Next Article in Journal
Green NADES-Based Pretreatment Combined with Microwave-Assisted Hydrodistillation for Enhanced Fennel Essential Oil Production
Previous Article in Journal
Recent Advances in Elucidating the Mechanism of the NADPH–Cytochrome P450 Reductase-Mediated Electron Transfer Cycle: Experimental and Computational Perspectives
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 30
Issue 18
10.3390/molecules30183730
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner–Wadsworth–Emmons Reaction

by
Sindy Anahi Perez-Aniceto
1,
Erica Cano-Tapia
1,
Mario Ordoñez
1,*,
José Luis Viveros-Ceballos
1,* and
Ivan Romero-Estudillo
2
1
Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Morelos, Mexico
2
Secihti-Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Cuernavaca 62209, Morelos, Mexico
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(18), 3730; https://doi.org/10.3390/molecules30183730
Submission received: 15 August 2025 / Revised: 3 September 2025 / Accepted: 10 September 2025 / Published: 13 September 2025
(This article belongs to the Special Issue A Themed Issue in Honor of the 20th Anniversary of the Mexican Academy of Organic Chemistry (AMQO))
Browse Figures
Versions Notes

Abstract

An efficient and practical procedure for the synthesis of (E)-α,β-unsaturated amides incorporating α-aminophosphonates, derived from readily accessible phosphonoacetamides, via the Horner–Wadsworth–Emmons (HWE) reaction was developed. The influence of reaction parameters, including base, solvent, and temperature, as well as the scope of the method with different aldehydes, was examined, affording the target compounds in good yields and with high (E)-selectivity. The required phosphonoacetamides were conveniently prepared through a Kabachnik–Fields reaction of aldehydes, benzylamine and dimethyl phosphite followed by hydrogenolytic cleavage of the N-Bn bond, acylation with bromoacetyl bromide, and a subsequent Arbuzov reaction. This HWE protocol provides straightforward access to a broad range of (E)-α,β-unsaturated amides incorporating α-aminophosphonates under mild conditions, offering valuable scaffolds with potential pharmacological relevance as anticancer agents.

1. Introduction

Cinnamic acid and derivatives, both isolated from natural sources and by synthetic methods, are important compounds characterized by low toxicity and a broad spectrum of biological activities and chemical applications [1,2]. Among them, cinnamic acid amides exhibit a wide range of biological activities [3,4], mainly those that incorporate an α-amino acid moiety in their structure 1 (Figure 1), which have been evaluated as anticancer agents [5], antimalarial [6], antioxidant [7,8], and as agents for the treatment of Alzheimer’s disease [9].
On the other hand, the α-aminophosphonic and α-aminophosphonate analogues of the corresponding α-amino acids and α-amino esters 2 and 3 (Figure 1), respectively, represent an important class of compounds with multiple applications in medicinal and organic chemistry, due to the ability of the phosphonic group to mimic the high-energy transition state of peptide bond hydrolysis, enabling them to act as enzyme inhibitors or receptor ligands in pathological conditions associated with α-amino acid metabolism [10,11,12,13,14]. Due to the importance of these compounds as a bioisosters of carboxylates, excellent methods for their preparation have been published in recent decades [15,16,17,18,19,20].
In contrast to the different methods for the synthesis of (E)-α,β-unsaturated amides bearing α-amino acids, the (E)-α,β-unsaturated amides incorporating α-aminophosphonates has been little explored, and there are few reports has been described in the literature, mainly α-aminophosphonates 2a–d carrying the cinnamic and acrylic acid fragment (Scheme 1a–d) [21,22,23,24,25,26,27]. Considering the importance of these non-proteinogenic α-aminophosphonic acids as pharmacophores in the discovery of new drugs, which is in line with our current research interest in the synthesis of α-aminophosphonic acids [28], we herein report an alternative and practical method for the preparation of α,β-unsaturated amides 3 bearing α-aminophosphonates via the Horner–Wadsworth–Emmons reaction using phosphonoacetamides 7a–c (Scheme 1e).

2. Results and Discussion

For the preparation of (E)-α,β-unsaturated amides incorporating α-aminophosphonates, initially we carried out the synthesis of α-aminophosphonates 5a–c through the Kabachnik–Fields reaction [29,30] of isobutyraldehyde, benzaldehyde, or 4-methoxybenzaldehyde with benzylamine and dimethyl phosphite in the presence of 10 mol% of PhB(OH)2 at 50 °C under solvent-free conditions [31], obtaining the corresponding N-benzyl α-aminophosphonates 4a–c in 72 to 87% yield. Subsequent debenzylation over Pd/C in methanol under hydrogen pressure using a balloon, afforded the α-aminophosphonates 5a–c in 98% yield, which were used in the following reactions without further purification (Scheme 2).
With the α-aminophosphonates 5a–c in hand, we decided to explore the preparation of (E)-α,β-unsaturated amide 3a incorporating the α-aminophosphonate 5a moiety through the reaction of 5a with trans-cinnamic acid, using several coupling reagents, such as acyl chloride, hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (PyBOP), N,N’-Dicyclohexylcarbodiimide (DCC) and mixed anhydrides [i-BuOC(O)Cl, (Boc)2O]. In this context, initially the trans-cinnamic acid was reacted with SOCl2 and N,N-diisopropylethylamine (DIPEA) in dichloromethane at 0 to 25 °C to obtain the corresponding cinnamoyl chloride which, without isolation was reacted with the α-aminophosphonate 5a, obtaining the (E)-α,β-unsaturated amide 3a in 56% yield (Table 1, entry 1). In the next experiment, the trans-cinnamic acid was activated with HBTU and DIPEA in dichloromethane, to give the compound 3a in 76% yield (Table 1, entry 2). Similar results were obtained when PyBOP was used as the coupling reagent and DIPEA in MeCN at 0 to 25 °C (Table 1, entry 3). Additionally, we carried out the reaction of trans-cinnamic acid with DCC and 4-dimethylaminopyridine (DMAP) in dichloromethane followed by the addition of 5a, affording the (E)-α,β-unsaturated amide 3a in 74% (Table 1, entry 4). Similar results were obtained when the mixed anhydride derived from trans-cinnamic acid and isobutyl chloroformate was reacted with the α-aminophosphonate 5a (Table 1, entry 5). Finally, the reaction of 5a with the mixed anhydride obtained from trans-cinnamic acid and di-tert-butyl dicarbonate [(Boc)2O], produced (E)-α,β-unsaturated amide 3a in 68% (Table 1, entry 6).
With the optimized reaction conditions established for the synthesis of (E)-α,β-unsaturated amide 3a, we turned our attention to investigate the scope and versatility of this method in the synthesis of several (E)-α,β-unsaturated amides incorporating the α-aminophosphonate 5a. Thus, the scope of this reaction was evaluated by reacting the α-aminophosphonate 5a with several cinnamic acids, using PyBOP as the coupling agent and DIPEA in MeCN at 0 to 25 °C, obtaining the corresponding (E)-α,β-unsaturated amides 3b–f in 68 to 74% yield (Scheme 3).
Although the method described above produced the desired (E)-α,β-unsaturated amides in good yields, an important limitation is the limited commercial availability of the corresponding acrylic acid and derivatives. Therefore, we decided to explore a more general method to access (E)-α,β-unsaturated amides bearing aryl or alkyl substituents at the β-position, via the Horner–Wadsworth–Emmons (HWE) reaction, a method with which we have previous experience [32,33]. To accomplish the above, it was necessary to prepare the phosphonoacetamides 7a–c, our starting materials. Thus, the α-aminophosphonates 5a–c were reacted with bromoacetyl bromide and potassium carbonate in a dichloromethane:water mixture (4:1) at room temperature, producing the bromoamides 6a–c in 72 to 79% yield, which were subjected to a Michaelis-Arbuzov reaction with trimethyl phosphite at 100 °C, to obtain the corresponding phosphonoacetamides 7a–c in 92 to 96% yield (Scheme 4).
With the phosphonoacetamides 7a–c successfully prepared, the next step was to identify suitable conditions for the preparation of the target α,β-unsaturated amides bearing an α-aminophosphonate moiety through the Horner–Wadsworth–Emmons reaction. Initially, the phosphonoacetamide 7a was reacted with cesium carbonate and benzaldehyde in acetonitrile at 50 °C for 12 h, obtaining the α,β-unsaturated amide 3a in 72% yield with an E:Z ratio of 93:07 (Table 2, entry 1). In a second attempt, the reaction was conducted at 80 °C for 6 h, producing 3a in 70% yield and with similar E-selectivity 92:08 (Table 2, entry 2). When the reaction was carried out in toluene at 100 °C, the α,β-unsaturated amide 3a was obtained in 65% yield and 93:07 E:Z selectivity (Table 2, entry 3). Subsequently, the reaction of phosphonoacetamide 7a with benzaldehyde and potassium carbonate in acetonitrile at 50 and 80 °C for 24 and 12 h, respectively, afforded the α,β-unsaturated amide 3a in 63 and 68% yield and E:Z ratios of 91:09 and 87:13 (Table 2, entries 4 and 5). Performing the same reaction in toluene at 100 °C generated the α,β-unsaturated amide 3a in 68% yield and E:Z ratio 61:39 (Table 2, entry 6). Finally, following the protocol developed by our research group [32,33], the phosphonoacetamide 7a was reacted with benzaldehyde, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and LiCl in THF at 25 °C [34], obtaining the α,β-unsaturated amide 3a in 90% yield with high E-selectivity 94:06 (Table 2, entry 7). The stereochemistry in the C=C double bond of the α-unsaturated amide 3a was assigned on the basis of the value of 1H NMR coupling constant between the olefinic protons.
As shown in Table 2, the use of Cs2CO3, K2CO3 and DBU at room temperature afforded the α,β-unsaturated amide 3a with high E-selectivity; however, the highest yield was achieved when DBU is used as the base. For this reason, we turned our attention to exploring the scope and versatility of this method in the synthesis of the α,β-unsaturated amides 3b and 3d–l incorporating dimethyl phosphovalinate via the Horner–Wadsworth–Emmons reaction using DBU as the most appropriate base. In this context, the phosphonoacetamide 7a was reacted under HWE reaction with different aromatic aldehydes such as 4-methoxybenzaldehyde, 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde, O-benzylvanillin, trans-cinnamaldehyde and N-methyl-2-pyrrolecarboxaldehyde, in the presence of DBU and lithium chloride in anhydrous THF at room temperature, obtaining the α,β-unsaturated amides incorporating the dimethyl phosphovalinate (E)-3b and 3d–i in 80% to 88% and E:Z selectivities ranging from 90:10 to 98:02. It is worth noting that the electronic nature of the substituents on the aromatic ring had no significant effect on E:Z selectivity. Similarly, the reaction of phosphonoacetamide 7a with aliphatic aldehydes such as isovaleraldehyde, isobutyraldehyde, trimethylacetaldehyde and 1-cyclohexenecarboxaldehyde under the same conditions, gave the α,β-unsaturated amides 3j–m in 54 to 85% yield and E:Z selectivities ranging from 80:20 to 98:02. The E:Z ratio was determined by 1H NMR in the crude product and isolated yields after purification by column chromatography (Scheme 5).
Additionally, the HWE reaction of the phosphonoacetamide 7b with benzaldehyde, 4-methoxybenzaldehyde, 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde, trans-cinnamaldehyde and N-methyl-2-pyrrolecarboxaldehyde in the presence of DBU and LiCl in THF at 25 °C, produced the α,β-unsaturated amides 8a–g in 50 to 85% yield and E:Z selectivities ranging from 90:10 to 98:02. In a similar way, the HWE reaction of the phosphonoacetamide 7b with isobutyraldehyde and trimethylacetaldehyde, gave the α,β-unsaturated amides 8h,i in good yield and E:Z selectivities of 75:25 and 98:02, respectively. The E:Z ratio was determined by 1H NMR in the crude product and isolated yields after purification by column chromatography (Scheme 6).
Finally, the HWE reaction of phosphonoacetamide 7c with various aldehydes including benzaldehyde, 4-methoxybenzaldehyde, 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde, isobutyraldehyde and trimethylacetaldehyde in the presence of DBU and LiCl in THF at 25 °C, afforded the α,β-unsaturated amides 9a–i in 60% to 93% and E:Z selectivities from 85:15 to 98:02 The E:Z ratio was determined by 1H NMR in the crude product and isolated yields after purification by column chromatography (Scheme 7).

