It was not possible to use non-nucleophilic tertiary nitrogen bases such as triethylamine for the known reactivity of the trialkyl amines with TiCl4 [39, 40]. The poor outcome of the reaction prompted us to use a base to covert the carboxylic acid into the corresponding carboxylate. Chem Commun 46:1813–1823, Allen CL, Chhatwal AR, Williams JMJ (2012) Direct amide formation from unactivated carboxylic acids and amines. Chiral GC–MS analyses of enantiomeric compounds 27–28 were performed by using a 25 m × 0.25 mm, Diethyl tertbutyldimethylisilyl-β-cyclodextrine chiral capillary column. Date: Sep. 07, 1972, Nordahl A, Carlson R (1988) Carboxamides from carboxylic acids by lewis acid catalysis. Eur J Org Chem 21:4437–4441, Di Gioia ML, Leggio A, Guarino IF, Leotta V, Romio E, Liguori A (2015) A simple synthesis of anilines by LiAlH4/TiCl4 reduction of aromatic nitro compounds. J Org Chem 78:4512–4523, Huang W, Sha WB (2013) Direct amide formation from N-arylglycine ethyl esters and carboxylic acids catalysed by phenylboronic acid. Protein Pept Lett 12:357–362, Leggio A, Belsito EL, Di Gioia ML, Leotta V, Romio E, Siciliano C, Liguori A (2015) Reduction of amide carbonyl group and formation of modified amino acids and dipeptides. Chem Eur J 18:3822–3826, Tinnis F, Lundberg H, Kivijärvi T, Adolfsson H (2015) Zirconium (IV) chloride catalyzed amide formation from carboxylic acid and amine: (S)-tert-Butyl 2-(Benzylcarbamoyl)pyrrolidine-1-carboxylate. J Med Chem 54:3451–3479, Deming TJ (2002) Methodologies for preparation of synthetic block copolypeptides: materials with future promise in drug delivery.

The direct formation of amides by condensing non-activated carboxylic acids and amines is extremely attractive because of its low environmental impact. Solid (94%), mp = 74–76 °C; Rf = 0.81; 1H NMR (300 MHz, CDCl3) δ: 5.49 (sbroad, 1H), 3.27–3.14 (m, 2H), 2.20–2.09 (m, 2H), 1.73–1.58 (m, 2H), 1.57–1.41 (m, 2H), 1.40–1.11 (m, 24H), 0.98–0.78 (m, 6H); 13C-NMR (75 MHz, CDCl3) δ: 173.1, 41.2, 37.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 25.9, 22.9, 22.7, 14.1, 11.4; GC/MS (EI) m/z (% rel. Then, to the resulting solution heated at 85 °C, were added TiCl4 (3 mmol) and aniline (1 mmol). Solid (95%); mp = 177–179 °C; Rf = 0.69; 1H NMR (300 MHz, DMSO-d6) δ: 10.06 (s, 1H), 7.99–7.88 (m, 2H), 7.80–7.74 (m, 2H), 7.39–7.24 (m, 2H), 7.13–6.99 (m, 3H), 3.83 (s, 3H); 13C-NMR (75 MHz, DMSO-d6) δ: 165.4, 162.4, 139.9, 130.0, 129.0, 127.5, 123.9, 120.9, 114.1, 55.9; GC/MS (EI) m/z (% rel.

The amidation reaction was performed in pyridine at 85 °C with a wide range of substrates providing the corresponding amide products in moderate to excellent yields and high purity. Both aliphatic and aromatic carboxylic acids were converted in secondary and tertiary amides in 62–99% yield with 2–10 mol% catalyst loading. Optimization of amidation reaction conditions was performed by choosing benzoic acid as model substrate. The main synthetic catalysts employed for direct amidation are boronic acids and esters together with Lewis acid metal complexes.

