Highly Effective Asymmetric Henry Reaction Catalyzed by Chiral Complex of Cu (II)-Aziridine-Functionalized Organophosphorus Compounds

Abstract

A synthesis of organophosphorus compounds containing an aziridine ring, previously described by our group, has been performed and the catalytic activity of the aforementioned chiral heterorganic compounds has been investigated in the asymmetric nitroaldol (Henry) reaction between aromatic/aliphatic aldehydes and nitromethane in the presence of catalytic amounts of copper (II) acetate. In several cases, the chiral β-nitroalcohols have been obtained with high chemical yields and exhibited very high enantiomeric excess values (over 95%). Notably, the use of two enantiomerically pure catalysts, differing in the absolute configuration of the aziridine unit, resulted in the formation of two enantiomeric products of the Henry reaction.

1. Introduction

The application of asymmetric synthesis techniques for the enantioselective formation of carbon-carbon bonds has sustained unwavering interest among contemporary chemists involved in modern organic synthesis for many decades [1]. This technology has long served as a research platform in both academia and industry [2]. Moreover, it plays a critical role in the design of potential pharmaceutical molecules and, consequently, in medicinal chemistry [3]. The ongoing development of synthetic methods in asymmetric synthesis underscores its profound significance across various fields of life [4].

The nitroaldol (Henry) reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry, enabling the synthesis of nitroalcohols [5]. Numerous chiral catalysts promoting the asymmetric Henry reaction have been reported in the literature [6], including chiral tridentate ligands derived from L-proline [7], chiral thiols and C2-symmetrical disulfides [8], chiral salan ligands with bulky substituents [9], bisoxazoline-cobalt complexes [10], N-substituted-3,4-dihydroxypyrrolidines [11], β-amino alcohol-copper (II) complexes [12], and sulfur-containing chiral tridentate ligands explored by our group [13].

The chiral products of the asymmetric Henry reaction are highly valuable building blocks in various research fields [14], including pharmaceutical chemistry for the synthesis of β-adrenergic blockers [15], the preparation of β-aminoalcohols [16], and the construction of tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent [17].

Our previous studies on the synthesis and catalytic activity of chiral organophosphorus aziridine derivatives demonstrated that these compounds can efficiently promote several asymmetric transformations, including Michael addition, a three-component asymmetric Mannich reaction, Friedel–Crafts alkylation, Simmons–Smith cyclopropanation, diethylzinc addition to aldehydes, the asymmetric Morita–Baylis–Hillman reaction, its vinylogous variant (Rauhut–Currier transformation), and, more recently, an asymmetric [3+2]-cycloaddition of azomethine ylides to trans-β-nitrostyrene [18].

Despite these reports, there are relatively few studies in the chemical literature describing organophosphorus compounds containing a chiral aziridine ring and their application in asymmetric synthesis [19]. In light of this, and with the goal of broadening the applicability of chiral aziridine derivatives incorporating phosphine or phosphine oxide fragments, we decided to test their catalytic potential in the asymmetric Henry reaction between aromatic/aliphatic aldehydes and nitromethane. Drawing on our prior experience in asymmetric synthesis, particularly in the nitroaldol reaction [13], we aimed to explore interesting stereochemical relationships.

2. Results and Discussion

2.1. Synthesis of Chiral Catalysts 1–12

The enantiomerically pure organophosphorus derivatives of aziridines used in this research include chiral aziridine phosphines (1–4), chiral aziridine phosphine oxides (5–8), an aziridine phosphine oxide with a free NH aziridinyl moiety (9), and aziridine functionalized imines (10–12) (Figure 1).

Phosphine oxides (5–8) were synthesized from o-bromoanisole and diphenylphosphinic chloride in the presence of magnesium turnings and a catalytic amount of iodine, as described earlier [20]. In turn, phosphines (1–4) were obtained via titanium (IV) isopropoxide and triethoxysilane-mediated reduction of the corresponding phosphine oxides (5–8) [21]. Phosphine oxide (9), bearing a free NH group on the aziridine subunit, was prepared from (S)-2-phenylaziridine and diphenylphosphinic chloride according to our previous findings [22]. Finally, chiral imines (10–12) were synthesized from the corresponding aminoalkyl aziridines and aldehydes, as reported previously [23].

2.2. Asymmetric Nitroaldol (Henry) Reaction Catalyzed by Complexes of Cu (II) with Chiral Systems 1–12

With all the chiral catalysts in hand, we proceeded to evaluate their efficiency in catalyzing the asymmetric Henry reaction. As a model transformation, we selected the reaction of benzaldehyde with nitromethane in the presence of 5 mol% copper (II) acetate as the metal component (Scheme 1). The reactions were conducted in ethanol at room temperature, following our previous findings [13]. A summary of the screening results for all the chiral catalysts is presented in

Table 1. Model asymmetric nitroaldol reaction promoted by aziridine derivatives 1–12 in the presence of Cu (II).

