A facile synthesis of β-amino carbonyl compounds through an aza-Michael addition reaction under solvent-free conditions

Abstract

An efficient and eco-friendly process for the synthesis of β-amino carbonyl compounds was introduced in this paper. The oxanorbornene β-amino esters and β-enamine esters were successfully prepared from oxabornene and amines by using solvent-free aza-Michael addition reaction in the absence of any catalyst. Oxanorbornene β-amino esters were the major product at room temperature, but higher temperature (e.g. 90 °C) led to the formation of β-enamine esters. In addition, all of the target compounds were characterized by IR, ¹H NMR, ¹³C NMR, and HR-MS. A possible reaction pathway was also proposed.

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Introduction

β-Amino carbonyl structural units exist extensively in natural products and bioactive compounds.¹ They are usually used as intermediates for the preparation of amino alcohols, diamines, β-amino acid derivatives and other nitrogen-containing molecules.² As a result, their synthesis and application have received a great deal of recent attention in the fields of organic chemistry and medicinal chemistry.³

The Mannich-type reaction could be a useful and practical protocol for constructing β-amino carbonyl units.⁴ Unfortunately, harsh reaction conditions and longer reaction time are commonly required.⁵ On the other hand, aza-Michael addition reaction, addition of an amine to an electron deficient alkene, offers an easy access to β-amino carbonyl compounds.^6,7 To date, a number of synthetic approaches to β-amino carbonyl compounds have been established through aza-Michael addition.⁸ A variety of catalysts, such as acetic acid, boric acid,⁹ ionic liquid,¹⁰ cyclodextrin, transition metal,¹¹ lanthanide halides, triflates or silica gel, solid salts and quaternary ammonium salt, have been developed for this purpose.¹² However, drawbacks including use of expensive reagents or organic solvents, or an excess of catalyst and high temperature still exist.¹³ Thus, the development of an efficient and environmentally benign protocol could be highly desirable for the synthesis of β-amino carbonyl compounds.

Herein, an efficient and eco-friendly procedure for the synthesis of β-amino carbonyl compounds from oxabornene and amine via aza-Michael addition as depicted in Scheme 1 was disclosed without use of any catalyst and solvent. Oxanorbornene β-amino esters 3 and (Z)-β-enamine esters 4 were successfully prepared at r.t. and 90 °C, respectively.

Scheme 1 Synthesis of β-amino carbonyl compounds 3 and 4.

Results and discussion

To establish the synthetic process for β-amino carbonyl compounds from oxabornene 1 and amines 2 through solvent-free aza-Michael addition reaction, the reaction of oxabornene 1 and 1-phenylpiperazine 2a were initially selected as a model reaction. As a result, diethyl 2-(4-phenylpiperazin-1-yl)-7-oxabicyclo [2.2.1]hept-5-ene-2,3-dicarboxylate 3a was obtained as the product. As shown in Table 1, acetone, THF, DCE and toluene as the solvent, the reaction gave poor results (Table 1, entries 1–4). To be delighted, the reaction ran well at r.t. without solvent under other identical conditions, leading to 75% isolated yield of 3a (entry 5). Accordingly, the solvent-free aza-Michael addition reaction was chosen for the further investigation.

Table 1 Effect of solvent, temperature and role of molar-ratio on the formation of oxanorbornene β-amino esters 3a

Entry	Solvent	1 : 2a	Temp. (°C)	Time	Yield^a (%)
a Isolated yield by neutral alumina column chromatography.
1	Acetone	1 : 1.5	r.t.	12 h	60
2	THF	1 : 1.5	r.t.	12 h	59
3	DCE	1 : 1.5	r.t.	12 h	64
4	Toluene	1 : 1.5	r.t.	12 h	62
5	Solvent-free	1 : 1.5	r.t.	30 min	75
6	Solvent-free	1 : 1.5	30	30 min	70
7	Solvent-free	1 : 1.5	50	30 min	63
8	Solvent-free	1 : 1.5	70	30 min	48
9	Solvent-free	2 : 1	r.t.	1 min	53
10	Solvent-free	1 : 1	r.t.	1 min	51
11	Solvent-free	1 : 1.5	r.t.	1 min	75
12	Solvent-free	1 : 2	r.t.	1 min	83
13	Solvent-free	1 : 3	r.t.	1 min	68

