( E )-4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde Oxime Oxime

: Reaction of 4-oxo-3,4-dihydroquinazoline-2-carbaldehyde with hydroxylamine hydrochloride (1.1 equiv) in the presence of K 2 CO 3 (1 equiv) gave ( E )-4-oxo-3,4-dihydroquinazoline-2-carbaldehyde oxime ( 8 ) in 58% yield. The compound was fully characterized and the conformation of the oxime was supported by single crystal x-ray diffractometry. Abstract: Reaction of 4-oxo-3,4-dihydroquinazoline-2-carbaldehyde with hydroxylamine hydrochloride (1.1 equiv) in the presence of K 2 CO 3 (1 equiv) gave ( E )-4-oxo-3,4-dihydroquinazoline-2-carbaldehyde oxime ( 8 ) in 58% yield. The compound was fully characterized and the conformation of the oxime was supported by single crystal x-ray diffractometry.


Introduction
Quinazolines are important aromatic N-heterocycles that have wide pharma applications. Among the 6-membered aromatic nitrogen-containing heter quinazolines rank 3rd in the most frequently used U.S. FDA-approved dr Examples of quinazoline-containing drugs are the anticancer drug erlotinib antihypertensive prazosin (Figure 1). The chemistry and applications of quin have been reviewed [2].
We were interested in developing an independent synthesis for thiadiazole 5 to investigate its chemistry. The proposed independent synthesis started from 2-aminobenzamide 6, which can be converted to quinazolinone-2-carbaldehyde 7 in two steps with 51% overall yield [6] (Scheme 2). The conversion of aldehyde 7 into oxime 8, followed by the addition 2 of 6 of cyanide should give hydroxylamine 9 [7]. The subsequent reduction to aminoacetonitrile 10 [8] followed by reaction with S 2 Cl 2 was expected to give the desired thiadiazole 5 [9]. We were interested in developing an independent synthesis for thiadiazole 5 to investigate its chemistry. The proposed independent synthesis started from 2 aminobenzamide 6, which can be converted to quinazolinone-2-carbaldehyde 7 in two steps with 51% overall yield [6] (Scheme 2). The conversion of aldehyde 7 into oxime 8 followed by the addition of cyanide should give hydroxylamine 9 [7]. The subsequen reduction to aminoacetonitrile 10 [8] followed by reaction with S2Cl2 was expected to give the desired thiadiazole 5 [9]. The reaction of quinazolinone-2-carbaldehyde 7 with hydroxylamine hydrochloride (1.1 equiv), in the presence of K2CO3 (1 equiv), in EtOH, at ca. 60 °C led after 3 h to complete consumption of the starting aldehyde and on work-up isolation of oxime 8 in 58% yield (Scheme 3). We were interested in developing an independent synthesis for thiadiazole 5 to investigate its chemistry. The proposed independent synthesis started from 2 aminobenzamide 6, which can be converted to quinazolinone-2-carbaldehyde 7 in two steps with 51% overall yield [6] (Scheme 2). The conversion of aldehyde 7 into oxime 8 followed by the addition of cyanide should give hydroxylamine 9 [7]. The subsequen reduction to aminoacetonitrile 10 [8] followed by reaction with S2Cl2 was expected to giv the desired thiadiazole 5 [9]. The reaction of quinazolinone-2-carbaldehyde 7 with hydroxylamine hydrochloride (1.1 equiv), in the presence of K2CO3 (1 equiv), in EtOH, at ca. 60 °C led after 3 h to complete consumption of the starting aldehyde and on work-up isolation of oxime 8 in 58% yield (Scheme 3). The reaction of quinazolinone-2-carbaldehyde 7 with hydroxylamine hydrochloride (1.1 equiv), in the presence of K 2 CO 3 (1 equiv), in EtOH, at ca. 60 • C led after 3 h to complete consumption of the starting aldehyde and on work-up isolation of oxime 8 in 58% yield (Scheme 3).
Product 8 was isolated as colorless needles, mp 237-238 • C (from EtOH/H 2 O). FTIR spectroscopy showed an oxime ν(O-H) stretch at 3280 cm −1 along with an amide ν(N-H) stretch at 3173 cm −1 , an oxime ν(C-H) stretch at 2876 cm −1 and a broad ν(C=O) stretch at 1678 cm −1 . Meanwhile, mass spectrometry revealed a molecular ion (MH + ) peak of m/z 190, agreeing with the addition of NH 2 OH and loss of H 2 O from the starting aldehyde 7. 13 C NMR spectroscopy showed the presence of five CH resonances and four quaternary carbon resonances (see Supplementary Materials for the complete spectra). At the same time, a correct elemental analysis (CHN) was obtained for the molecular formula C 9 H 7 N 3 O 2 , agreeing with the structure shown above. Structural support was also provided by single-crystal X-ray diffraction studies (Figure 2). To the best of our knowledge, compound 8 has not been reported in the literature and could have many potential uses. Importantly, the structurally similar isomer quinoxalin-2(1H)-one-3-carbaldoxime (11) (Scheme 3) has been used as a scaffold for the preparation of benzimidazoles [10]. At the same time, other analogs were investigated as neurologically active compounds for the treatment of Alzheimer's disease [11] or as ligands to ruthenium and osmium complexes with anticancer properties [12]. . At the same time, a correct elemental analysis (CHN) was obtained for the molecular formula C9H7N3O2, agreeing with the structure shown above. Structural support was also provided by single-crystal X-ray diffraction studies (Figure 2). To the best of our knowledge, compound 8 has not been reported in the literature and could have many potential uses. Importantly, the structurally similar isomer quinoxalin-2(1H)-one-3carbaldoxime (11) (Scheme 3) has been used as a scaffold for the preparation of benzimidazoles [10]. At the same time, other analogs were investigated as neurologically active compounds for the treatment of Alzheimer's disease [11] or as ligands to ruthenium and osmium complexes with anticancer properties [12]. X-ray crystallography indicated that quinazoline 8 is planar in the crystalline state Scheme 3. Synthesis of (E)-4-oxo-3,4-dihydroquinazoline-2-carbaldehyde oxime (8) and structure of the isomeric (E)-3-oxo-3,4-dihydroquinoxaline-2-carbaldehyde oxime (11). Scheme 3. Synthesis of (E)-4-oxo-3,4-dihydroquinazoline-2-carbaldehyde oxime (8) and structure o the isomeric (E)-3-oxo-3,4-dihydroquinoxaline-2-carbaldehyde oxime (11).
Product 8 was isolated as colorless needles, mp 237-238 °C (from EtOH/H2O). FTIR spectroscopy showed an oxime ν(O-H) stretch at 3280 cm −1 along with an amide ν(N-H stretch at 3173 cm −1 , an oxime ν(C-H) stretch at 2876 cm −1 and a broad ν(C=O) stretch a 1678 cm −1 . Meanwhile, mass spectrometry revealed a molecular ion (MH + ) peak of m/z 190 agreeing with the addition of NH2OH and loss of H2O from the starting aldehyde 7. 13 C NMR spectroscopy showed the presence of five CH resonances and four quaternary carbon resonances (see Supplementary Materials for the complete spectra). At the same time, a correct elemental analysis (CHN) was obtained for the molecular formula C9H7N3O2, agreeing with the structure shown above. Structural support was also provided by single-crystal X-ray diffraction studies (Figure 2). To the best of our knowledge, compound 8 has not been reported in the literature and could have many potential uses. Importantly, the structurally similar isomer quinoxalin-2(1H)-one-3 carbaldoxime (11) (Scheme 3) has been used as a scaffold for the preparation o benzimidazoles [10]. At the same time, other analogs were investigated as neurologically active compounds for the treatment of Alzheimer's disease [11] or as ligands to ruthenium and osmium complexes with anticancer properties [12].  After the synthesis of oxime 8, the addition of cyanide was attempted, but unfortunately, no reaction occurred with KCN (10 equiv), in dry DMF at ca. 20 • C for 2 d, as well as, with 18-crown-6 (1 equiv) at ca. 100 • C for 3 d. This reaction will be further investigated in the future. After the synthesis of oxime 8, the addition of cyanide was attempted, but unfortunately, no reaction occurred with KCN (10 equiv), in dry DMF at ca. 20 °C for 2 d, as well as, with 18-crown-6 (1 equiv) at ca. 100 °C for 3 d. This reaction will be further investigated in the future.

