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Communication

Rapid and One-Pot Synthesis of Aryl Ynamides from Aryl Alkynyl Acids by Metal-Free C-N Cleavage of Tertiary Amines

by
Yong Liu
1,*,
Xiaoyong Liu
2,
Hongwei Li
1 and
Shengmei Guo
2,*
1
Ganzhou Institute for Cancer Research, Ganzhou 341000, China
2
Department of Chemistry, Nanchang University, Nanchang 330031, China
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(14), 2955; https://doi.org/10.3390/molecules30142955
Submission received: 17 June 2025 / Revised: 30 June 2025 / Accepted: 10 July 2025 / Published: 13 July 2025
(This article belongs to the Special Issue Advances in Alkyne Chemistry)
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Abstract

Herein a rapid, metal-free, and highly efficient synthesis of aryl ynamides from aryl alkynyl acids has been described. This approach, utilizing tertiary amines as an amino source via metal-free C-N cleavage, enabled the construction of a diverse range of aryl ynamides with medium to excellent yields (33 examples, up to 95% yield). This reaction exhibits significantly enhanced efficiency compared to the conventional stepwise approach involving aryl alkynyl acids and secondary amines. It can be successfully scaled up, providing a practical and environmentally benign strategy for alkynamide synthesis.

1. Introduction

Ynamides are pivotal structural motifs in natural and pharmaceutical molecules [1,2,3]. They are also recognized as versatile intermediates in heterocyclic synthesis, making them a focal point of extensive research in organic synthesis [4,5,6,7,8]. Traditionally, ynamides are synthesized via amidation of alkynyl acids and amines in the presence of DCC and DMAP or by two steps (Scheme 1a) [9,10,11,12,13]: (1) aryl propiolic acids are first converted into chlorides via reaction with oxalyl chloride or thionyl chloride; (2) Subsequently, the chlorides are treated with primary or secondary amines in the presence of a base to afford the corresponding products. Though efficient, this method produces a large amount of waste, lacks step economy, and needs long reaction times. Recently, the Pd/Cu-catalyzed cross-coupling reaction between alkynes and amineformyl chloride successfully realized the preparation of these ynamides (Scheme 1b) [14,15,16]. The Cu/TBHP-mediated synthesis of these compounds was also accomplished between secondary amines or formamides with alkynyl acids (Scheme 1c) [17,18,19,20,21,22]. Nevertheless, these approaches are plagued by issues such as multi-step synthesis procedures and poor stability of amine formyl chloride [23]. Further progress was achieved by Shi and co-workers, who demonstrated a Ni-catalyzed coupling between alkynyl acids and tetraalkylthiuram disulfides under ligand-free conditions (Scheme 1d) [24].
Tertiary amines have garnered significant interest in organic synthesis due to their exceptional stability and ready availability [25,26,27,28,29,30]. Since 2010 and the pioneering work by Huang on the selective C-N bond cleavage of tertiary amines by transition-metal catalysis [31], tremendous progress has been achieved in the development of powerful methods for the introduction of amino groups into molecules [32,33,34]. This strategy has also been employed in the ynamide synthesis. The Bhanage and Lee groups independently developed Pd-catalyzed N-dealkylation/carbonylation protocols for the synthesis of ynamides (Scheme 1e) [35,36]. While these methods depend on noble metal catalysts, they face challenges in terms of sustainability, cost-effectiveness, and operational simplicity [37]. To address this unmet need, we herein report a rapid, one-pot synthesis of aryl ynamides of alkynyl acids employing inexpensive tertiary amines as amino sources under catalyst-free conditions [38,39,40,41,42,43,44].

