Synthesis and Single Crystal Structures of N-Substituted Benzamides and Their Chemoselective Selenation/Reduction Derivatives

A series of N-aryl-N-(2-oxo-2-arylethyl) benzamides and cinnamides has been prepared. The reaction of the benzamides with Woollins’ reagent, a highly efficient chemoselective selenation/reduction reagent, gave the corresponding N-aryl-N-(arylenethyl) benzoselenoamides in good yields. Five representative single crystal X-ray structures are discussed.

Organoselenium compounds have received growing attention during the last decades due to their importance as useful precursors in synthetic chemistry [19,20], as new synthetic materials [20], and their biological and medicinal significance [21]. To continue our interest in the chemistry of Woollins' reagent towards various organic substrates, we report an investigation on the use of WR as a selenation/reduction reagent for transferring N-aryl-N-(2-oxo-2-arylethyl) benzamides into the corresponding N-aryl-N-(arylenethyl) benzoselenoamides.

Synthesis and Characterization
The synthesis of anilinoacetophenones 1-3, N-aryl-N-arylamidoacetophenones 4-6 and N-aryl-N-cinnamidoacetophenones 7-9 was carried out using a modified literature method [22]. The reaction of anilines and an equivalent of the appropriate bromoacetophenones in dry acetonitrile at room temperature gave anilinoacetophenones 1-3 in 81-87% yields, respectively. Anilinoacetophenones 1 and 2 are new compounds, while 3 is a known compound, prepared previously by a similar method [23,24]; however, its single-crystal X-ray structure has not been reported previously. Acylation of anilinoacetophenones 1-3 with the appropriate acid chlorides in 1,2-dichloroethane at reflux led to the N-aryl-Narylamidoacetophenones 4-6 and N-aryl-N-cinnamidoacetophenones 7-9 in 76-91% yields, as shown in Scheme 1. All the new compounds were characterized by standard analytical and spectroscopic techniques. 1-9 show the anticipated [M] + or [M + H] + peak in their mass spectra, satisfactory accurate mass measurements, and appropriate isotopic distributions; the 1 H NMR spectra display all the characteristic peaks of the phenyl backbones in compounds and the characteristic peaks of the NH group in compound 1-3. The 13 C NMR spectra of compounds 1-9 display the characteristic signals of the C=O groups. Selenation of N-aryl-N-arylamidoacetophenones 4-6 by WR gave rise to N-aryl-Narylethylbenzoselenoamides 10-12 in 50%, 46% and 40% yields, respectively, rather than the expected 1,3-selenazole products (Scheme 2). One C=O group has been converted to C=Se and the other reduced to CH 2 to give the final product N-Aryl-N-arylethylbenzoselenoamides 10-12. It is well known that WR is an efficient chemoselective reduction agent for diketones [16], α,β-unsaturated thioazo and selenoazolidinones [6]. Based on the literature research and our findings, a possible mechanism for the selective reduction of N-substituted-N-phenylamidoacetophenones 4-6 is broadly similar to that of NaSeH and LiSeH as selective reducing agents of α,β-unsaturated carbonyl compounds [13] and of PhSe-SePh as a reducing agent for electron deficient olefins [25], and it is probable that the reduction proceed through a Micheal reaction [26][27][28].
Reacting N-aryl-N-cinnamidoacetophenones 7-9 with WR under similar reaction conditions did not lead to a reaction, with the starting materials being recovered (Scheme 3). We speculate that the extra C=C bond in N-substituted-N-phenylamidoacetophenones 7-9 which gives a conjugated structure, may be more stable and robust than N-substituted-Nphenylamidoacetophenones 4-6 towards WR. The new selenium derivatives 10-12 are quite stable both as solids and in solution, in air and moist atmospheres, and are soluble in common organic solvents. They show the anticipated molecular ion peaks [M + H] + in their CI spectra and [M] + in their EI spectra, and satisfactory accurate mass measurements (EI). All the characteristic peaks of the phenyl backbones were found, and the characteristic peaks of the NH group disappeared in their 1 H NMR spectra. Their 13 C NMR spectra all show the normal signals for the C=Se groups (δ C , 204.8-206.8 ppm). Their 77 Se NMR spectra exhibit singlet signals at δ Se = 598.4, 601.5 and 601.4 ppm for 10-12, respectively.

