Mechanistic and Exploratory Investigations into the Synthesis of 1,3,5-Triaroylbenzenes from 1-Aryl-2-propyn-1-ones and 1,3,5-Triacetylbenzene from 4-Methoxy-3-buten-2-one by Cyclotrimerization in Hot Water in the Absence of Added Acid or Base

Abstract

Neat 1-phenyl- and 1-(p-tolyl)-2-propyn-1-ones (1 and 1', respectively) were heated in water without any additive at 150 °C for 2 h to give 1,3,5-tribenzoyl- and 1,3,5-tri-(p-toluoyl)benzenes (2 and 2', respectively) in 74 and 52% yields, respectively. The crossed reactions of 1 with the enolate of p-toluoylacetaldehyde (3') and 1' with the enolate of benzoylacetaldehyde (3) were carried out to give unsymmetrically substituted 1-toluoyl-3,5-dibenzoylbenzene (Ph2Tol) and 1,3-ditoluoyl-5-benzoylbenzene (PhTol2), respectively, corroborating the previously proposed reaction mechanism in which 3 and 3' that are formed by rate-determining nucleophilic attack of HO(-) on 1 and 1' or its conjugate acids formed by subsequent protonation would serve as a common intermediate for the formation of 2, 2' and the acetophenone derivatives as byproducts. When 4-methoxy-3-buten-2-one (4) was heated in hot pure water without any additive at 150 °C for 30 min, 1,3,5-triacetylbenzene (5) was obtained in an isolated yield of 77% just by removing water by filtering the crystalline product from the cooled reaction mixture. The reaction did not take place in the absence of water. Slow decompositions of 5 in water set in at the temperature of 300 °C for 30 min.

Flow Synthesis in Hot Water: Synthesis of the Atypical Antipsychotic Iloperidone

“…The Brçnstedt-or Lewis acidpromoted trimerization of 4-methoxy-3-butene-2-one 1 in water is known to yield triacetyl benzene 2 at around1 50 8C. [13] We found that this reaction also smoothly proceeds in an aqueous suspension with toluene in the absence of any acid under high temperature conditions. [14] Triacetyl benzene 2 wasi solated in 89 %y ield at 240 8Ci nl ess than 2min residence time and in the absence of aphase-transfer catalyst.…”

“…Multiplicities are described with the following abbreviations:s :s inglet;d :d oublet;t :t riplet;q : quartet;m:m ultiplet;b:broad. 13 CNMR spectra were recorded at 100 MHz with aB ruker Avance-400 and at 125 MHz with aB ruker DRX-500. Chemical shifts of 1 Hand 13 CNMR spectra are reported in d (ppm) relative to TMS as the internal standard.…”

“…13 CNMR spectra were recorded at 100 MHz with aB ruker Avance-400 and at 125 MHz with aB ruker DRX-500. Chemical shifts of 1 Hand 13 CNMR spectra are reported in d (ppm) relative to TMS as the internal standard. Multiplicities are described with the following abbreviations:s :s inglet (due to quaternary carbon), d: doublet (methine), t: triplet (methylene), q: quartet (methyl), m: multiplet.…”

“…All coupling constants J are expressed in Hertz. Supporting 1 H-1 H correlation (COSY) and 1 H- 13 Cc orrelation (HSQC, HMBC) experiments were performed for interpretation of mutaproducts spectra. Mass spectra were recorded with at ype QTOFp remier (MICRO-MASS) spectrometer (ESI mode) in combination with aW aters Acquity S2 UPLC system equipped with aW aters Acquity UPLC BEH C18 1.7 mm( SN 01473711315545) column (solvent A: water + 0.1 % (v/v) formic acid, solvent B: MeOH + 0.1 %( v/v) formic acid;f low rate = 0.4 mL min À1 ;g radient (t [min]/solvent B[ %]): 0/5;2 .5/95; 6.5/95;6 .6/5;8 /5).…”

“…The mixture was injected into the loop and pumped through a1/8" steel reactor (V = 1.2 mL) with distilled water at 0.4 mL min À1 .T he reactor was heated by ah igh frequency field (300 kHz) to 260 8Ca nd pressurized to 4.5 MPa. The collected reaction solution was extracted with ethyl acetate (3 15mL 1-(4-Hydroxy-3-methoxyphenyl)ethan-1-one (13): Synthesis in ar ound-bottom flask:2 -Methoxyphenylacetate (250 mL, 1.70 mmol, 1.0 equiv,0 .68 m)w as added to am ixture of 2.0 mL CH 2 Cl 2 ,m ethane sulfonic acid (440 mL, 6.73 mmol, 4.0 equiv) and phosphor(V)oxide (62 mg, 0.43 mmol, 0.25 equiv) and stirred for 16 ha tr oom temperature. The reaction mixture was diluted with CH 2 Cl 2 (10 mL) and washed three times with bicarbonate solution.…”