Sulfated polyborate catalyzed enamines, enaminones synthesis via Methyl Ketones, Active Methylenes, and DMF-DMA activation: Application to Imatinib, Nilotinib intermediates †

Sulfated polyborate catalyzed enamines, enaminones synthesis via Methyl Ketones, Active Methylenes, and DMF-DMA activation: Application to Imatinib, Nilotinib intermediates † | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Sulfated polyborate catalyzed enamines, enaminones synthesis via Methyl Ketones, Active Methylenes, and DMF-DMA activation: Application to Imatinib, Nilotinib intermediates † Priyanka V. Bandivadekar, Kanchan D. Gavali, Ganesh U. Chaturbhuj This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1893656/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract An activation of methyl ketones or active methylenes and N,N -dimethylformamide dimethyl acetal (DMF-DMA) at 110 °C by sulfated polyborate under solvent-free conditions has been developed for enamines and enaminones synthesis. Selected Brønsted acid, optimized reaction conditions, and easy separation method lead to 82-97% yield, making this process cost-effective and eco-friendly. We chose boric acid for scale-up activity in the interest of readers and industries. The optimized reaction condition was applied to demonstrate a 10 gm scale-up for intermediate of Imatinib and Nilotinib with 80% yield from 3-acetylpyridine. This method is extendable to produce Ocinaplon intermediate using 4-acetyl pyridine as starting material. Enamine Enaminone Sulfated polyborate Imatinib Nilotinib Ocinaplon Figures Figure 1 Introduction Enaminones are a group of organic compounds that carry an amine group adjacent to a conjugation system of carbon linked with carbonyl carbon. Enamines are built with an amine next to an unsaturated carbon. 1-2 The preparation of enamines and enaminones from methyl ketone and active methylenes respectively with N,N -dimethylformamide diethyl (or methyl) acetal as a formylating agent was first reported by Meerwin et al. in 1961. 3 Several approaches for synthesizing heteroaromatics such as quinolines, dibenzodiazepines, pyridines, pyrazoles, and oxazoles utilizes enaminone and enamine as attractive scaffolds. 4-7 Enamines and enaminones have a vital role in synthesizing anti-obesity, anti-inflammatory, 8 anticonvulsant, 9 antibacterial, 10 antitumor, 11 as well as antileukemic drugs like Imatinib and Nilotinib. 12 Moreover, it has also been utilized for synthesizing 3-amino sugars, 13 azo compounds, 14 hexahydroazulenes, 15 β-amino ketones, 16 and indolizidine alkaloids. 17 (Figure 1) There are very limited reports in the literature for catalyst-promoted activation of carbonyl compounds and active methylenes to react with DMF-DMA. Kumar et al. reported L-proline as a catalyst for (2 E )-3-dimethylamino-2-proper-1-ones by activating methyl ketones or active methylenes and DMF-DMA. Acetic acid was reported as a catalyst during screening, but it was practically found to be ineffective and produced merely a 20% yield; which led the authors to conclude that Brönsted acid catalysis was unsuitable for enaminone synthesis. 18 Bindal et al. demonstrated 2-guanidino acetic acid as an organocatalyst to prepare enaminones ( Scheme 1a ). 19 However, contamination was probable from the cyclization of enaminone product with guanidine moiety of 2-guanidino acetic acid form amino pyrimidine ring similar to Imatinib synthesis. 20 The literature methods limited substrate scope as the products required flash chromatography for purification. 18,19 The most common approach to preparing enaminone was from the mixture of acetophenone and DMF-DMA reflux in toluene. 21 There was a broad scope to develop methods that circumvent isolation problems and broaden substrate choices. Reagents and conditions: (i) 10 mol% L -proline or guanidino acetic acid, Solvent-free, 100 °C, (ii) Sulfated polyborate, Solvent-free, 110 °C In a mission to develop greener synthetic methods, our research group synthesized eco-friendly, inexpensive catalysts. Sulfated polyborate from boric acid is a readily available, economical, non-toxic material, and was applied for various organic transformations. 22-44 We herein report the application of sulfated polyborate and other Brönsted acids as catalysts to synthesize enaminones and enamines of methyl ketones and active methylenes ( Scheme 1b ). It was believed that boric acid would be equally effective as a catalyst because sulfated polyborate was derived from it. After screening it during the acid selection study, boric acid was used for synthesizing the intermediate of Imatinib and Nilotinib at a 10 g scale for ready availability to readers and industries. Experimental All reactions were carried out under the fuming hood. The melting points of products were recorded with Analab Thermo Cal apparatus in an open capillary tube and uncorrected. Infrared spectra were recorded on Bruker FTIR-attenuated total reflectance (ATR) Spectrometer, USA. Solvents and chemicals were of LR grade, purchased from Avra Synthesis, Spectrochem, and SD fine chemicals, and used without purification. Starting material purity assessment and reaction monitoring were done by thin-layer chromatography (TLC) on Merck silica gel G F 254 plates. 1 H NMR spectra were recorded on MR400 Agilent Technology NMR spectrometer using CDCl 3 as a solvent. All the products are known compounds identified by 1 H NMR spectroscopy. General procedure for the synthesis of enaminone: To the mixture of acetophenone (0.5 g, 4.1 mmol), DMF-DMA (1.49 g, 12.4 mmol), was added sulfated polyborate (0.05 g, 10 wt%) and stirred in an oil bath preheated to 110 °C, monitored by TLC. Upon completion of the reaction, cooled to room temperature and evaporated to remove the unreacted DMF-DMA and methanol; the product was extracted by ethyl acetate (3 X 5 mL). The organic layer was dried over anhyd. sodium sulfate, condensed in a vacuum, and the solid obtained was recrystallized from hexanes: ethyl acetate (75:25). All the products were identified by 1 H NMR. Gram Scale procedure for ( E )-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one ; intermediate for the synthesis of Imatinib and Nilotinib: (Scheme 3) To a mixture of 3-acetyl pyridine (10 g, 82 mmol) and DMF-DMA (29.4 g, 247 mmol), added boric acid (0.51 g, 10 mol%) without solvent in an oil bath preheated to 110 °C for 50 minutes. The reaction was monitored by TLC. On completion, the unreacted DMF-DMA and methanol formed were recovered by distillation. The traces of DMF-DMA were removed under vacuum for 30 minutes to produce a solid product. The product was extracted with ethyl acetate (3 X 20 mL), and the organic layer was dried over anhyd. sodium sulfate, evaporated under vacuum to obtain 13.76 g, 94.58% of crude solid. After recrystallization from hexane: ethyl acetate (40:20), obtained 11.65 g, 80%, 3o as orange-red solid, m.p. 70-73 °C. Spectroscopic Data synthesized compounds: ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one (Table 4, entry 1): Yellow crystals, 97% yield, m.p. 81-84 °C (lit. 18 82-83 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 6.6 Hz, 2H), 7.80 (d, J = 12.4 Hz, 1H), 7.42 (dt, J = 14.1, 6.8 Hz, 3H), 5.72 (d, J = 12.4 Hz, 1H), 3.13 (s, 3H), 2.93 (s, 3H). (E)-1-(4-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one (Table 4, entry 2): White crystals, 95% yield, m.p. 75-80 °C (lit. 18 70-72 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (t, J = 11.0 Hz, 3H), 7.37 (d, J = 8.7 Hz, 2H), 5.66 (d, J = 12.4 Hz, 1H), 3.16 (s, 3H), 2.94 (s, 3H). (E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (Table 4, entry 3): Yellow crystals, 82.63% Yield, m.p. 81-83 °C (lit. 18 82-83 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (dd, J = 19.3, 10.4 Hz, 3H), 7.51 (d, J = 8.5 Hz, 2H), 5.63 (d, J = 12.3 Hz, 1H), 3.15 (s, 3H), 2.92 (s, 3H). (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (Table 4, entry 4): Yellow crystals. 88.65% yield, m.p. 80-83 °C (lit. 47 83-84 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 – 7.84 (m, 2H), 7.78 (d, J = 12.3 Hz, 1H), 7.05 (t, J = 8.7 Hz, 2H), 5.65 (d, J = 12.3 Hz, 1H), 3.02 (d, J = 75.7 Hz, 6H). (E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1- one(Table 4, entry 5): Orange crystals. 