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

Article abstract of DOI:10.24820/ark.5550190.p009.875

A series of thirteen novel 2-aryl-3-phenyl-2,3-dihydro-4H-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. ¹H-¹⁹F and ¹³C-¹⁹F couplings were observed in the NMR spectra of fluorinated compounds. Through-space interactions were observed in the ¹H and ¹³C NMR spectra of the ortho-nitro compound. Trends were observed in the IR and UV absorptions of the ortho/meta/para-nitro series.

Full text of DOI:10.24820/ark.5550190.p009.875

General Papers
ARKIVOC 2016 (vi) 122-143
Synthesis and spectroscopic properties of a series of novel
-aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones
2
a
b
c
d
Lee J. Silverberg,* Carlos Pacheco, Anthony Lagalante, John Tierney, Joshua T.
a
a
a
a
a
Bachert, J. Austin Bayliff, Ryan V. Bendinsky, Aaron S. Cali, Liuxi Chen, Avril D.
a
a
a
a
Cooper, Michael J. Minehan, Caitlin R. Mroz, Duncan J. Noble, Alexander K.
a
a
a
Weisbeck, Yiwen Xie, and Ziwei Yang
a
Pennsylvania State University, Schuylkill Campus, 200 University Drive, Schuylkill Haven, PA,
USA 17972
Pennsylvania State University, University Park Campus, 104 Chemistry Building, Room 14,
b
University Park, PA, USA 16802
Villanova University, Department of Chemistry, Mendel Science Center, 800 Lancaster Avenue,
Villanova, PA, USA 19085
c
d
Pennsylvania State University, Brandywine Campus, 25 Yearsley Mill Road, Media, PA, USA
9063
E-mail: ljs43@psu.edu
1
DOI: https://doi.org/10.24820/ark.5550190.p009.875
Abstract
A series of thirteen novel 2-aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones was prepared
at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thiosalicylic
1
19
13
19
acid. The spectroscopic and physical properties are reported and discussed. H- F and C- F
couplings were observed in the NMR spectra of fluorinated compounds. Through-space
1
13
interactions were observed in the H and C NMR spectra of the ortho-nitro compound. Trends
were observed in the IR and UV absorptions of the ortho/meta/para-nitro series.
Keywords: Benzothiazinone, T3P, fluorine, imine, spectroscopy
Introduction
Compounds with a 2,3-dihydro-4H-1,3-benzothiazin-4-one scaffold (Figure 1) have shown a wide
1
.2
3-5
6
range of bioactivity, including HIV-RT inhibitory,
antitumor,
antimicrobial, and
7
1
antimalarial. More narrowly, N-aryl (R = aryl or heteroaryl) compounds in this family have
cyclooxygenase COX-2 enzyme inhibition, HIV-RT inhibition, and
antimicrobial activity. Although this structure is not yet considered to be a privileged scaffold,
3
,5,8
9
1
shown antitumor,
1
0
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in 2010 Welsch, Snyder, and Stockwell identified 46 privileged scaffolds, of which a remarkable
1
1
2
3 contained a benzene ring fused to a heterocycle.
O
R1
4
3N
2
2
S
1
R
1
2
Figure 1. 2,3-Dihydro-4H-1,3-benzothiazin-4-one skeleton (R = H, alkyl, aryl, heteroaryl, R =
alkyl, aryl, heteroaryl).
A variety of methods have been reported for the synthesis of 2,3-dihydro-4H-1,3-benzothiazin-
4
-ones.12 The most commonly used method for preparation of these compounds is the
condensation of an imine with thiosalicylic acid, which can be done by premaking the imine or by
a three-component coupling of an amine, an aldehyde or ketone, and a thioacid. However, while
1
compounds where R is hydrogen or alkyl are readily prepared by this method, the N-aryl
1
3
compounds are more difficult, due to the reduced nucleophilicity of the nitrogen. This may
explain why the number of N-aryl and N-heteroaryl compounds that have been synthesized is
1
,5,8-10,13-25
13,18
relatively small (approximately 40 out of 500).
Our initial investigations
into the
synthesis of 2,3-diphenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1j) were unsuccessful using
1
3
refluxing toluene, refluxing xylenes, and reaction using dicyclohexylcarbodiimide, as well as
published methods for preparation of N-aryl-2,3-dihydro-4H-1,3-benzothiazin-4-ones, including
5
9
Na
tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) as a coupling agent.
method has now been applied to a full series of new 2-aryl-3-phenyl-2,3-dihydro-4H-1,3-
2
SO /1,4-dioxane and p-toluenesulfonic acid/toluene/reflux. We succeeded using 2,4,6-
4
1
3,18
This
1
7-19,25
benzothiazin-4-ones, the crystal structures of some of which we have previously reported.
Herein, we report the synthesis and physical and spectroscopic properties of the full series.