3. Materials and Methods

All commercial materials were used as received unless otherwise noted. Flash chromatography was performed with 230–400 mesh Silica Flash 60®. Thin layer chromatography was performed with pre-coated TLC sheets of silica gel (60 F254, Merck) and the plates were visualized with UV-light and ninhydrin and phosphomolybdic acid. Melting points were determined with a Fisher-Johns apparatus and are uncorrected. 1H, 13C, 31P NMR spectra were recorded in CDCl3 or CD3OD on a Bruker AVANCE III HD (500.13 MHz) and JEOL (600 MHz) using tetramethylsilane (TMS) as internal reference and (85% H3PO4) for 31P NMR. Chemical shifts (δ) are expressed in parts per million (ppm) and coupling constants (J) in Hertz. High resolution FAB(+) and CI(+) mass spectra (HRMS) were obtained on a JEOL MStation MS-700.
  • General procedure for the synthesis of N-benzyl α-aminophosphonates (4a–c).
To a mixture of the corresponding aldehyde; isobutyraldehyde, benzaldehyde and 4-methoxybenzaldehyde (1.0 equiv) and benzylamine (1.0 equiv) was added phenylboronic acid (10 mol%). The reaction mixture was stirred at room temperature for 15 min. After this time, dimethyl phosphite (1.1 equiv) was added and the reaction mixture was stirred at 50 °C. The crude was purified by flash chromatography on silica gel using ethyl acetate-hexane (70:30), obtaining the pure N-benzyl α-aminophosphonates 4a–c. The spectroscopic data for 4a [31], 4b,c [35], are identical to those described in the literature.
  • General procedure for the synthesis of α-aminophosphonates (5a–c).
A mixture of N-benzyl α-aminophosphonates (1.0 equiv) and Pd/C (10%) in 20 mL of methanol was stirred under hydrogen pressure using a balloon for 2 h at 25 °C. The crude was filtered using celite and 20 mL of ethyl acetate. The solvent was evaporated under vacuum, obtaining the α-aminophosphonates 5a–c. The spectroscopic data for 5a,b [36,37], are identical to those described in the literature. Compound 5c was used without further purification
  • General procedure for the synthesis of bromoamides (6a–c).
To a mixture of α-aminophosphonates 5a–c (1.0 equiv) and potassium carbonate (2.3 equiv) in dichloromethane:water (40:10) (50 mL) was cooled at 0 °C and stirred for 15 min, followed by the dropwise addition of bromoacetyl bromide (1.1 equiv), and the reaction mixture was stirred at 25 °C for 2 h. After this time, water (20 mL) was added and extracted with dichloromethane (3 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuum. The crude products were purified by flash column chromatography on silica gel using ethyl acetate-hexane (80:20) as eluent, obtaining the corresponding bromoamides 6a–c.
Dimethyl (1-(2-bromoacetamido)-2-methylpropyl)phosphonate (6a). α-Aminophosphonate 5a (1.10 g, 6 mmol), potassium carbonate (1.98 g, 14 mmol) and bromoacetyl bromide (1.4 g, 0.581 mL, 6.9 mmol) were reacted, obtaining the product 6a (77% yield) as a white solid, Mp: 108–110 °C. 1H NMR (CDCl3, 500 MHz): δ 1.03 (d, J = 6.8 Hz, 3H, (CH3)2CH), 1.05 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.26 (oct, J = 6.9 Hz, 1H, CH(CH3)2), 3.77 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.78 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.92 (AB system, J = 13.2 Hz, 1H, CH2Br), 3.96 (AB system, J = 13.4 Hz, 1H, CH2Br), 4.36 (ddd, J = 17.9, 10.4, 4.5 Hz, 1H, CH-P), 6.83 (d, J = 10.4 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 17.9 (d, J = 4.6 Hz, (CH3)2CH), 20.4 (d, J = 12.4 Hz, (CH3)2CH), 28.8 (CH2Br), 28.9 (d, J = 3.6 Hz, CH(CH3)2), 50.5 (d, J = 152.9 Hz, C-P), 53.0 (d, J = 6.8 Hz, (CH3O)2P), 53.2 (d, J = 6.8 Hz, (CH3O)2P), 165.7 (d, J = 5.6 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 25.9 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C8H18BrNO4P + H+ 302.0151; Found 302.0161.
Dimethyl ((2-bromoacetamido)(phenyl)methyl)phosphonate (6b). α-Aminophosphonate 5b (0.46 g, 2.1 mmol), potassium carbonate (0.70 g, 5 mmol) and of bromoacetyl bromide (0.47 g, 0.20 mL, 2.3 mmol) were reacted, obtaining the product 6b (72% yield) as a white solid, Mp: 143–145 °C. 1H NMR (CDCl3, 500 MHz): δ 3.50 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.84 (d, J = 10.8 Hz, 3H, (CH3O)2P), 3.87 (s, 2H, CH2Br), 5.55 (dd, J = 20.7, 9.6 Hz, 1H, CH-P), 7.31–7.40 (m, 3H, Harom), 7.48–7.52 (m, 2H, Harom), 8.33 (d, J = 9.6 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 28.6 (CH2Br), 50.5 (d, J = 155.3 Hz, C-P), 54.1 (d, J = 6.8 Hz, (CH3O)2P), 54.3 (d, J = 6.8 Hz, (CH3O)2P), 128.3, 128.4, 128.7, 129.1 (2C), 134.3, 166.0 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.0 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C11H16BrNO4P + H+ 335.9995; Found 335.9998.
Dimethyl ((2-bromoacetamido)(4-methoxyphenyl)methyl)phosphonate (6c). α-Aminophosphonate 5c (0.60 g, 2.4 mmol), potassium carbonate (0.80 g, 5.7 mmol) and bromoacetyl bromide (0.54 g, 0.23 mL, 2.6 mmol) were reacted, obtaining the product 6c (80% yield) as a white solid, Mp: 134–135 °C. 1H NMR (CDCl3, 500 MHz): δ 3.51 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.80 (s, 3H, CH3O), 3.83 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.87 (s, 2H, CH2Br), 5.49 (dd, J = 20.3, 9.6 Hz, 1H, CH-P), 6.89 (AA’BB’ system, J = 8.7 Hz, 2H, Harom), 7.42 (AA’BB’ system, J = 8.7, Hz, 2H, Harom), 8.24 (d, J = 9.6 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 28.6 (CH2Br), 49.8 (d, J = 156.7 Hz, C-P), 53.9 (d, J = 6.8 Hz, (CH3O)2P), 54.2 (d, J = 6.8 Hz, (CH3O)2P), 55.5 (CH3O), 114.5 (2C), 126.3, 129.6, 129.7, 159.9, 165.9 (d, J = 8.2 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.3 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C12H18BrNO5P + H+ 366.0100; Found 366.0110.
  • General procedure for the synthesis of phosphonoacetamides (7a–c).
A mixture of bromoamides 6a–c (1.0 equiv) and trimethyl phosphite (4.0 equiv) without solvent was heated for 4 h at 105–110 °C. After this time, the reaction mixture was purified by flash column chromatography using ethyl acetate-methanol (90:10) as the eluent, obtaining the phosphonoacetamides 7a–c.
Dimethyl (2-((1-(dimethoxyphosphoryl)-2-methylpropyl)amino)-2-oxoethyl)phosphonate (7a). Bromoamide 6a (0.50 g, 1.6 mmol) and trimethyl phosphite (0.62 g, 0.52 mL, 4.9 mmol) were reacted, obtaining the product 7a (98% yield) as a white solid, Mp: 80–83 °C. 1H NMR (CDCl3, 500 MHz): δ 1.02 (dd, J = 6.8, 1.4 Hz, 3H, (CH3)2CH), 1.05 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.21–2.26 (m, 1H, CH(CH3)2), 2.99 (dd, J = 24.3, 14.7 Hz, 1H, CH2P), 3.03 (dd, J = 24.3, 14.8 Hz, 1H, CH2P), 3.76 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.78 (d, J = 10.7 Hz, 3H, (CH3O) 2P), 3.80 (d, J = 11.1 Hz, 3H, (CH3O)2P), 3.82 (d, J = 11.1 Hz, 3H, (CH3O)2P), 4.42 (ddd, J = 17.9, 10.4, 4.4 Hz, 1H, CH-P), 7.27 (d, J = 10.4 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 17.8 (d, J = 4.5 Hz, (CH3)2CH), 20.4 (d, J = 13.2 Hz, (CH3)2CH), 28.9 (d, J = 3.6 Hz, CH(CH3)2), 34.1 (d, J = 152.4 Hz, C-P), 50.0 (d, J = 153.0 Hz, C-P), 52.9 (d, J = 6.8 Hz, (CH3O)2P), 52.9 (d J = 6.8 Hz (CH3O)2P), 53.0 (d, J = 6.8 Hz, (CH3O)2P), 53.8 (d, J = 6.8 Hz, (CH3O)2P), 164.1 (d, J = 5.6 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.9, 26.3 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C10H24NO7P2 + H+ 332.1023; Found 332.1021.
Dimethyl (2-(((dimethoxyphosphoryl)(phenyl)methyl)amino)-2-oxoethyl)phosphonate (7b). Bromoamide 6b (0.62 g, 1.8 mmol) and trimethyl phosphite (0.68 g, 0.57 mL, 5.4 mmol) were reacted, obtaining the product 7b (95% yield) as a white solid, Mp: 101–104 °C. 1H NMR (CDCl3, 600 MHz): δ 2.99 (dd, J = 21.7, 14.9 Hz, 1H, CH2P), 3.02 (dd, J = 21.7, 14.8 Hz, 1H, CH2P), 3.54 (d, J = 11.1 Hz, 3H, (CH3O)2P), 3.67 (d, J = 11.3 Hz, 3H, (CH3O)2P), 3.77 (d, J = 11.2 Hz, 3H, (CH3O)2P), 3.80 (d, J = 10.7 Hz, 3H, (CH3O)2P), 5.59 (dd, J = 21.7, 9.6 Hz, 1H, CH-P), 7.31–7.36 (m, 3H, Harom), 7.49–730 (m, 2H, Harom), 8.40 (d, J = 9.6 Hz, 1H, NH). 13C NMR (CDCl3, 151 MHz): δ 34.3 (d, J = 132.6 Hz, C-P), 49.9 (d, J = 155.0 Hz, C-P), 53.1 (d, J = 6.3 Hz, (CH3O)2P), 53.2 (d, J = 6.5 Hz, (CH3O)2P, 53.8 (d, J = 7.0 Hz, (CH3O)2P, 53.9 (d, J = 6.9 Hz, (CH3O)2P), 128.2 (2C),128.4, 128.7 (2C), 134.5, 163.9 (dd, J = 8.3, 5.3 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.3, 24.6 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C13H22NO7P2 + H+ 366.0866; Found 366.0871.
Dimethyl (2-(((dimethoxyphosphoryl)(4-methoxyphenyl)methyl)amino)-2-oxoethyl)phosphonate (7c). Bromoamide 6c (0.32 g, 0.8 mmol) and trimethyl phosphite (0.33 g, 0.27 mL, 2.6 mmol) were reacted, obtaining the product 7c (96% yield) as a white solid, Mp: 133–135 °C. 1H NMR (CDCl3, 600 MHz): δ 2.96 (dd, J = 24.2, 14.9 Hz, 1H, CH2P), 3.01 (dd, J = 24.2, 14.9 Hz, 1H, CH2P), 3.55 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.68 (d, J = 11.2 Hz, 3H, (CH3O)2P), 3.78 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.79 (d, J = 11.1 Hz, 3H, (CH3O)2P), 3.79 (s, 3H, CH3O), 5.53 (dd, J = 20.4, 9.6 Hz, 1H, CH-P), 6.88 (AA’BB’ system, J = 8.6 Hz, 2H, Harom), 7.42 (AA’BB’ system, J = 8.6 Hz, 2H, Harom), 8.30 (d, J = 9.6 Hz, 1H, NH). 13C NMR (CDCl3, 151 MHz): δ 34.3 (d, J = 132.2 Hz, CH2-P), 49.3 (d, J = 156.1 Hz, C-P), 53.2 (d, J = 6.3 Hz, (CH3O)2P), 53.3 (d, J = 7.0 Hz, (CH3O)2P), 53.8 (d, J = 6.3 Hz, (CH3O)2P), 53.9 (d, J = 7.0 Hz, (CH3O)2P), 55.3 (CH3O), 114.2 (2C), 126.4, 129.4 (2C), 159.6, 163.7 (d, J = 5.1 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.5, 24.6 ppm.
  • General procedure for the synthesis of α,β-unsaturated amides 3a–f.