84% yield, m.p. 145-148 °C (lit. 47 148-149 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.28 (dd, J = 18.0, 8.4 Hz, 2H), 7.89 (d, J = 12.2 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 5.72 (d, J = 12.2 Hz, 1H), 3.10 (d, J = 87.3 Hz, 6H). (E)-3-(dimethylamino)-1-(p-tolyl)prop-2-en-1-one (Table 4, entry 6): Yellow solid, 87.9% yield, m.p. 88-89 °C (lit. 18 89-90 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (dd, J = 10.2, 6.2 Hz, 3H), 7.20 (d, J = 7.9 Hz, 2H), 5.71 (d, J = 12.4 Hz, 1H), 3.02 (d, J = 68.2 Hz, 6H), 2.38 (s, 3H). (E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (Table 4, entry 7): Yellow solid, 89.9% yield, m.p. 89-91 °C (lit. 47 90-91 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 12.4 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 5.70 (d, J = 17.2 Hz, 1H), 3.85 (s, 3H), 2.98 (s, 6H). (E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (Table 4, entry 8): Red-brown solid, 88.5% yield, m.p. 92-94 °C (lit. 3 90-91 °C). (E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one 2 (Table 4, entry 9): Red-brown thick liquid, 82.9% yield; 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 12.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 2H), 7.27 (d, J = 22.0 Hz, 2H), 6.97 (d, J = 11.6 Hz, 1H), 5.66 (d, J = 12.4 Hz, 1H), 3.82 (s, 3H), 2.99 (d, J = 85.9 Hz, 6H). (E)-3-(dimethylamino)-1-(naphthalen-1-yl)prop-2-en-1-one (Table 4, entry 10): Yellow thick oil,85.37% yield; 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 7.81 (s, 2H), 7.60 – 7.35 (m, 5H), 5.49 (d, J = 12.7 Hz, 1H), 2.92 (d, J = 67.1 Hz, 6H). (E)-3-(dimethylamino)-1-(naphthalen-2-yl)prop-2-en-1-one (Table 4, entry 11): Yellow solid, 98.22% yield, m.p. 106-109 °C (lit. 18 107-109 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.90 – 7.80 (m, 3H), 7.51 (d, J = 14.6 Hz, 2H), 5.86 (d, J = 12.3 Hz, 1H), 3.06 (d, J = 71.5 Hz, 6H). (E)-3-(dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one (Table 4, entry 12): Light brown solid, 98.85% yield. m.p. 116-118 °C (lit. 47 117-118 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 12.3 Hz, 1H), 7.60 (d, J = 3.7 Hz, 1H), 7.45 (d, J = 5.0 Hz, 1H), 7.09 – 7.01 (m, 1H), 5.60 (d, J = 12.3 Hz, 1H), 3.00 (d, J = 76.1 Hz, 6H). (E)-1-(5-bromothiophen-2-yl)-3-(dimethylamino)prop-2-en-1-one (Table 4, entry 13): Light brown solid, 86.71% yield, m.p. 112 °C (lit. 49 114 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 12.2 Hz, 1H), 7.35 (d, J = 3.9 Hz, 1H), 7.03 (d, J = 3.9 Hz, 1H), 5.50 (d, J = 12.3 Hz, 1H), 3.15 (s, 3H), 2.92 (s, 3H). (E)-3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (Table 4, entry 14): Yellow solid, 93.3% yield, m.p. 79-80 °C (lit. 47 80-81 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 12.5 Hz, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.46 (s, 1H), 5.67 (d, J = 12.5 Hz, 1H), 3.02 (d, J = 85.6 Hz, 6H). ( E )-3-(dimethylamino)-1-(1 H -pyrrol-2-yl)prop-2-en-1-one (Table 4, entry 15): Light brown solid, 74.66% yield; m.p. 93-95 °C ( lit. 18 94 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 9.85 (s, 1H), 7.73 (d, J = 12.5 Hz, 1H), 6.93 (td, J = 2.6, 1.4 Hz, 1H), 6.76 (dd, J = 3.6, 2.4, 1.3 Hz, 1H), 6.23 (dt, J = 3.6, 2.5 Hz, 1H), 5.57 (d, J = 12.5 Hz, 1H), 2.99 (s, 6H). (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (Table 4, entry 16): Yellow solid, 82.5% yield; m.p. 73-75 °C (lit. 18 71-73 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.19 (dd, J = 7.9, 1.8 Hz, 1H), 7.84 (d, J = 12.2 Hz, 1H), 7.35 (dd, J = 7.9, 4.8 Hz, 1H), 5.67 (d, J = 12.3 Hz, 1H), 3.18 (s, 3H), 2.95 (s, 3H). (E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (Table 4, entry 17): Yellow red solid, 80.6% yield; m.p. 114-116 °C (lit. 18 115-117 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (d, J = 6.0 Hz, 2H), 7.83 (d, J = 12.3 Hz, 1H), 7.67 (d, J = 6.0 Hz, 2H), 5.64 (d, J = 12.3 Hz, 1H), 3.18 (s, 3H), 2.94 (s, 3H). (1E,4E)-1-(dimethylamino)-5-phenylpenta-1,4-dien-3-one (Table 4, entry 18): Brown solid and after recrystallization with ethyl acetate: hexane (2:10) given yellow solid, 94% yield, m.p. 95-100 °C (lit. 47 99-100 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 12.5 Hz, 1H), 7.52 (dd, J = 5.7, 2.1 Hz, 3H), 7.37 – 7.26 (m, 3H), 6.77 (d, J = 15.8 Hz, 1H), 5.25 (d, J = 12.5 Hz, 1H), 2.99 (d, J = 87.2 Hz, 6H). (E)-2-((dimethylamino)methylene)-2,3-dihydro-1H-inden-1-one (Table 4, entry 19): Light brown solid, 95.3% yield; m.p. 159-161 °C (lit. 48 159-161 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.41 (s, 1H), 3.90 (s, 2H), 3.19 (s, 6H). (E)-3-(dimethylamino)-2-phenylacrylonitrile (Table 4, entry 20): White solid, 95% yield, m.p.73-76 °C (lit. 50 73-75 °C); FTIR 2181 and 1616 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 – 7.25 (m, 4H), 7.12 (t, J = 8.4 Hz, 1H), 6.89 (s, 1H), 3.22 (s, 6H). ethyl (E)-2-cyano-3-(dimethylamino)acrylate (Table 4, entry 21): White solid, 90% yield, m.p. 72-74 °C (lit. 51 72 °C); FTIR 2196, 1689, 1615 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 4.24 (s, 2H), 3.38 (s, 3H), 3.20 (s, 3H), 1.32 (s, 3H). ethyl (E)-2-((dimethylamino)methylene)-3-oxobutanoate (Table 4, entry 22): Orange liquid, 90% yield, 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.04 (s, 6H), 2.33 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). diethyl 2-((dimethylamino)methylene)malonate (Table 4, entry 23): colorless liquid, yield 95%, 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (s, 1H), 4.19 (dd, J = 29.8, 7.0 Hz, 4H), 2.97 (d, J = 16.3 Hz, 6H), 1.35 – 1.20 (m, 6H).; residual solvent impurities 8.00 (s, 0.5H), (CH, DMF), 2.95 and 2.87 (s, 1H), (CH 3, DMF). Results And Discussion Initially, the experiment was performed on a mixture of acetophenone and DMF-DMA in a 1: 1.5 mole ratio under solvent-free conditions at 110 °C without a catalyst for 16 hours to prepare standard ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one and understand the reaction rate. After complete conversion, the reaction mixture was concentrated in a vacuum to remove the excess DMF-DMA and methanol to get a crude solid. The crude was purified by recrystallization from a mixture of hexanes: ethyl acetate (75:25) to obtain 97% ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one as yellow crystals (Table 1, entry 1), confirmed by m.p. and 1 H NMR. 46 Thereafter, experiments were planned to study the suitability of different Brønsted acids as catalysts to synthesize ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one by the reaction of acetophenone with DMF-DMA in 1:3 molar ratio under the solvent-free condition at 110 °C. Table 1. Selection of Brönsted acids for the synthesis of ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one Entry Acid Amount Time Yield (%) HCl b 10 mol% (0.042 g) 4 h 10 min. 75 H 2 SO 4 c 10 mol% (0.040 g) 2 h 10 min. 90 p -TSA 10 mol% (0.078 g) 2 h 30 min. 91 N -(phenylsulfonyl) benzenesulfonamide 10 mol% (0.12 g) 4 h 11 min. 95 B(OH) 3 10 mol% (0.025 g) 1 h 30 min. 90 Sulfated polyborate 10 wt% (0.05 g) 1 h 20 min. 97 a Reaction condition: Acetophenone (0.5 g, 4 mmol), DMF-DMA (1.49 g, 12 mmol), and acid catalyst, b 35% w/w, c 98% w/w, 110 °C. Here, the commercially available Brönsted acids such as HCl, H 2 SO 4 , p -toluene sulfonic acid ( p -TSA), N -(phenylsulfonyl)benzenesulfonamide, boric acid, and in-house developed sulfated polyborate were screened during the catalyst selection study. It was revealed that H 2 SO 4 and p -TSA showed 90% and 91% yield respectively, which was better than HCl. The product was extracted in ethyl acetate, washed with sodium bicarbonate to remove acid catalysts, and the organic layer was evaporated to obtain solid products. (Table 1, entries 1-3). It was observed that the reaction darkened in strong acids like HCl and H 2 SO 4 might be due to degradation. N -(phenylsulfonyl)benzenesulfonamide and boric acid were seen as effective as sulfated polyborate to obtain a 90-95% yield. (Table 1, entries 4-6)., Sulfated polyborate, however, produced better results in terms of time and yield. For further investigation, water-soluble sulfated polyborate was selected as the optimum acid over organocatalysts like p -TSA and N -(phenylsulfonyl)benzenesulfonamide to avoid the problem associated with their separation. After foresaid selection of suitable acid, we decided to evaluate the effect of acetophenone: DMF-DMA molar ratio, catalyst loading, and temperature on the synthesis of ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one using sulfated polyborate as a catalyst. To examine temperature effect and mole ratio on time and yield, a reaction of acetophenone to DMF-DMA in 1:1.5 mole ratio at 70 °C and 100 °C with 10 wt% sulfated polyborate under solvent-free conditions was performed. Owing to insufficient DMF-DMA, the reaction showed incomplete conversion, and the product had to recrystallize to obtain 60 and 80% yield (Table 2, entries 2, 3). Further reactions were performed at 1:2.5 and 1:3 mole ratios with 10 wt% sulfated polyborate at 100 °C, completed in 2 hours, resulting in 80 and 90% yield, respectively (Table 2, entries 4, 5). To ascertain the temperature effect at a 1:3 mole ratio of acetophenone to DMF-DMA, a reaction was performed at 110 °C with 10 wt% sulfated polyborate, which yielded 97% product in 1 hour 20 minutes (Table 2, entry 8). Table 2. Effect of molar ratio, catalyst