Results and Discussion
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,13,17-19,25 using T3P as a promoter and pyridine as a base (Scheme 1). The reactions were
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ARKIVOC 2016 (vi) 122-143
run at room temperature, whereas the similar method reported by Kitsiou was run at 90 °C.16
Yields 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 N-
aryl example was reported by Kitsiou, and the yield of 53% was significantly lower than their
1
6
yields for N-alkyl compounds, 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. The synthesis and X-ray crystallographic structures of compounds 1a-c and 1j have been
1
3,17-19
previously reported.
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
1
3
common to each product compared. Spectroscopic data has only been previously reported for 1j,
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.
1H 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
2
6
27
to the ranges observed by Tierney and Woolston for meta- and para-substituted 2-aryl-3-
phenyl-1,3-thiazolidin-4-ones (five-membered heterocycles).
1H NMR Chemical Shifts at C2 (ppm, CDCl3)
7
.2
7
6
6
6
6
.8
.6
.4
.2
6
5
.8
1
Figure 2. H chemical shifts at C2 (ppm, CDCl
3
) (2-aryl moiety substitution: orange =
unsubstituted, red = para-substituted, blue = meta-substituted, green = ortho-substituted).
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Scheme 1. Preparation of 2-aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones.
Table 1. 2-Aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones 1 prepared and comparison of
key spectroscopic signals
Com-
pound
R
Yield
of 1
1H NMR 13C NMR 13C NMR
Chemical Chemical Chemical Absorbance
Shifts at Shifts at of Carbonyl
IR
UV/Vis λmax
and approx.
λmax of shoulder
from 2 Shifts at
%)
-1
(
C2 (ppm, C2 (ppm, C4 (ppm, (C4) (cm ) peak (CH
3
CN)
CDCl CDCl CDCl (nm)
3
)
3
)
3
)
a1
9
o-NO
p-NO
m-NO
14a
7.01
6.12
6.14
6.08
6.10
6.01
6.01
6.06
6.04
61.0
64.6
64.6
64.8
64.9
64.8
64.6
64.8
64.8
164.3
163.4
163.4
163.6
163.6
163.6
163.6
163.7
163.6
1658
1652
1654
1651
1649
1646
1652
1648
1647
275, 326
287, 326
281, 317
278, 314
275, 314
275, 314
278, 317
272, 314
275, 314
275, 314
278, 314
278, 314
284, 314
278, 314
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
1
9
b
b
30
40
1
7
b
c
2
d
e
f
p-CF
3
38b
c,e
m-CF
p-Br
m-Br
p-F
3
12
35
23
15
43
35
30
b
b
b
b
b
d
g
h
i
m-F
H
p-Me
m-Me
p-OMe
m-OMe
1
3,18
13
13
13
13
j
6.07
6.03
6.02
6.04
6.02
65.3
65.1
65.2
65.0
65.2
163.8
1682
1646
1648
1645
1653
k
l
163.8
163.8
163.8
163.8
a,e
16
32a
m
n
a,e
40
a
b
Isolated by chromatography and then two recrystallizations. Isolated by chromatography and
c
then recrystallization. Isolated by chromatography, then trituration with hexanes, and then
recrystallization.
toluene/hexanes. The imine 2 was used as a crude liquid.
d
Isolated by hot filtration in EtOH and then recrystallization from
e
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Hammett correlation attempts
1
13
Attempts were made to correlate H and 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-
4
H-1,3-benzothiazin-4-ones is the reason for the absence of clear correlations as witnessed by
2
6
27
Tierney and Woolston 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 m-
and 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
1
9
structure of 1a (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
2
8
enough that a C-H---O hydrogen bond may exist.
H on C2
Figure 3. Space-filling and Ball and Stick drawings of the X-ray crystal structure of 1a.19
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Fluorinated compounds
Four of the compounds prepared have one or more fluorines. These are of interest for two reasons.
2
9,30
One is the physical and biological properties that fluorine imparts to pharmaceuticals.
The
other is the potential to exploit H- F and C- F spin-spin coupling ( JHF and nJCF) for H and
1
19
13 19
n
1
1
3
31-37
C chemical shift assignments in NMR spectroscopy.
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 JHH and JHF couplings of the ortho proton to the meta
with respect to F) and to the fluorine itself, respectively. The JHH and JHF couplings apparently
3
3
3
3
(
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 m-
fluoro 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
1
19
carbons, did not show any noticeable extra splittings that would be due to H- F coupling.
13C NMR Spectroscopy
There was very little variation in the C4 (C=O) signal (Figure 4). The range was only 163.4-164.3
ppm, 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
2
6
38
Tierney and Woolston. Among the meta- and para-substituted compounds, the chemical shift
values increased as electron withdrawing decreased and electron donation increased.
13C NMR Chemical Shifts at C4 (ppm, CDCl3)
1
1
1
64.3
64.2
64.1
1
64
1
1
1
1
1
1
1
63.9
63.8
63.7
63.6
63.5
63.4
63.3
1
a
1b 1c 1d 1e 1f 1g 1h
1i
1j
1k
1l 1m 1n
Figure 4. 13C chemical shifts at C4 (ppm, CDCl
unsubstituted, red = para-substituted, blue = meta-substituted, green = ortho-substituted).