2. Results and Discussion

We chose phenylpropynoic acid (1a, 0.2 mmol) and triethylamine (2a, 0.7 mmol) as the model substrates (Table 1). Initially, DMF (0.6 equiv.) and (COCl)2 (1.5 equiv.) were employed as additives with DCM (0.5 mL) serving as the solvent. The reaction was conducted at room temperature for 2.0 h under a nitrogen atmosphere. Ultimately, the target product 3a (Table 1, entry 1) was successfully obtained in an excellent yield of 94%. Subsequently, the effect of the solvent on the reaction was screened. When MeCN, toluene, and dioxane were utilized as the solvents, only moderate to low yields were achieved (Table 1, entries 2–4). Additionally, when DMSO and MeOH were employed as solvents, there was no product detected in this reaction (Table 1, entries 5 and 6). Interestingly, DMF was found to promote the reaction efficiency significantly. Control experiments revealed that the reaction proceeded with only 66% yield in the absence of DMF, demonstrating its crucial role as a reaction accelerator (Table 1, entry 7). While increasing the loading of DMF to 0.8 eq., the yield of 3a was increased to 93% (Table 1, entries 8–10). Next, the reaction time was investigated. When the reaction time was shortened to 0.5 h, only 47% of 3a was produced. Further extending the reaction time to 1.0 h, 1.5 h, and 2.0 h, the desired products were obtained in progressively higher yields of 75%, 86%, and 94%, respectively (Table 1, entries 11–14).
After the optimal reaction conditions were determined, the substrate compatibility study on the 3-arylpropynoic acids was conducted (Scheme 2). First, the substrates with electron-rich substituent groups such as -CH3 (3b), -C(CH3)3 (3c), and -OCH3 (3d) at the para-position of the arene showed good reactivity, and the corresponding alkynamides could be obtained in good yields. In addition, halogen substituents on the benzene ring were also compatible with this reaction. For example, 3-(4-bromophenyl)propiolic acid delivered 3e in 81%. Electron-deficient groups such as -CN, -CHO, and -COCH3 were introduced to the aryl para-position, and it was found that the conversion was inhibited, with only moderate yields (3f–3h). Ortho-substituted arylpropylic acids were investigated, and it was found that there were no effects of steric hindrance on the reactions, with 86–90% yields, respectively (3i–3k). It is gratifying that except for phenyl, naphthyl (3l)- and heteroaryl (3m)-substituted arylpropylic acids were also compatible with the transformation, furnishing the target amides in 70% and 83% yields, respectively. Unfortunately, the substrates with -NO2 (3n) and -COOH (3o) groups did not participate in the reaction. Finally, ibuprofen (3p) was used as a partner with triethylamine under the standard conditions, but no product was produced.
Next, the scope of tertiary amines was expanded (Scheme 3). For symmetric alkyl tertiary amines such as Pr3N, Hex3N, and Oct3N, the reactions could be carried out smoothly, giving the desired products 3q–3s in good yields. The yield was drastically reduced when Bn3N was employed in the reactions (3t), which may be due to the large steric hindrance, making the reaction difficult. It is gratifying that the unsaturated triallylamine showed high compatibility, which achieved the corresponding product in 68% yield (3u). Subsequently, we turned our attention to asymmetric tertiary amines. TMMDA, TEEDA, and DIPEA—each containing two distinct C-N bond cleavage sites—demonstrated remarkable regioselectivity in their reactions; only a single product was detected under these reaction conditions (3v, 3a, and 3w). However, employing N,N-dimethylisopropylamine as the substrate led to the formation of two N-dealkylation/carbonylation products (3v and 3x) in an approximate 3:1 ratio. Unfortunately, we did not observe the amidation product when PhNEt2 was used as a tertiary amine source (3y). The secondary amine Et2NH was also added in the reaction, and the result showed inferior to Et3N (3a) under the same conditions, suggesting that this work provides an advantage over traditional methods.
Finally, the cyclic tertiary amines were also explored (Scheme 4). Our findings revealed that the majority of N-methyl cyclic tertiary amines underwent smooth conversion processes, offering the demethylation products in moderate yields (3aa, 3ab). Additionally, owing to the conjugation effect exerted by the benzyl group, the benzyl moiety proved to be a more favorable leaving group than the methyl group. Consequently, N-benzyl-substituted cyclic tertiary amines demonstrated notably higher yields (3ac, 3ad).
To quantify the improvements of our one-pot synthetic method relative to conventional methods, we performed control experiments using the conventional two-step approach with phenylpropynoic acid and Et2NH, which afforded the desired product in 72% yield. To further evaluate the scalability and practical applicability of this strategy, a gram-scale reaction was successfully conducted with a yield of 90% (Scheme 5).

