An approach to highly efficient reduction of β-enamino esters: A convenient synthesis of β-amino esters

Abstract

Chemoselective reduction of β-enamino esters with NaBH(OAc)₃ promoted by MgI₂ etherate affords the corresponding β-amino esters in excellent yields in a short time under mild conditions.

Introduction

The development of novel synthetic methods leading to β-amino esters or their derivatives constitutes an active area of investigation in synthetic organic chemistry. β-amino esters are also useful starting materials in the synthesis of γ-amino alcohols, β-peptides, and β-lactams, which are quite common building blocks in natural products^1–3 and frequently possess important biologically active properties.^4–5 Moreover, enantiomerically pure β-amino acids are ubiquitous and important structural motifs that can be found in a variety of pharmaceutical substances,^6–8 such as dapoxetine (treatment of premature ejaculation), ⁹ ezetimibe (reduction of plasma cholesterol levels), ¹⁰ sitagliptin (anti-diabetic), ¹¹ and maraviroc (treatment of HIV infection). ¹² Substitution of β-amino acids for α-amino acids in peptides has been recently used to prepare peptide analogs with increased potency and enzymatic stability.^13–15 Therefore, many approaches have been developed for the synthesis of chiral β-amino acids,^16–18 among which the catalytic asymmetric reduction of β-enamino esters represents a most efficient and straightforward one.^19–22 During the past decade, a number of transition-metal catalytic systems have been developed for the asymmetric hydrogenation of β-enamino esters.^23–27 Recently, a series of organic Lewis base–catalyzed asymmetric hydrosilylations of β-enamino esters for the preparation of chiral β-amino acids were reported.^28–32 In order to attain stereoinduction in the reduction of β-enamino esters and their derivatives, some chiral auxiliaries are also used.³³⁻³⁷ Among them, a chiral auxiliary [(R)-(+)-phenyl ethyl amine] based diastereoselective β-enamino amide reduction toward sitagliptin was accomplished by treatment with a reducing agent [NaBH₄/ methanesulfonic acid (MsOH)]. ³⁸ Despite these advances, however, many reductions have been limited to the utilization of costly transition metals as catalysts and require high hydrogen pressures. Therefore, it is important to replace strict reaction conditions, potential hazards, and polluting acid catalysts with environmentally conscious catalysts which are active under mild conditions.

In continuation of our investigations of MgI₂ etherate–promoted organic reactions,^39–41 herein, we report a highly efficient chemical reduction of chiral β-enamino esters 1 with sodium triacetoxyborohydride [NaBH(OAc)₃] promoted by MgI₂·(Et₂O)_n in MeCN at room temperature to give β-amino esters 2 in excellent yields (Scheme 1).

Scheme 1.

Reduction of β-enamino esters to β-amino esters with NaBH(OAc)₃/MgI₂·(Et₂O)_n.

Results and discussion

We initiated our studies by optimizing the reaction conditions for the reduction of β-enamino ester 1a as a model reaction, and the results are summarized in Table 1. No reduction was observed on the treatment with NaBH₄ or NaBH₃CN in the presence of MgI₂·(Et₂O)_n at room temperature using CH₃CN as the solvent (Table 1, entries 1 and 2). Gratifyingly, the reduction of β-enamino ester 1a to give β-amino ester 2a was possible within 20 min using the NaBH(OAc)₃/MgI₂·(Et₂O)_n system in excellent yield (Table 1, entry 3). Furthermore, we explored the use of a range of solvents. It is evident that an excellent yield was obtained using CH₃CN as the solvent and good yields were afforded in CH₂Cl₂ and THF, respectively (Table 1, entries 4 and 5). No reactions occurred in DMF and MeOH (Table 1, entries 6 and 7). It is worth noting that the reduction of β-enamino ester 1a could not be carried out when using NaBH(OAc)₃ without MgI₂·(Et₂O)_n (Table 1, entry 8). In addition, a variety of Lewis acids, such as MgBr₂, MgCl₂, Mg(ClO₄)₂, KI, and ZnI₂ were compared under similar conditions [200 mol% of NaBH(OAc)₃ and 200 mol% of Lewis acid] in CH₃CN. Only Mg(ClO₄)₂ promoted the reaction to give the desired product in moderate yield (71%). ZnI₂, KI, MgCl₂, and MgBr₂ did not promote this chemical reduction. Furthermore, we explored the effect of the temperature on the diastereoselectivity of this reduction. The results showed that the yield was decreased by lowering the temperature but without any obvious improvement of the diastereoselectivity (Table 1, entries 14 and 15).

Table 1.

Screening the reaction parameters for the reduction of β-enamino esters 1a ^a .