) (2-aryl moiety substitution: orange =
3
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The signal for C2 (Figure 5) showed a range of only 64.6-65.3 ppm, 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-3-
2
6
38
phenyl-1,3-thiazolidin-4-ones by Tierney and Woolston. Among the meta- and para-
substituted 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-CF
3
compound 1d had a higher value than the m-bromo compound 1g.
13C NMR Chemical Shifts at C2 (ppm, CDCl3)
6
6
5
4
3
2
1
0
6
6
6
6
6
6
1
a
1b 1c 1d 1e
1f
1g 1h
1i
1j
1k
1l 1m 1n
Figure 5. 13C chemical shifts at C2 (ppm, CDCl
) (2-aryl moiety substitution: orange =
3
unsubstituted, red = para-substituted, blue = meta-substituted, green = ortho-substituted).
Nitro compounds
1
3
In its C spectrum, the C2 carbon in the o-nitro compound 1a was significantly more upfield, at
6
1.0 ppm, than in the other nitro compounds,. This indicated a through-space interaction between
1
9
the carbon and the positively charged nitrogen in the ortho position. The X-ray crystal structure
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
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N in NO group
2
C2
Figure 6. Partial space-filling drawing of the X-ray crystal structure of 1a to allow visualization
1
9
of C2 and the nitro group.
Fluorinated compounds
The fluorinated compounds 1h, 1i, 1d, and 1e all displayed C- F coupling.
1
3
19
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
1
i displayed seven doublets from C-F coupling – 1 ipso, 2 ortho, 2 meta, 1 para, and at C2
(
4JCF = 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 (1JCF), ~20 Hz for the ortho carbons ( JCF), ~8 Hz
2
for the meta carbons (3JCF) and ~3 Hz for the para-carbon (4JCF).
37
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RVB_1-25.002.esp
meta
ortho
O
S
0.25
0.20
0.15
0.10
0.05
N
F
para
ipso
160
155
150
145
140
135
130
125
120
115
Chemical Shift (ppm)
1
3
19
13
Figure 7. Aromatic C- F couplings in the C NMR spectrum of p-fluoro compound 1h.
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 CF
3
carbon, the aromatic carbon connected to it, and the ortho carbons. The coupling constants were
35
2
72.7 Hz for 1JCF, 32.7 Hz for 2JCF, and between 3 and 4 Hz for 3JCF, all as expected. In the p-
trifluoromethyl compound 1d three C-F couplings were observed, also from the CF
271.7 Hz
, the aromatic carbon connected to it (2JCF = 32.6 Jz) , and one signal for the two ortho
carbons (3JCF = 3.7 Hz).
3
carbon (1JCF
=
)
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JTB_1-21_MARCH2016.002.ESP
O
N
S
0.065
0.060
0.055
0.050
0.045
0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005
HC
CH
3
C
q, J 4.0 Hz
CF
3
CF3
q, J 3.5 Hz
CF
1
q, J 272.7 Hz
CF
126.5
126.0
125.5
125.0
124.5
124.0
123.5
123.0
122.5
122.0
121.5
121.0
120.5
Chemical Shift (ppm)
JTB_1-21_MARCH2016.002.ESP
0
.10
.05
2
q, J 32.7 Hz
CF
0
132.5
132.0
131.5
131.0
130.5
130.0
129.5
129.0
128.5
128.0
127.5
Chemical Shift (ppm)
1
3
19
13
Figure 8. C- F splittings in the C NMR spectrum of m-CF
3
compound 1e.
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IR Spectroscopy
In the infrared spectra, the substituted compounds 1b-1i and 1k-1n showed bands in a range of
-
1
1
645-1658 cm (Figure 9). Interestingly, the carbonyl (C4) in the unsubstituted compound 1j
-1 13
showed absorption at a much higher wavenumber, 1682 cm , than for any of the substituted
compounds. This analysis was repeated in case of error, but the result was very close, 1684 cm .
There was no discernible electronic pattern to the absorptions.
-1
-1
IR at C4 (cm )
1
1
1
1
1
1
1
1
1
1
685
680
675
670
665
660
655
650
645
640
1
a
1b 1c 1d 1e 1f 1g 1h 1i
1j 1k 1l 1m 1n
-1
Figure 9. IR absorptions of the carbonyl (cm ) (2-aryl moiety substitution: orange = unsubstituted,
red = para-substituted, blue = meta-substituted, green = ortho-substituted).
Nitro compounds
In the nitro series 1a-c, the wavenumber increased slightly as the substituent moved closer to C2
-1
-1
-1
(
para 1652 cm , meta 1654 cm , ortho 1658 cm ).
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
1
3
the side peak when we recorded the spectrum of 1a in cyclohexane. The spectrum of 1a was
recorded again in cyclohexane, and there was in fact a shoulder as in the spectrum in acetonitrile.
