Organocatalytic Asymmetric Michael Addition of Ketones to α, β-Unsaturated Nitro Compounds

Abstract

An organic catalyst “(R, R)-1,2-diphenylethylenediamine(DPEN) derivative’’ was devel-oped as a chiral bifunctional organocatalyst and applied for asymmetric Michael additions of aromatic ketones to trans-β-nitroalkene compounds under neutral conditions. The isopropyl-subs-tituted thiourea catalyst in neutral condition provides high chemical yield and enantioselectivities (ee) (up to 96% yield, 98% ee).

1. Introduction

Metal catalysts have been used for asymmetric synthesis; however, recent research, excluding the metal catalysts, has attracted interest because of the high cost of metal catalysts and the instability of metal ions in moist air, which limits the reaction conditions [1]. In addition, metal catalysts can leave metal residues in the product. To identify alternatives to metal catalysts, asymmetric reactions using organocatalysts have been developed [2,3,4,5,6,7,8,9,10,11,12]. The Michael reaction is widely used as one of the most general methods for the formation of C–C bonds in organic synthesis. Owing to the easy conversion of the electron-deficient nitro group to various functional groups, such as keto, amino, cyano, and carboxylic acid groups, research on asymmetric Michael reactions using the nitro group as the Michael acceptor has been conducted [13,14,15,16,17,18,19,20,21]. Jacobsen and Ma utilized catalysts with substituents on the thiourea of (R, R)-1,2-cyclohexyldiamine. In the Michael addition of aromatic ketones and trans-β-nitroalkenes, the stereoselectivity was high, but the yield was low [22,23]. In 2009, Lao et al. reported the Michael reaction of acetone and trans-β-unsaturated nitroalkene using (R, R)-1,2-cyclohexyldiamine derivatives as the catalyst and compared the reactivity according to the acidity of amine in the catalyst. For catalysts with electron-withdrawing groups, the stereoselectivity was lower than for catalysts with electron-donating groups. In addition, the reactivity increased when the electrophile was activated via double hydrogen bonding of the catalyst. The effects of the N–H bond and hydrogen bond acidity on catalyst activity and the stereotactic properties of functional primary amino catalysts influenced the Michael C–C reaction (Scheme 1) [24,25,26].

Shao and Kokotos [27,28] used (R, R)-1,2-diphenylethylenediamine thiourea derivatives as the catalyst and benzoic acid as the additive. During the reaction, aromatic ketones were activated by acid additives, leading to accelerated enamine formation of the catalyst. Asymmetric reactions of aromatic ketones and α, β-unsaturated nitroalkenes led to a high selectivity and high yield.

Nevertheless, it is necessary to develop catalysts for simple synthesis. Therefore, in this study, (R, R)-1,2-diphenylethylene-diamines were introduced into the basic framework of a chiral catalyst. We used ketones and trans-β-nitrostyrene, which has a powerful electro-withdrawing group, to conduct an enantioselective Michael reaction.

2. Results and Discussion

2.1. Asymmetric Michael Addition of α, β-Unsaturated Nitroolefins and Ketones

2.1.1. Catalyst Screening

The Michael addition was performed using acetophenone and nitrostyrene to examine the catalytic effects of enantioselective Michael addition on ketones and α, β-unsaturated nitroalkenes. The catalysts used in the reaction are listed in (Figure 1.) First, N-mono-alkylated thiourea with 3-pentyl-substituted amine was used with benzoic acid as an additive.

The reaction carried out in the toluene solvent at room temperature (

Table 1. Catalyst screening.

Entry	Cat.	Yield [a]	ee [b]
1	1a	N.R. [c]	-
2	1b	N.R. [c]	-
3	1c	73	98
4	1d	85	98
5	1e	76	90
6	1f	58	92
7	1g	46	90
8	1h	78	94
9	1i	60	94
10	1j	51	92
11	1k	53	90

[a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column. [c] N.R. = No Reaction.