Entry	[H]	Lewis acid	Solvent	Temperature	Time	Yield (%) b (dr) c
1	NaBH4	MgI2·(Et2O)n	CH3CN	r.t.	4 h	N.R.
2	NaBH3CN	MgI2·(Et2O)n	CH3CN	r.t.	4 h	N.R.
3	NaBH(OAc)3	MgI2·(Et2O)n	CH3CN	r.t.	20 min	94 (46/54)
4	NaBH(OAc)3	MgI2·(Et2O)n	CH2Cl2	r.t.	2 h	86 (52/48)
5	NaBH(OAc)3	MgI2·(Et2O)n	THF	r.t.	2 h	82 (54/46)
6	NaBH(OAc)3	MgI2·(Et2O)n	MeOH	r.t.	4 h	N.R.
7	NaBH(OAc)3	MgI2·(Et2O)n	DMF	r.t.	4 h	N.R.
8	NaBH(OAc)3	–	CH3CN	r.t.	10 h	N.R.
9	NaBH(OAc)3	MgBr2	CH3CN	r.t.	4 h	N.R.
10	NaBH(OAc)3	MgCl2	CH3CN	r.t.	4 h	N.R.
11	NaBH(OAc)3	Mg(ClO4)2	CH3CN	r.t.	4 h	71 (52/48)
12	NaBH(OAc)3	KI	CH3CN	r.t.	4 h	N.R.
13	NaBH(OAc)3	ZnI2	CH3CN	r.t.	4 h	<5
14	NaBH(OAc)3	MgI2	CH3CN	0 °C	4 h	88 (53/47)
15	NaBH(OAc)3	MgI2	CH3CN	−20 °C	4 h	74 (56/44)

r.t.: room temperature; NMR: nuclear magnetic resonance.

a

Reaction conditions: β-enamino ester 1a (2.0 mmol), borohydride species (4.0 mmol), Lewis acid (4.0 mmol), and solvent (10 mL).

b

Isolated yields after silica gel column chromatography.

c

The diastereoisomeric ratio was determined by ¹H NMR analysis.

With optimized reaction conditions in hand, we next studied a variety of structurally diverse β-enamino esters 1 possessing a wide range of functional groups to understand the scope and generality of the NaBH(OAc)₃/MgI₂·(Et₂O)_n–promoted reduction to form β-amino esters 2. The results are summarized in Table 2. A variety of substrates smoothly underwent reduction with NaBH(OAc)₃/MgI₂·(Et₂O)_n to afford the corresponding β-amino esters 2 in short reaction times (20 min). Nearly quantitative yields were obtained with substrates possessing electron-withdrawing groups at the para position of the aromatic ring (Table 2, entries 2 and 3), and excellent yields were afforded with ortho- and meta-substituted aromatic substrates (Table 2, entries 4–6). β-enamino esters with electron-donating groups on the aromatic rings also afforded excellent yields of the desired products (Table 2, entries 7 and 8).

Table 2.

The reduction of β-enamino esters to β-amino esters with NaBH(OAc)₃/MgI₂·(Et₂O)_n ^a .

Entry	Substrate	Product a	Yield (%) b (dr) c
1			94 (46/54)
2			99 (45/55)
3			99 (46/54)
4			93 (58/42)
5			92 (52/48)
6			93 (52/48)
7			95 (60/40)
8			94 (55/45)

NMR: nuclear magnetic resonance.

a

Reaction conditions: β-enamino ester 1 (2.0 mmol), NaBH(OAc)₃ (4.0 mmol), MgI₂·(Et₂O)_n (4.0 mmol), CH₃CN (10 mL), and room temperature.

b

Isolated yields after silica gel column chromatography.

c

The diastereoisomeric ratio was determined by ¹H NMR analysis.

Conclusion

In conclusion, we have developed a facile and highly efficient method for the reduction of β-enamino esters to the corresponding β-amino esters by treatment with NaBH(OAc)₃/MgI₂·(Et₂O)_n at room temperature. This methodology offers several advantages, including operational simplicity, and inexpensive reagents. Further investigations are in progress in our laboratories to improve the stereoselectivity, and to attempt the preparation of chiral building blocks which might function as important synthetic targets in drugs and natural products.