The wavelengths of λmax in CH CN ranged from 272-287 nm (Figure 10). There was no discernible
3
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overall electronic pattern to the absorptions. The shoulders ranged from approximately 314-326
1
3
nm. The side peak was not present in 2,3-diphenyl-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-one, so
it is apparently due to the fused benzene ring.
max (nm, CH CN)
3
2
2
2
2
2
2
2
2
2
2
88
86
84
82
80
78
76
74
72
70
1
a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m 1n
Figure 10. UV Absorptions at λmax (nm) (2-aryl moiety substitution: orange = unsubstituted, red
para-substituted, blue = meta-substituted, green = ortho-substituted).
=
Nitro compounds
The nitro series 1a-c showed increasing λmax progressing from ortho to meta to para.
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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
1
13
13
there was little variation in H and C NMR signals at C2, and the same was true of the 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
1
3
the C NMR signals for C2 and C4 generally increased. The o-nitro compound 1a displayed
through-space interactions in the H and C NMR spectra, consistent with the X-ray structure.
The fluorinated compounds 1f, 1g, 1d, and 1e displayed C- F couplings and 1h and 1i also
showed H- F coupling. The UV spectra all showed two absorptions, the second being due to the
fused benzene ring.
1
13
1
3
19
1
19
Investigation of the biological properties is in the early stages, while the syntheses of a second (3-
aryl-2-phenyl) and third (2,3-diaryl) series of compounds are well underway.
Experimental Section
General. Toluene, tetrahydrofuran, 2-methyltetrahydrofuran, pyridine, aniline, thiosalicylic acid,
3
-methoxybenzaldehyde, 4-bromobenzaldehyde, 3-bromobenzaldehyde, m-tolualdehyde, 3-
fluorobenzaldehyde, 4-fluorobenzaldehyde, and 3-nitrobenzaldehyde, were purchased from
Sigma-Aldrich
(St.
Louis,
MO).
3-(Trifluoromethyl)benzaldehyde
and
4-
(trifluoromethyl)benzaldehyde were purchased from Matrix Scientific (Columbia, SC). 2-
Nitrobenzaldehyde was purchased from Eastman Kodak Co. (Rochester, NY).
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 I
2
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
-1
powder analysis (Villanova University). Spectra were recorded at a resolution 4 cm , 16 scans
1
13
averaged. H and C NMR experiments (Penn State University Park) were carried out on a Bruker
Avance-III-HD 500.20-MHz instrument using a 5 mm CPPBBO BB-1H/19F/D Z-GRD probe.
1
Samples were dissolved in CDCl
3
and analyzed at RT. Typical conditions for 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
1
3
Hz) prior to FT. For 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
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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.
N-[(2-Nitrophenyl)methylidene]aniline (2a). Recrystallized from EtOH to yield yellow powder
4
0
(
9.43 g, 83%). mp: 62-67 °C (lit. 63-64 °C ).
N-[(4-Nitrophenyl)methylidene]aniline (2b). Recrystallized from EtOAc/hexanes to give bright
4
1
yellow crystals (8.13 g, 73%). mp: 91-93 °C (lit. 92-93 °C ).
N-[(3-Nitrophenyl)methylidene]aniline (2c). Run on 0.034 mol scale. Recrystallized from
4
2
EtOAc/hexanes to give light yellow crystals (5.48 g, 72%). mp: 64-65 °C (lit. 68-69 °C ).
N-{[4-(Trifluoromethyl)phenyl]methylidene}aniline (2d). Recrystallized from toluene to
4
3
produce white crystals (4.80 g, 35%). mp: 75-76 C (lit. 78 °C ).
N-{[3-(Trifluoromethyl)phenyl]methylidene}aniline (2e). Yellow liquid (lit. mp 47-47.5 C ).
This crude material was used for cyclization.
4
4
N-[(4-Bromophenyl)methylidene]aniline (2f). Recrystallized from toluene to yield white
4
5
crystals (4.94 g, 38%). mp: 72-73 °C (lit. 72.5-73 °C ).
N-[(3-Bromophenyl)methylidene]aniline (2g). Recrystallized from cold 2-propanol to give an
olive green solid, which remained solid at 6 °C but was liquid at room temperature (8.57 g, 66%).
4
6
(
Reported as oil. )
N-[(4-Fluorophenyl)methylidene]aniline (2h). Recrystallized from hexanes to give white
4
7
crystals (6.72 g, 67%). mp: 43-45 °C (lit. 44 °C ).
N-[(3-Fluorophenyl)methylidene]aniline (2i). Recrystallized from EtOH to produce white
4
8
crystals (3.99 g, 40%). mp: 33-34 °C (lit. 33-34 °C ).
N-[(4-Methylphenyl)methylidene]aniline (2k). Recrystallized from hexanes to give pale yellow
4
9
crystals (9.76 g, 67%). mp: 44-46 C (lit. 49-51.5 °C ).
N-[-(3-Methylphenyl)methylidene]aniline (2l). Brown liquid (reported as pale brown oil ).
5
0
This crude material was used for cyclization.