loading, and temperature on the synthesis of ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one a Entry Catalyst (wt%) Acetophenone: DMF-DMA Temp. (°C) Time Yield (%) 0 1:1.5 110 16 h 97% 10 1:1.5 70 6 h 60% 10 1:1.5 100 4 h 80% 10 1:2.5 100 2 h 80% 10 1:3 100 2 h 90% 5 1:3 110 7 h 15 min. 85% 7.5 1:3 110 1 h 40 min. 88% 10 1:3 110 1 h 20 min. 97% 15 1:3 110 1 h 30 min. 88% 20 1:3 110 1 h 40 min. 95% a Reaction conditions: Acetophenone (0.5 g, 4 mmol), DMF-DMA, and Sulfated polyborate Temperature played a vital role in enhancing the yield of ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one to 97% (Table 1, entries 5, 8). The sulfated polyborate loading was screened at 5, 7.5, 15, and 20 wt%; increasing the catalyst loading resulted in increased product yield in a shorter reaction time, but this effect stalled at 10 wt% and any further increase in sulfated polyborate loading was ineffective. (Table 2, entries 6-10). The effect of solvents like ethanol, toluene, DMSO, and DMF was ascertained with 10 wt% sulfated polyborate. Solvent-free condition at 110 °C resulted in 97% yield (Table 3, entry 1), and ethanol gave 20% yield with difficulty in isolation (Table 3, entry 2). DMF and toluene resulted in 60% and 70% yield, respectively, with an extended reaction time of 2.5 and 5 h, respectively (Table 3, entries 3, 4). Reaction in DMSO produced 92% yield in 1 hour 10 minutes was the best amongst the solvents used (Table 3, entry 5). However, the solvent-free condition was selected due to its better reaction performance and being economical and environment friendly. (Table 3, entries 1-6). Substrate scope The optimized solvent-free condition with 10 wt% sulfated polyborate at 110 °C was applied to various aromatic, heteroaromatic, alicyclic methyl ketones, and active methylenes to demonstrate the substrate scope (Table 4). Notably, acetophenone resulted in a 97% yield (Table 4, entry 1), while halogenated acetophenones were smoothly converted to the products in moderate to high yields (Table 4 entries 2-4). Electron-deficient 3-nitro acetophenone produced 84% yield in a short period (Table 4, entry 5). The electron-rich substrate like 4-methyl gives 88% yield. Heterocyclic ketones (2-acetyl thiophene, 2-acetyl furan, 3-acetylpyridine, 4-acetylpyridine) were appropriate for enaminone preparation to obtain 95-86% yield (Table 4, entries 9-18). Various active methylenes were also attempted, taking a shorter reaction time than methyl ketones. Active methylenes like benzyl cyanide, ethyl cyanoacetate, and β-ketoester ethyl acetoacetate reaction completed in reasonable time with excellent yield (Table 4, entries 19-23) while diester, diethyl malonate as an exception took a longer reaction time (Table 4, entry 23). Liquid products (Table 4, entries 10, 22, 23) were isolated by water quenching, and ethyl acetate extraction after excess DMF-DMA and methanol were removed under vacuum. During the aqueous quenching, the presence of the acid catalyst led to the formation of DMF from the traces of DMF-DMA. This DMF gets carried ahead during ethyl acetate extraction and causes a hindrance in obtaining NMR pure compounds. Table 3. Effect of the solvents for synthesizing ( E )-3-(dimethylamino)-1-phenylprop-2-en-1-one. a Entry Solvent Temp. (°C) Time Yield (%) Solvent-free 110 1 h 20 min. 97 EtOH reflux 2 h 40 min. 20 DMF 110 2 h 30 min. 60 Toluene 110 5 h 70 DMSO 110 1 h 10 min. 92 a Reaction condition: Acetophenone (0.5 g, 4 mmol), DMF-DMA (1.49 g, 12 mmol ), and Sulfated polyborate (0.050 g, 10 wt%). The products were co-distilled with toluene (3 X 5 ml) under vacuum, followed by chloroform (5 X 5 ml) to remove traces of DMF. Electron-rich 4’-methoxy acetophenone was smoothly converted to enaminone (Table 4, entry 7) within 3 hours and 40 minutes. We were keen to use other electron-rich acetophenones, viz. 3- and 4-hydroxy acetophenones. To our surprise, the reaction of 4’-hydroxy acetophenone with DMF-DMA initially in a 1:3 mole ratio showed multiple products. During TLC investigation of the reaction mixture in comparison with ( E )-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one, it was observed that sulfated polyborate not only activates DMF-DMA for enaminone formation but also methylating 45 hydroxy group of 4-hydroxy acetophenone leads to unreacted 4-hydroxy acetophenone along with its enaminone. Out of curiosity, the reaction was continued; with additional 3 equivalents of DMF-DMA, all the multiple products were converted to ( E )-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one in 4 hours 10 minutes (Section 1.0 and Figure 1, Supporting information). A similar result was observed for 3-hydroxy acetophenone at a 1:6 mole ratio with DMF-DMA to produce ( E )-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one within 2 hours ( Scheme 2 ). Owing to the substrate scope, we were keen on scaling up Imatinib and Nilotinib intermediates. During substrate study, 3-acetyl pyridine was converted successfully to ( E )-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one, using sulfated polyborate in 82.5% yield in 40 minutes at a small scale of 0.5 g, 2.9 mmol. Based on the acid selection study, boric acid showed comparable results in converting acetophenone to its enaminone (Table 1, entry 5). As sulfated polyborate is an in-house developed catalyst, we chose boric acid for scale-up activity in the interest of readers and industries. The developed protocol to prepare ( E )-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one utilized boric acid as an eco-friendly and cost-effective catalyst. ( Scheme 3 ). The reaction of 10g 3-acetyl pyridine and 3 equivalents of DMF-DMA with 10 mole% boric acid at 110 °C was performed. The reaction color turned from yellow to orange and complete conversion on TLC was observed within 50 minutes. The excess DMF-DMA and methanol formed were recovered by downward distillation at atmospheric pressure and traces under vacuum, giving a crude red-brown solid. The crude product was recrystallized using a mixture of hexanes: ethyl acetate (40:20) to obtain ( E )-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one as orange-red solid, in 80% yield, confirmed by melting point. The plausible reaction mechanism is depicted in Scheme 4 . Presumably, sulfated polyborate acts as a hydrogen bond-donor to activate the carbonyl group of ketones to form an enolate ion [C]. The enolate ion [C] converts to enol [E]. Simultaneously, it may have protonated the DMF-DMA to eliminate the methoxy group and generate an iminium ion [F]. Consequently, the enol [E] might have instantly attacked iminium ion [F] followed by the elimination of methanol, leading to the formation of enaminone [H]. Conclusion In conclusion, the current method proved that Brönsted acids catalytically activate methyl ketones or active methylenes and DMF-DMA to synthesize enamines and enaminones under solvent-free conditions. Best results were obtained with sulfated polyborate and boric acid. The method was applied to various aromatic, bicyclic, heteroaromatic, alicyclic methyl ketones, and active methylenes wherein the reaction times ranged from 10 minutes to 3 h 40 minutes, with good to excellent yields. The developed method was successfully applied for the scale-up to 10 g intermediate for Nilotinib and Imatinib, using boric acid as a commercially available and eco-friendly catalyst. The technique was extendable to Ocinaplon intermediate using 4-acetyl pyridine with necessary optimization. Declarations Acknowledgment: The authors are grateful for generous funding from the All India Council for Technical Education (DIPSAR/AICTE/QIP/Nodal/2019-20/43/Ph.D./20), New Delhi, and Council for Scientific and Industrial Research (09/991(0062)/2020-EMR-I). Notes: †Indian Patent Application No. 202121059848 A, Date of Application filing Dec. 21, 2021. Ethical Approval Not Applicable. Competing interests The authors declare no competing financial interest. Authors' contributions Priyanka V. Bandivadekar did the experiments and wrote the manuscript. Kanchan D. Gavali did experiments and prepared supplementary information. Ganesh U. Chaturbhuj conceptualized the work and monitored the process at each stage. Funding All India Council for Technical Education (DIPSAR/AICTE/QIP/Nodal/2019-20/43/Ph.D./20), New Delhi, and Council for Scientific and Industrial Research (09/991(0062)/2020-EMR-I). Availability of data and materials Not applicable. References Greenhill, J. V. Chem. Soc. 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Ganwir G.; Jaydeokar S; Chaturbhuj G U. Results Chem. 2022, 4 , 100293. Patil, N. B., and Chaturbhuj, G. U. Sulfated polyborate catalyzed rapid and efficient electrophilic thiocyanate of activated arenes. Tetrahedron Lett., 2022, 96 , 153763. Belov, P.; Campanella, V. L.; Smith, A. W.; Priefer, R. Tetrahedron Lett. 2011, 52 , 2776–2779. Zhang, Ni. M.; Liang, J., X.; Jiang, Y.; Loh, T. P. Chem. Commun. 