Single Crystal Structure Analysis
Single crystals of 3, 7, 10-12 suitable for X-ray crystallographic analysis were grown by slow evaporation of dichloromethane solutions of the compound in air at room temperature. Selected crystallographic data are given in Table 1 and the resulting molecular structures are illustrated in Figures 1 and 2.
The molecular structure of anilinoacetophenone 3 ( Figure 1) shows a planar arrangement, with a mean deviation of non-hydrogen atoms from the plane of 0.047 Å. Adjacent molecules of 3 interact to form hydrogen-bonded dimers via a pair of NH···O hydrogen bonds at a H···O distance of 2.59(4) Å, and N···O separation of 3.360(5) Å. The structure of the N-aryl-N-cinnamidoacetophenone 7 shows the compound in a twisted-T conformation ( Figure 1). As expected, the acetophenone group retains its planarity (mean deviation of non-hydrogen atoms from the plane of 0.004 Å). Meanwhile, the other two phenyl ring planes are twisted out of the acetophenone plane, with angles between planes of 71.36 and 50.74 • for C(10)-C(15) and C(21)-C(26), respectively.   . [29] The conformations of 10-12 are all very similar, that between 10 and 11, being almost identical. The difference between this conformation and that adopted by 12 is in the orientation of ring 1, which differs by~67 • between the two conformations.

General
Unless otherwise stated, all reactions were carried out under an oxygen-free nitrogen atmosphere using pre-dried solvents and standard Schlenk techniques, subsequent chromatographic and work up procedures were performed in air. 1 H (400.1 MHz), 13 C (100.6 MHz) and 77 Se-{ 1 H} (51.5 MHz, referenced to external Me 2 Se) NMR spectra were recorded at 25 • C (NMR Jeol GSX270). IR spectra were recorded as KBr pellets in the range of 4000-250 cm −1 on a Perkin-Elmer 2000 FTIR/Raman spectrometer Mass spectrometry was performed by the EPSRC National Mass Spectrometry Service Centre, Swansea. Crystallography X-ray diffraction data for compounds 3, 7 and 10-12 were collected at either 93 K or 173 K using a Rigaku FR-X Ultrahigh Brilliance Microfocus RA generator/confocal optics with XtaLAB P200 diffractometer [Mo Kα radiation (λ = 0.71075 Å)]. Intensity data were collected using ω steps accumulating area detector images spanning at least a hemisphere of reciprocal space. Data for all compounds were collected using CrystalClear 2.1 [30] and processed (including correction for Lorentz, polarization and absorption) using either CrystalClear [30] [32]) or Patterson (PATTY [33]) methods and refined by fullmatrix least-squares against F 2 (SHELXL-2018/3 [34]). Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model, except for the amine hydrogen in 3 which was located from the difference Fourier map and refined isotropically subject to a distance restraint. All calculations were performed using the CrystalStructure 4.3 interface [35]. Selected crystallographic data are presented in Table 1. Deposition numbers 2071413-2071417 contains the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service www.ccdc. cam.ac.uk/structures.

General Procedure for Synthesis of Compounds 1-3
The appropriate aniline (20 mmol) and the phenacyl bromide (10 mmol) were combined in MeCN (40 mL) and allowed to stir at room temperature for 24 h. The amine salt was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (40 mL) and washed sequentially with H 2 O (50 mL), 5% citric acid (50 mL) and brine (25 mL). The organic layer was dried over Na 2 SO 4 , filtered through a pad of silica gel and the solvent was evaporated to give the product aminoacetophenones 1-3 in good yield.  (CDCl 3 , δ), 194.2, 145.0, 140.3, 133.9, 133.3, 129.3, 129.2, 129.2, 128.7, 113.2, 50.8 The appropriate aminoacetophenone (5.0 mmol) was dissolved in dichloroethane (25 mL) and refluxed for 2 h with the appropriate acid chloride (5.0 equiv). Volatiles were evaporated in vacuo, and the residue was recrystallized from ethyl acetate to give the expected products 4-9. N

Conclusions
In summary, we have disclosed Woollins' reagent used as a highly efficient chemoselective selenation/reduction reagent for benzamide leading to N-aryl-N-(arylenethyl)benzoselenoamides. The reported results enhance the application of Woollins reagent further, providing an efficient route to the preparation of the unusual substituted selenoamides.