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The temperature has detrimental effect on the formation of oxanorbornene β-amino ester 3a. The yield decreased from 75% to 48% as the temperature went from r.t. up to 70 °C (Table 1, entries 5–8), indicating oxanorbornene β-amino ester may have poor stability at higher temperature. Interestingly, 1 min was enough to get better 3a yield (entry 11 vs. 5); on the other hand, excellent yield up to 83% was reached at 1 : 2 molar ratio of 1 to 2a (entries 9–13).

The applicability of various amines on solvent-free aza-Michael addition reaction was further investigated. The results showed that it is a general method to produce oxanorbornene β-amino esters 3 as listed in Table 2. Aliphatic amines have higher activity than aromatic counterparts (Table 2, entries 1–7 vs. 8–10), especially cyclic amines, ran much faster (entries 1–4), being in well agreement with the literature results.¹⁴ Whereas, longer reaction time was needed for aromatic amines for completing the reaction (entries 8–10), probably due to the electronic and steric effect. The yield of oxanorbornene β-amino esters 3 was also affected by the basicity and steric factor of the amino group and the nature of the carbonyl group (entries 3, 5 and 8).

Table 2 Preparation of various oxanorbornene β-amino esters 3 through solvent-free aza-Michael addition reaction at r.t.

Entry	Amine 2	Product 3	Time	Isolated yield^a (%)
a The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was monitored by TLC.
1			1 min	83
2			1 min	86
3			1 min	89
4			1 min	97
5			0.5 h	76
6			1 h	54
7			5 h	93
8			12 h	62
9			10 h	78
10		—	24 h	Trace

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Unexpectedly, (Z)-β-enamine esters 4 and furan 5 can be obtained during the solvent-free aza-Michael addition reaction. When aliphatic amines as the substrates, e.g. 2b and 2e, just a trace amount of β-enamine ester 4 was formed and oxanorbornene β-amino ester 3 became the major product (Table 3, entries 1 and 2). In the case of aromatic amines, the yield of product 4 was slightly increased (entries 3 and 4). Those results encouraged us to further explore the reaction in order to develop novel access to β-amino carbonyl compound 4.

Table 3 Preparation of β-amino carbonyl compounds 3 and 4 through solvent-free aza-Michael addition reaction at r.t.

Entry	Amine 2	Time	Product 3	3 Yields^a (%)	Product 4	4 Yields (%)
a The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was monitored by TLC.
1		1 min		86	—	Trace
2		0.5 h		76	—	Trace
3		12 h		62		12
4		10 h		78		8

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To establish the synthetic process for (Z)-β-enamine esters 4, a variety of reaction parameters and the results are summarized in Table 4. THF, toluene, acetone and DMF as the solvent, yields of diethyl 2-(phenylamino)fumarate 4a were found to be in the range of 27% to 63% at 90 °C for 24 h (Table 4, entries 1–4). Surprisingly, better yield was achieved for 6 h under solvent-less conditions (entries 5 vs. 1–4), suggesting solvent-free was favourable for the reaction. In addition, higher temperature is beneficial for the generation of β-amino ester 4a. The yield of 4a reached to 77% at 90 °C (entries 5). Further increasing the reaction temperature to 110 °C had negative effect on 4a yield (entries 10). And excellent yield was achieved at 1 : 2 molar ratio of 1 to 2a (entries 5 vs. 11–14).