, entries 1 and 2) did not proceed, likely because the steric hindrance of secondary amine thiourea with 3-pentyl-substituted amine hindered enamine formation, making the catalyst ineffective. Therefore, the reaction was carried out with N-mono-thiourea as the primary amine catalyst prior to amine alkylation. The amine was preserved from alkylation to promote enamine formation, which was activated through dehydration condensation between ketones and amines. The other amine was allowed to react with isothiocyanate to ensure that thiourea could create conditions suitable for double activation, thus, inducing hydrogen-bond formation at the nitro group. The reaction was carried out in toluene with benzoic acid as the additive at room temperature. The use of the isopropyl-substituted primary amine thiourea catalyst led to the highest product yields and enantioselectivities (Table 1, entry 4). This finding indicates that the enantioselectivity and yield of the reaction are improved by the appropriate steric hindrance impaired on the substituent rather than the hydrogen acidity of thiourea. Therefore, less steric hindrance leads to higher yields and enantioselectivity.

2.1.2. Solvent Effects

The previous experiment reported in Section 2.1.1 confirms that the use of an isopropyl-substituted catalyst leads to the highest yield and enantioselectivity. Using this catalyst, reactivity and enantioselectivity in different solvents were investigated. The reaction proceeded smoothly in all solvents; high enantioselectivity was obtained regardless of the solvent polarity, although differences in the yield were observed. It is predicted that polar solvents would obstruct hydrogen bond formation between the reactant and the catalyst, thereby decelerating the reaction (

Table 2. Solvent effects.

Entry	Solvent	Yield [a]	ee [b]
1	H2O	63	88
2	neat	91	92
3	toluene	85	98
4	ether	80	98
5	CH2Cl2	79	98
6	Tetrahydrofuran	74	94
7	methanol	60	94
8	CH3CN	54	94

[a] Isolated yield [b] The ee values were decided by chiral phase HPLC using an AD-H column.

, entry 1). In addition, when the reaction was performed without a solvent, the enantioselectivity decreased despite the high yield (Table 2, entry 2). Among the non-polar solvents tested, toluene generated the highest enantioselectivity and yield (Table 2, entry 3); hence, it was selected as the reaction solvent for subsequent experiments.

2.1.3. Additive Effect

The catalyst used in the previous experiment catalyst (1d) and toluene (solvent) were applied to the reaction to investigate the reactivity and stereoselectivity in the presence of different additives (

Table 3. Additive effects.

Entry	Additive	Yield [a]	ee [b]
1	-	N.R. [c]	-
2	Trifluoroacetic acid	N.R. [c]	-
3	Oxalic acid	N.R. [c]	-
4	Salicylic acid	80	90
5	Terephthalic acid	73	86
6	Benzoic acid	85	98
7	Acetic acid	68	94
8	H2O	74	98
9	H2O (1 eq.)	70	98

[a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column. [c] N.R. = No Reaction.

). The reaction carried out without an additive did not proceed (Table 3, entry 1); therefore, an acid additive was employed to facilitate enamine formation. Nonetheless, certain acid additives prevented the progress of the reaction (Table 3, entries 2 and 3), presumably because binding between highly acidic additives and the catalyst degraded the catalytic activity. In addition, water as an additive was conducive to the reaction progress (Table 3, entries 8 and 9). These results confirm that the use of benzoic acid as additive leads to improved yields and enantioselectivities (Table 3, entry 6).

2.1.4. Equivalence Effect

The acetophenone equivalent (eq.) did not cause any differences in the yield and enanti-oselectivity of the reaction (

Table 4. Equivalence effect.

Entry	X (equiv)	Y (mol%)	Z (mol%)	Yield (%) [a]	ee (%) [b]
1	2	10	15	85	98
2	5	10	15	86	96
3	2	5	15	51	98
4	2	20	15	88	96
5	2	10	5	87	98
6	2	10	10	85	98

[a] Isolated yield. [b] The ee values were determined by chiral phase HPLC u-sing an AD-H column.

, entries 1 and 2). The use of 5 mol% of the catalyst resulted in a decreased yield, and 20 mol% of the catalyst produced a yield and enantioselectivity similar to those obtained with 10 mol% of the catalyst (entries 1, 3, and 4). The results obtained with 5–15 mol% of benzoic acid were similar (Table 4, entries 1, 5, and 6). Thus, the use of 2 eq. acetophenone, 10 mol% catalyst, and 5 mol% benzoic acid additives produced the optimal results (Table 4, entry 5).