A solution of trans-cinnamic acid (1.1 equiv), PyBOP (1.3 equiv) in anhydrous MeCN (2 mL) and DIPEA (3.0 equiv) was treated at 0 °C under nitrogen atmosphere with dimethyl (1-amino-2-methylpropyl)phosphonate 5a (1.0 equiv) in MeCN (1 mL) and the reaction mixture was stirred at room temperature for 24 h. After this time, the solvent was evaporated in vacuum, and the resulting residue was purified by column chromatography using ethyl acetate:hexane (80:20) as the eluent, to give the α,β-unsaturated amides 3a–f.
Dimethyl N-[3-phenyl-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3a). trans-Cinnamic acid (120 mg, 0.81 mmol), PyBOP (500 mg, 0.96mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3a (77% yield, only the diastereoisomer E) as white solid, Mp: 133 °C. 1H NMR (CD3OD, 500 MHz): δ 1.05 (dd, J = 6.8, 1.4 Hz, 3H, (CH3)2CH), 1.06 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.22 (oct, J = 6.9 Hz, 1H, CH(CH3)2), 3.77 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.79 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.48 (dd, J = 17.9, 5.8 Hz, 1H, CH-P), 6.77 (d, Jtrans = 15.9 Hz, 1H, CH=CH), 7.35–7.43 (m, 3H, Harom), 7.59–7.55 (m, 2H, Harom), 7.60 (d, Jtrans = 15.6 Hz, 1H, CH=CH). 13C NMR (CD3OD, 126 MHz): δ 17.7 (d, J = 4.5 Hz, (CH3)2CH), 19.6 (d, J = 12.5 Hz, (CH3)2CH), 29.1 (d, J = 3.2 Hz, CH(CH3)2), 50.4 (d, J = 152.4 Hz, C-P), 52.5 (d, J = 6.8 Hz, (CH3O)2P), 52.6 (d, J = 6.4 Hz, (CH3O)2P), 119.8 (C=C), 127.7, 128.8, 129.8, 135.0, 141.7 (C=C), 167.4 (d, J = 5.9 Hz, C=O). 31P NMR (CD3OD, 202 MHz): δ 27.0 ppm. HRMS-FAB(+) m/z: [M + H]+ Calcd for C15H23NO4P + H+ 312.1365; Found 312.1332.
Dimethyl N-[3-(4-methoxyphenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3b). (E)-4-Methoxycinnamic acid (140 mg, 0.81 mmol), PyBOP (500 mg, 0.96 mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21 mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3b (74% yield, only the diastereoisomer E) as a white solid, Mp: 136–137 °C. 1H NMR (CDCl3, 600 MHz): δ 1.04 (dd, J = 6.8, 1.3 Hz, 3H, (CH3)2CH), 1.07 (d, J = 6.8 Hz, 3H, (CH3)2CH), 2.30–2.20 (m, 1H, CH(CH3)2), 3.77 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.79 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.83 (s, 3H, CH3O), 4.62 (ddd, J = 17.9, 10.4, 4.7 Hz, 1H, CH-P), 6.52 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.80 (d, J = 10.4 Hz, 1H, NH), 6.88 (AA’BB’ system, J = 8.8 Hz, 2H, Harom), 7.47 (AA’BB’ system, J = 8.8 Hz, 2H, Harom), 7.63 (d, Jtrans = 15.6 Hz, 1H, CH=CH). 13C NMR (CDCl3, 151 MHz): δ 18.2 (d, J = 4.5 Hz, (CH3)2CH), 20.4 (d, J = 12.3 Hz, (CH3)2CH), 29.2 (d, J = 4.0 Hz, CH(CH3)2), 49.7 (d, J = 152.4 Hz, C-P), 52.7 (d, J = 6.8 Hz, (CH3O)2P), 53.4 (d, J = 6.8 Hz, (CH3O)2P), 55.4 (CH3O), 114.3, 117.8 (C=C), 127.6, 129.5, 141.5 (C=C), 161.0, 166.5 (d, J = 5.8 Hz, C=O). 31P NMR (CDCl3, 243 MHz): δ 27.5 ppm. HRMS-FAB(+) m/z: [M + H]+ Calcd for C16H25NO5P + H+ 342.1465; Found 342.1489.
Dimethyl N-[3-(3,4-dimethoxyphenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3c). (E)-3,4-Dimethoxycinnamic acid (140 mg, 0.81 mmol), PyBOP (500 mg, 0.96 mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21 mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3c (68% yield, only the diastereoisomer E) as a colorless liquid. 1H NMR (CDCl3, 500 MHz): δ 1.05 (dd, J = 6.9, 1.3 Hz, 3H, (CH3)2CH), 1.08 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.26 (oct, J = 6.9 Hz, 1H, CH(CH3)2, 3.75 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.81 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.83 (s, 3H, CH3O), 3.92 (s, 3H, CH3O), 4.63 (ddd, J = 18.0, 10.5, 4.6 Hz, CH-P), 6.48 (d, Jtrans = 15.5 Hz, 1H, CH=CH), 6.60 (d, J = 10.5 Hz, 1H, NH), 6.86 (d, J = 8.3 Hz, 1H, Harom), 7.06 (d, J = 2.0 Hz, 1H, Harom), 7.10 (dd, J = 8.3, 2.0 Hz, 1H, Harom), 7.62 (d, Jtrans = 15.5 Hz, 1H, CH=CH). 13C NMR (CDCl3, 126 MHz): δ 18.1 (d, J = 4.8 Hz, (CH3)2CH), 20.4 (d, J = 12.4 Hz, (CH3)2CH), 29.1 (d, J = 3.8 Hz, CH(CH3)2), 49.7 (d, J = 152.4 Hz, C-P), 52.8 (d, J = 6.9 Hz, (CH3O)2P), 53.3 (d, J = 6.9 Hz, (CH3O)2P), 55.8 (CH3O), 55.9 (CH3O), 109.5 (C=C), 111.0 (C=C), 117.8, 122.2, 127.7, 141.8, 149.1, 150.7, 166.3 (d, J = 5.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.8 ppm. HRMS-FAB(+) m/z: Calcd for C17H27NO6P + H+ 372.1571; Found 372.1609.
Dimethyl N-[3-(4-chlorophenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3d). (E)-4-Chlorocinnamic acid (150 mg, 0.81 mmol), PyBOP (500 mg, 0.96 mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21 mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3d (72% yield, only the diastereoisomer E) as a white solid, Mp: 109–110 °C. 1H NMR (CDCl3, 500 MHz): δ 1.05 (dd, J = 6.9, 1.2 Hz, 3H, (CH3)2CH), 1.09 (d, J = 7.0 Hz, 3H, (CH3)2CH), 2.25 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.74 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.84 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.64 (ddd, J = 17.7, 10.2, 5.0 Hz, 1H, CH-P), 6.75 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.32 (AA’BB’ system, J = 8.5 Hz, 2H, Harom), 7.44 (AA’BB’ system, J = 8.5 Hz, 2H, Harom), 7.59 (d, J = 10.2 Hz, 1H, NH), 7.64 (d, Jtrans = 15.7 Hz, 1H, CH=CH). 13C NMR (CDCl3, 151 MHz): δ 18.2 (d, J = 5.4 Hz, (CH3)2CH), 20.4 (d, J = 11.9 Hz, (CH3)2CH), 29.2 (d, J = 3.6 Hz, CH(CH3)2), 49.8 (d, J = 152.1 Hz, C-P), 52.8 (d, J = 6.9 Hz, (CH3O)2P), 53.5 (d, J = 6.9 Hz, (CH3O)2P), 120.9 (C=C), 129.1 (2C), 133.5 (2C), 140.5 (C=C), 166.1 (d, J = 5.8 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.4 ppm. HRMS-FAB(+) m/z: [M + H]+ Calcd for C15H22ClNO4P + H+ 346.0969; Found 346.0973.
Dimethyl N-[3-(4-fluorophenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3e). (E)-4-Fluorocinnamic acid (160 mg, 0.81 mmol), PyBOP (500 mg, 0.96 mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21 mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3e (70% yield, only the diastereoisomer E) as a white solid, Mp: 138–140 °C. 1H NMR (CDCl3, 500 MHz): δ 1.05 (dd, J = 6.9, 1.2 Hz, 3H, (CH3)2CH), 1.09 (d, J = 7.0 Hz, 3H, (CH3)2CH), 2.25 (oct, J = 6.7 Hz, 1H, CH(CH3)2), 3.74 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.84 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.64 (ddd, J = 17.7, 10.2, 5.0 Hz, 1H, CH-P), 6.75 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.04 (dd, J = 8.7, 5.7 Hz, 2H, Harom), 7.50 (dd, J = 8.8, 5.3 Hz, 2H, Harom), 7.59 (d, J = 10.2 Hz, 1H, NH), 7.64 (d, Jtrans = 15.7 Hz, 1H, CH=CH). 13C NMR (CDCl3, 151 MHz): δ 18.1 (d, J = 4.7 Hz, (CH3)2CH), 20.5 (d, J = 12.6 Hz, (CH3)2CH), 29.2 (d, J = 3.6 Hz, CH(CH3)2), 49.7 (d, J = 152.4 Hz, C-P), 52.9 (d, J = 6.9 Hz, (CH3O)2P), 53.3 (d, J = 7.2 Hz, (CH3O)2P), 116.0 (2C, J = 22.0 Hz), 119.8 (C=C), 129.8 (2C, J = 8.3 Hz), 140.9 (C=C), 163.7 (d, J = 250.7 Hz, C-F), 165.8 (d, J = 5.8 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.5 ppm. HRMS-FAB(+) m/z: [M + H]+ Calcd for C15H22FNO4P + H+ 330.1265; Found 330.1250.
Dimethyl N-[3-(4-(trifluoromethyl)phenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3f). (E)-4-(Trifluoromethyl)cinnamic acid (160 mg, 0.81 mmol), PyBOP (500 mg, 0.96 mmol), anhydrous MeCN (2 mL), DIPEA (300 mg, 0.4 mL, 2.21 mmol) and dimethyl (1-amino-2-methylpropyl)phosphonate 5a (134 mg, 0.73 mmol) were reacted, obtaining the product 3f (71% yield, only the diastereoisomer E) as a white solid, Mp: 139–140 °C. 1H RMN (CDCl3, 600 MHz): δ 1.05 (dd, J = 6.8, 1.3 Hz, 3H, (CH3)2CH), 1.08 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.27 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.75 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.83 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.62 (ddd, J = 18.0, 10.1, 4.7 Hz, 1H, CH-P), 6.73 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 6.88 (d, J = 10.1 Hz, 1H, NH), 7.62 (s, 4H, Harom), 7.69 (d, Jtrans = 15.7 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.3 (d, J = 5.0 Hz, (CH3)2CH), 20.6 (d, J = 12.3 Hz, (CH3)2CH), 29.3 (d, J = 3.6 Hz, CH(CH3)2), 49.9 (d, J = 152.6 Hz, C-P), 53.0 (d, J = 6.8 Hz, (CH3O)2P), 53.6 (d, J = 6.8 Hz, (CH3O)2P), 122.9 (C=C), 124.1 (q, J = 272.0 Hz, CF3), 126.0 (2C, J = 4.1 Hz), 128.2, 131.5 (q, J = 32.2 Hz, C-CF3), 138.5, 140.3 (C=C), 165.7 (d, J = 5.4 Hz, C=O). 31P NMR (CDCl3, 243 MHz): δ 26.5 ppm. HRMS-FAB(+) m/z: [M + H]+ Calcd for C16H22F3NO4P + H+ 380.1233; Found 380.1250.
  • General procedure for the synthesis of α,β-unsaturated amides 3, 8 and 9.
A solution of phosphonoacetamides 7a–c (1.0 equiv), lithium chloride (3.0 equiv) in dry THF (10 mL) was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.0 equiv) under a nitrogen atmosphere at 25 °C. After stirring for 5 min, the corresponding aldehyde (1.0 equiv) was added and the reaction mixture was stirred at 25 °C for 4 h (the progress of the reaction was monitored by thin-layer chromatography). When the reaction was complete, a saturated ammonium chloride solution (10 mL) was added, and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuum. The crude products were purified by flash column chromatography using ethyl acetate as the eluent, obtaining the corresponding (E)-α,β-unsaturated amides incorporating α-aminophosphonates. Compounds 9f and 9g were unstable and clean NMR spectra could not be obtained.
Dimethyl N-[3-phenyl-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3a). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and benzaldehyde (60 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 3a (90% yield, only the diastereoisomer E) as a white solid, Mp: 133 °C. The spectroscopic data are identical to those described above.