Table 4 Effect of solvent reagent, temperature and molar ratio of materials on preparation of 4a

Entry	Solvent	1 : 2a	Temp. (°C)	Time	Yield^a/%
a Isolated yield by alumina column chromatography; the progress of the reaction was monitored by TLC.
1	THF	1 : 2	90	24 h	63
2	Toluene	1 : 2	90	24 h	41
3	Acetone	1 : 2	90	24 h	27
4	DMF	1 : 2	90	24 h	27
5	Solvent-free	1 : 2	90	6 h	77
6	Solvent-free	1 : 2	r.t.	5 d	62
7	Solvent-free	1 : 2	30	4 d	65
8	Solvent-free	1 : 2	50	3 d	70
9	Solvent-free	1 : 2	70	17 h	72
10	Solvent-free	1 : 2	110	6 h	65
11	Solvent-free	2 : 1	90	38 h	13
12	Solvent-free	1 : 1	90	36 h	44
13	Solvent-free	1 : 1.5	90	19 h	59
14	Solvent-free	1 : 3	90	5 h	72

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The generality of the reaction was examined and the results are presented in Table 5. A wide range of amines 2 reacted with oxabornene 1 to afford (Z)-β-enamine esters 4a–f. The reactions with alkylamine were easier to perform (Table 4, entries 3–6) in 0.5 h or 1 min. But aromatic amines needed longer time to react, as the weaker activity (entries 1 and 2 vs. 3–6). Generally, cyclic amines can produce enamines faster than open-chain amines (entries 4–6 vs. 3).

Table 5 Synthesis of (Z)-β-enamine esters 4 under solvent-free condition at 90 °C

Entry	Amine 2		Product 4	Time	Isolated yield^a (%)
a The molar ratio of oxabornene 1 to amines 2 was 1 : 2; isolated yield by neutral alumina column chromatography; the progress of the reaction was monitored by TLC.
1	PhNH2	4a		6 h	77
2	p-MePhNH2	4b		4 h	54
3		4c		0.5 h	42
4		4d		1 min	70
5		4e		1 min	61
6		4f		1 min	73

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The plausible mechanism for the formation of oxanorbornene β-amino esters 3 and (Z)-β-enamine esters 4 was also proposed on the basis of the experimental results. As showed in Scheme 2, the reaction of the amine and oxabornene 1 generate the oxanorbornene β-amino ester 3 through aza-Michael addition reaction. Subsequently, 3 goes at higher temperature through retro-Diels–Alder reaction to produce (Z)-β-enamine esters 4. This is understandable that the thermodynamic product 4 forms at higher temperature; while oxanorbornene β-amino ester 3 is a major product at room temperature.¹⁵ Indeed, compound 4a and 5 were obtained from thermal degradation of 3h at 90 °C, identified by spectroscopy (see, ESI†).

Scheme 2 Plausible mechanism for solvent-free aza-Michael addition reaction.

Experimental

General method

All compounds were fully characterized by spectroscopic techniques. The NMR spectra were recorded on a Bruker-Avance 400 MHz spectrometer (¹H: 400 MHz, ¹³C: 100 MHz) with tetramethylsilane (TMS) as the internal standard (δ 0.0 ppm), chemical shifts (δ) are expressed in ppm, and J values are given in Hz. Deuterated CDCl₃ was used as a solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions were monitored by thin layer chromatography (TLC) using neutral alumina. The melting points were determined on an XT-4A melting point apparatus and are uncorrected. HRMS was performed on an Agilent LC-MSD TOF instrument.

All chemicals and solvents were used as received without further purification unless otherwise stated. Column chromatography was performed on neutral alumina.

Preparation of diethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate 1

Diethyl acetylenedicarboxylate 12 mmol and furan 60 mmol were placed in a sealed tube, which was heated at 100 °C for 20 hours. The reaction mixture was distilled under vacuum. The endoxide was obtained as a light yellow oil.¹⁶

General procedure for the synthesis of oxanorbornene β-amino esters 3 through solvent-free aza-Michael addition reaction

A Schlenk was charged with 1 (0.4 mmol, 95.3 mg), amine 2 (0.8 mmol), and the solution was stirred for 1 minute to 6 days at room temperature until the 1 was completely consumed. The mixture was purified by flash column chromatography. The desired compounds (3a–j) were formed from 1 in yields: 54–97%.

