Catalytic Asymmetric Synthesis of Both Enantiomers of 4‑Substituted 1,4-Dihydropyridines with the Use of Bifunctional Thiourea-Ammonium Salts Bearing Different Counterions

Organoammonium salts composed of a Brønsted acid and an anilinothiourea promoted the Michael addition of β-keto esters and α,β-unsaturated aldehydes in the presence of primary amines to give functionalized 1,4-dihydropyridines enantioselectively. With the use of the different Brønsted acids such as DFA and HBF4 with the same bifunctional thiourea, both enantiomers of 4-substituted 1,4-dihydropyridine were synthesized from the same starting materials.


Introduction
Asymmetric catalysis using bifunctional catalysts has attracted considerable attention in synthetic organic chemistry. Various types of bifunctional metal- [1][2][3][4] and organo-catalysts [5,6] have been developed and used for catalytic enantioselective reactions over the past decade. Generally, bifunctional acid-base catalysts concurrently activate both nucleophiles and electrophiles to promote addition reactions with high catalytic activity and excellent stereoselectivity via a dual activation mechanism [7,8]. We have previously reported that bifunctional aminothiourea 1 could be used for the asymmetric 1,2-and 1,4-addition of various active methylene compounds to imines and nitroolefins [see (a) in OPEN ACCESS Figure 1)] [9][10][11]. A different approach to asymmetric organocatalysis has been realized through the use of conjugated acid systems, such as in Diels-Alder and aldol reactions [12][13][14][15]. By combining these two concepts, we recently realized Brønsted acid-bifunctional thiourea co-catalysis, in which bifunctional thiourea not only activates an achiral Brønsted acid, but also changes its reaction mode to give the alternative regioisomer as a major product, albeit with moderate enantioselectivity [16]. Our working hypothesis is shown in Figure 1, (b) and (c). When thiourea 1 and a Brønsted acid (HX) are mixed in a 1:1 ratio, ammonium salt complexes A and B are equilibrated with the starting materials 1 and HX, depending on the acidity of HX and the hydrogen-bonding (H-bonding) ability of the conjugate base (X -). If the conjugate base is a strong H-bonding acceptor, H-bonding complex A, in which Xis anchored to the thiourea moiety by H-bonds, would be predominant. Otherwise, ion-pair complex B might prevail. The difference between the original bifunctional thiourea 1 and ammonium salt A is that the conjugate base (X -) acts not as a nucleophile, but as a base, which activates a co-existing nucleophile (Nu-H) such as enamino ester or β-keto ester. To explore this hypothesis, a wide range of Brønsted acid-bifunctional thiourea co-catalysts were synthesized and examined. In this article, we describe the details of the versatility of various Brønsted acid-bifunctional thiourea co-catalysts [17,18] together with their application to the asymmetric synthesis of functionalized 1,4-dihydropyridines.

Results and Discussion
1,4-Dihydropyridines (1, and their derivatives are important bioactive compounds and versatile synthetic intermediates in the pharmaceutical industry and in process chemistry. Due to the need for 1,4-DHP derivatives, various synthetic methods have been developed [19][20][21][22]. Although symmetrical 1,4-DHP can be easily prepared by the well-known Hantzsch method [23], new methods for the synthesis of unsymmetrical DHPs are still needed. Furthermore, there have been only a few reports on the organocatalytic enantioselective synthesis of 1,4-DHP [24][25][26]. These routes are shown in Scheme 1. The highly enantioselective synthesis of 1,4-DHP via route a from cinnamaldehyde, arylamine, and a 1,3-dicarbonyl compound with a chiral phosphoric acid was achieved by Gong's group [24]. Similarly, Renaud et al. reported that another chiral phosphoric acid catalyzed three-component cyclization to afford the product with moderate selectivity (50% ee) via route b [25]. Therefore, we examined three-component cyclization via both routes a and b in the presence of the Brønsted acidbifunctional thiourea co-catalysts to test their abilities in asymmetric reactions.