2.1.5. Temperature and Time Effects

The yield varied substantially when the reaction time ranged between 24 and 48 h (

Table 5. Temperature and time effects.

Entry	Temp (℃)	Time (h)	Yield (%) [a]	ee (%) [b]
1	r.t.	24	55	98
2	r.t.	48	87	98
3	r.t.	72	88	98
4	40	48	92	86
5	50	48	91	80

[a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column.

, entries 1 and 2). However, a slight difference in the yield and enantioselectivity was observed between the reaction times of 48 and 72 h (Table 5, entries 2 and 3). Thus, the optimal reaction time was determined as 48 h. Furthermore, when the temperature was increased, the rate constant increased with the reactivity, but the enantioselectivity decreased, indicating that the optimal result can be obtained when the reaction is carried out at room temperature (Table 5, entries 2, 4, and 5).

2.1.6. Reaction Conditions According to the Type of Aromatic Ketones

In the preceding experiments, the optimal conditions for the asymmetric Michael addition of acetophenone and various trans-β-nitrostyrenes were investigated. Under the optimal conditions, reactions between various aromatic ketones and trans-nitrostyrene were carried out (

Table 6. Reaction conditions according to the type of aromatic ketones.

Entry	Ar	Product	Yield (%) [a]	ee (%) [b]
1	4-FC6H4	3a	89	92
2	2-FC6H4	3b	81	96
3	4-NO2C6H4	3c	85	94
4	4-MeOC6H4	3d	91	86
5	2-naphthyl	3e	84	80

[a] Isolated yield. [b] The ee values were decided by chiral phase HPLC using an AD-H column.

). There was difference in the enantioselectivity and yield according to the position of substitution in the aromatic ketones because of the steric hindrance (Table 6, entries 1 and 2). The enantioselectivity in the presence of an electron-donor substituent (Table 6, entries 4 and 5) was lower than that in the presence of an electron-acceptor substituted because of more nucleophilic (Table 6, entries 1, 2, and 3).

2.1.7. Reaction by Unsaturated β-Nitroalkenes

Under the optimal conditions established in the preceding experiments, reactions were carried out between acetophenone and various α, β-unsaturated nitroalkenes (

Table 7. Reaction by unsaturated nitroalkene type.

Entry	Ar	Product	Yield (%) [a]	ee (%) [b]
1	4-MeC6H4	4a	95	88
2	4-BrC6H4	4b	89	92
3	4-ClC6H4	4c	83	92
4	4-MeOC6H4	4d	85	94
5	2-MeOC6H4	4e	76	82

[a] Isolated yields [b] The ee values were determined by chiral phase HPLC using an AD-H column.

). The resulting enantioselectivity were high when α, β-unsaturated nitroalkene was substituted with electron acceptors (Table 7, entry 2 and 3) as well as electron donors (Table 7, entry 4). And when α, β-unsaturated nitroalkene was substituted with 4-Me, it has a higher yield (Table 7, entry 1). When α, β-unsaturated nitroalkene was substituted with 2-MeO, the reactivity and enantioselectivity decreased compared to those observed when the substituent was 4-MeO because of the steric hindrance (Table 7, entries 4 and 5).

2.1.8. Reaction of Acetone with α, β-Unsaturated Nitroalkenes

To investigate whether the addition proceeds with aliphatic ketones, reactions were carried out between acetone and various α, β-unsaturated nitroalkenes under the optimal conditions determined in previous experiments. The reactivity of acetone was lower than that of aromatic ketones; thus, 10 eq. acetone was used in the experiment (

Table 8. Reaction of acetone with α, β-unsaturated nitroalkenes.

Entry	Ar	Product	Yield (%) [a]	ee (%) [b]
1	C6H5	5a	88	94
2	4-MeC6H4	5b	81	86
3	4-MeOC6H4	5c	85	82
4	4-ClC6H4	5d	76	86
5	2-MeOC6H4	5e	83	94

[a] Isolated yields [b] The ee values were determined by chiral phase HPLC using an AD-H column.