The data of the oxanorbornene β-amino esters 3

Diethyl- 2-(4-phenylpiperazin-1-yl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3a). Yield 83%; white solid; mp: 114–115 °C; IR (KBr) (ν_max, cm⁻¹) 3447, 2333, 1731, 1597, 1452, 1263, 1127, 1136, 1060, 860, 755, 568 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.23 (2H, m), 6.91–6.83 (3H, m), 6.59–6.57 (1H, m), 6.25–6.23 (1H, m), 5.31 (1H, s), 5.24 (1H, s), 4.23–4.11 (4H, m), 3.42 (1H, s), 3.08–2.93 (8H, m), 1.34–1.31 (3H, t, J = 7.1 Hz), 1.29–1.25 (3H, t, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ 171.1, 169.9, 151.3, 140.7, 135.0, 129.2, 120.0, 116.2, 81.2, 80.2, 78.2, 61.2, 61.0, 53.3,50.2, 48.2, 14.6, 14.4; HRMS (TOF ES⁺): m/z calcd for C₂₂H₂₈N₂O₅Na⁺ [(M + Na)⁺], 423.1890; found, 423.1885.

Diethyl- 2-(4-methylpiperazin-1-yl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3b). Yield 86%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3447, 3136, 2838, 2345, 1733, 1455, 1378, 1266, 1127, 1056, 859, 808, 558 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.53–6.51 (1H, m), 6.17–6.16 (1H, m), 5.23–5.17 (2H, m), 4.20–4.09 (4H, m), 3.35–3.34 (1H, m), 2.82 (4H, m), 2.20–2.19 (7H, m), 1.30–1.23 (6H, m); ¹³C NMR (100 MHz, CDCl₃): δ 170.1, 169.8, 140.5, 134.8, 81.0, 79.9, 77.9, 60.9, 60.7, 55.8, 53.0, 46.0, 14.3, 14.2; HRMS (TOF ES⁺): m/z calcd for C₂₂H₂₈N₂O₅Na⁺ [(M + Na)⁺], 423.1890; found, 423.1885.

Diethyl 2-(piperidin-1-yl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3c). Yield 89%; white solid; mp: 81–82 °C; IR (KBr) (ν_max, cm⁻¹) 3448, 3134, 2332, 1728, 1452, 1265, 1126, 1061, 860, 568 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.54–6.53 (1H, m), 6.20–6.18(1H, m), 5.29 (1H, s), 5.18 (1H, s), 4.25–4.11 (4H, m), 3.36 (1H, s), 2.72–2.67 (4H, m), 1.46–1.36 (6H, m), 1.32–1.26 (6H, m); ¹³C NMR (100 MHz, CDCl₃): δ 171.3, 170.3, 140.6, 135.2, 81.3, 80.2, 80.1, 79.1, 60.0, 60.9, 60.8, 53.0, 50.6, 49.3, 27.0, 24.6, 14.6, 14.3; HRMS (TOF ES⁺): m/z calcd for C₁₇H₂₅NO₅Na⁺ [(M + Na)⁺], 346.1624; found, 346.1622.

Diethyl 2-morpholino-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3d). Yield 97%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3447, 3134, 2332, 1730, 1453, 1262, 1122, 1061, 860, 553 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.58–6.57 (1H, dd, J = 5.8, 1.6 Hz), 6.23–6.21 (1H, dd, J = 5, 1.7 Hz), 5.26–5.23 (2H, d, J = 9.5 Hz), 4.28–4.11 (4H, m), 3.61–3.59 (4H, t, J = 4.5 Hz), 3.38 (1H, s), 2.86–2.82 (2H, m), 2.74–2.73 (2H, m), 1.60 (1H, s), 1.35–1.25 (7H, m); ¹³C NMR (100 MHz, CDCl₃): δ 171.1, 169.8, 140.8, 134.9, 81.2, 79.8, 78.3, 67.8, 61.2, 60.9, 53.3, 49.7, 48.7, 14.6, 14.4; HRMS (TOF ES⁺): m/z calcd for C₁₆H₂₃NO₆Na⁺ [(M + Na)⁺], 348.1417; found, 348.31407.