Molecules 18:6230–6268, Roughley SD, Jordan AM (2011) The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. Chemical shifts (δ) are reported in ppm. Privacy

): 197 [M+∙] (46), 105 (100), 77 (46); 65 (4), 51 (9). The reaction was designed in dichloromethane excluding ethereal solvents such as THF because, in the presence of TiCl4, O-heterocycle ring opening reaction occurs [41, 42]. No. The reaction of the sterically hindered pivalic acid with diethylamine resulted with very low conversions and provided, after 2 h, the corresponding amide 26 in 9% yield. ZrCl4 and ZrCp2Cl2 were particularly effective resulting in high conversions of the substrates after 4 h of reaction time at 110 °C using a 5 mol% catalyst. ACS Catal 5:3271–3277, Leggio A, Belsito EL, Gallo S, Liguori A (2017) One-pot conversion of aldehydes to nitriles mediated by TiCl4. ): 264 [M+∙] (17), 208 (25), 191 (29), 144 (18), 120 (28), 93 (100), 77 (25), 57 (87). In 1972 Werdehausen et al. statement and Solid (98%); mp = 218–220 °C; Rf = 0.65; 1H NMR (300 MHz, DMSO-d6) δ: 10.53 (s, 1H), 8.35 (d, J = 9.0 Hz, 2H), 8.18 (d, J = 9.0 Hz,2H), 7.78 (d, J = 7.5 Hz, 2H), 7.46–7.27 (m, 2H), 7.13 (t, J = 7.4 Hz, 1H); 13C-NMR (75 MHz, DMSO-d6) δ: 164.3, 149.6, 141.1, 139.2, 129.7, 129.1, 124.6, 124.0, 121.0; GC/MS (EI) m/z (% rel. The reaction was previously investigated under catalytic conditions. In fact, the presence of chlorine and nitro group on the aromatic ring of carboxylic acids results in higher yields in amide (18, 20, Table 4) than substrates that have no substituents or have electron donor groups on the aromatic ring.

Solid (95%); mp = 105–107 °C; Rf = 0.73; 1H NMR (300 MHz, CDCl3) δ: 7.63 (sbroad, 1H), 7.49–7.42 (m, 2H), 7.39–7.21 (m, 7H), 7.09 (t, J = 7.4 Hz, 1H), 3.70 (s, 2H); 13C-NMR (75 MHz, CDCl3) δ: 169.4, 137.8, 134.6, 129.5, 129.1, 128.9, 127.6, 124.4, 120.0, 44.7; GC/MS (EI) m/z (% rel. To log in and use all the features of Khan Academy, please enable JavaScript in your browser. ): 297 [M+∙] (3), 268 (3), 239 (3), 114 (24), 101 (100), 43 (14). Therefore the amidation reaction was carried out in dichloromethane under reflux by treating benzoic acid (1 mmol) with pyridine (1 mmol) and TiCl4 (1.5 mmol), then aniline was added (1 mmol). In these reactions, steric effects play a key role when both amine and carboxylic acid are sterically hindered. Org Biomol Chem 4:2337–2347, CAS  All reagents were purchased commercially without further purification.

): 225 [M+∙] (49), 133 (12), 107 (100), 91 (46), 77 (9), 65 (12). 1:1) of the two enantiomers (Fig. Simultaneously, Adolfsson et al.
The results reported in Table 4 also suggested that, when diethyl amine is used as amine component, the reaction is affected by the electronic nature of the substituent on the aromatic ring of the benzoic acid (entry r, entry t Table 4) which probably characterize the reactivity of the reaction intermediates. The direct reaction of a carboxylic acid with an amine would be expected to be difficult because the basic amine would deprotonate the carboxylic acid to form a highly unreactive carboxylate. Then the reaction was repeated for a longer reaction time (24 h). 1H and 13C NMR spectra were recorded on a Bruker Avance 300 instrument at 300 MHz and 75 MHz, respectively. Boron-based compounds are reported as catalysts promoting the condensation of carboxylic acids and amines in refluxing toluene [20, 21].