Entry	Catalyst	Yield (%)	ee (%) a	Abs. Conf. b
1	1	70	40	(R)
2	2	68	55	(S)
3	3	67	44	(S)
4	4	62	34	(S)
5	5	90	96	(R)
6	6	92	90	(S)
7	7	85	56	(S)
8	8	82	55	(S)
9	9	65	56	(S)
10	10a	89	80	(R)
11	11a	70	74	(S)
12	11b	78	62	(S)
13	12a	64	50	(S)

^a Determined by chiral HPLC using Chiralcel OD-H. ^b According to literature data [13] and based on comparison of HPLC chromatograms. Conditions: 5.5 mol% of the catalyst, Cu(OAc)₂·H₂O (5 mol%), benzaldehyde (1.0 mmol), nitromethane (10.0 mmol), EtOH (1.5 mL), rt, 72 h.

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A quick glance at the results in Table 1 indicates that all the chiral catalysts tested are capable of promoting the target reaction. Chiral aziridinyl phosphines (1–4) produced the desired β-nitroalcohol in fairly good chemical yields (62–70%), though with relatively low enantiomeric excess values (34–55%) (Table 1, entries 1–4). In contrast, chiral aziridinyl phosphine oxides (5–8) afforded the same product in higher yields in most cases (Table 1, entries 5–8), with one instance of excellent enantioselectivity (96% ee, Table 1, entry 5).

Interestingly, catalyst 9, which contains a free NH group on the aziridine subunit, exhibited only moderate catalytic activity, resulting in a medium yield (65%) and enantiomeric excess (56%) (Table 1, entry 9). Finally, imines (10–12) demonstrated robust catalytic activity, though without any outstanding results (Table 1, entries 10–13). Notably, the use of enantiomeric catalysts containing (S)-2-isopropylaziridine and (R)-2-isopropylaziridine units led to the formation of both enantiomers of the β-nitroalcohol (Table 1, entries 1, 2, 5, 6, 10, and 11). It is also worth mentioning that the title reaction, when catalyzed by chiral organophosphorus aziridine derivatives, did not proceed in the absence of a metal component.

2.3. Asymmetric Henry Reaction Promoted by Aziridinyl Phosphine 5Cu (II) Complex—Scope of the Starting Materials

Based on previous screening studies of the catalysts, it was determined that aziridinyl phosphine oxide 5, bearing an (R)-2-isopropylaziridine group, exhibited the highest catalytic activity. Consequently, this system was employed to perform further asymmetric nitroaldol reactions using various aromatic/aliphatic aldehydes as substrates (Scheme 2). The results are summarized in

Table 2. Asymmetric nitroaldol reaction in the presence of Cu (II)-catalyst 5 complex.

Entry	R	Product	Yield (%)	ee (%) a	Abs. Conf. b
1	2-CH3OC6H4	14	92	90	(R)
2	2-NO2C6H4	15	90	84	(R)
3	4-ClC6H4	16	88	80	(R)
4	4-CH3OC6H4	17	91	84	(R)
5	4-NO2C6H4	18	78	94	(R)
6	1-Naphthyl	19	70	64	(R)
7	1-Furyl	20	0	–	n.d.
8	4-BrC6H4	21	85	86	(R)
9	C2H5	22	traces	–	n.d.
10	C3H7	23	traces	–	n.d.

^a Determined by chiral HPLC using Chiralcel OD-H column. ^b According to literature data [7,13] and based on comparison of HPLC chromatograms. Conditions: 5.5 mol% of the catalyst 5, Cu(OAc)₂·H₂O (5 mol%), aldehyde (1.0 mmol), nitromethane (10.0 mmol), EtOH (1.5 mL), rt, 72 h.

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The results summarized in Table 2 clearly confirm that chiral aziridine phosphine oxide 5 in the presence of copper (II) source, bearing an (R)-2-isopropylaziridine group, is an efficient catalyst for the asymmetric nitroaldol reaction, yielding chiral aromatic β-nitroalcohols with high chemical yields and excellent enantiomeric excess. Although the substrate scope in our study was limited chiefly to aromatic aldehydes, this choice was deliberate and motivated by several factors: For aliphatic (non-aromatic) aldehydes, the absence of stabilizing interactions from an aromatic system can result in lower reactivity or reduced enantioselectivity. In many catalytic reactions, aromatic groups contribute to stabilization through π-π interactions, electronic effects, or steric influences, which can enhance both the reactivity of the substrate and the enantiocontrol of the reaction. Without these stabilizing effects, aliphatic aldehydes may interact less efficiently with the catalyst, leading to diminished activation and weaker stereochemical discrimination. This could explain why only trace amounts of products were obtained in our experiments and why assessing their optical purity was not feasible (Table 2, entries 9, 10). In contrast, aromatic aldehydes can enhance the enantioselectivity of the asymmetric Henry reaction due to their ability to influence the electronic properties of the carbonyl carbon through inductive and resonance effects. This modulation can improve chirality control in the final product. Additionally, aromatic systems often enable better enantioselectivity because they facilitate noncovalent interactions (e.g., π–π stacking) between the aldehyde and the chiral catalyst, which helps to stabilize the preferred addition pathway of the nitroalkane to the carbonyl group.

