiourea moiety. Therefore, we modified the synthetic route towards creation of the desired thioureas to the following sequence: i) Rucatalyzed Huisgen cycloaddition of alkynyl substrates and azide partners, ii) installation of thiourea moiety (Scheme 3). Scheme 3. Synthesis of chiral thioureas bearing a 1,5-disubstituted triazole tether Chemical yields of 18 are summarized in Table 1. For example, regioselective Huisgen cycloaddition of alkyne 5a with benzylazide (16) was smoothly activated by [Cp * RuCl] 4 in THF at ambient temperature giving 1,5-disubstituted triazole 17a in 71% yield (entry 1). Conversely, the reaction with phenol 8 under the same conditions resulted in poor conversion to the desired triazole 17b. It was found that microwave irradiation in DMF (110 o C) was effective for the cycloaddition, giving 17b in 42% yield (entry 2). Huisgen cycloaddition of 5a,b with azides 8, 10, 12, 15a and 16 , respectively, under the same conditions, afforded 17 in moderate yield (entries 2-7 and 9). The regioselectivity in the cyloaddition was controlled to furnish 1,5-disubstited 1,2,3-triazoles exclusively. However, it was found that the reactivity of arylazide 15b in the Ru-catalyzed Huisgen reaction was poor and, consequently, only a trace amount of triazole 17h was produced under all conditions tested (entry 8). Transformation of 17 into 18 was achieved over a couple of steps, namely, deprotection of the Boc group of 17, followed by treatment with 3,5-bis(trifluoromethyl)isothiocyanate and hydrolysis (only for 17c-f), furnished thiourea 18a-g,i in fair yield. The synthetic sequence involving Huisgen cycloaddition would be a facile and new methodology to prepare new classes of multifunctional thioureas. Although a thiourea function is incompatible, it was found that various functionalities, such as phenol, amine, amide, carbamate, imide and ester groups, are tolerant of the Ru-catalyzed Huisgen reaction.

Michael Reaction of α,β-Unsaturated Imides Bearing a Thiourea Auxiliary: Identification of Adequate Hydrogen Bond Network
We have reported that thiourea 1 smoothly catalyzes a conjugate addition of malononitrile to α,βunsaturated imides to give the corresponding Michael adducts with high enantioselectivity [24][25][26]. We proposed a ternary complex as the transition state model [27], in which the thiourea moiety of 1 would interact with the imide function of the substrate by two sets of hydrogen bonding to create an adequate chiral catalytic site, and, moreover, malononitrile would be activated by an amino moiety of 1 ( Figure  3, left). However, because the binding constant of thiourea 1 with an imide substrate was very small, it was difficult to observe the binding structure by NMR in order to elucidate the mechanistic insight. The correct structure of the transition state remains to be cleared. We envisaged that thioureas 18g and 18i tethered with an α,β-unsaturated imide moiety would be utilized as appropriate mimic for the transition state model. For this purpose, we examined the reactivity of 18g and 18i in a Michael addition with malononitrile. If the thiourea moiety of 18 interacts with the imide group via the appropriate hydrogen bonds like the transition state shown in Figure 3, the conjugate addition should proceed much more smoothly as compared with a substrate possessing no or less hydrogen bond Interaction. When 18g was treated with two equivalents of malononitrile in dichloromethane at room temperature, almost no reaction producing Michael adduct 21g occurred within 48 h (Scheme 5). In contrast, 18i, whose tether is one methylene unit longer than that of 18g, furnished the corresponding adduct 21i in 32% yield [28]. The diastereomeric selectivity of 21i was determined to be 55%de after transesterification of 21i to give the corresponding methyl ester. The chirality of the stereogenic center was assigned to be (R), which is identical to that reported ones using thiourea 1 [24]. The results indicated that the α,βunsaturated imide moiety would be activated by the thiourea function through the hydrogen bonding and the length of the tether between thiourea and imide functions would be very important. Although we next attempted the conformational analysis of 18g,i to throw light on their hydrogen bond network, no suitable crystal on which X-ray crystallography could be performed was obtained and it was, unfortunately, difficult to analyze the conformation via NMR. We anticipate that further studies employing another approach will be indispensable to elucidate the transition state for the Michael addition catalyzed by thiourea 1.