2017, 53 , 12286–12289. Zhang, Ni. M.; Liang, J., X.; Jiang, Y.; Loh, T. P. Chem. Comm. 2017, 53 , 12286–12289. Philip D. H.; Geroge M. M. 1972, United States Patent. RamaRao, R. J.; Rao, A. K. S.; Sreenivas, N.; Kumar, B. S.; Murthy, Y. L. N. J. Korean Chem. Soc. 2011, 55 , 243–250. Gupton, J.T.; Crawford, E.; Mahoney, M.; Clark, E.; Curry, W.; Lane, A.; Shimozono, A.; Moore-Stoll, V.; Elofson, K.; Juekun, W.; Newton, M. Tetrahedron 2018, 74, 7408–7420. Gupton, J. T.; Lizzi, M. J.; Polk, D. Synth. Commun. 1982, 12 , 939–946. Tables Table 4 is available in the Supplemental Files section. Scheme Scheme 1-4 are available in supplementary section. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Table4.docx Scheme01.png Reagents and conditions: (i) 10 mol% L -proline or guanidino acetic acid, Solvent-free, 100 °C, (ii) Sulfated polyborate, Solvent-free, 110 °CScheme 1: Synthesis of enaminones and enamines Scheme02.png Scheme 2: Unexpected reaction of 3- and 4-hydroxy acetophenone with DMF-DMA Scheme03.png Scheme 3 Development of ( E )-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one as intermediate for Imatinib and Nilotinib synthesis Scheme04.png Scheme 4. Plausible reaction mechanism Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1893656","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":124318680,"identity":"635f0b84-f7b9-4567-81b4-a85ce3f1de52","order_by":0,"name":"Priyanka V. Bandivadekar","email":"","orcid":"","institution":"Institute of Chemical Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Priyanka","middleName":"V.","lastName":"Bandivadekar","suffix":""},{"id":124318684,"identity":"e47d7f57-e5da-43fa-be54-cb326e3a8dce","order_by":1,"name":"Kanchan D. 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Chaturbhuj","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYJACZjApwQPEFSAucwMxWgygWs6AuIykaGFsA/EJaJGPSGD8XFDzJ3H77N5jEpbzaqP524FaflRsw6nF8EYCs/SMYwaJc+6cS5OQ3HY8d8ZhxgbGnjO3cWuZkcDGzMNmkDhDIscMqOVYbgNQCzNjGyEt/2Ba5hzLnU9Ii7wEUAtvG0xLQ03uBkJaDHgeNkvz9hkbz5A5Y2whcexA7kagloP4/CLfnnzwM883OdkZ0j2GtyVq6nLnnT988MGPCjy2HECKBWYJhsNgxgGc6kG2NCBxGD8w1OFTPApGwSgYBSMUAADJglTY0BF8CAAAAABJRU5ErkJggg==","orcid":"","institution":"Institute of Chemical Technology","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ganesh","middleName":"U.","lastName":"Chaturbhuj","suffix":""}],"badges":[],"createdAt":"2022-07-25 11:44:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1893656/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1893656/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":24617730,"identity":"8c1ac41a-4855-41bc-bb87-c5e6055c001e","added_by":"auto","created_at":"2022-08-01 18:04:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59797,"visible":true,"origin":"","legend":"\u003cp\u003eEnaminone as a building block for the synthesis of heteroaromatics and therapeutic agents\u003c/p\u003e","description":"","filename":"Fig01.png","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/f50a7a4602ea7a21363b6a68.png"},{"id":24691164,"identity":"68812435-0691-47f2-b6d1-0b96a04957ba","added_by":"auto","created_at":"2022-08-03 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18:09:05","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":230462,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/1decdce971b7ab14e9fc2dd7.docx"},{"id":24617734,"identity":"7b5a5031-029c-4e2c-bdb9-92b95bacf93e","added_by":"auto","created_at":"2022-08-01 18:04:05","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":7886,"visible":true,"origin":"","legend":"\u003cp\u003eReagents and conditions: (i) 10 mol% \u003cem\u003eL\u003c/em\u003e-proline or guanidino acetic acid, Solvent-free, 100 °C, (ii) Sulfated polyborate, Solvent-free, 110 °C\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eScheme 1:\u003c/strong\u003e Synthesis of enaminones and enamines\u003c/p\u003e","description":"","filename":"Scheme01.png","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/1ba025388e225c332153d025.png"},{"id":24618771,"identity":"dbb4ef8d-d5dc-40da-b430-f411c1c28a9e","added_by":"auto","created_at":"2022-08-01 18:14:04","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17466,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2\u003c/strong\u003e: Unexpected reaction of 3- and 4-hydroxy acetophenone with DMF-DMA\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Scheme02.png","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/833769219e0930216b410417.png"},{"id":24618289,"identity":"11624587-ca6d-46cb-b51a-63dd6dee2a7b","added_by":"auto","created_at":"2022-08-01 18:09:04","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":19842,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3\u003c/strong\u003e Development of (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one as intermediate for Imatinib and Nilotinib synthesis\u003c/p\u003e","description":"","filename":"Scheme03.png","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/f6273673bf76b80973657f75.png"},{"id":24619591,"identity":"db678e8e-6fce-46f7-a623-d7a8a491e282","added_by":"auto","created_at":"2022-08-01 18:19:04","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":24226,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 4.\u003c/strong\u003e Plausible reaction mechanism\u003c/p\u003e","description":"","filename":"Scheme04.png","url":"https://assets-eu.researchsquare.com/files/rs-1893656/v1/f36d71f983be0971f71bd39c.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Sulfated polyborate catalyzed enamines, enaminones synthesis via Methyl Ketones, Active Methylenes, and DMF-DMA activation: Application to Imatinib, Nilotinib intermediates †","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEnaminones are a group of organic compounds that carry an amine group adjacent to a conjugation system of carbon linked with carbonyl carbon. Enamines are built with an amine next to an unsaturated carbon.\u003csup\u003e1-2\u003c/sup\u003e The preparation of enamines and enaminones from methyl ketone and active methylenes respectively with \u003cem\u003eN,N\u003c/em\u003e-dimethylformamide diethyl (or methyl) acetal as a formylating agent was first reported by Meerwin \u003cem\u003eet al.\u003c/em\u003e in 1961.\u003csup\u003e3\u003c/sup\u003e Several approaches for synthesizing heteroaromatics such as quinolines, dibenzodiazepines, pyridines, pyrazoles, and oxazoles utilizes enaminone and enamine as attractive scaffolds.\u003csup\u003e4-7\u003c/sup\u003e Enamines and enaminones have a vital role in synthesizing anti-obesity, anti-inflammatory,\u003csup\u003e8\u003c/sup\u003e anticonvulsant,\u003csup\u003e9\u003c/sup\u003e antibacterial,\u003csup\u003e10\u003c/sup\u003e antitumor,\u003csup\u003e11\u003c/sup\u003e as well as antileukemic drugs like Imatinib and Nilotinib.\u003csup\u003e12\u003c/sup\u003e\u0026nbsp; Moreover, it has also been utilized for synthesizing 3-amino sugars,\u003csup\u003e13\u003c/sup\u003e azo compounds,\u003csup\u003e14\u0026nbsp;\u003c/sup\u003ehexahydroazulenes,\u003csup\u003e15\u003c/sup\u003e \u0026beta;-amino ketones,\u003csup\u003e16\u003c/sup\u003e and indolizidine alkaloids.\u003csup\u003e17\u003c/sup\u003e (Figure 1)\u003c/p\u003e\n\u003cp\u003eThere are very limited reports in the literature for catalyst-promoted activation of carbonyl compounds and active methylenes to react with DMF-DMA. Kumar \u003cem\u003eet al.\u003c/em\u003e reported L-proline as a catalyst for (2\u003cem\u003eE\u003c/em\u003e)-3-dimethylamino-2-proper-1-ones by activating methyl ketones or active methylenes and DMF-DMA. Acetic acid was reported as a catalyst during screening, but it was practically found to be ineffective and produced merely a 20% yield; which led the authors to conclude that Br\u0026ouml;nsted acid catalysis was unsuitable for enaminone synthesis.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eBindal \u003cem\u003eet al.\u003c/em\u003e demonstrated 2-guanidino acetic acid as an organocatalyst to prepare enaminones (\u003cstrong\u003eScheme 1a\u003c/strong\u003e).\u003csup\u003e19\u003c/sup\u003e However, contamination was probable from the cyclization of enaminone product with guanidine moiety of 2-guanidino acetic acid form amino pyrimidine ring similar to Imatinib synthesis.\u003csup\u003e20\u003c/sup\u003e The literature methods limited substrate scope as the products required flash chromatography for purification.\u003csup\u003e18,19\u003c/sup\u003e The most common approach to preparing enaminone was from the mixture of acetophenone and DMF-DMA reflux in toluene.\u003csup\u003e21\u0026nbsp;\u003c/sup\u003e There was a broad scope to develop methods that circumvent isolation problems and broaden substrate choices.