3. Materials and Methods

3.1. General Information

All commercially available reagent-grade chemicals were purchased from Adamas (Shanghai, China), Aldrich (St. Louis, MO, USA), Accela (San Ramon, CA, USA), Alfa Aesar (Ward Hill, MA, USA), and TCI (Portland, OR, USA) and were used as received without further purification unless otherwise stated. 1H NMR, 13C NMR were recorded in CDCl3 on a Bruker Avance III 400 spectrometer with TMS as internal standard (400 MHz 1H, 101 MHz 13C, Bruker, Billerica, MA, USA) at room temperature; the chemical shifts (δ) were expressed in ppm, and J values were given in Hz. HRMS was performed by the Analysis and Testing Center, Nanchang University. The following abbreviations are used to indicate the multiplicity: singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt), and multiplet (m). All first-order splitting patterns were assigned based on the appearance of the multiplet. Splitting patterns that could not be easily interpreted were designated as multiplet (m). Column chromatography was performed on silica gel (200–300 mesh).

3.2. Experimental Procedure for Ynamides

To a dry round-bottom flask, aryl alkynyl acids, oxalyl chloride, DMF, tertiary amines, and CH2Cl2 were added. The mixture was stirred under an N2 atmosphere for 2 h at room temperature. After the reaction was completed, the solvent was removed by rotary evaporation, and the residual solution was extracted with CH2Cl2 (3 × 15 mL). Then, the organic layer was dried with anhydrous Na2SO4. Finally, after filtration, the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compounds.
  • N,N-Diethyl-3-phenylpropiolamide (3a): Yellow liquid and the yield is 94%; 1H NMR (400 MHz, CDCl3) δ 7.50–7.45 (m, 2H), 7.38–7.27 (m, 3H), 3.61 (q, J = 7.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.71, 132.05, 129.66, 128.27, 120.49, 88.71, 81.73, 43.39, 39.10, 14.18, 12.64. HRMS: calcd for C13H16ON [M + H]+: 202.1226, found: 202.1222.
  • N,N-Diethyl-3-(p-tolyl)propiolamide (3b): Yellow liquid and the yield is 84%; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 3.69–3.61 (m, 2H), 3.46 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 154.09, 140.29, 132.22, 129.20, 117.57, 89.34, 81.44, 43.54, 39.22, 21.58, 14.34, 12.83. HRMS: calcd for C14H18ON [M + H]+: 216.1383, found: 216.1329.
  • 3-(4-(Tert-butyl)phenyl)-N,N-diethylpropiolamide (3c): Yellow liquid and the yield is 87%; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 3.65 (q, J = 7.1, 6.6 Hz, 2H), 3.46 (q, J = 7.1 Hz, 2H), 1.30 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 154.05, 153.31, 132.05, 125.43, 117.58, 89.24, 81.41, 43.52, 39.22, 34.84, 30.97, 14.30, 12.79. HRMS: calcd for C17H24ON [M + H]+: 258.1852, found: 258.1845.
  • N,N-Diethyl-3-(4-methoxyphenyl)propiolamide (3d): Yellow liquid and the yield is 95%; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.0 Hz, 2H), 6.86 (d, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.64 (q, J = 7.2 Hz, 2H), 3.45 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 160.82, 154.23, 134.02, 114.12, 112.59, 89.46, 81.12, 55.30, 43.52, 39.20, 14.33, 12.84. HRMS: calcd for C14H18O2N [M + H]+: 232.1332, found: 232.1328.