Scheme 5.
Michael addition of 18g and 18i with malononitrile.

Asymmetric Michael addition with Thiourea-Pyrrolidine Based Trifunctional Catalyst
We next examined the utility of trifunctional catalysts 18 and 20 having a triazole tether to elucidate the effect of the remote functional group. Asymmetric Michael addition is one of the representative C-C bond formation reactions in organocatalysis. In particular, extensive efforts have been devoted to the enantioselective Michael reaction of ketones with nitroalkenes [29][30][31][32][33][34][35][36][37][38] since the nitroalkanes produced bearing contiguous stereogenic centers would be versatile synthetic intermediates. Several pyrrolidine-based derivatives have been reported to catalyze the reaction with good to high diastereoand enantioselectivity. Chiral thiourea-pyrrolidine-based bifunctional catalysts have been also found to give excellent enantioselectivities [7]. However, some problems, such as the slow reaction rates still persist with most of the pyrrolidine-based organocatalysts.
During the course of our study, Kilburn et al. reported on some thiourea-pyrrolidine based bifunctional catalysts [7] in which both functions are placed at considerably distant positions tethered with a simple alkyl chain. Some of these bifunctional catalysts demonstrated excellent rate acceleration with good stereoselectivity in the reaction of cyclohexanone with trans-β-nitrostyrene. They clarified the fact that the tether between thiourea and pyrrolidine of the optimized catalyst consists of five atoms.
The catalytic activity of thiourea-pyrrolidine catalyst 18d-f and 20d was evaluated under the same conditions as Kilburn's study [7] ( Table 2). The thiourea moiety of 18d and 18e is separated from the imide function by seven atoms, whereas the spacing of 18f and 20d is eight atoms. Catalyst 18d which has a 1,5-disubstituted triazole tether produced nitroalkane 23a in 91% yield with good diastereo-and enantioselectivities (91:9 syn/anti selectivity, 92% ee of syn-23a; entry 1). The stereochemistry of major isomer 23a was determined to be syn by comparison with reported data [5][6][7][8][9]. The chirality of 23a obtained from 18d was opposite to that from 18e (entry 2). Thus, the enantioselection in the reaction appears to be mainly dominated by the chirality of the pyrrolidinyl moiety. Although the difference in the value of enantiomeric excess is not so significant, it was observed that the chirality of the 1,2-diaminocyclohexyl moiety affects the selectivity somewhat (entries 1 vs 2). Catalyst 18f having a tether that is one methylene longer also afforded 23a in good yield, however, with lower syn/anti selectivity and enantioselectivity (entry 3). The results clearly indicated that tether length would be important for asymmetric induction in the Michael addition. Interestingly, we have found that the rate of reaction with 20d having a 1,4-disubstituted triazole tether was much slower than that with 18d-f, although the enantioselectivity was comparable to that of 18d (entry 4). This result points out that the relative position of the thiourea and pyrrolidine moieties are a critical factor for the rate acceleration in the Michael addition reaction. Although the catalysts 18f and 20d possess a tether that is eight atoms in length, the acceleration rate of the conjugate addition by catalyst 18f was, interestingly, greater than that of 20d. Thus, the direction of the substituents on the triazole ring of the catalyst would affect the rate enhancement in the reaction. In other word, the tether of 18f would be more flexible than that of 20d. Therefore, both of the thiourea and pyrrolidine moieties of 18f could participate in the synergistic activation of the substrates.
As Kilburn reported that the reaction rate drastically decreased in the reaction with monofunctional pyrrolidine catalyst 24 (entry 5), it has been made clear that the thiourea function of the catalyst system can positively participate in the activation of the substrate. The absolute configuration of the major enantiomer syn-23a in the reaction with 18d was determined to be (2R,1'S) by the comparison of HPLC data with reported data [5][6][7][8][9]. The configuration is consistent with a synclinal transition state for pyrrolidine-based chiral organocatalysis. A suggested transition state model is shown in Figure 4. The hydrogen bond network among the thiourea moiety, tertiary ammonium and the nitro group would direct the nitrostyrene to attack of si-face of the enamine.  Furthermore, we examined the scope of the asymmetric Michael addition using 18d (Table 3). Nitroolefins 22b-f bearing a variety of aryl group gave the corresponding Michael adducts in high yield with a good stereoselectivity [39].