N-[(4-Methoxyphenyl)methylidene]aniline (2m). Recrystallized from hexanes to give off-white
5
1
powder (8.99 g, 85%). mp: 61-62 °C (lit. 63 °C ).
N-[(3-Methoxyphenyl)methylidene]aniline (2n). Orange liquid (reported as oil ). This crude
5
2
material was used for cyclization.
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General Procedure for Preparation of 2-Aryl-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-
ones (1a-n). A two-necked 25-mL round bottom flask was oven-dried, cooled under N , and
2
charged with a stir bar and an imine (6 mmol). Tetrahydrofuran or 2-methyltetrahydrofuran (2.3
mL) was added and the solution was stirred. Pyridine (1.95 mL, 24 mmol) and then thiosalicylic
acid (0.931 g, 6 mmol) were added. Finally, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-
2
,4,6-trioxide (T3P) in 2-methyltetrahydrofuran (50 weight percent; 7.3 mL, 12 mmol) was added.
The reaction was stirred at room temperature at least overnight and followed by TLC, then poured
into a separatory funnel with CH Cl (20 mL). The mixture was washed with water (10 mL). The
aqueous layer was then extracted twice with CH Cl (10 mL each). The organic solutions were
combined and washed with saturated NaHCO (10 mL) and then saturated aq NaCl (10 mL). The
2
2
2
2
3
organic phase was dried over sodium sulfate and concentrated under vacuum to give a crude
mixture. Further purification was carried out as indicated below for each compound.
1
9
2
R
8
(
-(2-Nitrophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1a). Melting point and
1
9 1
3
f
previously reported. H NMR (CDCl
3
): (ppm): 8.25 (1H, d, J 7.3 Hz, Ar connected to C5),
.10 (1H, d, 3JHH 8.5 Hz), 7.63 (2H, m), 7.52 (1H, t, JHH 7.3 Hz,), 7.47-7.41 (3H, m), 7.36-7.32
3
3H, m), 7.29 (1H, t, JHH 7.3 Hz), 7.11 (1H, d, JHH 8.5 Hz), 7.01 (1H, s, C2). 13C NMR (CDCl
3
3
3
):

1
3
(ppm): 164.3 (C=O), 146.4, 142.5, 137.5, 135.4, 133.1, 132.9, 132.8, 131.6, 130.6, 130.4, 129.5,
+
29.4, 128.5, 128.1, 127.8, 127.7, 126.7, 126.6, 125.8, 61.0 (C2). HRMS (m/z): [M+H] of
+
-1
63.0794 is consistent with calculated [M+H] of 363.0798. IR (neat, cm ): 1658 (s, C=O), 1526
CN): λmax: 275 nm (shoulder at approx. 326 nm).
(s, N-O). UV/Vis (CH
3
1
9
2
R
-(4-Nitrophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1b). Melting point and
1
9
f
previously reported.
Updated procedure: after chromatography on 30 g silica gel with
mixtures of EtOAc and hexanes, recrystallization from EtOH gave off-white crystals 0.67 g (30%).
1
3
4
H NMR (CDCl
3
): (ppm): 8.23 (1H, dd, JHH 7.9, JHH 1.3 Hz, Ar connected to C5), 8.14 (2H, d,
3JHH 8.8 Hz), 7.63 (2H, d, JHH 8.8 Hz), 7.42 (2H, m), 7.38 (1H, td, JHH 7.6, JHH 1.7 Hz,), 7.33
3
3
4
3H, d, 3JHH 7.7 Hz), 7.31 (1H, m), 7.19 (1H, dd, 3JHH 7.7, JHH 0.7 Hz), 6.12 (1H, s, C2). C NMR
): (ppm): 163.4 (C=O), 147.7, 146.8, 142.2, 137.5, 132.9, 132.2, 131.6, 130.6, 129.5,
29.3, 127.8, 127.6, 127.5, 127.0, 125.6, 123.8, 64.6 (C2). HRMS (m/z): [M+H] of 363.0795 is
4
13
(
(
CDCl
3
+
1
+
-1
consistent with calculated [M+H] of 363.0798. IR (neat, cm ): 1652 (s, C=O), 1515 (s, N-O).
UV/Vis (CH CN): λmax: 287 nm (shoulder at approx. 326 nm).
2
3
1
7
-(3-Nitrophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1c). Melting point and
1
7 1
3
R
f
previously reported. H NMR (CDCl
3
): (ppm): 8.36 (1H, s), 8.24 (1H, d, JHH 9.8 Hz, Ar
3
3
connected to C5), 8.12 (1H, d, JHH 6.1 Hz), 7.79 (1H, d, JHH 7.3 Hz), 7.49-7.29 (8H, m), 7.20
(
1H, d, JHH 7.3 Hz), 6.14 (1H, s, C2). 13C NMR (CDCl
3
): (ppm): 163.4 (C=O), 148.4, 142.2,
3
1
6
42.0, 132.8, 132.3, 132.1, 130.7, 129.52, 129.48, 129.4, 127.8, 127.6, 127.0, 125.8, 123.3, 121.7,
+
+
4.6 (C2). HRMS (m/z ): [M+H] of 363.0796 is consistent with calculated [M+H] of 363.0798.