Dimethyl N-[3-(4-methoxyphenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3b). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-methoxybenzaldehyde (80 mg, 0.07 mL, 0.6 mmol) were reacted, obtaining the product 3b (80% yield, only the diastereoisomer E) as a white solid, Mp: 136–137 °C. The spectroscopic data are identical to those described above.
Dimethyl N-[3-(4-chlorophenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3d). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-chlorobenzaldehyde (80 mg, 0.6 mmol) were reacted, obtaining the product 3d (85% yield, only the diastereoisomer E) as a white solid, Mp: 109–110 °C. The spectroscopic data are identical to those described above.
Dimethyl N-[3-(4-fluorophenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3e). phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-fluorobenzaldehyde (70 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 3e (84% yield, only the diastereoisomer E) as a white solid, Mp: 138–140 °C. The spectroscopic data are identical to those described above.
Dimethyl N-[3-(4-(trifluoromethyl)phenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3f). phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-trifluoromethylbenzaldehyde (0.10 g, 0.08 mL, 0.6 mmol) were reacted, obtaining the product 3f (88% yield, only the diastereoisomer E) as a white solid, Mp: 139–140 °C. The spectroscopic data are identical to those described above.
Dimethyl N-[3-((4-benzyloxi)-3-methoxyphenyl)-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3g). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-benzyloxy-3-methoxybenzaldehyde (0.15 g, 0.6 mmol) were reacted, obtaining the product 3g (80% yield, only the diastereoisomer E) as a white solid, Mp: 135–137 °C. 1H NMR (CDCl3, 500 MHz): δ 1.04 (dd, J = 6.7, 1.4 Hz, 3H, (CH3)2CH), 1.07 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.25 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.74 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.79 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.92 (s, 3H, CH3O), 4.61 (ddd, J = 18.0, 10.4, 4.6 Hz, 1H, CH-P), 5.18 (s, 2H, CH2Ph), 6.44 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.42 (d, J = 10.4 Hz, 1H, NH), 6.86 (d, J = 8.4 Hz, 1H, Harom), 7.02 (d, J = 8.3 Hz, 1H, Harom), 7.06–7.07 (m, 1H, Harom), 7.59 (d, Jtrans = 15.5 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.2 (d, J = 5.0 Hz, (CH3)2CH), 20.6 (d, J = 12.7 Hz, (CH3)2CH), 29.3 (d, J = 3.6 Hz, CH(CH3)2), 49.8 (d, J = 152.6 Hz, C-P), 53.0 (d, J = 6.8 Hz, (CH3O)2P), 53.5 (d, J = 6.8 Hz, (CH3O)2P), 56.2 (CH3O), 71.1 (CH2Ph), 110.5, 113.7, 118.2, 122.2 (C=C), 127.4 (2C), 128.2, 128.3, 128.8 (2C), 126.8, 142.0 (C=C), 149.9, 150.1, 166.4 (d, J = 5.9 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.7 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C23H31NO6P + H+ 448.1884; Found 448.1866.
Dimethyl N-[(2E,4E)-5-phenylpenta-2,4-dien-1-oxo]-2-(methylpropyl)phosphonate (3h). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and trans-cinnamaldehyde (80 mg, 0.07 mL, (0.6 mmol) were reacted, obtaining the product 3h (80% yield, only the diastereoisomer E) as a yellow solid, Mp: 146–147 °C. 1H NMR (CDCl3, 500 MHz): δ 1.04 (dd, J = 6.8, 1.3 Hz, 3H, (CH3)2CH), 1.06 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.24 (oct, J = 6.7 Hz, 1H, CH(CH3)2), 3.75 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.81 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.59 (ddd, J = 18.0, 10.4, 4.7 Hz, 1H, CH-P), 6.14 (d, Jtrans = 15.0 Hz, 1H, CH=CH), 6.46–6.48 (m, 1H, CH=CH), 6.82–6.90 (m, 2H, Harom), 7.28–7.31 (m, 1H, Harom), 7.33–7.36 (m, 2H, Harom), 7.42–7.47 (m, 3H, Harom and CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.3 (d, J = 5.0 Hz, (CH3)2CH), 20.6 (d, J = 12.3 Hz, (CH3)2CH), 29.3 (d, J = 3.6 Hz, CH(CH3)2), 49.8 (d, J = 152.6 Hz, C-P), 52.9 (d, J = 7.3 Hz, (CH3O)2P), 53.5 (d, J = 6.8 Hz, (CH3O)2P), 123.4 (C=C), 126.4 (C=C), 127.3, 129.0, 136.4, 139.9 (C=C), 142.1 (C=C), 166.3 (d, J = 5.4 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.7 ppm.
Dimethyl N-[N-methylpyrrol-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3i). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and N-methyl-2-pyrrolecarboxaldehyde (60 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 3i (80% yield, only the diastereoisomer E) as a brown solid, Mp: 125 °C. 1H NMR (CDCl3, 500 MHz): δ 1.04 (dd, J = 6.9, 1.4 Hz, 3H, (CH3)2CH), 1.06 (d, J = 6.9 Hz, 3H, (CH3)2CH), 2.25 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.70 (s, 3H, CH3-N), 3.75 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.80 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.61 (ddd, J = 18.3, 10.5, 4.4 Hz, 1H, CH-P), 6.15–6.16 (m, 1H, Harom), 6.22 (d, J = 10.3 Hz, 1H, NH), 6.27 (d, Jtrans = 15.3 Hz, 1H, CH=CH), 6.61–6.62 (m, 1H, Harom), 6.71–6.72 (m, 1H, Harom), 7.61 (d, Jtrans = 15.3 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.0 (d, J = 5.0 Hz, (CH3)2CH), 20.4 (d, J = 12.7 Hz, (CH3)2CH), 29.2 (d, J = 4.1 Hz, CH(CH3)2), 34.3 (CH3-N), 49.6 (d, J = 152.1 Hz, C-P), 52.8 (d, J = 6.8 Hz, (CH3O)2P), 53.2 (d, J = 7.3 Hz, (CH3O)2P), 109.1, 110.6, 114.7 (C=C), 126.3, 129.5, 129.9 (C=C), 166.6 (d, J = 5.9 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.8 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C14H23N2O4P + H+ 315.1468; Found 315.1481.
Dimethyl N-[5-methylhex-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3j). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg,1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and isovaleraldehyde (60 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 3j (80% yield, only the diastereoisomer E) as a white solid, Mp: 125 °C. 1H NMR (CDCl3, 500 MHz): δ 0.92 (d, J = 6.6 Hz, 3H, (CH3)2CH), 0.93 (d, J = 6.7 Hz, 3H, (CH3)2CH), 1.01 (dd, J = 6.8, 1.3 Hz, 3H, (CH3)2CH), 1.04 (d, J = 6.9 Hz, 3H, (CH3)2CH), 1.76 (sept, J = 6.7 Hz, 1H, CH(CH3)2), 2.08 (t, J = 7.9 Hz, 2H, CH2CH), 2.27 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.73 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.79 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.54 (ddd, J = 18.0, 10.4, 4.6 Hz, 1H, CH-P), 5.96 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.55 (d, J = 10.4 Hz, 1H, NH), 6.89 (dt, Jtrans = 15.0, 7.9 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.3 (d, J = 5.4 Hz, (CH3)2CH), 20.5 (d, J = 12.3 Hz, (CH3)2CH), 22.6 (d, J = 4.5 Hz, (CH3)2CH), 28.0 (d, J = 4.5 Hz, (CH3)2CH), 29.3 (d, J = 4.5 Hz, CH(CH3)2), 29.8 (d, J = 12.3 Hz, CH(CH3)2), 41.7 (CH2CH), 49.6 (d, J = 152.6 Hz, C-P), 52.8 (d, J = 6.8 Hz, (CH3O)2P), 53.4 (d, J = 6.8 Hz, (CH3O)2P), 124.1 (C=C), 145.0 (C=C), 166.2 (d, J = 5.5 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.7 ppm.
Dimethyl N-[4-methylpent-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3k). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol), and isobutyraldehyde (40 mg, 0.05 mL, 0.6 mmol) were reacted, obtaining the product 3k (65% yield, E/Z 85:15 ratio) as a white solid, Mp: 100–102 °C. 1H NMR (CDCl3, 500 MHz): δ 1.02 (d, J = 6.7 Hz, 3H, (CH3)2CH), 1.04 (d, J = 6.8 Hz, 3H, (CH3)2CH), 1.07 (d, J = 6.7 Hz, 6H, (CH3)2CH), 2.23 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 2.46 (sept, J = 6.7 Hz, 1H, CH(CH3)2), 3.73 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.78 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.55 (ddd, J = 18.3, 10.5, 4.4 Hz, 1H, CH-P), 5.84 (d, Jtrans = 15.4 Hz, 1H, CH=CH), 6.09 (d, J = 10.5 Hz, 1H, NH), 6.89 (dd, Jtrans = 15.4, 6.5 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.2 (d, J = 4.3 Hz, (CH3)2CH), 20.6 (d, J = 12.6 Hz, (CH3)2CH), 21.6 (d, J = 5.4 Hz, (CH3)2CH), 27.7 (d, J = 12.3 Hz, (CH3)2CH), 29.3 (d, J = 3.6 Hz, CH(CH3)2), 31.0 (d, J = 3.6 Hz, CH(CH3)2), 49.6 (d, J = 152.6 Hz, C-P), 52.9 (d, J = 6.8 Hz, (CH3O)2P), 53.3 (d, J = 6.8 Hz, (CH3O)2P), 120.3 (C=C), 152.5 (C=C), 166.3 (d, J = 5.8 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.8 ppm.
Dimethyl N-[4,4-dimethylpent-2-ene-1-oxo]-2-(methylpropyl)phosphonate (3l). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol), and trimethylacetaldehyde (50 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 3l (54% yield, only the diastereoisomer E) as a white solid, Mp: 104–105 °C. 1H NMR (CDCl3, 500 MHz): δ 1.02 (dd, J = 6.9, 1.4 Hz, 3H, (CH3)2CH), 1.05 (d, J = 7.0 Hz, 3H, (CH3)2CH), 1.09 (s, 9H, (CH3)3C), 2.23 (oct, J = 6.8 Hz, 1H, CH(CH3)2), 3.73 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.78 (d, J = 10.7 Hz, 3H, (CH3O)2P), 4.56 (ddd, J = 18.3, 9.9, 4.5 Hz, 1H, CH-P), 5.84 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.33 (d, J = 9.9 Hz, 1H, NH), 6.91 (d, Jtrans = 15.6 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.3 (d, J = 5.0 Hz, (CH3)2CH), 20.6 (d, J = 12.3 Hz, (CH3)2CH), 29.0 ((CH3)3C), 29.3 (d, J = 4.1 Hz, CH(CH3)2), 33.8 (C(CH3)3), 49.6 (d, J = 152.6 Hz, C-P), 52.8 (d, J = 6.8 Hz, (CH3O)2P), 53.5 (d, J = 6.8 Hz, (CH3O)2P), 118.4 (C=C), 155.9 (C=C), 166.8 (d, J = 5.9 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.7 ppm.