  • 3-(4-Bromophenyl)-N,N-diethylpropiolamide (3e): Yellow liquid and the yield is 81%; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 3.63 (q, J = 7.2 Hz, 2H), 3.46 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.64, 133.60, 131.79, 124.41, 119.59, 87.76, 82.79, 43.54, 39.28, 14.36, 12.77. HRMS: calcd for C13H15BrON [M + H]+: 280.0332, found: 280.0329.
  • 3-(4-Cyanophenyl)-N,N-diethylpropiolamide (3f): Yellow liquid and the yield is 38%; 1H NMR (400 MHz, CDCl3) δ 7.63 (q, J = 8.4, 7.9 Hz, 4H), 3.64 (q, J = 7.1 Hz, 2H), 3.47 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.11, 132.66, 132.12, 125.53, 117.95, 113.21, 86.53, 85.22, 43.58, 39.40, 14.39, 12.73. HRMS: calcd for C14H15ON2 [M + H]+: 227.1179, found: 227.1174.
  • N,N-Diethyl-3-(4-formylphenyl)propiolamide (3g): Yellow liquid and the yield is 32%; 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 3.66 (q, J = 7.1 Hz, 2H), 3.48 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 191.20, 153.34, 136.49, 132.76, 129.52, 126.73, 87.43, 84.83, 43.59, 39.37, 14.42, 12.78. HRMS: calcd for C14H16O2N [M + H]+: 230.2870, found: 230.2867.
  • 3-(4-Acetylphenyl)-N,N-diethylpropiolamide (3h): Yellow liquid and the yield is 55%; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 3.65 (q, J = 7.0 Hz, 2H), 3.47 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.05, 153.44, 137.40, 132.35, 128.21, 125.34, 87.65, 84.31, 43.58, 39.33, 26.60, 14.36, 12.74. HRMS: calcd for C15H18O2N [M + H]+: 244.1332, found: 244.1328.
  • N,N-Diethyl-3-(o-tolyl)propiolamide (3i): Yellow liquid and the yield is 86%; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.66 (q, J = 6.7 Hz, 2H), 3.47 (q, J = 7.1, 6.6 Hz, 2H), 2.46 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 154.03, 141.06, 132.88, 129.81, 129.57, 125.68, 120.52, 87.98, 85.67, 43.52, 39.28, 20.58, 14.40, 12.81. HRMS: calcd for C14H18ON [M + H]+: 216.1383, found: 216.1328.
  • N,N-Diethyl-3-(2-methoxyphenyl)propiolamide (3j): Yellow liquid and the yield is 90%; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.70 (q, J = 7.1 Hz, 2H), 3.46 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.08, 154.17, 134.13, 131.41, 120.41, 110.57, 109.96, 86.00, 85.53, 55.62, 43.50, 39.17, 14.28, 12.83. HRMS: calcd for C14H18O2N [M + H]+: 232.1332, found: 232,1328.
  • 3-(2-Chlorophenyl)-N,N-diethylpropiolamide (3k): Yellow liquid and the yield is 87%; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 5.6 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 3.71 (q, J = 7.0 Hz, 2H), 3.46 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.61, 136.67, 134.42, 130.89, 129.35, 126.65, 120.88, 86.44, 85.13, 43.56, 39.34, 14.45, 12.78. HRMS: calcd for C13H15ClON [M + H]+: 236.0837, found: 286.0834.
  • N,N-Diethyl-3-(naphthalen-2-yl)propiolamide (3l): Yellow liquid and the yield is 70%; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.81 (dd, J = 7.3, 4.4 Hz, 3H), 7.56–7.48 (m, 3H), 3.70 (q, J = 7.1 Hz, 2H), 3.49 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.94, 133.39, 132.99, 132.60, 128.20, 128.05, 127.92, 127.76, 127.46, 126.81, 117.87, 89.37, 82.06, 43.59, 39.27, 14.40, 12.82. HRMS: calcd for C17H18ON [M + H]+: 252.3370, found: 252.3368.