). The reaction between acetone and α, β-unsaturated nitroalkenes was found to proceed well, regardless of whether the substituent was an electron donor or electron acceptor. Contrary to the case of aromatic ketones, no general trend in enantioselectivity was observed for different substituent positions in α, β-unsaturated nitroalkenes.

2.1.9. Reaction Mechanism to Predicted Transition State

The stereoselective Michael reaction was conducted using ketone and trans-β-nitrostyrene. The results suggest the catalytic mechanism in the reaction (Scheme 2). First, via the reaction of ketone with the acid catalyst, the reactivity of ketone would increase, leading to the formation of enamine by the reaction with the primary amine thiourea catalyst [29,30]. Double hydrogen bonding of hydrogen of the thiourea catalyst and oxygen of α, β-unsaturated nitroalkene led to selective reactions. Enamine approached from the si-face of trans-β-nitrostyrene, leading to the S-selective product (Figure 2).

2.1.10. Synthesis of (S)-GABA Derivatives and Pyrrolidinone Derivatives

We investigated the Michael reaction of the ketone compounds to various nitroolefins. Through oxidation and reduction of products 2a and 4c, respectively, phenibut and baclofen were formed [31]. The selective antagonist of the GABA_B receptor in phenibut inhibited the antidepressant and anti-adaptive effects. The optional GABA_B receptor agonist baclofen has previously reversed social deficits in mouse models and reduced repetitive behavior [32]. The GABA_B receptor blockage does not modify the inhibitor of ethanol ingestion induced by Hypericum perforation in rats [33,34].

3. Materials and Methods

3.1. General Information

IR spectra were measured on a NICOLET 380 FT–IR spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA, USA). Optical rotations were performed with a Rudolph Automatic polarimeter (model name: A20766 APV/6w, Rudolph Research Analytical, Hackettstown, NJ, USA). ¹H, ¹³C NMR spectra were operated on a Bruker Avance 500 (500, 125 MHz, Bruker BioSpin GmbH, Silberstreifen 4, 76287 Rheinstetten, Billerica, MA, USA), Varian Mercury 400 (400, 100 MHz, Agilent, Santa Clara, CA, USA), or Varian Germini 300 (300, 75 MHz, Agilent, Santa Clara, CA, USA) with TMS as an internal reference. Chiral HPLC analysis was measured on a Jasco LC-1500 Series HPLC system (JASCO, 4-21, Sennin-cho 2-chome, Hachioji, Tokyo 193-0835, Japan) with a UV detector. All experiments were performed in dried flasks under an argon filler. Toluene and THF were dried by chemical (CaH₂, Na, benzophenone) distillation before use. Commercial grade reagents were purchased from Aldrich (Louis, MO, USA), TCI (Tokyo, Japen) and were used without purification.

3.2. Synthesis of Catalysts (1a-n); General Procedure

3.2.1. Synthesis of Monoalkylated Thiourea Catalysts

To a solution of (R, R)-1,2-diphenylethylenediamine (1.0 equiv.) in toluene (0.1 M) was added a solution of 3-pentanone (1.1 equiv.), MgSO₄ and the mixture was refluxed for 48 h. Then, MgSO₄ was removed and the mixture concentrated in vacuo. NaBH₄ (4.0 equiv.) and ethanol were added, and the mixture was stirred at ambient temperature for 1h, quenched with 1N NaOH solution and the mixture was extracted with 50 mL ethyl acetate (EA) (2 × 30 mL). The combined organic extracts were washed with brine, dried (Magnesium sulfate, anhydrous), and enriched in vacuo. The product was purified by chromatography on a silica-gel column (methanol/methylene chloride, 1:20). To monoalkylated DPEN (1.0 equiv.) in CH₂Cl₂ (0.1 M) thiourea (1.1 equiv.) was added, and the mixture was stirred at ambient temperature for 1 h and purified by flash column chromatography on silica gel with EA/hexane (hex) (1:5) to give the pure amide product (quantitative yield) as a white, foamy gel. (Scheme 3)