Diethyl 2-(ethylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3e). Yield 76%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3447, 2980, 2357, 1733, 1457, 1377, 1257, 1126, 1061, 859, 709, 558 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.73–6.71 (1H, dd, J = 5.8, 1.7 Hz), 6.36–6.34 (1H, dd, J = 5.8, 1.8 Hz), 5.07–5.06 (1H, m), 4.79 (1H, m), 4.14–4.09 (4H, m), 3.07–3.05 (1H, d, J = 4.3 Hz), 2.81–2.78 (1H, m), 2.65–2.60 (1H, m), 1.78 (1H, s), 1.26–1.22 (6H, t, J = 7.1 Hz), 1.17–1.13 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 170.6, 170.4, 137.7, 132.8, 85.5, 80.3, 75.6, 61.1, 60.8, 55.9, 39.8, 15.6, 14.2, 14.0. HRMS (TOF ES⁺): m/z calcd for C₁₄H₂₁NNaO₅⁺ [(M + Na)⁺], 306.1312; found, 306.1316.

Diethyl 2-(butylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3f). Yield 54%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3381, 2357, 1734, 1664, 1460, 1259, 1127, 860, 550 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.73–6.71 (1H, dd, J = 5.8, 1.6 Hz), 6.36–6.34 (1H, dd, J = 5.8, 1.8 Hz), 5.08–5.06 (1H, m), 4.79 (1H, m), 4.14–4.09 (4H, m), 3.06–3.05 (1H, d, J = 4.3 Hz), 2.80–2.73 (1H, m), 2.58–2.52 (1H, m), 1.84 (1H, s), 1.53–1.46 (2H, m), 1.38–1.33 (2H, m) 1.26–1.22 (6H, m), 0.90 (3H, t, J = 7.28 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 170.8, 170.6, 137.8, 133.0, 85.6, 80.4, 75.7, 61.3, 60.9, 60.0, 45.3, 32.5, 20.5, 14.3, 14.1, 14.0; HRMS (TOF ES⁺): m/z calcd for C₁₆H₂₅NO₅Na⁺[(M + Na)⁺], 334.1624; found, 334.1625.

Diethyl 2-(allylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3g). Yield 93%; colorless oil; IR (KBr) (ν_max, cm⁻¹) 3323, 2985, 1734, 1659, 1606, 1459, 1376, 1254, 1170, 1062, 914, 859, 786, 710, 554 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 6.75–6.74 (1H, dd, J = 5.8, 1.7 Hz), 6.35–6.33 (1H, dd, J = 5.8, 1.8 Hz), 5.98–5.88 (1H, m), 5.23–5.18 (1H, m), 5.11–5.07 (2H, m), 4.80–4.79 (1H, m), 4.16–4.08 (4H, m), 3.46–3.41(1H, m), 3.24–3.19 (1H, m), 3.08 (1H, d, 4.3 Hz), 2.00 (1H, s), 1.26–1.22 (6H, m); ¹³C NMR (100 MHz, CDCl₃): δ 170.5, 170.4, 137.9, 136.0, 132.8, 116.7, 85.8, 80.4, 75.5, 61.3, 60.9, 55.9, 48.5, 14.2, 14.1; HRMS (TOF ES⁺): m/z calcd for C₁₅H₂₂NO₅⁺[(M + H)⁺], 296.1498; found, 296.1501.

Diethyl 2-(phenylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3h). Yield 62%; white solid; mp: 107–108 °C; IR (KBr) (ν_max, cm⁻¹) 3385, 2974, 2331, 1735, 1604, 1511, 1449, 1377, 1321, 1254, 1062, 1011, 859, 749, 689, 551 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.26–7.16 (2H, m), 6.84–6.80 (4H, m), 6.47–6.46 (1H, dd, J = 5.8, 1.9 Hz), 5.15–5.14 (1H, m), 5.06–5.05 (1H, m), 4.41 (1H, s), 4.20–4.09 (4H, m), 3.19 (1H, d, J = 4.4 Hz), 1.30 (3H, t, J = 7.2 Hz), 1.15 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 170.6, 169.8, 144.9, 138.3, 132.3, 129.1, 119.5, 115.8, 86.5, 80.6, 72.4, 61.9, 61.2, 58.2, 14.1, 14.0. HRMS (TOF ES⁺): m/z calcd for C₁₈H₂₂NO₅⁺ [(M + H)⁺], 332.1492; found, 332.1483.