  • N,N-Diethyl-3-(thiophen-2-yl)propiolamide (3m): Yellow liquid and the yield is 83%; 1H NMR (400 MHz, CDCl3) δ 7.38 (t, J = 3.4 Hz, 2H), 7.02 (t, J = 4.3 Hz, 1H), 3.61 (q, J = 7.2 Hz, 2H), 3.45 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.70, 134.79, 129.72, 127.30, 120.36, 85.83, 82.69, 43.47, 39.21, 14.34, 12.79. HRMS: calcd for C11H14OSN [M + H]+: 208.2990, found: 208.2986.
  • 3-Phenyl-N,N-dipropylpropiolamide (3q): Yellow liquid and the yield is 73%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.3 Hz, 2H), 7.42–7.33 (m, 3H), 3.56 (t, J = 7.4 Hz, 2H), 3.36 (t, J = 7.4 Hz, 2H), 1.73–1.66 (m, 2H),1.63–1.56 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 154.53, 132.25, 129.82, 128.46, 120.78, 89.26, 82.11, 50.84, 46.50, 22.17, 20.69, 11.32, 11.23. HRMS: calcd for C15H20ON [M + H]+: 230.1539, found: 230.1536.
  • N,N-Dihexyl-3-phenylpropiolamide (3r): Yellow liquid and the yield is 94%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.0 Hz, 2H), 7.42–7.33 (m, 3H), 3.58 (t, J = 7.5 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 1.69–1.61 (m, 2H), 1.60–1.53 (m, 2H), 1.37–1.25 (m, 12H), 0.90–0.84 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 154.33, 132.21, 129.76, 128.42, 120.79, 89.13, 82.14, 54.09, 49.11, 44.81, 31.78, 31.53, 28.82, 27.41, 26.59, 26.38, 22.51, 13.96, 13.90. HRMS: calcd for C21H32ON [M + H]+: 314.2478, found: 314.2474.
  • N,N-Dioctyl-3-phenylpropiolamide (3s): Yellow liquid and the yield is 80%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.3 Hz, 2H), 7.41–7.41 (m, 3H), 3.58 (t, J = 7.5 Hz, 2H), 3.38 (t, J = 7.5 Hz, 2H), 1.65 (t, J = 7.3 Hz, 2H), 1.56 (t, J = 7.4 Hz, 2H), 1.34–1.23 (m, 20H), 0.89–0.83 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 154.40, 132.26, 129.80, 128.46, 120.83, 89.22, 82.17, 53.91, 49.18, 44.87, 31.77, 31.74, 29.34, 29.26, 29.20, 28.89, 27.48, 26.98, 26.75, 22.61, 22.58, 14.05, 14.03. HRMS: calcd for C25H40ON [M + H]+: 370.3104, found: 370.3100.
  • N,N-Dibenzyl-3-phenylpropiolamide (3t): Yellow liquid and the yield is 33%; 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.50 (s, 1H), 7.43–7.24 (m, 13H), 4.76 (s, 2H), 4.57 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 154.98, 136.19, 136.03, 132.41, 130.09, 128.85, 128.66, 128.47, 128.43, 127.93, 127.69, 127.62, 120.31, 90.80, 81.60, 51.41, 46.34. HRMS: calcd for C23H20ON [M + H]+: 326.1539, found: 326.1534.
  • N,N-Diallyl-3-phenylpropiolamide (3u): Yellow liquid and the yield is 68%; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.2 Hz, 2H), 7.44–7.32 (m, 3H), 5.89–5.71 (m, 2H), 5.27–5.15 (m, 4H), 4.22 (d, J = 5.8 Hz, 2H), 4.06 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.41, 132.69, 132.33, 132.09, 129.99, 128.45, 120.43, 118.07, 117.94, 89.87, 81.47, 50.72, 46.37. HRMS: calcd for C15H16ON [M + H]+: 226.1226, found: 226.1221.