3.2.2. Synthesis of Arylated Thiourea Catalysts

To a solution of (R, R)-1,2-diphenylethylenediamine (1.0 equiv.) in toluene (0.5 M) thourea (1.0 equiv.) was added at 0 °C and the mixture product was stirred for 30 s. The product was concentrated in vacuo, the products filtered, and extracted with EA. The combined organic products were washed with brine, dried (Magnesium sulfate, anhydrous), and enriched in vacuo. They were purified by flash column chromatography on silica gel with mixed solvent (methanol/methylene chloride, 1:20) to give the pure amide product (quantitative yield) as a white foamy gel. (Scheme 4)

3.3. Synthesis of Product Compounds

3.3.1. General Procedure of the Asymmetric Michael Addition

The trans-β-nitrostyrene (0.3 mmol), ketone (2.0 equiv.), and 10 mol% of cat. were added to toluene (0.1 M), 5 mol% of acid, and the reaction mixture was stirred at ambient temperature. The reaction conversion was monitored by TLC. After completion, ethyl acetate (0.2 mL) was added to the reaction product. This solution was washed twice with water (2 × 1.0 mL), dried over magnesium sulfate(anhydrous) and concentrated to yield the desired product. The product was purified by chromatography on a silica-gel column eluted with mixed solvent (hexanes/EA, 5:1).

3.3.2. Synthesis of (S)-Phenibut^® and Baclofen^®

A solution of the Michael adducts (2a or 4c) (0.10 mmol) in dry dichloromethane (1 mL) was added to a pressure vessel equipped with a stirring bar and cooled at 0 °C. Then, m-CPBA (0.30 mmol) and TFA (0.10 mmol) were added, and the mixture product was heated at 70 °C for 72 h. The crude product was washed with water and extracted with CH₂Cl₂ (2 × 10 mL). The organic phase was dried over anhydrous MgSO₄, enriched under reduced pressure, and purified by flash column chromatography using hexanes/ethyl acetate (8:2) to afford the desired product. Under an argon atmosphere, to the suspension of 6a or 6b (1.0 equiv.) and NiCl₂·6H₂O (1.0 equiv.) in MeOH (8.0 mL), NaBH₄ (10 equiv.) was added at 0 °C. After the crude mixture was stirred for 7.5 h in ambient temperature, the crude mixture was quenched with NH₄Cl and diluted with CHCl₃. The organic layer was separated and dried over MgSO₄ (anhydrous), filtrated, and enriched in vacuo. The mixture product was purified by column chromatography on silica gel (MeOH/CHCl₃ = 1/20 as eluent) to afford the desired product (98%) as colorless powder. The powder (1.0 equiv.) in 6N HCl (2.7 mL) was refluxed at 100 °C. After 12 h, the pure product was enriched in vacuo to afford (S)-(–)-Phenibut^® (95%) and Baclofen^® (92%) as white solids.

3.4. Results of DFT Calculations and Discussion

Density functional theory(DFT) calculations were performed with the Gaussian 16 and Gauss-View 6.0 programs. DFT computations were performed to show the mechanism of the substrates and catalysis. The solvation effects in toluene and the energy of the optimized geometries were accounted for by using the CPCM continuum solvation model parametrized at the B3LYP/6-31G(d,P) level. The geometries of the reactants, intermediates (IM), transition states (TS), and products were fully optimized, followed by vibrational frequency calculations at the same levels of theory to obtain the zero-point energies (ZPE) and to verify whether it is a minimum or a transition state on the potential energy surfaces (PES). The temperature-dependent enthalpy corrections and the entropy effects are computed at 298 K and 1 atm of pressure (Figure S3).

4. Conclusions

We developed an efficient method for the organocatalytic asymmetric Michael reaction of aromatic ketones to trans-β-nitro compounds and obtained excellent enantioselectivity (up to 80–90% ee). Catalyst 1d was found to be suitable for the simple synthesis of organocatalyst. The synthetic utility of the present catalytic asymmetric Michael addition was established by transformation to highly enantioselective products (Scheme 5). Baclofen is used as a muscle relaxant, whereas Phenibut is a sleep inducer. These substances are derivatives of γ-aminobutyric acid, which is an inhibitory neurotransmission inhibitor acting on GABA receptors and receptors in our bodies. Therefore, further investigations on their synthesis are necessary because of their high applicability in medicine.