Diethyl 2-(p-tolylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (3i). Yield 78%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3386, 2356, 1730, 1519, 1454, 1257, 1126, 1061, 858, 814, 567 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 7.00 (2H, d, J = 8.4 Hz), 6.79 (1H, dd, J = 5.8, 1.6 Hz), 6.74–6.71 (2H, m), 6.46 (1H, dd, J = 5.8, 1.8 Hz), 5.13–5.12 (1H, m), 5.04 (1H, s), 4.26 (1H, s), 4.19–4.09 (4H, m), 3.18 (1H, d, J = 4.4 Hz), 2.25 (3H, s), 1.29 (3H, t, J = 7.13 Hz), 1.17 (6H, t, J = 7.13 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 170.7, 170.40, 142.5, 138.1, 132.5, 129.6, 129.1, 116.4, 86.3, 72.8, 61.9, 61.2, 58.1, 20.6, 14.2, 14.1; HRMS (TOF ES⁺): m/z calcd for C₁₉H₂₄NO₅⁺[(M + H)⁺], 346.1468; found, 346.1649.

General procedure for the synthesis of (Z)-β-enamine esters 4

A Schlenk was charged with diethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate 1 (0.4 mmol, 95.3 mg), amine 2 (0.8 mmol), and the solution was stirred for 1 minute to 6 days at 90 °C until 1 was completely consumed. The mixture was purified by flash column chromatography. The desired compounds 4 were formed from 1 in yields 42–77%.

The data of the (Z)-β-enamine esters 4

Diethyl 2-(phenylamino)fumarate (4a). Yield 77%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3279, 2984, 2344, 1735, 1668, 1607, 1498, 1382, 1274, 1208, 1137, 1039, 861, 755, 693, 553 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 9.68 (1H, s), 7.30–7.25 (2H, m), 7.11–7.07 (1H, m), 6.92 (2H, d, J = 7.7 Hz), 5.38 (1H, s), 4.22–4,13 (4H, m), 1.30 (3H, t, J = 7.1 Hz), 1.09 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 169.7, 164.5, 148.5, 140.5, 129.2, 124.3, 121.1, 93.9, 62.2, 60.1, 14.5, 13.7. HRMS (TOF ES⁺): m/z calcd for C₁₄H₁₇NO₄Na⁺ [(M + Na)⁺], 286.1050; found, 286.1055.

Diethyl 2-(p-tolylamino)fumarate (4b). Yield 54%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3448, 2331, 1735, 1666, 1613, 1519, 1457, 1274, 1207, 1071, 859, 811, 551; 1H NMR (400 MHz, CDCl₃): δ 9.62 (1H, s), 7.07–7.05 (2H, m), 6.83–6.81 (2H, m), 5.32 (1H, s), 4.21–4.12 (4H, m), 2.29 (3H, s), 1.29 (3H, t, J = 7.1 Hz), 1.10 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 168.8, 163.5, 147.9, 136.9, 133.1, 128.7, 120.3, 91.8, 61.1, 58.9, 19.9, 13.4, 12.8.

Diethyl 2-((1-phenylethyl)amino)fumarate (4c). Yield 42%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3449, 3134, 2981, 2356, 1733, 1662, 1605, 1453, 1372, 1264, 1209, 1132, 1045, 861, 779, 698, 564 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.43 (1H, d, J = 6.7 Hz), 7.32–7.28 (2H, m), 7.23–7.19 (3H, m), 5.09 (1H, s), 5.07–5.00 (1H, m), 4.19–4.14 (2H, m), 4.08–4.03 (2H, m), 1.51 (3H, d, J = 6.9 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.12 (3H, t, J = 7.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ 170.4, 163.8, 151.7, 145.0, 128.8, 127.3, 126.1, 88.5, 61.8, 59.5, 53.8, 24.9, 14.6, 14.0; HRMS (TOF ES⁺): m/z calcd for C₁₆H₂₁NO₄Na⁺[(M + Na)⁺], 314.1362; found, 314.1364.