Unfortunately, the reaction with furfural as the starting aldehyde did not yield any detectable amount of the desired product (Table 2, entry 7). This may be because copper (II) can coordinate with the oxygen atoms of the furan ring, potentially deactivating the aldehyde for nucleophilic attack by the nitronate ion, which is the key step in the nitroaldol reaction.

To propose a tentative complexation model for the asymmetric nitroaldol reaction, we drew on our earlier considerations regarding the mechanistic considerations of the asymmetric [3+2]-cycloaddition reaction [18], while also consulting proposed reactive intermediates for similar reactions available in the literature [24,25,26,27,28,29]. Consequently, we proposed enantiomeric complexes for ligands 5 and 6, which resulted in chiral products with opposite absolute configurations (Figure 2). The reaction may involve dual activation of both the nitro compound and the aldehyde via an in situ generated Cu (II) complex [26,28]. Upon coordination of the aziridine phosphine oxide ligand 6 to copper (II) acetate, an exchange of the acetate anion for the nitro compound may occur. In the chiral complex, the nucleophilic carbon atom of the nitro compound attacks the aldehyde from the Si face, yielding the (S)-isomer as the major product. This is enforced by the (S) configuration of the aziridine ligand 6. Similarly, using a ligand 5 with the (R) configuration directs the attack from the Re face, resulting in the (R)-isomer as the major product. The attack from the opposite face is not favorable due to steric interactions between the R group of the aldehyde and the aziridine ligand. While the proposed complexation model may be subject to debate, it provides a satisfactory explanation for the formation of products with opposite configurations, when enantiomeric ligands 5 and 6 were used. The proposed complexation model suggests that the coordination cavity formed by the ligand-Cu bond promotes the stereoselective formation of a new carbon-carbon bond between the substrates, as only in this specific arrangement can the substrates fit appropriately.

3. Materials and Methods

3.1. Materials

n-Hexane and ethyl acetate were purchased from Merck (Merck KGaA, Darmstadt, Germany) and distilled prior to use. NMR spectra were recorded on a Bruker instrument (600 MHz) (Bruker, Billerica, MA, USA) using CDCl₃ as the solvent and TMS as the internal standard. Column chromatography was performed with Merck 60 silica gel, and TLC was carried out on Merck 60 F₂₅₄ silica gel plates (Merck KGaA, Darmstadt, Germany). Enantiomeric excess (ee) was determined by HPLC using a column with chiral support (Chiralcel OD-H) (Daicel Corporation, Osaka, Japan). Chiral catalysts 1–12 were prepared as previously reported [20,21,22,23].

3.2. Methods

3.2.1. Asymmetric Nitroaldol (Henry) Reaction—General Procedure

In a round-bottom flask, the appropriate catalysts (0.055 mmol, 5.5 mol%) and copper (II) acetate monohydrate (0.05 mmol, 5 mol%, 10 mg) were added. Ethanol (1.5 mL) was introduced, and the mixture was stirred at room temperature for 1 h. After this period, nitromethane (10 mmol, 0.54 mL) and the corresponding aromatic/aliphatic aldehyde (1 mmol) were added, and the reaction mixture was stirred magnetically at room temperature for 72 h. Upon completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (SiO₂, hexane:ethyl acetate from 97:3 to 90:10) to afford the corresponding β-nitroalcohols. The chemical yields and enantiomeric excess values are summarized in Table 1 and Table 2.

1-Phenyl-2-nitroethanol 13

Colorless oil, 150.3 mg; 90% yield, 96% ee; ¹H NMR (600 MHz, CDCl₃): δ = 2.84 (s, 1H, OH), 4.55 (dd, J = 3.0, 13.2 Hz, 1H, CH₂NO₂), 4.62 (dd, J = 9.6, 13.2 Hz, 1H, CH₂NO₂), 5.49 (dd, J = 3.1, 9.6, 1H, CHOH), 7.39–7.44 (m, 5H, CH_ar).