; 13C-NMR (75 MHz, CDCl3) δ: 164.7, 142.2, 138.2, 134.6, 129.9, 129.1, 128.8, 128.0, 124.5, 121.2, 120.4; GC/MS (EI) m/z (% rel. The molecular structure of the obtained amides was assigned by 1H NMR, 13C NMR and GC/MS analyses. Our procedure was successfully applied to a broad spectrum of readily available carboxylic acids and amines affording, in short times and after a simple work up, the corresponding amides in high purity and yields. If you're behind a web filter, please make sure that the domains *.kastatic.org and *.kasandbox.org are unblocked. Solid (98%), mp = 108–110 °C; Rf = 0.73; 1H NMR (300 MHz, CDCl3) δ: 7.52 (sbroad, 1H), 7.43–7.28 (m, 7H), 7.07 (d, J = 8.3 Hz, 2H), 3.69 (s, 2H), 2.29 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ: 169.3, 135.2, 134.7, 134.0, 129.5, 129.4, 129.1, 127.5, 120.1, 44.6, 20.9; GC/MS (EI) m/z (% rel. Our mission is to provide a free, world-class education to anyone, anywhere. Synlett 23:2201–2204, Lundberg H, Tinnis F, Adolfsson H (2012) Direct amide coupling of non-activated carboxylic acids and amines catalysed by Zirconium(IV) Chloride. Diethylamine was chosen as a representative dialkyl amine for studying the influence of steric hindrance on the course of the reaction (Scheme 1; Table 4). Some substrates were converted in the corresponding amides before this time. ): 242 [M+∙] (75), 150 (100), 120 (21), 104 (32), 92 (20), 76 (25). use of principal properties for exploring different reaction conditions. By using this website, you agree to our The oven temperature program was initially set at 50 °C, with a hold of 2 min, ramped to 250 °C at 0.5 °C/min with a hold of 5 min. © 2020 BioMed Central Ltd unless otherwise stated. Methyl esters are often prepared by the reaction of carboxylic acids with diazomethane. Chem Soc Rev 40:3405–3415, Ishihara K, Ohara S, Yamamoto H (1996) 3,4,5-Trifluorobenzeneboronic acid as an extremely active amidation catalyst.

Reactions were magnetically stirred and monitored by thin layer chromatography using Merck-Kieselgel 60 F254 plates.

Oil (88%); Rf = 0.80; 1H NMR (300 MHz, CDCl3) δ: 8.86 (sbroad, 1H), 7.58–7.45 (m, 2H), 7.36–7.19 (m, 2H), 7.13–7.01 (m, 1H), 5.50 (d, J = 7.5 Hz, 1H), 4.53–4.31 (m, 1H), 1.48–1.38 (m, 12H); 13C-NMR (75 MHz, CDCl3) δ: 171.2, 155.9, 137.9, 128.9, 124.2, 119.9, 80.4, 50.4, 28.3, 17.8; GC/MS (EI) m/z (% rel. Have questions or comments? The tightly sealed screw-capped vial containing the reaction mixture was then heated at 85 °C. . The importance of amides has promoted the development of new protocols and reagents based on these approaches and alternative methods for amide bond formation [13,14,15,16]. Tetrahedron Lett 56:5341–5344, Shi M, Jiang J-K, Feng Y-S (2000) Titanium(IV) chloride and the amine-promoted Baylis–Hillman reaction. The calculated enantiomeric excess was for both enantiomers satisfactory. Correspondence to Donate or volunteer today! Benzoic acid (1 mmol) and a catalytic amount of TiCl4 (30 mol%) were treated with aniline (1 mmol) in refluxing dry dichloromethane. Diagram of the formation of amide. Prof. Steven Farmer (Sonoma State University). Watch the recordings here on Youtube! Solid (95%); mp = 66–69 °C; Rf = 0.68; 1H NMR (300 MHz, CDCl3) δ: 7.42–7.17 (m, 5H), 5.65 (sbroad, 1H), 3.55 (s, 2H), 3.22–3.07 (m, 2H), 1.58–1.31 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ: 171.0, 135.1, 129.4, 129.0, 127.3, 43.8, 41.3, 22.7, 11.2; GC/MS (EI) m/z (% rel. 1b). During the addition of TiCl4 to the carboxylic acid, the production of hydrochloric acid was observed. : DE2110060; Pub. AL designed research and analyzed data; JB performed research; ELB and AC did the spectral analyses, MG participated in writing and editing results, and AL proposed the subject and approved the final manuscript. Cite this article. ): 211 [M+∙] (49), 119 (11), 91(68), 93 (100), 77 (11), 65 (21). Solvents were purified according to well-known laboratory methods and freshly distilled prior to use.
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