Dimethyl N-[1-(3-cyclohex-2-ene-1-oxo)-2-(methylpropyl)phosphonate (3m). Phosphonoacetamide 7a (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol), and 1-cyclohexenecarboxaldehyde (60 mg, 0.07 mL, 0.6 mmol) were reacted, obtaining the product 3m (80% yield, only the diastereoisomer E) as a yellow liquid. 1H NMR (CDCl3, 500 MHz): δ 1.01 (dd, J = 6.9, 1.4 Hz, 3H, (CH3)2CH), 1.03 (d, J = 6.9 Hz, 3H, (CH3)2CH), 1.58–1.66 (m, 2H, CH2), 1.67–1.73 (m, 2H, CH2), 2.12–2.16 (m, 2H, CH2), 2.17–2.26 (m, 3H, CH2 and CH(CH3)2), 3.72 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.77 (d, J = 10.7 Hz, 3H, (CH3O)2P), 5.84 (d, Jtrans = 15.0 Hz, 1H, CH=CH), 5.99 (d, J = 9.3 Hz, 1H, NH), 6.14–6.15 (m, 1H, CH-CH2), 6.91 (d, Jtrans = 15.0 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 18.2 (d, J = 4.5 Hz, (CH3)2CH), 20.6 (d, J = 12.7 Hz, (CH3)2CH), 22.3 (d, J = 5.4 Hz, CH(CH3)2), 24.5, 26.6, 29.3 (2C), 49.6 (d, J = 152.1 Hz, C-P), 52.9 (d, J = 6.8 Hz, (CH3O)2P), 53.4 (d, J = 6.8 Hz, (CH3O)2P), 116.3 (C=C), 134.8 (C=C), 138.3 (C=C), 145.7 (C=C), 166.8 (d, J = 5.8 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 26.8 ppm.
Dimethyl N-[3-phenyl-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8a). Phosphonoacetamide 7b (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and benzaldehyde (60 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 8a (80% yield, only the diastereoisomer E) as a white solid, Mp: 165–167 °C. 1H NMR (CDCl3, 600 MHz): δ 3.53 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.85 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.84 (dd, J = 20.8, 9.8 Hz, 1H, CH-P), 6.68 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.31–7.24 (m, 4H, Harom), 7.33 (t, J = 7.8 Hz, 2H, Harom), 7.40–7.37 (m, 2H, Harom), 7.63–7.59 (m, 2H, Harom), 7.63 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 8.43 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 151 MHz): δ 49.7 (d, J = 154.9 Hz, C-P), 53.9 (d, J = 7.0 Hz, (CH3O)2P), 53.9 (d, J = 7.1 Hz, (CH3O)2P), 120.7 (C=C), 127.8 (2C), 128.4 (2C), 128.5, 128.7 (2C), 128.8 (2C), 129.7, 135.0, 135.1, 141.5 (C=C), 165.7 (d, J = 7.9 Hz, C=O). 31P NMR (CDCl3, 243 MHz): δ 24.0 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C18H20NO4P + H+ 346.1203; Found 346.1218.
HRMS-CI(+) m/z: [M + H]+ Calcd for C13H22NO7P2 +H+ 366.0866; Found 366.0871.
Dimethyl N-[3-(4-methoxyphenyl)-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8b). Phosphonoacetamide 7b (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.27 g, 0.27 mL, 1.7 mmol) and 4-methoxybenzaldehyde (70 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 8b (50% yield, only the diastereoisomer E) as a white solid, Mp: 163–165 °C. 1H NMR (CDCl3, 500 MHz): δ 3.52 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.81 (s, 3H, CH3O), 3.83 (d, J = 10.7 Hz, 3H, (CH3O)2P), 5.78 (dd, J = 20.8, 9.6 Hz, 1H, CH-P), 6.47 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.84 (AA’BB’ system, J = 8.8 Hz, 2H, Harom), 7.29 (d, J = 7.4 Hz, 1H, Harom), 7.32–7.35 (m, 2H, Harom), 7.37 (d, J = 9.2 Hz, 2H, Harom), 7.57 (AA’BB’ system, J = 8.9 Hz, 2H, Harom), 7.59 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.63 (d, J = 9.6 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.8 (d, J = 154.4 Hz, C-P), 54.0 (d, J = 8.6 Hz, (CH3O)2P), 54.0 (d, J = 7.7 Hz, (CH3O)2P), 55.5 (CH3O), 114.4 (2C), 118.1 (C=C), 127.8, 128.5 (2C), 129.0, 129.6 (2C), 135.2, 141.7 (C=C), 161.2, 165.9 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.1 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C19H22NO5P + H+ 376.1308; Found 376.1314.
Dimethyl N-[3-(4-chlorophenyl)-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8c). Phosphonoacetamide 7b (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and 4-chlorobenzaldehyde (70 mg, 0.6 mmol) were reacted, obtaining the product 8c (80% yield, only the diastereoisomer E) as a white solid, Mp: 151–153 °C. 1H NMR (CDCl3, 600 MHz): δ 3.52 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.85 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.81 (dd, J = 20.7, 9.8 Hz, 1H, CH-P), 6.61 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 7.36–7.26 (m, 7H, Harom), 7.57 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 7.58 (AA’BB’ system, J = 7.7 Hz, 2H, Harom), 8.21 (d, J = 9.7 Hz, 1H, NH). 13C NMR (CDCl3, 151 MHz): δ 49.7 (d, J = 155.0 Hz, C-P), 53.9 (d, J = 7.2 Hz, (CH3O)2P), 53.9 (d, J = 7.2 Hz, (CH3O)2P), 121.2 (C=C), 128.3, 128.4 (2C), 128.5, 128.9 (2C), 129.0 (2C), 129.1 (2C), 133.6, 134.9, 135.5, 140.2 (C=C), 165.3 (d, J = 7.6 Hz, C=O). 31P NMR (CDCl3, 243 MHz): δ 24.7 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C18H20 ClNO4P + H+ 380.0813; Found 380.0786.
Dimethyl N-[3-(4-fluorophenyl)-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8d). Phosphonoacetamide 7b (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and 4-fluorobenzaldehyde (70 mg, 0.6 mmol) were reacted, obtaining the product 8d (80% yield, only the diastereoisomer E) as a white solid, Mp: 145–146 °C. 1H NMR (CDCl3, 500 MHz): δ 3.52 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.85 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.82 (ddd, J = 20.8, 9.8, 4.6 Hz, 1H, CH), 6.57 (dd, Jtrans = 15.7, 5.6 Hz, 1H, CH=CH), 6.97–7.00 (m, 2H, Harom), 7.26–7.37 (m, 5H, Harom), 7.57–7.60 (m, 2H, Harom), 8.24 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.8 (d, J = 154.9 Hz, C-P), 54.0 (d, J = 7.3 Hz, (CH3O)2P), 54.1 (d, J = 7.3 Hz, (CH3O)2P), 116.0 (2C, J = 21.3 Hz), 120.5 (C=C), 128.5 (2C), 129.0 (2C), 129.7 (2C, J = 8.6 Hz), 131.4, 135.0, 140.5 (C=C), 140.5, 163.7 (d, J = 250.2 Hz, C-F), 165.6 (C=O). 31P NMR (CDCl3, 202 MHz): δ 24.0 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C18H20FNO4P + H+ 364.1108; Found 364.1121.
Dimethyl N-[3-(4-trifluoromethyl)phenyl)-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8e). Phosphonoacetamide 7b (0.20 g, 0.6 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and 4-trifluoromethylbenzaldehyde (90 mg, 0.07 mL, 0.6 mmol) were reacted, obtaining the product 8e (85% yield, only the diastereoisomer E) as a white solid, Mp: 153–154 °C. 1H NMR (CDCl3, 500 MHz): δ 3.54 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.88 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.85 (dd, J = 20.8, 9.8 Hz, 1H, CH-P), 6.75 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.25–7.28 (m, 1H, Harom), 7.33 (dd, J = 8.1 Hz, 2H, Harom), 7.46 (d, J = 8.5 Hz, 2H, Harom), 7.54 (AA’BB’ system, J = 8.4 Hz, 2H, Harom), 7.61–7.63 (m, 2H, Harom), 7.63 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 8.56 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.6 (d, J = 154.4 Hz, C-P), 53.9 (d, J = 7.3 Hz, (CH3O)2P), 53.9 (d, J = 7.3 Hz, (CH3O)2P), 123.2 (C=C), 123.9 (q, J = 272.0 Hz, CF3), 125.6 (2C, J = 4.1 Hz), 127.9 (3C), 128.3, 128.4, 128.8, 131.1 (q, J = 32.3 Hz, C-CF3), 134.7, 138.5, 139.6 (C=C), 165.0 (d, J = 7.3 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.8 ppm.
Dimethyl N-[(2E,4E)-5-phenylpenta-2,4-dien-1-oxo]-(phenyl-methyl)phosphonate (8f). Phosphonoacetamide 7b (0.20 g, 0.5 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and trans-cinnamaldehyde (70 mg, 0.07 mL, 0.6 mmol) were reacted, obtaining the product 8f (85% yield, only the diastereoisomer E) as a yellow solid, Mp: 75–76 °C. 1H NMR (CDCl3, 500 MHz): δ 3.53 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.85 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.82 (dd, J = 20.9, 9.8 Hz, 1H, CH-P), 6.19 (d, Jtrans = 15.0 Hz, 1H, CH=CH), 6.74 (d, Jtrans = 15.6 Hz, 1H, CH), 6.83 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 7.38–7.27 (m, 6H, Harom), 7.46–7.39 (m, 2H, Harom), 7.58–7.60 (m, 2H, CH=CH and Harom), 8.11 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.8 (d, J = 154.9 Hz, C-P), 54.0 (d, J = 7.6 Hz, (CH3O)2P), 54.1 (d, J = 7.7 Hz, (CH3O)2P), 123.7 (C=C), 126.6 (C=C), 127.2, 128.5, 128.6 (2C), 129.0 (4C), 135.1, 136.5, 139.6 (C=C), 141.9 (C=C), 165.9 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.0 ppm.
Dimethyl N-[N-methylpyrrol-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8g). Phosphonoacetamide 7b (0.20 g, 0.5 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and N-methyl-2-pyrrolecarboxaldehyde (60 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 8g (85% yield, only the diastereoisomer E) as a white solid, Mp: 143–144 °C. 1H NMR (CDCl3, 500 MHz): δ 3.52 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.64 (s, 3H, CH3-N), 3.82 (d, J = 10.7 Hz, 3H, (CH3O)2P), 5.78 (dd, J = 20.9, 9.6 Hz, 1H, CH-P), 6.10–6.11 (m, 1H, Harom.), 6.33 (d, Jtrans = 15.4 Hz, 1H, CH=CH), 6.48–6.49 (m, 1H, Harom.), 6.67–6.68 (m, 1H, Harom.), 7.28–7.30 (m, 1H, Harom), 7.33–736 (m, 2H, Harom), 7.55–7.58 (m, 3H, CH=CH, Harom), 7.71 (d, J = 9.7, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 34.5 (CH3-N), 49.9 (d, J = 154.9 Hz, C-P), 54.0 (d, J = 7.7 Hz, (CH3O)2P), 54.1 (d, J = 7.7 Hz, (CH3O)2P), 109.2, 110.8, 115.3 (C=C), 126.4, 128.5 (3C), 129.0 (2C), 129.8, 129.9 (C=C), 135.3, 166.4 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.1 ppm.
Dimethyl N-[4-methylpent-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8h). Phosphonoacetamide 7b (0.20 g, 0.5 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and isobutyraldehyde (40 mg, 0.05 mL, 0.6 mmol) were reacted, obtaining the product 8h (80% yield, only the diastereoisomer E) as a white solid, Mp: 116–118 °C. 1H NMR (CDCl3, 500 MHz): δ 0.99 (d, J = 6.8 Hz, 3H, (CH3)2CH), 1.00 (d, J = 6.8 Hz, 3H, (CH3)2CH), 2.37 (oct, J = 6.7 Hz, 1H, CH(CH3)2), 3.49 (d, J = 10.6 Hz, 3H, (CH3O)2P), 3.82 (d, J = 10.6 Hz, 3H, (CH3O)2P), 5.72 (dd, J = 20.9, 9.5 Hz, 1H, CH-P), 5.92 (dd, Jtrans = 15.4, 1.5 Hz, 1H, CH=CH), 6.88 (dd, Jtrans = 15.4, 6.8 Hz, 1H, CH=CH), 7.37–7.39 (m, 3H, Harom), 7.57–7.52 (m, 2H, Harom), 7.78 (d, J = 9.5 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 21.4 ((CH3)2CH), 21.5 ((CH3)2CH), 30.9 (CH(CH3)2), 49.6 (d, J = 154.9 Hz, C-P), 53.9 (d, J = 9.5 Hz, (CH3O)2P), 53.9 (d, J = 6.8 Hz, (CH3O)2P), 120.5 (C=C), 128.4, 128.6 (2C), 128.9 (2C), 135.2, 152.2 (C=C), 165.9 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.0 ppm.