Synthesis of chiral bifunctional thioureas 1a-h for Brønsted acid-thiourea co-catalysts
To investigate the catalytic potential of various Brønsted acid-thiourea co-catalysts, we first synthesized several bifunctional thioureas 1a-h bearing a functional group, such as a hydroxy or Narylamino group, which have different Brønsted basicities ( Figure 2). By changing the basicity of the second functional group of the thiourea catalyst as well as the acidity of Brønsted acid, we can tune both the acidity of the oxonium or ammonium proton and the basicity of the counterion (X − ).
To synthesize N-arylaminothioureas 1d-h, we examined two synthetic routes. In the first Buchwaldtype amination of (R,R)-1,2-cyclohexyldiamine with appropriate aryl iodides was used as a key step (Scheme 2). However, the key reaction gave the desired products 1d and 1e in low yields. We then used the second route to synthesize more functionalized catalysts 1f-h, which involved the diastereoselective ring-opening of chiral aziridine 2 [27] with functionalized anilines, as shown in Scheme 3. The ringopening of 2 with the corresponding anilines produced the two diastereomers 3f-h and 4f-h. The absolute configurations of 3f and 4f were determined to be (1S,2S,1S') and (1R,2R,1S'), respectively, based on the results of an X-ray single crystallographic analysis of 4f. The stereochemistries of other products 3g-h and 4g-h were deduced from this result for 4f (Scheme 3). The hydrogenation and thiocarbamoylation of 3f-h provided the desired thioureas 1f-h in good yields.

Brønsted acid-bifunctional thiourea co-catalysts for the synthesis of 3,4-disubstituted 1,4-DHPs
We initially investigated the reaction of enamino ester 5a and α,β-unsaturated aldehyde 6a in toluene with Brønsted acid-bifunctional thiourea co-catalysts as well as achiral Brønsted acids. Representative results are summarized in Table 1. Notably, strong Brønsted acids such as HBF 4 and TfOH provided the desired 1,4-DHP 7aa as a major product, while the same reactions with TFA (trifluoroacetic acid) and DFA (difluoroacetic acid) afforded mixtures of 1,4-DHP 7aa and 1,2-DHP 8aa in ratios of 2:1 and 1:2, respectively. In contrast, a weak Brønsted acid such as AcOH did not give any products, and only the starting materials were recovered. These results indicate that the acidity of the catalyst significantly affected the yield and regioselectivity of the products. On the other hand, neither aminothiourea 1a nor DFA-1a co-catalyst furnished any of the desired DHP's in the same reaction. In an attempt to decrease the Brønsted basicity of bifunctional thiourea, we used hydroxythioureas 1b and 1c with DFA, but this only had marginal effects on the chemical yield and stereoselectivity. However, the desired product 7aa was obtained in 74% yield with better regio-and enantioselectivities (7aa/8aa = 72/17 and 39% ee) with the use of 10 mol% of DFA-chiral N-arylaminothiourea 1f as a co-catalyst.  1  None  HBF 4  24  40  6  ---2  None  TfOH  24  40  1  ----3  None  TFA  24  64  35  ----4  None  DFA  24  35  64  ----5 None Since the co-catalysts DFA and N-arylaminothiourea 1f gave good results, a wide range of Brønsted acids were next examined in the presence of 1f ( Table 2). As a result, while the addition of acids [HBF 4 , TfOH, TFA, TCA, perfluorobenzoic acid (PFB)] stronger than DFA (entries 2-6) led to a decrease in enantioselectivity, the concurrent use of 1f and a weak acid such as AcOH or BzOH significantly improved the enantioselectivity to give the same enantiomer (R)-7aa with more than 70% ee, albeit in low yield (entries 7 and 8). Since the reaction did not occur with either AcOH or bifunctional thiourea 1f, we can surmise that bifunctional thiourea 1f would activate AcOH by forming H-bond complex A or ion-pair complex B. Since AcO − is well-known to be a good H-bond acceptor, in contrast to BF 4 − and OTf − , the H-bond complex A could be the actual catalyst. Unfortunately, despite many trials with AcOH and BzOH under various conditions, the chemical yield could not be enhanced without a decrease in ee. BzOH 48 17 75 a The reactions were carried out with 5a (0.1 mmol), 6a (0.1 mmol), thiourea (S, S)-1f (10 mol%) and Brøsted acid (10 mol%) in toluene (1 mL) at room temperature; b Isolated yield. c Determined by HPLC.
Therefore, we selected DFA as an optimized Brønsted acid and turned our attention to N-arylaminothioureas 1d-h to improve the stereoselectivity (Table 3). Due to the instability of enamino ester 5a under the reaction conditions, the slow addition of 5a to the reaction mixture of 6a and co-catalyst 1f•DFA in toluene was examined, which resulted in the exclusive formation of 4aa in 86% yield with 50% ee (entry 1). Thus, DFA-catalyzed reactions with several bifunctional thioureas 1e-h were carried out under slow-addition conditions. The use of phenyl-and mono-substituted anilines 1d and 1e as catalysts led to a slight decrease in ee (entries 2 and 3). In contrast, the catalysts 1g bearing a 2,4dimethoxyphenyl group gave the same product with a slightly enhanced enantioselectivity, while a similar result was obtained with more bulky catalyst 1h bearing a 2-fluoro-4-isopropoxyaniline group (entries 4 and 5). Furthermore, other enamino esters 5b and 5c, prepared from different primary amines, also underwent cyclization to afford the corresponding products 7ba and 7ca with moderate ee's (entries 6 and 7). Despite several trials, we could not improve the enantioselectivity of 3,4-disubstituted 1,4-DHP's 7aa-7ca. (S, S)-1h 5c 7ca 83 45 (R) a Reaction conditions: Slow addition (0.01 mmol/30 min) of β-enamino esters 5a-c (0.1 mmol) to a mixture of α,β-unsaturated aldehydes 6a (0.1 mmol), thiourea 1 (10 mol%) and DFA (10 mol%) in toluene (1 mL) at room temperature. The mixture was stirred for an additional 12 h after completion of the addition; b Isolated yield; c Determined by HPLC.