General
All reactions were carried out under a positive atmosphere of argon in dried glassware unless otherwise noted. Solvents and materials were obtained from commercial suppliers and used without further purification. Column chromatography was performed on Merck silica gel 60 (230-400 mesh). Reactions and chromatography fractions were analyzed employing pre-coated silica gel plate (Merck Silica Gel 60 F 254 ). All melting points were measured on YANACO MP-500P micro melting point apparatus and are uncorrected. IR spectra were measured on JASCO FT/IR-410. The 1 H-and 13 C-NMR spectra were recorded on JEOL AL-400 or JEOL ECP-500 instruments with tetramethylsilane as internal standard. Low-resolution and high-resolution mass spectra were recorded on JEOL JMS-01SG-2 or JMS-HX/HX 110A mass spectrometer.

General Procedure for Ru-Catalyzed Huisgen Reactions
To a solution of [Cp * RuCl] 4 (2.5 mol%) in DMF, 5 (1.0 eq) and azide (1.0 eq) were successively added at room temperature .The mixture was heated to 110 °C under microwave irradiation with stirring for 20 min. The resulting mixture was diluted with AcOEt and brine, and then extracted with AcOEt twice and washed with brine three times. The extracts were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography.

General Procedure for Cu-Catalyzed Huisgen Reaction
To a solution of CuSO 4 (10 mol%) and sodium ascorbate (20 mol%) in t-BuOH-H 2 O (1 : 1 v/v), 5a (1.0 eq) and azide (1.0 eq) were successively added at room temperature. After being stirred for an appropriate time (4-6 h), the mixture was diluted with H 2 O. The residue was extracted with CHCl 3 three times. The combined organic layers were washed with water twice and brine. The organic phase were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography.

General Procedure for the Synthesis of Thioureas 18 and 20
To a stirred mixture of appropriate substrates in CH 2 Cl 2 at room temperature, TFA was added (CH 2 Cl 2 : TFA = 1:1). After being stirred at room temperature for 1-3 h, the mixture was made basic with sat. aq NaHCO 3 and extracted three times with CHCl 3 . The combined organic layers were dried over NaSO 4, filtered, and concentrated in vacuo to give the corresponding amine. A solution of the crude amine and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.0 eq) in THF was stirred at room temperature for 2-10 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the corresponding thiourea. If necessary, the following deprotonation reaction was carried out. To a mixture of the protected compound in THF, LiOH (10 eq) in H 2 O was added (THF/ H 2 O = 1:1). After being stirred at room temperature for 2-10 h, the mixture was quenched with sat. aq NaHCO 3 or sat. aq NH 4 Cl. The mixture was extracted three times with AcOEt. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. silica gel column without concentration, and purified by column chromatography. Spectral data of all products 23a-f were identical with the reported ones [8,38].

Conclusions
In conclusion, we have described the synthesis of trifunctional thioureas bearing a 1,2,3-triazole tether, in which one of the functional groups is placed at a considerable distance from the thiourea moiety. Regioisomeric catalysts having a 1,5-and 1,4-disubstituted triazole were readily prepared using ruthenium and copper catalyzed Huisgen cycloadditions, respectively. To the best of our knowledge, this is the first reported case of preparation of asymmetric catalysts by Ru-catalyzed azidealkyne click chemistry [40,41]. We utilized the synthetic thioureas bearing an imide moiety as transition state mimics of the catalytic Michael reaction of α,β-unsaturated imides with malononitrile. Moreover, we demonstrated the catalytic activity of synthesized thiourea-pyrrolidine based catalysts in the enantioselective Michael addition. It was found that thiourea and pyrrolidine functions would synergistically activate substrates, although they are placed at sequentially remote positions (seven atoms' tether length) to accelerate the reaction rate. , 568-576. 28. Against our expectations, the reaction rate of 18g,i was much slower. According to our previous reports, thiourea catalysts bearing a bulky amino group as a basic function displayed less catalytic activity than 1 possessing a dimethylamino group in the conjugate additions [24,42]. We have examined a Michael addition to α,β-unsaturated imide 25 with 1 or 18a.