Dimethyl N-[4,4-dimethylpent-2-ene-1-oxo]-(phenyl-methyl)phosphonate (8i). Phosphonoacetamide 7b (0.20 g, 0.5 mmol), lithium chloride (70 mg, 1.6 mmol), DBU (0.25 g, 0.24 mL, 1.7 mmol) and trimethylacetaldehyde (50 mg, 0.06 mL, 0.6 mmol) were reacted, obtaining the product 8i (85% yield, only the diastereoisomer E) as a white solid, Mp: 118–120 °C. 1H NMR (CDCl3, 500 MHz): δ 1.01 (s, 9H, (CH3)3C), 3.49 (d, J = 10.7 Hz, 3H, (CH3O)2P), 3.82 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.73 (dd, J = 20.9, 8.1 Hz, 1H, CH-P), 5.88 (d, Jtrans = 15.8 Hz, 1H, CH=CH), 6.89 (d, Jtrans = 15.5 Hz, 1H, CH=CH), 7.37–7.28 (m, 3H, Harom), 7.53–7.55 (m, 2H, Harom). 13C NMR (CDCl3, 125 MHz): δ 28.9 ((CH3)3C), 33.7 (C(CH3)3), 49.6 (d, J = 155.3 Hz, C-P), 53.9 (d, J = 7.3 Hz, (CH3O)2P), 54.0 (d, J = 7.3 Hz, (CH3O)2P), 118.5 (C=C), 128.4, 128.6 (2C), 128.9 (2C), 135.3, 155.9 (C=C), 166.1 (C=O). 31P NMR (CDCl3, 202 MHz): δ 24.1 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C16H25NO4P + H+ 326.1516; Found 326.1536.
Dimethyl N-[3-phenyl-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9a). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and benzaldehyde (50 mg, 0.05 mL, 0.6 mmol) were reacted, obtaining the product 9a (93% yield, only the diastereoisomer E) as a white solid, Mp: 134–135 °C. 1H NMR (CDCl3, 500 MHz): δ 3.54 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.71 (s, 3H, CH3O), 3.84 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.77 (dd, J = 20.4, 9.7 Hz, 1H, CH-P), 6.65 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 6.85–6.90 (m, 3H, Harom), 7.29–7.31 (m, 3H, Harom), 7.39–7.41 (m, 2H, Harom), 7.51 (d, J = 8.7 Hz, 1H, Harom), 7.63 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 8.17 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.1 (d, J = 156.2 Hz, C-P), 54.0 (d, J = 6.8 Hz, (CH3O)2P), 54.0 (d, J = 6.8 Hz, (CH3O)2P), 55.4 (CH3O), 114.4 (3C), 120.8 (C=C), 127.0, 128.0 (2C), 128.9 (2C), 129.8 (2C), 135.2, 141.6 (C=C), 159.7, 165.7 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 23.0 ppm.
Dimethyl N-[3-(4-methoxyphenyl)-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9b). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and 4-methoxybenzaldehyde (90 mg, 0.08 mL, 0.5 mmol) were reacted, obtaining the product 9b (90% yield, only the diastereoisomer E) as a white solid, Mp: 137–138 °C. 1H NMR (CDCl3, 500 MHz): δ 3.56 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.68 (s, 3H, CH3O), 3.78 (s, 3H, CH3O), 3.84 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.81 (dd, J = 20.5, 9.8 Hz, 1H, CH-P), 6.57 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.80 (AA’BB’ system, J = 8.7 Hz, 2H, Harom), 6.83 (AA’BB’ system, J = 8.7 Hz, 2H, Harom), 7.32 (AA’BB’ system, J = 8.9 Hz, 2H, Harom), 7.53 (AA’BB’ system, J = 8.8, 2.1 Hz, 2H, Harom), 7.59 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 8.51 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.1 (d, J = 156.2 Hz, C-P), 53.9 (d, J = 7.7 Hz, (CH3O)2P), 54.0 (d, J = 7.8 Hz, (CH3O)2P), 55.4 (CH3O), 55.5 (CH3O), 114.3 (3C), 118.6 (C=C), 127.2, 128.0, 129.5 (3C), 129.8 (2C), 141.1 (C=C), 159.7, 161.0, 166.2 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.3 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C20H25NO6P + H+ 406.1414; Found 406.1442.
Dimethyl N-[3-(4-chlorophenyl)-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9c). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and 4-chlorobenzaldehyde (90 mg, 0.5 mmol) were reacted, obtaining the product 9c (85% yield, only the diastereoisomer E) as a white solid, Mp: 156–157 °C. 1H NMR (CDCl3, 500 MHz): δ 3.53 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.73 (s, 3H, CH3O), 3.84 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.73 (dd, J = 20.4, 9.7 Hz, 1H, CH-P), 6.58 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.86 (AA’BB’ system, J = 8.4 Hz, 2H, Harom), 7.28 (AA’BB’ system, J = 8.7 Hz, 2H, Harom), 7.33 (AA’BB’ system, J = 8.5 Hz, 2H, Harom), 7.49 (AA’BB’ system, J = 8.7, 2.0 Hz, 2H, Harom), 7.57 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 7.96 (d, J = 9.7 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.1 (d, J = 156.2 Hz, C-P), 54.0 (d, J = 7.8 Hz, (CH3O)2P), 54.1 (d, J = 7.7 Hz, (CH3O)2P), 55.4 (CH3O), 114.4 (2C), 121.4 (C=C), 126.9, 129.1 (2C), 129.2 (2C), 129.7 (2C), 133.7, 135.6, 140.3 (C=C), 159.8, 165.4 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.1 ppm.
Dimethyl N-[3-(4-fluorophenyl)-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9d). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and 4-fluorobenzaldehyde (60 mg, 0.05 mL, 0.5 mmol) were reacted, obtaining the product 9d (62% yield, only the diastereoisomer E) as a white solid, Mp: 143–145 °C. 1H NMR (CDCl3, 500 MHz): δ 3.53 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.73 (s, 3H, CH3O), 3.84 (d, J = 10.7 Hz, 3H, (CH3O)2P), 5.74 (dd, J = 20.4, 9.7 Hz, 1H, CH-P), 6.54 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.85 (AA’BB’ system, J = 8.5 Hz, 2H, Harom), 7.00 (AA’BB’ system, J = 8.6 Hz, 2H, Harom), 7.38 (AA’BB’ system, J = 8.8 Hz, 2H, Harom), 7.50 (AA’BB’ system, J = 8.8 Hz, 2H, Harom), 7.59 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 8.00 (d, J = 9.7 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.1 (d, J = 156.2 Hz, C-P), 54.0 (d, J = 7.3 Hz, (CH3O)2P), 54.1 (d, J = 7.3 Hz, (CH3O)2P), 55.4 (CH3O), 114.4 (2C), 116.0 (2C, J = 22.3 Hz), 120.5 (C=C), 127.0, 129.7, 129.8 (2C, J = 8.5 Hz), 131.4 (2C, J = 3.2 Hz), 140.5 (C=C), 159.8, 163.7 (d, J = 250.2 Hz, C-F), 165.5 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.2 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C19H21FNO5P + H+ 394.1214; Found 394.1191.
Dimethyl N-[3-(4-(trifluoromethyl)phenyl)-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9e). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and 4-trifluoromethylbenzaldehyde (90 mg, 0.07 mL, 0.5 mmol) were reacted, obtaining the product 9e (50% yield, only the diastereoisomer E) as a white solid, Mp: 158–159 °C. 1H NMR (CDCl3, 500 MHz): δ 3.54 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.72 (s, 3H, CH3O), 3.85 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.75 (dd, J = 20.3, 9.8 Hz, 1H, CH-P), 6.71 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 6.86 (AA’BB’ system, J = 8.7 Hz, 2H, Harom), 7.37–7.40 (m, 4H, Harom), 7.56 (AA’BB’ system, J = 8.4 Hz, 2H, Harom), 7.64 (d, Jtrans = 15.7 Hz, 1H, CH=CH), 8.22 (d, J = 9.8 Hz, 1H, NH). 13C NMR (CDCl3, 125 MHz): δ 49.2 (d, J = 156.2 Hz, C-P), 54.0 (d, J = 7.3 Hz, (CH3O)2P), 54.1 (d, J = 6.8 Hz, (CH3O)2P), 55.4 (CH3O), 114.4 (2C), 123.3 (C=C), 124.1 (q, J = 272.0 Hz, CF3), 125.9 (2C, J = 3.6 Hz), 126.8, 128.1 (2C), 129.8 (2C), 131.4 (q, J = 32.2 Hz, C-CF3), 138.6, 139.9 (C=C), 159.8, 165.0 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.1 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C20H22F3NO5P + H+ 444.1182; Found 444.1219.
Dimethyl N-[4-methylpent-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9h). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and isobutyraldehyde (40 mg, 0.05 mL, 0.5 mmol) were reacted, obtaining the product 9h (60% yield, only the diastereoisomer E) as a white solid, Mp: 122–124 °C. 1H NMR (CDCl3, 500 MHz): δ 1.00 (d, J = 6.7 Hz, 3H, (CH3)2CH), 1.01 (d, J = 6.7 Hz, 3H, (CH3)2CH), 2.39 (oct, J = 6.9 Hz, 1H, CH(CH3)2), 3.50 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.79 (s, 3H, CH3O), 3.80 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.65 (dd, J = 20.5, 8.7 Hz, 1H, CH-P), 5.87 (dd, Jtrans = 15.4, 1.5 Hz, 1H, CH=CH), 6.87 (AA’BB’ system, J = 8.3 Hz, 2H, Harom), 7.41 (d, J = 8.7 Hz, 1H, NH), 7.45 (AA’BB’ system, J = 8.9 Hz, 2H, Harom), 7.45 (d, Jtrans = 15.2 Hz, 1H, CH=CH). 13C NMR (CDCl3, 125 MHz): δ 21.4 ((CH3)2CH), 21.5 ((CH3)2CH), 30.9 (CH(CH3)2), 48.9 (d, J = 156.2 Hz, C-P), 53.8 (d, J = 7.3 Hz, (CH3O)2P), 54.0 (d, J = 6.8 Hz, (CH3O)2P), 55.5 (CH3O), 114.4 (2C), 120.5 (C=C), 127.3 (2C), 129.8, 152.2 (C=C), 159.7, 165.7 (d, J = 7.3 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.0 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C16H24NO5P + H+ 342.1465; Found 342.1483.
Dimethyl N-[4,4-dimethylpent-2-ene-1-oxo]-(4-methoxyphenyl-methyl)phosphonate (9i). Phosphonoacetamide 7c (0.20 g, 0.5 mmol), lithium chloride (60 mg, 1.6 mmol), DBU (0.23 g, 0.23 mL, 1.6 mmol) and trimethylacetaldehyde (40 mg, 0.05 mL, 0.5 mmol) were reacted, obtaining the product 9i (52% yield, only the diastereoisomer E) as a white solid, Mp: 148–150 °C. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 9H, ((CH3)3C), 3.50 (d, J = 10.5 Hz, 3H, (CH3O)2P), 3.79 (s, 3H, CH3O), 3.80 (d, J = 10.8 Hz, 3H, (CH3O)2P), 5.65 (dd, J = 20.4, 9.6 Hz, 1H, CH-P), 5.82 (d, Jtrans = 15.6 Hz, 1H, CH=CH), 6.84 (AA’BB’ system, J = 8.5 Hz, 2H, Harom), 7.32 (d, J = 9.6 Hz, 1H, NH), 7.45 (d, Jtrans = 15.4, 1H, CH=CH), 7.45 (AA’BB’ system, J = 8.5 Hz, 2H, Harom). 13C NMR (CDCl3, 125 MHz): δ 28.9 ((CH3)3C), 33.7 (C(CH3)3), 48.9 (d, J = 156.7 Hz, C-P), 53.8 (d, J = 7.3 Hz, (CH3O)2P), 54.0 (d, J = 6.8 Hz, (CH3O)2P), 55.5 (CH3O), 114.4 (2C), 118.5 (C=C), 127.3, 129.8 (2C), 156.0 (C=C), 159.7, 165.9 (d, J = 7.7 Hz, C=O). 31P NMR (CDCl3, 202 MHz): δ 24.3 ppm. HRMS-CI(+) m/z: [M + H]+ Calcd for C17H26NO5P + H+ 356.1621; Found 356.1638.