\u003c/p\u003e\n\u003cp\u003eReagents and conditions: (i) 10 mol% \u003cem\u003eL\u003c/em\u003e-proline or guanidino acetic acid, Solvent-free, 100 \u0026deg;C, (ii) Sulfated polyborate, Solvent-free, 110 \u0026deg;C\u003c/p\u003e\n\u003cp\u003eIn a mission to develop greener synthetic methods, our research group synthesized eco-friendly, inexpensive catalysts. Sulfated polyborate from boric acid is a readily available, economical, non-toxic material, and was applied for various organic transformations.\u003csup\u003e22-44\u003c/sup\u003e We herein report the application of sulfated polyborate and other Br\u0026ouml;nsted acids as catalysts to synthesize enaminones and enamines of methyl ketones and active methylenes (\u003cstrong\u003eScheme 1b\u003c/strong\u003e). It was believed that boric acid would be equally effective as a catalyst because sulfated polyborate was derived from it. After screening it during the acid selection study, boric acid was used for synthesizing the intermediate of Imatinib and Nilotinib at a 10 g scale for ready availability to readers and industries. \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Experimental","content":"\u003cp class=\"TESupportingInformation\"\u003eAll reactions were carried out under the fuming hood. The melting points of products were recorded with Analab Thermo Cal apparatus in an open capillary tube and uncorrected. Infrared spectra were recorded on Bruker FTIR-attenuated total reflectance (ATR)\u0026nbsp;Spectrometer, USA. Solvents and chemicals were of LR grade, purchased from Avra Synthesis, Spectrochem, and SD fine chemicals, and used without purification. Starting material purity assessment and reaction monitoring were done by thin-layer chromatography (TLC) on Merck silica gel G F\u003csub\u003e254\u0026nbsp;\u003c/sub\u003eplates. \u003csup\u003e1\u003c/sup\u003eH NMR spectra were recorded on MR400 Agilent Technology NMR spectrometer using CDCl\u003csub\u003e3\u003c/sub\u003e as a solvent. All the products are known compounds identified by \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy.\u003c/p\u003e\n\u003cp class=\"TESupportingInfoTitle\"\u003eGeneral procedure for the synthesis of enaminone:\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003eTo the mixture of acetophenone (0.5 g, 4.1 mmol), DMF-DMA (1.49 g, 12.4 mmol), was added sulfated polyborate (0.05 g, 10 wt%) and stirred in an oil bath preheated to 110 \u0026deg;C, monitored by TLC. Upon completion of the reaction, cooled to room temperature and evaporated to remove the unreacted DMF-DMA and methanol; the product was extracted by ethyl acetate (3 X 5 mL). The organic layer was dried over anhyd. sodium sulfate, condensed in a vacuum, and the solid obtained was recrystallized from hexanes: ethyl acetate (75:25). All the products were identified by \u003csup\u003e1\u003c/sup\u003eH NMR.\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cstrong\u003eGram Scale procedure for (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one\u003cem\u003e;\u0026nbsp;\u003c/em\u003eintermediate for the synthesis of Imatinib and Nilotinib: (Scheme 3)\u003c/strong\u003e\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003eTo a mixture of 3-acetyl pyridine (10 g, 82 mmol) and DMF-DMA (29.4 g, 247 mmol), added boric acid (0.51 g, 10 mol%) without solvent in an oil bath preheated to 110 \u0026deg;C for 50 minutes. The reaction was monitored by TLC. On completion, the unreacted DMF-DMA and methanol formed were recovered by distillation. The traces of DMF-DMA were removed under vacuum for 30 minutes to produce a solid product. The product was extracted with ethyl acetate (3 X 20 mL), and the organic layer was dried over anhyd. sodium sulfate, evaporated under vacuum to obtain 13.76 g, 94.58% of crude solid. After recrystallization from hexane: ethyl acetate (40:20), obtained 11.65 g, 80%, 3o as orange-red solid, m.p. 70-73 \u0026deg;C.\u0026nbsp;\u003c/p\u003e\n\u003cp class=\"MsoNormal\"\u003e\u003cstrong\u003eSpectroscopic Data\u003c/strong\u003e\u003cstrong\u003esynthesized compounds:\u003c/strong\u003e\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e(\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one (Table 4, entry 1): Yellow crystals, 97% yield, m.p. 81-84 \u0026deg;C (lit.\u003csup\u003e18\u0026nbsp;\u003c/sup\u003e82-83 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.89 (d, \u003cem\u003eJ\u0026nbsp;\u003c/em\u003e= 6.6 Hz, 2H), 7.80 (d, \u003cem\u003eJ\u003c/em\u003e = 12.4 Hz, 1H), 7.42 (dt, \u003cem\u003eJ\u0026nbsp;\u003c/em\u003e= 14.1, 6.8 Hz, 3H), 5.72 (d, \u003cem\u003eJ\u0026nbsp;\u003c/em\u003e= 12.4 Hz, 1H), 3.13 (s, 3H), 2.93 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-1-(4-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 2): White crystals, 95% yield, \u0026nbsp;m.p. 75-80 \u0026deg;C (lit.\u003csup\u003e18\u0026nbsp;\u003c/sup\u003e70-72 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.82 (t, \u003cem\u003eJ\u003c/em\u003e = 11.0 Hz, 3H), 7.37 (d, \u003cem\u003eJ\u003c/em\u003e = 8.7 Hz, 2H), 5.66 (d, \u003cem\u003eJ\u003c/em\u003e = 12.4 Hz, 1H), 3.16 (s, 3H), 2.94 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 3): Yellow crystals, 82.63% Yield, m.p. 81-83 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e18\u003c/sup\u003e 82-83 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.77 (dd, \u003cem\u003eJ\u003c/em\u003e = 19.3, 10.4 Hz, 3H), 7.51 (d, \u003cem\u003eJ\u003c/em\u003e = 8.5 Hz, 2H), 5.63 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.15 (s, 3H), 2.92 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 4): Yellow crystals. 88.65% yield, m.p. 80-83 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e47\u003c/sup\u003e 83-84 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.96 \u0026ndash; 7.84 (m, 2H), 7.78 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 7.05 (t, \u003cem\u003eJ\u003c/em\u003e = 8.7 Hz, 2H), 5.65 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.02 (d, \u003cem\u003eJ\u003c/em\u003e = 75.7 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-\u003c/em\u003eone(Table 4, entry 5): Orange crystals. 84% yield, m.p. 145-148 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e47\u003c/sup\u003e148-149 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 8.70 (s, 1H), 8.28 (dd, \u003cem\u003eJ\u003c/em\u003e = 18.0, 8.4 Hz, 2H), 7.89 (d, \u003cem\u003eJ\u003c/em\u003e = 12.2 Hz, 1H), 7.60 (t, \u003cem\u003eJ\u003c/em\u003e = 7.9 Hz, 1H), 5.72 (d, \u003cem\u003eJ\u003c/em\u003e = 12.2 Hz, 1H), 3.10 (d, \u003cem\u003eJ\u003c/em\u003e = 87.3 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(p-tolyl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 6): Yellow solid, 87.9% yield, m.p. 88-89 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e18\u003c/sup\u003e 89-90 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.79 (dd, \u003cem\u003eJ\u003c/em\u003e = 10.2, 6.2 Hz, 3H), 7.20 (d, \u003cem\u003eJ\u003c/em\u003e = 7.9 Hz, 2H), 5.71 (d, \u003cem\u003eJ\u003c/em\u003e = 12.4 Hz, 1H), 3.02 (d, \u003cem\u003eJ\u003c/em\u003e = 68.2 Hz, 6H), 2.38 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 7): Yellow solid, 89.9% yield, m.p. 89-91 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e47\u0026nbsp;\u003c/sup\u003e90-91 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.90 (d, \u003cem\u003eJ\u003c/em\u003e = 8.9 Hz, 2H), 7.78 (d,\u003cem\u003e\u0026nbsp;J\u003c/em\u003e = 12.4 Hz, 1H), 6.91 (d, \u003cem\u003eJ\u003c/em\u003e = 8.9 Hz, 2H), 5.70 (d, \u003cem\u003eJ\u003c/em\u003e = 17.2 Hz, 1H), 3.85 (s, 3H), 2.98 (s, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 8): \u0026nbsp; Red-brown solid, 88.5% yield, m.p. 92-94 \u0026deg;C (lit.\u003csup\u003e3\u0026nbsp;\u003c/sup\u003e90-91 \u0026deg;C).\u0026nbsp;\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e(Table 4, entry 9): Red-brown thick liquid, 82.9% yield; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.77 (d, \u003cem\u003eJ\u003c/em\u003e = 12.4 Hz, 1H), 7.43 (d, \u003cem\u003eJ\u003c/em\u003e = 2.4 Hz, 2H), 7.27 (d, \u003cem\u003eJ\u003c/em\u003e = 22.0 Hz, 2H), 6.97 (d, \u003cem\u003eJ\u003c/em\u003e = 11.6 Hz, 1H), 5.66 (d, \u003cem\u003eJ\u003c/em\u003e = 12.4 Hz, 1H), 3.82 (s, 3H), 2.99 (d, \u003cem\u003eJ\u003c/em\u003e = 85.9 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(naphthalen-1-yl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 10): Yellow thick oil,85.37% yield; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 8.22 (s, 1H), 7.81 (s, 2H), 7.60 \u0026ndash; 7.35 (m, 5H), 5.49 (d, \u003cem\u003eJ\u003c/em\u003e = 12.7 Hz, 1H), 2.92 (d, \u003cem\u003eJ\u003c/em\u003e = 67.1 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(naphthalen-2-yl)prop-2-en-1-one\u003c/em\u003e(Table 4, entry 11): Yellow solid, 98.22% yield, m.p. 106-109 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e18\u003c/sup\u003e 107-109 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 8.37 (s, 1H), 7.99 (d, \u003cem\u003eJ\u003c/em\u003e = 8.5 Hz, 1H), 7.92 (d, \u003cem\u003eJ\u003c/em\u003e = 8.8 Hz, 1H), 7.90 \u0026ndash; 7.80 (m, 3H), 7.51 (d, \u003cem\u003eJ\u003c/em\u003e = 14.6 Hz, 2H), 5.86 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.06 (d, \u003cem\u003eJ\u003c/em\u003e = 71.5 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one\u003c/em\u003e (Table 4, entry 12): Light brown solid, 98.85% yield. m.p. 116-118 \u0026deg;C (lit.