-1
IR (neat, cm ): 1654 (s, C=O), 1520 (s, N-O). UV/Vis (CH
3
CN): 281 nm (shoulder at approx.
3
17 nm).
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3
-Phenyl-2-[4-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,3-benzothiazin-4-one (1d). After
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
isopropanol/water gave fine white crystals, 0.87 g (38%), mp: 137-139 C.
R (20%
f
1
3
EtOAc/hexanes): 0.50. H NMR (CDCl
7
3
): (ppm): 8.24 (1H, d, JHH 7.3 Hz, Ar connected to C5),
.57 (4H, t, JHH 8.5 Hz), 7.43-7.29 (7H, m, 7.19 (1H, d, 3JHH 8.5 Hz), 6.08 (1H, s, C2). C NMR
3
13
2
(CDCl
3
): (ppm): 163.6 (C=O), 143.7, 142.3, 132.7, 132.6, 130.5, 130.4 (q, JCF 32.6 Hz, Ar C
3
connected to CF
CF
3
3
), 129.4, 127.8, 127.4, 126.9, 126.8, 125.7, 125.5 (q, JCF 3.7 Hz, Ar ortho to
), 1243.8 (q, 1JCF 271.7 Hz, CF
), 64.8 (C2). HRMS (m/z ): [M+H] of 386.0814 is consistent
+
3
+
-1
with calculated [M+H] of 386.0821. IR (neat, cm ): 1651 (s, C=O). UV/Vis (CH
3
CN): λmax: 278
nm (shoulder at approx. 314 nm).
-Phenyl-2-[3-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,3-benzothiazin-4-one (1e). The
3
imine was used as a crude liquid. After chromatography on 30 g silica gel with mixtures of EtOAc
and hexanes, the material was triturated with hexanes to give a pale yellow solid, 0.4959 g.
Recrystallization from cyclohexane gave white flakes, 0.28 g (12%), mp: 114-115 C. R
f
(25%
1
3
EtOAc/hexanes): 0.50. H NMR (CDCl
3
): (ppm): 8.23 (1H, d, JHH 7.6 Hz, Ar connected to C5),
3
3
7
J
1
1
1
.71 (1H, s), 7.63 (1H, d, JHH 7.3 Hz), 7.51 (1H, d, JHH 7.3 Hz), 7.41-7.29 (8H, m), 7.20 (1H, d,
3
HH 7.6 Hz), 6.10 (1H, s, C2). 13C NMR (CDCl
30.64 (q, 2JCF 32.7 Hz, Ar C connected to CF
), 130.5, 129.7; 129.43, 129.41, 129.0, 127.8, 127.5,
26.8, 125.8, 125.24-125.15 (q, 3JCF 3.5 Hz), 123.55-123.46 (q, 3JCF 4.0 Hz, Ar ortho to CF
3
): (ppm): 163.6, 142.3, 140.7, 132.7, 131.42-
3
3
);
1
27.0, 124.8, 122.6, and 120.5 (q, JCF 272.7 Hz, CF3, Ar ortho to CF
3
); 64.9 (C2), 26.9. HRMS
+
+
-1
(
m/z): [M+H] of 386.0817 is consistent with calculated [M+H] of 386.0821. IR (neat, cm ):
1
649 (s, C=O). UV/Vis (CH
3
CN): λmax: 275 nm (shoulder at approx. 314 nm).
2
-(4-Bromophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one
(1f).
After
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
isopropanol gave fine off-white crystals, 0.83 g (35%), mp: 148-151 C. R
f
(30% EtOAc/hexanes):
1
3
3
0
7

1
.50. H NMR (CDCl
3
): (ppm): 8.22 (1H, d, JHH 7.3 Hz, Ar connected to C5), 7.40 (4H, t, JHH
3
13
.9 Hz,), 7.37-7.27 (7H, m), 7.19 (1H, d, JHH 8.5 Hz,), 6.01 (1H, s, C2). C NMR (CDCl
(ppm): 163.6 (C=O), 142.3, 138.7, 132.9, 132.6, 131.6, 130.5, 129.4, 129.3, 128.3, 127.8, 127.3,
3
):
+
79
26.6, 125.7, 122.4, 64.8 (C2). HRMS (m/z): [M+H] of 396.0049 for Br is consistent with
+
+
81
calculated [M+H] of 396.0052 and [M+H] of 398.0032 for Br is consistent with calculated
+
-1
[
M+H] of 398.0032. IR (neat, cm ): 1646 (s, C=O). UV/Vis (CH
at approx. 314 nm).
-(3-Bromophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one
3
CN): λmax: 275 nm (shoulder
2
(1g).