4. Conclusions

In conclusion, the easy access to α-aminophosphonates 5a–c through the Kabachnik–Fields reaction and phosphonoacetamides 7a–c in combination with high selectivity E/Z and good chemical yields in the Horner–Wadsworth–Emmons reaction, thus as the optimization of the HWE reaction using DBU as a base in the presence of LiCl, make this experimental procedure an excellent, practical and general methodology to obtain (E)-α,β-unsaturated amides bearing an α-aminophosphonate moiety. The biological evaluation of the obtained (E)-α,β-unsaturated amides as potential anticancer agents is currently underway.
Optimization of the HWE reaction was achieved using DBU as a base in the presence of LiCl.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30183730/s1, Figures S1–S105: Spectroscopic data.

Author Contributions

Conceptualization, M.O., J.L.V.-C. and I.R.-E.; methodology, S.A.P.-A. and E.C.-T.; formal analysis, M.O., J.L.V.-C. and I.R.-E.; investigation, S.A.P.-A. and E.C.-T.; writing—original draft preparation, M.O.; writing—review and editing, M.O. and J.L.V.-C.; supervision, M.O. and J.L.V.-C.; project administration, M.O. and J.L.V.-C.; funding acquisition, M.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI), project numbers 286614 and 140607.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data contained within the article or Supplementary Materials.