Diethyl 2-(4-phenylpiperazin-1-yl)fumarate (4d). Yield 70%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3449, 2331, 1738, 1691, 1586, 1498, 1447, 1382, 1277, 1154, 1063, 858, 803, 755, 689, 548; ¹H NMR (400 MHz, CDCl₃): δ 7.30–7.26 (2H, m), 6.92–6.89 (3H, m), 4.83 (1H, s), 4.40–4.39 (2H, m), 4.14–4.09 (2H, m), 3.34–3.32 (4H, m), 3.24–3.22 (4H, m), 1.39 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 167.4, 165.6, 154.5, 150.7, 129.4, 120.8, 116.7, 87.5, 62.3, 59.6, 48.8, 47.1, 14.5, 14.0; HRMS (TOF ES⁺): m/z calcd for C₁₈H₂₅N₂ O₄Na⁺[(M + Na)⁺], 333.1808; found, 333.1807.

Diethyl 2-(4-methylpiperazin-1-yl)fumarate (4e). Yield 61%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3450, 2980, 2801, 2331, 1739, 1693, 1582, 1450, 1379, 1285, 1201, 1159, 1049, 1007, 801, 750, 552; ¹H NMR (400 MHz, CDCl₃): δ 4.68 (1H, s), 4.32–4.27 (2H, m), 4.03–3.98 (2H, m), 3.09 (3H, t, J = 5.1 Hz), 2.37–2.35 (4H, m), 2.21 (3H, s), 1.27 (3H, t, J = 7.2 Hz), 1.13 (3H, t, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 166.3, 164.4, 153.4, 85.8, 61.0, 58.2, 52.9, 45.8, 44.9, 13.3, 12.8; HRMS (TOF ES⁺): m/z calcd for C₁₃H₂₂N₂O₄Na⁺[(M + Na)⁺], 2 931 471; found, 293.1477.

Diethyl 2-morpholinofumarate (4f). Yield 73%; yellow oil; IR (KBr) (ν_max, cm⁻¹) 3451, 2980, 2330, 1739, 1694, 1585, 1444, 1380, 1276, 1158, 1113, 1041, 917, 861, 802, 748, 552; ¹H NMR (400 MHz, CDCl₃): δ 4.73 (1H, s), 4.34–4.29 (2H, m), 4.06–4.01 (2H, m), 3.69–3.66 (4H, m), 3.08 (4H, t, J = 4.9 Hz), 1.32–1.29 (3H, m), 1.19–1.15 (3H, m); ¹³C NMR (100 MHz, CDCl₃): δ 166.2, 164.4, 153.7, 86.7, 64.9, 61.2, 58.5, 46.1, 13.4, 12.9; HRMS (TOF ES⁺): m/z calcd for C₁₂H₁₉NO₅Na⁺[(M + Na)⁺], 280.1155; found, 280.1161.

Conclusions

In summary, an efficient and eco-friendly protocol for the synthesis of β-amino carbonyl compounds through solvent-free aza-Michael addition reaction was disclosed. Meanwhile, two kinds of β-amino carbonyl compounds were obtained by tuning the reaction temperature. We believe these results stimulate further research efforts to develop β-amino carbonyl compounds and extend solvent-free aza-Michael addition reaction to pharmaceutical synthesis.

Acknowledgements

The work was supported by the National Natural Science Foundation of China (Nos. 21202142, 21162042), the Key Project of Chinese Ministry of Education (No. 212161) and the Opening Foundation of Key Laboratory of Chemistry in Ethnic-medicine Resources (Yunnan Nationalities University), Ministry of Education (MZY1115).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra46789a

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