\u003csup\u003e47\u0026nbsp;\u003c/sup\u003e117-118 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.77 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 7.60 (d, \u003cem\u003eJ\u003c/em\u003e = 3.7 Hz, 1H), 7.45 (d, \u003cem\u003eJ\u003c/em\u003e = 5.0 Hz, 1H), 7.09 \u0026ndash; 7.01 (m, 1H), 5.60 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.00 (d, \u003cem\u003eJ\u003c/em\u003e = 76.1 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-1-(5-bromothiophen-2-yl)-3-(dimethylamino)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 13): Light brown solid, 86.71% \u0026nbsp; yield, m.p. 112 \u0026deg;C (lit.\u003csup\u003e49\u003c/sup\u003e 114 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.76 (d, \u003cem\u003eJ\u003c/em\u003e = 12.2 Hz, 1H), 7.35 (d, \u003cem\u003eJ\u003c/em\u003e = 3.9 Hz, 1H), 7.03 (d, \u003cem\u003eJ\u003c/em\u003e = 3.9 Hz, 1H), 5.50 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.15 (s, 3H), 2.92 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 14): Yellow solid, 93.3% yield, m.p. 79-80 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e47 \u0026nbsp;\u003c/sup\u003e80-81 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.79 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.46 (s, 1H), 5.67 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 3.02 (d, \u003cem\u003eJ\u003c/em\u003e = 85.6 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e(\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(1\u003cem\u003eH\u003c/em\u003e-pyrrol-2-yl)prop-2-en-1-one (Table 4, entry 15): Light brown solid, 74.66% yield; m.p. 93-95 \u0026deg;C \u003cspan lang=\"EN-IN\"\u003e(\u003c/span\u003elit.\u003csup\u003e18\u003c/sup\u003e 94 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 9.85 (s, 1H), 7.73 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 6.93 (td, \u003cem\u003eJ\u003c/em\u003e = 2.6, 1.4 Hz, 1H), 6.76 (dd, \u003cem\u003eJ\u003c/em\u003e = 3.6, 2.4, 1.3 Hz, 1H), 6.23 (dt, \u003cem\u003eJ\u003c/em\u003e = 3.6, 2.5 Hz, 1H), 5.57 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 2.99 (s, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one\u003c/em\u003e(Table 4, entry 16): Yellow solid, 82.5% \u0026nbsp;yield; m.p. 73-75 \u0026deg;C (lit.\u003csup\u003e18\u003c/sup\u003e 71-73 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 9.06 (s, 1H), 8.65 (d, \u003cem\u003eJ\u003c/em\u003e = 4.8 Hz, 1H), 8.19 (dd, \u003cem\u003eJ\u003c/em\u003e = 7.9, 1.8 Hz, 1H), 7.84 (d, \u003cem\u003eJ\u003c/em\u003e = 12.2 Hz, 1H), 7.35 (dd, \u003cem\u003eJ\u003c/em\u003e = 7.9, 4.8 Hz, 1H), 5.67 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.18 (s, 3H), 2.95 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 17): Yellow red solid, 80.6% yield; m.p. 114-116 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e18\u003c/sup\u003e 115-117 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 8.68 (d, \u003cem\u003eJ\u003c/em\u003e = 6.0 Hz, 2H), 7.83 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 7.67 (d, \u003cem\u003eJ\u003c/em\u003e = 6.0 Hz, 2H), 5.64 (d, \u003cem\u003eJ\u003c/em\u003e = 12.3 Hz, 1H), 3.18 (s, 3H), 2.94 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(1E,4E)-1-(dimethylamino)-5-phenylpenta-1,4-dien-3-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 18): Brown solid and after recrystallization with ethyl acetate: hexane (2:10) given yellow solid, 94% yield, m.p. 95-100 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e47\u003c/sup\u003e 99-100 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.73 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 7.52 (dd, \u003cem\u003eJ\u003c/em\u003e = 5.7, 2.1 Hz, 3H), 7.37 \u0026ndash; 7.26 (m, 3H), 6.77 (d, \u003cem\u003eJ\u003c/em\u003e = 15.8 Hz, 1H), 5.25 (d, \u003cem\u003eJ\u003c/em\u003e = 12.5 Hz, 1H), 2.99 (d, \u003cem\u003eJ\u003c/em\u003e = 87.2 Hz, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-2-((dimethylamino)methylene)-2,3-dihydro-1H-inden-1-one\u0026nbsp;\u003c/em\u003e(Table 4, entry 19): Light brown solid, 95.3% yield; m.p. 159-161 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e48\u0026nbsp;\u003c/sup\u003e159-161 \u0026deg;C); \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.86 (d, \u003cem\u003eJ\u003c/em\u003e = 7.6 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 2H), 7.41 (s, 1H), 3.90 (s, 2H), 3.19 (s, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003e(E)-3-(dimethylamino)-2-phenylacrylonitrile\u003c/em\u003e(Table 4, entry 20): White solid, 95% yield, m.p.73-76 \u0026deg;C\u0026nbsp;(lit.\u003csup\u003e50 \u0026nbsp;\u003c/sup\u003e73-75 \u0026deg;C); FTIR 2181 and 1616 cm\u003csup\u003e-1\u003c/sup\u003e; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.32 \u0026ndash; 7.25 (m, 4H), 7.12 (t, \u003cem\u003eJ\u003c/em\u003e = 8.4 Hz, 1H), 6.89 (s, 1H), 3.22 (s, 6H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003eethyl (E)-2-cyano-3-(dimethylamino)acrylate\u003c/em\u003e (Table 4, entry 21): White solid, 90% yield, \u0026nbsp; m.p. 72-74 \u0026deg;C (lit.\u003csup\u003e51\u003c/sup\u003e 72 \u0026deg;C); FTIR 2196, 1689, 1615 cm\u003csup\u003e-1\u003c/sup\u003e; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.68 (s, 1H), 4.24 (s, 2H), 3.38 (s, 3H), 3.20 (s, 3H), 1.32 (s, 3H).\u003c/p\u003e\n\u003cp class=\"TESupportingInformation\"\u003e\u003cem\u003eethyl (E)-2-((dimethylamino)methylene)-3-oxobutanoate\u0026nbsp;\u003c/em\u003e(Table 4, entry 22): Orange liquid, 90% \u0026nbsp;yield, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.68 (s, 1H), 4.23 (q, \u003cem\u003eJ\u003c/em\u003e = 7.1 Hz, 2H), 3.04 (s, 6H), 2.33 (s, 3H), 1.32 (t, \u003cem\u003eJ\u003c/em\u003e = 7.1 Hz, 3H).\u0026nbsp;\u003c/p\u003e\n\u003cp class=\"MsoNormal\"\u003e\u003cem\u003ediethyl 2-((dimethylamino)methylene)malonate\u0026nbsp;\u003c/em\u003e(Table 4,\u0026nbsp;entry\u0026nbsp;23): colorless liquid, yield 95%,\u003csup\u003e\u0026nbsp;1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) \u0026delta; 7.48 (s, 1H), 4.19 (dd, \u003cem\u003eJ\u003c/em\u003e = 29.8, 7.0 Hz, 4H), 2.97 (d, \u003cem\u003eJ\u003c/em\u003e = 16.3 Hz, 6H), 1.35 \u0026ndash; 1.20 (m, 6H).; residual solvent impurities 8.00 (s, 0.5H), (CH, DMF), 2.95 and 2.87 (s, 1H), (CH\u003csub\u003e3,\u0026nbsp;\u003c/sub\u003eDMF).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Results And Discussion","content":"\u003cp\u003eInitially, the experiment was performed on a mixture of acetophenone and DMF-DMA in a 1: 1.5 mole ratio under solvent-free conditions at 110 \u0026deg;C without a catalyst for 16 hours to prepare standard (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one and understand the reaction rate. After complete conversion, the reaction mixture was concentrated in a vacuum to remove the excess DMF-DMA and methanol to get a crude solid. The crude was purified by recrystallization from a mixture of hexanes: ethyl acetate (75:25) to obtain 97% (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one as yellow crystals (Table 1, entry 1), confirmed by m.p. and \u003csup\u003e1\u003c/sup\u003eH NMR.\u003csup\u003e46\u0026nbsp;\u003c/sup\u003e Thereafter, experiments were planned to study the suitability of different Br\u0026oslash;nsted acids as catalysts to synthesize (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one by the reaction of acetophenone with DMF-DMA in 1:3 molar ratio under the solvent-free condition at 110 \u0026deg;C.