Acknowledgments

The authors thank Victoria Labastida for her valuable technical support in obtaining MS spectra and the Laboratorio Nacional de Estructura de Macromoléculas (LANEM) (CIQ-UAEM 315896) for spectroscopic analyses. S.A.P.-A. and E.C.-T. also thank to SECIHTI for the scholarships 837580 and 815938, respectively.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sova, M. Antioxidant and Antimicrobial Activities of Cinnamic Acid Derivatives. Mini-Rev. Med. Chem. 2012, 12, 749–767. [Google Scholar] [CrossRef]
  2. De, P.; Baltas, M.; Bedos-Belval, F. Cinnamic Acid Derivatives as Anticancer Agents-A Review. Curr. Med. Chem. 2011, 18, 1672–1703. [Google Scholar] [CrossRef]
  3. Silva, A.T.; Bento, C.M.; Pena, A.C.; Figueiredo, L.M.; Prudêncio, C.; Aguiar, L.; Silva, T.; Ferraz, R.; Gomes, M.S.; Teixeira, C.; et al. Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs. Molecules 2020, 25, 66. [Google Scholar] [CrossRef] [PubMed]
  4. Gaikwad, N.; Nanduri, S.; Madhavi, Y.V. Cinnamamide: An insight into the pharmacological advances and structure–activity relationships. Eur. J. Med. Chem. 2019, 181, 111561. [Google Scholar] [CrossRef] [PubMed]
  5. Çalışkan, E.; Öztürk, D.A.; Koran, K.; Tekin, S.; Sandal, S.; Erkan, S.; Görgülü, A.O.; Çetina, A. Synthesis of New Cinnamoyl-Amino Acid Conjugates and in Vitro Cytotoxicity and Genotoxicity Studies. Chem. Biodivers. 2022, 19, e202200426. [Google Scholar] [CrossRef] [PubMed]
  6. Pérez, B.C.; Teixeira, C.; Figueiras, M.; Gut, J.; Rosenthal, F.J.; Gomes, J.R.B.; Gomes, P. Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials. Eur. J. Med. Chem. 2012, 54, 887–899. [Google Scholar] [CrossRef]
  7. Fan, Q.; Jiang, H.; Yuan, E.-d.; Zhang, J.-x.; Ning, Z.-x.; Qi, S.-j.; Wei, Q.-y. Tyrosinase inhibitory effects and antioxidative activities of novel cinnamoyl amides with amino acid ester moiety. Food Chem. 2012, 134, 1081–1087. [Google Scholar] [CrossRef]
  8. Spasova, M.; Kortenska-Kancheva, V.; Totseva, I.; Ivanova, G.; Georgiev, L.; Milkova, T. Synthesis of cinnamoyl and hydroxycinnamoyl amino acid conjugates and evaluation of their antioxidant activity. J. Peptide Sci. 2006, 12, 369–375. [Google Scholar] [CrossRef]
  9. Huang, S.; Liu, W.; Li, Y.; Zhang, K.; Zheng, X.; Wu, H.; Tang, T. Design, Synthesis, and Activity Study of Cinnamic Acid Derivatives as Potent Antineuroinflammatory Agents. ACS Chem. Neurosci. 2021, 12, 419–429. [Google Scholar] [CrossRef]
  10. Mucha, A.; Kafarski, P.; Berlicki, L. Remarkable Potential of the α-Aminophosphonate/Phosphinate Structural Motif in Medicinal Chemistry. J. Med. Chem. 2011, 54, 5955–5980. [Google Scholar] [CrossRef]
  11. Orsini, F.; Sello, G.; Sisti, M. Aminophosphonic Acids and Derivatives. Synthesis and Biological Applications. Curr. Med. Chem. 2010, 17, 264–289. [Google Scholar] [CrossRef]
  12. Naydenova, E.D.; Todorov, P.T.; Troev, K.D. Recent synthesis of aminophosphonic acids as potential biological importance. Amino Acids 2010, 38, 23–30. [Google Scholar] [CrossRef]
  13. Gluza, K.; Kafarski, P. Drug Discovery; El-Shemy, H., Ed.; InTech: Rijeka, Croatia, 2013; pp. 325–372. [Google Scholar] [CrossRef]
  14. Lejczak, B.; Kafarski, P. Biological Activity of Aminophosphonic Acids and Their Short Peptides. Top. Heterocyclic Chem. 2009, 20, 31–63. [Google Scholar] [CrossRef]
  15. Ordoñez, M.; Viveros-Ceballos, J.L.; Romero-Estudillo, I. Chap. 6 stereoselective synthesis of α-aminophosphonic acids through Pudovik and Kabachnik Fields-reaction. In Amino Acid-New Insights and Roles in Plant and Animal; Asao, T., Asaduzzaman, M.D., Eds.; InTech: Rijeka, Croatia, 2017; pp. 127–151. [Google Scholar] [CrossRef]
  16. Mayorquín-Torres, M.C.; Simoens, A.; Bonneure, E.; Stevens, C.V. Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004–2024. Chem. Rev. 2024, 124, 7907–7975. [Google Scholar] [CrossRef]
  17. Amira, A.; Aouf, Z.; K’tir, H.; Chemam, Y.; Ghodbane, R.; Zerrouki, R.; Aouf, N.-E. Recent Advances in the Synthesis of α-Aminophosphonates: A Review. ChemistrySelect 2021, 6, 6137–6149. [Google Scholar] [CrossRef]
  18. Varga, P.R.; Keglevich, G. Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction. Molecules 2021, 26, 2511. [Google Scholar] [CrossRef]
  19. Kudzin, Z.H.; Kudzin, M.H.; Drabowicz, J.; Stevens, C.V. Aminophosphonic acids-phosphorus analogues of natural amino acids. Part 1: Syntheses of α-aminophosphonic acids. Curr. Org. Chem. 2011, 15, 2015–2071. [Google Scholar] [CrossRef]
  20. Ali, T.E.; Abdel-Kariem, S.M. Methods for the synthesis of α-heterocyclic/heteroarylα-aminophosphonic acids and their esters. Arkivoc 2015, 2015, 246–287. [Google Scholar] [CrossRef]
  21. Golovchenko, A.V.; Pilyo, S.G.; Brovarets, V.S.; Chernega, A.N.; Dracha, B.S. A Facile Synthesis of Derivatives of (1,3,4-Thiadiazol-2-yl)glycine and Its Phosphonyl Analogue. Synthesis 2003, 2851–2857. [Google Scholar]
  22. Hu, D.; Wan, Q.-Q.; Yang, S.; Song, B.; Bhadury, P.S.; Jin, L.-H.; Yan, K.; Liu, F.; Chen, Z.; Xue, W. Synthesis and antiviral activities of amide derivatives containing the α-aminophosphonate moiety. J. Agric. Food Chem. 2008, 56, 998–1001. [Google Scholar] [CrossRef]
  23. Lan, X.; Xie, D.; Yin, L.; Wang, Z.; Chen, J.; Zhang, A.; Song, B.; Hu, D. Novel α,β-unsaturated amide derivatives bearing α-aminophosphonate moiety as potential antiviral agents. Bioorg. Med. Chem. Lett. 2017, 27, 4270–4273. [Google Scholar] [CrossRef] [PubMed]
  24. Jackson, D.S.; Fraser, S.A.; Ni, L.-M.; Kam, C.-M.; Winkler, U.; Johnson, D.A.; Froelich, C.J.; Hudig, D.; Powers, J.C. Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase. J. Med. Chem. 1998, 41, 2289–2301. [Google Scholar] [CrossRef] [PubMed]
  25. Moreno-Cinos, C.; Sassetti, E.; Salado, I.G.; Witt, G.; Benramdane, S.; Reinhardt, L.; Cruz, C.D.; Joossens, J.; Van der Veken, P.; Brötz-Oesterhelt, H.; et al. α-Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease. J. Med. Chem. 2019, 62, 774–797. [Google Scholar] [CrossRef]
  26. Akgun, B.; Savci, E.; Avci, D. Synthesis and Polymerizations of Phosphonated-bis(methacrylamide)s for Dental Applications. J. Polym. Sci. Part A 2012, 50, 801–810. [Google Scholar] [CrossRef]
  27. Anandhan, R.; Prasanth, K.; Nithishkumar, P. Purple light-induced Ritter-type reaction of diazophosphonates: Access to α-amido-β-keto phosphonates. Org. Biomol. Chem. 2024, 22, 8401–8406. [Google Scholar] [CrossRef]
  28. Morales-Solís, J.C.; Ordoñez, M.; Viveros-Ceballos, J.L. Stereodivergent Synthesis of the Four Stereoisomers of Diethyl 4-Hydroxyphosphopipecolate from Ethyl (R)-4-Cyano-3-hydroxybutanoate. Synthesis 2024, 56, 2588–2594. [Google Scholar] [CrossRef]
  29. Kabachnik, M.I.; Medved, T. Нoвый метoд синтеза сс-аминoфoсфинoвых кислoт». Dokl. Akad. Nauk SSSR 1952, 83, 689. [Google Scholar]
  30. Fields, E.K. The synthesis of esters of substituted amino phosphonic acids. J. Am. Chem. Soc. 1952, 74, 1528–1531. [Google Scholar] [CrossRef]
  31. Bedolla-Medrano, M.; Hernández-Fernández, E.; Ordoñez, M. Phenylphosphonic acid as efficient and recyclable catalyst in the synthesis of α-aminophosphonates under solvent-free conditions. Synlett 2014, 25, 1145–1149. [Google Scholar] [CrossRef]
  32. Hernández-Fernández, E.; Fernandez-Zertuche, M.; García-Barradas, O.; Muñoz-Muñiz, O.; Ordoñez, M. Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Bearing (S)-α-Methylbenzylamine from 2-Phosphonamides via Horner-Wadsworth-Emmons Reaction. Synlett 2006, 440–444. [Google Scholar] [CrossRef]
  33. Ordoñez, M.; Hernández-Fernández, E.; Montiel-Pérez, M.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.; García-Barradas, O. A convenient Method for the Preparation of Chiral Phosphonoacetamides and their Horner-Wadsworth-Emmons Reaction. Tetrahedron Asymmetry 2007, 18, 2427–2436. [Google Scholar] [CrossRef]
  34. Blanchette, M.A.; Choy, W.; Davis, J.T.; Essenfeld, A.P.; Masamune, S.; Roush, W.R.; Sakai, T. Horner-wadsworth-emmons reaction: Use of lithium chloride and an amine for base-sensitive compounds. Tetrahedron Lett. 1984, 25, 2183–2186. [Google Scholar] [CrossRef]
  35. Bhagat, S.; Chakraborti, A.K. An Extremely Efficient Three-Component Reaction of Aldehydes/Ketones, Amines, and Phosphites (Kabachnik-Fields Reaction) for the Synthesis of α-Aminophosphonates Catalyzed by Magnesium Perchlorate. J. Org. Chem. 2007, 72, 1263–1270. [Google Scholar] [CrossRef] [PubMed]
  36. Zielinska, K.; Mazurkiewicz, R.; Szymanska, K.; Jarzebski, A.; Magiera, S.; Erfurt, K. Penicillin G acylase-mediated kinetic resolution of racemic 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters. J. Mol. Catal. B Enzym. 2016, 132, 31–40. [Google Scholar] [CrossRef]
  37. Azizi, N.; Rajabi, F.; Saidi, M.R. A mild and highly efficient protocol for the one-pot synthesis of primary α-amino phosphonates under solvent-free conditions. Tetrahedron Lett. 2004, 45, 9233–9236. [Google Scholar] [CrossRef]
Molecules 30 03730 g001
Figure 1. (E)-α,β-unsaturated amides incorporating α-amino acids and α-aminophosphonates with biological properties.
Figure 1. (E)-α,β-unsaturated amides incorporating α-amino acids and α-aminophosphonates with biological properties.
Molecules 30 03730 g001
Molecules 30 03730 sch001
Scheme 1. Methods for the synthesis of (E)-α,β-unsaturated amides incorporating α-aminophosphonates [21,22,23,24,25,26,27].
Scheme 1. Methods for the synthesis of (E)-α,β-unsaturated amides incorporating α-aminophosphonates [21,22,23,24,25,26,27].
Molecules 30 03730 sch001
Molecules 30 03730 sch002
Scheme 2. Synthesis of α-aminophosphonates 4a–c and 5a–c.
Scheme 2. Synthesis of α-aminophosphonates 4a–c and 5a–c.
Molecules 30 03730 sch002
Molecules 30 03730 sch003
Scheme 3. Synthesis of (E)-α,β-unsaturated amides 3b–f incorporating the α-aminophosphonate 5a.
Scheme 3. Synthesis of (E)-α,β-unsaturated amides 3b–f incorporating the α-aminophosphonate 5a.
Molecules 30 03730 sch003
Molecules 30 03730 sch004
Scheme 4. Synthesis of phosphonoacetamides 7a–c.
Scheme 4. Synthesis of phosphonoacetamides 7a–c.
Molecules 30 03730 sch004
Molecules 30 03730 sch005
Scheme 5. HWE reaction for the synthesis of α,β-unsaturated amides 3b–m.
Scheme 5. HWE reaction for the synthesis of α,β-unsaturated amides 3b–m.
Molecules 30 03730 sch005
Molecules 30 03730 sch006
Scheme 6. HWE reaction for the synthesis of α,β-unsaturated amides 8a–i.
Scheme 6. HWE reaction for the synthesis of α,β-unsaturated amides 8a–i.
Molecules 30 03730 sch006
Molecules 30 03730 sch007
Scheme 7. HWE reaction for the synthesis of α,β-unsaturated amides 9a–i.
Scheme 7. HWE reaction for the synthesis of α,β-unsaturated amides 9a–i.
Molecules 30 03730 sch007
Table 1. Optimization of reaction conditions for the preparation of α,β-unsaturated amide 3a.
Table 1. Optimization of reaction conditions for the preparation of α,β-unsaturated amide 3a.
Molecules 30 03730 i001
EntryConditionsYield (%)
1SOCl2, DMF, DIPEA, CH2Cl256
2HBTU, DIPEA, CH2Cl276
3PyBOP, DIPEA, MeCN77
4DCC, DMAP, CH2Cl274
5i-BuOC(O)Cl, NMM, CH2Cl272
6(Boc)2O, Py, DMAP, THF68
Table 2. Optimization of HWE reaction conditions for the preparation of α,β-unsaturated amide 3a.
Table 2. Optimization of HWE reaction conditions for the preparation of α,β-unsaturated amide 3a.
Molecules 30 03730 i002
EntryConditionsTime (h)Yield (%) 1E:Z 2
1Cs2CO3, MeCN, 50 °C127293:07
2Cs2CO3, MeCN, 80 °C67092:08
3Cs2CO3, PhMe, 100 °C46593:07
4K2CO3, MeCN, 50 °C246091:09
5K2CO3, MeCN, 80 °C206387:13
6K2CO3, PhMe, 100 °C166861:39
7DBU, LiCl, THF, 25 °C39094:06
1 Isolated yields after purification by column chromatography. 2 The E:Z ratio was determined by 1H NMR in the crude product.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Perez-Aniceto, S.A.; Cano-Tapia, E.; Ordoñez, M.; Viveros-Ceballos, J.L.; Romero-Estudillo, I. Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner–Wadsworth–Emmons Reaction. Molecules 2025, 30, 3730. https://doi.org/10.3390/molecules30183730

AMA Style

Perez-Aniceto SA, Cano-Tapia E, Ordoñez M, Viveros-Ceballos JL, Romero-Estudillo I. Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner–Wadsworth–Emmons Reaction. Molecules. 2025; 30(18):3730. https://doi.org/10.3390/molecules30183730

Chicago/Turabian Style

Perez-Aniceto, Sindy Anahi, Erica Cano-Tapia, Mario Ordoñez, José Luis Viveros-Ceballos, and Ivan Romero-Estudillo. 2025. "Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner–Wadsworth–Emmons Reaction" Molecules 30, no. 18: 3730. https://doi.org/10.3390/molecules30183730

APA Style

Perez-Aniceto, S. A., Cano-Tapia, E., Ordoñez, M., Viveros-Ceballos, J. L., & Romero-Estudillo, I. (2025). Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner–Wadsworth–Emmons Reaction. Molecules, 30(18), 3730. https://doi.org/10.3390/molecules30183730

Article Metrics

Back to TopTop