Materials and Methods
The reaction mixture was monitored by TLC using commercial glass-backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F254, Darmstadt, Germany). The plates were observed under UV light at 254 and 365 nm. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany). The solvent used for recrystallization is indicated after the melting point. The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV-vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf". The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA), and strong, medium, and weak peaks were represented by s, m, and w, respectively. 1 H and 13 C NMR spectra were recorded on a Bruker Avance 500 machine [at 500 and 125 MHz, respectively, (Bruker, Billerica, MA, USA)]. Deuterated solvents were used for homonuclear lock, and the signals are referenced to the deuterated solvent peaks. Attached proton test (APT) NMR studies were used to assign the 13 C peaks as CH3, CH2, CH, and Cq (quaternary). The Matrix-Assisted Laser Desorption/Ionization-Time Of Flight (MALDI-TOF) mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker). The elemental analysis was run by the London Metropolitan University Elemental Analysis Service. 4-Oxo-3,4-dihydroquinazoline-2-carbaldehyde (7) was prepared according to the literature procedure [6].

Materials and Methods
The reaction mixture was monitored by TLC using commercial glass-backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F 254 , Darmstadt, Germany). The plates were observed under UV light at 254 and 365 nm. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner X-ray crystallographic studies on (E)-4-oxo-3,4-dihydroquinazoline-2-carbaldehyde oxime (8). Data were collected on an Oxford-Diffraction Supernova diffractometer, equipped with a CCD area detector utilizing Cu-Kα radiation (λ = 1.5418 Å). A suitable crystal was attached to glass fibers using paratone-N oil and transferred to a goniostat, where they were cooled for data collection. Unit cell dimensions were determined and refined using 6738 (4.485 • ≤ θ ≤ 77.063 • ) reflections. Empirical absorption corrections (multi-scan based on symmetry-related measurements) were applied using CrysAlis RED software. 17 The structures were solved by direct method and refined on F 2 using full-matrix least-squares using SHELXL97. 18 Software packages used: CrysAlis CCD 17 for data collection, CrysAlis RED 17 for cell refinement and data reduction, WINGX for geometric calculations, 19 and DIAMOND 20 for molecular graphics. The non-H atoms were treated anisotropically. The hydrogen atoms were placed in calculated, ideal positions and refined as riding on their respective carbon atoms.