Utility of thiourea-ammonium salts derived from strong Brønsted acids and anilinothioureas
We have demonstrated that H-bonding complexes A, prepared from anilinothiourea and DFA, efficiently catalyzed the three-component coupling via route b to give the functionalized 1,4-DHP's with moderate to good enantioselectivity. We next examined the alternative reaction path via route a with the Brønsted acid-anilinothiourea co-catalysts. The reaction was performed as follow. β-Keto ester 10 was added to the preformed imines, prepared from α,β-unsaturated aldehyde 6a and p-anisidine 9, in the presence of various co-catalysts composed of bifunctional thioureas 1d-h and Brønsted acids such as DFA, TFA, TfOH, and HBF 4 ( Table 5). Initially we examined the best co-catalyst DFA•(S,S)-1h for route b, which gave the same product (R)-7da in 64% yield with a slightly low ee (entry 1). Although the same treatment of imine and 10 with co-catalyst TFA•(S,S)-1h led to a similar result, an enantiomer of the product (S)-7da was obtained, albeit with poor enantioselectivity, with the use of strong Brønsted acids (TfOH, and HBF 4 ) as co-catalysts (entries 2-4). The same trend was observed with other bifunctional thioureas (S,S)-1f, g and (R,R)-1d, e (entries [5][6][7][8][9][10][11][12][13][14]. Among the various co-catalysts prepared from 1d-h, HBF 4 •(R,R)-1e gave (R)-7da with the highest ee (69% ee) (entry 14). Consequently, we have established a method for the synthesis of both enantiomers of highly functionalized 1,4-DHP's by simply switching the Brønsted acids (DFA and HBF 4 ) used as the co-catalysts, starting from the same substrates. Brønsted acid (10 mol%) in toluene (1 mL) was stirred at room temperature for 30 min. After keto ester 10 (0.2 mmol) was the added, the resulting mixture was stirred at rt; b Isolated yield. c Determined by HPLC.

