Synthesis and spectroscopic properties of a series of novel 2-aryl-3-phenyl-2,3-dihydro-4 H -1,3-benzothiazin-4-ones

A series of thirteen novel 2-aryl-3-phenyl-2,3-dihydro-4 H -1,3-benzothiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N -phenyl- C -aryl imines with thiosalicylic acid. The spectroscopic and physical properties are reported and discussed. 1 H-19 F and 13 C-19 F couplings were observed in the NMR spectra of fluorinated compounds. Through-space interactions were observed in the 1 H and 13 C NMR spectra of the ortho -nitro compound. Trends were observed in the IR and UV absorptions of the ortho / meta / para -nitro series.


Synthesis
Imines 2a-i and 2k-n for this study, all of which are known compounds, were prepared by heating aldehydes 3a-i and 3k-n with aniline 4 at reflux in toluene while removing water via a Dean-Stark trap.Imines 2a-d, 2f-i, 2k, and 2m were recrystallized.Imines 2e, 2l, and 2n were liquids, which were used as obtained.No attempt was made to optimize yields.Imine 2j is available commercially.
The condensation of thiosalicylic acid 5 with imines 2a-n was performed as previously reported, 13,[17][18][19]25 using T3P as a promoter and pyridine as a base (Scheme 1). Thereactions were run at room temperature, whereas the similar method reported by Kitsiou was run at 90 °C. 16ields were modest (Table 1), but no attempt was made to optimize yields, which were calculated from the imines 2a-n, whether 2 was a recrystallized solid or crude liquid.Only one Naryl example was reported by Kitsiou, and the yield of 53% was significantly lower than their yields for N-alkyl compounds, 16 so it can again be seen that N-aryl compounds in this family are more difficult in general to prepare than N-alkyl compounds, and the yields reported here are partly a function of that.What is most notable about the syntheses reported here is that the reaction succeeded with every C-aryl substituent attempted, including both electron-withdrawing and electron-donating, and in either ortho, meta or para positions.Fourteen compounds are reported herein.8][19] Preparation of compound 1b was repeated and the revised yield is reported here.Yields and spectroscopic data are compiled in Table 1, with only key signals common to each product compared.Spectroscopic data has only been previously reported for 1j, 13 which is included in Table 1, along with a remeasurement of the ultraviolet-visible (UV-Vis) spectrum, for comparison.Full spectral data and physical properties are provided in the Experimental Section.

H NMR Spectroscopy
The signals from the C2 proton of compounds 1a-n corresponding to each of the substituted 2-aryl moieties are compared in Figure 2. The signal for the ortho-nitro compound 1a was at 7.01 ppm, but the others (all meta-or para-substituted) ranged only from 6.01 to 6.14 ppm.This is similar to the ranges observed by Tierney 26 and Woolston 27 for meta-and para-substituted 2-aryl-3phenyl-1,3-thiazolidin-4-ones (five-membered heterocycles).

Hammett correlation attempts
Attempts were made to correlate 1 H and 13 C substituent chemical shifts with Hammett  constants.There were some general trends that could be discerned for both electron-withdrawing and electron-donating groups on the C-2 aryl, but they were not robust correlations.The same was true when UV max values were plotted against Hammett  constants.It is believed that the more complex structure and competing electronic influences within the fused 2,3-diaryl-2,3-dihydro-4H-1,3-benzothiazin-4-ones is the reason for the absence of clear correlations as witnessed by Tierney 26 and Woolston 27 in the simpler 1,3-thiazolidin-4-one systems.

Nitro compounds
The C2 proton resonance in o-nitro compound 1a was significantly more downfield than in the mand p-nitro compounds 1b and 1c.This indicated a through-space interaction between the proton and a negatively charged oxygen in the nitro group.The previously reported X-ray crystal structure of 1a 19 (Figure 3) showed that in the solid state one of the nitro oxygens is near the hydrogen on C2, with an intramolecular distance of 2.404 Å between the H and the O.This is close enough that a C-H---O hydrogen bond may exist.