  • N,N-Dimethyl-3-phenylpropiolamide (3v): Yellow liquid and the yield is 87%; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 2H), 7.43–7.32 (m, 3H), 3.28 (s, 3H), 3.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.59, 132.28, 129.91, 128.45, 120.56, 90.12, 81.53, 38.34, 34.13. HRMS: calcd for C11H12ON [M + H]+: 174.0913, found: 174.0908.
  • N-Ethyl-N-isopropyl-3-phenylpropiolamide (3w): Yellow liquid and the yield is 95%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 6.8 Hz, 2H), 7.53–7.32 (m, 3H), 4.74–4.65 (m, 1H), 3.55 (q, J = 7.2 Hz, 1H), 3.34 (q, J = 7.0 Hz, 1H), 1.32 (t, J = 7.4 Hz, 1H), 1.25 (d, J = 7.3 Hz, 4H), 1.19 (d, J = 7.2 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 154.35, 153.85, 132.20, 132.18, 129.75, 129.70, 128.40, 128.37, 89.35, 88.53, 82.54, 81.91, 50.52, 45.33, 39.22, 35.36, 21.21, 20.30, 16.58, 14.45. HRMS: calcd for C14H18ON [M + H]+: 216.1383, found: 216.1379.
  • N-Isopropyl-N-methyl-3-phenylpropiolamide (3x): Yellow liquid and the yield is 23%; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 6.7 Hz, 2H), 7.42–7.33 (m,3H), 4.89–4.71 (m, 1H), 3.12 (s, 1H), 2.86 (s, 2H), 1.24 (d, J = 6.7 Hz, 4H), 1.15 (d, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.31, 154.09, 132.28, 129.83, 128.44, 120.72, 90.03, 89.95, 82.16, 81.50, 50.09, 43.96, 29.79, 25.57, 20.36, 19.22. HRMS: calcd for C13H16ON [M + H]+: 202.1226, found: 202.1222.
  • 3-Phenyl-1-(piperidin-1-yl)prop-2-yn-1-one (3aa): Yellow liquid and the yield is 68%; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.4 Hz, 2H), 7.42–7.33 (m, 3H), 3.77 (t, J = 5.1 Hz, 2H), 3.62 (t, J = 5.5 Hz, 2H), 1.66 (t, J = 7.4 Hz, 4H), 1.61–1.55 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 152.89, 132.26, 129.81, 128.42, 120.68, 90.20, 81.41, 48.17, 42.32, 26.40, 25.34, 24.48. HRMS: calcd for C14H16ON [M + H]+: 214.1226, found: 214.1223.
  • 1-(4-Chloropiperidin-1-yl)-3-phenylprop-2-yn-1-one (3ab): Yellow liquid and the yield is 67%; 1H NMR (400 MHz, CDCl3)δ7.56–7.51 (m, 2H), 7.45–7.33 (m, 3H), 4.36–4.31 (m, 1H), 4.07–3.98 (m, 1H), 3.88–3.79 (m, 2H), 3.77–3.69 (m, 1H), 2.18–2.02 (m, 2H), 1.99–1.83 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 152.94, 132.32, 130.07, 128.49, 120.32, 90.81, 80.89, 56.17, 44.01, 38.23, 35.12, 34.14. HRMS: calcd for C14H15ClON [M + H]+: 248.0837, found: 248.0836.
  • 3-Phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-one (3ac): Yellow liquid and the yield is 93%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.3 Hz, 2H), 7.41–7.32 (m, 3H), 3.71 (t, J = 6.5 Hz, 2H), 3.51 (t, J = 6.4 Hz, 2H), 1.99–1.90 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 152.65, 132.31, 129.85, 128.41, 120.56, 88.61, 82.59, 48.08, 45.29, 25.31, 24.65. HRMS: calcd for C13H14ON [M + H]+: 200.1070, found: 200.1068.
  • 1-Morpholino-3-phenylprop-2-yn-1-one (3ad): Yellow liquid and the yield is 91%; 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.43–7.33 (m, 3H), 3.82 (t, J = 4.6 Hz, 2H), 3.73 (t, J = 4.5 Hz, 2H), 3.68 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 153.13, 132.30, 130.12, 128.49, 120.19, 91.11, 80.68, 66.82, 66.41, 47.24, 41.90. HRMS: calcd for C13H14O2N [M + H]+: 216.1016, found: 216.1018.