Proposed reaction mechanism of Brønsted acid-anilinothiourea co-catalysis
In a former reaction with carboxylic acid-thiourea co-catalysts, H-bonded ammonium complex A would be equilibrated with free acid (HX) and uncomplexed thiourea 1 due to the weak acidity of HX ( Figure 1). If the free acid can promote the reaction, both the catalyzed and uncatalyzed reactions would proceed, to give the product in low enantioselectivity. This is why DFA, which has medium acidity, gave better results than strong acids such as TFA and TCA. In contrast, high enantioselectivity was achieved with the AcOH•(S,S)-1f co-catalyst, since free AcOH has no catalytic activity for the cyclization. This result obviously indicates that an appropriate bifunctional thiourea can activate weak acids to catalyze three-component cyclization, even though the co-catalysts must be weaker acids than the free acids. To explain this result, we speculate that the conjugate base (X -) should play an important role for acceleration of the reaction. Based on this assumption, a proposed reaction mechanism is shown in Figure 3. Initially, the ammonium carboxylate complex A, in which each of two ammonium protons interacts with the carboxylate anion or ortho-substituent of the aniline via H-bond, would be formed from the catalyst 1 and HX. The aldehyde would then interact with one of the ammonium protons of the co-catalyst from the less-hindered side. The protonated aldehyde would be attacked from the bottom face (Si-face) by the enamino ester, which is concurrently deprotonated by the conjugate base. In this transition-state TS-(a), which is energetically more stable than TS-(b), both nucleophile 5 and electrophile 6 are activated simultaneously by HX complexed with the bifunctional anilinothiourea, to generate the desired (S)-product, when (R,R)-thiourea is used.
Similarly, the reaction of α,β-unsaturated imine and β-keto ester with DFA-(R,R)-thiourea 1 can be explained by TS-(c) in Figure 3. In this case, (Z)-imine [28] should coordinate to the ammonium proton of the same co-catalyst and the nucleophile approaches from the same Si-face to predominantly give the (S)-isomer. On the other hand, the ion-pair complex B would be exclusively generated when strong acids such as TfOH, and HBF 4 are reacted with bifunctional thiourea 1. As shown in Figure 3, in TS-(d), the (Z)-imine coordinates to the ammonium proton of the ion-pair complex B in the same way as in TS-(c), but the nucleophile is considered to approach from the less-hindered upper side (Re-face) without any assistance of the conjugate base, since the ammonium proton of the ion-pair complex B should be more acidic than that of the H-bonding complex A, to predominantly give the (R)-isomer.

General
All non-aqueous reactions were carried out under a positive atmosphere of argon in dried glassware unless otherwise noted. Solvents were dried and distilled according to standard protocols. Materials were obtained from commercial suppliers and used without further purification except when otherwise noted. All melting points were determined on a Yamamoto micro melting point apparatus and are uncorrected. 1 H-and 13 C-NMR spectra were recorded in CDCl 3 at 500 or 400 MHz, and at 125 or 100 MHz, respectively; Tetramethylsilane (TMS) was used as an internal standard. IR spectra were recorded on a JASCO FT/IR-410 Fourier-tranfer infrared spectrometer. Low and High resolution mass spectra were obtained by EI or FAB method. Optical rotations were recorded on a JASCO DIP-360 polarimeter with a path length of 1 cm; concentrations are quoted in mg (2 mL).

Preparation of (Z)-ethyl 3-(4-methoxyphenylamino)acrylate (5a)
To a solution of ethyl 3-oxopropanoate (1.16 g, 10.0 mmol) in CH 2 Cl 2 (20 mL) was added p-anisidine (1.23 g, 10.0 mmol) at ambient temperature. After the mixture was stirred at the same temperature overnight, the reaction mixture was concentrated. The resulting residue was passed through silica gel pad (hexane-ethyl acetate = 4:1) to afford the desired material as a E/Z mixture, which was recrystallized from hexane-ethyl acetate to give the title material 5a (352 mg, 1.

Preparation of enamino esters 5b-k
Enaminoesters 5b-k were prepared using literature procedures [29]. Enaminoesters 5b-k was used in the reactions without further purification.
To a solution of thiourea 1 (0.010 mmol) and Brønsted acid (0.010 mmol) in toluene (1.0 mL) were added 5a (0.10 mmol) and 6a (0.10 mmol) at ambient temperature. After being stirred at the same temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate = 5:1) to give 7aa and 8aa.