(R)-1-(2-Methoxyphenyl)-2-nitroethanol 14

Colorless oil, 181.2 mg; 92% yield, 90% ee; ¹H NMR (600 MHz, CDCl₃): δ = 3.13 (s, 1H, OH), 3.91 (s, 3H, OCH₃), 4.60 (dd, J = 9.3, 13.0 Hz, 1H, CH₂NO₂), 4.68 (dd, J = 3.0, 13.0 Hz, 1H, CH₂NO₂), 5.66 (dd, J = 3.0, 8.8 Hz, 1H, CHOH), 6.93–6.95 (m, 1H, CH_ar), 7.03–7.05 (m, 1H, CH_ar), 7.34–7.37 (m, 1H, CH_ar); 7.46–7.48 (m, 1H, CH_ar).

(R)-1-(2-Nitrophenyl)-2-nitroethanol 15

Yellowish oil, 190.8 mg; 90% yield, 84% ee; ¹H NMR (600 MHz, CDCl₃): δ = 3.18 (s, 1H, OH), 4.58 (dd, J = 9.0, 13.9 Hz, 1H, CH₂NO₂), 4.90 (dd, J = 2.0, 13.9 Hz, 1H, CH₂NO₂), 6.08 (dd, J = 2.8, 9.0 Hz, 1H, CHOH), 7.57–7.59 (m, 1H, CH_ar), 7.76–7.78 (m, 1H, CH_ar), 7.97–7.98 (m, 1H, CH_ar); 8.10–8.11 (m, 1H, CH_ar).

(R)-1-(4-Chlorophenyl)-2-nitroethanol 16

Colorless oil, 177.3 mg; 88% yield, 80% ee; ¹H NMR (600 MHz, CDCl₃): δ = 3.02 (s, 1H, OH), 4.51 (dd, J = 3.1, 13.4 Hz, 1H, CH₂NO₂), 4.58 (dd, J = 9.3, 13.4 Hz, 1H, CH₂NO₂), 5.46 (dd, J = 3.1, 9.3 Hz, 1H, CHOH), 7.36–7.41 (m, 4H, CH_ar).

(R)-1-(4-Methoxyphenyl)-2-nitroethanol 17

Colorless oil, 179.3 mg; 91% yield, 84% ee; ¹H NMR (600 MHz, CDCl₃): δ = 2.85 (br.s, 1H, OH), 3.83 (s, 3H, OCH₃), 4.49 (dd, J = 3.0, 13.1 Hz, 1H, CH₂NO₂), 4.61 (dd, J = 9.6, 13.1 Hz, 1H, CH₂NO₂), 5.42 (dd, J = 3.0, 9.6 Hz, 1H, CHOH), 6.93–6.95 (m, 2H, CH_ar), 7.33–7.34 (m, 2H, CH_ar).

(R)-1-(4-Nitrophenyl)-2-nitroethanol 18

Yellowish oil, 165.4 mg; 78% yield, 94% ee; NMR (600 MHz, CDCl₃): δ = 3.22 (s, 1H, OH), 4.57–4.65 (m, 2H, CH₂NO₂), 5.63 (dd, J = 3.3 Hz, J = 8.7 Hz, 1H, CHOH), 7.64–7.66 (m, 2H, CH_ar), 8.28–8.30 (m, 2H, CH_ar).

(R)-1-(naphthalen-1-yl)-2-nitroethanol 19

Colorless oil, 205.1 mg; 70% yield, 64% ee; ¹H NMR (600 MHz, CDCl₃): δ = 2.91–2.93 (m, 1H, OH), 4.66–4.74 (m, 2H, CH₂NO₂), 6.27–6.29 (m, 1H, CHOH), 7.53–7.59 (m, 2H, CH_ar), 7.61–7.64 (m, 1H, CH_ar), 7.78–7.79 (m, 1H, CH_ar), 7.88–7.95 (m, 2H, CH_ar), 8.06–8.08 (m, 1H, CH_ar).

(R)-1-(4-bromophenyl)-2-nitroethanol 21

Colorless oil, 209.1 mg; 85% yield, 86% ee; ¹H NMR (600 MHz, CDCl₃): δ = 2.90 (s, 1H, OH), 4.52 (dd, J = 3.0, 13.5 Hz, 1H, CH₂NO₂), 4.60 (dd, J = 9.5, 13.5 Hz, 1H, CH₂NO₂), 5.46 (dd, J = 3.0, 9.5 Hz, 1H, CHOH), 7.31–7.33 (m, 2H, CH_ar), 7.55–7.57 (m, 2H, CH_ar).

4. Conclusions

A series of chiral organophosphorus derivatives containing a three-membered aziridine ring were synthesized and screened for their catalytic activity in the asymmetric nitroaldol reaction of aromatic/aliphatic aldehydes with nitromethane in the presence of copper (II). These chiral heteroorganic derivatives proved effective in producing the desired chiral products with reasonable chemical yields and enantiomeric excess. Additionally, changing the absolute configuration of the catalyst resulted in a corresponding change in the absolute configuration of the obtained β-nitroalcohols.