After
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
1
MeOH gave tan crystals, 0.54 g (23%), mp: 118-120 C. R
f
(30% EtOAc/hexanes): 0.49. H NMR
3
(CDCl
3
): (ppm): 8.23 (1H, d, JHH 9.8 Hz, Ar connected to C5), 7.60 (1H, s), 7.42-7.28 (9H, m),
.20 (1H, d, JHH 7.3 Hz), 7.15 (1H, m), 6.01 (1H, s, C2). C NMR (CDCl ): (ppm): 163.6
3
13
7
3
(
1
C=O), 142.3, 141.9, 132.8, 132.6, 131.5, 130.5, 129.9, 129.7, 129.40, 129.36, 127.8, 127.4, 126.7,
+
79
25.8, 125.2, 122.7, 64.6 (C2). HRMS (m/z): [M+H] of 396.0051 for Br is consistent with
+
+
81
calculated [M+H] of 396.0052 and [M+H] of 398.0031 for Br is consistent with calculated
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+
-1
[
M+H] of 398.0032. IR (neat, cm ): 1652 (s, C=O). UV/Vis (CH
3
CN): 278 nm (shoulder at
approx. 317 nm).
-(4-Fluorophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
EtOH/water gave white crystals, 0.30 g (15%), mp: 100-105 C. R (30% EtOAc/hexanes): 0.54.
): (ppm): 8.23 (1H, d, JHH 8.1 Hz, Ar connected to C5), 7.43-7.27 (9H, m),
2
(1h).
After
f
1
3
H NMR (CDCl
3
3
3
3
13
7
.20 (1H, d, JHH 7.7 Hz), 6.96 (2H, triplet, JHH, JHF 8.3 Hz ), 6.06 (1H, s, C2). C NMR (CDCl
3
):
1

(ppm): 163.7 (C=O); 163.26 and 161.62 (d, JCF 248.5 Hz, C-F); 142.3, 135.23 and 135.21 (d,
CF 3.3 Hz Ar para to CF); 133.1, 132.5, 130.5, 129.4, 129.3; 128.44 and 128.38 (d, JCF 8.8 Hz
4
3
J
2
Ar meta to CF); 127.7, 127.3, 126.5, 125.8; 115.54 and 115.39 (d, JCF 22.0 Hz, Ar ortho to CF);
6
+
+
4.8 (C2). HRMS (m/z): [M+H] of 336.0846 is consistent with calculated [M+H] of 336.0853.
-1
IR (neat, cm ): 1648 (s, C=O). UV/Vis (CH
-(3-Fluorophenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
dichloromethane/hexanes gave off-white powder, 0.86 g (43%), mp: 102-103 C. R (20%
): (ppm): 8.23 (1H, dd, JHH 7.8, JHH 1.1 Hz, Ar
3
CN): 272 nm (shoulder at approx. 314 nm).
2
(1i).
After
f
1
3
4
EtOAc/hexane): 0.33. H NMR (CDCl
3
connected to C5), 7.42-7.16 (11H, m), 6.95 (1H, apparent t with fine splitting), 6.04 (1H, s, C2).
1
3
): (ppm): 163.7 and 161.7 (d, 1JCF 248 Hz, C-F); 163.6 (C=O); 142.4; 142.29
C NMR (CDCl
3
and 142.24 (d, 3JCF 7.3 Hz, Ar meta to CF); 135.7, 130.5; 130.03 and 129.97 (d, JCF 8.2 Hz Ar
meta to CF); 129.4, 129.3, 127.7, 127.3, 126.6, 125.8; 125.35 and 122.33 (d, JCF 2.8 Hz, Ar para
to CF); 115.48 and 115.32 (d, JCF 20.9 Hz Ar ortho to CF); 114.00 and 113.81 (d, JCF 23.6 Hz,
Ar ortho to CF); 64.8 (d, JCF 2 Hz, C2). HRMS (m/z): [M+H] of 336.0856 is consistent with
3
4
2
2
4
+
+
-1
calculated [M+H] of 336.0853. IR (neat, cm ): 1647 (s, C=O). UV/Vis (CH CN): max: 275 nm
3
(
2
shoulder at approx. 314 nm).
,3-Diphenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1j).13,18 All data previously reported.13
CN): 272 (shoulder at approx. 308) nm.
max (cyclohexane): 275 nm (shoulder at approx. 314 nm)
-(4-Methylphenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1k). Hot filtration in
New measurements of UV-Visible spectrum: λmax (CH
λ
2
3
EtOH followed by recrystallization from toluene/hexanes gave yellowish crystals, 0.57 g (30%),
1
3
mp: 108-111 C. R
8
Hz), 6.03 (1H, s, C2), 2.30 (3H, s, CH
f
(20% EtOAc/hexanes): 0.34. H NMR (CDCl
3
): (ppm): 8.24 (1H, d, JHH
3
3
.1 Hz, Ar connected to C5), 7.39-7.25 (10H, m), 7.18 (1H, d, JHH 7.7 Hz), 7.08 (1H, d, JHH 7.7
1
3
3
). C NMR (CDCl ): (ppm): 163.8 (C=O), 142.6, 138.1,
3
1
2
36.5, 133.4, 132.4, 130.4, 129.5, 129.19, 129.17, 127.7, 127.1, 126.5, 126.3, 125.9, 65.1 (C2),
+
+
1.0 (CH ). HRMS (m/z): [M+H] of 332.1104 is consistent with calculated [M+H] of 332.1104.