4. Conclusions

In summary, we developed an efficient metal-free strategy for the synthesis of aryl alkynamides via C-N bond cleavage using inert tertiary amines and aryl alkynyl acids. This method employs inexpensive and readily available tertiary amines as starting materials and demonstrates broad substrate scope and excellent functional group compatibility. Notably, the aryl alkynamides are obtained in a one-pot manner under mild conditions, offering significant environmental and economic advantages. The successful scale-up of this synthesis demonstrates the potential practical relevance of this reaction.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30142955/s1. Experimental details: p. S2, General information and Synthesis of 3-arylpropiolic acids; pp. S3–S6, Experimental characterization data for products; pp. S7–S35, Copies of product 1H NMR, 13C NMR.

Author Contributions

Conceptualization, Y.L.; methodology, X.L.; investigation, X.L.; data curation, H.L.; writing—original draft preparation, S.G.; funding acquisition, Y.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by Jiangxi Provincial Natural Science Foundation (20232BAB203008).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The author declares no conflicts of interest.

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Molecules 30 02955 sch001
Scheme 1. Synthesis of ynamides.
Scheme 1. Synthesis of ynamides.
Molecules 30 02955 sch001
Molecules 30 02955 sch002
Scheme 2. Scope of propionic acids. Reaction condition: 1 (0.2 mmol), 2a (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Scheme 2. Scope of propionic acids. Reaction condition: 1 (0.2 mmol), 2a (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Molecules 30 02955 sch002
Molecules 30 02955 sch003
Scheme 3. Scope of propionic acids. Reaction condition: 1a (0.2 mmol), 2 (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields. TAA = triallylamine; TMMDA = N,N,N’,N’-tetramethylmethanediamine; TEEDA = N1,N1,N2,N2-tetraethylethane-1,2-diamine.
Scheme 3. Scope of propionic acids. Reaction condition: 1a (0.2 mmol), 2 (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields. TAA = triallylamine; TMMDA = N,N,N’,N’-tetramethylmethanediamine; TEEDA = N1,N1,N2,N2-tetraethylethane-1,2-diamine.
Molecules 30 02955 sch003
Molecules 30 02955 sch004
Scheme 4. Scope of propynoic acids. Reaction condition: 1a (0.2 mmol), 2 (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Scheme 4. Scope of propynoic acids. Reaction condition: 1a (0.2 mmol), 2 (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Molecules 30 02955 sch004
Molecules 30 02955 sch005
Scheme 5. Scope of propionic acids. Reaction condition: 1 (0.2 mmol), 2a (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Scheme 5. Scope of propionic acids. Reaction condition: 1 (0.2 mmol), 2a (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2.0 h; Isolated yields.
Molecules 30 02955 sch005
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 30 02955 i001
EntryVariation from Standard ConditionsYield b (%)
1none94
2MeCN as a solvent84
3Toluene as a solvent52
4Dioxane as a solvent27
5DMSO as a solventNR
6MeOH as a solventNR
7without DMF66
8DMF (0.2 equiv.)78
9DMF (0.4 equiv.)87
10DMF (0.8 equiv.)90
110.5 h47
121.0 h75
131.5 h86
142.5 h93
a Reaction conditions: 1a (0.2 mmol), 2a (3.5 equiv.), (COCl)2 (1.5 equiv.), DMF (0.6 equiv.), DCM (0.5 mL), rt, under nitrogen atmosphere for 2 h; b Isolated yields.
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Liu, Y.; Liu, X.; Li, H.; Guo, S. Rapid and One-Pot Synthesis of Aryl Ynamides from Aryl Alkynyl Acids by Metal-Free C-N Cleavage of Tertiary Amines. Molecules 2025, 30, 2955. https://doi.org/10.3390/molecules30142955

AMA Style

Liu Y, Liu X, Li H, Guo S. Rapid and One-Pot Synthesis of Aryl Ynamides from Aryl Alkynyl Acids by Metal-Free C-N Cleavage of Tertiary Amines. Molecules. 2025; 30(14):2955. https://doi.org/10.3390/molecules30142955

Chicago/Turabian Style

Liu, Yong, Xiaoyong Liu, Hongwei Li, and Shengmei Guo. 2025. "Rapid and One-Pot Synthesis of Aryl Ynamides from Aryl Alkynyl Acids by Metal-Free C-N Cleavage of Tertiary Amines" Molecules 30, no. 14: 2955. https://doi.org/10.3390/molecules30142955

APA Style

Liu, Y., Liu, X., Li, H., & Guo, S. (2025). Rapid and One-Pot Synthesis of Aryl Ynamides from Aryl Alkynyl Acids by Metal-Free C-N Cleavage of Tertiary Amines. Molecules, 30(14), 2955. https://doi.org/10.3390/molecules30142955

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