Experimental

General

For product purification by flash column chromatography, Qingdao silica gel (200~300 mesh) and light petroleum ether (PE, b.p. 60~90 ^oC) were used. ¹H NMR (nuclear magnetic resonance) spectra were recorded on a Bruker AM-500 spectrometer with TMS as an internal standard and CDCl₃ as the solvent. The reactions were monitored by TLC on silica gel, polygram SILG/UV 254 plates. HRMS were obtained on a Waters GCT Premier spectrometer. Magnesium perchlorate is an oxidising agent and may cause explosion on contact with combustible material. β-Enamino esters 1 were prepared according to the literature. ⁴²

General procedure for the reduction of β-enamino esters to β-amino esters

To a solution of β-enamino ester 1 (2.0 mmol) in CH₃CN was added NaBH(OAc)₃ (4.0 mmol), followed by MgI₂·(Et₂O)_n solution (4.0 mmol, 1.0 mol/L in Et₂O). The homogeneous reaction mixture was stirred for 20 min at room temperature and then quenched with saturated Na₂S₂O₃ aqueous solution. Extractive workup with ethyl acetate and chromatographic purification of the crude product on silica gel gave the β-amino ester 2 in 92%–99% yield.

Spectroscopic data for the products 2a–h (Table 2, entries 1–8)

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(2,4,5-trifluorophenyl)butanoate (2a): Yellowish oil; yield: 94%. IR (film): υ 3355, 2967, 1746, 1684, 1525, 1422, 1253, 1160 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.52 (s, 0.46H), 7.32–7.35 (m, 5H), 6.86–6.94 (m, 2H), 6.50 (s, 0.54H), 6.32 (s, 0.46H), 6.12 (s, 0.54H), 5.73 (s, 1H), 4.43 (s, 0.46H), 4.40 (s, 0.54H), 3.71 (s, 1.38H), 3.64 (s, 1.62H), 2.97–3.27 (m, 1H), 2.63–2.67 (m, 1H), 2.49–2.53 (m, 1H), 2.29–2.34 (m, 1H). HRMS (ESI): m/z calcd for C₁₉H₁₉F₃N₂NaO₃ [M+Na]⁺: 403.1245; found: 403.1235.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(4-fluorophenyl)butanoate (2b): Yellowish oil; yield: 99%. IR (film): υ 3360, 3057, 1735, 1674, 1555, 1432, 1243, 1122 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.61 (s, 0.45H), 7.50–7.52 (m, 1H), 7.31–7.41 (m, 4H), 6.93–7.05 (m, 4H), 6.88 (s, 0.55H), 6.09 (s, 0.45H), 5.94 (s, 0.55H), 4.95 (s, 0.45H), 4.59 (s, 0.55H), 3.68 (s, 1.65H), 3.65 (s, 1.35H), 3.32–3.35 (m, 0.55H), 3.19 (t, J = 6.1 Hz, 0.45H), 2.95–3.03 (m, 1H), 2.86–2.89 (m, 0.45H), 2.63–2.70 (m, 1H), 2.48–2.54 (m, 1H), 2.33 (dd, J = 8.7, 16.4 Hz, 0.55H). HRMS (ESI): m/z calcd for C₁₉H₂₁FN₂NaO₃ [M+Na]⁺: 367.1434; found: 367.1425.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(4-chlorophenyl)butanoate (2c): Colorless oil; yield: 99%. IR (film): υ 3358, 3037, 1738, 1685, 1545, 1442, 1223, 1080 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.48 (s, 0.46H), 7.15–7.43 (m, 9H), 6.49 (s, 0.54H), 5.82 (s, 0.46H), 5.46 (s, 0.54H), 4.51 (s, 0.46H), 4.44 (s, 0.54H), 3.70 (s, 1.38H), 3.65 (s, 1.62H), 3.35–3.39 (m, 0.54H), 3.22–3.27 (m, 1H), 2.98–3.03 (m, 0.46H), 2.94 (q, J = 6.7 Hz, 0.46H), 2.63–2.67 (m, 0.54H), 2.55 (d, J = 5.6 Hz, 1H), 2.51 (d, J = 4.2 Hz, 0.46H), 2.34 (dd, J = 8.7, 16.3 Hz, 0.54H). HRMS (ESI): m/z calcd for C₁₉H₂₁35ClN₂NaO₃ [M+Na]⁺: 383.1138; found: 383.1158.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(2-fluorophenyl)butanoate (2d): Yellowish oil; yield: 93%. IR (film): υ 3336, 2987, 1735, 1677, 1544, 1440, 1211, 1153 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.66 (s, 0.58H), 7.20–7.35 (m, 6H), 7.00–7.12 (m, 3H), 7.00 (s, 0.42H), 5.97 (s, 0.58H), 5.57 (s, 0.42H), 4.49 (s, 0.58H), 4.31 (s, 0.42H), 3.69 (s, 1.74H), 3.64 (s, 1.26H), 3.36–3.40 (m, 0.58H), 3.15–3.17 (m, 0.42H), 3.06–3.10 (m, 0.58H), 2.85 (d, J = 6.9 Hz, 0.84H), 2.72 (dd, J = 7.7, 13.7 Hz, 0.58H), 2.51–2.55 (m, 1.42H), 2.28 (dd, J = 9.3, 16.3 Hz, 0.58H). HRMS (ESI): m/z calc for C₁₉H₂₁FN₂NaO₃ [M+Na]⁺: 367.1434; found: 367.1426.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(2-bromophenyl)butanoate (2e): Yellowish oil; yield: 92%. IR (film): υ 3436, 2997, 1740, 1687, 1514, 1444, 1208, 1130 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.57 (s, 0.52H), 7.27–7.36 (m, 7H), 6.70–7.14 (m, 2H), 6.38 (s, 0.48H), 5.87 (s, 0.52H), 5.38 (s, 0.48H), 4.53 (s, 0.52H), 4.29 (s, 0.48H), 3.68 (s, 1.56H), 3.64 (s, 1.44H), 3.40–3.45 (m, 0.52H), 3.27–3.35 (m, 0.48H), 3.22–3.26 (m, 0.52H), 2.95–2.97 (m, 0.96H), 2.64 (dd, J = 8.7, 13.3 Hz, 0.52H), 2.53–2.58 (m, 1.48H), 2.34 (dd, J = 8.8, 16.2 Hz, 0.52H). HRMS (ESI): m/z calcd for C₁₉H₂₁79BrN₂NaO₃ [M+Na]⁺: 427.0633; found: 427.0648.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(2-chlorophenyl)butanoate (2f): Pale yellowish oil; yield: 93%. IR (film): υ 3456, 2998, 1744, 1675, 1533, 1452, 1228, 1160 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.58 (s, 0.48H), 7.12–7.38 (m, 9H), 6.46 (s, 0.52H), 5.93 (s, 0.48H), 5.49 (s, 0.52H), 4.52 (s, 0.48H), 4.36 (s, 0.52H), 3.69 (s, 1.44H), 3.64 (s, 1.56H), 3.38–3.43 (m, 0.52H), 3.24–3.31 (m, 1H), 2.93–3.01 (m, 0.96H), 2.66 (dd, J = 8.5, 13.3 Hz, 0.52H), 2.52–2.56 (m, 1.48H), 2.34 (dd, J = 8.8, 16.3 Hz, 0.52H). HRMS (ESI): m/z calcd for C₁₉H₂₁35ClN₂NaO₃ [M+Na]⁺: 383.1138; found: 383.1155.