H on C2
Fluorinated compounds Four of the compounds prepared have one or more fluorines.These are of interest for two reasons.One is the physical and biological properties that fluorine imparts to pharmaceuticals. 29,30][33][34][35][36][37] The p-flouro compound 1h showed a signal at 6.96 ppm for the two hydrogens ortho to the fluorine.The signal displayed a triplet pattern with ~8.3 Hz separation between the peaks.This separation is believed to stem from the 3 JHH and 3 JHF couplings of the ortho proton to the meta (with respect to F) and to the fluorine itself, respectively.The 3 JHH and 3 JHF couplings apparently overlap.Raising the temperature from room to 40 °C led to sharpening of the triplet, believed to be the result of faster equilibration between aryl ring-rotation conformers.The spectrum of the mfluoro compound 1i also showed an apparent triplet, with additional fine splitting, of one hydrogen at 6.95 ppm, which was assigned to the position which is para to the thiazine ring and ortho to the fluorine.
The spectra of trifluoromethyl compounds 1d and 1e, which have no hydrogens on adjacent carbons, did not show any noticeable extra splittings that would be due to 1 H-19 F coupling.

C NMR Spectroscopy
There was very little variation in the C4 (C=O) signal (Figure 4).The range was only 163.4-164.3ppm, and only 163.4-163.8 with the o-nitro excluded.The variance of 0.5 ppm for the meta-and para-substituted compounds is similar to that seen for 2-aryl-3-phenyl-1,3-thiazolidin-4-ones by Tierney 26 and Woolston. 38Among the meta-and para-substituted compounds, the chemical shift values increased as electron withdrawing decreased and electron donation increased.The signal for C2 (Figure 5) showed a range of only 64.6-65.3ppm, except for o-nitro 1a, which showed the signal at 61.0 ppm.The chemical shifts for the meta-and para-substituted compounds spanned a smaller variance (0.7 ppm) than that reported (~1.4-1.5 ppm) for 2-aryl-3phenyl-1,3-thiazolidin-4-ones by Tierney 26 and Woolston. 38Among the meta-and parasubstituted compounds, the chemical shift values increased overall as electron withdrawing decreased and electron donation increased, but was not always consistent among two data points, e.g. the m-CF3 compound 1d had a higher value than the m-bromo compound 1g. Figure 5. 13 C chemical shifts at C2 (ppm, CDCl3) (2-aryl moiety substitution: orange = unsubstituted, red = para-substituted, blue = meta-substituted, green = ortho-substituted).

Nitro compounds
In its 13 C spectrum, the C2 carbon in the o-nitro compound 1a was significantly more upfield, at 61.0 ppm, than in the other nitro compounds,.This indicated a through-space interaction between the carbon and the positively charged nitrogen in the ortho position.The X-ray crystal structure 19 showed an intramolecular distance of 2.999 Å between C2 and the nitrogen in the solid state (Figure 6), close enough to indicate a non-bonded interaction. 39

Fluorinated compounds
The fluorinated compounds 1h, 1i, 1d, and 1e all displayed 13 C- 19 F coupling.The p-fluoro compound 1h showed four doublets attributable to the carbons that were ipso, ortho (2 carbons), meta (2 carbons), and para to the fluorine (Figure 7).The m-fluoro compound 1i displayed seven doublets from C-F coupling -1 ipso, 2 ortho, 2 meta, 1 para, and at C2 ( 4 JCF = 2 Hz).The coupling constants for the aromatic carbons in all cases were close to the expected values of ~250 Hz for the ipso carbon ( 1 JCF), ~20 Hz for the ortho carbons ( 2 JCF), ~8 Hz for the meta carbons ( 3 JCF) and ~3 Hz for the para-carbon ( 4 JCF).Similarly, multiple quartets due to C-F splitting were observed in the spectra of the trifluoromethyl compounds 1d and 1e.In m-trifluoromethyl compound 1e, four quartets were identified resulting from splitting by the three fluorines (Figure 8).These originated from the CF3 carbon, the aromatic carbon connected to it, and the ortho carbons.The coupling constants were 272.7 Hz for 1 JCF, 32.7 Hz for 2 JCF, and between 3 and 4 Hz for 3 JCF, all as expected. 35In the ptrifluoromethyl compound 1d three C-F couplings were observed, also from the CF3 carbon ( 1 JCF = 271.7 Hz), the aromatic carbon connected to it ( 2 JCF = 32.6 Jz) , and one signal for the two ortho carbons ( 3 JCF = 3.7 Hz).

IR Spectroscopy
In the infrared spectra, the substituted compounds 1b-1i and 1k-1n showed bands in a range of 1645-1658 cm -1 (Figure 9).Interestingly, the carbonyl (C4) in the unsubstituted compound 1j showed absorption at a much higher wavenumber, 1682 cm -1 , 13 than for any of the substituted compounds.This analysis was repeated in case of error, but the result was very close, 1684 cm -1 .There was no discernible electronic pattern to the absorptions.