3
-1
IR (neat, cm ): 1646 (s, C=O). UV/Vis (CH
3
CN): λmax: 278 nm (shoulder at approx. 314 nm).
2
-(3-Methylphenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1l). The imine was
used as a crude liquid. After chromatography on 30 g silica gel with mixtures of EtOAc and
hexanes, recrystallization from acetonitrile/water gave colorless crystals (0.31 g, 16% from crude
1
imine), mp: 91-95 C. R
J
f
(15% EtOAc/hexanes): 0.25. H NMR (CDCl
3
): (ppm): 8.24 (1H, d,
3
HH 8.5 Hz, Ar connected to C5), 7.40-7.34 (5H, m), 7.30-7.26 (2H, m), 7.23 (2H, s), 7.18 (2H,
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m), 7.06 (1H, d, 3JHH 7.3 Hz), 6.02 (1H, s, C2), 2.30 (3H, s, CH
). 13C NMR (CDCl
): (ppm):
3
3
1
1
63.8 (C=O), 142.6, 139.4, 138.3, 133.3, 132.4, 130.4, 129.5, 129.2, 129.1, 128.3, 127.7, 127.3,
+
27.1, 126.3, 125.9, 123.7, 65.2 (C2), 21.5 (CH
3
). HRMS (m/z): [M+H] of 332.1098 is consistent
+
-1
with calculated [M+H] of 332.1104. IR (neat, cm ): 1648 (s, C=O). UV/Vis (CH
3
CN): λmax
:
2
78 nm (shoulder at approx. 314 nm).
2
-(4-Methoxyphenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one
(1m).
After
chromatography on 30 g silica gel with mixtures of EtOAc and hexanes, recrystallization from
EtOH gave fine white solid, 0.70 g. Recrystallization of the solid from dicloromethane/hexanes
produced shiny white crystals, 0.67 g (32%). mp: 136.5-139.5 C R
f
(40% EtOAc/hexanes): 0.48.
1
3
4
H NMR (CDCl
3
): (ppm): 8.23 (1H, dd, JHH 8.1, JHH 1.1 Hz, Ar connected to C5), 7.39-7.34
1
3
(
7H, m), 7.29-7.26 (2H, m), 7.19 (1H, m), 6.80 (2H, m), 6.04 (1H, s, C2), 3.76 (3H, s, OCH
3
).
C
NMR (CDCl
3
): (ppm): 163.8 (C=O), 159.4, 142.5, 133.5, 132.4, 131.6, 131.3, 130.4, 129.5,
+
1
3
29.2, 127.9, 127.7, 127.1, 126.3, 125.9, 113.8, 65.0 (C2), 55.3 (OCH
48.1046 is consistent with calculated [M+H] of 348.1053. IR (neat, cm ): 1645 (s, C=O).
3
). HRMS (m/z): [M+H] of
+
-1
UV/Vis (CH
3
CN): λmax: 284 nm (shoulder at approx. 314 nm).
2
-(3-Methoxyphenyl)-3-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one (1n). The imine was
used as a crude liquid. After chromatography on 30 g silica gel with mixtures of EtOAc and
hexanes, recrystallization from EtOH gave fine white crystals, 0.84 g (40% from crude imine),
1
3
mp: 125-127 C. R
7
f
(30% EtOAc/hexanes): 0.44. H NMR (CDCl ): (ppm): 8.23 (1H dd, JHH
3
4
.9, JHH 1.3 Hz, Ar connected to C5), 7.40-7.34 (5H, m), 7.30-7.26 (2H, m), 7.19 (2H, m), 7.01
1H, m), 6.97 (1H, m), 6.79 (1H, dd, JHH 8.3 Hz, JHH 2.4 Hz), 6.02 (1H, s, C2), 3.74 (3H, s,
3
4
(
1
3
OCH
3
). C NMR (CDCl ): (ppm): 163.8 (C=O), 159.6, 142.5, 141.1, 133.3, 132.4, 130.4, 129.6,
3
1
29.5, 129.2, 127.7, 127.2, 126.4, 125.9, 119.1, 113.8, 112.4, 65.2 (C2), 55.2 (OCH
3
). HRMS
+
+
-1
(
m/z): [M+H] of 348.1045 is consistent with calculated [M+H] of 348.1053. IR (neat, cm ):
1
653 (s, C=O). UV/Vis (CH CN): λmax: 278 nm (shoulder at approx. 314 nm).
3
Acknowledgements
The authors thank SP Controls, Inc. for summer support of RVB and ASC; Euticals, Inc. for the
gift of T3P in 2-methyltetrahydrofuran; Dr. Phillip Smith (Penn State University Park
Metabolomics Core Facility, grant NSF MRI 1126373) for HRMS analyses; and Penn State
Schuylkill for financial support.
Supplementary Material
1
13
H NMR, C NMR, and FTIR spectra.
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