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(4-methoxyphenyl)butanoate (2g): Pale yellowish oil; yield: 95% ⁴³ . IR (film): υ 3374, 2968, 1743, 1681, 1563, 1461, 1235, 1130 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.70 (s, 0.6H), 7.16–7.35 (m, 7H), 6.66–6.79 (m, 2H), 6.57 (s, 0.4H), 6.11 (s, 0.6H), 5.73 (s, 0.4H), 4.45 (s, 0.6H), 4.33 (s, 0.4H), 3.79 (s, 1.2H), 3.69 (s, 1.8H), 3.68 (s, 1.8H), 3.64 (s, 1.2H), 3.33–3.36 (m, 0.6H), 3.12–3.15 (m, 0.4H), 2.97 (dd, J = 4.8, 13.5 Hz, 0.6H), 2.74–2.76 (m, 0.6H), 2.67 (dd, J = 7.5, 13.5 Hz, 0.8H), 2.49–2.53 (m, 1.4H), 2.26 (dd, J = 9.2, 16.2 Hz, 0.6H).

Methyl 3-(((S)-2-Amino-2-oxo-1-phenylethyl)amino)-4-(3-methoxyphenyl)butanoate (2h): Pale yellowish oil; yield: 94%. IR (film): υ 3372, 2966, 1744, 1680, 1566, 1462, 1240, 1128 cm⁻¹. δ_H (500 MHz, CDCl₃): 7.69 (s, 0.55H), 7.12–7.36 (m, 6H), 6.68–6.82 (m, 3H), 6.58 (s, 0.45H), 6.54 (s, 0.55H), 5.99 (s, 1H), 5.59 (s, 0.45H), 4.45 (s, 0.55H), 4.31 (s, 0.45H), 3.80 (s, 1.5H), 3.69 (s, 3H), 3.65 (s, 1.5H), 3.32–3.36 (m, 0.55H), 3.12–3.15 (m, 0.45H), 2.96 (dd, J = 4.8, 13.5 Hz, 0.55H), 2.74–2.78 (m, 0.9H), 2.66 (dd, J = 7.5, 13.5 Hz, 0.55H), 2.49–2.51 (m, 1.45H), 2.26 (dd, J = 9.1, 16.2 Hz, 0.55H). HRMS (ESI): m/z calcd for C₂₀H₂₄N₂NaO₄ [M+Na]⁺: 379.1634; found: 379.1655.