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;1. Selection of Br\u0026ouml;nsted acids for the synthesis of (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEntry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcid\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmount\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e\u003cstrong\u003eYield (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003eHCl\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 mol%\u003c/p\u003e\n \u003cp\u003e(0.042 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e4 h 10 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003eH\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 mol%\u003c/p\u003e\n \u003cp\u003e(0.040 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e2 h 10 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-TSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 mol% (0.078 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e2 h 30 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003e\u003cem\u003eN\u003c/em\u003e-(phenylsulfonyl)\u003c/p\u003e\n \u003cp\u003ebenzenesulfonamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 mol%\u003c/p\u003e\n \u003cp\u003e(0.12 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e4 h 11 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003eB(OH)\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 mol%\u003c/p\u003e\n \u003cp\u003e(0.025 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e1 h 30 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.625850340136054%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.931972789115648%\"\u003e\n \u003cp\u003eSulfated polyborate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\"\u003e\n \u003cp\u003e10 wt%\u003c/p\u003e\n \u003cp\u003e(0.05 g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.93877551020408%\"\u003e\n \u003cp\u003e1 h 20 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.115646258503402%\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eReaction condition: Acetophenone (0.5 g, 4 mmol), DMF-DMA (1.49 g, 12 mmol), and acid catalyst, \u003csup\u003eb\u003c/sup\u003e35% w/w, \u003csup\u003ec\u003c/sup\u003e98% w/w, 110 \u0026deg;C.\u003c/p\u003e\n\u003cp\u003eHere, the commercially available Br\u0026ouml;nsted acids such as HCl, H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e, \u003cem\u003ep\u003c/em\u003e-toluene sulfonic acid (\u003cem\u003ep\u003c/em\u003e-TSA), \u003cem\u003eN\u003c/em\u003e-(phenylsulfonyl)benzenesulfonamide, boric acid, and in-house developed sulfated polyborate were screened during the catalyst selection study. It was revealed that H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e and \u003cem\u003ep\u003c/em\u003e-TSA showed 90% and 91% yield respectively, which was better than HCl. The product was extracted in ethyl acetate, washed with sodium bicarbonate to remove acid catalysts, and the organic layer was evaporated to obtain solid products. (Table 1, entries 1-3). It was observed that the reaction darkened in strong acids like HCl and H\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e might be due to degradation. \u003cem\u003eN\u003c/em\u003e-(phenylsulfonyl)benzenesulfonamide and boric acid were seen as effective as sulfated polyborate to obtain a 90-95% yield. (Table 1, entries 4-6)., Sulfated polyborate, however, produced better results in terms of time and yield. For further investigation, water-soluble sulfated polyborate was selected as the optimum acid over organocatalysts like \u003cem\u003ep\u003c/em\u003e-TSA and \u003cem\u003eN\u003c/em\u003e-(phenylsulfonyl)benzenesulfonamide to avoid the problem associated with their separation. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter foresaid selection of suitable acid, we decided to evaluate the effect of acetophenone: DMF-DMA molar ratio, catalyst loading, and temperature on the synthesis of (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one using sulfated polyborate as a catalyst. To examine temperature effect and mole ratio on time and yield, a reaction of acetophenone to DMF-DMA in 1:1.5 mole ratio at 70 \u0026deg;C and 100 \u0026deg;C with 10 wt% sulfated polyborate under solvent-free conditions was performed. Owing to insufficient DMF-DMA, the reaction showed incomplete conversion, and the product had to recrystallize to obtain 60 and 80% yield (Table 2, entries 2, 3). Further reactions were performed at 1:2.5 and 1:3 mole ratios with 10 wt% sulfated polyborate at 100 \u0026deg;C, completed in 2 hours, resulting in 80 and 90% yield, respectively (Table 2, entries 4, 5). To ascertain the temperature effect at a 1:3 mole ratio of acetophenone to DMF-DMA, a reaction was performed at 110 \u0026deg;C with 10 wt% sulfated polyborate, which yielded 97% product in 1 hour 20 minutes (Table 2, entry 8).\u003c/p\u003e\n\u003cp\u003eTable 2. Effect of molar ratio, catalyst loading, and temperature on the synthesis of (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eEntry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eCatalyst\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(wt%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcetophenone:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDMF-DMA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTemp.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u0026deg;C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eYield\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e97%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e80%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 h 15 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e85%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 h 40 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 h 20 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e97%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 h 30 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1:3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 h 40 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e95%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eReaction conditions: Acetophenone (0.5 g, 4 mmol), DMF-DMA, and Sulfated polyborate\u003c/p\u003e\n\u003cp\u003eTemperature played a vital role in enhancing the yield of (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one to 97% (Table 1, entries 5, 8). The sulfated polyborate loading was screened at 5, 7.5, 15, and 20 wt%; increasing the catalyst loading resulted in increased product yield in a shorter reaction time, but this effect stalled at 10 wt% and any further increase in sulfated polyborate loading was ineffective. (Table 2, entries 6-10).\u003c/p\u003e\n\u003cp\u003eThe effect of solvents like ethanol, toluene, DMSO, and DMF was ascertained with 10 wt% sulfated polyborate. \u0026nbsp;Solvent-free condition at 110 \u0026deg;C resulted in 97% yield (Table 3, entry 1), and ethanol gave 20% yield with difficulty in isolation (Table 3, entry 2). DMF and toluene resulted in 60% and 70% yield, respectively, with an extended reaction time of 2.5 and 5 h, respectively (Table 3, entries 3, 4). Reaction in DMSO produced 92% yield in 1 hour 10 minutes was the best amongst the solvents used (Table 3, entry 5). However, the solvent-free condition was selected due to its better reaction performance and being economical and environment friendly. (Table 3, entries 1-6).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe optimized solvent-free condition with 10 wt% sulfated polyborate at 110 \u0026deg;C was applied to various aromatic, heteroaromatic, alicyclic methyl ketones, and active methylenes to demonstrate the substrate scope (Table 4). Notably, acetophenone resulted in a 97% yield \u0026nbsp;(Table 4, entry 1), while halogenated acetophenones were smoothly converted to the products in moderate to high yields (Table 4 entries 2-4). Electron-deficient 3-nitro acetophenone produced 84% yield in a short period (Table 4, entry 5). The electron-rich substrate like 4-methyl gives 88% yield. Heterocyclic ketones (2-acetyl thiophene, 2-acetyl furan, 3-acetylpyridine, 4-acetylpyridine) were appropriate for enaminone preparation to obtain 95-86% yield (Table 4, entries 9-18). Various active methylenes were also attempted, taking a shorter reaction time than methyl ketones. Active methylenes like benzyl cyanide, ethyl cyanoacetate, and \u0026beta;-ketoester ethyl acetoacetate reaction completed in reasonable time with excellent yield (Table 4, entries 19-23) while diester, diethyl malonate as an exception took a longer reaction time (Table 4, entry 23). Liquid products (Table 4, entries 10, 22, 23) were isolated by water quenching, and ethyl acetate extraction after excess DMF-DMA and methanol were removed under vacuum. During the aqueous quenching, the presence of the acid catalyst led to the formation of DMF from the traces of DMF-DMA. This DMF gets carried ahead during ethyl acetate extraction and causes a hindrance in obtaining NMR pure compounds.\u003c/p\u003e\n\u003cp\u003eTable 3. Effect of the solvents for synthesizing (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-phenylprop-2-en-1-one.\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEntry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSolvent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTemp.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u0026deg;C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e\u003cstrong\u003eYield\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003eSolvent-free\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e1 h 20 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003eEtOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003ereflux\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e2 h 40 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003eDMF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e2 h 30 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003eToluene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e5 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.464720194647203%\"\u003e\n \u003col\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.708029197080293%\"\u003e\n \u003cp\u003eDMSO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.817518248175183%\"\u003e\n \u003cp\u003e1 h 10 min.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.004866180048662%\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eReaction condition: Acetophenone (0.5 g, 4 mmol), DMF-DMA (1.49 g, 12 mmol ), and Sulfated polyborate (0.050 g, 10 wt%).\u003c/p\u003e\n\u003cp\u003eThe products were co-distilled with toluene (3 X 5 ml) under vacuum, followed by chloroform (5 X 5 ml) to remove traces of DMF.\u003c/p\u003e\n\u003cp\u003eElectron-rich 4\u0026rsquo;-methoxy acetophenone was smoothly converted to enaminone (Table 4, entry 7) within 3 hours and 40 minutes. We were keen to use other electron-rich acetophenones, \u003cem\u003eviz.\u003c/em\u003e 3- and 4-hydroxy acetophenones. To our surprise, the reaction of 4\u0026rsquo;-hydroxy acetophenone with DMF-DMA initially in a 1:3 \u0026nbsp;mole ratio showed multiple products. During TLC investigation of the reaction mixture in comparison with (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one, it was observed that sulfated polyborate not only activates DMF-DMA for enaminone formation but also methylating\u003csup\u003e45\u003c/sup\u003e hydroxy group of 4-hydroxy acetophenone leads to unreacted 4-hydroxy acetophenone along with its enaminone. Out of curiosity, the reaction was continued; with additional 3 equivalents of DMF-DMA, all the multiple products were converted to (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one in 4 hours 10 \u0026nbsp;minutes (Section 1.0 and Figure 1, Supporting information). A similar result was observed for 3-hydroxy acetophenone at a 1:6 mole ratio with DMF-DMA to produce (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one within 2 hours (\u003cstrong\u003eScheme 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOwing to the substrate scope, we were keen on scaling up Imatinib and Nilotinib intermediates. During substrate study, 3-acetyl pyridine was converted successfully to (\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one, using sulfated polyborate in 82.5% yield in 40 minutes at a small scale of 0.5 g, 2.9 mmol. Based on the acid selection\u0026nbsp;study, boric acid showed comparable results in converting acetophenone to its enaminone\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(Table 1, entry 5).\u003c/p\u003e\n\u003cp\u003eAs sulfated polyborate is an in-house developed catalyst, we chose boric acid for scale-up activity in the interest of readers and industries. The developed protocol to prepare\u0026nbsp;(\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one\u0026nbsp;utilized boric acid as an eco-friendly and cost-effective catalyst. (\u003cstrong\u003eScheme 3\u003c/strong\u003e). The reaction of 10g 3-acetyl pyridine and 3 equivalents of DMF-DMA with 10 mole% boric acid at 110 \u0026deg;C was performed. The reaction color turned from yellow to orange and complete conversion on TLC was observed within 50 minutes. The excess DMF-DMA and methanol formed were recovered by downward distillation at atmospheric pressure and traces under vacuum, giving a crude red-brown solid. The crude product was recrystallized using a mixture of hexanes: ethyl acetate (40:20) to obtain\u0026nbsp;(\u003cem\u003eE\u003c/em\u003e)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one\u0026nbsp;as orange-red solid, in 80%\u0026nbsp;yield, confirmed by melting point.\u003c/p\u003e\n\u003cp\u003eThe plausible reaction mechanism is depicted in \u003cstrong\u003eScheme 4\u003c/strong\u003e. Presumably, sulfated polyborate acts as a hydrogen bond-donor to activate the carbonyl group of ketones to form an enolate ion [C]. The enolate ion [C] converts to enol [E]. Simultaneously, it may have protonated the DMF-DMA to eliminate the methoxy group and generate an iminium ion [F]. Consequently, the enol [E] might have instantly attacked iminium ion [F] followed by the elimination of methanol, leading to the formation of enaminone [H].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, the current method proved that Br\u0026ouml;nsted acids catalytically activate methyl ketones or active methylenes and DMF-DMA to synthesize enamines and enaminones under solvent-free conditions. Best results were obtained with sulfated polyborate and boric acid. The method was applied to various aromatic, bicyclic, heteroaromatic, alicyclic methyl ketones, and active methylenes wherein the reaction times ranged from 10 minutes to 3 h 40 minutes, with good to excellent yields. The developed method was successfully applied for the scale-up to 10 g intermediate for Nilotinib and Imatinib, using boric acid as a commercially available and eco-friendly catalyst. The technique was extendable to Ocinaplon intermediate using 4-acetyl pyridine with necessary optimization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful for generous funding from the All India Council for Technical Education (DIPSAR/AICTE/QIP/Nodal/2019-20/43/Ph.D./20), New Delhi, and Council for Scientific and Industrial Research (09/991(0062)/2020-EMR-I).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNotes: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026dagger;Indian Patent Application No. 202121059848 A, Date of Application filing Dec. 21, 2021.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePriyanka V. Bandivadekar did the experiments and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003eKanchan D. Gavali did experiments and prepared supplementary information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGanesh U. Chaturbhuj conceptualized the work and monitored the process at each stage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll India Council for Technical Education (DIPSAR/AICTE/QIP/Nodal/2019-20/43/Ph.D./20), New Delhi, and Council for Scientific and Industrial Research (09/991(0062)/2020-EMR-I).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGreenhill, J. V. Chem. Soc. 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Commun. 1982, \u003cb\u003e12\u003c/b\u003e, 939\u0026ndash;946.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 4 is available in the Supplemental Files section.\u003c/p\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1-4 are available in supplementary section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Enamine, Enaminone, Sulfated polyborate, Imatinib, Nilotinib, Ocinaplon","lastPublishedDoi":"10.21203/rs.3.rs-1893656/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1893656/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAn activation of methyl ketones or active methylenes and \u003cem\u003eN,N\u003c/em\u003e-dimethylformamide dimethyl acetal (DMF-DMA) at 110 °C by sulfated polyborate under solvent-free conditions has been developed for enamines and enaminones synthesis. Selected Brønsted acid, optimized reaction conditions, and easy separation method lead to 82-97% yield, making this process cost-effective and eco-friendly. We chose boric acid for scale-up activity in the interest of readers and industries. The optimized reaction condition was applied to demonstrate a 10 gm scale-up for intermediate of Imatinib and Nilotinib with 80% yield from 3-acetylpyridine. This method is extendable to produce Ocinaplon intermediate using 4-acetyl pyridine as starting material.\u003c/p\u003e","manuscriptTitle":"Sulfated polyborate catalyzed enamines, enaminones synthesis via Methyl Ketones, Active Methylenes, and DMF-DMA activation: Application to Imatinib, Nilotinib intermediates †","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-01 18:04:01","doi":"10.21203/rs.3.rs-1893656/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83369229-a0e2-4ea4-8023-5cf5b658b269","owner":[],"postedDate":"August 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-03T00:14:13+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-01 18:04:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1893656","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1893656","identity":"rs-1893656","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}