UV-Vis Spectroscopy
All ultraviolet-visible spectra were run in acetonitrile.In each case, the λmax peak showed a shoulder peak.The wavelength of the top of the side peak must be considered an estimate, since it was difficult to ascertain the wavelength of the crest of the peak.We had not previously noted the side peak when we recorded the spectrum of 1a in cyclohexane. 13The spectrum of 1a was recorded again in cyclohexane, and there was in fact a shoulder as in the spectrum The wavelengths of λmax in CH3CN ranged from 272-287 nm (Figure 10).There was no discernible IR at C4 (cm -1 ) overall electronic pattern to the absorptions.The shoulders ranged from approximately 314-326 nm.The side peak was not present in 2,3-diphenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one, 13 so it is apparently due to the fused benzene ring.

Nitro compounds
The nitro series 1a-c showed increasing λmax progressing from ortho to meta to para. max (nm, CH 3 CN)

Conclusions
A series of novel 2-aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones was synthesized at room temperature using T3P as a promoter.Among the meta-and para-substituted compounds there was little variation in 1 H and 13 C NMR signals at C2, and the same was true of the 13 C NMR and IR signals at C4.The carbonyl (C4) IR signal of 1j (unsubstituted) was significantly different, however.As electron withdrawing decreased/electron donating increased, the chemical shifts of the 13 C NMR signals for C2 and C4 generally increased.The o-nitro compound 1a displayed through-space interactions in the 1 H and 13 C NMR spectra, consistent with the X-ray structure.
The fluorinated compounds 1f, 1g, 1d, and 1e displayed 13 C- 19 F couplings and 1h and 1i also showed 1 H- 19 F coupling.The UV spectra all showed two absorptions, the second being due to the fused benzene ring.Investigation of the biological properties is in the early stages, while the syntheses of a second (3aryl-2-phenyl) and third (2,3-diaryl) series of compounds are well underway.
N-Benzylideneaniline 2j, 4-methoxybenzaldehyde, p-tolualdehyde, and 4-nitrobenzaldehyde were purchased from Alfa Aesar (Ward Hill, MA).T3P in 2-methyltetrahydrofuran (50 weight%) was obtained from Euticals, Inc. TLC plates (silica gel GF, 250 micron, 10 x 20 cm, cat.No. 21521) were purchased from Analtech (Newark, DE) and were visualized under short wave UV, and then with I2 and then by spraying with ceric ammonium nitrate/sulfuric acid and heating.Infrared spectra were run on a Perkin-Elmer Spectrum One using a diamond-ATR attachment for the direct powder analysis (Villanova University).Spectra were recorded at a resolution 4 cm -1 , 16 scans averaged. 1H and 13 C NMR experiments (Penn State University Park) were carried out on a Bruker Avance-III-HD 500.20-MHzinstrument using a 5 mm CPPBBO BB-1H/19F/D Z-GRD probe.Samples were dissolved in CDCl3 and analyzed at RT.Typical conditions for 1 H acquisition were 1 sec relaxation delay, acquisition time of 2.76 sec, spectral width of 12 kHz, 16 scans.Spectra were zero-filled to 128k points, and multiplied by exponential multiplication (EM with LB = 0.3 Hz) prior to FT.For 13 C experiments a 2 sec relaxation delay was employed, with acquisition time of 0.9088 sec, spectral width of 36 kHz, and 128 scans.Spectra were zero-filled once, and multiplied by EM with LB = 2 Hz prior to FT. High resolution mass spectrometry was performed on an AB Sciex 5600 TripleTOF instrument (Penn State University Park).Ultraviolet/Visible spectroscopy was performed on a Thermo Electron Corp. Genesys 10 UV (Penn State Schuylkill).Melting points were performed on an Arthur H. Thomas Co. Thomas Hoover Capillary Melting Point Apparatus (Penn State Schuylkill).
General Procedure for Preparation of Imines 2a-i, k-n.A 100-mL round bottom flask with a stir bar was charged with a substituted benzaldehyde (0.05 mol), aniline (4.56 mL, 4.66 g, 0.05 mol) and toluene (12.5 mL) and stirred.A Dean-Stark apparatus was attached and the trap was filled with toluene.The solution was heated and distilled into the trap until water was no longer being produced, generally 30 minutes or less.After cooling, the toluene was removed under vacuum.The product was recrystallized from an appropriate solvent or used crude if liquid.Recrystallization solvents, yields, and melting points (where appropriate) are reported below.

Figure 3 .
Figure 3. Space-filling and Ball and Stick drawings of the X-ray crystal structure of 1a.19

Figure 6 .
Figure6.Partial space-filling drawing of the X-ray crystal structure of 1a to allow visualization of C2 and the nitro group.19